MXPA00001743A - N-aroylphenylalanine derivatives - Google Patents

Abstract

Compounds of formula (I) are disclosed which have activity as inhibitors of binding between VCAM-1 and cells expressing VLA-4. Such compounds are useful for treating diseases whose symptoms and /or damage are related to the binding of VCAM-1 to cells expressing VLA-4.

Description

DERIVATIVES OF N-ARILFENILA1ANINA The molecule 1 of adhesion to vascular cells (VCAM-1), a member of the family of immunoglobulin (Ig) supergenes. it is expressed in the activated endothelium, but not in the non-activated endothelium. The integrin VLA-4 (a4b?), Which is expressed in many cell types, including lymphocytes. eosinophils. basophils and circulating monocytes, but not neutrophils. it is the main recipient of VCAM-1. The antibodies of VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes. as well as the melanoma cells, to the activated endothelium in vi tro. Antibodies to either of the two proteins have been effective in inhibiting the infiltration of leukocytes and in the prevention of tissue lesions in various models of animal inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell migration in induced arthritis with adjuvants, prevent the accumulation of eosinophils and bronchoconstriction in asthma models, and reduce paralysis and inhibit the infiltration of monocytes and lymphocytes. in experimental autoimmune encephalitis (EAE). Anti-VCA-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. REF: Recent studies 32,806 have shown that anti-VLA-4 Abs can prevent insulitis and diabetes in nonobese diabetic mice, and significantly attenuate inflammation in the "cotton-top tamarin" model of colitis. Thus, compounds that inhibit the interaction between a4-containing integrins, such as VLA-4 and VCAM-1, will be useful as therapeutic agents for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), lung inflammation (eg, asthma), and inflammatory bowel disease (IBD). Accordingly, the present invention relates to new compounds of formula: and pharmaceutically acceptable salts and esters thereof, wherein X, X ', Z and Y are defined below, which inhibit the binding of VCAM-1 to VLA-4, to the methods for the preparation of these compounds, medicaments. , a process for the production of said medicaments and the use of new compounds in the treatment of diseases, especially inflammatory diseases, which act this union causing the disease. As used in this specification, the term "lower alkyl", alone or in combination, means a straight chain or branched chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. utilo, isobutyl, tere.butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be substituted with one or more groups independently selected from cycloalkyl, nitro, aryloxyl, aryl, hydroxyl, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, and substituted amino, p. eg, "lower alkoxycarbonyl amino" Examples of substituted lower alkyl groups include 2-hydroxylethyl, 3-oxobutyl, cyanomethyl, and 2-nitropropyl The term "cycloalkyl" means a carbocyclic ring of 3 to 7 members, unsubstituted or substituted The useful substituents according to the present invention are hydroxyl, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino. "heterocycloalkyl" means a 5 to 6 membered unsubstituted or substituted carbacyclic ring in which one or two carbon atoms have been replaced by heteroatoms independently selected from 0, S and N. Preferred heterocycloalkyl groups are pyrrolidinyl and morphillinyl. The term "lower alkoxy" means a straight-chain or branched-chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy ?, n-butoxy, tert-butoxy and the like. The term "lower alkylthio" means a lower alkyl group attached through a divalent sulfur atom, for example, a methyl mercapto and isopropyl mercapto group. The term "aryl" means a mono and bicyclic aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted with conventional substituent groups. Preferred substituents are lower alkyl, lower alkoxy, lower hydroxyalkyl, hydroxyl, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl alkynyl, heteroaryl (especially tetrazolyl), lower alkynyl and lower alkanoylamino. Examples of aryl groups that can be used according to this invention are unsubstituted phenyl, m- or o-nitrophenyl. p-tolyl, p-metosiphenyl, p-chlorophenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2, 6-dichlorephenyl, m-perfluorophenyl, 1-nephthyl and the like. The term "arylalkyl" means a lower alkyl group as defined above in which one or more hydrogen atoms are / are replaced by an aryl or heteroaryl group as defined herein. Any conventional arylalkyl according to this invention, such as benzyl, phenyl ethyl, and the like can be employed. The term "heteroaryl" means an unsubstituted or substituted 5-or 6-membered heteroaromatic monocyclic ring of a 9- or 10-membered bicyclic heteroaromatic ring containing 1,2,3 or 4 heteroatoms which independently are N, S or O Examples of heteroaryl rings are pyridine, benzimidazole. indole, imidazole, thiophene, isoquinoline, quinozoline, tetrasol, and the like. Substituents defined above as "aryl" are included in the definition of heteroaryl. The wide variety of heteroaryl groups of utility according to the invention is illustrated by Examples 56, 57, 74, 364 and 381-386. The term "lower alkoxycarbonyl" means a lower alkoxy group linked by a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like. The term "lower alkylcarbonyloxy" means lower alkylcarbonyloxy groups attached by an oxygen atom, for example an acetoxy group. The term "lower alkanoyl" means lower alkyl groups linked by a carbonyl group and encompasses, in the sense of the above definition, groups such as acetyl, propionyl and the like. Lower alkanoyl groups may be substituted by one or more group selected from hydroxycarbonyl. aroyl or aryloxy, lower alkoxy, fluoro, phenyl, cycloalkyl, lower alkoxycarbonyl, amino or lower alkoxycarbonyl amino. The term "lower alkylcarbonylamino" means lower alkylcarbonyl groups attached through a nitrogen atom, such as acetylamino. The term "aroyl" means a mono- or bicyclic aryl or heteroaryl group bonded by a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, 2-naphthyl and the like.

In the first aspect, the present invention relates to a compound of formula: wherein one of X and X 'is hydrogen, halogen or lower alkyl and the other is a group of formula wherein: Ri is hydrogen or lower alkyl, R15 is hydrogen, halogen, nitro, lower alkylsulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxyl, lower alkylaminosulfonyl, perfluoroalkyl lower, lower alkylthio, lower hydroxyalkyl, lower alkoxyalkyl, alkylthioalkyl lower, alkylsulfinylalkyl, lower alkylsulfonylalkyl, lower alkylsulfinyl, lower alkanoyl, aryloxy. aroyl, aryl or a group of formula R_.7-C = C-, R16 is H, halogen, nitro, cyano, lower alkyl, OH, perfluoroalkyl lower or lower alkylthio, Ri7 is H, aryl, heteroaryl, or lower alkyl the which is unsubstituted or substituted with OH, aryl or heteroaryl, is already 0 or 1; or one of X and X 'is a group of formula: where Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, 0 and S. or Het is a 9- or 10-membered bicyclic heteroaromatic ring, containing 1, 2, 3 or 4 heteroatoms selected from O, S and N; a, Ri, R15 and Rie are as defined for X-6 and R30 is hydrogen or lower alkyl, or does not exist; or one of X and X 'is a group of formula: where: RIA, is hydrogen, substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, R19 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkio, heteroarylalkyl, and R20 is substituted or unsubstituted lower alkyl, aroyl, alkanoyl lower, optionally substituted with carboxyl, aroyl or aryloxy; and Y is a group of formula: R? ? -i where: R22 and R23 are independently aryl, heteroaryl or lower alkyl which is unsubstituted or substituted by one or more chloro, bromo, nitro, hydroxyl, lower alkoxy, aryl, lower alkanoyl, aroyl or cyano, R24 is aryl, cyano, alkylsulfonyl or unsubstituted lower alkyl or alkenyl or substituted with an aryl or heteroaryl ring, and when R22 is aryl and R23 is aryl or lower alkyl, R2 is H, and the total number of carbon atoms in R22, R23 and R24 is from 6 to 14.; or Y is a ring of 3-7 members of formula: wherein: R25 is lower alkyl, unsubstituted or unsubstituted lower alkenyl with fluorine, or a group of formula R26 ~ (CH2) e-, R26 is aryl, heteroaryl, azido, cyano, hydroxyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl , lower alkylthio, lower alkylsulfonyl, lower alkylsufinyl, lower perfluoroalkanoyl, nitro or R26 is a group of formula -NR28R29, wherein: R28 is H or lower alkyl, R2g is hydrogen, lower alkyl, lower alkoxycarbonyl, optionally substituted aminocarbonyl, lower alkanoyl optionally substituted, aroyl, heteroaroyl, heterocycloalkylcarbonyl, lower alkylsulfonyl, lower alkylaminothiocarbonyl, or R28 and R29 taken together with the nitrogen atom to which they are attached, form a 4, 5 or 6 membered saturated heterocyclic ring, containing one or two heteroatoms with a second heteroatom which is O, S or N-R27; Q is - (CH2) fO-, - (CH2) fS-, - (CH2) f-, or when f = o, a ring, R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, the carbon atoms of the ring are unsubstituted or substituted with lower alkyl or halogen, e is an integer from 0 to 4, f is an integer number from 0 to 3 and the dotted line means a bond that may or may not exist; Z is hydrogen or lower alkyl; and the pharmaceutically acceptable salts and esters thereof. In a compound of formula 1, X 'is preferably hydrogen which means that a is then a group X-6, X-7 or X-10. When Z is lower alkyl, methyl is preferred. Z is preferably hydrogen. In a compound of formula 1, wherein the group is X-6, the groups R15 and Rie are preferably independently hydrogen, lower alkyl (especially methyl), nitro, halogen (especially chloro or fluoro), perfluoro-lower alkyl (especially trifluoromethyl) , cyano or phenoxy or Ri 5 is phenoxy and R 6 is H. Ri is preferably hydrogen is already preferably 0. Especially preferred groups X-6 are In the group X-7 Het is preferably a 5- or 6-membered monocyclic heteroaromatic ring, containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen. The most preferred heteroaromatic ring is When in X-7, Het is a bicyclic heteroaromatic ring, it preferably contains from 1 to 3 nitrogens as heteroatoms. The most preferred bicyclic heteroaromatic ring is 4-quinolinyl, 1-isoquinolinyl or R15 is preferably hydrogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluoro lower alkyl, lower alkylthio, lower alkanoyl, or aryl. The most preferred Ri5 is isopropyl, methyl or phenyl. R 25 is preferably hydrogen, halogen, nitro, cyano, lower alkyl or perfluoro-lower alkyl, in particular Ri 6 is methyl or trifluoromethyl. R30 in X-7 is preferably hydrogen or lower alkyl, especially methyl. the most preferred group X-7 is selected from the group consisting of: In a group of X-10, R 8 is preferably phenyl, wherein the phenyl ring is unsubstituted or monosubstituted with halogen, or is phenyl lower alkyl, with phenyl being chlorophenyl, especially 4-chlorophenyl or phenylethyl, most preferred . Ri9 is preferably lower alkyl, unsubstituted or substituted with pyridyl or phenyl, wherein the phenyl ring is unsubstituted or monosubstituted with lower alkoxy or halogen. R19 / more preferred is methyl, isobutyl, benzyl, 4-chlorobenzyl, 4-methoxybenzyl or 2-pyridylmethyl. R20 is preferably optionally substituted lower alkanoyl. The most preferred R20 is acetyl, butyryl, phenoxyacetyl, succinyl or glutaryl. The most preferred X-10 groups are selected from the group consisting of: In the group Y-1, R 22 and R 23 are preferably lower alkyl or phenyl, and R 24 is preferably lower alkyl except when R 22 is aryl and R 23 is aryl or lower alkyl, then R 24 is preferably hydrogen. The most preferred Y-1 groups are:In group Y-2, which is more preferred than Yl, Q is preferably ~ (CH2) f- or when f = 0, a bond. Preferably Q is 1,2 or 3. Preferably the additional bond does not exist. R 2 is preferably lower alkyl, lower alkenyl, preferably 3-buten-1-yl, lower alkenyl substituted with fluoro, preferably 3, 3-difluoro-2-propen-1-yl, OR a group of formula 526_ (CH 2) ) e.- where e is an integer from 0 to 4. preferably R26 is aryl, heteroaryl, azido, mire, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkylsulfonyl, lower alquilsulfinito, nitro, or R26 is a group of formula -R28R2_, where R28 is H or lower alkyl, R29 is preferably hydrogen, lower alkyl, lower alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted lower alkanoyl, aroyl, lower alkylsulfonyl or R28 and R29 taken together with the nitrogen to which they are both attached, they form a saturated heterocyclic ring of 4, 5 or ß members, which may contain an oxygen atom.

Preferably R28 is H. Preferably R26 is CH3S (0) 2-, CH2S-, CH3SO-, CH30-, CH3CO-, NC-, N3-, or HO- and when R26 is aryl, then phenyl is preferably unsubstituted or monosubstituted with cyano, halogen, preferably chlorine, lower alkoxy, preferably methoxy, lower alkyl, preferably methyl, or tetrazolyl which is unsubstituted or substituted by methyl or R26 is phenyl disubstituted by lower alkoxy, preferably methoxy, being 3, 4-dimethoxyphenyl is most preferred. Preferably the alkyl group in the lower alkanoyl group of R29 is unsubstituted or substituted with lower alkoxy, fluoro, phenyl, cycloalkyl, lower alkoxycarbonyl, amino or lower alkoxycarbonyl amino. The lower alkanoyl group unsubstituted or substituted more preferred is CH2CO-, (CH3) 3CCO-, CH3 (CH2) 3CHCH3C0-, CH3OCH2CO-, OF3CO-, C6H5CH2CO-, CH30C0 (CH2) 2C0-, ciclopentilCH2CO-, H2NCH2CO-or (CH3) 3COCONH (CH2) 2CO-. In R9 the aminocarbonyl group is preferably unsubstituted or substituted with lower alkoxycarbonyl, benzyl and preferably lower alkyl or monocyclic aryl. The unsubstituted or substituted aminocarbonyl group is H2NC0-, CH3NHC0-, CH3OCONHCO-, C6H4N02NHCO- or C6H5CH2NHCO-.

In other preferred embodiments, R29 is (CH3) 3COCO-methylaminothiocarbonyl, 4-methoxyphenylcarbonyl, 3-trifluoromethyl phenylcarbonyl, -NR8R2g is -NH2 or N (CH3) 2 and R28 and 29 taken together is 4-morpholinyl. The most preferred Y-2 is selected from a group consisting of one of the following formulas: Compounds of the invention include the pharmaceutically acceptable salts and esters of the same. It was found that certain preferred esters of the invention were useful for improving the bioavailability of the compounds of this invention. These preferred esters are of the formula: wherein X, X ", Z and Y are as described above, and R3i is lower alkyl or R31 is a group of formula P-1: wherein: R32 is hydrogen or lower alkyl, R33 is hydrogen, lower alkyl, aryl, R34 is hydrogen or lower alkyl, h is an integer from 0 to 2, g is an integer number from 0 to 2, the sum of hyg it's 3; or R31 is a group of formula P-2: where : R32 g, and h have the above meanings, T is O, S, - (CH2) r, a bond (when j = 0) or a group of formula N-R35, R35 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl , and j is 0, 1 or 2. R31 is preferably ethyl or 2- (4-morpholinyl) ethyl. The compounds of the invention may exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention. The preferred compounds of the invention are selected from the group consisting of: 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L- phenylalanineN [[1- [(4-methoxyphenyl) methyl] (cyclopentyl] carbonyl] -4- [[(2-nitrophenyl) carbonyl] amino] -L-phenylalanine, N - [[1- [(4-methoxyphenyl)] methyl] cyclopentyl] carbonyl] -4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -L-phenylalanine, N - [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine, N - [[1- (phenylmethyl) cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine, 4- [[(2, 6 -dichlorophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl) carbonyl] -L-phenylalanine, 4- [[(2-nitrophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] ) carbonyl] -L-phenylalanine, 4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2)] , 6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[N- (1,1-dimethylethyl) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[( 2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(trifluoroacetyl) amino] ethyl] cyc loblent] carbonyl] -L-phenylalanine, 4- [[(2, β-dichlorophenyl) carbonyl] amino] -N- [[l- [2 - [- 2-amino-1-oxoethyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[2- [[(1,1-dimethylethoxy) carbonyl] amino] - 1-oxoethyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[2- [[(methoxy) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(methylsulfonyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(acetyl) (methyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[ (2,6-dichlorophenyl) carbonyl] amino] -N - [[1- [2- [[(methylamino) carbonyl] (methyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2 , 6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(methoxycarbonyl) - (methyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalkyl anin, 4- t [(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] ] amino] -N- [[1- [(2- [(ethylsulfonyl) ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [(2- (methylsulfinyl) ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [(2,6-dimethyl- 4-trifluoromethyl-3-pyridinyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) util] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,4-dimethylpyridin-3-yl) carbonyl] anino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, or 4- [[(2 , 6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl-L-phenylalanine, Other preferred compounds have the formula selected from the group consisting of: twenty The compounds of the invention inhibit the binding of VCAM-1 and fibronectin to VLA-4 in circulating lymphocytes, eosinophils, basophils and monocytes ("VLA-4 expression cells"). The binding of VCAM-1 and fibronectin to VLA-4 in said cells is known to be involved in certain disease states, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and particularly in the binding of eosinophils. to the pulmonary endothelium which is the cause of the pulmonary inflammation that takes place in asthma. Thus, the compounds of the present invention should be useful for the treatment of asthma. In another aspect, on the basis of its ability to inhibit the binding of VGAM-1 and fibronectin to VLA-4 in lymphocytes, eosinophils. Basophils and circulating monocytes, the compounds of the invention can be used as medicaments for the treatment of disorders that are known to be associated with this binding. Examples of these disorders are rheumatoid arthritis, multiple sclerosis, asthma and inflammatory bowel disease. The compounds of the invention are preferably used in the treatment of diseases that encompass lung inflammation, such as asthma. The pulmonary inflammation that takes place in asthma is related to the infiltration of eosinophils in the lungs where the eosinophils join the endothelium which has been activated by some phenomenon or substance that triggers the asthma. In addition, the compounds of the invention also inhibit the binding of VCAM-1 and MadCAM to the cellular receptor alpha4-beta7, also known as LPAM, which is expressed in lymphocytes, eosinophils and T cells. While the precise role of the interaction of alpha4-beta7 with several ligands under inflammatory conditions such as asthma is not fully explained, the compounds of the invention which inhibit both the alpha4-beta7 and alpha4-beta7 receptor binding, are particularly effective in the animal models of asthma. Other work with monoclonal antibodies to alpha4-beta7 has indicated that compounds that inhibit the binding of alpha4-beta7 to MadCAM or VCAM are useful for the treatment of inflammatory bowel disease. They are also useful in the treatment of other diseases in which said union is implicated as a cause of injury or symptoms of disease. The compounds of the invention can be administered orally, rectally or parentally. p. ex. , intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingual, or as ophthalmological preparations or as an aerosol for the treatment of pulmonary inflammations. Capsules, tablets, suspensions or solutions for oral administration, suppositories, solutions for injection, eye drops, ointments or solutions for spraying are examples of administration forms. Administration by intravenous, intramuscular, oral or by inhaling is one of the preferred forms of administration. The dosages to which the compounds of the invention are administered in effective amounts, depend on the nature of the specific active ingredient, the age and needs of the patient and the mode of administration. The dosages can be determined by any conventional means, p. ex. through clinical trials for dose limitation. In this way, the invention further comprises a method of treating a host suffering from a disease in which the binding of VCAM-1 or fibronectin to the expression cells of VLA-4 is a causative factor of the symptoms or lesions of the disease by administering an amount of a compound of the invention sufficient to inhibit the binding of VCAM-1 or fibronectin to the expression cells of VLA-4 such that said symptoms or lesions are reduced. In general, dosages of approx. 0.1-100 mg / kg of body weight per day are preferred, being 0 dosages of 1-25 mg / kg per day are particularly preferred, and dosages of 1-10 mg / kg of body weight per day are especially preferred. The invention further relates to pharmaceutical compositions or medicaments containing a pharmaceutically effective amount of a compound of the invention and a pharmaceutically and therapeutically acceptable carrier. Said compositions can be formulated by any conventional means converting a compound according to the present invention into a galenic administration form together with a therapeutically inert support material. If desired, one or more therapeutically active substances may be added. The tablets or granules can contain a series of binders, fillers, carriers or diluents. The liquid compositions can be, for example, in the form of a sterile, water-miscible solution. The capsules may contain a filler or thickener in addition to the active ingredient. In addition, additives to improve the aroma as well as substances commonly used as preservatives, stabilizers, moisture fixers and emulsifying agents as well as oils for varying the osmotic pressure, buffers and other additives may also be present. The above-mentioned support materials and diluents can comprise any conventional pharmaceutically acceptable organic or inorganic substance, e.g. ex. , water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. The oral dosage unit forms, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of a compound of the invention. The compounds of the present invention can be prepared by any conventional means. In general, the process for the preparation of a compound of formula 1 Where X, X ', Z and Y have the meanings defined in claim 1, characterized in that a compound of formula Ib wherein X, X ', Z and Y, have the meanings defined above, and R is a protecting group or a solid support, the protecting group or the solid support is cleaved, and if desired, the compound of Formula 1 in a pharmaceutically acceptable salt. The protecting group may be an alkyl group, e.g. ex. methyl, ethyl or terebutyl, and the solid support may be a resin used in the synthesis in solid phase, eg. a Wang resin. The conditions of the cleavage depend on the substitution pattern of the final compound and the protection group employed, are indicated in detail below in connection with the synthesis routes for the preparation of compounds of formula 1 as well as the salts and esters of the same. In reaction scheme 1, a compound of formula 1 in which Ri is H or lower alkyl, and which is a known compound or can be prepared by standard methodology, is treated with a reducing agent capable of selectively reducing a group nitro in the presence of a 3 benzyl alcohol. This process is advantageously carried out in the presence of a derivatization agent of formula R2-0C0X wherein X is a leaving group and R2 is tere-alkyl, benzyl or the like forming an easily cleavable protection group, leading directly to a compound of formula 2. For example, this process can be conveniently effected by catalytic hydrogenation of 1 with Pd (C) in ethyl acetate in the presence of di-tert-butyl dicarbonate to give a derivative of 2 in which R2 is tert-butyl . the conversion to an aldehyde of formula 3 can be effected using one of several oxidation agents capable of oxidizing a benzyl alcohol in the corresponding aldehyde, for example activated manganese dioxide in a suitable solvent, for example dichloromethane. the reaction of 3 to give a dehydroamino acid of formula 5 can be effected by treatment with a Wittig reagent of formula 4 in which R3 is lower alkyl and R is an alkoxy group, for example benzyloxy or tert-butoxy or represents a part of one of the acyl groups of the compounds of the invention, for example substituted lower alkyl or substituted cycloalkyl. For example, the treatment of 3 with trimethyl ester of (+) - N- (benzyloxycarbonyl) -phosphonoglycine in the presence of a suitable base for example tetramethyl guanidine leads directly to a dehydroamino acid of formula 5, R3 = methyl and R4 = benzyloxy. The selective reduction of enantiomers of 5 to L-amino acid 6 can be effected by employing a number of reducing agents suitable for this purpose, for example, the recently described ethyl-DuPHOS reagent rhodium (Burk, M.J., Feaster, J.E.; Nugent, W.A .; Harlow, R.L. J. Am. Chem. Soc. 1993, 115, 10125) using essentially the literature procedure. Reaction scheme 1 A process for the conversion of compounds of structure 6 into compounds of the invention is represented in the reaction scheme 2. The protection group containing R2 can be eliminated under conditions that depend on the particular choice of R2 as well as of R3 and R4 . The choice of these groups will depend on the particular target compound. A variety of commonly protected groups and their use are described in "T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (" Protection Groups in Organic Synthesis "), 2nd edition, Wiley Interscience, New York, 1991." For example, when R2 is a tert-butyl group and R3 is lower alkyl and R4 is either a benzyloxy group or represents a part of one of the acyl groups of the compounds of the invention, for example substituted lower alkyl or substituted cycloalkyl treatment with trifluoroacetic acid alone or in solution with dichloromethane in the presence of suitable scavengers, for example, triethylsilane or anisole, leads to a compound of formula 7. This compound can be coupled to a carboxylic acid of formula 8 using standard conditions of peptide coupling , for example HBTU in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature to give a compound of formula 9. In the carboxylic acid of formula 8, R5 can represent an alkyl group substituted, a substituted aromatic ring or a substituted heteroaromatic ring. R5 may also contain conveniently protected reactive functionalities to allow final conversion to compounds of the invention. The choice and employment of said groups will be easily deductible by those skilled in the art. Reaction scheme 2 Depending on the choice of R5 and whether the final objective of the synthesis is an ester or an acid, the compound 9 can be a compound of the invention or in case R4 is a protection group, for example a benzyloxy group, can be removed under appropriate conditions, for example by catalytic hydrogenation with Pd (C) in a suitable solvent such as a lower alcohol to give a compound of formula 10. This intermediate product can be coupled with a carboxylic acid of formula employing standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature to give a compound of formula 12. In the carboxylic acid of formula , R may represent a part of a compound of the invention, for example, a substituted alkyl or substituted cycloalkyl. These compounds are known compounds or can be prepared by known methods. Re may also contain conveniently protected reactive functionalities to allow final conversion to compounds of the invention. The selection and use of said groups will be easily deductible for experts in the specialty. General methods for the preparation of said compounds are illustrated in the reaction scheme 13. If the acid 13 is the target compound, the conversion of a compound of the formula 12 can be carried out using the standard hydrolysis conditions suitable for the particular choice of R3 and any functional group present as part of R5 and R6. In the case where R3 is a lower alkyl, treatment with an alkali metal hydroxide, for example lithium hydroxide in aqueous THF, is generally effective. In reaction scheme 3, a compound of formula 14 in which R7 is a lower alkyl group which can serve as a protecting group or a group suitable for use in a prodrug, for example methyl, ethyl, tare-butyl or similar, or represents a connection to a solid phase resin, for example a Wang resin, is coupled "with a carboxylic acid of formula 11 employing standard conditions of peptide coupling, for example HVTU in the presence of DIPEA in a polar aprotic solvent, such as DMF at a temperature between 0 ° C and room temperature to give a compound of formula 15. The reduction of the nitro group of 15 can be effected by catalytic hydrogenation using for example Pd (C) as a catalyst or by treatment with a standard reducing agent, for example SnCl2. The resulting compound of structure 16 is useful as an intermediate key for several series of compounds. In the example highlighted in scheme 3, it can be coupled with an acid of formula 8 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature, to give a compound of formula 17. The compound 17 can be a compound of the invention depending on the nature of R7 or can be converted into a compound of the invention by a suitable hydrolysis process, for example, in the case wherein R7 is lower alkyl, by hydrolysis by treatment with excess alkali metal hydroxide, such as lithium hydroxide in aqueous alcohol. When R7 represents a resin suitable for solid base synthesis, the appropriate hydrolysis conditions will depend on the selection of the resin. In the case of Wang resin, treatment with trifluoroacetic acid in the presence of appropriate sequestrants will lead to an acid of formula 18.

Reaction scheme 3 14 15 18 In a particularly suitable method for solid phase synthesis, a N'-Alloc-amino-Na-Fmoc-protected phenylalanine derivative of formula 19 can be coupled to a resin suitable for solid phase synthesis, for example a resin Wang employing standard coupling procedures, for example, by forming a mixture of anhydride and 2,6-dichlorobenzoyl chloride and effecting the coupling reaction in a polar aprotic solvent such as N-methyl pyrrolidone to give a compound of structure 20 in the which R7, represents the resin. The Alloc group can be removed by standard methods, for example, by treatment with a reducing agent such as nBu3SnH in the presence of a catalyst which is a source of Pd °, eg, Pd (PhP) 2Cl2 to give an amine derivative of structure 21. This compound can be coupled with a carboxylic acid of formula 8 using standard conditions of peptide coupling, for example HBTU 'in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature to give a compound of formula 22. The FMoc protecting group can be removed from 22 using a standard treatment with a base, already known to those skilled in peptide chemistry, for example with piperidine in DMF, to obtain an amine of formula 23. The resulting compound 23 can be coupled with a carboxylic acid of formula 11 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature to give a compound of formula 24. Finally the compound of structure 24 can be cleaved from the resin under conditions depending on the particular chosen resin. For example in the case of a Wang resin, the acid treatment with trifluoroacetic acid in dichloromethane in the presence of the necessary sequestrants will give a compound of formula 18. Depending on the particular synthetic objective, the order of elimination of the protecting groups of 19 can being altered so that the Fmoc group is first removed, coupling the resulting amine with an acid of formula 11 is carried out, and then the Alloc group is removed and the resulting product is coupled with an acid of formula 8, and It is split from the resin. The choice of protection groups can also be modified to reflect the reectivities of the resin and the nature of any of the functional groups contained in R5 and R6.

Reaction scheme 4 21 22 23 24 18 The compounds derived from the 3- or 4- (alkylamino) phenylalanine derivatives can be prepared as indicated in reaction scheme 5. A compound of formula 16 or 7 can be treated with diazomethane in a suitable solvent, for example, ethyl ether to give the products of formulas 25 and 26 respectively in which R8 is methyl. Alternatively, the compound of structure 16 or 7 can be treated with a lower alkyl aldehyde or ketone, for example acetone, to give an intermediate Schiff base which in turn undergoes catalytic hydrogenation or reduction with sodium cyanoborohydride in the presence of a organic acid, for example, acetic acid to give a compound of formula 25 or 26, in which R8 is a lower alkyl other than methyl. The conversion of compounds 25 or 26 into prodrug esters 27 or 28 or into corresponding acids 29 or 30, respectively, can be carried out as described above in Reaction Schemes 2 and 3.

Reaction scheme 5 For the preparation of the 3- or 4-sulfonylamino phenylalanine derivatives, the compounds of formula 7, 16, 25 or 26 can be reacted with a sulfonyl chloride of formula 31, in which Rg is a substituted aryl or heteroaryl group , in an inert solvent, for example, dichloromethane in the presence of a non-nucleophilic base, for example triethylamine or aprex pyridine. 0 ° C at room temperature, to give compounds of structure 32 or 33 respectively as indicated in reaction scheme 6 for compounds 7 and 26. These can subsequently be converted to compounds of formulas 34 and 35 if desired using the methods described above in the reaction schemes 2 and 3. In addition, the group R4CO- can be replaced by a group R6CO- using the general chemistry described in scheme 2. For the preparation of the compounds derived from the 3- or 4-aminomethylphenylalanine, the procedure indicated in reaction scheme 7 can be used. A 3- or 4-hydroxymethylbenzoate of formula 36 in which Rio is lower alkyl, which are known compounds, or can be prepared by known methods, it is treated with a silylating agent in which Ru-Ru is lower alkyl or phenyl, for example tert-butyldimethylsilyl chloride in an inert solvent, for example dimethylformamide in presence of imidazole approx. at 0 ° C to give a silyl protected compound of formula 37. The reduction of 37 can be effected using a wide variety of suitable reducing agents, for example, lithium aluminum hydride in an inert solvent such as ether or tetrahydrofuran to a temperature of approx. 0 ° C and then, treatment with water to give the intermediate alcohol, which can be oxidized by any one of several oxidation agents suitable for the oxidation of the benzylic alcohols in the corresponding aldehydes, for example the activated manganese dioxide, to give an aldehyde of formula 38. the monosilyl-protected diols can be obtained optionally from the 3- or 4-hydroxymethylbenzylalcohols by monosylation and separation of the side products. Alternatively, an ester of formula 37 can be reduced directly in an aldehyde of formula 38 using diisobutylaluminum hydride at low temperature, for example at -78 ° C. The reaction of 38 to give a dehydroamino acid of formula 39 can be effected by treatment with a Wittig reagent of formula 4 in which R3 is lower alkyl and R4 is an alkoxy group, for example, benzyloxy or tert-butoxy or represents a part of the acyl groups of the compounds of the invention, for example, substituted lower alkyl or substituted cycloalkyl. For example the treatment of 38 with the trimethyl ester of the (+) - N- (benzyloxycarbonyl) -a-phosphonoglycine in the presence of a suitable base for example the tetramethyl quanidine leads directly to the dehydroamino acid of the formula 39, R3 = methyl and R4 = benzyloxy. The selective reduction of the enantiomers of 39 in L-amino acid 40 can be effected by one of the reduction agents suitable for this purpose, for example, the recently described ethyl-DuPHOS rhodium reagent. It will be readily deduced by those skilled in the art, that the optimal procedure for the subsequent conversion of 40 into compounds of the invention, will depend on the selection of R4 and R3. For the case where R3 is lower alkyl and R4 is benzyloxy, the conversion to an amine of formula 41 can conveniently be effected by the catalytic hydrogenation of Pd (C) transfer in a suitable solvent, for example, methanol in the presence of Ammonium formate as a reducing agent. The acylation of 41 with a carboxylic acid of formula 11 can be carried out as described above in reaction scheme 2 to give a compound of formula 42. The removal conditions of the protecting silyl group will depend on the particular selection of Rn - R13. In the case of Rn, R 2 = methyl and Ri 3 = tert-butyl, this group is easily removed by treatment with a strong acid, for example hydrochloric acid in an appropriate solvent according to the choice of R 3, for example when R 3 is methyl , methanol. The resulting benzyl alcohol of formula 43 can be converted to an amine of formula 45 using well-established procedures for similar transformations. For example, the alcohol of formula 43 can be converted to a leaving group, for example a mesylate by treatment with methanesulfonyl chloride in the presence of a proton receptor, for example, pyridine, and then displacement with an alkali metal azide, for example azide of sodium in a polar aprotic solvent such as dimethylformamide. Alternatively, the transformation of 43 into an azide of formula 44 can be effected directly by treatment with diphenyl phosphorazidate as described in: Thompson, A.S. Humphrey, G R.; DeMarco, A.M .; Mathre, D.J .; Grabowski, E.J.J. J. Org. Chem. 1993, 58, 5886-5888. The reduction of azide 44 to an amide of formula 45 can be effected by a number of means suitable for the conversion of azides to amines, for example, by treatment with a phosphine, for example triphenylphosphine in an inert solvent such as dichloromethane or TMF, and then an aqueous treatment or by catalytic hydrogenation with a suitable catalyst, for example Pd (C) in a suitable solvent for catalytic hydrogenations such as a lower alkanol or tetrahydrofuran. The resulting amine of formula 45 can be converted into the corresponding compounds of the invention employing procedures applicable to the free amines described in the other reaction schemes. For example, the coupling of the 45 with a carboxylic acid of formula 8 under the conditions described is reaction scheme 2 leads to an amide of formula 46 which can be further converted to an acid of formula 47 if desired, by hydrolysis catalyzed by a base, as described in the reaction scheme 2.

Reaction Reactor 6 26 Rg- SO2CI 10 31 34 35 Reaction Scheme 7 For the synthesis of urea derivatives, a compound of formula 26 can be treated with an isocyanate of formula 49, wherein Ri 4 is substituted with aryl, substituted heteroaryl, or substituted lower alkyl with appropriately protected reactive substituents, employing the strategy of a conventional protecting group, in a suitable inert solvent, for example, dichloromethane, to give a urea of formula 50. More generally, a compound of formula 26 can be treated with one equivalent of phosgene, for example, triphosgene in an inert solvent such as dichloromethane in the presence of a non-nucleophilic proton receptor, for example diisopropylethylamine, to give an intermediate of formula 48. The subsequent treatment of a compound of formula 48 with an amine of formula 51 in which Ri5 and R16 are independently of each other hydrogen, substituted lower alkyl, substituted aryl, substituted heteroaryl or conjunct They form a substituted ring of 5, 6 or 7 members, leading to a compound of formula 52. Subsequent conversion, if necessary, of 50 or 52 into the compounds of the invention can be carried out as described in the reaction scheme 8 Reaction scheme 8 For the synthesis of the imides, an aminophenylalanine derivative of structure 53 is used, in which Ri is H or lower alkyl, R6 has the meaning already given above, and R7"is H or an easily cleavable group such as substituted benzyl , tert-butyl, allyl or the like, or in the case where it is desired to obtain a prodrug ester as a final product, this ester group is, for example, ethyl The compounds of formula 53 can be obtained easily from the intermediates described above in the reaction scheme 2. The reaction of a compound of formula 53 with a cyclic anhydride of formula 54 in an inert solvent, for example dichloromethane leads to an open-ring intermediate of formula 55. The assumed structure of 54 includes bicyclic molecules that may contain fused aromatic or heteroaromatic rings, instead of 54, it is also possible to use dicarboxylic aggregates which are capable of forming imides c In the latter case, a condensing agent must be used in the first step, for example carbonyl diimidazole. Treatment of the compound of formula 55 with a reagent such as carbonyl diimidazole capable of carrying out the cyclodes idratation leads to an imide of formula 56. Further manipulation of the functional groups that were present in the anhydride of formula 54 and the modification of R7"can be carried out in compound 56 if desired, to obtain other analogs using standard chemistry which is compatible with the presence of the imide function For the synthesis of compounds of the invention in which R__ is halogen, preferably chlorine, the appropriate halogen atom can be incorporated into a starting material or inserted at various points during the course of the synthesis depending on the nature of the additional functionality in the molecule.A chlorine atom can be incorporated into the compound of structure 1 indicated in Scheme 1 and maintained through the compounds of the invention, avoiding the reagents that could be expected e would react with a halogen atom. For example, a compound of formula 6 in which Ri is hydrogen, can be treated with a mild chlorinating agent, for example, N-chlorosuccinimide in the presence of a proton receptor, for example, sodium acetate to give the corresponding compound of formula 6 in which Ri is chlorine. In the case where 6 is derived from 3-amino-L-phenylalanine, a mixture of regioisomers that can be separated at a convenient point from the total synthesis may result. Other intermediates described in the above schemes may be more suitable starting materials for halogenation in the case of a particular target molecule. The particular merits of the candidates to be starting materials will be easily deductible by the experts in the specialty.

Reaction scheme 9 53 33 56 For the synthesis of the thiazolidinones of formula 62 described in reaction scheme 10, an aminophenylalanine derivative of structure 16 can be used, in which R6 and R7 have the meanings given above. The reaction of 16 with an a-mercapto carboxylic acid of formula 59 in which R 20 can be hydrogen, lower alkyl or aryl, for example a-mercapto acetic acid, and an aldehyde of formula 60 in which R 21 can be lower alkyl , arylalkyl or a substituted aryl group, for example benzaldehyde, in an appropriate solvent such as benzene, THF or a lower alcohol, for example methanol, in the presence of a water scavenger such as molecular sieves 4A of 60 to 80 ° C , results in the preparation of the compound of formula 61. The compound 61 can be a compound of the invention depending on the nature of R7 or can be converted into a compound of the invention by a suitable hydrolysis process, for example in the case that R7 is lower alkyl, by treatment with an excess of alkali metal hydroxide, such as sodium hydroxide in aqueous alcohol. When R represents a resin suitable for solid phase synthesis, the appropriate conditions of the hydrolysis will depend on the chosen resin. In the case of a Wang resin, treatment with trifluoroacetic acid in the presence of suitable sequestrants will lead to an acid of formula 62. The sequence can be initiated with related anilines, for example a compound of formula 7 in which Ri is lower alkyl or halogen, to give the corresponding thiazolidinones Reaction scheme For the synthesis of the imidazolidinones of formula 67 indicated in reaction scheme 11, an aminophenylalanine derivative of structure 16 may be employed in which R6 and R are as defined above. Compound 16 can be obtained easily through the synthesis described in reaction scheme 3. This compound can be coupled with an N-protected a-amino acid of formula 63, in which R22 can be a lower alkyl or an aryl group, R23 it can be the side chain of a natural or unnatural D or La-amino acid or R22 and 23 can together form a ring, for example a proline or pipicolinic acid ring and R24 can be a standard amine protection group suitable for the particular selection of R6, R7, R22 and R23 for example tarc-butoxycarbonyl. The coupling reaction can be carried out using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature, to give a compound of formula 64. Depending on the nature of the R24 protection group, a suitable deprotection method is employed to give a compound of formula 65. In case the R24 protecting group is a Boc group, the deprotection can be carried out by the reaction of 64 with HCl in dioxane at room temperature. The reaction of compound 65 with an aldehyde of formula 60, in which R2? has the above meanings, in the presence of a water sequestrant such as molecular sieves 4A of 60 to 80 ° C in an appropriate solvent, for example THF, results in the preparation of a compound of formula 66. Compound 66 can being a compound of the invention depending on the nature of R7 or it can be converted into a compound of the invention by a suitable hydrolysis process, for example in the case where R7 is lower alkyl, by hydrolysis by treatment with a metal hydroxide alkali, such as sodium hydroxide in aqueous alcohol to give a carboxylic acid of formula 67. Reaction Scheme 11 For the synthesis of the imidazolidinones of formula 68 described in reaction scheme 12, a derivative of the aminophenylalanine of structure 16 is employed in which Re and R7 have the above meanings. Compound 16 can be obtained easily through the synthesis described in reaction scheme 3 in case R7 is lower alkyl. This compound can be coupled with an N-protected a-amino acid of formula 69, wherein R25 can be a natural or unnatural D or A-amino acid side chain, and R26 is a nitrogen protecting group of the type conventionally employed in peptide chemistry, eg, an Fmoc group, employing standard conditions of coupling of peptides, for example HBTU in the presence of DIPEA in a polar aprotic solvent such as DMF at a temperature between 0 ° C and room temperature, to give a compound of formula 70. Depending on the nature of the protecting group R26, employs a suitable deprotection method to give the compound of formula 71. In the case that the protection group R26 is an Fmoc group, you can eliminate 70 using a standard treatment with a base, already known to those skilled in the chemistry of the peptides, for example with piperidine in DMF, to obtain an amine of formula 71. The compound 71 can then react with an aldehyde 60, in which R2? has the meanings indicated above, in the presence of a water fixative such as 4A molecular sieves in an appropriate solvent such as dichloromethane or THF at 25-80 ° C (bath temperature) to give an imine of formula 72. The imine 72 it may then be treated with an acylating agent such as the acyl chloride of formula 74 in which R27 may be an alkyl group or aryl group in the presence of a base such as DIPEA or DBU in an appropriate solvent such as dichloromethane or THF at 25-80 ° C (bath temperature) to give an imidazolidinone acyl of formula 73. Other acylating groups can be employed eg, acid anhydrides, and when appropriate, 74 can carry protected substituents which can later be removed at the necessary point of synthesis. The compound 73 can be a compound of the invention, or depending on the nature of R7 can be converted into a compound of the invention by a suitable hydrolysis process, for example, in the case where R7 is lower alkyl, by hydrolysis by treatment with an alkali metal hydroxide, for example, with sodium hydroxide in aqueous alcohol to give, after acidification, a carboxylic acid of formula 68. The sequence can be initiated with related anilines, for example a compound of formula 7 in the which Ri is lower alkyl or halogen, to give the corresponding 3-acyl imidazolidinones. Reaction scheme 12 The acids of formula 11 are already known compounds or can be prepared using standard methodologies. For the preparation of substituted alkyl or cycloalkylcarboxylic acids, alkylation reactions can be employed using a dianion or monoanion of alkali metal acid of the corresponding ester. For example, an ester of cycloalkylcarboxylic acid of formula 75 can be treated with a strong base, for example lithium diisopropylamide in an inert solvent, for example THF and then the addition of a group R28-Lv, wherein R28 represents a desired side chain , such as a substituted benzyl, lower alkyl, lower alkoxyalkyl, lower azidalkyl and the like and Lv represents a leaving group such as bromine, iodine, mesylate or similar group known to participate in alkylation reactions of the enolate ester. The ester product 76 can be hydrolyzed to obtain the acid 77 using an alkali metal hydroxide in an appropriate solvent, for example aqueous alcohol. Depending on the nature of R29 and the eventual target, compound 77 can be coupled to an amine such as compound 23 and converted directly to the target or R28 can be subjected to further manipulation at a suitable point in the synthesis. For example, if R28 is an azido lower alkyl group, the azide can be produced using for example a trialkyl phosphine reagent followed by functionalization of the amine product by alkylation, acylation, sulfonylation and related procedures well known to those skilled in the art. If R28 possesses a leaving group, for example, a terminal bromine atom, this group can be displaced by an appropriate nucleophile, for example, sodium methyl mercaptide to give in this case, a thioether which can be the desired product or can he himself will be manipulated later, for example, by oxidation in a sulfoxide or a sulfone using standard reaction conditions. Other nucleophiles that can be used to obtain intermediates that lead to compounds of this invention include: sodium cyanide, sodium methoxide, sodium azide, morpholine and others. When R28 contains a ketal group, this group can be hydrolyzed at a convenient point in the synthesis to give a ketone group. This group in turn can be further manipulated, for example by reduction to an alcohol or conversion to a derivative such as an oxime. 75 76 77 General The melting points are taken is a Thomas-Hoover device and were not correct. Optical rotations were determined with a Perkin-Elmer model 241 polarimeter. The ^? - NMR spectra were recorded with the Varian XL-200 and Unityplus 400 MHZ spectrometers, using tetramethylsilane (TMS) as the internal standard. The electron impact spectrum (El, 70 ev) and the mass spectrum by fast atom bombardment (FAB) were measured in the VG Autospec or VG 70E-HF mass spectrometers. The silica gel used in the column chromatography was Mallinkrodt SiliCar silica gel 230-400 meshes for flash chromatography; The columns were traversed at 0-5 psi nitrogen head to aid flow. Thin layer chromatograms were recorded on thin-film glass plates coated with silica gel supplied by E Merck (E. Merck # 1.05719) and visualized at 254 nm with UV light in a viewing chamber, by exposure to I2 vapor, or by spraying either with phosphomolybdic acid (PMA) or aqueous ethanol, or after exposure with Cl2, with a 4,4'-tetramethyldiaminodiphenylmethane reagent, prepared according to E. von Arx, M. Faupel and M. Brugger , J. chromatography, 1976, 120, 224-228. Was done inverted phase high pressure liquid chromatography (RP-HPLC), using well a Waters Delta Prep 4000 using a column 3 x 30 cm Waters Delta Pak 15 ß? C-18, with a flow of 40 ml / minute using a gradient of acetonitrile: water (each containing 0.75% TFA) typically 5 tp 95% acetonitrile for 35-40 minutes or a Rainin HPLC using a column 41.4 m x 30 cm, 8, Dynamax ™ C-18, with a flow of 49 ml / minute and a similar gradient of acetonitrile: water as indicated above. Dichloromethane (CH2C12), 2-propanol, DMF, THF, toluene, hexane, ether, and methanol, were Fischer of reactive quality, and were employed without further purification except where indicated, the acetonitrile was Fischer of HPLC grade and used as such. Definitions: THF is tetrahydrofuran, DMF is N, N-dimethylformamide, HOBT is 1-hydroxybenzotriazole, BOP is [(benzotriazol-1-yl) oxy] tris- (dimethylamino) phosphonium hexafluorophosphate HATU is o- (7-azabenzotriazole-1- il) -l, l, 3,3 tetramethyluronium hexafluorophosphate HBTU is 0-benzotriazole-N, N, N ', N', -tetramethyluronium hexafluorophosphate DIPEA is diisopropylethylamine, DMAP is 4- (N, N-dimethylamino) pyridine DPPA is diphenylphosphoryl azide DBU is 1, 8-diazabicyclo [5.4.0] undec-7-ene NaH is sodium hydride Salt is saturated aqueous sodium chloride solution TLC is thin layer chromatography LDA is lithium diisopropylamide B0P-C1 is bis chloride (2-OXO-3-oxazolidinyl) phosphinic NMP is N-methyl-pyrrolidinone Examples Example 1. Synthesis of ethyl ester of acid 1-benzylcyclopentane carboxylic acid. A solution of diisopropylamine (1.0 ml, 7.7 mmol) in 20 ml of anhydrous THF was cooled to -78 ° C in a "dry ice-acetone" bath under an argon atmosphere.N-butyl lithium in hexanes was added ( 2.5 M, 3. 6 ml, 7.7 mmol) all at once and the mixture is stirred for 0.5 hours and passed to a precooled (-30 ° C) solution of 1.0 g (7.0 mmol) of ethyl cyclopentanecarboxylate in 10 g. ml of THF After another 45 minutes, benzyl bromide (0.92 ml, 7.7 mmol) was added, and the mixture was allowed to warm to room temperature overnight.The resulting mixture was concentrated, and the residue was treated with 70 ml of ether, washed with water, 1 N HCl, water, saturated salt, and dried (MgSO) The residue obtained after filtration and evaporation was purified by flash chromatography on 100 g of silica gel, eluting with 3% of ethyl acetate-hexane to obtain the ethyl ester of 1-benzylcyclopentane carboxylic acid (0.80 g, 45%) in the form of an Colorless Example 2 Synthesis of 1-benzylcyclopentane carboxylic acid. A solution of the ethyl ester of 1-benzylcyclopentane carboxylic acid (0.40 g, 1.7 mmol) in 10 ml of THF and 5 ml of methanol was treated with a solution of 200 mg of lithium hydroxide hydrate in 5 ml of water and the mixture is stirred for 3 days at room temperature and at 40 ° C for 3 days. The mixture is diluted with water, washed with ether and acidified with an excess of 6N HCl. The aqueous layer was extracted with ether and the combined extracts were washed with water and brine and dried (MgSO). By evaporation, 0.34 g (96%) of 1-benzylcyclopentane carboxylic acid was obtained in the form of a thick yellow oil. Example 3. Synthesis of l - [(4-methoxyphenyl) methyl] cyclopentane carboxylic acid. A solution of diisopropylamine (58 mL, 0.44 mol) in 400 mL of THF was cooled to below 0 ° C and n-butyl lithium in hexane (170 mL, 2.5 N, 0.43 mol) was added dropwise, maintaining the temperature below 0 ° C. After the addition was complete, ethyl cyclopentylcarboxylate (55 g, 0.39 mol) in THF (175 ml) was added dropwise maintaining the internal temperature between -60 and -70 ° C. Once the addition was complete, the internal temperature was allowed to rise to -40 ° C and was maintained for 20 minutes and cooled again to -70 ° C. A solution of 4-methoxybenzyl bromide (75 g, 0.58 mol) in 175 ml of THF was added dropwise and the mixture allowed to warm to room temperature overnight. A solution of 20% ammonium chloride in water (225 ml) and then 450 ml of ethyl acetate was added, the layers were separated, the aqueous layer was extracted with ethyl acetate (450 ml) and the combined organic phases were dried. washed with saturated salt (2 x 450 ml) and dried (MgSO). The crude product was chromatographed on a clear gel, eluting with 1-5% ether in hexane to give the l - [(4-methoxyphenyl) methyl] cyclopentanecarboxylic acid ethyl ester (80.8 g, 79%) as an oil. The material obtained above was dissolved in methanol (620 ml) and sodium hydroxide (350 ml) and the mixture was heated to reflux overnight. The mixture was allowed to cool and is concentrated. The basic yellow residue was washed with ether (2 x 500 ml) and acidified with an excess of 6 N hydrochloric acid until pH < 2. This solution was extracted with dichloromethane (2 x 500 ml), the extracts were combined, dried (MgSO 4), and evaporated to a white solid (69.6 g, 89%), m.p. 63.5-64.5 ° C. Example 4. Synthesis of l- (2-azidoethyl) cyclopentane carboxylic acid. To an ice cooled solution of diisopropylamine (56 ml, 0.396 mole) in THF (85 ml), n-butyl lithium ene hexane solution (240 ml, 1.6 M, 0.393 mole) was added over 20 minutes. The mixture was stirred at 0 ° C for 30 minutes, cooled in a bath at -65 ° C and ethyl cyclopentane carboxylate (37.4 g, 0.263 mol) in THF (50 ml) was added over 20 minutes. After 1 hour, a solution of 1,2-dibromoethane (47 ml, 0.545 mol) in THF (50 ml) was added, the mixture was kept at -65 ° C for 3 hours and it is allowed to warm to room temperature overnight. The reaction was quenched by the addition of ammonium chloride solution (200 ml), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined extracts were washed with 1: 1 brine: water (250 ml) and dried (Na2SO). The solution was filtered and concentrated, diluted with toluene (100 ml) and concentrated. Dilution and concentration were repeated twice to give ethyl l- (2-bromoethyl) cyclopentane carboxylate (52.5 g). A solution of the above bromide (52.5 g, 0.211 mol) and sodium azide (54 g, 0.831 mol) in DMF (200 ml) is stirred at 50 ° C for 5 hours under nitrogen atmosphere and filtered. The filtrate was concentrated almost to dryness, diluted with ethyl acetate (500 ml), filtered and concentrated to give the crude ethyl 1- (2-azidoethyl) cyclopentane carboxylate (40.9 g) as a color oil. brown. This material is combined with the product of a previous operation (total 63.5 g) and purified by chromatography on 250 g of silica gel, eluting with 5% ethyl acetate in hexane to give 50.3 g of product in the form of a crude oil. light brown. The above oil (50.3 g, 0.238 mol) was dissolved in THF (700 ml) and methanol (375 ml) and a solution of LiOH hydrate (15 g, 0.357 mol) in water (300 ml) was added. The resulting solution was stirred at 40 ° overnight and concentrated. The residue was dissolved in 2 liters of water containing 40 ml of IN NaOH, and washed with hexane (1 liter). The aqueous layer was acidified with IN HCl (375 ml) and extracted with ether (2 1 liter). The combined extracts were dried (Na2SO4) and concentrated to give 1- (2-azidoethyl) cyclopentane carboxylic acid (37.5 g) as an amber liquid. Example 5. Synthesis of 4- (chloromethyl) -N-methylbenzamide. To a solution of 4-chloromethyl benzoic acid (17.5 g, 100 mmol) in toluene (anhydrous by molecular sieves 4A) was added thionyl chloride (11 mL, 150 mmol). The mixture was heated to 80 ° C and stirred overnight and then 2 hours at 105 ° C. The reaction mixture was cooled to room temperature and the excess of thionyl chloride and toluene was removed in vacuo. The resulting oily residue was azeotroped with toluene (50 ml), then dried under high vacuum for 45 minutes to give the crude acid chloride. To the crude acid chloride in dichloromethane (200 ml, dried with 4A molecular sieves) was added ethylamine hydrochloride (7.5 g, 110 mmol) at -10 ° C at one time. To the mixture was added diisopropylamine (35 ml, 201 mmol) dropwise over 15 minutes while maintaining the temperature of the reaction mixture below 2 ° C. After the addition, the suspension was allowed to warm to room temperature and stirred for 30 minutes. Then, the reaction mixture was diluted with water (125 ml) and the layers were waited. The aqueous layer was extracted with dichloromethane (2 x 60 ml) and the combined extracts were washed successively with water (150 ml) and dye solution (150 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated to 50 ml. The precipitated white solid was collected by filtration and washed with dichloromethane and hexane to obtain 4- (chloromethyl) -N-methylbenzamide (12.02 g) as a white solid. A second crop of material (3.05 g) was obtained from the mother liquor, by concentration and dilution with hexane to give a toral of 15.07 g, 82%, m.p. 138-139.5 ° C. Example 6. Synthesis of 4- (l-methyltetrazol-5-yl) benzyl chloride. To a suspension of 4- (chloromethyl) -N-methylbenzamide (12 g, 65.3 mmol) in toluene (anhydrous with molecular sieves 4A), thionyl chloride (7.15 mL, 98 mmol) was added. The mixture was heated to reflux (~90 ° C) and the resulting solution light yellow, was stirred at reflux overnight. The reaction mixture was cooled to room temperature and the excess of thionyl chloride and toluene was removed in vacuo. The resulting oily residue was azeotroped with toluene (50 ml), then dried under high vacuum for 1.5 hours to give the crude imidoyl chloride. To the suspension of sodium azide (5.1 g, 78.5 mmol) in acetonitrile (62 ml) was added chlorotrimethylsilane (10.5 ml, 82.5 mmol) and the mixture was stirred for 1.5 hours at room temperature. After cooling to 0 ° C a solution of the crude imidoyl chloride prepared above in acetonitrile (20 ml) was added. This mixture is stirred for 1.5 hours at 0 ° C, and then allowed to warm to room temperature, and stirred for 18 hours. TLC analysis indicated the presence of traces of the starting amide. Then, the reaction mixture was diluted with water (70 ml) and ethyl acetate (70 ml), and poured into a mixture of saturated ammonium chloride (70 ml) and ethyl acetate (70 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 90 ml). The combined extracts were washed successively with water (90 ml) and brine solution (90 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated to 40 ml to obtain a white precipitate. The solid was collected by filtration washing with hexane. The purification was tested by crystallization in several solvents without result. Thus, it was purified by preparative HPLC using ethyl acetate and hexane, or the ratio 1: 2 as eluent, obtaining 4- (1-methyltetrazol-5-yl) benzyl chloride (11.35 g, 83%) as a solid white; p.f. 90-92 ° C. Example 7. Synthesis of l - [[4- (l-methyltetrazol-5-yl) phenyl] methyl] cyclobutane carboxylic acid. A solution of diisopropylamine (1.05 ml, 7.5 mmol) in THF (5 ml) was cooled to -10 ° C and a solution of n-butyl lithium (2.9 ml, 7.25 mmole) in hexanes was added dropwise, maintaining the temperature below 0 ° C. After the addition, the solution was stirred for 30 minutes at 0 ° C. The solution was cooled to -70 ° C and a solution of methyl cyclobutane carboxylate (0.57 g, 5 mmol) in THF (2 ml) was added dropwise, keeping the internal temperature between -60 and -70 ° C. After the addition, the reaction mixture was stirred for 30 minutes at -50 to -60 ° C. Then, a solution of 4- (1-methyltetrazol-5-yl) benzyl chloride (0.94 g, 4.5 mmol) in THF (5 ml) was added dropwise, and the reaction mixture was stirred for 1 hour of -60 to -70 ° C. It was then allowed to warm to room temperature and stirred overnight at which time the TLC analysis indicated the absence of 4- (1-methyltetrazol-5-yl) benzyl chloride (note, the product and 4- ( l-methyltetrazol-5-yl) benzyl have the same Rf value, although they were differentiated by spraying with PMA). The mixture was poured into a mixture of water (70 ml) and ethyl acetate (70 ml). An emulsion was formed and filtered through celite. The two resulting layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated salt and dried with anhydrous magnesium sulfate. After filtration, the solution was concentrated in vacuo and the residue was purified by chromatography with silica gel eluting with 1: 2 ethyl acetate: hexane to give 1- [[4- (l-methyltetrazol-5-yl) phenyl] ] methyl] cyclobutane carboxylate methyl (0.42 g, 32%) in the form of a syrup. HR MS: observed mass, 301.1668. Calculated mass, 301.1664. Example 8-14. Using the procedure described in Example 7, the following cyclopentane carboxylate derivatives were prepared: Example 15. Synthesis of 1- [[4- (l-methyl-5-tetrazolyl) phenyl] methyl] cyclobutane carboxylic acid. To a solution of methyl l - [[4- (l-methyltetrazol-5-yl) phenyl] methyl] cyclobutane carboxylate (0.33 g, 1.15 mmol) in a mixture of THF (7 ml) and methanol (7 ml) was added sodium hydroxide IN (7 ml). The mixture was heated to 55 ° C and stirred for 4 hours at which time the TLC analysis indicated the absence of the starting material. After cooling to room temperature, the solvent was removed in vacuo and the residue was diluted with water and extracted with ethyl acetate to remove all neutral impurities. Then, the aqueous layer was neutralized with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated salt and dried with sodium sulfate. After filtration, the solution was concentrated in vacuo and the residue was dried under high vacuum to obtain 1- [[4- (1-methyl-5-tetrazolyl) phenyl] methyl] cyclobutane carboxylic acid (180 mg, 57%) in Form of a light yellow syrup. Examples 16-23. Using the procedure described in Example 15, the following cyclopentane carboxylic acids were prepared from the corresponding methyl esters: R ^ / C02H c_5 * The performance is that of the two steps according to procedures described is examples 13 and 15.

Example 24. Synthesis of l - [(4-methoxyphenyl) methyl] cyclohexane carboxylic acid. Using the procedures described in Examples 7 and 15, from 4-methoxybenzyl chloride, 1- [(4-methoxyphenyl) methyl] cyclohexane carboxylic acid was prepared with 23% total yield. HRMS: observed mass 248.1426. Calculated mass 248.1412 (M +) Example 25. Synthesis of 1- [3- (l-methyl-5-tetrazolyl) phenyl] methyl] cyclohexane carboxylic acid. Using the procedures described in Examples 7 and 15, from 1- [3- (1-methyl-5-tetrazolyl) benzyl chloride, the 1- [3- (1-methyl-5-tetrazolyl) acid was prepared phenyl] methyl] cyclohexane carboxylic acid, with 77% total yield. HRMS: observed mass, 301.1667. Calculated mass, 301.1664 (M + H). Example 26. Synthesis of N- [(1-phenylcyclopentyl) carbonyl] -4-amino-L-phenylalanine methyl ester. To a solution of the methyl ester of 4-nitrophenylalanine hydrochloride (3.90 g, 15 mmol) and 1-phenylcyclopentane carboxylic acid (3.4 g, 18 mmol) in 30 ml of DMF was added HBTU (6.8 g, 18 mmol) and diisopropylethyl amine (6.4 ml, 30 mmol) at room temperature. The mixture was then stirred at this temperature for 8 hours. The reaction was diluted with 250 ml of ethyl acetate and washed with 0.5 N HCl (40 ml), saturated NaHCO 3 (2 x 40 ml) and saturated salt (2 x 40 ml). After removing the solvent, the residue was purified on a column of silica gel eluting with ethyl acetate: hexene (1: 3) to give the methyl ester of N- [(1-phenylcyclopentyl) carbonyl] -4-nitro- L-phenylalanine (4.5 g, 75.7%). A suspension of the methyl ester of N - [(1-phenylcyclopentyl) carbonyl] -4-nitro-L-phenylalanine (3.5 g, 8.99 mmol) and stannous chloride (10 g, 44 mmol) in 60 ml of ethanol was heated reflux for 50 minutes under an argon atmosphere. Then, the ethanol was removed under reduced pressure, and the residue was treated with 50 ml of saturated NaHCO 3 followed by sodium carbonate to adjust the pH above 9. The white suspension was extracted with ethyl acetate (3 × 300 ml). The combined extracts were washed with water (100 ml) and brine (100 ml) and dried (MgSO4). Removal of the solvent afforded the methyl ester of 4-amino-H- [(1-phenylcyclopentyl) carbonyl] -L-phenylalanine (2.9 g, 89%). Example 27. Synthesis of the sodium salt of the N- [(1-phenylcyclopentyl) carbonyl] -4- [(4-quinolinylcarbonyl) amino) -L-phenylalanine. To a solution of the methyl ester of 4-amino-N- [(1-phenylcyclopentyl) carbonyl] -L-phenylalanine (81 mg, 0.2 mmol) and 4-quinolinecarboxylic acid (43.3 mg, 0.25 mmol) in 1 ml of DMF was added HBTU (95 mg, 0.25 mmol) and diisopropylethylamine (65 μl, 0.5 mmol) at room temperature. The mixture was then stirred at this temperature overnight. The reaction was then diluted with 15 ml of ethyl acetate and washed with water (2 ml), saturated NaHC03 (2 x 2 ml) and saturated salt (2 x 2 ml). The solution was dried (MgSO4) and concentrated. The residue was hydrolyzed with 0.5 ml of NaOH LN in 5 ml of ethanol at 25 ° C overnight. The crude product was purified by passing through an open C-18 column eluting with water (200 ml), 30% methanol in water (200 ml), 40% methanol in water (200 ml) and pure methanol (200 ml). ). The fractions containing the product were concentrated and lyophilized to give the sodium salt of N- [(1-phenylcyclopentyl) carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine (79.5 mg, 75% ), HR-FABMS: Observed mass 530,2056. Calculated mass 530,2058. Example 28-31. Using the general method described in Example 27, the following analogous products were prepared from the product of Example 26 and the appropriate benzoic or heteroaromatic carboxylic acids: Example 32. Synthesis of methyl ester of 4-nitro- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine. A solution of 1-benzylcyclopentane carboxylic acid (0.135 g, 0.66 mmol), methyl ester of 4-nitro-L-phenylalanine (0.187 g, 0.72 mmol) and HBTU (0.272 g, 0.72 mmol) in 2 ml of DMF , it was treated with diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred overnight, concentrated, diluted with ethyl acetate, washed with water, IN HCl, water, saturated NaHCO3 and anhydrous (NgSO4). Yes residue obtained after evaporation was purified by chromatography on 30 g of silica gel, eluting with 40% ethyl acetate: hexane to obtain the methyl ester of 4-nitro-N- [(1- (phenylmethyl) cyclopentyl] carbonyl] ) -L-phenylalanine (194 mg, 71%) in the form of a white foam. Example 33. Synthesis of methyl ester of 4-amino-N- [(1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine A solution of the methyl ester of 4-nitro-N- [[1- (phenylmethyl ) cyclopentyl] carbonyl] -L-phenylalanine (185 mg, 0.45 mmol) in 10 ml of ethanol was hydrogenated at atmospheric pressure with 47 mg of Pd (C) 10% for 3 hours.The reaction mixture was filtered through of a celite bed and evaporated to dryness to obtain the methyl ester of 4-amino-N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine (170 mg, 99%) as a white solid. white color suitable for use in the next step Example 34. Synthesis of N - [[1- (phenylmethyl) cyclopentyl] carbonyl] -4-]) 4-quinolinylcarbonyl) amino) -L-phenylalanine A solution of the methyl ester of 4-amino-N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine (29.5 mg, 0.078 mmol), quinoline-4-carboxylic acid (17 mg, 0.10 mmol) and HBTU (38 mg, 0.10 mmol) in 1 ml of DMF was treated with diisopropylethylamine (30 μl, 0.17 mmol). The mixture is stirred overnight and diluted with 10 ml of ethyl acetate and 10 ml of ether and washed with portions of water (2 x 10 ml), saturated NaHCO 3 (10 ml) and dried (MgSO 4). When concentrating, they obtained 48 mg that was dissolved in 3 ml of methanol. A solution of sodium hydroxide (0.10 ml, 4N, 0.4 mmol) was added and the mixture was stirred for 2 hours. The excess base was neutralized by the addition of 0.1 ml of acetic acid, the solution was filtered through a 0.2 μ nylon filter and the filtrate was purified by RP-HPLC with a column 4 x 30 cm Rainin C-18 using a gradient of 5 to 95% acetonitrile: water containing 0.75% trifluoroacetic acid, with a flow of 49 ml / minute for 30 minutes. The peak that eluted with 74.5% acetonitrile was N- [[1- (phenylmethyl) cyclopentyl] carbonyl) -4- ((4-quinolinylcarbonyl) amino) -L-phenylalanine (15 mg), HR-FBA- MS: observed mass 522.2393. Calculated mass 522.2393 (M + H), the peak that eluted with 83% acetonitrile was N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] - methyl ester - L-phenylalanine (15 mg) recovered, HR-FAB-MS: observed mass 536.2556. Calculated mass: 536.2549 (M + H). Example 35. Synthesis of 4 - [[(2-nitrophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine The methyl ester of 4-amino-N was reacted - [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine (31.7 mg, 0.083 mmole) and 2-nitrobenzoic acid (38 mg, 0.10 mmole), as described in example 34, 26.7 mg of 4- [ [(2-nitrophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbunyl] -L-phenylalanine, HR-FAB-MS: observed mass 516.2113. Calculated mass 516.2134 (M + H). Example 36. Synthesis of 4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -N- [[1-. { phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine The methyl ester of 4-anino-N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine was reacted (35.3 mg, 0.093 mmole) and 2-methyl-5-nitrobenzoic acid (20 mg, 0.11 mmole), as described in Example 34 to obtain 4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine (34 mg, 69%), HR-FAB-MS: observed mass 530.2298. Calculated mass 530.2291 (M + H). Example 37. Synthesis of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine. The 4-amino-N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine methyl ester (67 mg, 0.176 mmole) and the 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmole) were dissolved. ) in 5 ml of dichloromethane and 2,6-lutidine (50 μl, 0.43 mmol) was added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with IN HCl, water and NaHCO 3, saturated and dried (MgSO). The crude product was dissolved in 4 ml of methanol and treated with 4 N NaOH (0.1 ml). After 2 hours, the excess base was neutralized with 0.1 ml of acetic acid, the solution was filtered through a 0.2 μ nylon filter and the filtrate was purified by RP-HPLC on a 4 x 30 cm column Rainin C -18, using a gradient of 5 to 95% acetonitrile: water containing 0.75% trifluoroacetic acid, with a flow of 49 ml / minute for 30 minutes. The peak eluting with 87% acetonitrile was concentrated and lyophilized to yield 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine ( 46 mg), LR (+) LSIMS: m / z 539 (M + H) (2 Cl).

Example 38. Synthesis of N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4-nitro-L-phenylalanine methyl ester. A solution of l- (4-methoxy) benzylcyclopentane carboxylic acid (0.020 G, 0.86 mmol), methyl ester of 4-nitro-L-phenylalanine (0.24 g, 0.94 mmol), and HBTU (0.36 g, 0.94 mmol) in 3 ml of DMF. it was treated with 0.52 ml (3 mmolee) of diisopropylethylamine. The mixture was stirred overnight, concentrated, diluted with ethyl acetate, washed with water, 1N HCl, water, saturated MaHC03 and dried (MgSO4). The residue obtained after evaporation was purified by chromatography on 30 g of silica gel, eluting with 40% ethyl acetate: hexane, to give the N- [[1- [(4-mthoxyphenyl) methyl] methyl ester] 'iclopentyl] carbonyl] -4-nitro-L-phenylalanine (256 mg, 68%) in the form of a white foam, HR-FAB-MS: observed mass 441.2027. Calculated mass: 441.2025 (M + H). Example 39. Synthesis of methyl ester of 4-amino-N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine. A solution of the N - [[1 - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4-nitro-L-phenylalanine methyl ester (253 mg, 0.575 mmol) in 10 ml of ethanol was hydrogenated to the Atmospheric pressure with 45 mg of Pd (C) 10% for 3 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness to give 4-amino-N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] methyl ester. phenylalanine (225 mg, 95%) as a white solid suitable for use in the next step, HR-FAB-MS: observed mass 410.2196- Calculated mass 410.2200 (M +). Example 40. Synthesis of N - [[1 - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine. A solution of the methyl ester of 4-amino-N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (30.7 mg, 0.075 mmol), quinoline-4-carboxylic acid (17 mg , 0.10 mmole), and HBTU (38 mg, 0.10 mmole) in 1 ml of DMF, was treated with diisopropylethylamine (30 μl, 0.17 mmole). The mixture is stirred overnight and is diluted with 15 ml of ethyl acetate and 10 ml of ether and washed with water (2 x 10 ml), saturated NaHCO 3 (1 x 10 ml) and dried (MgSO 4). By concentration, 42 mg were obtained and dissolved in 3 ml of methanol. Sodium hydroxide (0.10 ml, 4 N, 0.4 mmol) was added and the sample was stirred for 2 hours. The excess base was neutralized by the addition of acetic acid (0.1 ml), the solution was filtered through a 0.2 μ nylon filter, and the filtrate was purified by RP-HPLC on a 4 x 30 cm column Rainin C- 18, using a gradient of 5 to 95% acetonitrile: water containing 0.75% trifluoroacetic acid with a flow of 49 ml / minute for 30 minutes. The peak which eluted with 74% acetonitrile was concentrated and lyophilized to give N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L- phenylalanine (22.8 mg), HR-FAB-MS: observed mass 552.2482. Calculated mass 552.2498 (M + H). In the peak eluting with 82.6% of ecetonitrile, the N - [[1 - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] - methyl ester was obtained. L-phenylalanine (11.2 mg), HR-FAB-MS: observed mass 566.2675. Calculated mass 566.2455 (M + H). Example 41. Synthesis of N - [[l - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [[(2-nitrophenyl) carbonyl] amino] -L-phenylalanine. The methyl ester of 4-amino-N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (32.3 mg, 0.079 mmol) and 2-nitrobenzoic acid (17 mg) were reacted. , 0.10 mmol) as described in example 40 to give 22 mg of N - [[l - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [[(2-nitrophenyl) carbonyl] amino] - L-phenylalanine, HR-FAB-MS: observed mass 546.2235. Calculated mass 546.2240 (M + H).

Example 42. Synthesis of N [[l - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -L-phenylalanine. The methyl ester of 4-amino-N- [[1- [(4-methoxyphenyl) ethyl] cyclopentyl] carbonyl] -L-phenylalanine (23.4 mg., 0.057 mmole) and 2-methyl-5-nitrobenzoic acid (13 mg, 0.07 mmol) as described in example 40 to give 23 mg (69%) of N - [[1- (4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -L-phenylalanine, HR-FAB-MS: observed mass 560.2413. Calculated mass 560.2397 (M + H). Example 43. Synthesis of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1 - [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine. The 4-amino-N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine methyl ester (66 mg, 0.17 mmol) and the 2,6-dichlorobenzoyl chloride were dissolved ( 50 mg, 0.23 mmoles), in 5 ml of dichloromethane and 2,6-lutidine (50 μl, 0.43 mmol) is added. After 4 hours, the mixture was diluted with ether and dichloromethene and washed with 1N HCl, water, and saturated NaHCO 3 and dried (MgSO 4). The crude product is dissolved in methanol (4 ml) and treated with 4N NaOH (0.1 ml). After 2 hours, the base was neutralized in excess, with acetic acid (0.1 ml), the solution was filtered through a 0.2 μ nylon filter and the filtrate was purified by RP-HPLC on a 4 x 30 cm column Rainin C-18 using a gradient of 5 to 95% acetonitrile: water containing 0.75% trifluoroacetic acid with a flow of 49 ml / minute for 35 minutes. The peak which eluted with 79% acetonitrile was concentrated and lyophilized to give 4- [[(2,6-dichlorophenyl) carbonyl] amine] -H- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (28.2 mg), HR-FABMS: observed mass 591.1445. Calculated mass 591.1430 (M + Na). Example 44. Synthesis of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester. To a solution of methyl ester of 4- (amino) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (2.6 mg, 8.6 mmol) in dichloromethane (20 ml) were added diisopropylethylamine (2.3 ml, 13 mmol) followed by 2,6-dichlorobenzoyl chloride (1.99 g, 9.0 mmol) at room temperature. The mixture was stirred for 15 hours to form a white precipitate. The mixture was diluted with 30 ml of dichloromethane and 50 ml of water. The layers were separated and the aqueous layer was extracted with 100 ml (2 x 50 ml) of dichloromethane. The combined organic extracts were washed with brine and dried with anhydrous magnesium sulfate. Filtration and concentration of the solvent afforded 4.03 g (quantitative) of the mathic ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalenine in form of a white solid of pf 148-151 ° C. Example 45. Synthesis of the hydrochloride salt of the methyl ester of 4- [[(2,6-dicluru-phenyl) carbonyl] amino] -L-phenylalanine The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl]] amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (1.86 g, 4.0 mmol) was treated with hydrochloric acid in dioxane (10 ml) at room temperature. After 5 minutes, the solids had dissolved and the mixture was stirred for 1 hour. Then, 25 ml of ethyl ether was added to precipitate the product. The solids were collected by filtration and washed with hexane. The resulting solid was very hygroscopic and of gummy consistency. This material was dissolved in 50 ml of methanol and concentrated. After drying under high vacuum, the hydrochloride salt of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine (1.64 g, 97%) was obtained as a solid of color light yellow: pf 158-161 ° C. Example 46. Synthesis of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl] -L-phenylalanine methyl ester. To a solution of the hydrochloride salt of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine (0.2 g, 0.5 mmol) and l- (4-methoxyphenylmethyl) cyclohexanecarboxylic acid (0.15 g, 0.60 mmole) in DMF (2 ml), HBTU (0.23 g, 0.60 mmol) and diisopropylethylamine (0.20 ml, 1.2 mmol) were added at room temperature. The mixture was stirred overnight and diluted with 25 ml of ethyl acetate. The ethyl acetate layer was washed successively with 0.5N hydrochloric acid (2 x 20 ml), saturated sodium bicarbonate solution (2 x 20 ml), brine (1 x 20 ml) and dried with anhydrous magnesium sulfate. . Filtration and concentration gave 350 mg of a white solid which was purified by column chromatography with 15 g of silica gel, eluting with 20-30% ethyl acetate in hexane to give the methyl ester of 4- [[ (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl] -L-phenylalanine (0.20 g, 84%) as a white solid, m.p. 85-87 ° C. HR MS: observed mass 597.1913. Calculated mass 597.1923 (M + H). Example 47. Synthesis of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl] -L-phenylalanine. To a suspension of the methyl ester of 4- [[(2, 6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl] -L-phenylalanine (0.15 g, 0.25 mmol) in ethanol (2 ml) was added 1.0 N aqueous sodium hydroxide (1.5 ml, 3 mmol) at room temperature. The mixture was heated to 50 ° C and the resulting clear solution was stirred overnight. The mixture was concentrated, the residue was diluted with 5 ml of water and extracted with 25 ml of ether to remove all neutral impurities. The aqueous layer was acidified with IN HCl and the precipitated white solid was collected by filtration and washed with water (20 ml) and hexane (20 ml). After air drying, 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl] -L-phenylalanine (0.12 g 82%) was obtained. in the form of a white solid, pf 136-140 ° C. HR MS: observed mass 583.1763. Calculated mass 583.1766 (M + H). Examples 48 to 60. The compounds indicated below were prepared according to the procedures described in Examples 46 and 47.

Example 61. Coupling of N- [(9H-Fluoren-9-yl-ethoxy) carbonyl] -4- [[(2-propenyloxy) carbonyl] amino] -L-phenylalanine, to a Wang resin A 250 ml cylindrical glass vessel equipped with a granular glass frit was charged with 10 g of Wang resin (loading factor: 1.15 mmole / g, 300 mesh). The resin was washed with dichloromethane (2 x 100 ml), methanol (2 x 100 ml) and dimethylformamide (2 x 100 ml). To the swollen resin was added N- [(9H-fluoren-9-ylmethoxy) carbonyl] -4- [[(2-propenyloxy) carbonyl] amino] -L-phenylalanine (11.2 g, 23 mmol) and 2-chlorocarbonyl chloride. , 6-dichlorobenzoyl (8.06 ml, 57.5 mmol) in N-methylpyrrolidone (70 ml) and the mixture was stirred for 30 minutes. Pyridine (6.45 ml, 80.5 mmol) was added and the resulting mixture was stirred for 24 hours. The substitution was determined to be 0.75 mmole of N - [[(9H-fluoren-9-ylmethoxy) carbonyl] -4- [[(2-propenyloxy) carbonyl] amino] -L-phenylalanine per gram of resin, by measurement UV quantitative of the Fmoc present in the resin. Example 62. Synthesis of 4-amino-N- [(9H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine in Wang resin. A 500 ml cylindrical glass vessel equipped with a granular glass frit was charged with Wang resin substituted with N- [(9H-fluoren-9-ylmethoxy) carbonyl] -4- [[(2-propenyloxy) carbonyl] amino] -L-phenylalanine (10 g, 7.5 mmol) obtained in Example 61 and a solution prepared with bis (triphenylphosphine) palladium dichloride (1.6 g 2.3 mmoles) and acetic acid (5 ml, 80 mmoles) in anhydrous dichloromethane (150 ml). The resulting mixture was stirred for 30 minutes and then tri-n-butyl tin hydride (20 ml, 74.3 mmol) was added. The resulting mixture was stirred for 1 hour. Tri-n-butyl tin hydride was added to the mixture (10 ml, 37 mmol). Stirring was continued for 1 hour and the mixture was filtered. To the resulting resin was added a solution prepared from the bis (triphenylphosphine) palladium dichloride (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mol) in anhydrous dichloromethane (150 mL). The mixture was stirred for 30 minutes and then tri-n-butyl tin hydride (20 ml, 74.3 mmol) was added. The resulting mixture was stirred one hour. To the mixture was added more tri-n-butyl tin hydride (10 ml, 37.15 mol). Stirring was continued for one hour. After the second deprotection cycle, the mixture was washed with dichloromethane (2 x 100 ml), methanol (2 x 100 ml) and dimethylformamide (2 x 100 ml) to give 4-amino-N- [(9H-fuoren-9) -ylmethoxy) carbonyl] -L-phenylalanine in Wang resin suitable for use in the subsequent steps. Example 63. Synthesis of 4 - [(4-quinolinylcarbonyl) amino] -L-phenylalanine in Wang resin. A 250 ml glass cylindrical vessel, equipped with a grained glass frit was charged with the 4-amino-N- [(9H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine (10 g) obtained in Example 62 and a solution prepared from quinoline-4-carboxylic acid (5.2 g, 30 mmol), BOP (13.75 g) , 30 immoles) and diisopropylethylamine (6.8 ml) in 70 ml of N-methylpyrrolidinone. The suspension was stirred for 4 bocee. The mixture was filtered and washed with dichloromethane (2 x 100 ml), methanol (2 x 100 ml) and dimethylformamide (2 x 100 ml). To the washed resin was added a 25% piperidine solution in N-methylpyrrolidinone (80 ml), the mixture was stirred at room temperature for 20 minutes and filtered. The process was repeated and. The resulting suspension was filtered and washed with dichloromethane (2 x 100 ml), methanol (2 x 100 ml) and dimethylformamide (2 x 100 ml). Filtration gave 4- [(4-quinolinecarbon'yl) amino] -L-phenylalanine in Wang resin suitable for direct use in the next weight. Example 64. Synthesis of N- [(2, 2-dichloro-l-methyl-cyclopropyl) carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine. The 4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine in Wang resin (300 mg) obtained in Example 63 was washed with dichloromethane (2 x 10 ml), methanol (2 x 10 ml) and dimethylformamide (2 x 10 ml). To the resin was added a solution prepared from 2,2-dichloro-l-methylcyclopropylcarboxylic acid (180 mg, 1.02 mmol), BOP (450 mg, 1.02 mmol) and diisopropylethylamine (0.23 ml) in 4 ml of N-methylpyrrolidinone. at room temperature. The resulting mixture was stirred for 2 hours. The reaction mixture was then filtered and washed with dichloromethane (2 x 10 ml), methanol (2 x 10 ml) and dichloromethane (2 x 10 ml). The cleavage was carried out with 90% trifluoroacetic acid (TFA) in dichloromethane for 5 minutes. The mixture was filtered and the TFA was removed under high vacuum. The addition of ether (25 ml) caused the precipitation of N- [(2, 2-dichloro-l-methylcyclopropyl) carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine. The compound was purified by inverted phase HPLC (Dupont Rx C18, 7 μM, 2.12 cm x 25 cm) using acetonitrile and water as the mobile phase with a linear gradient of 20-50% acetonitrile for 180 minutes. LRMS (M + H) observed table 486.5. Calculated mass 486.3. Examples 65-81. Using the procedure described in Example 64, the following compounds were prepared: Examples 82 to 106. Using the method described in Examples 63 and 64, the following derivatives were prepared: Example 107. Synthesis of phenylmethyl ester of N- [(1,1-dimethylethoxy) carbonyl] -4- [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -L-phenylalanine. The N- [( 1, 1-dimethylethoxy) carbonyl] -4- [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -L-phenylalanine (5.02 g, 10 mmol) and the benzyl bromide (3.5 ml, 29 mmol) in DMF (25 ml) with KHC03 (1.75 g, 17.5 mmol). After 18 hours a white precipitate had formed. The majority of the DMF was evaporated under reduced pressure, and the residue was treated in 100 ml of dichloromethane and washed with water (2 x 50 ml). Most of the dichloromethane was evaporated and ether (100 ml) was added to precipitate the product. Filtration and washing with ether gave the phenylmethyl ester of N- [(1,1-dimethylethoxy) carbonyl] -4- [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -L-phenylalanine (5.3 g) pf 186-187 ° C. Example 108. Synthesis of 4-amino-N- [El- [(4-methoxyphenyl) methyl] cyclopentyl] carbenyl] -L-phenylalanine. The methyl ester of 4-emino-N- [[1- [[(4-methomiphenyl) methyl] cyclopentyl] cbonyl] -L-phenylalanine was treated (280 mg, 0.68 mmol) in THF (12 ml), with a solution of lithium hydroxide hydrate (100 mg, 2.4 mmol) in water (2 ml) and the mixture was stirred for 3 hours. The mixture was concentrated and the residue was acidified with 6 N HCl to give a viscous white solid. Trituration with water and drying the high vacuum provided crude 4-amino-N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (200 mg), suitable for direct use in the next He passed. Example 109. Synthesis of 4- (2,3-dihydro-l, 3-dioxo-lH-pyrrolo [3,4-c] pyridin-2-yl) -N- [[l- [(4-methoxyphenyl)] methyl] cyclopentyl] carbonyl] -L-phenylalanine. A solution of 4-amino-N- [El- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (98 mg, 0.23 mmole), DIPEA (30 μl, 0.23 mmole) and 3-anhydride, 4-pyridinedicarboxylic acid (114 mg, 0.77 mmol) in dichloromethane (10 ml) was stirred for 18 hours at room temperature. The mixture was concentrated to remove most of dichloromethane and the residue was treated with DMF (3 ml). Carbonyl diimidazole (103 mg, 0.64 mmol) was added to the resulting solution and the reaction was allowed to proceed for 18 hours. The resulting mixture was purified directly by RP-HPLC on a 4 x 30 cm column Rainin C-18 using a gradient of 5 to 95% acetonitrile: water containing 0.75% trifluoroacetic acid with a flow of 49 ml / minute for 35 minutes . The peak was eluted with 45.6% acetonitrile was concentrated and lyophilized to give 4- (2,3-dihydro-l, 3-dioxo-lH-pyrrolo [3,4-c] pyridin-2-yl) -N - [[l- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (28 mg) HR FABMS: observed mass 528.2146. Calculated mass 528.2134 (M + H). Example 110. Synthesis of 4- (1, 3-dioxo-2H-isoindol-2-yl) -N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-prolyl] -L- phenylalanine Using the procedure described in Example 109, from phthalic anhydride, 4- (1,3-dioxo-2H-isoindol-2-yl) -N [[1 - [(4-methoxyphenyl) methyl] cyclopentyl was obtained ] carbonyl] -L-prolyl] -L-phenylalanine, HR FABMS: observed mass 527.2172. Calculated mass 527.2182 (M + H). Example 111. Synthesis of 4- [(RS) -2, 3, 5, 6, 7, 7a-haxahydro-1,3-dioxo-lH-pyrrolo [3, 4-c]? Iridin-2-yl] -N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine and N-E [1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(3aRS, 7aRs) - (octahydro-1,3-dioxo-lH-pyrrolo [3,4-c] pyridin-2-yl] -L-phenylalanine A solution of 4- (2,3-dihydro-l, 3-dioxo) -lH-pyrrolo [3,4-c] pyridin-2-yl] -N - [[l- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine (30 mg, 0.057 mol) in ethanol ( 4 ml) containing a few drops of TFA, hydrogenated with Pd (C) 10% (6 mg) for 18 hours.The mixture was filtered and evaporated and the residue was purified by RP-HPLC on a 4 x 30 cm column Rainin C-18 using a gradient of 5 to 95% ecetonitrile: water containing 0.75% trifluoroacetic acid with a flow of 49 ml / min for 35 minutes.The peak eluting with 59.5% acetonitrile was concentrated and the mixture was concentrated. lyophilized to give the N - [(l - [(4-me Toxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(3aRS, 7aRS) - (octahydro-1,3-dioxo-lH-pyrrolo [3,4-c] pyridin-2-yl] -L-phenylalanine (4.2mg), HR FABMS: observed mass 534.2602, calculated mass 534.2604 (M + H) .The peak that eluted with 62% acetonitrile was concentrated and the mixture was lyophilized to give 4- [(RS) -2, 3, 5, 6, 7, 7a-hexahydro-l, 3-dioxo -lH-pyrrolo [3,4-c] pyridin-2-yl] -N- [[1 - [(4-methoxyphenyl) methyl) cyclopentyl] carbonyl] -L-phenylalanine (4.9 mg), HR FABMS: observed mass 532.2452. Calculated mass 532.2447 (M + H). Example 112. Synthesis of 4 - [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine in Wang resin. 4-amino-N- [(9H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine in Wang resin (3.0 g, 2 28 mmol) obtained in Example 62, was suspended in pyridine (15 ml), and the suspension was cooled to 0 ° C and 2,4,6 chloride was added. -trimethylphenylsulfonyl (2.49 g, 11.4 mmol). The resulting mixture was stirred for 2 hours. The mixture was filtered and washed with dichloromethane and methanol. The coupling operation was repeated. The resulting resin was treated with 25% piperidine in N-methylpyrrolidinone (2 x 15 minutes) and washed with dichloromethane and methanol to give the 4- (2, 4, 6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine in Wang resin. Example 113. Synthesis of N- [(2,2-dichloro-l-methylcyclopropyl) carbonyl] -4- [[(2,4,6-trimethylphenyl) carbonyl] amino] -L-phenylalanine. 4- [[(2,4,6-Trimethylphenyl) sulfonyl] amino] -L-phenylalanine was stirred in Wang resin (0.30 g, 0.23 mmole), 2,2-dichloro-l-methylcyclopropane carboxylic acid (0.19 g, 1.14 mmol), BOP (0.50 g, 1.14 mmol) and DIPEA (0.26 ml, 1.5 mmol) in N-methylpyrrolidinone (3 ml), for 3 hours. The mixture was filtered and the resin was washed with dichloromethane and methanol and air dried. Treatment with 90% TFA in dichloromethane for 3 minutes caused the resin to be cleaved. The mixture was filtered, the filtrate was concentrated and lyophilized from water to give N- [(2,2-dichloro-l-methylcyclopropyl) carbonyl] -4- [[(2,4,6-trimethylphenyl) carbonyl] amino] ] -L-phenylalanine in the form of a white solid. Example 114. Synthesis of N - [[1- (4-methoxyphenyl) cyclohexyl] carbonyl] -4- [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine. N- [[1- (4-methoxyphenyl) cyclohexyl) carbonyl) -4- [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine, was prepared using the procedure described in Example 113 , from 1- (4-methoxyphenyl) cydohexane carboxylic acid.

Example 115. Synthesis of N - [(l-adamantyl) carbonyl] -4- [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine. N- [(1-adamantyl) carbonyl] -4- [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine, was prepared using the procedure described in example 113, from acid 1 -carboxylic adamantane. Example 116. Synthesis of 4- [[(4-cyano-4-phenyl-1-piperidinyl) carbonyl] amino] -L-phenylalanine in Wang resin The 4-amino-N- [(9H-fluoren-9-ylmethoxy) carbonyl] -1-phenylalanine in Wang resin (300 mg, 0.228 mmol) obtained in Example 62, was placed in a vessel equipped with a glass frit. and washed with dichloromethane (2 x 10 ml), methanol (2 x 10 ml) and dichloromethane (2 x 10 ml). To the resin was added carbonyl diimidazole (0.22 g, 1.4 mmol) and triethylamine (0.38 ml, 2.7 mmol) in 3 ml of dichloromethane. The mixture was stirred overnight. The mixture was then filtered and washed with dichloromethane (3 x 5 ml). To the resin was added 4-cyano-4-phenylpiperidine hydrochloride (0.25 g, 1.14 mmol) and DMAP (0.14 g, 1.14 mmol) in 3 ml of N-methylpyrrolidinone. The resulting mixture was stirred for 3 hours. Then, the reaction mixture was filtered and washed with dichloromethane (2 x 10 ml), methanol (2 x 10 ml) dimethylformamide (2 x 10 ml) and methanol (2 x 10 ml). Cleavage of the Fmoc group took place with 25% piperidine in N-methylpyrrolidinone (2 x 15 minutes) to give 4 - [[(4-cyano-4-phenyl-1-piperidinyl) carbonyl] amino] -L-phenylalanine in Wang resin. Example 117. Synthesis of 4- [[(4-cyano-4-phenyl-1-piperidinyl) carbonyl] amino] -N- [(2,2-dichloro-l-methylcyclopropyl) carbocyl] -L- phenylalanine A suspension of "4- [[(4-cyano-4-phenyl-1-piperidinyl) carbonyl] amino] -L-phenylalanine in Wang resin (0.30 g, 0.228 immoles), 2,2-dichloro-l-methylcyclopropane carboxylic acid (0.19 g, 1.14 mmol), BOP (0.50 g, 1.14 mmol) and DIPEA (0.26 mL, 1.5 mmol) in N-methylpyrrolidinone (3 mL) was stirred for 3 hours. The mixture was filtered and washed with dichloromethane and methanol. Cleavage of the resin took place by treatment with 90% TFA in dichloromethane for 3 minutes. The mixture was filtered and the filtrate was evaporated to give 4- [[(4-cyano-4-phenyl-1-piperidinyl) carbonyl] amino] -N- [(2,2-dichloro-1-methylcyclopropyl) carbonyl] - L-phenylalanine. FAB MS m / z 543 (M + H). Examples 118-122. Using the procedures described in Examples 116 and 117, the following Compounds were prepared: Example 123. General procedure for the preparation of the ethyl esters from the N-acyl-L-phenylalanine derivatives substituted in 4. To a suspension gives the N- (acyl) -4- [(aroyl) amino] - L-phenylalanine (10 mmol) and sodium bicarbonate powder (4.2 g, 50 mmol) in DMF (75 ml) was added an excess of yedoethane (7.8 g, 50 mmol) at room temperature. The resulting suspension was stirred until the TLC analysis of the mixture indicated the absence of the starting material, usually 20 hours. The excess iodomethane and some DMF were removed in a rotary evaporator under vacuum. The residue was diluted with 100 ml of ethyl acetate and washed successively with water (2 x 70 ml), brine solution (70 ml) and dried with MgSO4. Filtration of the drying agent and removal of the solvent provided a residue that was purified by crystallization or chromatography on silica gel. Example 124. N - [[1- (2-Methoxyethyl) cyclopentyl] carbonyl] -4-nitro-L-phenylalanine bound to Wang resin. A mixture of N-Fmoc-4-nitro-L-phenylalanine (2.30 g, 1.35 mmoles) bound to Wang resin, in 27 ml of 25% piperidine in NMP (N-methylpyrrolidinone), was stirred for 30 minutes at room temperature. The solvent was filtered through a sintered funnel. With the resin still in the funnel, another 27 ml of 25% piperidine in NMP was added and the suspension was allowed to stand at room temperature for 30 minutes. After removing the solvent by filtration, the resin was then washed successively with dichloromethane, DMF, isopropyl alcohol and dichloromethane, and dried under vacuum. The above resin was placed in a 50 ml round bottom flask containing 13 ml of NMP. To it was added 1- (2-methoxyethyl) cyclopentane carboxylic acid (930 mg, 5.4 mmol). The reaction was stirred overnight. A small aliquot was removed and analyzed by the Kaiser test which was negative for the amine. The resin was filtered off and washed with dichloromethane, DMF, isopropyl alcohol, dichloromethane and dried under reduced pressure to yield 1.97 g of N - [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -4-nitro- L-phenylalanine bound to Wang resin. Ejenplo 125. Synthesis of 4-amino-N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine bound to Wang resin. The N was placed in a scintillation vial. - [[l- (2-ethoxyethyl) cyclopentyl] carbenyl] -4-nitro-L-phenylalanine bound to Wang resin (1.91 g, 1.12 mmol) and a 2M solution of SnCl2.2H20 in DMF (8 ml). The reaction mixture was stirred overnight at room temperature. The resin was filtered off and washed with DMF, isopropyl alcohol, dichloromethane and Et20 to give the 4-amino-N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine bonded to Wang resin (2.21 g). A small sample of the resin was taken, cleaved with 50% TFA / dichloromethane and analyzed by ESPMS, demonstrating the presence of product but not the starting material, m / z 335 (M + H). Example 126. Synthesis of 4- [((2R) -2-amino-4-methyl-1-oxopentyl) amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, attached to Wang resin. In a 20 ml scintillation vial was placed '4-amino-N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine bound to Wang resin (200 mg, 0.118 mmol), Fmoc -D-Leu-OH (201 mg, 0.571 mmol), DIEA (164 μL, 0.95 mmol), HBTU (360 mg, 0.95 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature. The resin was filtered and washed with DMF, isopropyl alcohol, dichloromethane. A Kaiser test was negative for the amine. The obtained resin was treated with 5 ml of 25% piperidine in NMP for 49 minutes at room temperature. Then, it was filtered through a sintered funnel and washed with DMF, the resin was resuspended in 5 ml of piperidine 25% / NMP in the funnel and left to stand for 15 minutes at room temperature. This process was repeated once more and the resin was then washed with DMF, isopropyl alcohol and dichloromethane. The 4- [((2R) -2-amino-4-methyl-l-oxo-entyl) amino] -N- E [1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, linked to Wang resin (215 mg). Example 127. Synthesis of 4- [(2S, 4R) -3-acetyl-4- (2-methylpropyl) -5-oxo-2-phenyl-1-imidazolidinyl] -N- [[1- (2-methoxyethyl)] cyclopentyl] carbonyl] -L-phenylalanine, bound to Wang resin, and 4- [(2R, 4R) -3-acetyl-4- (2-methylpropyl) -5-oxo-2-phenyl-1-imidazolidinyl] -N - [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, bound to Wang resin. 0. 59 mmol / g __ ' The resin obtained in Example 126 (0.59 mmol / gram, 0.202 g, 0.11 mmol) was reacted with benzaldehyde (1.78 mmol, 182 μl) in 4 ml of a THF / trimethylol ortho-tolide solvent mixture (1/1) to room temperature and stirred for 4 days. Next, 3 ml of acetic anhydride was added to the previous suspension and the mixture was stirred at 95 ° C overnight. Once the suspension was cooled to room temperature, the solvent was removed by filtration and the resin was washed with dichloromethane, THF and then dichloromethane. Treatment of the resulting resin with 6 ml of TFA / dichloromethane (1/1) at room temperature for 3.5 hours resulted in a crude mixture containing products. The raw products gave the correct mass by ESPMS (M + H) = 578. The separation by RP-HPLC (column 41.4 mm x 30 m to Dynamax C18, gradient 5:95 e 95: 5 acetonitrile: water, for 30 minutes, monitoring the eluent at 214 A) gave two diastereomeric products to which the formulas were initially assigned, 4- [ (2S, 4R) -3-acetyl-4- (2-methylpropyl) -5-oxo-2-phenyl-1-imidazolidinyl] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine , retention time 25.06 minutes, yield 25% and 4- [(2R, 4R) -3-acetyl-4- (2-methylpropyl) -5-oxo-2-phenyl-1-imidazolidinyl] -N- [[1 - (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, retention time 26.98 minutes, 33% yield. Example 128-139 Using the procedure described in example 126-127, the compounds indicated below were prepared Example 140. Synthesis of N - [[1- (4-methoxyphenyl) cyclohexyl] carbonyl] -4-nitro-L-phenylalanine bound to Wang resin. A mixture of Fmoc-4-nitro-L-phenylalanine in Wang resin ( 581 mg, 0.36 mmoles) in 10 ml of 25% piperidine in NMP (N-methylpyrrolidinone), was stirred for 30 minutes at room temperature. The solvent was filtered through a sintered funnel. With the resin still in the funnel, another 27 ml of 25% piperidine in NMP was added, and the suspension was allowed to stand at room temperature for 30 minutes. After removal of the solvent by filtration, the resin was successively washed with dichloromethene, DMF, isopropyl alcohol, dichloromethane, and the vacuum was dried. The above resin was placed in a 25 ml round bottom flask, containing 4 ml of NMP. Thereto was added 1- (4-methoxyphenyl) cyclohexanecarboxylic acid (337 mg, 1.44 mmol), diisopropylethylamine (DiEA, 343 μl, 1.98 mmol), and BOP reagent (637 mg, 1.44 mmol). The reaction mixture was stirred overnight. A small aliquot was removed and analyzed by the Kaiser test which was negative for the amine. The resin was collected by filtration and washed with dichloromethane, DMF, isopropyl alcohol, dichloromethane and dried under reduced pressure to give 580 mg (0.59 mmol / gram) of N - [[1- (4-methoxyphenyl) cyclohexyl] carbonyl ] -4-Nitro-L-phenyl-alanine bound to Wang resin. Example 141. Synthesis of 4- [2- (4-hydroxyphenyl) -4-oxo-3-thiazolidinyl] -N- [[1- (4 -methoxyphenyl) cyclohexyl] carbonyl] -L-phenylalanine.

In a 20 ml scintillation vial was added N- [[1- (4-methoxyphenyl) cyclohexyl] carbonyl] -4-nitro-L-phenylalanine bound to Wang resin (241 mg, 0.14 mmole) prepared in Example 140 and 2 ml of a 2 M solution of NnCl2. 2H20 in DMF. The reaction mixture was stirred overnight at room temperature. The resulting resin was collected by filtration and washed with DMF, isopropyl alcohol, dichloromethane and ether to obtain 243 mg (0.14 mmoles) of 4-amino-N- [[(1- (4-methoxyphenyl) cyclohexyl] carbonyl] -L -phenylalanine in Wang resin.

The 4-amino-N- [[(1- (4-methoxyphenyl) cyclohexyl] carbonyl] -L-phenylalanine in Wang resin (243 mg, 0.149 mol) prepared above, was reacted with 4-hydroxybenzaldehyde (153 mg, 1.25 mmol) and mercaptoacetic acid (174 μl, 2.5 mmol) in the presence of 3 Á molecular sieves (100 mg) in THF (9 ml) at 90 ° C for 4 hours, after cooling to room temperature, the reaction mixture was filtered and the resin was washed with THF, dichloromethane, DMF, MeOH and ether (3 x 30 ml for each solvent). The resin was then treated with 50% TFA in dichloromethane at room temperature for 1 hour. Next, the suspension was filtered and the resin was washed with acetonitrile (2 x 10 ml). The combined filtrates were concentrated to dryness and purified by RP-HPLC to give 4- [2- (4-hydroxyphenyl) -4-oxo-3-thiazolidinyl] -N- E- (4-methoxyphenyl) cyclohexyl] carbonyl ] -L-phenylalanine (40 mg, 50% yield), HRMS (C32H34N2? 6S) observed mass 575.2199. Calculated mass 575.2216 (M + H). Example 142. Using the procedure described in Example 141, N - [[1- (4-methoxyphenyl) cyclohexyl] carbonyl] -4 [2- (2-naphthyl) -4-oxo-3-thiazolidinyl] - L-phenylalanine HR MS (C36H36N2? 5S) observed mass 608.1910. Calculated mass 608.1904 (M +). Example 143. Synthesis of (S) -4- (3,4-dimethyl-2,5-dioxo-l-imidazolidinyl) - N - [[1- (4-methoxyphenyl) cyclohexyl] carbonyl] -L-phenylalanine. Into a 20 ml scintillation vial was added 4-amino-N- [[(1- (4-methoxyphenyl) cyclohexyl] carbonyl] -L-phenylalanine in Wang resin (188 mg, 0.11 immoles, 0.59 charge per gram / gram) ) prepared in example 141, Fmoc-N-methyl-L-alanine-OH (114 mg, 0.341 mmol), DIEA (100 μl, 0.58 mmol), HBTU (220 mg, 0.58 mmol) in DMF (2 ml). The reaction mixture was stirred overnight at room temperature.The resin was filtered and rinsed with DMF, isopropyl alcohol, dichloromethane and dried under reduced pressure.A Kaiser test gave negative for the amine The resin obtained above (200 mg) was treated with 5 ml of 25% piperidine in NMP for 45 minutes at room temperature After filtering through a sintered glass funnel and rinsing with DMF, the resin was resuspended in 5 ml of piperidine 25% / NMP in the funnel and left to stand for 15 minutes at room temperature and filtered.This process was repeated and the resin was rinsed then with DMF, isopropyl alcohol, dichloromethane. The above resin was placed in a 20 ml scintillation vial with carbonyl diimidazole (CDI, 201 mg, 1.24 mmol) and DIEA (64 μl, 0.374 mmol) in dichloromethane (5 ml). The reaction mixture was stirred overnight at room temperature. The resin was then filtered and washed with dichloromethane, DMF, isopropyl alcohol, dichloromethane. The resulting resin was transferred to a 50 ml round bottom flask and stirred in 50% TFA / dichloromethane (10 ml) for 3 hours at room temperature. The resin was filtered and washed with MeCN. The mother liquors were concentrated. The residue was purified by inverted phase HPLC using a linear gradient from 10:95 to 90: 5 (MeCN: H20) for 40 minutes. The (S) -4- (3,4-dimethyl-2, 5-dioxo-l-imide-zolidinyl) -N- [[1- (4-methoxyphenyl) cyclohexyl] carbonyl] -L-phenylalanine (22 mg, 0.043 mmol) with a total yield of 39% calculated on the basis of a charge of 4-nitro-N-Fmoc-phenylalanine in Wang resin of 0.059 mmole / gram.HRMS: (C28H33N306), observed mass, 508.2456. Calculated mass, 508.2448 (M + H). Example 144 Using the procedure described in Example 143, N - [[(1- (4-methoxyphenyl) cyclohexyl] carbonyl] -4- [(4S) -3-methyl-4- (2-methylpropyl >) was synthesized.; -2, 5-dioxo-l-imidezolidinyl] -L-phenylalanine (46 mg, 0.082 mmol) with 52% yield. HRMS (C31H39 3O6): observed mass 550.2904. Calculated mass 550.2917 (M + H). EXAMPLE 145 2,6-Dimethyl-4-trifluoromethyl-3-pyridinecarboxylic acid.

A solution of 2,6-dimethyl-4-trifluoromethyl-2-pyridinecarboxylic acid ethyl ester in 40 ml of THF and 10 ml of sodium hydroxide solution was heated to reflux for 48 hours. TLC analysis of the mixture (3: 7: methanol: dichloromethane) indicated that the starting material had been completely consumed. The mixture was acidified with acetic acid (5 ml) and evaporated to dryness. The residue was triturated with THF and the solution was concentrated to give 0.7 g of material containing some THF and acetic acid as seen by NMR. This material was combined with the product of a similar experiment and chromatographed on 90 g of silica gel, eluting with (3: 7) methanol: dichloromethane to give 1.05 g of a solid. This material was diluted with toluene (6 ml) and evaporated several times to remove most of the acetic acid obtained after drying under high vacuum, 0.9 g of a white foam LR-ES-MS (C9H6F3N02): 218 ( MN). Example 146. Preparation of 4 - [[(2,6-dichlorophenyl) carbonyl] amino-N- [[1- (2-azidoethyl) cyclopentyl] carbonyl] -L-phenylalanine Cl7H17CI3N203 psoral; 403.73 C2SH27CI2N5O4 so? DL.: 532.42 Using the general procedure described in Example 46, the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino-N- [[1- (2-azidoethyl) was prepared ) cyclopentyl] carbonyl] -L-phenylalanine, with a total yield of 78%. HR MS (C35H27C12N504): observed mass 532.1519. Calculated mass 532.1518 (M + H). Example 147. Preparation of 4- E [(2,6-dichlorophenyl) carbonyl] amino-N- E [1- (2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine methyl ester. To a suspension of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino-N- [[1- (2-ezidoethyl) cyclopentyl] carbonyl] -L-phenylalanine (15.47 mmol, 8.24 g) in THF (70 mL) was added a solution of 1.0 M trimethylphosphine in toluene (25 mmol, 25 mL) at 0 ° C. The mixture was stirred 7 hours at room temperature, after which the TLC analysis indicated the absence of the starting material. Next, 3 equivalents of water (45 mmol, 0.82 ml) were added and the mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the residue was ezeotroped twice with toluene to give a pasty material which was dissolved in THF: dichloromethane (-250 ml) and dried with anhydrous sodium sulfate. The solution was filtered through a pad of celite and washed with THF (100 ml). The combined filtrates were evaporated in vacuo to obtain 5 g (64%) of the methyl ester of 4 - [[(2,6-dichlorophenyl) carboni] amino-N- [[1- (2-aminoeti) cyclopentyl] carbonyl] -L-phenylalanine, in the form of a pink solid. HR MS (C25H29C12N304): observed mass 506.1625. Calculated mass 506.1613 (M + H). Example 148. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino-N- [[1- (2- [(1-oxoethyl) amino] ethyl] cyclopentyl] carbonyl] -L- methyl ester phenylalanine To a solution of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino-N - [[1- (2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine (9.6 mmol, 5 g ) in pyridine (70 ml) was added 2 equivalents' of acetic anhydride (20 mmol, 2.04 g) at room temperature The colored solution was stirred for 15 hours at room temperature and then diluted with 200 ml of ethyl acetate. The ethyl acetate layer was washed successively with IN hydrochloric acid (2 x 100 ml), brine solution (100 ml) and dried with anhydrous magnesium sulfate, filtration of the drying agent and concentration of the solvent gave a solid. sponge which gave only an 85% purity by HPLC, this solid was triturated with ethyl acetate (40 ml) and then Exam (20 ml) The solid was collected by filtration and the air was dried to give 3.38 g (63%) of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino-N- [[1]). - (2- [(1-oxoethyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine in the form of a yellow solid, p.f. 190-194 ° C. HR MS (C27H3? Cl2N305): observed mass 548.1696. Calculated mass 548.1719 (M + H). Example 149. Preparation of the hydrochloride salt of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine. To a solution of the hydrochloride salt of the methyl ester of 4- E [(2,6-dichlorophenyl) carbonyl] amino-L-phenylalanine (30 mmol, 12.1 g) in ethanol (300 ml) was added sodium hydroxide IN ( 90 ml). The mixture was set at 40-45 ° C for 1 hour after which analysis of the reaction mixture indicated the absence of starting material, and cooled to room temperature. The solvent was evaporated in vacuo and the residue was extracted with ether (2 x 100 ml) to remove neutral impurities. Then, the basic aqueous layer was acidified with IN hydrochloric acid to pH 2 to give a clear solution.

The solution was lyophilized to high vacuum obtaining 11.7 g (100%) of the title compound as a white amorphous solid. HR MS (C 16 H 15 Cl 3 2 O 3) observed mass 354.2014. Calculated mass 354.2053 (M + H). Example 150. Preparation of 4- [[(2,6-dichlorophemyl) carbonyl] amino-N- [(9H-fluoren-9-ylmethoxy) carbomyl] -L-phenylalanine. To a mixture of the hydrochloride salt of 4- [[(2,6-dichlorophenyl) carbonyl] amino-L-phenylalanine (30 mmol, 10.59 g), N - [(9-fluorenylmethoxycarbonyloxy) succinimide (30 mmol, 10.12 g) and sodium carbonate (300 mmol, 31.8 g) were added dioxane (75 ml) and water (25 ml) at room temperature. The suspension. it was stirred for 15 hours at room temperature after which TLC analysis of the mixture indicated the absence of starting material. The inorganic solids were filtered through celite and washed with ethyl acetate. Upon washing with ethyl acetate, some organic compound was precipitated from the filtrate which was collected and air dried. The filtrate was concentrated in vacuo and the residue was combined with the above solid organic compound and the product was treated with hot THF and precipitated with ether to obtain 14.1 g (81%) as a white solid, m.p. 230-234 ° C. LR MS (C3? H24Cl2N205): observed mass 597. Calculated mass 597 (M + Na). Example 151. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N- [(9H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine was prepared in Wang resin, from the product of the example 150 with a load of 0.765 mmoles / gram of resin, using the general procedure described in Example 61.

Example 152. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin. A 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [ (9H-Fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine in Wang resin prepared above (12.1 mmoles, 17.4 g) was added 20% piperidine in NMP at room temperature. The mixture was stirred for 1.5 hours at room temperature and the resins was filtered and washed with DMF (2 x 20 ml). Then, the resin was suspended in 20% piperidine in NMP (100 ml) and the solvent was decanted. The resin was washed with dichloromethane (2 x 20 ml) and dried under high vacuum to obtain 13.5 g of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin. Example 153. prepared N - [[1- (2-azidoethyl) cyclopentyl] carbonyl] -4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin from the product of Example 152 using the method General described in Example 64. The load was 0.695 mmoles / gram of resin.

Example 154. Preparation of N - [[1- (2-aminoethyl) cyclopentyl] carbonyl] -4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin To a suspension of N- [[1- (2-azidoethyl) cyclopentyl] carbonyl] -4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin (9.33 mmol, 13.43 g, 0.695 mmol per gram) in THF (60 ml) was added a 1.0 M solution of trimethylphosphine in THF (37.3 mmol, 37.3 ml) at 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 4 hours after which a Kaiser test was positive for the amino. The resin was filtered and washed with DMF (2 x 20 ml), dichloromethane (4 x 10 ml), isoproponal (4 x 10 ml), DMF (2 x 20 ml) and dichloromethane (2 x 20 ml) respectively. After drying at high vacuum, 13.43 g of N - [[1- (2-aminoethyl) cyclopentyl] carbonyl] -4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine was obtained in Wang resin. .

Example 155. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[(1,1-dimethylethyl) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine in Wang resin. To a mixture of N - [[1- (2-amincetyl) cyclopentyl] carbonyl] -4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin (0.069 mmol, 100 mg, loading of 0.695 mmol per gram) in pyridine (2 ml), an excess of 2,2,2-trimethylacetyl chloride (0.28 mmol) was added., 33 mg) at 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 3 hours after which a Kaiser test was negative for the amino. The resin was filtered and washed with dichloromethane (2 x 10 ml) and dried at high vacuum to obtain 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N - [[1- [2 - [[ N- (1, 1-dimethylethyl) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine in Wang resin. Example 156. 4- [(2,6-Dichlorophenyl) carbonyl] amino] -N- was prepared [[1 - [2- [[N- (1,1-dimethylethyl) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, by cleaving the product of Example 159 from the resin with THF using the General procedure described in Example 64 to give 25. mg (62%) of a white solid. HR MS (C29H35C12 305): observed mass 576.2019. Calculated mass 576.2032 (M + H) Example 157, Preparation of the methyl ester of the N [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -N-methyl-4-nitro-L-phenylalanine. To a suspension of N - [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -4-nitro-L-phenylalanine methyl ester (2.73 mmol, 1.03 g) and silver oxide (10.9 mmol, 2.53 g) in DMF (25 ml) was added methyl iodide (160 mmol, ml) at room temperature. The suspension was stirred for 2 days at room temperature after which TLC analysis of the mixture indicated the presence of starting material. An additional 10 ml (160 mmoles) of methyl iodide and 2 g (8.6 mmoles) of silver oxide were added, respectively. The suspension was stirred for 24 h and the solid was filtered through a pad of celite and washed with ethyl acetate (30 ml) and methanol (30 ml). The filtrate was concentrated and the residue was extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with water (20 ml) and brine solution (20 ml) and dried with anhydrous magnesium sulfate. Filtration of the drying and solvent removal agent gave a crude compound which was purified by silica gel column chromatography to obtain 530 mg (50%) as a light brown oil. HR MS (C2oH28N206): observed mass 392.1940. Calculated mass 392.1947 (M +).

Example 158 to 167. Using the general procedure described in Examples 155 and 156, the analogous compounds indicated below were prepared from N- [[1- (2-aminoethyl) cyclopentyl] carbonyl] -4- [[ (2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine in Wang resin. 1. ion M + H unless otherwise indicated. Example 168. Preparation of 1- (4-bromobutyl) cyclopentane carboxylic acid methyl ester. To a solution of diisopropylamine (150 mmol, 21 ml) in THF (100 ml) was added dropwise a solution of n-butyl lithium (145 mmol, 58 ml, 2.5 M) in hexanes at -10 ° C keeping the temperature below 0 ° C. After the addition, the solution was stirred for 30 minutes at 0 ° C. To this, a solution of methyl cyclopentane carboxylate (100 mol, 13.1 g) in THF (20 ml) was added dropwise at -70 ° C maintaining the internal temperature between -60 ° C and -70 ° C. After the addition, the reaction mixture was stirred for 1 hour at -50 to -60 ° C. Then, a solution of 1,4-dibromobutane (100 mmol, 21.59 g) in THF (20 ml) was added dropwise and the brown chlorine suspension was stirred for 1 hour at -60 ° C to -70 ° C. C. It was then allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (200 ml) and the organic compound was extracted with ether (2 x 100 ml). The combined extracts were washed with a saturated solution of brine (150 ml) and dried with anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the resulting residue was distilled at 120-133 ° C / 2.5 mm Hg to obtain the methyl ester of 1- (4-bromobutyl) cyclopentane carboxylic acid in the form of a colorless oil (12.8 g, 48%). HR MS (CnH? 9Br02): observed mass 262.0565. Calculated mass 262.0568 (M +). Example 169. Preparation of 1- (4-cyanobutyl) cyclopentane carboxylic acid methyl ester.

A solution of the methyl ester of l- (4-bro obutil) cyclopentane carboxylic acid was treated with a solution of 0.5 molar lithium cyanide in DMF (5 mmol, 10 ml), stirred overnight at room temperature and then heated or 75 ° C for two hours. The reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (30 ml) and washed with saturated sodium bicarbonate solution (2 x 10 ml) and brine (5 ml) and dried with sodium sulfate. magnesium to give a yellow oil (860 mg). Chromatography with silica gel eluting with 1: 3 ethyl acetate: hexane gave a pale colored oil (83%, 693 mg). LR MS (C? 2H19N02): observed mass 227 (M + NH4), 248 (M + K). Example 170. Preparation of 1- (3-bromopropyl) cyclopentone carboxylic acid methyl ester. To a solution of 1.5 molar LDA in cyclohexane (60 mmoles, 40 ml), cooled or -70 ° C a solution of cyclopentane carboxylic acid matyl ester (42 mmoles, 5.6 g) in THF (15 ml) was added over 30 minutes. The mixture was stirred for 1 hour at 70 ° C. Then, a solution of 1,3-dibromopropane (60 mmol, 11.9 g) in THF (30 ml) was added which had been pre-cooled to -70 ° C, all at once and the reaction mixture was stirred at - 70 ° C for one hour and then at room temperature overnight. The reaction mixture was poured into a salt (200 ml), the layers were separated, the aqueous layer was extracted with ether (3 x 30 ml) and the combined organic layers were washed with brine (20 ml), removed ( magnesium sulfate) and concentrated to give a yellow oil (15 g). Distillation through a short path apparatus with a 3"vigreux column provided a yellow oil, 7.96 g (76%), eg 76-80 ° C at 0.3 mm Example 171. The methyl ester was prepared 1- (3-Cyanopropyl) cyclopentane carboxylic acid from 1- (3-bromopropyl) cyclopentane carboxylic acid methyl ester using the general method described in Example 169 to give a 79% yield of a pale yellow oil. LR MS (C ??H ?7N02) calculated mass 196. Observed mass, 196 (M + H) Example 172. Preparation of 1- [4- (methylthio) butyl] cyclopentane carboxylic acid methyl ester (29514-112) To a solution of the l- (4-bromobutyl) cyclopentane carboxylic acid methyl ester (38 mmol, 10 g) in DMF (100 ml) was added sodium thiomethoxide (72.6 mmol, 5.09 g). addition of sodium thiomethoxide, the reaction was exothermic and the mixture became a nebulous solution of color pa The mixture was stirred for 15 hours at room temperature and poured into water (200 ml). The organic compound was extracted with ether (2 x 150 ml). The combined extracts were washed with brine (150 ml) and dried with anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the resulting residue was purified by column chromatography with silica gel to obtain 4.43 g (51%) of a colorless oil. LR MS (C? 2H2202S): 230 (M +). Example 173. The l- (3-methylthiopropyl) cyclopentane carboxylic acid methyl ester was prepared or cleaved from the l- (3-bromopropyl) cyclopentane carboxylic acid methyl ester using the general procedure described in Example 172 to give 54% of yield of a pale yellow oil. Example 174. Preparation of 1- [(4- (methylsulfonyl) butyl] cyclopentane carboxylic acid methyl ester. To a solution of 1- [4- (methylthio) butyl] cyclopentane carboxylic acid methyl ester (19.2 mmol, 4.43 g) in AcOH (20 ml) was added 30% hydrogen peroxide (10 ml) The reaction mixture was heated to 70 ° C and stirred for 15 hours past which TLC analysis of the mixture indicated the absence of the material The reaction mixture was cooled to room temperature and concentrated in vacuo, the residue was poured into saturated sodium bicarbonate solution and extracted with ether (3 x 100 ml) The combined extracts were washed with a saturated solution of sodium bicarbonate. Sodium chloride (200 ml) and dried with anhydrous magnesium sulfate After filtering the drying agent, the solvent was removed in vacuo, and the resulting residue was purified by silica gel column chromatography to obtain 4.94 g (98%). ) f of a colorless oil, LR MS (C? 2H2204S): 263 (M + H). Example 175. Preparation of l- [4- (Methylsulfonyl) butyl] cyclopentane corboxylic acid. To a solution of l- [4- (Methylsulfonyl) butyl] cyclopentane carboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 ml) and methanol (38 ml), 1N sodium hydroxide was added ( 38 ml). The mixture was heated at 50-55 ° C for 15 hours, after which the TLC analysis of the reaction mixture indicated the absence of the starting material and the mixture was allowed to cool to room temperature. The solvent was removed in vacuo and the residue was diluted with water (100 ml) and extracted with ether (2 x 50 ml) to remove any neutral impurities. ThenThe basic aqueous layer was acidified with IN hydrochloric acid and the product was extracted with ethyl acetate (2 x 75 ml). The combined extracts were washed with brine solution and extracted with anhydrous sodium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the residue was dried under high vacuum, yielding 4.31 g (92%) of the title compound as a white solid of low melting point. LR MS (C11H20O4S): 249 (M + H). Example 176. Preparation of 1- (2-bromoethyl) cyclopentane carboxylic acid methyl ester. To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL), a solution of n-butyl lithium (145 mmol, 58 mL 2.9 M) in hexanes at -10 ° C was added dropwise or dropwise maintaining the temperature below 0 ° C. After the addition, the solution was stirred for 30 minutes at 0 ° C. Then a solution of cyclopentane carboxylic acid methyl ester (100 mmol, 13.1 g) in THF (20 ml) was added dropwise or drop at -70 ° C maintaining the internal temperature between -60 and -70 ° C. After the addition, the mixture was stirred for 1 hour at -50 to -60 ° C. Then, a solution of 1,2-dibromoethane (90 mmol, 16.91 g) in THF (20 ml) was added dropwise and the light brown suspension formed was stirred for 1 hour at -60 to -70 ° C. . The temperature was then allowed to rise to room temperature and was stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (200 ml) and the organic compound was extracted with ether (2 x 100 ml). The combined extracts were washed with a saturated solution of sodium chloride (150 ml) and dried with anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the resulting residue was distilled at 95-105 ° C / 2.5 mm Hg to obtain 11.5 g (49%) of a colorless oil. Example 177. Preparation of 1- [2- (4-morpholino) ethyl] cyclopentane carboxylic acid methyl ester. To a solution of the l- (2-bromoethyl) cyclopentane carboxylic acid methyl ester (2 mmol, 0.47 g) in DMF (10 ml), sodium iodide (0.3 mmol, 45 mg) and morpholine (10 mmol, 0.87) were added. g). The reaction mixture was stirred for 3 days at room temperature after which the TLC analysis of the mixture indicated the absence of the match material. The mixture was diluted with ethyl acetate (100 ml) and washed successively with water (2 x 50 ml) and a saturated solution of sodium chloride (100 ml) and dried with anhydrous magnesium sulfate. After filtering the extraction agent, the solution was concentrated in vacuo to obtain 0.44 g (92%) of a colorless oil. HR MS (C? 3 H23N03): observed mass, 241.1675. Calculated mass, 241.1678 (M +). Example 178. Preparation of l- [2- (4-morpholino) ethyl] cyclopentane carboxylic acid. To a solution of l- [2- (4-morpholino) ethyl] cyclopentane carboxylic acid methyl ester (1.75 mmole, 0.42 g) in a mixture of THF (5 ml) and methanol (5 ml) was added sodium hydroxide. (3.5 ml). The mixture was heated at 50-55 ° C for 40 hours in which the TLC analysis of the reaction mixture indicated the absence of the starting material and the mixture was allowed to cool to room temperature. The solvent was removed in vacuo and the residue was diluted with water (100 ml) and extracted with ether (2 x 50 ml) to remove any neutral impurities. Then, the basic aqueous layer was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate (2 x 75 ml). The aqueous layer was neutralized with saturated sodium carbonate solution and extracted with ethyl acetate (3 x 50 ml). TLC analysis of the aqueous layer indicated the presence of some more product. Thus, all the ethyl acetate extracts were combined with the aqueous layer and concentrated. The solid residue was triturated with methanol. The undissolved solids were filtered and the filtrate was concentrated in vacuo. The resulting solid was redissolved in methanol and concentrated HCl was added to form a salt. Then, methanol was eliminated obtaining the HCl salt of 1- [2- (morpholino) ethyl] cyclopentane carboxylic acid (1.09 g, may contain some NaCl) as a white solid. LR MS (Ci2H2? N03): 228 (M + H). Example 179. Preparation of methyl 1- (3, 3-difluoro-2-propylene) cyclopentane carboxyl. A 0.89 M solution of LDA (0.24 mmol, 27 ml) was prepared from diisopropylomino (75 mmol, 7. 58 g) in THF (59 ml) and 2.5 M n-butyl lithium in hexane (72 mmol, 29 ml). The solution was cooled to -70 ° C and cyclopentane carboxylic acid methyl ester (15 mmol, 1.92 g) in THF (10 ml) was added dropwise, over 20 minutes maintaining the temperature at -70 ° C. The mixture was stirred an additional 1 hour at -70 ° C and a solution of trifluoropropyl bromide (15 mmol, 2.65 g) in THF (10 ml) was added over 15 minutes. The reaction mixture was stirred 1 hour at -70 ° C and allowed to warm to room temperature overnight. The reaction mixture was poured into brine (150 ml) and the organic layer was separated. The aqueous layer was extracted with ether (30 ml), the combined organic layers were washed with brine (10 ml), dried with anhydrous magnesium sulfate and evaporated to dryness to obtain a yellow oil (4.1 g) which after chromatography on silica gel (120 g, 10% ethyl acetate in hexane) gave a pale yellow oil (58%, 1.72 g). Example 180. Preparation of 5-iodo-2-pentanono ethylene ketal. A solution of 5-chloro-2-pantanone (40 mmol, 6. 59 g) in acetone (40 ml) was treated with Nal (60 mmol, 9 g) and boiled under reflux overnight. After cooling to room temperature, the solids were removed by filtration and the supernatant was concentrated to a dark gummy solid. A 1: 1 mixture of ether and petroleum ether (20 ml) was added, the mixture was stirred for 30 minutes, filtered and evaporated to dryness to obtain 7.2 g of a red oil which was distilled (34-). 36 ° C to 0.3 mm) 5 g of the ketone. To a solution of this ketone (23.6 mmol, 5 g) in toluene (40 ml) in a 100 ml flask equipped with a Dean Stark trap, ethylene glycol (27 mmol, 1.67 g) and 100 mg para-acid were added. toluenesulfonic acid and the reaction mixture was boiled under reflux for 6 hours. After cooling, the toluene solution was washed with INN NaOH (20 ml), water (5 x 20 ml), and brine (5 ml), dried with potassium carbonate, filtered and evaporated to dryness to give after distillation, 4.8 g. (47%) of 5-iodo-2-pantanone ethylene ketal in the form of a colorless oil e.g. 44-48 ° C at 0.3 mm. Example 181. Preparation of 1- (4- (ethylenedioxy) pentyl) cyclopentane carboxylic acid methyl ester. A solution of lithium diisopropylomide »solution 1. 5 M tetrahydrofuran, in cyclohexane (15 mmol, 10 mL) was cooled to -70 ° C, and a solution of cyclopentane carboxylic acid methyl ester (10 mmol, 1.28 g) in THF (10 mL) was added dropwise or dropwise. , during 15 minutes, maintaining the internal temperature of -60 to -70 ° C the yellow solution was stirred 1 hour at -70 ° C and a solution of 5-iodo-2-pentonone ethylene ketal was added (10 mmoles, 1.28 g) in THF (10 ml) for 15 minutes, maintaining the temperature at -70 ° C. After stirring for 1 hour at -70 ° C, the temperature was allowed to rise to room temperature overnight. The reaction mixture was poured into brine (150 ml) and the organic layer was separated. The aqueous layer was extracted with ether (20 ml), the combined organic layers were washed with brine (10 ml), dried with anhydrous magnesium sulfate and evaporated to dryness to obtain 2.5 g (97%) of a color oil. pale yellow. Example 182. Preparation of 4-iodo-2-butanone ketal. A solution of ethylene 4-bromo-2-butanone ketal (16.4 mmoles, 3.2 g) in acetone (30 ml) was treated with sodium iodide (24 mmoles, 3.7 g) and sodium carbonate (50 mmoles, 5.1 g) and boiled under reflux overnight. The resulting mixture was filtered, washed with acetone (10 ml) and evaporated to dryness to give a white solid. The residue was triturated with a 1: 1 mixture of ether: petroleum ether (20 ml), stirred 30 minutes, filtered and evaporated to obtain 3.74 g (94%) of a pale yellow oil. LR ES (C? 3 H2204): 243 (M + H). Example 183. 1- [3- (ethylenedioxy) butyl] cyclocarboxylic acid methyl ester was prepared, using the general method described in Example 181 to give a 25% yield of a colorless oil. LR ES MS (C13H2204): 243 (M + H). weight Example 184. Preparation of the 4- [[(2,6-dichlorophenyl) carbonyl] amico] -N- [[1- (3- (methylsulfonyl) propyl] cyclopentyl] carbonyl] -L-phenylalanine methyl ester. of the methyl ester of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [3- ({(methylthio) propylcyclopentyl] carbonyl] -L-phenylalanine (110 mg, 0.2 mmol) ) in dichloromethane (10 ml) was cooled in an ice bath and treated with meta-chloroperbenzoic acid (0.7 mmole, 150 mg) After stirring at room temperature for 3 hours, the reaction mixture was diluted with dichloromethane (30 ml). ml) and washed with saturated sodium bicarbonate solution (10 ml), and brine (5 ml) and dried with magnesium sulfate.An evaporation a yellow oil was obtained and chromatography on silica gel eluting with 5 g. % methanol in dichloromethane gave a white viscous solid (96%, 113 mg) LR-ES MS (C27H32N206C12S): 583 (M + H) Example 185. Preparation of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [3- [(methylsulfinyl) propyl] cyclopentyl] carbonyl] -L-phenylalanine. A solution of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [3- (methylthio) propyl] cyclopentyl] carbonyl] -L-phenylalanine (110 mg, 0.2 mmoles) in a mixture of ethyl acetate (8 ml) and THF (3 ml) was treated with an oxone solution (0.05 mol, 31 mg) in water (2 ml) and the two-phase system was stirred vigorously for 2 hours at room temperature, and then oxone was added again ( 0.05 mmol, 31 mg) and stirring was continued overnight. After separating the layers, the aqueous phase was extracted with ethyl acetate (5 ml), and the combined organic layers were washed with brine (3 ral), dried with magnesium sulfate and evaporated to dryness to obtain a sodium solid. White color. Chromatography on silica gel eluting with methanol (7.5%) in dichloromethane gave a white solid (68%, 78 mg). LR-ES MS (C27H32N205C12S): 567 (M + H). Example 187. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- E [1- [2- [[methylamino) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine. To a solution of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine (40 mg, 0.080 mmol) in dichloromethane (1 ml) was added methyl isocyanate (5 mg, 0.095 mmol). The resulting mixture was stirred for 18 hours. The reaction mixture was concentrated in vacuo and the crude urea was used in the next step without purification. To a solution of the crude methyl ester (50 mg, 0.080 mmol) in MeOH (1 mL) was added a solution of LiOH (8 mg, 0.19 mmol) in water (0.5 mL). The mixture was stirred for 2 hours and then acidified (pH ~ 1-2) with 0.5M HCl. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. Purification by inverted phase HPLC, using a gradient of 15-95% acetonitrile-water for 25 minutes, yielded 30 mg (68% RH MS (C 26 H 3 o Cl 2 N 405): calculated mass, 549.1671, Observed mass, 549.1677 (M + H). Examples 188 to 191. Using the general procedure described in Example 187, and from the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-aminoethyl) cyclopentyl) ] carbonyl] -L-phenylalanine, the following analogs were obtained: 1. Starting material = trimethylsilyl isocyanate 2. Starting material = methoxycarbonyl isocyanate 3. Starting material = methyl isothiocyanate Example 193. 4 - [[(2,6-Dichlorophenyl) carbonyl] amino] -N- [[2- [[(methoxy) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L- phenylalanine To a solution of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine methyl ester (40 mg, 0.080 mmol) ) in dichloromerane (1 ml) was added diisopropylethylamine (20 mg, 0.16 mmol) and methyl chloroformate (7 mg, 0.080 mmol). The resulting mixture was stirred for 18 hours. The reaction mixture was concentrated in vacuo and the crude carbonate was used in the next step directly without purification. To a solution of the crude methyl ester (54 mg, 0.080 mmol) in MeOH (1 mL) was added a solution of LiOH (8 mg, 0.19 mmol) in water (0.5 mL). The mixture was stirred for 2 hours and then acidified (pU ~ 1-2) with 0.5M HCl. The reaction mixture was poured over a round bottom flask and concentrated in vacuo. Purification by reverse phase HPLC, using a gradient of 15-95% acetonitrile-water for 25 minutes, afforded 25 mg (57%). HR MS (C26H29, N306C12): calculated mass, 550.1511. Observed mass, 550.1524 (M + H). Example 194. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(merylsulfonyl) anino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine. To a solution of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino) -N- [[1- [2-aninoethyl] cyclopentyl] carbonyl] -L-phenylalanine (40 mg, 0.080 mmol) in dichloromethane (1 ml), diisopropylethylamine (12 mg, 0.095 mmol) and methanesulfonyl chloride (9 mg, 0.080 mmol) were added. The resulting mixture was stirred for 18 hours. The reaction mixture was concentrated in vacuo and the crude sulfonamide was employed in the next step directly without purification. To a solution of the crude methyl ester (55 mg, 0. 080 mol) in MeOH (1 ml) was added a solution of LiOH (8 g, 0.19 mmol) in water (0.5 ml). The mixture was stirred for 2 hours and then acidified (pH ~ 1-2) with 0.5M HCl. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. Purification by reverse phase HPLC, using a 15-95% ocetonitrile-water gradient over 25 minutes, afforded 28 mg (61%). HR MS (C25H29N306C12S): calculated mass 592.1052. Observed mass, 592.1068 (M + Na). Example 195. Preparation of l- [2 - [[(1, 1-dimethylethoxy) carbonyl] amino] ethyl] cyclopentyl-corboxylic acid methyl ester. To a solution of the l- (2-ozidoethyl) cyclopentane carboxylic acid methyl ester (5.00 g, 25.4 mmol) in ethyl acetate (100 ml) was added di-tert-butyl dicarbonate (55.4 g, 254 mmol) and Pd 10% on charcoal (1.5 g). The reaction mixture was stirred for 3 hours under a stream of hydrogen (50 psi) in a Parr shaker. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (2 x 150 ml). The combined organic phase was transferred to a round bottom flask and concentrated in vacuo. Purification by flash column chromatography, using hexane-ethyl acetate (9: 1), gave 5.30 g (76%) as a pale yellow oil. HR MS (C? H2sN04): calculated mass, 272.1862. Observed mass, 272.1856 (M + H). Example 196. Preparation of l- [2 - [[(1, 1-dimethylethoxy) carbonyl] amino] ethyl] cyclopentane carboxylic acid. To a solution of 1- [2- [[(1,1-dimethylethoxy) carbonyl] amino] ethyl] cyclopentane carboxylic acid methyl ester (10.6 g 39.0 mmol) in THP / MeOH (3: 1.40 mL) was added one solution of LiCH (4.20 g, 98.0 mmol) in water (10 ml). The mixture was stirred for 2.5 hours at 50 ° C and then cooled to room temperature. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. The mixture was diluted with H20 (60 ml) and acidified with 1M HCl. The aqueous phase was extracted with ethyl acetate (3 x 200 ml) and the combined organic layers were extracted with MgSO 4, filtered and concentrated in vacuo. Purification by flash column chromatography, using hexane-aryl acetate (3: 1), gave 5.80 g (58%) as a white powder. HR MS (C? 3H? 3N04): calculated mass, 258.1705. Observed mass, 258.1700 (M + H). Example 197. Preparation of l- [2 - [[(1, 1-dimethylethoxy) carbonyl] (methyl) amino] ethyl] cyclopentane carboxylic acid methyl ester. To a suspension of NaH (1.20 g, 47.5 mmol) in DMF (20 ml) at 0 ° C, a solution of l- [2 - [[(1, 1-dimethylethoxy) carbonyl] amino] was added dropwise. ethyl] cyclopentane carboxylic acid (5.8 g, 22.6 mmol) in THF (25 ml). The resulting mixture was stirred for 1 hour at 0 ° C and methyl iodide (3.3 ml, 52.3 mmol) was added dropwise. The reaction mixture was stirred for 1 hour at 0 ° C and 5 hours at room temperature. The reaction was quenched with saturated solution of ammonium chloride (20 ml), and transferred to a separatory funnel. The aqueous phase was extracted with ethyl acetate (3 x 100 ml) and the combined organic layers were dried with MgSO, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography, using hexane-ethyl acetate (9: 1), afforded 5.40 g (84%). HR MS (C15H27N0): calculated mass, 286.2018. Observed mass, 286.2021 (M + H). Example 198. Preparation of l- [2 - [[(1, 1-dimethylethoxy) carbonyl] (methyl) amino] ethyl] cyclopentane carboxylic acid. To a solution of 1- [2 - [[(1, 1-dimethylethoxy) carbonyl] (methyl) amino] ethyl] cyclopentane carboxylic acid methyl ester (4.00 g, 14.0 mmol) in THF / MeOH (2: 1, 24 ml) was added a solution of LiOH (1.50 g, 35.0 mmol) in water (8 ml). The mixture was stirred overnight at 50 ° C and then cooled to room temperature. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. The mixture was diluted with H20 (50 mL) and acidified with 1M HCl. The aqueous phase was extracted with ethyl acetate (3 x 150 ml) and the combined organic layers were dried with MgSO, filtered and concentrated in vacuo. Purification by flash column chromatography using hexane-ethyl acetate (5: 1) provided (3.60 g, 95%) of a white powder. HR MS (C? 4N25N04): calculated mass, 272.1862. Observed mass, 272.1872 (M + H).

Example 199. The preparation of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- (methylamino) ethyl] cyclopentyl] carbonyl] -L-phenylalanine. was carried out by coupling the methyl ester of 4 - [[(2,6-dichlorophenyl) carboni] amino] -L-phenylalanine, prepared in Example 45 with the product of Example 198 using the general procedure described in Example 146. The Boc protection group was removed from the product by treatment with 4N HCl in dioxane as described in Example 45, and the product was used directly in the following steps. EXAMPLE 200 Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(acetyl) (methyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine. Acetylation of the product of Example 199, employing the general procedure described in Example 148 and then hydrolysis of the ester using the general procedure described in Example 47, gave the title compound in 75% yield. HR MS (C27H3? Cl2N305): calculated mass, 548.1719. Observed mass, 548.1716 (M + H). Example 201. Preparation of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[(methylamino) carbonyl] (methyl) amino] ethyl] cyclopentyl) carbonyl] - L-phenylalanine. The reaction of the product of Example 199 with methyl isocyanate using the general procedure described in Example 187, and then hydrolysis of the ester using the general procedure described in Example 47 gave the title compound in 69% yield. HR MS (C2H32CÍ2N4? 5): calculated mass, 563.1828. Observed mass, 563.1816 (M + H). Example 202. Preparation of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(methoxy-norbonyl) - (methyl) amino] ethyl] cyclopentyl] carbonyl] -L- phenylalanine Reaction of the product of Example 199 with methyl chloroformate using the general procedure described in Example 193, and then hydrolysis of the ester using the general procedure described in Example 47, gave the title compound in 70% yield. HR MS (C27H3iCl2N306): calculated mass, 586.1488. Observed mass, 586.1465 (M + Na). Example 203. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [El- [2- [(trifluoroacetyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine. To a solution of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine, (0.041 mmol, 20 mg) in DMF (2 ml) were added 2 equivalents of trifluoroacetic anhydride (0.082 mol, 17.2 mg) at room temperature. The mixture was stirred for 15 hours at room temperature after which an HPLC analysis of the reaction mixture indicated the absence of the match material. Then, without any elaboration, it was purified by reverse phase HPLC obtaining 5.7 mg (21%) of a white solid. HR MS: (C26H26C12N305): observed mass, 588.1280. Calculated mass, 588.1269 (M + H). Example 204. Preparation of 4 - [[(2, -dichlorophenyl) carbonyl] amino] -N- [[1- [2- (dimethylanino) ethyl] cyclopentyl] carbonyl] -L-phenylalanine methyl ester. To a mixture of the N - [[1- (2-ominoethyl) cyclopentyl] carbonyl] -4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester (0.339 mmol, 0.17 g) , zinc chloride (1.36 mmol, 0.185 g) and parofo -maldehyde (1.36 mmol, 40.7 mg) was added dichloromethane (2 ml) at room temperature and the mixture was stirred for 1.5 hours. Then, sodium borohydride (1.36 mmol, 51.3 mg) was added and the resulting mixture was stirred for 15 hours at room temperature. The mixture was poured into NH 4 OH (10 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine solution (20 ml) and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude product which was purified by HPLC to obtain 18 mg (10%) of a light yellow solid. HR MS: (C27H33C12N30): observed mass, 534.1927. Calculated mass, 534.1926 (M + H). Example 205. Preparation of 4-EE (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2 - [[(4-methoxyphenyl) carbonyl] amino] ethyl] cyclopentyl] carbonyl] methyl ester -L-phenylalanine To a solution of the methyl ester of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine (0.2 mmoles, 101 mg) and 4-methoxybenzoyl chloride (0.25 mmol, 52.1 mg) in dichloromethane (1 ml) was added DIPEA (0.3 mmol, 38.7 mg) at room temperature.The reaction mixture was stirred for 15 hours at room temperature and then diluted with 20 ml of dichloromethane, the dichloromethane layer was washed successively with water (20 ml) and brine solution (20 ml) and dried with anhydrous magnesium sulfate. of the solvent provided a crude product which was purified by reverse phase HPLC obtaining 0.1 g (78%) of a yellow syrup MR MS: (C33H35Cl2 N3? 6): observed mass, 662.1778. Calculated mass, 662.1801 (M + Na). Example 206. The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[(2-trifluoromethylphenyl) carbonyl] amino] ethyl] cyclopentyl] carbonyl was prepared ] -L-phenylalanine, from the methyl ester of 4- E [(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-aminoethyl) cyclopentyl] carbonyl] -L-phenylalanine and the 3-trifluoromethylbenzoyl chloride using the general method described in Example 205 to give a yield of 99%, a white solid. HR MS: (C33632Cl2N3? 5): observed mass, 700.1596. Calculated mass, 700.1569 (M + Na). Example 207. 1- [4- (Azido) butyl] cyclopentane carboxylic acid methyl ester was prepared from 1- [4- (bromobutyl)] cyclopentane carboxylic acid methyl ester and sodium azide using the general procedure described in example 4 to give a syrup with 87% total yield. HR MS: (C11H19N3O2): observed mass, 225.1523. Calculated mass, 225.1536 (M +). Example 208. l- [4- (Azido) butyl] cyclopentane carboxylic acid was prepared by hydrolysis of the ester prepared in Example 207 using the general procedure described in Example 15 to give a brown syrup in quantitative yield. HR MS: (CioHíN302): observed mass, 211.1285. Calculated mass, 211.1267 (M +).

Example 209. The l- (3-azidopropyl) cyclopentane carboxylic acid was prepared from the methyl ester of 1- (3-bromopropyl) cyclopentane carboxylic acid using the general procedure described in Example 4. The acid was isolated in the form of an oil. LR ES MS: (C9H? 5N3? 2): 196.1 (M-H). EXAMPLE 210 The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-azidobutyl) cyclopentyl] carbonyl] -L-phenylalanine was prepared from acid 1. - [4- (azido) butyl] cyclopentane carboxylic acid and the hydrochloride salt of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] anino-L-phenylalanine, using the procedure described in Example 46 to give a solid white with a yield of 99%, mp 195-199 ° C HR MS: (C27H3? Cl2N504): observed mass, 560.1833. Calculated mass, 560.1831 (M + H). Example 211. The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-aminobutyl) cyclopentyl] carbonyl] -L-phenylalanine was prepared from the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-azidobutyl) cyclopentyl] carbonyl] -L-phenylalanine, employing the general procedure described in example 147 to give a solid White with a yield of 30%. HR MS (C27H33Cl2 304): observed mass, 534.1352. Calculated mass, 534.1368 (M + H). Example 212. The methyl ester of the 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4- [(acetyl) amino] butyl) cyclopentyl] carbonyl] -L-phenylalanine, from the methyl ester of the - [[((2,6-dichlorophenyl) carbonyl] amino] -N [[1- (4-aminobutyl) cyclopentyl] carbonyl] -L-phenylalanine, using the general procedure described in Example 148 to give a solid of color white with a yield of 80% .HR MS (C29H35C12N305): observed mass, 576.1690. Calculated mass 576. 1714 (M + H).

Example 213. Preparation of 1- [[5-tetrazolyl) methyl] cyclopentane methyl ester. To a solution of methyl 1- (1-cyanomethyl) cyclopentane carboxylate (5.5 mmol, 0.9 g) in toluene (15 ml) were added trimethylsilyl azide (11 mmol, 1.26 g) and dibutyltin oxide (0.55 mmol, 137 mg). at room temperature. The mixture was heated to 110 ° C and stirred for 15 hours. Then, the reaction mixture was cooled to room temperature and the toluene was removed in vacuo. The brown residue was diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (2 x 50 ml) and the starting material and some impurities left in the ethyl acetate. The aqueous sodium bicarbonate layer was neutralized with 3N HCl and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with brine solution (50 ml) and dried with anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the residue was dried under high vacuum to obtain 0.31 g (27%) of a white solid of low boiling point. HR MS: (C9H14N402): observed mass, 210.0218. Calculated mass, 210.0252 (M +). Example 214. Preparation of 1 - [(1-tetrazolyl) methyl] cyclopentane carboxylic acid Using the procedure described in Example 15, 1- [(5-tetrazolyl) ethyl] cyclopentane carboxylic acid was prepared from the corresponding ester with the 67% total yield in the form of a white solid: mp 192-196 ° C. HR MS: (C8H? 2N402): observed mass, 196.0329. Calculated mass, 196.0318 (M +). Example 215. Preparation of the 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (butyl) cyclopentyl] carbonyl-L-phenylalanine methyl ester. A mixture of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (3-butenyl) cyclopentyl] carbonyl] -L-phenylalanine (0.19 mmol, 100 mg) and 10% palladium on charcoal (200 mg) in EtOH (2 ml) was stirred under a hydrogen atmosphere at room temperature for 15 hours. The charcoal was then filtered and washed with EtOH (10 ml). The filtrate was evaporated in vacuo to obtain 37.5 mg (37%) of a white solid: m.p. 193-196 ° C. HR MS: observed mass, 519.1818. Calculated mass, 519.1817 (M + H). Example 216. 4- [[(2,6-dlclorephenyl) carbonyl] amino] -N- [[1- [2 - [[(1, 1-dimethylethoxy (carbonyl] amino] -1-oxoethyl] amino was prepared ] ethyl] cyclopentyl] carbohyl] -L-phenylalanine by coupling the product of example 147 with Boc-glycine using the general protocol of HBTU described in example 46, and then treating with NaOH to cause hydrolysis as described in Example 47 to give a 75% yield HR MS: (C3iH38Cl2N407): calculated mass, 671.2016 Observed mass, 671.2002 (M + Na) Example 2 ^ L7, 4- [[(2,6-dichlorophenyl) was prepared ) carbonyl] amino] -N- [[1- [2- [(2-anino) -1-oxoethyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine by treatment of the product of Example 216 with 4H HCl in dioxane HR MS: (C26H3o l2N405): calculated mass, 571.1419. Observed mass, 571.1419 (M + Na) Example 218. The l- (Cyanomethyl) cyclopentane carboxylic acid methyl ester was prepared from the methyl ester of the citric acid. carboxylic clopentane and chloroacetonitrile, using the procedure described in example 7 to give a 38% yield. HR MS: (C9H13NO2): observed mass, 167.0173. Calculated mass, 167.0146 (M +). Examples 219-229. Using the procedure described in Example 15, the following cyclopentane carboxylic acids were prepared: Example 229. Preparation of methyl l- (4-corobutilyl) cyclopentane carboxylate. The l- (4-chlorobutyl) cyclopentane carboxylic acid methyl ester was prepared from the methyl ester of the cyclopentane carboxylic acid and 4-chloro-l-bromobutane using the procedure described in Example 7 to give a 64% yield . HR MS: (C11H19CIO): observed mass, 218.1072. Calculated mass, 218.1074 (M +). Example 230. Preparation of 1- (3-butenyl) cyclopentane carboxylic acid methyl ester. To a solution of diisopropylamine (225 mmol, 31.6 mL) in THF (150 mL) was added dropwise a solution of n-butyl lithium (217.5 mmol, 87 mL, 2.5 M) in hexanes at -10 ° C maintaining the temperature by below 0 ° C. After the addition, the solution was stirred for 30 minutes at 0 ° C. To this, a solution of methyl cyclopentane carboxylate (150 mmol, 19.23 g) in THF (30 ml) was added dropwise at -70 ° C, keeping the internal temperature between -60 to -70 ° C. After the addition, the reaction mixture was stirred for 1 hour at -50 to -60 ° C. Then, a solution of 4-bromo-1-butene (142.2 mmol, 19.2 g) in THF (30 ml) was added dropwise, and the light brown suspension was stirred for 1 hour from -60 to -70. ° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (250 ml) and the mixture was extracted with ether (2 x 150 ml). The combined extracts were washed with a saturated solution of sodium chloride (150 ml) and dried over anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the residue was distilled at 63-67 ° C / 2.5 mm Hg to give 13.77 g (53%) of a colorless oil. HR MS: (C? H? 602): observed mass, 182.1311. Calculated mass, 182., 1307 (M +). Example 231. Preparation of 1- [2- (methylthio) ethyl] cyclopentane carboxylic acid methyl ester. To a solution of the l- (2-bromoethyl) cyclopentane carboxylic acid methyl ester (2.0 mmol, 472 mg) in DMF (5 mL), sodium thiomethoxide (2.65 mmol, 186 mg) was added. The reaction mixture was stirred for 15 hours at room temperature and poured into water (30 ml). The organic compound was extracted into diethyl ether (2 x 20 ml). The combined extracts were washed with a saturated solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography to obtain 334 mg (82%) of a colorless oil. HRMS: (C? 0Ri8O2S): observed mass, 202.1024. Calculated mass, 202.1028 (M +). Example 232. Preparation of l- [4- (methoxy) butyl] cyclopentane carboxylic acid. To a solution of the l- (4-chlorobutyl) cyclopentane carboxylic acid methyl ester (30 mmol, 6.56 g) in a mixture of THF (60 ml) and methanol (60 ml) was added IN sodium hydroxide (60 ml). The mixture was heated at 40-45 ° C for 15 hours after which TLC analysis of the reaction mixture indicated the absence of starting material and was cooled to room temperature. The solvent was removed in vacuo and the residue was diluted with water (100 ml) and extracted with ether (2 x 100) to remove any neutral impurities. Then, the basic aqueous layer was acidified with IN hydrochloric acid and the product was extracted with ethyl acetate (2 x 75 ml). The combined extracts were washed with brine solution and dried with anhydrous sodium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the residue was purified by silica gel column chromatography to obtain 4.2 g (68%) of l- (4-chlorobutyl) cyclopentane carboxylic acid in the form of a liquid and 1.3 g (22%) of 1- [4- (methoxy) butyl] cyclopentane carboxylic acid in the form of a viscous oil. HR MS: (C ?? H2o03): observed mass, 200.0175. Calculated mass, 200.0143 (M +).

Examples 233-248. Using the general coupling procedure described in Example 46, the following analogues were prepared: 1. M + H ion unless otherwise indicated Example 247. The methyl ester of 4- [[(2,6-diclothiophenyl) carbonyl) amino] -N- [[1- [(2-morpholinyl)] was prepared. ethyl] cyclopentyl] carbonyl] -L-phenylalanine, from the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine and l - [(2-morpholinyl) ethyl] cyclopentane carboxyl using the general coupling procedure described in Example 46 to provide a 62% yield. HRMS (C29H35C12N305): observed mass, 576.2531. Calculated mass, 576.2582, (M + H). Example 248. Preparation of the 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-hydroxybutyl) nyclopentyl] carbonyl] -L-phenylalanine methyl ester. To a suspension of the methyl ester of 4- [[(2,6-dichlorephenyl) carbonyl] amino] -7ST- [[1- (3-butenyl) cyclopentyl] carbonyl] -L-phenylalanine (3.13 mmol, 1.62 g) and anhydrous copper (I) chloride (5.0 mmol, 500 mg) in THF (30 ml) was added solid sodium borohydride (5.0 mmol, 200 mg) at -5 ° C for 5 minutes. After the addition, the reaction mixture was allowed to warm to room temperature and the brown reaction mixture was stirred for 36 hours after which a TLC analysis of the mixture indicated the absence of starting material. Then, the excess hydride was neutralized by the addition of water (5 ml) and the reaction mixture was cooled to 0 ° C. To this, a solution of sodium acetate (20 ml, 3.0 N) was added dropwise keeping the temperature below 10 ° C, and then H202 (25 ml, 30%) was added. After the addition of hydrogen peroxide, the reaction mixture was allowed to warm to room temperature and was stirred for 3 hours and then 1 hour at 40-45 ° C to complete the hydrolysis. It was then poured into a mixture of water (50 ml) and ethyl acetate (50 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 ml). The combined extracts were washed with brine solution and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude product which was purified by column chromatography on silica gel to obtain 1.04 g (62%) of a white amorphous solid HR MS (C27H32C12N205) observed mass, 535.1758. Calculated mass, 535.1766, (M + H). Examples 249-274. The compounds indicated below were prepared from the corresponding methyl esters according to the procedure described in example 47. 19 1. M + H ion unless otherwise indicated Example 275. The N- [[1-3- (acetylamino) propyl] cyclopentyl] carbonyl) -4- [[(2,6-dichlorophenyl) methyl ester was prepared. ) carbonyl] amino) -L-phenylalanine, with 50% yield from the methyl ester of N - [[1- (3- (acidopropyl) cyclopentyl) carbonyl) -4- [[(2,6-dichlorophenyl)] ) carbonyl] amino] -L-phenylalanins, using the general procedure described in Examples 211 and 212. Example 276. N- [[1- (3- (Acetylamino) propyl] cyclopentyl] carbonyl] -4- [ [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine, from the methyl ester of N - [[1- (3- (acetylamino) propyl] cyclopentyl] carbonyl] -4- [[(2, 6-dichlorephenyl) carbonyl] amino] -L-phenylalanine, by hydrolysis using the general procedure described in example 47 to give a yield of 70% HR MS (C2-7H3iCl2N3? 5): observed mass, 570.1533. Calculated mass, 570.1539, (M + Na) Example 277. General method for the preparation of the morpholinoethyl esters from the 4- (substituted) -N-acyl-L-phenylalanine derivatives. To a solution of a 4- (substituted) -N-acyl-L-phenylalanine (0.5 mmol) and 2-morpholinoethanol (0.131 g, 1.0 mmol) in THF (5 mL), diisopropylcarbodiimide (94.6 mg, 0.75 mmol) was added. and 4-dimethylaminopyridine (30.5 mg, 0.25 mmole) at room temperature. The resulting mixture was stirred at room temperature until the TLC analysis of the reaction mixture indicated the absence of acid, usually after 15 hours. Then, the mixture was diluted with water (50 ml) and the THF was removed in vacuo and the residue was extracted with dichloromethane (3 x 25 ml). The combined extracts were washed with water (2 x 50 ml), brine solution (50 ml) and dried with MgSO4. Filtration of the drying agent and concentration of the solvent provided a white residue which was purified by column chromatography on silica gel eluting with dichloromethane-ethyl acetate mixtures to obtain the desired product. Examples 278-356. Procedure for the preparation of 4- [(4R) -3-acyl'-5-oxo-2-substituted-4-substituted-1-imidazolidinyl] -N- [[1- [2- (acetylamino) ethyl] cyclopentyl ] carbonyl] -L-phenylalanine. A 250 ml flask was charged with 4-nitro-N-Fmoc-L-phenylalanine (20.7 g, 47.8 mmol) and NMP (30 ml). The mixture was heated to accelerate the dissolution. After cooling to room temperature, the mixture was treated with 2-6-dichlorobenzoyl chloride (20 g, 95.6 mmol) and pyridine (12 mL, 143.4 mmol). This mixture was stirred for 5 minutes and added to a suspension of Wang resin (21.7 g, 1.1 mmol / g in NMP (60 ml), then the mixture was stirred at room temperature overnight. The resin was washed with DMF (4 x 60 ml), MeOH (4 x 60 ml), DMF (4 x 60 ml) and finally dichloromethane (4 x 60 ml) The resin was then dried under vacuum at room temperature during the night obtaining 34.27 g of resin with a load of 0.668 mmoles / g determined by the UV method (Barry Bunin, The Combinatorial Index, ("combinatorial index") p 219 (Academic Presa, 1998)) Step 2 The above resin (25.5 g) was treated with 160 ml of 20% piperidine in NMP and stirred for 15 minutes and filtered. This process was repeated 2 times. The resin was then washed with DMF (4 x 100 ml), MeOH (4 x 100 ml), DMF (4 x 100 ml) and finally with dichloromethane (4 x 100 ml). The resin was then dried under vacuum at room temperature overnight obtaining 22 g of resin. A portion of this free amine resin (13 g) was suspended in 80 ml of NMP and treated with 1-1- (2-azidoethyl) cyclopentane carboxylic acid (4.8 g, 26.05 mmol) and then with DIEA (15 ml). and BOP reagent (15.4 g, 34.2 mmol). The reaction was stirred at room temperature overnight. After filtering, the resin was washed with DMF (4 x 60 ml), MeOH (4 x 60 ml), DMF (4 x 60 ml) and finally with dichloromethane (4 x 60 ml). The resin was then dried under vacuum at room temperature overnight to give the azide resin. This resin was reduced by treatment with trimethylphosphine (1.0 M in THF, (30 ml) in 20 ml of THF at room temperature for 4 hours and then treated with water (3 ml) for 30 minutes. resin with DMF (4 x 60 ml) MeOH (4 x 60 ml), DMF (4 x 60 ml) and finally with dichloromethane (4 x 60 ml) The resin was then dried under vacuum at room temperature overnight free aminoethyl resin (13.19 g) A portion of the above resin (6.3 g) was suspended in dichloromethane (40 ml) and treated with acetic anhydride (2 ml, 21 mmol) and DIEA (3.6 ml, 21 mmol). The above mixture was stirred at room temperature overnight After filtering, the resin was washed with DMF (4 x 40 ml), MeOH (4 x 40) DMF (4 x 40 ml) and finally with dichloromethane (4 x 40). ml) The tesin was then dried under vacuum at room temperature overnight to give acetamide resin (6.27 g). The resin sample was treated with 50% TFA in dichloromethane to give the cleavage product, N - [[1- [2- (acetylamino) ethyl] cyclopentyl] carbonyl] -4-nitro-L-phenylalanine. LS MS (M + H, m / z: 391). The remaining resin was then treated with SnCl 2 (2M in DMF, 40 ml) at room temperature overnight. After filtering, the resin was washed with DMF (4 x 40 ml), MeOH (4 x 40 ml), DMF (4 x 40 ml) and finally with dichloromethane (4 x 40 ml). It is then dried in vacuo at room temperature overnight to give 4-amino-N - [[(1- [2- (acetylamino) ethyl] -cyclopentyl] carbonyl] -L-phenylalanine on the tesin (6.1 g) Step 3. Synthesis of the Combinatorial Library The above free 4-amino-N- [[1- [2- (acetylamino) ethyl] cyclopentyl] carbonyl] -L-phenylalanine on the resin was partitioned into 5 reaction vessels. To each vessel was added, in parallel, 8 ml of DMF and then Fmoc-D-amino acid (selected from: Fmoc-D-phenylalanine (Cl), Fmoc-D-4-chlorophenylalanine (C2), Fmoc-D-3-pyridinilalanine (C3) Fmoc-D-4-methoxyphenylalanine (C4) and Fmoc-D-alanine (C5), 2.25 immoles), HBTU (1.4 g 3.75 immoles) and DIEA (0.75 ml). The above mixture was stirred at room temperature overnight. The resin in each container was filtered, washed with DMF (4 x 20 ml), MeOH (4 x 20 ml), DMF (4 x 20 ml) and finally with dichloromethane (4 x 20 ml): Next, these resins individually dried under vacuum at room temperature overnight obtaining 5 individual resins containing Fmoc-D-amino acid. Each of these five individual batches of resin obtained above was treated in parallel with 10 ml of 20% piperidine in NMP, stirring for 15 minutes and filtered. This process was then repeated twice to give the following five derivatives after drying individually: N - [[l- [2- (acetylamino) ethyl] cyclopentyl] carbonyl] -4- [[(2R) -2-amino- l-oxo-3-phenyl-propyl] amino] -L-phenylalanine on Wang resin, N- [[1- [2- (acetylamino) ethyl] cyclopentyl] carbonyl] -4- [[(2R) -2-amino-3- (4-chlorophenyl) -1-oxopropyl] amino] -L-phenylalanine on Wang resin2- (acetylamino) ethyl] cyclopentyl] carbonyl] -4- [[(2R) -2-amino-l-oxo-3- (3-pyridinyl) propyl] amino] -L- phenylalanine on Wang resin, N - [[l- [2- (acetylamino) ethyl] cyclopentyl] carbonyl] -4- [[(2R) -2-amino-3- (4-methoxyphenyl) -1-oxopropyl] amino] -L-phenylalanine on Wang resin, and N - [[l- [2- (acetylamino) ethyl] cyclopentyl] carbonyl] -4- [[(2R) -2-amino-l-oxopropyl] amino] -L-phenylalanine on Wang resin. A library of imidazolidin-4-ones was prepared as discrete compounds using the IRORI Combinatorial Chemical System AccuTAG_100_, ("IORI AccuTAG_100_ Combinatorial Chemistry System." The technique for the market of a reaction vessel and use of the reaction vessels, hereinafter referred to as MicroKans, is described in The User's Guide, 1996, IRORI, 11025 North Torrey Pines Road, La Jolla, CA 92037). IRORI is the registered trademark of IRORI. IRORI, AccuTag, Microkan and Synthesis Manager are registered trademarks of IRORI. Each of the five resin derivatives was divided into 16 Microkans containing radio frequency signals to give a total of 80 Microkan reaction vessels. Using the Synthesis Manager to read the radio frequency signals in each, they were then classified into 4 groups of 20 units so that each group had 4 Microkans containing each of the five resin-bound D-amino acids prepared above. Each group of 20 microkans was individually placed in a reaction vessel containing an anhydrous solvent mixture (THF / methyl orthoformate = 1/1, 80 ml) and one of the four aldehydes (benzaldehyde (Al), 4-pyridylaldehyde ( A2), 4-chlorobenzaldehyde (A3) or phenylpropionaldehyde (A4) (20 x 1.03 immoles) The above mixtures were stirred at room temperature for 3 days to form imide intermediates After removing the solvent by decanting, the Microkans groups Each was washed individually with anhydrous THF (2 x 20 ml) The resulting 80 Microkans were then classified into 4 groups of 20 units, each group incorporating an example of each of the D-amino acids (Cl to C5) combined with each one of the four aldehydes (Al to A4), according to the table below: A'-l = phenyl C -1 = benzyl A '-2 = 4-pyridyl C-2 = 4-chlorobenzyl A' -3 = 4-chlorophenyl C-3 = 3-pyridylmethyl A '! - 4 = 2-phenylethyl C-4 = 4-me oxybenzyl C'-5 = methyl Each group of 20 Microkans was individually placed in a reaction vessel containing anhydrous solvent (THF / ethyl orthoformate = 1/1, 10 ml). To the first reaction vessel was then added acetic anhydride (Bl) (5.5 mmol) and the resulting mixture was stirred at 90 ° C for 4 hours. The remaining three reaction vessels were treated individually with an anhydride: butyric anhydride (B2), succinic anhydride (B3) and phenoxyacetic anhydride (B4) and were subjected in parallel to the same reaction conditions. After filtering, each of the four groups of Microkans was washed individually with DMF (4 x 40 ml), MeOH (4 x 40 ml), DMF (4 x 40 ml) and finally dichloromethane (4 x 40 ml). The Microkans were then classified into separate vials using the Synthesis Manager to identify each by means of the individual radio frequency signals. Each vial was treated with the 50% TFA cleavage reagent / dichloromethane (2.5 ml). The vials were stirred for 2 hours at room temperature and the resulting mixtures were filtered. The filtration of each reaction was concentrated to remove the crude product which was washed with ether and dried under stirring at room temperature. The suspension was left at room temperature for 15-30 minutes and the ether was removed. It was washed with ether and the residues were dissolved with Me CN / H20 (2/1). A portion was separated and dried and solidified for analysis of crude product. A sample was analyzed with LCMS using a Micromass II linearly graduated with 5 minutes (5% of MeCN in water contains 0.01% of TFA) that determines the purity while MS spectra is recorded and the maximum point is verified. The total subtotal of this 4-pyridylaldehyde dirivate (A-2) was removed by low averages of purity. The remaining 60 components were purified opposite phase HPLC to release the imidazolidinone with a purity of 60%. During the separation, some diastereomers were separated to give the diastereomer in position 2 of the imidazolidine ring designates diastereomers 1 and 2 (based on the extraction order). The molecular weights of the purified products were confirmed by ESM (M-M, M or M + H) as shown in the following table "~ * _. ? ns eleven Example 357. Preparation of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [(2- (methylsulfinyl) ethyl] cyclopentyl] carbonyl] -L-fanylalanine. [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [(2- (methylthio) ethyl] cyclopentyl] carbonyl] -L-phenylalanine (0.095 mmol, "50 mg) in ethyl acetate ( 4 ml) THF (1.5 ml) was added to give a clear solution, then water (3 ml) and oxone (0.048 -inmol, 30 mg) were added at room temperature.The mixture was stirred for 15 hours after the strands , the TLC analysis of the sample indicated the absence of starting material.The solid was collected by filtration and washed with water.This material was purified by inverted phase HPLC obtaining 26.3 mg (51%) of a white solid: mp 255-258 ° C HR MS (C25H28C12N205S), observed mass, 539.1187. Calculated mass, 539.1174, (M + H) Example 358. Preparation of 4 [[(2,6-dichlorophenyl) carbonyl] amino] - N- [[1- [( 2- (Methylsulfonyl) ethyl] cyclopentyl] carbonyl] -L-phenylalanine. To a suspension of 4 [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [(2- (methylthio) ethyl] cyclopentyl] carbonyl] -L-fanylalanine (0.095 mmol, 50 mg) in Ethyl acetate (4 ml) was added THF (1 ml) to give a clear solution, then water (2 ml) and oxone (0.019 mmole, 12 mg) were added at room temperature The mixture was stirred for 15 hours and the precipitated sulfoxide was collected by filtration and washed with water, then the solid was redissolved in acetic acid (2 ml) and treated with 30% hydrogen peroxide (0.7 ml) The mixture was stirred for 15 hours at room temperature. After which the TLC analysis confirmed the absence of sulphoxide, this mixture was purified directly by inverted phase HPLC obtaining 14 mg (66%) of a white solid: mp 184-187 ° C. HR MS (C25H28C1206S) : observed mass, 577.0928. Calculated mass; 577.0944, (M + Na). Example 359. Preparation of the methyl ester of 4 [E (2-chloro-5-bromophenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine. To a mixture of the methyl ester of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (20 mmol, 5.88 g), 2-chloro-5-bromobenzoic acid (22 mmol, 5.18 g) ) and HBTU (22 mmoles, 8.34 g) in DMF (70 ml) was added diisopropylethylamine (50 mmoles, 8.7 ml) at room temperature. The suspension was stirred for 48 hours after which, TLC analysis of the sample indicated the absence of starting material. Then, the mixture was diluted with water (100 ml) and the solids were collected by filtration and washed with water (150 ml). After drying in the air, the crude product was purified by silica gel column chromatography, obtaining 1.02 g (10%) of a white solid: m.p. 158-161 ° C. HR MS (C22H24BrClN205): observed mass, 533.0442. Calculated mass, 533.0455, (M + Na). Example 360. Preparation of 4 [(2-chloro-5-cyanophenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester. To a mixture of the methyl ester of 4 - [(2-chloro-5-bromophenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (2 mmol, 1.02 g) zinc cyanide (1.3 mmoles, 152 mg) and Pd (PPh3) 4 (0.2 mmol, 231 mg), distilled and deoxygenated DMF (8 ml) was added at room temperature. The suspension was heated to 80-85 ° C and stirred for 15 hours after which TLC analysis of the mixture confirmed the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (70 ml) and washed with 20% aqueous ammonium hydroxide (50 ml) brine solution (50 ml) and dried with magnesium sulfate anhydrous. Filtration of the drying agent and concentration of the solvent gave a crude product which was purified by silica gel column chromatography, yielding 555 mg (61%) of a white solid, m.p. 185-187 °. HR MS (C23H2C1N305): observed mass, 480.1301. Calculated mass, 480.1302, (M + Na). Example 361. Preparation of the TFA salt of the 4 [(2-chloro-5-cyanophenylcarbonyl) anino] -L-phenylalanine methyl ester. To a solution of 4 - [(2-chloro-5-cyanophenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester (1.2 mmol, 0.55 g) in dichloromethane (12 ml) was added trifluoroacetic acid (3 ml) at room temperature. The reaction mixture was stirred for 15 hours at room temperature, after which the TLC analysis of the mixture confirmed the absence of starting material. Then, the solvent was removed in vacuo and the residue was azeotroped with toluene (2 x 10 ml) and dried under high vacuum to obtain 0.43 g (100%) of a yellow solid. HR MS (C? 8H? 6ClN303): observed mass, 358.0963. Calculated mass, 358.0959, (M + H). Example 362. Preparation of 4 - [(2-chloro-5-cyanophenylcarbonyl) amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine methyl ester. To a solution of the salt TFA of the methyl ester of the 4 [(2-chloro-5-cyanophenylcarbonyl) amino] -L-phenylalanine (0.55 mmoles, 0.35 g) HBTU (0.65 mmoles, 0.24 g) and acid 1- (2 -methoxyethyl) cyclopentane] carboxylic acid (0.65 mmole, 0.11 g) in DMF (3 ml) was added diisopropylethylamine (1.65 mmole, 0.29 ml) at room temperature. The clear solution was stirred for 15 hours at room temperature and diluted with 50 ml of ethyl acetate. The ethyl acetate layer was then washed successively with 0.5 N hydrochloric acid (2 x 20 ml), saturated sodium bicarbonate solution (2 x 20 ml) and brine solution and dried with anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product which was purified by silica gel column chromatography to obtain 0.25 g (87%) of a white solid: m.p. 172-175 ° C. HR MS (C27H30C1N305): observed mass, 512.1949. Calculated mass, 512.1953, (M + H). Example 363. Preparation of 4 [(2-chloro-5-cyanophenylcarbonyl) amino] -N- [[1- (2- (methoxyethyl) cyclopentyl] carbonyl-L-phenylalanine. To a mixture of the methyl ester of the E (2-chloro-5-cyanophenylcarbonyl) amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine (0.1 mmol, 51 mg) and lily iodide (1.0 mmol, 133 mg) pyridine (2 ml) was added at room temperature, the solution was heated to reflux for 15 hours, after which the TIC analysis of the mixture confirmed the absence of starting material, then the mixture was cooled to room temperature and diluted with water (15 ml) and most of the pyridine was removed under reduced pressure, then extracted with ether (2 x 15 ml) to remove any neutral impurity.The aqueous layer was acidified with IN HCl and the solid precipitate The white color was collected by filtration and washed with 20 ml of water and 20 ml of hexane, after drying in the air, the product cru The product was crystallized from acetonitrile to obtain 20 mg (40%) of a white solid: m.p. 169-172 ° C. HRMS (C26H26C1N305): observed mass, 498.1805. Calculated mass, 498.1795, (M + H). Example 364, Preparation of 4- [[(2,4-dimethylpyridin-3-yl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine. to. To a solution of 2,4-dimethylpyridinecarboxylic acid (0.6 mmol, 102 mg) in dichlorethane (3 ml) was added one drop of DMF and oxalyl chloride (0.78 mmol, 99 mg) at 0 ° C (ice bath). The solution was stirred at this temperature for 30 minutes, warmed to room temperature and stirred for a further 1 hour. Next, the solvent and excess oxalyl chloride were removed in vacuo and the residue was dried under high vacuum. To this, the 4-amino-N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylpyridine methyl ester (0.5 mmol, 212 mg) was added and the mixture dissolved in dichloromethane. (5 ml). To this clear solution was added DIPEA (2.0 mmole, 0.258 g) at room temperature. The mixture was stirred for 15 hours after which the TIC analysis of the mixture confirmed the absence of starting material. Then, the mixture was diluted with dichloromethane (20 ml) and water (100 ml). The two layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (20 ml), brine solution (30 ml) and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude product which was purified by column chromatography on silica gel to obtain 0.232 g (80%) of a white solid. HR MS (C29H39N306S): observed mass, 558.2629. Calculated mass, 558.2629, (M + H). b. Preparation of 4- [[(2,4-dimethyl-3-pyridinyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine.

C2sH37 306S C-gH-gN-OgS weight pt. .: 557.70 ag rrol 543.68 Using the procedure described in Example 47, the methyl ester of 4- [((2,4-dimethyl-3-pyridyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] was hydrolysed] cyclopentyl] carbonyl] -L-phenylpyridine, prepared above, with 88% yield to give a white solid, HR MS (C28H37N306S): observed mass, 544.2471, calculated mass, 544.2481, (M + H). 365. 4- [(4R) -3-acetyl-5-oxo-2-phenyl-4- (phenylmethyl) -1-imidazolidinyl] -N- [[1-4- (methylsulfonyl) butyl] cynylpentyl] carbonyl] - L-phenylalanine a) Synthesis of methyl ester of N - [(1, 1-dimethylethoxy) carbonyl] -4- [[((2R) -2-amino-l-oxo-3-phenylpropyl] amino] -L phenylalanine To the solution of the methyl ester of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (5.09 g, 17 mmol) in DMF (60 ml) was added Fmoc-D- phenylalanine (8.70 g, 22.5 mmol), DIPEA (12 ml, 65 mmol) and HBTU (8.50 g, 22. 5 mmoles). The mixture was then stirred at room temperature for 4 hours. The reaction mixture was diluted with water (150 ml) and the light yellow solid which precipitated was collected by filtration. This solid was then redissolved in 60 ml of acetone and the solution treated with 100 ml of water. The solid was collected by filtration and washed with MCI IN, H20. After drying at 60 ° C under vacuum overnight, a light yellow solid (13.2 g) was obtained. A portion of this solid (2.51 g, 3.76 mol) was dissolved in 15 ml of DMF and 1.5 ml of piperidine was added to the solution. The above solution was stirred at room temperature for 45 minutes. After removing the solvent, the residue was recrystallized from ethyl acetate-hexane to obtain the N- [(1,1-dimethylethoxy) carbonyl] -4- [[(2R) -2-amino-1-methyl ester. oxo-3-phenylpropyl] amino] -L-phenylalanine (1 {26 g, 3.0 mmole) with 81.5% yield. LR MS 442 (M + H). b. Synthesis of the 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester. A solution of the above amine (1.48, 3.35 mmol) and benzaldehyde (376 μl, 3.7 mmol) in dichloromethane (10 ml) and methyl orthoformate (10 ml) was stirred at room temperature for 3 days. The reaction flask was then heated to 90 ° C and acetic anhydride (neat, 1.8 ml) was added. The resulting mixture was stirred at 110 ° C for 4 hours. The solvent was then evaporated and the crude product was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1) to give diastereomer 1 (417 g) and diastereomer 2 (1.25 g) of the methyl ester of the 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine. These compounds are diastereomeric at the 2-position of the imidazolidinone ring. Both diastereomers gave LR MS (C33H37N306): 572 (M + H). c. the methyl ester of 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (diastereomer 1) ( 415 mg, 0.7 mmol) was treated with 10 ml of 4N HCl in dioxane at room temperature for 2 hours. After removing the solvent, the residue was dried overnight under vacuum. The residue (241 mg, 0.471 mmol) was dissolved in DMF (4 ml) and treated with l- (4-methylsulfonyl) butyl) cyclopentane carboxylic acid (153 mg, 0.617 mmol), HBTU (234 mg, 0.617 mmol) and DIEA (246 μl, 1.4m emoles) at room temperature for 4 hours. The mixture was diluted with 30 ml of ethyl acetate, washed with IN HCl, water and brine (8 ml each). After drying with MgSO 4, the solvent was removed and the residue was filtered through silica gel eluting with ethyl acetate: hexane = 4: 1 to give diastereomer 1 of the 4- (3-acetyl-5-oxo) methyl ester. -2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N- [[1- (4- (methyl-sulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine (147 mg, 0.2 mmol) with 44% of yield: LR MS: 702 (M + M) d) Diastereomer 1 of the 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -NE [1- methyl ester] (4- (Methyl-sulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine (90 mg, 0.128 mol) in EtOM (3 ml) was treated with NaOH (IN, 0.3 ml) at room temperature for 30 minutes. The resulting solution was acidified with 1 drop of HOAc and purified by MPLC (C-18, linear gradient from 5% 95% acetonitrile in water for 30 minutes) to give 84 mg (95%, 0.122 mmol) of diastereomer 1 of 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N-] [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine. LR MS: 688 (M + H). Example 366. 4- [(4R) -3-Acetyl-5-oxo-2-phenyl-4- (3-pyridinylmethyl) -1-imidazolidinyl] -N- [(1-phenylcyclopentyl) carbonyl] -L was prepared phenylalanine, starting from Fmoc-D-3-pyridinilalanine, benzaldehyde and methyl ester of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine, using the general procedure described in the example 365 MS: 631 (M + H). Example 367. Preparation of methyl ester of 4- (5-bromo-1,3-dioxo-2H-isoindol-2-yl) -N- [(1,1-dimethylethoxy) carbonyl. ] -L-phenylalanine. To a suspension of the methyl ester of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (6.78 mmol, 1.99 g) in dichloromethane (90 ml) was added a solution of 4-bromophthalic anhydride. (6.78 mmol, 1.54 g) in dichloromethane (30 ml) and 1,1 '-carbonyldiimidazole (6.78 mmol, 1.1 g) at room temperature. The resulting solution was stirred for 15 hours after which TLC analysis of the mixture confirmed the absence of starting material. The mixture was diluted with water (100 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2 x 100 ml) and the combined extracts were washed with brine solution and dried with anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent in vacuo gave a crude product which was purified by silica gel column chromatography to obtain 2.4 g (70%) of a white solid: m.p. 168-170 ° C. HR MS (C23H238rN206): Observed mass, 525.0656. Calculated mass, 525.0637, (M + Na). Example 368. Preparation of the 4- (5-cyano-l, 3-dioxo-2H-isoindol-2-yl) -N- [(1,1-dimethyl-ethoxy) carbonyl] -L-phenylalanine methyl ester.

To a mixture of the methyl ester of 4- (5-bromo-1,3-dioxo-2H-isoindol-2-yl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (0.5 mmol, 0.25 g), zinc cyanide (0.2 mmol, 35 mg) and Pd (PPh3) (0.05 mmol, 57.7 mg) was added distilled and deoxygenated DMF (2 ml) at room temperature. The suspension was heated to 80-85 ° C and stirred for 15 hours under an argon atmosphere. After this time the TLC analysis of the mixture confirmed the absence of starting material. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 ml) and washed with 20% aqueous ammonium hydroxide (50 ml) and brine solution (50 ml) and dried with magnesium sulfate arhidro . Filtration of the drying agent and concentration gave a crude product which was purified by silica gel column chromatography to obtain 170 mg (75%) of a white solid. HR MS (C24H23N306): observed mass, 472.1472. Calculated mass, 472.1485 (M + Na). Example 369. Preparation of the TFA salt of the methyl ester of 4- (cyano-1,3-dioxo-2H-isoindol-2-yl) -1-phenylalanine. To a solution of the methyl ester of 4- (5-cyano-1,3-dioxo-2H-isoindol-2-yl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (1.33 emoles, 0.6 g) in dichloromethane (12 ml) was added trifluoroacetic acid (3 ml) at room temperature. The reaction mixture was stirred for 15 hours at room temperature, after which TLC analysis of the mixture confirmed the absence of starting material. The solvent was removed in vacuo and the residue was azeotroped with toluene (2 x 10 ml) and the high vacuum was dried obtaining 0.46 g (100%) of a yellow solid. HR MS (Ci9H15N30) Observed mass, 350.0156. Calculated mass, 350.0183 (M + H). Example 370. Preparation of the 4- [(4-cyano) 1,3-dioxo-2H-isoindol-2-yl] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] methyl ester] -L- phenylalanine To a solution of the methyl ester of 4- (5-cyano-l, 3-dioxo-2H-isoindol-2-yl) -N - [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (0.5 mmol, 0.22 g) HBTU (0.7 mmol, 0.26 g, and l- (2-methoxyethyl) cyclopentane carboxylic acid (0.7 mmol, 0.12 g) in DMF (3 mL), diisopropylethylamine (2.0 mmol, 0.35 mL) was added to The clear solution was stirred 24 hours at room temperature and diluted with 50 ml of ethyl acetate.The ethyl acetate layer was washed successively with 0.5N hydrochloric acid (2 x 20 ml), saturated sodium bicarbonate solution, sodium (2 x 20 ml), brine solution and dried with anhydrous magnesium sulfate The filtration of the drying agent and the concentration of the solvent gave a crude product which was purified by silica gel column chromatography to obtain 0.25 g ( 77%) of a white solid: mp 122-126 ° C.HR MS (C26H29 306): Observed mass, 504.2135. Calculated mass, 504.2134 (M + H). Example 371. Preparation of 4- (5-cyano-l, 3-dioxo-2H-isoindol-2-yl) -N- [(1- (2-methoxyethyl) cyclopentyl] carbunyl] -L-phenylalanine (Ro 27) -5853/000, 29156-154) To a mixture of the methyl ester of 4- (5-cyano-1,3-dioxo-2H-isoindol-2-yl) -N- [[1- (2-methoxyethyl) ) cyclopentyl] carbonyl] -L-phenylalanine (0.3 mmol, 151 mg) and lithium iodide (3.0 mmol, 397 mg) was added pyridine (6 ml) at room temperature.The solution was heated to reflux for 15 hours, after which the The TLC analysis of the mixture confirmed the absence of starting material, then it was cooled to room temperature and diluted with water (15 ml) and most of the pyridine was removed by concentration under reduced pressure. it was extracted with ether (2 x 15 ml) to remove any neutral impurity The aqueous layer was acidified with IN HCl and the white solid precipitate was collected by filtration and was washed with 20 ml of water and 20 ml of hexane. of s Air, the crude product was purified by inverted phase HPLC to obtain 50 mg (34%) of a white solid, m.p. 143-146 ° C. HR MS (C27H27N3? 6): observed mass, 490.1990. Calculated mass, 450.1978 (M + H) Example 372. The ethyl ester of 4- E [(2,4-dimethyl-3-pyridinyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, using the general method described in Example 123 starting with 4- [[(2,4-dimethylpyridin-3-yl) carbonyl] amino] -N- [[ 1- [4- (Methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine. Example 373. The ethyl ester of le 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1-2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine was prepared using the general method described in Example 123 starting from '4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl) -L-phenylalanine. Example 374. The ethyl ester of 4- [[(2,6-diclothiophenyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine was prepared using the general method described in Example 123 starting with 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine. Example 375. The ethyl ester of 4- [(4R) -3-acetyl-4- (phenylmethyl) -5-oxo-2-phenyl-1-imidazolidinyl] -N- [[1- [4- ( methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, using the method described in example 123 starting from 4- [(4R) -3-acetyl-4- (phenylmethyl) -5-oxo-2-phenyl-1 -imidazolidinyl] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine Example 377. The 2- (4-morpholino) ethyl ester of 4- [[(1 , 6-dichlorophenyl) carbonyl] amino] -N - [[1- [2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, using the general method described in Example 277 p with 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-methoxy-phenyl) -cyclopentyl] -carbonyl] -L-phenylalanine. Example 378. _ Prepared. the 2- (4-morpholino) ethyl ester of 4- [(2,4-dimethyl-3-pyridinyl) carbonyl] amino] -Nl- [(4-methylsulfonyl) util] cyclopentyl] carbonyl] -L-phenylalanine, starting from 4- [(2,4-dimethyl-3-pyridinyl) carbonyl] amino] -Nl- [(4-methylsulfonyl) butyl] cyclopentyl] carbonyl-L-phenylalanine, using the procedure described in Example 277. Example 379. The 2- (4-morpholino) ethyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyolopentyl] carbonyl] was prepared. -L-phenylalanine, from 4- [[(2,6-dichlorophenyl) cerbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, using the procedure described in Example 277. Example 380. The 2- (4-morfolioo) ethyl ester of 4- [(4R) -3-acetyl-4-phenylmethyl) -5-oxo-2-phenyl-l- was prepared imidazolidinyl] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine: starting from 4- [(4R) -3-acetyl-4- (phenylmethyl) -5-oxo] -2-phenyl-1-imidazolidinyl] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, using the procedure described in example 277. Example 380a. The 2- (N, N-diethylamino) ethyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino) -N- [[1- [2-methoxyethyl] cyclopentyl] carbonyl] -L- was prepared phenylalanine, using the general method ecxlLu in example 277 a tendo de la 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2- eti ietií) ciclopent.i 1] carboni 1] -r, -f? n lalanin, Example 381. 4- [(2,6-dimethyl-4-trifluoromethyl-3-pyridinyl) carbonyl] amino] -N- [[1- (4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -T.-f ^ pi 7 to the anion, Ue LcL r ': - 4 - (methyl butyl) butyl] cydopentyl] carbonyl] -L-phenylalanine and acid 2, 6-dimethyl-4-trifluoromethyl-3-pyrridine carboxylic acid using the general procedure described in example 364 Example 382. Preparation of 4-trifluoromethyl-5-pyrimidine carboxylic acid A solution of 2-chloro-4-trifluoromethyl benzyl ester -5-pyrimidine carboxylic acid in cyclohexene (3 ml, 30 mmoles) and ethanol (9 ml) are .raro with? A_.aoxo ± --_ soore csruop and _.a m.ezc_.a esu? _ -e is csien-c to reflux uranLe 1 hour. The mixture was cooled to room temperature and filtered through a pad of celite and concentrated to give a quantitative yield of an off-white, gummy solid: LR ES MS (C6H3F3N202): 191 (M-H) Example 383-387. The derivatives of the 4- [[(heteroethyl) cerbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine listed in the table below were prepared from of the methyl ester of 4-amino-N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine and the appropriate heteroaromatic carboxylic acids, using the general procedure described in Example 34.

Example 388. Preparation of the methyl ester of 4-amino-N-methyl-N- [(1- (2-methoxy-yl) -cyclopentyl] carbonyl] -L-phenylalanine To a mixture of N - [[1- (2-methoxyethyl) -cyclopentyl] -carbonyl methyl ester ] -N-methyl-4-nitro-L-phenylalanine (1.35 mols, 530 mg), zinc powder (-325 nicks, 13.5 mmoles, 0.88 g, 10 equivalents) and ammonium chloride (20.2 mmoles, 1.08 g, 15 equivalents), methanol (10 ml) and water (5 ml) were added at room temperature.After the addition of water an exothermic reaction was produced.The suspension was stirred for 2 hours at room temperature, after which the TLC analysis of the mixture confirmed the absence of the starting material, the reaction mixture was filtered through a cetile bed and the filter cake was washed with methanol (50 ml) and water (40 ml) .The mixture was concentrated and extracted. with ethyl acetate (3 x 30 ml) The combined extracts were washed with brine solution (30 ml) and dried with anhydrous magnesium sulfate. Extraction and concentration of the solvent gave 490 mg (100%) of a yellow oil. HR MS (C2oH3oN20): Observed mass, 362.2202. Calculated mass, 362.2206 (M +). Example 389. The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N-methyl-N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine was prepared, from the methyl ester of 4-amino-N-methyl-N- [[1- (2-methoxyethit) cyclopentyl] carbonyl] -L-phenylalanine and 1- (2-methoxyethyl) cyclopentane carboxylic acid, using the procedure described in Example 44 to obtain a white solid in 64% yield. HR MS (C27H32Cl2N2? 5) Observed mass, 535.1742. Calculated mass, 535.1766 (M + H). Example 390. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N-methyl-N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine was prepared from the ester 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -N-methyl-L-phenylalanine methyl ester, using the general procedure described in example 47 to obtain a white solid with 43% yield. HR MS (C26H3oCl2N2? 5): Observed mass, 519.1453. Calculated mass, 519.1454 (M-H). Example 391. Preparation of the methyl 1- (2-methoxyethyl) cyclopentane carboxylate ester. To a solution of diisopropylamine (21 ml, 150 mmol) in THF (100 ml) was added dropwise a solution of n-butyl lithium (58 ml). 145 mmole) in hexanes at -10 ° C keeping the temperature below 0 ° C. After the editing, the solution was stirred for 30 minutes at 0 ° C. To this, a solution of methyl cyclopentane carboxylate (12.8 g, 100 mmol) in THP (20 ml) was added dropwise at -70 ° C keeping the internal temperature between -60 and -70 ° C. After the addition, the reaction mixture was stirred for 30 minutes at -50 to -60 ° C. Next, a solution of 2-methoxy ethyl bromide (12.5 g, 90 mmol) in THF (20 ml) was added dropwise and the light brown suspension was stirred for 30 minutes at -60 to -70 ° C. . Then, the temperature was allowed to rise to room temperature and was stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (250 ml) and extracted with ether (2 x 100 ml). The combined extracts were washed with a saturated solution of sodium chloride (100 ml) and dried with anhydrous magnesium sulfate. After filtering the drying agent, the solution was concentrated in vacuo to obtain 16.55 g of crude product in the form of a black liquid. Distillation at 70-75 ° C / 1.5 mm Hg yielded 7.98 g of a colorless oil and another 2.76 g in the form of a light yellow oil for a total yield of 10.74 g (64%). HR MS (C? O H? 803): Observed mass, 186.1257. Calculated mass, 186.1256 (M +). Example 392. Preparation of 1- (2-methoxyethyl) -cyclopentane-carbuxyl acid. To a solution of the methyl l- (2-methoxyethyl) cyclopentane carboxylate ester (7,987 g, 42.9 mmol) in a mixture of THF (170 ml) and methanol (170 ml) was added 1N sodium hydroxide (170 ml). The mixture was heated at 40 ° C for 2 hours after which TLC analysis (ether: hexane 1: 1, iodine chamber) confirmed the absence of starting material and the mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was diluted with water (100 ml) and extracted with ether (2 x 200 ml) to remove the neutral impurities. The basic aqueous layer was acidified with IN hydrochloric acid and the product was extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with brine and dried with sodium sulfate. After filtering the drying agent, the solution was concentrated in vacuo and the residue was dried under high vacuum to obtain 6.183 g (82%) of a light brown oil. HR MS (C9H16O3): Observed mass, 172.0154. Calculated mass, 172.0126 (M +). Example 393. Preparation of the N-E (1,1-dimethylethoxy) carbonyl] -4-nitro-L-phenylalanine methyl ester. To a suspension of 4-nitro-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (226.2 mmol, 70.2 g) and sodium carbonate (1.13 mol, 95 g) in DMF (500 ml) was added Methyl iodide (1.13 moles, 70.4 ml) at room temperature. The suspension was stirred for 15 hours at room temperature, after which the TLC analysis of the mixture confirmed the absence of the starting acid and the excess methyl iodide and a small amount of DMF was removed to the empty ally, the residue was poured in water (2 liters) and stirred at room temperature whereby a precipitate formed slowly for 72 hours. The precipitated solids were collected by filtration and washed with water (2 liters). After drying in air and under vacuum, 72 g (98%) of a pale yellow solid, m.p. 95-96 ° C. XH-NMR, (DMSO-de) (400 MHz) d 8.16 (d, 2H, J = 20 Hz), 7.53 (d, 2H, J = 20 Mz), 7.39 (d, lH, J = 22 Hz ), 4.26-4.28 (m, 1H), 3.6 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H) 13, NMR, CDC13, (100 Mhz) d 172.04, 155.29, 146.27, 145.96, 130.48, 123.18, 78.36, 54.44, 51.9, 36.1, 27.99, HR MS: Observed mass, 325.1404. Calculated mass, 325.1400 (M + N). Example 394. Preparation of the 4-emino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester. To a mixture of the N - [(1, 1-dimethylethoxy) carbonyl] -4-nitro-L-phenylalanine methyl ester (222 mmol, 72 g) zinc powder (-325 mesh, 2.2 moles, 145.2 g, equivalents) and ammonium chloride (3.3 moles, 178.1 g, 15 equivalents) was added methanol (1 liter) and water (500 ml) at room temperature. After the addition of water an exothermic reaction occurred and the internal temperature increased to 45-50 ° C. The suspension was stirred for 30 minutes at 1 hour at room temperature, after which a TLC analysis of the mixture confirmed the absence of starting material, and the reaction mixture was filtered through a bed of celite and the cake of filtration was washed with methanol (1 liter) and water (500 ml). The concentration to remove most of the methanol gave a white solid which was collected by filtration and washed with water. After air drying, 65.5 g of a white solid, m.p. 86-89 ° C. XH-NMR, (DMSO-de) (400 MHz) d 6.9 (d, 2H, J = 20 Mz), 6.62 (d, 2H, J = 2 ° Hz), 7.39 (d, lM, J = 22 Mz) , 4.26-4.28 (m, lH), 3.68 (s, 3M), 2.96-3.19 (m, 2H), 1.25 (s, 9H). HR MS: Observed mass, 294.1614. Calculated mass, 294.1621 (M +). Example 395, Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N - [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester. To a solution of the methyl ester of 4-amino- N - [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) g) in dichloromethane (350 ml) was added diisopropylethylamine (192 mmol, 33.4 ml) at room temperature. The brown solution was stirred for 15 hours at room temperature to obtain a white suspension. At the end of this time, a TLC analysis of the mixture confirmed the absence of starting material. The solids were collected by filtration and washed with dichloromethane (150 ml) and air dried to obtain 52.75 g (88.4%) of a white solid: m.p. 192-194 ° C. 1 H-NMR, (DMSO-de) (400 MHz) d 10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.17 (m, lH), 3.62 ( s, 3H) 2.79-2.99 (m, 2H), 1.33 (s, 9H), 13C NMR, CDC13 (100Mhz) d 172.49, 161.82, 155.37, 136.99, 136.36, 131.28, 131.16, 129.48, 128.19, 119.31, 78.27 , 55.3, 51.76, 35.9, 27.77. MR MS: Observed mass, 466.1069. Calculated mass, 466.1062). Example 396. Preparation of the hydrochloride salt of the methyl ester of 4- [[(2,6-diclolophenyl) carbonyl] amino] -L-phenylalanine. The solid methyl ester 4- [[(2,6-dichloropheni) carbonyl] amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (92.97 mmol, 43.45 g) in dioxane (90 ml) was treated with 166 ml of 4.0 N hydrochloric acid in dioxane at room temperature. After 5 minutes the solids were dissolved and the mixture was stirred for 2 hours. The reaction mixture was concentrated to a yellow syrup and 250 ml of ethyl ether was added. A gum was formed which was dissolved in THF (100 ml) and methanol (100 ml). The solvent was removed under vacuum to obtain 43.7 (100%) of a white solid: m.p. 180-195 ° C. XH-NMR, (DMSO-de) (400 MHz) d 10.81 (s, lH), 7.76 (d, 2H, J = 22 Hz), 7.58 (d, 2H, J = 18 Hz), 7.51 (t, lH , J = 15 Hz), 7.24 (d, 2H, J = 22 Hz), 4.23-4.26 (m, lH), 3.56 (s, 3H), 3.14-3.17 (m, 2H). 13C NMR, CDC13 (100Mhz) d 169.03, 161.72, 137.56, 136.11, 131.19, 130.95, 129.93, 129.79, 128.06, 119.46, 53.17, 52.6, 35.13. HR MS (C? 7H? 6Cl2N2? 3.HCl): Observed mass, 367.0611. Calculated mass, 367.0616 (M + H). Example 397: Preparation of the 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine methyl ester. To a solution of the hydrochloride salt of the methyl ester of La 4- [[(2, 6-dichlorophenyl) carbonyl] amino] -L-phenylalanine (43.03 mmole, 11.75 g) and 1- (2-meloxyethyl) cyclopetane carboxylic acid (43.5 mmole, 7.5 g) in DMF (130 ml) was added HBTU (43.5 mmole , 16.5 g) and diisopropylethylethylamine (108.6 mmol, 19.02 ml) at room temperature. The clear solution was stirred 23 hours at room temperature and diluted with 200 ml of ethyl acetate. The ethyl acetate layer was washed successively with 0.5N hydrochloric acid (2 x 100 ml), saturated sodium bicarbonate solution (2 x 100 ml) and dried salt solution was dried with anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave 18.86 g (84%) of a white solid, m.p. 85-87 ° C. XH-NMR, (DMSO-de) (400 MHz) d 10.65 (s, lH), 7.88 (d, lH, J = 19 Hz), 7.47-7.59 (m, 5H), 7.21 (d, 2H, J = 19 Hz), 4.47-4.53 (m, lH), 3.64 (s, 3H), 2.88-3.1 (m, 7H), 1.76-1.98 (m, 4H), 1.23-1.47 (m, 6H). HR MS (C_6H3? Cl2N_0_): Observed mass, 521.1586. Calculated mass, 521.1610 (M + H). Example 398. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(1- (2-meloxyethyl) cydopentyl] carbonyl] -l-phenylalanine To a suspension of the methyl ester of the 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- E [1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine (20.17 mmol, 10.52 g) in ethanol (80 ml) and tetrahydrofuran (10 ml) 1.0 N aqueous sodium hydroxide (80 ml) was added at room temperature The mixture was heated to 50 ° C and the resulting clear solution was stirred overnight.

The ethanolic solution was then concentrated and diluted with 50 ml of water and extracted with 200 ml of ether to remove the neutral impurities. The aqueous layer was acidified with IN HCl and the white solid precipitate was collected by filtration and washed with 200 ml of water and 200 ml of hexane. After drying the air, 8.4 g (82%) of a white solid was obtained: m.p. 136-140 ° C. ^ -RMN, (DMSO-de) (400 MHz) d 10.64 (s, lH), 7.73 (d, lH, J = 22 Hz), 7.46-7.59 (m, 5H), 7.22 (d, 2H, J = 22 Hz), 4. 43-4.48 (m, lH), 2.87-3.11 (m, 7H) 1.76-2.01 (m, 4H), 1.23- 1.47 (m, 6H). MR MS (C25H28C12N205): Observed mass, 507.1464. Calculated mass, 507.1454 (M + H). Example 399. Preparation of 3- (1-methyltetrazol-5-yl) benzyl chloride. to. Preparation of 3-chloromethylbenzoic acid. A 2-liter round-bottomed, two-liter flask equipped with a mechanical stirrer, thermometer and condenser with an open end (no nitrogen inlet tube was connected to prevent pressure build-up in the apparatus), was charged with 109 g (800 mmol) of m-toluic acid and 320 ml of chlorobenzene. The mixture was heated to approx. 90 ° C with a steam bath to give a homogeneous solution and 53.4 g (400 mmol, 0.5 equivalents) of N-chlorosuccinimide (NCS) and 800 mg (3.3 mmol) of benzoyl peroxide < (BPO). The yellow solution was stirred at approx. 95 ° C for 2.5 hours. Next, 26.7 g (200 mmoles, 0.25 equivalents) of NCS and 400 mg (1.65 mmules) of BPO were added, and the mixture was stirred at 95 ° C for 2.5 hours. Then another 26.7 g (200 mmoles), 0.25 equivalents) of NCS and 400 mg (1.65 mmoies) of BPO were added and the mixture was stirred at 95 ° C for 2.5 hours. To the reaction mixture was added 480 ml of water and the resulting suspension was allowed to cool to room temperature by stirring overnight. To the suspension was added 480 ml of hexane. The resulting suspension was stirred at room temperature for 30 minutes, then filtered through a large-grain sintered glass filter. The collected solid was washed thoroughly with 2 x 130 ml of water and then with 2 x 130 ml of hexane, and dried by aspiration for 2.5 hours. Then, the solid was suspended in 800 ml of water and the mixture was heated in a steam bath for 30 minutes. After standing at room temperature overnight, the white solid was collected by filtration and dried by aspiration for 1.5 hours. Subsequent drying at 55 ° C under high vacuum overnight gave 73.7 g (54.0%) of chloromethylbenzoic acid; p.f. 134-136 ° C. b. Preparation of 3- (chloromethyl) -N-methylbencamide. A 250 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and calcium chloride drying tube was charged with 34.1 g (200 mmol) of 3-cyclohexylbenzoic acid and 125 ml of toluene (dried with 4A molecular sieves). To this suspension was added 21.9 ml (300 mmol) of thionyl chloride and the mixture was heated at 85-90 ° C for 15 hours. While continuing to heat, the evolution of the gas, presumably hydrogen chloride and sulfur dioxide, was observed. The reaction mixture was cooled to room temperature and the excess of thionyl chloride and toluene were removed in vacuo. The resulting oily residue was azeotroped with 100 ml of toluene, then dried under high vacuum for 1 hour to give the crude acid chloride. A 3-liter round bottom flask equipped with a magnetic stirrer, addition funnel, thermometer and argon sparger was charged with the crude acid chloride obtained above, and 400 ml of dichloromethane (dried with 4A molecular sieves). ). After the solution was cooled to -5 -0 ° C (using an ice-sodium chloride bath), 14.9 g (220 mmol) of methylamine hydrochloride were added in a single portion. To this mixture was added 69.6 ml (400 mmol) of diisopropylethylamine (DIPEA) dropwise over 15-20 minutes, keeping the temperature of the reaction mixture below 2 ° C. After the addition was complete, the mixture was stirred for 45 minutes at 0-5 ° C, and then allowed to warm to room temperature. After stirring for 15 minutes at room temperature, TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with 250 ml of water, and stirred for 5 minutes, the two layers were separated and the aqueous phase was extracted with 2 x 100 ml of dichloromelane. The combined organic layers were washed successively with 300 ml of water and 300 ml of saturated sodium chloride solution. After drying with anhydrous magnesium sulfate, the solution was concentrated by rotary evaporation with the laboratory vacuum. Then, the residue was dried in vacuo to obtain a light yellow solid. This solid was dissolved in 110 ml of toluene at ~60-70 ° C. The resulting solution was allowed to cool to room temperature, seeded with crystals of the product, and then stored in the refrigerator overnight. The resulting precipitate was collected by filtration and washed with 30 ml of hexane. After drying under high vacuum, 29.4 (80.0% yield) of 3- (chloromethyl) -N-methylbenzamide was obtained as a yellow-colored solid: m.p. 59-61 ° C. c. Preparation of 3- (l-methyltetrazol-5-yl) benzyl chloride. A 250 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and calcium chloride drying tube was charged with 27.2 g (148 mmol) of 3- (chloromethyl) -N-methylbenzamide, 100 ml of toluene ( dried with 4A molecular sieves). To this solution was added 16.2 ml (222 mmol) of thionyl chloride and the mixture was heated to 85-90 ° C for 15 hours (Note 6). Upon heating, a gas evolution was observed, presumably hydrogen chloride and sulfur dioxide. After cooling to room temperature, excess thionyl chloride and toluene were removed, the vacuum. The resulting residue was azeotroped with 100 ml of toluene, then dried under high vacuum for 1 hour to give the crude imidoyl chloride. A 500 ml three-necked, round bottom flask equipped with a magnetic stirrer, thermometer and argon sparger was charged with 11.6 (178 mmol) of sodium ezide and 140 ml of acetonitrile (from a freshly opened flask). To this suspension was added 23.7 ml (187 mmoles) of chlorotrimethylsilane and the mixture was stirred for 1.5 hours at room temperature. After cooling to 0 ° C, a solution of crude imidoyl chloride, prepared above, was added in 40 ml of acetonitrile, this heterogeneous mixture was stirred for 1-2 hours at 0 ° C, and then allowed to warm to room temperature. environment and stirred for 15 hours. TLC analysis indicated that the reaction had been complete, the reaction mixture was paralyzed by the addition of 150 ml of water, then diluted with 150 ml of ethyl acetate.The two layers were separated and the aqueous phase was separated. extracted with 2 x 100 ml of ethyl acetate The combined organic phases were successively washed with 200 ml of water and 200 ml of saturated sodium chloride solution After drying with anhydrous magnesium sulfate, the solution was concentrated. The residue was then dried under vacuum to obtain a light yellow solid (29.7 g) This solid was dissolved in 220 ml of 5.5: 4.5 hexane: ethyl acetate at ~ 60-70 ° C. The resulting solution was allowed to cool to room temperature. Room temperature was then seeded with crystals of the product and then stored in the refrigerator overnight.The resulting precipitate was collected by filtration and washed with 50 ml of hexane.

After drying by aspiration, 24.5 g (79.59% yield) of 3- (1-methyltetrazol-5-yl) benzyl chloride was obtained as a white amorphous solid, m.p. 63-65 ° C. Example 400. 1- [[3- (1-Methyltetrazol-5-yl) phenyl] methyl] ciu-butanecarboxylic acid methyl ester was prepared from 3- (1-methyltetrazol-5-yl) encyl chloride using the general method described in Example 7 to give a 77% yield of a viscous oil. HR MS: Observed mass, 287.1514. Calculated mass, 287.1508 (M + H). Example 401. l - [[3- (1-Methyltetrazol-5-yl) phenyl] methyl] cyclobutane carboxylic acid was prepared from the methyl ester of 1 [[3- (1-methyltetrazol-5-yl)] phenyl] methyl] cyclobutane carboxylic acid, using the general procedure described in Example 15 to yield 83% yield of a viscous oil. HR MS: Observed mass, 273.1226. Calculated mass, 273.1238 (M + N). Example 402. The 4-amino-N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine methyl ester was prepared from the methyl ester of 4-nitro-L- phenylalanine and the acid. 4- (methylsulfonyl) butyl] cyclopentane carboxylic acid, using the general procedure described in Example 26. HR MS (C2? H32N205S): Observed mass, 425.2121. Calculated mass, 425.2110 (M * H). Example 403. 1- (4-Bromobutyl) cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and methyl ester of cyclobutane cerboxylic acid, using the general procedure described is example 168. Example 404. prepared the 1- [4- (methylthio) butyl] cyclobutane carboxylic acid methyl ester, from the l- (4-bromobutyl) cyclobutane carboxylic acid methyl ester, and sodium methylmerceptane, using the procedure described in the example 172. Example 405. l- [4- (Methylsufonyl) butyl] cyclobutane carboxylic acid was prepared from the methyl ester of 1- [4- (methylthio) butyl] cyclobutane carboxylic acid, using the general procedures described in Examples 174 and 175 Example 406. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclobutane] carbonyl] -L-phenylalanine was prepared from the ester. Methyl 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine and 1- [4- (methylsulfonyl) butyl] cyclobutane carboxylic acid, using the procedure described in Examples 46 and 47. Example 407. 4- [(4R) -3-acetyl-4- (phenylmethyl) -5-oxo-2-phenyl-1-imidazolidinyl] -N- [(1-phenylcyclopentyl) carbonyl] -L-phenylalanine was prepared, from Fmoc-D-phenylalanine, benzaldehyde and the methyl ester of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine, using the general procedure described in Example 365. Example 408 Prepare or the methyl ester of 4- [3-acetyl-5-oxo-2- [(3-pyridinyl) methyl] -4-phenylmethyl-1-imidazolidinyl] -N- [[1- [4- (methylsulfonyl) butyl] ] cyclopentyl] carbonyl] -L-phenylalanine, from the methyl ester of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine, and Fmoc-D-pyridinalanine, using the general method described in Example 365. Example 409. Selection assay of VLA-4 / VCAH-1 The antagonist activity of VLA-4, defined as the ability to compete in binding to immobilized VCAH-1, was quantified using a dual-phase solid-phase ELISA assay. VLA-4 (integrin a4ßl) bound to VCAM-1 was detected by a complex of anti-integrin antibody ßl: anti-mouse IgG conjugated to HRP: chromogenic substrate (blue K). Initially, this involved the coating of 96 well plates (Nunc Maxisorp) with recombinant human VCAM-1 (0.4 μg in 100 μl of PSB), sealing each plate and then leaving the plates at rest at 4 ° C for ~ 18 hours. The VCAM coated plates were then blocked with 250 μl of BSA l% / HaN3 0.02% to reduce non-specific binding. On the day of the assay, the plates were washed twice with VCAM assay buffer (200 μl / well of 50 mM Tris-HCl, 100 mM NaCl, 1 mM EnCl2, 0.05% Tween 20; PH 7.4). The test compounds were dissolved in 100% DMSO and then diluted 1:20 in VCAM assay buffer supplemented with 1 mg / ml BSA (ie, final DMSO = 5%). Series of 1: 4 dilutions were prepared to have a concentration level of 0.005 nM-1563 μM for each test compound. 100 μl per well, from each dilution were added to the VCAH coated plates, and then 10 μl of VLA-4 derived from Ramos cells. These plates were mixed sequentially on a platform shaker for 1 minute, incubated for 2 hours at 37 ° C. ° C and then washed four times with 200 μl / well of VCAM assay buffer. 100 μl of mouse anti-human ßl integrin antibody was added to each well (0.6 μg / ml in VCAM + 1 mg / ml BSA assay buffer) and allowed to incubate for 1 hour at 37 ° C. After this incubation period, all plates were washed four times with VC7 [mu] M assay buffer (200 [mu] l / well). A corresponding second antibody, goat anti-mouse IgC conjugated to HRP (100 μl per well @ 1: 800 dilution in VCAm assay buffer + 1 mg / ml BSA), was then added to each well, followed by incubation of 1 hour at room temperature and finally three washes (200 μl / well) with VCAM assay buffer. The color development was initiated by the addition of 100 μl of blue K per well (15 minutes of incubation, room temperature) and ended with the addition of 100 μl of red interruption buffer, per well. All plates were then read on a VU / Vis spectrometer at 650 nM. The results were calculated as% inhibition of total binding (ie, VLA-4 + VCAM-1 in the absence of test compound). The results are shown in the following table: * 4-E (RS) -2,3,5, 6,7,7a-hexahydro-l, 3-dioxo-lH-pyrrolo E3, 4-c] pyridin-2-yl] -N- [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -L-phenylalanine Example 410. Protocol of the selection test based on Ramos cells (VLA-4) / VCAM-1 Materials: soluble human recombinant VCAM-1 VCAM-1 (mixture of domains 5- and 7-Ig) was purified from culture medium of CHO cells by immunoaffinity chromatography and kept in a solution containing 0.1 M Tris-glycine (pH 7.5), 0.1 M NaCl, mM of EDTA, 1 mM of PMSF, 0.02% of NaN3 and 10 μg / ml of leupeptin. Calcein-AM was purchased from Molecular Probes Inc. Methods: Antagonistic activity of VLA-4 (integrin a4ßl), defined as the ability to compete with cell surface VLA-4 for binding to immobilized VCAM-1, it was quantified using an adhesion assay of VCAM-1 to Ramos cells. Ramos cells carrying VLA-4 on the cell surface, were labeled with a fluorescent dye (calcein AM) and allowed to bind to VCAM-1 in the presence or absence of test compounds. A reduction in the intensity of fluorescence with the adherent cells (% inhibition) reflected a competitive inhibition of cell adhesion induced by VLA-4 by the test compound. Initially, this involved coating 96-well plates (Nunc Mazisorp) with recombinant human VCAM-1 (100 ng in 100 μl of PBS), sealing each plate and leaving the plates at rest at 4 ° C for ~ 18 hours. The VCAM-coated plates were then washed twice with 0.05% Tween-20 in PBS, and then blocked for 1 hour (room temperature) with 200 μl blocking buffer (1% BSA / 0.02% thimerosal) to reduce binding non-specific After incubation with blocking buffer, the plates were inverted, absorbed with blotting paper, and the residual buffer was aspirated. Each plate was then washed with 300 μl of PBS, inverted and the residual PBS was aspirated. The test compounds were dissolved in 100% DMSO and then diluted 1:25 in VCAM cell adhesion assay buffer (4 mM CaCl 2 4 mM MgCl 2 in 50 mM TRIS-HC1, pH 7.5) (final DMSO = 4% ). Series of 8 1: 4 dilutions were made for each compound (general concentration grade of 1 nM - 12,500 nM). 100 μl / well of each dilution was added to the VCAM coated plates, followed by 100 μl of Ramos cells (200,000 73 cells / well in BSA 1% / PBS). The plates containing the test compounds and the Ramos cells were allowed to incubate for 45 minutes at room temperature, after which 165 μl / well of PBS was added. The plates were inverted to remove the non-adherent cells, absorbed on blotting paper and 300 μl / well of PBS was added. The plates were inverted again, absorbed on blotting paper and the residual buffer was gently aspirated. 100 μl of lysis buffer (0.1% SDS in 50 nM TEIS-HC1, pH 8.5) was added to each well and agitated for 2 minutes on a rotating shaking platform. Next, the plates were read to determine the intensity of the fluorescence in a Cytofluor 2300 system (Millipore) for fluorescence measurement (excitation = 485 nm, emission = 530 nm). The results are shown in the following table: Table 3 Example 411. Oral dosage forms Processing procedure: 1. Mix samples 1,2,3 in an appropriate mixer for 15 minutes. 2. Granulate the mixed powder from step 1 with 20% PVP K30 solution. 3. Dry the granulate of weight 2 at 50 ° C. 4. Pass the granulate from Step 3 through suitable grinding equipment. 5.Add sample 5 to the ground granulate from step 4 and mix for 3 minutes. 6. Compress the granulate from step 5 in an appropriate press.

Example 412. Formulation for aerosol administration * depends on the activity of the compound E1 PH Can be adjusted with sodium hydroxide solution (IN) or HCl solution (10% w / v) Process : 1. Dissolve the active Substance in buffer 2. Filter the solution through a 0.22 micron filter The distribution of the tapping of the particles after the nebulization of the previous solution (measured using the Malvern Mastersizer X) is of the order of 1-6. mieras It is noted that in relation to this date, the best method known to the applicant, to put into practice the said invention which is clear from the present descrin of the invention. Having described the invention as above, the contents of the invention are claimed as property. the following.

Claims (51)

1. A compound of formula: characterized in that one of X and X 'is H, halogen or lower alkyl and the other is a group of formula wherein: Ri is hydrogen or lower alkyl, Ris is hydrogen, halogen, nitro, lower alkylsulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, cerboxyl, lower alkylaminosulfonyl, perfluoroalkyl lower, lower alkylthio, lower hydroxyalkyl, lower alkoxyalkyl, alkylthio lower alkyl, lower alkylsulfinylalkyl, lower alkylsulfonylalkyl, lower alkylsulfinyl, lower alkanoyl, aryloxyl, aryl, aryl or a group of formula R? 7-C = C-, R is H, halogen, nitro, cyano, lower alkyl, OH, perfluoroalkyl lower or lower alkylthio, and R17 is H, eryl, heteroaryl, or lower alkyl which is unsubstituted or substituted with OH, aryl or heteroaryl, a is 0 or 1; or one of X and X 'is a group of formula: where (Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S; or H Het) is a 9 or 10 membered bicyclic heteroaromatic ring, containing 1, 2, 3 or 4 heteroatoms selected between O, S and N; a, Ri R15 and Rie are as defined for X-6 and R30 is hydrogen or lower alkyl, or does not exist; or one of X and X 'is a group of formula: wherein: Ris is hydrogen, substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, R19 is unsubstituted or substituted lower alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, and R2o is unsubstituted or substituted lower alkyl, lower alkanoyl, optionally substituted with carboxyl, aroyl or aryloxy; and Y is a group of formula: ? -1 wherein: R22 and R23 are independently aryl, heteroaryl or lower alkyl which is unsubstituted or substituted with one or more chlorine, bromine, nitro, hydroxyl, lower alkoxy, aryl, lower alkanoyl, aroyl, or cyano, R24 is aryl, cyano, alkylsulfonyl or lower alkyl or alkenyl unsubstituted or substituted by an aryl or heteroaryl ring, and when R22 is aryl and R23 is aryl or lower alkyl, R24 is H, and the total number of carbon atoms in R22, R23, and R24 is from 6 to 14; or Y is a ring of 3-7 members of formula: wherein: R25 is lower alkyl, unsubstituted or unsubstituted lower alkenyl with fluorine or a group of formula R26 ~ (CH2) e-, R2e is aryl, heteroaryl, azido, cyano, hydroxyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, lower perfluoroalkanoyl, nitro or R26 is a group of formula -NR28R29 wherein: R28 is H or lower alkyl, R2g is hydrogen, lower alkyl, lower alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted lower alkanoyl , aroyl, heteroaroyl, heterocycloalkylcarbonyl, lower alkylsulfonyl, lower alkylaminothiocarbonyl, or R28 and R2g taken together with the nitrogen atom to which they are attached, form a 4, 5 or 6 membered saturated heterocyclic ring, containing one or two heterocyclics with a second heteroatom which is O, S or N-R2; Q is - (CH2) f0-, - (CH2) fS-, - (CH2) _-, or when f = 0, one bond, R7, is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, the carbon atoms of said ring being unsubstituted or substituted with lower alkyl or halogen; e is an integer from o to 4, f is an integer from 0 to 4, and the dotted line means a link that may or may not exist; and Z is hydrogen or lower alkyl; and the pharmaceutically acceptable salts and esters thereof.

2. A compound according to claim 1, characterized in that X1 is hydrogen.

3. A compound according to claim 1 or 2, characterized in that Z is hydrogen.

4. A compound according to any one of claims 1-3, characterized in that wherein in Y-1, R22 and R23 are lower alkyl or phenyl, and R24 is lower alkyl except when R22 is aryl and R3 is aryl or lower alkyl , then R24 is hydrogen.

5. A compound according to any one of claims 1-4, characterized in that Y-1 is selected from the group consisting of:

6. A compound according to any one of claims 1-3, characterized in that at Y-2, Q is - (CH2) f- or, when f = 0, a bond.

7. A compound according to claim 6, characterized in that where f is 1, 2 or 3.

8. A compound according to any one of claims 1-3, characterized in that in Y-2, R26 is aryl, heteroaryl, azido , cyano, hydroxyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, nitro, or R26 is a group of the formula -NR28R2g, wherein R28 is H or lower alkyl, R29 is hydrogen, lower alkyl , lower alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted lower alkanoyl, aroyl, lower alkylsulfonyl or R28 and R2g taken together with the nitrogen to which they are both attached, forms a 4, 5 or 6 membered saturated heterocyclic ring, which may contain a oxygen atom.

9. A compound according to any one of claims 1-3, characterized in that R28 is H.

10. A compound according to claim 8 or claim 9, characterized in that R26 is unsubstituted aryl or monosubstituted with halogen, elcoxyl lower, lower alkyl, cyano or tetrazolyl which is unsubstituted or substituted by methyl or R26 is phenyl disubstituted with lower alkoxy.

11. A compound according to claim 10, characterized in that R26 is phenyl unsubstituted or monosubstituted with chloro, methoxy or methyl.

12. A compound according to claim 8, characterized in that R2e is CH3S0 (O) 2-, CH3S-, CH3SO-, SH3O-, CH3CO-, NC-, N3-, or HO-.

13. A compound according to claim 8, characterized in that the alkyl group of the lower alkanoyl group of R29 is unsubstituted or substituted by lower alkoxy, fluoro, phenyl, cycloalkyl, lower alkoxycarbonyl, amino or lower alkoxycarbonylamino.

14. A compound according to claim 13, characterized in that the unsubstituted or substituted lower alkanoyl group is, CH3CO-, (CH3) 3CCO-, CH3 (CH2) 3CHCH3CO-, CH3OCH2CO-, CF3CO-, CeH5CH_CO-, CH3OCO ( CH2) 2CO-, cyclopentylCH2C0-, H2NCH2C0 or (CH3) 3COCONH (CH2) 2C0-.

15. A compound according to claim 8, characterized in that R2g, the aminocarbonyl group is unsubstituted or substituted with lower alkyl, lower alkoxycarbonyl, monocyclic aryl or benzyl.

16. A compound according to claim 15, characterized in that the unsubstituted or substituted aminocarbonyl group is H2NCO-, CH3NHCO-, CH3OCONHCO-, CeHN02NHCO- or C6H5CH2NHCO-.

17. A compound according to claim 1, characterized in that R29 is (CH3) 3COCO-, methylaminothiocarbonyl, 4-methoxy-phenylcarbonyl, 3-trifluoromethylphenylcerbonyl, -NR28R29 is -NH2 or -N (CH3) 2 and R28 and R29 taken together is 4-morpholinyl.

18. A compound according to any one of claims 1-3, characterized in that Y-2 is selected from a group represented by one of the following formulas:

19. A compound according to any one of claims 1-3, characterized in that X-6, R15 and R26 are independently from each other, H, aroyl, halogen, nitro, perfluoro lower alkyl, lower alkyl, cyano or R15 is phenoxy and R is H.

20. A compound according to claim 19, characterized in that X-6 the group R15 and Ri6 are independently from each other, hydrogen, methyl, nitro, chloro, trifluoromethyl or cyano.

21. A compound according to any one of claims 1-3, characterized in that X-6, Ri is hydrogen.

22. A compound according to any one of claims 1-3, characterized in that X-6 is 0.

23. A compound according to any one of claims 1 ~ 3, characterized in that X-6 is selected from the group formed by:

24. A compound according to any one of claims 1-3, characterized in that in X-7, Het is a 5- or 6-membered monocyclic atomic heterocyclic ring, containing 1, 2 or 3 nitrogens or a nitrogen and a sulfur, or a nitrogen and an oxygen. 25. A compound according to claim 24, characterized in that the heteroaromatic ring alone, is

-S r N = f. N-N T > ^ fT? ^^

26. A compound according to any one of claims 1-3, characterized in that X-7, Het is a bicyclic heteroaromatic ring containing from 1 to 3 nitrogens as hetternatoms.

27. A compound according to claim 26, characterized in that the bicyclic heteroaromatic ring is 4-quinolinyl, 1-isoquinolinyl or

28. A compound according to any one of claims 1-3, characterized in that X-7, R15 is hydrogen, nitro, lower alkylsulfonyl, cyano, lower alkyl, lower alkoxy, pefluoro lower alkyl, lower alkylthio, lower alkanoyl or aryl.

29. A compound according to claim 28, characterized in that R15 is isopropyl, methyl or phenyl.

30. A compound according to any one of claims 1-3, characterized in that Ri6 in X-7 is hydrogen, halogen, nitro, cyano, lower alkyl or perfluoro lower alkyl.

31. A compound according to claim 30, characterized in that Ri6 is methyl or trifluoromethyl.

32. A compound according to any one of claims 1-3, characterized in that R30 in X-7, is hydrogen, or lower alkyl.

33. A compound according to any one of claims 1-3, characterized in that X-7 is selected from the group consisting of:

34. A compound according to any one of claims 1-3, characterized in that X-10, R is phenyl, wherein the phenyl ring is unsubstituted or monosubstituted with halogen, or is phenyl lower alkyl.

35. A compound according to claim 34, characterized in that Ris is phenyl, clorophenyl or phenylethyl.

36. A compound according to any one of claims 1-3, characterized in that in X-10, R19 is lower alkyl which is unsubstituted or substituted with pyridyl or phenyl, wherein the phenyl ring is unsubstituted or monosubstituted with lower alkoxy or halogen.

37. A compound according to claim 36, characterized in that R19 is methyl, isobutyl, benzyl, 4-chlorobenzyl, 4-methobenzyl or 2-pyridylmethyl.

38. A compound according to any one of claims 1-3, characterized in that at X-10, R2o is optionally substituted lower alkanoyl.

39. A compound according to claim 38, characterized in that R2o is acetyl, butyryl, phenoxyacetyl, succinyl or glutaryl.

40. A compound according to any one of claims 1-3, characterized in that X-10 is selected from the group consisting of

41. A compound characterized in that it is selected from the group consisting of: 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[l- [(4-methoxy-phenyl) -methyl] -cyclopentyl] -carbonyl] -L-Phenylalanine , NE [1-E (4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [[(2-nitrophenyl) carbonyl] amino] -L-phenylalanine, N - [[1- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [[(2-methyl-5-nitrophenyl) carbonyl] amino] -L-phenylalanine,

N- [[l- [(4-methoxyphenyl) methyl] cyclopentyl] carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine, N - [[1- (phenylmethyl) cyclopenitre] carbonyl] -4- [(4-quinolinylcarbonyl) amino] -L-phenylalanine, 4- [E (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine, 4- [ [(2-nitrophenyl) carbonyl] amino] -N- [[1- (phenylmethyl) cyclopentyl] carbonyl] -L-phenylalanine, 4- EE (2-methyl-5-nitrophenyl) carbonyl] amino] -N- [[ 1- (phenylmethyl) cyclopentyl] carbonyl] -L-felilalanine 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[N- (1,1-dimethylethyl) carbonyl] ] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [E (2,6-dichlorophenyl) cerbonyl] mino] -N- [[1- [2-E (trifluoroacetyl) amino] ethyl] cyclopentyl] carbonyl ] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(2-amino-1-oxoethyl) amino] ethyl] cyclopentyl] carbonyl] - L-phenylalanine, 4- [E (2,6-dichlorphienyl) carbonyl] amino] -N- [[1- [2 -[ [twenty-one, 1-dimethylethoxy) carbonyl] amino] -1-oxoethyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[2- [ [(methoxy) carbonyl] amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [E (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(methylsulfonyl) amino]] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [E (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(acetyl (methyl) amino] ethyl] cyclopentyl] carbonyl ] -L-phenylalanine, 4- [E (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [[(methylamino) carbonyl] (methyl) amino] ethyl] cyclopentyl] carbonyl] - L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- [(methoxycarbonyl) - (methyl) amino] ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (2-methoxyethyl) cyclopentyl] carbonyl] -L-phenylalanine, 4- [E (2,6-dichlorophenyl) carbonyl] amino ] -N- [[1- [2- [(Methylsulfonyl) ethyl] cyclopentyl] carbonyl] ] -L-phenylalanine, 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[1- [2- (methylsulfonyl) ethyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[( 2,6-dimethyl-4-trifluoromethyl-3-pyridinyl) carbonyl] amino] -N- [[1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, 4- [[(2, 4 -dimethylpyridin-3-yl) carbonyl] amino] -N- E [1- [4- (methylsulfonyl) butyl] cyclopentyl] carbonyl] -L-phenylalanine, or 4-EE (2,6-dichlorophenyl) carbonyl] amino] -N- [[1- (4-methoxyphenylmethyl) cyclohexyl] carbonyl] -L-phenylalanine, 42. A compound characterized in that it has the formula selected from the group consisting of:

43. A process for the preparation of a compound of formula 1 wherein X, X ', Z and Y are as defined in claim 1, characterized in that in a compound of formula Ib wherein X, X ', Z and Y are as defined and R is a protecting group or a solid support, the protection group or the solid support is cleaved, and if desired, a compound of formula 1 is converted in a pharmaceutically acceptable salt

44. Compounds according to any one of claims 1-42 characterized to be used as a medicament.

45. Compounds according to any one of claims 1-42 characterized to be employed as a medicament in the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma.

46. A medicament containing a compound according to any one of claims 1-42 characterized in that it is a therapeutically inert support material.

47. A medicament for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma, containing a compound according to any one of claims 1-42 characterized in that it is a therapeutically inert carrier material.

48. A process for the manufacture of a medicament, especially for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma, which method comprises the conversion of a compound according to any one of claims 1-42. characterized in that in a galenic form of administration, together with a therapeutically inert support material and, if desired, one or more additional therapeutically active substances.

49. The use of a compound according to any one of claims 1-42, characterized in the treatment of diseases, especially in the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma.

50. Use of a compound according to any one of claims 1-42, characterized in that in the preparation of a medicament for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma

51. The new compounds, products intermediates, procedures, medications and methods as described so far. DERIVATIVES OF N-ARILFENIIAIANINA SUMMARY OF THE INVENTION Formula compounds are described which have activity as inhibitors of the binding between VCAM-1 and cells expressing VLA-. Said compounds are useful for the treatment of diseases whose symptoms and / or lesions are related to the binding of VCAM-1 to cells expressing VLA-4.