HRP980093A2 - Heterocyclic compounds, pharmaceutical compositions comprising same, and methods for inhibiting "beta"-amyloid peptide release and/or its synthesis by use of such compounds - Google Patents

Description

Related patent references

This patent application is based on U.S. Pat. Provisional Application No. 60/__,__, which was translated in accordance with 37 C.F.R. §1.53(b)(2)(ii) of U.S.C. Patent Application No. 08/808,263, filed Feb. 28, 1997, which is incorporated herein by reference in its entirety.

Field of invention

This invention relates to compounds that inhibit the release and/or synthesis of β-amyloid peptide and, accordingly, finds application in the treatment of Alzheimer's disease.

Literature references

The following publications, patents and patent applications are cited in this application as index numbers above:

Glenner, et al., "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein," Biochem. Biophys. Crisp. Commun., 120:885-890 (1984).

Glenner, et al., "Polypeptide Marker for Alzheimer's Disease and its Use for Diagnosis", U.S. Patent No. 4, 666, 829 of May 19, 1987.

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

Goate, et al., "Segregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer's Disease," Nature, 349:704-706 (1990).

Chartier-Harlan, et al., "Early-Onset Alzheimer's Disease Caused by Mutations at Codon 717 of the β-Amyloid Precursor Proteing Gene", Nature, 353:844-846 (1989).

Murrell, et al., "A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease", Science, 254: 97-99 (1991).

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

Schenk, et al., "Methods and Compositions for the Detection of Soluble β-Amyloid Peptide", International Patent Application Publication No. WO 94/10569, published May 11, 1994.

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

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

Losse, et al., Tetrahedron, 27:1423-1434 (1971)

Citron, et al., "Mutation of the β-Amyloid Precursor Protein in Familial Alzheimer's Disease Increases β-Protein Production, Nature, 360:672-674 (1992).

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

All of the above publications, patents and patent applications are incorporated herein by reference in their entirety to some extent unless individual publications, patents or patent applications are specifically and individually designated as being incorporated by reference in their entirety.

State of the art

Alzheimer's disease (AD) is a degenerative brain disease characterized by progressive loss of memory, recognition, reasoning, judgment and emotional stability that gradually leads to significant mental deterioration and ultimately death. AD is a very common cause of progressive mental decline (dementia) in the elderly and is believed to be the fourth leading cause of death in the United States. AD is found in racial and ethnic groups worldwide and represents a major current and future public health problem. An estimated two to three million people in the United States alone are currently affected by this disease. AD is currently incurable. There is currently no known drug that effectively prevents AD or reverses its symptoms and course.

The brain of people with AD shows characteristic lesions that we call senile (or amyloid) plaque, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. A large number of these lesions, especially amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain that are essential for memory and cognitive functions in AD patients. A smaller number of these lesions, but with a limited anatomical distribution, are found in the brains of most old people who do not have clinical AD. Amyloid plaques and amyloid angiopathy are also characteristic of the brains of individuals with trisomy 21 (Down syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). Today, a definitive diagnosis of Alzheimer's disease usually requires finding the above-mentioned lesions in the brain tissue of patients who have succumbed to the disease or, more rarely, in small biopsy samples of brain tissue taken during an invasive neurosurgical procedure.

The basic chemical constituent of amyloid plaques and vascular amyloid deposits (amyloid angiopathy) that are characteristic of AD and other diseases mentioned above is a protein of approximately 4.2 kilodaltons (kD) composed of approximately 39-43 amino acids, which we designate as β-amyloid peptide (βAP). or sometimes Aβ, AβP and β/A4. The β-amyloid peptide was the first to be purified and partially sequenced by Glenner and colleagues1. The isolation procedure and sequence data for the first 28 amino acids described in US Pat. No. 4, 666, 8292.

Molecular biological and chemical analyzes of the protein have shown that the β-amyloid peptide is a small part of a much larger precursor protein (APP), which is normally produced in the cells of many tissues in various animals and humans. Knowledge of the structure of the gene encoding APP showed that the β-amyloid peptide occurs as a peptide fragment obtained by cleaving APP with the protease enzyme(s). The exact biological mechanism by which β-amyloid peptide is formed by cleavage of APP and then deposited as amyloid plaque in the brain tissue and on the walls of cerebral blood vessels is currently unknown.

Several facts indicate that progressive brain deposition of β-amyloid peptide plays a role as a precursor in the pathogenesis of AD and may precede recognizable symptoms by years or decades. See, for example, Selkoe3. The most important evidence is the discovery that nonsense DNA mutations of amino acid 717 of the 770 amino acid APP isoform can be found in affected but not in unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier-Harlan, et al. .5; and Murrell, et al,6), and is listed in us as the Swedish version. A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) was found in a Swedish family and described in 1992 (Mullan, et al,7). Genetically related analyzes have shown that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in affected members of such families. Furthermore, a mutation at amino acid 693 of the 770-amino acid APP isoform has been identified as the cause of the β-amyloid peptide deposition disease, HCHWA-D, and an alanine to glycine change at amino acid 692 appears to cause an AD-like phenotype in some patients, and in HCHWA -D in others. The discovery of these and other mutations in APP in genetically based cases of AD proves that alteration of APP and subsequent deposition of its β-amyloid peptide can cause AD.

Regardless of the progress that has been made in understanding the mechanism of AD and other diseases associated with the release of β-amyloid peptide, there remains a need to develop methods and compounds for the treatment of this disease(s). Ideally, treatment methods should be primarily based on drugs that can inhibit the release of β-amyloid peptide and/or its in vivo synthesis.

Summary of the invention

This invention is directed to the discovery of a class of compounds that inhibit the release of β-amyloid peptide and/or its synthesis and are therefore useful for the prevention of Alzheimer's disease in patients who are susceptible to AD and/or in the treatment of patients with Alzheimer's disease, in order to prevent further deterioration of their condition. The class of compounds having the described properties is defined by formula I, below:

A-B-C

where A is selected from the set consisting of:

(i) [image]

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

Z is selected from the set it consists of

(a) a group of the formula -CX'X"C(O)- where X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group;

(b) a group of the formula -T-CX'X"C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; and

(c) a group of the formula -CX'X"-T-C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group;

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

R 6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound;

m is an integer equal to 0 or 1; and

p is an integer equal to 0 or 1;

(ii) [image]

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

T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group;

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;

and with the further condition that when W is oxygen, then X cannot be oxygen;

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

R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you

(iii) [image]

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

T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group;

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;

and with the further condition that when W is oxygen, then X cannot be oxygen;

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

R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you

B is selected from the set consisting of:

(i) [image]

wherein R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound;

(ii) [image]

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;

and with the further condition that when W is oxygen, then X cannot be oxygen;

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

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

(iii) [image]

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;

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

(iv) when A is of formula (ii) or (iii) defined above, then B may also be a covalent bond connecting A and C;

C is selected from the set consisting of:

-C(O)Y or -C(S)Y

where Y is selected from the set consisting of:

(a) alkyl or cycloalkyl,

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

(c) Alkoxy or Thioalkoxy,

(d) Substituted Alkoxy or Substituted ThioAlkoxy,

(e) hydroxy,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic compound,

(i) -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, where one of R' or R" hydroxy or alkoxy, and wherein R' and R" are linked to form a cyclic group having 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen , and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups,

(j) –NHSO2-R8 where R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound,

(k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and

(1) -ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;

(ii) –CR11R11Y'

wherein each R 11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkyl, substituted thioalkoxy, -OC(O)R9, -SSR9, and -SSC(O)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compounds; you

(iii) [image]

where A, together with -C=N-, forms a heterocyclic group which is arbitrarily joined to form a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl , cycloalkenyl, heterocyclic compound, aryl and heteroaryl group wherein, again, each such ring structure is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, nitro, cyano , carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O) NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N -disubstituted cycloalkylamino, N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic compound amino, N,N-diheterocyclic compound amino and mixed N,N-amino groups containing the first and second a substituent on said amino group where the substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and a heterocyclic compound provided that said first and second substituents are not identical;

with the condition that when A is of structure (i) and B has structure (i), then C does not have structure (i) or (ii);

with the further proviso that

A. when A has structure (i) where R1 is phenyl, Z is –CH2OC(O)-, R2 is methyl and p is zero, B has structure (iii) where W is -NH-, X is –CH2-, and R 4 is benzyl then C is not -C(O)OCH 3 ;

B. when A has structure (i) where R1 is 3,5-difluorophenyl, Z is –CH2C(O)-, R2 is methyl and p is zero, B has structure (ii) where W >NC(O)OC( CH3)3, X is –CH2-, and R4 is phenyl, then C is not -C(O)OCH3; and

C. when A has the structure (ii) where R1 is 3,5-difluorophenyl, T' is a bond connecting R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is the covalent bond that binds A to C, then C is not -C(O)OCH3.

In one preferred embodiment, compounds of formula I are further characterized by formula II below:

[image]

where R 1 , R 2 , R 5 , R 6 , A, Z, m and p are as defined above.

In the above formula II, when m is equal to one, Z is preferably -CX'X"C(O) where X" is preferably hydrogen, X' is preferably hydrogen or fluorine or X' and X" form an oxo group.

In the above formula II, preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred R1 substituted aryl groups in formula II include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3.5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not have more than 3 substituents.

Examples of substituted R1 phenyls which are preferred in formula II include, for example, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3, 5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4 ,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl , 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl. 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.

Preferred R 1 alkaryl groups in formula II include, for example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl and the like.

Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula II include, for example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, - CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2- cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl and the like.

Preferred R 1 heteroaryls and substituted heteroaryls of formula II include, for example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid- 3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2 -chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl and the like.

Preferably, in formula II, R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and a heterocyclic compound. Particularly preferred R 2 substituents include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, -CH 2 CH 2 SCH 3 and the like. As noted below, R 2 as well as R 5 and R 6 are preferably L-amino acid side chains.

Preferred R5 and/or R6 substituents in formula II are independently selected from the group consisting of, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2- cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p -methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl; p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3- tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t -butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, - CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -{CH2)4NH-Boc, -(CH2 )4NH2, -CH2-pyridyl (eg 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (eg 1-naphthyl and 2 -naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5 ,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth -2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl and the like.

In formula II, preferred [image] groups are further characterized by the following structures:

[image]

where Y” is a heteroatom which can be oxygen, sulfur and >NR8 where R8 as defined above and A', together with –Y”-C=N-, form a heterocyclic group which is arbitrarily joined to form a bi- or multi-membered ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each ring structure is optionally substituted with 1 to 4 substituents which are selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R1 0, -C(O)NH2, -C(O)NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 wherein each R 10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl.

Preferred heterocyclic structures include, for example, 3-methyl, 1,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 3-(methoxy- benzyl)-1,2,4-oxadiazol-5-yl and the like.

Preferred compounds of formula II include the following:

(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole

(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2-phenylethyl]-3-methyl-1,2,4-oxadiazole

2-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-2-thiazoline

(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-methyl-1,2,4-oxadiazole

(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-phenyl-1,2,4-oxadiazole

(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole.

In another preferred embodiment, the compounds of formula I are further characterized by formulas III and IV below:

[image]

and

[image]

where R 1 , R 2 , R 4 , R 6 , W, X, Y, Z, m and p are as defined above. In the formulas III and IV above, where m is one, Z is preferably -CX'X”C(O)- where X” is preferably hydrogen, X' is preferably hydrogen or fluorine and where X' and X” form an oxo group .

In the formulas III and IV above, preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred R1 substituted aryl groups in formulas III and IV include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3.5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not have more than 3 substituents.

Examples of preferred R 1 phenyls which are preferred in formulas III and IV include, for example, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2- trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4- trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3- dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3, 4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl 1, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2 -trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4 -phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.

Preferred R 1 alkaryl groups in formulas III and IV include, for example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl and the like.

Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formulas III and IV include, for example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH= CH2 , - CH2CH =CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, - CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl and the like.

Preferred R 1 heteroaryls and substituted heteroaryls in formulas III and IV include, for example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyridyl -3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl , 2-phenyloxazol-4-yl and the like.

Preferably, in formulas III and IV, R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound. Particularly preferred R 2 substituents include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, -CH 2 CH 2 SCH 3 and the like. As noted below, R 2 (as well as R 6 ) are preferably L-amino acid side chains.

Preferred R6 substituents in formulas III and IV include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH2)2, 2 -methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, - CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m -hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6 -yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, - CH2-(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2 CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl ( for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N- morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophene -2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien- 2-yl, thien-3-yl and the like.

Preferred Y in formula III or IV is hydroxy, alkoxy, substituted alkoxy and -NR'R" where R' and R" are as defined above. Preferred alkoxy and substituted alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3 -iodo-n-propoxy, 4-bromo-n-butoxy and the like.

Preferred –NR'R” groups include, for example, amino (-NH2), -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-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH( t-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-( pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N(CH2CH2CH3)2, -NHOH, -NH(p-NO2- φ), -NHCH2(p-NO2-φ), -NHCH2(m-NO2-φ), -N(CH3)OCH3, -N(CH3)CH2-φ, -NHCH2-(3,5-difluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-φ), -NHCH2(m-CH3O-φ), -NHCH2(p-CF3-φ), -N(CH3)CH2CH2OCH3, -NHCH2CH2φ, -NHCH(CH3)φ, -NHCH2-(p-F-φ), -N(CH3)CH2CH2N(CH3)φ, -NHCH2-(tetrahydrofuran-2-yl) and the like.

A further preferred Y group is an alkyl group such as -CH 2 CH 2 CH(CH 3 ) 2 and the like.

Preferred heterocyclic structures defined by W and X include, for example, 4,5-dihydrothiazoles, 3,4-dihydro-1,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-isodiazoles, 4,5 -dihydrooxazoles and the like.

Preferred compounds of formulas III and IV include the following:

(S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline

1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

1-tert-butoxycarbonyl-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-ethoxycarbonyl-2-thiazoline

1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

2-[(S)-1-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine

(S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-5(R,S)-ethoxycarbonyl-2-oxazoline

2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-methoxycarbonyl-2-thiazoline

[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

In another preferred embodiment, the compounds of formula I are further characterized by formulas V and VI below:

[image]

and

[image]

where R1, R4, R6, T', X', X", W, X, and Y are as defined above. In the formulas V and VI above, when m is equal to one, Z is preferably -CX'X”C(O)- where X is preferably hydrogen, X' is preferably hydrogen or fluorine or where X' and X” form an oxo group .

In the formulas V and VI above, preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred R1 substituted aryl groups in formulas VI and VI include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3.5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not have more than 3 substituents.

Examples of substituted R1 phenyls in formulas UV and VI include, for example, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4 -fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4 -hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2 ,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5 -dichlorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5 -trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri- (trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl , 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl .

Preferred R 1 alkaryl groups in formulas III and IV include, for example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl and the like.

Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formulas III and IV include, for example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2 , -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, - CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl and the like.

Preferred R 1 heteroaryls and substituted heteroaryls in formulas III and IV include, for example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5 -chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2- yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazole-5 -yl, 2-phenyloxazol-4-yl and the like.

Preferred R 4 substituents in formulas III and IV include, for example, hydrogen, methyl, phenyl, benzyl and the like.

Preferred R6 substituents in formulas III and IV include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH2)2, 2 -methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, - CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m -hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6 -yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, - CH2-(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2 CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl ( for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N- morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophene -2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien- 2-yl, thien-3-yl and the like.

Preferred Y in formulas V or VI is hydroxy, alkoxy, substituted alkoxy and -NR'R" where R' and R" are as defined above. Preferred alkoxy and substituted alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3 -iodo-n-propoxy, 4-bromo-n-butoxy and the like.

Preferred –NR'R” groups include, for example, amino (-NH2), -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-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH( t-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-( pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N(CH2CH2CH3)2, -NHOH, -NH(p-NO2- φ), -NHCH2(p-NO2-φ), -NHCH2(m-NO2-φ), -N(CH3)OCH3, -N(CH3)CH2-φ, -NHCH2-(3,5-difluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-φ), -NHCH2(m-CH3O-φ), -NHCH2(p-CF3-φ), -N(CH3)CH2CH2OCH3, -NHCH2CH2φ, -NHCH(CH3)φ, -NHCH2-(p-F-φ), -N(CH3)CH2CH2N(CH3)φ, -NHCH2-(tetrahydrofuran-2-yl) and the like.

A further preferred Y group is an alkyl group such as –CH2CH2CH(CH3)2 and the like.

Preferred heterocyclic structures defined by W and X include, for example, 4-methylthiazolin-4-yl.

Preferred compounds of formulas V and VI include the following:

(4R)-4-[N-(1S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline

4-[N-(S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline

4-[N-(S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline.

Also preferred compounds of this invention include lactams and related compounds of formula VII and VIII

[image]

and

[image]

where R1, R4, R6, T', X', X", W and X are as defined above.

W', together with -C(H)sC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic compound, substituted cycloalkyl or substituted cycloalkenyl group where each of said cycloalkyl, cycloalkenyl, heterocyclic compounds, substituted cycloalkyl or substituted cycloalkenyl group is arbitrarily combined to form a bi- or multiply fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each of the ring structures is arbitrarily substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkyloxy, thioalkyloxy, substituted thioalkyloxy, aryl, heteroaryl, heterocyclic compound, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N=alkylamino, N,N-dia lalkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O )NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 wherein each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl;

U is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);

s is an integer equal to 0 or 1; and

t is an integer equal to 0 or 1.

In the formulas VII and VIII above, X" is preferably hydrogen, X' is preferably hydrogen or fluorine or X' and X" form an oxo group, and T' is preferably a covalent bond connecting R' to -CX'X"-.

In the formulas VII and VIII above, preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred R1 substituted aryl groups in formulas VII and VIII include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3.5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not have more than 3 substituents.

Examples of substituted R 1 phenyls preferred in formulas VII and VIII include 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl , 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl , 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3 -difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl , 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl , 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri- (trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl , 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl .

Preferred R 1 alkaryl groups in formulas VII and VIII include, for example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl and the like.

Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formulas VII and VIII include, for example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2 , -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, - CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl and the like.

Preferred R 1 heteroaryls and substituted heteroaryls in formulas VII and VIII include, for example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyridyl -3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl , 2-phenyloxazol-4-yl and the like.

Preferred R 4 substituents in Formula VII and VIII include, for example, hydrogen, methyl, phenyl, benzyl and the like.

Preferred R 6 substituents in formulas VII and VIII include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, tert-butyl, -CH2CH(CH2CH2 )2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2 -cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl , benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, - aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophene-2- yl, -CH2-(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3 )3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH 3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2 , -CH2-pyridyl (e.g. 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N- morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophene -2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien- 2-yl, thien-3-yl and the like.

Preferred cyclic groups defined by W and -C(H)sC(=U)- include cycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine groups. In one preferred embodiment, the cyclic group defined by W' and -C(H)SC(=U)- forms a cycloalkyl group of the following formula:

[image]

where T" is selected from the group consisting of alkylenes and substituted alkylene.

A preferred cycloalkyl group is described by the formula:

[image]

wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, it is an integer equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W', together with -C(H)sC(=U)- is a ring of the following formula:

[image]

or

[image]

where s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13- where the Z substituent is selected from the group consisting of -O-, -S - and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve the participation of -O- or -S-, and q is an integer from 1 to 3.

Particularly preferred alcohol or thiol substituted groups include,

[image]

[image]

wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, it is an integer equal to 0 or 1.

Another preferred embodiment of the cyclic group defined by W', together with -C(H)sC(=U)-, is a ring of the following formula:

[image]

[image]

where s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13- where the Z substituent is selected from the group consisting of -O-, -S - and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve the participation of -O- or -S-, and q is an integer from 1 to 3.

Particularly preferred cyclic ketone and thioketone groups include:

wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, it is an integer equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W', together with -C(H)sC(=U)-, forms a lactam ring of the following formula:

[image]

[image]

or

[image]

where s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13- where the Z substituent is selected from the group consisting of -O-, -S - and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve the participation of -O- or -S-, and q is an integer from 1 to 3.

Particularly preferred lactone and thiolactone groups include:

[image]

wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, it is an integer equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W' and -C(H)sC(=U)- forms a lactam ring of the following formula:

[image]

or a thiolactam ring of the following formula:

[image]

where s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13- where the Z substituent is selected from the group consisting of -O-, -S - and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve the participation of -O- or -S-, and q is an integer from 1 to 3.

Particularly preferred lactam or thiolactam groups include:

[image]

[image]

[image]

where A-B are selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and -N=CH-; Q' is oxygen or sulfur; wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo and the like; Rb is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic compound and the like; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic compound, cycloalkyl and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an integer from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, it is an integer equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W', together with -C(H)sC(=U)-, forms a ring of the following formula:

[image]

where s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13- where the Z substituent is selected from the group consisting of -O-, -S - and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve the participation of -O- or -S-, and q is an integer from 1 to 3.

A further preferred embodiment is directed towards the ring group defined by W, together with -C(H)sC(=U)-, of the following formula:

[image]

where s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13- where the Z substituent is selected from the group consisting of -O-, -S - and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve the participation of -O- or -S-, and q is an integer from 1 to 3.

A further preferred compound of this invention includes the lactams and related compounds of formulas IX and X:

[image]

and

[image]

where R1, R2, R4, Z, U, W, W', X, m and s are as defined above.

Preferred R1, R2, R4, Z, W and W' are also as defined above.

In one of its method aspects, the present invention is directed to a method for inhibiting β-amyloid peptide release and/or synthesis in a cell, said method comprising administering to such a cell an amount of a compound or a mixture of compounds of the aforementioned formulas I, VII or VIIII to inhibit of cellular release and/or synthesis of β-amyloid peptide.

Since the in vivo formation of β-amyloid peptide is associated with the pathogenesis of AD 8,9 , the compounds of formulas I, VII and VIII may also be used in conjunction with pharmaceutical compositions to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its methodological aspects, this invention is directed towards a prophylactic method for preventing the occurrence of AD in patients at risk of developing AD, and the method in question comprises administering to said patient a pharmaceutical composite containing a pharmaceutically inert carrier and an effective amount of the compound or mixture of compounds above of the above formulas I, VII and VIII.

In a further of its methodological aspects, this invention is directed towards a therapeutic method for the treatment of a patient with AD to prevent further deterioration of the condition of such a patient, said method comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds above of the above formulas I, VII and VIII.

This invention also defines new pharmaceutical composites containing a pharmaceutically inert carrier and a compound of the above formula I, VII or VIII.

Furthermore, this invention defines new compounds of formula I, VII or VIII.

Further preferred compounds of formula I are listed in the following Tables I-IV which list preferred subsets of these structures.

TABLE I

[image]

TABLE II

[image]

TABLE III

[image]

TABLE IV

[image]

Detailed description of the invention

As previously stated, the invention relates to methods for inhibiting the release and/or synthesis of β-amyloid peptide and, therefore, has application in the treatment of Alzheimer's disease. However, before describing this invention in further detail, the following terms should be defined.

Definitions

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

[image]

or a sequence that is completely homologous to this one.

The term "alkyl" refers to monovalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. The term can be represented by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like.

The term "substituted alkyl" refers to an alkyl group, preferably of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy ester, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, mono- and di-alkylamino, mono- and do- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, asymmetric disubstituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compounds .

The term "alkylene" refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. The term is represented by groups such as methyl (-CH2-), ethylene (-CH2CH2-) and propylene isomers (eg –CH2CH2CH2- and –CH(CH3)CH2-) and the like.

The term "alkaryl" refers to -alkylene-aryl groups having preferably from 1 to 10 carbon atoms in the alkylene portion and from 6 to 10 carbon atoms in the aryl portion. Such alkaryl groups are represented by benzyl, phenethyl and the like.

The term "Alkoxy" refers to the group "Alkyl-O-". Preferred alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like.

The term "substituted alkoxy" refers to the group "substituted alkyl-O-" where substituted alkyl is defined above.

The term "alkenyl" refers to alkenyl groups having from 2 to 10 carbon atoms and preferably from 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3) and the like.

The term "substituted alkenyl" refers to an alkenyl group as defined above having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxylic esters, cyano, halogen, hydroxyl, carboxyl, carboxyalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic compound, nitro, and mono- and di-alkylamino, mono- and do-(substituted alkyl)amino, mono- and di- arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, asymmetric disubstituted amines having various substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compounds.

The term "alkenylene" refers to divalent alkenylene groups preferably having from 2 to 8 carbon atoms and more preferably from 2 to 6 carbon atoms. The term can be illustrated by groups such as ethenylene (-CH=CH-), propenylene isomers (eg -CH2CH=CH- and -C(CH3)=CH-) and the like.

"Substituted alkenylene" refers to an alkenylene group, preferably of 2 to 8 carbon atoms, having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano , halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic compound, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino , mono- and di-heteroarylamino, mono- and di-heterocyclic compound amino, and asymmetric di-substituted amines having different substituents selected from the groups: alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compound. Furthermore, such substituted alkylene groups include those where 2 substituents on the alkylene group are joined to form one or more cycloalkyl, aryl, heterocyclic compound or heteroaryl group which are joined to the alkylene group.

The term "alkynyl" refers to alkynyl groups that preferably have from 2 to 10 carbon atoms and more preferably from 2 to 6 carbon atoms and have at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-CH≡CH2), propargyl (-CH2C≡CH) and the like.

The term "substituted alkynyl" refers to an alkynyl group as defined above having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxylic esters, cyano, halogen, hydroxyl, carboxyl, carboxyalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic compound, nitro, and mono- and di-alkylamino, mono- and do-(substituted alkyl)amino, mono- and di- arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, asymmetric disubstituted amines having various substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compounds.

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

The term "aminoacyl" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and wherein each is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound as defined herein.

The term "oxyacyl" refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl- and -C(O)O-heterocyclic compounds, where alkyl, aryl, heteroaryl and heterocyclic compound as defined herein.

The term "oxyacylamino" refers to the groups -OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NR-aryl, -OC(O)NR-heteroaryl- and -OC(O )NR-heterocyclic compound, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compound, and each alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compound is as defined herein.

The term "aminocarboxylic esters" refers to the groups -NRC(O)O-alkyl, -NRC(O)O-substituted alkyl, -NRC(O)O-aryl, -NRC(O)O-heteroaryl and -NRC(O )O-heterocyclic compound, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compound, and each alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compound is as defined herein.

The term "aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.

While not limited by the definition of an aryl substituent, such an aryl group may be optionally substituted with 1 to 5 and preferably 1 to 3 substituents selected from the group consisting of hydroxy, biotinamidyl, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, acylamino, cyano, halo, nitro, heteroaryl, heterocyclic compound, oxyacyl, oxyacylamino, thioalkyl, substituted thioalkyl, trihalomethyl, mono - and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetrical disubstituted amines having different substituents that are selected between alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compound, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy.

The term "aryloxy" refers to the group aryl-O- where the aryl group is as defined above including optionally substituted aryl groups which are also defined above.

The term "cycloalkyl" refers to ring alkyl groups of 3 to 10 carbon atoms having a single ring or multiple fused rings which may be optionally substituted with 1 to 3 alkyl groups. Such cycloalkyl groups include, for example, single-ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like, or multi-ring structures such as adamantanyl and the like.

The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl , alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.

The term "cycloalkenyl" refers to ring alkenyl groups of 4 to 8 carbon atoms having one ring and at least one point of internal unsaturation which can be arbitrarily substituted with 1 part of 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.

The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine, and preferably chlorine or bromine.

The term "heteroaryl" refers to a monovalent aromatic group of 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur within the ring.

While not limited by the definition of a heteroaryl substituent, such heteroaryl group may be optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl , aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic compound, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono and di-( substituted alkyl)amino, mono- and di-arylamino, mono- and diheteroarylamino, mono- and di-heterocyclic compound amino, and asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic connections, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy.

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

The terms "heterocycle" or "heterocyclic compound" refer to monovalent (ie, one point of attachment) saturated or unsaturated groups having one ring or multiple fused rings, from 1 to 8 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen , sulfur or oxygen inside the ring.

While not limited by the definition of a heterocyclic substituent, such heterocyclic group may be arbitrarily substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxylic esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic compound, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amine, and unsymmetrical di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compound, and the like. Such a heterocyclic group may have a single ring or multiple fused rings. Preferred heterocyclic compounds include morpholine, piperidinyl and the like.

Examples of heterocyclic and heteroaryl compounds include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolysine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, quinoline , pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6 ,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, piperidinyl, pyrrolidine, tetrahydrofuranyl and the like.

The term "oxyacyl" refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl- and -C(O)O-heterocyclic compounds, where alkyl, aryl, heteroaryl and heterocyclic compound as defined herein.

The term "oxyacylamino" refers to -OC(O)NH-alkyl groups. -OC(O)NH-substituted alkyl, -OC(O)NH-aryl, -OC(O)NH-heteroaryl- and -OC(O)NH-heterocyclic compound, where alkyl, aryl, heteroaryl and heterocyclic compound are here defined.

The term "thiol" refers to the group –SH.

The term "thioalkyl" refers to the group -S-alkyl.

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

The term “thioaryloxy” refers to the group aryl-S- where the aryl group is as defined herein, including substituted aryl groups as defined above.

The term "thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups also as defined above.

The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of compounds of formula I wherein the salts are derived from a variety of inorganic ions known in the art and include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and a molecule containing basic functional groups, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Arranging a date

Compounds of the formula I can be easily prepared by several different synthetic routes, where each route is selected relatively according to the ease of preparation of the compound, the commercial availability of the starting materials, etc.

The heterocyclic ring(s) in the compounds of the above formula I can be prepared using or adapting known chemical syntheses and methods, which are well known in the art. For example, the synthesis of various heterocyclic compounds is exhaustively illustrated in the examples below. Using these procedures, other suitable heterocyclic compounds can be prepared by modifying the starting materials used in these procedures.

In certain cases, compounds of formula I can be prepared by attaching a suitable heterocyclic compound having one or more attached functional groups to other components necessary to form the A-B-C structure of formula I. Typical functional groups used for such attachment include, for example, carboxyl acid and an amino group. Coupling reactions are generally carried out using conventional coupling reagents such as carbodiimides with or without the use of well-known additives such as N-hydroxysuccinimide, 1-hydroxybenzotritol, etc. which may be used to facilitate coupling. The reaction is typically carried out in an inert aprotic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and the like.

Compounds of formula VII and VIII can be easily prepared by conventional carboxylic acid amidation as shown in reaction (1) below:

[image]

where R1, R4, R6, T', X', X", W, X, W', U, t and s are as defined above.

The reaction is usually carried out using at least stoichiometric amounts of the carboxylic acid 1a or 1b and the amine 2. The reaction is usually carried out for peptide synthesis and the synthetic methods used there can be used to prepare compounds VII and VIII. For example, well-known coupling reagents such as carbodiimides with or without well-known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is typically carried out in an inert aprotic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and the like. Alternatively, the acid halide of compound 1a or 1b can be used in reaction (1) and, when used, is typically used in the presence of a suitable base which removes the acid formed during the reaction. Suitable bases include, for example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.

Synthesis of starting materials of carboxylic acid

Carboxylic acids 1a and 1b can be prepared by different synthetic routes that are chosen relatively according to the ease of preparation of the compound, the commercial availability of the starting materials, whether t is equal to zero or one. One method of preparing these compounds (when t is equal to one) is hydrolysis of esters of compounds of the above formula V or VI. Similar methods can be used to prepare related compounds when t is equal to zero.

Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2 can also be prepared using polymer-supported forms of carbodiimide peptide binding reagents. For example, a polymer-bearing form of EDC has been described (Tetrahedron Letters, 34(48), 7685 (1993))10. Furthermore, a new carbodiimide coupling reagent, PEPC, has been discovered and its polymer-supported forms are very useful in the preparation of such compounds.

Polymers suitable for obtaining the polymer-bearing binding reagent are either commercially available or can be prepared by methods well known to those skilled in the art of polymers. A suitable polymer must have attached side chains that carry reactive species with the carbodiimide terminal amine. Such reactive species include chloro, bromo, iodo, and methanesulfonyl. Preferably, the reactive species is a chloromethyl group. Furthermore, the polymer backbone must be inert both to the carbodiimide and to the reaction conditions under which the final polymer-linked binding reagent will be applied.

Some hydroxymethylated resins can be converted to chloromethylated resins which are useful for preparing a polymer-bearing binding reagent. Examples of these hydroxylated resins include 4-hydroxymethylphenylacetamidomethyl resins (Pam Resin) and 4-benzyloxybenzyl alcohol resins (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see Advanced Chemtech 1993-1994 catalog, p. 115). The hydroxymethyl groups of these resins can be converted to chloromethylated groups by any of a number of methods well known to those skilled in the art.

Preferred resins are chloromethylated styrene/divinylbenzene resins due to their wide commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical change before application. These resins are known commercially as Merrifield resins offered by Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich 1994-1995 catalog, p. 899). Methods for the preparation of PEPC and its polymer-bearing forms are generally shown in the following scheme:

[image]

Such methods are more fully described in U.S. Pat. Patent Application No. 60/019,790 filed Jun. 14, 1996, which is incorporated herein by reference in its entirety. Briefly, PEPC was prepared by first reacting ethyl isocyanate with 1-(3-aminopropyl)pyrrolidine. The resulting urea was treated with 4-toluenesulfonyl chloride to give PEPC. The polymer-bearing form is prepared by reacting PEPC with the appropriate resin under standard conditions to obtain the desired reagent.

Carboxylic acid binding reactions using these reagents are carried out at room temperature to about 45°C, from about 3 to 120 hours. Typically, the product can be isolated by washing the reaction mixture with CHCl3 and concentrating the remaining organic portion under reduced pressure. As discussed above, recovery of the product from a reaction mixture where the reagent is polymer bound is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.

Preparation of cyclic amino compounds

Cyclic amino compounds 2 used in the above reaction (1) are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula:

[image]

where U and s are as defined above, Q is preferably selected from the group consisting of -O-, -S-, >NR16 and >CR17R18 where each R16, R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic compound provided that if Q is -O-, -S- or >NR 16 , then X is oxo or dihydro.

Aminolactams, aminolactones and aminothiolactones of the above formula can be prepared by adapting known chemical syntheses that are well described in the literature. See, for example, Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, et al. Editor, J. Wiley & Sons, New York, New York, USA, pp. 1085 et seq (1993).

Specifically, 3-amino substituted lactams 13 with 5, 6, or 7 ring atoms can be prepared by direct cyclization of the appropriate alpha, omega-diamino acid ester 12 as shown in reaction (5) below:

[image] Reaction (5)

where L is a linking group (typically an alkylene group) of 2-4 atoms, Pr is a suitable protecting group such as t-butoxycarbonyl, carbobenzyloxy or the like and R19 is an alkoxy or aryloxy group such as methoxy, ethoxy, p-nitrophenoxy, N -succinimidoxy and the like. The reaction can be carried out in a solvent such as water, methanol, ethanol, pyridine and the like. Examples of such reactions are the cyclization of lysine lysine ester to caprolactam as described in Ugi, et al, Tetrahedron, 52(35):11657-11664 (1996). Alternatively, such cyclization can be carried out in the presence of a dehydrating agent such as alumina or silica to form lactams as described in Blade-Font, Tetrahedron Lett. , 21:2443 (1980).

The preparation of aminolactams which are alkylated at the amino group of a cyclic lactam is described in Freidinger, et al., J. Org. Chem. , 47:104-109 (1982) and is shown in reaction (6), below:

[image] Reaction (6)

where L and R16 are as defined above.

In reaction (6), reductive amination of 14 with aldehyde 15 and subsequent ring closure by methods using, for example, EDC affords aminolactam 16. The formation of 6-membered lactams using this general procedure is described in Semple, et al, J. Med. Chem., 39: 4531-4536 (1996).

Internal cyclization of the amide anion with a halide or its equivalent can sometimes prove advantageous in the synthesis of lactams with a smaller ring where the stereochemistry of the amino-lactam center is available from a standard set of amino acids. This approach is shown in the reaction (7) below:

[image] Reaction (7)

where R 16 is as defined above.

An approach to reaction (7) is presented in Semple, et al, supra, and Freidinger, et al, J. Org. Chem., 47:104-109 (1982) where the dimethylsulfonium leaving group is formed by methyl iodide treatment of alkyl methyl sulfide 17 to give lactam 18. A similar approach, using the Mitsunobu reaction on omega alcohol was found by Holladay, et al, J. Org. Chem., 56:3900-3905 (1991).

In another method, lactams 20 can be prepared from cyclic ketones 19 using either the well-known Beckmann cleavage (eg, Donaruma, et al, Organic Reactions, 11:1-156 (1960)) or the well-known Schmidt reaction (Wolff, Organic Reactions, 3:307-336 (1946)) as shown in reaction (8), below:

[image] Reaction (8)

where L is as defined above.

The application of these two reactions leads to a wide range of lactams, especially lactams having two hydrogen atoms on the carbon in the alpha position to the lactam carbonyl, whereby the lactams form a desirable group of lactams in the synthesis of compounds of the above formula I. In these reactions, the L group can be very variable , including, for example, substituted alkylene and hetero containing alkylene provided that the heteroatom is not adjacent to the carbonyl group of compound 19. Furthermore, Beckmann partitioning can be applied to bicyclic ketones as described in Krow, et al., J. Org. Chem., 61:5574-5580 (1996).

The preparation of lactones can be similarly carried out using peracids in the Baeyer-Villiger reaction for ketones. Alternatively, thiolactones can be prepared by cyclization of the omega -SH group to a carboxylic acid and thiolactams can be prepared by converting the oxo group to a thiooxo group with P2S5 or using commercially available Lawesson's reagent, Tetrahedron, 35:2433 (1979).

One recently reported route for lactam synthesis is a variation of the Schmidt reaction using an alkyl azide, either intramolecularly or intramolecularly, via a tethered alkylazide function that attacks the ketone under acidic conditions. Gracias, et al., J. Am. Chem. Soc., 117:8047-8048 (1995) describes the intermolecular version while Milligan, et al, J. Am.

Chem. Soc., 117:10449-10459 (1995) describes an intramolecular version. One example of the intramolecular version is shown in the reaction of reactions (9) below:

[image] Reaction (9)

where R 10 denotes alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic compound.

In this reaction, ketone 21 is converted to �-(ω-alkyl)ketone 22 which is cyclized to form bicyclic lactam 23. Such intramolecular reactions are useful in the formation of 5-7 membered bicyclic lactams and 6-13 membered lactam rings. The use of hetero atoms at non-reactive sites in these rings is possible in the synthesis of heterobicyclic lactams.

Another recent approach to lactam synthesis is described by Miller, et al, J. Am. Chem. Soc., 118:9606-9614 (1996) and references cited therein and is shown in reaction (10), below:

[image] Reaction (10)

where R6 and Pr are as defined above and R11 is represented by the following groups: halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic compound, where the groups aryl, heteroaryl, cycloalkyl and heterocyclic compound are arbitrarily joined to the lactam ring structure.

Specifically, in reaction (10), lactam 26 is generated from the corresponding unsaturated amide (eg, 24) via ruthenium or molybdenum complexes catalyzing an olescine metathesis reaction to form unsaturated lactam 25 which can be used here without modification. However, the unsaturation in 25 enables numerous techniques such as hydroboration, Sharpless or Jacobsen epoxidation, Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloaddition reactions and many others, which allows obtaining a wide range of substituents on the lactam ring. Moreover, subsequent changes of the substitutions made lead to other additional substituents (eg mesylation of alcohols and then nucleophilic substitution reactions). See, for example, March, et al. Advanced Organic Chemistry, Reaction Mechanisms and Structure, 2nd Edition, McGraw-Hill Book Company, New York, USA (1977) for sources of numerous such possible reactions. The saturated amides used in this reaction are consistent with amide 24 which is commercially available.

Related chemistry for the cyclization of amides to give lactams is described in Colombo, et al, Tetrahedron Lett., 35 (23):4031-4034 (1994) and is illustrated in the reaction (11) below:

[image] Reaction (11)

In this reaction, the proline derivative 27 was cyclized via tributyltin radical cyclization to give lactam 28.

Some of the lactams described above contain the necessary amino group in the alpha position to the lactam carbonyl, while other lactams do not. Introduction of the requisite amino group, however, can be accomplished by any of several routes outlined below which outline several recent literature sources regarding this synthesis.

For example, in the first general process of synthesis, an amide or amine replacement of the leaving group in the alpha position over the carbonyl group of a lactam leads to an alpha-aminolactam. Such general synthetic procedures are shown by introduction of a halogen atom followed by replacement with a phthalimide anion or azide and subsequent conversion to an amine typically by hydrogenation of the azide as described in Rodriguez, et al., Tetrahedron, 52:7727-7736 (1996), Parsons, et al. al., Biochem. Biophys. Crisp. Comm., 117:108-113 (1983) and Wathey, et al., J. Med. Chem., 28:1511-1516 (1985). One method involves iodination and azide substitution on, for example, benzyl lactams as described in Armstrong, et al, Tetrahedron Lett., 35:3239 (1994) and King, et al., J. Org. Chem., 58:3384 (1993).

Another example of this first general procedure for synthesizing an alpha-aminolactam from the corresponding lactam involves replacing the triflate group with an azido group as described in Hu, et al., Tetrahedron Lett. , 36(21):3659-3662 (1995).

The following example of this first general procedure uses the Mitsunobu reaction of an alcohol and a nitrogen equivalent (either –NH 2 or a phthalimido group) in the presence of azodicarboxylate and triarylphosphine as described in Wada, et al, Bull. Chem. Soc. Japan, 46:2833-2835 (1973) using an open chain reagent.

Another example of this first general procedure involves the reaction of alpha-chlorolactams with anilines or alkyl amines in neat mixture at 120°C to give 2-(N-aryl or N-alkyl)lactams as described in Gaetz, Chem. Abs., 66:28690m.

In another general synthetic procedure, reaction of an enolate with an alkyl nitrite ester to prepare an alpha oxime and reduction gives an alpha-aminolactam compound. This general synthetic procedure is described in Wheeler, et al, Organic Syntheses, Coll. Vol. VI, p. 840 which describes the reaction of isoamyl nitrite with a ketone to give the desired oxime. Reduction of oxime methyl ester (which is prepared from oxime by reaction with methyl iodide) is described in J. Med. Chem., 28(12):1886 (1985) while the reduction of alpha-oximino caprolactam with Raney-nickel and palladium catalyst is described in Brenner, et al, U.S. Patent No. 2,938,029.

In a third synthesis procedure, direct reaction of the enolate with an electrophilic nitrogen transfer agent can be used. The original reaction used toluenesulfonyl azide but was improved as described in Evans, et al., J. Am. Chem. Soc., 112:4011-4030 (1990). Specifically, the direct introduction of an azido group that can be reduced to an amine by hydrogenation is described in Micouin, et al, Tetrahedron, 52:7719-7726 (1996). Similarly, the use of triisopropylbenzenesulfonyl azide as an azide transfer reagent for the reaction with the enolate is described in Evans, et al, supra. The use of triphenylphosphine to reduce alpha-azidolactams to the corresponding aminolactams in the benzodiazepine series is described in Butcher, et al, Tetrahedron Lett., 37(37):6685-6688 (1996). Finally, diazo transfer of betadiketone followed by reduction of the diazo group to an amino group was reported by Hu, et al, Tetrahedron Lett., 36(21):3659-3662 (1995) using Raney-nickel and hydrogen in acetic acid and acetic anhydride as solvent. .

In a fourth general procedure, N-substituted lactams are first converted to 3-alkoxycarbonyl derivatives by reaction of a dialkyl carbonate with a base such as sodium hydride. See, for example, M. L. Reupple, et al. , J. Am. Chem. Soc., 93:7021 and references (1971). The obtained esters serve as starting substances for conversion into 3-amino derivatives. This translation is achieved by the Curtius reaction as shown in the reaction (12) below:

[image] Reaction (12)

where Pr is as defined above and R 12 is typically hydrogen, an alkyl or aryl group.

The Curtius reaction is described in P.A.S. Smith, Organic Reactions, 3:337-449 (1946). Depending on the chosen reaction conditions, whether Pr = H or a protecting group such as Boc. For example, when R = H, treatment of the acid with diphenylphosphoryl azide in the presence of t-butanol gives a product where Pr = Boc.

The alpha-aminolactams used as cyclic amino compounds 2 in the above reaction (1) include an N-substituted lactam ring in addition to an N-H lactam ring. Some methods for the preparation of N-substituted lactams are described above. In general, however, the preparation of these compounds ranges from direct introduction of the substituent after lactam formation to actual introduction prior to lactam formation. The former methods typically use a base and a primary alkyl, although it is believed that a secondary alkyl halide can also be used although lower yields may occur.

Thus, the first general procedure for the preparation of N-substituted lactams is carried out by reacting the lactam with a base and an alkyl halide (or acrylates in some cases). This reaction is quite well known and bases such as sodium hydride, sodium hydride, LDA, LiHMDS in suitable solvents such as THF, DMF, etc. are used provided the base chosen is compatible with the solvent. See, for example: K. Orito, et al, Tetrahedron, 36:1017-1021 (1980) and J.E. Semple, et al., J. Med. Chem., 39:4531-4536 (1996) (using as electrophiles LiHMDS with either R-X or acrylates).

Another general method uses reductive amination at the amino functional group which is then cyclized to the corresponding ester or other carbonyl functional group.

The third general method achieves N-substitution during lactam formation. The literature states that such formation occurs either by photolytic or thermal decomposition of oxaziridine, especially N-compounds. See, for example, Krimm, Chem. Ber., 91:1057 (1958) and Suda, et al, J. Chem. Soc. Chem Comm., 949-950, (1994). Also, the use of methyl hydroxylamine for the formation of nitrones and their partitioning to N-methyl derivatives is presented in Barton, et al., J. Chem. Soc., 1764-1767 (1975). Furthermore, the use of the oxaziridine procedure in chiral synthesis is reported in Kitagawa, et al., J. Am. Chem. Soc., 117: 5169-5178 (1975).

A more direct route to obtain N-phenyl-substituted lactams from the corresponding NH lactams using t-butyltetramethylguanidine and triphenylbismuth dichloride is described in Akhatar, et al, J. Org. Chem., 55:5222-5225 (1990) as shown in reaction (13) below.

[image] Reaction (13)

There are numerous methods available to introduce an alpha-amino group onto the lactam (or lactone) ring, the following lactams (or corresponding lactones) being intended for the synthesis of compounds of the above formula I. Similar alcohol functional groups at the carbonyl position are derivatives of either amine opening of the cyclic epoxide, opening of the acridine ring, replacement of corresponding halides with amine or alcohol nucleophiles, or most often reduction of corresponding ketones. These ketones are also of interest to the present invention.

Monocyclic lactams are described in Nedenskov, et al, Acta Chem. Scand., 12:1405-1410 (1958) and the following formulas are:

[image]

where R 1 and R 2 denote alkyl, aryl or alkenyl (eg allyl).

Monocyclic lactams containing a secondary nitrogen ring are described in Sakakida, et al, Bull. Chem. Soc. Japan, 44:478-480 (1971) and are the following formulas:

[image]

where R denotes CH3- or PhCH2-.

Monocyclic lactams having hydroxyl substitution on the ring are described in Hu, et al, Tetrahedron Lett., 36(21):3659-3662 (1995) and have the following formulas:

[image]

where R denotes benzyl (including cis and trans hydroxy lactams).

The direct preparation of 5-8 membered N-substituted lactams from the corresponding ketones is described in Hoffman, et al, Tet. Lett. , 30:4207-4210 (1989). Such lactams have the following formulas:

[image]

where R is alkyl, alkenyl, alkynyl, cycloalkyl or benzyl.

N-Methoxylactams prepared from cyclohexanone and dimethoxyamine are described in Vedejs, et al, Tet. Lett., 33:3261-3264 (1992). Such structures have the following formulas:

[image]

Substituted 3-aminoazetidinone derivatives prepared by a variety of routes include those described in van der Steen, et al, Tetrahedron, 47, 7503-7524 (1991), Hart, et al, Chem Rev., 89: 1447-1465 (1989) and in the references mentioned there, and the following are the formulas:

[image]

where R1 and R2 are independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, a heterocyclic compound or are joined to form a cyclic group.

Ring substituted lactams are described in Lowe, et al, Bioorg. Honey. Chem. Lett., 4:2877-2882 (1994) and are the following formulas:

[image]

where R 2 and R 3 denote aryl and substituted aryl and R 1 denotes alkyl or hydrogen.

The synthesis of substituted 3-aminopyrrolidones from alphabromoketones is described in McKennis, Jr., et al., J. Org. Chem. , 28:383-387 (1963). These compounds have the following formulas:

[image]

where R1 is aryl or heteroaryl and R2 denotes any substituent for which there is a corresponding amine R2-NH2.

Additional references for alpha aminolactam synthesis are as follows:

1. Shirota, et al., J. Med. Chem. , 20:1623-1627 (1977) which describes the synthesis of a compound of the following formula:

[image]

2. Overberger, et al., J. Am. Chem. Soc., 85: 3431 (1963) which describes the preparation of optically active β-methylcaprolactam of the following formula:

[image]

3. Herschmann, Helv. Chem. Acta. 32:2537 (1949) describes the synthesis of a disubstituted caprolactam Beckman partitioning menthone of the following formula:

[image]

4. Overberger, et al, Macromolecules, 1:1 (1968) describes the synthesis of eight-membered lactams from 3-methylcycloheptanone as shown below:

[image]

5. The synthesis of benzolactams (benzazepinones) is reported in Busacca, et al, Tet. Lett., 33:165-168 (1992):

[image]

and in Croisier, et al, U.S. Patent No. 4,080,449:

[image]

as well as in J.A. Robl, et al., Tetrahedron Lett. , 36(10): 1593-1596 (1995) which uses an internal Friedel-Crafts synthesis such as cyclization to prepare the tricyclic benzyllactams shown below, where Pht is a phthalimidio protecting group:

[image]

Another series of tricyclic lactams is described in Flynn, et al, J. Med. Chem., 36:2420-2423 (1993) and references cited therein.

6. Orito, et al, Tetrahedron, 36:1017-1021 (1980) describes phenyl substituted benzazepinones of the following formula:

[image]

where R = H or CH3-;

Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) describes an N-methoxy benzazepinone of the following formula:

[image]

7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994) describes several synthetic routes for substituted benzazepinones of the following formula:

[image]

where R 1 is substituted aryl or cyclohexyl, X is a suitable substituent and R 2 can be H or alkyl. The syntheses described in Lowe's work, however, are adaptable to a number of R1 substituents.

8. Robl, et al., Bioorg. Honey. Chem. Lett. , 4:1789-1794 (1994) and references cited therein as well as Skiles, et al., Bioorg. Honey. Chem. Lett. , 3:773-778 (1993) describe benzo-fused lactams containing additional heteroatoms in the lactam ring. These compounds are represented by the following formula:

[image]

where X is O and R 2 = H or CH 3 or X = S and R 2 = H. In each case, R 1 = H or alkyl. Also, in the work of Skiles, the thio group of thiolactam can be oxidized to the SO2 group. These structures also represent the Beckmann-obo partitioning in Grunewald, et al., J. Med. Chem., 39(18):3539 (1996).

9. Syntheses of the benzoheterolactam series are also reported in Thomas, et al., J. Chem. Soc. , Perkin II, 747 (1986) which lead to compounds of the following formula:

[image]

where X equals O or H and R is CO2R:

10. Further examples of benzazepinones can be found in Warshawsky, et al., Bioorg. Honey. Chem. Lett., 6:957-962 (1996) which describes compounds of the following formula:

[image]

The synthesis can be generalized to give R = alkyl or aryl.

11. Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987) describes syntheses leading to several benzolactams of the following formula:

where n = 0, 1 or 2 and R = -CH3, PhCH2- and H.

12. van Niel et al., Bioorg. Honey. Chem. Lett., 5:1421-1426 (1995) gives syntheses of compounds of the following formulas:

[image]

where X is -OH, -NH2 or -NR6R6 where R6 is as defined above. Said ketone is a convenient synthetic intermediate that can be modified by conventional methods such as reductive amination, reduction, etc.

13. Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) describes a synthetic method for preparing:

[image]

In addition to the above, saturated bicyclic alpha-aminolactams have also been contemplated in the synthesis of compounds of formula I. Such saturated bicyclic alpha-aminolactams are well known in the art. For example, Edwards, et al., Can. J. Chem., 49:1648-1658 (1971) describes several syntheses of bicyclic lactams of the following formula:

[image] [image]

Similarly, Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) and references therein report the synthesis of lactams of the following formula:

[image]

where R 1 and R 2 are H or -CH 3 , ring A may have 6-13 members and ring B may have 5-7 members. R can be alkyl, aryl, cycloalkyl and the like.

The introduction of a heteroatom into a saturated cyclic structure fused to a lactam ring is described in Curran et al., Tet. Lett., 36:191-194 (1995), which describes a synthetic method that can be used to prepare a lactam of the following formula:

[image]

and in Slusarchyk, et al., Bioorg. Honey. Chem. Lett., 5:753-758 (1995), which describes syntheses leading to lactams of the following formula:

[image]

and in Wyvratt, et al., Eur. Pat. Appl. 61187 (1982), which describes lactams of the following formula:

[image]

Lactams having a second heteroatom(s) in the cyclic structure of the lactam (in addition to the nitrogen of the amide group of the lactam) are described by Cornille, et al., J. Am. Chem. Soc., 117:909-917 (1995), which describes lactams of the following formula:

[image]

and J. Kolc, Coll. Czech. Chem. Comm., 34:630 (1969), which describes lysines suitable for cyclization to lactams having a hete atom in the lactam ring, as shown by the formula:

[image]

where X=O, S and NR where R is, for example, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic compound and the like.

Similarly, each of Dickerman, et al., J. Org. Chem., 14:530 (1949)86, Dickerman, et al., J. Org. Chem., 20:206 (1955) and Dickerman, et al., J. Org. Chem., 19:1855 (1954) use the Schmidt or Beckmann reaction on substituted 4-piperidones to obtain lactams of the following formula:

[image]

wherein R is acyl, alkyl, substituted alkyl, aryl, heteroaryl or a heterocyclic compound, provided that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic compound, heterocyclic oxy compound, halo, cyano, nitro, trihalomethyl and the like.

Internal cyclization of the corresponding ethylenediamine amide to a ketone or aldehyde is described in Hoffman. et al., J. Org. Chem. , 27:3565 (1962) as follows:

[image]

A ring expansion methodology based on beta-lactams containing an aza group is reported twice in Wasserman, et al., J. Am. Chem. Soc., 103:461-2 (1981) and in Crombie, et al., Tetrahedron Lett., 27(42):5151-5154 (1986).

Dieckmann's methodology was used to prepare aza-caprolactams from unsymmetrical amines as shown below by Yokoo, et al., Bull, Chem. Soc. Jap., 29:631 (1956).

[image]

where R is defined in this reference. The description given by Yokoo, et al. may be extended such that R is alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic compound, alkenyl, substituted alkenyl, and the like.

The synthesis of various members of the oxalactam series is reported by Burkholder, et al., Bioorg. Honey. Chem. Lett., 2:231 (1993) and references cited therein, where oxalactams are represented by the formula:

[image]

where 'R is defined in the reference and R can be alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic compound, alkenyl, substituted alkenyl and the like.

The synthesis of thialactams (in general, oxalactams can be made by identical methodology) is described by Freidinger, et al., J. Org. Chem., 47:104-109 (1982), who prepared thialactams of the following formula:

[image]

In this reference, a whole series of procedures is given that have a wide application in the synthesis of lactams, which allows R in the above formula to be derived from any amine (alkyl, aryl, heteroaryl, etc.) with the restriction that the R-group does not contain any functional group which reacts with formaldehyde (eg primary or secondary amine). The general synthetic scheme given by Freidlinger, et al., is:

[image]

The coupling agent is any standard reagent used to form a typical peptide or amide bond, for example, a carbodiimide reagent. See also Karanewsky, U.S. Patent No. 4,460,579 and Kametani, et al., Heterocycles, 9:831-840 (1978).

The Friedinger procedure can be extended to obtain disubstituted thialactams of the following structure:

[image]

In this procedure, the thiolactam ring is prepared as follows:

[image]

From a practical point of view, R2 will be limited to aryl and heteroaryl groups and sterically unfavorable groups such as t-butyl. R1 can be highly variable and is limited only by the reaction steps that follow.

Furthermore, there is the Kametani process, which produces lactams as follows:

[image]

In principle, the Kametani procedure allows for a wide choice of R1 or R2 groups that are limited primarily by the stability of the reaction conditions.

See, for example, Yanganasawa, et al., J. Med. Chem., 30:1984-1991 (1987) and J. Das et al., Bioorg. Honey. Chem. Lett., 4:2193-2198 (1994) which describes general methods for the synthesis of isomeric 7-membered thialactams of the following structure:

[image]

The first synthetic pathway is:

[image]

R2 can be highly variable (e.g., alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic compound, and the like) according to a number of well-documented routines that exist for the synthesis of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration. R 1 is limited by groups amenable to alkylation reactions.

[image]

In this synthesis, R 2 can be very different. The starting material required to introduce R2 can be simply made by reducing some known alpha-BOC-amino acid to an alcohol derivative and then forming a mesylate.

As noted above, the primary approach to preparing lactams is the Beckmann/Schmidt ring enlargement reaction using either inter- or intramolecular approaches that serve to prepare lactams of different ring sizes. The intermolecular approach creates bicyclic materials with the lactam nitrogen incorporated into the ring fusion. Additional approaches mentioned above in the basis of the methodology are internal cyclization of omega-amino acids/esters where the creation of a distribution of substituents is preferred over cyclization, and internal cyclization of an electrophilic center on nucleophilic functional groups as in the Friedel-Crafts type of cyclization at the Ben center - Ishal's procedure for obtaining benzazepinone. This latter procedure is applicable across a range of heteroaromatics as well as benzenoid rings, and can also be applied to non-aromatic double and triple bonds to generate a full spectrum of substituents and ring fusions.

Deoxygenation of lactams with reagents such as diborane, LiAlH4 and the like leads to azaheterocyclic compounds (=X is dihydro).

Similarly, for X = H, OH, such compounds can be prepared by epoxidation of cycloalkenyl groups and then oxirane opening with, for example, ammonia. After formation of a compound of formula I, =X is H, OH can be oxidized to give cycloalkylonicane (=X is oxo).

Furthermore, the 5,7-dihydro-6H-diben[b,d]azepin-6-one derivatives of this invention can be prepared using conventional methods and chemicals. For example, the corresponding substituted N-tert-Boc-2-amino-2'-methylbiphenyl compound can be cyclized to give the corresponding 5,7-dihydro-6H-diben[b,d]azepin-6-one derivative by first treating the biphenyl compound with about 2.1 to about 2.5 equivalents of a strong base, such as sec-butyl lithium. This reaction is typically carried out at a temperature ranging from about -80°C to about -60°C in an inert solvent such as THF. The resulting dianion is then treated with dry carbon dioxide at a temperature of about -78°C to give 5,7-dihydro-6H-diben[b,d]azepin-6-one. This procedure is described in R.D. Clark et al, Tetrahedron, 49(7), 1351-1356 (1993) and references therein.

After the formation of 5,7-dihydro-6H-diben[b,d]azepin-6-one, the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 1.1 to about 1.5 equivalents of a strong base, such as sodium hydride , in an inert solvent such as DMF.

This reaction is typically carried out at a temperature ranging from about -10°C to about 80°C for 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is carried out at a temperature of from about 0°C to about 100°C for 1 to about 48 hours.

An amino group can be introduced into the 5-position of 7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and chemicals. For example, treatment of 7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one with excess butyl nitrite in the presence of a strong base, such as potassium 1,1,1,3,3,3 -hexamethyldisilazane (KHMDS), gives 5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequent reduction of the oximo group by hydrogenation in the presence of a catalyst, such as palladium on carbon, affords 5-amino-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Other common amination procedures can be used, such as azide transfer followed by reduction of the azido group.

Similarly, the various benzodiazepine derivatives suitable for use in the present invention can be prepared by conventional methods and chemicals. For example, 2-aminobenzophenone can be readily attached to �-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxalyl chloride, then coupling the acid chloride with 2-aminobenzophenone in the presence of a base, such as 4-methylmorpholine , to give 2-[�-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]aminobenzophenone. Treatment of this compound with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents of mercury(II) chloride then gives 2-[N-(�-amino)-N'-(benzyloxycarbonyl)glycinyl]aminobenzophenone. This intermediate can then be easily cyclized by treatment with glacial acetic acid and ammonium acetate to give 3-(benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-one.

Subsequent removal of the Cbz group gives 3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-one.

Alternatively, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-ones can be easily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to give the corresponding amino group. The conditions for these and related reactions are described in the examples that follow below. Then, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-ones can be readily alkylated at the 1-position using conventional procedures and reagents. For example, this reaction is typically carried out by first treating the benzodiazepineone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1,1.3,3,3-hexamethyldisilazane, cesium carbonate, in an inert solvent such as DMF. This reaction is typically carried out at a temperature ranging from about -78°C to about 80°C for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is carried out at a temperature of about 0°C to about 100°C for about 1 to about 48 hours.

Furthermore, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines used in this invention are typically prepared by first coupling malonic acid with 1,2-phenylenediamine. The conditions for this reaction are well known in the art and are described, for example, in PCT application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents gives various 3-amino-1,5-bis(alkyl)-2, 4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. Such procedures are described in detail in the examples that follow.

Thus, there are a large number of lactams, lactones and thiolactones that are available in the art by known procedures. Similarly, the art abounds with examples of aminocycloalkyl compounds used in the synthesis of formula I above.

In these synthetic methods, starting substances can have a chiral center (eg alanine) and, when racemic starting material is used, the obtained product is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the starting material can be used and, if the reaction protocol used does not racemize the starting material, a chiral product is obtained. Such reaction protocols may involve inversion of the chiral center during the synthesis.

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

Pharmaceutical formulations

When used as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical composites. These compounds can be administered by many routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are effective as injectable and oral composites. Such composites are prepared in a manner well known in the pharmaceutical art and include at least one active compound.

This invention also encompasses pharmaceutical composites containing, as an active substance, one or more of the above-mentioned compounds of formula I which are bound to pharmaceutically acceptable carriers. When making the composite of this invention, the active substance is usually mixed with an excipient, diluted with an excipient, or enclosed within such a carrier, which may be in the form of a capsule, bag, paper, or other container. When an excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that serves as a propellant, carrier, or medium for the active ingredient. Thus, composites can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in the form of a solid or in a liquid medium), ointments containing, for example, up to 10% ( wt.) of active substances, soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.

In preparing the formulation, it may prove necessary to grind the active compound to obtain the appropriate particle size before combining with the other ingredients. If the active substance is practically insoluble, it is usually ground to a particle size of less than 200 mesh. If the active substance is insoluble in water, the particle size is normally determined by grinding to obtain a completely uniform distribution of the formulation, eg 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gummation, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose. Formulations may additionally contain: a lubricant such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propylhydroxybenzoates; sweeteners and flavor enhancers. The composites of this invention can be formulated to achieve rapid, delayed or delayed release of the active substance after administration to the patient by methods known in the art.

The composites are preferably formulated as unit doses, each dose containing from about 5 to about 100 mg, usually from about 10 to about 30 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable for unit dosage to humans and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, in conjunction with a suitable pharmaceutical excipient. Preferably, the above compound of formula I is used with no more than about 20 weight percent of the pharmaceutical composite, more preferably no more than about 15 weight percent, with the remainder being a pharmaceutically inert carrier(s).

The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It is understood, however, that the amount of compound actually administered is determined by the physician, in light of the relevant circumstances, including the condition being treated, the route of administration chosen, the composition of the compound being administered, the age, weight and response of the individual patient, his symptoms, and the like.

To prepare solid composites such as tablets, the base active ingredient is mixed with a pharmaceutical excipient to obtain a solid reformulated composite containing a homogeneous mixture of the compound of the present invention. When we label these reformulations as homogeneous, it means that the active substance is dispersed uniformly throughout the composite so that the composite can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. The solid reformulation is then divided into unit dosage forms of the types described above containing from, for example, 0.1 to about 500 mg of the active ingredient of this invention.

Tablets or pills of the present invention may be coated or otherwise bound to provide a dosage form which has the advantage of prolonged action. For example, a tablet or pill may contain an internal dosing component and an external dosing component, the latter being in the form of an envelope on the former. The two components can be separated by an enteric layer that acts as a resistance to disintegration in the stomach and allows the internal component to pass undamaged into the duodenum or to delay its release. A variety of substances can be used for such enteric layers or coatings, and such substances include a number of polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms into which the novel compounds of this invention may be incorporated for oral or injectable administration include aqueous solutions in the form of syrups, aqueous or oily suspensions, and flavoring syrups with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical substances for application.

Composites for inhalation and inhalation include solutions and suspensions in a pharmaceutically acceptable aqueous or organic solvent, mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients such as those described above. The composites are preferably applied by oral or nasal respiratory route for local or systemic effect. Composites in preferred pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions may be inhaled directly from a nebulizer or the nebulizer may be connected to a face mask or intermittent positive pressure breathing apparatus. The solution, suspension or powder composites can be administered preferably orally or nasally, using devices that can administer the formulation appropriately.

The following examples illustrate the pharmaceutical compositions of this invention.

Example of formulation 1

Prepared hard gelatin capsules contain the following components:

Component Amount (mg/capsule)

active substance 30.0

starch 305.0

magnesium stearate 5.0

The above components were mixed and filled into a hard gelatin capsule in the amount of 340 mg.

Example of formulation 2

The tablet formulation was prepared using the following components:

Component Quantity (mg/tablet)

active substance 25.0

cellulose, microcrystalline 200.0

colloidal silicon dioxide 10.0

stearic acid 5.0

These components are mixed and pressed into a tablet with a weight of 240 mg.

Example of formulation 3

A dry powder formulation for inhalation containing the following components was prepared:

Component Weight share (%)

active substance 5.0

lactose 95.0

The active substance is mixed with lactose and the mixture is made into a dry powder for inhalation.

Example of formulation 4

Tablets containing 30 mg of active substance are made as follows:

Component Quantity (mg/tablet)

active substance 30.0

starch 45.0

microcrystalline cellulose 35.0

polyvinylpyrrolidone (as a 10% solution in sterile water) 4.0

sodium carboxymethyl starch 4.5

magnesium stearate 5.0

talc 1.0

a total of 120.0

The active substance, starch and cellulose were passed through sieve no. 20 (mesh, U.S. sieve) and thoroughly mixed. The solution of polyvinyl-pyrrolidone was mixed with the resulting powder, which was then passed through sieve no. 16 (mesh, U.S. sieve). The granules thus obtained were dried at 50° to 60°C and passed through sieve no. 16 (mesh, U.S. sieve). Sodium carboxymethyl starch, magnesium stearate and talc were previously passed through sieve no. 30 (mesh, U.S. sieve), and then added to the granules, which, after mixing, were compressed on a tableting machine to obtain tablets weighing 150 mg.

Example of wording 5

Capsules containing 40 mg of medication are made as follows:

Component Amount (mg/capsule)

active substance 40.0

starch 109.0

magnesium stearate 1.0

a total of 150.0

Active substance, starch and magnesium stearate are mixed, passed through sieve no. 20 (mesh, U.S. sieve) and a hard gelatin capsule was filled with 150 mg of the mixture.

Example of formulation 6

Suppositories containing 25 mg of active substance are made as follows:

Component Quantity (mg)

active substance 25.0

glycerides of saturated fatty acids up to 2000.0

The active substance was passed through sieve no. 60 (mesh, U.S. sieve) and suspended in glycerides of saturated fatty acids that have previously been melted with the minimum necessary amount of heat. The mixture was placed in a suppository mold with a nominal capacity of 2.0 g and left to cool.

Example of wording 7

Suspensions containing 50 mg of medication per dose of 5.0 ml are made as follows:

Component Quantity

active substance 50.0 mg

xanthan gum 4.0 mg

sodium carboxymethyl cellulose (11%) microcrystalline cellulose (89%) 50.0 mg

sucrose (sucrose) 1.75 mg

sodium benzoate 10.0 mg

smell and color q.v.

purified water up to 5.0 ml

The active substance, sucrose and xanthan gum are mixed, passed through sieve no. 10 (mesh, U.S. sieve) and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, fragrance and color were dissolved in some water and added with stirring. Sufficient water was then added to obtain the required volume.

Example of wording 8

Component Amount (mg/capsule)

active substance 15.0

starch 407.0

magnesium stearate 3.0

a total of 425.0

Active substance, starch and magnesium stearate are mixed, passed through sieve no. 20 (mesh, U.S. sieve) and a hard gelatin capsule in the amount of 560 mg was filled with the mixture.

Example of wording 9

The subcutaneous formulation was prepared as follows:

Component Quantity

active substance 5.0 mg

corn oil 1 ml

Example of wording 10

The formulation for local use is prepared as follows:

Component Quantity

active substance 1-10 g

emulsifying wax 30 g

liquid paraffin 20 g

white soft paraffin up to 100 g

The white soft paraffin was heated until it melted. Liquid paraffin and emulsifying wax were added and mixed until dissolved. The active substance was added and mixing was continued until dispersed. The mixture was then cooled until it solidified.

Another preferred formulation used in the methods of this invention utilizes means for transdermal administration ("patches"). Such transdermal patches can be used to achieve continuous or discontinuous infusion of the compounds of this invention in controlled amounts. The construction and use of transdermal patches for delivery of pharmaceutical agents is well known in the art. See, for example, US Patent 5,023,252, dated June 11, 1991, which is incorporated herein by reference. Such patches can be designed for continuous, pulsed or on-demand delivery of pharmaceutical agents.

It is often necessary or desirable to introduce a pharmaceutical composition into the brain, either directly or indirectly. Direct techniques usually involve placing a catheter to deliver the drug into the ventricular system to bypass the blood brain barrier. One such implantable delivery system used to deliver biological agents to specific anatomical areas of the body is described in US Patent 5,011,472, which is incorporated herein by reference.

Intermediate techniques, which are generally preferred, usually involve formulating a composite to achieve drug latency by converting a hydrophilic drug into a fat-soluble drug. Latency is generally achieved by blocking the hydroxyl, carbonyl, sulfate and primary amine groups present in the drug to make it more fat soluble and thus able to cross the blood brain barrier. Alternatively, the uptake of the hydrophilic drug can be enhanced by intra-arterial infusion of a hypertonic solution that can transiently open the blood brain barrier.

Other suitable formulations of this invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

Usability

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

As indicated above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Furthermore, to prolong the in vivo serum half-life of the administered compound, the compounds can be encapsulated, delivered into the lumen of liposomes, prepared as a colloid, or other conventional techniques can be used to prolong the serum half-life of the compound. The full range of methods available for preparing liposomes is described in, e.g., Szoka, et al, US Pat. 4,235,871, 4,501,728 and 4,837,028, each of which is incorporated herein by reference.

The amount of compound administered to the patient may vary depending on what was administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the method of administration, and the like. In therapeutic applications, the compounds are administered to patients who already suffer from Alzheimer's disease in an amount that is sufficient to at least partially stop the further progression of the symptoms of the disease and its complications. The amount that is adequate to do this is defined as a "therapeutically effective dose". The amount corresponding to this will depend on the doctor's judgment which depends on a number of factors such as the degree or advancedness of Alzheimer's disease in the patient, his age, weight and general condition and the like. Preferably, for use as therapeutics, the compounds described herein are administered in doses ranging from about 1 to 500 mg/kg/day.

In prophylactic applications, the composites are administered to a patient at risk of developing Alzheimer's disease (as determined by genetic screening or family treatment) in an amount sufficient to stop the onset of symptoms of the disease. The amount sufficient to achieve this is defined as a "prophylactically effective dose". The amount that corresponds to this will depend on the doctor's judgment which depends on a number of factors such as his age, weight and general condition and the like. Preferably, for use as therapeutics, the compounds described herein are administered in doses ranging from about 1 to 500 mg/kg/day.

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

The compounds described herein are also suitable for use in administering the compounds to cells for diagnostic purposes or for drug screening. Specifically, the compounds can be used in the diagnosis of cells that release and/or synthesize β-amyloid peptide. Furthermore, the compounds described herein are useful for measuring and evaluating the activity of another potential drug in inhibiting cellular release and/or synthesis of β-amyloid peptide.

The following synthetic and biological examples are provided by way of illustration and should not be considered in any way to limit the scope of this invention.

Examples

In the examples below, the following abbreviations have the meanings indicated. If an abbreviation is not specified, it has the generally accepted meaning.

BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine

Boc = t-butoxycarbonyl

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

bd = wide doublet

bs = broad singlet

d = doublet

dd = double doublet

DIC = diisopropylcarbodiimide

DCM = dichloromethane

DMF = dimethylformamide

DMAP = dimethylaminopyridine

DMSO = dimethylsulfoxide

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

eq. = equivalents

EtOAc = ethyl acetate

EtOH = ethanol

g = gram

HOBT = 1-hydroxybenzotriazole hydrate

Hunig's

base = diisopropylethylamine

L = liter

m = multiplet

M = molar

max = maximum

MeOH = methanol

meq = milliequivalent

mg = milligram

mL = milliliter

mm = millimeter

mmol = millimol

MOC = methoxyoxycarbonyl

N/A = none

N = normal

ng = nanogram

nm = nanometer

OD = optical density

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

PT-HOBT = piperidine-piperidine-1-hydroxybenzotriazole

psi = pounds per square inch

φ = phenyl

q = quartet

quint. = quintet

rpm = revolutions per minute

s = singlet

t = triplet

TFA = trifluoroacetic acid

THF = tetrahydrofuran

tlc = thin layer chromatography

μL = microliter

UV = ultraviolet.

Furthermore, the following abbreviations are used to indicate the commercial source for certain compounds and reagents:

Aldrich - Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA

Fluka - Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA

Lancaster - Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087 USA

Sigma - Sigma, P.O. Box 14508, St. Louis MO 63178 USA

Chemservice - Chemservice Inc., Westchester, PA

Bachem - Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA

Maybridge - Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom

TCl - TCl America, 9211 North Harborgate Street, Portland OR 97203

Alfa - Johnson Matihey Catalog Company, Inc. 30 Bond Street, Ward Hill, MA 01835-0747

Novabiochem - Calbiochem-Novabiochem Corp. 10933 North Torrey Pines Road, P.O. Box 12087, La Jolla CA 92039-2087

Oakwood - Oakwood, Columbia, South Carolina

Advanced Chemtech - Advanced Chemtech, Louisville, KY

Pfaltz & Bauer - Pfaltz & Bauer, Waterbury, CT, USA

In the examples that follow, all temperatures are in degrees Celsius (unless otherwise noted) and each of the compounds listed in these examples was prepared by one of the following standard procedures, unless otherwise noted.

GENERAL PROCEDURE A

EDC bonding – Procedure I

Carboxylic acid (1.0 equiv), 1-hydroxybenzotriazole hydrate (1.1 equiv) and amine (1.0 equiv) were mixed in THF under a desiccator atmosphere. To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 eq.) followed by a suitable base, such as Hunig's base (1.1 eq. of base if using a free amine, and 2 ,1 equiv of base if amine hydrochloride is used). After stirring for about 4 h to 17 h at room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was separated and washed successively with aqueous sodium bicarbonate, dilute hydrochloric acid, and brine. The organic layer was then dried (sodium sulfate) and concentrated under reduced pressure. The product was then used either without further purification or was purified using standard procedures, such as silica gel chromatography and/or recrystallization.

GENERAL PROCEDURE B

EDC binding – Procedure II

The carboxylic acid (1 eq.) was stirred in a suitable solvent (such as THF, dioxane or DMF) and the alcohol or oxime (1-5 eq.) was added. To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 eq.) and 1-hydroxybenzotriazole hydrate (1 eq.) followed by a suitable base, such as 4-methylmorpholine, triethylamine, or Hunig's base (0-1 eq.). A catalytic amount (0.1 eq.) of 4-dimethylaminopyridine was added and the mixture was stirred at ambient temperature and under a dry nitrogen atmosphere. After 20 hours, the mixture was concentrated under reduced pressure and the resulting concentrate was partitioned between ethyl acetate and water. The organic part was separated and washed with an aqueous solution of sodium bicarbonate and saline, then dried (sodium sulfate) and concentrated under reduced pressure. The crude product was either used without further purification or purified using standard procedures, such as silica gel chromatography and/or recrystallization.

GENERAL PROCEDURE C

EDC binding – Procedure III

To a solution of the amine (1 eq.) in THF (0.08-0.06 M) at 0°C under a nitrogen atmosphere was added 3,5-difluorophenylacetic acid (1.10 eq.), 1-hydroxybenzotriazole hydrate (1.15 -1.20 eq.), N,N-diisopropylethylamine (2.30 eq.), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15-1.20 eq.). The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring for 12-14 hours. The solution was then diluted with ethyl acetate, washed with 0.2-0.5M aqueous HCl solution (2×), diluted aqueous NaHCO3 solution (1×), brine (1×), and then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by flash chromatography to give the product.

GENERAL PROCEDURE D

Removal of the N-tert-BOC protecting group – Procedure I

Trifluoroacetic acid (0.07-0.08 M) and then anisole (6.2-8.0 equiv) were added to N-Boc-protected imidazoline (1 equiv.) in a round-bottomed flask, cooled to 0°C. . The resulting solution was stirred at 0°C for 1 hour, then allowed to warm to ambient temperature with stirring for 1-1.5 hours. The solution was then concentrated in vacuo, Et 2 O was added and the mixture was concentrated again in vacuo. The residues were dissolved in either CH2Cl2 or EtOAc and washed with dilute aqueous NaHCO3 (1 or 2×), sometimes brine (1×), then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the product.

GENERAL PROCEDURE E

Removal of the N-tert-BOC protecting group – Procedure II

N-tert-Boc-amine was dissolved in a suitable dry solvent (such as 1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. HCl gas was introduced into the solution until the mixture was saturated with HCl and the mixture was then stirred until the starting material was consumed. The resulting mixture was concentrated under reduced pressure to give the amine hydrochloride. The amine hydrochloride was then either used without further purification or eluted from diethyl ether and the resulting solid collected by filtration.

GENERAL PROCEDURE F

Synthesis of thiazolines – Procedure I

With stirring, 2-mercaptoethylamine (1-3 equiv) was added to a solution of nitrile (1 equiv) in dry ethanol under a nitrogen atmosphere. The reaction mixture was then heated under reflux until the nitrile was consumed. The mixture was then concentrated under reduced pressure and the resulting product was purified by chromatography and/or recrystallization.

GENERAL PROCEDURE G

Synthesis of thiazolines – Procedure II

With stirring, to a solution of the nitrile (1 eq.) in dry ethanol under a nitrogen atmosphere was added L-cysteine ethyl ester hydrochloride (1-3 eq.) (Aldrich) and a stoichiometric amount of N,N-diisopropylethylamine (based on L-cysteine ethyl ester hydrochloride). The reaction mixture was heated under reflux for three hours and then concentrated under reduced pressure. The obtained product was purified by chromatography and/or crystallization.

GENERAL PROCEDURE H

Cyclization using Burgess's reagent

To a solution of N-[N-(3,5-dichlorophenyl)-L-alaninyl]-L-serine methyl ester (178 mg, 0.5 mmol) in 2.5 mL of THF was added 147 mg (0.62 mmol, 1 ,1 eq.) of (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt

(available from Aldrich Chemical Co., Milwaukee, Wisconsin). The solution was refluxed for 5 hours and then stirred at room temperature for 36 hours. The solvent was then removed and the residue was purified by preparative thin layer chromatography using 3:2 hexane/ethyl acetate as eluent to give 50 mg of 2-[(S)-1-(3,5dichloroanilino)ethyl]-(S)-4- methoxycarbonyl-2-oxazolidine as a yellow oil. Various other (S)-4-Alkoxycarbonyl-2-oxazolidines can be prepared from N-substituted (amino acid)-L-serine esters using this procedure.

GENERAL PROCEDURE I

Synthesis of 5-aminoalkyl-1,2,4-oxadiazole

The N-tert-Boc-protected amino acid and amidoxime are reacted according to general procedure B above to give the corresponding O-acyloxime. The o-acyloxime was then heated to reflux in xylenes with azeotropic removal of water to give the N-tert-Boc-protected 5-aminoalkyl-1,2,4-oxadiazole derivative, which was then typically purified by silica gel chromatography. The N-tert-Boc protecting group was then removed according to general procedure E above to give 5-aminoalkyl-1,2,4-oxadiazole.

The following Examples A-L illustrate a procedure for the synthesis of intermediate heterocyclic compounds that can be used to prepare the compounds of this invention.

Example A

Synthesis of (S)-5-(1-aminoethyl)-3-ethyl-1,2,4-oxadiazole hydrochloride

According to general procedure I above, the title compound was prepared using N-tert-Boc-L-alanine (Sigma) and propanamidoxime.

Example B

Synthesis of (S)-5-(1-amino-2-phenylethyl)-3-methyl-1,2,4-oxadiazole hydrochloride

According to general procedure I above, the title compound was prepared using N-tert-Boc-L-phenylalanine (Sigma) and acetamidoxime.

Example C

Synthesis of (S)-5-(1-amino-1-phenylmethyl)-3-methyl-1,2,4-oxadiazole hydrochloride

According to general procedure I above, the title compound was prepared using N-tert-Boc-L-phenylglycine (Sigma) and acetamidoxime.

Example D

Synthesis of (S)-5-(1-amino-1-phenylmethyl)-3-phenyl-1,2,4-oxadiazole hydrochloride

According to general procedure I above, the title compound was prepared using N-tert-Boc-L-phenylglycine (Sigma) and benzamidoxime.

Example E

Synthesis of (S)-5-(1-amino-1-phenylmethyl)3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole hydrochloride

According to general procedure I above, the title compound was prepared using N-tert-Boc-L-phenylglycine (Sigma) and 4-methoxyphenylacetamidoxime.

Example F

Synthesis of (2S)-2-(1-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline

Stage A - Synthesis of N-carbobenzyloxy-L-alanine-D,L-isoserine ethyl ester

Following general procedure A above and using N-carbobenzyloxy-L-alanine (Sigma) and D,L-isoserine ethyl ester hydrochloride, the title compound was prepared.

Stage B - Synthesis of (2S)-2-[1-(N-carbobenzyloxy)aminoethyl]-S(R,S)-ethoxycarbonyl-2-oxazoline

To a solution of N-carbobenzyloxy-L-alanine-D,L-isoserine ethyl ester from Step A above in dry THF was added triphenylphosphine (2 eq.). The mixture was cooled to 0°C and a solution of diethyl azodicarboxylate (2 eq.) in THF was added dropwise. The resulting mixture was allowed to warm to room temperature and, after 20 hours, the mixture was concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to give the title compound as an oil which was used without further purification.

Step C - Synthesis of (2S)-2-(1-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline

The crude oil from the above-mentioned step B was dissolved in ethanol, the solution was degassed and stirred under a nitrogen atmosphere. Palladium on carbon (10%) was added and the nitrogen atmosphere was replaced by hydrogen under flask pressure. The mixture was stirred for 2 hours and then filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel chromatography to give the title compound as an oil.

Example G

Synthesis of (S)-2-(1-aminoethyl)-4(R,S)-ethoxycarbonyl-2-thiazoline hydrochloride

Stage A - Synthesis of (S)-2-[1-(N-tert-butoxycarbonyl)aminoethyl]-4-ethoxycarbonyl-2-thiazoline

The title compound was prepared according to the procedure described in C. D. J. Boden, et al., Synlett, 5, 417 (1995).

Stage B - Synthesis of (S)-2-(1-aminoethyl)-4(R,S)-ethoxycarbonyl-2-thiazoline hydrochloride

The N-tert-Boc protecting group was removed from the product of step A using general procedure E above to afford the title compound.

Example H

Synthesis of 2-(3,5-difluorophenylmethyl)-4-carboxy-2-thiazoline

Stage A - Synthesis of 2-(3,5-difluorophenylmethyl)-5-ethoxycarbonyl-2-thiazoline

According to general procedure G and using 3,5-difluorophenylacetonitrile and L-cysteine ethyl ester hydrochloride (Aldrich), the title compound was prepared.

Stage B - Synthesis of 2-(3,5-difluorophenylmethyl)-5-carboxy-2-thiazoline

The title compound was prepared by hydrolysis of the product of Step A above using 1 equivalent of LiOH in moist dioxane as described in General Procedure II-A, Method B.

Examples

Synthesis of N-(3,5-difluorophenylacetyl)phenylglycinonitrile

Following general procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and 2-phenylglycinonitrile hydrochloride (Lancaster), the title compound was prepared. The crude product was purified by chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent, and then by crystallization from 1-chlorobutane/acetonitrile.

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 3.61 (s, 2H), 6.13 (d, 1H), 6.98 (m, 2H), 7.12 (m, 1H), 7.46 (m, 5H), 9.40 (d , 1H).

C16H12F2N2O (MW = 286.28); mass spectroscopy (M+) 286.

Example J

Synthesis of 2-(1-aminoethyl)-1-tert-butoxycarbonyl-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

Step A - Synthesis of 1-[2-(N-carbobenzyloxy)amino-thiopropionyl] piperidine

According to the procedure described in Gilbert, et al., Tetrahedron, 1995, 51, 6315-6336 and using N-carbobenzyloxy-D,L-alanine (Sigma), the title compound was prepared in two steps (51% overall yield) in in the form of a solid with a melting point

68-69°C. The reaction was monitored by thin layer chromatography (Rf = 0.59 in 24:1 DCM/EtOAc) and the product was purified by flash column chromatography.

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.37-7.29 (m, 5H), 6.46 (bd, 1H, J = 8.26 Hz), 5.10 (ABq, 2H, JAB= 12.38 Hz ΔνAB = 9.12 Hz), 4.92 (p, 1H, J = 7.07 Hz), 4.41-4.34 (m, 1H), 4.17-4.06 (m, 1H), 3.86-3.65 (m, 2H), 1.75-1.65 (bm, 6H), 1.35 (d , 3H, J = 6.75 Hz).

C16H22N2O2S (MW = 306.43); mass spectroscopy (MH+) 306.2.

Stage B - Synthesis of methyl 2,3-diamino-2-phenylmethylpropionate

According to the procedure described in Gilbert, et al., Tetrahedron, 1995, 51, 6315-6336 and using L-phenylalanine methyl ester hydrochloride (Aldrich), the title compound was prepared in three steps (14% overall yield). The reaction was monitored by thin layer chromatography (Rf = 0.26 in 9:1 DCM/MeOH) and the product was purified by "flash" column chromatography and then by recrystallization from cyclohexane/ethyl acetate (20:1).

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): ����7.32-7.17 (m, 3H), 7.14-7.09 (m, 2H), 3.70 (s, 3H), 2.96 (ABq, 2H, JAB = 13.13 Hz, ΔνAB = 114.63 Hz), 2.90 (ABq, 2H, JAB = 13.38 Hz, ΔνAB = 86.35 Hz), 1.55 (bs, 4H).

C11H16N2O2 (MW = 208.26); mass spectroscopy (MH+) 209.1.

Stage C - Synthesis of 2-[1-(N-carbobenzyloxy)aminoethyl)-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

The product from the above step A (1 equivalent) in iodomethane (35 equivalents) was heated under reflux in nitrogen for 8 hours. The dark yellow solution was concentrated in vacuo to a golden yellow foam, then azeotroped with methanol (2×) to remove the remaining iodomethane. The residues were dissolved in methanol (0.2 M) and the product from step B above (1 equivalent) was added. The resulting clear colorless solution was heated under reflux for 1 hour in nitrogen and then stirred at ambient temperature for 14 hours, then heated again under reflux for a further 1 hour. The solution was allowed to cool to ambient temperature and then concentrated in vacuo. The reaction was monitored by thin layer chromatography (Rf = 0.27 in 95:5 DCM/MeOH) and the residue was purified by flash column chromatography to afford the title compound as a 1:1 mixture of diastereomers (75% yield).

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): ����7.36-7.20 (m, 8H), 7.14-7.08 (m, 2H), 5.84-5.74 (m, 1H), 5.15-5.02 (m, 2H), 4.96 (bs, 1H), 4.44-4.30 (m, 1H), 4.03-3.97 (m, 1H), 3.72-3.66 (m, 1H), 3.70 (s, 1.5H), 3.69 (s, 1.5H ), 3.07 (ABq, 1H, JAB = 13.38 Hz, ΔνAB = 54.25 Hz), 3.06 (ABq, 1H, JAB = 13.51 Hz, ΔνAB = 52.03 Hz), 1.39 (d, 1.5H, J = 7.00 Hz), 1.35 (d, 1.5H, J = 7.00 Hz).

C22H25N3O4 (MW = 395.46); mass spectroscopy (MH+) 396.1.

Stage D - Synthesis of 1-tert-butoxycarbonyl-2-[1-(N carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

To a 1:1 mixture of the product from Step C above (1.815 g, 1 eq.) in THF (9 mL)/H2O (9 mL) at ambient temperature was added NaHCO3 (0.377 g, 1.50 eq.) and di- tert-butyl dicarbonate (1.304 g, 2.00 equiv) (Aldrich) in THF (6 mL). The resulting pale yellow solution was stirred at ambient temperature for 1 hour and then NaHCO3 (0.188 g, 0.75 equiv) and di-tert-butyl dicarbonate (0.652 g, 1.00 equiv) in THF (3 mL) were added, and the mixture was stirred for another hour. The mixture was then diluted with ethyl acetate, washed with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo, and purified by flash column chromatography using 3:2 hexane/EtOAc as eluent to afford the title compound with 77 % yield as a viscous oil (Rf = 0.31 in 3:2 hexane/EtOAc). A racemic 1:1 mixture of diastereomers could not be resolved by flash chromatography.

The NMR data are as follows:

1H-nmr (DMSO-d3, 250 MHz): � = 7.38-7.09 (m, 10H), 6.00 (bd, 1H, J = 7.75 Hz), 5.21-5.05 (m , 3H), 4.15 (d, 1H, J = 11.76 Hz), 4.08 (d, 1H, J = 11.26 Hz), 3.85-3.80 (m, 2H), 3.78 (s , 3H), 3.20-3.00 (m, 2H), 1.43 (s, 9H), 1.36 (d, 1.5H, J = 6.75 Hz), 1.24 (d, 1, 5H, J = 6.75 Hz).

C27H33N3O6 (MW = 495.58); mass spectroscopy (MH+) 496.4.

Stage E - Synthesis of 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

A racemic mixture of the N-Cbz-protected amine from Step D above and 20% Pd(OH)2 on carbon (20% wt eq) in MeOH (0.010-0.015 M) under hydrogen (35-40 psi) was shaken 4 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo to give the title compound as a viscous oil (Rf = 0.26 in 95:5 DCM/MeOH).

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.32-7.15 (m, 5H), 4.19-4.05 (m, 2H), 3.87-3.78 (m, 1H), 3.80 (s, 3H), 3.21-3.03 (m, 2H), 1.98 (bs, 2H), 1.43 (s, 9H), 1.33 (d, 1,5H, J = 7.00 Hz), 1.26 (d, 1,5H, J = 6.50 Hz).

C19H27N3O4 (MW = 361.44); mass spectroscopy (MH+) 361.

Example K

Synthesis of 2-(1-aminoethyl)-1-tert butoxycarbonyl-4-methoxycarbonyl-4-phenyl-2-imidazoline

Stage A - Synthesis of methyl 2,3-diamino-2-phenylpropionate

According to the procedure described by Gilbert; et al., Tetrahedron, 1995 51, 6315-6336 and using (S)-(+)-2-phenylglycine methyl ester hydrochloride (Aldrich), the title compound was prepared in three steps (16% overall yield). The reaction was monitored by thin layer chromatography (Rf = 0.34 in 9:1 CH2Cl2/MeOH) and the product was purified by flash column chromatography.

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.52-7.47 (m, 2H), 7.39-7.25 (m, 3H), 3.74 (s, 3H), 3.42 (d, 1H, J = 13.26 Hz), 2.89 (d, 1H, J = 13.26 Hz), 1.88 (bs, 4H).

C10H14N2O2 (MW = 194.23); mass spectroscopy (MH+) 195.

Stage B - Synthesis of 2-[1-(N-carbobenzyloxy)aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline

The product of Example J - Stage A (5.206 g, 1.1 eq.) in iodomethane (36.5 mL, 38 eq.) was heated under reflux under nitrogen for 16 h. The dark yellow solution was concentrated in vacuo to a golden yellow foam, then azeotroped with methanol (30 mL) to remove the remaining iodomethane. The residue was dissolved in methanol (30 mL) and the product from above step A (3.00 g, 1 eq.) was added. The resulting pale yellow solution was heated under reflux in nitrogen for 3.5 hours. The solution was allowed to cool to room temperature, concentrated in vacuo, and purified by flash chromatography to give (5.08 g, 86%) the title compound as an indistinguishable 1:1 mixture of racemic diastereomers. The reaction was monitored by thin layer chromatography (Rf = 0.32 in 95:5 CH2Cl2/MeOH) and the product was purified by flash column chromatography.

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.38-7.28 (m, 10H), 6.09-6.00 (m, 1H), 5.11-5.04 (m, 2H), 4.10 (bs, 1H), 3.84-3.68 ( m, 4H), 1.53 (d, 3H, J = 7.00 Hz).

C20H23N3O4 (MW = 381.43); mass spectroscopy (MH+) 382.4

Stage C - Synthesis of 1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

To the product from Step B above (4.94 g, 1 eq.) in THF (35 mL)/H2O (35 mL) at ambient temperature was added NaHCO3 (2.00 g, 1.84 eq.) and di-tert -butyl dicarbonate (7.30 g, 2.65 eq.) (Aldrich). The resulting pale yellow mixture was stirred at ambient temperature for 1 hour and NaHCO3 (0.45 g, 0.41 eq.) and di-tert-butyl dicarbon (0.98 g, 2.65 eq.) were added and the mixture was further stirred 1 hour. The mixture was then diluted with ethyl acetate, washed with H2O (1×), brine (2×), dried over Na2SO4, filtered, concentrated in vacuo and purified by flash chromatography. The racemic diasteremeric products [Rf = 0.38 (isomer A as a racemic mixture) and 0.28 (isomer B as a racemic mixture) eluting with 5:1 toluene/EtOAc] were separated by flash chromatography using 6:1 toluene/EtOAc with by a one-step gradient to 5:1 toluene/EtOAc as eluent to give two sets of racemic enantiomeric pairs with

73% yield, isomer A (1.122 g) as a viscous oil and isomer B (1.0868 g) as a white solid.

The NMR data are as follows (isomer A):

1H-nmr (CDCl3, 250 MHz): � = 7.39-7.27 (m, 10H), 6.20 (bd, 1H, J = 8.00 Hz), 5.40-5.30 (m, 1H), 5.13 (s, 2H), 4.84 (d, 1H, J = 11.26 Hz), 3.87 (d, 1H, J = 11.26 Hz), 3.70 (s, 3H), 1.52-1.50 (m, 12H).

C26H31N3O6 (MW = 481.55); mass spectroscopy (MH+) 482.3.

Stage D - Synthesis of 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline

Isomer A of the above step C and 20% Pd(OH) 2 on carbon (20% wt eq) in methanol (0.010-0.015 M) under hydrogen (35-40 psi) were shaken for 4 hours. The catalyst was removed by filtration through a plug of celite and the filtrate was concentrated in vacuo and purified by flash chromatography to give the title compound (88%) as a viscous oil (Rf = 0.28 in 95:5 DCM/MeOH).

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.43-7.27 (m, 5H), 4.80 (d, 1H, J = 11.26 Hz), 4.41 (q, 1H, J = 6.75 Hz), 3.87 (d, 1H , J = 11.51 Hz), 3.73 (s, 3 H), 2.02 (s, 2H), 1.49 (s, 9H), 1.45 (d, 3H, J = 6.75 Hz).

C18H25N3O4 (MW = 347.42); mass spectroscopy (MH+) 348.2.

Example L

Synthesis of (4R)-4-carboxy-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline

Stage A - Synthesis of methyl 3,5-difluorophenylacetimidate hydrochloride

The title compound was prepared according to the procedure described in S. C. Zimmerman, et al., J Org. Chem. 1989, 54, 1256-1264, for the synthesis of imidates. Specifically, a stream of anhydrous HCl gas was passed through a solution of 3,5-difluorophenylacetonitrile (5.045 g, 1 eq.) and methanol (2.00 mL, 1.5 eq.) in diethyl ether (100 mL) at 0°C for 20 minutes. The solution was then allowed to warm to room temperature under nitrogen with stirring for 23 hours, whereupon a white precipitate formed. The white precipitate was collected by filtration and washed with diethyl ether to give the title compound (6.6756 g, 91%) as a solid, mp 156.5-157.5°C.

The NMR data are as follows:

1H-nmr (CDCl3, 300 MHz): � = 13.01 (bs, 1H), 11.93 (bs, 1H), 7.04-6.97 (m, 2H), 6.83-6.75 (m, 1H), 4.30 (s, 3H) , 4.08 (s, 2H).

Stage B - Synthesis of methyl (R)-2-methylcysteine hydrochloride

The title compound was prepared as a viscous oil in five steps (35% overall yield) from D-(S)-cysteine methyl ester hydrochloride as described in G. Pattenden, et al., Tetrahedron, 1993, 49, 2131-2138 and the references given there. D-(S)-cysteine methyl ester hydrochloride was prepared in one step (98% yield) from D-cysteine hydrochloride monohydrate (Aldrich) as described in J.E. Baldwin, et al., Tetrahedron, 1989, 45, 4537-4550 .

The NMR data are as follows:

1H-nmr (D2O, 250 MHz): � = 4.83 (bs, 4H), 3.92 (s, 3H), 3.27 (d, 1H, J = 15.26 Hz), 3.02 (d, 1H, J = 15.01 Hz), 1.69 (s, 3H).

Optical rotation: [α]20 = 2.44 (c 1.15, H2O)

C5H12NO2SCl (MW = 185.67); mass spectroscopy (MH+) 149.1.

Stage C - Synthesis of (4R)-2-(3,5-difluorophenylmethyl)-4-methoxycarbonyl-4-methyl-2-thiazoline

The title compound was prepared according to the procedures described in G. Pattenden, et al., Tetrahedron, 1995, 51, 7313-7320, for the synthesis of thiazolines. Specifically, to a solution of methyl (R)-2-methylcysteine hydrochloride (1.7109 g, 1.00 equiv) from Step B above in CH2Cl2 (55 mL) at ambient temperature under nitrogen was added imidate hydrochloride (2.042 g, 1, 00 eq.) from the above step A, and then triethylamine (1.28 mL, 1.00 eq.) was added dropwise over 20 minutes.

The resulting opaque pale yellow solution was stirred at ambient temperature for 40 hours, during which an off-white suspension was formed. The mixture was diluted with CH2Cl2, washed with 1N aqueous HCl (1×), H2O (1×), and brine (1×); then the organic phase was dried over MgSO4, filtered, concentrated in vacuo and the residue was purified by flash chromatography using 20:1 DCM/EtOAc as eluent to give the title compound (1.6669 g, 63%) as a colorless oil (Rf = 0.34 in 20:1 DCM/EtOAc).

The NMR data are as follows:

1H-nmr (CDCl3, 300 MHz): � = 6.85-6.79 (m, 2H), 6.74-6.67 (m, 1H), 3.81 (s, 2H), 3.80 (s, 3H), 3.79 (d, 1H, J = 11.30 Hz), 3.17 (d, 1H, J = 11.30 Hz), 1.56 (s, 3H).

Optical rotation: [α]20 = 3.71 (c 1.02, CHCl3).

C13H13NO2SF2 (MW = 285.32); mass spectroscopy (MH+) 285.2.

Stage D - Synthesis of (4R)-4-carboxy-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline

To the above product of step C (0.7265 g, 1.0 eq.) in 1,4-dioxane (15 mL) at ambient temperature was added LiOH (0.0671 g, 1.1 eq.) in water (1 mL ) by dripping for 2 minutes. More water (2 mL) was added and the resulting opaque colorless solution was stirred at ambient temperature for 1.25 hours, during which time the solution became clear and colorless. The solution was concentrated in vacuo to a volume of approximately 5 mL and the concentrate was diluted with ethyl acetate and washed with 1N aqueous HCl (2×) and water (1×); then dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound (0.6111 g, 88% yield) as a white solid, mp 119.5-122.0°C.

The NMR data are as follows:

1H-nmr (CDCl3, 300 MHz): � = 10.88 (bs, 1H), 6.86-6.78 (m, 2H), 6.766.69 (m, 1H), 3.89 (ABq, 2H, JAB = 15.14 Hz, ΔνAB 20.57 Hz), 3.84 (d, 1H, J = 11.48 Hz), 3.21 (d, 1H, J = 11.61 Hz), 1.61 (s, 3H).

The following General Procedures II-A through II-E and Examples II-A through II-S illustrate the synthesis of carboxylic acid intermediates that can be used to prepare the compounds of this invention.

GENERAL PROCEDURE II-A

Hydrolysis of esters to free acid

Hydrolysis of the ester into the free acid was carried out by the usual methods. The following are two examples of such common de-esterification methods.

Method A: 2-5 equivalents of K2CO3 were added to the carboxyl ester compound in a 1:1 CH3OH/H2O mixture. The mixture was heated at 50°C for 0.5 to 1.5 hours until tlc indicated completion of the reaction. The reaction mixture was cooled to room temperature and methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ~2 and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was desolvated on a rotary evaporator to give the product.

Method B: The amino acid ester was dissolved in a mixture of dioxane/water (4:1) to which was added LiOH (~2 equiv.) which was dissolved in water so that the total solvent after the addition was about 2:1 dioxane:water. The reaction mixture was stirred until the reaction was complete and dioxane was removed under reduced pressure. The residues were dissolved in water and washed with ether. The layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were dried over Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residues were purified by usual methods (eg recrystallization).

GENERAL PROCEDURE II-B

Preparation of acid chloride

3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0°C. DMF (0.5 mL, catalytic amount) was added followed by oxalyl chloride (18 mL, 0.20 mol) dropwise over 5 minutes. The reaction mixture was stirred for 3 hours and then evaporated under reduced pressure on a rotary evaporator to give an oil which was put on a high vacuum pump for 1 hour to give 3,5-difluorophenylacetyl chloride as a light yellow oil. Other acid chlorides can be prepared in a similar way.

GENERAL PROCEDURE II-C

Schotten-Baumann Procedure

3,5-difluorophenylacetyl chloride from general procedure II-B) was added dropwise to a 0°C solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol) . The reaction mixture was stirred for 1 hour at 0°C and then overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was then washed with brine (200 mL), dried over MgSO4 and evaporated under reduced pressure on a rotary evaporator to a residue. Recrystallization of the residue from ethyl acetate/hexane gives the desired product (34.5 g, 82% yield). Other acid chlorides can be used in this process to provide intermediates useful in this invention.

GENERAL PROCEDURE II-D

Reductive amination

1 equivalent of 2-oxocarboxylic acid ester (i.e., pyruvate ester) was added to a solution of arylamine in ethanol in a hydrogenation flask, followed by 10% palladium on carbon (25% by weight of the arylamine). The reaction mixture was hydrogenated at 20 psi H 2 in a Parr shaker until tlc indicated completion of the reaction (30 minutes to 4 hours). The reaction mixture was then filtered through a plug made of Celite 545 (Aldrich Chemical Company, Inc.) and freed from solvent on a rotary evaporator. The crude product residues were then chromatographically purified.

GENERAL PROCEDURE II-E

EDC bonding procedure

1.5 equivalents of triethylamine, then 2.0 equivalents of hydroxybenzotriazole monohydrate and then 1.25 equivalents of ethyl-3-(3-dimethylamino) were added to a 1:1 mixture of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH2Cl3 at 0°C )propyl carbodiimide⋅HCl. The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO3 solution, 1N HCl solution and saturated aqueous NaCl solution, then dried over MgSO4. The resulting solution was desolvated on a rotary evaporator to give the crude product.

Example II-A

Synthesis of N-(phenylacetyl)-L-alanine

Using the general procedure II-C, the titled compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) in the form of a solid with a melting point of 102-104°C.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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).

13C-nmr (CDCl3): δ = 176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2, 17.9.

Example II-B

Synthesis of N-(3,5-difluorophenylacetyl)-L-alanine

Using general procedure II-C, the title compound was prepared from 3,5-difluorophenylacetyl chloride (general procedure II-B) and L-alanine (Aldrich).

The NMR data are as follows:

1H-nmr (CD3OD): � = 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 Hz, 3H).

13C-nmr (CD3OD): � = 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.

Example II-C

Synthesis of N-(cyclopentylacetyl)-L-phenylglycine

Step A - Preparation of N-(cyclopentylacetyl)-L-phenylglycine methyl ester

Following general procedure II-E above using cyclopentylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Novabiochem), the title compound was prepared as a solid, mp 83-86°C. The reaction was followed by thin layer chromatography on silica gel (Rf = 0.28 in 25% ethyl acetate/hexane) and purification was carried out by recrystallization from the ethyl acetate/hexane mixture.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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).

13C-nmr (CDCl3): � = 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.

C16H21NO3 (MW = 275.35); mass spectroscopy (M+Na) 298.

Step B - Preparation of N-(cyclopentylacetyl)-L-phenylglycine

Following general procedure II-A above using N-(cyclopentylacetyl)-L-phenylglycine methyl ester (from step A), the title compound was prepared as a solid, mp 155-158°C. The reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.18 in 10% methanol/dichloromethane).

The NMR data are as follows:

1H-nmr (CDCl3): � = 8.60 (d, J = 7.8 Hz, 1H), 7.45 (m, 5H0, 5.41 (d, J = 7.2 Hz, 1H); 2.20 (m, 3H), 1.8-1.1 (m, 8H).

13C-nmr (CDCl3): ? = 172.3, 172.0, 137.3, 128.7, 128.1, 127.8, 56.2, 40.9, 36.8, 31.8, 24.5.

C15H19NO3 (MW = 261.32); mass spectroscopy (M+Na) 284.

Example II-D

Synthesis of N-(cyclopentylacetyl)-L-alanine

Step A - Preparation of N-(cyclopentylacetyl)-L-alanine methyl ester

Following general procedure II-E above using cyclopentylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid, mp 43-46°C. Purification was carried out by recrystallization from a mixture of ethyl acetate/hexane.

The NMR data are as follows:

1H-nmr (CDCl3): � = 6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H) , 11H).

13 C-nmr (CDCl 3 ): δ = 173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 18.0.

C11H19NO3 (MW = 213.28); mass spectroscopy (MH+) 214.

Step B - Preparation of N-(cyclopentylacetyl)-L-alanine

According to general procedure II-A above using N-(cyclopentylacetyl)-L-alanine methyl ester (from step A), the title compound was prepared. The reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.18 in 10% methanol/dichloromethane).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 12.45 (bs, 1H), 8.12 (d, J = 7.2 Hz, 1H), 4.24 (quint, J = 7.2 Hz, 1H), 2.14 (m, 3H), 1.8 -1.4 (m, 6H), 1.29 (d, J = 7.2 Hz, 3H), 1.2-1.0 (m, 3H).

13C-nmr (DMSO-d6): ? = 174.6, 171.9, 47.3, 41.1, 36.7, 31.8, 24.5, 17.2.

C10H17NO3 (MW = 199.25); mass spectroscopy (MH+) N/A.

Example II-E

Synthesis of N-(cyclopropylacetyl)-L-alanine

Step A - Preparation of N-(cyclopropylacetyl)-L-alanine methyl ester

Following general procedure II-E above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.15 in 25% ethyl acetate/hexane) and purification was performed by flash column chromatography using 25% ethyl acetate/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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.

C9H15NO3 (MW = 185.22); mass spectroscopy (MH+) N/A.

Step B - Preparation of N-(cyclopentylacetyl-L-alanine).

Following general procedure II-A above using N-(cyclopropylacetyl)-L-alanine methyl ester (from step A), the title compound was prepared as an oil. The reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.27 in 10% methanol/dichloromethane).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 8.18 (d, 1H), 4.25 (m, 1H), 2.08 (m, 2H), 1.30 (d, 3H), 1.00 (m, 1H), 0.50 (m, 2H), 0.19 (m, 2H).

13C-nmr (DMSO-d6): ? = 174.6, 171.7, 47.4, 17.3, 7.6, 4.12, 4.06.

C8H13NO3 (MW = 199.25); mass spectroscopy (MH+) N/A.

Example II-F

Synthesis of N-(cyclopropylacetyl)-L-phenylglycine

Step A - Preparation of N-cyclopropylacetyl)-L-glycine methyl ester

Following general procedure II-E above using cyclopropylacetic acid (Aldrich) and L-phenylglycine methyl ester, the title compound was prepared as a solid, mp 74-76°C. The reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.61 in 50% ethyl acetate/hexane) and purification was carried out by recrystallization from the ethyl acetate/hexane mixture.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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), 0.20 (m, 2H).

13C-nmr (CDCl3): 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.

C14H17NO3 (MW = 247.30); mass spectroscopy (MH+) N/A.

Step B - Preparation of N-(cyclopentylacetyl)-L-phenylglycine

Following general procedure II-A above using N-(cyclopropylacetyl)-L-phenylglycine methyl ester (from step A), the title compound was prepared as a solid, mp 152-157°C. The reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.23 in 10% methanol/dichloromethane) and purification was carried out by recrystallization from a mixture of ethyl acetate/hexane.

The NMR data are as follows:

1H-nmr (CDCl3): � = 8.47 (d, J = 7.69 Hz, 1H), 7.35 (m, 5H), 5.34 (d, J = 7.69 Hz, 1H), 2.10 (m, 2H), 0.90 (m , 1H), 0.40 (m, 2H), 0.10 (m, 2H).

13 C-nmr (CDCl 3 ): δ = 172.3, 171.8, 137.6, 128.7, 56.2, 7.7, 4.0.

C13H15NO3 (MW = 233.27); mass spectroscopy (MH+) N/A.

Example II-H

Synthesis of N-(2-biphenyl)-D,L-alanine

2-Aminobiphenyl (2 g, 11.8 mmol, Aldrich), triethylamine (1.2 eq.) and ethyl 2-bromopropionate (1.1 eq., Aldrich) were combined and heated with stirring to 85°C. After 7 days, the mixture was diluted with chloroform and washed with water. The organic part was dried and concentrated to give an oil which was purified by chromatography on silica gel (1:1 CH2Cl2/hexane). The resulting oil was dissolved in a 1:2 mixture of water/dioxane (200 mL) and LiOH (2 eq.) was added. After 2 hours the mixture was concentrated to obtain an oil which was dissolved in water. The aqueous solution was washed with ether and then the pH was adjusted to 3 with 5N HCl solution, and extraction was performed with ethyl acetate. The organic portion was dried and concentrated to give an oil which was purified by silica gel chromatography (EtOAc) to give the title compound.

Example II-I

Synthesis of N-(phenyl-furazan-3-yl)-D,L-alanine

4-phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich) were dissolved in dry ethanol. Platinum on carbon disulfide (5%) was added and the resulting mixture was hydrogenated (1000 psi, H2) at 150°C for 8 hours. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using CHCl 3 as eluent to give the title compound as its ethyl ester. The ethyl ester was then hydrolyzed using general procedure II-A, method B (LiOH/H2O/dioxane) to give the title compound.

Example II-L

Synthesis of S-(+)-3,5-difluoromandelic acid

Step A - Preparation of methyl S-(+)-3,5-difluoromandelate

To a solution of 3,5-difluorobenzaldehyde (Aldrich) in CH 2 Cl 2 (100 mL) was added ZnCl 2 (6.7 g, 21.1 mmol) to give a slurry. Trimethylsilyl cyanide (21.0 g, 211.2 mmol) was dissolved in CH2Cl2 (100 mL) and added to the slurry at 0°C. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was then diluted with water and the organic layers were separated.

The combined organic layers were concentrated to a residue. The residue was dissolved with MeOH (200 mL) at 0°C and gaseous HCl was bubbled through the solution for 10 min. After stirring at room temperature for 18 h, the solution was concentrated to a solid. The solid was dissolved in CH2Cl2/H2O and the aqueous portion was extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4 and concentrated to a solid (37.4 g, 87.6%), m.p. = 77-78°C.

1H-NMR (300 MHz, CDCl3): � = 6.97 (dd, J = 9.6 Hz, J = 1.79 Hz, 2H), 6.74 (dt, J = 8.82, J = 2.28 Hz, 1H), 5.14 (d, J = 4.64 Hz, 1H), 3.78 (s, 3H), 3.54 (d, J = 5.1 Hz, 1H).

Step B - Preparation of methyl S-(+)-3,5-difluoromandelate

Methyl (±)-3,5-difluoromandelate was separated by preparative chiral HPLC to give a white solid, mp 70-71 °C.

C9H8F2O3 (MW = 202.17); mass spectroscopy - found (M+NH4-) 220.0.

Analysis - calculated for C9H8F2O3: C, 53.47; H, 3.99. Found: C, 53.40; H, 3.89.

Step C - Preparation of S-(+)-3,5-difluoromandelic acid

A solution of methyl S-(+)-3,5-difluoromandelate (1 eq.) in 74% aqueous THF was cooled to 0°C and treated with lithium hydroxide. After 40 minutes at 0°C, the reaction was complete according to TLC. The contents were transferred to a separatory funnel and partitioned between CH2Cl2 and saturated aqueous NaHCO3. The aqueous layer was acidified with 0.5 N NaHSO4 solution and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to a white solid, mp 119-122°C. 1H-NMR corresponded to the known 3,5-difluoromandemic acid.

Example II-M

Synthesis of 2-azido-(3,5-difluorophenyl)acetic acid

Step A: 3,5-difluorophenylacetic acid (Aldrich) and THF were added to a three-neck flask with a mechanical stirrer and nitrogen inlet. The reaction mixture was cooled to -78°C and 1.2 equiv was added. triethylamine, and then adding trimethylacetyl chloride (1.05 eq.) (Aldrich) dropwise. During the addition, the temperature was maintained at -78°C. The cold bath was then removed and replaced with an ice bath. The temperature was then naturally raised to 0°C and stirring was continued for 1 hour. The reaction mixture was then recooled to -78°C. Into another flask which was charged with THF, triphenylmethane (catalytic amount, 0.1 mol %) and (S)-(-)-4-benzyl-2-oxazolidione (1.1 equiv) (Aldrich) at -78° C solution of n-butyllithium was added until an orange color was present. This reaction mixture was then stirred at -78°C for 30 min. and then it was transferred into the first reaction mixture with a cannula. The resulting mixture was allowed to stir at -78°C for 1 hour and then the reaction was quenched with 2.2 equiv. acetic acid. The solvent was removed under reduced pressure and the residue was redissolved in dichloromethane and this solution was washed with water, then with 1 M potassium carbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated. The residues were purified by LC 2000 chromatography, eluting with EtOAC/hexanes (15:85). The resulting oil was triturated in hexane to give a white solid which was collected by filtration to give (S)-(-)-3-(3,5-difluorophenylacetyl)-4-benzyl-2-oxazolidione.

Step B: To (S)-(-)-3-(3,5-difluorophenylacetyl)-4-benzyl-2-oxazolidione (3.0 mM) in 20 mL of dry THF cooled to -78°C was added dropwise LiHMDS (1.05 eq.) while maintaining the temperature at -78°C. The reaction mixture was stirred at -78°C for 15 min. and then a pre-cooled (-60°C) solution of trisilium azide (1.12 eq.) in 10 mL THF was added. The reaction mixture was stirred for a further 10 min and then the reaction was quenched with 4.4 equiv. acetic acid. Using a hot water bath, the temperature was raised to 30-40°C for 6 hours. The reaction mixture was then placed in a separatory funnel and extracted with dichloromethane. The organic layer was washed with bicarbonate solution, then with brine, and dried over sodium sulfate, filtered and the solvent was removed. The residues were purified by LC 2000 chromatography to give methyl 2-azido-2-(3,5-difluorophenyl)acetate.

Step C: To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in THF/H2O (2.6:1) cooled to 0°C was added 1.7 equiv. lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then placed in a separatory funnel. The mixture was extracted in water and washed with ether. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The organic layer was then washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-2-(3,5-difluorophenyl)acetic acid.

Example II-N

Synthesis of (R)-N,N'-di-BOC-2-hydrazinopropionic acid

Step A: Na (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF cooled to

-50°C was added dropwise with 1.1 equiv. n-butyllithium (1.6 M in hexane). The reaction mixture was allowed to warm to -20°C and then recooled to -78°C and propionyl chloride (1.1 eq.) was added in one portion. The reaction mixture was allowed to stir for an additional 15 minutes at -78°C and then allowed to warm to room temperature. The reaction was then quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were washed with water, then with brine and dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone.

Step B: To a solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone in THF at -78°C, KHMDS (1.05 eq) (Aldrich) was added dropwise. The reaction mixture was allowed to stir at -78°C for 30 min. and then a pre-cooled solution of di-tert-butyl-azodicarboxylate (Aldrich) was added by cannula. After 5 min. 2.6 equiv was added. acetic acid. The reaction mixture was then extracted with dichloromethane and the organic layer was washed with 1M potassium phosphate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2- oxazolidone.

Step C: To (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2-oxazolidanone (0.49 mol) at 0°C to 8 mL of THF and 3 mL of water was added LiOH (1.7 equiv.) and H2O2 (3.0 equiv.) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then placed in a separatory funnel and diluted with water. The aqueous mixture was extracted with ethyl acetate and then acidified to pH 2.0 with 1N HCl and extracted with ethyl acetate. The organic layer was then dried over sodium sulfate, filtered and the solvent removed to give (R)-N,N'-di-BOC-2-hydrazinopropionic acid which was used without further purification.

Example II-O

Synthesis of 3,5-difluorophenyl-�-oxoacetic acid

Step A: Ethyl 3,5-difluorophenyl-�-oxoacetate was prepared from 1-bromo-3,5-difluorobenzene (Aldrich) according to the procedure described in J. Org. Chem. 45 (14), 2883-2887 (1980).

Step B: Ethyl 3,5-difluorophenyl-�-oxoacetate was hydrolyzed according to general procedure II-A (Method B) to give 3,5-difluorophenyl-�-oxoacetic acid.

Example II-P

Synthesis of cyclopentyl-�-hydroxyacetic acid

The title compound (CAS No. 6053-71-0) was prepared in two steps from cyclopentylmethanol (CAS No. 872-53-7, Wiley) using the procedure described in Gibby, W. A.; Gubler, C.J. Biochemical Medicine 1982, 27, 15-25.

Example II-Q

Synthesis of N-(3,4-dichlorophenyl)alanine

According to the procedure shown in the U.S. Patent No. 3,598,859, the disclosure of which is hereby incorporated by reference in its entirety, prepared N-(3,4-dichlorophenyl)alanine. Specifically, to a solution of 3,4dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) was added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) ( Aldrich). This mixture was heated to 40°C and sodium bicarbonate (0.25 equivalent) was added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture was poured into water and unreacted 3,4-dichloroaniline was removed by filtration. The filtrate was acidified to pH pH 3-4 with concentrated hydrochloric acid and the resulting precipitate was filtered, washed and dried to give the title compound, m.p. = 148-149°C.

Example II-R

Synthesis of N-(3,5-difluorophenyl)alanine

According to the procedure set forth in the U.S. Patent No. 3,398,859 and Example Q above, N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).

Example II-S

Synthesis of �-fluoro-3,5-difluorophenylacetic acid

Stage A - Synthesis of methyl 3,5-difluoromandelate

Gaseous HCl was bubbled through a solution of 3,5-difluoromandelic acid (Fluorochem) in methanol for 10 minutes. The reaction mixture was refluxed overnight. The mixture was then concentrated in vacuo and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the title intermediate as a white solid.

C9H8F2O3 (MW=202.17); mass spectroscopy 202.

1H-NMR (300 MHz, CDCl3): � = 7.00 (2H, d, J = 6.58 Hz), 6.76 (1H, t, J = 8.86 Hz), 5.16 (1H, d, J = 5.29 Hz), 3.81 ( 3H, s), 3.54 (1H, d, J = 5.39 Hz).

Stage B - Synthesis of methyl �-fluoro-3,5-difluorophenylacetate

A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq.) in methylene chloride was cooled to 0°C and a pre-cooled solution of methyl 3,5-difluoromandelate (1 eq.) in methylene chloride was added. The portable flask was washed with a small amount of methylene chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred for a further 40 minutes at ambient temperature. The mixture was placed on ice and the layers were separated. The organic phase was washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC eluting with 7% ethyl acetate/hexane to give the title intermediate as a yellow oil.

C9H7F3O2 (MW=204.16); mass spectroscopy 204.

Analysis - calculated for C9H7F3O2: C, 52.95; H, 3.46. Found: C, 52.80; H, 3.73.

Stage C - Synthesis of �-fluoro-3,5-difluorophenylacetic acid

According to general procedure II-A, method B and using methyl �-fluoro-3,5-difluorophenylacetate, the titled intermediate was prepared in the form of a white solid with a melting point of 100-102°C.

C8H5F3O2 (MW = 190.13); mass spectroscopy 190.

Analysis - calculated for C8H5F3O2: C, 50.54; H, 2.65. Found: C, 50.47; H, 2.79.

The following Examples 1-20 illustrate the synthesis of the compounds of this invention.

Example 1

Synthesis of (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-phenylethyl]-3-methyl-1,2,4-oxadiazole

According to the general procedure A above and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(1-amino-2-phenylethyl)-3-methyl-1 ,2,4-oxadiazole hydrochloride (example B), the title compound was prepared as a solid with a melting point of 159-162°C. The reaction was followed by thin-layer chromatography (Rf = 0.6 in 10% MeOH/CHCl3) and the product was purified by chromatography on silica gel using 7% MeOH/CHCl3 as eluent, and then by recrystallization from 1-chlorobutane.

The NMR data are as follows:

1H-nmr (DMSO-d6): ����4.30 (m, 1H), 5.26 (m, 1H).

C21H22F2N4O3 (MW = 428.44); mass spectroscopy (MH+) 428.

Example 2

Synthesis of (S)-2-[ 1-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazotine

According to the general procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-4-ethoxycarbonyl-2-thiazoline

hydrochloride (Example G), the title compound was prepared as a semi-solid. The reaction was monitored by thin layer chromatography (Rf = 0.2 in 1:1 EtOAc/hexane) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 1.33 (t, 3H), 1.44 (t, 3H), 3.55 (s, 2H), 3.60 (m, 2H), 4.37 (m, 2H), 4.85 (m, 1H) , 5.05 (m, 1H), 6.46 (t, 1H), 6.74 (t, 1H), 6.84 (d, 2H).

C16H18F2N2O3S (MW = 356.39); mass spectroscopy (MH+) 356.

Example 3

Synthesis of 1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

To a 1:1 mixture of the product from Example J, stage C (1.815 g, 1 eq.) in THF (9 mL)/H2O (9 mL) at ambient temperature was added NaHCO3 (0.377 g, 1.50 eq.) and di-tert- butyl dicarbonate (1.304 g, 2.00 equiv) (Aldrich) in THF (6 mL). The resulting pale yellow mixture was stirred at ambient temperature for 1 h and then more NaHCO3 (0.188 g, 0.75 eq) and di-tert-butyl dicarbonate (0.652 g, 1.00 eq) in THF (3 mL) were added and the mixture was stirred for another hour. The mixture was then diluted with ethyl acetate, washed with brine (2×), dried over Na2SO4, filtered, concentrated in vacuo and purified by flash chromatography using 3:2 hexane/EtOAc as eluent to give the title compound in 77% yield in as a viscous oil (Rf = 0.31 in 3:2 hexane/EtOAc). A racemic 1:1 mixture of diastereomers could not be resolved by flash chromatography.

The NMR data are as follows:

1H-nmr (DMSO-d3, 250 MHz): � = 7.38-7.09 (m, 10H), 6.00 (bd, 1H, J = 7.75 Hz), 5.21-5.05 (m, 3H), 4.15 (d, 1H, J = 11.76 Hz), 4.08 (d, 1H, J = 11.26 Hz), 3.85-3.80 (m, 2H), 3.78 (s, 3H), 3.20-3.00 (m, 2H), 1.43 (s, 9H), 1.36 (d, 1.5H, J = 6.75 Hz), 1.24 (d, 1.5H, J = 6.75 Hz).

C27H33N3O6 (MW = 495.58); mass spectroscopy (MH+) 496.4.

Example 4

Synthesis of 1-tert-butoxycarbonyl-2-[1-(3,S-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

According to the general procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline (Example J), prepared is the title compound in the form of an amorphous solid. The reaction was monitored by thin layer chromatography (Rf = 0.34 in 2:1 hexane/EtOAc) and the product was purified by flash column chromatography.

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.28-7.20 (m, 3H), 7.16-7.12 (m, 1H), 7.07-7.03 (m, 1H), 6.91-6.80 (m, 3H), 6.77- 6.67 (m, 1H), 5.35-5.21 (m, 1H), 4.17-4.05 (m, 1H), 3.86-3.79 (m, 1H), 3.79 (s, 3H), 3.55 (s, 1H), 3.52 ( s, 1H), 3.18-2.99 (m, 2H), 1.43 (s, 4.5H), 1.41 (s, 4.5H), 1.33 (d, 1.5H, J = 6.75 Hz), 1.21 (d, 1.5H , J = 6.75 Hz).

C27H31F2N3O5 (MW = 515.56); mass spectroscopy (MH+) 516.2.

Example 5

Synthesis of 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline

According to the general procedure D above and using the product from Example 4 above, the title compound was prepared as a white solid (93%) with a melting point of 158-160°C. The reaction was monitored by thin layer chromatography (Rf = 0.31 in 95:5 DCM/MeOH).

The NMR data are as follows:

1H-nmr (DMSO-d6 and CDCl3, 250 MHz): � = 8.09 (bt, 1H, J = 7.75 Hz), 7.28-7.19 (m, 3H), 7.14-7.09 (m, 2H), 6.89 (bd, 2H, J = 7.25 Hz), 6.74 (bt, 1H, J = 9.13 Hz), 4.62-4.48 (m, 1H), 3.88 (bd, 1H, J = 12.51 Hz), 3.68 (s, 3H), 3.613. 54 (m, 1H), 3.50 (s, 2H), 3.11-2.92 (m, 2H), 1.31 (d, 1.5H, J = 6.75 Hz), 1.30 (d, 1.5H, J = 7.00 Hz).

C22H20F2N3O3 (MW = 415.44); mass spectroscopy (MH+) 416.1.

Example 6

Synthesis of (S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-5(R,S)-ethoxycarbonyl-2-oxazoline

According to general procedure A and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-5-(R,S)-ethoxycarbonyl-2-oxazoline (Example F), the title compound was prepared in the form of a semi-solid. The reaction was monitored by thin layer chromatography (Rf = 0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 1.20 (t, 3H), 1.30 (d, 3H), 3.50 (s, 2H), 3.80 (m, 1H), 4.05 (m, 1H), 4.15 (q, 2H), 4.55 (m, 1H), 5.10 (m, 1H), 6.97 (d, 2H), 7.08 (m, 1H), 8.60 (d, 1H).

C16H18F2N2O4 (MW = 340.33); mass spectroscopy (MH+) 340.

Example 7

Synthesis of 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

Stage A - Synthesis of 1-tert-butoxycarbonyl-2-[1-(3,5difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

According to the general procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline (Example K), prepared is the title compound in the form of a white foam (90%). The reaction was monitored by thin layer chromatography (Rf = 0.39 in 3:2 hexane/EtOAc) and the product was purified by flash column chromatography.

The NMR data are as follows:

1H-nmr (CDCl3, 250 MHz): � = 7.38-7.31 (m; 5H), 7.09 (d, 1H, J = 7.50 Hz), 6.90-6.82 (m, 2H), 6.76-6.66 (m, 1H) , 5.57 (p, 1H, J = 7.50 Hz), 4.83 (d, 1H, J = 11.26 Hz), 3.87 (d, 1H, J = 11.26 Hz), 3.72 (s, 3H), 3.56 (s, 2H) , 1.49 (s, 9H), 1.48 (d, 3H, J = 7.00 Hz).

C26H29F2N3O5 (MW = 501.53); mass spectroscopy (MH+) 502.

Stage B - Synthesis of 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline

According to the general procedure D above and using the product of step A above, the title compound was prepared as a white foam (89%). The reaction was monitored by thin layer chromatography (Rf = 0.24 in 95:5 DCM/MeOH) and the product was purified by flash column chromatography.

The NMR data are as follows:

1H-nmr (DMSO-d6, 300 MHz): � = 8.47 (d, 1H, J = 7.89 Hz), 7.34-7.27 (m, 5H), 7.12-7.06 (m, 1H), 7.03-7.00 (m, 2H), 4.55 (p, 1H, J = 7.35 Hz), 4.34 (bm, 1H), 3.62 (s, 2H), 3.53 (s, 2H), 1.31 (d, 3H, J = 7.00 Hz).

C21H21F2N3O3 (MW = 401.41); mass spectroscopy (MH+) 402.

Example 8

Synthesis of 1-tert-butoxycarbonyl-2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyl-4-methyl-2-imidazoline

Stage A - Synthesis of ethyl 2,3-diamino-2-methylpropionate

According to the procedures described in Gilbert, et al., Tetrahedron, 1995 51, 6315-6336, the title compound was prepared as an oil. Purification was carried out by "kugelrohr" distillation.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 4.06 (m, 2H), 2.70 (d, 1H), 2.46 (d, 1H), 2.18 (bs, 4H), 1.18 (t, 3H), 1.10 (s, 3H).

C6H44N2O2 (MW = 146.19); mass spectroscopy (MH+) 147.

Stage B - Synthesis of 2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyl-4-methyl-2-imidazoline

2.25 g (9.55 mmol) of the product of example L - stage A, and 20 mL of ethanol were added to a round bottom flask equipped with an addition funnel. The flask was cooled to 0°C and stirring under a nitrogen atmosphere was started. The product of the above step A (1.40 g, 9.55 mmol) in 20 ml of ethanol was slowly added to the reaction mixture using an addition funnel. The reaction mixture was allowed to slowly warm to room temperature with stirring

over night. The mixture was then filtered through a sintered glass funnel and the filtrate was concentrated on a rotary evaporator. The residue was partitioned between 50 mL of 1.0N sodium hydroxide and 50 mL of dichloromethane.

The organic phase was separated and the aqueous layer was washed three times with 50 mL of dichloromethane. The combined organic layers were washed with 50 mL of saturated brine and dried over sodium sulfate. Filtration and concentration on a rotary evaporator gave a yellow oil which was purified by flash chromatography on silica gel 60 (230-400 mesh) using 95:5 DCM/MeOH as eluent. Concentration of the fractions afforded 2.61 g (82% yield) of the title compound (Rf = 0.17 in 95:5 DCM/MeOH).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 7.05 (m, 3H), 4.04 (m, 2H), 3.75 (d, J = 11.71 Hz, 1H), 3.49 (s, 2H), 3.27 (d, J = 11.73 Hz, 1H), 1.29 (s, 3H), 1.17 (t, 3H).

C14H16F2N2O2 (MW = 282.29); mass spectroscopy (MH+) 282.1.

Stage C - Synthesis of 1-tert butoxycarbonyl-2-(3,5-difluorophenyltmethyl)-4-ethoxycarbonyl-4-methyl-2-imidazoline

To a round-bottomed flask equipped with an addition funnel was added the product of step B above (2.00 g, 7.08 mmol), 0.743 g (8.85 mmol) of sodium bicarbonate, 30 mL of water, and 30 mL of THF. Stirring was started under nitrogen and di-tert-butyl dicarbonate (3.47 g; 15.90 mmol) (Aldrich) in 15 mL of THF was added to the reaction mixture via an addition funnel. After stirring for 1 hour, a further 627 mg (7.05 mmol) of sodium bicarbonate and 1.17 g (5.40 mmol) of di-tert-butyl dicarbonate were added to the reaction mixture. The course of the reaction was monitored by thin-layer chromatography, and when the reaction was complete, the reaction mixture was partitioned between 250 mL of ethyl acetate and 250 mL of saturated saline solution. The organic layer was washed twice with 250 mL of saturated saline and then dried over sodium sulfate. Filtration and concentration on a rotary evaporator gave a yellow oil which was purified by flash chromatography on silica gel 60 (230-400 mesh) using 15:85 ethyl acetate/dichloromethane as eluent.

Concentration of the fractions afforded 2.10 g (78% yield) of the title compound (Rf = 0.15 in 15:85 EtOAc/hexane).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 7.07 (m, 1H), 6.94 (m, 2H), 4.05 (m, 5H), 3.57 (d, 1H), 1.38 (d, 12H), 1.19 (t, 3H).

13c-NMR (DMSO-D6): � = 172.116, 163.99, 160.348, 157.624, 149.352, 140.855, 111.511, 101.584, 81.677, 69.950, 60.758, 55.442, 34.855, 27.423, 24.203, 13.581.

C19H24F2N2O4 (MW = 382.41); mass spectroscopy (MH-) 382.1.

Example 9

Synthesis of 2-(1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl)methyl-2-thiazoline

Following general procedure F above and using N-(1-cyano-1-phenylmethyl)-N'-(3,5-difluorophenylacetyl)-L-alanine amide and 2-mercaptoethylamine, the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.3 in 5% MeOH/CHCl3) and the product was purified by chromatography on silica gel using 5% MeOH/CHCl3 as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����1.31 (m, 3H), 3.31 (m, 2H), 3.50 (d, 2H), 4.24 (m, 2H), 4.55 (m, 1H), 4.64 (d, 1H), 6.30 (m, 1H), 6.76 (m, 2H), 7.33 (d, 5H), 7.52 (m, 1H).

C21H21F1N3O2S (MW = 417.48); mass spectroscopy (MH+) 417.

Example 10

Synthesis of 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-ethoxycarbonyl-2-thiazoline

Following general procedure G above and using N-(3,3-difluorophenylacetyl)-phenylglycinonitrile from Example I above and L-cysteine ethyl ester hydrochloride (Aldrich), the title compound was prepared as an amorphous solid. The reaction was monitored by thin-layer chromatography (Rf = 0.5 in 1:1

EtOAc/hexane) and the product was purified by silica gel chromatography using 40% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 1.36 (t, 3H), 3.6 (m, 4H), 4.30 (m, 2H), 5.10 and 5.20 (t, 1H), 5.84 (d, 1H), 6.72 (m, 1H), 6.84 (m, 2H), 7.38 (m, 5H).

C21H20F2N2O3S (MW = 418.47); mass spectroscopy (MH+) 418.

Example 11

Synthesis of 2-[(S)-1-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine

According to the general procedure H mentioned above, the title compound was prepared in the form of an oil. The reaction was monitored by thin layer chromatography (Rf = 0.5 in 3:2 hexane/EtOAc) and the product was purified by preparative thin layer chromatography using 3:2 hexane/EtOAc as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 1.5 (d, J = 7 Hz, 3H), 3.79 (s, 3H), 4.15-4.3 (m, 1H), 4.3-4.65 (m, 3H), 4.7-4.85 ( m, 1H), 6.45 (s, 2H), 6.7 (s, 1H).

13C-nmr (CDCl3): ? = 14.2, 42.08, 42.15, 47.9, 62.9, 65.3, 106.67, 106.72, 113.0, 130.7, 143.3, 166.3.

C13H14Cl2N2O3 (MW = 317); mass spectroscopy (MH+) N/A.

Example 12

Synthesis of (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino1-phenyl] methyl-3-methyl-1,2,4-oxadiazole

According to the general procedure A above and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-3-(1-amino-1-phenylmethyl)-3-methyl-1 ,2,4-oxadiazole hydrochloride (Example C), the title compound was prepared as a solid (3:2 mixture of diastereomers). The reaction was monitored by thin layer chromatography (Rf = 0.6 in 7% MeOH/CHCl3) and the product was purified by chromatography on silica gel using 7% MeOH/CHCl3, and then by recrystallization from 1-chlorobutane/acetonitrile.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 1.21 (d, 3H), 2.32 (s, 3H), 3.53 (s, 2H), 4.43 (m, 1H), 6.35 (d, 1H), 6.97 (d, 2H), 7.07 (m, 1H), 7.38 (broad s, 5H), 8.38 (d , 1H), 9.27 (d, 1H).

C20H20F2N4O3 (MW = 414.41); mass spectroscopy (MH+) 414.

Example 13

Synthesis of (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl] methyl-3-phenyl-1,2,4-oxadiazole

According to the general procedure A above and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(1-amino-1-phenylmethyl)-3-phenyl-1 ,2,4-oxadiazole hydrochloride (Example D), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.4 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 1.31 (d, 3H), 3.51 (s, 2H), 4.47 (m, 1H), 6.42 (d, 1H), 6.97 (d, 2H), 7.07 (m, 1H), 7.35-7.60 (m, 8H), 7.97 (d, 2H), 8.40 (d, 1H), 9.27 (d, 1H).

C26H22F2N4O3 (MW = 476.49); mass spectroscopy (MH+) 476.

Example 14

Synthesis of (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole

According to the general procedure A above and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(1-amino-1-phenylmethyl)-3-(4- methoxyphenylmethyl)-1,2,4-oxadiazole hydrochloride (Example E), the title compound (1:2 mixture of diastereomers) was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.25 in 3.5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3.5% MeOH/CHCl3) as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d3): � = 1.22 (d, 3H), 3.49 (s, 2H), 3.72 (s, 3H), 3.98 (s, 2H), 4.42 (m, 1H), 6.28 (d, 1H), 6.86 (d, 2H), 6.96 (d, 2H), 7.07 (m, 1H), 7.18 (d, 2H), 7.38 (broad s, 5H), 8.36 (d, 1H), 9.18 (d, 1H).

C28H26F2N4O4 (MW = 520.54); mass spectroscopy (MH+) 520.

Example 15

Synthesis of (4R)-4-[N-(1S)-(1-methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline

Solutions of (4R)-4-carboxy-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline (0.2509 g, 1.00 equiv) from Example L above in THF (20 mL) at (S)-(+)-2-phenylglycine methyl ester hydrochloride (0.2052 g, 1.10 eq.) (Aldrich), 1-hydroxybenzotriazole hydrate (0.1437 g, 1 .15 eq.) (Aldrich), N,N-diisopropylethylamine (0.371 mL, 2.30 eq.), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2039 g, 1.15 eq.) (Aldrich). The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring for 19 hours. The solution was diluted with ethyl acetate, washed with 0.5 M aqueous HCl solution (2×), diluted aqueous NaHCO3 solution (1×), and saline solution (1×); then the organic phase was dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by flash column chromatography using 2:1 hexane/EtOAc as eluent to give the title compound as a clear colorless viscous oil (0.3465 g, 90% ).

The NMR data are as follows:

1H-nmr (CDCl3, 300 MHz): � = 7.59 (d, 1H, J = 7.25 Hz), 7.36-7.27 (m, 5H), 6.80-6.78 (m, 2H), 6.75-6.68 (m, 1H) , 5.51 (d, 1H, J = 7.37 Hz), 3.78 (s, 2H), 3.74 (s, 3H), 2.63 (d, 1H, J = 11.59 Hz), 2.22 (d, 1H, J = 11.60 Hz) , 1.55 (s, 3H).

Optical rotation: [a]20 = 65.3 (c 1.0, CHCl3).

C21H20F2N2O3S (MW = 418.47); mass spectroscopy (MH+) 418.3.

Example 16

Synthesis of 4-[N-(S)-(1-methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline

Following general procedure A above and using L-phenylglycine methyl ester and 2-(3,5-difluorophenylmethyl)-4-carboxy-2-thiazoline from Example H above, the title compound was prepared as two separate diastereomeric isomers. The reaction was monitored by thin layer chromatography (Rf = 0.6 and 0.4 in 1:1 EtOAc/hexane) and the products were purified by silica gel column chromatography using 40% EtOAc/hexane as eluent.

The first diastereomeric isomer (amorphous solid):

The NMR data are as follows:

1H-nmr (CDCl3): � = 3.58-3.82 (m, 5H), 3.94 (s; 2H), 5.10 (t, 1H), 5.57 (d, 1H), 6.75 (m, 1H), 6.90 (d, 2H), 7.35 (m, 5H), 7.84 (d, 1H).

C19H18F2N2O3S (MW = 404.44); mass spectroscopy (MH+) N/A.

Second diastereomeric isomer (oil):

The NMR data are as follows:

1H-nmr (CDCl3): � = 3.61 (d, 2H), 3.75 (s, 3H), 3.84 (s, 2H), 5.13 (t, 1H), 5.56 (d, 1H), 6.72 (m, 1H) , 6.80 (d, 2H), 7.33 (m, 5H), 7.66 (d, 1H).

C19H18F2N2O3S (MW = 404.44); mass spectroscopy (MH+) 404.

Example 17

Synthesis of (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole

According to general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(1-aminoethyl)-3-ethyl-1,2,4-oxadiazole hydrochloride (example A), the title compound was prepared as a solid, mp 181-183°C. The reaction was monitored by thin layer chromatography (Rf = 0.3 in 7% MeOH/CHCl3) and the product was purified by chromatography on a silica gel column using 7% MeOH/CHCl3 as eluent, and then by recrystallization from 1-chlorobutane.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 1.20 (m, 6H), 1.45 (d, 3H), 2.70 (q, 2H), 3.1 (s, 2H), 4.32 (m, 1H), 5.13 (m, 1H), 6.98 (d, 2H), 7.10 (m, 1H), 8.38 (d, 1H), 8.73 (d, 1H).

Optical rotation: [�]20 = +53.1 @ 589 nm (c 1.08, DMSO).

C17H20F2N4O3 (MW = 366.37); mass spectroscopy (MH+) 367.

Example 18

Synthesis of 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-(4R)-4-methoxycarbonyl-2-thiazoline

Following general procedure G above and using N-(3,5-difluorophenylacetyl)phenylglycinonitrile from Example I above and (R)-cysteine methyl ester hydrochloride (CAS No. 2485-62-3), the title compound was prepared. The product was purified by silica gel chromatography using 1:1 EtOAc/hexane as eluent, followed by recrystallization from 1-chlorobutane.

The first diastereomeric isomer (higher Rf):

The NMR data are as follows:

1H-nmr (CDCl3): δ = 5.08 (t, 1H), 5.18 (t, 1H), 5.47 (t, 1H), 5.82 (m, 1H).

C20H18F2N2O3S (MW = 404.44); mass spectroscopy (M+) 404.

The second diastereomeric isomer (lower Rf):

The NMR data are as follows:

1H-nmr (CDCl3): δ = 5.12 (t, 1H), 5.21 (t, 1H), 5.47 (t, 1H), 5.83 (m, 1H).

C20H18F2N2O3S (MW = 404.44); mass spectroscopy (M+) 404.

Example 19

Synthesis of 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-(4S)-4-methoxycarbonyl-2-thiazoline

According to the general procedure G above and using N-(3,5-difluorophenylacetyl)phenylglycinonitrile from Example I above and (S)-cysteine

methyl ester hydrochloride (Aldrich), the title compound was prepared. The product was purified by chromatography on silica gel using 2:3 EtOAc/hexane as eluent, and then by recrystallization from a mixture of 1-chlorobutane/hexane.

The first diastereomeric isomer (higher Rf):

The NMR data are as follows:

1H-nmr (CD3OD): δ = 3.76 (s, 3H), 5.20 (t, 1H), 5.85 (s, 1H).

C20H18F2N2O3S (MW = 404.44); mass spectroscopy (M+) 404.

The second diastereomeric isomer (lower Rf):

The NMR data are as follows:

1H-nmr (CD3OD): δ = 3.78 (s, 3H), 5.22 (t, 1H), 5.83 (s, 1H).

C20H18F2N2O3S (MW = 404.44); mass spectroscopy (M+) 404.

Example 20

Synthesis of N-[2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline-4-carboxamido]-L-phenylglycine methyl ester

Stage A - Synthesis of 1-tert-butoxycarbonyl-2-(3,5-difluorophenylmethyl)-4-carboxy-4-methyl-2-imidazoline

A round bottom flask equipped with a magnetic stirrer was charged with 150 mL THF, 50 mL 0.1N aqueous lithium hydroxide solution, and 1-tert-butoxycarbonyl-2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyl-4-methyl-2- imidazoline (Example 8, step C) (2.58 g, 6.75 mmol). The reaction mixture was stirred for 1 hour and then a further 75 mL of 0.1 N aqueous lithium hydroxide solution was added and stirring was continued for 3.5 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and 0.5N aqueous hydrochloric acid. The organic phase was separated and washed with additional 0.5N aqueous hydrochloric acid. The organic phase was then dried over Na2SO4. The desiccant was removed by filtration and the filtrate was partially concentrated in vacuo. The resulting solid was separated by vacuum filtration through a sintered glass funnel, and then vacuum drying at 80°C.

Mass spectroscopy was as follows:

C17H20N2O4 (MW = 354.36); mass spectroscopy (MH+) 255.2.

Stage B - Synthesis of N-[1-tert-butoxycarbonyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline-4-carboxamido]-L-phenylglycine methyl ester

According to the general procedure A above and using (S)-(+)-2-phenylglycine methyl ester hydrochloride and the product of step A, the title compound was prepared. The product was purified by flash chromatography on silica gel (230-400 mesh) using 95:5 DCM/MeOH as eluent.

The first diastereomeric isomer (viscous oil):

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.60 (bs, 1H), 7.35 (s, 5H), 6.90 (m, 2H), 6.69 (m, 1H), 5.49 (d, 1H), 4.12 (m, 3H) , 3.72 (s, 3H), 3.61 (d, 1H), 1.46 (s, 9H), 1.41 (s, 3H).

Second diastereomeric isomer (viscous oil):

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 7.55 (bs, 1H), 7.31 (m, 5H), 6.84 (m, 2H), 6.67 (m, 1H), 5.49 (d, 1H), 4.08 (m, 3H), 3.72 (s, 3H), 3.56 (m, 1H), 1.50 (s, 1H), 1.43 (s, 9H).

Stage C - Synthesis of N-[2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline-4-carboxamido]-L-phenylglycine methyl ester

According to the general procedure D above and using the individual isomers of grade B, the title compound was prepared as two separate isomers. These products were purified by flash chromatography on silica gel (230-400 mesh) using 97.5:2.5 DCM/MeOH as eluent.

The first diastereomeric isomer:

The mass spectroscopy data are as follows:

C21H21F2N2O3S (MW = 401.42); mass spectroscopy (MH+) 402.0.

Another diastereomeric isomer:

The mass spectroscopy data are as follows:

C21H21F2N2O3S (MW = 401.42); mass spectroscopy (MH+) 402.0.

Below, the following procedures and examples illustrate the preparation of various carboxylic acids (and esters of carboxylic acids that can be hydrolyzed using general procedures AC or BD, below, to provide the corresponding carboxylic acids) that can be used to prepare additional compounds that are within the scope of this invention.

GENERAL PROCEDURE AA

Reductive amination

1 equivalent of 2-oxocarboxylic acid ester (e.g. pyruvate ester) was added to the arylamine solution in ethanol in the hydrogenation bottle, followed by 10% palladium on carbon (25% by weight of the arylamine). The reaction mixture was hydrogenated at 20 psi H 2 in a Parr shaker until completion of the reaction was detected by thin layer chromatography (30 minutes to 16 hours). The reaction mixture was then filtered through a plug of Celite 545 (Aldrich Chemical Company, Inc.) and freed from solvent on a rotary evaporator. The crude product residues were then chromatographically purified.

GENERAL PROCEDURE AB

The first transesterification technique

A solution of 1-5 equivalents of the desired alcohol was added to 1 equivalent of sodium hydride in toluene. When gas evolution stopped, the compound to be transesterified, dissolved in toluene, was added. After half an hour, the reaction mixture was heated to 40°C and placed under house vacuum (~20 mmHg) or nitrogen was passed through the solution that was heated to 90°C. The reaction was monitored by thin-layer chromatography, and when the reaction was complete

the solution was cooled and the reaction was stopped with water or 1 M HCl, and the reaction mixture was diluted to a lesser extent with ethyl acetate. The organic phase was extracted with saturated aqueous NaHCO3 solution, then washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was desolvated on a rotary evaporator and the crude product residue was then purified by chromatography. Alternatively, the reaction mixture was worked up by evaporation of the solvent and direct chromatography of the crude mixture.

This procedure is particularly useful in the case of expensive and/or high-boiling alcohols.

GENERAL PROCEDURE AC

Another transesterification technique

The compound to be transesterified is placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added and the reaction was monitored by thin-layer chromatography until the presence of starting substances was no longer detected. The reaction was stopped with a few milliliters of 1N HCl and after a few minutes a saturated aqueous solution of NaHCO3 was added with stirring. The organic phase was washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was desolvated on a rotary evaporator and the crude product residue was then purified by chromatography.

GENERAL PROCEDURE AD

The third transesterification technique

The compound to be transesterified is placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added and the course of the reaction was followed by thin-layer chromatography until the presence of starting substances was no longer detected. The reaction was stopped with a few milliliters of 1N HCl and after a few minutes a saturated aqueous solution of NaHCO3 was added with stirring. The volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up with ethyl acetate and water was added. The organic phase was washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was desolvated on a rotary evaporator and the crude product residue was then purified by chromatography.

This procedure is mainly used in the case of low-boiling alcohols and cheap alcohols, which are mixed with water.

GENERAL PROCEDURE AE

O-alkylation technique

1.5 equivalents of K2CO3 and then 1 equivalent of an alkylating agent (e.g. tert-butyl bromoacetate) were added to the carboxylic acid compound (prepared, for example, by reductive amination by the general procedure AA to obtain the N-aryl ester of an amino acid, and then by hydrolysis by the procedure AF) in DMF ). The reaction mixture was stirred at room temperature for 2 hours, then the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 solution, water and saturated aqueous NaCl solution, and was dried over MgSO4. The solution was desolvated on a rotary evaporator to give the crude product.

GENERAL PROCEDURE AF

Hydrolysis of esters to free acid

2-5 equivalents of K2CO3 were added to the carboxylic acid compound (prepared, for example, by reductive amination by the general procedure AA to obtain the N-aryl ester of the amino acid) in a 1:1 mixture of CH3OH/H2O. The mixture was heated at 50°C for 0.5 to 1.5 hours until TLC showed completion of the reaction. The reaction mixture was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ~2 and ethyl acetate was added to extract the product. The organic phase was washed with saturated aqueous NaCl solution and dried over MgSO4.

The solution was desolvated on a rotary evaporator to give the crude product.

GENERAL PROCEDURE AG

N-heteroarylation of amines

A solution of 1.1 equivalents of L-alanine and 2 equivalents of NaOH in DMSO was stirred at room temperature and stirred at room temperature for 1 hour, then 1 equivalent of 2-chlorobenzothiazole was added. The mixture was heated at 100°C for 4 hours, then cooled to room temperature and placed on ice. The pH of the obtained aqueous solution was set to ~2, and the settled solid was removed by filtration. This solid was then dissolved in 1N NaOH and the resulting solution was filtered through a plug of Celite 545. The pH of the filtrate was adjusted to ~2, then the white precipitate was removed by filtration and washed with water to give the crude product.

GENERAL PROCEDURE AH

EDC binding

1.5 equivalents of triethylamine, then 2.0 equivalents of hydroxybenzotriazole monohydrate, then 1.25 equivalents of ethyl-3-(3-dimethylamino)-propyl carbodiimide⋅HCl were added to a 1:1 mixture of the desired acid and alcohol in CH2Cl2 at 0°C (EDC). The reaction mixture was stirred overnight at room temperature, then transferred to a separatory funnel and washed with water, saturated aqueous NaHCO3 solution, 1N HCl solution, and saturated aqueous NaCl solution, and dried over MgSO4. The solution was desolvated on a rotary evaporator to give the crude product.

GENERAL PROCEDURE AI

Oxime or amine bonding technique

The trichlorophenyl ester (1 eq.) of the carboxylic acid was stirred in DMF or THF. The oxime or amine (1.2 eq.) was added and the mixture was stirred at ambient temperature for 1-4 hours. In cases where the hydrochloride salt of the amine was used, a suitable base such as N,N-diisopropylethylamine (1.2 eq.) was also added. The resulting mixture was concentrated under reduced pressure to give the crude product which was used without purification or was purified by silica gel chromatography and/or crystallization.

GENERAL PROCEDURE AJ

Alkylation technique

The amine (1 eq.), the �-bromo ester (1.1 eq.) and a suitable base (such as triethylamine) (2 eq.) were mixed in chloroform. The resulting solution was heated under reflux for 4-12 hours. After cooling, the mixture was diluted with chloroform and washed with water. The organic part was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel.

GENERAL PROCEDURE AC

Oxime or alcohol binding technique

The carboxylic acid (1 eq.) was stirred in a suitable solvent (such as THF, dioxane or DMF). Alcohol or oxime (1-5 eq.) was added. EDC hydrochloride (1.1 eq.) and hydroxybenzotriazole hydrate (1 eq.) were added. A suitable base (such as 4-methylmorpholine or triethylamine) is added (0-1 eq.). A catalytic amount (0.1 eq.) of 4-dimethylaminopyridine was added. The mixture was stirred at ambient temperature under a dry nitrogen atmosphere. After 20 hours, the mixture was concentrated under reduced pressure. The resulting concentrate was partitioned between ethyl acetate and water. The organic part was separated and washed with an aqueous sodium bicarbonate solution and a saline solution. The organic part was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was used without purification or purified by silica gel chromatography and/or crystallization.

GENERAL PROCEDURE AL

EDC binding

Carboxylic acid is dissolved in methylene chloride. Amino acid (1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.1 eq.) were added sequentially. A cooling bath was applied to the round bottom flask until the temperature reached 0°C. After that, 1.1 equiv was added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The solution was allowed to stir overnight and reach room temperature under nitrogen pressure. The reaction mixture was then refined by washing the organic phase with a saturated aqueous solution of sodium carbonate, 0.1M citric acid and brine, before drying with sodium sulfate acid. The solvents were then removed to obtain the crude product. Pure products were obtained by "flash" chromatography in the appropriate solvent.

GENERAL PROCEDURE AM

Triflate substitution

To a solution at 0°C of iso-butyl R-(+)-lactate in CH2Cl2 was added 1.1 equivalents of trifluoromethanesulfonic anhydride. After stirring at room temperature for 20 min, 1.1 equivalents of 2,6-lutidine was added and stirring was continued for 10 min. The solution was then transferred to a flask containing 1 equivalent of arylamine and 1 equivalent of N,N-diisopropylethylamine in CH 2 Cl 2 or CH 3 NO 2 at 0°C. The reaction mixture was kept overnight at room temperature and freed from solvent on a rotary evaporator. The residues were dissolved in ethyl acetate, washed with 5% citric acid, then with saturated aqueous NaCl solution, dried over magnesium sulfate or sodium sulfate, and the solution was desolvated on a rotary evaporator to obtain the crude product, which was purified by chromatography.

GENERAL PROCEDURE AN

Removal of BOC

The BOC-protected compound was added to a 1:1 mixture of CH 2 Cl 2 and trifluoroacetic acid and stirred until TLC showed complete conversion, typically 2h. The solution was evaporated to dryness and the residue was taken up in ethyl acetate and extracted with dilute HCl. The acid reaction mixture was neutralized and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaCl solution and dried over MgSO4. The solvent was desolvated on a rotary evaporator to give the product.

GENERAL PROCEDURE OF AO

Synthesis of pyruvate esters

To a mixture of pyruvic acid (8.8 g, 0.1 mol) (Aldrich) in 100 mL of benzene was added iso-butanol (14.82 g, 0.2 mol) and a catalytic amount of p-toluenesulfonic acid. The mixture was then refluxed using a Dean-Stark apparatus. After 4 hours, the reaction was complete with the separation of 1.8 g (0.1 mol) of water. Benzene and iso-butanol were removed on a rotary evaporator. Residues (14 g, 0.1 mol), which are primarily pyruvate iso-butyl ester by nmr [1H-NMR (CDCl3): ����4.0 (d, 2H), 2.5 (s, 3H), 2.0 (m , 1H), 1.0 (d, 6H)], were used without further purification. By using other alcohols instead of iso-butanol (e.g., ethanol, isopropanol, n-butanol, benzyl alcohol and the like), other pyruvate acid esters can be prepared in a similar way.

GENERAL PROCEDURE AP

Aromatic nucleophilic substitution of fluorobenzene

A mixture of 1.82 g (10 mmol) of D,L-alanine iso-butyl ester hydrochloride, fluorobenzene (10 mmol) and 3 g of anhydrous potassium carbonate in 10 mL of DMSO was stirred at 120°C for 2-5 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL of ethyl acetate. The ethyl acetate extract was washed with water (3×), dried over MgSO4 and evaporated to dryness to give the crude product, which was further purified by column chromatography.

GENERAL PROCEDURE AQ

The fourth transesterification technique

The ester to be transesterified was dissolved in a large excess of alcohol and 0.3 equivalents of titanium (IV) isopropoxide (Aldrich) was added. The course of the reaction was monitored by thin-layer chromatography until completion and the eluables were removed under reduced pressure. The resulting crude material was then chromatographed to give the desired product.

GENERAL PROCEDURE AR

Synthesis of N-BOC aniline

To a solution of aniline in THF, 1 equivalent of di-tert-butyl dicarbonate (Aldrich) in THF and then 1.5 equivalents of a 10N aqueous sodium hydroxide solution at 0°C were added dropwise. After stirring at room temperature for 16 hours or heating at 80°C for 3 hours, if necessary, the reaction mixture was diluted with ether and washed with NaHCO3, brine, dried over sodium sulfate and potassium carbonate, concentrated under reduced pressure and chromatographed to give N-BOC aniline is obtained.

GENERAL PROCEDURE AS

Formation of oxime esters

Trichlorophenyl ester (1 eq.) was stirred in DMF or THF. Oxime (1.1 eq.) was added and the mixture was stirred at ambient temperature for 1 to 4 hours. The resulting mixture was concentrated under reduced pressure and the residues were purified by silica gel chromatography and/or crystallization.

Example AA

Synthesis of D,L-alanine iso-butyl ester hydrochloride

A mixture of 35.64 g (0.4 mol) D,L-alanine (Aldrich), 44 mL (0.6 mol) thionyl chloride (Aldrich) and 200 mL iso-butanol was refluxed for 1.5 hours. The volatiles were removed under reduced pressure at 90°C to give the title compound as an oil, which was used without further purification.

The NMR data are as follows:

1H-nmr (CDCl3): � = 8.72 (br s, 3H), 4.27 (q, J = 7.4 Hz, 1H), 3.95 (m, 2H), 1.96 (s, 1H), 1.73 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H).

13C-nmr (CDCl3): ? = 170.0, 72.2, 49.2, 27.5, 18.9, 16.1.

Example AB

Synthesis of N-(3,4-dichlorophenyl)alanine

Using the procedure shown in the U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety, prepared N-(3,4-dichlorophenyl)alanine. Specifically, to a solution of 3,4-dichloroaniline (1 equiv) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) was added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equiv. ) (Aldrich). The mixture was heated to 40°C and sodium bicarbonate (0.25 equivalent) was added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture was poured into water and unreacted 3,4-dichloroaniline was removed by filtration. The filtrate was acidified to pH 3-4 with concentrated hydrochloric acid and the resulting precipitate was filtered, washed and dried to give the title compound, m.p. = 148-149°C.

Alternatively, according to the general procedure AF above and using N-(3,4-dichlorophenyl)alanine ethyl ester (from Example A1 below), the title compound was prepared.

Example AC

Synthesis of N-(3,5-difluorophenyl)alanine

Using the procedure described in U.S. Patent No. 3,598,859, N-(3,5difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).

Example AD

Synthesis of iso-butyl 2-bromopropionate

To a mixture of iso-butanol and 1.0 equivalents of pyridine in dry diethyl ether was added dropwise 1.3 equivalents of 2-bromopropionyl bromide at 0°C. After stirring at room temperature for 16 hours, the reaction mixture was diluted with diethyl ether, washed with 1N HCl, water, aqueous NaHCO 3 , brine and dried over magnesium sulfate or sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as a clear oil.

Example AE

Synthesis of N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester

N-(2-Naphthyl)alanine methyl ester (5.0 g, 20.6 mmol) (from Example A44 below) was dissolved in dioxane (100 mL). NaOH (30 mL, 1N) was added and the resulting solution was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting solid was dissolved in water and the aqueous mixture was washed with ether. The resulting solid was dissolved in water and the aqueous mixture was washed with ether. The aqueous portion was adjusted to pH 3 with 1N HCl and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate or sodium sulfate and concentrated under reduced pressure to give a white solid (4.35 g, 98%).

The resulting solid (4.35 g, 20 mmol) was dissolved in dichloromethane (300 mL). 2,4,5-trichlorophenol (4.9 g, 25 mmol) (Aldrich) was added followed by dicyclohexylcarbodiimide (25 mL, 1 M in dichloromethane) (Aldrich). After stirring for 18 hours, the mixture was filtered and concentrated to give an oil which was purified by silica gel chromatography using chloroform as eluent (Rf = 0.6). The title compound is obtained in the form of a thick oil that slowly crystallizes.

Example A1

Synthesis of N-(3,4-dichlorophenyl)alanine ethyl ester

Following the general AA procedure above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.2 (d, 1H); 6.7 (d, 1H,); 6.4 (dd, 1H); 4.30 (bs, 1H); 4.2 (q, 2H); 4.1 (q, 1H); 1.5 (d, 3H); 1.3 (t, 3H).

13C-nmr (CDCl3): � = 175; 146.7; 133; 131; 121; 114.9; 112.6: 72.0; 52.4; 28.3; 19.5.

C11H13Cl2NO2 (MW = 262.14).

Example A2

Synthesis of N-(3-trifluoromethyl-4-chlorophenyl)alanine ethyl ester

According to the general AA procedure above and using 4-chloro-3-(trifluoromethyl)aniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.

Analysis - calculated: C, 48.74; H, 4.43; N, 4.74. Found: C, 48.48; H, 4.54; N, 4.94.

C12H23F3ClNO2 (MW = 295.69); mass spectroscopy (MH+) 295.

Example A3

Synthesis of N-(3,5-dichlorophenyl)alanine ethyl ester

According to the general AA procedure above and using 3,5-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.

Analysis - calculated: C, 50.40; H, 5.00; N, 5.34. Found: C, 50.50; H, 5.06; N, 5.25.

C11H13Cl2NO2 (MW = 262.14); mass spectroscopy (MH+) NA.

Example A4

Synthesis of N-(3,4-difluorophenyl)alanine ethyl ester

According to the general AA procedure above and using 3,4-difluoroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.

The course of the reaction was followed by thin layer chromatography on silica gel (Rf = 0.4 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.4 (m, 1H), 6.8 (d, 1H), 6.5 (m, 1H), 4.30 (bs 1H), 4.2 (q, 2H), 4.1 (q, 1H), 1.5 (d, 3H), 1.3 (t, 3H).

13C-nmr (CDCl3): � = 175, 146.7, 135, 132, 125, 116, 113, 72, 52, 28, 19.

C11H13F2NO2 (MW = 229.23); mass spectroscopy (MH+) 230.

Example A5

Synthesis of N-(3,4-dichlorophenyl)alanine benzyl ester

Following general procedure AA above and using 3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared according to general procedure AO above using benzyl alcohol instead of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.18 (d, 1H); 7.0 (m, 5H); 6.6 (d, 1H,); 6.4 (dd, 1H); 5.1 (s, 2H); 4.30 (bs, 1H); 4.08 (q, 1H); 1.94 (m, 1H); 1.47 (d, 3H); 0.91 (d, 6H).

13C-nmr (CDCl3): � = 174.5; 146.7; 133.5; 131.3; 121.3; 120.1; 114.9; 113.6; 72.0; 60.1; 52.4; 28.3; 19.5; 19.3.

C16H15Cl2NO2 (MW = 324.31); mass spectroscopy (MH+) 325.

Example A6

Synthesis of N-(3,4-dichlorophenyl)alanine iso-butyl ester

According to general procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared as an oil. The course of the reaction was monitored by TLC on silica gel (Rf = 0.55 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.18 (d, 1H, J = 8.7 Hz), 6.66 (d, 1H, J = 2.7 Hz), 6.43 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz), 4.30 (bs, 1H), 4.08 (q, 1H, J = 6.9 Hz), 1.94 (sept, 1H, J = 6.7 Hz), 1.47 (d, 3 H, J = 6.9 Hz), 0.91 (d, 6H, J = 6.6 Hz).

13C-nmr (CDCl3): ? = 174.5, 146.7, 133.5, 131.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

C13H17Cl2NO2 (MW = 290.19); mass spectroscopy (MH+) 290.

Example A7

Synthesis of N-(3,4-dichlorophenyl)alanine iso-propyl ester

According to general procedure AA above and using 3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared according to general procedure AO above using isopropanol instead of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.18 (d, 1H); 6.66 (d, 1H,); 6.43 (dd, 1H); 4.30 (bs, 1H); 4.08 (m, 1H); 1.94 (m, 1H); 1.47 (d, 3H); 0.91 (d, 6H).

13C-nmr (CDCl3): � = 174.5; 146.7; 133.5; 131.3; 121.3; 114.9; 113.6; 72.0; 52.4; 19.5.

C12H15Cl2NO2 (MW = 276.16); mass spectroscopy (MH+) 277.

Example A8

Synthesis of N-(3,4-dichlorophenyl)alanine n-butyl ester

Following general procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-butyl pyruvate (prepared according to general procedure AO above using n-butanol instead of iso-butanol), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.7 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.18 (d, 1H); 6.66 (d, 1H); 6.43 (dd, 1H); 4.30 (bs, 1H); 4.2 (m, 2H); 4.08 (q, 1H); 1.94 (m, 1H); 1.47 (m, 4H); 0.91 (t, 3H).

13C-nmr (CDCl3): � = 174.5; 146.7: 133.5; 131.3; 121.3; 114.9; 113.6; 72.0; 52.4; 28.3; 20.2; 19.5.

C13H17Cl2NO2 (MW = 290.19); mass spectroscopy (MH+) 291.

Example A9

Synthesis of N-(3,4-dichlorophenyl)alanine methyl ester (R,S isomers)

Following the general AA procedure above and using 3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.55 in 25% EtOAc/hexane) and purification was performed by flash chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, J = 8.73 Hz, 1H), 6.66 (d, J = 2.75 Hz, 1H), 6.43 (dd, J = 8.73 Hz, 2.80 Hz, 1H), 4.25 ( bd, J = 8.25 Hz, 1H), 4.08 (m, 1H), 3.76 (s, 3H), 1.47 (d, J = 6.90 Hz).

13C-nmr (CDCl3): �� = 174.35, 145.96, 132.87, 130.70, 120.76, 114.38, 112.90, 52.43, 51.70, 18.67.

C10H11Cl2NO2 (MW = 248.11); mass spectroscopy (MH+) 247.

Example A10

Synthesis of N-(3,4-dichlorophenyl)alanine cyclopentyl ester

Following the general procedure for the transesterification of AB and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclopentanol (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.66 in 25% EtOAc/hexane). Purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, 1H, J = 8.7 Hz), 6.66 (d, 1H, J = 2.7 Hz), 6.43 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz), 5.22 (m, 1H), 4.27 (d, 1H, J = 8.1 Hz), 4.02 (quint, 1H, J = 7.5 Hz), 1.74 (m, 8H), 1.43 (d, 3H, J = 6.9 Hz).

13C-nmr (CDCl3): � = 174.3, 146.7, 133.4, 131.2, 121.2, 114.9, 113.7, 78.9, 52.5, 33.2, 24.2, 24.1, 19.1.

C14H17Cl2NO2 (MW = 302.20); mass spectroscopy (MH+) 301.

Example A11

Synthesis of N-(3,4-dichlorophenyl)alanine n-propyl ester

Following general procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-propyl pyruvate (prepared according to general procedure AO above using n-propanol instead of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.5 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.30 (bs, 1H); 4.2 (q, 2H); 4.08 (q, 1H); 1.94 (m, 2H); 1.3 (d, 3H); 0.95 (t, 3H).

13C-nmr (CDCl3): � = 178; 144.7; 130.2; 120.62; 115.11; 71.82; 52.90.

C12H15Cl2NO2 (MW = 276.16); mass spectroscopy (MH+) 277.

Example A12

Synthesis of N-(3,4-dichlorophenyl)alanine allyl ester

Following the general procedure for the transesterification of AB and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and allyl alcohol (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.62 in 25% EtOAc/hexane). Purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, 1H, J = 8.7 Hz), 6.67 (d, 1H, J = 2.8 Hz), 6.44 (dd, 1H, J = 8.7 Hz, J = 2.8 Hz), 5.90 (m, 1H), 5.30 (m, 2H), 4.64 (m, 2H), 4.26 (m, 1H), 4.10 (m, 1H), 1.48 (d, 3H, J = 6.9 Hz).

13C-nmr (CDCl3): � = 174.1, 146.6, 133.5, 132.1, 131.3, 121.4, 119.6, 115.0, 113.6, 66.5, 52.4, 19.3.

C12H13Cl2NO2 (MW = 274.15); mass spectroscopy (MH+) 273.

Example A13

Synthesis of N-(3,4-dichlorophenyl)alanine 4-methylpentyl ester

Following the general procedure for the transesterification of AB and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and 4-methylpentanol (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.70 in 25% EtOAc/hexane). Purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.18 (d, 1H, J = 8.7 Hz), 6.66 (d, 1H, J = 2.7 Hz), 6.43 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz), 4.28 (m, 1H), 4.10 (m, 3H), 1.55 (m, 6H), 1.19 (m, 2H), 0.87 (d, 3H, J = 6.6 Hz).

13C-nmr (CDCl3): � = 174.6, 146.7, 133.4, 131.3, 121.3, 115.0, 113.6, 66.4, 52.4, 35.4, 28.2, 27.0, 23.0, 19.3.

C15H21Cl2NO2 (MW = 318.25); mass spectroscopy (MH+) 317.

Example A14

Synthesis of N-(3,4-dichlorophenyl)alanine 2,2-dimethyl-1,3-dioxolane-4-methyl ester

According to the general procedure for the transesterification of AB and using N-(3,4-dichlorophenyl)alanine methyl ester (from the above example A9) and 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal) (Aldrich), prepared is the title compound as a mixture of diastereomers. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.32 in 25% EtOAc/hexane). Purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, 1H, J = 8.7 Hz), 6.66 (d, 1H, 2.7 Hz), 6.43 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz); 4.22 (m, 6H), 3.70 (m, 1H), 1.43 (m, 9H).

13C-nmr (CDCl3): � = 174.34, 174.32, 146.5, 133.5, 131.3, 121.5, 115.0, 113.6, 110.52, 110.51, 73.97, 73.89, 66.6, 66.01, 65.95, 52.4. 52.37, 27.3, 25.8, 19.3.

C15H19Cl2NO4 (MW = 348.23); mass spectroscopy (MH+) 347.

Example A15

Synthesis of N-(3,4-dichlorophenyl)alanine cyclohexylmethyl ester

Following the general procedure for the transesterification of AB and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclohexylmethanol (Aldrich), the title compound was prepared.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, 1H), 6.68 (d, 1H), 6.45 (dd, 1H), 4.26 (bd, 1H), 4.10 (m, 1H), 3.95 (d, 2H) , 1.70-1.55 (m, 6H), 1.50 (d, 3H), 1.35-0.85 (m, 5H).

13C-nmr (CDCl3): δ = 174.58, 146.72, 133.48, 131.27, 121.34. 114.98, 113.72, 71.06, 52.52. 37.68, 30.10, 26.83, 26.17, 19.32.

C15H21Cl2NO2 (MW = 318.25); mass spectroscopy (MH+) 317.

Example A16

Synthesis of N-(3,4-dichlorophenyl)alanine tert-butyloxycarbonylmethyl ester

According to general procedure AE and using N-(3,4-dichlorophenyl)alanine (from Example AB above) and tert-butyl bromoacetate (Aldrich), the title compound was prepared as a solid. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.57 in 25% EtOAc/hexane). Purification was carried out by recrystallization from ethanol.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, 1H), 6.68 (d, 1H), 6.45 (dd, 1H), 4.55 (m, 2H), 4.20 (m, 2H), 1.55 (d, 3H) , 1.45 (s, 9H).

13C-nmr (CDCl3): ? = 173.9, 166.9, 146.5, 133.5, 131.3, 115.1, 113.6, 83.4, 62.2, 52.2, 28.6, 19.3.

C15H19Cl2NO4 (MW = 348.23); mass spectroscopy (MH+) 347.

Example A17

Synthesis of N-(3,4-dichlorophenyl)leucine iso-butyl ester

According to general procedure AA and using 3,4-dichloroaniline (Aldrich) and iso-butyl 4-methyl-2-oxopentanoate (prepared according to general procedure AO above using 4-methyl-2-oxovaleric acid (Fluka) and iso-butanol ), the titled compound was prepared in the form of an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.6 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.2 (d, 1H); 6.5 (d, 1H); 6.4 (dd, 1H); 4.30 (bs, 1H); 4.08 (q, 1H); 3.8 (m, 2H); 1.8 (m, 3H); 0.91 (m, 12H).

13C-nmr (CDCl3): � = 174.5; 146.7; 133.5; 131.3; 121.3; 114.9: 113.6; 72.0; 52; 28.3; 20.1; 19.5.

C16H23Cl2NO2 (MW = 332.27); mass spectroscopy (MH+) 333.

Example A18

Synthesis of 2-[N-(3,4-dichlorophenyl)amino]pentanoic acid iso-butyl ester

According to general procedure AA and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxopentanoate (prepared according to general procedure AO above using 2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared in the form oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.5 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.3 (d, 1H); 3.8 (m, 3H); 1.9 (m, 6H); 1.0 (t, 3H), 0.9 (m, 6H).

13C-nmr (CDCl3): � = 178; 144.7; 130.2; 120.62; 115.11; 71.82; 52.90; 28.30; 19.53.

C15H21Cl2NO2 (MW = 318.3); mass spectroscopy (MH+) 319.

Example A19

Synthesis of N-(4-cyanophenyl)alanine iso-butyl ester

Following the general procedure of AP and using 4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared as an oil. The product was isolated by silica gel column chromatography using 1:5 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.44 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 4.74 (d, J = 8.1 Hz, 1H), 4.18 (t, J = 7.4 Hz, 1H), 3.95 (m, 2H), 1.94 (m, 1H), 1.51 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.7 Hz, 6H).

13C-nmr (CDCl3): ? = 173.4, 149.7, 133.8, 120.1, 112.7, 99.8, 71.6, 51.2, 27.7, 18.9, 18.6.

C14H18N2O2 MW = 246.31; mass spectroscopy (MH+) 247.

Example A20

Synthesis of N-(3-chloro-4-cyanophenyl)alanine iso-butyl ester

According to the general procedure AP and using 2-chloro-4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from the above example AA), the title compound was prepared. The product was isolated by silica gel column chromatography using 1:5 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.40 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 6.48 (dd, J = 2.4, 8.6 Hz, 1H), 4.90 (d , J = 7.6 Hz, 1H), 4.16 (quintet, J = 7.1 Hz, 1H), 3.96 (dd, J = 2.2, 6.7 Hz, 2H), 1.97 (m, 1H), 1.51 (d, J = 7.0 Hz , 3H), 0.93 (d, J = 6.7 Hz, 6H).

13C-nmr (CDCl3): � = 173.0, 150.4, 138.3, 134.9, 117.3, 112.8, 111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18.4.

C14H17N2O2Cl MW = 280.76; mass spectroscopy (MH+) 281.

Example A21

Synthesis of N-(3,4-dichloro)alanine iso-butyl ester (S isomer)

According to the general procedure of AM and using 3,4-dichloroaniline (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.55 in 25% EtOAc/hexane). Purification was carried out by column chromatography.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, J = 8.73, 1H), 6.67 (d, J = 2.75, 1H), 6.45 (dd, J = 8.73, J = 2.75, 1H), 4.28 (bd, J = 8.36, 1H), 4.09 (quint, 1H), 3.94 (d, J = 6.66, 2H), 1.95 (hept, J = 6.71, 1H), 1.49 (d, J = 6.90, 3H), 0.92 (d , J = 6.04, 6H).

13C-nmr (CDCl3): δ = 174.57, 146.67, 133.47, 131.28, 121.29, 114.93. 113.63, 71.01, 52.43, 28.30, 19.55, 19.33.

C13H17Cl2NO2 (MW = 290.19); mass spectroscopy (MH+) 290.

Example A22

Synthesis of N-(3,4-dichloro)alanine tetrahydrofuran-3-yl-methyl ester

According to the general AB transesterification procedure described above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and tetrahydro-3-furanmethanol (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.33 in 25% EtOAc/hexane). Purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.18 (d, 1H, J = 8.7 Hz), 6.65 (d, 1H, J = 2.7 Hz), 6.42 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz), 4.30 (m, 1H), 4.09 (m, 3H), 3.78 (m, 3H), 3.53 (m, 1H), 2.56 (m, 1H), 1.94 (m, 1H), 1.58 (m, 1H), 1.46 (d, 3H, J = 6.9 Hz).

13C-nmr (CDCl3): � = 174.5, 146.6, 133.5, 131.3, 121.4, 114.9, 113.6, 70.86, 70.83, 68.2, 67.31, 67.29, 52.4, 38.7, 29.36, 29.33, 19.

C14H17C12NO3 (MW = 318.20); mass spectroscopy (MH+) 318.

Example A23

Synthesis of N-(3,5-dichlorophenyl)alanine n-propyl ester

According to general procedure AA above and using 3,5-dichloroaniline (Aldrich) and n-propyl pyruvate (which can be prepared according to general procedure AO above using n-propanol instead of iso-butanol), the title compound can be prepared.

Example A24

Synthesis of 2-[N-(3,4-dichlorophenyl)amino]butanoic acid iso-butyl ester

According to the general procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxobutanoate (prepared according to the general procedure AO above using 2-oxobutyric acid (Aldrich) and iso-butanol), the titled compound in oil form. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.3 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.3 (d, 1H); 3.8 (m, 3H); 1.9 (m, 3H); 1.0 (t, 3H); 0.9 (m, 6H).

13C-nmr (CDCl3): � = 178; 144.7; 130.2; 120.62; 115.1 l; 71.82; 52.90; 28.30; 20.5: 19.53.

C14H19Cl2NO2 (MW = 304.22); mass spectroscopy (MH+) 305.

Example A25

Synthesis of N-(4-chlorophenyl)alanine iso-butyl ester

According to general procedure AA above and using 4-chloroaniline (Aldrich) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.6 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.18 (d, 2H), 6.66 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H) , 0.91 (d, 6H).

13C-nmr (CDCl3): δ =174.5, 146.7, 133.5, 131.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

C13H18ClNO2 (MW = 255.75): mass spectroscopy (MH+) 256.

Example A26

Synthesis of N-(3,5-dichlorophenyl)alanine iso-butyl ester

According to general procedure AA above and using 3,5-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.18 (d, 2H), 6.66 (m, 1H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (m, 1H), 1.47 (d, 3H) , 0.91 (d, 6H).

13C-nmr (CDCl3): � = 175; 146.7; 133; 131; 121; 114.9: 112.6; 72.0: 52.4; 28.3; 19.5.

C13H17Cl2NO2 (MW = 290.2); mass spectroscopy (MH+) 291.

Example A27

Synthesis of N-(4-ethylphenyl)alanine methyl ester

A solution of 0.68 g (5 mmol) 4'-aminoacetophenone (Aldrich), 0.60 mL 90% methyl pyruvate (Aldrich) and 0.05 g (0.25 mmol) p-toluenesulfonic acid in ethanol was hydrogenated in the presence of catalytic amounts of 10% Pd/C at 30 to 15 psi hydrogen for 16 hours. The catalyst was removed by filtering the reaction mixture through Celite and the solvent was evaporated to give the crude product. The product was purified by column chromatography (silica gel using 1:9 EtOAc/hexane as eluent) to give the title compound.

The NMR data are as follows:

1H-nmr (CDCl3): � = 1.19 (t, J = 7.6 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H), 2.54 (q, J = 7.6 Hz, 2H), 3.74 (s, 3H ), 4.04 (bs, 1H), 4.13 (m, 1H), 6.57 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H).

13C-nmr (CDCl3): ? = 15.8, 18.0, 27.9, 52.17, 52.19, 113.5, 128.6, 134.1, 144.4, 175.3.

C12H17NO2 MW = 207.27; mass spectroscopy (MH+) 208.

Example A28

Synthesis of N-(4-(1-ethoxy)ethylphenyl)alanine methyl ester

Following the procedure of Example A27 above, the title compound was isolated by column chromatography as the second reaction product (silica gel using 1:9 EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 1.15 (t, J = 7.0 Hz, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1.47 (d, J = 6.1 Hz, 3H), 3.31 (q, J = 5.1 Hz, 2H), 3.74 (s, 3H), 4.14 (m, 2H), 4.29 (q, J = 6.4 Hz, 1H), 6.57 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H).

13C-nmr (CDCl3): ? = 15.4, 19.0, 23.9, 51.9, 52.2, 63.4, 77.3, 113.1, 127.3, 133.6, 145.8, 175.1.

C14H21NO3 MW = 251.33; mass spectroscopy (MH+) 251.

Example A29

Synthesis of N-(3,4-dichloro)alanine 2,2-dimethylpropyl ester (R,S isomers)

Following the general procedure for the transesterification of AQ described above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and neopentyl alcohol (Aldrich), the title compound was prepared. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.72 in 25% EtOAc/hexane). Purification was performed by flash chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (d, 1H, J = 8.7 Hz), 6.68 (d, 1H, J = 2.7 Hz), 6.45 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz), 4.29 (m, 1H), 4.11 (m, 1H), 3.85 (m, 2H), 1.49 (d, 3H, J = 6.9 Hz), 0.93 (s, 9H).

13C-nmr (CDCl3): ? = 174.6, 146.7, 133.5, 131.3, 121.3, 114.9, 113.7, 75.2, 52.4, 32.0, 26.9, 19.4.

C14H19Cl2NO2 (MW = 304.22); mass spectroscopy (MH+) 303.

Example A30

Synthesis of N-(3,4-dichlorophenyl)glycine iso-butyl ester

3,4-Dichloroaniline (Aldrich) was treated with di-tert-butyl dicarbonate (Aldrich) using conventional procedures to give N-BOC aniline. NBOC aniline was treated with sodium hydride in THF and then with iso-butyl 2-bromoacetate (from Example AD above) to give N-BOC N-(3,4dichlorophenyl)glycine iso-butyl ester. The BOC group was then removed using the general procedure AN above to give the title compound. The course of the reaction

was followed by thin layer chromatography on silica gel (Rf = 0.78 in 50% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 50% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.19 (dd, J = 4.1, 4.7, 3.4, 1H); 6.65 (d, J = 2.7, 1H); 6.44 (dd, J = 2.7, 4.5, 4.2, 1H); 4.4 (m, 1H); 3.97 (dd, J = 3.6, 3.0, 2.3, 2H); 3.87 (s, 2H); 1.9 (m, 1H); 0.93 (d, J = 6.7, 6H).

13C-nmr (CDCl3): ? = 171.2, 147.0, 133.5, 131.3, 121.2, 114.5, 113.3, 72.2, 46.0, 28.2, 19.6.

C12H15Cl2NO2 (MW = 276); mass spectroscopy (MH+) 277.

Example A31

Synthesis of N-(3,4-dichlorophenyl)alanine 2-ethylbutyl ester

According to the general procedure AA above and using 3,4-dichloroaniline (Aldrich) and 2-ethylbutyl pyruvate (prepared according to the general procedure AO above using 2-ethylbutanol (Aldrich) instead of iso-butanol), the title compound was prepared in the form oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.6 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.2 (t, 2H); 4.1 (q, 1H); 1.5 (d, 3H); 1.4 (m, 4H); 1.0 (m, 6H).

13C-nmr (CDCl3): � = 178; 144.7; 130.2; 120.62; 115.11; 70.7; 51.90; 26.3; 19.53, 18.5.

C15H21Cl2NO2 (MW = 318.25); mass spectroscopy (MH+) 319.

Example A32

Synthesis of N-(3-chloro-4-iodophenyl)alanine iso-butyl ester

According to the general AR procedure above and using 3-chloro-4-iodaniline (Aldrich), N-BOC-3-chloro-4-iodaniline was prepared. With stirring, 1.0 equivalent of N-BOC- was added to a slurry of 5.0 equivalents of sodium hydride in DMF.

of 3-chloro-4-iodaniline and then 1.1 equivalent of iso-butyl 2-bromopropionate (from Example AD above) was slowly added. The reaction mixture was heated to 100°C for 10 hours, cooled, diluted with dichloromethane and washed with cold 1N HCl, water and brine. The solvents were removed under reduced pressure and the residue was chromatographed to give N-BOC-N-(3-chloro-4iodophenyl)alanine iso-butyl ester as a clear oil. According to the general procedure AN above, the BOC group was removed from N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester to give the title compound. The course of the BOC removal reaction was monitored by silica gel thin layer chromatography (Rf = 0.58 in 30% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 30% EtOAc/hexane as eluent). The compound was further purified by chromatography on an HPLC chiral column (Chiralcel OD).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.52 (d, J = 8.7, 1H); 6.72 (d, J = 2.7, 1H); 6.25 (dd, J = 2.7, 5.9, 2.7, 1H); 4.35 (d, J = 6.6, 1H); 4.08 (quintex, J = 7.2, 6.7, 1H); 3.93 (d, J = 6.7, 2H); 1.94 (m, 1H); 1.47 (d, J = 6.9, 3H); 0.92 (d, J = 6.9, 6H).

13C-nmr (CDCl3): ? = 174.5, 148.3, 140.7, 139.5, 114.4, 114.3, 82.6, 72.0, 52.2, 28.3, 19.6, 19.3.

C13H17ClINO2 (MW = 381.5); mass spectroscopy (MH+) 382.

Example A33

Synthesis of N-(4-azidophenyl)alanine iso-butyl ester

According to general procedure AA above and using 4-azidoaniline (Aldrich) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.3 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.3 (d, 2H), 6.8 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H) , 0.91 (d, 6H).

13C-nmr (CDCl3): ? = 174.5, 148.7, 131.5, 130.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

C13H18N4O2 (MW = 262.31); mass spectroscopy (MH+) 263.

Example A34

Synthesis of N-[(4-phenylcarbonyl)phenyl)alanine iso-butyl ester

According to general procedure AA above and using 4'-aminobenzophenone (Aldrich) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in 25% EtOAc/hexane) and purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.7 (d, 2H), 7.1 (m, 5H), 6.9 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H) , 1.47 (d, 3H), 0.91 (d, 6H).

13C-nmr (CDCl3): � = 199, 178.5, 149.7, 131.5, 130.3, 126, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

C20H23NO3 (MW = 325.41); mass spectroscopy (MH+) 326.

Example A35

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

Following the general procedure AH above and using N-(3,5-difluorophenyl)alanine (from Example AC above) and iso-butanol, the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.9 in 3% methanol/methylene chloride) and purification was performed by preparative plate chromatography (silica gel using 3% methanol/methylene chloride as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 6.1 (m, 3H), 4.5 (bs, 1H), 4.1 (d, 1H), 3.95 (m, 2H), 2.0 (m, 1H), 1.5 (d, J = 7 Hz, 3H), 0.95 (d, J = 6 Hz, 6H).

13C-nmr (CDCl3): δ = 174.44, 166.40, 166.19, 163.16, 162.95, 149.43, 96.73, 96.60, 96.48, 96.35. 94.06, 93.72, 93.37, 72.03, 32.30, 28.29, 19.47, 19.23.

C13H17F2NO2 (MW = 290.2); mass spectroscopy (MH+) 291.

Example A36

Synthesis of N-(3,4-dichlorophenyl)alanine O-acylacetamidoxime ester

According to the general procedure AK above and using N-(3,4-dichlorophenyl)alanine (from Example AB above) and acetamide oxime (prepared according to the procedure described in J. Org. Chem., 46, 3953 (1981 )), the titled compound was prepared in the form of a semi-solid. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in ethyl acetate) and purification was performed by preparative plate chromatography (silica gel using ethyl acetate as eluent).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 7.27 (d, 1H), 6.81 (s, 1H), 6.4 (broad s, 2H), 6.62 (d, 1H), 6.45 (d, 1H), 4.22 (m , 1H), 1.74 (s, 3H), 1.40 (d, 3H).

C11H13Cl2N2O2 (MW = 290.15); mass spectroscopy (MH+) 291.

Example A37

Synthesis of N-(3,4-dichlorophenyl)alanine pyrrolyl amide

Following the general procedure AL above and using N-(3,4-dichlorophenyl)alanine (from Example AB above) and pyrrole (Aldrich), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.28 in 10% ethyl acetate/hexane) and purification was performed by preparative plate chromatography (silica gel using 10% ethyl acetate/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): δ = 7.36 (d, J = 2.2, 2H); 7.20 (d, J = 8.7, 1H); 6.71 (d, J = 2.7, 1H); 6.5 (m, 1H); 6.38 (t, J = 2.4, 2H); 4.8 (m, 1H); 4.57 (d, J = 8.7, 1H); 159 (d, J = 6.8, 3H).

13C-nmr (CDCl3): ? = 171.9, 146.1, 133.6, 131.5, 121.9, 119.6, 115.4, 114.7, 113.8, 51.8, 20.2.

C13H21Cl2N2O (MW = 283); mass spectroscopy (MH+) 284.

Example A38

Synthesis of N-(3,4-dichlorophenyl)alanine O-acylbutiramidoxime ester

According to the general procedure AI above and using N-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared from N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9) using an identical procedure described in Example AE above) and butyramide oxime (prepared according to procedures described in J. Org Chem., 46, 3953 (1981)), the title compound was prepared as a semi-solid. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.25 in 50% ethyl acetate/hexane) and purification was performed by preparative plate chromatography (silica gel using 50% ethyl acetate/hexane as eluent).

The NMR data are as follows:

1H-nmr (d6-DMSO): � = 7.27 (d, 1H), 6.83 (s, 1H), 6.38 (broad s, 2H), 6.61 (d, 1H), 6.46 (d, 1H), 4.25 (m , 1H), 2.02 (t, 2H), 1.55 (m, 2H), 1.40 (d, 3H), 0.88 (t, 3H).

C13H17Cl2N3O2 (MW = 318.20); mass spectroscopy (MH+) 319.

Example A39

Synthesis of 2-[N-(naphth-2-yl)amino]butanoic acid ethyl ester

According to the general procedure of AJ above and using 2-aminonaphthalene (Aldrich) and ethyl 2-bromobutyrate (Aldrich), the title compound was prepared as a solid, m.p. 81-83°C. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.5 in CHCl3). Purification was performed by chromatography (silica gel using chloroform as eluent).

The NMR data are as follows:

1H-nmr (d6-DMSO): � = 7.63 (m, 2H), 7.54 (d, 1H), 7.31 (t, 1H), 7.12 (t, 1H), 7.03 (d, 1H), 6.62 (s, 1H), 6.32 (d, 1H), 4.15 (m, 3H), 1.42 (d, 3H), 1.19 (t, 3H).

C16H19NO2 (MW = 257.34); mass spectroscopy (MH+) 258.

Example A40

Synthesis of N-(2-naphthyl)alanine iso-butyl ester

According to general procedure AA above and using 2-aminonaphthalene (Aldrich) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared as an oil. Purification was performed by preparative plate chromatography (silica gel using 25% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.65 (m, 3H), 7.38 (t, 1H, J = 6.9 Hz), 7.23 (t, 1H, J = 6.9 Hz), 6.93 (m, 1H), 6.81 (d , 1H, J = 2.3 Hz), 4.31 (q, 1H, J = 6.9 Hz), 3.95 J = 6.7 Hz, J = 1.6 Hz), 1.96 (sept, 1H, J = 6.7 Hz), 1.57 (d, 3H , J = 6.9 Hz), 0.93 (dd, 6H, J = 6.7 Hz, J = 1.6 Hz).

13C-nmr (CDCl3): � = 174.6, 144.2, 134.9, 129.1, 127.8, 127.6, 126.3, 126.0, 122.3, 118.1, 105.3, 71.2, 52.0, 27.7, 18.9, 18.8.

Example A41

Synthesis of N-(2-methylquinolin-6-yl)alanine iso-butyl ester

According to general procedure AA above and using 6-amino-2-methylquinoline (Lancaster) and iso-butyl pyruvate (prepared according to general procedure AO above), the title compound was prepared. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.44 in 50% EtOAc/hexane). Purification was performed by flash chromatography (silica gel using 50% EtOAc/hexane as eluent).

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.90 (m, 2H), 7.10 (m, 2H), 6.66 (d, 1H, J = 2.6), 4.50 (bd, 1H), 4.24 (m, 1H), 3.91 ( d, 2H, J = 6.6 Hz), 2.64 (s, 3H), 1.91 (sept, 1H, J = 6.7 Hz), 1.52 (d, 3H, J = 6.9 Hz), 0.87 (d, 6H, J = 6.7 Hz).

13C-nmr (CDCl3): � = 173.0, 155.4, 144.6, 143.4, 134.9, 130.2, 128.4, 122.8, 121.8, 104.9, 7l.8, 32.7, 28.3, 23.4, 19.3, 19.4.

C17H22Cl2N2O2 (MW = 286.38); mass spectroscopy (MH+) 287.

Example A42

Synthesis of N-(3,1-methylenedioxyphenyl)alanine iso-butyl ester

N-(3,4-methylenedioxyphenyl)alanine methyl ester was prepared according to the general, above-mentioned reductive amination procedure of AA and using 3,4-methylenedioxyaniline (Aldrich) and methyl pyruvate (Aldrich). The methyl ester was then transesterified according to the general AQ procedure above using isobutanol to give the title compound as an oil. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.61 in 25% EtOAc/hexane). Purification was performed by preparative chromatography on a silica gel plate using 25% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 6.63 (d, 1H, 8.3 Hz), 6.25 (d, 1H, J = 2.3 Hz), 6.04 (dd, 1H, J = 8.3 Hz, J = 2.3 Hz), 5.83 ( s, 2H), 3.96 (m, 4H), 1.92 (sept, 1H, J = 6.7 Hz), 1.44 (d, 3H, J = 6.9 Hz), 0.90 (d, 6H, J = 6.6 Hz).

13C-nmr (CDCl3): � = 175.4, 148.9, 142.9, 140.8, 109.2, 105.8, 101.2, 97.4, 71.6, 53.6, 28.3, 19.6, 19.5.

C14H19NO4 (MW = 265.31); mass spectroscopy (MH+) 265.

Example A43

Synthesis of N-(3,4-ethylenedioxyphenyl)alanine iso-butyl ester

N-(3,4-ethylenedioxyphenyl)alanine methyl ester was prepared according to the general, above-mentioned reductive amination procedure of AA and using 1,4-benzodioxa-6-amine (Aldrich) and methyl pyruvate (Aldrich). The methyl ester was then transesterified according to the general AQ procedure above using iso-butanol to give the title compound. Purification was performed by preparative plate chromatography.

The NMR data are as follows:

1H-nmr (CDCl3): � = 0.91 (d, J = 7 Hz, 6H), 1.42 (d, J = 7 Hz, 3H), 1.82.0 (m, 1H), 3.8-3.95 (m, 3H) , 4.0-4.1 (m, 1H), 4.15-4.25 (m, 4H), 6.12-6.2 (m, 2H), 6.65-6.75 (m, 1H).

13C-nmr (CDCl3): � = 19.55, 19.56, 19.67, 28.3, 53.4, 64.7, 65.3, 71.7, 103.1, 108.0, 118.3, 142.1, 144.6, 175.4.

C15H21NO4 (MW = 279.34); mass spectroscopy (MH+) 280.

Example A44

Synthesis of N-(2-naphthyl)alanine methyl ester

Following the general procedure for reductive amination of AA described above and using 2-aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.50 in 25% EtOAc/hexane). Purification was performed by flash chromatography on silica gel using 25% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.65 (m, 3H), 7.48 (m, 1H), 7.25 (m, 1H), 6.91 (m, 1H), 6.79 (m, 1H), 4.31 (m, 2H) , 3.76 (s, 3H), 1.55 (d, 3H).

13C-nmr (CDCl3): � = 175.66, 144.78, 135.55, 129.78, 128.47, 128.22, 126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45.

C14H15NO2 (MW = 229.28); mass spectroscopy (MH+) 229.

Example A45

Synthesis of N-(benzothiazol-6-yl)alanine ethyl ester

To a solution of 6-aminobenzothiazole (Lancaster) in dichloromethane was added 1.1 equivalents of pyridine, followed by 1.5 equivalents of trifluoroacetic anhydride. The reaction mixture was stirred at room temperature for 3 hours and then washed with 5% citric acid, dried over MgSO 4 and desolvated on a rotary evaporator to give 6-trifluoroacetamidothiazole. This material was dissolved in THF and then added to a suspension of KH in THF at 0°C. A catalytic amount of 18-crown-6 was added, followed by ethyl 2-bromopropionate (Aldrich). The reaction mixture was kept at room temperature for 1 hour and then heated under reflux for 24 hours and cooled to room temperature. The reaction mixture was freed from the solvent on a rotary evaporator and the obtained residues were dissolved in ether. This solution was washed with water, saturated aqueous NaCl solution, and dried over MgSO4. The solution was desolvated on a rotary evaporator and the title compound was obtained by chromatography of the residue using 5% methanol/dichloromethane (Rf = 0.59) as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 8.69 (s, 1H), 7.90 (d, 1H, J = 8.8 Hz), 7.04 (d, 1H, J = 2.3 Hz), 6.84 (dd, 1H, J = 8.8 Hz , J = 2.4 Hz), 4.41 (bd, 1H, J = 7.5 Hz), 4.20 (m, 3H), 1.53 (d, 3H, J = 6.9 Hz), 1.27 (t, 3H, J = 7.1 Hz).

13C-nmr (CDCl3): � = 174.9, 150.2, 147.1, 145.6, 136.3, 124.6, 115.7, 103.5, 61.9, 52.9, 19.4, 14.8.

C12H14N2O2S (MW = 250.32); mass spectroscopy (MH+) 251.

Example A46

Synthesis of N-(indol-5-yl)alanine iso-butyl ester (S isomer)

According to the general procedure of AM and using 5-aminoindole (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.46 in 33% EtOAc/hexane). Purification was performed by preparative chromatography on a silica gel plate using 33% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 8.11 (bs, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H ), 6.61 (m, 1H), 6.32 (m, 1H), 4.18 (q, J = 6.9 Hz, 1H), 3.95 (bs, 1H), 3.87 (d, J = 6.7 Hz, 2H), 1.89 (hept , J = 6.7 Hz, 1H), 1.48 (d, J = 6.96 Hz, 3H), 0.86 (dd, J = 6.7 Hz, J = 1.6 Hz, 6H).

13C-nmr (CDCl3): � = 176.15, 141.06, 131.28, 129.24, 125.34, 113.34, 112.53, 104.21, 102.17, 71.65, 54.28, 28.36, 19.87, 19.62.

C15H20N2O2 (MW = 260.34); mass spectroscopy (MH+) 261.

Example A47

Synthesis of N-(naphth-2-yl)alanine O-acylacetamidoxime ester

According to the general procedure AI above and using N-(naphth-2-yl)alanine 2,4,6-trichlorophenyl ester (from Example AE above) and acetamide oxime (prepared according to the procedure described in J. Org. Chem ., 46, 3953 (1981)), the title compound was prepared as a semi-solid. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.4 in ethyl acetate) and purification was performed by preparative plate chromatography (silica gel using ethyl acetate as eluent).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 7.64 (t, 2H), 7.54 (d, 1H), 7.32 (t, 1H), 7.13 (t, 1H), 7.04 (d, 1H), 6.78 (s, 1H), 6.42 (broad s, 2H), 6.32 (d, 1H), 4.33 (m, 1H), 1.72 (s, 3H), 1.46 (d, 3H).

C14H17N3O2 (MW = 271.32); mass spectroscopy: 271.

Example A48

Synthesis of N-(2-naphthyl)alanine ethyl ester

According to the general procedure for the reductive amination of AA described above and using 2-aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as a solid with a melting point of 52-56°C. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.50 in 25% EtOAc/hexane). Purification was performed by flash chromatography on silica gel using 25% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.65 (m, 3H), 7.48 (m, 1H), 7.25 (m, 1H), 6.91 (m, 1H), 6.79 (m, 1H), 4.31 (m, 2H) , 3.76 (s, 3H), 1.55 (d, 3H).

13C-nmr (CDCl3): � = 175.66, 144.78, 135.55, 129.78, 128.47, 128.22, 126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45.

C14H15NO2 (MW = 229.28); mass spectroscopy (MH+) 229.

Example A49

Synthesis of N-(3,4-dichlorophenyl)alanine O-acylpropionamidoxime ester

According to the general procedure AI above and using N-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared from N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9) using an identical procedure described in Example AE above) and propionamide oxime (prepared according to procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as a semi-solid. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.2 in 50% ethyl acetate/hexane) and purification was performed by preparative plate chromatography (silica gel using 50% ethyl acetate/hexane as eluent).

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 7.27 (d, 1H), 6.83 (s, 1H), 6.64 (d, 1H), 6.47 (d, 1H), 6.38 (broad s, 2H), 4.24 (m , 1H), 2.07 (q, 2H), 1.41 (d, 3H).

C12H15Cl2N3O2 (MW = 304.17); mass spectroscopy (MH+) 305.

Example A50

Synthesis of N-(4-ethoxycarbonylphenyl)alanine iso-butyl ester (S isomer)

According to the general AM procedure above and using ethyl 4-aminobenzoate (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.21 in 10% EtOAc/hexane). Purification was performed by preparative plate chromatography using 25% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.82 (d, J = 8.73 Hz, 2H), 6.51 (d, J = 8.79 Hz, 2H), 4.81 (d, J = 7.82 Hz, 1H), 4.25 (q, J = 7.14 Hz, 2H), 4.15 (quint, J = 7.40 Hz, 1H), 3.87 (m, 2H), 1.87 (sept, J = 6.70 Hz, 1H), 1.43 (d, J = 6.95 Hz, 3H), 1.30 (t, J = 7.14 Hz, 3H), 0.84 (d, J = 6.71 Hz, 6H).

13C-nmr (CDCl3): ? = 174.5, 167.3, 151.0, 132.0, 119.9, 112.5, 71.9, 60.8, 51.9, 28.2, 19.5, 19.2, 15.0.

C16H23NO4 (MW = 293.37); mass spectroscopy (MH+) 294.

Example A51

Synthesis of N-[3,5-di(trifluoromethyl)phenyl]alanine iso-butyl ester (S isomer)

According to the general AM procedure above and using 3,5-di(trifluoromethyl)aniline (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.38 in 10% EtOAc/hexane). Purification was performed by preparative plate chromatography using 10% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.13 (s, 1H), 6.91 (s, 2H), 4.97 (d, J = 8.24 Hz, 1H), 4.18 (m, 1H), 3.93 (d, J = 6.59 Hz , 2H), 1.93 (sept, J = 6.71 Hz, 1H), 1.49 (d, J = 7.02 Hz, 3H), 0.89 (d, J = 6.59 Hz, 6H).

13c-NMR (CDCL3): � = 174.4, 147.9, 133.6, 133.2, 132.7, 132.3, 129.4, 125.8, 122.2, 118.6, 112.81, 112.76, 111.42, 111.37, 111.27, 111.22, 72.2, 52.0, 32.1, 28.24 , 28.17, 23.2, 19.5, 19.3, 19.2, 18.9, 14.6.

C15H17F6NO2 (MW = 357.30); mass spectroscopy (MH+) 358.

Example A52

Synthesis of N-(3,5-dimethoxyphenyl)alanine iso-butyl ester

N-(3,5-dimethoxyphenyl)alanine (crude, 454 mg) (prepared according to the procedure described in U.S. Patent No. 3,598,859 using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich)) was treated in dry iso-butanol (10 mL) with 0.1 mL chlorotrimethylsilane and the reaction mixture was refluxed overnight. Excess alcohol was removed under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO 3 , dried with Na 2 SO 4 , and the solvent was removed to give the title compound. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.3 in 20% EtOAc/hexane). Purification was performed by preparative thin layer chromatography using 20% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����0.9 (d, J = 7, 6H), 1.47 (d, J = 7, 3H), 1.9-2.0 (m, 1H), 3.7 (s, 6H), 3.85 -4.0 (m, 2H), 4.1-4.2 (m, 1H), 4.3 (brs, 1H), 5.8 (s, 2H), 5.9 (s, 1H).

13C-nmr (CDCl3): ����19.49, 19.52, 19.54, 28.3, 52.5, 55.6, 71.7, 91.1, 92.7, 149.2, 162.3, 175.2.

C15H23NO4 (MW = 281.35).

Example A53

Synthesis of N-(2-naphthyl)alanine O-acylpropionamidoxime ester

According to the general AS procedure above and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from the above example AE) and propionamide oxime (prepared according to the procedures described in J. Org Chem., 46, 3953 (1981)), the titled compound was prepared. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.5 in EtOAc). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): δ = 1.03 (t, 3H), 1.45 (d, 3H).

C16H19N3O2 (MW = 285.35); mass spectroscopy (M+) 285.

Example A54

Synthesis of N-(2-naphthyl)alanine O-acylbutiramidoxime ester

According to the general procedure of AS above and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE above) and butyramide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared in the form of an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.6 in EtOAc). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 0.86 (t, 3H), 1.46 (d, 3H).

C17H21N3O2 (MW = 299.37); mass spectroscopy (MH+) 299.

Example A55

Synthesis of N-(2-naphthyl)alanine O-acylisovaleramidoxime ester

According to the general procedure AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from the above-mentioned example AE) and isovaleramide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared in the form of an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.3 in 1:1 EtOAc/hexane). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 0.86 (t, 3H), 1.45 (d, 3H).

C18H23N3O2 (MW = 313.40); mass spectroscopy (MH+) 313.

Example A56

Synthesis of N-(2-naphthyl)alanine O-acylbenzamidoxime ester

According to the general procedure of AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE above) and benzamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981 )), the titled compound was prepared in the form of an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.3 in 1:1 EtOAc/hexane). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): δ = 4.42 (m, 1H), 1.53 (d, 3H).

C20H19N3O2 (MW = 333.39); mass spectroscopy (MH+) 333.

Example A57

Synthesis of N-(2-naphthyl)alanine O-acylcyclopropanecarboxamidoxime ester

According to the general procedure AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE above) and cyclopropanecarboxamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981 )), the titled compound was prepared in the form of an oil. The course of the reaction was monitored by thin layer chromatography on silica gel (Rf = 0.3 in 1:1 EtOAc/hexane). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): � = 0.85 (m, 4H), 1.43 (d, 3H).

C17H19N3O2 (MW = 297.36); mass spectroscopy (MH+) 297.

Example A58

Synthesis of N-(2-naphthyl)alanine O-acylcyclopropylacetamidoxime ester

According to the general procedure AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from the above-mentioned example AE) and cyclopropylacetamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared in the form of an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.3 in 1:1 EtOAc/hexane). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): δ = 1.43 (d, 3H), 1.91 (d, 2H).

C18H21N3O2 (MW = 311.39); mass spectroscopy (MH+) 311.

Example A59

Synthesis of N-(2-naphthyl)alanine O-acylcyclopentanecarboxamidoxime ester

According to the general procedure of AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE above) and cyclopentanecarboxamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981 )), the titled compound was prepared in the form of an oil. The course of the reaction was monitored by thin-layer chromatography on silica gel (Rf = 0.3 in 1:1 EtOAc/hexane). Purification was performed by chromatography on silica gel using 1:1 EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): δ = 1.43 (d, 3H), 2.43 (m, 1H).

C17H19N3O2 (MW = 297.36).

GENERAL PROCEDURE BA

Bonding of R1C(X')(X”)C(O)Cl with H2NCH(R2)C(O)XR3

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

GENERAL PROCEDURE BB

Bonding of R1C(X')(X”)C(O)OH with H2NCH(R2)C(O)XR3

A solution of the acid (3.3 mmol) and CDI in 20 mL of THF was stirred for 2 h. L-alanine iso-butyl ester hydrochloride (from Example BB 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 diethyl ether, washed with 10% HCl three times, brine once, once with 20% potassium carbonate solution and brine once. The solution was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the product. Other amino acid esters can also be used in this process.

GENERAL PROCEDURE BC

Esterification of R1C(X')(X”)C(O)NHCH(R2)C(O)OH with HOR3

With stirring, to a solution of phenylacetylvaline (1.6470 g, 7.0 mmol) in 20 mL of THF was added CDI (1.05 g, 6.5 mmol) and the mixture was stirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added to the mixture, followed by NaH (0.16 g, 6.5 mmol). There was instant bubble development. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL diethyl ether, washed with 10% HCl three times, brine once, once with 20% potassium carbonate solution and brine once. The solution was dried above

magnesium sulfate, filtered and evaporated under reduced pressure to give the product. Other N-acyl amino acids and alcohols can also be used in this process.

GENERAL PROCEDURE BD

Hydrolysis of esters to free acid

Hydrolysis of the ester into the free acid was carried out by the usual methods. Two examples of such common deesterification methods are given below.

2-5 equivalents of K2CO3 were added to the ester in a 1:1 CH2OH/H2O mixture. The mixture was heated at about 50°C for about 0.5 to 1.5 hours until thin layer chromatography indicated completion of the reaction. The reaction mixture was cooled to room temperature and methanol was removed under reduced pressure. The pH of the remaining aqueous solution was adjusted to 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was desolvated under reduced pressure to give the product.

The amino acid ester was dissolved in a mixture of dioxane/water (4:1) to which was added LiOH (~2 equiv.) which was dissolved in water so that the solvent after the addition was approximately 2:1 dioxane:water. The reaction mixture was stirred until the reaction was complete and dioxane was removed under reduced pressure. The residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was back extracted with EtOAc, the combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure after filtration. The residues were purified by usual methods (eg recrystallization).

The following examples illustrate the latter example. 3-NO2 phenylacetyl alanine methyl ester 9.27 g (0.0348 mol) was dissolved in 60 mL dioxane and 15 mL H2O and LiOH (3.06 g, 0.0731 mol) dissolved in mL H2O was added. After stirring for 4 h, dioxane was removed under reduced pressure and the residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was back extracted with EtOAc (4×100 mL), the combined organic layers were dried over Na2SO4, and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane to give 7.5 g (85%) of 3-nitrophenylacetyl alanine.

C11H12N2O5 requires C = 52.38; H = 4.80 and N = 11.11. The analysis found: C = 52.54; H = 4.85 and N = 11.08.

[�]23 = - 29.9 @ 589 nm.

GENERAL PROCEDURE BE

Low-temperature BOP acid-alcohol bonding

A methylene chloride solution containing carboxylic acid (100 M%) and N-methyl morpholine (150 M%) was cooled to -20°C under nitrogen. BOP (105 M%) was added in one portion and the reaction mixture was maintained at -20°C for 15 minutes. The appropriate alcohol (120 M%) was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (3×). The combined ethyl acetate portions were backwashed with saturated aqueous citric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over anhydrous magnesium sulfate or sodium sulfate, and the solvent was removed under reduced pressure. to obtain a raw product.

GENERAL PROCEDURE BF

EDC binding of acid and amine

The acid derivative was dissolved in methylene chloride. Amine (1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.1 eq.) were added sequentially. The reaction mixture was cooled to about 0°C and then 1.1 eq. was added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution was allowed to stir overnight at room temperature under N2 pressure. The reaction mixture was worked up by washing the solution with saturated aqueous Na2CO3, 0.1 M citric acid, and brine before drying with Na2SO4 and removing the solvent to give the crude product. Pure products were obtained by "flash" chromatography in the appropriate solvent.

GENERAL PROCEDURE BG

EDC binding of acid and amine

A round-bottomed flask was charged with carboxylic acid (1.0 equiv), hydroxy-benzotriazole hydrate (1.1 equiv), and amine (1.0 equiv) in THF under a nitrogen atmosphere. An appropriate amount of base (1.1 eq. for free amines and 2.2 eq. for hydrochloride amine salts), such as Hunig's base, was added with stirring, followed by EDC (1.1 eq.). After stirring for 4 to 17 hours at room temperature, the solvent was removed under reduced pressure, the residue was taken up with EtOAc (or similar solvent)/water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1N HCl solution, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product was analytically pure at this stage, while in others it was purified by chromatography and/or recrystallization prior to biological testing.

GENERAL PROCEDURE BH

Binding of R1C(X')(X”)C(O)Cl with H2NCH(R2)C(O)XR3

An excess of oxalyl chloride in dichloromethane was added to the acid derivative along with one drop of DMF. The resulting mixture was stirred for 2 hours or until the development of bubbles stopped. The solvent was then removed under reduced pressure and dilution with dry methylene chloride was carried out. About 1.1 equiv was added to the resulting solution. the corresponding amino acids and triethylamine (1.1 eq. in methylene chloride). The system was stirred at room temperature for 2 hours and the solvent was removed under reduced pressure. The residues were dissolved in ethyl acetate, washed with 1N HCl and then with 1N NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give the desired product.

GENERAL PROCEDURE BI

P-EPC binding

P-EPC binding uses an amino acid ester and a substituted acetic acid compound. An acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester was prepared by conventional methods using the well-known and commercially available NBOC amino acid as described in GENERAL PROCEDURE BJ below.

Specifically, the corresponding free base amino ester (0.0346 mmol) and substituted phenylacetic acid (0.069 mmol) were dissolved in 2.0 mL of CHCl3 (without EtOH), treated with 150 mg of P-EPC (0.87 meq./g ) and the reaction mixture was stirred for 4 days at 23°C. The reaction mixture was filtered through a cotton plug, washed with 2.0 mL of CHCl3 and the filtrate was evaporated under a stream of nitrogen. The purity of each sample was determined by 1H-NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of the final product was obtained in each reaction, which was tested without further purification.

GENERAL PROCEDURE BJ

Synthesis of amino acid esters from the corresponding N-BOC amino acid

A. Acid esterification.

The N-BOC amino acid was dissolved in dioxane and treated with excess alcohol (~ 1.5 eq.) and a catalytic amount of DMAP (100 mg) at 0°C. Stirring was continued until the end of the reaction, after which the product was collected by the usual methods.

B. Removal of the N-BOC group.

The N-BOC-protected amino acid was dissolved in methylene chloride (0.05 M) and treated with 10 equiv. TFA at room temperature under a nitrogen atmosphere.

The reaction is monitored by thin layer chromatography until the starting material is consumed, usually within 1-5 hours. An additional 10 equiv was added to the reaction mixture. TFA if starting material is present after 5 hours. The reaction mixture was carefully neutralized with Na2CO3, separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The crude amine was used without further purification.

Specific examples of these procedures are as follows:

Racemic (+/-)-N-BOC-�-aminobutyric acid (Aldrich) (9.29 g, 0.0457 mol) was dissolved in 100 mL of dioxane and treated with iso-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) and a catalytic amount of DMAP (100 mg) at 0°C. After stirring for 17 h, the organic portion was evaporated under reduced pressure, the residue was diluted with EtOAc and washed with NaHCO 3 , brine and dried over Na 2 SO 4 . Evaporation yields 8.42 g (71%) of oil.

C13H25NO4 requires: C = 60.21, H = 9.72 and N = 5.40. The analysis found: C = 59.91, H = 9.89 and N = 5.67.

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

L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in 100 mL CH2Cl2, iso-butyl alcohol (21.9 mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10, 0 g, 0.52 mol) at 0°C. The mixture was stirred for 17 h, diluted with H 2 O, washed with 1.0 N HCl, NaHCO 3 , then brine and the organic portion was dried over Na 2 SO 4 . Filtration and evaporation gave 11.8 g (quantitative) of L-N-BOC alanine iso-butyl ester which was contaminated with small amounts of solvent. The sample was dried under vacuum for analytical purposes.

C12H23NO4 requires: C = 58.79, H = 9.38 and N = 5.71. The analysis found: C = 58.73, H = 9.55 and N = 5.96.

The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was deprotected as above. The free base was converted to the corresponding HCl salt using saturated HCl (g)/EtOAc to give L-N-alanine iso-butyl ester hydrochloride. 4.2 g (48%) of a colorless solid was obtained.

C7H15NO2⋅HCl requires: C = 46.28, H = 8.88 and N = 7.71. Analysis found: C = 46.01, H = 8.85 and N = 7.68.

GENERAL PROCEDURE BK

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 passed through this solution for 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed under reduced pressure to give the methyl ester hydrochloride of the desired amino acid. The product was usually used without further purification.

Example BA

Synthesis of free and polymer bound PEPC

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

To a solution of 27.7 g (0.39 mol) of ethyl isocyanate in 250 mL of chloroform, 50 g (0.39 mol) of 3-(1-pyrrolidinyl)propylamine was added dropwise with cooling. When the addition was complete, 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 was added 62.6 g (0.62 mol) of triethylamine and the solution was cooled to 0°C. To this solution was then added 59.17 g (0.31 mol) of 4-toluenesulfonyl chloride in 400 mL of dichloromethane, dropwise, at such a rate as to maintain the temperature at 0-5 °C. After the addition was complete, the reaction mixture was warmed to room temperature and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated potassium carbonate solution (3×150 mL). The aqueous phase was combined and extracted with dichloromethane. All organic phases are combined and concentrated under reduced pressure. The obtained orange pulp was suspended in 250 mL of diethyl ether and the solution was decanted from the solid. The grinding/decanting procedure was repeated 3 more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as a crude orange oil. Part of the oil was distilled under vacuum to give a colorless oil distilling at 78-82 °C (0.4 mm Hg).

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

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

Example BB

Preparation of alanine iso-butyl ester hydrochloride

A mixture of 35.64 g (0.4 mol) (D,L)-alanine (Aldrich) (or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of isobutanol were 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 pure enough to be used for further reactions.

Example BC

Preparation of 3,5-dichlorophenylacetic acid

To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0°C was added 1.8 mL of methane sulfonyl chloride and then 3.5 mL of triethylamine was added dropwise. After 2 hours, the solution was diluted with 150 mL of dichloromethane, washed with 3N HCl, sat.

The crude sulfonate was dissolved in 50 mL of DMF at 0°C and then 3 g of KCN was added. After 2 hours, a further 50 mL of DMF was added and the solution was stirred for 16 hours. The red solution was diluted with 1 L of water and acidified to pH 3 with 3N HCl solution. The aqueous solution was extracted with dichloromethane. The combined organic layers were washed with 3N HCl, dried over Na2SO4 and the solvent was removed under reduced pressure to give crude 3,5-dichlorophenylacetonitrile which was used without further purification.

Nitrile was added to a mixture of 40 mL of concentrated sulfuric acid and 50 mL of water and heated under reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction mixture was diluted with 1 L of crushed ice, warmed to room temperature and extracted with 2×200 mL of dichloromethane and 2×200 mL of ethyl acetate. Both organic parts were combined and washed with saturated aqueous NaHCO3 solution. NaHCO3 fractions were combined and acidified to pH 1 with 3N HCl solution. The white solid was too fine to filter and was extracted with 2×200 mL dichloromethane. The combined organic portion was dried with Na 2 SO 4 and the solvents were removed under reduced pressure to give crude 3,5-dichlorophenylacetic acid as a white solid. The solid was triturated with hexane and filtered to give 1.75 g of a white solid.

NMR (CDCl3): (ppm) 3.61 (s, 2H), 7.19 (s, 1H), 7.30 (s, 1H)

Example BD

Synthesis of N-(3-chlorophenylacetyl)alanine

The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) according to general procedures BF or BG, followed by hydrolysis using general procedure BD.

Example B1

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

Following the general procedure BA above and using phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from example BB above), the title compound was prepared. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.23-7.36 (m, 5H), 6.18 (d, 1H), 4.58 (t, J = 7.3 Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H) , 1.90 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H).

13C-nmr (CDCl3): ? = 172.7, 170.3, 134.5, 129.2, 128.8, 127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3.

C15H21NO3 (MW = 263.34; mass spectroscopy (MH+ = 264))

Example B2

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

According to general procedure BA and using 3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from the above-mentioned example BB), the title compound was prepared as a solid with a melting point of 51-54°C. The reaction was monitored by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

NMR data are as follows: 1H-nmr (CDCl3): � = 7.25 (m, 2H), 7.19 (m, 3H), 6.28 (d, J = 7.2 Hz, 1H), 4.58 (quint., J = 7.2 Hz, 1H), 3.89 (m, 2H), 2.95 (t, J = 7.7 Hz, 2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.33 (d, J = 7.1 Hz, 3H), 0.91 ( d, J = 6.7 Hz, 6H).

13C-nmr (CDCl3): � = 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.

C16H23NO3 (MW = 277.37, mass spectroscopy (MH+ 278))

Example B3

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

Following the general procedure of BB and using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was followed by thin-layer chromatography on silica gel, purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 6.08 (d, J = 5.9 Hz, 1H), 4.62 (quint., J = 7.3 Hz, 1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84- 2.00 (m, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.35 (m, 1H), 1.20 (m, 1H), 0.85-0.96 (m, 12H).

13C-nmr (CDCl3): � = 173.3, 172.1, 71.4, 47.9, 43.9, 32.3, 29.38, 29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3.

C13H25NO3 (MW = 243.35, mass spectroscopy (MH+ 244))

Example B4

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

According to the general procedure of BB and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid with a melting point of 111-113°C. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.30 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.18 (d, J = 5.5 Hz, 1H), 4.57 (quint., J = 7.2 Hz, 1H), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6-H).

13C-nmr (CDCl3): ? = 172.8, 169.8, 133.1, 133.0, 130.6, 128.9, 71.4, 48.2, 42.6, 27.6, 18.85, 18.82, 18.4.

C15H20NO3Cl (MW = 297.78, mass spectroscopy (MH+ 298))

Example B5

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

Following the general procedure of BB and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid, mp 81-83°C. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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).

13C-nmr (CDCl3): � = 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.

C15H19NO3Cl2 (MW = 332.23, mass spectroscopy (MH+ 332))

Example B6

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

According to the general procedure of BB and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid, mp 102°-104°C. The reaction was followed by thin-layer chromatography on silica gel (Rf = 0.6 in 33% ethyl acetate/hexane) and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 0.90 (d, J = 6.7 Hz, 6H), 1.35 (d, J = 7.2 Hz, 3H), 1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s , 2H), 3.88 (m, 2H), 4.58 (m, 1H), 6.05 (bd, 1H), 7.16 (s, 4H).

13C-nmr (CDCl3): ? = 18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1, 71.3, 129.2, 129.6, 131.3, 136.9, 170.6, 172.8.

C16H23NO3 (MW = 277.37, mass spectroscopy (MH+ 278))

Example B7

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

According to the general procedure BF and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid, mp 62-64°C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.48 in 10% methanol/dichloromethane) and purification was carried out by chromatography on silica gel.

The NMR data are as follows:

1H-nmr (CDCl3): δ = 8.40 (d, J = 2.8, 2H); 7.6 (m, 1H): 7.16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, 1H); 3.8 (m, 2H); 3.48 (s, 2H); 1.8 (m, 1H); 1.30 (d, J = 7.2, 3H); 0.81 (d, J = 6.7, 6H).

13C-nmr (CDCl3): � = 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.

C14H20N2O3 (MW = 264, mass spectroscopy (MH+ 265))

Example B8

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

According to the general procedure of BB and using 1-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid, mp 69-73°C. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 0.83 (m, 6H), 1.25 (d, J = 7.1 Hz, 3H), 1.81 (m, 1H), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57 (quint., J = 7.3 Hz, 1H), 5.99 (d, J = 7.1 Hz, 1H), 7.44 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7.98 (m, 1H ).

13C-nmr (CDCl3): � = 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, 170.93, 173.93.

C19H23NO3 (MW = 313.40, mass spectroscopy (MH+ 314))

Example B9

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

According to the general procedure of BB and using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid, mp 128-129°C. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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 Hz, 1H), 6.13 (d, J = 7.1 Hz, 1H), 7.41 (m, 1H), 7.48 (m, 2 H), 7.74 (s, 1H), 7.83 (m, 3 H).

13C-nmr (CDCl3): � = 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, 17.8.3, 173.5.

C19H23NO3 (MW = 313.40, mass spectroscopy (MH+ 314))

Example B10

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

Following the general procedure of BB and using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 0.92 (d, J = 6.7 Hz, 6H), 1.38 (d, J = 7.1 Hz, 3H), 1.96 (m, 3H), 2.21 (t, J = 7.1 Hz, 2H ), 2.64 (t, J = 7.3 Hz, 2H), 3.90 (m, 2H), 4.59 (quint., J = 7.2 Hz, 1H), 6.31 (d, 1H), 7.16 (m, 3H), 7.24 ( m, 2H).

13C-nmr (CDCl3): � = 18.3, 18.75, 18.78, 26.8, 27.5, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0.

C17H25NO3 (MW = 291.39, mass spectroscopy (MH+ 292)).

Example B11

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

Following the general procedure of BB and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 4.59 (quint., J = 7.3 Hz, 1H), 3.91 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.93 (m, 1H), 1.66 (m, 4H), 1.38 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H).

13C-nmr (CDCl3): � = 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.

C18H27NO3 (MW= 305.39; mass spectroscopy (MH+ 306)).

Example B12

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

According to the general procedure BF and using 4-pyridylacetic acid hydrochloride (Aldrich) and (D,L)-alanine iso-butyl ester hydrochloride (from the above-mentioned example BB), the title compound was prepared as a solid, mp 64°-66°C . The reaction was followed by thin layer chromatography on silica gel (Rf = 0.43 in 10% methanol/dichloromethane) and purification was carried out by chromatography on silica gel.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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, 1H): 4.56 (quint., J = 7.3, 7.2, 1H); 3.88 (m, 2H); 3.53 (s, 2H); 1.89 (m, 1H); 1.36 (d, J = 7.2, 3H); 0.88 (d, J = 6.7, 6H).

13C-nmr (CDCl3): ? = 173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 19.5, 18.9.

C14H20N2O3 (MW = 264, mass spectroscopy (MH+ 264))

Example B13

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

According to the general procedure of BB and using phenylacetyl chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid with a melting point of 45-47°C. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by extraction with Et2O and then washing with aqueous K2CO3 and HCl solution.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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).

13C-nmr (CDCl3): � = 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.

C15H21NO3 (MW = 263.34, mass spectroscopy (MH+ 264)).

Example B14

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

According to general procedure BI and using 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to procedure BJ above) the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B15

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

According to general procedure BI and using 3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����6.75 (m, 4H), 5.93 (bd, 1H), 4.51 (m, 1H), 3.83 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82 (m, 2H), 1.60 (m, 1H), 0.84 (d, 6H), 0.74 (t, 3H).

C17H25NO4 (MW = 307.39; mass spectroscopy (MH+ 309)).

Example B16

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

According to general procedure BI above and using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C16H22N2O5 (MW = 322.36; mass spectroscopy (MH+ 323)).

Example B17

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

According to general procedure BI and using 3,4-(methylenedioxy)phenyl acetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B18

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

According to general procedure BI and using 3-thiophenacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B19

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

According to general procedure BI and using 4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B20

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

According to general procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B21

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

According to general procedure BI above and using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B22

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

According to general procedure BI above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C20H25NO3 (MW = 327.42; mass spectroscopy (MH+ 328)).

Example B23

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B24

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

According to general procedure BI and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.43 (d, 2H), 7.19 (d, 2H), 5.85 (m, 1H), 4.s1 (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).

C16H22NO3Br (MW = 356.26; mass spectroscopy (MH+ 358)).

Example B25

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

According to general procedure BI above and using 3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C16H22NO3Cl (MW = 311.81; mass spectroscopy (MH+ 313)).

Example B26

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

According to general procedure BI and using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.31 (m, 1H), 7.01 (m, 3H), 5.95 (m, 1H), 4.54 (m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H), 1.65 (m, 1H), 0.87 (d, 6H), 0.81 (t, 3H).

C16H22NO3F (MW = 295.35; mass spectroscopy (MH+ 296)).

Example B27

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

According to general procedure BI above and using 4-benzothiazol-4-yl acetic acid (Chemservice) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B28

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

According to general procedure BI above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H), 0.87 (d, 6H), 0.77 (t, 3H).

C17H25NO3 (MW = 291.39; mass spectroscopy (M+ 291)).

Example B29

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

According to general procedure BI above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The course of the reaction was followed by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 B30

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

According to general procedure BI above and using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.20 (m, 2H), 6.97 (m, 2H), 5.87 (m, 1H), 4.492 (m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m, 2H), 1.60 (m, 1H), 0.87 (d, 6H), 0.78 (t, 3H).

C16H22NO3F (MW = 295.35; mass spectroscopy (MH+ 296)).

Example B31

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

According to general procedure BI above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.45 (m, 2H), 7.23 (m, 2H), 5.95 (m, 1H), 4.55 (m, 1H), 3.84 (m, 2H), 3.55 (s, 2H), 1.89 (m, 2H), 1.68 (m, 1H), 0.91 (d, 6H), 0.81 (t, 3H).

C16H22NO3Br (MW = 356.26; mass spectroscopy (M+ 357)).

Example B32

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����7.52 (m, 1H), 7.47 (m, 2H), 6.01 (m, 1H), 4.56 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H), 0.87 (d, 6H), 0.80 (t, 3H).

C17H22NO3F3 (MW = 345.36; mass spectroscopy (MH+ 345)).

Example B33

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

According to general procedure BI above and using 2-thiophenacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C14H21NO3S (MW = 283.39; mass spectroscopy (MH+ 284)).

Example B34

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

According to the general procedure BH above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to the general procedure BJ above), the title compound was prepared. The course of the reaction was monitored by thin layer chromatography on silica gel and purification was carried out by chromatography on silica gel using 9:1 toluene:EtOAc as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C16H23NO3 (MW = 277.36; mass spectroscopy (MH+ 277)).

Example B35

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

Step A. Preparation of N-(phenylacetyl) valine

With stirring, 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich) was added dropwise to a solution of 5.13 g (44 mmol) of valine (Bachem) in 30 mL (100 mmol) of 2N NaOH cooled to 0°C. A colorless oil settled out. The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours, washed with 50 mL of diethyl ether, acidified to pH 2-3 with an aqueous HCl solution. The resulting white precipitate was filtered off, washed well with water, then with diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.

The NMR data are as follows:

1H-nmr (DMSO-d6): ����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 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 2.05 (m, 1H), 0.87 (d, J = 6.8, Hz, 3H), 0.84 (d, J = 6.8 Hz, 3 )

13C-nmr (DMSO-d6): ����173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0.

C13H17NO3 (MW=235.29; mass spectroscopy (MH+ = 236))

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

13C-nmr (CDCl3): ����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, 16.4, 17.4 11.12, 11.07.

C18H27NO3 (MW = 305.42; mass spectroscopy (MH 306)).

Example B36

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

L-methionine (0.129 g, 0.869 mmol) (Aldrich) was placed in dioxane (5.0 mL) and treated with saturated sodium bicarbonate solution (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmol). After stirring for 17 hours at room temperature, the mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was acidified to pH 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, dried in vacuo and used without further purification.

N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL of dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and a catalytic amount of DMAP (0.015 g). After stirring for 17 hours at 23°C, the mixture was evaporated under reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate solution. Chromatography on silica gel using 98:2 CHCl3/MeOH as eluent gave the pure product.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C17H25NO3S (MW = 323.17; mass spectroscopy (M+ 323)

Example B37

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

L-leucine (Aldrich) (0.114 g, 0.869 mmol) in dioxane (5.0 mL) was treated with saturated aqueous sodium bicarbonate (5.0 mL) and then with phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmol). After stirring for 17 hours at room temperature, the mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was acidified to pH 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, dried in vacuo and used without further purification.

N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL of CHCl3 (without EtOH) and iso-butyl alcohol (0.055 mL) and treated with PEPC (100 mg, 0.87 milliequivalents). was rotated for 4 days, filtered through a cotton plug and the filtrate evaporated under reduced pressure to give an oil that was pure enough for testing.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.22 (m, 3H), 5.57 (d, 1H), 4.35 (m, 1H), 3.33 (m, 3H), 1.35 (m, 4H), 0.68 (m, 9H).

C18H27NO3 (MW = 305.40; mass spectroscopy (M+ 305)).

Example B38

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

According to the general procedure BC above and using N-(3-chlorophenylacetyl alanine (from example BD above) and 3-methylbut-2-en-1-ol (Aldrich), the title compound was prepared. The course of the reaction was monitored by thin layer chromatography on silica gel and purification was performed by liquid chromatography using 30% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.39-7.16 (m, 4H), 6.06 (bd, 1H), 5.38-5.29 (m, 1H), 4.63 (d, J = 9 Hz, 2H), 3.56 ( s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J = 9 Hz, 3H).

Example B39

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

Following the general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from Example BD above) and cyclopropylmethanol (Aldrich), the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.2-7.1 (m, 4H), 6.09 (bs, 1H), 4.6 (dq, J = 9 Hz, 1H), 3.96 (dd, J = 9 Hz, 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 B40

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

According to the general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from example BD above) and 2-thiophene methanol (Aldrich) the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.37-6.97 (m, 7H), 5.97 (q, J = 14 Hz, 2H), 4.6 (dq, J = 9 Hz, 1H), 3.76 (s, 2H) , 1.38 (d, J = 9 Hz, 3H).

Example B41

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

Following general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from Example BD above) and (1-methylcyclopropyl)methanol (Aldrich) the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����8.6 (bd, J = 9 Hz, 1H), 3.86 (q, J = 14 Hz, 2H), 3.4 (s, 2H), 2.29 (q, J = 9 Hz , 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 B42

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

According to the general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from example BD above) and 3-thiophene methanol (Aldrich) the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����8.03 (bd, J = 9 Hz, 1H), 7.56-7.5 (m, 1H), 7.=17 (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 B43

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

Following general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from example BD above) and 2-methylcyclopentanol (Aldrich) the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.39-7.16 (m, 4H), 6.3 (bd, 1H), 4.79-4.7 (m, 1H), 4.6-4.25 (m, J = 9 Hz, 1H), 3.577 (s, 2H), 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J = 9 Hz, 3H), 1.2 (dt, J = 9 Hz, 1H), 0.979 (dd, J = 9 Hz, 2H)

C17H22NO3Cl (MW = 323.82, mass spectroscopy (MH+ 323).

Example B44

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

According to the general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from example BD above) and 2-methylprop-2-en-1-ol (Aldrich) the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.39-7.16 (m, 4H), 6.03 (bs, 1H), 4.77 (s, 2H), 4.74.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3H), 1.43 (d, J = 9 Hz, 3H)

C15H18NO3C1 (MW = 295.76, mass spectroscopy (MH+ 295)).

Example B45

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

Following the general procedure BC above and using N-(3-chlorophenyl)acetyl alanine (from Example BD above) and cyclohex-2-en-1-ol (Aldrich) the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����8.6 (bd, J = 9 Hz, 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)

C17H20NO3C1 (MW = 321.8; mass spectroscopy (MH+ 321.2)).

Example B46

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

According to general procedure BI above and using 5-(2-phenylbenzoxazol)-yl-acetic acid (CAS# 62143-69-5) and alanine iso-butyl ester (prepared according to general procedure BJ above), the titled compound.

The NMR data are as follows:

1H-nmr (CDCl3): ����8.24 (m, 3H), 7.68 (m, 1H), 7.51 (m, 5H), 6.04 (m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, 1H), 1.35 (d, 3H), 0.87 (d, 6H).

C22H24N2O4 (MW = 380, mass spectroscopy (MH+ 381)).

Example B47

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

According to general procedure BI above and using 3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C16H23NO3S (MW = 309, mass spectroscopy (MH+ 310)).

Example B48

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����7.36 (m, 1H), 6.34 (m, 1H), 6.21 (m, 1H), 4.36 (m, 1H), 3.91 (m, 2H), 3.61 (s, 2H), 1.92 (m, 1H), 1.38 (d, 3H), 0.89 (d, 6H).

C13H19NO4 (MW = 253, mass spectroscopy (MH+ 254)).

Example B49

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

According to general procedure BI above and using benzofuran-2-yl-acetic acid (Maybridge) and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C17H21NO4 (MW = 303, mass spectroscopy (MH+ 304)).

Example B50

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

According to general procedure BI above and using thianaphten-3-yl-acetic acid (Lancaster) and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C17H21NO3S (MW = 319, mass spectroscopy (MH+ 320)).

Example B51

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

According to general procedure BI above and using (5-chloro-2-thienyl)acetic acid (CAS# 13669-19-7) and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared . The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C13H18NO3SCl (MW = 303, mass spectroscopy (MH+ 303)).

Example B52

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

According to the general procedure BI above and using (3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanine iso-butyl ester (prepared according to the general procedure BJ above) was prepared titled compound. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����6.07 (s, 2H), 4.56 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.89 (d, 3H), 0.91 (d, 6H).

C13H20N2O4 (MW= 268, mass spectroscopy (MH+ 269)).

Example B53

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

According to general procedure BI above and using (2-phenylthiothienyl)acetic acid and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.21-7.11 (m, 6H), 6.92 (d, 1H), 4.56(m, 1H), 3.87 (m, 2H), 3.72 (s, 2H), 1.94 ( m, 1H), 1.38 (d, 3H), 0.89 (d, 6H).

C19H23NO3S2 (MW = 377, mass spectroscopy (MH+ 378)).

Example B54

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����7.59 (d, 1H), 7.33 (d, 1H), 7.16 (s, 1H), 7.03 (dd, 1H), 4.56 (m, 1H), 3.87 (s, 3H), 3.84 (m, 2H), 3.76 (s, 2H), 1.85 (m, 1H), 1.30 (d, 3H), 0.86 (d, 6H).

C18H23NO4S (MW = 349, mass spectroscopy (MH+ 350)).

Example B55

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C17H21N3O3S (MW = 347, mass spectroscopy (MH+ 348)).

Example B56

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

According to general procedure BI above and using (2-phenyloxazol-4-yl)acetic acid (CAS# 22086-89-1) and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared . The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

Example B57

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C16H23NO2 (MW = 277, mass spectroscopy (MH+ 278)).

Example B58

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C15H19NO3F2 (MW = 299, mass spectroscopy (MH+ 300)).

Example B59

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����6.81 (m, 2H), 6.74 (m, 1H), 6.06 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, 1H), 1.36 (d, 3H), 0.87 (d, 6H).

C15H19NO3F2 (MW = 299, mass spectroscopy (MH+ 300)).

Example B60

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

According to general procedure BI above and using 3-thiophenacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to general procedure BJ above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data are as follows:

1H-nmr (CDCl3): ����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: [a]23 -52 (c 1 MeOH) @ 589 nm.

C13H19NO3S (MW = 269, mass spectroscopy (MH+ 269)).

Example B61

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����7.11 (s, 4H), 5.93 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89 (m, 1H), 1.32 (d, 3H), 0.89 (d, 6H).

C16H23NO3 (MW = 277.35; mass spectroscopy (MH+ 278)).

Example B62

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

According to the general procedure of BK and using (S)-(+)-2-hydroxy-2-methylbutyric acid (Aldrich) instead of amino acid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was prepared.

Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled with carbobenzyloxy-L-alanine (Aldrich) using the general BE procedure to give carbobenzyloxy-L-alanine S-1-(methoxycarbonyl)iso-butyl ester.

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

L-alanine S-1-(methoxycarbonyl) iso-butyl ester hydrochloride was then coupled to phenylacetic acid using the general procedure of BG to give the title compound.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

13C-nmr (CDCl3): ����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 B63

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

Following the general procedure BH above and using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from example BB above), the title compound was prepared. The reaction was followed by thin-layer chromatography on silica gel and purification was carried out by recrystallization from butyl chloride.

The NMR data are as follows:

1H-nmr (CDCl3): ����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, 3H).

Optical rotation: [�]23 -49 (c 5, MeOH).

Example B64

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

According to the general procedure of BG and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid, mp 93-95°C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.8 in EtOAC) and purification was carried out by chromatography on silica gel using EtOAc as eluent and then by recrystallization from 1-chlorobutane.

The NMR data are as follows:

1H-nmr (DMSO-d6): ����1.30 (d, 3H); 3.52 (s, 2H).

C13H15NO3F2 (MW = 271.26, mass spectroscopy (MH+ 271)).

Example B65

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

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

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

Optical rotation: [�]23 -30 (c 3, MeOH).

Example B66

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

According to the general procedure BG above and using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to the general procedure BJ above), the title compound was prepared. The reaction was monitored by thin-layer chromatography on silica gel.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

Optical rotation: [�]23 -45 (c 5, MeOH).

C15H20NO3Cl (MW = 297.78; mass spectroscopy (MH+ 297)).

Example B67

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

Following the general procedure BC above and using N-(3-chlorophenylacetyl)alanine (from Example BD above) and 2-(N,N-dimethylamino)ethanol (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was performed by liquid chromatography using 0.1:2:0.79 NH4OH:EtOH:CHCl3 as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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).

C15H21N2O3Cl (MW = 313.799; mass spectroscopy (M+ 313)).

Example B68

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

Following the general procedure BF above and using 3,5-dichlorophenylacetic acid (from example BC above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid, mp 77-78°C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.70 in 40% EtOAC/hexane) and purification was performed by flash chromatography on silica gel using 40% EtOAc/hexane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.20 (s), 7.18 (s), 6.6 (m), 4.55 (m), 3.7 (s), 3.5 (s), 3.4 (s), 2.0 (s) , 1.8 (m), 1.6 (m), 1.2 (m), 0.8 (t).

13C-nmr (CDCl3): ����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

Example B69

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

According to the general procedure BF above and using 3,5-dichlorophenylacetic acid (in addition to the above-mentioned example BC) and L-alanine iso-butyl ester hydrochloride (from the above-mentioned example BB), the title compound was prepared as a solid with a melting point of 115- 116°C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.40 in 3% methanol/dichloromethane) and purification was performed by "flash" chromatography on silica gel using 3% methanol/dichloromethane as eluent.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.27 (d, J = 2 Hz, 1H), 7.19 (s, 2H), 6.22 (d, J = 6 Hz, 1H), 4.59 (quint., J = 7 Hz, 1H), 3.9 (q, J = 4 Hz, 2H), 3.5 (s, 2H), 1.9 (m, 1H), 1.4 (d, J = 7 Hz, 3H), 0.91 (d, J = 7 Hz, 6H).

13C-nmr (CDCl3): ����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.

C15H19NO3Cl2 (MW = 331.9; mass spectroscopy (MH+ 332)).

Example B70

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

Following the general procedure of BB above and using cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid, mp 92-93°C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.39 in 1:3 EtOAc:hexane) and purification was carried out by extraction with Et2O followed by washing with aqueous K2CO3 and aqueous HCl.

The NMR data are as follows:

1H-nmr (CDCl3): ����0.93 (d, J = 6.7 Hz, 6H), 0.85-1.01 (m, 2H), 1.051.35 (m, 3H), 1.40 (d, J = 7.1 Hz, 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 ).

13C-nmr (CDCl3): ����18.7, 18.9, 26.0, 26.1, 27.6, 33.0, 35.3, 44.6, 47.9, 71.4, 171.8, 173.3.

C15H27NO3 (MW = 269.39, mass spectroscopy (MH+ 270)).

Example B71

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

Following the general procedure of BB above and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid, mp 62-64°C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.37 in 1:3 EtOAc:hexane) and purification was carried out by extraction with Et2O followed by washing with aqueous K2CO3 and aqueous HCl.

The NMR data are as follows:

1H-nmr (CDCl3): ����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 Hz, 1H ).

13C-nmr (CDCl3): ����18.4, 18.78, 18.80, 24.8 (very high), 27.5, 32.27, 32.32, 36.9, 42.5, 47.7, 71.2, 172.2, 173.2.

Elemental analysis - calculated (%): C, 65.85; H, 9.87; N, 5.49; Found (%): C, 66.01; H, 10.08; N, 5.49.

C14H25NO3 (MW = 255.36; mass spectroscopy (MH+ 256)).

Example B72

Synthesis of N-[(cyclohex-1-enyl)acetyl)-L-alanine iso-butyl ester

According to the general procedure BB above and using cyclohex-1-enyl acetic acid (Alfa) and L-alanine iso-butyl ester hydrochloride (from the above example BB), the title compound was prepared as a solid with a melting point of 49-51°C . The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.40 in 1:3 EtOAc:hexane) and purification was carried out by extraction with Et2O followed by washing with aqueous K2CO3 and aqueous HCl.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

13C-nmr (CDCl3): ����18.7, 18.91, 18.93, 21.9, 22.7, 25.3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1.

Elemental analysis - calculated (%): C, 67.38; H, 9.42; N, 5.24. Found (%): C, 67.34; H, 9.54; N, 5.16.

C15H25NO3 (MW = 267.37; mass spectroscopy (MH+ 268)).

Example B73

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

According to the general procedure BC above and using N-[(3-chlorophenyl)acetyl] alanine and 3-methyl-2-butene thioester (TCI), the title compound was prepared. The reaction was monitored by silica gel thin layer chromatography and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): ����5.2-5.075 (m, 1H), 4.37 (dq, J = 9 Hz, 1H), 3.56 (s), 3.43 (d, J = 12 Hz, 2H) , 1.266 (d, J = 12 Hz, 6H), 1.3 (d, J = 9 Hz, 3H).

C16H20NO2ClS (MW = 325.86; mass spectroscopy (M+ 325)).

Example B74

Synthesis of N-[(2-phenyl)-2-fluoroacetyl]alanine ethyl ester

According to the general BF procedure above and using �-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.75 in 1:1 EtOAc:hexane) and purification was performed by chromatography on silica gel using 1:2 ethyl acetate/hexane as eluent.

The NMR data are as follows:

1H-nmr (DMSO-d6): ����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).

C13H16NO3F (MW = 253.27; mass spectroscopy (MH+ 253)).

Example B75

Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine methyl ester

According to the general procedure BF above and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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, 3H ), 3.57 (s, 2H).

13C-nmr (CDCl3): ����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, 57.5, 3.4, 3.4, 4.3, 453

C17H15NO3F2 (MW = 319.31; mass spectroscopy (MH+ 320)).

Example B76

Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine iso-butyl ester

3,6-Difluorophenylacetic acid (Aldrich) was EDC-coupled to L-phenylglycine methyl ester hydrochloride (Bachem) by the above general procedure BF.

The resulting compound was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the course of the reaction was followed by thin-layer chromatography until the presence of the starting substance was no longer observed. The reaction was stopped by the addition of several milliliters of 1N HCl, and after a few minutes of mixing, a saturated aqueous solution of NaHCO3 was added. The volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residues were collected with ethyl acetate and water was added. The organic phase was washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was freed from the solvent on a rotary evaporator and the crude product residues were then further chromatographically purified.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

13C-nmr (CDCl3): ����171.3, 169.3, 165.4, 138.5, 137.0, 129.5, 129.2, 127.6, 113.1, 113.0, 1 12.8, 112.7, 103.8, 103.5, 103.2, 75.3, 4, 5.3, 5.4 28.2, 19.3

C20H21NO3F2 (MW = 361.39; mass spectroscopy (MH+ 362)).

Example B77

Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methyl ester

According to the general procedure of BD above and using cyclopentylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem) the title compound was prepared.

The NMR data are as follows:

1H-nmr (CDCl3): � = 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)

13C-nmr (CDCl3): ����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 B78

Synthesis of N-(cyclopentylacetyl)-L-alanine methyl ester

Following the general procedure of BD above and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) the title compound was prepared.

The NMR data are as follows:

1H-nmr (CDCl3): ����6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H).

13C-nmr (CDCl3): ����173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 18.0.

C11H19NO3 (MW = 213.28; mass spectroscopy (MH+ 214)).

Example B79

Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methyl ester

According to the general procedure of BD above and using cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR data are as follows:

1H-nmr (CDCl3): ����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)

13C-nmr (CDCl3): ����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 B80

Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester

Following the general procedure of BD above and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.

The NMR data are as follows:

1H-nmr (CDCl3): ����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)

13C-nmr (CDCl3): ����173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7, 4.27, 4.22.

Example B81

Synthesis of N-[(3-nitrophenyl)acetyl]-L-methionine iso-butyl ester

Following the general BH procedure above and using nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich), the title compound was prepared as a brown oil. The reaction was monitored by thin-layer chromatography on silica gel.

The NMR data are as follows:

1H-nmr (CDCl3): ����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).

C17H24N2O5S (MW = 368.4; mass spectroscopy (MH+ 368)).

The following general procedures and examples illustrate the synthesis of various lactams and related compounds that can be used to prepare, for example, the compounds of formulas VII and VIII above.

GENERAL PROCEDURE III-A

The first EDC-bonding procedure

1.5 equivalents of triethylamine, then 2.0 equivalents of hydroxybenzotriazole monohydrate and 1.25 equivalents of ethyl-3-(3-dimethylamino)propyl were added to a 1:1 mixture of the appropriate carboxylic acid and the appropriate amino acid ester or amide in CH2Cl2 at 0°C. carbodiimide⋅HCl. The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO3, 1N HCl and saturated aqueous NaCl, and dried over MgSO4. The resulting solution was desolvated on a rotary evaporator to give the crude product.

GENERAL PROCEDURE III-B

Another EDC bonding procedure

A mixture of the appropriate acid (1 equiv), N-1-hydroxybenzotriazole (1.6 equiv), the appropriate amine (1 equiv), N-methylmorpholine (3 equiv) and dichloromethane (or DMF for insoluble substrates) was cooled in ice-cold bath and stirred until a clear solution was obtained. EDC (1.3 eq.) was added to the reaction mixture. The cooling bath was allowed to warm to ambient temperature for 1-2 h and the reaction mixture was stirred overnight. The reaction mixture was then evaporated to dryness under vacuum. A 20% aqueous solution of potassium carbonate was added to the residue and the mixture was vigorously shaken and allowed to stand until the oily product solidified (overnight, if necessary). The solid product was then collected by filtration, washed well with 20% aqueous potassium carbonate solution, water, 10% HCl solution, and water to give the product, usually sufficiently pure. No racemization was observed.

GENERAL PROCEDURE III-C

The third procedure of EDC binding

Carboxylic acid is dissolved in methylene chloride. The appropriate amino acid or amide (1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.1 eq.) were added sequentially. The round bottom flask was placed in a cooling bath until the temperature was lowered to 0°C. Then 1.1 equiv was added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution was allowed to stir overnight and reach room temperature under nitrogen pressure. The reaction mixture was refined by washing the organic phase with saturated aqueous sodium carbonate solution, 0.1 M aqueous citric acid solution, and brine before drying with sodium sulfate. The solvents were removed to give the crude product.

GENERAL PROCEDURE III-D

The fourth procedure of EDC bonding

A round bottom flask was charged with the appropriate carboxylic acid (1.0 equiv), hydroxybenzotriazole hydrate (1.1 equiv) and the appropriate amine (1.0 equiv) in THF under a nitrogen atmosphere. An appropriate amount (1.1 eq. for free amines and 2.2 eq. for amine hydrochloride salts) of Hunig's base was added to the mixture, with good mixing, followed by EDC (1.1 eq.). After stirring for 4 to 17 hours at room temperature under reduced pressure, the solvent was removed, the residues were collected with ethyl acetate (or a similar solvent) and water, washed with saturated aqueous sodium bicarbonate solution, 1N HCl solution, brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the product.

GENERAL PROCEDURE III-E

BOP bonding procedure

BOP (2.4 mmol) and N-methylmorpholine (6 mmol) were added to a stirred solution of N-(3,5-difluorophenylacetyl)alanine (2 mmol) in DMF cooled in an ice-cold bath. The reaction mixture was stirred for 50 min. and then a solution of �-amino-γ-lactam (2 mmol) in DMF cooled to 0°C was added. The cooling bath was allowed to warm to ambient temperature for 1-2 h and the reaction mixture was stirred overnight. A 20% aqueous solution of potassium carbonate (60 mL) was added and the reaction mixture was shaken vigorously. No solid was formed. The mixture was then washed with ethyl acetate (150 mL) and evaporated to dryness to give a white solid. Then water (50 mL) was added and the mixture was shaken well. A precipitate formed which was collected by filtration, then washed well with water and 1 mL of diethyl ether to give the product (51 mg, 0.16 mmol, 7.8%).

GENERAL PROCEDURE III-F

Binding of an acid chloride with an amino acid ester

With stirring, 4.6 mmol of acid chloride was added to a solution of (D,L)-alanine isobutyl ester hydrochloride (4.6 mmol) in 5 ml of pyridine. There was a momentary settling. The mixture was stirred for 3.6 h, dissolved in 100 mL of diethyl ether, washed with 10% HCl solution three times, brine once, once with 20% potassium carbonate solution and brine once. The solution was dried over magnesium sulfate, filtered and evaporated to give the product. Esters of other amino acids can also be used in this process.

GENERAL PROCEDURE III-G

Bonding of a carboxylic acid to an amino acid ester

A solution of carboxylic acid (3.3 mmol) and 1,1'-carbodiimidazole (CDI) in 20 mL of THF was stirred for 2 h. (D,L)-alanine isobutyl ester hydrochloride (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 dissolved in 100 mL diethyl ether, washed with 10% HCl three times, brine once, once with 20% potassium carbonate solution and brine once. The solution was dried over magnesium sulfate, filtered and evaporated to give the product. Esters of other amino acids can also be used in this process.

GENERAL PROCEDURE III-H

The fifth procedure of EDC bonding

To a round bottom flask was added carboxylic acid (1.1 eq.) in THF, amine hydrochloride (1.0 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.), N,N-diisopropylethylamine (2.1 eq. .), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.1 eq.). The reaction mixture was stirred at room temperature for 10-20 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc and washed with 0.1 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), H2O (1×10 mL), and brine and dried over MgSO4. The drying agent was removed by filtration and the filtrate was concentrated in vacuo. The residues were purified by "flash" chromatography on a silica-gel column, and extracted from EtOAc and hexane.

GENERAL PROCEDURE III-I

The sixth procedure of EDC bonding

To a solution or suspension of amine or amine hydrochloride (1.0 eq.) in THF (0.05-0.1 M) under N2 at 0°C was added carboxylic acid (1.0-1.1 eq.), hydroxybenzotriazole monohydrate (1.1-1.15 equiv.), Hunig's base (1.1 equiv. for free amines and 1.1-2.3 equiv. for amine hydrochloride salts), then 1-(3dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.1-1.15 eq.). The cooling bath was removed and the mixture was allowed to warm to room temperature for 10-24 hours. The solution or mixture was diluted with EtOAc in 3-5 volumes which are multiples of the initial volume of THF, and washed with 0.1-1.0 M aqueous HCl (1 or 2×), diluted NaHCO3 (1 or 2×), and saline solution (1×). Then the organic phase was dried over MgSO4 or Na2SO4, filtered, concentrated to give the crude product, which was either further purified or used without further purification.

GENERAL PROCEDURE III-J

EEDO binding procedure

To a solution of the amine in THF (1.0 equiv, 0.05-0.08 M, final molarity) under N2 at room temperature was added the N-t-Boc protected amino acid (1.1 equiv, either as a solid or in THF by cannula), then EEDQ (Aldrich. 1.1 eq.). The pale yellow solution was stirred at room temperature for 16-16.5 hours, then diluted with EtOAc (in 3-5 multiples of the initial THF volume), and washed with 1 M aqueous HCl (2×), diluted aqueous NaHCO3 (2×); and saline solution (1×). The organic phase was dried over either Na2SO4 or MgSO4, filtered and concentrated.

Example 2-A

Synthesis of 5-amino-5,7-dihydro-6H-dibenzo(a,c)cyclohepten-6-ol hydrochloride

Stage A - Synthesis of 5-oximo-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one

A round bottom flask was charged with 5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one (1.0 g, 4.81 mmol) (CAS# 1139-82-8), prepared as described in Tetrahedron Letters, Vol. 28, No. 23. (1987), pp 2633-2636) and butyl nitrite (0.673 ml, 5.77 mmol) (Aldrich) in Et2O. The solution was cooled to 0°C and treated by dropwise addition of a saturated solution of HCl(g)/Et2O. After 5 h at 0 °C the resulting precipitate was filtered, washed with cold Et 2 O and dried in vacuo to afford the title compound as a colorless solid.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.26-7.74 (m, 8H), 3.84 (m, 2H).

C15H11NO2 (MW = 237.26); mass spectroscopy (MH+) 238.

Analysis - calculated for C15H11NO2: C, 75.93 H, 4.67 N, 5.90. Found: C, 75.67 H, 4.83 N, 5.67.

Stage B- Synthesis of 5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol hydrochloride

The compound isolated above (0.489 g, 2.04 mmol) was dissolved in THF and added dropwise to a well-stirred mixture of LAH (10.2 mL, 10.2 mmol)/THF. After heating under reflux for 25 hours under a nitrogen atmosphere, the reaction was stopped and the mixture was refined by the Fieser method. The resulting solid was washed with NH3-sat./CHCl3, the filtrate was evaporated and the title compound was purified by chromatography (SiO2, CHCl3).

C15H15NO (MW = 225.290); mass spectroscopy (MH+) 226.

Analysis – calculated for C15H15NO: C, 79.97 H, 6.71 N, 6.22. Found: C, 80.19 H, 6.71 N, 5.91.

GENERAL PROCEDURE 5-A

N-alkylation with lactams

97% NaH (1.08 g, 45 mmol) was added portionwise to a solution of BOC-protected �-aminocaprolactam (6.87 g, 30 mmol) in DMF (150 mL) with stirring. There was immediate bubbling and heavy settling. After 10 minutes, benzyl bromide (3.93 mL, 33 mmol) was added. The precipitate was quickly dissolved and after 10 minutes a clear solution was obtained. The reaction mixture was stirred overnight and then evaporated as best as possible on a rotary evaporator at 30°C. Ethyl acetate (100 mL) was added to the residue and the mixture was washed with water, brine and dried over magnesium sulfate. After filtration and concentration, a thick liquid (10 g) was obtained which was chromatographed on silica gel with 1:3 ethyl acetate/hexane as eluent to give 5.51 g (58%) of the N-benzylated product as an oil. Other lactams and alkylating agents can be used in this process to obtain a whole range of N-alkylated lactams. Different bases can also be used, such as LiN(SiMe3).

GENERAL PROCEDURE 5-B

BOC removal procedure

The BOC-protected compound in a 1:1-2:1 mixture of CH 2 Cl 2 and trifluoroacetic acid was stirred until TLC showed completion of the transition, typically 2 hours. The solution was then evaporated to dryness and the residue was taken up with ethyl acetate or CH 2 Cl 2 . The solution was washed with saturated aqueous NaHCO 3 and the aqueous phase was then adjusted to basic pH, extracted with ethyl acetate or CH 2 Cl 2 . The organic phase was washed with saturated aqueous NaCl solution and dried over MgSO4. The solution was desolvated on a rotary evaporator to give the product.

GENERAL PROCEDURE 5-C

Synthesis of �-Aminolactams

The Schmidt reaction was carried out in 4-ethylcyclohexanone using hydroxyamine sulfonic acid as described in Olah, Org. Synth. Collective, Vol. VII, page 254, to obtain 5-ethylcaprolactam with a yield of 76%. Using the procedure described in Watthey, et al., J. Med. Chem., 1985, 28, 1511-1516, this lactam was then dichlorinated with PCl5 in the alpha position and reduced by hydrogenation to give four isomeric monochlorides (two racemic mixtures). The two racemic mixtures were separated from each other by column chromatography using silica gel and each racemic mixture was reacted with sodium azide to give the corresponding azide which was hydrogenated to give the corresponding �-aminolactams. Other cycloalkanones can be used in this process to obtain a whole series of �-aminolactams.

In some cases, such as the preparation of 9-membered rings with �-aminolactams, longer reaction times, higher reaction temperatures, and excess sodium azide may prove necessary. For example, the 9-membered ring of �-aminolactam requires 5 equivalents of sodium azide, a reaction temperature of 120 °C and a reaction time of 4 days. Such conditions can be easily determined by someone who knows this area.

GENERAL PROCEDURE 5-D

Synthesis of 4-amino-1,2,3,4-tetrahydroisoquinolin-3-one

The 4-amino-1,2,3,4-tetrahydroisoquinolin-3-one derivatives used in the present invention can be prepared by the following methods known in the art. The conditions for these reactions are described in detail in D. Ben-Ishai, et al., Tetrahedron, 43, 439-450 (1987). These procedures prepared the following intermediates:

3-amino-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

cis and trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

9-amino(fluoren-1-yl)glycine �-lactam-1,2,3,4-tetrahydroisoquinolin-3-one.

Step A - Preparation of N-bismethoxycarbonylaminoacetic acid: Two molar equivalents of methyl carbamate and 0.1 molar equivalent of naphthalene sulfonic acid were added to one molar equivalent of glyoxylic acid in 2 liters of ethanol-free chloroform. The reaction mixture was then refluxed for 6 hours. Water was removed using an inverse Dean-Stark trap. The reaction mixture was cooled and the product was filtered and washed with chloroform. The white solid was recrystallized from ethyl acetate/hexane to give a white powder in 65% yield.

Stage B – binding procedure: One molar equivalent of EDC·HCl, benzylamine, HOBT and diisopropylethylamine was added to 0.0291 mol of N-bismethoxycarbonylaminoacetic acid (or corresponding carboxylic acid) in 200 mL of THF. The reaction mixture was stirred at room temperature for 18 hours and then placed in a separatory funnel and extracted with ethyl acetate. The ethyl acetate solution was washed with 1 molar solution of K 2 CO 3 and then with 1 molar solution of HCl. The organic layer was dried over Na 2 SO 4 , filtered and the solvent was removed to give crystalline N bismethoxycarbonylaminoacetic acid benzylamide. This substance was used without further purification. A typical yield is in the range of 40-55%.

Step C – cyclization procedure: Benzylamide of N-bismethoxycarbonylaminoacetic acid (0.008 mol) was dissolved in 75 mL of methanesulfonic acid and allowed to stir overnight at room temperature. The reaction mixture was placed on ice and extracted into ethyl acetate. The ethyl acetate extract was washed with 1 molar K2CO3 solution and then with 1N HCl solution. The organic layer was dried over Na2SO4, filtered and the solvent removed to give crystalline 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinolin-3-one in 50-90% yield. This substance was used without further purification.

Step D - Removal of the methoxyoxycarbonyl group (MOC): To 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinolin-3-one (3.4 mmol) in 30 mL of acetonitrile was added 2 molar equivalents of trimethylsilyl iodide (TMSI). The reaction mixture was heated at 50-80°C for 3 hours, cooled and placed in a separatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 solution and then with 5% NaHSO3 solution. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinolin-3-one derivative. Typical yield was in the range of 50-87%.

Step E – Alternative procedure for removal of the methoxycarbonyl group: To 3.8 mmol of the MOC-protected compound was added 10 mL of 30% HBr in acetic acid and the reaction mixture was heated at 60°C for 3 hours. The mixture was then cooled and hexane was added. The hexane layer was decanted and the residue was placed under reduced pressure to give a brown solid. The solid was triturated in ether and filtered to give the hydrobromide salt of 4-amino-1,2,3,4-tetrahydroisoquinolin-3-one. Typical yield is in the range of 57-88%.

Example 5-A

Synthesis of 3-amino-1,2,3,4-tetrahydroquinolin-2-one

Step A: Sodium (0.30 g, 110M%) was added to anhydrous ethanol (45 mL) and the reaction mixture was stirred until homogeneous. Diethyl N-acetylaminomalonate (2.51 g, 100M%) was added in one portion and the reaction mixture was stirred for 1 hour. 2-Nitrobenzyl bromide (2.5 g, 100M%) was added in one portion and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×) and back-extracted with water (3×) and brine (1×). Treatment with MgSO4, evaporation on a rotary evaporator and chromatography (30% EtOAc/hexane) gave diethyl N-acetylamino-2-nitrobenzylmalonate in 82% yield.

Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (1 g, 100M%) was dissolved in a minimal amount of EtOH. Pd/C (10%, 0.05 g) was added and the reaction mixture was exposed to 50 psi of hydrogen for 3 hours. The reaction mixture was then filtered through a plug of Celite. EtOH (25 mL) and TsOH (catalytic amount, 0.01 g) were added and the mixture was refluxed for 2 hours. The reaction mixture was evaporated on a rotary evaporator and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined ethyl acetate extracts were washed with water (3×) and brine (1×). Treatment with MgSO4 and evaporation on a rotary evaporator gave pure 3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89% yield).

Step C: 3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (0.75 g, 100M%) was suspended in 6N HCl (25 mL) and the mixture was heated at 100°C for 3 hours. The reaction mixture was cooled, evaporated on a rotary evaporator to a residue which was partitioned between water and ethyl acetate. Water was extracted with ethyl acetate (3×) and the combined ethyl acetate extracts were washed with water (3×) and brine (1×). Treatment with MgSO4 followed by evaporation on a rotary evaporator gives 3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72% yield).

Example 5-B

Synthesis of 4-amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150 mol) in 300 mL of dry ether was added dropwise 1.1 equiv. phenylmagnesium bromide (Aldrich). The reaction mixture was refluxed for 2 hours and then stirred overnight at room temperature. Sodium borohydride (1.0 eq.) was added dropwise as a solution in 200 mL of methanol (CAUTION – very exothermic). The reaction mixture was then heated under reflux for 6 hours, cooled and the reaction was stopped by the addition of saturated ammonium chloride solution. The solution was decanted from the salt in the reaction mixture and acidified with 1N HCl. After washing the aqueous layer with ethyl acetate, the pH of the aqueous layer was adjusted to about 9.0 with 1N sodium hydroxide (cold). The aqueous layer was then extracted with ethyl acetate and the organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give 4-pyridyl-�-benzyl amine as a thick yellow oil.

Step B: According to the general procedure of 5-D and using 4-pyridyl-�-benzyl amine, the title compound was prepared.

Example 5-C

Synthesis of 4-amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: 2-pyridyl-�-benzyl amine was prepared by replacing 2-cyanopyridine (Aldrich) with 4-cyanopyridine in the procedure described in Example 5-B.

Step B: According to the general procedure of 5-D and using 4-pyridyl-�-benzyl amine, the title compound was prepared.

Example 5-D

Synthesis of 4-amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

Grade A: According to the procedure described in J. Med. Chem., 1982, 25, 1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-�-benzyl amine was prepared.

Step B: According to the general procedure of 5-D and using 3-pyridyl-�-benzyl amine, the title compound was prepared.

Example 5-E

Synthesis of 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a Farr flask containing 3-benzoylbenzoic acid (0.044 mol) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated H2SO4 was added 10 grams of 5% Pd/C. The mixture was hydrogenated in a Parr apparatus under hydrogen (45 psi) overnight. The reaction mixture was then filtered through Hyflo, eluting with ethyl acetate. The filtrate was dried over Na2SO4, filtered and concentrated to give an oil. The oil was slurried in hexane and the resulting white solid was collected by filtration to give 3-benzylbenzoic acid, which was used without further purification.

Stage B: 150 mL of CH2Cl2, one drop of DMF, 10 mL of oxalyl chloride were added to the product from stage A (0.0119 mol), and the mixture was stirred at room temperature for 3 hours. After cooling to 10°C, 30 mL was added

NH 4 OH (exothermic) and the mixture was stirred for 30 min. The reaction mixture was then concentrated and the obtained residues were diluted with ethyl acetate. The organic layer was washed with 1N NaOH, brine, dried over Na2SO4, and concentrated to give the 3-(benzyl)benzamide as a white solid, which was used without further purification.

Step C: To a solution of 3-(benzyl)benzamide (0.0094 mol) from step B in 70 mL of toluene was added 8 mL of Red-Al® (65+ wt.% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION – very exothermic). The reaction mixture was then heated to 60°C for 2 hours and placed on ice. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. The organic layer was extracted with 1N HCl and the aqueous layer was washed with ethyl acetate. The pH of the aqueous layer was adjusted to about 9.0 with 1N NaOH and the layer was extracted with ethyl acetate. The organic extracts were washed with water and brine and concentrated to give 3-(benzyl)benzyl amine.

Step D: Following the general procedure of 5-D and using 3-(benzyl)benzyl amine, the title compound was prepared.

Example 5-F

Synthesis of 4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mol) in 150 mL of THF cooled to 10°C, 1.5 equiv was added dropwise. LAH (1 M in THF). The reaction mixture went from a white slurry to a green homogeneous solution and then to a yellow homogeneous solution. The reaction was then quenched with 2.5 mL of 1N NaOH. The mixture was filtered through Hyflo and extracted with ethyl acetate. The organic layer was then washed with 1N HCl. The pH of the resulting aqueous layer was adjusted to about 9 with 1N NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine, then dried over Na 2 SO 4 , filtered and concentrated to give 4-(phenyl)benzyl amine as a white solid.

Step B: According to the general procedure of 5-D and using 4-(phenyl)benzyl amine, the title compound was prepared.

Example 5-G

Synthesis of cis- and trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: According to the general procedure of 3-D and using �-phenylbenzylamine (Aldrich), 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one was prepared.

Step B: To a solution of 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one (0.00158 mol) from step A in 20 mL of CH2Cl2 was added 2.0 equiv. of triethylamine and Boc anhydride (1.1 eq.). The reaction mixture was stirred overnight at room temperature and then concentrated. The residues were diluted with ethyl acetate and water. The pH of the aqueous layer was adjusted to 3.0 with sodium bisulfite and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by LC 2000, eluting with ethyl acetate/hexane (70:30) to give a white solid containing a 1:1 mixture of cis- and trans-4-(N-Boc-amino)-1-phenyl-1 ,2,3,4-tetrahydroisoquinolin-3-one isomers. The mixture was recrystallized from ethyl acetate to give the pure trans isomer and a cis-isomer-enriched mixture of cis and trans isomers. This mixture was recrystallized again from ethyl acetate/hexane (70:30) to give the pure cis isomer.

Step C: The cis isomer and trans isomer from step B were separately deprotected using general procedure 8-J to give cis-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one and trans- 4-amino-1-phenyl-1,2,3,4tetrahydroisoquinolin-3-one.

Example 5-H

Synthesis of 4-amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858 mol) in 300 mL of dry THF cooled to -78°C was added tert-butyllithium (2 eq) (1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at -78°C and then the reaction was stopped with 2 equiv. DMF (13.24 mL). The resulting mixture was stirred for 20 min. and then placed in a separatory funnel and extracted with CH2Cl2. The organic extracts were washed with water, dried over Na 2 SO 4 , filtered and concentrated to give a brown oil. This oil was purified by LC 2000 chromatography, eluting with ethyl acetate/hexane (5:95) to give 3-biphenylcarboxaldehyde.

Step B: To a solution of 3-biphenylcarboxaldehyde (0.011 eq.) in 30 mL methanol was added 10 eq. 7N NH3/MeOH and NaCNBH4 (2 equiv). A yellow gummy substance settled out of the solution. The solution was then heated to 60°C until the gum was dissolved and the solution stirred at room temperature overnight. The reaction mixture was then concentrated and the obtained residues were diluted with ice water and ethyl acetate. The organic layer was then washed with brine and extracted with 5N HCl. The pH of the aqueous layer was adjusted to 12 and the aqueous layer was extracted with cold ethyl acetate. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give 3-(phenyl)benzyl amine as an oil.

Step C: According to the general procedure of 5-D and using 3-(phenyl)benzyl amine, the title compound was prepared.

Example 5-I

Synthesis of 4-amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of benzoyl chloride (0.123 mol) (Aldrich) in 600 mL of CH2Cl2 was added dropwise 2.0 equiv. phenethylamine (Aldrich).

The reaction mixture was stirred at room temperature for 3 hours and then placed in a separatory funnel and extracted with CH2Cl2. The organic extracts were washed with water and 1N HCl, dried over Na2SO4, filtered and concentrated to give N-phenethyl benzamide.

Step B: Reduction of N-phenethyl benzamide using the procedure of Example 5-E, step C, gave N-benzyl-N-phenethylamine as an oil.

Step C: According to the general procedure of 5-D and using N-benzyl-N-phenethylamine, the title compound was prepared.

Example 5-J

Synthesis of 3-amino-1-methyl-2-indolinone monohydrochloride

Step A: (2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)carbamic acid methyl ester (CAS No. 110599-56-9) was prepared using the procedure described in Ben-Ishai, D.; Sataty, I.; Peled, N.; Goldshare, R. Tetrahedron, 1987, 43, 439-450. The starting substances for the synthesis were N-methylaniline (CAS# 100-61-8, Eastman Kodak Co.), glyoxylic acid (CAS# 29812-4, Aldrich) and methyl carbamate (CAS# 598-55-0, Aldrich) .

Step B: The product from step A (333.5 mg) in 31% HBr in AcOH (10 mL) was heated at 50-60°C for 2 hours. The resulting orange solution was concentrated to a thick orange oil which was dissolved in EtOAc (15 mL) and the product was extracted into 1M aqueous HCl (10 mL). The aqueous acid solution was neutralized with aqueous NaHCO3 solution and the product was extracted into CH2Cl2 (10×10 mL). HCl (gas) was passed through the combined CH2Cl2 extracts to give a purple solution. The solution was concentrated to give the title compound (262.8 mg) as a purple solid.

Example 5-K

Synthesis of 3-amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/tin complex

Step A - Synthesis of 4-phenyl-3,4-dihydrocarbostyryl

4-Phenyl-3,4-dihydrocarbostyryl (CAS# 4888-33-9) was prepared in two steps using the procedure described in Conley, R. T.; Button. W. N. J. Org. Chem. 1964, 29, 496-497. The starting substances for this synthesis were cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH2Cl2/EtOAc (4:1).

Step B - Synthesis of 1-methyl-4-phenyl-3,4-dihydrocarbostyryl

To a suspension of NaH (1.1 eq., 0.537 g of a 60% dispersion in mineral oil) in THF (50 mL) under N 2 at 0 °C was added the product from step A (1.0 eq., 2.50 g) in THF (50 mL) by cannula over 5 minutes. The resulting pale yellow mixture was stirred at 0°C for 10 min, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to warm slowly (the ice bath was removed) to ambient temperature with stirring for 15 hours. 1 M aqueous HCl (50 mL) and EtOAc (250 mL) were added and the phases were separated. The organic phase was washed with dilute NaHCO3 solution (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residues were purified by "flash" chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to give 1-methyl-4-phenyl-3,4-dihydrocarbostyryl.

Stage C - Synthesis of 3-azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyryl

According to general procedure 8-K, 3-azido-1-methyl-4-phenyl-3,4-trans dihydrocarbostyril was prepared as a white solid. The product was purified by flash chromatography eluting with CH2Cl2/hexane/EtOAc 15:15:1.

Selected 1H-NMR data for the title compound (CDCl3): ����4.46 (d, 1H, J = 10.57 Hz), 4.18 (d, 1H, J = 10.63 Hz).

Stage D - Synthesis of 3-amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/tin complex

To a mixture of SnCl2 (350.7 mg) in MeOH (7 mL) under N2 at 0 °C was added the product from step C (257.4 mg) in MeOH/THF (5 mL/5 mL) by cannula over 1 min. The cooling bath was removed and the solution was allowed to warm to ambient temperature for 8 hours (no starting material according to TLC). The solution was concentrated to a yellow foam, THF (10 mL) was added and the mixture was concentrated again without further purification.

Example 5-L

Synthesis of 3-amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyryl

Stage A - Synthesis of 3-amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyryl

3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyryl was prepared according to general procedure 8-F using 3-azido-1-methyl-4-phenyl-3,4-transdihydrocarbostyryl from Example 5-K , grade C. The product was purified by L.C. 2000 eluting with EtOAc/hexane (4:1) to give a white solid.

Selected 1H-NMR data for the title compound (CDCl3): ����4.03 (d, 1H, J = 12.8 Hz), 3.92 (d, 1H, J = 12.7 Hz).

Stage B - Synthesis of 3-(4-chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyryl

To a solution of the product from Step A (1 equiv, 239.6 mg) in CH2Cl2 (10 mL) under N2 at ambient temperature was added 4-chlorobenzaldehyde (1.05 equiv, 140 mg, Aldrich), Et3N (1.4 equiv ., 185 mL) and MgSO4 (3.6 eq., 411 mg). The resulting mixture was stirred at room temperature for 73 hours. The solids were removed by filtration through a plug of Celite, washing with CH 2 Cl 2 and the filtrate was concentrated to give 3-(4-chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyryl as a thick white foam.

Stage C - Synthesis of 3-amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyryl

To a solution of diisopropylamine (1.05 equiv, 0.132 mL) in THF (5 mL) under N2 at -78°C was added a solution of n-BuLi (1.05 equiv, 0.588 mL of a 1.6 M solution in hexane) to give the solution was stirred for 30 minutes. To this solution was added by cannula the product from step B (1.0 equiv, 336 mg) in THF (2 mL). The solution was allowed to warm to 0°C, then the reaction was quenched with 1 M aqueous HCl (3 mL) and allowed to warm to room temperature with stirring overnight. The product was extracted in water and washed with EtOAc (1×), then the aqueous acid solution was basified with 1 M K2CO3 solution and the product was extracted into EtOAc. The EtOAc extract was dried over Na 2 SO 4 , filtered and concentrated to give 3-amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyryl.

Selected 1H-NMR data for the title compound (CDCl3): ����4.31 (d, 1H, J = 6.6 Hz).

Example 5-M

Synthesis of 3-amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyryl/tin complex

Step A - Synthesis of 1-tert-butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril

1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyryl was prepared from the product of Example 5-K, Step A (CAS# 4888-33-9) by the Boc procedure for aryl amines described in Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta Chemica Scandinavica B 1986, 40, 743-750; using (Boc)2O (Aldrich) and catalytic DMAP (Aldrich) in acetonitrile. The product was purified by flash chromatography eluting with a CH2Cl2 gradient to CH2Cl2/EtOAc (19:1) and isolated as a pale yellow oil.

Stage B - Synthesis of 3-azido-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyryl

According to the general procedure 8-K using the product from step A, the title compound was prepared as a 12.4:1 mixture of trans/cis isomers which were separated by flash chromatography eluting with a mixture of hexane/Et2O (6:1 gradient to 4:1) in in the first column and with a mixture of hexane/EtOAc (12:1) in the second column. The pure trans isomer was used in step C.

Selected 1H-NMR data for the title compound (CDCl3): ����4.45 (d, 1H, J = 11.1 Hz), 4.24 (d, 1H, J = 11.2 Hz).

Stage C - Synthesis of 3-amino-1-tert butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyryl/tin complex

To a mixture of SnCl2 (450.6 mg) in MeOH (9 mL) under N2 at 0 °C, the product from part D (433.0 mg) in MeOH (15 mL) was added by cannula over 1 min. The cooling bath was removed and the solution was allowed to warm to ambient temperature for 17 hours. The solution was concentrated to a yellow amorphous solid and used without further purification.

Example 5-N

Synthesis of (S)-3-amino-1-benzyl-δ-valerolactam

Stage A - Synthesis of L-(+)-ornithine methyl ester hydrochloride

With stirring, anhydrous hydrogen chloride gas was passed through a suspension of L-(+)-ornithine hydrochloride (Aldrich) in methanol until the solution became saturated. The reaction mixture was sealed with a rubber stopper and stirring was continued overnight at room temperature. The solvent was then removed under reduced pressure and the residue was triturated with ether. The resulting solid was dried and dried under reduced pressure to give L-(+)-ornithine methyl ester hydrochloride as a white solid (yield 97%).

Stage B - Synthesis of (S)-3-amino-δ-valerolactam

Sodium beads in oil (2.0 eq) (Aldrich) were washed with hexane (2×) and methanol (2.3 mL mmol) was slowly added. The reaction mixture was stirred under nitrogen until the sodium dissolved and L-(+)-ornithine methyl ester hydrochloride (1 eq.) in methanol (2.3 mL/mmol) was added dropwise. The reaction mixture was stirred for 16 h and diluted with diethyl ether (5 mL/mmol) and filtered to remove solids. The solvent was removed under reduced pressure and the residue was heated at 70°C for 3 hours under reduced pressure. The residues were triturated with a dichloromethane/ether mixture. The solvent was decanted and the resulting residue dried under reduced pressure to give (S)-3-amino-δ-valerolactam (44% yield).

Step C - Synthesis of N-Boc-(S)-3-amino-δ-valerolactam

(S)-3-amino-δ-valerolactam (1 eq.) was dissolved in dioxane and the solution was cooled to 0°C. BOC-anhydride (1.3 eq) was added and the ice bath was removed to allow the solution to reach ambient temperature and stirring was continued for 16 h. The solution was evaporated on a rotary evaporator to give N-Boc-(S)-3-amino-δ-valerolactam.

Step D - Synthesis of (S)-3-amino-1-benzyl-δ-valerolactam

According to general procedure 5-A and using N-Boc-(S)-3-amino-δ-valerolactam and benzyl bromide, N-Boc-(S)-3-amino-1-benzyl-δ-valerolactam was obtained. Removal of the Boc group using general procedure 5-B afforded the title compound.

Example 5-O

Synthesis of 4-amino-2-aza-2-benzyl-3-oxobicyclo[3,2,1]octane hydrochloride

Stage A - Synthesis of 2-aza-3-oxobicyclo[3,2,1]octane and 3-aza-2-oxobicyclo[3,2,1]octane (9:1 mixture)

1.5 equiv was added to (±)-norcamphor (Aldrich) in 1 mL/mmol acetic acid. hydroxylamine-O-sulfonic acids. The reaction mixture was heated under reflux under nitrogen for 1 hour and then saturated sodium carbonate solution and dilute sodium hydroxide solution were added. The resulting mixture was extracted with dichloromethane and the organic extracts were washed with alkaline solution, dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography gave a 9:1 mixture of 2-aza-3-oxobicyclo[3,2,1]octane and 3-aza-2-oxobicyclo[3,2,1]octane.

Stage B - Synthesis of 2-aza-2-benzyl-3-oxobicyclo[3,2,1]octane

According to general procedure 5-A and using the product from step A and benzyl bromide, 2-aza-2-benzyl-3-oxobicyclo[3,2,1]octane was prepared.

Stage C - Synthesis of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3,2,1]octane

To a solution of 2-aza-2-benzyl-3-oxobicyclo[3,2,1]octane in THF was added 2.5 equiv. 1 M t-BuOK/THF (Aldrich) and the resulting mixture was stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was added dropwise and the reaction mixture was stirred overnight. 3N HCl was added to the reaction mixture and this mixture was extracted with ethyl acetate and the organic extracts were washed with water, dried and concentrated under reduced pressure. The residue was triturated with ether/hexane, the solvent was decanted and the residue was dried under reduced pressure to give 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3,2,1]octane as a brown liquid (yield 41%). This procedure is described in Y. Kim, Tetrahedron Lett. 30(21), 2833-2636 (1989).

Stage D - Synthesis of 2-aza-2-benzyl-4-amino-3-oxobicyclo[3,2,1]octane

A solution of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3,2,1]octane in 10 mL/mmol ethanol and 5.8 mL/mmol 3N HCl containing 0.5 g/mmol 10% Pd /C is saturated with hydrogen gas at 45 psi. The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a solid (86% yield). This procedure is described in E. Reimann, Arch. Pharm. 310, 102-109 (1977).

GENERAL PROCEDURE 6-A

Alkylation of 1-amino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

Step A: 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one was prepared according to the procedure of Ben-Ishai et al.. Tetrahedron, 1987, 43, 430.

Step B: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (2.0 g, 100 M%) was dissolved in DMF (30 mL) and NaH (95%, 0.17 g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and the mixture was stirred for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The ethyl acetate extracts were then washed with water (3×) and saline (1×). Workup with MgSO4, evaporation on a rotary evaporator, and chromatography (30% EtOAc/hexane) gave 1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 87% yield.

Step C: 1-Ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.0 g, 100M%) was suspended in 30 mL of 30% HBr/HOAc and heated to 100°C. The reaction mixture was stirred for 5 hours at this temperature and then the reaction mixture was cooled and evaporated on a rotary evaporator to give 1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepine-2- it in the form of hydrobromide salt (yield 100%).

GENERAL PROCEDURE 6-B

Alkylation of 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from �-tetralone using the methods described in Armstrong et al. Tetrahedron Letters, 1994, 35, 3239. The following compounds were prepared by this procedure for use in the following grades:

5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4-methyl-�-tetralone (Aldrich)); and

5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4,4-dimethyl-�-tetralone (Aldrich)).

Step B: 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4.43 g, 100 M %) was suspended in t-butanol (30 mL) and BOC- anhydride (7.5 mL, 130 M %). The reaction mixture was stirred for 2 hours and then rotary evaporated to a residue which was chromatographed with 60% ethyl acetate/hexane to give BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepine- 2-one with a yield of 87 %.

Step C: BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.5 g, 100 M %) was dissolved in DMF (20 mL) and added in one portion NaH (95 % , 0.13 g, 100 M %). The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M %) was added and stirring was continued for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with water (3×) and then with saline (1×). Treatment with MgSO4, evaporation on a rotary evaporator, and chromatography (30% EtOAc/hexane) gave the BOC-protected 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in yield 80%.

Step D: The BOC-protected 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.0 g, 100M %) was suspended in 30 mL of 1: 1 CH2Cl2/trifluoroacetic acid and the mixture was stirred for 4 hours. The reaction mixture was evaporated on a rotary evaporator to give 3-amino-1-alkyl-1,3,4,5tetrahydro-2H-1-benzazepin-2-one (yield 100%).

Example 6-A

Synthesis of 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from 4-methyl-�-tetralone using the methods described in Armstrong et al. Tetrahedron Letters, 1994, 35, 3239.

Step B: 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (9.3 g, 100 M%) was dissolved in dioxane (300 mL) and the solution was cooled at 0°C. BOC-anhydride (13.89 g 130M%) was added and the ice bath was removed to allow the solution to reach room temperature and stirring was continued for 16 hours. The solution was evaporated on a rotary evaporator to remove dioxane to give an off-white solid. The solution was recrystallized from CHCl3 to give BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 55% yield.

Step C: BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100M %) was dissolved in DMF (20 mL) and added in one portion NaH (95%, 100M %) and the reaction mixture was stirred for 1 hour. Methyl iodide (300M%) was added and the mixture was stirred for 12 hours. The reaction mixture was placed in water and extracted with ethyl acetate (3×) and backwashed with water (3×) and then with saline solution (1×). Treatment with MgSO4, evaporation on a rotary evaporator, and chromatography (5% MeOH/CH2Cl2) afforded the BOC-protected 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one with a yield of 75%.

Step D: BOC-protected 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100M%) was suspended in 30 mL of 1:1 CH2Cl2/trifluoroacetic acid acid. The reaction mixture was stirred for 4 hours. The reaction mixture was then rotary evaporated to give 3-amino-1,5-dimethyl-1,3,4,5tetrahydro-2H-1-benzazepin-2-one (yield 100%).

Example 6-B

Synthesis of 5-(L-alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride

Following the procedure of Example 7-I and using 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared.

Example 6-C

Synthesis of 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride

Step A: According to general procedure 5-A and using N-t-Boc-5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one (general procedure 6-B, then Boc protection) and methyl iodide, N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one was prepared.

Step B: According to the general procedure of 8-N and using N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one, the title compound was prepared.

Example 6-D

Synthesis of 3-(S)-amino-1-methyl-5-oxa-1,3, 4, 5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-(S)-amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro- of 1-nitrobenzene (Aldrich) using the method of R. J. DeVito et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286.

Step B: Following general procedure 5-A and using the product from step A, the title compound was prepared.

Example 6-E

Synthesis of 3-(S)-amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-(S)-amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro- of 1-nitrobenzene (Aldrich) using the method of R. J. DeVito et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286.

Step B: Following general procedure 5-A and using the product from step A, the title compound was prepared.

Example 6-F

Synthesis of 3-(S)-amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

The title compound was prepared from N-Boc-cystine (Novabio) and 2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVito et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286, and then general procedure 5-A.

GENERAL PROCEDURE 7-A

Preparation of 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivatives

Step A: According to general procedure 5-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one and an alkyl halide, 7-alkyl-5,7-dihydro-6H-dibenz was prepared [b,d]azepin-6-one.

Step B: 7-Alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq) was dissolved in THF and isoamyl nitrite (1.1 eq) was added. The mixture was cooled to 0°C in an ice bath. NaHMDS (1.1 equiv, 1M in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture was concentrated and acidified with 1N HCl and extracted with EtOAc. The organic portion was dried and concentrated to give the crude product which was purified by silica gel chromatography.

Step C: The resulting oxime was dissolved in EtOH/NH3 (20:1) and hydrogenated in a flask using Raney nickel and hydrogen (500 psi) at 100°C for 10 hours. The resulting mixture was filtered and concentrated to give an oil which was purified by silica gel chromatography to give the title compound.

GENERAL PROCEDURE 7-B

Preparation of fluorine-substituted 5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivatives

A modification of the procedure of Robin D. Clark and Jahangir, Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993. Specifically, the appropriately substituted N-t-Boc-2-amino-2'-methylbiphenyl was dissolved in THF and cooled to -78°C. s-Butyllithium (1.3M in cyclohexane, 2.2 equiv) was slowly added so that the temperature remained below -65°C. The resulting mixture was allowed to warm to -25°C and was stirred at that temperature for 1 hour. The mixture was cooled to -78°C. Dry CO2 was bubbled through the mixture for 30 seconds. The mixture was allowed to warm to ambient temperature and then the reaction was carefully quenched with water. The mixture was concentrated under reduced pressure and the pH was adjusted to 3 with a 1N HCl solution. The mixture was extracted with EtOAc and the organic portion was dried and concentrated to give the crude material. The crude material was dissolved in methanol and the solution was saturated with HCl. The mixture was heated under reflux for 12 hours and then allowed to cool. The mixture was concentrated to give the crude lactam which was purified by chromatography or crystallization.

GENERAL PROCEDURE 7-C

Separation of 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

In a round-bottom flask, racemic free base amine (1.0 eq.) in methanol was added followed by di-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.). The mixture was concentrated in vacuo to a residue and redissolved in a moderate volume of methanol and allowed to stir at room temperature open to atmosphere (8-72 hours). The solid was removed by filtration. Enantiomeric excess was determined by chiral HPLC (Chiracel ODR) using 15% acetonitrile and 85% H2O with 0.17 trifluoroacetic acid and a flow rate of 1.0 mL/min at 35°C. The separated di-p-toluoyl-D-tartrate salt was then dissolved in EtOAc and saturated NaHCO3 until pH 9-10 was reached. The layers were separated and the organic layer was washed again with saturated NaHCO 3 , H 2 O and brine. The organic layer was dried over MgSO4 and the drying agent was removed by filtration. The filtrate was concentrated in vacuo.

The free amine was dissolved in MeOH and HCl (12M, 1.0 equiv) was added. The salt was concentrated in vacuo and the resulting thin layer was triturated with EtOAc. The HCl salt was filtered and washed with EtOAc. Ee was determined by chiral HPLC.

Example 7-A

Synthesis of 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one Hydrochloride

Stage A - Synthesis of 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 mL DMF and treated with 5,7-dihydro-6H-dibenz[b,d)azepin-6-one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein). After stirring at 60°C for 1 hour, the solution was treated with methyl iodide (1.16 ml, 18.6 mmol) and stirring was continued for 17 h with no access to light. After cooling, the reaction mixture was diluted with CH2Cl2/H2O, washed with NaHSO4 solution, water and dried over Na2SO4. Evaporation and flash chromatography (SiO 2 , CHCl 3 ) afforded 0.885 g (63%) of the title compound as a colorless solid.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H), 3.32 (s, 3H).

C15H13NO (MW = 223.27); mass spectroscopy (MH+) 223.

Analysis – calculated for C15H13NO: C, 80.69 H, 5.87 N, 6.27. Found: C, 80.11 H, 5.95 N, 6.23.

Stage B - Synthesis of 7-methyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

The compound isolated above (0.700 g, 3.14 mmol) was dissolved in 20 ml of toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol). The reaction temperature was lowered to 0 °C and the solution was treated with KHMDS (9.42 mL, 0.5 M) under N 2 atmosphere. After stirring for 1 hour, the reaction was stopped by the addition of saturated NaHSO4 solution, diluted with CH2Cl2 and separated. The organic layer was dried over Na 2 SO 4 and the title compound was purified by chromatography (SiO 2 , 98:2 CHCl 3 /MeOH) to give 0.59 g (80 %) as a colorless solid.

C15H12N2O2 (MW = 252.275); mass spectroscopy (MH+) 252.

Analysis – calculated for C15H12N2O2: C, 71.42 H, 4.79 N, 11.10. Found: C, 71.24 H, 4.69 N, 10.87.

Stage C - Synthesis of 5-amino-7-methyl-5 7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parr apparatus at 35 psi over 10% Pd/C (0.46 g) in 3A ethanol. After 32 h, the reaction mixture was filtered through a plug of Celite, the filtrate was evaporated to foam and treated with a saturated solution of HCl (g) in Et2O. The resulting colorless solid was filtered, washed with cold Et 2 O and dried in vacuo to give 0.66 g (61%) of the title compound.

The NMR data are as follows:

1H-nmr (DMSO-d6): ����9.11 (bs, 3H), 7.78-7.41 (m, 8H), 4.83 (s, 1H), 3.25 (s, 3H).

C15H14N2O·HCl (MW = 274.753); mass spectroscopy (MH+ free base) 238.

Analysis - calculated for C15H14N2O · HCl: C, 65.57 H, 5.50 N, 10.19 Found: C, 65.27 H, 5.67 N, 10.13.

Example 7-B

Synthesis of (S)- and (R)-5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Stage A - Synthesis of (S)- and (R)-5-(N-Boc-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azenin-6-one

Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.305 g, 2.26 mmol) and 5-amino-7-methyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89 mmol) (Example 7-A). The temperature was lowered to 0°C and the reaction mixture was treated with EDC (0.449 g, 2.26 mmol) (Aldrich) and stirred for 17 h under N 2 . The reaction mixture was evaporated, the residue was diluted with EtOAc/H2O, washed with 1.0 N HCl, saturated NaHCO3, brine and dried over Na2SO4. Diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.

Isomer 1: retention time 3.37 minutes.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.62-7.33 (m, 9H), 5.26 (d, 1H), 3.08 (m, 1H), 4.34 (m, 1H), 3.35. (s, 3H), 1.49 (s, 9H), 1.40 (d, 3H).

Optical rotation: [�]20 = - 96 @ 589 nm (c = 1, MeOH).

C23H27N3O4 (MW = 409.489); mass spectroscopy (MH+) 409.

Analysis – calculated for C23H27N3O4: C, 67.46 H, 6.64 N, 10.26. Found: C, 68.42 H, 7.02 N, 9.81.

Isomer 2: Retention time 6.08 minutes.

The NMR data are as follows:

1H-nmr (CDCl3): ����7.74 (bd, 1H), 7.62-7.32 (m, 8H), 3.28 (d, 1H), 4.99 (m, 1H), 4.36 (m, 1H), 3.35 ( s, 3H), 1.49 (s, 9H), 1.46 (d, 3H).

Optical rotation: [�]20 = 69 @ 589 nm (c = 1, MeOH).

C23H27N3O4 (MW = 409.489); mass spectroscopy (MH+) 409.

Analysis – calculated for C23H27N3O4: C, 67.46 H, 6.64 N, 10.26. Found: C, 67.40 H, 6.62 N, 10.02

Stage B - Synthesis of (S)- and (R)-5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

The compounds isolated in part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and drying in vacuo.

Isomer 1:

C18H19N3O2·HCl (MW = 345.832); mass spectroscopy (MH+ free base) 309.

Optical rotation: [�]20 = -55 @ 589 nm (c = 1, MeOH).

Isomer 2:

C18H19N3O2·HC1 (MW = 345.832); mass spectroscopy (MH+ free base) 309.

Optical rotation: [�]20 = 80 @ 589 nm (c = 1, MeOH).

Example 7-C

Synthesis of (S)- and (R)-5-(L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Step A - Synthesis of (S)- and (R)-5-(N-Boc-L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Boc-L-valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipe (1.05 ml, 6.05 mmol) and 5-amino -7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol) (Example 7-A). The temperature was lowered to 0°C and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred for 17 h under nitrogen. The reaction mixture was evaporated, the residue was diluted with EtOAc/H2O, washed with 1.0 N HCl, saturated NaHCO3, brine and dried over Na2SO4. Diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.

Isomer 1: retention time 3.23 minutes.

Optical rotation: [�]20 = - 120 @. 589 nm (c = 1, MeOH).

C25H31N3O4 (MW = 437.544); mass spectroscopy (MH+) 438

Isomer 2: retention time 6.64 minutes.

Optical rotation: [�]20 = 50 @ 589 nm (c = 1, MeOH).

C25H31N3O4 (MW = 437.544); mass spectroscopy (MH+) 438

Stage B - Synthesis of (S)- and (R)-5-(L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

The compounds isolated in part A (each isomer separately) were dissolved in dioxane and treated with excess HC1 (g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.

Isomer 1:

C20H23N3O2·HC1 (MW = 373.88); mass spectroscopy (MH+ free base) 338.

Optical rotation: [�]20 = - 38 @ 589 nm (c = 1, MeOH).

Isomer 2:

C20H23N3O2·HC1 (MW = 373.88); mass spectroscopy (MH+ free base) 338.

Optical rotation: [�]20 = 97 @ 589 nm (c = 1, MeOH).

Example 7-D

Synthesis of (S)- and (R)-5-(L-tert-leucine)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Stage A - Synthesis of (S)- and (R)-S-(N-Boc-L-tert-leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepine-6 -she

Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipe (1.05 ml, 6.05 mmol) and 5 -amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol) (Example 7-A). The temperature was lowered to 0 °C and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Aldrich) and stirred for 17 h under N 2 . The reaction mixture was evaporated, the residue was diluted with EtOAc/H2O, washed with 1.0 N HCl, saturated NaHCO3, brine and dried over Na2SO4. Diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.

Isomer 1: retention time 3.28 minutes.

Optical rotation: [�]20 = - 128 @ 389 nm (c = 1, MeOH).

C16H33N3O4 (MW = 451.571); mass spectroscopy (MH+) 452

Isomer 2: retention time 5.52 minutes.

Optical rotation: [�]20 = 26 @ 389 nm (c = 1, MeOH).

C16H33N3O4 (MW = 451.571); mass spectroscopy (MH+) 452

Stage B - Synthesis of (S)- and (R)-5-(L-tert-leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d] azepin-6-one hydrochloride

The compounds isolated in part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 h, the title compound was isolated as a colorless solid after evaporation and drying in vacuo.

Isomer 1:

C21H25N3O2·HC1 (MW = 387.91); mass spectroscopy (MH+ free base) 352.

Optical rotation: [�]20 = - 34 @ 589 nm (c = 1, MeOH).

Isomer 2:

C21H25N3O2·HC1 (MW = 387.91); mass spectroscopy (MH+ free base) 352.

Optical rotation: [�]20 = 108 @ 589 nm (c = 1, MeOH).

Example 7-E

Synthesis of 5-(N-Boc-amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

Stage A - Synthesis of 5-iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 7-A) and Et 3 N (2.66 mL, 19.12 mmol) was stirred for 5.0 min at -15°C in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 min, I2 (1.81 g, 7.16 mmol) was added in one portion and the reaction mixture was allowed to warm to 5-10°C over 3 h. The reaction was quenched with saturated Na2SO3 solution, diluted with CH2Cl2 and separated. The organic part was washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organic portion was concentrated to approximately 20 ml and diluted with an additional 20 ml of hexane. The title compound was isolated as a brown precipitate by filtration.

Stage B - Synthesis of 5-azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

The above iodine isolate was dissolved in DMF and treated with 1.2 equivalents of NaN3. After stirring for 17 h at 23°C, the mixture was diluted with EtOAc/H2O, separated and washed with brine and dried over MgSO4. The title compound was extracted from hot EtOAc as a brown powder.

Stage C - Synthesis of 5-(N-Boc-amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

The azide was dissolved in THF/H2O and stirred at 23°C for 17 h in the presence of 3.0 equivalents of Ph3P. The reaction mixture was diluted with 50% HOAc/toluene, separated, the aqueous layer was extracted with toluene and evaporated to an oily residue. They were collected to pH 7.0 by the addition of 1N NaOH solution, the resulting HOAc salt was collected and dried under vacuum. Finally, the compound was treated with Boc anhydride (1.05 equiv) and Et 3 N (2.1 equiv) in THF. After stirring for 5 h at 23°C, the reaction mixture was filtered and the title compound was isolated as a colorless powder.

Example 7-F

Synthesis of 5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Stage A - Synthesis of 5-(N-Boc-amino)-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (0.22 g, 0.678 mmol) and heated to 60°C. To the reaction mixture was added 1-iodo-2-methylpropane (0.078 ml, 0.678 mmol) and stirring was continued for 17 h. After cooling to 23°C, the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3/MeOH 9:1).

C23H28N2O3 (MW = 380.41); mass spectroscopy (MH+) 381

Analysis - calculated for C23H28N2O3: C, 72.61 H, 7.42 N, 7.36. Found: C, 72.31 H, 7.64 N, 7.17.

Stage B - Synthesis of 5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

The compound isolated in part A was deprotected in dioxane saturated with HCl gas. The title compound was isolated as a faintly colored solid after evaporation and drying in vacuo.

Example 7-G

Synthesis of 5-amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Stage A- Synthesis of 5-(N-Boc-amino)-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin6-one (1.03, 3.08 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (1.10 g, 3.39 mmol) and heated to 60°C. Bromomethylacetate (0.321 mL, 3.39 mmol) (Aldrich) was added to the reaction mixture and stirring was continued for 17 h. After cooling to 23°C, the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3).

C22H24N2O5 (MW = 396.44); mass spectroscopy (MH+) 397

Analysis – calculated for C22H24N2O5: C, 66.65 H, 6.10 N, 7.07. Found: C, 66.28 H, 5.72 N, 6.50.

Stage B - Synthesis of 5-amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

The compound isolated in part A was deprotected in dioxane saturated with HCl gas. The title compound was isolated as a colorless solid after evaporation and drying in vacuo.

C17H16N2O3·HCl (MW = 332.78); mass spectroscopy (MH+ free base) 297.

Example 7-H

Synthesis of 5-amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Stage A- Synthesis of 5-(N-Boc-amino)-7-(3,3-dimethyl-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and heated to 60°C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring was continued for 17 h. After cooling to 23°C, the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid.

C25H30N2O4 (MW = 422.522); mass spectroscopy (MH+) 423

Stage B - Synthesis of 5-amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

The compound isolated in part A was deprotected in dioxane saturated with HCl gas. The title compound was isolated as a colorless solid after evaporation and drying in vacuo.

Example 7-I

Synthesis of L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Step A: According to general procedure III-D and using N-t-Boc-L-alanine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t -Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Step B: Following the general procedure of 8-N and using N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the titled compound. Other substituted N-t-Boc-L-alaninyl-5-amino-7-

methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this process.

Example 7-J

Synthesis of L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Step A: According to general procedure III-D and using N-t-Boc-L-valine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t -Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Step B: Following the general procedure of 8-N and using N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the titled compound. Other substituted N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.

Example 7-K

Synthesis of 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

According to the general procedure of 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al.. Tetrahedron Letters, No. 8, 667- 670, (1971) and references cited therein) and 1-chloro-4-phenylbutane (Aldrich), the title compound was prepared.

Example 7-L

Synthesis of 5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

According to the general procedure of 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667- 670, (1971) and references cited therein) and (bromomethyl)cyclopropane (Aldrich), the title compound was prepared.

Example 7-M

Synthesis of 5-amino-7-(2',2',2'-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

According to the general procedure of 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667- 670, (1971) and references cited therein) and 1-bromo-2,2,2-trifluoroethane (Aldrich), the title compound was prepared.

Example 7-N

Synthesis of 5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

According to the general procedure of 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667- 670, (1971) and references cited therein) and bromocyclohexane (Aldrich), the title compound was prepared.

Example 7-O

Synthesis of 5-(L-alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Step 1: 2-bromo-5-fluorotoluene was stirred in THF at -78ºC. s-BuLi (1.05 equiv, 1.3M in cyclohexane) was added slowly and the mixture was stirred for 45 minutes. Trimethylborate (1.5 eq.) was added and the mixture was allowed to warm to ambient temperature. After stirring for 1 hour, pinacol (2 eq.) was added. The mixture was stirred for 16 hours and then concentrated under reduced pressure. The obtained residues were slurried in CH2Cl2 and filtered through Celite. The filtrate was concentrated to give an oil which was purified by chromatography on deactivated silica gel (Et 3 N) to give the aryl borate ester.

Step 2: 2-bromoaniline (1 eq.) and di-t-butyl dicarbonate (1.1 eq.) were stirred at 80°C for 20 hours. The resulting mixture was allowed to cool and directly distilled using a house vacuum to give N-t-Boc-2-bromoaniline.

Step 3: N-t-Boc-2-bromoaniline (step 2.1 eq), aryl borate ester (step 1, 1.1 eq), K2CO3 (1.1 eq) and tetrakis(triphenylphosphine)palladium(0) ( 0.02 eq.) were mixed in 20% water/dioxane under nitrogen. The solution was heated under reflux for 10 hours. The mixture was allowed to cool and then concentrated. The resulting residue was partitioned between water and chloroform. The organic portion was dried and concentrated to give an oil which was purified by silica gel chromatography using 1:1 CH 2 Cl 2 /hexane.

Step 4: According to general procedure 7-B and using the substituted biphenyl from step 3, 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

Step 5: 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature for 16 h. The mixture was concentrated under reduced pressure to a residue which was partitioned between EtOAc and water. The organic portion was dried and concentrated to give an oil which was purified by silica gel chromatography to give 9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Step 6: Following General Procedure 7-A, Step B and using 9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 5, the 5-amino -9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Step 7: Following the procedure of Example 7-I and using 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 6, the title compound was prepared .

Example 7-P

Synthesis of 5-(L-alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-0 and using 2-bromo-4-fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich), the title compound was prepared.

Example 7-Q

Synthesis of 5-(L-alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-O and using 2-bromo-4-fluorotoluene (Step 1), the title compound was prepared.

Example 7-R

Synthesis of 5-(L-alanyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-I and using 5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one (Example 7-L), the title compound was prepared.

Example 7-S

Synthesis of 5-(L-alaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-I and using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared.

Example 7-T

Synthesis of 5-(L-valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-J and using 5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared.

Example 7-U

Synthesis of 5-(L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,c]azepin-6-one hydrochloride

Following the procedure of Example 7-J and using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-U), the title compound was prepared.

Example 7-V

Synthesis of 5-(L-valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Step A: According to general procedure 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8 , 667-670, (1971) and references cited therein) and 1-bromohexane (Aldrich), 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepine-6- he.

Step B: Following the procedure of Example 7-J and using 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.

Example 7-W

Synthesis of S-(L-valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

According to the procedure of Example 7-J and using 5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared in Example 7-Q), there was prepared titled compound.

Example 7-X

Synthesis of 5-(L-valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-J and using 5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared in Example 7-P), was prepared titled compound.

Example 7-Y

Synthesis of 5-(L-valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

Following the procedure of Example 7-J and using 6-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared in Example 7-O), was prepared titled compound.

Example 7-Z

Synthesis of (5-amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one

5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-A) was dissolved in a 1:1 mixture of EtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at 60°C under 60 psi of hydrogen. After 3 days the mixture was filtered and the filtrate was concentrated to give an oil which was purified by SCX-cation exchange chromatography to give the title compound.

Example 7-AA

Synthesis of 5-(S)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride

According to general procedure 7-C using racemic 5-amino-7-methyl-5,7dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) and monohydrate di-p-toluoyl-D- of tartaric acid (1.0 eq.) in methanol, the title compound was prepared as a solid.

The product was collected by filtration. The enantiomeric excess was determined by chiral HPLC.

Preferred enantiomer 1: retention time 9.97 minutes.

Undesired enantiomer 2: retention time 8.62 minutes.

The NMR data are as follows:

1H-nmr (CDCl3): ����9.39 (s, 2H), 7.75-7.42 (m, 8H), 4.80 (s, 1H), 3.30 (s, 3H).

C15H15ClN2O3 (MW = 274.75); mass spectroscopy (MH+) 239.1.

Analysis – calculated for C15H15ClN2O3: C, 65.57; H, 5.50; N, 10.20; Found: C, 65.51, H, 5.61; N, 10.01.

GENERAL PROCEDURE 8-A

N-1-methylation of benzodiazepines

A solution of benzodiazepines (1 equiv) in DMF (0.1 M concentration) at 0°C was treated with potassium tert-butoxide (1.0 equiv, 1.0 M solution in THF). After stirring for 30 min at 0°C, iodomethane (1.3 eq.) was added and stirring was continued for 25 min. The mixture was diluted with methylene chloride and washed with water and saline solution. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified either by elution with 1:1 ether/hexane or chromatographed by HPLC using ethyl acetate/hexane as eluent.

GENERAL PROCEDURE 8-B

Cbz removal procedure

The flask was charged with Cbz-protected 3-aminobenzodiazepine (1 eq.). To this was added HBr (34 eq.; 30% solution in acetic acid). Within 20 minutes, all the starting material was dissolved. The reaction mixture was stirred for 5 hours at ambient temperature. Ether was added to the orange solution causing precipitation of the HBr·amine salt. The mixture is decanted. The procedure of adding ether and decanting was repeated three times in an effort to remove acetic acid and benzyl bromide. Toluene was added and the mixture was concentrated in vacuo.

This stage was also repeated. The HBr salt was partitioned between ethyl acetate and 1 M K2CO3 solution. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated.

GENERAL PROCEDURE 8-C

Removal procedure Boc

A solution of the Boc-protected amine (1 eq.) in methylene chloride (0.15 M concentration) was cooled to 0°C and treated with trifluoroacetic acid (30 eq.). After 10 minutes at 0°C the cooling bath was removed and stirring was continued at ambient temperature for 20 minutes to 1 hour. The mixture was concentrated in vacuo to remove excess trifluoroacetic acid. The residues were dissolved in methylene chloride and washed with aqueous NaHCO3 solution or 1 M K2CO3 solution and saline. The organic layer was dried over Na2SO4, filtered and concentrated.

GENERAL PROCEDURE 8-D

Azide transfer reaction using KHMDS

Azide derivatives were prepared by the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).

GENERAL PROCEDURE 8-E

Azide transfer reaction using LDA

To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry THF cooled to -78°C, n-butyllithium (1.6M in hexane) (1.1 eq.) was added dropwise while maintaining the temperature at -78°C. The reaction mixture was stirred for 30 min. at -78°C and then the lactam (0.471 mM) was added dropwise as a solution in 1 mL of dry THF. The reaction mixture was stirred at -78°C for 30 min. and then a pre-cooled solution of trisil-azide (1.1 eq.) in 1 mL of dry THF was added. The reaction mixture was stirred at -78°C for 20 min. and then the reaction was quenched with acetic acid (4.0 eq.). The reaction mixture was then stirred at 40°C for 2 hours. The reaction mixture was taken up in EtOAc and

washed with water, sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The residues were purified by LC 2000 chromatography.

GENERAL PROCEDURE 8-F

Reduction of the azide group

The azide group was reduced to the corresponding primary amine using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).

GENERAL PROCEDURE 8-G

N-alkylation of amides or lactams

Using sodium hydride or potassium tert-butoxide

To a slurry of sodium hydride or potassium tert-butoxide (1.1 eq.) in 15 mL dry DMF was added the corresponding amide (0.0042 mol) as a solution in 10 mL DMF. Then alkyl iodide was added and a thick slurry was obtained. The reaction mixture became thinner over time and when TLC showed the completion of the reaction, it became homogeneous. The reaction mixture was placed over ice and extracted into ethyl acetate. The organic layer was washed with water, then with brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by HPLC HPLC (LC 2000), eluting with an ethyl acetate/hexane system.

GENERAL PROCEDURE 8-H

A-alkylation of amides or lactams using KHMDS

KHMDS was added dropwise to the corresponding amide or lactam cooled to -78°C and the reaction mixture was stirred for 30 min. at -78°C. Alkyl iodide was added dropwise while maintaining the temperature at -70°C. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was then placed on ice and extracted into ethyl acetate. The organic extracts were washed with water, then with saline solution. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by HPLC HPLC (LC 2000), eluting with an ethyl acetate/hexane system.

GENERAL PROCEDURE 8-I

N-alkylation of amides or lactams using cesium carbonate

To a solution of the amide or lactam in DMF was added cesium carbonate (1.05 eq.) and alkyl iodide (1.1 eq.). The mixture was allowed to stir overnight at room temperature and the reaction mixture was diluted with ethyl acetate and washed with water, then brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by HPLC HPLC (LC 2000), eluting with an ethyl acetate/hexane system.

GENERAL PROCEDURE 8-J

BOC removal procedure

CH2Cl2/TFA (4:1) was added to the N-Boc-protected compound at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was extracted into dichloromethane and washed with water, saturated sodium bicarbonate, dried over Na 2 SO 4 , filtered and concentrated to give the free amine.

GENERAL 8-K PROCEDURE

Azide transfer procedure

The azide transfer procedure is a modification of the procedure described in Evans. D. A.; Britton, T.C.; Ellman, J.A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030. To a solution of the lactam substrate (1.0 equiv.) in THF (~0.1M) under N2 at -78 °C was added dropwise a solution of KN(TMS)2 (1.1 equiv. of a 0.5M solution in toluene, Aldrich) during period of 2-10 minutes. A weak release of heat was observed by the internal thermometer, and the resulting solution was stirred for 5-15 minutes, with re-cooling to -78°C. Trisyl-azide (1.1-1.5 eq., CAS No. 36982-84-0, prepared as described in Evans reference above) in THF (~0.5M), either precooled to -78 °C or at room temperature, it was added by cannula over a period of 0.5-5 minutes. Again, weak heat generation was observed. The resulting solution was stirred for 5-10 minutes, with re-cooling to -78°C. AcOH (4.5-4.6 eq., glacial) was then added. The cooling bath was removed and the mixture was allowed to warm to room temperature with stirring for 12-16 hours. The mixture was diluted with EtOAc, in 2-5 multiple volumes compared to the initial volume of THF, and washed with dilute aqueous NaHCO3 solution (1-2×), 0.1-1.0 M aqueous HCl solution (0-2×), and saline solution (1×). The organic phase was dried over MgSO4, filtered and concentrated to give the crude product

GENERAL PROCEDURE 8-L

Reduction of azide to amine

A mixture of azide in absolute EtOH (0.03-0.07 M) and 10% Pd/C (~1/3 by weight of azide) was shaken in a Parr apparatus under H2 (35-45 psi) at room temperature for 3 - 6 hours. The catalyst was removed by filtration through a plug of Celite, washing with absolute EtOH, and the filtrate was concentrated to give the crude amine product.

GENERAL PROCEDURE 8-M

Alkylation of amides using cesium carbonate

This procedure is a modification of the procedure described in Claremon. D. A.; et al. PCT Application: WO 96-US8400 960603. Mixtures of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6) in DMF (1.0 eq ., 0.7 M) under N 2 at room temperature, Cs 2 CO 3 (2.2 eq.) and the corresponding alkyl halide (2.2 eq.) were added. The mixture was stirred at room temperature for 5.5-16 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (1-2×) and the combined EtOAc extracts were dried over Na 2 SO 4 , filtered and concentrated to give the crude product.

GENERAL PROCEDURE 8-N

BOC removal procedure

A stream of anhydrous HCl gas was passed with stirring through a solution of the N-t-Boc-protected amino acid in 1,4-dioxane (0.03-0.09 M), cooled to ~10°C under N2, for 10-15 min. The solution was stoppered, the cooling bath was removed, and the solution was allowed to warm to room temperature with stirring for 2-8 hours, monitoring by TLC consumption of the starting material. The solution was concentrated (and in some cases dissolved in CH2Cl2 and re-concentrated and placed in a vacuum oven at 60-70°C to remove most of the residual dioxane) and used without further purification.

Example 8-A

Synthesis of 3-amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepine-2-one

Step A - Preparation of 1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepine-2-one

To a solution of phosphorus pentachloride (1.1 eq.) in methylene chloride was added dropwise a solution of 1-methyl-1,2,3,4-tetrahydro-3H-1,4-benzodiazepine-2,5-dione (Showell, G. A. ; Bourrain, S.; Neduvelil, J. G.; Fletcher, S. R.: Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.; Kemp, J. A.; Marshall, G. R.; Patel, S.: Smith, A. J.; Matassa. V. G. J. Med. Chem. 1994, 37, 719.) in methylene chloride. The resulting yellow-orange solution was stirred at ambient temperature for 2.5 hours; the solvent was removed in vacuo. The orange residues were redissolved in methylene chloride, cooled to 0°C, and treated with a solution of piperidine (2 eq.) and triethylamine (2 eq.) in methylene chloride. The cooling bath was removed and the reaction mixture was stirred for 18 hours. The reaction mixture was washed with saturated aqueous NaHCO3 (back-extracted with methylene chloride) and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC eluting with a 4 to 10% methanol/methylene chloride gradient to give the title intermediate as a yellow solid, mp 103-105°C.

C15H19N3O (MW 257.37); mass spectroscopy 257.

Analysis – calculated for C15H19N3O; C, 70.01; H, 7.44; N, 16.33. Found: C, 69.94; H, 7.58: N, 16.23.

Step B - Preparation of 1,2-dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,4-benzodiazepine-2-one

Potassium tert-butoxide (2.5 eq.) was added in two portions to a -20°C solution of 1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepine-2-one (1 eq.) in toluene. After stirring at -20°C for 20 min, isoamyl nitrite (1.1 eq., Aldrich) was added to the red reaction mixture. The reaction mixture was stirred at -20 °C for 5 hours, during which time the reaction was completed according to TLC. The cooling bath was removed and the reaction quenched with 0.5 M citric acid solution. After stirring for 10 minutes, diethyl ether was added. The suspension was stirred at ambient temperature overnight and then filtered, washing with ether. The obtained cream-colored solid had a melting point of 197-200°C.

1H-NMR data for E/Z isomers are as follows:

1H-NMR (300 MHz, CDCl3): ����7.64 (1H. bs), 7.48 (2H, d, J = 7.4 Hz), 7.35-7.20 (6H. m). 6.75 (1H, bs), 3.8-3.2 (8H, m). 3.46 (3H, s), 3.42 (3H, s). 1.90-1.40 (12H. m).

C15H18N4O2 (MW = 286.37); mass spectroscopy 286.

Step C - Preparation of 1,2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1-piperidinyl)-1,4-benzodiazepine-2-one

A mixture of 1,2-dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,4-benzodiazepine-2-one (1 eq.) in THF was treated with ethyl isocyanate (1.7 eq. .) and triethylamine (0.6 eq.). The mixture was heated at 64°C for 4 hours. The mixture was concentrated and the residue was purified by HPLC eluting with 5% methanol/methylene chloride.

1H-NMR data for E/Z isomers are as follows:

1H-NMR (300 MHz, CDCl3): ����7.50 (2H. dd, J = 8.4, 1.5 Hz), 7.35-7.22 (6H, m), 6.42 (1H, bt), 6.20 (1H, bt) , 3.7-3.4 (8H, m), 3.46 (3H, s), 3.44 (3H, s), 3.25 (4H, m), 1.9-1.4 (12H, m), 1.12 (3H, t, J = 6.3 Hz), 1.10 (3H, t, J = 6.3 Hz).

C18H23N5O3 (MW = 357.46); mass spectroscopy 357.

Step D - Preparation of 3-amino-1,3-dihydro-2H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepine-2-one

1,2-Dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1-piperidinyl)-1,4-benzodiazepine-2-one (1 eq.) was hydrogenated in methanol at 5% palladium on carbon (0.15 eq) at 43 psi for 3.25 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The residues were collected with methylene chloride and filtered a second time through Celite. The filtrate was concentrated and the resulting foam was used immediately.

Example 8-B

Synthesis of 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

Step A - Preparation of (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one, (1S)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptane-1-methanesulfonate

The title compound was prepared according to Reider, P. J.; Davis, P.; Hughes, D.L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 955 using 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one (Bock M.G.; DiPardo, R.M.; Evans, B.E.; Rittle, K.E. ; Veber, D. F.: Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987, 52, 3232.) as starting material.

Step B - Preparation of 3-[N'-(tert-butylcarbamate)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one, (1S)-7,7-dimethyl-2-oxobicyclo[2.2. 1]heptane-1-methanesulfonate was liberated by partitioning between methylene chloride and 1M potassium carbonate solution. The free amine is then coupled with N-Boc-alanine according to general procedure III-D.

C24H28N4O4 (MW = 436.56); mass spectroscopy 436.

Analysis - calculated for C24H28N4O4: C, 66.03; H, 6.47; N, 12.84. Found: C, 65.79; H, 6.68; N, 12.80.

Step C - Preparation of 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2- he, the titled compound was prepared in the form of white foam.

Analysis - calculated for C19H19N4O2: C, 69.21; H, 6.64; N, 15.37. Found: C, 70.11; H, 6.85; N, 15.01.

Example 8-C

Synthesis of 3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

A solution of 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-one (1 eq., Neosystem) in DMF was cooled to 0°C and treated with potassium tert-butoxide (1 eq., 1.0 M solution in THF). The resulting yellow solution was stirred at 0°C for 30 min and then the reaction was quenched with methyl iodide (1.3 eq.). After stirring for a further 25 minutes, the reaction mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residues were purified by HPLC chromatography with a gradient of 20→30% ethyl acetate/hexane.

C24H20ClN3O3 (MW = 433.92); mass spectroscopy 433.

Analysis - calculated for C24H20ClN3O3: C, 66.44; H, 4.65; N, 9.68. Found: C, 66.16; H, 4.50; N, 9.46.

Stage B - Preparation of 3-amino-7-chloro-13-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared in in the form of white foam that was directly used in grade C.

Step C - Preparation of 3-[N'-tert-butylcarbamate)-L-alaninyl]amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepine-2-one

According to general procedure III-D using N-Boc-L-alanine and 3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one, titled the intermediate is prepared in the form of white foam.

C24H28ClN4O4 (MW = 471.18); mass spectroscopy 471.

Analysis - calculated for C24H28ClN4O4: C, 61.21; H, 5.78; N, 11.90. Found: C, 61.24; H, 5.59; N, 11.67.

Step D - Preparation of 3-(L-alaninyl)amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazenin-2-one

According to general procedure 8-C using 3-[N'-tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-one, the title intermediate was prepared as a white foam. The raw material was used immediately.

Example 8-D

Synthesis of 3-(L-alaninyl)amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-one

According to general procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-one (Neosystem) the title intermediate is prepared in the form of white foam.

C24H19BrFN3O3 (MW = 496.36); mass spectroscopy 497.

Analysis - calculated for C24H19BrFN3O3: C, 58.08; H, 3.86; N, 8.47. Found: C, 57.90; H, 4.15; N, 8.20.

Stage B - Preparation of 3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-one, the title the intermediate was prepared in the form of a white foam that was used directly in step C.

Step C - Preparation of 3-[N'-(tert-butylcarbamate)-L-alaninyl]amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl), 2H-1,4- benzodiazepine-2-one

According to general procedure III-D using N-Boc-L-alanine (Novo) and 3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4- benzodiazepine-2-one, the title intermediate was prepared as a white foam.

C24H26BrFN4O4 (MW = 533.12); mass spectroscopy 533.2.

Analysis - calculated for C24H26BrFN4O4: C, 54.04; H, 4.91; N, 10.50. Found: C, 53.75; H, 4.92; N, 10.41.

Step D - Preparation of 3-(L-alaninyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H- 1,4-benzodiazepine-2-one, the title intermediate was prepared as a white foam. The raw material was used immediately.

Example 8-E

Synthesis of 3-(N'-methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 3-(N'-tert-butylcarbamate)-N'-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2 -she

According to general procedure III-D and using (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one (Example 8-B) and N- tert -Boc-N-methyl-alanine (Sigma), the title intermediate was prepared as a white solid.

C25H30N4O4 (MW = 450.2); mass spectroscopy (M+1) 451.2.

Analysis - calculated for C25H30N4O4: C, 66.65; H, 6.71; N, 12.44. Found: C, 66.66; H, 6.89; N, 12.21.

Step A - Preparation of 3-(N'-methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

According to general procedure 8-C and using 3-[N'-(tert-butylcarbamate)-N'-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepine-2-one, the title intermediate was prepared as a white foam.

C20H22N4O2 (MW = 350.46); mass spectroscopy (M+1) 351.4.

Analysis - calculated for C20H22N4O2: C, 68.35; H, 6.33; N, 13.99. Found, C, 68.36; H, 6.20; N, 15.79.

Example 8-F

Synthesis of 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2-one

According to general procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2-one (Neosystem), the title intermediate is prepared in the form of a white solid with a melting point of 232-233°C.

C24H19Cl2N3O3 (MW = 468.36); mass spectroscopy 468.

1H-NMR (300 MHz, CDCl3): � = 7.67 (1H, m), 7.52 (1H, dd, J = 2.4, 8.7 Hz), 7.42-7.26 (9H, m), 7.07 (1H, d, J = 2.4 Hz), 6.70 (1H, d, J = 8.3 Hz), 5.35 (1H, d, J = 8.4 Hz), 5.14 (2H, ABq, J = 19.6 Hz), 3.47 (3H, s).

13c NMR (75 MHz, CDCl3): � = 166.66, 163.65, 155.72, 140.32, 136.99, 136.0, 132.87, 131.99, 131.47, 131.40, 131.38, 131.16, 130.54, 130.06, 128.45, 128.08, 128.03, 127.28 , 122.01, 68.95, 67.02, 35.32.

Stage B - Preparation of 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2-one, the title the intermediate was prepared in the form of a white foam that was used directly in step C.

Step C - Preparation of 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4 -benzodiazepine-2-one

According to general procedure III-D using N-Boc-L-alanine and 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepine-2 -on, the titled intermediate is prepared in the form of a white foam.

C24H26Cl2N4O4 (MW = 505.44); mass spectroscopy 505.2.

Step D - Preparation of 3-(L-alaninyl)-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-(N'-(tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2 H -1,4-benzodiazepine-2-one, the title intermediate was prepared as a white foam.The crude material was used immediately.

Example 8-G

Synthesis of 3-(L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine-2-one

According to general procedure 8-A using 3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one (Neosystem), the title intermediate was prepared as a white solid with a m.p. 205-206°C.

C24H27N3O3 (MW = 405.54); mass spectroscopy 405.

1H-NMR (300 MHz, CDCl3): � = 7.54 (1H, d, J = 7.9 Hz), 7.48 (1H, d, J = 7.7 Hz), 7.36-7.26 (7H, m), 6.54 (1H, d , J = 8.3 Hz), 5.15 (1H, d, J = 8.0 Hz), 5.09 (2H, ABq, J = 17.1 Hz), 3.39 (3H, s), 2.77 (1H, m), 2.01 (1H, bd , J = 13.6 Hz), 1.85 (1H, bd, J = 12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02 (4H, m).

Stage B - Preparation of 3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B using 3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared as a white foam which was used continuously in grade C.

C16H21N3O (MW+H = 272.1763); mass spectroscopy 272,1766

Step C - Preparation of 3-(N'-(tert-butylcarbamate)-L-alaninyl]amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one

According to general procedure III-D using N-Boc-L-alanine and 3-amino5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one, the title intermediate was prepared as a white foam.

C24H34N4O4 (MW = 442.62); mass spectroscopy (M+H) 443.2.

Step D - Preparation of 3-(L-alaninyl]amino-3-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-(N'-(tert-butylcarbamate)-L-alaninyl)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2 -he,

the titled intermediate is prepared in the form of a white foam. The raw material was used immediately.

C19H26N4O2 (M+H = 343.2136); mass spectroscopy - found 343.2139.

Example 8-H

Synthesis of 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 2-[N-(a-isopropylthio)-N'(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone

A solution of �-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq., diluted according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0°C and treated oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed and stirring was continued at ambient temperature for 40 minutes. The solution was cooled again to 0°C. A solution of 2-amino-5-nitrobenzophenone (0.9 eq.; Acros) and 4-methylmorpholine (2.0 eq.) in dry THF acid chloride was added by cannula. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with methylene chloride and washed with 0.5 M citric acid solution, saturated aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative LC2000 chromatography eluting with a gradient of 15→20% ethyl acetate/hexane to give an off-white foam.

C26H25N3O6S (MW = 507.61); mass spectroscopy - found 507.9.

Analysis - calculated for C26H25N3O6S: C, 61.53; H, 4.96; N, 8.28. Found: C, 61.70; H, 4.99; N. 8.22.

Step B - Preparation of 2-[N-(�-amino)-N'-(benzyloxycarbonyl)glycinyl]-amino-5-nitrobenzophenone

Ammonia gas was passed through a solution of 2-(N-(�-isopropylthio)-N'-(benzyloxycarbonyl)-glycinyl)-amino-5-nitrobenzophenone (1 eq) in THF at 0°C. After 35 minutes mercury(II) chloride (1.1 eq.) was added. The ice bath was removed and ammonia flow was continued through the suspension for 4 hours. The bubbler was removed and the reaction mixture was stirred for 16 h. The mixture was filtered through Celite eluting with THF. The filtrate was concentrated in vacuo. The crude solid was used in stage C without further purification.

Step C - Preparation of 3-(benzyloxycarbonyl)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-one

2-[N-(α-Amino)-N'-(benzyloxycarbonyl)-glycinyl)-amino-5-nitrobenzophenone (1 eq.) was treated with glacial acetic acid and ammonium acetate (4.7 eq.). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction mixture in vacuo, the residues were partitioned between ethyl acetate and 1N NaOH solution. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residues were purified by "flash" chromatography eluting with a 2→3% isopropyl alcohol/methylene chloride gradient.

C23H18N4O5 (MW = 430.45); mass spectroscopy - found (M+H) 431.2.

Analysis - calculated for C23H18N4O5: C, 64.18; H, 4.22; N, 13.02. Found: C, 64.39; H, 4.30; N, 13.07.

Step D - Preparation of 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-one

Following general procedure 8-A and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared as a yellow foam .

C24H20N4O5 (MW = 444.48); mass spectroscopy - found (M+H) 445.2.

Analysis - calculated for C24H20N4O5: C, 64.86; H, 4.54; N, 12.60. Found: C, 65.07; H, 4.55; N, 12.46.

Stage E - Preparation of 3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B and using 3-(benzyloxycarbonyl)amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared in in the form of yellow foam that was used directly in stage F.

Step F - Preparation of 3-[N'-(tert-butylcarbamate)-L-alaninyl]amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2- she

According to general procedure III-D using N-Boc-L-alanine and 3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one, titled the intermediate is prepared as a yellow solid.

C24H27N5O6 (MW = 481.56); mass spectroscopy - found (M+H) 482.3.

Analysis - calculated for C24H27N5O6: C, 59.88; H, 5.61; N, 14.55. Found: C, 60.22; H, 5.75; N, 13.91.

Stage G - Preparation of 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-[N'-(tert-butylcarbamate)-Lalaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine- 2-one, the titled intermediate was prepared as a yellow foam. The raw material was used immediately.

Example 8-I

Synthesis of 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one

The flask was charged with 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-one (1 eq; example 8-D, grade A) and 10% palladium on carbon. Methanol was added, and the flask was placed under the hydrogen bottle. The reaction mixture was stirred for 21 hours. The mixture was filtered through Celite eluting with methanol. The filtrate was concentrated to a white solid.

C16H14FN3O (MW = 283.33); mass spectroscopy - found (M+H) 248.1.

Step B - Preparation of 3-(N'-(tert-butylcarbamate)-L-alaninyl]amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2- she

According to general procedure III-D using N-Boc-L-alanine and 3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one, titled the intermediate is prepared as a white solid.

C24H27FN4O4 (MW = 454.50); mass spectroscopy - found (M+H) 455.4.

Analysis - calculated for C24H27FN4O4: C, 63.44; H, 5.95; N, 12.33. Found: C, 63.64; H, 6.08; N, 12.16.

Step C - Preparation of 3-(L-alaninyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4- benzodiazepine-2-one, the title intermediate was prepared as a white foam. The raw material was used immediately.

Example 8-J

Synthesis of 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 2-amino-3'-fluorobenzophenone

A solution of 3-bromofluorobenzene (1 eq.) in THF was cooled to -78°C under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not rise above 74°C. The orange solution was stirred at -78°C for 30 min before the addition of anthranylnitrile (0.6 equiv) as a solution in THF. The reaction mixture was heated to 0°C and stirred for 2 hours. 3N HCl solution was added to the mixture and stirring was continued for 30 minutes. The reaction mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted three times with ethyl acetate. The combined extracts were washed with saline, dried over Na2SO4, filtered and concentrated. The residues were purified by HPLC eluting with 93:7 hexane/ethyl acetate.

C13H10FNO (MW = 215.24); mass spectroscopy - found (M+H) 216.3.

1H-NMR (300 MHz, CDCl3) � = 7.44-7.19 (6H, m), 6.74 (1H, d, J = 8.0 Hz), 6.61 (1H, dd, J = 0.94, 7.9 Hz), 6.10 (2H, bs).

Step B - Preparation of 2-[N-(α-isopropylthio)-N'(benzyloxycarbonyl)-glycinyl]-amino-3'fluorobenzophenone

A solution of �-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq.; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0°C and treated oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed and stirring was continued at ambient temperature for 40 minutes. The solution was cooled again to 0°C. A solution of 2-amino-3'-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0 eq.) in dry THF acid chloride was added by cannula. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with methylene chloride and washed with 0.5 M citric acid solution, saturated aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residues were purified by preparative LC2000 chromatography eluting with a 13→20% ethyl acetate/hexane gradient to give an off-white foam.

C26H25N2O2S (MW = 480.60); mass spectroscopy - found (M+NH4+) 498.3

1H NMR (300 MHz, CDCl3) � = 11.39 (1H, s), 8.59 (1H, d, J = 6.0 Hz), 7.63-7.55 (2H, m), 7.48-7.27 (9H, m), 7.14 (1H , dt, J = 1.2, 8.4 Hz), 5.94 (1H, d, J = 7.2 Hz), 5.58 (1H, d, J = 8.7 Hz), 5.17 (2H, ABq, J = 14.7 Hz), 3.25 (1H , sep, J = 6.6 Hz), 1.44 (3H, d, J = 6.0 Hz), 1.28 (3H, d, J = 6.6 Hz).

Step C - Preparation of 2-[N-(α-amino)-N'-(benzyloxycarbonyl)glycinyl]-amino-3'-fluorobenzophenone

Ammonia gas was passed through a solution of 2-[N-(�-isopropylthio)-N'(benzyloxycarbonyl)-glycinyl)-amino-3'-fluorobenzophenone (1 equiv) in THF at 0°C. After 35 minutes, mercury(II) chloride (1.1 eq.) was added. The ice bath was removed and ammonia flow was continued through the suspension for 4 hours. The bubbler was removed and the reaction mixture was stirred for 16 h. The mixture was filtered through Celite eluting with THF. The filtrate was concentrated in vacuo. The crude solid was used in step D without further purification.

Step D - Preparation of 3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepine-2-one

2-[N-(�-amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq.) was treated with glacial acetic acid and ammonium acetate (4.7 eq.). The suspension was stirred at ambient temperature for 21 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residues were purified by "flash" chromatography eluting with a 2→3% isopropyl alcohol/methylene chloride gradient.

C23H18FN3O3 (MW = 403.44); mass spectroscopy - found (M+H) 404.4.

Analysis - calculated for C23H18FN3O3·0.5H2O: C, 66.98; H, 4.64; N, 10.18. Found: C, 67.20; H, 4.64; N, 9.77.

Stage E - Preparation of 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepine-2-one

Following general procedure 8-A and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-3-(3-fluorophenyl)-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared as a yellow foam .

C24H20FN3O3 (MW = 417.47); mass spectroscopy - found (M+H) 418.3.

Analysis - Calcd for C24H20FN3O3: C, 69.06: H, 4.83; N, 10.07. Found: C, 69.33; H, 4.95: N, 9.82.

Step F - Preparation of 3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared in the form of yellow foam which was directly used in the G degree.

Step G - Preparation of 3-[N'-(tert-butylcarbamate)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4 benzodiazepine-2-one

According to general procedure III-D using N-Boc-L-alanine and 3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepine-2-one, titled the intermediate is prepared as a yellow solid.

C24H27FN4O4 (MW = 454.50); mass spectroscopy - found (M+H) 433.3.

Analysis - calculated C24H27FN4O4: C, 63.42; H, 5.99; N, 12.33. Found: C, 63.34; H, 6.01; N, 12.08.

Step H - Preparation of 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazenin-2-one

According to general procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4- benzodiazepine-2-one, the title intermediate was prepared as a yellow foam. The raw material was used immediately.

Example 8-K

Synthesis of 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepine-2-one

Step A - Preparation of 2-amino-4'-fluorobenzophenone

A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to -78°C under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not exceed 74°C. The orange solution was stirred at -78°C for 30 min before the addition of anthranylnitrile (0.6 equiv) as a solution in THF. The reaction mixture was heated to 0°C and stirred for 2 hours. 3N HCl solution was added to the mixture and stirring was continued for 30 minutes. The reaction mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted three times with ethyl acetate. The combined extracts were washed with saline, dried over Na2SO4, filtered and concentrated. The residues were purified by HPLC eluting with 93:7 hexane/ethyl acetate.

C13H10FNO (MW = 215.24); mass spectroscopy - found (M+H) 216.3.

Analysis - calculated for C13H10FNO: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.80; H, 4.51; N, 6.74.

Step B - Preparation of 2-[N-(α-isopropylthio)-N' (benzyloxycarbonyl)-glycinyl]-amino-4'fluorobenzophenone

A solution of �-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq.; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0°C and treated oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed and stirring was continued at ambient temperature for 40 minutes.

The solution was cooled again to 0°C. A solution of 2-amino-4'-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0 eq.) in dry THF acid chloride was added by cannula. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with methylene chloride and washed with 0.5 M citric acid solution, saturated aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated. the residue was purified by preparative LC2000 chromatography eluting with a 15→20% ethyl acetate/hexane gradient to give an off-white foam.

C26H25N2O4S (MW = 480.60); mass spectroscopy - found (M+NH4+) 498.2.

1H-NMR (300 MHz, CDCl3) � = 11.28 (1H, s), 8.56 (1H. d, J = 8.4 Hz), 7.78-7.73 (2H, m), 7.61-7.53 (2H, m), 7.36- 7.32 (5H, m), 7.20-7.14 (3H, m), 5.98 (1H, d, J = 7.5 Hz), 5.57 (1H, d, J = 7.8 Hz), 5.16 (2H, ABq, J = 14.7 Hz ), 3.25 (1H, sep, J = 6.0 Hz), 1.43 (3H, d, J = 6.3 Hz), 1.27 (3H, d, J = 6.6 Hz).

Step C - Preparation of 2-[N-(α-amino)-N'-(benzyloxycarbonyl)glycinyl-amino-4'-fluorobenzophenone

Ammonia gas was passed through a solution of 2-[N-(α-isopropylthio)-N'(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq.) in THF at 0°C. After 35 minutes, mercury(II) chloride (1.1 eq.) was added. The ice bath was removed and ammonia flow was continued through the suspension for 4 hours. The bubbler was removed and the reaction mixture was stirred for 16 h. The mixture was filtered through Celite eluting with THF. The filtrate was concentrated in vacuo. The crude solid was used in step D without further purification.

Step D - Preparation of 3-(benzyloxycarbonyl)amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepine-2-one

2-[N-(α-amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-4'-fluorobenzophenone (1 eq.) was treated with glacial acetic acid and ammonium acetate (4.7 eq.). The suspension was stirred at ambient temperature for 21 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residues were purified by "flash" chromatography eluting with a 2→3% isopropyl alcohol/methylene chloride gradient.

C23H18FN3O3 (MW = 403.44); mass spectroscopy - found (M+H) 404.4.

Analysis - calculated for C23H18FN3O3·1.25H2O: C, 64.85: H, 4.85. Found.: C, 64.80; H, 4.55.

Step E - Preparation of 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepine-2-one

Following general procedure 8-A and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared as a yellow foam. .

C24H20FN3O3 (MW = 417.47); mass spectroscopy - found (M+H) 418.2.

Analysis - calculated for C24H20FN3O3: C, 69.06; H, 4.83; N, 10.07. Found: C, 69.35; H, 4.93; N, 9.97.

Step F - Preparation of 3-amino-1,3-dihydro-1-methyl-5-(4-fluorophenyl)-2H-1,4-benzodiazepine-2-one

According to general procedure 8-B and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepine-2-one, the title intermediate was prepared in the form of yellow foam which was directly used in the G degree.

Step G - Preparation of 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepine-2 -she

According to general procedure III-D using N-Boc-L-alanine and 3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepine-2-one, titled the intermediate is prepared as a yellow solid.

C24H27FN4O4 (MW = 454.50); mass spectroscopy - found (M+H) 455.4.

Analysis - calculated for C24H27FN4O4·1.5H2O: C, 59.86; H, 6.28; N, 11.64. Found: C, 60.04; H, 5.62; N, 11.27.

Step H - Preparation of 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepine-2-one

According to general procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4- benzodiazepine-2-one, the title intermediate was prepared as a yellow foam. The raw material was used immediately.

Example 8-L

Synthesis of 3-(N'-L-alaninyl)amino-2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-benzodiazepine-2-one

Grade A: 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (prepared according to the procedure described in M. G. Bock et al., J. Org. Chem. 1987, 52, 3232- 3239)

was alkylated with isobutyl iodide using general procedure 8-G to give 1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepine-2-one.

Step B: According to general procedures 8-D and 8-F and using the product from step A, 3-amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepine-2- he.

Step C: The product from step B and N-Boc-L-alanine (Sigma) were coupled using general procedure III-D, then the Boc group was removed using general procedure 8-J, to give 3-(N'-L- alaninyl)amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepine-2-one.

By replacing isopropyl iodide, n-propyl iodide, cyclopropylmethyl iodide and ethyl iodide with isobutyl iodide in the above step A, the following intermediates were prepared:

3-(N'-L-alaninyl)amino-1,3-dihydro-1-isopropyl-5-phenyl-2H-1,4-benzodiazepine-2-one

3-(N'-L-alaninyl)amino-1,3-dihydro-1-propy1-5-phenyl-2H-1,4-benzodiazepine-2-one

3-(N'-L-alaninyl)amino-1,3-dihydro-1-cyclopropylmethyl-5-phenyl-2H-1,4-benzodiazepine-2-one

3-(N'-L-Alaninyl)amino-1,3-dihydro-1-ethyl-5-phenyl-2H-1,4-benzodiazepine-2-one.

Example 8-M

Synthesis of 3-(N'-L-alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-one

Step A: 1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one (CAS No. 32900-17-7) was methylated using general procedure 8-I to give 1methyl -5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-one.

Step B: According to general procedures 8-E and 8-F and using the product from step A, 3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5- benzodiazepine-2-one.

Step C: The product from step B and N-Boc-L-alanine (Sigma) were coupled using general procedure III-D, then the Boc group was removed using general procedure 8-N, to give 3-(N'-L- alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one.

Example 8-N

Synthesis of 3-(N'-L-alaninyl)amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 131604-75-6) is linked with N- with Boc-L-alanine (Sigma) using general procedure III-D, then the Boc group was removed using general procedure 8-N, to give the title compound.

Example 8-O

Synthesis of 3-((R)-hydrazinopropionyl)amino-2,3-dihydro-1-methyl-5-phenyl)-1H-1,4-benzodiazepine-2-one

3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one is attached to (R)-N,N'-di-BOC-2-hydrazinepropionic acid ( example N) using general procedure III-D. Removal of the Boc group using general procedure 5-B gives the title compound.

Example 8-P

Synthesis of 3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Step A: Synthesis of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

2,4-dioxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (CAS No. 49799-486) was prepared from 1,2-phenylenediamine (Aldrich) and malonic acid (Aldrich) using the procedure in Claremon, D. A.; et al, PCT Application: WO 96-U58400 960603.

Step B: Synthesis of 2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 113021-84-4) was prepared according to the general procedure 8-M using the product from step A and 2-iodopropane (Aldrich). Purification was performed by flash chromatography eluting with EtOAc/hexane (3:7 gradient to 1:1), then recrystallization from EtOAc/hexane.

Step C: Synthesis of 3-azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

According to the general procedure 8-K using the product from step B, 3-azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1, 5-benzodiazepine (CAS No. 186490-50-6) in the form of a white solid. The product was purified by flash chromatography eluting with hexane/EtOAc (4:1) to afford a separable 23:1 mixture of pseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide was used in the next step.

Step D: Synthesis of 3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

According to general procedure 8-L using the product from step C, 3amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine (CAS No. 186490-51-7) in the form of a white solid. Purification by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5). The isolated pseudo-axial amine atropisomer was completely converted into the pseudo-equatorial amine atropisomer by heating in toluene at 100-105°C for 15 minutes, and the pseudo-equatorial amine atropisomer was used in the next step. The isomers were differentiated from each other by 1H-NMR in CDCl3.

Selected 1H-NMR (CDCl3): Pseudo-axial amine 4.40 (s, 1H); Pseudo-equatorial amine 3.96 (s, 1H).

Example 8-Q

Synthesis of 3-(R-2-thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of N-(t-butoxycarbonyl)-R-2-thienylglycine

N-(t-butoxycarbonyl)-R-2-thienylglycine (CAS No. 74462-03-1) was prepared from L-�-(2-thienyl)glycine (Sigma) by the procedure described in Bodansky, M. et al. ; The Practice of Peptide Synthesis; Springer Verlag; 1994, p. 17.

Step B: Synthesis of 3-[N'-(t-butoxycarbonyl)-R-2-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5 -tetrahydro-1H-1,5-benzodiazepine

3-[N'-(t-butoxycarbonyl)-R-2-thienylglycinyl]-amino-2,4 -dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white foam. Purification was performed by flash chromatography eluting with CH2Cl2/EtOAc (9:1 gradient to 5:1).

Step C: Synthesis of 3-(R-2-thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Following the general procedure 8-N above using the product from step B, the title compound was prepared as a white solid.

Example 8-R

Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of 2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-dioxo-1,3-bis-methyl-2,3,4,5-tetrahydro-1H-1,3-benzodiazepine (CAS No. 23954-54-3) was prepared according to general procedure 8-M using the product of Example 8-P, grade A and iodomethane (Aldrich). A white solid settled during partial concentration of the reaction mixture after work-up, and was separated by filtration.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

For this substrate, the general 8-K procedure was modified as follows. Initially, the product from step A was suspended (not dissolved) in THF at -78°C, and after the addition of KN(TMS)2 solution, this solution was allowed to warm to -35°C for 12 minutes, whereupon the suspension went into solution, which was cooled again to -78°C; and then processed as described in the general procedure. 3-azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by flash chromatography eluting with CHCl3/EtOAc (7:1 ), then extracted from hot CHCl3 with hexane and cooled to -23°C. The product was isolated as a white solid.

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

According to general procedure 8-L using the product of step B, 3-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared in in the form of a white solid. The crude product was used without further purification.

Step D: Synthesis of 3-[N'-(t-butoxycarbonyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1, 5-benzodiazepines

According to the general procedure III-I above and using N-Boc-L-alanine (Novabiochem) and the product from step C, 3-[N'-(t-butoxycarbonyl)-L-alaninyl)-amino-2, 4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white foam. Purification was performed by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 1:1).

Step E: Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bismethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Following the general procedure 8-N above and using step D, the title compound was prepared as an off-white amorphous solid.

Example 8-S

Synthesis of 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of 2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared according to general procedure 8-M using the product of example 8-P , grade A and 1-iodo-2-methylpropane (Aldrich). Purification was performed by flash chromatography eluting with EtOAc/hexane (3:7 gradient to 1:1) and then recrystallizing from EtOAc/hexane.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

According to the general procedure 8-K (a precipitate formed during the addition of KN(TMS)2, but was dissolved after the addition of trisil-azide) using the product from step A, 3-azido-2,4-dioxo-1,5-bis was prepared -(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white solid. The product was purified by flash chromatography eluting with hexane/EtOAc (4:1) and another flash chromatography eluting with CH2Cl2/hexane/EtOAc (10:10:1 gradient to 8:6:1).

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,3-benzodiazepine

According to general procedure 8-L using the product of step B, 3-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1, 5-benzodiazepine in the form of a white solid. Purification was performed by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in MeOH).

Step D: Synthesis of 3-[N'-(t-butoxycarbonyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepines

According to the general procedure III-I above and using N-Boc-L-alanine (Novabiochem) and the product from step C, 3-[N'-(t-butoxycarbonyl)-L-alaninyl]-amino-2, 4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white foam. Purification was carried out by elution with CH2Cl2/EtOAc (3:1 gradient to 3:2).

Step E: Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Following the general procedure 8-N above and using the product from step D, the title compound was prepared as an amorphous white solid.

Example 8-T

Synthesis of 3-(S-phenylglycinyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of 3-[N'-(t-butoxycarbonyl)-S-phenylglycinyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepines

According to the general procedure III-J above using the product of Example 8-S, step C and Boc-L-phenylglycine (Novabiochem, CAS No. 2900-27-8), 3-[N'-(t-butoxycarbonyl) was prepared -S-phenylglycinyl]-amino-2,4-dioxo-1,5-bis(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white foam. Purification was performed by flash chromatography eluting with CH2Cl2/EtOAc (9:1 gradient to 5:1).

Step B: Synthesis of 3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

According to the general procedure 8-N mentioned above and using the product from step A, 3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3, was prepared. 4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride in the form of an off-white solid.

Example 8-U

Synthesis of 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of 2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines was prepared according to general procedure 8-M using the product of example 8-P, stage A, and (bromomethyl)cyclopropane (Lancaster). Purification was carried out by elution with EtOAc/hexane (3:7 gradient to pure EtOAc), then recrystallization from EtOAc/hexane.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5benzodiazepine

For this substrate, the general 8-K procedure was modified as follows. First, the product from stage A was suspended (not dissolved) in THF at -78°C, and after the addition of the KN(TMS)2 solution, the suspension was allowed to warm to -30°C, during which the suspension went into solution, and cooled again to -78°C. After cooling again to -78°C, a precipitate began to form, and the flask containing the mixture was partially raised above the cooling bath until the internal temperature rose to -50°C; and trisil-azide solution was added. The cooling bath was removed and the mixture was allowed to warm to -20°C after which the mixture became a nearly homogeneous solution, and AcOH was added. Then, with the treatment described in the general procedure, the purified 3-azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by excretion from hot and to room temperature EtOAc, after which it was recrystallized from a hot to -23°C CHCl3/EtOAc/EtOH mixture (5:5:1) and isolated as a white solid.

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5benzodiazepine

According to general procedure 8-L using the product of step B, 3-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine in the form of a white solid. Purification was carried out by "flash" chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in MeOH) and recrystallization from a hot mixture of CH2Cl2/hexane (1:1) down to -23°C.

Step D: Synthesis of 3-[N'-(t-butoxycarbonyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepines

According to the general procedure III-I above and using N-Boc-L-alanine (Novabiochem) and the product from step C, 3-[N'-(t-butoxycarbonyl)-L-alaninyl]-amino-2, 4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white foam. Purification was performed by flash chromatography eluting with CH2Cl2/EtOAc (3:1 gradient to 2:1).

Step E: Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Following the general procedure 8-N above and using the product from step D, the title compound was prepared as an off-white solid.

Example 8-V

Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of 2,4-Dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Neopentyl iodide (43.01 g, 2.24 eq) was added to a suspension of the product of Example 8-P, Stage A (1.0 eq., 17.08 g) in DMSO (500 mL) at room temperature with stirring. , Aldrich) and Cs2CO3 (72.65 g, 2.3 eq., Aldrich). The resulting mixture was heated at 75°C for 30 minutes, then more Cs2CO3 (31.59 g, 1.0 eq.) was added and the mixture was vigorously stirred at 75°C for 6 hours. The mixture was allowed to cool and water (500 mL) and EtOAc (1000 mL) were added. The phases were separated and the organic phase was washed with water (1×500 mL), 1 M aqueous HCl (2×500 mL), and brine (1×500 mL). The organic phase was dried over MgSO4, filtered, concentrated and purified by flash chromatography eluting with hexane/EtOAc (3:2 gradient to 2:3) to give 2,4-dioxo-1,5-bis-(2,2 -dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white solid.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5benzodiazepine

According to the general procedure 8-K using the product from step A, 3-azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine in the form of a white solid. The product was purified by flash chromatography eluting with hexane/CH2Cl2/EtOAc (10:3:1 gradient to 5:5:1) to give a separable 13:1 mixture of pseudo-axial/pseudo-equatorial azides. Pure pseudoaxial azide was used in the next step. Selected 1 HNMR (CDCl 3 ): Pseudo-axial azide 5.12 (s, 1H); Pseudo-equatorial azide 4.03 (s, 1H).

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5benzodiazepine

According to the general procedure 8-L and using the product from step B, 3-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-H -1,5-benzodiazepine in the form of a white solid. Purification was performed by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in MeOH). The isolated white solid was identified as a ∼4:1 mixture of pseudo-axial and pseudo-equatorial amine atropisomers by 1H-NMR. The mixture was heated in toluene at 100°C for 20 min, then concentrated again to give the pure pseudo-equatorial amine atropisomer as a white solid, and used for the next step. Selected 1H-NMR (CDCl 3 ): Pseudo-axial amine 4.59 (s, 1H); pseudo-equatorial amine 4.03 (s, 1H).

Step D: Synthesis of 3-[N'-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5 -tetrahydro-1H-1,5-benzodiazepine

According to the general procedure III-I above and using N-Boc-L-alanine (Novabiochem) and the product from step C, 3-(N'-(t-butoxycarbonyl)-L-alaninyl]-amino-2, 4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine in the form of a white foam Purification was carried out by flash chromatography eluting with CH2Cl2 /EtOAc (4:1 gradient to 5:2).

Step E: Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine hydrochloride

Following the general procedure 8-N above and using the product from step D, the title compound was prepared as an off-white solid.

Example 8-W

Synthesis of 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Step A: Synthesis of 2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

This procedure is a modification of the procedure described in Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016. A mixture of the product from Example 8-P, Grade A (1.0 eq., 7.50 g), Ph 3 Bi (2.2 eq., 41.26 g, Aldrich), Cu(OAc) 2 (2.0 eq. .15.48 g, Aldrich), Et 3 N (2.0 eq., 8.62 g) in CH 2 Cl 2 (100 mL) was stirred under N 2 at room temperature for 6 days (monitored by TLC).

The solids were removed by filtration through a plug of Celite, eluting with CH2Cl2/MeOH (3×75 mL). The filtrate was concentrated, dissolved in hot CH2Cl2/MeOH (9:1) and filtered through a large plug of silica gel eluting with CH2Cl2/MeOH (9:1, 2L). The filtrate was concentrated and the residue was purified by flash chromatography eluting with a CH2Cl2 gradient to CH2Cl2/MeOH (9:1). 2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine crystallized during concentration of fractions containing the product, and was isolated by filtration as a white solid.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

For this substrate, the general 8-K procedure was modified as follows. Initially, the product from step A was suspended (not dissolved) in THF at -78°C, and after the addition of KN(TMS)2 solution, this solution was allowed to warm to -35°C for 12 minutes, whereupon the suspension went into solution, which was cooled again to -78°C; and then processed as described in the general procedure. The title compound was purified by eluting from hot CHCl3/hexane (1:1) to give 3-azido-2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine in the form of a white solid.

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

According to general procedure 8-L using the product of step B, 3-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared in in the form of a white solid. Purification was performed by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in MeOH).

Step D: Synthesis of 3-[N'-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,3-bis-phenyl-2,3,4,5-tetrahydro-1H-1 ,5-benzodiazepines

According to the general procedure III-I above and using N-Boc-L-alanine (Novabiochem) and the product from step C, 3-[N'-(t-butoxycarbonyl)-L-alaninyl]-amino-2, 4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in the form of a white foam. Purification was performed by flash chromatography eluting with CH2Cl2/EtOAc (4:1 gradient to 3:1).

Sten E: Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride

Following the general procedure 8-N above and using step D, the title compound was prepared as a white amorphous solid.

Example 8-X

Synthesis of 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

According to the method of R. G. Sherrill et al., J. Org. Chem., 1995, 60, 730-734 and using glacial acetic acid and HBr gas, the title compound was prepared.

Example 8-Y

Synthesis of 3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

Step A: Synthesis of 3-[N'-(tert-butylcarbamate)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one, (1S)-7,7-dimethyl-2-oxobicyclo[2.2. 1]heptane-1-methanesulfonate (Example 8-B, step A) was obtained in free form by partitioning between methylene chloride and 1 M potassium carbonate. The free amine was then coupled to N-Boc-tert-leucine according to general procedure III-D to give the title compound.

C26H32N4O4 (MW 464.62); mass spectroscopy 464.3.

Analysis - calculated for C26H32N4O4: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.29; H, 6.79; N, 11.20.

Step B: Synthesis of 3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

According to general procedure 8-C and using 3-[N'-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2 -on, the titled compound was prepared in the form of white foam.

C21H23N4O2 (MW 363.48); mass spectroscopy (M+H) 364.2.

Example 8-Z

Synthesis of 3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl3-phenyl-1H-1,4-benzodiazepine-2-one

Step A: Synthesis of 3-[N'-(tert-butylcarbamate)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one, (1S)-7,7-dimethyl-2-oxobicyclo[2.2. 1]heptane-1-methanesulfonate (Example 8-B, step A) was obtained in free form by partitioning between methylene chloride and 1 M potassium carbonate. The free amine was then coupled to N-Boc-tert-leucine according to general procedure III-D to give the title compound.

C27H35N4O4 (MW 479.66); mass spectroscopy 479.

Step B: Synthesis of 3-(L-tert-leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one

According to general procedure 8-C and using 3-[N'-(tert-butylcarbamate)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepines -2-on, the titled compound was prepared in the form of a white foam.

Analysis - calculated for C22H25N4O2·0.5H2O: C, 68.19; H, 7.02; N, 14.40. Found: C, 68.24; H, 7.00; N, 14.00.

Example 8-AA

Synthesis of 3-(L-alaninyl)-amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine

2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine was prepared according to general procedures 8-I (using methyl iodide), 8-D and 8-F. Coupling the intermediate with Boc-L-alanine (Novo) using general procedure III-D, followed by deprotection according to general procedure 5-B afforded the compound which was used without further purification.

Example 8-AB

Synthesis of 3-(L-3-thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Step A: Synthesis of N-(t-butoxycarbonyl)-L-3-thienylglycine

N-(t-butoxycarbonyl)-L-3-thienylglycine was prepared from L-�-(3-thienyl)glycine (Sigma) by the procedure described in Bodansky. M. et al; The Practice of Peptide Synthesis; Springer Verlag; 1994, p. 17.

Step B: Synthesis of 3-[N'-(t-butoxycarbonyl)-L-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2dimethylpropyl)-2,3,4,5 -tetrahydro-1H-1,5-benzodiazepine

According to the general procedure III-D above and using the product of Example 8-V, step C and the product of step A above, 3-[N'-(t-butoxycarbonyl)-L-3-thienylglycinyl]-amino was prepared -2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine.

Step C: Synthesis of 3-(L-3-thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5 -benzodiazepines

Following the general procedure 8-N above and using the product from step B, the title compound was prepared.

Example Bio-1

Cell monitor for detecting inhibitors of β-amyloid production

A number of compounds of formula I have been tested for their ability to inhibit β-amyloid production in a cell line possessing the Swedish mutation. This "screening" assay uses cells (K293 = human kidney cell line) stably transfected with the gene for amyloid precursor protein 751 (APP751) containing a double mutation Lys651Met652 to Asn651Leu652 (APP751 numbering) as described in international patent publication no. . 94/105698 and Citron et al.12. This mutation is commonly referred to as the Swedish mutation and the cells, labeled “293 751 SWE”, were plated in Corning 96-well plates at 1.5-2.5×104 cells per well in Dulbecco's minimal essential medium with 10% fetal with ox serum. The number of cells is essential to obtain β-amyloid ELISA results within the linear range of analysis (~0.2 to 2.5 ng/mL).

After overnight incubation at 37°C in an incubator equilibrated with 10% carbon dioxide, medium was removed and replaced with 200 μL compound of formula I (drug) containing medium per well for a two-hour pretreatment period and cells were incubated as jr mentioned above. "Stock" solutions of the drug were prepared in 100% dimethylsulfoxide so that at the final concentration of the drug used in the processing, the concentration of dimethylsulfoxide did not exceed 0.5% and, in fact, was usually 0.1%.

At the end of the pretreatment time, the medium was again removed and replaced with fresh drug containing medium as above and the cells were incubated for a further two hours. After processing, the plates were centrifuged in a Beckman GPR at 1200 rpm for 5 min at room temperature to separate the cellular fraction from the conditioned medium. From each well, 100 μL of conditioned medium or its appropriate dilution was transferred to an ELISA plate precoated with antibody 26614 against amino acids 13-28 of the β-amyloid peptide as described in international patent publication no. 94/105698, and was placed at 4°C overnight. ELISA analysis used labeled antibody 6C614 against amino acids 1-16 of β-amyloid peptide and was performed the next day to measure the amount of β-amyloid peptide produced.

The cytotoxic effect of the compounds was measured by modifying the method of Hansen et al.13. 25 μL of 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole bromide (MTT) “stock” solution (5 mg/mL) was added to the cells remaining in the tissue culture plate to a final concentration of 1 mg /mL. Cells were incubated at 37°C for 1 hour and cellular activity was stopped by adding an equal volume of MTT lysis buffer (20% w/v sodium dodecyl sulfate in 50% dimethylformamide, pH 4.7). Complete extraction was achieved by shaking overnight at room temperature. The difference in OD562nm and OD650nm was measured in a Molecular Device Uvmax microplate reader as an indicator of cell viability.

ELISA results for β-amyloid peptide were plotted against a standard curve and expressed as ng/mL of β-amyloid peptide. To be normalized for cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the results of the drug-free control. All results are mean values and standard deviations of at least six repeated analyses.

The tested compounds were analyzed for their inhibitory activity against the production of β-amyloid peptide in cells. The results of this analysis show that each of the compounds of this invention reduces the production of β-amyloid peptide by at least 30% compared to the control.

Example of Bio-2

In vivo suppression of β-amyloid release and/or synthesis

This example demonstrates how compounds of the present invention can be tested for in vivo suppression of β-amyloid peptide release and/or synthesis. In these experiments, 3- to 4-month-old PDAPP mice were used [Games et al., (1995) Nature 373:523-527). Depending on which compound is tested, the compound is usually formulated as either 5 or 10 mg/ml. Because of the poor solubility of these compounds, they can be formulated with various carriers such as corn oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil (Safeway); 2-hydroxypropyl-β-cyclodextrin (Research Biochemicals International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis MO). Specifically, for example, for example 141, the carrier was carboxy-methyl-cellulose (Sigma).

Mice were dosed subcutaneously with a 26 gauge needle and 3 hours later the animals were sacrificed using CO2 anesthesia and blood was collected by cardiac puncture using a 1 cc 25G 5/8” tuberculin needle/syringe coated with 0.5 M EDTA, pH 8.0 . Blood was placed in a Becton-Dickinson vacutainer containing EDTA and spun for 15 minutes at 1500 g at 5°C. The mouse brain was then removed, the cerebral cortex and hippocampus were excised and placed on ice.

1. Brain analysis

To prepare cortical and hippocampal tissue for enzyme-linked immunosorbent assay (ELISA), each brain region was homogenized in 10 volumes of ice-cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0) using a Kontes motorized taring machine (Fisher, Pittsburgh PA). The homogenates were shaken gently on a rotating plate for 3 hours at room temperature and placed at -20°C before quantitative determination of β-amyloid.

Brain homogenates were diluted 1:10 with ice-cold casein buffer [0.25% casein, phosphate-buffered saline (PBS), 0.05% sodium azide, 20 μg/ml aprotinin, 5 mM EDTA, pH 8.0, 10 μg/ml leupeptin], so that the final guanidine concentration was reduced to 0.5 M, before centrifugation at 16,000 g for 20 min at 4°C. β-amyloid standards (1-40 or 1-42 amino acids) were prepared so that the final composition corresponded to 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).

"Sandwich" ELISA of total β-amyloid, which quantitatively determines β-amyloid (aa 1-40) and β-amyloid (aa 1-42) consisting of two monoclonal antibodies (mAb) to β-amyloid. The capture antibody, 26614, is specific for amino acids 13-28 of β-amyloid. Antibody 3D615, which is specific for amino acids 1-15 of β-amyloid, is biotinylated and serves as a reference antibody in the analysis. The 3D6 biotinylation procedure used the manufacturer's protocol (Pierce, Rockford IL) for NHS-biotin labeling of immunoglobulin except that 100 mM sodium bicarbonate, pH 8.5 was used. The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP, but only detects β-amyloid species with a terminal aspartic acid. The assay has a lower sensitivity limit of ~50 pg/ml (11 pM) and shows no detection of endogenous β-amyloid peptide at concentrations up to 1 ng/ml.

Configuring a “sandwich” ELISA that quantitatively determines the level of β-amyloid (aa 1-42) uses mAb 21F1215 (which recognizes amino acids 33-42 of β-amyloid) as a capture antibody. Biotinylated 3D6 is also a reference antibody in this assay that has a lower sensitivity limit of ~125 pg/ml (28 pM).

266 and 21F12 capture mAb were coated at 10 μg/ml in a 96-well immunoassay plate (Costar, Cambidge MA) 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 then dried at 4°C until use. Plates were then 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. Plates were washed ≥ 3 times with wash buffer between each assay step. Biotinylated sD6, diluted to 0.5 μg/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) was incubated in the well for 1 hour at room temperature. Avidin-HRP

(Vector, Burlingame CA) was diluted 1:4000 in casein incubation buffer and added to the wells for 1 hour at room temperature. The colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA) was added and reacted for 15 minutes, after which the enzymatic reaction was stopped by the addition of 2N H2SO4. The reaction product was quantified using Molecular Devices UVmax (Molecular Devices, Menlo Park CA) by measuring the difference in absorbance at 450 nm and 650 nm.

2. Blood analysis

EDTA plasma was diluted 1:1 with sample diluent (0.2 gm/l sodium phosphate⋅H2O (monobasic), 2.16 gm/l sodium phosphate⋅7H2O (dibasic), 0.5 gm/l thimerosal, 8.5 gm/l sodium chloride, 0.5 ml TritonX-405, 6.0 g/l globulin-free bovine serum albumin and water). Samples and sample diluent standards were analyzed using the total β-amyloid assay (266 capture/3D6 reference) described above for brain analysis, except that sample diluent was used instead of the casein diluent described.

For oral and intravenous administration, other formulations than those described above may also be used. For oral administration, the compound can be mixed with either 100% corn oil or, alternatively, with a liquid containing 80% corn oil, 19.5% oleic acid and 0.5% labraphyll. The compound may be mixed with the above solutions at concentrations ranging from 1 mg/mL to 10 mg/mL. The compound in solution is primarily administered orally to mammals in a dose volume of 5 mL/kg of body weight. For intravenous administration, the compound is preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% saline. The compound is preferably mixed with the above solution at concentrations ranging from 0.25 mg/mL to 5 mg/mL. The compound in solution is preferably administered intravenously to the mammal in a dose volume of 2 mL/kg of body weight.

According to the above description, those familiar with this field know that various modifications and changes in composition and methods are possible. All such modifications are within the scope and scope of the attached requirements.

Claims (98)

1. A method for inhibiting the release of β-amyloid peptide and/or its synthesis in a cell, characterized by the fact that it includes administering to such a cell a certain amount of a compound or a mixture of compounds that are effective in inhibiting the cellular release and/or synthesis of β-amyloid peptide, wherein are listed compounds designated by formula I: A-B-C where A is selected from the set consisting of: (and) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; Z is selected from the set it consists of (a) a group of the formula -CX'X"C(O)- where X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; (b) a group of the formula -T-CX'X"C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; and (c) a group of the formula -CX'X"-T-C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 a hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; R 6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; (ii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , under condition in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you (iii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you B is selected from the set consisting of: (and) [image] wherein R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (ii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iv) when A is of formula (ii) or (iii) defined above, then B may also be a covalent bond connecting A and C; C is selected from the set consisting of: -C(O)Y or -C(S)Y where Y is selected from the set consisting of: (a) alkyl or cycloalkyl, (b) substituted alkyl provided that the substitution on said alkyl does not include �-haloalkyl, �-diazoalkyl, �-OC(O)alkyl, or �-OC(O)aryl groups, (c) Alkoxy or Thioalkoxy, (d) Substituted Alkoxy or Substituted ThioAlkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic compound, (i) -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, where one of R' or R" hydroxy or alkoxy, and wherein R' and R" are linked to form a cyclic group having 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen , and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, (j) –NHSO2-R8 where R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above; (ii) –CR11R11Y' wherein each R 11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkyl, substituted thioalkoxy, -OC(O)R9, -SSR9, and -SSC(O)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compounds; you (iii) [image] where A, together with -C=N-, forms a heterocyclic group which is arbitrarily joined to form a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each such ring structure is optionally substituted with 1 to 4 substituents selected from the group consisting of Hydroxyl, Halo, Alkoxy, Substituted Alkoxy, Thioalkoxy, Substituted Thioalkoxy, Nitro, Cyano, Carboxyl, Carboxyl Esters, Alkyl, Substituted Alkyl, Alkenyl, Substituted Alkenyl, Alkynyl, Substituted Alkynyl, Aryl, Heteroaryl, Heterocyclic Compound, -NHC(O) R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S( O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N, N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalc ylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylamino, N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic compound amino, N,N- a diheterocyclic compound of amino and mixed N,N-amino groups containing the first and second substituents on said amino group where the substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound provided that said first and second substituents are not identical; with the condition that when A is of structure (i) and B has structure (i), then C does not have structure (i) or (ii); with the further proviso that A. when A has structure (i) where R1 is phenyl, Z is –CH2OC(O)-, R2 is methyl and p is zero, B has structure (iii) where W is -NH-, X is –CH2-, and R 4 is benzyl then C is not -C(O)OCH 3 ; B. when A has structure (i) where R1 is 3,5-difluorophenyl, Z is –CH2C(O)-, R2 is methyl and p is zero, B has structure (ii) where W >NC(O)OC( CH3)3, X is –CH2-, and R4 is phenyl, then C is not -C(O)OCH3; and C. when A has the structure (ii) where R1 is 3,5-difluorophenyl, T' is a bond connecting R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is the covalent bond that binds A to C, then C is not -C(O)OCH3. 2. A method for preventing the onset of AD in a patient at risk of developing AD, characterized in that it includes administering to said patient a pharmaceutical composition containing a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of formula I: A-B-C where A is selected from the set consisting of: (and) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; Z is selected from the set it consists of (a) a group of the formula -CX'X"C(O)- where X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; (b) a group of the formula -T-CX'X"C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; and (c) a group of the formula -CX'X"-T-C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; R 6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; (ii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . a heteroaryl, a heterocyclic compound or a cycloalkyl group with an ethylene group, provided that if the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you (iii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you B is selected from the set consisting of: (and) [image] wherein R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (ii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iv) when A is of formula (ii) or (iii) defined above, then B may also be a covalent bond connecting A and C; C is selected from the set consisting of: -C(O)Y or -C(S)Y where Y is selected from the set consisting of: (a) alkyl or cycloalkyl, (b) substituted alkyl provided that the substitution on said alkyl does not include �-haloalkyl, �-diazoalkyl, �-OC(O)alkyl, or �-OC(O)aryl groups, (c) Alkoxy or Thioalkoxy, (d) Substituted Alkoxy or Substituted ThioAlkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic compound, (i) -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, where one of R' or R" hydroxy or alkoxy, and wherein R' and R" are linked to form a cyclic group having 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen , and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, (j) –NHSO2-R8 where R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above; (ii) –CR11R11Y' wherein each R 11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkyl, substituted thioalkoxy, -OC(O)R9, -SSR9, and -SSC(O)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compounds; you (iii) [image] where A, together with -C=N-, forms a heterocyclic group which is arbitrarily joined to form a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl , cycloalkenyl, heterocyclic compound, aryl and heteroaryl group wherein, again, each such ring structure is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, nitro, cyano , carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O) NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N -disubstituted cycloalkylamino, N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic compound amino, N,N-diheterocyclic compound amino and mixed N,N-amino groups containing the first and second a substituent on said amino group where the substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and a heterocyclic compound provided that said first and second substituents are not identical; with the condition that when A is of structure (i) and B has structure (i), then C does not have structure (i) or (ii); with the further proviso that A. when A has structure (i) where R1 is phenyl, Z is –CH2OC(O)-, R2 is methyl and p is zero, B has structure (iii) where W is -NH-, X is –CH2-, and R 4 is benzyl then C is not -C(O)OCH 3 ; B. when A has structure (i) where R1 is 3,5-difluorophenyl, Z is –CH2C(O)-, R2 is methyl and p is zero, B has structure (ii) where W >NC(O)OC( CH3)3, X is –CH2-, and R4 is phenyl, then C is not -C(O)OCH3; and C. when A has the structure (ii) where R1 is 3,5-difluorophenyl, T' is a bond connecting R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is the covalent bond that binds A to C, then C is not -C(O)OCH3. 3. A method for treating a patient with AD to prevent further deterioration of the patient's condition, characterized in that it includes administering to such a patient a pharmaceutical composite containing a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of formula I: A-B-C where A is selected from the set consisting of: (and) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; Z is selected from the set it consists of (a) a group of the formula -CX'X"C(O)- where X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; (b) a group of the formula -T-CX'X"C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; and (c) a group of the formula -CX'X"-T-C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; R 6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; (ii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl , cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxylic esters and a heterocyclic compound and furthermore, when q equals 2, the R7 group on each carbon atom can be arbitrarily joined to form an aryl, heteroaryl, heterocyclic compound or cycloalkyl group with an ethylene group, provided that if the group is unsaturated, the remaining The R7 group on each carbon atom participates in unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you (iii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , the floor provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you B is selected from the set consisting of: (and) [image] wherein R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (ii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iv) when A is of formula (ii) or (iii) defined above, then B may also be a covalent bond connecting A and C; C is selected from the set consisting of: -C(O)Y or -C(S)Y where Y is selected from the set consisting of: (a) alkyl or cycloalkyl, (b) substituted alkyl provided that the substitution on said alkyl does not include �-haloalkyl, �-diazoalkyl, �-OC(O)alkyl, or �-OC(O)aryl groups, (c) Alkoxy or Thioalkoxy, (d) Substituted Alkoxy or Substituted ThioAlkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic compound, (i) -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, where one of R' or R" hydroxy or alkoxy, and wherein R' and R" are linked to form a cyclic group having 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen , and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, (j) –NHSO2-R8 where R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above; (ii) –CR11R11Y' wherein each R 11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkyl, substituted thioalkoxy, -OC(O)R9, -SSR9, and -SSC(O)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compounds; you (iii) [image] where A, together with -C=N-, forms a heterocyclic group which is arbitrarily joined to form a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl , cycloalkenyl, heterocyclic compound, aryl and heteroaryl group wherein, again, each such ring structure is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, nitro, cyano , carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O) NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N -disubstituted cycloalkylamino, N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic compound amino, N,N-diheterocyclic compound amino and mixed N,N-amino groups containing the first and second a substituent on said amino group where the substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and a heterocyclic compound provided that said first and second substituents are not identical; with the condition that when A is of structure (i) and B has structure (i), then C does not have structure (i) or (ii); with the further proviso that A. when A has structure (i) where R1 is phenyl, Z is –CH2OC(O)-, R2 is methyl and p is zero, B has structure (iii) where W is -NH-, X is –CH2-, and R 4 is benzyl then C is not -C(O)OCH 3 ; B. when A has the structure (i) where R 1 is 3,5-difluorophenyl, Z is –CH2C(O)-, R2 is methyl and p is zero, B has structure (ii) where W >NC(O)OC(CH3)3, X is –CH2-, and R4 is phenyl, then C is not -C (O)OCH3; and C. when A has the structure (ii) where R1 is 3,5-difluorophenyl, T' is a bond connecting R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is the covalent bond that binds A to C, then C is not -C(O)OCH3. 4. The method according to claims 1, 2 or 3, characterized in that the compound of formula I is further characterized by the following formula II: [image] where R1, R2, R5, R6, A, Z, m and p are as defined in claim 1. 5. The method according to claim 4, characterized in that, where m is equal to one, Z is -CX'X"C(O), X" is hydrogen, X' is hydrogen or fluorine or X' and X" form an oxo group. 6. The method according to claim 5, characterized in that R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 7. The method according to claim 5, characterized in that R1 is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls and trisubstituted phenyls. 8. The method according to claim 7, characterized in that R1 is a phenyl group selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-isopropylphenyl, 4- phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,4 5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5 -trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluoro rphenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3 -trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl. 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl. 9. The method according to claim 4, characterized in that R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 10. The method according to claim 4, characterized in that R1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group. 11. The method according to claim 10, characterized in that R1 is selected from the group consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, -CH2CH= CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2cyclohexyl and -CH2CH2-cyclopentyl. 12. The method according to claim 4, wherein R1 is heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3 -yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran- 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1 ,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 13. The method according to claim 4, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl and -CH2CH2SCH3. 14. The method according to claim 4, wherein R5 and R6 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl , -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m -methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl; p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3- tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t -butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, - CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -{CH2)4NH-Boc, -(CH2 )4NH2, -CH2-pyridyl (eg 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (eg 1-naphthyl and 2 -naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5 ,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth -2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl and the like. 15. The method according to claim 4, characterized by where [image] 15. group which is further characterized by the following heterocyclic structure: [image] where Y” is a heteroatom which can be oxygen, sulfur and >NR8 where R8 as defined above and A', together with –Y”-C=N-, form a heterocyclic group which is arbitrarily joined forming a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures which are selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each ring structure is optionally substituted with 1 to 4 substituents which are selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl , substituted thioalkoxy, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N- substituted alkylamino, N,N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O)NR10R10, -S (O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl. 16. The method according to claim 15, characterized in that the heterocyclic structure is selected from 3-methyl-1,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-phenyl-1,2,4-oxadiazol- 5-yl and 3-(p-methoxy-benzyl)-1,2,4-oxadiazol-5-yl. 17. The method according to claim 4, characterized in that the compound of formula II is selected from the group consisting of: (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2-phenylethyl]-3-methyl-1,2,4-oxadiazole 2-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-2-thiazoline (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-methyl-1,2,4-oxadiazole (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-phenyl-1,2,4-oxadiazole (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole. 18. The method according to claims 1, 2 or 3, characterized in that the compound of formula I is further characterized by formulas III and IV below: [image] and [image] where R 1 , R 2 , R 4 , R 6 , W, X, Y, Z, m and p are as defined above. 19. The method according to claim 18, wherein m is one, Z is -CX'X"C(O)-, X" is hydrogen, X' is hydrogen or fluorine and where X' and X" form an oxo group. 20. The method according to claim 19, characterized in that R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 21. The method according to claim 19, characterized in that R1 is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls and trisubstituted phenyls. 22. The method according to claim 21, characterized in that the substituted R1 phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-methylphenyl trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4, 5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phen il, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl , 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4 ,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl. 23. The method according to claim 18, characterized in that R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 24. The method according to claim 18, wherein R1 is selected from the group of alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl. 25. The method according to claim 24, characterized in that R1 is selected from the group consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, -CH2CH= CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl. 26. The method according to claim 18, wherein R1 is heteroaryl or substituted heteroaryl selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3 -yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran- 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1 ,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 27. The method according to claim 18, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl and -CH2CH2SCH3. 28. The method according to claim 18, characterized in that R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl. 29. The method according to claim 18, characterized in that R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH (CH2CH2)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl , phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N -morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2-(1-methyl) cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH , -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g. 2-pyridyl, 3-pyridyl and 4 -pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholino -CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b] thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl . 30. The method according to claim 18, characterized in that, where Y is hydroxy, alkoxy, substituted alkoxy and -NR'R". 31. The method according to claim 30, characterized in that Y is selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2- phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, amino (-NH2), -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-methylyl, -NHCH2-(furan -2-yl), -NHCH2-cyclopropyl, -NH(t-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3 )2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N(CH2CH2CH3)2, -NHOH, -NH(p-NO2-φ), -NHCH2(p-NO2-φ), -NHCH2(m-NO2-φ), -N(CH3)OCH3, -N( CH3)CH2-φ, -NHCH2-(3,5-difluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-φ), -NHCH2(m-CH3O-φ), -NHCH2(p-CF3-φ), -N(CH3)CH2CH2OCH3, -NHCH2CH2φ, -NHCH(CH3)φ, -NHCH2-(p-F-φ), -N(CH3)CH2CH2N(CH3)φ, -NHCH2-(tetrahydrofuran-2-yl) and –CH2CH2CH (CH3)2. 32. The method according to claim 18, wherein the heterocyclic structures are defined by W and X selected from the group consisting of 4,5-dihydrothiazole, 3,4-dihydro-1,3-isodiazole, 3,4-dihydro- 3-N-t-butoxy-3-isodiazole and 4,5-dihydrooxazole. 33. The method according to claim 18, characterized in that the compound of formula II is selected from the group consisting of: (S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline 1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 1-tert-butoxycarbonyl-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-ethoxycarbonyl-2-thiazoline 1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 2-[(S)-1-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine (S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-5(R,S)-ethoxycarbonyl-2-oxazoline 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-methoxycarbonyl-2-thiazoline [1-(N-Carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline. 34. The method according to claims 1, 2 or 3, characterized in that the compound of formula I is further characterized by formulas V and VI below: [image] and [image] where R1, R4, R6, T', X', X", W, X, and Y are as defined above. 35. The method according to claim 34, characterized in that, where m is equal to one, Z is -CX'X”C(O)-, X is hydrogen, X' is preferably hydrogen or fluorine or where X' and X” form an oxo group . 36. The method according to claim 35, characterized in that R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 37. The method according to claim 35, characterized in that R1 is a substituted aryl group consisting of monosubstituted phenyls, disubstituted phenyls and trisubstituted phenyls. 38. The method according to claim 37, wherein R1 is a phenyl group selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-methylphenyl trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4, 5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifl uorphenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3 -trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl , 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl. 39. The method according to claim 34, characterized in that R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 40. The method according to claim 34, wherein R1 is selected from the group of alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl. 41. The method according to claim 40, characterized in that R1 is selected from the group consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, -CH2CH= CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl. 42. The method according to claim 34, wherein R1 is heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3 -yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran- 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1 ,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 43. The method according to claim 34, characterized in that R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl. 44. The method according to claim 34, wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH (CH2CH2)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl , phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2 -imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2-(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH( CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g. 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl ), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5 -chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl , benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl. 45. The method according to claim 34, characterized in that, where Y is hydroxy, alkoxy, substituted alkoxy and -NR'R". 46. The method according to claim 45, characterized in that Y is selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2- phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, amino (-NH2), -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-methylyl, -NHCH2-(furan -2-yl), -NHCH2-cyclopropyl, -NH(t-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3 )2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N( CH2CH2CH3)2, -NHOH, -NH(p-NO2-φ), -NHCH2(p-NO2-φ), -NHCH2(m-NO2-φ), -N(CH3)OCH3, -N(CH3)CH2-φ, -NHCH2-(3,5-difluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-φ), -NHCH2(m-CH3O-φ), -NHCH2(p-CF3-φ), -N(CH3)CH2CH2OCH3, -NHCH2CH2φ, -NHCH(CH3)φ, -NHCH2-(p-F-φ), -N(CH3 )CH2CH2N(CH3)φ and -NHCH2-(tetrahydrofuran-2-yl). 47. The method according to claim 34, characterized in that the heterocyclic structures defined by W and X are selected from the group consisting of 4,5-dihydrothiazoles, 3,4-dihydro-1,3-isodiazoles, 3,4-dihydro-3 -N-t-butoxy-3-isodiazoles and 3,4-dihydrooxazoles. 48. The method according to claim 34, characterized in that the specified compound of formulas V and VI is selected from the group consisting of: (4R)-4-[N-(1S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline 4-[N-(S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline 4-[N-(S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline. 49. A method for inhibiting the release and/or synthesis of β-amyloid peptide in a cell, characterized by the fact that it includes administering to such a cell a certain amount of a compound or a mixture of compounds that are effective in inhibiting the cellular release and/or synthesis of β-amyloid peptide, where said compounds represented by formulas VII and VIII: [image] and [image] where R1, R4, R6, T', X', X", W and X are as defined above. W', together with -C(H)sC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic compound, substituted cycloalkyl or substituted cycloalkenyl group where each of said cycloalkyl, cycloalkenyl, heterocyclic compounds, substituted cycloalkyl or substituted cycloalkenyl group is arbitrarily combined to form a bi- or multiply fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each of the ring structures is arbitrarily substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkyloxy, thioalkyloxy, substituted thioalkyloxy, aryl, heteroaryl, heterocyclic compound, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N=alkylamino, N,N-dia lalkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O )NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 wherein each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl; U is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 50. A method for preventing the onset of AD in a patient at risk of developing AD, characterized in that it includes administering to said patient a pharmaceutical composite containing a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of formulas VII and VIII: [image] and [image] where R1, R4, R6, T', X', X", W and X are as defined above. W', together with -C(H)sC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic compound, substituted cycloalkyl or substituted cycloalkenyl group where each of said cycloalkyl, cycloalkenyl, heterocyclic compounds, substituted cycloalkyl or substituted cycloalkenyl group is arbitrarily combined to form a bi- or multiply fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each of the ring structures is arbitrarily substituted by 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, aryl, heteroaryl, heterocyclic compound, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N=alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R10, -NHSO2R10, -C(O) NH2, -C(O)NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from consisting of alkyl, substituted alkyl or aryl; U is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 51. A method for treating a patient with AD to prevent further deterioration of the patient's condition, characterized in that it includes administering to said patient a pharmaceutical composite containing a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of formulas VII and VIII: [image] and [image] where R1, R4, R6, T', X', X", W and X are as defined above. W', together with -C(H)sC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic compound, substituted cycloalkyl or substituted cycloalkenyl group where each of said cycloalkyl, cycloalkenyl, heterocyclic compounds, substituted cycloalkyl or substituted cycloalkenyl group is arbitrarily combined to form a bi- or multiply fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each of the ring structures is arbitrarily substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkyloxy, thioalkyloxy, substituted thioalkyloxy, aryl, heteroaryl, heterocyclic compound, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N=alkylamino, N,N-dia lalkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O )NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 wherein each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl; U is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 52. Compound of formula I: A-B-C indicated by where A is selected from the set consisting of: (and) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; Z is selected from the set it consists of (a) a group of the formula -CX'X"C(O)- where X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; (b) a group of the formula -T-CX'X"C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; and (c) a group of the formula -CX'X"-T-C(O)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; R 6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound; m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; (ii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you (iii) [image] where R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compound; T' is selected from the group consisting of a bond that covalently connects R1 to -CX'X"-, oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; you B is selected from the set consisting of: (and) [image] wherein R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (ii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further condition that when W is oxygen, then X cannot be oxygen; X' is hydrogen, hydroxy or fluorine; X" is hydrogen, hydroxy or fluorine, or X' and X" together form an oxo group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iii) [image] W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl . , provided that in case the group is unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound; (iv) when A is of formula (ii) or (iii) defined above, then B may also be a covalent bond connecting A and C; C is selected from the set consisting of: -C(O)Y or -C(S)Y where Y is selected from the set consisting of: (a) alkyl or cycloalkyl, (b) substituted alkyl provided that the substitution on said alkyl does not include �-haloalkyl, �-diazoalkyl, �-OC(O)alkyl, or �-OC(O)aryl groups, (c) Alkoxy or Thioalkoxy, (d) Substituted Alkoxy or Substituted ThioAlkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic compound, (i) -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, where one of R' or R" hydroxy or alkoxy, and wherein R' and R" are linked to form a cyclic group having 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen , and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, (j) –NHSO2-R8 where R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic compound, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above; (ii) –CR11R11Y' wherein each R 11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic compound and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkyl, substituted thioalkoxy, -OC(O)R9, -SSR9, and -SSC(O)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic compounds; you (iii) [image] where A, together with -C=N-, forms a heterocyclic group which is arbitrarily joined to form a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl , cycloalkenyl, heterocyclic compound, aryl and heteroaryl group wherein, again, each such ring structure is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, nitro, cyano , carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O) NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and –S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino , N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylamino, N-arylamino, N,N-diarylamino , N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic compound amino, N,N-diheterocyclic compound amino and mixed N,N-amino groups containing the first and second substituents on the specified amino group where the substituents are selected from comprise an alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic compound provided that said first and second substituents are not identical; with the condition that when A is of structure (i) and B has structure (i), then C does not have structure (i) or (ii); with the further proviso that A. when A has structure (i) where R1 is phenyl, Z is –CH2OC(O)-, R2 is methyl and p is zero, B has structure (iii) where W is -NH-, X is –CH2-, and R 4 is benzyl then C is not -C(O)OCH 3 ; B. when A has structure (i) where R1 is 3,5-difluorophenyl, Z is –CH2C(O)-, R2 is methyl and p is zero, B has structure (ii) where W >NC(O)OC( CH3)3, X is –CH2-, and R4 is phenyl, then C is not -C(O)OCH3; and C. when A has the structure (ii) where R1 is 3,5-difluorophenyl, T' is a bond connecting R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is the covalent bond that binds A to C, then C is not -C(O)OCH3. A compound according to claim 52, characterized in that the compound of formula I is further characterized by formula II below: [image] where R1, R2, R5, R6, A, Z, m and p are as defined in claim 52. 52. A compound according to claim 53, characterized in that, where m is equal to one, Z is -CX'X"C(O), X" is hydrogen, X' is hydrogen or fluorine or X' and X" form an oxo group. 53. A compound according to claim 53, characterized in that R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 54. A compound according to claim 53, characterized in that R1 is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls and trisubstituted phenyls. 55. A compound according to claim 56, characterized in that R1 is a phenyl group selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-isopropylphenyl, 4- phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl )phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri -(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl , 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl , 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl. 56. A compound according to claim 53, wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 57. A compound according to claim 53, wherein R1 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups. 58. Compound according to claim 59, characterized in that R1 is selected from the group consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, -CH2CH= CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2cyclohexyl and -CH2CH2-cyclopentyl. 59. A compound according to claim 53, wherein R1 is heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3 -yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran- 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 60. Compound according to claim 53, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl and -CH2CH2SCH3. 61. The compound according to claim 53, characterized in that, where R5 and R6 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl , -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m -methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl; p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3- tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t -butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, - CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -{CH2)4NH-Boc, -(CH2 )4NH2, -CH2-pyridyl (eg 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (eg 1-naphthyl and 2 -naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5 ,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl and the like. 62. The compound according to claim 53, characterized in that, where [image] Group 62 which is further characterized by the following heterocyclic structure: [image] where Y” is a heteroatom which can be oxygen, sulfur and >NR8 where R8 as defined above and A', together with –Y”-C=N-, form a heterocyclic group which is arbitrarily joined forming a bi- or multi-joined ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each ring structure is optionally substituted with 1 to 4 substituents which are selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkyloxy, thioalkyloxy, substituted thioalkyloxy, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N ,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic compound, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R 10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl. 63. The compound according to claim 64, characterized in that the heterocyclic structure is selected from 3-methyl-1,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-phenyl-1,2,4-oxadiazol- 5-yl and 3-(p-methoxy-benzyl)-1,2,4-oxadiazol-5-yl. 64. The compound according to claim 53, characterized in that the compound of formula II is selected from the group consisting of: (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2-phenylethyl]-3-methyl-1,2,4-oxadiazole 2-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-2-thiazoline (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-methyl-1,2,4-oxadiazole (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-phenyl-1,2,4-oxadiazole (S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole. 65. The compound according to claim 52, wherein the compound of formula I is further characterized by formulas III and IV below: [image] and [image] where R 1 , R 2 , R 4 , R 6 , W, X, Y, Z, m and p are as defined above. 66. A compound according to claim 67, wherein m is one, Z is -CX'X"C(O)-, X" is hydrogen, X' is hydrogen or fluorine and where X' and X" form an oxo group. 67. A compound according to claim 67, wherein R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 68. A compound according to claim 67, characterized in that R1 is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls and trisubstituted phenyls. 69. The compound according to claim 70, characterized in that the substituted R1 phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-methylphenyl trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4 ,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4- fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5- dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl. 70. A compound according to claim 67, wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 71. A compound according to claim 67, wherein R1 is selected from the group of alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl. 72. The compound according to claim 73, characterized in that R1 is selected from the group consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, -CH2CH= CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl. 73. A compound according to claim 67, wherein R1 is heteroaryl or substituted heteroaryl selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3 -yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran- 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 74. The compound according to claim 67, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl and -CH2CH2SCH3. 75. A compound according to claim 67, wherein R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl. 76. The compound according to claim 67, characterized in that R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH (CH2CH2)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl , phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl , 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophene -2-yl, -CH2-(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2- C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -( CH2)4NH2, -CH2-pyridyl (e.g. 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N- morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl. 77. A compound according to claim 67, characterized in that Y is hydroxy, alkoxy, substituted alkoxy and -NR'R". 78. A compound according to claim 78, characterized in that Y is selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2- phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, amino (-NH2), -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-methylyl, -NHCH2-(furan -2-yl), -NHCH2-cyclopropyl, -NH(t-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3 )2, -NHCH2C-(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N (CH2CH2CH3)2, -NHOH, -NH(p-NO2-φ), -NHCH2(p-NO2-φ), -NHCH2(m-NO2-φ), -N(CH3)-OCH3, -N(CH3 )CH2-φ, -NHCH2-(3,5-difluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-φ), -NHCH2(m-CH3O-φ), -NHCH2(p-CF3-φ), - N(CH3)CH2CH2OCH3, -NHCH2CH2φ, -NHCH(CH3)φ, -NHCH2-(p-F-φ), -N(CH3)CH2CH2N( CH3)φ, -NHCH2-(tetrahydrofuran-2-yl) and –CH2CH2CH(CH3)2. 79. A compound according to claim 67, wherein the heterocyclic structures are defined by W and X selected from the group consisting of 4,5-dihydrothiazole, 3,4-dihydro-1,3-isodiazole, 3,4-dihydro- 3-N-t-butoxy-3-isodiazole and 4,5-dihydrooxazole. 80. The compound according to claim 67, characterized in that the compound of formula II is selected from the group consisting of: (S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline 1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 1-tert-butoxycarbonyl-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-ethoxycarbonyl-2-thiazoline 1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 2-[(S)-1-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine (S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-5(R,S)-ethoxycarbonyl-2-oxazoline 2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-methoxycarbonyl-2-thiazoline [1-(N-Carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline. 81. The compound according to claim 52, characterized in that the compound of formula I is further characterized by the following formula V and VI: [image] and [image] where R1, R4, R6, T', X', X", W, X, and Y are as defined above. 82. A compound according to claim 83, characterized in that, where m is equal to one, Z is -CX'X”C(O)-, X is hydrogen, X' is preferably hydrogen or fluorine or where X' and X” form an oxo group . 83. A compound according to claim 83, wherein R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 84. A compound according to claim 83, characterized in that R1 is a substituted aryl group consisting of monosubstituted phenyls, disubstituted phenyls and trisubstituted phenyls. 85. A compound according to claim 86, characterized in that R1 is a phenyl group selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3, 4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4 ,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2- fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5, 6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenyl lphenyl and 2-fluoro-3-trifluoromethylphenyl. 86. A compound according to claim 83, wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 87. A compound according to claim 83, wherein R1 is selected from the group of alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl. 88. A compound according to claim 89, characterized in that R1 is selected from the group consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2CH=CH2, -CH2CH= CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl. 89. A compound according to claim 83, wherein R1 is heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3 -yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran- 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythiophen-2-yl, 3-phenyl-1 ,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 90. A compound according to claim 83, wherein R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl. 91. A compound according to claim 83, characterized in that R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH (CH2CH2)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl , phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl , 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophene -2-yl, -CH2-(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2- C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2)COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -( CH2)4NH2, -CH2-pyridyl (e.g. 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g. 1-naphthyl and 2-naphthyl), -CH2-(N- morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2- yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl. 92. A compound according to claim 83, characterized in that Y is hydroxy, alkoxy, substituted alkoxy and -NR'R". 93. A compound according to claim 94, characterized in that Y is selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2- phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, amino (-NH2), -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-methylyl, -NHCH2-(furan -2-yl), -NHCH2-cyclopropyl, -NH(t-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3 )2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N( CH2CH2CH3)2, -NHOH, -NH(p-NO2-φ), -NHCH2(p-NO2-φ), -NHCH2(m-NO2-φ), -N(CH3)OCH3, -N(CH3)CH2 -φ, -NHCH2-(3,5-difluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-φ), -NHCH2(m-CH3O-φ), -NHCH2(p-CF3-φ), -N( CH3)CH2CH2OCH3, -NHCH2CH2φ, -NHCH(CH3)φ, -NHCH2-(p-F-φ), -N(CH3)CH2CH2N(CH 3)φ and -NHCH2-(tetrahydrofuran-2-yl). 94. A compound according to claim 83, wherein the heterocyclic structures are defined by W and X and are selected from the group consisting of 4,5-dihydrothiazoles, 3,4-dihydro-1,3-isodiazoles, 3,4-dihydro-3 -N-t-butoxy-3-isodiazoles and 3,4-dihydrooxazoles. 95. The compound according to claim 83, characterized in that the said compound of formulas V and VI is selected from the group consisting of: (4R)-4-[N-(1S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline 4-[N-(S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline 4-[N-(S)-(1-Methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline. 96. Compound of formulas VII and VIII, characterized by: [image] and [image] where R1, R4, R6, T', X', X", W and X are as defined above; W', together with -C(H)sC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic compound, substituted cycloalkyl or substituted cycloalkenyl group where each of the mentioned cycloalkyl, cycloalkenyl, heterocyclic compounds, substituted cycloalkyl or substituted cycloalkenyl groups are arbitrarily combined to form a bi- or multiply fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the set they comprise cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group wherein, again, each of the ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, aryl, heteroaryl, heterocyclic compound, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N=alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N -substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR 10, -C(O)NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl; U is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 97. Compound of formulas IX and X, characterized by: [image] and [image] where R1, R4, R6, T', X', X", W and X are as defined above; W', together with -C(H)sC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic compound, substituted cycloalkyl or substituted cycloalkenyl group where each of said cycloalkyl, cycloalkenyl, heterocyclic compounds, substituted cycloalkyl or substituted cycloalkenyl group is arbitrarily combined to form a bi- or multiply fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic compound, aryl and heteroaryl group where, again, each of the ring structures is arbitrarily substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkyloxy, thioalkyloxy, substituted thioalkyloxy, aryl, heteroaryl, heterocyclic compound, nitro, cyano, carboxyl, carboxylic esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N=alkylamino, N,N-dia lalkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R10, -NHSO2R10, -C(O)NH2, -C(O)NHR10, -C(O )NR10R10, -S(O)R10, -S(O)2R10, -S(O)2NHR10 and -S(O)2NR10R10 wherein each R10 is independently selected from the group consisting of alkyl, substituted alkyl or aryl; U is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 98. A pharmaceutical composite, characterized in that it contains a pharmaceutically acceptable carrier and an effective amount of a certain compound, according to any of claims 52-99.