KR20000069064A - Methods and Compounds for Inhibiting β-Amyloid Peptide Release and(or) Its Synthesis - Google Patents

Abstract

The present invention describes compounds that inhibit the release and / or synthesis of β-amyloid peptides and are therefore useful for treating Alzheimer's disease. The present invention also describes pharmaceutical compositions containing compounds that inhibit the release and / or synthesis of β-amyloid peptides, and methods for the prophylactic and therapeutic treatment of Alzheimer's disease using such pharmaceutical compositions. Doing.

Description

Methods and Compounds for Inhibiting β-Amyloid Peptide Release and (or) Its Synthesis

<Cross literature of related application>

This application claims the benefit of the following US provisional application.

1. 37 C.F.R. from US patent application Ser. No. 08 / 755,442, filed November 22, 1996. US Provisional Application No. 60 /, converted under §1.53 (b) (2) (ii);

2. From US patent application Ser. No. 08 / 808,528, filed Feb. 28, 1997, 37 C.F.R. US Provisional Application No. 60 /, converted under §1.53 (b) (2) (ii);

3. From US patent application Ser. No. 08 / 807,528, filed Feb. 28, 1997, 37 C.F.R. US Provisional Application No. 60 /, converted under §1.53 (b) (2) (ii);

4. 37 C.F.R. from US patent application Ser. No. 08 / 807,427, filed February 28, 1997. US Provisional Application No. 60 /, converted under §1.53 (b) (2) (ii).

The entire contents of each of these applications are incorporated herein by reference.

〈Background of the invention〉

The present invention relates to methods useful in inhibiting the release and / or synthesis of intracellular β-amyloid peptides and thus treating Alzheimer's disease. The present invention also relates to pharmaceutical compositions and methods comprising a compound that inhibits the release of β-amyloid peptide.

<references>

The following documents, patents and patent applications are cited herein:

Each document, patent, or patent application is incorporated herein by reference in its entirety, as if each and every such content were specifically and individually described.

〈Technical explanation〉

Alzheimer's disease (AD) is a degenerative brain disease with clinical features that progressively diminish memory, cognition, logic, judgment, and emotional stability, leading to increasingly severe mental decline and eventually death. AD is a very common cause of progressive mental disorders (dementia) in older people, believed to represent the fourth most common cause of medical mortality in the United States. AD is observed in peoples and races around the world and is emerging as a major public health issue now and in the future. There are currently about 2-3 million AD patients in the United States alone. AD is currently incurable. Therapies that effectively prevent AD or reverse its symptoms or progression are currently unknown

The brain of AD patients exhibits the characteristic etiology of senile (or amyloid) plaques, amyloid vasculature (vascular amyloid deposition) and entanglement of nerve fibers. Numerous such etiologies, especially amyloid plaques and nerve fiber entanglements, are commonly found in AD patients in several areas of the human brain that are important for memory and recognition. In the brains of most elderly people who do not have clinically AD, fewer of these pathologies are found in the more restrictive anatomical distribution. In addition, amyloid plaques and amyloid vasculatures are characterized by the brains of individuals with Trisomy 21 (Down syndrome) and Dutch type genotyping hereditary cerebral hemorrhage (HCHWA-D). Definite diagnosis of AD now requires monitoring the etiology in brain tissues of patients who have typically died of the disease or, in rare cases, small autopsy brain tissue samples taken during neurosurgery.

The major chemical components of amyloid plaques and vascular amyloid deposits (amyloid vasculature) characteristic of AD and other diseases mentioned above are the β-amyloid peptides (βAP) or sometimes about 39 to 43, designated Aβ, AβP or β / A4. About 4.2 kilodalton (kD) protein of dog amino acids. The β-amyloid peptide was first purified by Glenner et al. ¹ and provided with partial amino acid sequences. Isolating and sequencing techniques, and data for the first 28 amino acids are described in U.S. Patent No. 4,666,829 ^2.

Molecular biology and protein chemistry analysis have shown that β-amyloid peptides are small fragments of larger precursor proteins (APP), which are typically produced by cells in many tissues of several animals, including humans. Knowledge of the gene structure encoding APP has demonstrated that β-amyloid peptides occur as peptide fragments that are degraded from APP by protease enzymes. No clear biochemical mechanism is presently known in which β-amyloid peptide fragments are cleaved from APP and subsequently deposited as amyloid plaques in brain tissue and brain and dural wall.

Some evidence has shown that the gradual deposition of β-amyloid peptides into the brain acts as a pathogenesis of AD and can advance cognitive symptoms for years or decades. See, eg, the literature of Selkoe ³ . The most important evidence is that members affected with the genetically determined (similar) AD form may find missense DNA mutations at amino acid 717 of the 770 amino acid isoform of APP, but not in unaffected members. (Goate et al. ⁴ ; Chartier-Harlan et al. ⁵ ; and Murrell et al. ⁶ ) are discoveries and call this Swedish variant. In 1992 a double mutation was reported that alters lysine ⁵⁹⁵ -methionine ⁵⁹⁶ to asparagine ⁵⁹⁵ -leucine ⁵⁹⁶ (as opposed to the ^isoform of 695) found in the Swedish species (Mullan et al. ⁷ ). Analyzes of genetic binding have demonstrated that these and other mutations in the APP gene are the specific molecular cause of AD in those types of members affected. In addition, mutations in amino acid 693 of the 770-amino acid isoform of APP have been identified as a cause of the disease caused by β-amyloid peptide deposition, HCHWA-D, and changes from alanine to glycine, causing an AD-like phenotype at amino acid 692 Was present in some patients, but HCHWA-D was present in the remaining patients. The discovery of these and other mutations in APP in the genetically basic case of AD demonstrates a change in APP, and subsequent deposition of β-amyloid peptide fragments thereof can lead to AD.

Despite advances in understanding the above mechanisms of AD and other β-amyloid peptide related diseases, there remains a need to develop compositions and methods for treating diseases. Preferably, a therapy based on drugs that can inhibit the release of β-amyloid peptide and / or its in vivo synthesis would be advantageous.

<Summary of invention>

The present invention relates to compounds useful for the treatment of inhibiting the release and / or synthesis of β-amyloid peptides and thus preventing AD in patients sensitive to AD and / or worsening the condition of AD patients. will be. Compound classes having the properties described are defined by the following 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 heterocyclic;

R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;

Each R ³ is independently selected from the group consisting of hydrogen and methyl, or R ³ may be fused together with R ⁴ to form a 3-8 membered ring structure 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 Become;

R ⁵ is each selected from hydrogen and methyl, or together with R ⁴ form a cycloalkyl group of 3 to 6 carbon atoms;

X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is

(a) alkyl or cycloalkyl,

(b) substituted alkyl, provided that the substitution on the substituted alkyl does not include α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl or α-OC (O) aryl groups,

(c) alkoxy or thioalkoxy,

(d) substituted alkoxy or substituted thioalkoxy,

(e) hydroxy,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic,

(i) -NR'R "where R 'and R" are independently hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl Is selected from heterocyclic, or one of R 'or R "is hydroxy or alkoxy, or R' and R" combine to optionally contain 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen. To form a cyclic group of 2 to 8 carbon atoms optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups);

(j) -NHS0 ₂ -R ⁸ , wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic;

(k) —NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl, and R ¹⁰ is each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl , Heterocyclic); And

(l) -ONR ⁹ [C (O) O] _z R ¹⁰ , wherein z is 0 or 1 and R ⁹ and R ¹⁰ are as defined above

It is selected from the group consisting of;

X is also -CR ⁶ R ⁶ Y 'wherein R ⁶ is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and Y' is hydroxy , Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is alkyl, substituted alkyl, Selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic),

X 'is hydrogen, hydroxy or fluoro;

X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group;

Z is selected from the group consisting of a bond, oxygen and sulfur, which covalently bond R ¹ to -CX'X "-;

n is an integer of 1 or 2; only,

A. 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 When Z is a bond and n is 1, X is not -C (O) OH;

B. R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is —CH (OH) CH ₃ derived from D-threonine, R ⁵ is hydrogen, X ′ and X ″ are When hydrogen is Z is a bond and n is 1, X is not -C (O) OH or -C (O) OCH ₃ ;

C. 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, n is When 1, R ³ is not methyl;

D. R ¹ is iso-propyl, R ² is -CH ₂ C (O) NH ₂ , R ³ is hydrogen, R ⁴ is iso-butyl, R ⁵ is hydrogen, X 'and X " When hydrogen, Z is a bond and n is 1, 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 , The nitrogen atom bonded to R ³ , R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl;

F. 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 when n is 1, R ⁴ is not 4-amino-n-butyl;

G. 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, When Z is a bond and n is 1, X is not -C (O) NH ₂ or -CH ₂ 0H;

H. 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 when n is 1, R ⁴ is not benzyl or ethyl;

I. 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 When n is 1, X is not -CHOHψ;

J. R^OneIs 3,5-difluorophenyl, R²Is methyl and R³end Hydrogen, R⁴Is phenyl derived from D-phenylglycine and R⁵Is hydrogen, X 'and X "are hydrogen, Z is a bond, and n is 1, X is -CHOHψ or -CH₂Not OH;

K. R ¹ is N- (2-pyrrolidinyl), R ² is methyl, R ³ is hydrogen, R ⁴ is benzyl, R ⁵ is hydrogen, X 'and X "are hydrogen, When Z is a bond and n is 1, X is not -C (O) OCH ₃ ;

L. R ¹ is 3,5-difluorophenyl, R ² is methyl derived from D-alanine, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, and R ⁵ is hydrogen When X 'and X "are hydrogen, Z is a bond and n is 1, X is not -C (O) NH-benzyl;

M. 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 When n is 1, X is not -CH ₂ 0H;

N. 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 When Z is a bond and n is 1, X is not -C (O) NHC (CH ₃ ) ₃ ;

0. R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, R ⁵ is hydrogen, X 'and X When "is hydrogen, Z is a bond and n is 1, X is not -C (O) NHCH (CH ₃ ) ψ.

Preferably, the compounds of the present invention are derived from L-amino acids and represented by the formula (IA) below.

Thus, in one method of the invention, the invention consists in administering to a cell an amount of a compound of formula (I) or a mixture thereof effective to inhibit the release and / or synthesis of intracellular β-amyloid peptides in the cell. To inhibit β-amyloid peptide release and / or synthesis of

Since in vivo formation of β-amyloid peptides is associated with the pathogenesis of Alzheimer's disease ^8.9 , the compounds of formula (I) may also be used in connection with pharmaceutical compositions for preventing and / or therapeutically preventing Alzheimer's disease. Thus, in another method aspect of the invention, the invention comprises administering to a patient at risk of developing Alzheimer's disease a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of the compound of formula I or a mixture thereof Thus, it relates to a prophylactic method for preventing the onset of AD in the patient.

In another aspect of the invention, the present invention further comprises administering to the AD patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound of formula (I) or a mixture thereof, wherein the condition of the patient is further exacerbated. To a method of treating AD patients to prevent them.

Compounds suitable for use in the claimed method include the following examples:

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-histidine methyl ester,

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

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

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

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

N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide,

N- (3-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide,

N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate tert-butyl ester,

N- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (deck-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester,

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 methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tyrosine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (carboxymethoxy) phenylalanine methyl ester,

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 methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-pyridyl) propionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (3-pyridyl) propionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyll-L-proline methyl ester,

1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-pyridyl) propionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-morpholinopropionate methyl ester,

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

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester,

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

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate methyl ester,

2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester, 4

N- (3-methoxybenzyl) -N '-[N- (3.5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (1-naphthyl) propionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-naphthyl) propionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-thienyl) propionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine benzyl ester,

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

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

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

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

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

N- [N- (3,5- difluoro-phenyl-acetyl) -L- al Raney carbonyl] -N _ε - (tert- butoxycarbonyl) -L- lysine methyl ester,

Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-4-phenylbutanoate,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 2-phenylethyl ester,

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

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide,

N- [N- (phenylacetyl) -L-alaninyl] -L-threonine methyl ester,

N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide,

N '-[N- (phenylacetyl) -L-alaninyl] -L-alanineamide,

N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide,

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-leucineamide,

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

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

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

N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide,

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

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

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

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-methoxyphenyl) acetate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-methoxyphenyl) acetate methyl ester,

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 ethyl ester,

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 methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -l-aminocyclopropane-1-carboxylate methyl ester,

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

N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine benzyl ester,

N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine ethyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alanine ethyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine ethyl ester,

N-hydroxy-N '-[N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threonineamide,

N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate methyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-tyrosine ethyl ester,

N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester,

N- [N- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester,

N- [N- (isovaleryl) -L-phenylalaninyl] -L-alanine iso-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanine ethyl ester,

1- [N- (3-nitrophenylacetyl) -L-alaninyl] -indolin- (S) -2-carboxylate ethyl ester,

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

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

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

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

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

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

N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

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

N-iso-butyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide,

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

N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- (4-nitrophenyl) -N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-alanineamide,

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

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

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

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

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

N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophan methyl ester,

N- (4-methoxybenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester,

N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine methyl ester,

N- [N- (cyclohexylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine methyl ester,

N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-phenylglycine methyl ester,

N- (2-phenylethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

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

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

N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-nitrophenyl Propionamide,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-serine ethyl ester,

N-[(R) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl-L-alanineamide,

N-[(S) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- (4-fluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- (4-pyridylmethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- (4-trifluoromethylbenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-phenylpropionate ethyl ester,

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-methylpropionate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclosilacetate ethyl ester,

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

N- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -L-alanine 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) -L-alaninyl] -L-phenylglycinamide,

N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine neopentyl ester,

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

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

N '-[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 methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester,

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

4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isorushinyl] morpholine,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine methyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine,

N- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine ethyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine methyl ester,

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

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

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

N-neopentyl-N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

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

N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

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

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

N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester,

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

1- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] pyrrolidine,

N- (S) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valine methyl ester,

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

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

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,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-fluorophenyl) acetate methyl ester,

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate methyl ester,

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 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 ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (IH-tetrazol-5-yl) acetate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (6-methoxy-2-naphthyl) acetate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate Methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2.3b] thiophen-2-yl) acetate methyl ester,

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,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohex-4-enoate methyl ester,

N- [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,

N- [N- (3,5-difluorophenylacetyl)-(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-rucinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -L-alanine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -L-leucine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -N- (tert-butoxycarbonyl) -L-lysine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl] -L-valine methyl ester,

N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester,

N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester,

N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine,

N- [N- (phenylacetyl) -L-alaninyl] -L-N-methylalanine methyl ester,

N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester,

N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester,

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-hydroxyproline ethyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-lysine methyl ester,

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

1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester,

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

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

N- [N- (3,5-difluorophenyl-α-fluoroacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester,

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-alanineamide,

N-[(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

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

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

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

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

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

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

N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide,

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

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

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

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

N- [1-hydroxy-3-methyl-but-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (6-aminopyrid-2-yl) acetate methyl ester,

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

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

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

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

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

N- [2-hydroxy-1- (thien-2-yl) ethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N-[(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N- [N- (3,5-difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine tert-butyl ester,

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

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

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

N- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycineamide,

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

N- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycineamide,

N- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycineamide,

N- [N- (3,5-difluorophenylacetyl) -L-norrousinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-tert-rushinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-isorushinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (cyclopropyl) acetyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-3-yl) acetyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-2-yl) acetyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester,

N- [N- (cyclopropylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester,

N- [N- (cyclopentylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester,

N- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycineamide,

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,

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] -D-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) -L-alaninyl] -D, L-phenylglycinamide,

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) phenylglycineamide,

N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (phenyl) phenylglycinamide,

N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2 (benzyl) phenylglycineamide,

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

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

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

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

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

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

N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester,

N-tert-butyl-N '-[N- (3,5-difluorophenyl-α, α-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide,

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

N-[(S) -1-oxo-1-phenylprop-2-yl] -N- (3,5-difluorophenylacetyl) -L-alanineamide,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (pyrid-3-yl) glycine tert-butyl ester,

[N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (2-methoxy) phenylglycine methyl ester,

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) -L-alaninyl] -D, L-phenylglycinamide,

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

[N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine,

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

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

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

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

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

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

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

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

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

N-4-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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 N-tert-butyl (hydroxylamine) ester,

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

N- (1-ethoxyethen-1-yl)-[N '-(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide,

N- [N- (phenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester,

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

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

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

N-1- (phthalimido) pent-2-yl-N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N- [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycinyl] -L- (3,5difluorophenyl) glycine methyl ester,

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

N- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine isopropyl ester,

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

N- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester,

N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine iso-butyl ester,

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

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3-α-phenyl) proline methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-azetidine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (5-chlorobenzothiophen-2-yl) acetate methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycineamide tert-butyl ester,

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

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

N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (3-trifluoromethylphenylacetyl) -L-alaninyl] -D-phenylglycinamide,

N- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide,

N- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycineamide,

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

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

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

N '-[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) -L-alaninyl] glycinamide,

N "-methyl-N" -phenyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide,

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

N "-methyl-N" -benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide,

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

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (4-fluoro) phenylglycine neopentyl ester,

N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine tert-butyl ester,

N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) serinyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) threoninyl] -L-phenylglycine methyl ester,

N- [N- (3,5-difluorophenylacetyl) -L-threonyl] -L-phenylglycine methyl ester,

N- [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-alaninyl] -L-phenylglycinamide,

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

N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N- [1-phenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N- [1-phenyl-2-oxo-pentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide,

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

N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide,

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-α-hydroxyphenylalanine methyl ester,

N "-[4-((2-hydroxy-4-azido) -phenyl) -NHC (O)-) butyl] N '-[N- (3,5-difluorophenylacetyl) -L- Alaninyl] -L-phenylglycineamide,

N-[(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

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

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) methyl ester,

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-phenylglycinethioamide,

N- [1,3-diphenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

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

N- [1-phenyl-2-oxo-hexane-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide,

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

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

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

N '-[N- (2-tert-BOC-amino) propionyl) -L-alaninyl] -L-phenylglycine methyl ester,

N "-tert-butyl N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2-fluorophenyl glycineamide,

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-2-phenylglycine methyl ester,

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

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

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

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

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

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

N- [2-hydroxyeth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide,

N '-[N- (3,5-difluorophenyl-2-oxo-acetyl) -L-alaninyl] -L-2-phenylglycine tert-butyl ester,

[N- (2,5-dichlorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester,

[N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester,

[N- (3,4-dichlorothiophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester,

[N- (3-aminopropionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, and

[N- (3-tert-butoxycarbonylamino) propionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester.

The pharmaceutical composition described above contains the compound of formula I and a pharmaceutically inert carrier.

In the above formula (I), X "is preferably hydrogen and X 'is preferably hydrogen or fluoro.

In the above formula (I), X "is preferably hydrogen and X 'is preferably hydrogen or fluoro.

In the above formula (I), Z is preferably a bond which covalently bonds R ¹ to -CX'X "-.

In formula (I), preferred unsubstituted R ¹ aryl groups are, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred substituted aryl groups as R ^{1 are} , for example, monosubstituted phenyl (preferably 3 or 5 substituents); Di-substituted phenyl (preferably 3, 5 substituents); and trisubstituted phenyl (preferably 3, 4, 5 substituents). Preferably, the substituted phenyl group does not contain more than three substituents.

Substituted phenyls are, for example, 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-methylene-dioxyphenyl , 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-chlorophenyl and 2,5-difluorophenyl.

Preferred alkali groups as R ^{1 are} , for example, benzyl, 2-phenylethyl and 3-phenyl-n-propyl.

Preferred alkyl, cycloalkyl, alkenyl and cycloalkenyl groups as R ^{1 are} , for example, iso-propyl, 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, cyclohexyl-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.

Preferred heteroaryl and substituted heteroaryl groups as R ^{1 are} , for example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyl (5-fluoropyrid-3 -Yl), chloropyridyl (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl , Furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thi Offen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thioxadiazol-5-yl and 2-phenyloxazol-4-yl.

Preferably, R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. In particular, preferred R ² substituents are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro -Phenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ 0CH ₂ kill, It is selected from the group consisting of aryl, heteroaryl and heterocyclic. R ² (and R ⁴ ) is preferably the side chain of the L-amino acid.

Preferably, R ³ is hydrogen, or methyl, R ³ is coupled with R ⁴ is a nitrogen-pyrrolidin-2-yl, 2,3-dihydro-indol-2-yl, piperidin-2-one, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl and the like.

Preferred R ⁴ substituents are, for example, 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-fluoro Phenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p Nitrobenzyl, m-trifluoromethylphenyl, p- (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ 0-benzyl, p- (CH ₃ ) ₃ COC (O) CH ₂ 0-benzyl, p-phenylphenyl, 3,5-difluorophenyl, p- (HOOCCH ₂ 0) -benzyl, 2-aminopyrid-6-yl, 4- (N-morpholino-CH ₂ CHO) 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) Ot-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 ₂ (Cis and trans), -CH ₂ 0H, -CH (OH) CH ₃ , -CH (Ot-butyl) CH ₃ , -CH ₂ 0CH ₃ ,-(CH) 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-morpholino), p- (N- Morpholino-CH ₂ CH ₂ 0) -benzyl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-2-yl, 4 , 5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, tetrazol-5-yl, 5-chlorobenzo [b] thiophen-3- 1, benzo [b] thiophen-5-yl, 6-methoxynaphth- ₂ -yl, -CH ₂ -N-phthalimidyl, 2-methylthiazol-4-yl, 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-ethylfe Yl) phenyl, 4-tert-butylphenyl, 4-n-butylphenyl, o- (4-chlorophenoxy) phenyl, furan-2-yl, 4-phenylacetylenylphenyl and the like.

Preferably, R ⁵ is hydrogen. However, in another embodiment, R ⁴ and R ⁵ fuse to form a cycloalkyl group selected from the group consisting of cyclopropyl and cyclobutyl.

One preferred X is -C (O) Y. Preferably, Y is hydroxy, alkoxy or substituted alkoxy such as 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-nbutoxy, -ONHC (O) OC (CH ₃ ) ₃ , -ONHC (CH ₃ ) _3, and the like. Another preferred Y is -NR'R ", wherein R 'and R" are as defined above. Such preferred Y groups are, for example, amino (-NH ₂ ), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N- Morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethyleneimino, N-pyrrolidinyl, -NH-metallyl, -NHCH ₂ -(Furan-2-yl), -NHCH ₂ cyclopropyl, -NH (tert-butyl), -NH (p-methylphenyl), -NHOCH ₃ , -NHCH ₂ (p-fluorophenyl), -NHCH ₂ CH ₂ 0CH _3, -NH- cyclopentyl, cyclohexyl _{-NH-, -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-thiazolininyl, -N (CH ₂ CH ₂ CH ₃ ) ₂ , -N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -NH (p-NO ₂ -φ), -NHCH ₂ (P-NO ₂ -φ), -NHCH ₂ (m-N0 ₂ -φ), -N ( CH ₃ ) OCH ₃ , -N (CH ₃ ) CH ₂ -φ, -NHCH _2- (3,5-di-fluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ 0- φ), -NHCH ₂ (M-CH ₃ 0-φ), -NHCH ₂ (P-CF ₃ -φ), -N (CH ₃ ) CH ₂ CH ₂ 0CH ₃ , -NHCH ₂ CH _{2 φ, -NHCH (CH 3)} φ, -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] -piperidine- 4-day, -NHOC (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ -φ, -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 ) φ, -NH (CH ₂ ) ₄ NHC (O)-(2-hydroxy-4 -Azido-phenyl, -NH (CH ₂ ) _6- (biotinamidyl), and the like.

Such preferred Y groups are, for example, 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 - greener-2-yl and the like; Substituted alkyl groups such as benzyl; Substituted cycloalkyl groups such as cyclopentyl; And aryl groups such as phenyl.

Another preferred Y group is -NHSO ₂ -R wherein R is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Such groups are, for example, -NHSO ₂ -CH ₃ .

Preferred Y 'groups are, for example, --CH ₂ 0H, -CH (OH) CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH (OH) φ, -CH (OH) CH ₂ C (O) OCH ₃ , -C (OH) (CH ₃ ) ₂ , -CH ₂ 0CH ₃ , -CH ₂ 0C (O) OCH ₃ , -CH ₂ 0C (O) C (CH ₃ ) _3, and the like.

Preferred compounds for use in the process of the invention are the compounds shown in the following table.

As mentioned above, the present invention relates to methods useful in inhibiting β-amyloid peptide release and / or synthesis and thus treating Alzheimer's disease. However, prior to describing the present invention in detail, the following terms will be defined first.

<Justice>

The term "β-amyloid peptide" refers to 39 to 43 amino acids having a molecular weight of about 4.2 kilodaltons, the peptides described by Glenner et al. ¹ including mutations and post-transcriptional modifications of normal β-amyloid peptides. Is essentially a homologue with its form. In any form, the β-amyloid peptide is about 39 to 43 amino acid fragments of the polymer membrane-spanning glycoprotein and is called β-amyloid precursor protein (APP). Its 43 amino acid sequence or sequence essentially homologous thereto is as follows:

One

Asp Ala Glu Phe Arg His Asp Ser Gly Tyr

11

Glu Val His His Gln Lys Leu Val Phe Phe

21

Ala Glu Asp Val Gly Ser Asn Lys Gly Ala

31

Ile Ile Gly Leu Met Val Gly Gly Val Val

41

Ile Ala Thr (SEQ ID NO: 1)

"Alkyl" preferably refers to a monovalent alkyl group having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. This is for example a group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like.

"Substituted alkyl" refers to alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy ester, cyano, halogen, hydroxy, carboxyl, carbon Heteroalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thiolalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro and mono- and di-alkylamino, mono- and di- (substituted Alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono and di-heterocyclic amino, and other substituents selected from alkyl, substituted alkyl, aryl, heteroaryl, and heterocycle It refers to an alkyl group having 1 to 3 substituents, preferably 1 to 10 carbon atoms, selected from the group consisting of asymmetric di-substituted amines.

"Alkylene" preferably refers to a divalent alkylene group having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. It is, for example, methylene (-CH _2- ), ethylene (-CH ₂ CH _2- ), propylene isomers (e.g., -CH ₂ CH ₂ CH ₂ -and -CH (CH ₃ ) CH _2- ) and the like. It is the same group.

"Alkaryl" refers to an -alkylene-aryl group having preferably 1 to 10 carbon atoms in the alkylene moiety and 6 to 10 carbon atoms in the aryl moiety. Such alkali groups are, for example, benzyl, phenethyl and the like.

"Alkoxy" refers to "alkyl-O-". Preferred alkoxy groups are, for 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" refers to "substituted alkyl-O-", where substituted alkyl is as defined above.

"Alkoxyalkoxy" refers to a "-alkylene-O-alkyl" group, where alkylene and alkyl are as defined above. Such groups are, for 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 ) or methylene-t-butoxy (-CH ₂ -OC (CH ₃ ) ₃ ) and the like.

"Alkylthioalkoxy" refers to a "-alkylene-S-alkyl" group, where alkylene and alkyl are as defined above. Such groups are, for example, methylthiomethoxy (-CH ₃ SCH ₃ ), ethylthiomethoxy (-CH ₂ CH ₂ SCH ₃ ), n-propyl-iso-thiopropoxy (-CH ₂ CH ₂ CH ₂ SCH (CH ₃ ) ₂ ), methylthio-t-butoxy (-CH ₂ SC (CH ₃ ) ₃ ), and the like.

"Alkenyl" preferably refers to an alkenyl group having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms and alkenyl unsaturation at one or more, preferably 1 to 2 positions. Such groups are, for example, ethenyl (-CH = CH ₂ ), n-propenyl (-CH ₂ CH = CH ₂ ), iso-propenyl (C (CH ₃ ) = CH ₂ ), but- ₂ -ethyl (-CH ₂ CH = CHCH ₃ ) and the like.

"Substituted alkenyl" refers to alkoxy, substituted alkoxy, aryloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy ester, cyano, halogen, hydroxy, carboxyl, carboxyalkyl, cycloalkyl, oxyacyl , Oxyacylamino, thiol, thiolalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro and mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di -Arylamino, mono and di-heteroaryl amino, mono and di-heterocyclic amino, and asymmetric di-substituted amines with other substituents selected from alkyl, substituted alkyl, aryl, heteroaryl, and heterocycle Alkenyl group as defined above having 1 to 3 substituents selected from.

"Alkynyl" refers to alkenyl groups which preferably have 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms and alkynyl unsaturation at one or more, preferably 1 to 2 positions. Such groups are, for example, ethynyl (-CH≡CH ₂ ), propargyl (-CH ₂ C≡CH) and the like.

"Substituted alkynyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy ester, cyano, halogen, hydroxy, carboxyl, carboxyalkyl, cycloalkyl, oxyacyl, oxyacyl Amino, thiol, thiolalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro and mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino , 1 selected from the group consisting of mono and di-heteroaryl amino, mono and di-heterocyclic amino, and asymmetric di-substituted amines with other substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocycle. It refers to an alkynyl group as defined above having from 3 substituents.

"Acyl" refers to alkyl-C (O)-, substituted alkyl-C (O)-, cycloalkyl-C (O)-, aryl-C (O)-, heteroaryl-C (O)-and heterocy Refers to click-C (O) —, wherein alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle are each as defined herein.

"Acylamino" refers to the group -C (O) NRR, wherein R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic, each alkyl, substituted alkyl, cycloalkyl , Aryl, heteroaryl, and heterocycle as defined herein).

"Aminoacyl" refers to the group -NRC (O) R, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and each alkyl, substituted alkyl, cycloalkyl, aryl , Heteroaryl and heterocycle as defined herein).

"Oxyacyl" refers to -OC (O) -alkyl, -OC (O) -aryl, -OC (O) -heteroaryl and -OC (O) -heterocyclic, wherein alkyl, aryl, heteroaryl And heterocycle as defined herein).

"Oxyacylamino" refers to -OC (O) NR-alkyl, -OC (O) NR-substituted alkyl, -OC (O) NR-aryl, -OC (O) NR-heteroaryl and -OC (O) NR-heterocyclic, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, respectively Is as defined herein).

"Aminocarboxy ester" includes -NRC (O) O-alkyl, -NRC (O) O-substituted alkyl, -NRC (O) O-aryl, -NRC (O) O-heteroaryl and -NRC (O) O-heterocyclic, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, respectively Is as defined herein).

"Aryl" refers to an unsaturated aromatic carboxyl group having 6 to 14 carbon atoms having one ring (eg phenyl) or multiple condensed rings (eg naphthyl or anthryl).

Unless otherwise limited by the definition of aryl substituents, such aryl groups are hydroxy, biotinamidyl, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted Alkynyl, amino, aminoacyl, aminocarboxy ester, alkaryl, aryl, aryloxy, azido, carboxyl, carboxyalkyl, acylamino, cyano, halogen, nitro, heteroaryl, heterocyclic, oxyacyl, oxy Acylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-hetero Arylamino, mono and di-heterocyclic amino, and a 1 selected from the group consisting of asymmetric di-substituted amines having other substituents selected from alkyl, substituted alkyl, aryl, heteroaryl, and heterocycle To 5, and preferably, it may be optionally substituted with one to three substituents.

"Aryloxy" is aryl-O comprising a substituted aryl group as defined above, wherein the aryl group is as defined above.

"Carboxy terminated R ⁴ group" refers to those in which the R ⁴ group is closest to the X group in the compound of Formula I (where n is 2).

"Carboxyalkyl" refers to -C (O) O-alkyl and -C (O) O-substituted alkyl groups, wherein alkyl and substituted alkyl are as defined above.

"Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 carbon atoms having one ring and having multiple condensed rings which may be optionally substituted with 1 to 3 alkyl groups. Such cycloalkyl groups are, for example, one ring structure such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 1-methylcyclopentyl, 2-methylcyclooctyl or the like or multiple such as adamantanyl or the like. It is a ring structure.

"Cycloalkenyl" refers to a cyclic alkenyl group of 4 to 8 carbon atoms having one ring and having at least one point of internal unsaturation which may be optionally substituted with 1 to 3 alkyl groups. Suitable cycloalkenyl groups are, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.

"Halo" or "halogen" refers to fluorine, chlorine, bromine and iodo, preferably chlorine or bromine.

"Heteroaryl" refers to a monovalent aromatic group of 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring.

Unless otherwise limited by the definition for heteroaryl substituents, such heteroaryl groups are hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl , Amino, aminoacyl, aminocarboxy ester, alkaryl, aryl, aryloxy, carboxy, carboxyalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, Substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono and di 1 to 3 values selected from the group consisting of heterocyclic amino and asymmetric di-substituted amines having other substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocycle Body may be optionally substituted. Preferred substituents are alkyl, alkoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy.

Such heteroaryl groups may have one ring (eg pyridyl or furyl) or multiple condensed rings (eg indolizinyl or benzothienyl). Preferred heteroaryl is pyridyl, pyrrolyl or furyl.

"Heteroaryloxy" refers to a heteroaryl-O- group comprising an optionally substituted heteroaryl group as defined above, wherein the heteroaryl group is as defined above.

"Heterocycle" or "heterocyclic" means a monovalent (i.e., one having one to eight carbon atoms and one to four heteroatoms selected from nitrogen, sulfur or oxygen in the ring or multiple condensed rings) Bonds) to a saturated or unsaturated group.

Unless otherwise defined by the definition for heterocyclic substituents, such heterocyclic groups are hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted Alkynyl, amino, aminoacyl, aminocarboxy ester, alkaryl, aryl, aryloxy, carboxy, carboxyalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thio Alkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono And asymmetric di-substituted amines having di-heterocyclic amino and other substituents selected from alkyl, substituted alkyl, aryl, heteroaryl, heterocycle and the like. Substituents may be optionally substituted. Such heterocyclic groups may have one ring or multiple condensed rings. Preferred heteroaryls are morpholino, piperidinyl and the like.

Examples of heterocycles and heteroaryls are furan, thiophene, thiazole, oxazole, pyrrole, amidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, Quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothia Sol, phenazine, isoxazole, phenoxazine, phenothiazine, imidazodine, imidazoline, piperidine, piperazine, indolin, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, pineridinyl, pyrrolidine, tetrahydrofuranyl Etc.

"Heterocyclyloxy" refers to a heterocyclyl-O- group comprising an optionally substituted heterocyclic group as defined above, wherein the heterocyclyl group is as defined above.

"Oxyacyl" refers to -OC (O) -alkyl, -OC (O) -aryl, -C (O) O-heteroaryl and -C (O) O-heterocyclic groups (where alkyl, aryl, Heteroaryl and heterocycle as defined above).

"Oxyacylamino" refers to -OC (O) NH-alkyl, -OC (O) NH-substituted alkyl, -OC (O) NH-aryl, -OC (O) NH-heteroaryl and -OC (O) NH-heterocyclic, where alkyl, aryl, heteroaryl and heterocycle are as defined above.

"Thiol" refers to the group -SH.

"Thioalkoxy" refers to an -S-alkyl group.

"Substituted thioalkoxy" refers to an -S-substituted alkyl group.

"Thioaryloxy" refers to an aryl-S- group comprising an optionally substituted aryl group as defined above, wherein the aryl group is as defined above.

"Thioheteroaryloxy" refers to a heteroaryl-S- group comprising an optionally substituted aryl group as defined above, wherein the heteroaryl group is as defined above.

"Pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts of compounds of Formula I, the salts thereof being derived from a variety of well known organic and inorganic counter ions, for example sodium, potassium, calcium, magnesium And ammonium, tetraalkylammonium, and the like, and when the molecule contains a basic functional group, salts of organic and inorganic acids such as hydrogen chloride, hydrogen bromide, tartrate, acetate, maleate, oxalate and the like.

Compound manufacture

Compounds of formula (1) are readily prepared by several different synthetic routes with specific routes chosen taking into account the ease of compound preparation, the commercial availability of starting materials, and the like.

The first synthetic method involves conventional coupling of an acetic acid derivative with a primary amine of an esterified amino acid as shown in Scheme 1 below:

Wherein R ¹ , R ² , R ³ , X 'and X "are as defined above and X is oxygen or -NH-.

Scheme 1 simply comprises the coupling of a suitable acid derivative (1) with a primary amine (2) of an amino acid ester under conditions to provide an N-acetyl derivative (3). This reaction is commonly carried out for peptide synthesis, and the synthetic method used herein can also be used to prepare the N-acetyl amino acid ester (3) of the present invention. For example, known coupling agents such as carbodiimide can be used to facilitate coupling with or without known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, and the like. . This reaction is usually carried out in an inert aprotic diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound (1) can be used in Scheme 1, where used, it is usually used in the presence of a suitable base to remove the acid produced during the reaction. Suitable bases are, for example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.

Scheme 1 is preferably performed at about 0 ° C. to about 60 ° C. until the reaction is complete (typically occurring within 1 to about 24 hours). When the reaction is complete, the N-acetyl amino acid ester (3) is recovered by conventional methods including precipitation, chromatography, filtration and the like, or alternatively conventional post-treatment (eg, aqueous extraction, etc.) Hydrolysis to the corresponding acid without further purification and / or separation processes. Alternatively, the synthesis described in Scheme 1 can be performed on amino acids (XR ³ = OH), followed by N-acetyl formation as described above.

In any case, when an N-acetyl amino acid ester is formed, it is converted to the corresponding acid before the coupling step with another amino acid ester / amide, HNR ³ CR ⁴ R ⁵ C (O) Y. Coupling may be combined with a known coupling reagent such as carbodiimide with or without known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc., which may be used to facilitate coupling. It is carried out using known peptide coupling chemistry of. The reaction is usually carried out in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.

This coupling forms a compound of Formula 1 wherein n is 1. Synthesis of a compound of formula 1 wherein n is 2 is carried out by a second coupling reaction. In particular, in the first coupling reaction, HNR ³ CR ⁴ R ⁵ C (O) Y is chosen to be an amino acid ester. That is, Y is -O-alkyl. After coupling, the ester is hydrolyzed by conventional conditions known in the art to provide a corresponding carboxylic acid that can be used to couple the second amino acid ester / amide.

In Scheme 1, each of the reactants is known in the art, where the majority of [Compound (1) and amino acid ester (2)] are commercially available.

Alternatively, the compounds of formula 1 can be prepared by first forming dipeptide esters and then N-acylating these esters. That is, the amino acid ester or amide HNR ³ CR ⁴ R ⁵ C (O) Y is coupled to the amino acid block NHCHR ² COOH N-blocked by conventional coupling conditions to dipeptide block NHCHR ² C (O) N (R ³ ) CR ⁴ R ⁵ C (O) Y is provided. Subsequently, the blocking group is removed by conventional conditions to form the free amine, and then N-acylated in the manner described above to provide the compound of formula 1.

After completion of coupling and N-acylation (no order), the resulting esters and amides can be derived by conventional chemistry to provide derivatives of the synthetic compounds. For example, lithium borohydride is typically used to reduce terminal ester groups to form terminal -CH ₂ OH groups. Alternatively, ammonia in methanol can be converted to the primary amide [-C (O) NH ₂ ] by heating the ester group with a catalytic amount of sodium cyanide.

Similarly, the reactor blocked on the R ² and / or R ³ groups can be deblocked and then led to. For example, the (eg lysine side chain) BOC protected amino group on R ³ is deblocked after synthesis, and the amino group can be acylated or otherwise derived.

Terminal esters can also undergo transesterification to form other esters. Various techniques for carrying out the transesterification reaction are known in the art, with each technique replacing only one ester group with another ester group derived from the corresponding alcohol or thioalcohol, and in some cases titanium (IV) iso- A catalyst such as propoxide is used to facilitate the completion of the reaction. In one technique, alcohol or thioalcohol is first treated with sodium hydride in a suitable diluent such as toluene to form the corresponding sodium alkoxide or thioalkoxide, which is then used to carry out the transesterification reaction. The effects of this technique are particularly useful for using high boiling and / or expensive alcohols or thioalcohols.

In another transesterification technique, the ester to be transesterified is replaced with excess alcohol or thioalcohol to carry out the transesterification reaction. Subsequently, the catalytic amount of sodium hydride is added and the reaction proceeds rapidly under normal conditions to form the desired transesterified product. Since this method requires an excess of alcohol or thioalcohol, this method is particularly useful when the alcohol or thioalcohol is inexpensive.

The transesterification reaction provides an easy means to provide a number of different ester substituents on the compound of Formula 1 above. In all cases, the alcohols or thioalcohols used to carry out the transesterification reaction are known in the art and many are commercially available.

Other methods of preparing the esters of the present invention include, for example, first hydrolyzing the esters with the free acid, followed by O-alkylation with a halo-R ³ group in the presence of a base such as potassium carbonate. Alternatively, the method of esterifying an alcohol containing an ester group can be carried out using a method such as Rosse.

In addition, the compounds described herein can be prepared using polymer supported forms of carbodiimide peptide coupling reagents. For example, EDCs in polymer supported form are described in Tetrahedron Letters, 34 (48), 7685 (1993). In addition, a novel carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been disclosed, which are very useful for the preparation of the compounds of the present invention.

Suitable polymers for use in the preparation of polymer supported coupling reagents are typically commercially available or may be prepared by methods known to those skilled in the polymer arts. Suitable polymers should have pendant side chains having residues that react with the terminal amines of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. In addition, the backbone of the polymer should be inert to both the reaction conditions and the carbodiimide in which the final polymer bound to the coupling reagent may be used.

Certain hydroxymethylated resins can be converted to chloromethylated resins useful in the preparation of polymer supported coupling reagents. Examples of such hydroxylated resins are 4-hydroxymethyl-phenylacetamidomethyl resin [Pam resin] and 4 available from Advanced Chemtech of Louisville, Kentucky, USA. Benzyloxybenzyl alcohol resin [Wang resin] (Advanced Chemtech 1993-1994 catalog, p. 115). The hydroxymethyl group of such resins can be converted to the desired chloromethyl group by a number of methods known to those skilled in the art.

Preferred resins are chloromethylated styrene / divinylbenzene resins due to their easy availability. As these names indicate, these resins are easily chloromethylated and do not require chemical modification before use. These resins are commercially available from Aldrich Chemical Company, Milwaukee, WI (see Aldrich 1994-1995 Catalog Page 399). The process for producing PEPC and its polymer supported forms is outlined in the following scheme:

The method is described more fully in US Application No. 60 / 019,790, filed June 14, 1996, the disclosure of which is incorporated herein by reference. That is, PEPC is prepared by first reacting ethyl isocyanate with 1- (3-aminopropyl) pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to prepare PEPC. Polymer supported forms are prepared by reacting PEPC with a suitable resin under standard conditions to form the desired reagent.

Carboxylic acid coupling reactions using such reagents are performed at about ambient temperature to about 45 ° C. for about 3 to 120 hours. Typically, the product can be isolated by washing the reaction with CHCl ₃ and remaining organics concentrated under reduced pressure. As mentioned above, isolating the product from the reaction with a polymer binding reagent is very simple and only requires filtering the reaction mixture and then concentrating the filtrate under reduced pressure.

Another method of making the ester is provided in the examples below.

Compounds wherein X is —CR ⁶ R ⁶ Y ′ may be used with known coupling reagents such as carbodiimide, with or without known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, and the like. Under standard coupling conditions known in the peptide coupling chemistry, for example amino alcohols H ₂ NCR ⁴ R ⁵ CR ⁶ R ⁶ OH to R ¹ ZCX'X "C (O) NHCHR ² C (O) OH Coupling is easily prepared by coupling to a carboxyl group If desired, known blocking groups on Y 'can be used to protect the groups during coupling, which blocking groups are particularly preferred when Y' is an amino group.

The reaction is usually carried out in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Upon completion of the reaction, any blocking groups on Y 'are selectively removed to provide the desired compound.

If Y 'is -OH or -SH, this group is subjected to postsynthesis conversion to the corresponding ester (ie -OC (O) R ⁷ ), disulfide (ie -SSR ⁷ ) and -SSC (O) R ⁷ groups. This is done using known chemistry. For example, ester synthesis requires reaction with a suitable acid such as acetic acid (R ⁷ = methyl), acid halide (eg acid chloride) or acid anhydride only under suitable esterification conditions.

When one of R ⁶ is hydrogen, postsynthetic oxidation of the —CHR ⁶ OH group forms a ketone derivative. Alternatively, such ketones may be prepared by coupling a suitable aminoketone HCl salt with the terminal carboxyl groups of the amino acids described in Example 168 below.

In this method of synthesis, the starting material may contain chiral centers (eg alanine), and when using racemic starting materials, the resulting product is a mixture of R, S enantiomers. Alternatively, chiral isomers of the starting materials can be used and if the reaction scheme used does not racemize these starting materials, a chiral product is obtained. Such reaction schemes may involve the conversion of chiral centers during synthesis.

Thus, unless otherwise indicated, the products of the present invention are mixtures of R, S enantiomers or diastereomers. However, preferably, if a chiral product is desired, the chiral product corresponds to an L-amino acid derivative. Alternatively, the chiral product is obtained by a purification technique that separates the enantiomers from the R, S mixture and provides one or more stereoisomers. Such techniques are known in the art.

Pharmaceutical formulation

When used as a pharmaceutical, the compound of formula 1 is usually administered in the form of a pharmaceutical composition. Such compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal administration. These compounds are effective both as injections and as oral compositions. Such compositions are prepared by methods known in the pharmaceutical art and comprise one or more active compounds.

The present invention also encompasses pharmaceutical compositions containing, as active ingredient, at least one compound of formula 1 and a pharmaceutically acceptable carrier. In the preparation of the compositions of the present invention, the active ingredient is usually mixed with excipients and wrapped in a carrier which may be diluted by the excipients or in the form of capsules, sachets, paper or other containers. If the excipient acts as a diluent, it may be a solid, semisolid, or liquid substance, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may comprise tablets, pills, powders, lozenges, bags, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example up to 10% by weight of active compound. And ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders containing.

In the preparation of the formulation, it may be necessary to mill the active compound to form a suitable particle size before mixing with other components. If the active compound is substantially insoluble, it is typically milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is typically adjusted to, for example, about 40 mesh by milling to provide a substantially uniform distribution in the formulation.

Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragagant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , Sterile water, syrup and methyl cellulose. Formulations also include lubricants such as talc, magnesium stearate, and mineral oils; Wetting agents; Emulsifying and suspending agents; Preservatives such as methyl- and propylhydroxybenzoate; Sweeteners; And flavoring agents. Compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using methods known in the art.

The composition is preferably formulated in unit dosage form, with each dosage containing about 5 to about 100 mg, more typically about 10 to about 30 mg of the active ingredient. The term “unit dosage form” means physically discrete units suited as unitary dosages for human patients and other mammals, each unit having a predetermined amount calculated to produce the desired therapeutic effect with suitable pharmaceutical excipients. Contains the active substance. Preferably, the compound of formula 1 is used in less than about 20% by weight of the pharmaceutical composition, more preferably in less than about 15% by weight, with the remainder being the pharmaceutical inert carrier (s).

The active compounds are effective in a wide range of dosages and are generally administered in pharmaceutically effective amounts. However, the amount of compound administered substantially may be determined by the physician in consideration of the relevant circumstances, including the condition to be treated, the choice of route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. Will be understood.

To prepare solid compositions, such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid, preliminary formulation containing a homogeneous mixture of the compounds of the present invention. Homogeneous such a preparative composition means that the active ingredient is dispersed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preliminary preparation is then divided into unit dosage forms of the type described above which contain, for example, from 0.1 to about 500 mg of the active ingredient of the invention.

Tablets or pills of the present invention may be provided in dosage forms that are coated or combined to allow the benefit of long term action. For example, tablets or pills may consist of an internal dosage component and an external dosage component, the external dosage component being in the form of packaging an internal dosage component. The two components can be separated by an enteric layer that acts to inhibit degradation in the stomach, allowing the internal components to pass through the duodenum or delay secretion. Various materials can be used in such enteric layers or enteric coatings, which include a plurality 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 incorporated for oral administration or by injection are aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and edible such as cottonseed oil, sesame oil, coconut oil, or peanut oil. Oily flavored emulsions, and elixirs and similar pharmaceutical vehicles.

Inhalation or blowing compositions include solutions and suspensions, or mixtures thereof, and powders in pharmaceutically acceptable aqueous or organic solvents. The liquid or solid composition may comprise a suitable pharmaceutically acceptable excipient as described above. The composition is preferably administered orally or by nasal breathing route for local or systemic effects. Preferably the composition in a pharmaceutically acceptable solvent can be sprayed using an inert gas. The nebulized solution may be breathed directly from the nebulizer, or the nebulizer may be attached to a face mask tent, or an intermittent positive pressure breathing machine. The solution, suspension, or powder composition may be administered orally or intranasally, preferably from a device that delivers the formulation in a suitable manner.

The following formulation examples illustrate the pharmaceutical compositions of the present invention.

Formulation Example 1

A hard gelatin capsule is prepared containing the following ingredients:

ingredient Amount (mg / tablet) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0

The ingredients are mixed and filled with 340 mg in hard gelatin capsules.

Formulation Example 2

Tablet formulations are prepared using the following ingredients:

ingredient Amount (mg / tablet) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The ingredients are mixed and compressed to form tablets each 240 mg.

Formulation Example 3

A dry powder inhalation formulation is prepared containing the following ingredients:

ingredient weight (%) Active ingredient 5 Lactose 95

The active ingredient is mixed with lactose and the mixture is added to dry powder for inhalation.

Formulation Example 4

Tablets containing 30 mg each of the active ingredient are prepared as follows:

ingredient Amount (mg / tablet) Active ingredient 30.0 Starch 45.0 Microcrystalline cellulose 35.0 Polyvinylpyrrolidone (10% solution in sterilized water) 4.0 Sodium carboxymethyl starch 4.5 Magnesium stearate 0.5 talc 1.0 gun 120

The active ingredient, starch and cellulose were treated with 20 mesh U.S. Pass the sieve and mix thoroughly. After mixing the polyvinyl pyrrolidone solution with the resulting powder, 16 mesh U.S. Passed through a sieve. The particles thus produced are dried at 50 ° C. to 60 ° C., and 16 mesh U.S. Pass it through a sieve. Go ahead and use mesh 30 U.S. Sodium carboxymethyl starch, magnesium stearate, and talc, which have passed through a sieve, are added to the granules, then mixed and compressed in a tableting machine to form tablets of 150 mg each.

Formulation Example 5

Capsules containing 40 mg of each agent are prepared as follows:

ingredient Amount (mg / tablet) Active ingredient 40.0 Starch 109.0 Magnesium stearate 1.0 gun 150.0

The active ingredient, starch, and magnesium stearate are mixed and mesh 20. U.S. Pass through a sieve and fill the hard gelatin capsules with 150 mg amount.

Formulation Example 6

Suppositories containing 25 mg each of the active ingredient are prepared as follows:

ingredient amount Active ingredient 25 mg Saturated Fatty Acid Glyceride Up to 2,000 mg

The active ingredient is 60 mesh U.S. Pass through a sieve and suspend in pre-melted saturated fatty acid glycerides using the minimum heat required. Subsequently, the mixture is poured into a 2.0 g suppository mold and cooled.

Formulation Example 7

Suspending agents containing 50 mg of drug per 5.0 ml of each dose are prepared as follows:

ingredient amount Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium Carboxymethyl Cellulose (11%) Microcrystalline Cellulose (89%) 50.0 mg Sucrose 1.75 mg Sodium benzoate 10.0 mg Flavors and Colorants Enough Purified water Up to 5.0 ml

The active ingredient, sucrose and xanthan gum are mixed and mesh 10. U.S. After passing through a sieve, it is mixed with a pre-made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavors and colorants are diluted with some water and added with stirring. Subsequently, a sufficient amount of water is added to form the desired volume.

Formulation Example 8

ingredient Amount (mg / capsules) Active ingredient 15.0 Starch 407.0 Magnesium stearate 3.0 gun 425.0

The active ingredient, starch and magnesium stearate are mixed and mesh No. 20 U.S. Pass through a sieve and fill a hard gelatin capsule with an amount of 560 mg.

Formulation Example 9

Subcutaneous formulations can be prepared as follows:

ingredient amount Active ingredient 5.0 mg Corn oil 1 ml

Formulation Example 10

Topical formulations can be prepared as follows:

ingredient amount Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g White soft paraffin Up to 100 g

Heat the white soft paraffin until it melts. The liquid paraffin and emulsifying wax are mixed and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until it is solid.

Another preferred formulation used in the method of the invention uses a transdermal delivery device ("patch"). Such transdermal delivery patches can be used to inject a controlled amount of a compound of the invention continuously or discontinuously. The structure and use of transdermal patches for the delivery of pharmaceutical formulations are known in the literature (see US Pat. No. 5,023,252, issued June 11, 1991, the disclosure of which is incorporated herein by reference). Such patches may be configured for continuous, pulsatile, or on-demand delivery of the pharmaceutical formulation.

Often, it will be desirable or necessary to introduce pharmaceutical compositions directly or indirectly into the brain. Direct techniques typically involve placing a drug delivery catheter in the ventricular system of the host to cross the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to define the anatomical region of the body is described in US Pat. No. 5,011,472, the disclosure of which is incorporated herein by reference.

Generally preferred indirect techniques typically involve the formulation of a composition to provide drug latency by converting a hydrophilic agent into a fat soluble agent. Latency is generally accomplished by blocking the hydroxy, carbonyl, sulfate and primary amine groups present in the drug to make the drug more soluble and transported through the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs can be enhanced by intraarterial injection of hypertonic solution that can temporarily open the blood-brain barrier.

Other suitable formulations for use in the present invention are described in Remington's Pharmaceutical Sciences, Mace Publlishing Company, Philadelphia, PA, 17th ed. (1985).

Usage

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

As noted above, the compounds described herein are suitable for use in the various drug delivery systems described above. In addition, to increase the serum half-life in vivo of the administered compound, the compound may be encapsulated, incorporated into the lumen of the liposome, prepared as a colloid, or other conventional techniques may be used to extend the serum half-life of the compound. . Various methods are useful for preparing liposomes, and are described, for example, in US Patent Application Nos. 4,235,871 and 4,837,028 to Szoka et al., The disclosures of which are incorporated herein by reference.

The amount of compound administered to a patient will vary depending upon the substance being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the patient, the mode of administration and the like. In therapeutic use, the composition is administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further development of the symptoms of the disease and its complications. An amount sufficient to achieve this is defined as "therapeutically effective dosage". The effective amount for this use will depend on the judgment of the attending physician, depending on factors such as the degree or severity of the patient's AD, the patient's age, weight and general symptoms. Preferably, for use as a therapeutic agent, the compounds described above are administered at a dosage ranging from about 1 to about 500 mg / kg / day.

In prophylactic use, the composition is administered to a patient at risk of developing AD (as measured by genetic screening or household surveys) in an amount sufficient to inhibit the development of disease symptoms. An amount suitable for carrying out this is defined as a "prophylactically effective dosage". The effective amount for this use will depend on the judgment of the attending physician, depending on factors such as the age, weight and general symptoms of the patient. Preferably, for use as a prophylactic agent, the aforementioned compounds are administered at a dosage ranging from about 1 to about 500 mg / kg / day.

As mentioned above, the compound administered to the patient is in the form of the pharmaceutical composition described above. Such compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The resulting aqueous solution can be packaged on its own or as lyophilized and the lyophilized formulation is mixed with a sterile aqueous carrier prior to administration. The pH of the compound formulation is usually 3 to 11, more preferably 5 to 9, most preferably 7 and 8. It is to be understood that the particular use of such excipients, carriers or stabilizers may form pharmaceutical salts.

The following synthesis and biological examples are provided to illustrate the invention and should not be construed to limit the scope of the invention in any way. Unless otherwise stated, all temperatures are in degrees Celsius.

In the following examples, the following abbreviations have the following meanings. If the abbreviation is not defined, it has a generally accepted meaning.

BOC = tert-butoxycarbonyl

BOP = Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate

bd = wide double line bs = wide single line

c = concentration (g / ml) CDI = 1,1'-carbonyldiimidazole

d = doublet dd = doublet of doublet

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

eq. = Equivalent EtOAc = ethyl acetate

EtOH = Ethanol g = Gram

ℓ = liter m = multiple

max = maximum MeOH = methanol

meq = milligram equivalent mg = milligram

Ml = milliliters mm = millimeters

mmol = millimolar N / A = not allowed

N = normal ng = nanogram

Nm = nanometer OD = optical density

ψ = phenyl

PEPC = 1- (3- (1-pyrrolidinyl) propyl) -3-ethylcarbodiimide

psi = pounds per square inch q = quartet

quint. = Quinine rpm = revolutions per minute

s = singlet t = triplet

TFA = trifluoroacetic acid THF = tetrahydrofuran

tlc = thin layer chromatography μl = microliters

UV = UV

In the examples below, all temperatures are in degrees Celsius (unless otherwise indicated), and the compounds shown in these examples were each prepared according to one of the following general methods unless otherwise indicated.

The term "Aldrich" is also used in the following method, commercially available from Aldrich Chemical Company, Inc., Milwaukee, West St. Paul Avenue 1001, 53233, USA. A compound or reagent; The term “Fluka” refers to a compound or reagent commercially available from Fluka Chemical Corp. of Ronconcoma 980 South Second Street 980, NY 11779; The term "Lancaster" is based on Lancaster Synthesis, Inc., Wyndham P. O. Box 100, New Hampshire, USA 03087. Compound or reagent commercially available from Lancaster Synthesis, Inc .; The term “Sigma” refers to a compound or reagent available from Sigma, St. Louis P. Box 14508, Missouri, 63178, USA; The term "Chemservice" refers to a compound or reagent available from Chemservice Inc. of Westchester, PA; The term “Bachem” is Bachem Bioscience Inc., King of Prussia Renaissance at Gulf Mills Horizon Drive 3700, 19406 PA, USA. Compounds or reagents commercially available from Bachem Biosciences Inc .; The term “maveridge” refers to a compound or reagent commercially available from Maybridge Chemical Co. of Pt 34 O. Double Oil Cornwall Tintagel Trevlet, UK; The term “TCI” refers to a compound or reagent available from TCI America, North Harborgate Street 9211, Portland, Oregon, USA 97203; The term "Alfa" is a Johnson Matty catalog company, Inc., Ward Hill Bond Street 30, 01835-0747, Massachusetts. Represents a compound or reagent available from Johnson Matthey Catalog Company, Inc .; The term “Novabiochem” is a compound commercially available from Calbiochem-Novabiochem Corp., North Toray Pines Road 10933, La Jolla P. O. Box 12087 North Torrey Pines Road 10933, USA 92039-2087. Or a reagent; The term "Oakwood" refers to a compound or reagent available from Oakwood, Columbia, South Carolina, USA; The term “Advanced Chemtech” refers to a compound or reagent commercially available from Advanced Chemtech, Louisville, Kentucky, USA; The term "Pfalze & Bauer" refers to a compound or reagent commercially available from Pfalze & Bauer, Waterbury, Connecticut.

The general methods A'-P 'and Examples A1-A74 below are N- (aryl / heteroarylacetyl) amino acid esters which can be hydrolyzed to provide the N- (aryl / heteroarylacetyl) amino acid starting material of the invention To illustrate the synthesis. Other N- (aryl / heteroarylacetyl) amino acid esters can be prepared using these methods from commercially known or known starting materials.

General method A '

Coupling of R ¹ C (X ') (X ") C (O) Cl and H ₂ NCH (R ² ) C (O) XR ³

To a stirred solution of (D, L) -alanine iso-butyl ester hydrochloride (obtained from Example B below) (4.6 mmol) in 5 ml of pyridine was added 4.6 mmol of acid chloride. The mixture was stirred for 3.5 h, diluted with 100 mL of diethyl ether, washed three times with 10% HCl, once with brine, once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the product. In addition, other amino acid esters may be used in the present method.

General method B '

Coupling of R ¹ C (X ') (X ") C (O) OH with H ₂ NCH (R ² ) C (O) XR ³

A solution of acid (3.3 mmol) and CDI in 20 mL THF was stirred for 2 hours. L-alanine iso-butyl ester hydrochloride (obtained from Example B below) (3.6 mmol) was added followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether and washed three times with 10% HCl, once with brine, once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the product. In addition, other amino acid esters may be used in the present method.

General method C '

Esterification of R ¹ 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 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 NaH (0.16 g, 6.5 mmol). Foaming immediately occurred. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether and washed three times with 10% HCl, once with brine, once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the product. Other N-acyl amino acids and alcohols may also be used in the present method.

General method D '

Hydrolysis of Ester to Free Acid

Ester hydrolysis to the free acid was carried out in a conventional manner. Two examples of such conventional deesterification methods are described below.

To the ester in a 1: 1 mixture of CH ₃ OH / H ₂ O was added 2-5 equivalents of K ₂ CO ₃ . The mixture was heated to about 50 ° C. for about 0.5 to 1.5 hours until tlc indicated completion of the reaction. The reaction was cooled to room temperature and methanol was removed at reduced pressure. The pH of the remaining aqueous solution was adjusted to about 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO ₄ . The solution was solvent stripped at reduced pressure to yield the product.

The amino acid ester was dissolved in dioxane / water (4: 1) and LiOH (about 2 equivalents) dissolved in water was added thereto to give a total solvent of about 2: 1 dioxane: water. The reaction mixture was mixed until the reaction was complete and dioxane was removed under reduced pressure. The residue was diluted with EtOAc, the layers separated and the aqueous layer acidified to pH 2. The aqueous layer was reextracted with EtOAc and the combined organics were dried over Na ₂ SO ₄ and after filtration the solvent was removed under reduced pressure. The residue was purified by conventional methods (eg recrystallization).

The following illustrates the following examples. 3-NO ₂ phenylacetyl alanine 9.27 g (0.0348 mole) of the methyl ester in dioxane is dissolved in 60 ㎖ and H ₂ O 15 ㎖ of, were added to the LiOH (3.06 g, 0.0731 mol) dissolved in H ₂ O 15 ㎖ . After stirring for 4 hours, the dioxane is removed under reduced pressure, the residue is diluted with EtOAc, the layers are separated and the aqueous layer is acidified to pH 2. The aqueous layer was reextracted with EtOAc (4 × 100 mL) and the combined organics were dried over Na ₂ SO ₄ and after filtration the solvent was removed under reduced pressure. The residue was recrystallized from EtOAc / isooctane to give 7.5 g (85%) of 3-nitrophenylacetyl alanine. C ₁₁ H ₁₂ N ₂ O ₅ requires C = 52.38, H = 4.80, and N = 11.11. The analysis showed C = 52.54, H = 4.85, and N = 11.08. [α] ₂₃ = -29.9 at 589 nm.

General method E '

Low Temperature BOP Coupling of Acids and Alcohols

The methylene chloride solution containing carboxylic acid (100 M%) and N-methyl morpholine (150 M%) was cooled under nitrogen to -20 ° C. BOP (105 M%) was added in one portion and the reaction mixture was kept at -20 ° C for 15 minutes. The corresponding alcohol (120 M%) was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The combined ethyl acetate portions were rewashed twice with saturated aqueous citric acid, twice with saturated aqueous sodium bicarbonate, once with brine, dried over anhydrous magnesium sulfate or sodium sulfate, and the solvent was removed under reduced pressure to give crude product.

General method F '

EDC Coupling of Acids and Amines

Acid derivatives were dissolved in methylene chloride. An amine (1 equiv), N-methylmorpholine (5 equiv), and hydroxybenzotriazole monohydrate (1.2 equiv) were added in this order. The reaction was cooled to about 0 ° C. and then 1.2 equivalents of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added. The solution was stirred overnight and allowed to come to room temperature under N ₂ pressure. The reaction mixture was washed with a solution with saturated aqueous Na ₂ CO ₃ , 0.1 M citric acid, and brine, worked up, dried over Na ₂ SO ₄ , and the solvent was removed to afford crude product. Flash chromatography in a suitable solvent gave the pure product.

General method G '

EDC Coupling of Acids and Amines

Carboxylic acid (1.0 equiv), hydroxy-benzotriazole hydrate (1.1 equiv) and amine (1.0 equiv) in THF were charged to a round bottom flask under nitrogen atmosphere. A suitable amount (1.1 equivalents for free amines and 2.2 equivalents for hydrochloride amine salts), for example Hunig's base, was added to a well stirred mixture followed by EDC (1.1 equivalents). . After 4 to 17 hours of stirring at room temperature, the solvent was removed at reduced pressure and the residue was dissolved in EtOAc (or similar solvent) / water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1 N HCl, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product is analytically pure at this stage, but in some other cases, purification by chromatography and / or recrystallization was required prior to biological evaluation.

General method H '

Coupling of R ¹ C (X ') (X ") C (O) Cl and H ₂ NCH (R ² ) C (O) XR ³

Excess oxalyl chloride in dichloromethane was added to the acid derivative with 1 drop of DMF. The resulting mixture was stirred for about 2 hours or until bubble evolution ceased. The solvent was then removed under reduced pressure and re-diluted with dry methylene chloride. To the resulting solution was added about 1.1 equivalents of a suitable amino acid ester and triethylamine (1.1 equivalents in methylene chloride). The system was stirred for 2 hours at room temperature, then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 N HCl and washed with 1 N NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to afford the desired product.

General method I '

P-EPC Coupling

P-EPC coupling uses amino acid esters and substituted acetic acid compounds. Acetic acid derivatives are known in the art and are typically commercially available. Amino acid esters are prepared by known conventional methods and are typically commercially available N-BOC amino acids as described in general method J 'below.

In particular, a suitable amino ester free base (0.0346 mmol) and substituted phenylacetic acid (0.069 mmol) are dissolved in 2.0 mL of CHCl ₃ (without EtOH), reacted with 150 mg (0.87 meq./g) of P-EPC and the reaction Was mixed at 23 ° C. for 4 days. The reaction was filtered through a cotton plug, rinsed with 2.0 mL CHCl ₃ and the filtrate was evaporated under a stream of nitrogen. The purity of each sample was measured by ¹ H NMR, ranging from 50% to> 95%. 8.0-15.0 mg final product was obtained from each reaction and tested without further purification.

General way J '

Synthesis of Amino Acid Esters from Corresponding N-BOC Amino Acids

A. Esterification of Acids

N-BOC amino acid was dissolved in dioxane and reacted with excess alcohol (up to 1.5 equivalents) and catalytic DMAP (100 mg) at 0 ° C. Stirring was continued until the reaction was completed, and the product was recovered by a conventional method.

B. Removal of N-BOC Groups

N-BOC protected amino acid was dissolved in methylene chloride (0.05 M) and reacted with 10 equivalents of TFA under room temperature and nitrogen atmosphere. The reaction was monitored by tlc, usually within 1-5 hours, until the starting material was consumed. If after 5 hours the starting material was still present, 10 equivalents of TFA was added to the reaction. The reaction 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 further purification.

Specific examples of these methods are as follows:

1. Racemic (+/-)-N-BOC-α-aminobutyric acid (Aldrich) (9.29 g, 0.0457 mol) is dissolved in 100 ml of dioxane and iso-butyl alcohol (6.26 ml, 0.0686 mole), EDC (8.72 g, 0.0457) and catalytic DMAP (100 mg). After stirring for 17 h, the organics were evaporated at reduced pressure and the residue diluted with EtOAc, washed with NaHCO ₃ and brine and dried over Na ₂ SO ₄ . Evaporation gave 8.42 g (71%) of oil. C ₁₃ H ₂₅ NO ₄ requires C = 60.12, H = 9.72, and N = 5.40. The analysis showed C = 59.91, H = 9.89, and N = 5.67.

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

2. Dissolve LN-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) in 100 ml CH ₂ Cl ₂ and iso-butyl alcohol (21.9 ml, 0.238 mol) and DMAP (100 mg) at 0 ° C. And EDC (10.0 g, 0.52 mol). 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 (quant) of LN-BOC alanine iso-butyl ester, which was contaminated with a small amount of solvent. Samples were vacuum dried for analysis. C ₁₂ H ₂₃ NO ₄ requires C = 58.79, H = 9.38, and N = 5.71. The analysis showed C = 58.73, H = 9.55, and N = 5.96.

The N-BOC amino acid ester (11.8 g, 0.0481 mole) was deprotected as above. The free base was converted to the corresponding HCl salt using saturated HCl (g) / EtOAc to give LN-alanine iso-butyl ester hydrochloride. 4.2 g (48%) of a colorless solid were obtained. C ₇ H ₁₅ NO ₂ .HCl requires C = 46.28, H = 8.88, and N = 7.71. The analysis showed C = 46.01, H = 8.85, and N = 7.68.

General method K '

Formation of Methyl Ester from Amino Acids

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 was allowed to warm to room temperature and then stirred for 4 hours. The solvent was then removed under reduced pressure to afford the desired amino acid methyl ester hydrochloride. The product is usually used without further purification.

Example A '

Synthesis of Glass PEPC and Polymer Bonded 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 dropwise cooling 50 g (0.39 mol) of 3- (1-pyrrolidinyl) propylamine. Once the dropwise addition was completed, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 g (96.4%) of the desired urea as a clear oil.

1- (3- (1-pyrrolidinyl) propyl) -3-ethylcarbodiimide (P-EPC)

To a solution of 31.0 g (0.156 mol) of N-ethyl-N'-3- (1-pyrrolidinyl) propylurea in 500 ml of dichloromethane, 62.6 g (0.62 mol) of triethylamine were added and the solution was cooled to 0 ° C. I was. Subsequently, 59.17 g (0.31 mol) of 4-toluenesulfonyl chloride in 400 ml of dichloromethane were added dropwise to this solution at a rate to maintain the reaction at 0 to 5 ° C. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and then heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous potassium carbonate (3 × 150 mL). The aqueous phases were combined and extracted with dichloromethane. All organic phases were combined and concentrated under reduced pressure. The resulting orange slurry was suspended in 250 ml of diethyl ether and the solution was decanted from the solid. The slurry / decant process was repeated three more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as a crude orange oil. A portion of the oil was distilled under vacuum to give a colorless oil which distilled at 78-82 ° C. (0.4 mmHg).

Preparation of Polymer Supports of 1- (3- (1-pyrrolidinyl) propyl) -3-ethylcarbodiimide (P-EPC)

8.75 g (48.3 mmol) of 1- (3- (1-pyrrolidin-yl) propyl) -3-ethylcarbodiimide in dimethylformamide and Merrifield's resin (2% crosslinked, 200-400 A suspension of 24.17 g (24.17 mmol) of chloromethylated styrene / divinylbenzene copolymer 1 meq.Cl/g) of the mesh was heated at 100 ° C. for 2 days. The reaction was cooled, filtered and the resulting resin was washed with 1 L DMF, 1 L THF and 1 L diethyl ether. The resulting resin was then dried under vacuum for 18 hours.

Example B '

Preparation of Alanine Iso-Butyl Ester Hydrochloride

(D, L) -alanine (Aldrich) (or L-alanine (Aldrich)) 35.64 g (0.4 mol), thionyl chloride (Aldrich) 44 ml (0.6 mol) and 200 ml of isobutanol The mixture was refluxed for 1.5 hours and the volatiles were completely removed on 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 It was pure enough to be used for further modification.

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 was added 1.8 ml of methane sulfonylchloride at 0 ° C., followed by the dropwise addition of 3.5 ml of triethylamine. After 2 hours, the solution is diluted with 150 ml of dichloromethane, washed with 3N HCl and saturated aqueous NaHCO ₃ , dried using Na ₂ SO ₄ , and the solvent removed to remove the desired 3,5-dichlorobenzyl. Methanesulfonate was obtained as a yellow oil and used without purification.

The crude sulfonate was dissolved in 50 mL of DMF at 0 ° C., then 3 g KCN were added. After 2 hours, further 50 ml of DMF was added and the solution was stirred for 16 hours. The red solution was diluted with 1 L of H ₂ O and acidified to pH 3 with 3 N HCl. The aqueous solution was extracted with dichloromethane. The combined organics were washed with 3 N HCl, dried over Na ₂ SO ₄ , the solvent was removed at reduced pressure to form crude 3,5-dichlorophenylacetonitrile and used without further purification.

Nitrile was added to a mixture of 40 mL concentrated sulfuric acid and 50 mL H ₂ O, heated to reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction was diluted with 1 L of crushed ice, warmed to room temperature and extracted with 2 x 200 mL of dichloromethane and 2 x 200 mL of ethyl acetate. All of the organic sets were combined and washed with saturated aqueous NaHCO ₃ . NaHCO ₃ fractions were combined and acidified to pH 1 with 3 N HCl. The white solid was too fine to filter and extracted with 2 × 200 mL of dichloromethane. The combined organics were dried using Na ₂ SO ₄ and the solvent was removed at reduced pressure to afford crude 3,5-dichlorophenylacetic acid as a white solid. The solid was slurried with hexane and filtered to give 1.75 g of a white solid.

NMR (CDCl ₃ ): (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 by hydrolysis using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) according to the following general methods F 'or G', followed by general method D '.

Example A1

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

Following the general method A 'above, the title compound was prepared using phenylacetyl chloride (Aldrich) and D, L-alanine iso-butyl ester hydrochloride (obtained from Example B' above). The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

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 kPa, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H).

¹³ C-nmr (CDCl 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.

C ₁₅ H ₂₁ NO ₃ (molecular weight = 263.34; mass spectrometry (MH ⁺ = 264))

Example A2

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

Melting point is 51-54 ° C. according to General Method A ′ above, using 3-phenylpropionyl chloride (Aldrich) and D, L-alanine iso-butyl ester hydrochloride (obtained from Example B ′ above) The title compound was prepared as a solid. The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.25 (m, 2H), 7.19 (m, 3H), 6.28 (d, J = 7.2 ㎐, 1H), 4,58 (quint., J = 7.2 ㎐, 1H ), 3,89 (m, 2H), 2.95 (t, J = 7.7 ㎐, 2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.33 (d, J = 7.1 ㎐, 3H), 0.91 (d, J = 6.7 Hz, 6H).

¹³ C-nmr (CDCl ₃ ): δ = 173.0, 171.5, 140.6, 128.3, 128.1, 126.0, 71.2, 47.8, 37.9, 31.4, 27.5, 18.79, 18.77, 18.3.

C ₁₅ H ₂₁ NO ₃ (molecular weight = 277.37; mass spectrometry (MH ⁺ = 278))

Example A3

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

The title compound was prepared as an oil according to General Method B ′ above, using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B ', above). The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.08 (d, J = 5.9 kPa, 1 H), 4.62 (quint., J = 7.3 kPa, 1 H), 3.92 (m, 2 H), 2.22 (m, 1 H), 1.84-2.00 (m, 3H), 1.40 (d, J = 7.2 kPa, 3H), 1.35 (m, 1H), 1.20 (m, 1H), 0.85-0.96 (m, 12H).

¹³ C-nmr (CDCl 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.

C ₁₃ H ₂₅ NO ₃ (molecular weight = 243.35; mass spectrometry (MH ⁺ = 244))

Example A4

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

Titled as a solid according to General Method B 'above, using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above) with a melting point of 111-113 ° C. The compound was prepared. The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.30 (d, J = 8.2 μs, 2H), 7.21 (d, J = 8.3 μs, 2H), 6.18 (d, J = 5.5 μs, 1H), 4.57 (quint ., J = 7.2 ㎐, 1H), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.36 (d, J = 7.1 ㎐, 3H), 0.90 (d, J = 6.8 Iii, 6H).

¹³ C-nmr (CDCl 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.

C ₁₅ H ₂₀ NO ₃ Cl (Molecular Weight = 297.78; Mass Spectrometry (MH ⁺ = 298))

Example A5

Synthesis of N-[(3,4-dichlorophenyl) acetyl] -L-alanine iso-butyl ester

Solid according to the general method B 'above, using a 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above) with a melting point of 81 to 83 ° C. The title compound was prepared. The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

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, 1H), 3.50 (s, 2H), 3.90 (m, 2H), 4.57 (quint., J = 7.1 Hz, 1H), 6.31 (d, J = 4.9 Hz, 1H), 7.12 (m, 1H), 7.38 (m, 2H).

¹³ C-nmr (CDCl 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.

C ₁₅ H ₁₉ NO ₃ Cl ₂ (molecular weight = 332.23; mass spectrometry (MH ⁺ = 332))

Example A6

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

As a solid having a melting point of 102 to 104 ° C. according to General Method B ′ above, using 4-methylphenylacetic acid (Aldrich) and D, L-alanine iso-butyl ester hydrochloride (obtained from Example B ′ above). The title compound was prepared. The reaction was monitored by tlc on silica gel (Rf = 0.6 in 33% ethyl acetate / hexanes), extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.90 (d, J = 6.7 μs, 6H), 1.35 (d, J = 7.2 μs, 3H), 1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H), 4.58 (m, 1H), 6.05 (bd, 1H), 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.

C ₁₆ H ₂₃ NO ₃ (molecular weight = 277.37; mass spectrometry (MH ⁺ = 278))

Example A7

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

Solid according to the general method F ′ above, with a melting point of 62 to 64 ° C. using 3-pyridylacetic acid (Aldrich) and D, L-alanine iso-butyl ester hydrochloride (obtained from Example B ′ above) The title compound was prepared. The reaction was monitored by tlc on silica gel (Rf = 0.48 in 10% methanol / dichloromethane) and purified by silica gel chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.40 (d, J = 2.8 Hz, 2H), 7.6 (m, 1H), 7.16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, 1H); 3.8 (m, 2 H); 3.48 (s, 2 H); 1.8 (m, 1 H); 1.30 (d, J = 7.2 Hz, 3H), 0.81 (d, J = 6.7, 6H).

¹³ C-nmr (CDCl 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.

C ₁₄ H ₂₀ N ₂ O ₃ (molecular weight = 264; mass spectrometry (MH ⁺ = 265))

Example A8

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

Titled as a solid according to the general method B 'above, using 1-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above) with a melting point of 69 to 73 ° C. The compound was prepared. The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

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

¹³ C-nmr (CDCl 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.

C ₁₉ H ₂₃ NO ₃ (molecular weight = 313.40; mass spectrometry (MH ⁺ = 314))

Example A9

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

Titled as a solid according to General Method B 'above, using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above) with a melting point of 128 to 129 ° C. The compound was prepared. The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.86 (m, 6H), 1.35 (d, J = 7.1 Hz, 3H), 1.78 (m, 1H), 3.76 (s, 2H), 3.87 (m, 2H) , 4.62 (quint., J = 7.2, 1H); 6.13 (d, J = 7.1 μs, 1H), 7.41 (m, 1H), 7.48 (m, 2H), 7.74 (s, 1H), 7.83 (m, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 18.4, 18.82, 18.85, 27.6, 43.7, 48.2, 71.4, 125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7, 132.0, 132.5, 133.5, 170.3, 172.8.

C ₁₉ H ₂₃ NO ₃ (molecular weight = 313.40; mass spectrometry (MH ⁺ = 314))

Example A10

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

The title compound was prepared as an oil according to General Method B 'above, using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B', above). The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.92 (d, J = 6.7 μs, 6H), 1.38 (d, J = 7.1 μs, 3H), 1.96 (m, 3H), 2.21 (t, J = 7.1, 2H), 2.64 (t, J = 7.3 kPa, 2H), 3.90 (m, 2H), 4.59 (quint., J = 7.2, 1H); 6.31 (d, 1 H), 7.16 (m, 3 H), 7.24 (m, 2H).

¹³ C-nmr (CDCl ₃ ): δ = 18.3, 18.75, 18.78, 26.8, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0.

C ₁₇ H ₂₅ NO ₃ (molecular weight = 291.39; mass spectrometry (MH ⁺ = 292))

Example A11

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

Following the general method B 'above, the title compound was prepared as an oil using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above). The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 4.59 (quint., J = 7.3 ㎐, 1H), 3.91 (m, 2H ), 2.61 (t, J = 7.2 ㎐, 2H), 2.22 (t, J = 7.2 ㎐, 2H), 1.93 (m, 1H), 1.66 (m, 4H), 1.38 (d, J = 7.2 ㎐, 3H ), 0.92 (d, J = 6.7 μs, 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.

C ₁₈ H ₂₇ NO ₃ (molecular weight = 305.39; mass spectrometry (MH ⁺ = 306))

Example A12

Synthesis of N-[(4-pyridyl) acetyl] -D, L-alanine iso-butyl ester

Melting point 64 to 66, according to the general method F ′ above, using 4-pyridylacetic acid hydrochloride (Aldrich) and (D, L) -alanine iso-butyl ester hydrochloride (obtained from Example B 'above) The title compound was prepared as a solid at ° C. The reaction was monitored by tlc on silica gel (Rf = 0.43 in 10% methanol / dichloromethane) and purified by silica gel chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): 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, 1 H); 4.56 (quint., J = 7.3, 7.2 Hz, 1H), 3.88 (m, 2H); 3.53 (s, 2 H); 1.89 (m, 1 H); 1.36 (d, J = 7.2 Hz, 3H); 0.88 (d, J = 6.7 Hz, 6H).

¹³ C-nmr (CDCl ₃ ): δ = 173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 19.5, 18.9.

C ₁₄ H ₂₀ N ₂ O ₃ (molecular weight = 264; mass spectrometry (MH ⁺ = 265))

Example A13

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

The title compound is obtained as a solid having a melting point of 45 to 47 ° C. according to the general method B ′ above and using phenylacetyl chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B ′ above). Prepared. The reaction was monitored by tlc on silica gel, extracted using Et ₂ O, and then purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.24-7.39 (m, 5H), 6.14 (d, 1H), 4.58 (t, J = 7.3 Hz, 1H); 3.88 (m, 2H), 3.58 (s, 2H), 1.90 (m, 1H), 1.35 (d, J = 7.2 Hz, 3H); 0.89 (d, 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.

C ₁₅ H ₂₁ NO ₃ (molecular weight = 263.34; mass spectrometry (MH ⁺ = 264))

Example A14

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

The title compound was prepared according to General Method I 'above, using 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared from General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general methods above.

NMR data were as follows:

¹ 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

The title compound was prepared according to General Method I 'above, using 3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₇ H ₂₅ NO ₄ (molecular weight = 307.39; mass spectrometry (MH ⁺ = 309))

Example A16

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

The title compound was prepared according to General Method I 'above, using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.16 (d, 2H), 7.44 (d, 2H), 6.04 (bd, 1H), 4.55 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.67 (m, 1H), 0.85 (d, 6H), 0.81 (t, 3H).

C ₁₆ H ₂₂ N ₂ O ₅ (Molecular weight = 322.36; Mass spectrometry (MH ⁺ = 323))

Example A17

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

According to the general method I 'above, using 3,4- (methylenedioxy) -phenyl acetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general method J' above) The compound was prepared. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.72 (m, 3H), 5.92 (bd, 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

The title compound was prepared according to General Method I 'above, using 3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 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

The title compound was prepared according to General Method I ′ above, using 4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J ′ above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

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

The title compound was prepared according to General Method I 'above, using 3-nitrophenyl acetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

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 the general method I 'above, the title compound was prepared using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.14 (m, 1H), 7.01 (m, 1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.46 (m, 1H), 4.51 (m, 1H), 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

The title compound was prepared according to General Method I ′ above, using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J ′ above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.83 (m, 7H), 5.95 (m, 1H), 4.58 (m, 1H), 3.84 (m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63 (m, 1H), 0.91 (d, 6H), 0.81 (t, 3H).

C ₂₀ H ₂₅ NO ₃ (molecular weight = 327.42; mass spectrometry (MH ⁺ = 328))

Example A23

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

The title compound was prepared according to General Method I 'above, using 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ 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), 1.84 (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

The title compound was prepared according to General Method I 'above, using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (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).

C ₁₆ H ₂₂ NO ₃ Br (molecular weight = 356.26; mass spectrometry (MH ⁺ = 358))

Example A25

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

The title compound was prepared according to General Method I 'above, using 3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl 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).

C ₁₆ H ₂₂ NO ₃ Cl (molecular weight = 311.81; mass spectrometry (MH ⁺ = 313))

Example A26

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

The title compound was prepared according to General Method I 'above, using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

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).

C ₁₆ H ₂₂ NO ₃ F (molecular weight = 295.35; mass spectrometry (MH ⁺ = 296))

Example A27

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

The title compound is prepared according to General Method I ′ above, using 4-benzothiazol-4-yl acetic acid (chemservice) and iso-butyl 2-aminobutyrate (prepared according to General Method J ′ above). It was. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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

The title compound was prepared according to General Method I 'above, using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₇ H ₂₅ NO ₃ (molecular weight = 291.39; mass spectrometry (MH ⁺ = 291))

Example A29

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

Following the general method I 'above, the title compound was prepared using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ 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

The title compound was prepared according to General Method I 'above, using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

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).

C ₁₆ H ₂₂ NO ₃ F (molecular weight = 295.35; mass spectrometry (MH ⁺ = 296))

Example A31

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

The title compound was prepared according to General Method I 'above, using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₆ H ₂₂ NO ₃ Br (molecular weight = 356.26; mass spectrometry (MH ⁺ = 357))

Example A32

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

Following the general method I 'above, the title compound was prepared using 3-trifluoromethylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ 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).

C ₁₇ H ₂₂ NO ₃ F ₃ (molecular weight = 345.36; mass spectrometry (MH ⁺ = 345))

Example A33

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

The title compound was prepared according to General Method I 'above, using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.89 (m, 3H), 6.07 (bd, 1H), 4.50 (m, 1H), 3.82 (m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62 (m, 1H), 0.81 (d, 6H), 0.75 (t, 3H).

C ₁₄ H ₂₁ NO ₃ S (molecular weight = 283.39; mass spectrometry (MH ⁺ = 284))

Example A34

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

Following the general method H 'above, the title compound was prepared using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general method J' above). The reaction was monitored by tlc on silica gel and purified by chromatography on silica gel using 9: 1 toluene: EtOAc as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.17-7.28 (m, 5H), 6.23 (bd, 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).

C ₁₆ H ₂₃ NO ₃ (molecular weight = 277.36; mass spectrometry (MH ⁺ = 277))

Example A35

Synthesis of N- (phenylacetyl) valine 2-methylbutyl ester

Step A. Preparation of N- (phenylacetyl) valine

5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich) was added dropwise to a stirred solution of 5.15 g (44 mmol) of valine (bachem) in 50 mL (100 mmol) of 2 N NaOH cooled to 0 ° C. Colorless oil precipitated out. The reaction mixture was allowed to warm to room temperature, stirred for 18 hours, washed with 50 ml of diethyl ether and acidified to pH 2-3 with aqueous HCl. The resulting white precipitate was filtered, washed thoroughly with water and then with diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 12.63 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H), 3.56 (d, J = 13.8 ㎐, 1H), 3.47 (d, J = 13.8 ㎐, 1H), 2.05 (m, 1H), 0.87 (d, J = 6.8 ㎐, 3H), 0.84 (d, J = 6.8 ㎐, 3H) .

¹³ C-nmr (DMSO-d ₆ ): δ = 173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0.

C ₁₃ H ₁₇ NO ₃ (molecular weight = 235.29; mass spectrometry (MH ⁺ = 236))

Step B. Synthesis of N- (phenylacetyl) valine 2-methylbutyl ester

The title compound was prepared as an enantiomeric mixture using N- (phenylacetyl) valine and 2-methylbutan-1-ol (Aldrich) prepared according to General Method C ′ above, in step A above. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.25-7.40 (m, 5H), 5.95 (d, 1H), 4.56 (m, 1H), 3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m, 1H), 1.68 (m, 1H), 1.38 (m, 1H), 1.15 (m, 1H), 0.82-0.94 (m, 9H), 0.76 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 171.84, 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.

C ₁₈ H ₂₇ NO ₃ (molecular weight = 305.42; mass spectrometry (MH ⁺ = 306))

Example A36

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

L-Methionine (0.129 g, 0.869 mmol) (Aldrich) was dissolved 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 rt, the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer was acidified to pH 2 with 5 N HCl. The crude product was extracted with ethyl acetate, dried over sodium sulfate, dried in vacuo and used without further purification.

N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) is dissolved in 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol) and catalyst DMAP (0.015 g) It was. After stirring at 23 ° C. for 17 h, the mixture was evaporated to reduced pressure to 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.

NMR data were as follows:

¹ 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).

C ₁₇ H ₂₅ NO ₃ S (molecular weight = 323.17; mass spectrometry (MH ⁺ = 323))

Example A37

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

L-Leucine (Aldrich) (0.114 g, 0.869 mmol) was dissolved 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 rt, the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer was acidified to pH 2 with 5 N HCl. The crude product was extracted with ethyl acetate, dried over sodium sulfate, dried in vacuo and used without further purification.

N-phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHCl ₃ (without EtOH) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalent). It was. The mixture was spun for 4 days, filtered through a cotton plug, and the filtrate was evaporated under reduced pressure to form an oil pure enough for testing.

NMR data were as follows:

¹ H-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).

C ₁₈ H ₂₇ NO ₃ (molecular weight = 305.40; mass spectrometry (MH ⁺ = 305))

Example A38

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

Following General Method C ′ above, using N- (3-chlorophenylacetyl) alanine (obtained from Example D 'above) and 3-methylbut-2-en-1-ol (Aldrich) The title compound can be prepared. The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 30% EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.39-7.16 (m, 4H), 6.06 (bd, 1H), 5.38-5.29 (m, 1H), 4.63 (d, J = 9 ㎐, 2H), 3.56 ( s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J = 9 Hz, 3H).

Example A39

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

Following the general method C ′ above, the title compound can be prepared using N- (3-chlorophenylacetyl) alanine (obtained from Example D ′ above) and cyclopropylmethanol (Aldrich). The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.2-7.1 (m, 4H), 6.09 (bs, 1H), 4.6 (dq, J = 9 ㎐, 1H), 3.96 (dd, J = 9 ㎐, 2H) , 3.59 (s, 2H), 1.2 (d, J = 9 Hz, 3H), 1.2-1.0 (m, 1H), 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 method C ′ above, the title compound can be prepared using N- (3-chlorophenylacetyl) alanine (obtained from Example D ′ above) and 2-thiophenmethanol (Aldrich). . The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

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

Example A41

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

The title compound is prepared according to General Method C ′ above, using N- (3-chlorophenylacetyl) alanine (obtained from Example D ', above) and (1-methylcyclopropyl) methanol (Aldrich) can do. The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.6 (bd, J = 9 ㎐, 1H), 3.86 (q, J = 14 ㎐, 2H), 3.4 (s, 2H), 2.29 (q, J = 9 ㎐ , 1H), 1.3 (d, J = 9 Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H).

Example A42

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

Following the general method C ′ above, the title compound can be prepared using N- (3-chlorophenylacetyl) alanine (obtained from Example D ′ above) and 3-thiophenmethanol (Aldrich). . The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.03 (bd, J = 9 Hz, 1H), 7.56-7.5 (m, 1H), 7.47 (bs, 1H), 7.4-7.17 (m, 4H), 7.06 ( d, J = 9 Hz, 1H), 5.1 (s, 2H), 4.3 (dq, 1H), 1.3 (d, J = 9 Hz, 3H).

Example A43

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

Following the general method C ′ above, the title compound can be prepared using N- (3-chlorophenylacetyl) alanine (obtained from Example D ′ above) and 2-methylcyclopentanol (Aldrich) have. The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.39-7.16 (m, 4H), 6.3 (bd, 1H), 4.79-4.7 (m, 1H), 4.6-4.25 (m, J = 9 ㎐, 1H), 3.577 (s, 2H), 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J = 9 ㎐, 3H), 1.2 (dt, J = 9 ㎐, 1H), 0.979 (dd, J = 9 μs, 2H).

C ₁₇ H ₂₂ NO ₃ Cl (Molecular Weight = 323.82; Mass Spectrometry (MH ⁺ = 323))

Example A44

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

According to the general method C 'above, using N- (3-chlorophenylacetyl) alanine (obtained from Example D' above) and 2-methylprop-2-en-1-ol (Aldrich) To give the title compound. The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.39-7.16 (m, 4H), 6.3 (bs, 1H), 4.77 (s, 2H), 4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3 H), 1.43 (d, J = 9 Hz, 3 H).

C ₁₅ H ₁₈ NO ₃ Cl (molecular weight = 295.76; mass spectrometry (MH ⁺ = 295))

Example A45

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

The title compound according to General Method C ′ above, using N- (3-chlorophenylacetyl) alanine (obtained from Example D ', above) and cyclohex-2-en-1-ol (Aldrich) Can be prepared. The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.6 (bd, J = 9 ㎐, 1H), 7.4-7.2 (m, 4H), 6.0-5.8 (m, 1H), 5.7-5.5 (m, 1H), 5.1 (bs, 1H), 4.13-4.29 (m, 1H), 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).

C ₁₇ H ₂₀ NO ₃ Cl (Molecular Weight = 321.8; Mass Spectrometry (MH ⁺ = 321.2))

Example A46

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

In accordance with general method I 'above, 5- (2-phenylbenzoxazol) -yl-acetic acid (CAS # 62143-69-5) and alanine iso-butyl ester (prepared according to general method J' above) May be used to prepare the title compound.

NMR data were as follows:

¹ H-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).

C ₂₂ H ₂₄ N ₂ O ₄ (molecular weight = 380; mass spectrometry (MH ⁺ = 381))

Example A47

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

The title compound can be prepared according to the general method I 'above, using 3-methylthiophenylacetic acid (CAS # 18698-73-2) and alanine iso-butyl ester (prepared according to general method J' above). Can be. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.14 (m, 2H), 7.01 (m, 1H), 4.56 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89 (m, 1H), 1.35 (d, 3H), 0.85 (d, 6H).

C ₁₆ H ₂₃ NO ₃ S (molecular weight = 309; mass spectrometry (MH ⁺ = 310))

Example A48

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

Following the general method I 'above, the title compound can be prepared using 2-furylacetic acid (CAS # 2745-26-8) and alanine iso-butyl ester (prepared according to general method J' above). . The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₃ H ₁₉ NO ₄ (molecular weight = 253; mass spectrometry (MH ⁺ = 254))

Example A49

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

According to the general method I 'above, the title compound can be prepared using benzofuran-2-ylacetic acid (mabridge) and alanine iso-butyl ester (prepared according to general method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ 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 ₂₁ NO ₄ (molecular weight = 303; mass spectrometry (MH ⁺ = 304))

Example A50

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

The title compound was prepared according to General Method I 'above, using thianaphthene-3-ylacetic acid (Lancaster) and alanine iso-butyl ester (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.89 (m, 1H), 7.76 (m, 1H), 7.38 (m, 3H), 6.07 (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).

C ₁₇ H ₂₁ NO ₃ S (molecular weight = 319; mass spectrometry (MH ⁺ = 320))

Example A51

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

Titled according to General Method I 'above, using 5-chloro-2-thienyl) acetic acid (CAS # 13669-19-7) and alanine iso-butyl ester (prepared according to General Method J' above) Compounds can be prepared. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.77 (m, 1H), 6.68 (d, 1H), 6.31 (bm, 1H), 4.59 (m, 1H), 3.91 (m, 2H), 3.38 (s, 2H), 1.90 (m, 1H), 1.39 (d, 3H), 0.89 (d, 6H).

C ₁₃ H ₁₈ NO ₃ SCl (molecular weight = 303; mass spectrometry (MH ⁺ = 303))

Example A52

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

According to general method I 'above, (3-methyl-isoxazol-5-yl) acetic acid (CAS # 19668-85-0) and alanine iso-butyl ester (prepared according to general method J' above) To prepare the title compound. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

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).

C ₁₃ H ₂₀ N ₂ O ₄ (Molecular weight = 268; Mass spectrometry (MH ⁺ = 269))

Example A53

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

The title compound can be prepared according to General Method I ′ above, using (2-phenyl-thiothienyl) acetic acid and alanine iso-butyl ester (prepared according to General Method J ′ above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

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).

C ₁₉ H ₂₃ NO ₃ S ₂ (molecular weight = 377; mass spectrometry (MH ⁺ = 378))

Example A54

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

The title compound was prepared according to General Method I ′ above, using (6-methoxythianaphthen-2-yl) acetic acid and alanine iso-butyl ester (prepared according to General Method J ′ above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

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).

C ₁₆ H ₂₃ NO ₄ S (molecular weight = 349; mass spectrometry (MH ⁺ = 350))

Example A55

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

According to general method I ′ above, (3-phenyl-1,2,4-thiadiazol-5-yl) acetic acid (CAS # 90771-06-5) and alanine iso-butyl ester (general method J above) Prepared according to ') to prepare the title compound. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.47 (m, 5H), 4.66 (m, 1H), 4.16 (s, 2H), 3.91 (m, 2H), 1.93 (m, 1H), 1.48 (d, 3H), 0.93 (d, 6H).

C ₁₇ H ₂₁ N ₃ O ₃ S (molecular weight = 347; mass spectrometry (MH ⁺ = 348))

Example A56

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

According to general method I 'above, using (2-phenyloxazol-4-yl) acetic acid (CAS # 22086-89-1) and alanine iso-butyl ester (prepared according to general method J' above) To give the title compound. The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

Example A57

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

The title compound was prepared according to General Method I 'above, using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ 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).

C ₁₆ H ₂₃ NO ₃ (molecular weight = 277; mass spectrometry (MH ⁺ = 278))

Example A58

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

The title compound was prepared according to General Method I 'above, using 2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₅ H ₁₉ NO ₃ F ₂ (molecular weight = 299; mass spectrometry (MH ⁺ = 300))

Example A59

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

The title compound was prepared according to General Method I 'above, using 3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₅ H ₁₉ NO ₃ F ₂ (molecular weight = 299; mass spectrometry (MH ⁺ = 300))

Example A60

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

The title compound was prepared according to General Method I 'above, using 3-thiopheneacetic acid (Aldrich) and Alanine iso-butyl ester (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (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] ₂₃ -52 (c 1 MeOH) @ 589 nm.

C ₁₃ H ₁₉ NO ₃ S (molecular weight = 269; mass spectrometry (MH ⁺ = 269))

Example A61

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

The title compound was prepared according to General Method I 'above, using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared according to General Method J' above). The reaction was monitored by tlc on silica gel and purified by filtration as described in the general method above.

NMR data were as follows:

¹ H-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).

C ₁₆ H ₂₃ NO ₃ (molecular weight = 277.35; mass spectrometry (MH ⁺ = 278))

Example A62

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

Methyl (S)-(+)-2-hydroxy-2- in accordance with general method K 'and using (S)-(+)-2-hydroxy-2-methylbutyric acid (Aldrich) instead of amino acids Methyl butyrate was prepared.

Subsequently, methyl (S)-(+)-2-hydroxy-2-methylbutyrate is coupled with carbobenzyloxy-L-alanine (Aldrich) using general method E 'to carbobenzyloxy -L-alanine S-1- (methoxycarbonyl) iso-butyl ester was prepared.

Carbobenzyloxy-L-alanine S-1- (methoxycarbonyl) iso-butyl ester (1.0 g) was then dissolved in 20 mL of methanol, 6 N HCl (0.5 mL) and 10% palladium on carbon ( 0.1 g) was added. The reaction mixture was hydrogenated at 40 psi of hydrogen in a Parr apparatus for 5 hours at room temperature and then filtered through a pad of celite. The filtrate was concentrated at reduced pressure to give L-alanine S-1- (methoxycarbonyl) iso-butyl ester hydrochloride (98% yield).

The L-alanine S-1- (methoxycarbonyl) iso-butyl ester hydrochloride was then coupled to phenylacetic acid and the title compound was prepared using general method G '.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.35-7.20 (m, 5H), 6.22 (bd, 1H), 4.83 (d, 1H), 4.65 (p, 1H), 3.68 (s, 3H), 3.55 ( s, 2H), 2.21 (m, 1H), 1.40 (d, 3H), 0.97 (d, 3H), 0.93 (d, 3H).

¹³ C-nmr (CDCl 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-nitrophenyl) acetyl] -L-alanine iso-butyl ester

Following the general method H 'above, the title compound was prepared using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B', above). The reaction was monitored by tlc on silica gel and purified by recrystallization from butyl chloride.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.17 (m, 2H), 7.68 (d, 1H), 7.52 (t, 1H), 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, 6H).

Light rotation: [α] ₂₃ -49 (c 5, MeOH).

Example A64

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

The title compound was prepared as a solid having a melting point of 93 to 95 ° C. according to the general method G ′ above, using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich). The reaction was monitored by tlc on silica gel (Rf = 0.8 in EtOAC), chromatographed on silica gel using EtOAc as eluent, and then purified by recrystallization from 1-chlorobutane.

NMR data were as follows:

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

C ₁₃ H ₁₅ NO ₃ F ₂ (molecular weight = 271.26; mass spectrometry (MH ⁺ = 271))

Example A65

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

Following the general method G ′ above, the title compound was prepared using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich). The reaction was monitored by tlc on silica gel and purified by recrystallization from butyl chloride.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.18 (s, 1H), 8.15 (d, 1H), 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2H), 2.08 (s, 3H), 1.27 (t, 3H).

Light rotation: [α] ₂₃ -30 (c 5, MeOH).

Example A66

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

The title compound was prepared according to General Method G ′ above, using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to General Method J ′ above). The reaction was monitored by tlc on silica gel.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.29 (m, 3H), 7.18 (m, 1H), 6.0 (m, 1H), 4.56 (m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.39 (d, 3H), 0.91 (d, 3H).

Light rotation: [α] ₂₃ -45 (c 5, MeOH).

C ₁₅ H ₂₀ NO ₃ Cl (Molecular Weight = 297.78; Mass Spectrometry (MH ⁺ = 297))

Example A67

Synthesis of N-[(3-chlorophenyl) acetyl] alanine 2- (N, N-dimethylamino) ethyl ester

The title compound according to the general method C ′ above, using N- (3-chlorophenylacetyl) alanine (obtained from Example D 'above) and 2- (N, N-dimethyl amino) ethanol (Aldrich) Can be prepared. The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 0.1: 2: 0.79 NH ₄ OH: EtOH: CHCl ₃ as eluent.

NMR data were as follows:

¹ 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 ₂₁ N ₂ O ₃ Cl (Molecular Weight = 313.799; Mass Spectrometry (MH ⁺ = 313))

Example A68

Synthesis of 2-[(3,5-dichlorophenyl) acetamido] hexanoic acid methyl ester

The title compound as a solid according to the general method F ′ above, using a 3,5-dichlorophenylacetic acid (obtained from Example C 'above) and L-norleucine methyl ester hydrochloride (Bachem) with a melting point of 77-78 ° Was prepared. The reaction was monitored by tlc on silica gel (Rf = 0.70 in 40% EtOAc / hexanes) and purified by flash chromatography on silica gel using 40% EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): 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).

¹³ C-nmr (CDCl ₃ ): δ = 173.54, 169.67, 138.43, 135.72, 128.33, 128.07, 78.04, 77.62, 77.19, 53.04, 52.90, 43.14, 32.57, 27.87, 22.81, 14.41.

Example A69

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

Melting point from 115 to 3,5-dichlorophenylacetic acid (obtained from Example C ') and L-alanine iso-butyl ester hydrochloride (obtained from Example B') above according to the general method F 'above. The title compound was prepared as a solid at 116 ° C. The reaction was monitored by tlc on silica gel (Rf = 0.40 in 3% methanol / dichloromethane) and purified by flash chromatography on silica gel using 3% methanol / dichloromethane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): 7.27 (d, J = 2 ㎐, 1H), 7.19 (s, 2H), 6.22 (d, J = 6 1, 1H), 4.59 (quint., J = 7 ㎐, 1H), 3.9 (q, J = 4 ㎐, 2H), 3.5 (s, 2H), 1.9 (m, 1H), 1.4 (d, J = 7 ㎐, 3H), 0.91 (d, J = 7 ㎐, 6H).

¹³ C-nmr (CDCl ₃ ): δ = 173.45, 169.37, 138.31, 135.75, 128.39, 128.11, 78.04, 77.61, 77.19, 72.19, 54.03, 48.97, 43.12, 28.24, 19.52, 19.49, 19.09.

C ₁₅ H ₁₉ NO ₃ Cl ₂ (molecular weight = 331.9; mass spectrometry (MH ⁺ = 332))

Example A70

Synthesis of N- (cyclohexylacetyl) -L-alanine iso-butyl ester

The title compound is obtained as a solid having a melting point of 92 to 93 DEG C according to the general method B 'above and using cyclohexyl acetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above). Prepared. The reaction was monitored by tlc on silica gel (Rf = 0.39 in 1: 3 EtOAc: hexanes), extracted with Et ₂ O and purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.93 (d, J = 6.7 μs, 6H), 0.85-1.01 (m, 2H), 1.05-1.35 (m, 3H), 1.40 (d, J = 7.1 μs, 3H), 1.60-1.85 (m, 6H), 1.95 (m, 1H), 2.06 (d, J = 7.0 Hz, 2H), 3.92 (m, 2H), 4.61 (m, 1H), 6.08 (bd, 1H ).

¹³ C-nmr (CDCl ₃ ): 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.

C ₁₅ H ₂₇ NO ₃ (molecular weight = 269.39; mass spectrometry (MH ⁺ = 270))

Example A71

Synthesis of N- (cyclopentylacetyl) -L-alanine iso-butyl ester

The title compound is obtained as a solid having a melting point of 62 to 64 ° C. according to the general method B ′ above and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (obtained from Example B ′ above). Prepared. The reaction was monitored by tlc on silica gel (Rf = 0.37 in 1: 3 EtOAc: hexanes), extracted with Et ₂ O and purified by washing with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ 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, 3H), 1.40-1.62 (m, 4H), 1.70-1.83 (m, 2H), 1.89 (m, 1H), 2.15 (m, 3H), 3.86 (m, 2H), 4.55 (m, 1H), 6.30 (d, J = 7.1 ㎐, 1H ).

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 Value (%): C, 65.85; H, 9.87; N, 5.49; Found (%): C, 66.01; H, 10.08; N, 5.49.

C ₁₄ H ₂₅ NO ₃ (molecular weight = 255.36; mass spectrometry (MH ⁺ = 256))

Example A72

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

According to the general method B 'above, using cyclohex-1-enyl acetic acid (alpha) and L-alanine iso-butyl ester hydrochloride (obtained from Example B' above) as a solid having a melting point of 49-51 ° C. The compound was prepared. The reaction was monitored by tlc on silica gel (Rf = 0.40 in 1: 3 EtOAc: hexanes), extracted with Et ₂ O and washed with aqueous K ₂ CO ₃ and aqueous HCl.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.91 (d, J = 4.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.52-1.70 (m, 4H), 1.97 (m, 3H), 2.06 (bs, 2H), 2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m, 1H), 5.65 (s, 1H), 6.33 ( d, J = 6.6 Hz, 1H).

¹³ C-nmr (CDCl 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 Value (%): C, 67.38; H, 9. 42; N, 5.24; Found (%): C, 67.34; H, 9.54; N, 5.16.

C ₁₅ H ₂₅ NO ₃ (molecular weight = 267.37; mass spectrometry (MH ⁺ = 268))

Example A73

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

Following the general method C ′ above, the title compound can be prepared using N-[(3-chlorophenyl) acetyl] alanine and 3-methyl-2-butene thioester (TCI). The reaction was monitored by tlc on silica gel and purified by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 5.2-5.075 (m, 1H), 4.37 (dq, J = 9 ㎐, 1H), 3.56 (s), 3.43 (d, J = 12 ㎐, 2H) , 1.266 (d, J = 12 kPa, 6H), 1.3 (d, J = 9 kPa, 3H).

C ₁₆ H ₂₀ NO ₂ ClS (molecular weight = 325.86; mass spectrometry (MH ⁺ = 325))

Example A74

Synthesis of N-[(2-phenyl) 2-fluoroacetyl] alanine ethyl ester

Following the general method F ′ above, the title compound was prepared using α-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich). The reaction was monitored by tlc on silica gel (Rf = 0.75 in 1: 1 EtOAc: hexanes) and purified by chromatography on silica gel using 1: 2 ethyl acetate / hexanes as eluent.

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, 1H), 5.84 (d, 1H), 6.01 ( d, 1H), 7.40-7.55 (m, 5H), 8.87 (m, 1H).

C ₁₃ H ₁₆ NO ₃ F (molecular weight = 253.27; mass spectrometry (MH ⁺ = 253))

Example A75

Synthesis of N- (3,5-difluorophenylacetyl) -L-phenylglycine methyl ester

Following the general method F above, the title compound was prepared using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem).

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, 1H, 7.1 Hz), 5.56 (d, 1H, 7 Hz), 3.72 (s, 3 H), 3.57 (s, 2 H).

¹³ C-nmr (CDCl ₃ ): δ = 197.6, 177.6, 171.8, 169.3, 136.7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3 .

C ₁₇ H ₁₅ NO ₃ F ₂ (molecular weight = 319.31; mass spectrometry (MH ⁺ = 320))

Example 76

Synthesis of N- (3,5-difluorophenylacetyl) -L-phenylglycine iso-butyl ester

3,5-difluorophenylacetic acid (Aldrich) was EDC coupled to L-phenylglycine methyl ester hydrochloride (Bachem) according to General Method F above.

The resulting compound was taken up in a very excess of the desired alcohol. A catalytic amount of dry NaH was added and the reaction was tlc until the presence of starting material was no longer detected. The reaction was quenched with several milliliters of 1 N HCl, stirred for several minutes, and then saturated aqueous NaHCO ₃ was added. The volume of the reaction mixture was reduced in a rotary evaporator until excess alcohol was removed, then the remaining residue was dissolved in ethyl acetate and additional water was added. The organic phase was washed with saturated aqueous NaCl and dried over MgSO ₄ . The solution was stripped free of solvent on a rotary evaporator, and then the crude product residue was further purified by chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.35-7.3 (m, 5H), 6.8-6.7 (m, 3H), 6.60 (d, 1H, 7 Hz), 5.55 (d, 1H, 7.1 Hz), 3.9 (m, 2H), 3.60 (s, 2H), 1.85 (m, 1H, 7 Hz), 0.8 (q, 6H, 7 Hz).

¹³ C-nmr (CDCl 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 ₂₀ H ₂₁ NO ₃ F ₂ (molecular weight = 361.39; mass spectrometry (MH ⁺ = 362))

Example A77

Synthesis of N- (cyclopentylacetyl) -L-phenylglycine methyl ester

Following the general method D ′ above, the title compound was prepared using cyclopentylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem).

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 the general method D ′ above, the title compound was prepared using cyclopentylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma).

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (1.30, d at 3H) ), 11H).

¹³ C-nmr (CDCl ₃ ): δ = 173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 18.0.

C ₁₁ H ₁₉ NO ₃ (molecular weight = 213.28; mass spectrometry (MH ⁺ = 214))

Example A79

Synthesis of N- (cyclopropylacetyl) -L-phenylglycine methyl ester

Following the general method D ′ above, the title compound was prepared using cyclopropylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem).

NMR data were as follows:

¹ 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), 1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.02 (m, 2H).

¹³ C-nmr (CDCl 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 the general method D ′ above, the title compound was prepared using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma).

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.60 (d, 1H), 4.55 (m, 1H), 3.69 (s, 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] -L-methionine iso-butyl ester

Following the general method H ′ above, the title compound was prepared as a dark brown oil using nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich). The reaction was monitored by tlc on silica gel.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.16 (m, 2H), 7.67 (d, 1H), 7.32 (t, 1H), 6.31 (bd, 1H), 4.69 (m, 1H), 3.90 (d, 2H), 3.68 (s, 2H), 2.47 (t, 2H), 2.15 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 0.91 (d, 6H).

C ₁₇ H ₂₄ N ₂ O ₅ S (molecular weight = 368.4; mass spectrometry (MH ⁺ = 368))

General Methods A "-B" and Examples B1-B2 below illustrate the synthesis of N- (aryl / heteroarylacetyl) amino acids which are useful starting materials for the present invention. Other N- (aryl / heteroarylacetyl) amino acids can be prepared using these methods from commercially known or known starting materials.

General method A "

Preparation of Acid Chloride

3,5-difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and the solution was cooled to 0 ° C. After DMF (0.5 mL, catalyst) was added, oxalyl chloride (18 mL, 0.20 mol) was added dropwise over 5 minutes. The reaction was stirred for 3 hours and then rotary evaporated at reduced pressure to the residue, which was placed in a high vacuum pump for 1 hour to form 3,5-dichlorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.

General method B "

Schotten-Bauman method

3,5-difluorophenylacetyl chloride (obtained from General Method A ") was added to an L-alanine 0 ° C. solution (Aldrich) (16.7 g, 0.187 mol) in 2N sodium hydroxide (215 mL, 0.43 mol). The reaction was stirred for 1 hour at 0 ° C. and then overnight at room temperature The reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3 × 150 mL). Washed with brine (200 mL), dried over MgSO ₄ and rotary evaporation to reduced residue under reduced pressure. The residue from ethyl acetate / hexanes was recrystallized to give the desired product (34.5 g, 82% yield). May be used in this method to provide intermediates useful in the present invention.

Example B1

Synthesis of N- (phenylacetyl) -L-alanine

According to General Method B ″ above, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102 to 104 ° C.

NMR data were as follows:

¹ H-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 Hz, 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

According to General Method B ″ above, the title compound was prepared from 3,5-difluorophenylacetyl chloride (obtained from General Method A ″ above) and L-alanine (Aldrich).

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 8.32 (br s, 0.3H), 6.71 (m, 2H), 6.60 (m, 1H), 4.74 (br s, 1.7H), 4.16 (m, 1H) , 3.36 (s, 2H), 1.19 (d, J = 7.3 kPa, 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.

The general methods A '"-C"' and Examples C1-C8 below illustrate dipeptid esters which are useful starting materials for the present invention. Other dipeptide esters can be prepared using commercially known or known starting materials using these methods.

General method A '"

EDC Coupling Method

The round bottom flask containing the magnetic stir bar was prepared in THF, carboxylic acid (1.0 equiv), amine or amine hydrochloride (1.1 equiv), 1-hydroxybenzotriazole hydrate (1.15-1.2) at 0 ° C. or at room temperature under nitrogen atmosphere. Equivalents), N, N-diisopropylethylamine (2.2-2.9 equivalents), and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.15-1.2 equivalents) Charged. The cold bath was removed and the mixture was allowed to warm to room temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc, washed with 0.5 N aqueous HCl (twice), diluted with aqueous NaHCO ₃ (once) and brine (once) and dried over Na ₂ SO ₄ or MgSO ₄ . The desiccant was removed by filtration and the filtrate was concentrated in vacuo. The residue was used without further purification or purified using standard methods such as flash chromatography on silica gel and / or recrystallization.

General method B '"

Removal of N-3 Class-Boc Protectors

N-tert-Boc-amine was dissolved in a suitable dry solvent (eg 1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. Gaseous HCl was introduced into the solution until the mixture was saturated with HCl. The mixture was then stirred until the reaction was complete. The resulting mixture was concentrated under reduced pressure to form amine hydrochloride. Amine hydrochloride was used without purification or masticated using, for example, diethyl ether, and the resulting solid was collected by filtration.

General method C '"

EEDO coupling method

In a round bottom flask containing a magnetic stir bar, THF, carboxylic acid (1 equiv), amine hydrochloride (1.1 equiv), and 2-ethoxy-1-ethoxycarbonyl-1,2-di under nitrogen atmosphere at room temperature Hydroquinoline (EEDQ) (1.1 equiv) was charged. The reaction mixture was stirred for 15 minutes, then 4-methylmorpholine (1.1 equiv) was added and stirring continued for 15-20 hours at room temperature. 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 (2 times), saturated aqueous NaHCO ₃ (2 times), and brine (1 time). The organic phase was then dried over Na ₂ SO ₄ , the desiccant was removed by filtration and the filtrate was concentrated in vacuo. The residue was used without further purification or purified using standard processes such as flash chromatography on silica gel and / or recrystallization.

Example C1

Synthesis of N- (L-Methionine) -L-phenylglycine Methyl Ester Hydrochloride

According to the general method A ′ ″ above, Boc- as a crude solid or foam using N- (tert-butoxycarbonyl) -L-methionine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem) Protected dipeptides were prepared. The resulting crude dipeptides were deprotected using the general method B ′ ″ to afford the title compound as a crude solid or foam.

Example C2

Synthesis of N- (2-aminobutanoyl) -L-phenylglycine methyl ester hydrochloride

Boc as a crude solid or foam using N- (tert-butoxycarbonyl) -2-aminobutyric acid (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), according to the general method A ′ ″ above. -Protected dipeptides were prepared. The resulting crude dipeptides were deprotected using the general method B '"to afford the title compound as a crude solid or foam.

Example C3

Synthesis of N- (L-Leucine) -L-phenylglycine Methyl Ester Hydrochloride

According to the general method A ′ ″ above, Boc- as a crude solid or foam using N- (tert-butoxycarbonyl) -L-leucine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem) Protected dipeptides were prepared. The resulting crude dipeptides were deprotected using the general method B ′ ″ to afford the title compound as a crude solid or foam.

Example C4

Synthesis of N- (L-phenylalanine) -L-phenylglycine methyl ester hydrochloride

According to the general method A ′ ″ above, Boc- as a crude solid or foam using N- (tert-butoxycarbonyl) -L-phenylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem) Protected dipeptides were prepared. The resulting crude dipeptides were deprotected using the general method B ′ ″ to afford the title compound as a crude solid or foam.

Example C5

Synthesis of N- (glycine) -L-phenylglycine methyl ester hydrochloride

According to the general method A ′ ″ above, Boc-protected di as a crude solid or foam using N- (tert-butoxycarbonyl) glycine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem) Peptides were prepared. The resulting crude dipeptides were deprotected using general method B ′ ″ to afford the title compound as a crude solid or foam.

Example C6

Synthesis of N- (L-phenylglycine) -L-phenylglycine methyl ester hydrochloride

According to the general method C ′ ″ above, Boc- as a crude solid or foam using N- (tert-butoxycarbonyl) -L-phenylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem) Protected dipeptides were prepared. The resulting crude dipeptides were deprotected using the general method B ′ ″ to afford the title compound as a crude solid or foam.

Example C7

Synthesis of N- (L-valine) -L-phenylglycine methyl ester hydrochloride

According to the general method A ′ ″ above, Boc- as a crude solid or foam using N- (tert-butoxycarbonyl) -L-valine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem) Protected dipeptides were prepared. The resulting crude dipeptides were deprotected using the general method B ′ ″ to afford the title compound as a crude solid or foam.

Example C8

Synthesis of N-[(S) -2-aminocyclohexylacetyl] -L-phenylglycine methyl ester hydrochloride

N- (tert-butoxycarbonyl)-(S) -aminocyclohexylacetic acid (e.g., Boc-L-cyclohexylglycine) and L-phenylglycine methyl ester Hydrochloride (Bachem) was used to prepare Boc-protected dipeptides as crude solids or foams. The resulting crude dipeptides were deprotected using the general method B '"to give the title compound as a crude solid or foam. Obtained.

Examples D1-D4 below illustrate the synthesis of various intermediates useful as starting materials of the invention. Similar intermediates can be prepared using this method and commercially known or known starting materials.

Example D1

Synthesis of 3,5-difluorophenyl-α-fluoroacetic acid

Methyl 3,5-difluoromandelate was prepared using the following general method G and commercially available 3,5-difluoromandelic acid. The resulting α-hydroxy methyl ester is described in Middle et al., Org. Synth. Col. Vol. VI. 835 fluorinated according to the general method described. In particular, treated with CH ₂ Cl ₂ diethylamino sulpeo trifluoride (1.1 eq.) Del rate (1.0 equivalents) only methyl 3,5-difluoro the solution was cooled to 0 ℃, as a solution in CH ₂ Cl ₂ in the It was. After 10 minutes, the cooling bath was removed and the reaction stirred at ambient temperature for 30 minutes. The reaction was monitored by tlc (Rf = 0.65 in 1: 1 ethyl acetate / hexanes). Subsequently, the mixture was poured on ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The product was purified by LC2000 chromatography (180 mL / min) using 10% EtOAc / hexanes as eluent. The resulting methyl 3,5-difluoromethyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treated with lithium hydroxide (2.0 equiv). After 2 hours no starting material remained by tlc. Dioxane was removed by rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer 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 having a melting point of 90 to 110 ° C.

C ₈ H ₅ F ₃ O ₂ (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 methyl magnesium bromide to a solution of L-phenylglycine methyl ester hydrochloride in THF at 0 ° C. The reaction mixture was stirred for 1 hour and then quenched with sodium bicarbonate. After standard workup conditions, 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

See J. Amer, DA Evans et al. Chem. Soc., (1990), 112, 4011-4030 from (S) -2- (tert-butoxycarbonyl) from 2- (6-methoxy-2-naphthyl) acetic acid according to the general method described in Amino) -2- (6-methoxy-2-naphthyl) acetic acid was prepared. Namely, (S) -3- (6-methoxy-2-naphthylacetyl) -4-benzyl-2-oxazolidinone at -78 ° C potassium 1,1,1,3,3,3-hexamethyl (S) -3-[(S) -6-methoxy-2-naphthyl-α-azidoacetyl) -4 by standard enolate azide process using disilazane and trimethylsilyl azide Benzyl-2-oxazolidinone. Subsequently, the azide derivative was treated with 3 equivalents of lithium hydroxide in THF to prepare (S) -2-azido-2- (6-methoxy-2-naphthyl) acetic acid. This intermediate as sodium salt in 1: 1 1,4-dioxane / water (0.05 M) was reduced to hydrogen and 10% Pd / C 1 atm at 25 ° C. to give (S) -2-azido-2- (6 -Methoxy-2-naphthyl) acetic acid was prepared and then converted to its N-Boc derivative without isolation by treatment with 1.4 equivalents of di-tert-butyl dicarbonate and 0.47 equivalents of sodium carbonate. The product was isolated by acidification with 1 N NaHSO ₄ to pH 2 and extracted with 3 portions of ethyl acetate. The product was recrystallized from ethyl acetate / hexanes to give a white solid.

Melting point 176 ° C. (condensation); 197-199 ° C. (decomposition).

NMR data were as follows:

¹ HMR (DMSO-d ₆ ): δ = 12.78 (s, 1H), 7.84-7.77 (m, 3H), 7.62 (d, J = 8 Hz, 1H), 7.49 (d, J = 8 Hz, 1H) , 7.31 (d, J = 2 ㎐, 1H), 7.17 (dd, J = 9, 2 ㎐, 1H), 5.22 (d, J = 8 ㎐, 1H), 3.87 (s, 3H), 1.39 (s, 9H).

Subsequently, (S) -2- (tert-butoxycarbonylamino) -2- (6-methoxy-2-naphthyl) acetic acid was converted to methyl ester using the following general method G. 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 was allowed to warm to room temperature and stirring continued for 2 hours. The reaction mixture was then concentrated, the residue was extracted with CH ₂ Cl ₂ and washed with sodium bicarbonate solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give methyl (S) -2-amino-2- (6-methoxy-2-naphthyl) acetate.

Example D4

Synthesis of Methyl 2-amino-2- (thieno [2,3-b] thiophen-2-yl) acetate

DMF was added to 3.75 molar equivalents of sodium hydride (without oil) and the resulting mixture was cooled to 0 ° C. Subsequently, methyl thieno [2,3-b] thiophene-2-carboxylate (1 molar equivalent) and methyl methylsulfinyl methyl sulfide (1.1 molar equivalent) in DMF were added dropwise, and the reaction mixture was 0 deg. After stirring for 30 minutes at room temperature, the mixture was warmed to room temperature and stirring was continued for 3 hours. The reaction was then quenched with methanol and the product extracted with EtOAc. The organic extract was washed with water and subsequently brine, then dried over Na ₂ SO ₄ , filtered and concentrated to give a brown oil like gum. The residue was slurried in diethyl ether and the resulting solid was collected. The solid was then dissolved in hot ethyl acetate and decolorized carbon was added. The mixture was then filtered and the solvent removed to give a solid that was used without further purification.

Acetic anhydride (10 molar equivalents) and acetic acid (1.8 molar equivalents) were mixed together, heated to 70 ° C. for 15 minutes and then cooled to 65 ° C. Solid sulfone from above was added in portions and the reaction was stirred at 70 ° C. for 30 minutes, then cooled and concentrated. The resulting solid was dissolved in ethyl acetate, washed with sodium bicarbonate solution and then with 1 N Na ₂ S ₂ O ₃ solution. The solution is then dried over MgSO ₄ , filtered and concentrated to afford methyl 2-keto-2- (thieno [2,3-b] thiophen-2-yl) thioacetate as a solid and further Used without purification.

To 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 was stirred at rt for 6 h, then methoxyamine (1.38 g, 0.0165 mol) was added and stirring continued for 18 h. The reaction mixture was then concentrated, the residue dissolved in ethyl acetate and washed with water. The aqueous layer was then acidified in HCl and the oily product was extracted with 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.

Subsequently, methyl ester is prepared using the following general method G, and the oxime is reduced to an amino group using the following general method R, followed by methyl 2-amino-2- (thieno [2,3-b] thiophene 2-yl) acetate was obtained.

Example D5

Synthesis of N-methyl-N'-BOC-leucineamide

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 hour, followed by 0.5402 g (8 mmol) of methylamine hydrochloride (Aldrich). And 0.8092 g (8 mmol) of N-methylmorpholine were added. The mixture was stirred for 16 h, evaporated to dryness under reduced pressure, and the residue was washed thoroughly with water, 1 N NaOH, water, and then diethyl ether to give 0.886 g (3.09 mmol, 70%) of the title compound. .

Example D6

Synthesis of N-BOC-norleucine amide

3.45 g (1.2 mmol) EDC in a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine (bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate and 50 ml of dichloromethane at 0 ° C. Was added. The resulting mixture was stirred at 0 ° C. for 1 hour and then ammonia gas was bubbled through the mixture for 10 minutes. The cold bath was warmed to room temperature and the mixture was stirred for 18 hours. The mixture was evaporated to dryness under reduced pressure and 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 N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanine

60 ml of dioxane and 1.98 g (0.006 mol) of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanine ethyl ester (obtained from Example 85 below) and Dissolve in 15 ml of water and LiOH (0.25 g, 0.006 mol) dissolved in 15 ml of water to prepare the title compound. After stirring for 3 hours, the dioxane is removed under reduced pressure, the residue is diluted with EtOAc, the layers are separated and the aqueous layer is acidified to pH 2 with EtOAc. The aqueous layer was extracted again with EtOAc (4 × 100 mL) and the combined organics were dried over Na ₂ SO ₄ , the solvent was filtered off and removed under reduced pressure. The residue was recrystallized from EtOAc / isooctane to give 1.7 g (90%). C ₁₄ H ₁₆ F ₂ N ₂ O ₄ requires C, 53.50 H, 5.13 N, 8.91. The analysis result was C, 53.30 H, 5.26 N, 8.98.

Example D8

Synthesis of m-nitrophenylacetyl-L-alanine 2,4,5-trichlorophenyl ester

m-nitrophenylacetyl-L-alanine (1 equiv) and 2,4,5-trichlorophenol (1.3 equiv) were stirred in dichloromethane. 1.0 M of 1,3-dicyclohexylcarbodiimide in dichloromethane (1.2 equiv) was added and the mixture was stirred at ambient temperature for 16 h. 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 eluent to afford the title compound as a pink solid. Calculated for C ₁₇ H ₁₃ Cl ₃ N ₂ O ₅ 47.30% C, 3.04% H, 6.49% N. found 47.57% C, 3.18% H, 6.47% N.

Example D9

Synthesis of D, L-α-methylphenylglycine ethyl ester

See J. Org. Of J. J. Fitt and H.W. Gschwend. Chem., 42, No. 15, 2639 (1977) to provide the title compound. More specifically, D, L-phenylglycine (Aldrich) was stirred in dimethylformamide dimethyl acetal and the mixture was heated at reflux for 4 hours under a dry nitrogen atmosphere. After cooling, the mixture was concentrated at reduced pressure to yield a yellow oil solid. The mixture was stirred in diethyl ether and filtered through celite. The filtrate was concentrated to an orange oil and purified by vacuum distillation to form a yellow oil, which solidified. The yellow solid was stirred in dry THF at −20 ° C. under dry nitrogen. Lithium bis (trimethylsilyl) amide (1.05 equiv, 1.0 M solution in THF) was added dropwise. The resulting mixture was warmed to −10 ° C. and stirring continued at this temperature for 1 hour. Methyl iodide (1.05 equiv) was added and the mixture was warmed 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 concentrated ethanol. Dry zinc chloride (4 equiv) was added and the mixture was heated at reflux. After 14 hours, the mixture was concentrated under reduced pressure to yield 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 equiv) (Aldrich) was stirred in dry THF at −78 ° C. under an atmosphere of dry nitrogen. Lithium bis (trimethylsilyl) amide (1.02 equiv, 1.0 M solution in THF) was added dropwise. The resulting mixture was stirred at -78 ° C for 1 hour. A THF solution of N- (bromomethyl) phthalimide (1.1 equiv) (Aldrich) was added and the mixture was allowed to warm up to ambient temperature and stirring continued for 1 hour. Hydrochloric acid (600 mL, 2 N) 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 concentrated (up to 100 mL) to give a thick slurry. 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 D11

Synthesis of N- (3-nitrophenylacetyl) -L-alanine

In dioxane 60 ㎖ and H ₂ O 15 ㎖ N- (3- nitro-phenylacetyl) -L- alanine The methyl ester was dissolved 9.27 g (0.0348 mol), dissolved in _{H 2 O 15 ㎖ LiOH (3.06} g, 0.0731 Mole) was added to prepare the title compound. After stirring for 4 hours, the dioxane was removed at reduced pressure, the residue was diluted with EtOAc, the layers separated and the aqueous layer acidified to pH 2. The aqueous layer was reextracted with EtOAc (4 × 100 mL) and the combined organics were dried over Na ₂ SO ₄ and the solvent was removed after filtration under reduced pressure. The residue was recrystallized from EtOAc / isooctane to give 7.5 g (85%). C ₁₁ H ₁₂ N ₂ O ₅ requires C 52.38, H 4.80, N 11.11. The result was C 52.54, H 4.85, N 11.08. [α] ₂₃ = -29.9 at 589 nm.

Example D12

Synthesis of Methyl 2-amino-2- (3-fluorophenyl) acetate Hydrochloride

Potassium cyanide (6.3, 0.1 mol) and ammonium carbonate (15.7 g, 0.2 mol) were dissolved in 50 ml of water (in a well ventilated exhaust hood). 3-fluorobenzaldehyde (5.0 g, 0.04 mole) was dissolved in 50 mL EtOH and added to the reaction. After stirring for 17 hours at reflux under a nitrogen atmosphere, the reaction was cooled to 23 ° C, the pH was adjusted to 2.0 by addition of 5 N HCl and cooled to 5 ° C. The resulting hydantoin was collected, rinsed with cold water and dried in vacuo to yield 3.59 as an off-white solid. Hydantoin was hydrolyzed at reflux with 1 N NaOH to afford 2-amino-2- (3-fluorophenyl) acetic acid and esterified by Method H in methanol to afford the title compound.

Example D13

Synthesis of N- [N- (S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester

N- [N- (benzyloxycarbonyl)-(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester (4.13 g) in EtOH (200 mL) [N using General Method D -(Benzyloxycarbonyl)-(S) -2-aminobutanoic acid (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem)] and 20% Pd (OH) ₂ / C (0.360 g) was shaken on a Parr apparatus for 4 hours under nitrogen atmosphere (40 psi). The solids were removed by filtration through a plug 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 up to 10% trans-esterification with ethyl occurred during this reaction. After the subsequent reaction of the compound the ethyl ester was removed by flash chromatography.

Example D14

Synthesis of N- [N-L-valinyl] -L-phenylglycine tert-butyl ester

N- [N- (benzyloxycarbonyl) -L-valinyl] -L-phenylglycine tert-butyl ester (4.63 g) in EtOH (200 mL) [N- (benzyloxycarboxe using General Method D) Carbonyl) -L-valine (Aldrich) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem)] and 20% Pd (OH) ₂ / C (0.360 g) were added to a nitrogen atmosphere (40 psi) in a Parr apparatus for 4 hours. The solids were removed by filtration through a plug 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 up to 1% trans-esterification with ethyl occurred during this reaction. After the subsequent reaction of the compound the ethyl ester was removed by flash chromatography.

Example D15

Synthesis of (S) -phenylglycinol methyl ether

(S)-(+)-2-phenylglycinol (1 equiv) (Aldrich) was stirred in dry THF under a dry nitrogen atmosphere. Sodium hydride (1 equiv) was added and the resulting mixture was stirred at ambient temperature for 1 hour. A THF solution of iodomethane (1 equiv) was added and the mixture was stirred for 1 h. The mixture was concentrated to form a residue, which was dissolved in water and extracted with chloroform. The organic extract was concentrated under reduced pressure to form the title compound as an oil, which was purified by silica gel chromatography to form 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 dry THF, methylmagnesium bromide (46.3 mL, 138.9 mmol, 3.0 M in diethyl ether) ) Was added. During the addition, the internal temperature was increased to 24 ° C. After continuing stirring for 1 hour, the reaction was carefully quenched by addition of saturated sodium bicarbonate solution. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the aqueous layer was reextracted using 3 volumes of ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel eluting with 10% methanol in chloroform (neutralized with ammonium hydroxide) to 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 dropwise with n-butyllithium (1.6 M in hexane; 1.1 molar equivalent). The resulting yellow solution was stirred at −78 ° C. for 40 minutes. Dimethylformamide (1.1 molar equivalents) was added dropwise and the reaction stirred and further stirred for 30 minutes. 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 Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by HPLC eluting with 15% ethyl acetate / hexanes to afford the title compound.

Example D18

Synthesis of (S)-(-)-α-methylbenzylisocyanide

Chem. Of Wolber, EKA and Ruchardt, C. Ber. It was prepared according to the general method of 1991, 124, 1667. To a suspension of 1,1'-carbonyldiimidazole (1.6 molar equivalents; Aldrich) in acetonitrile was treated dropwise at 0 ° C. with methanesulfonic acid (3.2 molar equivalents; Aldrich). A very thick suspension formed. (S)-(-)-α-methylbenzyl formamide (1 molar equivalent; obtained from Example D19 below) was added via cannula as a solution in acetonitrile. The mixture was stirred at ambient temperature overnight. The suspension was filtered and washed with acetonitrile. The filtrate was concentrated and purified by flash chromatography eluting with 30% ethyl acetate / hexanes. The oil was further purified by bulb to bulb distillation (80 ° C., 0.04 mmHg) to give a pale yellow oil (yield; 51%). For C ₉ H ₉ N the calculated value is 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-methylbenzyl Formamide

(S)-(-)-α-methylbenzylamine (1 molar equivalent) was treated with ethyl formate (80 molar equivalent; Aldrich). A precipitate formed immediately. The suspension was heated to reflux (55 ° C.) for 3 hours. The precipitate was made into a solution while 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 dry THF was cooled to -78 ° C and treated by dropwise addition of tert-butyllithium (Aldrich; 1.7 M in hexane, 2 molar equivalents) It was. The reaction was stirred at -78 ° C for 40 minutes. Dimethylformamide (Aldrich; 2.5 molar equivalents) was added and stirring continued for 20 minutes. The mixture was partitioned between methylene chloride and water in a separatory funnel. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by HPLC eluting with 5% ethyl acetate / hexanes. The desired aldehyde was obtained in 71% yield.

Example D21

Synthesis of 4- (cyclohexyl) benzaldehyde

18-crown-6 (Aldrich; 4 molar equivalents) and pyridinium chlorochromate (Aldrich; 4 molar equivalents) were added together in chloroform and stirred for 20 minutes. 4-cyclohexylbenzyl alcohol (obtained from Example D22 below; 1 molar equivalent) was added and stirring was continued for 3 hours. Ether was added and the mixture was filtered through a plug of silica eluting with ether. Solvent was removed via rotary evaporator. The residue was dissolved in ether and washed with water. The organic layer was dried over Na ₂ S0 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 diiso-butylaluminum hydride (Aldrich; 1 M in toluene; 4 molar equivalents) over 2 hours. After completion of the addition, the reaction was heated to 60 ° C. for 1 hour. The reaction was cooled to 5 ° C. and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics 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 (obtained from Example D24 below; 1 molar equivalent) in 50% aqueous ethanol was treated with lithium hydroxide (1.5 equiv). The solution was stirred at ambient temperature for 3 hours and then concentrated by rotary evaporation. The residue was dissolved in water and made basic by addition of a small amount of 1N NaOH. The aqueous mixture was extracted with ether. The aqueous layer was acidified to pH 3 with 1 N HCl. The acid was extracted three times 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 was stirred at ambient temperature for 72 hours and then heated to 50 ° C. for 6 hours. The mixture was poured onto ice and extracted using methylene chloride. The organic layer was washed with saturated sodium bicarbonate, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC eluting with 2% ethyl acetate / hexanes.

Example D25

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -D, L-phenylglycine

N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycine methyl ester (obtained from Example 111 below) was hydrolyzed according to the AF method. The acid was recrystallized from isooctane / EtOAc to form a mixture of enantiomers at the phenylglycine center. Elemental Analysis: C ₁₉ H ₁₈ F ₂ N ₄ O ₄ is C, 60.63; H, 4. 82; N, 7.44 was required. 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 equiv, Aldrich), 4-iodophenol (1 equiv, Aldrich) and potassium carbonate (2 equiv) were stirred in acetonitrile. The mixture was heated at reflux. After 64 hours, the reaction mixture was concentrated to a thick mixture, which was then slurried in water. The white solid was collected, washed with water and dried in vacuo.

The white solid was stirred in ethanol. Anhydrous hydrazine (2 equiv) was added and the mixture was heated at reflux for 18 h. The reaction mixture was concentrated to give a solid, which was treated with 1 N NaOH and extracted with CHCl ₃ . The organic portion was dried, concentrated and diluted with ether. The mixture was treated with dry HCl. The title compound was collected 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 equiv) 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 using 1: 1 ethyl acetate / hexanes.

The product was dissolved in THF. Triethylamine (1.1 equiv) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (1.1 equiv) 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 layer was separated, dried (sodium sulfate) and concentrated to give a white solid, which was chromatographed on silica gel with 30% ethyl acetate in hexanes and finally crystallized from 1-chlorobutane / hexane.

The crystalline product was stirred in dry DMF and potassium phthalimide (1.1 equiv) 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 dissolved in chloroform and filtered through a silica plug. The product containing the eluate was concentrated to give the crude product as a white solid.

The white solid was dissolved in dry dioxane and the resulting solution was saturated with gaseous HCl. 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 g), LiCl (2.95 g), saturated aqueous ammonia (20 mL), and benzyltriethylammonium chloride (0.805 g) were stirred and cooled in CH ₂ Cl ₂ (17 mL). Gas ammonia was bubbled into the mixture until it was saturated (0 ° C.) with cooling. To the resulting mixture was added 3,5-difluorobenzaldehyde (5.0 g) (Lancaster) and chloroform (4.46 mL), dissolved in CH ₂ Cl ₂ (17.5 mL) and simultaneously saturated with ammonia gas. The resulting mixture was stirred cold for 4 hours and stirred at 22.5 ° C. for 96 hours. Water (60 mL) and CH ₂ Cl ₂ (20 mL) were added; The layers were separated and the aqueous layer was extracted three more times with CH ₂ Cl ₂ . The aqueous layer was reduced by 50% in vacuo. The pH was adjusted to 6.5 using cold concentrated HCl, at which time crystals of D, L-3,5-difluorophenylglycine were formed (3.4343 g).

Example D29

Synthesis of L-3,5-difluorophenylglycine methyl ester tartate salt

3.43 g of D, L-3,5 difluorophenylglycine (obtained from Example D28, above) was slurried in 50 mL methanol and 2.5 mL concentrated H ₂ SO ₄ . The reaction mixture was heated for 18 hours under mild reflux. The mixture was cooled in an ice bath and the pH of the solution was adjusted to 7.0 with saturated aqueous ammonia. The volatile organic solvents were removed in vacuo and the aqueous dispersion was extracted three times with CH ₂ Cl ₂ ; The combined organic layers were dried, filtered and reduced in vacuo to yield 2.680 g of crude ester. This ester, benzaldehyde (1.4085 g), and (-) tartaric acid (1.9921 g) were dissolved in 20.5 mL of hot ethanol and stirred slowly for 72 hours to crystallize the title compound. The product was filtered and dried to give 3.4805 g of (-) tartarate salt.

Example D30

Synthesis of N- (3,5-difluorophenylacetyl) -L-3,5-difluorophenylglycine

Prepared by neutralization from L-3,5-difluorophenylglycine (0.4291 g) [L-3,5-difluorophenylglycine (-)-tartarate salt (obtained from Example D29, above) And 0.367 g of 3,5-difluoroacetic acid were dissolved in THF. EEDQ coupling using the general method AN yielded 0.7441 g of the title compound as methyl ester. The ether 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 at 22.5 ° C for 2 h. EtOAc (30 mL) and 1 N HCl were added and the aqueous layer was extracted twice. The combined organic layers were dried (MgSO ₄ ) and reduced in vacuo to afford the title compound (700.8 mg).

The compounds prepared in the Examples below were prepared by one of the following general methods unless otherwise indicated.

General method A

EDC Coupling Method I

To a 1: 1 mixture of the corresponding carboxylic acid and aminoester / amide in CH ₂ Cl ₂ or DMF was added 1.5 equivalents of triethylamine at 0 ° C., followed by addition of 2.0 equivalents of hydroxybenzotriazole monohydrate, followed by 1- 1.25 equiv of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) was added. The reaction mixture was stirred overnight at room 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 stripped off by removing the solvent on a rotary evaporator to yield the crude product.

General method B

EDC Coupling Method II

The carboxylic acid was dissolved in methylene chloride in a round bottom flask. Amino acid (1 equiv), N-methylmorpholine (5 equiv) and hydroxybenzotriazole monohydrate (1.2 equiv) were added sequentially. The cooling bath was used in a round bottom flask until the solution reached 0 ° C. At this time, 1.2 equivalents of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added. The solution was then stirred overnight and allowed to come to room temperature under N ₂ pressure. Subsequently, the reaction mixture was washed with saturated aqueous Na ₂ CO ₃ , 0.1 M citric acid, and brine, dried using Na ₂ SO ₄ , and the solvent was removed to afford crude product. Typically, flash chromatography in a suitable solvent yields the pure product.

General method C

EDC Coupling Method III

A round bottom flask was charged under nitrogen atmosphere with suitable carboxylic acid (1.0 equiv), hydroxybenzotriazole hydroxide (1.1 equiv) and suitable amine (1.0 equiv) in THF. A suitable base (1.1 equivalent to free amine and 2.2 equivalent to amine hydrochloride salt), for example Hunig's base, is added to the stirred mixture followed by 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride (EDC) (1.1 equiv) was added. After stirring at room temperature for about 4 to 17 hours, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (or similar solvent) / H ₂ O. The extract was washed with saturated NaHCO ₃ , 1 N aqueous hydrochloric acid, brine and dried over Na ₂ SO ₄ . In some cases, the isolated product required further purification using standard processes such as chromatography and / or recrystallization.

General method D

EDC Coupling Method IV

THF, amine or amine hydrochloride (1.0 equiv), carboxylic acid (1.1 equiv), 1-hydroxybenzotriazole hydroxide (1.15 to 1.2 equiv) in a round bottom flask containing a magnetic stir bar at 0 ° C. under nitrogen atmosphere , N, N-diisopropylethylamine (2.3 equiv) was charged followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.15 to 1.2 equiv). The cooling bath was removed and the mixture was warmed for 10-20 hours with stirring to room temperature. The mixture was diluted with EtOAc, washed with 0.5 N aqueous HCl (2x), diluted aqueous NaHCO ₃ (1x), brine (1x) and dried over Na ₂ S0 ₄ or MgSO ₄ . The desiccant was removed by filtration and the filtrate was concentrated in vacuo. The residue was used without further purification or purified using standard processes such as flash chromatography on silica gel and / or recrystallization.

General method E

EDC Coupling Method V

THF, carboxylic acid (1.0 equiv), amine or amine hydrochloride (1.0-1.1 equiv), 1-hydroxybenzotriazole hydroxide (1.1 in a round bottom flask containing a magnetic stir bar at nitrogen atmosphere, 0 ° C. or room temperature To 1.2 equivalents), N, N-diisopropylethylamine (2.2 to 2.9 equivalents), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.1 to 1.2 Equivalent)). The cooling bath was removed and the mixture was warmed for 10-20 hours with stirring to room temperature. The mixture was diluted with EtOAc, washed with 0.5 N aqueous HCl (2x), diluted aqueous NaHCO ₃ (1x), brine (1x) and dried over Na ₂ S0 ₄ or MgSO ₄ . The desiccant was removed by filtration and the filtrate was concentrated in vacuo. The residue was used without further purification or purified using standard processes such as flash chromatography on silica gel and / or recrystallization.

General method F

EDC Coupling Method VI

THF, carboxylic acid (1.0 equiv), amine or amine hydrochloride (1.1 equiv), N, N-diisopropylethylamine (2.2-2.3 equiv) in a round bottom flask containing a magnetic stir bar at 0 ° C. under nitrogen atmosphere ) Was charged followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.1-1.2 equiv). The cooling bath was removed and the mixture was warmed for 10-20 hours with stirring to room temperature. The mixture was diluted with EtOAc, washed with 0.2 N aqueous HCl (twice), diluted aqueous NaHCO ₃ (once), brine (once) and dried over Na ₂ SO ₄ or MgSO ₄ . The desiccant was removed by filtration and the filtrate was concentrated in vacuo. The residue was used without further purification or purified using standard processes such as flash chromatography on silica gel and / or recrystallization.

General method G

Preparation of Methyl Ester

40% KOH was added to 1-methyl-3-nitro-1-nitrosoguanidine (1.2 equiv) in diethyl ether cooled to 0 ° C. until bubbling stopped. The mixture was then decanted into a plastic tube containing KOH pellets as desiccant. Subsequently, the solution was added to a suitable carboxylic acid and the mixture was stirred until the reaction was complete (e.g., determined by tlc). The reaction was then quenched with acetic acid and extracted with EtOAc. The solvent was removed to give the desired methyl ester.

General method H

Preparation of Carboxylic Acid Ester

Anhydrous HCl gas was bubbled until the solution was saturated with a suitable amino acid or carboxylic acid in a suitable alcohol. The reaction was stirred at 25 ° C. overnight, then the solvent was removed under reduced pressure. The residue was then dissolved in EtOAc and the solution was washed with sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and the solvent removed to afford the desired ester.

General method I

Preparation of Tert-Butyl Ester I

To an N-CBZ-protected amino acid solution in CH ₂ Cl ₂ was added 1.5 equivalents of N, N′-diisopropyl-Ot-butylisourea (prepared by standard literature method as described in Synthesis (1979)), The reaction was heated to reflux for 17 hours. Subsequently, an additional 1.5 equivalents of isourea was added and the reflux was continued for an additional 7 hours. The reaction was then cooled to room temperature, filtered through a bed of Celite 545 and stripped until dry to form a clear oil. The residue was dissolved in hexane, filtered to remove the 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 method J

Preparation of Tert-Butyl Ester II

The reaction was carried out at −20 ° C. in a sealed tube using a suitable carboxylic acid in dioxane or CH ₂ Cl ₂ , a catalytic amount of H ₂ SO ₄ (0.03 equiv), and an excess of concentrated iso-butylene. 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. The solution was washed with sodium bicarbonate solution and the organic layer was dried over sodium sulfate, filtered and the solvent removed. The resulting product was purified using standard processes such as, for example, HPLC or titration using diethyl ether / hexanes.

General method K

Amide Preparation I

To the solution of 3 equivalents of the desired amine in 1,2-dichloroethane, 5.2 equivalents or less of triethylaluminum surface were added. After stirring for 30 minutes at room temperature, the desired ester solution dissolved in 1,2-dichloroethane was added. The reaction was typically refluxed for 3 hours until tlc showed complete conversion. Subsequently, the reaction was cooled to 0 ° C. and quenched with 10% aqueous hydrochloric acid (note: acid must be added slowly, as some foaming is produced during acid addition). The mixture was transferred to a separatory funnel and the layers separated. The aqueous phase was washed with ethyl acetate and the organic phase was washed with saturated aqueous NaCl, dried over MgSO ₄ and concentrated under reduced pressure to afford crude product.

Alternatively, if the product is soluble in acid, after quenching the reaction, the reaction volume is reduced to about 의 of the initial volume under reduced pressure. To the resulting solution was added 20% aqueous sodium carbonate tartrate (Rochelle's salt) and ethyl acetate. Subsequently, the pH of the solution was adjusted to -13, and the aluminum salt was dissolved in the aqueous solution. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic solution was washed with saturated aqueous NaCl, dried over MgSO ₄ , and concentrated under reduced pressure to afford crude product.

General method L

Amide Preparation II

Hogberg, T. et al., J. Carboxamides were prepared from the corresponding esters using the method as described in Organic Chem., 1987, 52, 2033-2036.

General method M

Amide Preparation III

To a suitable carboxylic acid (1.0 equiv) in THF was added N-methylmorpholine (1.1 equiv) and the solution was cooled to -20 ° C to 0 ° C. Then, iso-butyl chloroformate (1.1-2.1 equiv) was added and the reaction mixture was stirred at -20 ° C to 0 ° C for 30 minutes. Subsequently, a mixture of suitable amino acids, water and 1.5 equivalents of potassium carbonate was added and the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was then poured into water and washed with EtOAc. The pH of the water layer was then adjusted to 2.0 with 5 N HCl and the water layer was extracted with EtOAc. The combined organic layers were dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The resulting crude amide was used without further purification or purified using standard processes such as chromatography or titration using diethyl ether / hexane, or EtOAc / hexane.

General method N

Hydrolysis of Carboxylic Acid Ester

To the ester in a 1: 1 mixture of CH ₃ OH / H ₂ O was added 2-5 equivalents of K ₂ CO ₃ . The mixture was heated to 50 ° C. for 0.5-1.5 hours until tlc showed complete reaction. The reaction was cooled to room temperature and methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to about 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO ₄ . The solution was removed by stripping off the solvent on a rotary evaporator to yield the product.

General method O

Removal of N-Carbobenzyloxy (CBZ) Protecting Groups

The N-CBZ-protected compound was dissolved in ethanol in a hydrogenation flask and a catalytic amount of 10% Pd / C was added. The mixture was hydrogenated in 20 psi H ₂ for 30 minutes on a Parr shaker. The reaction was then filtered through a pad of Celite 545 and the solvent was stripped off on a rotary evaporator to yield the product.

General method P

Removal of N-3 Class-Boc Protectors

N-tert-Boc-amine was dissolved in a suitable dry solvent (1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. Gaseous HCl was introduced into the solution until the mixture was saturated with HCl. The mixture was then stirred until the reaction was complete. The resulting mixture was concentrated under reduced pressure to give amine hydrochloride. Amine hydrochloride was used without purification, or triturated with diethyl ether, and the resulting solid was collected by filtration.

General method

Halide Exchange [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 was heated to 60 ° C and stirred overnight. The cooled reaction mixture was extracted with dichloromethane (2 × 30 mL) and the combined extracts were rotary evaporated at reduced pressure to afford crude product. Typically, flash chromatography in a suitable solvent yields the pure product.

General method R

Oxime Reduction I

Formic acid (500 equiv) and water (500 equiv) were added to the oxime ester in the alcohol corresponding to the ester. The reaction mixture was cooled to 5 ° C. and zinc powder (3.8 equiv) was added in portions over 20 minutes. The reaction was then warmed to room temperature and stirring continued for 3 hours. The reaction was then filtered over Hyflo (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 dried over sodium sulfate, filtered and the solvent removed to give the product.

General method S

Reduction of Esters to Alcohols

1.0 equivalent of LiBH ₄ in THF was added to a solution of 0 ° C. of the starting ester in anhydrous THF. The reaction was stirred at rt overnight then quenched with water. 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 an alcohol product.

General method T

CDI Coupling Method

A solution of suitable acid (3.3 mmol) and 1,1'-carbodiimidazole (CDI) in 20 mL of THF was stirred for 2 hours. 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, then dissolved in 100 ml of diethyl ether and washed three times with 10% HCl, once with brine, once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated at reduced pressure to give the product.

General method U

EDC Coupling Method VII

Suitable carboxylic acid (1 equiv), 1-hydroxybenzotriazole (1.6 equiv), suitable amine (1 equiv), N-methylmorpholine (3 equiv) and dichloromethane (or insoluble matter) cooled in an ice water bath For, the mixture of DMF) was stirred until a clear solution was obtained. EDC (1.3 equiv) was added to the reaction mixture and the cooling bath was warmed to ambient temperature over 1 to 2 hours. Subsequently, the reaction was stirred overnight. The reaction mixture was then evaporated to dryness under reduced pressure and 20% potassium carbonate was added to the residue. The mixture was vigorously shaken and left for several hours or overnight until the oily product solidified as needed. The solidified product was then filtered and washed thoroughly with 20% potassium carbonate, water, 10% HCl, and water to give the product. Using this method no racemization was observed.

General method V

O-acylation of Alcohol

Alcohols in pyridine (eg, N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L- from Example 228 below To the alanineamide) solution was added 4 equivalents of acetic anhydride and stirred at room temperature for 2.5 hours. The reaction was quenched on ice, 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 desolvated on a rotary evaporator to yield the product.

General method W

O-esterification of alcohol

Alcohol dissolved in THF in a 0.95 equivalent NaH suspension in THF (eg, N-[(S) -1-hydroxyhex-2-yl] -N '-(3, from Example 228 below) 5-difluorophenylacetyl) -L-alanineamide) was added. After cooling this solution to 0 ° C., 1.1 equivalents of acyl chloride (eg trimethylacetyl chloride) were added. The reaction was stirred overnight in Ceylon and 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 desolvated on a rotary evaporator to yield the crude product.

General method X

BOP Coupling Process

A solution of carboxylic acid (1.0 equiv) and N-methyl morpholine (1.5 equiv) in dichloromethane was cooled under nitrogen to −20 ° C. BOP (1.05 equiv) was added in portions and the reaction mixture was kept at -20 ° C for 15 minutes. Appropriate alcohol (1,2 equiv) was added and the reaction mixture was allowed to warm to room temperature and stirring continued for 12 hours. The reaction mixture is then watered and extracted with ethyl acetate (3 times), the combined organic phases are washed with saturated aqueous citric acid (2 times), saturated aqueous tartium bicarbonate (2 times), brine (1 time), and The crude product was prepared by rotary evaporation at reduced pressure.

General method Y

Removal of BOC Using TFA

Boc-protected compound was added to a dichloromethane and trifluoroacetic acid (TFA) 1: 1 mixture and the reaction mixture was stirred for typically 2 hours until tlc indicated complete conversion. The solution was then stripped to dryness. The residue was suspended in dichloromethane and stripped again to dryness to remove excess TFA. The residue was left under vacuum for several hours to prepare the desired TFA salt.

General method Z

Amide Preparation IV

Trichlorophenyl ester (1 equiv) was stirred in DMF or THF and oxime or amine (1.2 equiv) was added. The mixture was stirred at ambient temperature for 1-4 hours. When using an amine in the form of the hydrochloride salt, a suitable base such as diisopropylethylamine (1.2 equiv) was also added. The resulting mixture was concentrated under reduced pressure to use without further purification, or purified by standard processes such as gel chromatography and / or recrystallization to give an oil or residue.

General method AA

Reduction of sodium borohydride

The ketone was dissolved in MeOH and treated with 1 equivalent of sodium borohydride. The reaction was typically stirred for 1 hour until tlc indicated the starting material was consumed. The reaction mixture was then evaporated at reduced pressure and chromatographed to give an alcoholic product.

GENERAL METHOD AB

Preparation of Amino Acid Derivatives Using Chiral Amine

(S)-(+)-α-methylbenzyl amine was added dropwise to a solution of 4- (phenyl) benzaldehyde (1 molar equivalent) in THF, followed by 1.0 molar equivalent of zinc chloride. The reaction mixture was stirred at rt for 5 h. The cloudy mixture was then cooled to −30 ° C. and treated with t-butyl isocyanide (1.05 molar equivalents). After 20 minutes, N- (3,5-difluophenylacetyl) -L-alanine was added and stirring was continued at −30 ° C. for 120 hours. The reaction mixture was then poured into a separatory funnel, diluted with CH ₂ Cl ₂ and washed with sodium bicarbonate. The organic layer was then washed with 0.5 N HCl and then brine. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give Nt-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-as a mixture of isomers. N '-(S) -α-methylbenzyl-2-amino-2- (4-phenylphenyl) acetamide was prepared. In this step, the isomers are typically separated by HPLC chromatography, for example using a gradient of 30 to 35% EtOAc / hexanes. 10 molar equivalents of triethylsilane were then added to remove the α-methylbenzel protecting group from the S, S isomer. The reaction was then heated to 37 ° C. for 3 hours, then poured into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by recrystallization from ethyl acetate or ethyl acetate / hexanes. Various compounds useful in the present invention can be prepared using various other aldehydes and carboxylic acids in this process.

Common way AC

Oxime Reduction II

To the oxime ester solution in alcohol corresponding to the ester was added catalytic amount of acetic acid and 0.1 molar equivalent of 10% Pd / C. The reaction vessel (par shaker) was filled with hydrogen up to 40 PSI and the mixture was shaken for 3 hours. The reaction mixture was then filtered over 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 method AD

Mizunobu reaction

1.3 equivalents of triphenylphosphine and diethyl azodicarboxyl, respectively, in a solution of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tyrosine methyl ester in 20 ml of THF DEDE, and 1.0 equivalent of alcohol were added. The mixture was stirred at rt overnight, then the solvent was removed. The residue was purified by standard processes such as chromatography and / or recrystallization.

General method AE

O-alkylation of tyrosine derivatives

3.0 equivalents of potassium carbonate and catalytic amount as 1.3 equivalents of alkyl bromide and fines in a solution of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tyrosine methyl ester in 20 mL of acetone Sodium iodide was added. The reaction mixture was stirred overnight in Ceylon and then partitioned between DCM and water. The organic layer was dried over anhydrous sodium sulfate and purified by standard processes such as chromatography and / or recrystallization.

General method AE

Hydrolysis of Carboxylic Acid Ester

A solution of carboxylic acid ester (1.0 equiv) and lithium hydroxide (1.1 equiv) in 1: 2 water / dioxane was stirred at 23 ° C. for 1 hour. The reaction mixture was then acidified to pH 3 with 1 N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated to give the product. In some cases, the product was further purified using standard processes such as chromatography and / or recrystallization.

GENERAL METHOD AG

Methyl Ester Formation from Amino Acids

Amino acid (amino acid or amino acid hydrochloride) was suspended in methanol and cooled to 0 ° C. HCl gas was bubbled through this solution for 5 minutes. The reaction was allowed to warm up to room temperature and then stirred for 4 hours. The solvent was then removed to give the desired amino acid methyl ester hydrochloride. This product was typically used without further purification.

General method AH

EEDQ coupling process

Under a nitrogen atmosphere at room temperature a round bottom flask equipped with a magnetic stir bar was charged with THF, carboxylic acid (1 equiv), amine hydrochloride (1.1 equiv) and EEDQ (1.1 equiv) and the reaction mixture was stirred for 15 minutes. 4-Methylmorpholine (1.1 equiv) was added to the reaction and stirring was continued for 15-20 hours in Ceylon. The reaction mixture was then concentrated in vacuo and the resulting residue partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous NH ₄ Cl (2 times), saturated aqueous NaHCO ₃ (2 times) and then brine (1 time). The organic phase was dried over Na ₂ SO ₄ . The desiccant was filtered off and the filtrate was concentrated in vacuo. The residue was used without further purification or further purified using standard processes such as chromatography and / or recrystallization.

General method AI

N-t-BOC protein of amino acids

Under a nitrogen atmosphere at room temperature, a round bottom flask equipped with a magnetic stir bar was charged with dioxane, water, 1.0 N aqueous sodium hydroxide, and amino acid (1 equiv). Agitation was initiated and the flask was cooled in an ice bath. Di-t-butyldicarbonate (1.1 equiv) was added to the reaction mixture, then the ice bath was removed and slowly warmed to room temperature over 1 hour. The reaction was partially concentrated on a rotary evaporator and then ethyl acetate was added. The flask was recooled in an ice bath and the mixture was acidified to pH 2-3 by addition of sodium bisulfate. The reaction 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 Na ₂ SO ₄ . The desiccant was filtered off and the filtrate was concentrated in vacuo. The solid was used without further purification.

General method AJ

Removal of N-Carbobenzyloxy (CBZ) Protecting Groups

A round bottom flask equipped with a magnetic stir bar under nitrogen atmosphere at room temperature was charged with methanol, tetrahydrofuran, 20% Pd (OH) ₂ / C (1 weight equivalent), and CBZ-boro dipeptide. Agitation was initiated and the flask was purged with hydrogen (three times). The reaction mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction was filtered and the filtrate was concentrated in vacuo. The resulting solid is used as it is or purified using silica gel chromatography.

Common way AK

Addition of N-Carbobenzyloxy (CBZ) Protecting Group

Under a nitrogen atmosphere at room temperature, a round bottom flask equipped with a magnetic stir bar was filled with water, sodium carbonate (2.2 equiv) and amino acid (1.0 equiv). The slurry was stirred in Ceylon for 1 hour. The reaction mixture was extracted with CH ₂ Cl ₂ (3 times) and the combined organic extracts were acidified until pH was 2-3. The resulting solid was separated via vacuum filtration.

General method AL

Preparation of Amino Acid Derivatives Using Chiral Amine II

The aryl aldehyde (1 mon 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 t-butyl isocyanide (1.5-2.0 equiv) and N- (3,5-difluorophenylacetyl) -L-alanine (1.5-2.0 molar equivalent). . The reaction was stirred for 60 hours. The reaction was diluted with methylene chloride and washed with 0.01 N HCl and saturated aqueous NaHSO ₃ . Each aqueous wash was back extracted with methylene chloride. The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give Nt-butyl-N- [N ′-(3,5-difluorophenylacetyl) -L-alanyl] -N '-R-α-methylbenzyl-2-amino-2-DL- (aryl) acetamide was prepared. In this step, if possible, the isomers are separated by HPLC chromatography, for example using a gradient of 20-25% ethyl acetate / hexanes. 10 molar equivalents of triethylsilane and 20 molar equivalents of trifluoroacetic acid were then added to the compound to remove the α-methylbenzyl protecting group from the peptide. The reaction was heated to 37 ° C. for 3 hours, then poured into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by trituration with ether or ether / hexanes. Various compounds useful in the present invention can be prepared using various other aldehydes, isocyanides and carboxylic acids in this process.

General method AM

Preparation of Amino Acid Derivatives Using Chiral Amine III

A solution of aromatic aldehyde (3 molar equivalents) and S-(-)-[alpha] -methylbenzylamine (1 molar equivalent) in methanol was treated with titanium (IV) isopropoxide (1.5 molar equivalents). The mixture was stirred at ambient temperature for 6 hours, then 40 minutes after t-butyl isocyanide (1.1 molar equivalents) was added, N- (3,5-difluorophenylacetyl) -L-alanine (1.2 molar equivalents) ) Was added. Methanol was removed via a rotary evaporator. The residue was dissolved in methylene chloride and washed with 0.1 N HCl. The emulsion was filtered through celite washed with methylene chloride. The layers were separated and the organic layer was washed with saturated NHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to Nt-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -N'-R-α- Methylbenzyl-2-amino-2-DL- (aryl) acetamide was prepared. In this step, if possible, the isomers are separated by HPLC chromatography, for example using a gradient of 20-25% ethyl acetate / hexanes. 10 molar equivalents of triethylsilane and 20 molar equivalents of trifluoroacetic acid were then added to the compound to remove the α-methylbenzyl protecting group from the peptide. The reaction was heated to 37 ° C. for 3 hours, then poured into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by trituration with ether or ether / hexanes. Various compounds useful in the present invention can be prepared using various other aldehydes, isocyanides and carboxylic acids in this process.

General method AN

EEQD Coupling Process II

1.1 equivalents of EEDQ were added to a 1: 1 mixture of the corresponding carboxylic acid and amino acid ester / amide in THF. The solvent is removed under reduced pressure or under a stream of nitrogen and the residue is 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 afford the product.

General method AO

Preparation of Primary Amides

A sealed pressure tube equipped with a self stirring bar was filled with methyl ester (1 equiv), sodium cyanide (0.1 equiv) and a 7 M solution of ammonia in methanol under a nitrogen atmosphere at room temperature. The tube was sealed, heated to 45 ° C. with stirring for 18 hours, and the resulting precipitate was separated by vacuum filtration. The solid was washed with methanol or recrystallized from ethyl acetate / methanol.

Example 1

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexanoate

After performing General Method A (without 1 N HCl wash), N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and norleucine methyl ester hydrocloroid (Sigma) Using to prepare the title compound as a solid (melting point = 142-143 ° C.). The reaction was monitored by tlc (Rf = 0.71 in 10% CH ₃ OH / CH ₂ Cl ₂ , 0.22 in EtOAc / hexanes) and the product was purified by silica plug chromatography using CH ₂ Cl ₂ as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.90 (d, J = 7.69 Hz, 1H), 6.80 (m, 3H), 6.70 (m, 1H), 4.62 (quintet, J = 7.2 Hz, 1H), 4.48 (m, 1H), 3.72 (s, 3H), 3.51 (s, 2H), 1.78 (m, 1H), 1.60 (m, 1H), 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, 162.00, 139.01, 138.88, 138.76, 112.93, 112.83, 112.70, 112.60, 103.63, 103.30, 102.97, 52.94, 49.38, 43.32, 43.32, 43. , 27.95, 22.75, 19.23, 14.35.

C ₁₈ H ₂₄ N ₂ O ₂ F ₄ (MW = 370.40); Mass Spectroscopy (MH ⁺ ) 371.

Example 2

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-histidine methyl ester

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-histidine methyl ester dihydrochloride (manufactured by Sigma) were used as solids. The title compound was prepared (melting point = 195-197 ° C.). The reaction was monitored by tlc (0.29 in Rf = 10% CH ₃ OH / CH ₂ Cl ₂ ).

NMR data are as follows:

¹ H-nmr (CD ₃ OD): δ = 7.60 (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 = 174.46, 172.59, 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, 55. 53.31, 51.00, 43.21, 43.19, 30.36, 18.44.

C ₁₈ H ₂₀ N ₂ O ₄ F ₄ (MW = 394.38); Mass Spectroscopy (MH ⁺ ) 395.

Example 3

Synthesis of N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out general method K, methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexanoate (Example 1) and benzylamine Using the product of Aldrich, the title compound was prepared as a solid (melting point = 200 ° C. or higher). The reaction was monitored by tlc (0.29 in Rf = 5% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by preparative plate chromatography.

NMR data are as follows:

¹ 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 (CDCl 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, 103.60, 103. , 103.56, 103.22, 55.43, 51.26, 44.53, 43.21, 33.38, 29.59, 23.91, 18.18, 14.78.

C ₂₄ H ₂₉ N ₂ O ₃ F ₃ (MW = 445.51); Mass Spectroscopy (MH ⁺ ) 446.

Example 4

Synthesis of N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out general method K, methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexanoate (Example 1) and N, Using N-dimethylmethylethylenediamine (Aldrich), the title compound was prepared as a solid (melting point = 182-187 ° C.). The reaction was monitored by tlc (0.5f in Rf = 15% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by preparative plate chromatography using 15% CH ₃ OH / CH ₂ Cl ₂ as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.21 (d, 1H), 6.80 (m, 5H), 4.64 (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 (CDCl 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.

C ₂₁ H ₃₂ F ₂ N ₄ O ₃ (MW = 426.51); Mass Spectroscopy (MH ⁺ ) 427.

Example 5

Synthesis of N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out general method K, methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexanoate (Example 1) and 2- The title compound was prepared as a solid (melting point = 200 ° C. or more) using methoxyethylamine (manufactured by Aldrich). The reaction was monitored by tlc (0.42 in Rf = 10% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by preparative plate chromatography using 12% CH ₃ OH / CH ₂ Cl ₂ as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.85 (bd, J = 8.79 Hz, 0.5H), 7,64 (bd, J = 7.81 Hz, 0.5H), 7.35 (m, 1H), 7.16 (bd, J = 7.27 Hz, 0.5H), 7.06 (bs, 0.5H), 6.83 (m, 2H), 6.68 (m, 1H), 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 (CDCl ₃ ): δ = 172.62, 172.58, 172.14, 172.04, 172.02, 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, 71.44 , 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.

C ₂₀ H ₂₉ F ₂ N ₃ O ₄ (MW = 413.47); Mass Spectroscopy (MH ⁺ ) 414.

Example 6

Synthesis of N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method K, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester (Example 94) and N, N-dimethylmethylethylenediamine Using the product of Aldrich, the title compound was prepared as a solid (melting point = 174-182 ° C.). The reaction was monitored by tlc (0.31 in Rf = 10% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by preparative plate chromatography using 10% CH ₃ OH / CH ₂ Cl ₂ as eluent.

NMR data are as follows:

¹ H-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).

¹³ C-nmr (CDCl ₃ ): δ = 176.03, 175.50, 174.20, 173.99, 176.50, 173.22, 166.63, 166.46, 163.36, 163.19, 141.65, 141.52, 141.39, 139.38, 139.00, 130.90, 130.01, 130.01, 130.01. , 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, 37.85 , 17.73.

C ₂₄ H ₃₀ F ₃ N ₄ O ₃ (MW = 460.53); Mass Spectroscopy (MH ⁺ ) 461.

Example 7

Synthesis of N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method K, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester (Example 94) and 4- (aminomethyl) pyridine ( The Aldrich product) was used to prepare the title compound as a solid (melting point = 200 ° C. or higher). The reaction was monitored by tlc (0.46 in Rf = 10% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by recrystallization from ethyl acetate.

NMR data are as follows:

¹ 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), 3.64 (s, 2H), 3.08 (m, 2H), 1.30 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 175.46, 174.04, 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, 113.75, 113.91 , 103.57, 103.23, 62.08, 57.01, 43.33, 43.12, 38.93, 21.41, 18.16, 15.02.

C ₂₆ H ₂₆ F ₂ N ₄ O ₃ (MW = 480.52); Mass Spectroscopy (MH ⁺ ) 481.

Example 8

Synthesis of N- (3-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method K, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester (Example 94) and 4- (aminomethyl) pyridine ( The Aldrich product) was used to prepare the title compound as a solid (melting point = 192-210 ° C.). The reaction was monitored by tlc (0.46 in Rf = 10% CH ₃ OH / CH ₂ Cl ₂ , trace isomer Rf = 0.50) and the product was purified by recrystallization from ethyl acetate.

NMR data are as follows:

¹ H-nmr (CD ₃ OD): δ = 8.42 (m, 2H), 7.61 (m, 1H), 7.29 (m, 6H), 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 (CDCl ₃ ): δ = 176.00, 175.35, 174.03, 173.81, 173.23, 166.61, 166.44, 163.55, 163.17, 149.93, 149.20, 141.48, 139.20, 138.72, 138.10, 138.03, 136.88, 130.88, 136.88, 136.88, 136.88. , 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, 38.88, 38.88, 38.88 , 18.18, 17.79.

C ₂₆ H ₂₆ F ₂ N ₄ O ₃ (MW = 480.52); Mass Spectroscopy (MH ⁺ ) 481.

Example 9

Synthesis of N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out General Method K, N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexanoate (Example 1) and 4- ( Using aminomethyl) pyridine (Aldrich), the title compound was prepared as a solid (melting point = 181-205 ° C.). The reaction was monitored by tlc (0.5f in Rf = 10% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by preparative plate chromatography using 10% CH ₃ OH / CH ₂ Cl ₂ as eluent.

NMR data are as follows:

¹ H-nmr (CD ₃ OD): δ = 8.48 (m, 0.8H), 8.42 (m, 1.2H), 7.37 (d, J = 6.10, 0 / 8H), 7.28 (d, J = 6.11, 1.2 H), 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 (CDCl ₃ ): 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, 124.85, 124.85, 124.85, 124.85 , 113.72, 113.62, 103.86, 103.57, 103.52, 103.18, 55.72, 55.64, 51.98, 43.38, 43.19, 43.82, 33.07, 32.57, 29.87, 29.67, 23.90, 23.82, 18.24, 17.86, 14.80.

C ₂₃ H ₂₈ F ₂ N ₄ O ₃ (MW = 446.50); Mass Spectroscopy (MH ⁺ )

Example 10

Synthesis of t-butyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexanoate

Step A-Form t-butyl ester

To the Z-norleucine-OH solution in CH ₂ Cl ₂ was added 1.5 equivalents of N, N'-diisopropyl-Ot-butylisourea (prepared by Synthesis (1979) p561) and the reaction was carried out for 17 hours. Heated to reflux. Then 1.5 equivalents of isourea were further added and refluxing was continued for 7 hours. The reaction was then cooled to room temperature, filtered through a Celite 545 bed and stripped to dryness to leave a colorless oil. The residue was dissolved in hexane, filtered to leave a solid, and the filtrate was washed with saturated aqueous NaHCO ₃ , saturated aqueous NaCl and dried over MgSO ₄ . The solution was concentrated under reduced pressure leaving a product.

Step A-Removal of CBZ

CBZ-protected amino esters were dissolved in ethanol in a hydrogenation flask and a catalytic amount of 10 Pd / C was added. The mixture was hydrogenated to 20 psi H ₂ on a Parr shaker for 30 minutes. The reaction was then filtered through a pad of Celite 545 and the solvent stripped on a rotary evaporator to yield the product norleucine t-butyl ester hydrochloride.

Step C

After carrying out general method D, the title compound is prepared as semi-solid using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and norleucine t-butyl ester hydrochloride. It was. The reaction was monitored by tlc (Rf = 0.41 in 50% EtOAc / hexanes) and the product was purified by preparative plate chromatography using 50% EtOAc / hexanes as eluent and then using 50% EtOAc / hexanes as eluent. Purification by flash chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.63 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 6.8 (m, 2H), 6.7 (m, 1H), 4.8 (m, 1H), 4.36 (q, J = 5.6 Hz, 1H), 3.52 (s, 2H), 1.18-1.1 (m, 15H), 0.8 (m, 3H).

¹³ C-nmr (CDCl 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, 82.3, 53.6, 49.3, 43.0 , 32.2, 28.4, 27.8, 22.7, 19.4, 14.7, 14.2.

C ₂₁ H ₃₀ F ₂ N ₂ O ₄ (MW = 412.48); Mass Spectroscopy (MH ⁺ ) 413.

Example 11

Synthesis of N- [N- (pent-4-enoyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method A, the N- (L-alanyl) -L-phenylalanine methyl ester [removed the BOC-group using general method Y, followed by N-BOC-L-alanine (sigma) using general method A Co.) and L-phenylalanine methyl ester (manufactured by Sigma Co., Ltd.) and pent-4-enoic acid (manufactured by Aldrich) to prepare the title compound as a solid (melting point = 125.5-126.5). ℃). The reaction was monitored by tlc (Rf = 0.32 in 50% EtOAc / hexanes; 0.51 in 10% CH ₃ OH / CH ₂ Cl ₂ ) and the product was flash chromatographed using 10% CH ₃ OH / CH ₂ Cl ₂ as eluent. Purification by chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.27 (bd, J = 7.82 Hz, 1H), 7.25-7.05 (m, 5H), 6.72 (bd, J = 7.57 Hz, 1H), 5.75 (m, 1H) , 4.96 (m, 2H), 4.59 (5 midline, J = 7.2 Hz, 1H), 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 (CDCl 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.

C ₁₈ H ₂₄ N ₂ O ₄ (MW = 332.40); Mass spectroscopy (MH ⁺ ) 355.0.

Example 12

Synthesis of N- [N- (deck-4-enoyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out General Method A, N- (L-alanyl) -L-phenylalanine methyl ester [N-BOC-L-alanine (Sigma Corporation) and L-phenylalanine methyl ester (Sigma Corporation) using General Method A Product), then prepared from the removal of the BOC-group using general method Y] and deck-4-enoic acid (produced from ethyl deck-4-enoate (product of ICM) using general method N). ], To give the title compound as a solid (melting point = 115.5-117.5 ° C). The reaction tlc (of Rf = 50% EtOAc / hexanes _{0.52; 10% CH 3 OH /} CH 2 Cl 2 of 0.60) to monitor, flash chromatography using the product of _{10% CH 3 OH / CH 2} Cl 2 as an eluent Purification by chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.54 (bd, J = 7.69 Hz, 1H), 7.22-7.04 (m, 5H), 6.91 (bd, J = 7.69 Hz, 1H), 5.37 (m, 2H) , 4.73 (q, J = 6.9 Hz, 1H), 4.63 (quintet, J = 7.2 Hz, 1H), 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 (CDCl ₃ ): δ = 173.26, 172.38, 136.65, 132.30, 129.74, 128.99, 128.66, 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 .

C ₂₃ H ₃₄ N ₂ O ₄ (MW = 402.54); Mass spectroscopy (MH ⁺ ) 425.0.

Example 13

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4- [3- (N, N'-dimethylamino) propoxy] phenylalanine methyl ester

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-4- [3- (N, N'-dimethylamino) propoxy] -Phenylalanine methyl ester [N-BOC-L-tyrosine methyl ester (made by Bachem) and 3-methylamino-1-propanol (made by Aldrich) substantially using the Matsunobu process as described in General Method AD After removal from BOC-groups using the general method Y], the title compound was prepared as a solid (melting point = 153-155 ° C). The reaction was monitored by tlc (0.36 in Rf = 10% MeOH / DCM / 1% TEA) and the product was purified by acid / base wash.

NMR data are as follows:

¹ H-nmr (CDCl 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), 3.9677-3.924 (t, 2H), 3.703 (s, 3H), 3.473 (s, 2H), 3.019-2.977 (t, 2H), 2.443-2.394 (t, 2H), 2.233 (s, 6H), 1.944-1.897 (t, 2H), 1.319-1.296 (d, 3H).

¹³ C-nmr (CDCl ₃ ): 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.

C ₂₆ H ₃₃ F ₂ N ₃ O ₅ (MW = 505); Mass Spectroscopy (MH ⁺ ) 506.

Example 14

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4-[(t-butyloxycarbonyl) methoxy] phenylalanine methyl ester

After performing General Method AE, t-butyl boroacetate (from Aldrich) and N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tyrosine methyl ester (Example 15) was used to prepare the title compound as a solid (melting point = 116-119 ° C.). The reaction was monitored by tlc (Rf = 0.54 in 50% EtOAc / hexanes) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ 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 + 5 midline, 2H), 4.382 (s, 2H), 3.571 (s, 3H), 3.406 (s, 2H), 3.006-2.684 (m, 2H), 1.417 (s, 9H), 1.243-1.221 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 173.14, 172.294, 170.273, 168.614, 168.546, 165.107, 161.861, 157.428, 139.493, 130.749, 129.385, 115.077, 112.803, 103.250, 828.270, 66.039, 54.361, 52.730, 49.172 , 37.288, 28.509, 19.018.

C ₂₇ H ₃₂ F ₂ N ₂ O ₇ (MW = 534); Mass Spectroscopy (MH ⁺ ) 535.

Example 15

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tyrosine methyl ester

After carrying out General Method A, the title compound was solid as a solid using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-tyrosine methyl ester (available from Bachem). Prepared (melting point = 85-88 ° C.). The reaction was monitored by tlc (Rf = 0.27 in 50% EtOAc / hexanes) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ H-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.

C ₂₁ H ₂₂ F ₂ N ₂ O ₅ (MW = 420); Mass Spectroscopy (MH ⁺ ) 421.

Example 16

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4- (carboxymethoxy) phenylalanine methyl ester

After carrying out general method N, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4- [t-butyloxycarbonyl) methoxy] phenylalanine methyl ester ( Example 14) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 10% MeOH / DCM + 0.49 in 1% AcOH) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.817 (s, 1H), 7.648-7.622 (d, 1H), 7.544-7.520 (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 (5 midline + 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, 65.3242.9 54. , 50.538, 49.384, 42.683, 37.168, 18.678.

C ₂₃ H ₂₄ F ₂ N ₂ O ₇ (MW = 478); Mass Spectroscopy (MH ⁺ ) 479.

Example 17

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4- (2-morpholinoethoxy) phenylalanine methyl ester

After conducting general method AD, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tyrosine methyl ester (Example 15) and 4- (2-hydroxyethyl Using the morpholine (Aldrich), the title compound was prepared as a solid (melting point = 138-141 ° C.). The reaction was monitored by tlc (Rf = 10% MeOH / DCM + 0.49 in 1% AcOH) and the product was triturated with diethyl ether and purified by silica gel column chromatography.

NMR data are as follows:

¹ 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 (5 midline, 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, 37.202, 37.202 , 19.028.

C ₂₇ H ₃₃ F ₂ N ₃ O ₅ (MW = 533); Mass Spectroscopy (MH ⁺ ) 534.

Example 18

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-6- (N, N'-dimethylamino) hexanoate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and Nε, Nε-dimethyl-L-lysine methyl ester hydrochloride (Bachem) were used. To give the title compound as a solid (melting point = 123-126 ° C.). The reaction was monitored by tlc (Rf = 10% MeOH / DCM + 0.49 in 1% AcOH) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.019-6.993 (d, 1H), 6.828-6.801 (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, 43.472, 43.403, 43.375, 31.870, 27.376, 23.378, 19.155.

C ₂₀ H ₂₉ F ₂ N ₃ O ₄ (MW = 413); Mass Spectroscopy (MH ⁺ ) 414.

Example 19

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (2-pyridyl) propionate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3- (2-pyridyl) propio The title compound was prepared as a solid using Nate Hydrochloride (manufactured by Cintectech) (melting point = 121-124 ° C). The reaction was monitored by tlc (0.39 in Rf = 10% MeOH / DCM) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ 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), 4.566-4.496 (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, 124.336, 124.328, 122.694, 113.032, 112.992, 112.661, 103.333, 53.032, 52.997, 52.349, 52.252, 49.427, 49.405, 43.405, 43. , 43.437, 38.486, 19.548, 19.232.

C ₂₀ H ₂₁ F ₂ N ₃ O ₄ (MW = 405); Mass Spectroscopy (MH ⁺ ) 406.

Example 20

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (3-pyridyl) propionate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3- (3-pyridyl) propio The title compound was prepared as a solid using Nate Hydrochloride (manufactured by Cintectech) (melting point = 101-103 ° C). The reaction was monitored by tlc (0.48 in Rf = 10% MeOH / DCM) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.492-8.396 (m, 1H), 8.359-8.322 (m, 1H), 7.505-7.452 (m, 1H), 7.248-7.170 (m, 1H), 6.976-6.908 (m, 1H), 6.855-6.668 (m, 3H), 6.352-6.288 (m, 1H), 4.866-4.798 (m, 1H), 4.784-4.429 (m, 1H), 3.750 (s, 3H), 3.513 (s, 2H), 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, 150.573, 148.907, 148.750, 137.523, 137.388, 132.460, 124.106, 124.034, 112.981, 112.7543, 103.228, 53.623, 53.4619.353 , 49.569, 43.137, 45.115, 43.086, 35.485, 18.664.

C ₂₀ H ₂₁ F ₂ N ₃ O ₄ (MW = 405); Mass Spectroscopy (MH ⁺ ) 406.

Example 21

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-proline methyl ester

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-proline methyl ester hydrochloride (available from Bachem) were used as viscous solids. The title compound was prepared. The reaction was monitored by tlc (0.57 in Rf = 10% MeOH / DCM) and the product was purified by acid / base wash.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.524-7.498 (d, 1H), 6.813-6.793 (d, 2H), 6.681-6.613 (m, 1H), 4.788-4.717 (m, 1H), 4.484-4.442 (m, 1H), 3.705-3.590 (m + s, 4H), 3.465 (s, 2H), 2.217-1.902 (m, 5H), 1.332-1.309 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 172.753, 172.152, 192.192, 170.275, 170.159, 165.189, 165.020, 161.897, 161.727, 139.167, 169.843, 165.185, 161.894, 112.953, 112.850, 112.727, 112.624, 103.331, 102.996, 102.996, 102.996 , 59.352, 52.735, 47.495, 47.267, 43.069, 29.472, 25.403, 18.243.

C ₁₇ H ₂₀ F ₂ N ₂ O ₄ (MW = 354); Mass Spectroscopy (MH ⁺ ) 355.

Example 22

Synthesis of Methyl 1- [N- (3,5-difluorophenylacetyl) -L-alanyl] piperidine-2-carboxylate

After carrying out General Method B, the title compound was prepared as an oil using N- (phenylacetyl) -L-alanine (Example B1) and methyl pipecolinate hydrochloride (from Aldrich). The reaction was monitored by tlc (Rf = 0.30 in 50% EtOAc / hexanes) and the product was purified by silica gel chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.2 (m, 5H), 6.85 (dd, J = 7.2, 15.2, 7.2 Hz, 1H), 5.21 (dd, J = 5.0, 11.0, 5.0 Hz, 1H), 4.89 (q, J = 7.1, 7.1 Hz, 1H), 3.7 (m, 1H), 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, 1.3, 4.4, 1.2 Hz, 3H).

¹³ C-nmr (CDCl 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.

C ₁₈ H ₂₄ N ₂ O ₄ (MW = 332); Mass Spectroscopy (MH ⁺ ) 333.

Example 23

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(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 acetamidomaronate (6.62 g, 30.5 mmol) and 3-picolin chloride hydrochloride (5.00 g, 30.5 mmol) were added. It was. The mixture was heated to reflux for 6 hours, then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was dissolved in saturated aqueous NaHCO ₃ (100 mL) and extracted with EtOAc (3 × 100 mL). The solvent was removed and the residue was purified by silica gel chromatography (95: 5 CH ₂ Cl ₂ / MeOH) to diethyl 2- (3-pyridylmethyl) -2-acetamidomalonate (2.84 g, 30%) Was prepared.

Diethyl 2- (3-pyridylmethyl) -2-acetamidoallonate is dissolved in 6 N HCl (30 mL), heated to reflux for 19 hours, then cooled to room temperature and the HCl solution Removal was by evaporation in vacuo. Intermediate amino acid and dihydrochloride salt were dissolved in MeOH (30 mL), saturated with HCl gas and stirred for 3.5 h. 3- (3-pyridyl) alanyl methyl ester dihydrochloride (2.235 g, 100%) was prepared by removing MeOH / HCl by evaporation in vacuo.

Step B-Preparation of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (4-pyridyl) propionate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3- (4-pyridyl) propio Nate hydrochloride (prepared by the method described above using 4-picolochloride hydrochloride) was used to prepare the title compound as a solid. The reaction was monitored by tlc (0.49 in Rf = 10% MeOH / DCM) and the product was purified by silica gel column chromatography.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.423-8.335 (dd, 2H), 7.832-7.754 (q, 1H), 7.342-7.246 (dd, 1H), 7.032-6.972 (dd, 2H), 6.764-6.667 (t, 2H), 6.659-6.599 (m, 1H), 4.837-4.768 (m, 1H), 4.590-4.515 (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, 17.0225, 165.201, 165.012, 161.904, 161.721, 150.183, 150.063, 146.115, 146.012, 139.100, 125.180, 125.122, 112.951, 112.915, 112.846, 103.492, 103.103 , 53.088, 49.318, 42.977, 37.593, 37.547, 19.297, 18.882.

C ₂₀ H ₂₁ F ₂ N ₃ O ₄ (MW = 405); Mass Spectroscopy (MH ⁺ ) 406.

Example 24

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3-methoxypropionate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 2-amino-3-methoxypropionate hydrochloride (from Bachem) Using to prepare the title compound as a solid (melting point = 165-168 ° C.). The reaction was monitored by tlc (0.48 in Rf = 10% MeOH / DCM) and the product was purified by acid / base wash.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.971-6.944 (d, 1H), 6.813-6.801 (m, 2H), 6.741-6.678 (m, 1H), 6.585-6.526 (m, 1H), 4.692-4.561 (Quintet + 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, 112.646, 103.347, 72.434, 72.405, 59.885, 59.837, 53.263, 53.240, 49.413, 49.329, 19.389, 18.9196.

C ₁₆ H ₂₀ F ₂ N ₂ O ₅ (MW = 358); Mass Spectroscopy (MH ⁺ ) 359.

Example 25

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3-morpholinopropionate

Step A-Methyl (2-N-CBZ-amino) -3-morpholino-propionate

To the solution of N-CBZ-dihydro-alanine methyl ester (from Sigma) in acetonitrile were added 2.0 equivalents of morpholine and 0.25 equivalents of anhydrous ferric chloride. The mixture was stirred for 16 h and monitored by TLC. Solvent was removed and the residue was extracted with ethyl ester and washed with 1N HCl. The aqueous layer was basified with 1 N potassium carbonate to pH = 9, extracted again with ethyl acetate, dried over sodium sulfate to dryness, and methyl (2-N-CBZ-amino) -3-mor as a clear tan oil. Polyno-propionate was prepared (see Perez at al. Tetrahedron 51 (3) 8355-62 (1955)).

Step B Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3-morpholinopropionate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 2-amino-3-morpholinopropionate hydrochloride [methyl (2 -N-CBZ-amino) -3-morpholino-propionate prepared by General Method O] to provide the title compound as a viscous oil. The reaction was monitored by tlc (0.44 in Rf = 10% MeOH / DCM) and the product was purified by acid / base wash.

NMR data are as follows:

¹ 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), 3.567-3.561 (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, 3 H).

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, 1121.533, 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.

C ₁₉ H ₂₆ N ₂ O ₃ F ₅ (MW = 413); Mass Spectroscopy (MH ⁺ ) 414.

Example 26

N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4- (2-morpholinoethoxy) phenylalanineamide synthesis

After carrying out general method K, 2-methoxyethylamine (from Aldrich) and N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-4- (2- Using the morpholinoethoxy) phenylalanine methyl ester (Example 17), the title compound was prepared as a solid (melting point = 165-168 ° C.). The reaction was monitored by tlc (Rf = 0.67 in 10% MeOH / DCM + 1% AcOH) and the product was purified by acid / base wash.

NMR data are as follows:

¹ 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), 6.482-6.630 (m, 5H), 4.980-4.905 (m, 1H), 4.794-4.772 (m, 1H), 4.026-3.992 (t, 2H), 3.713-3.642 (t, 4H), 3.594-3.453 (dd, 2H) , 3.404-3.267 (t, 2H), 3.179 (s, 3H), 2.930-2.914 (t, 2H), 2.763-2.914 (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, 58.232 , 54.636, 42.827, 42.800, 39.757, 39.642, 20.449, 20.135.

C ₂₉ H ₃₈ N ₂ O ₄ F ₆ (MW = 576); Mass Spectroscopy (MH ⁺ ) 577.

Example 27

Synthesis of N- (2-ethoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3-methoxypropionamide

After carrying out general method K, 2-methoxyethylamine (from Aldrich) and methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3- Using methoxypropionate (Example 24), the title compound was prepared as a solid (melting point = 181-184 ° C). The reaction was monitored by tlc (0.43 in Rf = 10% MeOH / DCM) and the product was purified by acid / base wash.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.728-6.706 (d, 2H), 6.648-6.586 (t, 1H), 4.244-4.213 (m, 1H), 4.092-4.068 (m, 1H), 3.553-3.503 (m, 2H), 3.393-3.347 (m, 2H), 3.210-3.073 (m + s, 7H), 3.053 (s, 3H), 1.183-1.138 (d, 3H).

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, 177.751.

C ₁₈ H ₂₅ N ₂ O ₃ F ₅ (MW = 401); Mass Spectroscopy (MH ⁺ ) 402.

Example 28

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] glycine methyl ester

After carrying out General Method A, the title compound was solid as a solid using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and glycine methyl ester hydrochloride (available from Bachem). Prepared (melting point = 158-160 ° C.). The reaction was monitored by tlc (0.61 in Rf = 10% MeOH / DCM) and the product was purified by silica gel chromatography.

NMR data are as follows:

¹ H-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 (5 midline, 1H), 4.00-3.99 (d, 2H), 3.746 (s, 3H), 3.528 (s, 1H), 1.389-1.366 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 172.926, 172.524, 113.056, 112.951, 111.723, 103.769, 103.437, 103.214, 103.105, 83.309, 53.009, 49.333, 43.292, 41.692, 18.810.

C ₁₄ H ₁₆ N ₂ O ₂ F ₄ (MW = 314); Mass Spectroscopy (MH ⁺ ) 315.

Example 29

Synthesis of N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3- (4-pyridyl) propionamide

After carrying out general method K, 2-methoxyethylamine and methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- ( Using the 4-pyridyl) propionate (Example 23), the title compound was prepared as a solid (melting point = 202-206 ° C). The reaction was monitored by tlc (0.72 in Rf = 10% MeOH / DCM) and the product was purified by acid / base wash.

NMR data are as follows:

¹ 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, 1H), 4.498-4.448 (m, 1H), 3.985-3.939 (q, 2H), 3.386 (s, 2H), 3.190-3.084 (m, 4H), 3.060 (s, 1H), 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, 1033.529, 72.081, 59.370, 55.201, 51.674, 42.949, 40.889, 38.350, 17.933

C ₂₂ H ₂₆ N ₂ O ₄ F ₄ (MW = 448); Mass Spectroscopy (MH ⁺ ) 449.

Example 30

Synthesis of N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3- (2-pyridyl) propionamide

After carrying out general method K, 2-methoxyethylamine and methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- ( Using 2-pyridyl) propionate (Example 19), the title compound was prepared as a solid (melting point = 183-187 ° C.). The reaction was monitored by tlc (0.39 in Rf = 10% MeOH / DCM) and the product was purified by recrystallization from MeOH / DCM.

NMR data are 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), 7.395-7.397 (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, 1H), 4.481-4.809 (q, 1H), 4.352-4.485 (5 midline , 1H), 3.537 (s, 2H), 3.342-3.118 (m, 6H), 3.248 (s, 3H), 1.394-1.371 (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, 771.376, 59.203, 53.143, 49.984, 43.355, 43.328, 39.685, 39.626, 19.295

C ₂₂ H ₂₆ N ₂ O ₄ F ₄ (MW = 448); Mass Spectroscopy (MH ⁺ ) 449.

Example 31

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (thiazol-4-yl) propionate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and glycine methyl (S) -2-amino-3- (thiazol-4-yl Propionate hydrochloride [prepared by the general method H using methanol and HCl on methyl (S) -2-amino-3- (thiazol-4-yl) propyl acid (from Cintectech)] To afford the title compound as a solid (melting point = 136-139 ° C.). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / DCM) and the product was purified by recrystallization from DCM.

NMR data are as follows:

¹ 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, 1H), 6.542-6,518 (d, 1H), 4.904-4.844 (q, 1H), 4.553-4.505 (5 midline, 1H), 3.678 (s, 3H), 3.515 (s, 2H), 3.402- 3.232 (dq, 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, 103.369, 53.113, 52.625, 49.476, 43.460, 43.435, 32.850, 19.422.

C ₁₈ H ₁₉ N ₂ O ₃ F ₄ (MW = 411); Mass Spectroscopy (MH ⁺ ) 412.

Example 32

Synthesis of methyl 2- [N- (3,5-difluorophenylacetyl) -L-alanyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate Using the product of Aldrich, the title compound was prepared as a solid (melting point = 37-40 ° C.). The reaction was monitored by tlc (0.64 in Rf = 10% MeOH / DCM).

NMR data are 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, 1H), 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 , 1.327-1.304 (d, 3 H).

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.

C ₂₂ H ₂₂ N ₂ O ₂ F ₄ (MW = 416); Mass Spectroscopy (MH ⁺ ) 416.

Example 33

Synthesis of N- (3-methoxybenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out general method B, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- (3,5-difluoro using general method E) Rophenylacetyl) -L-alanine (Example B2) and L-phenylalanine methyl ester (manufactured by Sigma), followed by hydrolysis using general method C] and 3-methoxybenzylamine ( TCI) was used to prepare the title compound as a solid (melting point = 117-130 ° C.). The reaction was monitored by tlc (Rf = 0.8% in 10% MeOH / methylene chloride) and the product was purified by recrystallization from MeOH.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.4 (t, 1H), 8.32 (d, 1H), 8.1 (d, 1H), 6.95-7.2 (m, 9H), 6.7 (m, 3H), 4.5 ( m, 1H), 4.2 (m, 3H), 3.7 (s, 3H), 3.5 (s, 2H), 3.3 (d, 2H0, 3.0 (m, 2H), 2.5 (s, 3H), 1.2 (m, 4H).

¹³ C-nmr (CDCl ₃ ): 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, 40.42, 40.42 , 40.03, 39.86, 39.70, 39.58, 39.46, 39.44, 39.31, 39.20, 39.03, 18.45.

C ₂₈ H ₂₉ N ₃ O ₄ F ₂ (MW = 509); Mass Spectroscopy (MH ⁺ ) 509.

Example 34

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (1-naphthyl) propionate

After carrying out general method B, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3- (1-naphthyl) propio Nate hydrochloride (available from Bachem) prepared the title compound as a solid (melting point = 103-130 ° C.). The reaction was monitored by tlc (Rf = 0.8 in 5% EtOAc / methylene chloride) and the product was purified by flash column chromatography using 6% EtOAc / methylene chloride as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.10 (d, 10H), 7.85 (d, 1H), 7.71 (d, 1H), 7.50 (m, 3H), 7.35 (t, 1H), 7.20 (d, 1H), 6.70 (m, 4H), 6.30 (d, 1H), 4.90 (m, 1H), 4.45 (m, 1H), 3.3-3.7 (m, 8H, 1.7 (bs, 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, 124.06, 123.96 , 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

C ₂₄ H ₂₄ N ₂ O ₄ F ₂ (MW = 442); Mass Spectroscopy (MH ⁺ ) 442.

Example 35

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (2-naphthyl) propionate

After carrying out General Method B, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3- (2-naphthyl) propio The title compound was prepared as a solid using Nate Hydrochloride (available from Bachem) (melting point = 166 ° C.). The reaction was monitored by tlc (Rf = 0.55 in 5% EtOAc / methylene chloride) and the product was purified by preparative tlc using 6% EtOAc / methylene chloride as eluent.

NMR data are 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 (quadruplex) , 1H), 6.7 (m, 4H), 7.05 (d, 1H), 7.20 (d, 1H), 7.45 (m, 2H), 7.55 (s, 1H), 7.80 (m, 3H).

¹³ C-nmr (CDCl 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, 77.62. , 53.05, 49.37, 43.12, 38.46, 18.81

C ₂₄ H ₂₄ N ₂ O ₄ F ₂ (MW = 442); Mass Spectroscopy (MH ⁺ ) 442.

Example 36

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (2-thienyl) propionate

After carrying out General Method B, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3- (2-thienyl) propio Nate hydrochloride (available from Bachem) prepared the title compound as a solid (melting point = 145-147 ° C.). The reaction was monitored by tlc (Rf = 0.9 in 100% EtOAc) and the product was purified by flash column chromatography using 6% EtOAc / methylene chloride as eluent.

NMR data are as follows:

¹ 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).

¹³ C-nmr (CDCl ₃ ): δ = 172.22, 171.56, 169.79, 137.47, 127.71, 125.55, 113.04, 112.71, 103.48, 78.03, 77.06, 77.18, 53.78, 53.25, 49.51, 43.41, 32.37, 18.97.

C ₁₉ H ₂₀ N ₂ O ₄ F ₂ (MW = 410); Mass Spectroscopy (MH ⁺ ) 410.

Example 37

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine benzyl ester

After performing General Method B, using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-phenylalanine benzyl ester hydrochloride (available from Bachem) as the title Compounds were prepared (melting point = 170-171 ° C.). The reaction was monitored by tlc (Rf = 0.7 in 5% MeOH / methylene chloride) and the product was purified by recrystallization from MeOH.

NMR data are as follows:

¹ H-nmr (MeOH): δ = 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.

C ₂₇ H ₂₆ N ₂ O ₄ F ₂ (MW = 480); Mass Spectroscopy (MH ⁺ ) 480.

Example 38

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine 3-bromopropyl ester

After carrying out general method B, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- (3,5-diflo using general method B] The title compound was prepared as a solid using orophenylacetyl) -L-alanine (Example B2) and L-phenylalanine (manufactured by Aldrich) and 3-bromo-1-propanol ( Melting point = 138-142 ° C.). The reaction was monitored by tlc (Rf = 0.75 in 5% EtOAc / hexanes) and the product was purified by recrystallization from MeOH.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.3-6.6 (m, 10H), 4.8 (m, 1H), 4.55 (m, 1H), 4.2 (t, J = 6 Hz, 2H), 3.51 (s, 2H), 3.3 (m, 2H), 3.05 (m, J = 6 and 8 Hz, 2H), 2.1 (m, 2H), 1.3-1.2 (m, J = 7 Hz, 3H).

¹³ C-nmr (CDCl ₃ ): 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, 02.127 , 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.

C ₂₃ H ₂₅ N ₂ O ₄ F ₂ (MW = 511.2); Mass Spectroscopy (MH ⁺ ) 512.

Example 39

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine 3-isopropyl ester

After carrying out general method B, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- (3,5-diflo using general method B] The title compound was prepared as a solid using orophenylacetyl) -L-alanine (Example B2) and L-phenylalanine (manufactured by Aldrich) and 3-iodine-1-propanol (melting point). = 138-142 ° C). The reaction was monitored by tlc (Rf = 0.45 in 5% EtOAc / hexanes) and the product was purified by preparative tlc with MeOH / methylene chloride.

NMR data are 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 (m, 1H), 4.5 (m, 1H), 4.2 (t, 2H), 3.5 (s, 2H), 3.1 (m, 4H), 2.1 (m, 2H), 1.7 (s, 1H), 1.35-1.25 (m, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 172.24, 171.72, 169.95, 136.12, 136.09, 129.77, 129.75, 129.28, 127.87, 113.06, 113.02, 112.73, 112.70, 103.80, 103.49, 103.47, 65.73, 65.70, 54.00, 54.00, 54.00 , 49.42, 49.33, 43.38, 38.54, 38.50, 32.57, 18.97, 18.91.

Example 40

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-leucine t-butyl ester

After carrying out General Method B, a solid was obtained using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-leucine t-butyl ester hydrochloride (available from Bachem). The title compound was prepared (melting point = 128 ° C.). The reaction was monitored by tlc (Rf = 0.85 in 5% MeOH / methylene chloride) and the product was purified by flash column chromatography using 5% MeOH / methylene chloride as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 6.9-6.5 (m, 5H), 4.6 (m, 1H), 4.4 (m, 1H), 3.5 (s, 1H), 1.7-1.4 (m, 15H ), 0.9 (t, 6H).

¹³ C-nmr (DMSO-d ₆ ): δ = 172.41, 172.20, 169.87, 165.30, 162.00, 161.83, 139.01, 138.89, 112.82, 112.69, 112.59, 103.62, 103.29, 102.95, 82.50, 78.03, 77.61, 77.18, 52.12, 52.12 , 49.39, 43.34, 41.86, 28.52, 25.42, 23.26, 22.46, 19.18.

C ₂₇ H ₃₀ N ₂ O ₄ F ₂ (MW = 412.48); Mass Spectroscopy (MH ⁺ ) 413.

Example 41

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (2-pyridyl) acetamide

After performing General Method L, ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (2-pyridyl) acetate (Example 65) The title compound was prepared as a solid using. The reaction was monitored by tlc (Rf = 0.1 in CHCl ₃ / MeOH) and the product was purified by recrystallization from EtOH.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.54 (m, 1H), 8.43 (d, 1H), 7.77 (m, 1H), 7.59 (bs, 1H), 7.46 (m, 1H), 7.33 ( m, 1H), 7.22 (m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 5.41 (m, 1H), 4.46 (m, 1H), 4.46 (m, 1H), 3.52 (s , 2H), 1.26 (m, 3H).

C ₁₈ H ₁₇ N ₃ O ₃ F ₂ (MW = 376.3); Mass Spectroscopy (MH ⁺ ) 377.

Example 42

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (3-pyridyl) acetamide

After carrying out General Method L, ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (3-pyridyl) acetate (Example 53) The title compound was prepared as a solid using. The reaction was monitored by tlc (Rf = 0.1 in CHCl ₃ / MeOH) and the product was purified by recrystallization from EtOH.

NMR data are as follows:

¹ 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).

C ₁₈ H ₁₇ N ₄ O ₃ F ₂ (MW = 376.3); Mass Spectroscopy (MH ⁺ ) 377.

Example 43

N- [N- (3,5- difluoro-phenyl-acetyl) -L- alanyl] -N _ε - Synthesis of (t- butoxycarbonyl) -L- lysine methyl ester

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N _ε- (t-butoxycarbonyl) -L-lysine methyl ester ( Vachem) was used to prepare the title compound as an oil. The reaction was monitored by tlc (Rf = 0.40 in 50% EtOH / hexanes) and the product was purified by flash chromatography using 50% EtOH / hexanes as eluent.

NMR data are as follows:

¹ 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), 1.20-1.30 (m, 2H).

¹³ C-nmr (DMSO-d ₆ ): 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, 43.25 , 29.98, 28.99, 22.95, 18.94.

C ₂₃ H ₃₃ N ₂ O ₃ F ₆ (MW = 485.53); Mass spectrometry (MH ⁺ ) N / A.

Example 44

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-4-phenylbutanoate

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-4-phenylbutanoate [General Method The title compound was prepared as a solid (melting point = 147-149.5 ° C.) using (+)-α-amino-4-phenylbutyric acid (manufactured by Bachem) using AG. The reaction was monitored by tlc (0.32 in Rf = 50% EtOH / hexanes) and the product was purified by flash chromatography using EtOH / hexanes as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.63 (bd, 2H), 7.04 (m, 5H), 6.56-6.82 (m, 3H), 4.80 (p, 1H), 4.48 (q, 1H), 3.65 ( s, 2H), 3.49 (s, 2H), 2.50-2.65 (m, 2H), 1.80-2.16 (m, 2H), 1.29 (d, 3H).

¹³ C-nmr (DMSO-d ₆ ): 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.

C ₂₂ H ₂₄ N ₂ O ₂ F ₄ (MW = 418.44); Mass Spectroscopy (MH ⁺ ) 419.

Example 45

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] glycine-2-phenylethyl ester

After carrying out general method X, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] glycine [N- [N- (3,5-difluoro using general method O) Rophenylacetyl) -L-alanyl] glycine benzyl ester (prepared from Example 73)] and 2-phenylethanol (from Aldrich) to prepare the title compound as a solid (melting point = 154.0-155.2 ° C.). ). The reaction was monitored by tlc (Rf = 0.15 in 15% EtOH / hexanes) and the product was purified by flash chromatography using 15% EtOH / hexanes as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.35-7.20 (m, 5H), 6.76 (bs, 1H), 6.72-6.67 (m, 3H), 6.54 (bd, 1H), 4.58 (p, 1H), 4.34 (t, 2H), 3.96 (d, 2H), 3.52 (s, 2H), 2.93 (t, 2H), 1.26 (d, 3H).

¹³ C-nmr (DMSO-d ₆ ): 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.

C ₂₁ H ₂₂ N ₂ O ₄ F ₂ (MW = 404.42); Mass Spectroscopy (MH ⁺ ) 405.

Example 46

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] glycine 3-phenylpropyl ester

After carrying out general method X, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] glycine [N- [N- (3,5-difluoro using general method O) Rophenylacetyl) -L-alanyl] glycine benzyl ester (prepared from Example 73)] and 3-phenyl-1-propanol (from Aldrich) to prepare the title compound as a solid (melting point = 137). ℃). The reaction was monitored by tlc (Rf = 0.15 in 50% EtOH / hexanes) and the product was purified by flash chromatography using 50% EtOH / hexanes as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.55-7.32 (m, 5H), 6.73 (d, 2H), 6.65 (m, 1H), 4.74 (p, 1H), 4.14 (t, 1H), 3.93 ( m, 2H), 3.49 (s, 2H), 2.66 (t, 2H), 1.94 (p, 2H), 1.41 (d, 3H).

¹³ C-nmr (DMSO-d ₆ ): 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, 103.1, 102.8, 65.4, 49.3, 42.9 , 41.8, 32.6, 30.6, 19.3.

C ₂₂ H ₂₄ N ₂ O ₄ F ₂ (MW = 418.44); Mass Spectroscopy (MH ⁺ ) 419.

Example 47

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (4-pyridyl) acetamide

After performing General Method L, ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (4-pyridyl) acetate (Example 66) Using to prepare the title compound as a solid. The reaction was monitored by tlc (0.1 in Rf = 9: 1 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 9: 1 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.53 (m, 2H), 8.88 (bs, 1H), 7.41 (m, 2H), 7.12 (m, 1H), 7.02 (m, 2H), 5.46 ( m, 1H), 4.46 (m, 1H), 3.55 and 3.52 (s, 2H), 1.21 (m, 3H).

C ₁₈ H ₁₈ N ₄ O ₃ F ₂ (MW = 376.3); Mass Spectroscopy (MH ⁺ ) 377.

Example 48

Synthesis of N- [N- (phenylacetyl) -L-alanyl] -L-threonine methyl ester

After carrying out General Method U, the title compound was prepared as a solid using N- (phenylacetyl) -L-alanine (Example B1) and L-threonine.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.54 (d, J = 8.9 Hz, 1H), 7.11-7.27 (m, 6H), 4.55 (quintet, J = 7.2 Hz, 1H), 4.43 (dd, J = 2.6, 8.8 Hz, 1H), 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).

¹³ C-nmr (DMSO-d ₆ ): δ = 172.8, 170.9, 134.5, 128.9, 128.4, 126.8, 67.5, 57.7, 52.1, 48.7, 42.8, 19.6, 18.3.

C ₁₆ H ₂₂ N ₂ O ₅ (MW = 322.36); Mass Spectroscopy (MH ⁺ ) 323

Example 49

Synthesis of N- [N- (phenylacetyl) -L-alanyl] -L-leucineamide

After carrying out General Method T, the title compound was prepared as a solid using N- (phenylacetyl) -L-alanine (Example B1) and L-leucineamide hydrochloride (Aldrich) (melting point = 207). -209 ° C). The product was extracted with EtOAc and purified and washed with aqueous potassium carbonate and aqueous hydrochloric acid.

NMR data are as follows:

¹ 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), 0.65-0.76 (m, 6H).

¹³ 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 N- [N- (phenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method U, the title compound was prepared as a solid using N- (phenylacetyl) -L-alanine (Example B1) and L-alanineamide hydrochloride (from Bachem) (melting point = 260). ℃ or more). The product was purified by washing with aqueous sodium hydroxide and aqueous acid.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.27 (d, J = 7.1 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 6.99 (s, 1H) , 4.25 (quintet, J = 7.1 Hz, 1H), 4.16 (quintet, J = 7.1 Hz, 1H), 3.46 (s, 2H), 1.19 (t, J = 6.3 Hz, 6H).

¹³ C-nmr (DMSO-d ₆ ): δ = 174.1, 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 N- [N- (phenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method T, the title compound was prepared as a solid using N- (phenylacetyl) -L-alanine (Example B1) and L-phenylalanineamide (from Bachem) (melting point = 224-225). ℃).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.24 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.13-7.34 (m, 10H), 7.11 (s, 1H), 4.40 (m, 1H), 4.21 (quintet, J = 7.1 Hz, 1H), 3.44 (d, 1H), 3.01 (dd, J = 4.9, 13.7 Hz, 1H) , 2.82 (dd, J = 9.0, 13.7 Hz, 1H), 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, 53.6, 48.5, 41.9, 37.3, 18.0.

Example 52

Synthesis of N- [N- (phenylacetyl) -L-alanyl] -L-valineamide

After carrying out General Method T, the title compound was prepared as a solid using N- (phenylacetyl) -L-alanine (Example B1) and L-valinamide hydrochloride (from Bachem) (melting point = 261). ℃ or more).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.31 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.38 (s, 1H), 7.15-7.30 (m, 5H), 7.05 (s, 1H), 4.34 (5 midline, J = 7.2 Hz, 1H), 4.08 (dd, J = 6.4, 15.3 Hz, 1H), 3.45 (s, 2H), 1.91 (m, 1H) , 1.19 (d, J = 7.0 Hz, 3H), 0.79 (d, 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-alanyl] -2-amino-2- (2-pyridyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 2-amino-2- (2-pyridyl) acetate hydrochloride [P. Kolar et al., Prepared by the method described in J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein, to prepare the title compound as a solid (melting point = 146-157 ° C.). . The reaction was monitored by tlc (0.1 in Rf = 98: 2 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 98: 2 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl 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, 2H), 5.55 (m, 1H), 4.69 (m, 1H), 4.17 (m, 2H0, 3.50 and 3.41 (s, 2H), 1.33 and 1.29 (d, 3H), 1.21 (m, 3 H), 1.18 (m, 3 H).

C ₂₀ H ₂₁ N ₃ O ₄ F ₂ (MW = 405.4); Mass Spectroscopy (MH ⁺ ) 405.

Example 54

Synthesis of N-methyl-N '-[N- (phenylacetyl) -L-alanyl] -L-leucineamide

After carrying out general method U, N- (phenylacetyl) -L-alanine (Example B1) and N-methyl-L-leucineamide [N-methyl-N'-BOC-L- using general method Y) Using Leucineamide (Example D5)], the title compound was prepared as a solid (melting point = 233-235 ° C). The product was purified by recrystallization from MeOH.

NMR data are as follows:

¹ H-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, 2H), 2.72 (s, 3H), 1.40-1.61 (m, 2H), 1.32 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.2 Hz, 3H), 0.86 ( d, J = 6.2 Hz, 3H).

Example 55

Synthesis of N, N-dimethyl-N '-[N- (phenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out general method U, N- (phenylacetyl) -L-alanine (Example B1) and N, N-dimethyl-L-phenylalanineamide [N-BOC-L-phenylalanine (bar using general method B) The title compound was prepared as a solid using Melch's product) and dimethylamine hydrochloride (Aldrich's product) and then the BOC group was removed using the general method Y (melting point = 152-155 ° C). ). The product was extracted and extracted with EtOAc, the aqueous sodium carbonate and aqueous hydrochloric acid washed and triturated with Et ₂ O.

NMR data are as follows:

¹ 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, 1H) , 5.08 (quartet, J = 8.0 Hz, 1H), 4.60 (quintet, J = 7.3 Hz, 1H), 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 (CDCl 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, 35.6, 18.8.

Example 56

Synthesis of N, N-dimethyl-N '-[N- (phenylacetyl) -L-alanyl] -L-leucineamide

After carrying out general method U, N- (phenylacetyl) -L-alanine (Example B1) and N, N-dimethyl-L-leucineamide [N-BOC-L-leucine (bar using general method B) The title compound was prepared as a solid (melting point = 130-132 ° C.) using Cem) and dimethylamine hydrochloride (manufactured by Aldrich), followed by removal of the BOC group using the general method Y]. ). The product was extracted and extracted with EtOAc, washed with aqueous sodium carbonate and aqueous hydrochloric acid and triturated with Et ₂ O.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.23-7.36 (m, 5H), 7.04 (d, 8.7 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 4.92 (m, 1H), 4.56 (5 midline, J = 7.2 Hz, 1H), 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 (CDCl ₃ ): δ = 172.0, 171.7, 170.4, 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-alanyl] -L-valinamide

After carrying out general method U, N- (phenylacetyl) -L-alanine (Example B1) and N, N-dimethyl-L-valinamide [N-BOC-L-valine (bar using general method B) The title compound was prepared as a solid using a Chem Corporation) and dimethylamine hydrochloride (Aldrich), which were then prepared by removing the BOC group using the general method Y (melting point = 147-149 ° C). ). The product was extracted and extracted with EtOAc, washed with aqueous sodium carbonate and aqueous hydrochloric acid and triturated with Et ₂ O.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.24-7.38 (m, 5H), 6.64 (d, 1H), 6.05 (d, 1H), 4.74 (dd, J = 5.9, 8.9 Hz, 1H), 4.50 ( 5-wire, J = 7.1 Hz, 1H), 3.59 (s, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 1.97 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H) , 0.91 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H).

¹³ C-nmr (DMSO-d ₆ ): 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.

C ₁₈ H ₂₇ N ₃ O ₃ (MW = 333.43): Mass spectrometry (MH ⁺ ) 334.

Example 58

Synthesis of N-methyl-N '-[N- (phenylacetyl) -L-alanyl] -L-phenylalanineamide

Following General Method U, N- (phenylacetyl) -L-alanine (Example B1) and N-methyl-L-phenylalanineamide [N-BOC-L-phenylalanine using General Method B (product of Bachem) ) And methylamine hydrochloride (manufactured by Aldrich), followed by removal of BOC groups using general method Y], to prepare the title compound as a solid. The product was purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.23 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 4.4 Hz, 1H), 7.10 -7.32 (m, 10H), 4.37 (5 midline, J = 5.4 Hz, 1H), 4.19 (5 midline, J = 7.1 Hz, 1H), 3.44 (s, 2H), 2.96 (dd, J = 5.5, 13.7 Hz, 1H), 2.78 (dd, J = 9.2, 13.7 Hz, 1H), 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, 126.31, 126.26, 53.9, 48.5, 41.9, 37.5, 25.5, 18.0.

Example 59

Synthesis of N-methyl-N '-[N- (phenylacetyl) -L-alanyl] -L-valinamide

After carrying out General Method U, N- (phenylacetyl) -L-alanine (Example B1) and N-methyl-L-valinamide [N-BOC-L-valine (general method B) ) And methylamine hydrochloride (manufactured by Aldrich), followed by removal of BOC groups using general method Y], to prepare the title compound as a solid. The product was purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.30 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 4.7 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.17-7.32 (m, 5H), 4.34 (quintet, J = 7.2 Hz, 1H), 4.04 (dd, J = 7.0, 8.9 Hz, 1H), 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, 123.3, 57.6, 48.2, 42.0, 30.6, 25.4, 19.2, 18.1, 17.9.

Example 60

Synthesis of N-methyl-N '-[N- (phenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out general method U, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N-methyl-L-norleucineamide [N-BOC using general method B] -L-Norleucine (made by Bachem) and methylamine hydrochloride (made by Aldrich), followed by removal of BOC group using general method Y], were used to prepare the title compound as a solid. . The product was purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): 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 (5-center, 7.0, 1H), 4.13 (quadrant, 5.5, 1H), 3.51 (s, 2H), 2.54 (d, 4.4, 3H), 1.58 (m, 1H) , 1.46 (m, 1 H), 1.19 (m, 7 H), 0.81 (t, 6.5, 3 H).

¹³ C-nmr (DMSO-d ₆ ): 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, 13.8.

C ₁₈ H ₂₅ N ₃ O ₃ F ₂ (MW = 369.42): mass spectrometry (MH ⁺ ) 384.

Example 61

Synthesis of N, N'-Dimethyl-N '-[N- (phenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out general method U, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N, N'-dimethyl-L-norleucineamide [general method B was used Coupling N-BOC-L-norleucine (available from Bachem) to methylamine hydrochloride (available from Aldrich), followed by removal of BOC group using general method Y]. Was prepared (melting point = 138-140 ° C.). The product was extracted with EtOAc and purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.11 (d, 8.1, 1H), 6.81 (m, 2H), 6.71 (m, 1H), 6.60 (d, 7.6, 1H), 4.89 (q, J =. 0, 1H), 4.57 (5 midline, J = 7.1, 1H), 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 (DMSO-d ₆ ): 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.

C ₁₉ H ₂₇ N ₃ O ₃ F ₂ (MW = 383.44): Mass spectrometry (MH ⁺ ) 384.

Example 62

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminohexaneamide

After carrying out general method U, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-norleucineamide [N-BOC-L-nor using general method Y] Using Leucineamide (Example D6)], the title compound was prepared as a solid (melting point = 215 ° C. or higher). The product was purified by precipitation from water.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.37 (d, 7.4, 1H), 7.83 (d, 8.0, 1H), 7.29 (s, 1H), 6.95-7.14 (m, 4H), 4.29 (5 midline, 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.

C ₂₀ H ₂₁ N ₃ O ₄ F ₂ (MW = 405.4): Mass spectrometry (MH ⁺ ) 405.

Example 63

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (3-methoxyphenyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 2-amino-2- (3-methoxyphenyl) acetate hydrochloride [JP Greenstein et al., "The Chemistry of Amino Acids", Vol. 1, p. Prepared by "Bucherer Modification of the Strecker procedure" as described in 698, Wiley, New York (1961), the title compound was prepared as a solid (melting point = 163-170 ° C.). The reaction was monitored by tlc (0.45 in Rf = 9: 1 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 93: 7 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.27 (m, 1H), 7.18 and 7.06 (m, 1H), 6.87-6.67 (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).

C ₂₁ H ₂₂ N ₂ O ₅ F ₂ (MW = 420.42); Mass Spectroscopy (MH ⁺ ) 421.

Example 64

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (4-methoxyphenyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 2-amino-2- (4-methoxyphenyl) acetate hydrochloride [JP Greenstein et al., "The Chemistry of Amino Acids", Vol. 1, p. Prepared by the “Bucherer Modification of the Strecker procedure” as described in 698, Wiley, New York (1961), the title compound was prepared as a solid (melting point = 170-174 ° C.). The reaction was monitored by tlc (0.1 in Rf = 98: 2 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 98: 2 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ 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), 1.39 and 1.29 (d, 3H).

C ₂₁ H ₂₂ N ₂ O ₅ F ₂ (MW = 420.42); Mass Spectroscopy (MH ⁺ ) 421.

Example 65

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (2-pyridyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 2-amino-2- (2-pyridyl) acetate hydrochloride [P. Kolar et al., Prepared by the methods described in J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein, to prepare the title compound as a solid (melting point = 123-125 ° C.). . The reaction was monitored by tlc (0.1 in Rf = 98: 2 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 95: 5 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.53 (m, 1H), 7.70 (m, 1H), 7.27 (m, 1H), 6.86 (m, 2H), 6.74 (m, 1H), 6.52 (m, 1H), 5.58 (m, 1H), 4.67 (m, 1H), 4.18 (m, 2H), 3.54 and 3.50 (s, 2H), 1.48 and 1.39 (d, 3H), 1.21 (m, 3H).

C ₂₀ H ₂₁ N ₃ O ₄ F ₂ (MW = 405.4); Mass Spectroscopy (MH ⁺ ) 405.

Example 66

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (4-pyridyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 2-amino-2- (4-pyridyl) acetate hydrochloride [P. Kolar et al., Prepared by the method described in J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein, to prepare the title compound as a solid (melting point = 175-181 ° C.). . The reaction was monitored by tlc (Rf = 98: 2 CHCl ₃ / MeOH) and the product was recrystallized from chlorobutane and purified by silica gel chromatography using 95: 5 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ 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).

C ₂₀ H ₂₁ N ₃ O ₄ F ₂ (MW = 405.4); Mass Spectroscopy (MH ⁺ ) 405.

Example 67

Synthesis of N- [N- (cyclohexylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method U, cyclohexyl acetic acid from Aldrich and N- (L-alanyl) -L-phenylalanine methyl ester [general method B using N-BOC-L-norleucine (from Bachem) ) And methylamine hydrochloride (manufactured by Aldrich), then prepared by removing the BOC group using the general method Y], to prepare the title compound as a solid (melting point = 156-158 ° C). The reaction was monitored by tlc (0.25 in 1: 1 EtOAc / hexanes).

NMR data are as follows:

¹ H-nmr (CDCl 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 Hz, 2H), 3.10 (m, 2H), 3.71 (s, 3H), 4.49 (m, 1H), 4.81 (m, 1H), 6.10 (d, J = 7.3 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1 H), 7.11 (m, 2 H), 7.26 (m, 3 H).

¹³ C-nmr (CDCl 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 ₂₁ H ₃₀ N ₂ O ₄ (MW = 374.48); Mass Spectroscopy (MH ⁺ ) 375.

Example 68

Synthesis of N- [N- (cyclopentylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method U, cyclopentylacetic acid (from Aldrich) and N- (L-alanyl) -L-phenylalanine methyl ester [general method B using N-BOC-L-norleucine (from Bachem) ) And methylamine hydrochloride (manufactured by Aldrich), then prepared by removing the BOC group using general method Y], to prepare the title compound as a solid (melting point = 137-139 ° C.). The reaction was monitored by tlc (0.23 in 1: 1 EtOAc / hexanes).

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 1.13 (m, 3H), 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.

C ₂₀ H ₂₈ N ₂ O ₄ (MW = 360.46); Mass Spectroscopy (MH ⁺ ) 361.

Example 69

Synthesis of N- [N- (cyclhex-1-enylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method U, N-BOC-L-norleucine using cyclic hex-1-enylacetyl (from Alpha) and N- (L-alanyl) -L-phenylalanine methyl ester [general method B is used. (Bakem Co., Ltd.) and methylamine hydrochloride (Aldrich Co., Ltd.) were then coupled to prepare the title compound as a solid by using the general method Y to remove the BOC group. 142 ° C.). The reaction was monitored by tlc (0.27 in 1: 1 EtOAc / hexanes).

NMR data are as follows:

¹ 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, 1H), 5.60 (s, 1H), 6.26 (d, J = 7.3 Hz, 1H) 6.67 (d, J = 7.7 Hz, 1H), 7.11 (m, 2H), 7.26 (m, 3H).

¹³ C-nmr (CDCl 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.

C ₁₈ H ₂₄ N ₂ O ₄ (MW = 332.40); Mass Spectroscopy (MH ⁺ ) 333.

Example 70

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -1-aminocyclopropane-1-carboxylate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 1-aminocyclopropane-1-carboxylate hygrochloride (manufactured by Sigma) ) Was used to prepare the title compound as a solid. The reaction was monitored by tlc (0.3 in 97: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 6.96 (bs, 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).

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-alanyl] -L-alaninamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and N, N, N'-trimethylethylenediamine Using the product of Aldrich, the title compound was prepared as a solid.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.37 (m, 2H), 8.19 (d, 1H), 8.08 (d, 2H), 7.10 (m, 1H), 6.99 (m, 2H), 4.67 ( m, 1H), 4.30 (m, 1H), 3.52 (s, 2H), 3.01 and 2.86 (s, 3H), 2.47 (t, 1H), 2.15 (s, 6H), 1.19 (m, 6H).

Optical rotation: [α] ₂₃ = -85。 (c 1, MeOH)

C ₁₉ H ₂₈ N ₄ O ₃ F ₂ (MW = 398.45); Mass Spectroscopy (MH ⁺ ) 398.

Example 72

Synthesis of N- [N- (cyclopropylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out General Method U, cyclopropylacetic acid (from Aldrich) and N- (L-alanyl) -L-phenylalanine methyl ester [N-BOC-L-alanine (from Bachem) using General Method B And methyl ester hydrochloride (manufactured by Bachem), followed by removal of BOC group using general method Y], were used to prepare the title compound as a solid (melting point = 128-131 ° C.). The reaction was monitored by tlc (0.14 in 1: 1 EtOAc / hexanes).

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.17 (m, 2H), 0.59 (m, 2H), 0.92 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H), 2.11 (m, 2H) , 3.05 (dd, J = 6.7, 13.9 Hz, 1H), 3.16 (dd, J = 5.5, 13.9 Hz, 1H), 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 (CDCl 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, 1772.3.

C ₁₈ H ₂₄ N ₂ O ₄ (MW = 332.40); Mass Spectroscopy (MH ⁺ ) 333.

Example 73

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] glycine benzyl ester

After carrying out General Method A, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and glycine benzyl ester [N-BOC-L-glycine (bar using general method X) From Chem) and benzyl alcohol (Aldrich), followed by removal of BOC groups using general method Y], to prepare the title compound as a solid (melting point = 167.5 ° C.). The reaction was monitored by tlc (0.35 in Rf = 2% MeOH / CH ₂ Cl ₂ ) and the product was purified by flash chromatography using 2% MeOH / CH ₂ Cl ₂ as eluent.

NMR data are as follows:

¹ 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

C ₂₀ H ₂₀ N ₂ O ₄ F ₂ (MW = 390.39); Mass Spectroscopy (MH ⁺ ) 391.

Example 74

Synthesis of N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine ethyl ester

After carrying out General Method C, N- (isovaleryl) -L-phenylglycine [prepared from Isovaleric acid (Aldrich) and L-phenylglycine methyl ester (Aldrich) using General Method C Then hydrolyzed using general method AF] to give the title compound as a solid (melting point = 198-201 ° C.). The reaction was monitored by tlc (Rf = 0.1 in EtOAc / hexanes) and the product was recrystallized from EtOAc and then purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 5 mixture of diastereomers): δ = 1.25 and 1.30 (2 d, 3H), 5,57 (d, 1H), 5.60 (d, 1H).

C ₁₈ H ₂₆ N ₂ O ₄ (MW = 334.42); Mass Spectroscopy (MH ⁺ ) 335.

Example 75

Synthesis of N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method Z, N- (3-nitrophenylacetyl) -L-alanine 2,4,5-trichlorophenyl ester (Example D8) and L-phenylalanine methyl ester hydrochloride (Sigma) To give the title compound as a solid (melting point = 154-158 ° C.). The reaction was monitored by tlc (Rf = 1: 1 EtOAc / hexanes) and the product was purified by silica gel chromatography using 50-100% EtOAc as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 3 mixture of diastereomers): δ = 1.00 and 1.18 (2 d, 3H), 2.96 (m, 2H).

C ₂₁ H ₂₃ N ₃ O ₆ (MW = 413.43); Mass Spectroscopy (MH ⁺ ) 413.

Example 76

Synthesis of N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-alanine methyl ester

After carrying out general method Z, N- (3-nitrophenylacetyl) -L-alanine 2,4,5-trichlorophenyl ester (Example D8) and L-alanine methyl ester hydrochloride (Sigma) were prepared. To give the title compound as a solid (melting point = 193-195 ° C.). The reaction was monitored by tlc (Rf = 0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 9H), 3.65 (s, 2H), 4.05 (m, 2H).

Optical rotation: [α] ₂₀ = -27.3。 @ 589 nm (c = 1.02, DMSO)

C ₁₆ H ₂₁ N ₃ O ₆ (MW = 351.360); Mass Spectroscopy (MH ⁺ ) 352.

Example 77

Synthesis of N- [N- (3-nitrophenylacetyl) -L-alanyl] glycine ethyl ester

After carrying out General Method C, N- (3-nitrophenylacetyl) -L-alanine [hydrolyzed using General Method AF, and then isovaleric acid (product of Aldrich) and L- using General Method C Phenylglycine methyl ester (manufactured by Aldrich) and glycine ethyl ester hydrochloride (manufactured by Sigma) were used to prepare the title compound as a solid (melting point = 164-165 ° C.). The product was purified by silica gel chromatography using EtOAc as eluent and then purified by recrystallization from EtOAc.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H), 4.08 (q, 2H), 4.32 (m, 1H).

Optical rotation: [α] ₂₀ = -25。 @ 589 nm (c = 1.00, DMSO)

C ₁₅ H ₁₉ N ₃ O ₆ (MW = 337.33); Mass Spectroscopy (MH ⁺ ) 338.

Example 78

Synthesis of N-hydroxy-N '-[N- (3-nitrophenylacetyl) -L-alanyl] -D, L-threonineamide

After carrying out General Method Z, N- (3-nitrophenylacetyl) -L-alanine 2,4,5-trichlorophenyl ester (Example D8) and D, L-threonineamide hydroxamate (manufactured by Sigma) ) Was prepared as a solid (melting point = 180-183 ° C). The reaction was monitored by tlc (Rf = 0.25 in 15% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH / CHCl ₃ as eluent and then recrystallized from EtOAc.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 1.22 (m, 3H), 0.98 (m, 3H).

C ₁₅ H ₂₀ N ₄ O ₇ (MW = 368.35); Mass Spectroscopy (MH ⁺ ) 368.

Example 79

Synthesis of N- [N- (isoisovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester

After carrying out General Method C, N- (isovaleryl) -L-phenylglycine [hydrolysed using General Method AF, and then isovaleric acid (Aldrich) and L-phenyl using General Method C Glycine methyl ester (manufactured by Aldrich)] and L-alanine iso-butyl ester hydrochloride [N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (general method C) After the preparation from Aldrich (using catalytic DMAP), the general procedure P is used to remove the BOC-groups], to prepare the title compound as a solid (melting point = 181-186 ° C.). The reaction was monitored by tlc (Rf = 0.4 in 1: 1 EtOAc / hexanes) and the product was purified by silica gel chromatography using 1: 1 EtOAc / hexanes as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.31 (d, 3H), 5.59 (d, 1H).

Optical rotation: [α] ₂₀ = +19.0。 @ 589 nm (c = 1.03, DMSO)

C ₂₀ H ₂₉ N ₂ O ₄ (MW = 362.47); Mass Spectroscopy (MH ⁺ ) 363.

Example 80

Synthesis of methyl N- [N- (3-nitrophenylacetyl) -L-alanyl] -2-amino-3- (3-hydroxyphenyl) propionate

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine [prepared from isovaleric acid (from Aldrich) and L-phenylglycine methyl ester (from Aldrich) using general method C Hydrolysis using general method AF] and methyl 2-amino-3- (3-hydroxyphenyl) propionate [2-amino-3- (3-pyridylphenyl using general method G). ) Was prepared from Propionate (Biosynth AG, Switzerland) and methanol to give the title compound as a solid (melting point = 155-159 ° C.). The reaction was monitored by tlc (Rf = 0.4 in EtOAc) and the product was purified by chromatography using EtOAc as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 1.02 and 1.20 (2 d, 3H), 3.62 (2 s, 3H).

C ₂₁ H ₂₃ N ₂ O ₇ (MW = 429.43); Mass Spectroscopy (MH ⁺ ) 429.

Example 81

Synthesis of N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-tyrosine ethyl acetate

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine [prepared from isovaleric acid (from Aldrich) and L-phenylglycine methyl ester (from Aldrich) using general method C Hydrolysis using general method AF] and L-tyrosine ethyl ester (Sigma) to prepare the title compound as a solid (melting point = 117-119 ° C.). The reaction was monitored by tlc (Rf = 0.5 in EtOAc) and the product was purified by chromatography using EtOAc as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.07 (t, 3H), 1.20 (d, 3H), 9.23 (s, 1H).

Optical rotation: [α] ₂₀ = -13.1。 @ 589 nm (c = 1.08, DMSO)

C ₂₂ H ₂₅ N ₃ O ₇ (MW = 443.46); Mass spectroscopy (MH ⁺ ) 443/444.

Example 82

Synthesis of N- [N- (isoisovaleryl) -L-isoleucineyl] -L-alanine iso-butyl ester

After carrying out General Method C, N- (isovaleryl) -L-isoleucine [prepared from Isovaleric acid (Aldrich) and L-isoleucine ester chloride (Aldrich) using General Method C, Hydrolysis using general method AF] and L-alanine iso-butyl ester hydrochloride [N-BOC-L-alanine (Sigma) using general method C) and 2-methyl-1-propanol (Aldrich) Product) (using catalytic DMAP) and then removing the BOC-group using the general method P] as a solid using the title compound (melting point = 142-146 ° C). The reaction was monitored by tlc (Rf = 0.4 in 1: 1 EtOAc / hexanes) and the product was purified by silica gel chromatography using 1: 1 EtOAc / hexanes as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 4 mixture of diastereomers): δ = 1.26 (d, 3H), 7.70 (doublet, 1H), 8.30, 8.40 (doublet, 1H).

C ₁₈ H ₃₄ N ₂ O ₄ (MW = 342.48); Mass Spectroscopy (MH ⁺ ) 343.

Example 83

Step A-Synthesis of N- [N- [N- (t-butoxycarbonyl) -L-valinyl] -D, L-phenylglycinyl] -L-alanine iso-butyl ester

After carrying out general method A, N- [N-BOC-L-valinyl) -D, L-phenylglycine [N-BOC-L-valine (available from Bachem) and L-phenyl using general method C Prepared from glycine methyl ester chloride (from Sigma) and then hydrolyzed using general method AF] and L-alanine iso-butyl ester hydrochloride [N-BOC-L-alanine (Sigma using general method C) Manufactured) and 2-methyl-1-propanol (manufactured by Aldrich), followed by removal of BOC-groups using general method P], to prepare the title compound as a solid. . The reaction was monitored by tlc (0.3 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 1.25 (d, 3H), 5.58 (d, 1H).

C ₂₅ H ₃₉ N ₃ O ₆ (MW = 477.61); Mass Spectroscopy (MH ⁺ ) 478.

Step B-Preparation of N- [N- (L-valinyl) -L-phenylglycine] -L-alanine iso-butyl ester hydrochloride

After carrying out General Method P, the product of Example 83-Step A above was used to prepare the title compound as a solid (melting point = 225-232 ° C.). The product was purified by trituration in Et ₂ O.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 2 mixture of diastereomers): δ = 1.26, 1.32 (doublet, 3H), 5.60, 5.65 (doublet, 1H).

C ₂₀ H ₃₂ N ₃ O ₄ (MW = 413.94); Mass Spectroscopy (MH ⁺ ) 378.

Step C-Synthesis of N- [N- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester

After carrying out General Method C, the title compound was prepared as a solid using isovaleric acid (Aldrich) and the product of Example 83-Step B above (melting point = 217-221 ° C.). The reaction was monitored by tlc (0.25 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 3 mixture of diastereomers): δ = 5.52, 5.28 (dual line, 1H).

C ₂₅ H ₃₉ N ₃ O ₅ (MW = 461.60); Mass Spectroscopy (MH ⁺ ) 462.

Example 84

Synthesis of N- [N- (isovaleryl) -L-phenylalanyl] -L-alanine iso-butyl ester

After carrying out General Method C, isovaleric acid (from Aldrich) and N- (L-phenylalanyl) -L-alanine iso-butyl ester hydrochloride [N-BOC-L-phenylalanine using General Method C] (From Sigma) and L-aniline iso-butyl ester hydrochloride (prepared as described in Example 83A above), followed by removal of BOC-groups using general method P]. The title compound was prepared (melting point = 135-138 ° C.). The reaction was monitored by tlc (0.3 in Rf = 3% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ 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] ₂₀ = +4.71。 @ 589 nm (c = 1.02, DMSO)

C ₂₁ H ₃₂ N ₂ O ₄ (MW = 376.50); Mass Spectroscopy (MH ⁺ ) 376.

Example 85

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine ethyl ester

After carrying out General Method C, the title compound was prepared as a solid using 3,5-difluorophenylacetic acid (manufactured by Oakwood) and L-alanine ethyl ester hydrochloride (manufactured by Sigma). (Melting point = 197-199 ° C.). The reaction was monitored by tlc (Rf = 0.6 in EtOAc) and the product was purified by silica gel chromatography using 3% MeOH / CHCl ₃ as eluent and then purified from the bicomponent product by recrystallization from EtOAc.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (m, 9H), 3.52 (s, 2H).

Optical rotation: [α] ₂₀ = -76.1。 @ 589 nm (c = 1.01, DMSO)

C ₂₀ H ₂₀ N ₄ O ₅ F ₂ (MW = 342.34); Mass Spectroscopy (MH ⁺ ) 343.

Example 86

Synthesis of ethyl 1- [N- (3-nitrophenylacetyl) -L-alanyl] indolin- (S) -2-carboxylate

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine [3-nitrophenylacetic acid (from Aldrich) and L-alanine ethyl ester hydrochloride (from Sigma) using general method C ), Followed by hydrolysis using general method AF] and (S) -indolin-2-carboxylate [(S) -indolin-2-carboxylic acid using general method H (Aldrich) Manufactured from ethanol), and the title compound as a solid. The reaction was monitored by tlc (0.4 in Rf = 2: 1 EtOAc / hexanes) and the product was purified by silica gel chromatography using 3 2: 1 EtOAc / hexanes as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 2 mixture of diastereomers): δ = 1.05, 1.17 (triple line, 3H), 1.29, 1.39 (double line, 3H).

C ₂₂ H ₂₃ N ₃ O ₆ (MW = 425.44); Mass Spectroscopy (MH ⁺ ) 425.

Example 87

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out general method C, the title compound as a solid, using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-alanineamide hydrochloride (Sigma) Was prepared (melting point = 285-288 ° C.). The reaction was monitored by tlc (0.35 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.21 (m, 6H), 7.95 (d, 1H), 8.37 (d, 1H).

Optical rotation: [α] ₂₀ = -26.84。 @ 589 nm (c = 1.01, DMSO)

C ₁₄ H ₁₇ N ₃ O ₃ F ₂ (MW = 313.31); Mass Spectroscopy (MH ⁺ ) 314.

Example 88

Synthesis of N-methoxy-N-methyl-N '-[N- (isovaleryl) -L-phenylglycidyl] -L-alanineamide

After carrying out general method C, N- [N- (isovaleryl) -L-phenylglycidyl] -L-alanine [N '-[N- (isovaleryl) -L using general method AF) -Phenylglycidyl] -L-alanine ethyl ester (prepared from Example 74)] and N, O-dimethylhydroxylamine (manufactured by Aldrich) to prepare the title compound as a solid. The reaction was monitored by tlc (Rf = 0.6 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 3.67, 3.73 (single line, 3H), 5.62 (m, 1H).

C ₁₈ H ₂₇ N ₃ O ₄ (MW = 349.43); Mass Spectroscopy (MH ⁺ ) 350.

Example 89

Synthesis of N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine [N- [N- (3, 5-Difluorophenylacetyl) -L-alanyl] -L-alanine ethyl ester (prepared from Example 85)] and iso-butylamine (from Aldrich) to prepare the title compound as a solid. (Melting point = 258-260 ° C.). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 0.80 (d, 6H), 1.20 (m, 6H).

Optical rotation: [α] ₂₀ = -30.4。 @ 589 nm (c = 1.01, DMSO)

C ₁₈ H ₂₅ N ₃ O ₃ F ₂ (MW = 369.41); Mass Spectroscopy (MH ⁺ ) 369.

Example 90

Synthesis of N, N-di-n-propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out general method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine [N- [N- (3,5-difluorophenylacetyl ) -L-alanyl] -L-alanine ethyl ester (prepared from Example 85)] and di-n-propylamine (from Aldrich) to prepare the title compound as a solid (melting point = 137-). 146 ° C.). The reaction was monitored by tlc (0.5 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data are 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 ₂₀ H ₂₉ N ₃ O ₃ F ₂ (MW = 397.46); Mass Spectroscopy (MH ⁺ ) 397.

Example 91

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-valinamide

After carrying out General Method C, a solid was obtained using N- [N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-valinamide hydrochloride (Sigma). The title compound was prepared. The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 4 mixture of diastereomers): δ = 1.22 (m, 3H), 1.97 (m, 1H).

C ₁₆ H ₂₁ N ₃ O ₃ F ₂ (MW = 341.36); Mass Spectroscopy (MH ⁺ ) 342.

Example 92

Synthesis of N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alaninamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (4-nitrophenyl) -L-alanineamide hydrochloride [Fluka ( Fluka)] was used to prepare the title compound as a solid (melting point = 242-244 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.24 (d, 3H), 1.33 (d, 3H).

Optical rotation: [α] ₂₀ = -5.18。 @ 589 nm (c = 1.00, DMSO)

C ₂₀ H ₂₀ N ₄ O ₅ F ₂ (MW = 434.40); Mass Spectroscopy (MH ⁺ ) 434.

Example 93

Synthesis of N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanyl] -L-phenylalanineamide

After carrying out General Method C, from N- (isovaleryl) -L-phenylglycine [isovaleric acid (from Aldrich) and L-phenylglycine methyl ester hydrochloride (from Aldrich) using General Method C Prepared and hydrolyzed according to general method AF] and N '-(L-alanyl) -L-phenylalanineamide hydrochloride [N-BOC-alanine (from Sigma) and L-phenylalanine according to general method C). After the amide (from Sigma) was prepared, the title compound was prepared as a solid using the general method P to remove the BOC group] (melting point = 272-276 ° C). The reaction was monitored by tlc (0.25 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 1.07, 1.17 (doublet, 3H), 5.40, 5.22 (doublet, 1H).

C ₂₅ H ₃₂ N ₄ O ₄ (MW = 452.55); Mass Spectroscopy (MH ⁺ ) 453.

Example 94

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide methyl ester

After carrying out general method C, 3,5-difluorophenylacetic acid (from Oakwood) and N- (L-alanyl) -L-phenylalanine methyl ester hydrochloride [according to general method C, N-BOC -The preparation of alanine (from Sigma) and L-phenylalanineamide (from Sigma) followed by removal of the BOC group using general method P], afforded the title compound as a solid (melting point = 173-175 ° C.). . The reaction was monitored by tlc (0.6 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 4% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H), 3.48 (s, 2H).

Optical rotation: [α] ₂₀ = -32.47。 @ 589 nm (c = 1.01, DMSO)

C ₂₁ H ₂₂ N ₂ O ₄ F ₂ (MW = 404.41); Mass Spectroscopy (MH ⁺ ) 404.

Example 95

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method C, 3,5-difluorophenylacetic acid (from Oakwood) and N '-(L-alanyl) -L-phenylalanineamide hydrochloride [N-BOC according to General Method C] -The preparation of alanine (from Sigma) and L-phenylalanineamide (from Sigma) followed by removal of the BOC group using general method P], afforded the title compound as a solid (melting point = 252-253 ° C). . The reaction was monitored by tlc (0.5 in Rf = 15% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.15 (d, 3H), 3.51 (s, 2H).

Optical rotation: [α] ₂₀ = -24.4。 @ 589 nm (c = 1.01, DMSO)

C ₂₀ H ₂₁ N ₃ O ₃ F ₂ (MW = 389.41); Mass Spectroscopy (MH ⁺ ) 389.

Example 96

Synthesis of N-iso-butyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide

After carrying out general method C, N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanine [N- [N- (isovaleryl) -L using general method AF) -Phenylglycinyl] -L-alanine ethyl ester (prepared from Example 74)] and iso-butylamine (from Aldrich) to prepare the title compound as a solid (melting point = 227-232 ° C). . The reaction was monitored by tlc (0.3 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 4 mixture of diastereomers): δ = 1.58 (m, 1H), 1.95 (m, 1H), 5.55 (d, 1H).

C ₂₀ H ₃₁ N ₃ O ₃ (MW = 361.48); Mass Spectroscopy (MH ⁺ ) 361.

Example 97

Synthesis of N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method C, N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- [N- (3, 5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester (prepared from Example 94)] and 2-methoxyethylamine (from Aldrich) to provide the title compound as a solid. Prepared (melting point = 206-208 ° C). The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.14 (d, 3H), 4.22 (m, 1H), 4.45 (m, 1H).

Optical rotation: [α] ₂₀ = -25。 @ 589 nm (c = 1.00, DMSO)

C ₂₃ H ₂₇ N ₃ O ₄ F ₂ (MW = 447.49); Mass Spectroscopy (MH ⁺ )

Example 98

Synthesis of N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out general method C, N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- [N- (3, 5-Difluorophenylacetyl) -L-alanyl] -L-alanine ethyl ester (prepared from Example 85)] and 4-nitrobenzylamine (manufactured by Aldrich) to prepare the title compound as a solid. (Melting point = 257-259 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH / acetonitrile. .

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.53 (s, 2H), 4.39 (d, 2H).

Optical rotation: [α] ₂₀ = -29.3。 @ 589 nm (c = 1.00, DMSO)

C ₂₁ H ₂₂ N ₄ O ₅ F ₂ (MW = 448.43); Mass Spectroscopy (MH ⁺ ) 448.

Example 99

Synthesis of N- (4-nitrophenyl) -N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanyl] -L-alanineamide

After carrying out general method C, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine [N- [N- (isovaleryl) -L- using general method AF) Phenylglycinyl] -L-alanine ethyl ester (prepared from Example 74) and N- (4-nitrophenyl) -L-alanineamide hydroxide (product of Fluka) as title solids Was prepared (melting point = 255-257 ° C.). The reaction was monitored by tlc (0.5 in Rf = 10% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 2 mixture of diastereomers): δ = 5.45, 5.55 (dual line, 1H), 10.20, 10.54 (single line, 1H).

C ₂₅ H ₃₁ N ₄ O ₆ (MW = 497.56); Mass Spectroscopy (MH ⁺ ) 497.

Example 100

Synthesis of N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (4-nitrophenyl) -L-phenylalanineamide hydrochloride [Lancaster Company] was used to prepare the title compound as a solid (melting point = 253-254 ° C.). The reaction was monitored by tlc (0.5 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 8% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H), 10.52 (s, 1H).

Optical rotation: [α] ₂₀ = +40.6。 @ 589 nm (c = 1.00, DMSO)

C ₂₆ H ₂₄ N ₄ O ₅ F ₂ (MW = 510.50; mass spectrometry (MH ⁺ ) 510.

Example 101

Synthesis of N-benzyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alaninamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine [N- [N- (3,5 using General Method AF) -Difluorophenylacetyl) -L-alanyl] -L-alanine ethyl ester (prepared from Example 85)] and N-4-benzylmethylamine (from Aldrich) to give the title compound as a solid. Prepared (melting point = 167-169 ° C.). The reaction was monitored by tlc (0.4 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 3 mixture of diastereomers): δ = 3.52 (single line, 2H), 2.92 (s, 2H).

Optical rotation: [α] ₂₀ = -55.8。 @ 589 nm (c = 1.01, DMSO)

C ₂₂ H ₂₅ N ₃ O ₃ F ₂ (MW = 417.45); Mass Spectroscopy (MH ⁺ ) 417.

Example 102

Synthesis of N- (3,5-difluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (3,5-difluorobenzyl) -L-alanineamide hydrochloride [Preparation from N-BOC-L-alanine (from Sigma) and 3,5-difluorobenzylamine (from Lancaster) using general method C, followed by removal of BOC-groups using general method P] Using to prepare the title compound as a solid (melting point = 267-269 ° C.). The reaction was monitored by tlc (0.25 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.21 (d, 3H), 1.24 (d, 3H).

Optical rotation: [α] ₂₀ = +26.9。 @ 589 nm (c = 1.01, DMSO)

C ₂₁ H ₂₁ N ₃ O ₃ F ₄ (MW = 439.41); Mass Spectroscopy (MH ⁺ ) 439.

Example 103

Synthesis of N- (3-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (3-nitrobenzyl) -L-alanineamide hydrochloride [General Method C Prepared from N-BOC-L-alanine (manufactured by Sigma) and 3-nitrobenzylamine hydrochloride (manufactured by Aldrich), followed by removal of BOC-groups using the general method P]. The title compound was prepared (melting point = 245-247 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.21 (d, 3H), 1.25 (d, 3H).

Optical rotation: [α] ₂₀ = -32.8。 @ 589 nm (c = 1.00, DMSO)

C ₂₁ H ₂₂ N ₄ O ₅ F ₂ (MW = 448.43); Mass Spectroscopy (MH ⁺ ) 449.

Example 104

Synthesis of N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out general method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N-benzyl-L-alanineamide hydrochloride [N- using general method C Prepared from BOC-L-alanine (manufactured by Sigma) and benzylamine (manufactured by Aldrich) and then removing the BOC-group using general method P], the title compound was prepared as a solid (melting point = 260-). 262 ° C.). The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (d, 3H), 1.24 (d, 3H).

Optical rotation: [α] ₂₀ = -29.3。 @ 589 nm (c = 1.03, DMSO)

C ₂₁ H ₂₃ N ₃ O ₃ F ₂ (MW = 403.43); Mass Spectroscopy (MH ⁺ ) 403.

Example 105

Synthesis of N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- [N- (3,5 using General Method AF) -Difluorophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester (prepared from Example 94)] and 4-nitrobenzylamine hydrochloride (from Aldrich) to give the title compound as a solid. Prepared (melting point = 248-250 ° C.). The reaction was monitored by tlc (0.4 in Rf = 12% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 12% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.15 (d, 3H), 7.35 (d, 1H), 8.12 (d, 2H).

Optical rotation: [α] ₂₀ = -27.6。 @ 589 nm (c = 1.01, DMSO)

C ₂₇ H ₂₆ N ₄ O ₅ F ₂ (MW = 524.52); Mass Spectroscopy (MH ⁺ ) 524.

Example 106

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tryptophan methyl ester

After carrying out general method C, using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-tryptophan methyl ester hydrochloride (Sigma) as the title Compounds were prepared (melting point = 191-193 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 5% MeOH / CHCl ₃ as eluent, followed by recrystallization from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-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)

C ₂₃ H ₂₃ N ₃ O ₄ F ₂ (MW = 443.45); Mass Spectroscopy (MH ⁺ ) 443.

Example 107

Synthesis of N- (4-methoxybenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out general method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (4-methoxybenzyl) -L-alanineamide hydrochloride [General method Prepared from N-BOC-L-alanine (manufactured by Sigma) and 4-methoxybenzylamine hydrochloride (manufactured by Aldrich) using C, followed by removal of BOC-groups using the general method P; The title compound was prepared as a solid (melting point = 234-236 ° C.). The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH / acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (d, 6H), 3.51 (s, 2H), 3.72 (s, 3H).

Optical rotation: [α] ₂₀ = +27.9。 @ 589 nm (c = 1.00, DMSO)

C ₂₂ H ₂₅ N ₃ O ₄ F ₂ (MW = 433.46); Mass Spectroscopy (MH ⁺ ) 433.

Example 108

Synthesis of N- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester

After carrying out general method C, phenylacetic acid (from Aldrich) and N- (L-phenylglycinyl) -L-alanine ethyl ester hydrochloride [N-BOC-L-phenylglinine using general method C] The title compound was prepared as a solid using [Advanced Chemtech Co., Ltd.] and L-alanine ethyl ester (Aldrich Co.), followed by removal of BOC-groups using general method P. Melting point = 208-210 ° C.). The reaction was monitored by tlc (0.4 in Rf = 5% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.55 (s, 2H), 5.55 (d, 1H).

Optical rotation: [α] ₂₀ = +44.8。 @ 589 nm (c = 1.02, DMSO)

C ₂₁ H ₂₄ N ₂ O ₄ (MW = 368.43); Mass Spectroscopy (MH ⁺ ) 369.

Example 109

Synthesis of N- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine] -L-phenylglycine methyl ester

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine [N- [N- (3,5 using General Method AF) -Difluorophenylacetyl) -L-alanyl] -L-phenylalanine methyl ester (prepared from Example 94)] and L-phenylglycine methyl ester hydrochloride (from Aldrich) as title solid Was prepared (melting point = 203-207 ° C.). The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from 1-chlorobutane.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.13 (d, 3H), 3.62 (s, 3H).

Optical rotation: [α] ₂₀ = +42.11。 @ 589 nm (c = 1.03, DMSO)

C ₂₉ H ₂₉ N ₃ O ₅ F ₂ (MW = 537.56); Mass Spectroscopy (MH ⁺ ) 537.

Example 110

Synthesis of N- [N- (cyclohexylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester

After carrying out general method C, cyclohexyl acetic acid (from Aldrich) and N- (L-phenylglycinyl) -L-alanine ethyl ester hydrochloride [N-BOC-L-phenylglycol using general method C] Prepared from Nin (Advanced Chemtech Co., Ltd.) and L-Alanine Ethyl Ester (from Aldrich), then the general procedure P was used to remove the BOC-group], to prepare the title compound as a solid (melting point = 196). -198 ° C). The reaction was monitored by tlc (0.3 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then purified by recrystallization from 1-chlorobutane.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 2.08 (d, 2H), 5.56 (d, 1H).

Optical rotation: [α] ₂₀ = +26.3。 @ 589 nm (c = 1.01, DMSO)

C ₂₁ H ₃₀ N ₂ O ₄ (MW = 374.48); Mass Spectroscopy (MH ⁺ ) 375.

Example 111

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycine methyl ester

After carrying out General Method C, a solid was obtained using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-phenylslysin methyl ester hydrochloride (Aldrich). The title compound was prepared (melting point = 198-200 ° C.). The reaction was monitored by tlc (0.4 in Rf = 4% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 4% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.26 (d, 3H), 3.64 (s, 3H).

Optical rotation: [α] ₂₀ = +69.9。 @ 589 nm (c = 1.01, DMSO)

C ₂₀ H ₂₀ N ₂ O ₄ F ₂ (MW = 390.39); Mass Spectroscopy (MH ⁺ ) 391.

Example 112

Synthesis of N- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycine methyl ester

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (L-alanyl) -L-phenylglycine methyl ester hydrochloride [general Prepared from N-BOC-L-alanine (manufactured by Sigma) and L-phenylglycine methyl ester hydrochloride (manufactured by Aldrich) using Method C, followed by removal of BOC-groups using the general method P. The title compound was prepared as a solid (melting point = 243-245 ° C.). The reaction was monitored by tlc (0.5 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH / acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.19 (d, 3H), 1.24 (d, 3H).

Optical rotation: [α] ₂₀ = +38.2。 @ 589 nm (c = 1.02, DMSO)

C ₂₃ H ₂₅ N ₃ O ₅ F ₂ (MW = 461.46); Mass Spectroscopy (MH ⁺ ) 461.

Example 113

Synthesis of N- (2-phenylethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alaninamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (2-phenylethyl) -L-alanineamide hydrochloride [General Method C Prepared from N-BOC-L-alanine (manufactured by Sigma) and phenylethylamine (manufactured by Aldrich), followed by removal of BOC-groups using general method P], to prepare the title compound as a solid. (Melting point = 241-243 ° C). The reaction was monitored by tlc (0.3 in Rf = 8% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 8% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.14 (d, 3H), 1.21 (d, 3H).

Optical rotation: [α] ₂₀ = -33.7。 @ 589 nm (c = 1.00, DMSO)

C ₂₂ H ₂₅ N ₃ O ₃ F ₂ (MW = 417.45); Mass Spectroscopy (MH ⁺ ) 417.

Example 114

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-tryptophanamide

After carrying out General Method C, 3,5-difluorophenylacetic acid (from Oakwood) and N '-(L-alanyl) -L-tryptophanamide hydrochloride [N-BOC using General Method C] Prepared from -L-alanine (from Sigma) and L-tryptophanamide hydrochloride (from Sigma), then the general procedure P was used to remove the BOC-groups, to prepare the title compound as a solid (melting point). = 199-202 ° C). The reaction was monitored by tlc (0.3 in Rf = 15% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H), 4.26 (m, 1H), 4.44 (m, 1H).

Optical rotation: [α] ₂₀ = -31.0。 @ 589 nm (c = 1.05, DMSO)

C ₂₂ H ₂₂ N ₄ O ₃ F ₂ (MW = 428.44); Mass Spectroscopy (MH ⁺ ) 428.

Example 115

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3-cyclohexylpropionate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl (S) -2-amino-3-cyclohexylpropionate [novabio From Novabiochem, the title compound was prepared as a solid (melting point = 116-119 ° C.). The reaction was monitored by tlc (0.4 in Rf = 4% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 4% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 3.62 (s, 3H).

Optical rotation: [α] ₂₀ = -21.2。 @ 589 nm (c = 1.01, DMSO)

C ₂₁ H ₂₇ N ₂ O ₄ F ₂ (MW = 410.46); Mass Spectroscopy (MH ⁺ ) 411.

Example 116

N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3- (4-nitrophenyl) Synthesis of Propionamide

After carrying out general method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N- (2-methoxyethyl)-(S) -2-amino- Prepared from 3- (4-nitrophenyl) propionamide hydrochloride [N-BOC-L-4-nitrophenylalanine (Advanced Chemtech) and 2-methoxyethylamine (Aldrich) using General Method C Then remove the BOC-group using the general method P], to prepare the title compound as a solid (melting point = 263-265 ° C.). The reaction was monitored by tlc (0.5 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH / acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.15 (d, 3H), 4.23 (m, 1H), 4.54 (m, 1H).

Optical rotation: [α] ₂₀ = -19.9。 @ 589 nm (c = 1.00, DMSO)

C ₂₃ H ₂₆ N ₄ O ₆ F ₂ (MW = 492/48); Mass Spectroscopy (MH ⁺ ) 493.

Example 117

Synthesis of N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-serine ethyl ester

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine [3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma SABE) using general method C ) And L-serine ethyl ester hydrochloride (Sigma) to prepare the title compound as a solid (melting point = 179-181 ° C.). The reaction was monitored by tlc (0.2 in Rf = 5% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H), 4.30 (m, 1H), 4.41 (m, 1H), 5.04 (t, 1H).

Optical rotation: [α] ₂₀ = -19.7。 @ 589 nm (c = 1.01, DMSO)

C ₁₆ H ₂₁ N ₃ O ₇ (MW = 367.36); Mass Spectroscopy (MH ⁺ ) 368.

Example 118

Synthesis of N-[(R) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alaninamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N-[(R) -α-methylbenzyl] -L-alanineamide hydro Chloride [Prepared from N-BOC-L-alanine (Sigma) and N-[(R) -α-methylbenzyl] amine (Aldrich) using General Method C, followed by General Method P Remove BOC-group], to prepare the title compound as a solid (melting point = 240-242 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.19 (t, 6H), 1.31 (d, 3H).

Optical rotation: [α] ₂₀ = +1.0。 @ 589 nm (c = 1.00, DMSO)

C ₂₂ H ₂₅ N ₃ O ₃ F ₂ (MW = 417.45); Mass Spectroscopy (MH ⁺ ) 417.

Example 119

Synthesis of N-[(S) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alaninamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N-[(S) -α-methylbenzyl] -L-alanineamide hydro Chloride [Prepared from N-BOC-L-alanine (Sigma) and N-[(S) -α-methylbenzyl] amine (Aldrich) using General Method C, then using General Method P Remove BOC-group], to prepare the title compound as a solid (melting point = 293-295 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H), 1.30 (d, 3H).

Optical rotation: [α] ₂₀ = -65.9。 @ 589 nm (c = 1.05, DMSO)

C ₂₂ H ₂₅ N ₃ O ₃ F ₂ (MW = 417.35); Mass Spectroscopy (MH ⁺ ) 417.

Example 120

Synthesis of N- (4-fluorobenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N- (4-fluorobenzyl] -L-alanineamide hydrochloride [general Prepared from N-BOC-L-alanine (manufactured by Sigma) and N- (4-fluorobenzyl] amine (manufactured by Aldrich) using Method C, followed by removal of BOC-groups using general method P]. The title compound was prepared as a solid (melting point = 257-259 ° C.) The reaction was monitored by tlc (0.4 in Rf = 0.4% 10% MeOH / CHCl ₃ ) and the product was used as eluent 10% MeOH / CHCl ₃ . After silica gel chromatography was purified by trituration using 1-chlorobutane.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H), 3.52 (s, 2H).

Optical rotation: [α] ₂₀ = -28.7。 @ 589 nm (c = 1.00, DMSO)

C ₂₁ H ₂₂ N ₃ O ₃ F ₃ (MW = 421.42); Mass Spectroscopy (MH ⁺ ) 421.

Example 121

Synthesis of N- (4-pyridylmethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N- (4-pyridylmethyl] -L-alanineamide hydrochloride [general Prepared from N-BOC-L-alanine (manufactured by Sigma) and 4- (aminomethyl) pyridine (manufactured by Aldrich) using Method C, followed by removal of BOC-groups using the general method P; The title compound was prepared as a solid (melting point = 244-247 ° C.) The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 10% MeOH / CHCl ₃ as eluent. After chromatography, it was purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-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)

C ₂₀ H ₂₂ N ₄ O ₃ F ₂ (MW = 404.42); Mass Spectroscopy (MH ⁺ ) 405.

Example 122

Synthesis of N- (4-trifluoromethylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N- (4-trifluoromethylbenzyl] -L-alanineamide hydrochloride [Preparation from N-BOC-L-alanine (Sigma) and 4- (trifluoromethyl) benzylamine (Aldrich) using general method C, followed by removal of BOC-groups using general method P ] Was prepared as a solid (melting point = 244-247 ° C.) The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product as 10% MeOH / CHCl ₃ as eluent. After silica gel chromatography using pulverized and purified using 1-chlorobutane.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.52 (s, 2H), 4.35 (d, 2H).

Optical rotation: [α] ₂₀ = -27.4。 @ 589 nm (c = 1.05, DMSO)

C ₂₂ H ₂₂ N ₃ O ₃ F ₅ (MW = 471.43); Mass Spectroscopy (MH ⁺ ) 471.

Example 123

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-phenylpropionate

After carrying out General Method C, 3,5-difluorophenylacetic acid (from Oakwood) and ethyl N- (L-alanyl) -2-amino-2-phenylpropionate hydrochloride [General Method C Prepared from N-BOC-L-alanine (manufactured by Sigma) and D, L-α-methylphenylglycine ethyl ester (Example D9), followed by removal of BOC-groups using general method P. The title compound was prepared as a solid (melting point = 128-130 ° C.). The reaction was monitored by tlc (0.2 in Rf = 3% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (a diastereomeric 1: 1 mixture): δ = 1.72, 1.77 (single line, 3H), 3.52 (s, 2H).

C ₂₂ H ₂₄ N ₂ O ₄ F ₂ (MW = 418.44); Mass Spectroscopy (MH ⁺ ) 418.

Example 124

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanine t-butyl ester

After carrying out General Method C, 3,5-difluorophenylacetic acid (from Oakwood) and ethyl N- (L-alanyl) -L-phenylalanine t-butyl ester hydrochloride [General Method C was used Prepared from N-BOC-L-alanine (manufactured by Sigma) and L-phenylalanine t-butyl ester hydrochloride (manufactured by Advanced Chemtech), followed by removal of BOC-groups using general method P] The title compound was prepared. The reaction was monitored by tlc (0.5 in Rf = 4% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 4% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.19 (d, 3H), 1.30 (s, 9H).

C ₂₄ H ₂₈ N ₂ O ₄ F ₂ (MW = 446.50); Mass Spectroscopy (MH ⁺ )

Example 125

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2-methylpropionate

After carrying out general method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 2-aminoisobutyrate [2-aminoisobutyric acid using general method H ( From Aldrich) to prepare the title compound as a solid. The reaction was monitored by tlc (Rf = 0.25 in 95: 5 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.32 (m, 3H), 7.13 (m, 1H), 7.00 (m, 2H), 4.31 (m, 1H), 3.53 (m, 5H), 7.08 ( m, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 1.19 (d, 3H).

Optical rotation: [α] ₂₀ = -25。 @ 589 nm (c = 1, MeOH)

C ₁₆ H ₂₀ N ₂ O ₄ F ₂ (MW = 342.34); Mass Spectroscopy (MH ⁺ ) 343.

Example 126

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2-cyclohexyl acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl-2-amino-2-cyclohexylacetate hydrochloride [general Method H are used] Using cyclohexylglycine (manufactured from Advanced Chemtech Co., Ltd.) to prepare the title compound as a solid (melting point = 146-150 ° C.). The reaction was monitored by tlc (0.3 in Rf = 3% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (diastereomeric 1: 1 mixture): δ = 1.60 (m, 6H), 3.50 (s, 2H).

C ₂₁ H ₂₈ N ₂ O ₄ F ₂ (MW = 410.46); Mass Spectroscopy (MH ⁺ ) 410.

Example 127

Synthesis of N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycinamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and N- (2-methoxyethyl) -L-phenylglycineamide hydrochloride [general Prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 2-methoxyethylamine (Aldrich) using Method C, followed by removal of BOC-groups using general method P]. To afford the title compound as a solid (melting point = 252-254 ° C.). The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 5.43 (d, 1H).

Optical rotation: [α] ₂₀ = +6.17。 @ 589 nm (c = 1.04, DMSO)

C ₂₂ H ₂₅ N ₃ O ₄ F ₂ (MW = 433.46); Mass Spectroscopy (MH ⁺ ) 434.

Example 128

Synthesis of N- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl-L-alanine ethyl ester

After carrying out General Method C, N- (isovaleryl) -2-amino-2-cyclohexylacetic acid {using General Method C isovaleric acid (Aldrich) and D, L-α-cyclohexylglycine Prepared from ethyl ester hydrochloride [produced from cyclohexylglycine (Advanced Chemtech Co., Ltd.) and ethanol using general method H] and then removing the BOC-group using general method P} as a solid Compounds were prepared (melting point = 220-224 ° C.). The reaction was monitored by tlc (0.2 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then purified by 1crystal from 1-chlorobutane / acetonitrile. It was.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 0.85 (d, 6H), 4.04 (s, 2H).

C ₁₈ H ₃₂ N ₂ O ₄ (MW = 340.46); Mass Spectroscopy (MH ⁺ ) 341.

Example 129

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

After carrying out General Method C, N- (3,5-difluorophenylacetyl) L-alanine (Example B2) and N-2- (N, N-dimethylamino) ethyl-L-phenylglycinamide di Hydrochloride [prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and N, N-dimethylethylenediamine (Aldrich) using General Method C, followed by BOC- using General Method P Remove the group] to prepare the title compound as a solid (melting point = 234-236 ° C.). The reaction was monitored by tlc (0.3 in Rf = 15% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH / CHCl ₃ as eluent and slurried in acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 5.41 (s, 2H).

Optical rotation: [α] ₂₀ = +5.7。 @ 589 nm (c = 1.01, DMSO)

C ₂₃ H ₂₈ N ₄ O ₃ F ₂ (MW = 446.50); Mass Spectroscopy (MH ⁺ )

Example 130

Synthesis of N- (2-pyridylmethyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycinamide

After carrying out general method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and methyl N- (2-pyridylmethyl] -L-phenylglycinamide hydrochloride [ Prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 2- (aminomethyl) pyridine (Aldrich) using General Method C, followed by removal of BOC-groups using General Method P] The title compound was prepared as a solid (melting point = 272-275 ° C.) The reaction was monitored by tlc (0.4 in Rf = 0.4% 10% MeOH / CHCl ₃ ) and the product was purified as 10% MeOH / CHCl ₃ as eluent. After silica gel chromatography used, it was purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.24 (d, 3H), 5.50 (d, 1H).

Optical rotation: [α] ₂₀ = +12.4。 @ 589 nm (c = 1.02, DMSO)

C ₂₅ H ₂₄ N ₄ O ₃ F ₂ (MW = 466.49); Mass Spectroscopy (MH ⁺ ) 467.

Example 131

Synthesis of N- (3-pyridylacetyl) -L-alanyl] -L-phenylalanine ethyl ester

After carrying out general method C, 3-pyridylacetic acid hydrochloride (from Aldrich) and N- (L-alanyl) -L-phenylalanine methyl ester hydrochloride [N-BOC-L- using general method C] Prepared from alanine (from Sigma) and L-phenylalanine methyl ester hydrochloride (from Sigma) and then removing the BOC-group using general method P], the title compound was prepared as a solid (melting point = 150). -152 ° C). The reaction was monitored by tlc (0.3 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.16 (d, 3H), 3.47 (s, 2H).

Optical rotation: [α] ₂₀ = -19.0。 @ 589 nm (c = 1.03, DMSO)

C ₂₀ H ₂₃ N ₃ O ₄ (MW = 369.42); Mass Spectroscopy (MH ⁺ ) 369.

Example 132

Synthesis of N- [N- (2-pyridylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method C, 2-pyridylacetic acid hydrochloride (from Aldrich) and N- (L-alanyl) -L-phenylalanine methyl ester hydrochloride [N-BOC-L- using general method C] Prepared from alanine (from Sigma) and L-phenylalanine methyl ester hydrochloride (from Sigma) and then removing the BOC-group using general method P], the title compound was prepared as a solid (melting point = 137). -139 ° C). The reaction was monitored by tlc (0.4 in Rf = 8% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 8% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H), 3.65 (s, 2H).

Optical rotation: [α] ₂₀ = -17.48。 @ 589 nm (c = 1.09, DMSO)

C ₂₀ H ₂₃ N ₃ O ₄ (MW = 369.42); Mass Spectroscopy (MH ⁺ ) 369.

Example 133

Synthesis of N- [N- (4-pyridylacetyl) -L-alanyl] -L-phenylalanine methyl ester

After carrying out general method C, 4-pyridylacetic acid hydrochloride (from Aldrich) and N- (L-alanyl) -L-phenylalanine methyl ester hydrochloride [N-BOC-L- using general method C] Prepared from alanine (from Sigma) and L-phenylalanine methyl ester hydrochloride (from Sigma) and then removing the BOC-group using general method P], the title compound was prepared as a solid (melting point = 152). -154 ° C). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H), 3.47 (s, 2H).

Optical rotation: [α] ₂₀ = -17。 @ 589 nm (c = 1.00, DMSO)

C ₂₀ H ₂₃ N ₃ O ₄ (MW = 369.42); Mass Spectroscopy (MH ⁺ ) 369.

Example 134

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (4-fluorophenyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 2-amino-2- (4-fluorophenyl) acetate hydrochloride [general Prepared from 4-fluorophenylglycine (manufactured by Fluka) and ethanol using Method H, the title compound was prepared as a solid (melting point = 169-183 ° C.). The reaction was monitored by tlc (0.3 in Rf = 4% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 4% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 3.49, 3.53 (single line, 2H), 5.40 (m, 1H).

C ₂₀ H ₂₃ N ₃ O ₄ (MW = 369.42); Mass Spectroscopy (MH ⁺ ) 369.

Example 135

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-2- (2-fluorophenyl) acetate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 2-amino-2- (2-fluorophenyl) acetate hydrochloride [general Prepared from 2-fluorophenylglycine (from Fluka) and ethanol using Method H, the title compound was prepared as a solid (melting point = 153-170 ° C.). The reaction was monitored by tlc (0.3 in Rf = 5% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 3.50, 3.54 (single line, 2H), 5.66 (m, 1H).

C ₂₁ H ₂₁ N ₂ O ₄ F ₃ (MW = 422.4); Mass Spectroscopy (MH ⁺ ) 422.

Example 136

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester

After carrying out General Method C, 3,5-difluorophenylacetic acid (from Oakwood) and ethyl N- (L-phenylglycinyl) -L-alanine ethyl ester hydrochloride [general Method C were used Prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanine ethyl ester hydrochloride (Aldrich), followed by removal of BOC-groups using general method P] as a solid. The title compound was prepared. The reaction was monitored by tlc (0.3 in Rf = 3% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 3% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / acetonitrile. Purified.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.50 (s, 2H), 5.53 (m, 1H).

C ₂₁ H ₂₂ N ₂ O ₄ F ₂ (MW = 404.42); Mass Spectroscopy (MH ⁺ ) 405.

Example 137

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -2-amino-3-phthalimidopropionate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 2-amino-3-phthalimidopropionate hydrochloride (Example D10) Using to prepare the title compound as a solid (melting point = 197-210 ° C.). The reaction was monitored by tlc (0.5 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 7.88 (m, 4H), 8.29 (t, 1H), 8.48, 8.55 (doublet, 1H).

C ₂₄ H ₂₃ N ₃ O ₆ F ₂ (MW = 487.46); Mass Spectroscopy (MH ⁺ ) 487.

Example 138

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycine neopentyl ester

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-phenylglycine neopentyl ester hydrochloride [N-BOC using General Method C] Prepared from -L-phenylglycine (Advanced Chemtech Co., Ltd.) and 2,2-dimethyl-1-propanol (Aldrich Co., Ltd.) (using catalytic DMAP), followed by removal of BOC-group using general method P] The title compound was prepared as a solid using (melting point = 133-136 ° C.). The reaction was monitored by tlc (0.7 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH / CHCl ₃ as eluent and then purified by recrystallization from 1-chlorobutane / hexane. It was.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.50 (s, 2H), 5.42 (d, 1H).

Optical rotation: [a] ₂₀ = + 45.9 ° @ 589 nm (c = 1.02, DMSO).

C ₂₄ H ₂₈ N ₂ O ₄ F ₂ (MW = 466.50); Mass Spectroscopy (MH ⁺ )

Example 139

Synthesis of N-t-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycinamide

After carrying out General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2), S-(+)-α-methylbenzylamine (Aldrich), benzylaldehyde (Aldrich) and t-butyl isocyanide (Aldrich) to prepare the title compound as a solid (melting point = 233-235 ° C.). The reaction was monitored by tlc (0.4 in Rf = 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 8% MeOH / CHCl ₃ as eluent and then recrystallized from 1-chlorobutane / hexane. It was.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ) (1: 1 mixture of diastereomers): δ = 3.52 (s, 2H), 5.40 (m, 1H).

C ₂₃ H ₂₇ N ₃ O ₃ F ₂ (MW = 431.49); Mass Spectroscopy (MH ⁺ ) 432.

Example 140

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycineamide t-butyl ester

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2), L-phenylglycine t-butyl ester hydrochloride (Advanced Chemtech Co., Ltd.) were used To give the title compound as a solid (melting point = 145-147 ° C.). The reaction was monitored by tlc (0.5 in Rf = 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 2.5% MeOH / CHCl ₃ as eluent and then purified by recrystallization from 1-chlorobutane / hexane. It was.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.26 (d, 3H), 5.20 (d, 1H).

Optical rotation: [a] ₂₀ = + 14.8 ° @ 589 nm (c = 1.01, MeOH).

C ₂₄ H ₂₆ N ₂ O ₄ F ₂ (MW = 432.47); Mass Spectroscopy (MH ⁺ ) 433.

Example 141

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylglycinamide

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2), L-phenylglycinamide hydrochloride [N-BOC-L using General Method C] The title compound was prepared as a solid using -phenylglycine (manufactured by Advanced Chemtech Co., Ltd.) and ammonia and then removing the BOC-group using the general method P] (melting point = 288-290 ° C). The reaction was monitored by tlc (0.4 in Rf = 15% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH / CHCl ₃ as eluent and then purified by recrystallization from EtOH.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 5.36 (d, 1H).

Optical rotation: [a] ₂₀ = -27.5 ° @ 589 nm (c = 1.03, DMSO).

C ₁₉ H ₁₉ N ₃ O ₃ F ₂ (MW = 375.38); Mass Spectroscopy (MH ⁺ ) 376.

Example 142

Synthesis of 4- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-valinyl] morpholine

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine (Example D11) and 4- (L-valinyl) morpholine [N-BOC-L- using general method C] Prepared from valine (from Aldrich) and morpholine (from Aldrich) followed by removal of BOC-groups using general method P], the title compound was prepared as a solid. The reaction was monitored by tlc (0.5 in Rf = 9: 1 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 98: 2 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.12 (d, 2H), 8.08 (dd, 1H), 7.59 (d, 1H, J = 7Hz), 7.42 (t, 1H), 7.32 (d, J = 8Hz , 1H), 7.03 (d, J = 8Hz, 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: [a] ₂₃ = -5 ° (c 5, MeOH).

Example 143

Synthesis of [N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-valine ethyl ester

After carrying out General Method C, the title compound was prepared as a solid using N- (3-nitrophenylacetyl) -L-alanine (Example D11) and L-valine ethyl ester (Aldrich). The reaction was monitored by tlc (0.2 in Rf = 97: 3 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 97: 3 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.13 (m, 2H), 7.62 (d, J = 7 Hz, 1H), 7.47 (t, 1H), 6.52 (m, 2H), 4.57 (m, 1H) , 4.4.6 (m, 1H), 4.19 (m, 2H), 3.65 (s, 2H), 2.13 (m, 1H), 1.38 (d, 3H), 1.22 (t, 3H), 0.82 (d, 3H ).

Optical rotation: [a] ₂₃ = -24.3 ° @ 589 nm (c 1, DMSO).

C ₁₈ H ₂₅ N ₃ O ₆ (MW = 379.32); Mass Spectroscopy (MH ⁺ ) 380.

Example 144

Synthesis of [N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-threonine methyl ester

After carrying out General Method C, the title compound was prepared as a solid using N- (3-nitrophenylacetyl) -L-alanine (Example D11) and L-threonine ethyl hydrochloride (Aldrich). The reaction was monitored by tlc (0.1 in Rf = 95: 5 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 95: 5 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.08 (d, 1H), 7.96 (d, 1H), 7.59 (d, 1H), 7.45 (d, 1H), 7.34 (t, 1H), 7.20 (d, 1H), 4.43 (m, 1H), 4.39 (dd, 1H), 4.13 (m, 1H), 3.59 (s, 3H), 3.51 (s, 2H), 1.20 (d, 3H), 1.03 (d, 3H) ).

Optical rotation: [a] ₂₃ = -20.8 ° (c 5, MeOH).

C ₁₆ H ₂₀ N ₂ O ₇ (MW = 367.3); Mass Spectroscopy (MH ⁺ ) 368.

Example 145

Synthesis of 4- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amino-3-t-butoxybutyryl] morpholine

After carrying out General Method C, N- (3-nitrophenylacetyl) -L-alanine (Example D11) and 4- (S) -2-amino-3-t-butoxybutyryl] morpholine [general Prepared from N-BOC-Ot-butyl-L-threonine (manufactured by Sigma) and morpholine (manufactured by Aldrich) using Method M, followed by removal of BOC-groups using the general method P; The title compound was prepared as a solid. The reaction was monitored by tlc (0.1 in Rf = 95: 5 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 96: 4 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.12 (m, 2H), 7.66 (d, 1H), 7.47 (t, 1H), 6.88 (d, 1H), 6.32 (d, 1H), 4.78 (m, 1H), 4.50 (m, 1H), 3.90-3.40 (m, 11H), 1.40 (d, 3H), 1.18 (s, 9H), 1.0 (d, 3H).

C ₂₃ H ₃₃ N ₃ O ₇ (MW = 478.5); Mass Spectroscopy (MH ⁺ ) 479.

Example 146

Synthesis of 4- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -isoleucineyl] morpholine

After carrying out General Method C, N- (3-nitrophenylacetyl) -L-alanine (Example D11) and 4- (L-isoleucineyl) morpholine [N-BOC- using General Method M] Prepared from L-isoleucine (Aldrich) and morpholine (Aldrich), then removing the BOC-group using general method P], to prepare the title compound as a solid (melting point = 156-160 ° C.). It was. The reaction was monitored by tlc (0.45 in Rf = 9: 1 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 98: 2 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.16 (d, 1H), 8.09 (s, 1H), 7.63 (d, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 6.89 (d, 1H), 4.78 (m, 1H), 4.62 (m, 1H), 3.6 (m, 10H), 1.65 (m, 1H), 1.4 (m, 1H), 1.29 (d, 3H), 1.03 (d, 3H) ), 0.90-0.76 (m, 6 H).

Optical rotation: [a] ₂₃ = -55 ° @ 589 nm (c 1, MeOH).

Example 147

Synthesis of [N- [N- (3,5-nitrophenylacetyl) -L-alanyl] -L-isoleucine methyl ester

After carrying out General Method C, the title compound was prepared as a solid using N- (3-nitrophenylacetyl) -L-alanine (Example D11) and L-isoleucine methyl ester hydrochloride (Aldrich). . The reaction was monitored by tlc (0.15 in Rf = 97: 3 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 97: 3 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ 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 (m, 1H), 1.32 (m, 4H), 1.07 (m, 1H), 0.81 (d, 6H).

Optical rotation: [a] ₂₃ = -7.3 ° (c 5, MeOH).

C ₁₈ H ₂₅ N ₂ O ₆ (MW = 379); Mass Spectroscopy (MH ⁺ ) 379.

Example 148

Synthesis of [N- [N- (3,5-nitrophenylacetyl) -L-alanyl] -L-isoleucine

After performing General Method AF, the title compound is prepared as a solid using [N- [N- (3,5-nitrophenylacetyl) -L-alanyl] -L-isoleucine methyl ester (Example 147). It was.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.41 (d, 1H), 8.15 (s, 1H), 8.07 (d, 1H), 7.91 (d, 1H), 7.68 (d, 1H), 7.53 ( t, 1H), 4.36 (m, 1H), 4.12 (m, 1H), 3.62 (s, 2H), 1.71 (m, 1H), 1.31 (m, 1H), 1.18 (d, 3H), 1.07 (m) , 1H), 0.79 (m, 6H).

Optical rotation: [a] ₂₃ = -42 ° (c 5, MeOH).

C ₁₇ H ₂₃ N ₂ O ₆ (MW = 365.3); Mass Spectroscopy (MH ⁺ ) 366.

Example 149

Synthesis of N- [N- [N- (3,5-nitrophenylacetyl) -L-alanyl] -L-threonyl] -L-valine ethyl ester

After carrying out general method C, N- [N- (3-nitrophenylacetyl) -L-alanyl] -L-threonine [N- [N- (3-nitrophenylacetyl)-using general method AF) L-threonine methyl ester (prepared from Example 144) and L-valine ethyl ester hydrochloride (Aldrich) to prepare the title compound as a solid. The reaction was monitored by tlc (0.1 in Rf = 96: 4 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 96: 4 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.12 (m, 1H), 8.04 (d, 1H), 7.48 (t, 1H), 7.05 (d, 1H), 6.98 (d, 1H), 6.48 (d, 1H), 4.60 (m, 1H), 4.47 (m, 3H), 4.22 (m, 2H), 3.65 (s, 2H), 2.19 (m, 1H), 1.38 (d, 3H), 1.28 (t, 3H) ), 1.09 (d, 3H), 0.87 (m, 6H).

Optical rotation: [a] ₂₃ = -85 ° (c 5, MeOH).

Example 150

Synthesis of Methyl N- [N- (3,5-nitrophenylacetyl) -L-alanyl]-(S) -2-aminopentanoate

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine (Example D11) and methyl (S) -aminopentanoate hydrochloride [(S) -2- using general method H) Aminopentanonoic acid (manufactured by Novabiochem Co., Ltd.) to prepare the title compound as a solid. The reaction was monitored by tlc (0.4 in Rf = 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.39 (m, 1H), 8.28 (m, 1H), 8.19 (m, 1H), 8.11 (m, 1H), 7.73 (d, 1H), 7.61 ( d, 1H), 4.36 (m, 1H), 4.22 (m, 1H), 3.64 (m, 5H), 1.62 (m, 2H), 1.26 (m, 2H), 1.22 (d, 3H), 0.86 (m , 3H).

Optical rotation: [a] ₂₃ = -29 ° (c 1, MeOH).

C ₁₇ H ₂₃ N ₃ O ₆ (MW = 365); Mass Spectroscopy (MH ⁺ ) 366.

Example 151

Synthesis of N- [N- (3,5-nitrophenylacetyl) -L-alanyl] -L-leucine methyl ester

After carrying out General Method C, the title compound was prepared as a solid using N- (3-nitrophenylacetyl) -L-alanine (Example D11) and L-leucine methyl ester hydrochloride (Aldrich). . The reaction was monitored by tlc (0.75 in Rf = 9: 1 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 97: 3 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.12 (m, 2H), 8.04 (m, 1H), 7.58 (m, 1H), 7.48-7.30 (m, 2H), 7.11 (d, 1H), 4.63 ( m, 1H), 4.48 (m, 1H), 3.68 (s, 2H), 3.64 (s, 3H), 1.63 (m, 1H), 1.31 (m, 2H), 0.85 (d, 3H0, 0.82 (m, 3H).

Optical rotation: [a] ₂₃ = -32 ° (c 1, MeOH).

C ₁₈ H ₂₅ N ₃ O ₆ (MW = 379); Mass Spectroscopy (MH ⁺ ) 380.

Example 152

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-leucine methyl ester

After carrying out general method C, using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and L-leucine methyl ester hydrochloride (Aldrich) as the title The compound was prepared. The reaction was monitored by tlc (0.5 in Rf = 9: 1 CHCl ₃ / MeOH).

NMR data are 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: [a] ₂₃ = -34 ° (c 1, MeOH).

C ₁₈ H ₂₄ N ₂ O ₄ F ₂ (MW = 370); Mass Spectroscopy (MH ⁺ ) 370.

Example 153

Synthesis of N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and 2-methoxyethylamine (from Aldrich) ) Was used to prepare the title compound as a solid. The reaction was monitored by tlc (Rf = 0.35 in 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-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: [a] ₂₃ = -50 ° (c 1, MeOH).

C ₁₇ H ₂₃ N ₃ O ₄ F ₂ (MW = 371); Mass Spectroscopy (MH ⁺ ) 371.

Example 154

Synthesis of N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and N, N-dimethylethylenediamine (Aldrich) Product) to give the title compound as a solid. The reaction was monitored by tlc (0.05 in Rf = 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ 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), 3.53 (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).

C ₁₈ H ₂₆ N ₄ O ₃ F ₂ (MW = 384); Mass Spectroscopy (MH ⁺ ) 384.

Example 155

Synthesis of N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and cyclohexylamine (manufactured by Aldrich) The title compound was prepared as a solid (melting point = 239-244 ° C.). The reaction was monitored by tlc (Rf = 0.25 in 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.39 (m, 1H), 7.94 (m, 1H), 7.56 (m, 1H), 7.08 (m, 1H), 6.97 (m, 2H), 4.20 ( m, 2H), 3.32 (s, 2H), 3.27 (m, 1H), 1.64 (m, 4H), 1.54 (m, 2H), 1.54 (m, 2H), 1.20 (m, 10H).

Optical rotation: [a] ₂₃ = -58 ° (c 1, MeOH).

C ₂₀ H ₂₇ N ₃ O ₃ F ₂ (MW = 395); Mass Spectroscopy (MH ⁺ ) 395.

Example 156

Synthesis of N-Neopentyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, using N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and neopentylamine (manufactured by Aldrich) To give the title compound as a solid. The reaction was monitored by tlc (Rf = 0.25 in 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.37 (d, 1H), 8.01 (m, 1H), 7.67 (m, 1H), 7.11 (m, 1H), 6.98 (m, 2H), 4.28 ( m, 2H), 3.51 (s, 2H), 2.88 (m, 2H), 1.23 (d, 3H), 0.80 (m, 9H).

Optical rotation: [a] ₂₃ = -54 ° (c 1, MeOH).

C ₁₉ H ₂₇ N ₃ O ₃ F ₂ (MW = 383); Mass Spectroscopy (MH ⁺ ) 383.

Example 157

Synthesis of N-tetrahydrofururil-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and tetrahydrofurfurylamine (from Aldrich) Using to prepare the title compound as a solid. The reaction was monitored by tlc (Rf = 0.20 in 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.36 (d, 1H), 8.01 (m, 1H), 7.81 (m, 1H), 7.11 (m, 1H), 6.99 (m, 2H), 4.25 ( m, 2H), 3.77 (m, 2H), 3.58 (m, 1H), 3.51 (s, 2H), 3.21 (m, 1H), 1.78 (m, 4H), 1.46 (m, 1H), 1.19 (m , 6H).

Optical rotation: [a] ₂₃ = -70 ° (c 1, MeOH).

C ₁₉ H ₂₅ N ₃ O ₄ F ₂ (MW = 397); Mass Spectroscopy (MH ⁺ ) 398.

Example 158

Synthesis of N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and 2- (aminomethyl) pyridine (Aldrich) Product) to give the title compound as a solid. The reaction was monitored by tlc (Rf = 0.1 in CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.49 (m, 1H), 8.41 (m, 2H), 8.14 (d, 1H), 7.74 (m, 1H), 7.28 (m, 2H), 7.09 ( m, 1H), 6.98 (m, 2H), 4.33 (m, 4H), 3.52 (s, 2H), 1.24 (m, 6H).

Optical rotation: [a] ₂₃ = -68 ° (c 5, MeOH).

C ₂₀ H ₂₂ N ₄ O ₃ F ₂ (MW = 404); Mass Spectroscopy (MH ⁺ ) 405.

Example 159

Synthesis of 3- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanyl] thiazolidine

After carrying out general method C, using N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and thiazolidine (manufactured by Aldrich) To give the title compound as a solid. The reaction was monitored by tlc (Rf = 0.25 in 9: 1 CHCl ₃ / MeOH).

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.34 (m, 2H), 8.22 (m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 4.68-4.23 (m, 4H), 3.81-3.6 (m, 2H), 3.52 (s, 2H), 3.01 (m, 2H), 1.19 (m, 6H).

Optical rotation: [a] ₂₃ = -67 ° (c 1, MeOH).

C ₁₇ H ₂₁ N ₃ O ₃ F ₂ (MW = 385); Mass Spectroscopy (MH ⁺ ) 385.

Example 160

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminobutanoate

After carrying out general method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B7) and methyl (S) -2-aminobutanoate hydrochloride [general method H are used] (S)-(+)-2-aminobutyric acid (manufactured by Aldrich)] to give the title compound as a solid (melting point = 103-106 ° C).

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.83 (m, 2H), 6.72 (m, 1H), 6.49 (d, 1H), 4.55 (m, 1H), 4.48 (m, 1H), 3.72 (s, 3H), 3.49 (s, 2H), 1.85 (m, 1H), 1.69 (m, 1H), 1.39 (d, 3H), 0.86 (t, 3H).

Optical rotation: [a] ₂₃ = -70 ° (c 1, MeOH).

C ₁₆ H ₂₀ N ₂ O ₄ F ₂ (MW = 342.35); Mass Spectroscopy (MH ⁺ ) 342.

Example 161

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminopentanoate

After carrying out General Method C, N- (3,5-difluorophenylacetyl) -L-alanine (Example B7) and methyl (S) -2-aminopentanoate hydrochloride [general Method H were used (S) -2-aminopentanoic acid (manufactured by Novabiochem Co., Ltd.), to prepare the title compound as a solid (melting point = 154-155 ° C).

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.80 (m, 2H), 6.69 (m, 1H), 6.45 (d, 1H), 6.28 (m, 1H), 4.52 (m, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 1.77 (m, 1H), 1.58 (m, 1H), 1.35 (d, 3H), 1.27 (m, 2H), 0.87 (t, 3H).

Optical rotation: [a] ₂₃ = -69 ° (c 1, MeOH).

Example 162

Synthesis of Methyl N- [N- (3-nitrophenylacetyl) -L-alanyl]-(S) -2-aminobutanoate

After carrying out general method C, N- (3-nitrophenylacetyl) -L-alanine (Example D11) and methyl (S) -2-aminobutanoate hydrochloride [(S) using general method H -(+)-2-aminobutyric acid (manufactured by Aldrich)] was used to prepare the title compound as a solid (melting point 154-157 ° C).

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.13 (m, 1H), 8.04 (m, 1H), 7.57 (m, 1H), 7.38 (m, 1H), 4.72 (m, 1H), 4.39 (m, 1H), 3.69 (s, 3H), 3.41 (s, 2H), 1.73 (m, 1H), 1.61 (m, 1H), 1.34 (d, 3H), 0.79 (t, 3H).

Optical rotation: [a] ₂₃ = -75 ° (c 1, MeOH).

Example 163

Synthesis of N- (R) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and (R)-(-)-sec- The title compound was prepared as a solid using butylamine (from Aldrich). The reaction was monitored by tlc (Rf = 0.15 in 95: 5 CHCl ₃ / MeOH) and the product was purified by chromatography using 95: 5 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.39 (m, 1H), 8.08 (m, 1H), 7.49 (m, 1H), 7.09 (m, 1H), 7.01 (m, 2H), 4.20 ( m, 4H), 3.61 (m, 1H), 3.52 (s, 1H), 1.34 (m, 2H), 1.21 (m, 6H), 0.97 (d, 3H), 0.79 (m, 3H).

Optical rotation: [a] ₂₃ = -50 ° (c 1, MeOH).

C ₁₈ H ₂₅ N ₃ O ₃ F ₂ (MW = 369.41); Mass Spectroscopy (MH ⁺ ) 370.

Example 164

Synthesis of 1- [N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanyl] pyrrolidone

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and pyrrolidone (from Aldice) Using to prepare the title compound as a solid. The reaction was monitored by tlc (0.15 in Rf = 95: 5 CHCl ₃ / MeOH) and the product was purified by chromatography using CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.31 (m, 1H), 8.08 (m, 1H), 7.09 (m, 1H), 6.99 (m, 2H), 4.48 (m, 1H), 4.29 ( m, 1H), 3.51 (s, 2H), 3.44-3.22 (m, 4H), 1.80 (m, 4H), 1.27 (m, 6H).

C ₁₈ H ₂₃ N ₃ O ₃ F ₂ (MW = 367.40); Mass Spectroscopy (MH ⁺ ) 367.

Example 165

Synthesis of N- (S) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and (S)-(+)-sec- The title compound was prepared as a solid using butylamine (from Aldrich). The reaction was monitored by tlc (Rf = 0.25 in 9: 1 CHCl ₃ / MeOH) and the product was purified by chromatography using CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.38 (m, 1H), 7.92 (m, 1H), 7.30 (m, 1H), 7.18 (m, 1H), 6.99 (m, 2H), 4.20 (m, 4H), 3.62 (m, 1H), 3.52 (s, 2H), 1.34 (m, 2H), 1.20 (m, 6H), 1.01 (m, 3H), 0.81 (t, 3H).

Optical rotation: [a] ₂₃ = -52 ° (c 1, MeOH).

C ₁₉ H ₂₅ N ₃ O ₃ F ₂ (MW = 369.41); Mass Spectroscopy (MH ⁺ ) 370.

Example 166

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-valine methyl ester

After carrying out General Method C, a solid was obtained using N- (3,5-difluorophenylacetyl) -L-alanine (Example B7) and methyl and L-valine methyl ester hydrochloride (Aldrich). The title compound was prepared.

NMR data are 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: [a] ₂₃ = -65 ° (c 1, MeOH).

C ₁₇ H ₂₂ N ₂ O ₄ F ₂ (MW = 356.37); Mass Spectroscopy (MH ⁺ ) 360.

Example 167

Synthesis of N-2-fluoroethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanineamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl] -L-alanine (Example D7) and 2-fluoroethylamine hydrochloride (Aldrich) Product) to give the title compound as a solid (melting point = 230-235 ° C.).

NMR data are as follows:

¹ H-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: [a] ₂₃ = -33 ° (c 1, MeOH).

C ₁₆ H ₂₀ N ₃ O ₃ F ₃ (MW = 359.37); Mass Spectroscopy (MH ⁺ ) 359.

Example 168

Synthesis of N-[(S) -6-methyl-3-oxohept-2-yl] -N '-[N- (3,5-difluorophenylacetyl) -L-alanineamide

After performing General Method M, N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) and (S) -6-methyl-3-oxohept-2-ylamine hydrochloride (N-BOC-L-alanine N-methoxy-N-methyl amide (Weinreb et al., Tetrahedron Lett., 22, 3815 (1981)) was prepared by treating with isopropyl magnesium bromide (Aldrich) Remove BOC group using general method P], to prepare the title compound as a solid, The product was purified by chromatography using CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.84 (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: [a] ₂₃ = -42 ° (c 1, MeOH).

C ₁₉ H ₁₆ N ₂ O ₃ F ₂ (MW = 368); Mass Spectroscopy (MH ⁺ ) 368.

Example 169

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

After carrying out general method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminobutanoate [methyl N using general method AF] -[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminobutanoate (Example 160)] and 4-nitrobenzylamine (Aldrich) Product) to give the title compound as a solid. The reaction was monitored by tlc (0.3 in Rf = 95: 5 CHCl ₃ / MeOH) and the product was purified by chromatography using 97: 3 CHCl ₃ / MeOH as eluent.

NMR data are as follows:

¹ 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), 4.17 (m, 1H), 3.59 (s, 2H), 1.64 (m , 2H), 1.21 (m, 3H), 0.83 (t, 3H).

Optical rotation: [a] ₂₃ = -42 ° (c 1, MeOH).

C ₂₂ H ₂₄ N ₄ O ₅ F ₂ (MW = 462.45); Mass Spectroscopy (MH ⁺ ) 462.

Example 170

Synthesis of N-4-nitrobenzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminopentanamide

After carrying out General Method C, N- [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-aminopentanoic acid [Methyl N- using General Method AF] [N- (3,5-difluorophenylacetyl) -L-alanyl]-(S) -2-amipentanoate (prepared from Example 161)] and 4-nitrobenzylamine (Aldrich) Product) to give the title compound as a solid. The reaction was monitored by tlc (0.3 in Rf = 95: 5 CHCl ₃ / MeOH) and the product was purified by recrystallization from acetonitrile.

NMR data are as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.57 (m, 1H), 8.41 (d, 1H), 8.22 (d, 2H), 8.06 (d, 1H), 7.51 (m, 1H), 7.00 ( m, 2H), 4.43 (d, 2H), 4.30 (m, 2H), 3.56 (s, 2H), 1.29 (m, 5H), 0.91 (t, 3H).

Optical rotation: [a] ₂₃ = + 97 ° (c 1, MeOH).

C ₂₃ H ₂₆ N ₄ O ₅ F ₂ (MW = 476.4); Mass Spectroscopy (MH ⁺ ) 476.

Example 171

Synthesis of Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-fluorophenyl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (3-fluorophenyl) acetate hydrochloride ( Obtained from Example D12, above, to provide the title compound as a solid. The reaction is monitored by tlc and (95: 5 CHCl ₃ / MeOH in a Rf = 0.2): it was purified by 5 CHCl ₃ / silica gel chromatography using MeOH as the eluent to 95.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.36 (m, 1H), 7.18 (m, 1H), 7.13 (m, 1H), 7.06 (m, 1H), 6.87 (m, 2H), 6.74 (m, 1H), 6.09 (m, 1H), 5.49 (d, 1H), 4.59 (m, 1H), 3.74 (s, 3H), 3.57 (s, 2H), 1.35 (d, 3H), 0.97 (d, 3H ).

C ₂₀ H ₁₉ N ₂ O ₄ F ₃ (molecular weight = 408.38); Mass Spectroscopy (MH ⁺ ) 408.

Example 172

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetamide

According to general method L, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate (Examples below) Obtained from 178) to give the title compound as a solid (melting point = decomposition at 190 ° C.). The reaction was purified by purified LC 2000 chromatography using 8: 2 EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ / DMSO-d ₆ ): δ = 8.9-6.14 (Ar + NH's 10H), 5.43-5.39 (m, 1H), 4.16-4.10 (m, J = 7 Hz, 1H), 3.19 (s, 2H), 1.15 (d, J = 7.05 Hz, 3H).

C ₁₇ H ₁₇ 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] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (5-chlorobenzothiophen-2-yl Acetate (Prepared from 5-Chlorobenzothiophene-2-acetic acid [CAS No. 23799-65-7] using General Method G and aminated using essentially the same procedure as described in Example D4 above) ) To give the title compound as a solid (melting point = 189-190 ° C). The product was purified by treatment with Et20 / hexanes.

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, 1H), 5.85 (dd , 1H), 4.7-4.53 (m, 1H), 3.83 (s, 1.5H), 3.8 (s, 1.5H), 3.59 (s, 1H), 3.5 (s, 1H), 1.4 (dt, 3H).

C ₂₂ H ₁₉ ClF ₂ N ₂ O ₄ S (molecular weight = 481); Mass Spectroscopy (MH ⁺ ) 480.

Example 174

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-2-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and ethyl 2-amino-2- (benzothiophen-2-yl) acetate [ CAS No. 98800-64-7] to prepare the title compound as a solid (melting point = 189-190 ° C). The product was purified by purified LC 2000 chromatography using 2: 8 EtOAc / hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.8-7.75 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.09 (m, 3H), 6.81-6.76 (m, 1H), 6.76-6.63 (m, 1H), 6.23 (dd, J = 7 Hz, 1H), 5.84 (d, J = 7.07 Hz, 1H), 4.61-4.59 (m, 1H), 4.33-4.2 (m, 2H), 3.54 ( s, 1H), 3.50 (s, 1H), 1.70 (d, J = 11.9 Hz, 1.5H), 1.38 (d, J = 11.9 Hz, 1.5H), 1.36-1.23 (dt, 3H).

C ₂₃ H ₂₂ N ₂ O ₄ SF ₂ (molecular weight = 460.49); Mass Spectroscopy (MH ⁺ ) 460.

Example 175

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-3-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (benzothiophen-3-yl) acetate ( As solid (melting point = 185-186 ° C.) using 2-amino-2- (benzothiophen-3-yl) acetic acid [prepared using CAS No. 95834-94-9] using general method H ) To give the title compound.

NMR data were as follows:

¹ 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).

C ₂₂ H ₂₀ N ₂ O ₄ F ₂ S (molecular weight = 446); Mass Spectroscopy (MH ⁺ ) 446.

Example 176

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-thienyl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from example B2 above) and methyl 2-amino-2- (2-thienyl) acetate (general method G Was prepared from L-α-2-thienylglycine (Sigma) to give the title compound as a solid (melting point = 161-162 ° C). The product was purified by purification LC 2000 chromatography with 1: 4 EtOAc / hexanes.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.3-6.65 (Ar, 7H), 6.25 (bt, 1H), 5.8 (dd, 1H), 4.68-4.5 (m, 1H), 3.85 (s, 1H), 3.75 (s, 1 H), 3.52 (s, 1 H), 3.5 (s, 1 H), 1.35 (overlaying d, 3 H).

C ₁₈ H ₁₈ N ₂ O ₄ F ₂ S (molecular weight = 396); Mass spectroscopy (MH ⁺ ) 391.1.

Example 177

Synthesis of ethyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-5-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and ethyl 2-amino-2- (benzothiophen-5-yl) acetate ( Prepared as described in S. Kukolja et al., J. Med. Chem., 1985, 28, 1896-1903), the title compound was prepared as a solid (melting point = 126.5-127.5 ° C.). The product was purified by purified LC 2000 chromatography using 1: 1 hexanes / EtOAc as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.1 (s, 1H), 8.05 (s, 1H), 7.6-7.5 (m, 2H), 7.4-7.25 (m, 3H), 7.15 (bd, J = 12 Hz, 5H), 7.05 (bd, J = 12 Hz, 5H), 6.89-6.675 (m, 2H), 6.225 (bd, J = 12 Hz, 5H), 6.075 (bd, J = 12 Hz, 5H), 4.55 (q, J = 7.5 Hz, 1H), 4.2 (dq, 2H), 3.575 (s, 1H), 3.242 (s, 1H), 1.4 (d, J = 7.05 Hz, 1.5H), 1.15 (d, J = 7.05 Hz, 1.5H).

C ₂₃ H ₂₂ N ₂ O ₄ F ₂ S (molecular weight = 460); Mass spectroscopy (MH ⁺ ) 460.1.

Example 178

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate

According to general method G, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid (Examples below) Obtained from 180) to give the title compound as a solid (melting point = 180-181 ° C.). The product was purified by purified LC 2000 chromatography using 6: 4 EtOAc / hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.3-6.6 (Ar + NH, 7H), 6.37 (bd, J = 7 Hz, 1H), 5.77 (d, J = 7 Hz, 1H), 4.6-4.56 ( m, J = 7 Hz, 1H), 3.7 (s, 3H), 3.4 (s, 2H), 1.38 (d, J = 7 Hz, 3H).

C ₁₈ H ₁₈ N ₂ O ₄ SF ₂ (molecular weight = 396); Mass Spectroscopy (MH ⁺ ) 396.1.

Example 179

Synthesis of tert-butyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate

According to general method J, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid (Examples below) Obtained from 180) to give the title compound as a solid (melting point = 117-118 ° C.). The product was purified by treatment with ether / hexanes.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.24 (d, J = 6.5 Hz, 1H), 7.05-6.63 (m, 6H), 6.19 (bd, J = 7.2 Hz, 1H), 5.66 (d, J = 7.5 Hz, 1H), 4.6-4.5 (m, 1H), 3.5 (s, 2H), 1.44 (s, 9H), 1.38 (d, J = 7.1 Hz, 3H).

C ₂₁ H ₂₄ N ₂ O ₄ SF ₂ (molecular weight = 438.5); Mass Spectroscopy (MH ⁺ ) 438.

Example 180

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid

Following the general method M and titled as a solid using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and L-α-2-thienylglycine (Sigma) The compound was prepared. The product was purified by treatment with EtOAc / hexanes.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.73 (d, J = 7 Hz, 1H), 8.38 (d, J = 7 Hz, 1H), 7.56-7.4 (m, 1H), 7.2-6.9 ( m, 4H), 5.54 (d, J = 8 Hz, 1H), 4.5-4.3 (m, 1H), 3.33 (s, 2H), 1.23 (d, J = 7 Hz, 3H).

C ₁₇ H ₁₆ N ₂ O ₄ SF ₂ (molecular weight = 382); Mass Spectroscopy (MH ⁺ ) 382.

Example 181

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (1H-tetrazol-5-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (1H-tetrazol-5-yl) acetate From ethyl 1H-tetrazol-5-acetate [CAS 173367-99-2] using essentially the same method as described in S. Kukolja, J. Med. Chem., 1985, 28, 1886-1896. Prepared) to prepare the title compound as a solid. The reaction was purified by treatment with EtOAc / hexanes.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 9.13 (d, J = 7.6 Hz, 1H), 8.39 (t, J = 7 Hz, 1H), 7.1-6.95 (m, 3H), 5.9 (dd, 1H), 4.4-4.3 (m, 1H), 4.14 (q, J = 7 Hz, 2H), 3.5 (s, 3H), 1.27-1.11 (m, 6H).

C ₁₆ H ₁₈ N ₆ O ₄ F ₂ (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

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl (S) -2-amino-2- (6-methoxy-2 -Naphthyl) acetate (obtained from Example D3, above) was used to prepare the title compound as a solid (melting point = 177-178 ° C.). The product was purified by treatment with hexanes / EtOAc.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.84 (d, J = 9 Hz, 1H), 8.4 (d, J = 9 Hz, 1H), 7.90-7.76 (m, 2H), 7.247-6.90 ( m, 5H), 5.5 (J = 7 Hz, 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).

C ₂₅ H ₂₄ N ₂ O ₅ F ₂ (molecular weight = 470.48); Mass Spectroscopy (MH ⁺ ) 470.

Example 183

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (3-trifluoromethylphenyl) acetate (above As a solid (melting point = 133-134) using 2- (hydroxyimino) -2- (3-trifluoromethylphenyl) acetic acid [CAS 179811-81-5] using general methods G and R ° C) The title compound was prepared. The product was purified by treatment with EtOAc / hexanes.

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 = 7.5 Hz, 1H), 3.7 ( s, 1.5H), 3.675 (s, 1.5H), 3.5 (s, 1H), 5.45 (s, 1H), 1.33 (d, J = 7.5 Hz, 1.5H), 1.275 (d, J = 7.5 Hz, 1.5H).

C ₂₁ H ₁₉ N ₂ O ₄ F ₅ (molecular weight = 458.39); Mass Spectroscopy (MH ⁺ ) 459.

Example 184

Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate Synthesis of

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (4,5,6,7-tetrahydro Benzothiophen-2-yl) acetate (N-Boc-2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetic acid using the above general method G [CAS 95361 -97-0] and prepared using the Boc removal procedure described in Example D3 above) to provide the title compound as a solid. The product was purified by treatment with Et ₂ O / hexanes.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.05 (d, J = 5 Hz, 1H), 7.02 (d, J = 5 Hz, 1H), 6.82-6.66 (m, 3H), 6.31 (bd, J = 8 Hz, 1H), 5.66 (dd, J = 7.2 Hz, 1H), 4.63-4.55 (m, 1H), 3.76 (s, 1.5H), 3.75 (s, 1.5H), 3.52 (s, 1H), 3.50 (s, 1H), 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 ₂₄ N ₂ O ₄ F ₂ S (molecular weight = 450); Mass Spectroscopy (MH ⁺ ) 450.

Example 185

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2,3-b] thiophen-2-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (thieno [2,3-b] thi Offen-2-yl) acetate (obtained from Example D4, above) was used to prepare the title compound as a solid. The product was purified by treatment with Et ₂ O / hexanes.

NMR data were as follows:

¹ 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, 1H), 5.8 (dd, 1H), 4.63-4.5 (m, 1H), 3.8 (s, 3H), 3.58 (s, 1H), 3.469 (1H), 1.4 (dd, 3H).

C ₂₀ H ₁₈ N ₂ O ₄ F ₂ S ₂ (molecular weight = 452); Mass Spectroscopy (MH ⁺ ) 452.

Example 186

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-methylthiazol-4-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (2-methylthiazol-4-yl) The title compound as a solid using acetate (prepared from N-Boc-2-amino-2- (2-methylthiazol-4-yl) acetic acid [CAS 105381-90-6] using the general method H above) Was prepared. The product was purified by treatment with Et ₂ O / hexanes.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.2-6.66 (pr + NH, 5H), 5.69-5.6 (m, 1H), 4.8-4.69 (m, 1H), 3.76 (s, 3H), 3.56 (s , 1H), 3.5 (s, 1H), 2.69 (s, 3H), 1.4 (d, J = 14 Hz, 1.5H), 1.35 (s, J = 14 Hz, 1.5H).

C ₁₈ H ₁₉ N ₃ O ₄ F ₂ S (molecular weight = 411); Mass Spectroscopy (MH ⁺ ) 411.

Example 187

Synthesis of methyl (3S, 4S) -N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -4-amino-3-hydroxy-5-phenylpentanoate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl (3S, 4S) -4-amino-3-hydroxy-5- Phenylpentanoate (Novabiochem) was used to prepare the title compound as a solid. Tlc reactants were purified by flash column chromatography using as eluent a _{5 CHCl 3 / MeOH: (95} : 5 CHCl 3 / MeOH in a Rf = 0.2) to monitor and 95 a.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.29 (d, 1H), 7.65 (d, 1H), 7.40-7.20 (m, 5 H), 7.10 (m, 1H), 6.99 (m, 2H), 5.27 (d, 1H), 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: [a] ₂₃ =-66 ° (c 1, MeOH).

C ₂₃ H ₂₆ N ₂ O ₅ F ₂ (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

9.50 g (83.2 mmol, 1.10 equiv) of 4-hexenoic acid (commercially available from Lancaster, catalog # 252-427-6) in 150 ml of dry THF, cooled to −78 ° C. under anhydrous N ₂ , and triethylamine To 13.9 ml (10.1 g, 99.7 mmol, 1.33 equiv) of mechanically stirred solution 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 minutes and then recooled to −78 ° C. 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(-)-(phenylmethyl) -2-oxazolidone (Aldrich) in 150 ml of dry THF stirred at -30 ° C to -45 ° C under N ₂ And a 22 mg solution of triphenylmethane (indicator) was added dropwise with n-butyllithium (˜2.5 M in hexane) (Aldrich) until orange persisted (˜30 ml required). The resulting solution was cooled to −78 ° C. and added via cannula to the stirred solution containing the quickly mixed anhydride. The remaining lithiated oxazolidone was washed twice with 10 ml of dry THF and the resulting mixture was stirred at -78 ° C for 1.5 h and 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 solution followed by _half saturated aqueous NaCl solution, dried (magnesium sulfate) and evaporated in vacuo. Residual cream solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm × 25 cm 10 μ Kromasil KR60-10SIL-5025 column) eluted with 85:15 hexanes / EtOAc. The chromatographed product was recrystallized from hexane to give 14.34 g (first obtained, 69%) of the title compound as fine white needles. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.37-7.20 (m, 5H, -C ₆ H ₅ ), 5.60-5.43 (m, 2H, CH = CHCH ₃ ), 4.71-4.63 (m, 1H, NCH (Ph) CH ₂ O), 4.23-4.14 (m, 2H, NCH (Ph) CH ₂ O), 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 = 13.3, 9.6 Hz, 1H, 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 in 60 ml of anhydrous THF stirred at -78 ° C. under anhydrous N ₂ was added potassium hexamethyldisilazide (0.505 M in toluene) (Aldrich) It was quickly added via cannula to 43.6 ml (22.0 mmol, 1.10 equiv) and 60 ml of anhydrous THF, stirred, cooled (-78 ° C.) solution. The residual imide solution was washed twice with 5 ml of dry THF. The resulting solution was stirred for 30 min at -78 ° C. To the K-enolate solution stirred at -78 ° C. under N ₂ , trisyl azide in 60 ml of dry THF (RE Harmon et al., J. Org. Chem., 1973, 38, 11-16) 7.43 g (24.0 mmol, 1.2 equiv) of the cooled (-78 ° C) solution was added quickly via cannula. (Note that this reaction exotherms to −68 ° C. during addition). After 1-2 minutes 4.24 ml (4.45 g, 74.1 mmol, 3.7 equiv) of glacial acetic acid were added in one portion. The resulting mixture was stirred for 15 min at -78 ° C and warmed to 25 ° C with stirring overnight. This mixture was partitioned between CH ₂ Cl ₂ and phosphate buffer (pH 7). The aqueous phase was extracted with CH ₂ Cl ₂ and the (3 ×) organic extracts were combined and washed with dilute NaHCO ₃ aqueous solution, dried (magnesium sulfate) and evaporated in vacuo. Chromatography of the residual oil (9.55 g) eluting with a 3 L linear gradient with 30:70 to 80:20 CH ₂ Cl ₂ / hexanes (Waters Prep 2000, 5.0 cm x 25 cm 10 μ Kromasil KR60-10SIL-5025 column) It was. After the mixed fractions were rechromatated (2X), a total of 5.27 g (84% yield) of the title compound was separated into a colorless viscous oil. ¹ H-NMR (300 MHz; CDCl ₃ ): δ 7.38-7.20 (m, 5H, -C ₆ H ₅ ), 5.73-5.62 (m, 1H, CH = CHCH ₃ ), 5.52-5.41 (m, 1H, CH = CHCH ₃ ), 5.011 (dd, J = 8.3, 5.5 Hz, 1H, CH (N ₃ ) C = O), 4.71-4.63 (m, 1H, NCH (Ph) CH ₂ O), 4.236 (d, J = 5.1 Hz, 2H, NCH (Ph) CH ₂ O), 3.338 (dd, J = 13.4, 3.3 Hz, 1H, CHHC ₆ H ₅ ), 2.827 (dd, J = 13.4, 9.5 Hz, 1H, CHHC ₆ H ₅ ), 2.64-2.46 (m, 2H, 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 stirred THF and 80 ml of deionized water at 0 ° C. under N ₂ was treated with 762 mg (31.8 mmol, 2.00 equiv) of LiOH (anhydrous powder). After stirring for 30 min at 0 ° C, 100 ml of 0.5 N NaHCO ₃ aqueous solution was added and THF was removed by rotary evaporation under vacuum. The residue was diluted with 400-500 ml of water and extracted 5 times with CH ₂ Cl ₂ . The aqueous phase was acidified to pH 1-2 with careful addition of 5 N HCl and extracted four times with EtOAc. EtOAc extracts were combined, dried (sodium sulfate) and evaporated in vacuo to yield 2.45 g (99%) of the title compound as a light amber oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 11.38 (br s, 1H, CO ₂ H), 5.73-5.62 (m, 1H, CH ₃ CH═CH), 5.48-5.38 (m, 1H, CH = CHCH ₂ ), 3.928 (dd, J = 7.8, 5.4 Hz, 1H, CH (N ₃ ) CO ₂ H), 2.66-2.47 (m, 2H, CH = CHCH ₂ ), 1.703 (dd, J = 6.4, 1.1 Hz, 3H, CH ₃ ).

Step D-Methyl N- [N-tert-butoxycarbonyl-L-alaninyl]-(S) -2-aminohex-enoate

A solution of 504.7 mg (3.25 mmol) of the product from step C in diethyl ether cooled to 0 ° C. was treated with etherial diazomethane (LF Fieser et al., “Reagents for Organic Synthesis” until yellow persisted. , Vol. 1, p. 191, prepared as described in Wiley & Sons (1967)). Entrained by the excess of diazomethane was removed with N ₂ and evaporation of the ether under a N ₂ stream. The residual oil was dissolved in 10 ml of absolute methanol. The solution was cooled to 0 ° C. under anhydrous N ₂ and 1.24 g (6.54 mmol, 2.0 equiv) of anhydrous SnCl ₂ were added. The mixture was stirred at 25 ° C. or below for 4 hours and the solvent was evaporated in vacuo to give a solid tin-amine complex.

1.23 g (6.50 mmol, 2.00 equiv) and 4-methylmorpholine (re-distilled), 99.5% N-Boc-L-alanine (Sigma) in 15 ml of dry THF cooled to -15 to -20 ° C. under dry N ₂ ) 0.715 ml (0.658 g, 6.50 mmol, 2.0 equiv) of solution was treated dropwise with 0.861 ml (0.907 g, 6.50 mmol, 2.00 equiv) of iso-butyl chloroformate (Aldrich). After stirring at −15 to −20 ° C. for 20 minutes, the resulting mixture containing mixed anhydride was added via solids to the solid tin-amine complex (see above). The remaining mixed anhydride was washed with 7 ml of THF and 1.1 g (13.1 mmol, 4.0 equiv) of NaHCO ₃ powder and 5 ml of water were added. The mixture was stirred at 0 ° C for 5 h. Further 1.1 g (13.1 mmol, 4.0 equiv) and 5 ml of NaHCO ₃ powder were added and the mixture was stirred at 20 ° C. for 1.5 h. The mixture was filtered to remove gelatinous precipitate and the filter cake was washed several times with EtOAc. The filtrate was washed with saturated aqueous NaHCO ₃ solution followed by phosphate buffer (pH 4-5) (the aqueous phase was back extracted three times with EtOAc). The organic phase was dried (sodium sulfate) and evaporated in vacuo. Chromatography (Waters Prep 2000, 5.0 cm x 25 cm 10 μ Kromasil KR60-10SIL-5025 column) eluted the residual pale yellow oil (1.21 g) with a 3-L linear gradient with 80:20 to 40:60 hexanes / EtOAc. 0.9088 g (89%) of the title compound were obtained as a white solid. Tlc R _f 0.25 [silica, hexanes / EtOAc 6: 4]; ¹ H-NMR (300 MHz, CDCl ₃ ): δ 6.61 (d, J = 7.6 Hz, 1H, NH), 5.60-5.48 (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-Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohex-4-enoate

A solution of 0.811 g (2.58 mmol) of the product from Step D above in 5 ml of CH ₂ Cl ₂ was cooled to 0 ° C. under anhydrous N ₂ and 5 ml of trifluoroacetic acid was placed in a syringe at 4 ° C. or lower. This solution was stirred at 0 ° C. for 40 minutes. Toluene (15 ml) was added and the mixture was evaporated in vacuo on a rotary evaporator. The addition of toluene and solvent evaporation were repeated. The residue was dissolved in 20 ml of CH ₂ Cl ₂ and the solution was cooled to 0 ° C. under anhydrous N ₂ . To this was added 1.35 ml (1.00 g, 7.74 mmol, 3.0 equiv) of ethyldiisopropylamine (Aldrich) followed by 3,5-difluorophenylacetyl chloride (using General Method H ′) at 3 ° C. or below. 0.728 ml (0.938 g, 5.16 mmol, 2.0 equiv.), Prepared from .5-difluorophenylacetic acid (Aldrich), was added dropwise. The resulting solution was stirred at 0 ° C. for 2 hours. Excess saturated aqueous NaHCO ₃ solution was added and the mixture with two phases was stirred in an ice bath for 30 minutes. The mixture was diluted with CH ₂ Cl ₂ and washed sequentially with NaHCO ₃ / Na ₂ CO ₃ (pH 10), 1N NaHSO ₄ aqueous solution and saturated NaCl aqueous solution. The CH ₂ Cl ₂ solution was dried (sodium sulfate) and evaporated in vacuo to yield 1.17 g of a yellow solid. This solid was recrystallized from EtOAc to give 602 mg (63%) of the title compound as a fluff white solid. This material was analyzed by 300 mHz ¹ H NMR and found to consist of a 92: 8 mixture of E and Z isomers, respectively.

NMR data were as follows:

¹ H-nmr (300 MHz, CDCl ₃ ): δ = 6.85-6.69 (m, 3H), 6.335 (br d, J = 7.8 Hz, 1H), 6.289 (br d, J = 7.0 Hz, 1H), 5.58 -5.47 (m, 1H), 5.28-5.18 (m, 1H), 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 = 6.5, 1.3 Hz, 3H), 1.58 (dm, J = 6.5 Hz, 0.08H), 1.375 (d, J = 7.0 Hz, 3H).

IR (CHCl ₃ ) 3421, 1742, 1667, 1626, 1597, 1503, and 1120 cm-1

C ₁₈ H ₂₂ F ₂ N ₂ O ₄ elemental analysis—calculated: C, 58.69; H, 6.02; N, 7.60. Found: C, 58.83; H, 5.89; N, 7.67.

C ₁₈ H ₂₂ F ₂ N ₂ O ₅ (molecular weight = 368); Mass Spectroscopy (MH ⁺ ) 368.

Example 189

Synthesis of N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester

General method of Z-alanine according to general method U and in cyclopropylacetic acid (lancaster) and N- (L-alaninyl) -L-phenylglycine tert-butyl ester (phenylglycine-t-butyl (nabbio)) U and general method O) were used to prepare the title compound as a solid (melting point = 105-107 ° C.). The reaction was monitored by tlc (Rf = 0.33 in 1: 1 EtOAc / hexanes, 0.13 in 5% MeOH / DCM).

NMR data were as follows:

¹ H-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, 1H), 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.

C ₂₀ H ₂₈ N ₂ O ₄ (molecular weight = 360.46); Mass Spectroscopy (MH ⁺ ) 361.

Example 190

N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (4-phenylphenyl) acetamide synthesis

According to the general method AB and using 3,5- (difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and 4-biphenylcarboxaldehyde (Aldrich) as solids (melting point = 266-267 ° C) The title compound was prepared. The product was purified by recrystallization from EtOAc and / or EtOAc / hexanes.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.42 (d, 1H, J = 7 Hz), 8.31 (d, 1H, J = 7 Hz), 7.91 (s, 1H), 7.6-7.56 (m, 4H), 7.42-7.59 (m, 5H), 7.2-7.69 (m, 3H), 5.42 (d, 1H, J = 8 Hz), 4.42 (pentet, 1H, J = 8 Hz), 3.5 (s, 1H ), 1.2 (doublet on top of a singlet, 12H).

C ₂₉ H ₃₁ N ₃ O ₃ F ₂ (molecular weight = 508); Mass Spectroscopy (MH ⁺ ) 508.4.

Example 191

Synthesis of N- [N- (3,5-difluorophenylacetyl)-(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester

According to General Method D, 3,5-difluorophenylacetic acid (Aldrich) and N-[(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester (from Example D13 above) Obtained) to give the title compound as a solid (melting point = 138.7-140.0 ° C). The reaction was monitored by tlc (Rf = 0.24 in 2/1 hexanes: EtOAc) and the product was purified by flash chromatography and HPLC.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ , 250 MHz): δ = 8.66 (d, J = 6.75 Hz, 1H), 8.30 (d, J = 8.26 Hz, 1H), 7.37 (bs, 5H), 7.11-6.96 (m, 3H), 5.23 (d, J = 7.00 Hz, 1H), 4.36 (td, J = 7.88, 5.50 Hz, 1H), 3.53 (AB _q , J _AB = 14.05 Hz, Δv _AB = 7.75 Hz, 2H ), 1.85-1.48 (m, 2H), 1.34 (s, 9H), 0.88 (t, J = 7.38 Hz, 3H).

Optical rotation: [a] ₂₀ = 21.8 ° (c 1.0, MeOH).

C ₂₄ H ₂₈ N ₂ O ₄ F ₂ (molecular weight = 446.50); Mass spectrometry (MH ⁺ , negative CO ₂ -tBu) 345.2.

Example 192

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine tert-butyl ester

According to general method D, using 3,5-difluorophenylacetic acid (Aldrich) and N- (L-valinyl) -L-phenylglycine tert-butyl ester (obtained from Example D14 above) The title compound was prepared as a solid (melting point = 170.5-171.8 ° C). The reaction was monitored by tlc (Rf = 0.39 in 2: 1 hexanes: EtOAc) and the product was purified by flash chromatography and HPLC.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ , 250 MHz): δ = 8.71 (d, J = 6.75 Hz, 1H), 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, 1H), 4.36 (dd, J = 8.88, 6.38 Hz, 1H), 3.55 (AB _q , J _AB = 13.88 Hz, Δv _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 = 6.5 Hz, 3H).

Optical rotation: [a] ₂₀ = 20.8 ° (c 1.0, MeOH).

C ₂₅ H ₃₀ N ₂ O ₄ F ₂ (molecular weight = 460.53); Mass spectrometry (MH ⁺ , negative CO ₂ -tBu) 359.2.

Example 193

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- (L-methioninyl) -L-phenylglycine methyl ester hydrochloride (N-BOC-L using general method E) The title compound was prepared as a solid (melting point = 189.3 ° C.) using solids (prepared from methionine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing BOC-groups using general method P). Prepared. The reaction was monitored by tlc (Rf = 0.53 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product was purified by recrystallization from ethyl acetate / hexanes.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.85 (d, J = 6.7 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.38 (m, 5H), 7.09 (m, 1H) , 6.98 (m, 2H), 5.38 (d, J = 6.6 Hz, 1H), 4.47 (m, J = 8.2 Hz, 1H), 2.62 (s, 3H), 3.51 (d, 2H), 2.46 (t, 2H), 2.04 (s, 3H), 1.89 (m, 2H).

¹³ C-nmr (DMSO-d ₆ ): 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, 102.684, 102.340, 93.065, 57.205, 53,063, 42.231, 33.075, 30.221, 15.465.

C ₂₂ H ₂₄ N ₂ O ₄ F ₂ S (molecular weight = 450.51); Mass Spectroscopy (MH ⁺ ) 450.

Example 194

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- (L-valinyl) -L-phenylglycine methyl ester hydrochloride (N-BOC-L using general method E) The title compound was prepared as a solid (melting point = 226.5 ° C.) using valine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing the BOC-group using the general method P). Prepared. The reaction was monitored by tlc (Rf = 0.49 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product was purified by recrystallization from MeOH / CH ₂ Cl ₂ .

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.84 (d, J = 6.2 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.38 (m, 5H), 7.07 (m, 1H) , 6.98 (m, 2H), 5.37 (d, J = 6.5 Hz, 1H), 4.34 (m, J = 8.9 Hz, 1H), 3.55 (m, 5H), 2.01 (m, 1H), 0.87 (m, 6H).

¹³ C-nmr (DMSO-d ₆ ): 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, 112.9022.9112. , 102.619, 102.281, 57.914, 57,262, 52.935, 42.274, 31.728, 19.845, 18.815.

C ₂₂ H ₂₄ N ₂ O ₄ F ₂ (molecular weight = 418.44); Mass spectroscopy (MH ⁺ ) 418.1.

Example 195

Synthesis of N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- (2-aminobutanoyl) -L-phenylglycine methyl ester hydrochloride (N-BOC- using general method E Prepared from L-aminobutyric acid (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing the BOC-group using the general method P) (melting point = 215.3 ° C.) The compound was prepared. The reaction was monitored by tlc (Rf = 0.46 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product was purified by recrystallization from ethyl acetate / hexanes.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.83 (d, J = 6.8 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.38 (m, 5H), 7.08 (m, 1H) , 6.98 (m, 2H), 5.38 (d, J = 6.8 Hz, 1H), 4.35 (m, J = 7.9 Hz, 1H), 3.61 (s, 3H), 3.52 (d, 2H), 1.64 (m, 2H), 0.88 (t, 3H).

¹³ C-nmr (DMSO-d ₆ ): δ = 171.684, 170.934, 168.984, 164.193, 163.980, 160.295, 160.083, 141.059, 140.902, 140.743, 135.857, 128.689, 128.372, 127.892, 112.387, 112.257, 112.131, 111.999, 102.254, 102.254 , 101.845, 101.438, 56.351, 53,441, 52.212, 41.436, 25.675, 10.067.

C ₂₁ H ₂₂ N ₂ O ₄ F ₂ (molecular weight = 404.42); Mass Spectroscopy (MH ⁺ ) 405.1.

Example 196

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-leucineyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- (L-leucineyl) -L-phenylglycine methyl ester hydrochloride (N-BOC-L using general method E) Prepared from -Leucine (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing BOC-groups using the general method P) (melting point = 178.4 ° C.) The compound was prepared. The reaction was monitored by tlc (Rf = 0.51 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product purified by flash chromatography using MeOH / CH ₂ Cl ₂ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.85 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 7.37 (m, 5H), 7.08 (m, 1H) , 6.95 (m, 2H), 5.37 (d, J = 6.8 Hz, 1H), 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, 168.888, 164.197, 163.984, 160.298, 160.086, 141.029, 140.887, 140.723, 135.875, 128.657, 128.348, 127.944, 112.340, 112.207, 112.084, 111.951, 102.251 , 101.842, 101.435, 56.343, 52,214, 50.697, 41.510, 40.982, 24.056, 21.575.

C ₂₃ H ₂₆ N ₂ O ₄ F ₂ (molecular weight = 432.47); Mass spectroscopy (MH ⁺ ) 432.1.

Example 197

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] -L-phenylglycine methyl ester

3,5-difluorophenylacetic acid (Aldrich) and N- (L-phenylalaninyl) -L-phenylglycine methyl ester hydrochloride according to general method E (N-BOC-L using general method E) Prepared from -phenylalanine (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing the BOC-group using the general method P) (melting point = 188.3 ° C) The compound was prepared. The reaction was monitored by tlc (Rf = 0.59 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product purified by flash chromatography using MeOH / CH ₂ Cl ₂ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.99 (d, J = 6.9 Hz, 1H), 8.44 (d, J = 8.6 Hz, 1H), 7.4 (m, 5H), 7.21 (m, 5H) , 7.03 (m, 1H), 6.77 (m, 2H), 5.42 (d, J = 6.9 Hz, 1H), 4.70 (m, J = 8.5 Hz, 1H), 3.63 (s, 3H), 3.40 (m, 2H), 3.08 (m, 1 H), 2.76 (m, 1 H).

¹³ C-nmr (DMSO-d ₆ ): 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.

C ₂₆ H ₂₄ N ₂ O ₄ F ₂ (molecular weight = 466.49); Mass Spectroscopy (MH ⁺ ) 466.

Example 198

Synthesis of N- [N- (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- (glycineyl) -L-phenylglycine methyl ester hydrochloride (N-BOC-glycine (al ) And L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing BOC-groups using general method P) to give the title compound as a solid (melting point = 142.3 ° C.). . The reaction was monitored by tlc (Rf = 0.33 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product was purified by recrystallization from diethyl ether / hexanes.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.82 (d, J = 7.2 Hz, 1H), 8.39 (t, 1H), 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, 112.360, 112.238, 112.104, 102.310, 101,900 , 101.492, 56.200, 52.321, 41.731, 41.464.

C ₁₉ H ₁₈ N ₂ O ₄ F ₂ (molecular weight = 376.36); Mass spectroscopy (MH ⁺ ) 376.0.

Example 199

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-phenylglycineyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- (L-phenylglycinyl) -L-phenylglycine methyl ester hydrochloride (N-BOC- using general method AH) Prepared from L-phenylglycine (Novabiochem) and L-phenylglycine methyl ester hydrochloride (Aldrich) and prepared by removing BOC-groups using the general method P) (melting point = 222.8 ° C.) ) To give the title compound. The reaction was monitored by tlc (Rf = 0.61 in 5:95 MeOH / CH ₂ Cl ₂ ) and the product was purified by recrystallization from ethyl acetate.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 9.22 (d, J = 6.8 Hz, 1H), 8.85 (d, J = 8.2 Hz, 1H), 7.37 (m, 10H), 7.08 (m, 1H) , 6.97 (d, 2H), 5.69 (d, J = 8.2 Hz, 1H), 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. , 112.340, 112.209, 112.082, 102.292, 101.884, 101.475, 56.431, 55.621, 52.203, 41.205.

C ₂₅ H ₂₂ N ₂ O ₄ F ₂ (molecular weight = 452.46); Mass Spectroscopy (MH ⁺ ) 452.2.

Example 200

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-alanine methyl ester

According to general method A and using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and L-alanine methyl ester hydrochloride (Aldrich) as a solid (melting point = 140.5-142 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.17 in 50% EtOAc / hexanes).

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 1.3-1.4 (m, 6H), 3.55 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.1-6.3 (brd, 1H ), 6.6-6.7 (brd, 1 H), 7.2-7.4 (m, 5 H).

¹³ C-nmr (CDCl ₃ ): δ = 18.4, 19.0, 44.1, 48.6, 49.3, 53.0, 127.5, 129.5, 129.8, 135.1, 171.5, 172.4, 173.6.

C ₁₅ H ₂₀ N ₂ O ₄ (molecular weight = 292.34); Mass Spectroscopy (MH ⁺ ) 293.

Example 201

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-leucine methyl ester

According to general method A, using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and L-leucine methyl ester hydrochloride (Aldrich) as a solid (melting point = 102.5-105 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.25 in 50% EtOAc / hexanes).

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 (CDCl 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.

C ₁₈ H ₂₆ N ₂ O ₄ (molecular weight = 334.42); Mass Spectroscopy (MH ⁺ ) 335.

Example 202

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine methyl ester

Following the general method A, the title compound was prepared using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and L-isoleucine methyl ester hydrochloride (Sigma). The reaction was monitored by tlc (Rf = 0.24 in 50% EtOAc / hexanes).

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.8-0.95 (m, 6H), 1.0-1.2 (m, 1H), 1.2-1.4 (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 (CDCl 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.

C ₁₈ H ₂₆ N ₂ O ₄ (molecular weight = 334.42); Mass Spectroscopy (MH ⁺ ) 335.

Example 203

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester

Following the general method A, the title compound was prepared as an oil using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and L-proline methyl ester hydrochloride (Bachem). The reaction was monitored by tlc (Rf = 0.12 in 50% EtOAc / hexanes).

NMR data were as follows:

¹ 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 (CDCl 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

C ₁₇ H ₂₂ N ₂ O ₄ (molecular weight = 318.38); Mass Spectroscopy (MH ⁺ ) 319.

Example 204

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester

According to general method A and using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and L-phenylalanine methyl ester hydrochloride (Aldrich) as a solid (melting point = 148-149.5 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.24 in 50% EtOAc / hexanes) and the product was not purified.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 1.25 (d, J = 7 Hz, 3H), 3.02 (dd, J = 7, 14 Hz, 1H), 3.12 (dd, J = 5, 14 Hz, 1H) , 3.53 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 1H), 4.75-4.85 (m, 1H), 5.9 (brd, 1H), 6.5 (brd, 1H), 7.0-7.5 (m, 10 H).

¹³ C-nmr (CDCl 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, 171.4, 172.2, 172.3

C ₂₁ H ₂₄ N ₂ O ₄ (molecular weight = 368.44); Mass Spectroscopy (MH ⁺ ) 369.

Example 205

N- [N- (phenylacetyl) -L- alanine yl] -N _ε - Synthesis of - (tert-butoxycarbonyl) -L- lysine methyl ester

Following the general method A, N- (phenylacetyl) -L- alanine (obtained from Example B1) and N _ε - (3-tert-butoxycarbonyl) -L- lysine methyl ester hydrochloride using (bakem) To give the title compound as a solid (melting point = 119-121 ° C.). The reaction was monitored by tlc (Rf = 0.46 in 90: 10: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH).

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, 1H), 6.2 (brd, 1H), 6.75 (brd, 1 H), 7.2-7.4 (m, 5 H).

¹³ C-nmr (CDCl 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.

C ₂₃ H ₃₅ N ₃ O ₆ (molecular weight = 449.55); Mass Spectroscopy (MH ⁺ ) 450.

Example 206

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] glycine methyl ester

According to the general method A and using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and glycine methyl ester hydrochloride (Aldrich) as a solid (melting point = 152-153.5 ° C.) the title compound Was prepared. The reaction was monitored by tlc (Rf = 0.10 in 50% EtOAc / hexanes).

NMR data were as follows:

¹ H-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, 1H), 6.1 (brd, 1H), 6.8 (brs, 1H), 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

C ₁₄ H ₁₈ N ₂ O ₄ (molecular weight = 278.31); Mass Spectroscopy (MH ⁺ ) 279.

Example 207

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-valine methyl ester

According to general method A and using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and L-valine methyl ester hydrochloride (Aldrich) as a solid (melting point = 112-115 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.33 in 50% EtOAc / hexanes) and the product was not purified.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.8-0.9 (overlapping d appearing as t, J = 6 Hz, 6H), 2.0-2.2 (m, 1H), 3.57 (s, 2H), 3.72 (s, 3H ), 4.4-4.5 (m, 1H), 4.5-4.65 (m, 1H), 6.2 (brd, 1H), 6.75 (brd, 1H), 7.2-7.4 (m, 5H).

¹³ C-nmr (CDCl 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

C ₁₇ H ₂₄ N ₂ O ₄ (molecular weight = 320.39); Mass Spectroscopy (MH ⁺ ) 321.

Example 208

Synthesis of Methyl N- [N- (phenylacetyl) -L-alaninyl] -2- (S) -aminobutanoate

According to general method A, L-2 using N- (phenylacetyl) -L-alanine (obtained from example B1 above) and methyl L-2-aminobutanoate hydrochloride (general method H (except extraction)) The title compound was prepared as a solid (melting point = 120 ° C.) using aminobutanoic acid (bakem). The reaction was monitored by tlc (Rf = 0.2 in 50% EtOAc / hexanes).

NMR data were as follows:

¹ H-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), 4.4-4.6 (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.

C ₁₆ H ₂₂ N ₂ O ₄ (molecular weight = 306.36); Mass Spectroscopy (MH ⁺ ) 307.

Example 209

Synthesis of Methyl N- [N- (phenylacetyl) -L-alaninyl] -2- (S) -aminopentanoate

According to general method A and using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and methyl 2- (S) -aminopentanoate hydrochloride (general method H (except extraction)) The title compound was prepared as a solid (melting point = 135-137 ° C.) using 2-aminovaleric acid (bakchem). The reaction was monitored by tlc (Rf = 0.30 in 50% EtOAc / hexanes).

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.87 (t, J = 6 Hz, 3H), 1.2-1.4 (m with d, J = 7 Hz, 5H), 1.5-1.8 (m, 2H), 3.57 ( s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 2H), 6.4 (brd, 1H), 7.0 (brd, 1H), 7.2-7.4 (m, 5H).

¹³ C-nmr (CDCl 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.

C ₁₇ H ₂₄ N ₂ O ₄ (molecular weight = 320.39); Mass Spectroscopy (MH ⁺ ) 321.

Example 210

Synthesis of N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine

Following the general method AF, the title compound was prepared as a solid using N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine ethyl ester (obtained from Example 143 above). The reaction was monitored by tlc (Rf = 0.05 in 9: 1 CHCl ₃ / MeOH).

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.41 (d, 1H), 8.13 (s, 1H), 8.09 (d, 1H), 7.91 (d, 1H), 7.68 (d, 1H), 7.56 ( t, 1H), 4.4 (m, 1H), 4.10 (m, 1H), 3.63 (s, 2H), 2.01 (m, 1H), 1.19 (m, 3H), 0.89 (d, 6H).

Optical rotation: [a] ₂₃ = -49 ° (c 1, MeOH).

C ₁₆ H ₂₁ N ₃ O ₆ (molecular weight = 351.3); Mass Spectroscopy (MH ⁺ ) 352.

Example 211

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-N-methylalanine methyl ester

LN-methylalanine hydrochloride according to general method A and using N- (phenylacetyl) -L-alanine (obtained from Example B1 above) and LN-methylalanine methyl ester hydrochloride (general method H (except extraction)) (From Bachem) to give the title compound as an oil. The reaction was monitored by tlc (Rf = 0.13 in 50% EtOAc / hexanes) and the product was purified by column chromatography using 60% EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): 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 (CDCl 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, 129.45, 129.48, 129.9, 135.2, 170.60 , 170.67, 172.19, 172.4, 173.25, 173.31.

C ₁₆ H ₂₂ N ₂ O ₄ (molecular weight = 306.36); Mass Spectroscopy (MH ⁺ ) 307.

Example 212

Synthesis of N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine isobutyl ester

According to general method C, prepared from N- (isovaleryl) -L-phenylglycine (isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) using general method C) Prepared by hydrolysis using general method AF) and N-Boc-L-alanine (sigma) and 2-methyl-1 using L-alanine isobutyl ester hydrochloride (general method C (by catalyst DMAP)) The title compound was prepared as a solid (melting point = 181-186 ° C.), prepared from propanol and prepared by removing BOC-groups using the general method P). The reaction was monitored by tlc (Rf = 0.4 in 1: 1 EtOAc / hexanes) and the product was purified by silica gel chromatography using 1: 1 EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 1.31 (d, 3H), 5.59 (d, 1H).

Optical rotation: [a] ₂₀ = +19 ° @ 589 nm (c 1.03, DMSO).

C ₂₀ H ₃₀ N ₂ O ₄ (molecular weight = 362); Mass Spectroscopy (MH ⁺ ) 363.

Example 213

Synthesis of N- [N- (isovaleryl) -L-isoleucineyl] -L-alanine isobutyl ester

According to general method C, prepared from N- (isovaleryl) -L-isoleucine (isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) using general method C) Then prepared by hydrolysis using general method AF) and N-BOC-L-alanine (Sigma) and 2-methyl-1 using L-alanine isobutyl ester hydrochloride (general method C (by catalyst DMAP)) The title compound was prepared as a solid (melting point = 142-146 ° C.) prepared from propanol and prepared by removing the BOC-group using the general method P). The reaction was monitored by tlc (Rf = 0.4 in 1: 1 EtOAc / hexanes) and the product was purified by silica gel chromatography using 1: 1 EtOAc / hexanes as eluent to give a diastereomeric 1: 4 mixture.

NMR data were as follows:

¹ 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).

C ₁₈ H ₃₄ N ₂ O ₄ (molecular weight = 342.48); Mass Spectroscopy (MH ⁺ ) 343.

Example 214

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

According to general method C and using N- (3,5-difluorophenylacetyl) -L-alanine (prepared from Example B2 above) and N-cyclohexyl-L-phenylglycineamide (general method M) The title compound was prepared as a solid using N-BOC-L-phenylglycine (Advanced Chemtech) and cyclohexylamine (Aldrich) and prepared by removing the BOC-group using the general method P). The reaction was monitored by tlc (Rf = 0.5 in 9: 1 CHCl ₃ / MeOH) and the product was purified by treatment from ethanol.

NMR data were as follows:

¹ H-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), 1.8-1.6 (m, 6H), 1.23-0.98 (m, 7H).

Optical rotation: [a] ₂₃ = -32.7 ° (c 1, MeOH).

C ₂₅ H ₂₉ F ₂ N ₃ O ₃ (molecular weight = 457); Mass Spectroscopy (MH ⁺ ) 458.

Example 215

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-hydroxyproline ethyl ester

According to general method F, using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and L-4-hydroxyproline ethyl ester hydrochloride (Paltz & Bauer) To give the title compound as a foam. The reaction was monitored by tlc (Rf = 0.32 in 95: 5 CH ₂ Cl ₂ / MeOH) and the product was purified by flash column chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ , 250 MHz): δ = 7.31 (d, 1H, J = 7.00 Hz), 6.83-6.64 (m, 3H), 4.67 (p, 1H, J = 7.09 Hz), 4.58 (t , 1H, J = 8.26 Hz), 4.47 (bs, 1H), 4.25-4.06 (m, 2H), 3.81 (bd, 1H, J = 11.01 Hz), 3.62 (dd, 1H, J = 10.76, 3.75 Hz) , 3.46 (s, 2H), 2.30 (dd, 1H, J = 13.51, 8.26 Hz), 1.96 (ddd, 1H, J = 13.44, 8.82, 4.56 Hz), 1.33 (d, 3H, J = 6.75 Hz), 1.24 (t, 3H, J = 7.13 Hz).

C ₁₈ H ₂₃ F ₂ N ₂ O ₅ (molecular weight = 384.38); Mass spectroscopy (MH ⁺ ) 385.1.

Example 216

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-lysine methyl ester

Following the general method Y, N- [N- (3,5- difluoro-phenyl-acetyl) -L- alanine yl] -N _ε - (3-tert-butoxycarbonyl) -L- lysine methyl ester (the embodiment Obtained from Example 43) to give the title compound as an oil. The title compound was isolated as trifluoroacetic acid salt (containing about 5% excess of trifluoroacetic acid).

NMR data were as follows:

¹ H-nmr (2 drops of CDCl ₃ + CD ₃ OD): δ = 6.40-6.52 (m, 3H), 4.17 (t, 1H), 4.40 (q, 1H), 3.42 (s, 3H), 3.23 (s , 3H), 2.53 (bs, 2H), 1.60 (m, 1H), 1.32 (m, 3H), 1.02-1.13 (m, 2H), 1.10 (d, 2H).

¹³ C-nmr (2 drops of CDCl ₃ + CD ₃ OD): δ = 174.1, 166.4, 166.4, 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.

C ₂₁ H ₂₆ F ₅ N ₃ O ₆ (molecular weight = 511.4); Mass Spectroscopy (MH ⁺ ) 512.

Example 217

Synthesis of N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide

According to general method B, using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and L-glutamide hydrochloride (Bachem) as a solid (melting point = 260-263 ° C.) to give the title compound. The reaction was monitored by tlc (Rf = 0.77 in 10% MeOH / DCM) and the product was purified by silica gel chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.40 (d, J = 7.1 Hz, 1H), 8.02 (d, J = 6.9, 1H), 7.2 (m, 2H), 7.0 (m, 4H), 6.76 ( s, 1H), 4.2 (m, 1H), 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.

C ₁₆ H ₂₀ F ₂ N ₄ O ₄ (molecular weight = 370); Mass Spectroscopy (MH ⁺ ) 371.

Example 218

Synthesis of Methyl 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate

According to general method A and using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl pipecolinate hydrochloride (Aldrich) as a solid (melting point) = 114-118 ° C) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.71 in 10% MeOH / DCM) and the product was purified by acid / base wash.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.95 (dd, J = 7.1, 7.1, 7.1 Hz; 1H), 6.81 (d, J = 6.1 Hz, 2H), 6.7 (m, 1H), 5.28 (dd, J = 5.0 Hz, 12.6, 5.4, 1H), 4.93 (q, J = 7.0, 6,9, 7.0 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 3H), 3.50 (s, 2H) , 3.2 (m, 1H), 2.27 (d, J = 3.5 Hz, 1H), 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; 169.1; 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.

C ₁₆ H ₂₂ F ₂ N ₂ O ₄ (molecular weight = 368); Mass Spectroscopy (MH ⁺ ) 369.

Example 219

Synthesis of N-[(S) -3-hydroxy-6-methylhept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method AA, N-[(S) -6-methyl-3-oxohept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example above) Obtained from 168) to give the title compound as a solid. The reaction was monitored by tlc (Rf = 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.

NMR data were as follows:

¹ 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, 1H), 1.4 (m, 5H), 1.09 (m, 3H), 0.9 (m, 6H).

Optical rotation: [a] ₂₃ = -39 ° (c 1, MeOH).

C ₁₉ H ₂₈ F ₂ N ₂ O ₃ (molecular weight = 448); Mass Spectroscopy (MH ⁺ ) 449.

Example 220

Synthesis of N-[(S) -2-hydroxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (S) -2-hydroxy-1-phenyleth-1-ylamine The title compound was prepared as a solid (melting point = 204-206 ° C.) using (eg, (S) -phenylglycineol) (Aldrich). The reaction was monitored by tlc (Rf = 0.5 in 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and recrystallized from acetonitrile.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.24 (d, 3H), 4.38 (m, 1H), 4.80 (m, 2H).

Optical rotation: [a] ₂₀ = +3.56 ° @ 589 nm (c 1.10, DMSO).

C ₁₉ H ₂₀ F ₂ N ₂ O ₃ (molecular weight = 362.38); Mass Spectroscopy (MH ⁺ ) 363.

Example 221

Synthesis of N- [N- (3,5-difluorophenyl-α-fluoroacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester

3,5-difluorophenyl-α-fluoroacetic acid (obtained from Example D1 above) and N- (L-alaninyl) -L-phenylglycine tert-butyl ester in accordance with general method M (general method) Using C using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) and removing BOC-groups using the general method P). The title compound was prepared as a clear oil. The reaction was monitored by tlc (Rf in 1: 1 EtOAc / hexanes = 0.51) and the product purified by LC 2000 chromatography using 20% EtOAc / hexanes as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ) (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, 1H), 4.62 (pent, J = 7.0 Hz, 2H), 5.36 (d, J = 7.1 Hz, 1H), 5.42 (d, J = 7.2 Hz, 1H), 5.60 (d, J = 4.7 Hz, 1H), 5.73 (d, J = 4.7 Hz, 1H), 6.80 (m, 2H), 6.97 (m, 4H), 7.20-7.33 (m , 12H).

C ₂₃ H ₂₅ F ₃ N ₂ O ₄ (molecular weight = 450.2); Mass Spectroscopy (MH ⁺ ) 451.

Example 222

Synthesis of N-[(S) -α-hydroxy-α'-phenylisopropyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (S) -α-hydroxy-α'-phenylisopropylamine (example For example, L-phenylalaninol) (Aldrich) was used to prepare the title compound as a solid. The reaction was monitored by tlc (Rf = 0.5 in 9: 1 CHCl ₃ / MeOH) and the product was purified by silica gel chromatography using 95: 5 CHCl ₃ / MeOH as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.33-7.17 (m, 5H), 6.72 (m, 3H), 6.62 (d, 1H), 6.32 (d, 1H), 4.43 (m, 1H), 4.10 ( m, 1H), 3.61 (m, 2H), 3.45 (s, 2H), 2.84 (m, 2H), 1.32 (d, 3H).

Optical rotation: [a] ₂₃ = -60 ° (c 1, MeOH).

C ₂₀ H ₂₂ F ₂ N ₂ O ₃ (molecular weight = 376); Mass Spectroscopy (MH ⁺ ) 377.

Example 223

Synthesis of N-[(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (1S, 2R) -1-hydroxy-1-phenylprop-2 The title compound was prepared as a solid using -ylamine hydrochloride (eg (1S, 2R) -norephedrine hydrochloride) (Aldrich). The reaction was monitored by tlc (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 eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.31 (m, 5H), 6.84-6.64 (m, 4H), 4.86 (m, 1H), 4.51 (m, 1H), 4.23 (m, 1H), 3.52 ( s, 2H), 1.38 (d, 3H), 0.97 (d, 3H).

Optical rotation: [a] ₂₃ = -44 ° (c 1, MeOH).

C ₂₀ H ₂₂ F ₂ N ₂ O ₃ (molecular weight = 376); Mass Spectroscopy (MH ⁺ ) 377.

Example 224

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

According to general method K, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester (obtained from Example 28 above) and 2-methoxyethylamine (Aldrich ) To give the title compound as a solid (melting point = 148-151 ° C). The reaction was monitored by tlc (Rf = 0.53 in 10% MeOH / DCM + 1% TEA) and the product was purified by silica gel chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 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, 72.2, 72.1, 59.4, 51.9, 44.0, 43.0, 40.7 , 17.9.

C ₁₆ H ₂₁ F ₂ N ₃ O ₄ (molecular weight = 357); Mass Spectroscopy (MH ⁺ ) 358.

Example 225

Synthesis of N- [N- (3,5-difluorophenylacetyl) -2- (S) -aminocyclohexylacetyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and N- [2- (S) -aminocyclohexylacetyl] -L-phenylglycine methyl ester hydrochloride (general method E is used As a solid using N-BOC-L-cyclohexylglycine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) and removing BOC-groups using general method P). (Melting point = 234.4 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.65 in 5:95 MeOH / DCN) and the product was purified by recrystallization from ethyl acetate.

NMR data were as follows:

¹ 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), 3.36 (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).

¹³ C-nmr (DMSO-d ₆ ): δ = 171.065, 170.865, 168.953, 164.179, 163.967, 160.282, 160.070, 141.210, 141.058, 135.766, 128.657, 128.374, 128.004, 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.

C ₂₅ H ₂₈ F ₂ N ₄ O ₂ (molecular weight = 458.51); Mass spectroscopy (MH ⁺ ) 458.1.

Example 226

Synthesis of N-[(1R, 2S) -1-hydroxy-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (1R, 2S) -1-hydroxy-1-phenylprop-2 The title compound was prepared as a foam using -ylamine hydrochloride (eg, (1R, 2S) -norephedrine hydrochloride) (Aldrich). The reaction was monitored by tlc (Rf = 0.5 in 9: 1 CHCl ₃ / MeOH).

NMR data were as follows:

¹ 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: [a] ₂₃ = -64 ° (c 1, MeOH).

C ₂₀ H ₂₂ F ₂ N ₂ O ₃ (molecular weight = 376); Mass Spectroscopy (MH ⁺ ) 377.

Example 227

Synthesis of N-[(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alaninamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (1R, 2S) -2-amino-1,2-diphenylethanol ( Aldrich) was used to prepare the title compound as a solid (melting point = 217-219 ° C.). The reaction was monitored by tlc (Rf = 0.4 in 10% MeOH / CHCl ₃ ) and the product was subjected to silica gel chromatography using 7% MeOH / CHCl ₃ as eluent and recrystallized from acetonitrile.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 0.76 (d, 3H), 5.43 (d, 1H).

Optical rotation: [a] ₂₀ = -6.9 ° @ 589 nm (c 1.10, DMSO).

C ₂₅ H ₂₄ F ₂ N ₂ O ₃ (molecular weight = 438.48); Mass Spectroscopy (MH ⁺ ) 439.

Example 228

Synthesis of N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method S, use methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate (obtained from Example 1 above) To give the title compound as a solid (melting point = 157-158.5 ° C.). The reaction was monitored by tlc (Rf = 0.62 in 10% CH ₃ OH / CH ₂ Cl ₂ ).

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.

C ₁₇ H ₂₄ F ₂ N ₂ O ₃ (molecular weight = 342.39); Mass Spectroscopy (MH ⁺ ) 343.

Example 229

Synthesis of N- [α-hydroxy-α '-(4-hydroxyphenyl) isopropyl] -N'-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method S and using N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tyrosine methyl ester (obtained from Example 15 above) as a solid (melting point = 179-183 ° C) to provide the title compound. The reaction was monitored by tlc (Rf = 0.42 in 10% MeOH / DCM) and the product was purified by recrystallization from MeOH / diethyl ether.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.82 (d, J = 8.3 Hz, 2H), 6.7 (m, 2H), 6.62 (t, J = 9.1, 9.1 Hz, 1H), 6.47 (d, J = 8.5 Hz, 2H), 4.1 (m, 1H), 3.7 (m, 1H), 3.34 (s, 2H), 3.2 (m, 2H), 2.5 (m, 2H), 1.08-0.94 (dd, J = 7.1 , 36.0, 7.1 Hz, 3H).

¹³ C-nmr (CDCl ₃ ): 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.

C ₂₀ H ₂₂ F ₂ N ₂ O ₄ (molecular weight = 392); Mass Spectroscopy (MH ⁺ ) 393.

Example 230

Synthesis of N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide

According to general method K, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester (obtained from Example 94 above) and 2- (aminomethyl) pyridine (Aldrich) was used to prepare the title compound.

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 8.45 (d, 1H), 7.75 (t, 1H), 7.2-7.4 (m, 6H), 7.1 (d, 1H), 6.8-7.0 (m, 3H) , 4.63 (t, 1H), 4.45 (s, 2H), 4.2-4.35 (m, 1H), 3.6 (s, 2H), 3.6 (s, 2H), 3.0-3.25 (m, 2H), 1.30 (d , 3H).

¹³ C-nmr (CD ₃ OD): 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, 113.6, 103.2, 56.9, 51.4, 45.8, 43.1, 39.0, 18.2.

C ₂₆ H ₂₆ F ₂ N ₄ O ₃ (molecular weight = 480.52); Mass Spectroscopy (MH ⁺ ) 481.

Example 231

Synthesis of N- [α-hydroxy-α'-pyrid-2-ylisopropyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method S, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-pyridyl) propionate (above Obtained from Example 19) to give the title compound as a solid (melting point = 225-229 ° C). The reaction was monitored by tlc (Rf = 0.66 in 10% MeOH / DCM) and the product was purified by recrystallization from MeOH / diethyl ether.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.21 (d, J = 4.5 Hz, 1H), 7.46 (t, J = 6.3, 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 5.5, 7.1 Hz, 1H), 6.70 (d, J = 6.3 Hz, 2H), 6.62 (t, J = 9.6, 9.0 Hz, 1H), 4.1 (m, 1H), 3.4 (m, 1H), 3.33 (s, 2H), 3.3 (m, 2H), 1.06 (d, J = 7.0 Hz, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 172.754, 160.222, 150.134, 139.137, 126.198, 123.680, 113.936, 113.602, 103.578, 64.854, 53.689, 51.191, 43.304, 40.394, 18.769.

C ₁₉ H ₂₁ F ₂ N ₃ O ₃ (molecular weight = 377); Mass Spectroscopy (MH ⁺ ) 378.

Example 232

Synthesis of N- [α-hydroxy-α'-pyrid-4-ylisopropyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method S, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-pyridyl) propionate (above The title compound was obtained as a solid (melting point = 189-193 ° C.) using Example 23). The reaction was monitored by tlc (Rf = 0.47 in 10% MeOH / DCM) and the product was purified by silica gel chromatography.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.18 (d, J = 5.6 Hz, 2H), 7.27 (d, J = 5.6 Hz, 2H), 6.7 (m, 2H), 6.6 (m, 1H), 4.0 (m, 1H), 3.9 (m, 1H), 3.32 (s, 2H), 3.10 (s, 2H), 2.9 (m, 2H), 1.07 (d, J = 7.2, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 175.8, 150.4, 150.2, 126.8, 113.9, 113.6, 103.6, 103.5, 72.0, 59.3, 55.2, 51.6, 42.9, 40.8, 38.3, 17.9.

C ₁₉ H ₂₁ F ₂ N ₃ O ₃ (molecular weight = 377); Mass Spectroscopy (MH ⁺ ) 378.

Example 233

Synthesis of N-[(S) -1-hydroxy-4-methylpent-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

Isomer A:

According to general method B, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (S) -1-hydroxy-4-methylpent-2-ylamine (Rusinol) (Bachem) was used to prepare the title compound as a solid (melting point = 141-151 ° C). The reaction was monitored by tlc (Rf = 0.5 in 5% MeOH / methylene chloride) and the product was purified by recrystallization from EtOAc / hexanes.

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 8.15 (s, 1H), 7.5 (t, J = 8 Hz, 1H), 6.80-6.55 (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 = 175.4, 175.3, 173.0, 113.9, 113.6, 113.5, 103.9, 103.2, 66.1, 51.6, 51.4, 51.3, 43.4, 41.7, 41.6, 26.5, 26.3, 24.3, 22.8, 22.7, 19.0, 18.7, 18.6.

C ₁₇ H ₂₄ F ₂ N ₃ O ₂ (molecular weight = 342.19); Mass Spectroscopy (MH ⁺ ) 343.

Isomer B:

According to general method B, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (S) -1-hydroxy-4-methylpent-2-ylamine (Rusinol) (Bachem) was used to prepare the title compound as a solid (melting point = 151-153 ° C). The reaction was monitored by tlc (Rf = 0.8 in 10% MeOH / DCM) and the product was recrystallized and flash column chromatographed and purified by purification tlc using 10% MeOH / DCM as eluent.

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 8.15 (s, 1H), 7.5 (t, J = 8 Hz, 1H), 6.80-6.55 (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.

C ₁₇ H ₂₄ F ₂ N ₃ O ₂ (molecular weight = 342.19); Mass Spectroscopy (MH ⁺ ) 342.

Example 234

Synthesis of N- [1-methoxyprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method B, solid using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and 2-amino-1-methoxypropane (Aldrich) (Melting point = 152 ° C.) as the title compound. The reaction was monitored by tlc (Rf = 0.45 in 5% MeOH / DCM) and the product was purified by recrystallization from methanol / water.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.9-6.7 (m, 3H), 6.6 (d, J = 7 Hz, 1H), 6.3 (m, 1H), 4.5 (m, J = 7 Hz, 1H) , 4.1 (m, 1H), 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 (CDCl ₃ ): 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.

C ₁₇ H ₂₀ F ₂ N ₃ O ₂ (molecular weight = 314.14); Mass Spectroscopy (MH ⁺ ) 315.

Example 235

Synthesis of N- [1-hydroxy-3-methylbut-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method B and using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and ballanol (bachem) as a solid (melting point = 176-179 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.4 in 5% MeOH / DCM) and the product was purified by recrystallization from EtOAc / hexanes.

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 7.5 (d, J = 9 Hz, 1H), 6.8-6.5 (m, 3H), 4.15 (m, 1H), 3.45 (m, 2H), 3.35 (m , 3H), 1.65 (m, J = 7 Hz, 1H), 1.20 (d, J = 5 Hz, 3H), 0.7 (m, 6H).

¹³ C-nmr (acetone-d ₆ ): 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, 20.4, 19.5, 19.1, 19.0, 18.8.

C ₁₆ H ₂₂ N ₂ O ₃ F ₂ (molecular weight = 329.19); Mass Spectroscopy (MH ⁺ ) 329.

Example 236

Synthesis of methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (6-aminopyrid-2-yl) acetate

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (6-aminopyrid-2-yl) Title compound using acetate (prepared from 2- (methoxyimino) -2- (6-aminopyrid-2-yl) acetic acid [CAS 71470-33-2] using the general methods G and AC described above) Was prepared. The reaction was purified by LC 2000 purification column chromatography using 1: 1 EtOAc / hexane as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.65-6.5 (m, 6H), 6.4 (d, J = 8.19 Hz, 1H), 5.49-5.33 (m, 1H), 4.8-4.5 (m, 2H), 3.7 (s, 3H), 3.6 (s, 1H), 3.5 (s, 1H), 2.06 (bs, 2H), 1.44 (d, J = 7.06 Hz, 1.5H), 1.35 (d, 7.06 Hz, 1.5H ).

C ₁₉ H ₂₀ N ₄ O ₄ F ₂ (molecular weight = 406.39); Mass Spectroscopy (MH ⁺ ) 406.3.

Example 237

Synthesis of N- [1-hydroxyprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method B, using N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and alanol (bachem) as a solid (melting point = 158-163 ° C.) The title compound was prepared. The reaction was monitored by tlc (Rf = 0.7 in 10% MeOH / DCM) and the product was recrystallized from ethyl acetate and purified by flash column chromatography using 10% MeOH / DCM.

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 8.2 (m, 1H), 7.6 (m, 1H), 4.1 (m, J = 7 Hz, 1H), 3.7 (m, J = 5 Hz, 1H), 3.35 (s, 2H), 3.25 (m, 2H), 1.15 (d, J = 7 Hz, 3H), 0.9 (d, J = 7 Hz, 3H).

¹³ C-nmr (CD ₃ OD): 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.

C ₁₄ H ₁₈ N ₂ O ₃ F ₂ (molecular weight = 300); Mass Spectroscopy (MH ⁺ ) 301.

Example 238

Synthesis of N-[(S) -2-methoxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

3,5-difluorophenylacetic acid (oakwood) and N-[(S) -2-methoxy-1-phenyleth-1-yl] -L-alanineamide according to general method C (general method C) Using N-BOC-L-alanine (Sigma) and (S) -phenylglycineol methyl ether (obtained from Example D15 above) and prepared by removing the BOC-group using the general method P). The title compound was prepared as a solid (melting point = 180-182 ° C.). The reaction was monitored by tlc (Rf = 0.4 in 10% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and recrystallized from 1-chlorobutane / acetonitrile.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 3.23 (s, 3H).

Optical rotation: [a] ₂₀ = +12.3 ° @ 589 nm (c 1.04, DMSO).

C ₂₀ H ₂₂ F ₂ N ₂ O ₃ (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-alanineamide

According to general method B, fluff with N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and L-phenylalanineol methyl ether hydrochloride (pluca). The title compound was prepared as a solid. The product was purified by recrystallization from MeOH / EtOAc.

NMR data were as follows:

¹ H-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 (m, 3H), 7.1-7.35 (m, 5 H).

¹³ C-nmr (CDCl 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] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

Following General Method V, N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (obtained from Example 228 above) ) To give the title compound as a solid (melting point = 144-145 ° C). The reaction was monitored by tlc (Rf = 0.42 in 10% CH ₃ OH / CH ₂ Cl ₂ ).

NMR data were as follows:

¹ H-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.

C ₁₉ H ₂₆ F ₂ N ₂ O ₄ (molecular weight = 384.43); Mass Spectroscopy (MH ⁺ ) 385.

Example 241

Synthesis of N-[(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

Following General Method W, N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (obtained from Example 228 above) ) And trimethylacetyl chloride (Aldrich) to prepare the title compound as a solid (melting point = 104-107.5 ° C.). The reaction was monitored by tlc (Rf = 0.43 in 10% CH ₃ OH / CH ₂ Cl ₂ ) and the product was purified by purified thin layer chromatography using 10% CH ₃ OH / CH ₂ Cl ₂ as eluent.

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.

C ₂₂ H ₃₂ F ₂ N ₂ O ₄ (molecular weight = 426.51); Mass spectroscopy (MH ⁺ ) 427.5.

Example 242

Synthesis of N- [2-hydroxy-1- (thien-2-yl) ethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to the general method S, methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate (performed above Obtained from Example 178) to give the title compound as a solid (melting point = 201-202 ° C). The product was purified by treatment with 1: 1 hexanes / EtOAc.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.4-8.25 (m, 2H), 7.4-7.35 (m, 2H), 7.3-6.91 (m, 4H), 5.1-4.85 (m, 1H), 4.4 -4.3 (m, 1H), 3.7-3.5 (m, 2H), 3.51 (s, 1H), 3.50 (s, 1H), 1.23-1.19 (overlaying doublets, 3H).

C ₂₁ H ₂₃ F ₂ N ₂ O ₃ (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-alanineamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and (S) -2-hydroxy-2-methyl-1-phenylprop The title compound was prepared as a solid using -1-ylamine (obtained from Example D16 above). The product was purified by recrystallization from methanol / ethyl acetate.

NMR data were as follows:

¹ 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: [a] ₂₃ = -11 1 @@ 589 nm (c 1, MeOH).

C ₂₁ H ₂₄ F ₂ N ₂ O ₃ (molecular weight = 390.42); Mass Spectroscopy (MH ⁺ ) 391.

Example 244

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L- (thienyl-2-yl) glycinyl] -L-phenylalanine tert-butyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L- (2-thienyl) glycinyl-L-phenylglycine tert-butyl ester (N- using general method AH) Dish in DMF and THF, using (9-fluorenylmethoxycarbonyl) -L- (2-thienyl) glycine (prepared as described below) and L-phenylglycine tert-butyl ester hydrochloride Prepared by deprotection with clohexylamine) to give the title compound as a solid (melting point = 176-177 ° C.). The product was purified by flash chromatography using EtOAc / dichloromethane as eluent.

NMR data were as follows:

C ₂₆ H ₂₆ N ₂ O ₄ F ₂ (molecular weight = 500.56); Mass spectroscopy (MH ⁺ ) 500.

Preparation of N- (9-fluorenylmethoxycarbonyl) -L- (2-thienyl) glycine:

Water, dioxane, sodium carbonate (2.5 equiv) and L-α- (2-thienyl) glycine (1.0 equiv) (sigma) were placed in a round bottom flask with a magnetic stir bar at room temperature under nitrogen atmosphere. Agitation was initiated and the slurry was cooled in an ice bath. 9-Flurenylmethyl chloroformate was added portionwise to the reaction and stirring was continued for 4 hours in an ice bath followed by 8 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The aqueous layer was cooled in an ice bath and acidified to pH 2 by vigorous stirring. The resulting solid was separated by vacuum filtration, washed with water (3 ×) and dried under reduced pressure.

Example 245

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

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycineol (N-BOC-L-phenylglycine (Novabi) using general method AH Ochem) and L-phenylglycineol (Novabiochem) and prepared by removing the BOC-group using the general method P) to prepare the title compound as a solid (melting point = 231.4 ° C.). The product was purified by recrystallization from ethyl acetate.

C ₂₄ H ₂₂ N ₂ O ₃ F ₂ (molecular weight = 424.45); Mass spectroscopy (MH ⁺ ) 424.9.

Example 246

Synthesis of N- [N- (cyclopropaneacetyl) -L-phenylglycineyl] -L-phenylglycineol

According to general method E, cyclopropaneacetic acid (Aldrich) and L-phenylglycineyl-L-phenylglycineol (N-BOC-L-phenylglycine (novabiochem) and L-phenyl using general method AH) The title compound was prepared as a solid (melting point = 202.5 ° C.) using glycineol (Novabiochem) and prepared by removing BOC-groups using the general method P. The product was purified by recrystallization from ethyl acetate.

C ₂₁ H ₂₄ N ₂ O ₃ (molecular weight = 352.43); Mass Spectroscopy (MH ⁺ ) 353.2.

Example 247

Synthesis of N- [N- (cyclopropaneacetyl) -L-phenylglycineyl] -L-phenylglycineol

According to general method E, cyclopentanoacetic acid (Aldrich) and L-phenylglycine yl-L-phenylglycineol (N-BOC-L-phenylglycine (novabiochem) and L-phenyl using general method AH) The title compound was prepared as a solid (melting point = 201.4 ° C.) using glycineol (Novabiochem) and prepared by removing the BOC-group using the general method P. The product was purified by flash chromatography using MeOH / CH ₂ CH ₂ as eluent.

C ₂₃ H ₂₈ N ₂ O ₃ (molecular weight = 380.49); Mass spectroscopy (MH ⁺ ) 381.4.

Example 248

Synthesis of N- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycineyl] -D, L-phenylglycineamide

According to the general method AO and using N- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycine methyl ester (obtained from Example 99 above) To give the title compound as a solid (melting point = 285.5-288.5 ° C.).

C ₂₄ H ₂₁ N ₃ O ₃ F ₂ (molecular weight = 437.45); Mass spectroscopy (MH ⁺ ) 437.1.

Example 249

Synthesis of N- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycineamide

Melting point according to the general method AO and using N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester (obtained from Example 94 above) as a solid = 260.3-264.3 ° C) The title compound was prepared. The product was purified by recrystallization from ethyl acetate / methanol.

C ₂₁ H ₂₃ N ₃ O ₃ F ₂ (molecular weight = 403.43); Mass Spectroscopy (MH ⁺ ) 404.

Example 250

Synthesis of N- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycinamide

The title compound was prepared according to the general method described herein.

Example 251

Synthesis of N- [N- (n-caproyl) -L-alaninyl] -L-phenylglycinamide

The title compound was prepared according to the general method described herein.

Example 252

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-norucinyl] -L-phenylglycine methyl ester

3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine methyl ester hydrochloride according to general method E (N-BOC-L-norleucine using general method E) (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich), prepared by removing BOC-groups using general method P), as a solid (melting point = 188-189.5 ° C.) Was prepared. The product was purified by flash chromatography using ethyl acetate / hexanes as eluent.

C ₂₃ H ₂₆ N ₂ O ₄ F ₂ (molecular weight = 432.47); Mass Spectroscopy (MH ⁺ ) 432.

Example 253

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L-norvalinyl-L-phenylglycine methyl ester hydrochloride (N-BOC-L-norvaline using general method E (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich), prepared by removing BOC-groups using the general method P), as a solid (melting point = 204-205 ° C.) Was prepared. The product was purified by flash chromatography using ethyl acetate / hexanes as eluent.

C ₂₂ H ₂₄ N ₂ O ₄ F ₂ (molecular weight = 418.44); Mass spectroscopy (MH ⁺ ) 418.3.

Example 254

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-tert-leucineyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L-tert-leucineyl-L-phenylglycine methyl ester hydrochloride (N-BOC-L- using general method E) As solid (melting point = 176.4 ° C.) using tert-leucine (bakem) and L-phenylglycine methyl ester hydrochloride (Aldrich) and using the general method P to remove BOC-groups The title compound was prepared. The product was purified by flash chromatography using ethyl acetate / hexanes as eluent.

C ₂₃ H ₂₆ N ₂ O ₄ F ₂ (molecular weight = 432.47); Mass spectroscopy (MH ⁺ ) 432.0.

Example 255

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-isoleucineyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L-isoleucineyl-L-phenylglycine methyl ester hydrochloride (N-BOC-L-isoleucine using general method E) (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich), prepared by removing the BOC-group using the general method P), as a solid (melting point = 228.8 ° C.) Was prepared. The product was purified by flash chromatography using ethyl acetate / hexanes as eluent.

C ₂₃ H ₂₆ N ₂ O ₄ F ₂ (molecular weight = 432.46); Mass spectroscopy (MH ⁺ ) 433.4.

Example 256

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalanylyl] -L-phenylglycine methyl ester

3,5-difluorophenylacetic acid (Aldrich) and L-cyclohexylalanylyl-L-phenylglycine methyl ester hydrochloride according to general method E (N-BOC-L-cyclo using general method E) Title compound as a solid (melting point = 174.8 ° C.) using hexylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) and removing the BOC-group using the general method P) Was prepared. The product was purified by flash chromatography using ethyl acetate / hexanes as eluent.

C ₂₆ H ₃₀ N ₂ O ₄ F ₂ (molecular weight = 472.53); Mass spectroscopy (MH ⁺ ) 473.2.

Example 257

Synthesis of N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (cyclopropyl) acetyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and (S) -2-amino-2- (cyclopropyl) acetyl-L-phenylglycine methyl ester hydrochloride (general method E N-BOC- (S) -2-amino-2-cyclopropylacetic acid (Evans et al., J. Am. Chem. Soc., 1990, 112, 4011-4030) and described herein. Prepared by using the method as described in the reference) and L-phenylglycine methyl ester hydrochloride (Aldrich) and by removing the BOC-group using the general method P) as a solid. (Melting point = 225-226.5 ° C.) The title compound was prepared. The product was purified by flash chromatography using MeOH / CHCl ₃ as eluent.

C ₂₂ H ₂₂ N ₂ O ₄ F ₂ (molecular weight = 416.42); Mass spectroscopy (MH ⁺ ) 417.3.

Example 258

Synthesis of N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-3-yl) acetyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L- (S) -2-amino-2- (thien-3-yl) acetyl-L-phenylglycine methyl ester hydrochloride (N-BOC-L-thien-3-ylglycine (prepared from L-α-2-thienylglycine (Sigma) using general method AJ)) and L-phenylglycine methyl ester hydrochloride (Aldrich) The title compound was prepared as a solid (melting point = 229.3 ° C.) using the method and prepared by removing the BOC-group using the general method P). The product was purified by crystallization from ethyl acetate / hexanes.

C ₂₃ H ₂₀ N ₂ O ₄ SF ₂ (molecular weight = 458.49); Mass Spectroscopy (MH ⁺ ) 458.

Example 259

Synthesis of N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-2-yl) acetyl] -L-phenylglycine methyl ester

3,5-difluorophenylacetic acid (Aldrich) and L- (S) -2-amino-2- (thien-2-yl) acetyl-L-phenylglycine methyl ester hydrochloride according to general method AH (N-BOC-L-thien-2-ylglycine using General Method E (prepared from L-α- (thien-2-yl) glycine (Sigma) using General Method AI) and L-phenylglycine The title compound was prepared as a solid (melting point = 230.8 ° C.) using methyl ester hydrochloride (Aldrich) and prepared by removing the BOC-group using the general method P. The product was purified by flash chromatography using MeOH / CH ₂ CH ₂ as eluent.

C ₂₃ H ₂₀ N ₂ O ₄ F ₂ S (molecular weight = 458.49); Mass Spectroscopy (MH ⁺ ) 458.

Example 260

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L- (4-fluorophenyl) glycinyl-L-phenylglycine methyl ester hydrochloride (N- using general method E Cbz- (4-fluorophenyl) glycine (prepared from (4-fluorophenyl) glycine (prepared as described below) using general method AK) and L-phenylglycine methyl ester hydrochloride (Aldrich) H), silica gel chromatography using 5% ethyl acetate / toluene as eluent and prepared by removing Cbz-group using the general method AJ) (melting point = 213.1 ° C.) as the solid Was prepared. The product was purified by flash chromatography using ethyl acetate / CHCl ₃ as eluent.

C ₂₅ H ₂₁ N ₂ O ₄ F ₂ (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 THF (100 ml). The solution was cooled to -70 ° C and the reaction flask was purged twice with nitrogen. n-butyl lithium (44.6 ml, 2.0 M, 89 mmol) was added to form a solid precipitate which was triturated upon stirring to give a slurry. 4-fluorophenylacetyl chloride (16.1 g, 93 mmol) (Aldrich) was added to give a bright green solution and stirring was continued for 45 minutes. The reaction mixture was then treated with saturated sodium hydrogen sulfate (100 ml) and ethyl acetate (100 ml). The organic phase was washed with water followed by brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. This oil was crystallized to give 24.4 g of 1- (4-fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone.

Potassium hexamethyldisilazane (140 ml, 0.5 M, 70.0 mmol) was added to THF (80 ml). The solution was cooled to −50 ° C. under nitrogen and 1- (4-fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone (15.0 g, 46) in THF (100 ml) Mmol) cold (-60 ° C) solution was added. The resulting mixture was stirred at -70 ° C for 1 hour and warmed to about -20 ° C. This mixture was recooled to -70 ° C and a cold solution of trasyl azide (21.6 g, 70.0 mmol) (-65 ° C) was added. This mixture was stirred for about 15 minutes. This mixture was then stirred at about 30 ° C. for 3 hours. A precipitate formed and was filtered off. The filtrate was concentrated in 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 Obtained.

Crude 1- [2- (4-fluorophenyl) -2-azidoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone (10.0 g, 28.0 mmol) was diluted with 100 ml of THF and Dissolve in 100 ml of methanol and add trifluoroacetic acid (4.31 ml, 75.3 mmol). Palladium on carbon (10%, 2.0 g) was added and the mixture was hydrogenated overnight on a Parr shaker at room temperature under 50 psi. The reaction mixture was then filtered through a plug of celite and the solid cake was washed with 100 ml of methanol. The filtrate was concentrated to give 1- [2- (4-fluorophenyl) -2-aminoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone trifluoroacetate salt as a yellowish oil. Obtained.

1- [2- (4-fluorophenyl) -2-aminoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone in a mixture of THF and deionized water (50 ml / 50 ml) Trifluoroacetate salt (4.14 g, 9.7 mmol) and lithium hydroxide monohydrate (1.22 g, 29 mmol) were added. The homogeneous solution was stirred at room temperature for 2 hours, at which time Tlc showed complete disappearance of starting material. This mixture was extracted with dichloromethane (3 × 100 ml) and acidified to pH 2-3 with cooling of the aqueous phase in an ice bath. A precipitate formed. The mixture was then cooled in an ice bath for 1.5 hours and filtered. The solid was washed with water and then pentane to afford 4-fluorophenylglycine hydrochloride.

Example 261

Synthesis of N- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and D- (4-fluorophenyl) glycinyl-L-phenylglycine methyl ester hydrochloride (N- using general method E L-phenylglycine methyl ester hydro using Cbz- (4-fluorophenyl) glycine (prepared as described in Example 260) using (4-fluorophenyl) glycine using the general method AK and general method E Prepared from chloride (Aldrich), silica gel chromatography using 5% ethyl acetate / toluene as eluent and prepared by removing Cbz-group using the general method AJ (melting point = 188.0 ° C.) The title compound was prepared The product was purified by flash chromatography using ethyl acetate / CHCl ₃ as eluent.

C ₂₅ H ₂₁ N ₂ O ₄ F ₃ (molecular weight = 470.44); Mass spectroscopy (MH ⁺ ) 470.1.

Example 262

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine methyl ester

According to general method E, 3,5-difluorophenylacetic acid (Aldrich) and L- (4-methoxyphenyl) glycinyl-L-phenylglycine methyl ester hydrochloride (N- using general method AK Cbz-L- (4-methoxyphenyl) glycine ((4-methoxyphenyl) glycine (Greenstein et al., "The Chemistry of Amino Acids", Vol. 1, p. 698, Wiley, New York ( 1961)), and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Method E), which is prepared from the Bucherer variant of the Strecker method. And the title compound was prepared as a solid (melting point = 224.6 ° C.) using the general method AJ, prepared by removing the Cbz- group. The product was purified by flash chromatography using MeOH / CHCl ₃ as eluent.

C ₂₆ H ₂₄ N ₂ O ₅ F ₂ (molecular weight = 482.48); Mass spectroscopy (MH ⁺ ) 482.1.

Example 263

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-phenylglycineyl] -L-phenylglycine tert-butyl ester

N-Cbz-L-phenyl according to general method E, using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl ester (general method AH) Prepared from Glycine (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) and prepared by removing Cbz-groups using the general method AJ (melting point = 185.0). ° C) The title compound was prepared. The product was purified by flash chromatography using ethyl acetate / CH ₂ CH ₂ as eluent.

C ₂₈ H ₂₈ N ₂ O ₄ F ₂ (molecular weight = 494.54); Mass Spectroscopy (MH ⁺ , minus C0 ₂ -t-Bu) 393.

Example 264

Synthesis of N- [N- (cyclopropylacetyl) -L-phenylglycineyl] -L-phenylglycine tert-butyl ester

According to general method E, cyclopropylacetic acid (Aldrich) and L-phenylglycineyl-L-phenylglycine tert-butyl ester hydrochloride (N-Cbz-L-phenylglycine (Novabi) using general method AH Ochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) and prepared by removing Cbz-groups using the general method AJ) (melting point = 187.5 ° C.) as the solid Was prepared. The product was purified by crystallization from ethyl acetate.

C ₂₅ H ₃₀ N ₂ O ₄ (molecular weight = 422.53); Mass spectroscopy (MH ⁺ ) 423.4.

Example 265

Synthesis of N- [N- (cyclopentylacetyl) -L-phenylglycineyl] -L-phenylglycine tert-butyl ester

According to general method E, cyclopropylacetic acid (Aldrich) and L-phenylglycineyl-L-phenylglycine tert-butyl ester hydrochloride (N-Cbz-L-phenylglycine (Novabi) using general method AH Ochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) and prepared by removing Cbz-groups using the general method AJ) (melting point = 190.8 ° C.) as the solid Was prepared. The product was purified by crystallization from ethyl acetate.

C ₂₅ H ₃₄ N ₂ O ₄ (molecular weight = 450.58); Mass Spectroscopy (MH ⁺ ) 451.

Example 266

Synthesis of N- [N- (t-butylacetyl) -L-alaninyl] -L-phenylglycinamide

The title compound was prepared according to the general method described herein.

Example 267

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

According to general method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 5-bromo-2-thiophenecarboxaldehyde (Aldrich), The title compound was prepared as a solid (melting point = 227-228 ° C.) using (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H ₂₄ N ₃ O ₃ BrS (molecular weight = 515); Mass Spectroscopy (MH ⁺ ) 515, 415.

Example 268

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

According to general method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 5-bromo-2-thiophenecarboxaldehyde (Aldrich), The title compound was prepared as a solid (melting point = 216-217 ° C.) using (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H ₂₄ N ₃ O ₃ BrS (molecular weight = 515); Mass Spectroscopy (MH ⁺ ) 515, 415.

Example 269

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

According to general method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4-bromo-2-thiophenecarboxaldehyde (Aldrich), The title compound was prepared as a solid (melting point = 246-247 ° C.) using (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H ₂₄ N ₃ O ₃ BrS (molecular weight = 515); Mass Spectroscopy (MH ⁺ ) 515, 415.

Example 270

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

According to General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 2-thiophenecaraldehyde (aldrich), (S)-( The title compound was prepared as a solid (melting point = 241-242 ° C.) using +)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H ₂₅ N ₃ O ₃ F ₂ S (molecular weight = 438); Mass spectroscopy (MH ⁺ ) 438, 338.

Example 271

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

According to General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 2-thiophenecaraldehyde (aldrich), (S)-( The title compound was prepared as a solid (melting point = 235-236 ° C.) using +)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H ₂₅ N ₃ O ₃ F ₂ S (molecular weight = 438); Mass spectroscopy (MH ⁺ ) 438, 338.

Example 272

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

Following General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 3-thiophenecaraldehyde (aldrich), (S)-( The title compound was prepared as a solid (melting point = 240-241 ° C.) using +)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H 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) -L-alaninyl] -D- (thien-3-yl) glycinamide

Following General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 3-thiophenecaraldehyde (aldrich), (S)-( The title compound was prepared as a solid (melting point = 245-246 ° C.) using +)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide. The product was purified by recrystallization from ethyl acetate / hexanes.

C ₂₁ H ₂₅ N ₃ O ₃ F ₂ S (molecular weight = 438); Mass spectroscopy (MH ⁺ ) 438, 338.

Example 274

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

According to general method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), benzaldehyde (aldrich), (S)-(+)-α-methyl Benzylamine (Aldrich) and tert-butylisocyanide were used to prepare the title compound as a solid (melting point = 239-240 ° C.). The reaction was monitored by tlc (Rf = 0.25 in 50% ethyl acetate / hexanes).

C ₂₃ H ₂₇ N ₃ O ₃ F ₂ (molecular weight = 431.53); Mass Spectroscopy (MH ⁺ ) 432.

Example 275

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

According to general method AL, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), benzaldehyde (aldrich), (S)-(+)-α-methyl The title compound was prepared as solid (melting point = 240-241 ° C.) using benzylamine (Aldrich) and tert-butylisocyanide.

C ₂₃ H ₂₇ N ₃ O ₃ F ₂ (molecular weight = 431.53); Mass Spectroscopy (MH ⁺ ) 432.

Example 276

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

According to general method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from example B2 above), 5-chloro-2-thiophenecarboxaldehyde (obtained from example D17 above) ), (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide to prepare the title compound as a solid (melting point = 195-198 ° C.). The reaction was monitored by tlc (Rf = 0.15 in 50% ethyl acetate / hexanes).

C ₂₁ H ₂₄ N ₃ O ₃ F ₂ Cl (molecular weight = 472); Mass Spectroscopy (MH ⁺ ) 472.

Example 277

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

Following General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4-biphenylcarboxaldehyde (Aldrich), (S)-( The title compound was prepared as a solid (melting point = 300 ° C. (degradation)) using +)-α-methylbenzylamine (Aldrich) and cyclohexylisocyanade (Aldrich). This reaction was monitored by tlc (Rf = 0.23 in 50% ethyl acetate / hexanes).

C₃₁H₃₃N₃O₃F₂(Molecular weight = 533.62); Mass spectroscopy (MH⁺, Negative cyclohexylamide) 408.2.

Example 278

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

According to the general method AM, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 3-phenoxybenzaldehyde (Aldrich), (S)-(+) The title compound was prepared using -α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). The reaction was monitored by tlc (Rf = 0.29 in 50% ethyl acetate / hexanes).

C ₂₉ H ₃₁ N ₃ O ₄ F ₂ (molecular weight = 523.63); Mass Spectroscopy (MH ⁺ ) 524.24.

Example 279

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

According to general method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), benzaldehyde (aldrich) and (S)-(-)-α-methyl Benzylisocyanide (obtained from Example D18, above) was used to prepare the title compound.

C ₂₇ H ₂₇ N ₃ O ₃ F ₂ (molecular weight = 479.53); Mass Spectroscopy (MH ⁺ ) 480.21.

According to the above-mentioned method, N- (R)-(+)-α-methylbenzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- Phenylglycinamide was prepared by substitution of only suitable isomers.

C ₂₇ H ₂₇ N ₃ O ₃ F ₂ (molecular weight = 479.53); Mass spectroscopy (MH ⁺ ) 480.1.

Example 280

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

According to general method AM, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from example B2 above), 3-phenylbenzaldehyde (obtained from example D20 above), (S)-( The title compound was prepared using +)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). This reaction was monitored by tlc (Rf = 0.25 in 50% ethyl acetate / hexanes).

C ₂₉ H ₃₁ N ₃ O ₃ F ₂ (molecular weight = 507.63); Mass Spectroscopy (MH ⁺ ) 508.2.

Example 281

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

According to general method AM, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4-ethylbenzaldehyde (Aldrich), (S)-(+)- The title compound was prepared using α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). This reaction was monitored by tlc (Rf = 0.20 in 50% ethyl acetate / hexanes).

C ₂₅ H ₃₁ N ₃ O ₃ F ₂ (molecular weight = 459.59); Mass spectroscopy (MH ⁺ ) 460.2.

Example 282

Synthesis of N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (phenyl) phenylglycinamide

According to the general method AM, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 2-phenylbenzaldehyde (Aldrich), (S)-(+)- The title compound was prepared using α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). This reaction was monitored by tlc (Rf = 0.15 in 50% ethyl acetate / hexanes).

C ₂₉ H ₃₁ N ₃ O ₃ F ₂ (molecular weight = 507.63); Mass Spectroscopy (MH ⁺ , negative tert-butylamide) 409.

Example 283

Synthesis of N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (benzyl) phenylglycineamide

According to general method AM, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 2- (benzyl) benzaldehyde (Aldrich), (S)-(+ ) The title compound was prepared using) -α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). This reaction was monitored by tlc (Rf = 0.19 in 50% ethyl acetate / hexanes).

C ₃₀ H ₃₃ N ₃ O ₃ F ₂ (molecular weight = 521.66); Mass Spectroscopy (MH ⁺ ) 522.26.

Example 284

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

Following the general method AM, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4-bromobenzaldehyde (Aldrich), (S)-(+) The title compound was prepared using -α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). This reaction was monitored by tlc (Rf = 0.06 in 50% ethyl acetate / hexanes).

C ₂₃ H ₂₆ N 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) -L-alaninyl] -L-4- (cyclohexyl) phenylglycinamide

According to general method AL, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from example B2 above), 4- (cyclohexyl) benzaldehyde (obtained from example D21 above), (S The title compound was prepared as a solid (melting point = 232-235 ° C.) using)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich).

C ₂₉ H ₃₇ N ₃ O ₃ F ₂ (molecular weight = 513.69); Mass Spectroscopy (MH ⁺ ) 514.29.

Example 286

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

According to general method AL, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4,4'-ethylbiphenylcarboxaldehyde (Aldrich), ( The title compound was prepared as a solid (melting point = 231-233 ° C.) using S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich).

C ₃₁ H ₃₅ N ₃ O ₃ F ₂ (molecular weight = 513.69); Mass Spectroscopy (MH ⁺ ) 514.29.

Example 287

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

According to general method AL, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4- (tert-butyl) benzaldehyde (Aldrich), (S) The title compound was prepared as a solid (melting point = 280 ° C. (decomposition)) using-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich). This reaction was monitored by tlc (Rf = 0.13 in 50% ethyl acetate / hexanes).

C ₂₇ H ₃₅ N ₃ O ₃ F ₂ (molecular weight = 487.65); Mass spectroscopy (MH ⁺ ) 488.27.

Example 288

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

According to general method AL, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 3- (4-chlorophenoxy) benzaldehyde (Aldrich), (S The title compound was prepared as a solid (melting point = 192-195 ° C.) using)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich).

C ₂₉ H ₃₀ N ₃ O ₄ F ₂ Cl (molecular weight = 588.07); Mass spectroscopy (MH ⁺ ) 558.20.

Example 289

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

Following General Method AB, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above), 4-biphenylcarboxaldehyde (Aldrich), (S)-( The title compound was prepared as a solid (melting point = 290-291 ° C. (decomposition)) using +)-α-methylbenzylamine (Aldrich) and cyclohexylisocyanide (Aldrich).

C ₃₁ H ₃₃ N ₃ O ₃ F ₂ (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

According to general method C, 3,5-difluoromandelic acid (fluorochem) and N- (L-alaninyl) -L-phenylglycine tert-butyl ester (N-BOC-L using general method C) Prepared from alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) and prepared by removing the BOC group using general method P), the title compound was prepared.

C ₂₃ H ₂₆ N ₂ O ₅ F ₂ (molecular weight = 479.53). Elemental Analysis: Calculated Value (%) 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-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide

According to general method C, 3,5-difluorophenyl-α, α-difluoroacetic acid (obtained from Example D23 above) and N- (L-alaninyl) -L-phenylglycine tert-butyl ester (Prepared from N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) using General Method C, prepared by removing BOC groups using General Method P) The compound was prepared. The reaction was monitored by tlc (Rf = 0.39 in 30% ethyl acetate / hexanes) and the product was purified by HPLC using 17% ethyl acetate / hexanes as eluent.

C ₂₃ H ₂₄ N ₂ O ₄ F ₄ (molecular weight = 468.49); Mass spectroscopy (MH ⁺ ) 469.17.

Example 292

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine tert-butyl ester

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from example B2 above) and D-phenylglycine tert-butyl ester (general method J) From Phenylglycine (Sigma)) to provide the title compound. This reaction was monitored by tlc (Rf = 0.1 in 10% MeOH / CHCl ₃ ).

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.64 (d, 1H), 8.38 (d, 1H), 7.34 (m, 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: [a] ₂₀ = -101.58 ° (c = 1, MeOH).

C ₂₃ H ₂₆ N ₂ O ₄ F ₂ (molecular weight = 432.47); Mass Spectroscopy (MH ⁺ ) 433.

Example 293

Synthesis of N-[(S) -1-oxo-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide

N-[(1R, 2S) -1-hydroxy-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanine using Jones reagent in acetone The title compound was prepared by oxidation of the amide (obtained from Example 266, above). The reaction was monitored by tlc (Rf = 0.7 in 9: 1 CHCl ₃ / MeOH) and the product was purified by flash chromatography using 97: 3 chloroform / methanol as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.98 (m, 2H), 7.26 (m, 1H), 7.50 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 6.25 (d, 1H), 5.49 (m, 3H), 4.54 (m, 3H), 3.54 (s, 2H), 1.41 (d, 3H), 1.38 (d, 3H).

Optical rotation: [α] ₂₀ = -106 ° @ 589 nm (c = 1, MeOH).

C ₂₀ H ₂₀ F ₂ N ₂ O ₃ (molecular weight = 374.39); Mass Spectroscopy (MH ⁺ ) 374.

Example 294

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-]-D, L- (pyrid-3-yl) glycine tert-butyl ester

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and tert-butyl 2-amino-2- (3-pyridyl) acetate ( The title compound was prepared using Kolar et al., Prepared as described in J. Heterocyclic Chem., 28, 171 (1991) and cited references. The reaction was monitored by tlc (Rf = 0.2 in 5% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.63 (m, 1H), 8.54 (m, 1H), 7.62 (m, 1H), 7.45 (t, 1H), 7.26 (m, 1H), 6.82 (m, 2H), 6.71 (m, 1H), 6.47 and 6.36 (d, 1H), 5.42 (d, 1H), 4.59 (m, 1H), 3.52 and 3.47 (two s, 2H), 1.38 and 1.36 (s, 9H ), 1.34 and 1.28 (two d, 3H).

C ₂₂ H ₂₅ N ₃ O ₄ F ₂ (molecular weight = 433.46); Mass Spectroscopy (MH ⁺ ) 434.

Example 295

Synthesis of [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and morpholine (Aldrich ) To prepare the title compound. The reaction was monitored by tlc (Rf = 0.4 in 5% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.60 and 8.49 (two d's, 1H), 8.49 (m, 1H), 7.25 (m, 5H), 7.18 (m, 2H), 6.95 (m, 1H) , 5.82 (m, 1H), 4.38 (m, 1H), 3.52 (m, 10H), 1.21 and 1.12 (two d's, 3H).

C ₂₃ H ₂₅ N ₃ O ₄ F ₂ (molecular weight = 445.47); Mass Spectroscopy (MH ⁺ ) 446.

Example 296

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (2-methoxy) phenylglycine methyl ester

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and methyl 2-amino-2- (2-methoxy) acetate (JP [JP] Greenmethoxy et al., "The Chemistry of Amino Acids", Wiley: New York 1961, Vol. 1, p. 698, using the Butcher variant of the Strecker method described above, 2-methoxybenzaldehyde (Aldrich) Prepared from) to prepare the title compound. The reaction was monitored by tlc (Rf = 0.3 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.28 (m, 2H), 6.93 (d, 1H), 6.88 (m, 2H), 6.69 (m, 2H), 6.34 (m, 1H), 5.67 (m, 1H), 4.52 (m, 1H), 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).

C ₂₁ H ₂₂ N ₂ O ₅ F ₂ (molecular weight = 420.42); Mass Spectroscopy (MH ⁺ ) 420.

Example 297

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine N-tert-butoxycarbonyl (hydroxy amine) ester

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and N-BOC hydroxy amine (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.35 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.79 (m, 1H), 7.41-7.28 (m, 5H), 6.78-6.59 (m, 3H), 5.52 (m, 1H), 3.38 (two s, 1H) , 1.38 (d, 3 H), 1.30 (s, 9 H).

C ₂₄ H ₂₇ N ₃ O ₆ F ₂ (molecular weight = 491.49); Mass Spectroscopy (MH ⁺ ) 492.

Example 298

Synthesis of N-Neopentyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and neopentylamine (Aldrich) H) was used to make the title compound. The reaction was monitored by tlc (Rf = 0.4 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.44 (m, 1H), 7.41 (m, 2H), 7.31 (m, 3H), 7.12 (m, 1H), 6.99 (m, 2H), 5.50 ( m, 1H), 4.47 (m, 1H), 3.52 (two s, 2H), 2.84 (m, 2H), 1.22 (m, 3H), 0.71 (s, 9H).

C ₂₄ H ₂₉ N ₃ O ₃ F ₂ (molecular weight = 460); Mass Spectroscopy (MH ⁺ ) 460.

Example 299

Synthesis of N-tetrahydrofurfuryl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and tetrahydrofurfurylamine ( Aldrich) was used to make the title compound. The reaction was monitored by tlc (Rf = 0.4 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.41 (m, 2H), 7.32 (m, 5H), 7.08 (m, 1H), 6.99 (m, 2H), 5.48 (m, 1H), 4.42 ( m, 1H), 3.85-3.54 (m, 3H), 3.48 (two s, 2H), 3.14 (m, 2H), 1.76 (m, 4H), 1.21 (m, 3H).

C ₂₄ H ₂₇ N ₃ O ₄ F ₂ (molecular weight = 459.49); Mass Spectroscopy (MH ⁺ ) 460.

Example 300

Synthesis of N-methoxy-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and methoxyamine hydrochloride ( Aldrich) was used to make the title compound. The reaction was monitored by tlc (Rf = 0.35 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.63 (m, 1H), 8.35 (m, 1H), 7.34 (m, 5H), 7.12 (m, 1H), 6.99 (m, 2H), 5.23 ( d, 1H), 4.42 (m, 1H), 3.58 (s, 3H), 3.51 (two s, 2H), 1.22 (d, 3H).

C ₂₀ H ₂₁ N ₃ O ₄ F ₂ (molecular weight = 405); Mass Spectroscopy (MH ⁺ ) 405.

Example 301

Synthesis of [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and azetidine (Aldrich ) To prepare the title compound. The reaction was monitored by tlc (Rf = 0.6 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.61 and 8.46 (two d, 1H), 8.33 (m, 1H), 7.34 (m, 5H), 7.19 (m, 1H), 6.99 (m, 2H) , 3.36 (two d, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 3.88 (m, 3H), 3.5 (two s, 2H), 2.36 (m, 2H), 1.18 (two d, 3H).

C ₂₂ H ₂₃ N ₃ O ₃ F ₂ (molecular weight = 415.44); Mass Spectroscopy (MH ⁺ ) 416.

Example 302

Synthesis of N-isobutyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and isobutylamine (Aldrich) H) was used to make the title compound. The reaction was monitored by tlc (Rf = 0.65 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.41 (m, 1H), 8.22 (m, 1H), 7.38 (m, 2H), 7.09 (m, 1H), 6.98 (m, 2H), 5.52 ( two d, 1H), 4.41 (m, 1H), 3.34 (two s, 2H), 2.85 (s, 2H), 1.61 (m, 1H), 1.20 (m, 3H), 0.92 (m, 6H).

C ₂₃ H ₂₇ N ₃ O ₃ F ₂ (molecular weight = 431.48); Mass Spectroscopy (MH ⁺ ) 432.

Example 303

Synthesis of N-cyclopropanemethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and (aminomethyl) cyclopropane (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.25 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH / CHCl ₃ as eluent.

C ₂₃ H ₂₅ N ₃ O ₃ F ₂ (molecular weight = 429.47); Mass Spectroscopy (MH ⁺ ) 374.

Example 304

Synthesis of N-methoxy-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and N-methoxy-N The title compound was prepared using -methylamine hydrochloride (Aldrich). The reaction was monitored by tlc (Rf = 0.3 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.65 and 8.53 (two d, 1H), 8.37 (m, 1H), 7.31 (m, 5H), 7.12 (m, 1H), 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 s, 3H), 1.21 and 1.16 (two d, 3H).

C ₂₁ H ₂₃ N ₃ O ₄ F ₂ (molecular weight = 419); Mass Spectroscopy (MH ⁺ ) 420.

Example 305

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

According to general method M, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 1-amino-2- Methylprop-2-ene (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.45 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.43 (m, 2H), 7.40 (m, 2H), 7.29 (m, 3H), 7.11 (m, 1H), 6.98 (m, 2H), 5.46 ( d, 1H), 4.68 (m, 2H), 4.42 (m, 1H), 3.6 (m, 2H), 3.49 (s, 2H), 1.56 (s, 3H), 1.21 (d, 3H).

C ₂₃ H ₂₅ N ₃ O ₃ F ₂ (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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 3- (aminomethyl) Pyridine (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.1 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-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), 5.43 (d, 2H), 4.44 (m, 1H), 4.30 (bd, 2H), 3.52 (s, 2H), 1.26 (d, 3H).

C ₂₃ H ₂₄ N ₄ O ₃ F ₂ (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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 4- (aminomethyl) Pyridine (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.1 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.88 (m, 1H), 8.54 (d, 1H), 8.43 (m, 3H), 7.37 (m, 4H), 7.12 (m, 3H), 6.9 ( m, 1H), 5.44 (d, 1H), 4.45 (m, 1H), 4.31 (d, 2H), 3.51 (s, 2H), 1.25 (d, 3H).

C ₂₃ H ₂₄ N ₄ O ₃ F ₂ (molecular weight = 466.49); Mass Spectroscopy (MH ⁺ ) 467.

Example 308

Synthesis of N-furfuryl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and furfurylamine (Aldrich) H) was used to make the title compound. The reaction was monitored by tlc (Rf = 0.5 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.66 (m, 1H), 8.45 (d, 1H), 8.39 (m, 1H), 7.57 (s, 1H), 7.33 (m, 5H), 7.09 ( m, 1H), 6.99 (m, 2H), 6.36 (m, 1H), 6.12 (s, 1H), 5.41 (d, 1H), 4.22 (m, 1H), 3.52 (s, 2H), 1.24 (d , 3H).

C ₂₄ H ₂₃ N ₃ O ₄ F ₂ (molecular weight = 455); Mass Spectroscopy (MH ⁺ ) 456.

Example 309

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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and cyclopentylamine (Aldrich) H) was used to make the title compound. The product was purified by recrystallization from ethanol.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.32 (m, 2H), 8.16 (m, 1H), 7.33-7.20 (m, 5H), 7.04 (m, 1H), 6.93 (m, 2H), 5.34 (d, 1H), 4.37 (m, 1H), 3.9 (m, 1H), 3.49 (s, 2H), 1.80-1.29 (m, 8H), 1.19 (d, 3H).

C ₂₄ H ₂₇ N ₃ O ₃ F ₂ (molecular weight = 443.49); Mass Spectroscopy (MH ⁺ ) 444.

Example 310

Synthesis of N-1-benzylpiperidin-4-yl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 4-amino-1- Benzylpiperidine (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.2 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-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, 3 H).

C ₃₁ H ₃₄ N ₄ O ₃ F ₂ (molecular weight = 548.64); Mass Spectroscopy (MH ⁺ ) 548.

Example 311

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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and dimethylamine (Aldrich ) To prepare the title compound. The reaction was monitored by tlc (Rf = 0.65 in 10% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.13 and 8.01 (two d, 1H), 7.32 (m, 5H), 6.78 (m, 2H), 6.63 (m, 1H), 5.88 (m, 1H) , 4.72 (m, 1H), 3.45 (two s, 2H), 2.94 (two s, 6H), 1.32 and 1.17 (two d, 3H).

C ₂₁ H ₂₃ N ₃ O ₃ F ₂ (molecular weight = 403.43); Mass Spectroscopy (MH ⁺ ) 404.

Example 312

N-2,2,6,6-tetramethylpiperidin-4-yl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine Synthesis of Amide

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 4-amino-2, The title compound was prepared using 2,6,6-tetramethylpiperidine (Aldrich). The reaction was monitored by tlc (Rf = 0.2 in 2% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.46 (d, 1H), 8.33 (d, 1H), 8.12 (bm, 1H), 7.33 (m, 5H), 7.13 (m, 1H), 6.99 ( m, 2H), 5.37 (d, 1H), 4.41 (m, 1H), 3.98 (m, 1H), 3.52 (s, 2H), 1.67 (bm, 1H), 1.44 (bm, 1H), 1.22 (d , 3H), 1.01 (bm, 14H).

C ₂₈ H ₃₆ N ₄ O ₃ F ₂ (molecular weight = 514.62); Mass Spectroscopy (MH ⁺ ) 514.

Example 313

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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 2-methylcyclohexylamine (Aldrich) was used to prepare the title compound. This reaction was monitored by tlc (Rf = 0.4 in 2% MeOH / CHCl ₃ ).

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).

C ₂₆ H ₃₁ N ₃ O ₃ F ₂ (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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 4-methylcyclohexylamine (Aldrich) was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.2 in 2% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.38 (m, 2H), 8.08 (m, 1H), 7.33 (m, 5H), 7.09 (m, 1H), 7.01 (m, 2H), 5.54 and 5.36 (two d, 1H), 4.43 (m, 2H), 3.76 (m, 1H), 3.52 (s, 2H), 1.79-1.17 (m, 11H), 0.84 (d, 3H).

C ₂₆ H ₃₁ N ₃ O ₃ F ₂ (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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and 4-amino-1- The title compound was prepared using ethoxycarbonylpiperidine (Aldrich). The reaction was monitored by tlc (Rf = 0.2 in 2% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.42 (m, 2H), 8.23 (m, 1H), 7.33 (m, 5H), 7.09 (m, 1H), 6.98 (m, 2H), 5.38 ( m, 1H), 4.41 (m, 1H), 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, 1 H), 1.2 (m, 6 H).

C ₂₇ H ₃₂ N ₄ O ₅ F ₂ (molecular weight = 530.57); Mass Spectroscopy (MH ⁺ ) 531.

Example 316

Synthesis of N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and N-methyl- (S) -2-amino-2-phenylacetamide [ CAS 129213-83-8] was used to prepare the title compound. The reaction was monitored by tlc (Rf = 0.2 in 5% MeOH / CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH / CHCl ₃ as eluent.

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).

C ₂₀ H ₂₁ N ₃ O ₃ F ₂ .0.75H ₂ O (molecular weight = 403.43); Mass Spectroscopy (MH ⁺ ) 404.

Example 317

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

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and O- (tertiary- Butoxy) hydroxyamine (Aldrich) was used to prepare the title compound. This reaction was monitored by tlc (Rf = 0.65 in 10% MeOH / CHCl ₃ ).

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.72 and 8.58 (two d, 1H), 8.39 (m, 1H), 7.37 (m, 5H), 7.10 (m, 1H), 6.99 (m, 2H) , 5.41 (m, 1H), 4.46 (m, 1H), 3.51 (two s, 3H), 1.22 (m, 3H), 1.09 (s, 9H).

C ₂₃ H ₂₇ N ₃ O ₄ F ₂ (molecular weight = 447.48); Mass Spectroscopy (MH ⁺ ) 448.

Example 318

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine N-tert-butyl (hydroxyamine) ester

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and N- (tertiary- Butoxy) hydroxyamine (Aldrich) was used to prepare the title compound. This reaction was monitored by tlc (Rf = 0.65 in 10% MeOH / CHCl ₃ ).

C ₂₃ H ₂₇ N ₃ O ₄ F ₂ .0.25H ₂ O (molecular weight = 447.48); Mass Spectroscopy (MH ⁺ ) 448.

Example 319

Synthesis of N- [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) (obtained from Example 111 above) was obtained from ethanol (40 ml). And anhydrous hydrazine (0.3 ml, 10 mmol) and stirred. The solution was heated to reflux for 12 hours and then cooled to ambient temperature with stirring. The title compound was collected as a white solid by filtration, washed with ethanol and dried in a vacuum oven (52% yield).

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (t, 3H), 5.41 (m, 1H).

C ₁₉ H ₂₀ N ₃ O ₄ F ₂ (molecular weight = 390.39); Mass Spectroscopy (MH ⁺ ) 390.

Example 320

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine acetohydrazonate

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide (0.5 g, 1.3 mmol) (obtained from Example 319 above) was obtained from triethylorthoacetate ( 40 ml). After 14 h, the reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (84% yield). The reaction was monitored by tlc (Rf in 0.6% MeOH / CHCl ₃ = 0.65) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 4.03 (q, 2H), 5.54 (m, 1H).

C ₂₃ H ₂₆ N ₄ O ₄ F ₂ (molecular weight = 460.49); Mass Spectroscopy (MH ⁺ ) 460.

Example 321

Synthesis of N- [N- (phenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester

According to general method C, phenylacetic acid (Aldrich) and L-alaninyl-L-phenylglycine tert-butyl ester (N-BOC-L-alanine (Sigma) and L-phenylglycine using general method C) The title compound was prepared using tert-butyl ester hydrochloride (Bachem) and prepared by removing the BOC group using the general method P). The reaction was monitored by tlc (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).

C ₂₃ H ₂₈ N ₂ O ₄ (molecular weight = 396.49); Mass Spectroscopy (MH ⁺ ) 397.

Example 322

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

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and N-4- (phenyl) butyl-L-phenylglycineamide (general method C The title compound was prepared using N-BOC-L-phenylglycine (Advanced Chemtech) and 4-phenylbutylamine (Aldrich) and removing the BOC group using general method P). Prepared. The reaction was monitored by tlc (Rf = 0.45 in 5% MeOH / CHCl ₃ ) and the product was purified by treatment with water and acetonitrile.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 4.42 (m, 1H), 5.37 (d, 1H).

C ₂₉ H ₃₁ N ₃ O ₃ F ₂ (molecular weight = 507.5); Mass Spectroscopy (MH ⁺ ) 507.

Example 323

Synthesis of N-3- (4-iodophenyl) propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and N-3- (4-iodophenyl) propyl-L-phenylglycinamide (N-BOC-L-phenylglycine (Advanced Chemtech) and 3- (4-iodophenyl) propylamine (obtained from Example D26, above) using General Method C, using General Method P Prepared by removing the BOC group) to prepare the title compound. The product was purified by treatment with water and with ethanol.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 4.41 (q, 2H), 5.35 (m, 1H).

C ₂₈ H ₂₈ N ₃ O ₄ F ₂ I (molecular weight = 635.45); Mass Spectroscopy (MH ⁺ ) 635.

Example 324

Synthesis of N-6- (amino) hexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide hydrochloride

According to general method C, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine (obtained from Example D25 above) and N-BOC-1, The title compound was prepared by using 6-hexanediamine (Fluka) and removing the BOC group using general method P. The product separated as a white solid.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 4.41 (m, 1H), 5.40 (t, 1H).

C ₂₅ H ₃₂ N ₄ O ₃ F ₂ (molecular weight = 474.56); Mass Spectroscopy (MH ⁺ ) 475.

Example 325

Synthesis of N-1- (phthalimido) pent-2-yl-N '-(3,5-difluorophenylacetyl) -L-alanineamide

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from example B2 above) and 2-amino-1-phthalimidopentane hydrochloride (obtained from example D27 above) ) To prepare the title compound. The reaction was monitored by tlc (Rf = 0.3 in 5% MeOH / CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH / CHCl ₃ as eluent and recrystallized from chlorobutane / acetonitrile.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 4.1 (m, 2H), 7.83 (bs, 4H).

C ₂₄ H ₂₅ N ₃ O ₄ F ₂ (molecular weight = 457.48); Mass Spectroscopy (MH ⁺ ) 457.

Example 326

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycinyl] -L- (3,5-difluorophenyl) glycine methyl ester

According to general method AN, N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycine (obtained from Example D30 above) and L-3,5-difluoro The title compound was prepared using rophenylglycine methyl ester (obtained from Example D29, above). The product was purified by crystallization.

NMR data were as follows:

¹ 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), 3.55-3.65 (m, 5H).

Example 327

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine

Following the general method AF, solid using THF / H ₂ O (1: 1) on N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine methyl ester (TiM = 158.5-160.5 ° C) was prepared to give the title compound. The reaction was monitored by tlc (Rf = 0.29 in 10% MeOH / CH ₂ Cl ₂ ).

NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 8.46 (bd, J = 6.71, 1H), 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, 172.9, 166.6, 166.5, 163.4, 163.2, 141.7, 141.6, 141.5, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 54.1, 50.9, 43.3, 32.9, 29.4, 23.8, 18.6, 14.8.

C ₁₇ H ₂₂ N ₂ O ₄ F ₂ (molecular weight = 356.37); Mass Spectroscopy (MH ⁺ ) 357.

Example 328

Synthesis of N- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester

Cyclopentylacetic acid (Aldrich) and L-alaninyl-L-phenylglycine tert-butyl ester according to general method D (N-CBZ-L-alanine (Sigma) and L-phenyl using general method C) The title compound was prepared as a solid (melting point = 133-138 ° C.) using Glycine tert-butyl ester hydrochloride (Bachem) and prepared by removing CBZ groups using general method Y. The reaction was monitored by tlc (Rf = 0.48 in 50% EtOAc / hexanes) and the product was purified by flash chromatography using 25-50% EtOAc / hexanes as eluent.

NMR data were as follows:

¹ 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, 1H), 5.34 (d, J = 7.20 Hz, 1HO, 4.72 (quint, J = 7.2 Hz, 1H), 2.04 (m, 3H), 1.75-1.28 (m (including s at 1.34, 9H) 18H), 1.1-0.9 (m, 2H).

¹³ C-nmr (CDCl 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.

C ₂₂ H ₃₂ N ₂ O ₄ (molecular weight = 388.51); Mass Spectroscopy (MH ⁺ ) 389.5.

Example 329

Synthesis of N- [N- (2,5-dichlorophenylmercaptoacetyl) -L-alaninyl] -L-phenylglycine methyl ester

2,5-dichlorophenylmercaptoacetic acid (Portland TCI Americas, Oregon) (237 mg) is converted to an acid chloride as described in general method A "and methyl L-alaninyl-L-phenyl as described in general method B". Glycinate was used to acylate. The title compound (210 mg) was isolated as crystals from ethyl ether.

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, 8H), 5.45 (d, 1H), 4.45-4.65 (m, 3H ), 3.65 (s, 3H), 1.30 (d, 3H).

C ₂₀ H ₂₀ Cl ₂ N ₂ O ₄ S (molecular weight = 455.363); Mass Spectroscopy (MH ⁺ ) 454.1.

C ₂₀ H ₂₀ Cl ₂ N ₂ O ₄ S Elemental Analysis—calculated: C, 52.75; H, 4. 42; N, 6. 15; Found: C, 53.58; H, 5.01; N, 6.34.

Example 330

Synthesis of N- [N- (3,4-dichlorophenylmercaptoacetyl) -L-alaninyl] -L-phenylglycine methyl ester

3,4-dichlorophenylmercaptoacetic acid (J. Med. Chem., 15 (9), 940-944 (1972)]) (237 mg) is converted to an acid chloride as described in General Method A "and Methyl L-alaninyl-L-phenylglycinate was used to acylate as described in Method B ". The title compound (182 mg) was isolated as crystals from ethyl ether.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.8 (d, 1H), 8.40 (d, 1H), 7.25-7.65 (m, 8H), 5.40 (d, 1H), 4.45 (m, 1H), 3.80 (m, 2 H), 3.65 (s, 3 H), 1.25 (d, 3 H).

C ₂₀ H ₂₀ Cl ₂ N ₂ O ₄ S (molecular weight = 455.363); Mass Spectroscopy (MH ⁺ ) 454.1.

C ₂₀ H ₂₀ Cl ₂ N ₂ O ₄ S Elemental Analysis—calculated: C, 52.75; H, 4. 42; N, 6. 15; Found: C, 53.05; H, 4.67; N, 6.26.

Example 331

Synthesis of N- [N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -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 prepared as general method A ". Conversion to acid chloride as described and used to acylate methyl L-alaninyl-L-phenylglycinate as described in general method B ". The title compound (210 mg) was isolated as crystals from ethyl ether.

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, 8H), 5.45 (d, 1H), 4.45-4.65 (m, 3H ), 3.65 (s, 3H), 1.30 (d, 3H).

C ₂₀ H ₂₀ Cl ₂ N ₂ O ₅ (Molecular weight = 406.39); Mass Spectroscopy (MH ⁺ ) 406.3.

C ₂₀ H ₂₀ Cl ₂ N ₂ O ₅ elemental analysis—calculated: C, 59.11; H, 4.96; N, 6.89; Found: C, 53.34; H, 4.80; N, 6.94.

Example 332

Synthesis of Methyl N- [N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -L-2,3-dihydroisoindole-1-carboxylate

According to the general method AN, L-2,3-dihydro-1H-isoindole-1-carboxylic acid methyl ester hydrochloride (Gazz. Chim. Ital., 106 (1-2) p. 65-75 (1976)]) (417 mg) was coupled to N- (3,5-difluorophenylacetyl-L-alanine (obtained from Example B2) to provide the title compound (150 mg).

NMR data were as follows:

¹ H-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).

C ₂₁ H ₂₀ F ₂ N ₂ O ₄ (molecular weight = 402.40); Mass Spectroscopy (MH ⁺ ) 402.3.

Example 333

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1-amino-1,3-diphenylpropan-2-one

N-methoxy-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide in THF (obtained from Example 304 above) To 200 mg of solution 1.91 ml of benzyl magnesium bromide 2M solution (Aldrich) in THF was added at 0 ° C. The reaction mixture was stirred at ambient temperature for 72 hours and quenched by addition of water. The reaction mixture was partitioned between ethyl acetate and water and the organic phase washed with 1N HCl solution. The solvent was removed under reduced pressure and the crude ketone was eluted with ethyl acetate and purified by chromatography on silica gel to give 62 mg of the title compound as a phenyl diastereomer 1: 1 mixture.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ) (about 1: 1 mixture of diastereomers) δ = 7.2-7.5 (m, 8H), 7.0-7.1 (m, 2H), 6.7-6.9 (m, 4H), 6.2 ( m, 1H), 5.5 (t, 1H), 3.5-3.6 (m, 2H), 1.28-1.45 (doublets in 1: 1 ratio, 3H).

Example 334

Synthesis of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine thiocarboxamide

Step A-Preparation of t-butoxycarbonyl-phenylglycine thiocarboxamide

808 mg (2.00 mmol) of Lawson's reagent (Aldrich) in a suspension of 500 mg (2.00 mmol) of t-butoxycarbonyl-L-phenylglycine carboxamide (prepared as in Example 141) in 50 ml of anhydrous toluene Was added. The reaction mixture was heated to 95 ° C for 5 minutes. Cool to ambient temperature and dilute with 1: 1 ethyl acetate / hexanes to obtain an insoluble material. The soluble phase was removed, the solid further washed, the soluble phases combined and the solvent removed to give crude thiocarboxamide as a semisolid. Elution with ethyl acetate purified by chromatography on silica gel yielded 364 mg of thiocarboxamide.

Step B-Preparation of Phenylglycine Thiocarboxamide Hydrobromide

A solution of 364 mg of t-butoxycarbonyl phenylglycine thiocarboxamide in 4 ml of 30% HBr dissolved in acetic acid was stirred for 1 hour. The volatiles were removed under reduced pressure to give crude phenylglycine thiocarboxamide hydrobromide as a pale solid. This material was used without further purification.

In 486 mg of a stirred solution of (3,5-difluorophenylacetyl) -L-alanine (obtained from B2) in 30 ml of dichloromethane was added 383 mg of EDCI, 270 mg of HOBT hydrate, followed by 350 μl of diisopropylethylamine. Added. To this suspension was added phenylglycine thiocarboxamide hydrobromide in dichloromethane. The reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was partitioned between water and dichloromethane and the organic phase was washed with 1N HCl solution followed by saturated sodium bicarbonate solution. The solvent was removed to give the crude product, eluted with ethyl acetate and purified by chromatography on silica gel to give 271 mg of the title compound (a mixture of about 3: 2 phenylglycine diastereomer) as a pale solid.

NMR data were as follows:

¹ H-nmr (CDCl ₃ ) (about 3: 2 mixture of diastereomers) δ = 7.3-7.7 (m, 8H), 6.7-6.8 (m, 4H).

Example 335

Synthesis of N- [N- (3,5-difluorophenyl-2-oxoacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester

According to general method C, L-alaninyl-L-phenylglycine tert-butyl ester (prepared as described in Example 321) and 3,5-difluorophenylglyoxylate (J. Org. Chem., 45 (14), 28883 (1980)) to prepare the title compound as a solid. The product was purified by slurrying with EtOAc / hexanes.

Elemental Analysis: Calculated Value (%) 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-1-phenyleth-1-yl) -N '-[N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanineamide

According to General Method C, N- (3,5-difluorophenylacetyl) -L-phenylglycinyl-L-alanine (N- (3,5-difluorophenylacetyl) -L-phenylglycinyl- Prepared from L-alanine ethyl ester) and (S) -phenylglycineol (Aldrich) to give the title compound (melting point = 269-272 ° C.). The reaction was monitored by tlc (Rf = 0.3 in 10% MeOH / CHCl ₃ ) and the product purified by chromatography using 10% MeOH / CHCl ₃ as eluent.

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: [a] ₂₀ =-62.7 ° @ 589 nm (c = 1.02, DMSO).

C ₂₇ H ₂₇ N ₃ O ₃ F ₂ (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

According to general method C, N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) and L-phenylglycine (2-hydroxyethyl) amide hydrochloride (general method C The title compound was prepared using N-BOC-L-phenylglycine (Bachem) and 2-aminoethanol (Aldrich), prepared by removing the BOC group using the general method P). The product was purified by chromatography using 10% MeOH / CHCl ₃ as eluent and crystallized from EtOH.

NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 5.42 (d, 1H).

Optical rotation: [a] ₂₀ = +8.77 ° @ 589 nm (c = 1.03, DMSO).

C ₂₁ H ₂₃ N ₃ O ₄ F ₂ (molecular weight = 419.43); Mass Spectroscopy (MH ⁺ ) 420.

Example 338

N- (4- (4-azido-2-hydroxybenzamido) but-1-yl) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl]- Synthesis of L-phenylglycineamide

According to General Method A, N- (3,5-difluorophenylacetyl) -L-alanyl-L-phenylglycine (prepared as described herein) and 4- (4-azidosalicylamido ) Butylamine (Pierce Chemical) was used to prepare the title compound as a photosensitive solid. The reaction was carried out under low light conditions and the reaction vessel was protected from light. The reaction was monitored by tlc (Rf = 0.2 in 2.5% MeOH / dichloromethane).

NMR data were as follows:

¹ H-nmr (CD ₃ OH / CDCl ₃ ): δ = 7.72 (d, 2H), 7.30 (m, 5H), 6.84 (m, 2H), 6.73 (m, 1H), 6.54 (m, 2H), 5.34 (s, 1H), 4.39 (q, 1H), 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) -N '-[N- (3,5-difluorophenylacetyl) -L-alanyl] -L-phenylalanamide

N-Cbz-L-phenylalanine (Sigma) was coupled to N-hydroxysuccinimide (Aldrich) using DCC in dichloromethane. The resulting intermediate was reacted with methanesulfonamide and diisopropylethylamine in DMF to afford N-methanesulfonyl-N'-Cbz-L-phenylalanamide amide. The Cbz group was removed using general method O and the resulting intermediate was coupled to N- (3,5-difluorophenylacetyl) -L-alanine (obtained from Example B2 above) using general method B. Compound (melting point = 203-205 ° C) was obtained.

Example 340-407

According to the method described above, the following additional compounds were prepared:

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine methyl ester (Example 340),

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3-α-phenyl) proline methyl ester (Example 341),

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),

t-butyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate (Example 344),

t-butyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycineamide (Example 345),

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycineamide (Example 346),

N- [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 347),

N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 348),

N- [N- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 349),

N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 350),

N- [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 351),

N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 352),

N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 353),

N- [N- (3-trifluoromethylphenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 354),

N- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 355),

N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 356),

N- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 357),

N- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 358),

N- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycineamide (Example 359),

N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine (Example 360),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-furanyl) acetamide (Example 361),

N '-[N- (3,4-difluorophenylacetyl) -D-alaninyl] -D-phenylglycineamide (Example 362),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine-N-methylsulfonamide (Example 363),

N "-Methyl-N" -phenyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -glycinamide (Example 364),

N "-methyl-N" -phenyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -alanineamide (Example 365),

N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide (Example 366),

N "-methyl-N" -benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -glycinamide (Example 367),

N "-4-fluorobenzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide (Example 368),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (4-fluoro) phenylglycine neopentyl ester (Example 369),

N- [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),

N- [N- (3,5-difluorophenylacetyl) -L-threoninyl] -L-phenylglycine methyl ester (Example 373),

N- [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) -L-alaninyl] -L-phenylglycinamide (Example 376),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenyl-glycinamide (Example 377),

N '-[N- (3,5-difluorophenylacetyl) -L-methionyl] -L-phenylglycineamide (Example 378),

N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycineamide (Example 379),

N '-[N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinamide (Example 380),

N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycineamide (Example 381),

N-[(R) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide (Example 382),

N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example 383),

N- [1-phenyl-2-oxo-protan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example 384),

N- [1-phenyl-2-oxo-pentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example 385),

N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide (Example 386),

N- [1-phenyl-2-oxo-butan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide (Example 387),

N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide (Example 388),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-α-hydroxyphenylalanine methyl ester (Example 389),

N "-[4-((2-hydroxy-4-azido) -phenyl) -NHC (O)-) butyl] N '-[N- (3,5-difluorophenylacetyl) -L- Alaninyl] -L-phenylglycineamide (Example 390),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine t-butyl ester (Example 391),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-phenylphenylglycine t-butyl ester (Example 392),

[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (2,3-benzo [b] proline) methyl ester (Example 393),

N "-t-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-n-butylphenylglycineamide (Example 394),

N "-t-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4- (phenylacetenyl) phenylglycineamide (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-alanineamide (Example 397),

N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example 398),

N- [1-phenyl-2-oxo-hexane-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example 399),

N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide (Example 400),

N "-n-hexyl-6-biotinamidyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinethioamide (Example 401) ,

N '-[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),

N "-t-butyl N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2-fluorophenylglycinamide (Example 404),

N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-2-phenylglycine methyl ester (Example 405),

N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine (Example 406),

N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine t-butyl ester (Example 407).

Example 408

According to the method described above, the following compounds of formula (I) may be present or prepared:

R ¹ is 3,5-difluorophenyl; X 'and X "are hydrogen; R ² is methyl; R ³ is hydrogen; R ⁴ is p-fluorophenyl; R ⁵ is hydrogen; Z is a single bond and X is -C (O) OCH ₂ C (CH ₃ ) ₃ ; n is 1,

R ¹ is 3,5-difluorophenyl; X 'and X "are hydrogen; R ² is methyl; R ³ is hydrogen; R ⁴ is p- (phenyl) phenyl; R ⁵ is hydrogen; X is -C (O) NHC (CH ₃ ) ₃ ; Z is a single bond; n is 1,

R ¹ is cyclopentyl; X 'and X "are hydrogen; R ² is methyl; R ³ is hydrogen; R ⁴ is phenyl; R ⁵ is hydrogen; X is -C (O) OC (CH ₃ ) ₃ ; Z is A single bond; n is 1,

R ¹ is cyclopropyl; X 'and X "are hydrogen; R ² is methyl; R ³ is hydrogen; R ⁴ is phenyl; R ⁵ is hydrogen; X is -C (O) OC (CH ₃ ) ₃ ; Z is A single bond; n is 1,

R ¹ is 3,5-difluorophenyl; X 'and X "are hydrogen; R ² is methyl; R ³ is hydrogen; R ⁴ is phenyl; R ⁵ is hydrogen; X is -C (O) OCH ₂ C (CH ₃ ) ₃ ; Z is a single bond and n is 1;

Example 409

Cellular Screen for Detection of Inhibitors of β-amyloid Preparation

Various compounds of formula (I) were analyzed for their ability to inhibit β-amyloid production in cell lines containing Swedish mutations. This screening analysis is described in International Patent Application Publication No. 94/10569 ⁸ and Citron et al. ¹² ] Genes for amyloid precursor protein 751 (APP751) containing a double mutation from Lys ₆₅₁ Met ₆₅₂ to Asn ₆₅₁ Leu ₆₅₂ (APP751 numbering) and stably transfected cells (K293 = human kidney cell line) Used. Corning 96-well plates at 1.5-2.5 × 10 ⁴ cells per well in Dulbecco's minimum essential medium containing 10% fetal bovine serum, which are commonly referred to as Swedish mutations and referred to as “293 751 SWE”. Plated. Cell number is important for achieving β-amyloid ELISA exhibiting a linear range of assay (˜0.2 to 2.5 ng / ml).

After overnight incubation at 37 ° C. in an incubator equilibrated with 10% carbon dioxide, the medium was removed and exchanged with a medium containing 200 μl of the compound of formula (I) per well for 2 hours of pretreatment and the cells were replaced with the above. Incubated together. Drug stocks are prepared in 100% dimethylsulfoxide so that the concentration of dimethylsulfoxide at the final drug concentration used for treatment does not exceed 0.5%, in fact is generally 0.1%.

At the end of the pretreatment period the medium was removed again and replaced with freshly prepared drug containing such medium and cells were incubated for an additional 2 hours. After treatment, the plates were pelleted with cellular debris from conditioned media by centrifugation at 1200 rpm for 5 minutes at Beckman GPR. 100 μl of conditioned medium or a suitable dilution from each well was transferred to an ELISA plate precoated with antibody 266 ¹⁴ against amino acids 13-28 of β-amyloid peptide and described at 4 ° C. as described in WO 94/10569 ⁸ . Stored overnight. An ELISA assay using labeled antibody 6C6 ¹⁴ against amino acids 1-16 of the β-amyloid peptide was analyzed until the next day to determine the amount of β-amyloid peptide prepared.

The cytotoxic effect of the compounds was measured by a modification of the method of Hansen et al. ¹³ . 25 μl of 3, (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) stock solution (5 mg / ml) was added to the remaining cells in the tissue culture plate and the final concentration was 1 mg. / ml. Cells were incubated at 37 ° C. for 1 hour and cell activity was stopped by addition of the same dose of MTT lysis buffer (20% w / v sodium dodecyl sulfate in 50% dimethylformamide, pH 4.7). Extraction was complete by shaking overnight at room temperature. The difference between OD _{562 nm} and OD _{650 nm} was measured with the UVmax microplate reader of the molecular apparatus as an indicator of cellular viability.

The results of the β-amyloid peptide ELISA were fitted to a standard curve and expressed as ng / ml β-amyloid peptide. To standardize cytotoxicity these results were divided by MTT results and expressed as percentage of results from the drug-free control group. All results were the mean and standard deviation of six or more replicate assays.

Test compounds were analyzed for β-amyloid peptide preparation inhibitory activity in the cells using this assay. This analysis showed that each compound tested in the present invention reduced β-amyloid peptide production by at least 30% compared to the control.

Example 410

In vivo inhibition of β-amyloid release and / or synthesis

This example illustrates how compounds of the invention can be tested for inhibition of β-amyloid release and / or synthesis in vivo. PDAPP mice aged 3-4 months were used for this experiment (Games et al., (1995) Nature 373: 523-527). Depending on which compound is tested, the compound is typically formulated at 5 or 10 mg / ml. Because of the low solubility factor of the compounds, the compounds may be used in various vehicles, such as corn oil (California, South San Francisco, Safeway); 10% EtOH in corn oil (Safeway); 2-hydroxypropyl-β-cyclodextrin (Natic, MA, Research Biochemicals International); And carboxy-methyl-cellulose (Missouri, St. Louis, Sigma Chemical Corporation). In particular, the vehicle in Example 141 was carboxy-methyl-cellulose (Sigma).

The mice were subcutaneously administered with a 26 gauge needle and 3 hours later euthanized through CO ₂ and blood was pierced through the heart using a 1 cc 25G 5/8 "tuberculin syringe / needle coated with a solution of 0.5 M EDTA (pH 8.0). The blood was placed in a Becton-Dickinson tubertain tube containing EDTA and spun for 15 minutes at 1500 xg at 5 ° C. The brains of the mice were then removed, the cortex and hippocampus ridges were incised and iced. Put on.

1. Cerebral Analysis

Hippocampus ridges and cortical tissue for enzyme-linked immunosorbent assay (ELISA) in each cerebral region were subjected to a 10-fold volume of ice cold guanidine buffer (5.0 M guanidine HCl, 50 mM Tris-HCl, pH 8.0). This homogenate was slowly shaken on a rotating platform for 3-4 hours at room temperature and stored at −20 ° C. before quantification of β-amyloid.

Cerebral homogenate was 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 μg / ml lupetin] The final concentration of guanidine was reduced to 0.5 M before 10 dilutions and centrifugation at 16,000 xg for 20 minutes at 4 ° C. β-amyloid standards (1-40 or 1-42 amino acids) were prepared such that the final composition was 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).

The total β-amyloid sandwich ELISA, which quantifies both β-amyloid (aa 1-40) and β-amyloid (aa 1-42), consists of two monoclonal antibodies (mAb) against β-amyloid . The capture antibody 266 ¹⁴ is specific for amino acids 13-28 of β-amyloid. Antibodies 3D6 ¹⁵ specific for amino acids 1-5 of β-amyloid were biotinylated and served as reporter antibodies in the assay. The 3D6 biotinylation method used the manufacturer's (Rockford Pierce, Ill.) Protocol for NHS-biotin labeling of immunoglobulins except with 100 mM sodium bicarbonate buffer (pH 8.5). The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full length APP, but detects only β-amyloid species with amino terminal aspartic acid. This assay has a lower sensitivity limit of ˜50 pg / ml (11 pM) and shows no cross reactivity to endogenous murine β-amyloid peptides at concentrations below 1 ng / ml.

An array of sandwich ELISAs to quantify the levels of β-amyloid (aa 1-42) uses mAb 21F12 ¹⁵ (recognizing amino acids 33-42 of β-amyloid) as capture antibody. Biotinylated 3D6 is also a reporter antibody in this assay with a lower sensitivity limit of ˜125 pg / ml (28 pM).

266 and 21F12 capture mAbs were coated at 10 μg / ml with 96 well immunoassay plates (Costa Costa, Mass.) Overnight at room temperature. Plates were then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature and stored dry at 4 ° C. until use. This plate was rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) before use. Samples and standards were added to the plates and incubated overnight at 4 ° C. The plates were washed three more times with wash buffer between each step of the assay. Biotinylated 3D6 diluted to 0.5 μg / ml in casein culture buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) was incubated in the wells for 1 hour at room temperature. Avidin-HRP (Burlingame Vector, CA) diluted 1: 4000 in casein culture buffer was added to the wells for 1 hour at room temperature. A colorimetric substrate, slow TMB-ELISA (Cambridge Pierce, Mass.) Was added and reacted for 15 minutes, after which the enzymatic reaction was stopped by addition of 2 NH ₂ SO ₄ . The reaction product was quantified using molecular apparatus Vmax (Mencular Park Molecular Devices, Calif.) To determine the difference in absorbance at 450 nm and 650 nm.

2. Blood analysis

EDTA plasma was diluted in sample dilution (0.2 gm / l sodium phosphate H ₂ O (monobasic), 2.16 gm / l sodium phosphate 7 H ₂ O (dibasic), 0.5 gm / l thimerosal, 8.5 gm / l sodium chloride, 0.5 ml Triton X-405, 6.0 g / l globulin-free bovine serum albumin; and water). Samples and standards in the samples were analyzed using the above-described total β-amyloid assay (266 capture / 3D6 reporter) for cerebral analysis, except that sample dilutions were used in place of the casein dilutions described.

From the foregoing description various modifications and variations in the compositions and methods can be made by those skilled in the art. All such modifications falling within the scope of the appended claims are included herein.

Claims (89)

Intracellular β-amyloid peptides comprising administering to said cells an amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a mixture thereof, effective to inhibit intracellular release and / or synthesis of the β-amyloid peptide Methods of Inhibiting Release and / or Synthesis. <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 heterocyclic; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Each R ³ is independently selected from the group consisting of hydrogen and methyl, or R ³ may be fused together with R ⁴ to form a 3-8 membered ring structure 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 Become; R ⁵ is each selected from hydrogen and methyl, or together with R ⁴ form a cycloalkyl group of 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is (a) alkyl or cycloalkyl, (b) substituted alkyl, provided that the substitution on the substituted alkyl does not include α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl or α-OC (O) aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "where R 'and R" are independently hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl Is selected from heterocyclic, or one of R 'or R "is hydroxy or alkoxy, or R' and R" combine to optionally contain 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen. To form a cyclic group of 2 to 8 carbon atoms optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups); (j) -NHS0 ₂ -R ⁸ , wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; (k) —NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl, and R ¹⁰ is each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl , Heterocyclic); And (l) -ONR ⁹ [C (O) O] _z R ¹⁰ , wherein z is 0 or 1 and R ⁹ and R ¹⁰ are as defined above It is selected from the group consisting of; X is also -CR ⁶ R ⁶ Y 'wherein R ⁶ is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and Y' is hydroxy , Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is alkyl, substituted alkyl, Selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic), X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group; Z is selected from the group consisting of a bond, oxygen and sulfur, which covalently bond R ¹ to -CX'X "-; n is an integer of 1 or 2; only, A. 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 When Z is a bond and n is 1, X is not -C (O) OH; B. R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is —CH (OH) CH ₃ derived from D-threonine, R ⁵ is hydrogen, X ′ and X ″ are When hydrogen is Z is a bond and n is 1, X is not -C (O) OH or -C (O) OCH ₃ ; C. 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, n is When 1, R ³ is not methyl; D. R ¹ is iso-propyl, R ² is -CH ₂ C (O) NH ₂ , R ³ is hydrogen, R ⁴ is iso-butyl, R ⁵ is hydrogen, X 'and X " When hydrogen, Z is a bond and n is 1, 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 , The nitrogen atom bonded to R ³ , R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. 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 when n is 1, R ⁴ is not 4-amino-n-butyl; G. 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, When Z is a bond and n is 1, X is not -C (O) NH ₂ or -CH ₂ 0H; H. 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 when n is 1, R ⁴ is not benzyl or ethyl; I. 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 When n is 1, X is not -CHOHψ; J. R^OneIs 3,5-difluorophenyl, R²Is methyl and R³end Hydrogen, R⁴Is phenyl derived from D-phenylglycine and R⁵Is hydrogen, X 'and X "are hydrogen, Z is a bond, and n is 1, X is -CHOHψ or -CH₂Not OH; K. R ¹ is N- (2-pyrrolidinyl), R ² is methyl, R ³ is hydrogen, R ⁴ is benzyl, R ⁵ is hydrogen, X 'and X "are hydrogen, When Z is a bond and n is 1, X is not -C (O) OCH ₃ ; L. R ¹ is 3,5-difluorophenyl, R ² is methyl derived from D-alanine, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, and R ⁵ is hydrogen When X 'and X "are hydrogen, Z is a bond and n is 1, X is not -C (O) NH-benzyl; M. 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 When n is 1, X is not -CH ₂ 0H; N. 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 When Z is a bond and n is 1, X is not -C (O) NHC (CH ₃ ) ₃ ; 0. R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, R ⁵ is hydrogen, X 'and X When "is hydrogen, Z is a bond and n is 1, X is not -C (O) NHCH (CH ₃ ) ψ. To a patient at risk of developing Alzheimer's disease, the pharmaceutical composition comprising an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or mixture thereof, and a pharmaceutically inert carrier: Method of inhibiting Alzheimer's disease initiation. <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 heterocyclic; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Each R ³ is independently selected from the group consisting of hydrogen and methyl, or R ³ may be fused together with R ⁴ to form a 3-8 membered ring structure 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 Become; R ⁵ is each selected from hydrogen and methyl, or together with R ⁴ form a cycloalkyl group of 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is (a) alkyl or cycloalkyl, (b) substituted alkyl, provided that the substitution on the substituted alkyl does not include α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl or α-OC (O) aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "where R 'and R" are independently hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl Is selected from heterocyclic, or one of R 'or R "is hydroxy or alkoxy, or R' and R" combine to optionally contain 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen. To form a cyclic group of 2 to 8 carbon atoms optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups); (j) -NHS0 ₂ -R ⁸ , wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; (k) —NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl, and R ¹⁰ is each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl , Heterocyclic); And (l) -ONR ⁹ [C (O) O] _z R ¹⁰ , wherein z is 0 or 1 and R ⁹ and R ¹⁰ are as defined above It is selected from the group consisting of; X is also -CR ⁶ R ⁶ Y 'wherein R ⁶ is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and Y' is hydroxy , Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is alkyl, substituted alkyl, Selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic), X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group; Z is selected from the group consisting of a bond, oxygen and sulfur, which covalently bond R ¹ to -CX'X "-; n is an integer of 1 or 2; only, A. 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 When Z is a bond and n is 1, X is not -C (O) OH; B. R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is —CH (OH) CH ₃ derived from D-threonine, R ⁵ is hydrogen, X ′ and X ″ are When hydrogen is Z is a bond and n is 1, X is not -C (O) OH or -C (O) OCH ₃ ; C. 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, n is When 1, R ³ is not methyl; D. R ¹ is iso-propyl, R ² is -CH ₂ C (O) NH ₂ , R ³ is hydrogen, R ⁴ is iso-butyl, R ⁵ is hydrogen, X 'and X " When hydrogen, Z is a bond and n is 1, 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 , The nitrogen atom bonded to R ³ , R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. 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 when n is 1, R ⁴ is not 4-amino-n-butyl; G. 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, When Z is a bond and n is 1, X is not -C (O) NH ₂ or -CH ₂ 0H; H. 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 when n is 1, R ⁴ is not benzyl or ethyl; I. 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 When n is 1, X is not -CHOHψ; J. R^OneIs 3,5-difluorophenyl, R²Is methyl and R³end Hydrogen, R⁴Is phenyl derived from D-phenylglycine and R⁵Is hydrogen, X 'and X "are hydrogen, Z is a bond, and n is 1, X is -CHOHψ or -CH₂Not OH; K. R ¹ is N- (2-pyrrolidinyl), R ² is methyl, R ³ is hydrogen, R ⁴ is benzyl, R ⁵ is hydrogen, X 'and X "are hydrogen, When Z is a bond and n is 1, X is not -C (O) OCH ₃ ; L. R ¹ is 3,5-difluorophenyl, R ² is methyl derived from D-alanine, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, and R ⁵ is hydrogen When X 'and X "are hydrogen, Z is a bond and n is 1, X is not -C (O) NH-benzyl; M. 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 When n is 1, X is not -CH ₂ 0H; N. 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 When Z is a bond and n is 1, X is not -C (O) NHC (CH ₃ ) ₃ ; 0. R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, R ⁵ is hydrogen, X 'and X When "is hydrogen, Z is a bond and n is 1, X is not -C (O) NHCH (CH ₃ ) ψ. Inhibiting aggravation of symptoms in said patient, comprising administering to a patient with Alzheimer's disease an effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or mixture thereof, and a pharmaceutically inert carrier: Method for the treatment of Alzheimer's disease patients. <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 heterocyclic; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Each R ³ is independently selected from the group consisting of hydrogen and methyl, or R ³ may be fused together with R ⁴ to form a 3-8 membered ring structure 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 Become; R ⁵ is each selected from hydrogen and methyl, or together with R ⁴ form a cycloalkyl group of 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is (a) alkyl or cycloalkyl, (b) substituted alkyl, provided that the substitution on the substituted alkyl does not include α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl or α-OC (O) aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "where R 'and R" are independently hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl Is selected from heterocyclic, or one of R 'or R "is hydroxy or alkoxy, or R' and R" combine to optionally contain 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen. To form a cyclic group of 2 to 8 carbon atoms optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups); (j) -NHS0 ₂ -R ⁸ , wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; (k) —NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl, and R ¹⁰ is each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl , Heterocyclic); And (l) -ONR ⁹ [C (O) O] _z R ¹⁰ , wherein z is 0 or 1 and R ⁹ and R ¹⁰ are as defined above It is selected from the group consisting of; X is also -CR ⁶ R ⁶ Y 'wherein R ⁶ is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and Y' is hydroxy , Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is alkyl, substituted alkyl, Selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic), X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group; Z is selected from the group consisting of a bond, oxygen and sulfur, which covalently bond R ¹ to -CX'X "-; n is an integer of 1 or 2; only, A. 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 When Z is a bond and n is 1, X is not -C (O) OH; B. R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is —CH (OH) CH ₃ derived from D-threonine, R ⁵ is hydrogen, X ′ and X ″ are When hydrogen is Z is a bond and n is 1, X is not -C (O) OH or -C (O) OCH ₃ ; C. 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, n is When 1, R ³ is not methyl; D. R ¹ is iso-propyl, R ² is -CH ₂ C (O) NH ₂ , R ³ is hydrogen, R ⁴ is iso-butyl, R ⁵ is hydrogen, X 'and X " When hydrogen, Z is a bond and n is 1, 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 , The nitrogen atom bonded to R ³ , R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. 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 when n is 1, R ⁴ is not 4-amino-n-butyl; G. 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, When Z is a bond and n is 1, X is not -C (O) NH ₂ or -CH ₂ 0H; H. 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 when n is 1, R ⁴ is not benzyl or ethyl; I. 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 When n is 1, X is not -CHOHψ; J. R^OneIs 3,5-difluorophenyl, R²Is methyl and R³end Hydrogen, R⁴Is phenyl derived from D-phenylglycine and R⁵Is hydrogen, X 'and X "are hydrogen, Z is a bond, and n is 1, X is -CHOHψ or -CH₂Not OH; K. R ¹ is N- (2-pyrrolidinyl), R ² is methyl, R ³ is hydrogen, R ⁴ is benzyl, R ⁵ is hydrogen, X 'and X "are hydrogen, When Z is a bond and n is 1, X is not -C (O) OCH ₃ ; L. R ¹ is 3,5-difluorophenyl, R ² is methyl derived from D-alanine, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, and R ⁵ is hydrogen When X 'and X "are hydrogen, Z is a bond and n is 1, X is not -C (O) NH-benzyl; M. 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 When n is 1, X is not -CH ₂ 0H; N. 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 When Z is a bond and n is 1, X is not -C (O) NHC (CH ₃ ) ₃ ; 0. R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, R ⁵ is hydrogen, X 'and X When "is hydrogen, Z is a bond and n is 1, X is not -C (O) NHCH (CH ₃ ) ψ. The method of claim 1, wherein R ¹ is an unsubstituted aryl group and Z is a bond that covalently bonds R ¹ to —CX′X ″-. The compound of claim 4, wherein R^Onesign Unsubstituted aryl group is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. The method of claim 1, wherein R ¹ is a substituted aryl group and Z is a bond that covalently bonds R ¹ to —CX′X ″-. The method of claim 6, wherein the substituted aryl group is a mono-, di-, or tri-substituted phenyl group. The substituted phenyl group according to claim 7, wherein the substituted phenyl group is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluoro Rophenyl, 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-methylene-di Oxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-chlorophenyl and 2,5-difluorophenyl. 4. The method of claim 1, wherein R ¹ is an alkali group and Z is a bond that covalently bonds R ¹ to —CX′X ″. 5. 10. The compound of claim 9 wherein R^Onesign Wherein the alkali group is selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. The method according to any one of claims 1 to 3, R ¹ is a alkyl, selected from alkenyl, cycloalkyl and cycloalkenyl group consisting alkenyl, Z is R ¹ -CX'X "- in covalently A method that is a bond that binds. The method of claim 11, wherein R ¹ is alkyl. The method of claim 11, wherein R ¹ is cycloalkyl. The method of claim 11, wherein R ¹ is alkenyl. The method of claim 11, wherein R ¹ is cycloalkenyl. 12. The compound of claim 11 wherein R^Onesign Alkyl, cycloalkyl, alkenyl and cycloalkenyl groups areo-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH₂CH = CH₂, -CH₂CH = CH (CH₂)₄CH₃, Cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH₂-Cyclopropyl, -CH₂-Cyclobutyl, -CH₂-Cyclohexyl, -CH₂-Cyclopentyl, -CH₂CH₂-Cyclopropyl, -CH₂CH₂-Cyclobutyl, -CH₂CH₂-Cyclohexyl, -CH₂CH₂Cyclopentyl, aminomethyl and N-tert-butoxycarbonylaminomethyl. 4. The compound of claim 1, wherein R ¹ is selected from the group consisting of heteroaryl and substituted heteroaryl groups, and Z is a bond that covalently bonds R ¹ to —CX′X ″-. Way. 18. The compound of claim 17, wherein R^Onesign Heteroaryl and substituted heteroaryl groups are pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyl (including 5-fluoropyrid-3-yl), chloropyridyl (Including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzo Furan-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thiophen-5-yl, 6- Methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. The process of claim 1, wherein R ² is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. The compound of claim 9, wherein R ² is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro-phenyl , 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ 0CH ₂ φ, -CH (CH ₃ ) OCH ₂ φ, —CH (OH) CH ₃ and —CH ₂ 0H. 4. The method of claim 1, wherein X ′ and X ″ are hydrogen and Z is a bond that covalently bonds R ¹ to —CX′X ″. 5. 22. The pyrrolidin-2-yl, 2,3-dihydroindole-2 of claim 21, wherein R ³ is selected from the group consisting of hydrogen, methyl, or together with the nitrogen atom to which R ⁴ and R ³ are attached -Yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. ^{4. The} substituent of claim 1, wherein the R ⁴ substituent is 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, p-fluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxy Benzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p- (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ 0-benzyl, p- (CH ₃ ) ₃ COC (O) CH ₂ 0-benzyl, p-phenylphenyl, 3,5-difluorophenyl, p- (HOOCCH ₂ 0) -benzyl, 2-aminopyrid-6-yl, 4- (N-morpholino-CH ₂ CHO ) 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 - 4-yl, -CH ₂ (1- methyl) cyclopropyl, -CH ₂ - thien-3-yl, T 3-yl, thien-2-yl, -CH ₂ -C (O) Ot- _{butyl, -CH 2 -C (CH 3)} 3, -CH 2 CH (CH 2 CH 3) 2, 2- methylcyclohexyl Pentyl, -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 ₂ (cis and trans), -CH ₂ 0H, -CH (OH) CH ₃ , -CH (Ot-butyl) CH ₃ , -CH ₂ 0CH ₃ ,-( CH) 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-morpholino), p- (N-morpholino-CH ₂ CH ₂ 0) -benzyl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, 5- Chlorobenzo [b] thiophen-2-yl, 4,5,6,7-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-methyl Thiazol-4-yl, thieno [2,3-b] thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2- 1, 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 The method is selected from the group consisting of. The group according to any one of claims 1 to 3, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, wherein R ⁴ and R ⁵ are fused to consist of cyclopropyl and cyclobutyl. A method of forming a cycloalkyl group selected from. The compound of claim 1, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, X is -C (O) Y, and Y is hydroxy, alkoxy. Or substituted alkoxy. The compound of claim 25, wherein Y is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy, 2-phenyl Ethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-nbutoxy, -ONHC (O) OC (CH ₃ ) ₃ , -ONHC (CH ₃ ) ₃ And alkoxy or substituted alkoxy selected from the group consisting of hydroxy. The compound of claim 1, wherein Z is a bond that covalently binds R ¹ to —CX′X ″ —, X is —C (O) Y, and Y is —NR′R. "How is it. The compound of claim 27, wherein Y is amino (-NH ₂ ), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N- Morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethyleneimino, N-pyrrolidinyl, -NH-metallyl, -NHCH ₂ -(Furan-2-yl), -NHCH ₂ cyclopropyl, -NH (tert-butyl), -NH (p-methylphenyl), -NHOCH ₃ , -NHCH ₂ (p-fluorophenyl), -NHCH ₂ CH ₂ 0CH _3, -NH- cyclopentyl, cyclohexyl _{-NH-, -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-thiazolininyl, -N (CH ₂ CH ₂ CH ₃ ) ₂ , -N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -NH (p-NO ₂ -φ), -NHCH ₂ (P-NO ₂ -φ), -NHCH ₂ (m-N0 ₂ -φ), -N ( CH ₃ ) OCH ₃ , -N (CH ₃ ) CH ₂ -φ, -NHCH _2- (3,5-di-fluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ 0- φ), -NHCH ₂ (m-CH ₃ 0-φ), -NHCH ₂ (P-CF ₃ -φ), -N (CH ₃ ) CH ₂ CH ₂ 0CH ₃ , -NHCH ₂ CH ₂ φ, -NHCH (CH ₃ ) _{φ, -NHCH 2 - (pF-} φ), -N (CH 3) CH 2 CH 2 N (CH 3) 2, -NHCH 2 - ( tetrahydrofuran-2-yl), -NHCH ₂ (p- tree Fluoromethylphenyl), -NHCH ₂ C (CH ₃ ) = CH ₂ , -NH-[(p-benzyl) pyrid-4-yl], -NH-[(2,6-dimethyl) pyrid-4- Il], -NH- (2-methylcyclohexyl), -NH- (4-methylcyclohexyl), -NH- [N-ethoxycarbonyl] -piperidin-4-yl, -NHOC (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ -φ, -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 ) φ, -NH (CH ₂ ) ₄ NHC (O)-(2-hydroxy-4-azido) -phenyl and -NH (CH ₂ ) _6- (biotinamidyl). The compound of claim 1, wherein X is —C (O) Y, and Y is —CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ , —CH ₂ 0H, —CH (OH). CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH (OH) φ, -CH (OH) CH ₂ C (O) OCH ₃ , -C (OH) (CH ₃ ) ₂ , -CH ₂ 0CH ₃ ,- CH ₂ 0C (O) OCH ₃ and -CH ₂ 0C (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 -pyrid-4-yl, -CH _2- Fur-2-yl, benzyl, cyclopentyl, phenyl and -NH-SO ₂ -CH _3- . 4. The method of claim 1, wherein Z is a bond that covalently bonds R ¹ to —CX′X ″. 5. The compound of claim 1, wherein the compound of formula I is N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-histidine methyl ester, N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (3-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate tert-butyl ester, N- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (deck-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tyrosine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (carboxymethoxy) phenylalanine methyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (3-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyll-L-proline methyl ester, 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-morpholinopropionate methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (2-morpholinoethoxy) phenylalanineamide , N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (4-pyridyl) propionamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (2-pyridyl) propionamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate methyl ester, 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester, 4 N- (3-methoxybenzyl) -N '-[N- (3.5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (1-naphthyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-naphthyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-thienyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine benzyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-bromopropyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-iodopropyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine tert-butyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetamide, N- [N- (3,5- difluoro-phenyl-acetyl) -L- al Raney carbonyl] -N _ε - (tert- butoxycarbonyl) -L- lysine methyl ester, Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-4-phenylbutanoate, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 2-phenylethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 3-phenylpropyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide, N- [N- (phenylacetyl) -L-alaninyl] -L-threonine methyl ester, N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide, N '-[N- (phenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, 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-leucineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-valinamide, N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-valinamide, N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N, N-dimethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-methoxyphenyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-methoxyphenyl) acetate methyl ester, 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 ethyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -l-aminocyclopropane-1-carboxylate methyl ester, N-2- (N, N-dimethylamino) ethyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine benzyl ester, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alanine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine ethyl ester, N-hydroxy-N '-[N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threonineamide, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-tyrosine ethyl ester, N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester, N- [N- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (isovaleryl) -L-phenylalaninyl] -L-alanine iso-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanine ethyl ester, 1- [N- (3-nitrophenylacetyl) -L-alaninyl] -indolin- (S) -2-carboxylate ethyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-methoxy-N-methyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide, N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N, N-di-n-propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valinamide, N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-iso-butyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-nitrophenyl) -N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-alanineamide, N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-benzyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (3,5-difluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (3-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophan methyl ester, N- (4-methoxybenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine methyl ester, N- [N- (cyclohexylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine methyl ester, N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-phenylglycine methyl ester, N- (2-phenylethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophanamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3-cyclohexylpropionate methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-nitrophenyl Propionamide, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-serine ethyl ester, N-[(R) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl-L-alanineamide, N-[(S) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-fluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-pyridylmethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-trifluoromethylbenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-phenylpropionate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-methylpropionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclosilacetate ethyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -L-alanine 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) -L-alaninyl] -L-phenylglycinamide, N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine neopentyl ester, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N '-[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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-amino-3-tert-butoxybutyryl] morpholine, 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isorushinyl] morpholine, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine, N- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine methyl ester, N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-neopentyl-N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-tetrahydrofurfuryl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, 3- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] thiazolidine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- (R) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, 1- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] pyrrolidine, N- (S) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valine methyl ester, N-2-fluoroethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-[(S) -6-methyl-3-oxohept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, 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, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-fluorophenyl) acetate methyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate methyl ester, 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 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 ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (IH-tetrazol-5-yl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (6-methoxy-2-naphthyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate Methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2.3b] thiophen-2-yl) acetate methyl ester, 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, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohex-4-enoate methyl ester, N- [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, N- [N- (3,5-difluorophenylacetyl)-(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-rucinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-alanine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-leucine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -N- (tert-butoxycarbonyl) -L-lysine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-valine methyl ester, N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine, N- [N- (phenylacetyl) -L-alaninyl] -L-N-methylalanine methyl ester, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-hydroxyproline ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-lysine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide, 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester, N-[(S) -3-hydroxy-6-methylhept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenyl-α-fluoroacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, 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-alanineamide, N-[(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide, N-[(S) -α-hydroxy-α-phenyl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-1,2-diphenylethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-hydroxy-α '-(4-hydroxyphenyl) -iso-propyl] -N'-(3,5-difluorophenylacetyl) -L-alanineamide, N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [α-hydroxy-α'-pyrid-2-yl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-hydroxy-α'-pyrid-4-yl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-hydroxy-4-methylpent-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-methoxy-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-hydroxy-3-methyl-but-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (6-aminopyrid-2-yl) acetate methyl ester, N- [1-hydroxy-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-methoxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-methoxy-2-phenyl-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-acetoxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] -N '-(3,5-difluorophenylacetyl) L-alanineamide, N- [2-hydroxy-1- (thien-2-yl) ethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (cyclopropaneacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (cyclopentaneacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycineamide, N- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycineamide, N- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -L-norrousinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-tert-rushinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-isorushinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (cyclopropyl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-3-yl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-2-yl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (cyclopropylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (cyclopentylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycineamide, 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, 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] -D-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) -L-alaninyl] -D, L-phenylglycinamide, 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) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (phenyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2 (benzyl) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4-bromophenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (cyclohexyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (4-ethylphenyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4- (tert-butyl) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-3- (4-chlorophenoxy) phenylglycineamide, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (phenyl) phenylglycinamide, N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N-tert-butyl-N '-[N- (3,5-difluorophenyl-α, α-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine tert-butyl ester, N-[(S) -1-oxo-1-phenylprop-2-yl] -N- (3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (pyrid-3-yl) glycine tert-butyl ester, [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (2-methoxy) phenylglycine methyl ester, 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) -L-alaninyl] -D, L-phenylglycinamide, N-methoxy-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine, N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide, N-cyclopropanemethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-methoxy-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-2-methylprop-2-enyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N- (pyrid-3-yl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N- (pyrid-4-yl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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) -L-alaninyl] -D, L-phenylglycinamide, N, N-dimethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide, N-2,2,6,6-tetramethylpiperidin-4-yl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenyl Glycineamide, N-2-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-4-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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 N-tert-butyl (hydroxylamine) ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide, N- (1-ethoxyethen-1-yl)-[N '-(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide, N- [N- (phenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N-4- (phenyl) butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N-3- (4-iodophenoxy) propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N-6- (amino) hexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide hydrochloride, N-1- (phthalimido) pent-2-yl-N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycinyl] -L- (3,5difluorophenyl) glycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine, N- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine isopropyl ester, N- (isopropyl) N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine iso-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3-α-phenyl) proline methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-azetidine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (5-chlorobenzothiophen-2-yl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycineamide tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycineamide, N- [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide, N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-trifluoromethylphenylacetyl) -L-alaninyl] -D-phenylglycinamide, N- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-furanyl) acetamide, N '-[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) -L-alaninyl] glycinamide, N "-methyl-N" -phenyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide, N "-methyl-N" -benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide, N "-4-fluorobenzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (4-fluoro) phenylglycine neopentyl ester, N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) serinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) threoninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-threonyl] -L-phenylglycine methyl ester, N- [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-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenyl-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) -L-alaninyl] -L-phenylglycinamide, N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-pentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N- [1-phenyl-2-oxo-butan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-α-hydroxyphenylalanine methyl ester, N "-[4-((2-hydroxy-4-azido) -phenyl) -NHC (O)-) butyl] N '-[N- (3,5-difluorophenylacetyl) -L- Alaninyl] -L-phenylglycineamide, N-[(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine tert-butyl ester, 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) methyl ester, 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-phenylglycinethioamide, N- [1,3-diphenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-hexane-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N "-n-hexyl-6-biotinamidyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinethioamide, N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-methionine, N '-[N- (2-tert-BOC-amino) propionyl) -L-alaninyl] -L-phenylglycine methyl ester, N "-tert-butyl N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2-fluorophenyl glycineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-2-phenylglycine methyl ester, N-[(S) -1-phenyl-2-oxo-3-phenylpropan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine, N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine tert-butyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine, N '-[N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine tert-butyl ester, N- [2-hydroxy-1- (S) phenyleth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanineamide, N- [2-hydroxyeth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenyl-2-oxo-acetyl) -L-alaninyl] -L-2-phenylglycine tert-butyl ester, [N- (2,5-dichlorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3,4-dichlorothiophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3-aminopropionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, and [N- (3-tert-butoxycarbonylamino) propionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester The method is selected from the group consisting of. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically inert carrier. <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 heterocyclic; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Each R ³ is independently selected from the group consisting of hydrogen and methyl, or R ³ may be fused together with R ⁴ to form a 3-8 membered ring structure 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 Become; R ⁵ is each selected from hydrogen and methyl, or together with R ⁴ form a cycloalkyl group of 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is (a) alkyl or cycloalkyl, (b) substituted alkyl, provided that the substitution on the substituted alkyl does not include α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl or α-OC (O) aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "where R 'and R" are independently hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl Is selected from heterocyclic, or one of R 'or R "is hydroxy or alkoxy, or R' and R" combine to optionally contain 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen. To form a cyclic group of 2 to 8 carbon atoms optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups); (j) -NHS0 ₂ -R ⁸ , wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; (k) —NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl, and R ¹⁰ is each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl , Heterocyclic); And (l) -ONR ⁹ [C (O) O] _z R ¹⁰ , wherein z is 0 or 1 and R ⁹ and R ¹⁰ are as defined above It is selected from the group consisting of; X is also -CR ⁶ R ⁶ Y 'wherein R ⁶ is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and Y' is hydroxy , Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is alkyl, substituted alkyl, Selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic), X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group; Z is selected from the group consisting of a bond, oxygen and sulfur, which covalently bond R ¹ to -CX'X "-; n is an integer of 1 or 2; only, A. 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 When Z is a bond and n is 1, X is not -C (O) OH; B. R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is —CH (OH) CH ₃ derived from D-threonine, R ⁵ is hydrogen, X ′ and X ″ are When hydrogen is Z is a bond and n is 1, X is not -C (O) OH or -C (O) OCH ₃ ; C. 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, n is When 1, R ³ is not methyl; D. R ¹ is iso-propyl, R ² is -CH ₂ C (O) NH ₂ , R ³ is hydrogen, R ⁴ is iso-butyl, R ⁵ is hydrogen, X 'and X " When hydrogen, Z is a bond and n is 1, 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 , The nitrogen atom bonded to R ³ , R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. 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 when n is 1, R ⁴ is not 4-amino-n-butyl; G. 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, When Z is a bond and n is 1, X is not -C (O) NH ₂ or -CH ₂ 0H; H. 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 when n is 1, R ⁴ is not benzyl or ethyl; I. 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 When n is 1, X is not -CHOHψ; J. R^OneIs 3,5-difluorophenyl, R²Is methyl and R³end Hydrogen, R⁴Is phenyl derived from D-phenylglycine and R⁵Is hydrogen, X 'and X "are hydrogen, Z is a bond, and n is 1, X is -CHOHψ or -CH₂Not OH; K. R ¹ is N- (2-pyrrolidinyl), R ² is methyl, R ³ is hydrogen, R ⁴ is benzyl, R ⁵ is hydrogen, X 'and X "are hydrogen, When Z is a bond and n is 1, X is not -C (O) OCH ₃ ; L. R ¹ is 3,5-difluorophenyl, R ² is methyl derived from D-alanine, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, and R ⁵ is hydrogen When X 'and X "are hydrogen, Z is a bond and n is 1, X is not -C (O) NH-benzyl; M. 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 When n is 1, X is not -CH ₂ 0H; N. 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 When Z is a bond and n is 1, X is not -C (O) NHC (CH ₃ ) ₃ ; 0. R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, R ⁵ is hydrogen, X 'and X When "is hydrogen, Z is a bond and n is 1, X is not -C (O) NHCH (CH ₃ ) ψ. 33. The pharmaceutical composition of claim 32, wherein R ¹ is an unsubstituted aryl group and Z is a bond that covalently bonds R ¹ to -CX'X "-. 34. The compound of claim 33, wherein R^Onesign Pharmaceutical composition wherein the unsubstituted aryl group is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 33. The pharmaceutical composition of claim 32, wherein R ¹ is a substituted aryl group and Z is a bond that covalently bonds R ¹ to -CX'X "-. The pharmaceutical composition of claim 35, wherein the substituted aryl group is a mono-, di-, or tri-substituted phenyl group. 37. The substituted phenyl group of claim 36, wherein the substituted phenyl group is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluoro Rophenyl, 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-methylene-di Pharmaceutical composition selected from the group consisting of oxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-chlorophenyl and 2,5-difluorophenyl. 33. The pharmaceutical composition of claim 32, wherein R ¹ is an alkali group and Z is a bond that covalently binds R ¹ to -CX'X "-. The compound of claim 38, wherein R^Onesign A pharmaceutical composition wherein the alkali group is selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 33. The pharmaceutical composition of claim 32, wherein R ¹ is selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl groups, and Z is a bond that covalently bonds R ¹ to -CX'X "-. The pharmaceutical composition of claim 40, wherein R ¹ is alkyl. 41. The pharmaceutical composition of claim 40, wherein R ¹ is cycloalkyl. The pharmaceutical composition of claim 40, wherein R ¹ is alkenyl. The pharmaceutical composition of claim 40, wherein R ¹ is cycloalkenyl. 41. The compound of claim 40, wherein R^Onesign Alkyl, cycloalkyl, alkenyl and cycloalkenyl groups areo-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH₂CH = CH₂, -CH₂CH = CH (CH₂)₄CH₃, Cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH₂-Cyclopropyl, -CH₂-Cyclobutyl, -CH₂-Cyclohexyl, -CH₂-Cyclopentyl, -CH₂CH₂-Cyclopropyl, -CH₂CH₂-Cyclobutyl, -CH₂CH₂-Cyclohexyl, -CH₂CH₂-A pharmaceutical composition selected from the group consisting of cyclopentyl, aminomethyl and N-tert-butoxycarbonylaminomethyl. 33. The pharmaceutical composition of claim 32, wherein R ¹ is selected from the group consisting of heteroaryl and substituted heteroaryl groups, and Z is a bond that covalently bonds R ¹ to -CX'X "-. 47. The compound of claim 46 wherein R^Onesign Heteroaryl and substituted heteroaryl groups are pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyl (including 5-fluoropyrid-3-yl), chloropyridyl (Including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzo Furan-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thiophen-5-yl, 6- Pharmaceutical composition selected from the group consisting of methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 33. The pharmaceutical composition of claim 32, wherein R ² is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 49. The compound of claim 48, wherein R ² is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro-phenyl , 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ 0CH ₂ φ, -CH A pharmaceutical composition selected from the group consisting of (CH ₃ ) OCH ₂ φ, -CH (OH) CH ₃ and -CH ₂ 0H. 33. The pharmaceutical composition of claim 32, wherein X 'and X "are hydrogen and Z is a bond that covalently bonds R ¹ to -CX'X"-. 51. The compound of claim 50, wherein R ³ is selected from the group consisting of hydrogen, methyl, or pyrrolidin-2-yl, 2,3-dihydroindole-2 with the nitrogen atom to which R ⁴ , and R ³ are attached Pharmaceutical compositions forming -yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. 33. The method of claim 32, wherein the R ⁴ substituent is 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-fluor Rophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p- (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ 0-benzyl, p- (CH ₃ ) ₃ COC (O) CH ₂ 0-benzyl, p-phenylphenyl , 3,5-difluorophenyl, p- (HOOCCH ₂ 0) -benzyl, 2-aminopyrid-6-yl, 4- (N-morpholino-CH ₂ CHO) 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 -thiazole-4- 1, -CH ₂ (1-methyl) cyclopropyl, -CH ₂ -thien-3-yl, thien-3-yl, thien- ₂ -yl, -CH ₂ -C ( O) Ot-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 ₂ (cis and trans ), -CH ₂ 0H, -CH (OH) CH ₃ , -CH (Ot-butyl) CH ₃ , -CH ₂ 0CH ₃ ,-(CH) 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-morpholino), p- (N-morpholino- 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 , 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, thieno [2,3-b] thi Offen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-ethyl Phenyl, 2-benzylphenyl, (4-ethylphenyl) Carbonyl, 4-tert- butylphenyl, 4-n- butylphenyl, o- (4-chlorophenoxy) phenyl, furan-2-yl, 4-acetyl pharmaceutical composition is selected from the group consisting of phenyl alkylenyl. 33. The compound of claim 32, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, wherein R ⁴ and R ⁵ fuse to form a cycloalkyl group selected from the group consisting of cyclopropyl and cyclobutyl Pharmaceutical compositions. 33. The compound of claim 32, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, X is -C (O) Y and Y is from the group consisting of hydroxy, alkoxy or substituted alkoxy Pharmaceutical Compositions Selected. 55. The compound of claim 54, wherein Y is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy, 2-phenyl Ethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-nbutoxy, -ONHC (O) OC (CH ₃ ) ₃ , -ONHC (CH ₃ ) ₃ And alkoxy or substituted alkoxy selected from the group consisting of hydroxy. 33. The pharmaceutical composition of claim 32, wherein Z is a bond that covalently binds R ¹ to -CX'X "-, wherein X is -C (O) Y and Y is -NR'R". The compound of claim 56, wherein Y is amino (-NH ₂ ), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N- Morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethyleneimino, N-pyrrolidinyl, -NH-metallyl, -NHCH ₂ -(Furan-2-yl), -NHCH ₂ cyclopropyl, -NH (tert-butyl), -NH (p-methylphenyl), -NHOCH ₃ , -NHCH ₂ (p-fluorophenyl), -NHCH ₂ CH ₂ 0CH _3, -NH- cyclopentyl, cyclohexyl _{-NH-, -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-thiazolininyl, -N (CH ₂ CH ₂ CH ₃ ) ₂ , -N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -NH (p-NO ₂ -φ), -NHCH ₂ (P-NO ₂ -φ), -NHCH ₂ (m-N0 ₂ -φ), -N ( CH ₃ ) OCH ₃ , -N (CH ₃ ) CH ₂ -φ, -NHCH _2- (3,5-di-fluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ 0- φ), -NHCH ₂ (m-CH ₃ 0-φ), -NHCH ₂ (P-CF ₃ -φ), -N (CH ₃ ) CH ₂ CH ₂ 0CH ₃ , -NHCH ₂ CH ₂ φ, -NHCH (CH ₃ ) _{φ, -NHCH 2 - (pF-} φ), -N (CH 3) CH 2 CH 2 N (CH 3) 2, -NHCH 2 - ( tetrahydrofuran-2-yl), -NHCH ₂ (p- tree Fluoromethylphenyl), -NHCH ₂ C (CH ₃ ) = CH ₂ , -NH-[(p-benzyl) pyrid-4-yl], -NH-[(2,6-dimethyl) pyrid-4- Il], -NH- (2-methylcyclohexyl), -NH- (4-methylcyclohexyl), -NH- [N-ethoxycarbonyl] -piperidin-4-yl, -NHOC (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ -φ, -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 ) φ, -NH (CH ₂ ) ₄ NHC (O)-(2-hydroxy-4-azido) -phenyl and -NH (CH ₂ ) _6- (biotinamidyl). 33. The compound of claim 32, wherein X is -C (O) Y, Y is -CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ 0H, -CH (OH) CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH (OH) φ, -CH (OH) CH ₂ C (O) OCH ₃ , -C (OH) (CH ₃ ) ₂ , -CH ₂ 0CH ₃ , -CH ₂ 0C (O) OCH ₃ And -CH ₂ 0C (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 - pyrid-4-yl, -CH ₂ - greener-2-yl, benzyl, A pharmaceutical composition selected from the group consisting of cyclopentyl, phenyl and -NH-SO ₂ -CH _3- . 33. The pharmaceutical composition of claim 32, wherein Z is a bond that covalently binds R ¹ to -CX'X "-. 33. The compound of claim 32, wherein the compound of formula N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-histidine methyl ester, N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (3-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate tert-butyl ester, N- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (deck-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tyrosine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (carboxymethoxy) phenylalanine methyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (3-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyll-L-proline methyl ester, 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-morpholinopropionate methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (2-morpholinoethoxy) phenylalanineamide , N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (4-pyridyl) propionamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (2-pyridyl) propionamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate methyl ester, 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester, 4 N- (3-methoxybenzyl) -N '-[N- (3.5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (1-naphthyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-naphthyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-thienyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine benzyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-bromopropyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-iodopropyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine tert-butyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetamide, N- [N- (3,5- difluoro-phenyl-acetyl) -L- al Raney carbonyl] -N _ε - (tert- butoxycarbonyl) -L- lysine methyl ester, Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-4-phenylbutanoate, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 2-phenylethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 3-phenylpropyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide, N- [N- (phenylacetyl) -L-alaninyl] -L-threonine methyl ester, N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide, N '-[N- (phenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, 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-leucineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-valinamide, N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-valinamide, N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N, N-dimethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-methoxyphenyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-methoxyphenyl) acetate methyl ester, 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 ethyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -l-aminocyclopropane-1-carboxylate methyl ester, N-2- (N, N-dimethylamino) ethyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine benzyl ester, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alanine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine ethyl ester, N-hydroxy-N '-[N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threonineamide, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-tyrosine ethyl ester, N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester, N- [N- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (isovaleryl) -L-phenylalaninyl] -L-alanine iso-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanine ethyl ester, 1- [N- (3-nitrophenylacetyl) -L-alaninyl] -indolin- (S) -2-carboxylate ethyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-methoxy-N-methyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide, N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N, N-di-n-propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valinamide, N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-iso-butyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-nitrophenyl) -N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-alanineamide, N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-benzyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (3,5-difluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (3-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophan methyl ester, N- (4-methoxybenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine methyl ester, N- [N- (cyclohexylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine methyl ester, N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-phenylglycine methyl ester, N- (2-phenylethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophanamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3-cyclohexylpropionate methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-nitrophenyl Propionamide, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-serine ethyl ester, N-[(R) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl-L-alanineamide, N-[(S) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-fluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-pyridylmethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-trifluoromethylbenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-phenylpropionate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-methylpropionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclosilacetate ethyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -L-alanine 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) -L-alaninyl] -L-phenylglycinamide, N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine neopentyl ester, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N '-[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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-amino-3-tert-butoxybutyryl] morpholine, 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isorushinyl] morpholine, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine, N- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine methyl ester, N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-neopentyl-N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-tetrahydrofurfuryl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, 3- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] thiazolidine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- (R) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, 1- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] pyrrolidine, N- (S) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valine methyl ester, N-2-fluoroethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-[(S) -6-methyl-3-oxohept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, 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, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-fluorophenyl) acetate methyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate methyl ester, 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 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 ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (IH-tetrazol-5-yl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (6-methoxy-2-naphthyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate Methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2.3b] thiophen-2-yl) acetate methyl ester, 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, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohex-4-enoate methyl ester, N- [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, N- [N- (3,5-difluorophenylacetyl)-(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-rucinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-alanine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-leucine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -N- (tert-butoxycarbonyl) -L-lysine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-valine methyl ester, N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine, N- [N- (phenylacetyl) -L-alaninyl] -L-N-methylalanine methyl ester, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-hydroxyproline ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-lysine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide, 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester, N-[(S) -3-hydroxy-6-methylhept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenyl-α-fluoroacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, 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-alanineamide, N-[(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide, N-[(S) -α-hydroxy-α-phenyl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-1,2-diphenylethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-hydroxy-α '-(4-hydroxyphenyl) -iso-propyl] -N'-(3,5-difluorophenylacetyl) -L-alanineamide, N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [α-hydroxy-α'-pyrid-2-yl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-hydroxy-α'-pyrid-4-yl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-hydroxy-4-methylpent-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-methoxy-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-hydroxy-3-methyl-but-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (6-aminopyrid-2-yl) acetate methyl ester, N- [1-hydroxy-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-methoxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-methoxy-2-phenyl-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-acetoxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] -N '-(3,5-difluorophenylacetyl) L-alanineamide, N- [2-hydroxy-1- (thien-2-yl) ethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (cyclopropaneacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (cyclopentaneacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycineamide, N- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycineamide, N- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -L-norrousinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-tert-rushinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-isorushinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (cyclopropyl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-3-yl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-2-yl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (cyclopropylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (cyclopentylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycineamide, 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, 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] -D-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) -L-alaninyl] -D, L-phenylglycinamide, 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) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (phenyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2 (benzyl) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4-bromophenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (cyclohexyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (4-ethylphenyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4- (tert-butyl) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-3- (4-chlorophenoxy) phenylglycineamide, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (phenyl) phenylglycinamide, N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N-tert-butyl-N '-[N- (3,5-difluorophenyl-α, α-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine tert-butyl ester, N-[(S) -1-oxo-1-phenylprop-2-yl] -N- (3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (pyrid-3-yl) glycine tert-butyl ester, [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (2-methoxy) phenylglycine methyl ester, 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) -L-alaninyl] -D, L-phenylglycinamide, N-methoxy-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine, N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide, N-cyclopropanemethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-methoxy-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-2-methylprop-2-enyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N- (pyrid-3-yl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N- (pyrid-4-yl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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) -L-alaninyl] -D, L-phenylglycinamide, N, N-dimethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide, N-2,2,6,6-tetramethylpiperidin-4-yl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenyl Glycineamide, N-2-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-4-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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 N-tert-butyl (hydroxylamine) ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide, N- (1-ethoxyethen-1-yl)-[N '-(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide, N- [N- (phenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N-4- (phenyl) butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N-3- (4-iodophenoxy) propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N-6- (amino) hexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide hydrochloride, N-1- (phthalimido) pent-2-yl-N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycinyl] -L- (3,5difluorophenyl) glycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine, N- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine isopropyl ester, N- (isopropyl) N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine iso-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3-α-phenyl) proline methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-azetidine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (5-chlorobenzothiophen-2-yl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycineamide tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycineamide, N- [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide, N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-trifluoromethylphenylacetyl) -L-alaninyl] -D-phenylglycinamide, N- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-furanyl) acetamide, N '-[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) -L-alaninyl] glycinamide, N "-methyl-N" -phenyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide, N "-methyl-N" -benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide, N "-4-fluorobenzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (4-fluoro) phenylglycine neopentyl ester, N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) serinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) threoninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-threonyl] -L-phenylglycine methyl ester, N- [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-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenyl-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) -L-alaninyl] -L-phenylglycinamide, N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-pentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N- [1-phenyl-2-oxo-butan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-α-hydroxyphenylalanine methyl ester, N "-[4-((2-hydroxy-4-azido) -phenyl) -NHC (O)-) butyl] N '-[N- (3,5-difluorophenylacetyl) -L- Alaninyl] -L-phenylglycineamide, N-[(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine tert-butyl ester, 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) methyl ester, 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-phenylglycinethioamide, N- [1,3-diphenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-hexane-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N "-n-hexyl-6-biotinamidyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinethioamide, N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-methionine, N '-[N- (2-tert-BOC-amino) propionyl) -L-alaninyl] -L-phenylglycine methyl ester, N "-tert-butyl N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2-fluorophenyl glycineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-2-phenylglycine methyl ester, N-[(S) -1-phenyl-2-oxo-3-phenylpropan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine, N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine tert-butyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine, N '-[N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine tert-butyl ester, N- [2-hydroxy-1- (S) phenyleth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanineamide, N- [2-hydroxyeth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenyl-2-oxo-acetyl) -L-alaninyl] -L-2-phenylglycine tert-butyl ester, [N- (2,5-dichlorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3,4-dichlorothiophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3-aminopropionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, and [N- (3-tert-butoxycarbonylamino) propionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester Pharmaceutical composition selected from the group consisting of. A compound of formula (I) or a pharmaceutically acceptable salt thereof. <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 heterocyclic; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Each R ³ is independently selected from the group consisting of hydrogen and methyl, or R ³ may be fused together with R ⁴ to form a 3-8 membered ring structure 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 Become; R ⁵ is each selected from hydrogen and methyl, or together with R ⁴ form a cycloalkyl group of 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is (a) alkyl or cycloalkyl, (b) substituted alkyl, provided that the substitution on the substituted alkyl does not include α-haloalkyl, α-diazoalkyl, α-OC (O) alkyl or α-OC (O) aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "where R 'and R" are independently hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl Is selected from heterocyclic, or one of R 'or R "is hydroxy or alkoxy, or R' and R" combine to optionally contain 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen. To form a cyclic group of 2 to 8 carbon atoms optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups); (j) -NHS0 ₂ -R ⁸ , wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; (k) —NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl, and R ¹⁰ is each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl , Heterocyclic); And (l) -ONR ⁹ [C (O) O] _z R ¹⁰ , wherein z is 0 or 1 and R ⁹ and R ¹⁰ are as defined above It is selected from the group consisting of; X is also -CR ⁶ R ⁶ Y 'wherein R ⁶ is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and Y' is hydroxy , Amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is alkyl, substituted alkyl, Selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic), X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group; Z is selected from the group consisting of a bond, oxygen and sulfur, which covalently bond R ¹ to -CX'X "-; n is an integer of 1 or 2; only, A. 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 When Z is a bond and n is 1, X is not -C (O) OH; B. R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is —CH (OH) CH ₃ derived from D-threonine, R ⁵ is hydrogen, X ′ and X ″ are When hydrogen is Z is a bond and n is 1, X is not -C (O) OH or -C (O) OCH ₃ ; C. 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, n is When 1, R ³ is not methyl; D. R ¹ is iso-propyl, R ² is -CH ₂ C (O) NH ₂ , R ³ is hydrogen, R ⁴ is iso-butyl, R ⁵ is hydrogen, X 'and X " When hydrogen, Z is a bond and n is 1, 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 , The nitrogen atom bonded to R ³ , R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. 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 when n is 1, R ⁴ is not 4-amino-n-butyl; G. 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, When Z is a bond and n is 1, X is not -C (O) NH ₂ or -CH ₂ 0H; H. 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 when n is 1, R ⁴ is not benzyl or ethyl; I. 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 When n is 1, X is not -CHOHψ; J. R^OneIs 3,5-difluorophenyl, R²Is methyl and R³end Hydrogen, R⁴Is phenyl derived from D-phenylglycine and R⁵Is hydrogen, X 'and X "are hydrogen, Z is a bond, and n is 1, X is -CHOHψ or -CH₂Not OH; K. R ¹ is N- (2-pyrrolidinyl), R ² is methyl, R ³ is hydrogen, R ⁴ is benzyl, R ⁵ is hydrogen, X 'and X "are hydrogen, When Z is a bond and n is 1, X is not -C (O) OCH ₃ ; L. R ¹ is 3,5-difluorophenyl, R ² is methyl derived from D-alanine, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, and R ⁵ is hydrogen When X 'and X "are hydrogen, Z is a bond and n is 1, X is not -C (O) NH-benzyl; M. 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 When n is 1, X is not -CH ₂ 0H; N. 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 When Z is a bond and n is 1, X is not -C (O) NHC (CH ₃ ) ₃ ; 0. R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is phenyl derived from D-phenylglycine, R ⁵ is hydrogen, X 'and X When "is hydrogen, Z is a bond and n is 1, X is not -C (O) NHCH (CH ₃ ) ψ. 62. The compound of claim 61, wherein R ¹ is an unsubstituted aryl group and Z is a bond that covalently bonds R ¹ to -CX'X "-. 63. The method of claim 62, wherein R^Onesign The unsubstituted aryl group is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 62. The compound of claim 61, wherein R ¹ is a substituted aryl group and Z is a bond that covalently bonds R ¹ to -CX'X "-. 65. The compound of claim 64, wherein said substituted aryl group is a mono-, di-, or tri-substituted phenyl group. 66. The substituted phenyl group of claim 65, wherein the substituted phenyl group is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluoro Rophenyl, 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-methylene-di A compound selected from the group consisting of oxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-chlorophenyl and 2,5-difluorophenyl. 62. The compound of claim 61, wherein R ¹ is an alkali group and Z is a bond that covalently bonds R ¹ to -CX'X "-. 68. The method of claim 67 wherein R^Onesign Alkyl group is selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 62. The compound of claim 61, wherein R ¹ is selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl groups, and Z is a bond that covalently bonds R ¹ to -CX'X "-. 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. The method of claim 69, wherein R^Onesign Alkyl, cycloalkyl, alkenyl and cycloalkenyl groups areo-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH₂CH = CH₂, -CH₂CH = CH (CH₂)₄CH₃, Cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH₂-Cyclopropyl, -CH₂-Cyclobutyl, -CH₂-Cyclohexyl, -CH₂-Cyclopentyl, -CH₂CH₂-Cyclopropyl, -CH₂CH₂-Cyclobutyl, -CH₂CH₂-Cyclohexyl, -CH₂CH₂-Cyclopentyl, aminomethyl and N-tert-butoxycarbonylaminomethyl. 62. The compound of claim 61, wherein R ¹ is selected from the group consisting of heteroaryl and substituted heteroaryl groups, and Z is a bond that covalently bonds R ¹ to -CX'X "-. 76. The method of claim 75 wherein R^Onesign Heteroaryl and substituted heteroaryl groups are pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyl (including 5-fluoropyrid-3-yl), chloropyridyl (Including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzo Furan-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thiophen-5-yl, 6- Methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 62. The compound of claim 61, wherein R ² is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 78. The compound of claim 77, wherein R ² is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro-phenyl , 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ 0CH ₂ φ, -CH (CH ₃ ) OCH ₂ φ, -CH (OH) CH ₃ and -CH ₂ 0H. 62. The compound of claim 61, wherein X 'and X "are hydrogen and Z is a bond that covalently bonds R ¹ to -CX'X"-. 80. The compound of claim 79, wherein R ³ is selected from the group consisting of hydrogen, methyl, or pyrrolidin-2-yl, 2,3-dihydroindole-2 with the nitrogen atom to which R ⁴ , and R ³ are attached To form -yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. 62. The compound of claim 61, wherein the R ⁴ substituent is 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-fluor Rophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p- (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ 0-benzyl, p- (CH ₃ ) ₃ COC (O) CH ₂ 0-benzyl, p-phenylphenyl , 3,5-difluorophenyl, p- (HOOCCH ₂ 0) -benzyl, 2-aminopyrid-6-yl, 4- (N-morpholino-CH ₂ CHO) 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 -thiazole-4- 1, -CH ₂ (1-methyl) cyclopropyl, -CH ₂ -thien-3-yl, thien-3-yl, thien- ₂ -yl, -CH ₂ -C ( O) Ot-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 ₂ (cis and trans ), -CH ₂ 0H, -CH (OH) CH ₃ , -CH (Ot-butyl) CH ₃ , -CH ₂ 0CH ₃ ,-(CH) 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-morpholino), p- (N-morpholino- 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 , 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, thieno [2,3-b] thi Offen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-ethyl Phenyl, 2-benzylphenyl, (4-ethylphenyl) Carbonyl, 4-tert- butylphenyl, 4-n- butylphenyl, o- (4-chlorophenoxy) phenyl, furan-2-yl, 4-acetyl compound is selected from the group consisting of phenyl alkylenyl. 62. The compound of claim 61, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, wherein R ⁴ and R ⁵ fuse to form a cycloalkyl group selected from the group consisting of cyclopropyl and cyclobutyl compound. 62. The compound of claim 61, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, X is -C (O) Y and Y is from the group consisting of hydroxy, alkoxy or substituted alkoxy Compound selected. 84. The compound of claim 83, wherein Y is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy, 2-phenyl Ethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-nbutoxy, -ONHC (O) OC (CH ₃ ) ₃ , -ONHC (CH ₃ ) ₃ And alkoxy or substituted alkoxy selected from the group consisting of hydroxy. 62. The compound of claim 61, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-, wherein X is -C (O) Y and Y is -NR'R". 86. The compound of claim 85, wherein Y is amino (-NH ₂ ), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N- Morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethyleneimino, N-pyrrolidinyl, -NH-metallyl, -NHCH ₂ -(Furan-2-yl), -NHCH ₂ cyclopropyl, -NH (tert-butyl), -NH (p-methylphenyl), -NHOCH ₃ , -NHCH ₂ (p-fluorophenyl), -NHCH ₂ CH ₂ 0CH _3, -NH- cyclopentyl, cyclohexyl _{-NH-, -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-thiazolininyl, -N (CH ₂ CH ₂ CH ₃ ) ₂ , -N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -NH (p-NO ₂ -φ), -NHCH ₂ (P-NO ₂ -φ), -NHCH ₂ (m-N0 ₂ -φ), -N ( CH ₃ ) OCH ₃ , -N (CH ₃ ) CH ₂ -φ, -NHCH _2- (3,5-di-fluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ 0- φ), -NHCH ₂ (m-CH ₃ 0-φ), -NHCH ₂ (P-CF ₃ -φ), -N (CH ₃ ) CH ₂ CH ₂ 0CH ₃ , -NHCH ₂ CH ₂ φ, -NHCH (CH ₃ ) _{φ, -NHCH 2 - (pF-} φ), -N (CH 3) CH 2 CH 2 N (CH 3) 2, -NHCH 2 - ( tetrahydrofuran-2-yl), -NHCH ₂ (p- tree Fluoromethylphenyl), -NHCH ₂ C (CH ₃ ) = CH ₂ , -NH-[(p-benzyl) pyrid-4-yl], -NH-[(2,6-dimethyl) pyrid-4- Il], -NH- (2-methylcyclohexyl), -NH- (4-methylcyclohexyl), -NH- [N-ethoxycarbonyl] -piperidin-4-yl, -NHOC (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ -φ, -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 ) φ, -NH (CH ₂ ) ₄ NHC (O)-(2-hydroxy-4-azido) -phenyl and -NH (CH ₂ ) _6- (biotinamidyl). The compound of claim 61, wherein X is -C (O) Y, Y is -CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ 0H, -CH (OH) CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH (OH) φ, -CH (OH) CH ₂ C (O) OCH ₃ , -C (OH) (CH ₃ ) ₂ , -CH ₂ 0CH ₃ , -CH ₂ 0C (O) OCH ₃ And -CH ₂ 0C (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 - pyrid-4-yl, -CH ₂ - greener-2-yl, benzyl, Cyclopentyl, phenyl and -NH-SO ₂ -CH _3- . 62. The compound of claim 61, wherein Z is a bond that covalently bonds R ¹ to -CX'X "-. 62. The compound of claim 61, wherein the compound of formula N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-histidine methyl ester, N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (3-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-pyridyl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexanoate tert-butyl ester, N- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (deck-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tyrosine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (carboxymethoxy) phenylalanine methyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (3-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyll-L-proline methyl ester, 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-pyridyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-morpholinopropionate methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (2-morpholinoethoxy) phenylalanineamide , N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (4-pyridyl) propionamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (2-pyridyl) propionamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate methyl ester, 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester, 4 N- (3-methoxybenzyl) -N '-[N- (3.5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (1-naphthyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-naphthyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (2-thienyl) propionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine benzyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-bromopropyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-iodopropyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine tert-butyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetamide, N- [N- (3,5- difluoro-phenyl-acetyl) -L- al Raney carbonyl] -N _ε - (tert- butoxycarbonyl) -L- lysine methyl ester, Methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-4-phenylbutanoate, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 2-phenylethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 3-phenylpropyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide, N- [N- (phenylacetyl) -L-alaninyl] -L-threonine methyl ester, N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide, N '-[N- (phenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, 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-leucineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-leucineamide, N, N-dimethyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-valinamide, N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-methyl-N '-[N- (phenylacetyl) -L-alaninyl] -L-valinamide, N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N, N-dimethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohexaneamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-methoxyphenyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-methoxyphenyl) acetate methyl ester, 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 ethyl ester, 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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -l-aminocyclopropane-1-carboxylate methyl ester, N-2- (N, N-dimethylamino) ethyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine benzyl ester, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alanine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine ethyl ester, N-hydroxy-N '-[N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threonineamide, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-tyrosine ethyl ester, N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester, N- [N- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (isovaleryl) -L-phenylalaninyl] -L-alanine iso-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanine ethyl ester, 1- [N- (3-nitrophenylacetyl) -L-alaninyl] -indolin- (S) -2-carboxylate ethyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-methoxy-N-methyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide, N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N, N-di-n-propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valinamide, N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-iso-butyl-N '-[N- (isovaleryl) -L-phenylglycinyl] -L-alanineamide, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-nitrophenyl) -N '-[N- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-alanineamide, N- (4-nitrophenyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N-benzyl-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (3,5-difluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (3-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-nitrobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophan methyl ester, N- (4-methoxybenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine methyl ester, N- [N- (cyclohexylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine methyl ester, N- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-phenylglycine methyl ester, N- (2-phenylethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophanamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3-cyclohexylpropionate methyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (4-nitrophenyl Propionamide, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-serine ethyl ester, N-[(R) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl-L-alanineamide, N-[(S) -α-methylbenzyl] -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-fluorobenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-pyridylmethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- (4-trifluoromethylbenzyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-phenylpropionate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-methylpropionate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclosilacetate ethyl ester, N- (2-methoxyethyl) -N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -L-alanine 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) -L-alaninyl] -L-phenylglycinamide, N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine neopentyl ester, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N '-[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 methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-amino-3-tert-butoxybutyryl] morpholine, 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isorushinyl] morpholine, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine, N- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine ethyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine methyl ester, N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-2- (N, N-dimethylamino) ethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-neopentyl-N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-tetrahydrofurfuryl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, 3- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] thiazolidine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- (R) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, 1- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] pyrrolidine, N- (S) -sec-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valine methyl ester, N-2-fluoroethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N-[(S) -6-methyl-3-oxohept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, 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, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-fluorophenyl) acetate methyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate methyl ester, 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 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 ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetate tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-thienyl) acetic acid, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (IH-tetrazol-5-yl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (6-methoxy-2-naphthyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate Methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2.3b] thiophen-2-yl) acetate methyl ester, 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, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-aminohex-4-enoate methyl ester, N- [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, N- [N- (3,5-difluorophenylacetyl)-(S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-rucinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-alanine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-leucine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -N- (tert-butoxycarbonyl) -L-lysine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester, N- [N- (phenylacetyl) -L-alaninyl] -L-valine methyl ester, N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminobutanoate methyl ester, N- [N- (phenylacetyl) -L-alaninyl]-(S) -2-aminopentanoate methyl ester, N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine, N- [N- (phenylacetyl) -L-alaninyl] -L-N-methylalanine methyl ester, N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester, N- [N- (isovaleryl) -L-isorushinyl] -L-alanine iso-butyl ester, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-hydroxyproline ethyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-lysine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide, 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] piperidine-2-carboxylate methyl ester, N-[(S) -3-hydroxy-6-methylhept-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenyl-α-fluoroacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, 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-alanineamide, N-[(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-2-methoxyethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide, N-[(S) -α-hydroxy-α-phenyl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-1,2-diphenylethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-hydroxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-hydroxy-α '-(4-hydroxyphenyl) -iso-propyl] -N'-(3,5-difluorophenylacetyl) -L-alanineamide, N-2-pyridylmethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanineamide, N- [α-hydroxy-α'-pyrid-2-yl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-hydroxy-α'-pyrid-4-yl-iso-propyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-hydroxy-4-methylpent-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [α-methoxy-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-hydroxy-3-methyl-but-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (6-aminopyrid-2-yl) acetate methyl ester, N- [1-hydroxy-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-methoxy-1-phenyleth-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-methoxy-2-phenyl-prop-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1-acetoxyhex-2-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] -N '-(3,5-difluorophenylacetyl) L-alanineamide, N- [2-hydroxy-1- (thien-2-yl) ethyl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N-[(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (cyclopropaneacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (cyclopentaneacetyl) -L-phenylglycinyl] -L-phenylglycinol, N- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycineamide, N- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycineamide, N- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -L-norrousinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-tert-rushinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-isorushinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (cyclopropyl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-3-yl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl)-(S) -2-amino-2- (thien-2-yl) acetyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (cyclopropylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (cyclopentylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester, N- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycineamide, 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, 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] -D-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) -L-alaninyl] -D, L-phenylglycinamide, 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) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (phenyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2 (benzyl) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4-bromophenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (cyclohexyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (4-ethylphenyl) phenylglycinamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-4- (tert-butyl) phenylglycineamide, N-tert-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-3- (4-chlorophenoxy) phenylglycineamide, N-cyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- (phenyl) phenylglycinamide, N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N-tert-butyl-N '-[N- (3,5-difluorophenyl-α, α-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine tert-butyl ester, N-[(S) -1-oxo-1-phenylprop-2-yl] -N- (3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (pyrid-3-yl) glycine tert-butyl ester, [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L- (2-methoxy) phenylglycine methyl ester, 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) -L-alaninyl] -D, L-phenylglycinamide, N-methoxy-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine, N-iso-butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide, N-cyclopropanemethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-methoxy-N-methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-2-methylprop-2-enyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N- (pyrid-3-yl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N- (pyrid-4-yl) methyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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) -L-alaninyl] -D, L-phenylglycinamide, N, N-dimethyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycineamide, N-2,2,6,6-tetramethylpiperidin-4-yl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenyl Glycineamide, N-2-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide, N-4-methylcyclohexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -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 N-tert-butyl (hydroxylamine) ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide, N- (1-ethoxyethen-1-yl)-[N '-(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine hydrazide, N- [N- (phenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N-4- (phenyl) butyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N-3- (4-iodophenoxy) propyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N-6- (amino) hexyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide hydrochloride, N-1- (phthalimido) pent-2-yl-N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycinyl] -L- (3,5difluorophenyl) glycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine, N- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine isopropyl ester, N- (isopropyl) N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine iso-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3-α-phenyl) proline methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-azetidine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (5-chlorobenzothiophen-2-yl) acetate methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-3- (thiazol-4-yl) propionate tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycineamide tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycineamide, N- [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide, N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3-trifluoromethylphenylacetyl) -L-alaninyl] -D-phenylglycinamide, N- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycineamide, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl]-(S) -2-amino-2- (2-furanyl) acetamide, N '-[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) -L-alaninyl] glycinamide, N "-methyl-N" -phenyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide, N "-methyl-N" -benzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide, N "-4-fluorobenzyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (4-fluoro) phenylglycine neopentyl ester, N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (pyrid-3-yl) glycine tert-butyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) serinyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) threoninyl] -L-phenylglycine methyl ester, N- [N- (3,5-difluorophenylacetyl) -L-threonyl] -L-phenylglycine methyl ester, N- [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-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenyl-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) -L-alaninyl] -L-phenylglycinamide, N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-pentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N- [1-phenyl-2-oxo-butan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -N '-(3,5-difluorophenyl-acetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-α-hydroxyphenylalanine methyl ester, N "-[4-((2-hydroxy-4-azido) -phenyl) -NHC (O)-) butyl] N '-[N- (3,5-difluorophenylacetyl) -L- Alaninyl] -L-phenylglycineamide, N-[(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycine tert-butyl ester, 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) methyl ester, 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-phenylglycinethioamide, N- [1,3-diphenyl-2-oxo-propan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-hexane-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N "-n-hexyl-6-biotinamidyl-N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinethioamide, N '-[N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-methionine, N '-[N- (2-tert-BOC-amino) propionyl) -L-alaninyl] -L-phenylglycine methyl ester, N "-tert-butyl N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2-fluorophenyl glycineamide, N '-[N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-2-phenylglycine methyl ester, N-[(S) -1-phenyl-2-oxo-3-phenylpropan-1-yl] -N '-(3,5-difluorophenylacetyl) -L-alanineamide, N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine, N '-[N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine tert-butyl ester, N '-[N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine, N '-[N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine tert-butyl ester, N- [2-hydroxy-1- (S) phenyleth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alanineamide, N- [2-hydroxyeth-1-yl] -N '-[(3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide, N '-[N- (3,5-difluorophenyl-2-oxo-acetyl) -L-alaninyl] -L-2-phenylglycine tert-butyl ester, [N- (2,5-dichlorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3,4-dichlorothiophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester, [N- (3-aminopropionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester, and [N- (3-tert-butoxycarbonylamino) propionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester Compound selected from the group consisting of.