MXPA00001744A - N-alkanoylphenylalanine derivatives - Google Patents

Abstract

Compounds of formula (1) as well as their salts and esters are disclosed wherein X, X', Z and Y are as described in the specification and 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

D E R I V D Y S D E N - .ARQ I LFENILALANTNA FIELD AND BACKGROUND OF THE INVENTION The molecule-1 of adhesion to vascular cells (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated endothelium, but not inactive. The integrin VLA-4 (a4b?), Which is expressed on many cell types including lymphocytes, eosinophils, basophils, and circulating onocites, but not neutrophils, is the major receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vivo. Antibodies to one or another protein have been effective in inhibiting leukocyte infiltration and preventing tissue damage in several models of animal inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell migration in adjuvant-induced arthritis, prevent eosinophil accumulation, and co-co-occur in Ref models. : 32782 of asthma, and reduce paralysis and inhibit monocytic and lymphocytic infiltration in experimental autoin encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have shown that anti-VLA-4 mAbs 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 integrins containing a and VCAM-1 will be useful as therapeutic agents for the treatment of chronic inflammatory diseases such as RA, multiple sclerosis (MS), asthma, and inflammatory bowel disease (IBD).

BRIEF DESCRIPTION OF THE INVENTION Thus, the present invention relates to new compounds of the formula and their pharmaceutically acceptable salts and esters, wherein X, X ', Z and Y have the meaning defined below that inhibit the binding of VCAM-1 to VLA-4, methods for the preparation of these compounds, medicaments, a method for the production of these drugs and the use of the new compounds in the treatment of diseases, especially inflammatory diseases where this link acts to cause 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 from one to six carbon atoms, such as methyl, ethyl, n- propyl, isopropyl n-butyl, i, butyl secondary, isobutyl, tertiary butyl, n-pentyl, n-hexyl and the like. The lower alkyl groups may be unsubstituted or substituted by one or more groups independently chosen from cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and amino substituted. Examples of substituted lower alkyl groups include 2-h-hydroxy, 3-oxobutyl, cyanomethyl, and 2-n-t-ypropyl.

The term "cycloalkyl" means a 3 to 7 membered unsubstituted or substituted carbacyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl heteroaryl and substituted amino.

The term "lower alkoxy" means a straight 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 linked through a divalent sulfur atom, for example, a methyl mercapto or isopropyl mercapto group.

The term "aryl" means an aromatic mono- or bicyclic group, such as phenyl or naphthyl, which is unsubstituted or substituted by conventional substituent groups. Preferred substituents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, idroxyalkoxy, halogen, lower alkylthio, lower alkyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl alkynyl, lower alkynyl already 1 cano and 1 ami not inferior. Especially preferred substituents are lower alkyl, hydroxy, and perfluoro lower alkyl. Examples of aryl groups that can be used in accordance with this invention are phenyl, p-tolyl, p-me t-oxy phenyl, p-c 1 or p-or p-1, m-hydroxy phenyl, m-me ti 11 iofeni lo, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl and s imines.

The term "arylalkyl" means a lower alkyl group as defined above wherein one or more hydrogen atoms is substituted by an aryl or heteroaryl group as herein defined. Any conventional aralkyl, such as benzyl and the like, can be used according to this invention.

The term "heteroaryl" means a monocyclic heteroaromatic ring of 5 or 6 unsubstituted or substituted members or a 9 or 10 membered bicyclic heteroaromatic ring containing 1, 2, 3 or 6 heteroatoms that are independently N, S or O. Examples of rings of heteroaryl are pyridine, benzimidazole, indole, imidazole, thiophene, and soquinol ina, quinzoline and the like. Substituents as defined above for "aryl" are included in the definition of het eroari lo.

The term "lower alkoxycarbon" means a lower alkoxy group linked via a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like.

The term "lower alkylcarbonyloxy" means lower alkyl carbonyloxy groups linked via an oxygen atom, for example an acetoxy group.

The lower alkanoyl group means lower alkyl groups linked via a carbonyl group and encompasses groups such as acetyl, propionyl and the like in the sense of the foregoing definition.

The term "lower alkylcarbonylamino" means lower alkylcarbonyl groups linked via a nitrogen atom, such as acetylamino.

The term "aroyl" means a mono- or bicyclic aryl or heteroaryl group linked via a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, 2-naphthyl, and the like.

The term "aryloxy" means an aryl group, as defined above, that is linked via an oxygen atom. The preferred aryloxy group is phenoxy.

DESCRIPTION OF THE INVENTION In the first aspect, the present invention relates to a compound of the formula: wherein: one of X and X 'is hydrogen, halogen, or lower alkyl, the other is a group of the formula wherein Ri is hydrogen or lower alkyl, R15 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, OH, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl amylsulphonyl, perfluoro lower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkyl halo, lower alkylthio lower alkyl, 1 to 1 to 1 lower alkyl, to 1 to 1 lower alkyl, to 1 to 1 to 1 lower 1, alkanoyl lower, aroyl, aryloxy or a group of the formula Rj7 C = C-, Ri6 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluoro lower alkyl or lower, lower alkylthio or lower alkylthio, R1 is hydrogen, aryl, heteroaryl or lower alkyl which is unsubstituted or substituted by OH, aryl or heteroaryl, and a is 0 or 1; not X and X 'is a group of the formula where Het is a heteroaromatic ring of or 6 members containing 1, 2 or 3 heteroatoms chosen from N, O, and S; or Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from 0, S and N, a, Ri, R15 and Ri6 are as indicated above, and R30 is hydrogen or lower alkyl, or is absent or one of X and X 'is a group of the formula where : Ri8 is lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, R19 is lower alkyl, which is unsubstituted or substituted by one or more of halogen, hydroxy, inner alkoxy, aryl, heteroaryl, alkylthio, or R19 is aryl or heteroaryl, and R2o is lower alkyl or lower alkanoyl, or R19 and R20 taken together are tet ramet ileno e Y is a group of the formula: wherein: R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, lower alkoxylalkyl, lower alkylamino, aryl, arylalkyl, nitro, cyano, lower alkylthio, at 1 qui 1 to 1 fini 1 or lower, lower alkylsulfonyl, alkanoyl lower, halogen, or perfluoroalkyl and • at least one of R22 and R23 is other than hydrogen, and R24 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, amino, aryl, nitro, cyano, halogen, or is a group of the formula: where R25 is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkoxy alkyl and R26 is hydrogen or lower alkyl, or R22 and R24 taken together are a fused benzene ring; or And it's a group Y-2 which is a five or six membered monocyclic heteroaromatic group containing 1, 2 or 3 heteroatoms chosen from N, O, and S, or a 9 or 10 membered bicyclic heteroaromatic group containing 1, 2, 3 or 6 heteroatoms chosen from O, S, and N, wherein said heteroaromatic group is linked via a carbon atom to the amide carbonyl and one or two carbon atoms of said heteroaromatic group is (are) suited by lower alkyl, halogen, cyano, perfluoroalkyl or aryl and at least one of said substituted carbon atoms is adjacent to the carbon atom bonded to the amide carbonyl; and its salts are far more effective and acceptable.

The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention.

In a compound of formula 1 X 'is preferably hydrogen, which means that then X is 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 Y1, which is preferred over Y-2, R22 and R23 are preferably hydrogen, lower alkyl, nitro, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfonyl, alkyl lower sulfonyl, lower alkanoyl, halogen, or perfluoroalkyl wherein at least one of R22 and R23 is not hydrogen, and R 2 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, amino, nitro, halogen or a group of the formula: where R25 is aryl lower alkyl and R26 is hydrogen or lower alkyl, or R22 and R24 taken together are a fused benzyl ring.

Preferably R22 is hydrogen (when R23 is other than hydrogen), lower alkyl or halogen. R24 is preferably hydrogen, hydroxy, lower alkylsulfonyl, lower alkyl, halogen, nitro or lower alkoxy or a group of the formula: wherein R 25 is phenyl unsubstituted lower alkyl or hydr oxy-su tido, and R 26 is hydrogen, or R22 and R24 taken together are a fused phenyl ring.

Most preferred R24 is hydrogen, hydroxy, amino, methyl, chloro, bromo, nitro, -OCH3, -SO2CH3 and R26 is H and R25 is R23 is preferably hydrogen (when R22 is other than hydrogen), lower alkyl, lower alkylamino, halogen, nitro, perfluoro lower alkyl, lower alkoxy, lower alkanoyl, at 1 qui 1 s or 1 f i n i 1 or lower or lower alkyl sulfonyl. R23 is more preferably methyl, ethyl, iso-propyl, tert-butyl, trifluoromethyl, chloro, bromo, fluoro, nitro, -COCH3, -SCH3, -SOCH3, -SO2CH3, -NHCH3 or -OCH3.

Y-l most preferred is chosen from the group consisting of: In a compound of formula 1 wherein Y-2 is a 9 or 10 membered bicyclic monocyclic or heteroaromatic heteroaromatic group, this heterocycle is chosen, preferably from the group: The most preferred Y-2 groups have the f or rmu l a: In a compound of formula 1, wherein X is X-6 the groups R15 and R1 are preferably, independently, hydrogen, lower alkyl, nitro, halogen, perfluoro-lower alkyl, cyano or aryloxy. R15 or Ri6 most preferred is H, methyl, nitro, chloro, fluoro, trifluoromethyl, cyano or phenoxy.

The most preferred X-6 groups have the formula 1 a: In a compound of formula 1, wherein X is X-7 Het is preferably a 5-6 membered monocyclic monocyclic 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 In a compound of formula 1 wherein X is X-7 and Het is a bicyclic heteroaromatic ring, it preferably contains from 1 to 3 nitrogens as the heteroatoms. More preferably, the bicyclic heteroaromatic ring is 4 -qu i n ol i n i 1, 1-i s oqu i no 1 in i 1 o o With respect to the substituents on the heterocycles X-7 R15 is preferably hydrogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluoro lower alkyl, lower alkylthio, lower alkanoyl or aryl. R15 more preferred is isopropyl, methyl or phenyl.

Ri6 in heterocycles X-7 is preferably hydrogen, halogen, nitro, cyano, lower alkyl or perfluoro lower alkyl. R 6 most preferred is methyl or trifluoromethyl.

R30 is X-7 is preferably hydrogen or lower alkyl, especially methyl.

The preferred X-7 groups have the formula 1 a: In a preferred embodiment of X-6 or X-7 Ri is hydrogen. In another a is 0.

In a compound of formula 1, wherein X is X-10, Rig is preferably lower alkyl or phenyl, wherein the phenyl ring is unsubstituted or monosubstituted by halogen, hydroxy, or is phenyl lower alkyl. R 8 most preferred is terbutyl, phenyl, phenoxy, chlorophenyl or phenylethyl.

Ri9 is preferably lower alkyl, which is unsubstituted or substituted by pyridyl or phenyl wherein the phenyl ring is unsubstituted or monosubstituted by lower alkoxy or halogen. R19 most preferred is methyl, isobutyl, benzyl, 4-c 1 or roben c i 1 o, 4-me t oxibe n c i 1 or 2 -p i r i di lme t i 1 o.

When R20 in X-10 is lower alkyl, methyl is preferred. Preferably it is lower alkanoyl, especially acetyl.

The most preferred X-10 groups have the fómumu la: The compounds of the invention include pharmaceutically acceptable salts and their esters. Certain preferred esters of the invention are useful for improving the bioavailability of compounds of this invention. These preferred esters have the formula 1 a: wherein X, X ', Z and Y have the meaning indicated above and R31 is lower alkyl, or R31 is a group of the 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 from 0 to 2, the sum of h and g is 1 to 3; or R31 is a group of formula P-2: R32 - (CHa C CHdü- T P-2 where: P-3 / g and are as previously defined, T is 0, S, - (CH2) j- a bond (when j = 0) or a group of the formula N-R35, R35 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl and j is 0, 1 or 2.

The particular lower alkyl ester groups are methyl, ethyl, butyl, 1-methylethyl, 2-methyl-1-yl, 2-methyl-1-yl and 2-hydroxyethyl. A particular Pl group is 2-dimethylaminoethyl. The particular P2 group is 2 - (4 -mor fo 1 ini 1) eti 1 o, 1 -me ti 1 - 2 - (4 -mor fol in i 1) eti lo, 1 -me ti 1 - 4 -p ipe r idi 1 ni, 2- (1 -pi pe ra zini 1) eti 1 o and 2- (4-methyl-lp i pe razini 1) eti 1 o.

R31 is preferably methyl, ethyl or 2- (4-morpholinyl) ethyl.

The preferred compounds of the formula and 2 are selected from the group: I The compounds of the invention inhibit the binding of VCAM-1 and fibronectin to VLA-4 in lymphocytes, eosinophils, basophils and circulating monocytes ("cells expressing VLA-4"). The binding of VCAM-1 and fibronectin to VLA-4 on these 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 lung inflammation that occurs in asthma. Thus, the compounds of the present invention should be useful for the treatment of asthma.

In another aspect, based on their ability to inhibit the binding of VCAM-1 and fibronectin to VLA-4 on lymphocytes, eosinophils, basophils and circulating monocytes, the compounds of the invention can be used as a medicament for the treatment of disorders that know associated with this link. 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 involving pulmonary inflammation, such as asthma. The pulmonary inflammation that occurs with asthma is related to infiltration of eosinophils in the lungs where the eosinophils are linked to the endothelium that has been activated by a certain event or substance that triggers 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 on lymphocytes, eosinophils and T cells. Although the precise rule is not completely understood of the interaction of alpha4-beta7 with several ligands under inflammatory conditions such as asthma, the compounds of the invention that inhibit the binding of both the alpha-4-beta receptor and the alpha4-beta7 receptor are particularly effective in animal asthma models. Further work with monoclonal antibodies to alpha4-beta7 indicates that compounds that inhibit alpha4-beta7 binding to MadCAM or VCAM are useful for the treatment of inflammatory bowel diseases. These should also be useful in the treatment of other diseases where this bond is involved as a cause of injury or symptoms of disease.

The compounds of the invention can be administered orally, rectally, or parenterally, for example intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingual, or as orally prepared preparations, or as an aerosol for the treatment of pulmonary inflammation. Examples of administration forms are capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, ointments or spray solutions.

A preferred form of administration is intravenous, intramuscular, oral or inhalation. The doses at which the compounds of the invention are administered in effective amounts depend on the nature of the specific active ingredient, the age and requirements of the patient and the manner of administration. The doses can be determined by any conventional means, for example by clinical dose-limiting tests. Thus, the invention also comprises a method for the treatment of a host suffering from a disease wherein the binding of VCAM-1 or fibronectin to cells expressing VLA-4 is a causative factor in the symptoms of the disease or injury by the administration of an amount of a compound of the invention sufficient to inhibit the binding of VCAM-1 or fibronectin to VLA-4 expression cells so as to reduce said symptoms or said injury. In general, doses of about 0.1-100 mg / kg of body weight per day are preferred, with doses of 1-25 mg / kg per day being particularly preferred, and doses of 1-10 mg / kg of body weight per day being 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. These compositions can be formulated with any conventional means giving galenic administration form to a compound according to the present invention together with a therapeutically inert carrier material. If desired, one or more additional therapeutically active substances can be added The tablets or granules can contain a series of binders, fillers, vehicles or diluents. The liquid compositions can take, for example, the form of a sterile water miscible solution. In addition, flavor improving additives may also be present, as well as substances usually used as preservatives, stabilizers, moisture retainers and emulsifiers, as well as salts for varying the osmotic pressure, buffers and other additives.

The above-mentioned carrier and diluent materials can comprise any conventional pharmaceutically acceptable organic or inorganic substance, for example water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, po 1 a 1 qu i 1 eng 1 co 1 It is and similar.

Oral unit dosage 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 Reaction Scheme 1, a compound of formula 1 wherein Ri is H or lower alkyl, and which is a known compound or that can be prepared by current methodology, is treated with a reducing agent capable of selectively reducing a nitro group in presence of a benzyl alcohol. This process is advantageously carried out in the presence of a der i vat i zant e agent of the formula R2-OCOX wherein X is a leaving group and R2 is ter-alkyl, benzyl or the like so as to form a protective group easily dissociable, thus leading, directly, to a compound of formula 2. For example, this process can be conveniently carried out by catalytic hydrogenation of 1 on Pd® in ethyl acetate in the presence of di-tert-butyl dicarbonate to give a derivative of 2 wherein R2 is tert-butyl.

The conversion to an aldehyde of formula 3 can be carried out using any of a number of oxidizing agents capable of oxidizing a benzyl alcohol to the corresponding aldehyde, for example activated manganese dioxide in an appropriate solvent, for example dichloromethane. The reaction of 3 to give a dehydroamino acid of formula 5 can be effected by treatment with an ittig reagent of formula 4 wherein R3 is lower alkyl and R4 is an alkoxy group, for example benzyloxy- or tert-butoxy- or represents a portion of one of the acyl groups of the compounds of the invention, for example substituted lower aryl. For example, the treatment of 3 with trimethyl ester (±) - N- (be nci 1 ox i -ca rb on i 1) - a - phosphonate in the presence of an appropriate base for example tetramethyl guanidine leads directly to a dehydroamino acid of the formula 5, R3 = methyl and R4 = benzyloxy. The reduction of the ectopy from 5 to L-amino 6 acid can be effected by using a series of reducing agents suitable for the purpose, for example, the recently described rhodium ethyl-DuPHOS reagent (Burk, MJ, Feaster, JE; Nugent, WA; Harlo, RLJ Am. Chem. Soc. 1993, 115, 10125) essentially using the literature procedure.

Reaction Scheme 1 In Reaction Scheme 2 a procedure for the conversion of compounds of structure 6 into compounds of the invention is shown. The protective group incorporating R2 can be separated under conditions that depend on the particular choice of R2, as well as R3 and R. The choice of these groups will depend on the particular target compound. A variety of common protecting groups and their use are described in "T.W. Green and P.G.M. Wuts, Protective 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 R is a benzyloxy group or represents a portion of one of the acyl groups of the compounds of the invention, for example ortho-substituted aryl the treatment with trifluoroacetic acid as such or in dichloromethane solution in the presence of appropriate sequestrants, for example, triethylidene or anisole leads to a compound of formula 7. This compound can be coupled with a carboxylic 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 9. In the carboxylic acid of formula 8, R5 may represent a group of substituted alkyl, a substituted aromatic ring, or a substituted heteroaromatic ring. R5 may also incorporate appropriately protected reactive functionalities to allow ultimate conversion to compounds of the invention. The choice and use of these groups will be apparent to those skilled in the art.

Depending on the choice of R4 and if the final objective of the synthesis is an ester or acid the compound 9 can be a compound of the invention or in the case that R is a protective group, for example, a benzyloxy group, can be separated under appropriate conditions, for example by catalytic hydrogenation over Pd® in an appropriate solvent such as a lower alcohol to give a compound of formula 10. This intermediate 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 12. In the acid carboxylic acid of the formula 11, R6 may represent a portion of a compound of the invention, for example aryl or t-their titido or heteroaryl. These compounds are known compounds or can be prepared by known methods. R6 may also incorporate appropriately protected reactive functionalities to allow the final conversion to compounds of the invention. The choice and employment of these groups will be evident to those skilled in the art. In case that the acid 13 is the objective compound, the conversion of a compound of the formula 12 can be effected using current hydrolysis conditions appropriate for the particular choice of R3 and any functional group present as part of R5 and R6. In the case where R3 is lower alkyl, treatment with an alkali metal hydroxide, for example, lithium hydroxide in aqueous THF, is generally effective.

Reaction Scheme 2 12 13 In Reaction Scheme 3, a compound of formula 14 wherein R is a lower alkyl group, which may serve as a protecting group or a group suitable for use in a prodrug for example methyl, ethyl, tert-butyl or the like or represents a connection to a solid phase resin, for example a Wang resin, is coupled to 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 15. The reduction of the nitro group of 15 can be effected by catalytic hydrogenation, for example using Pd © as a catalyst or by treatment with a common reducing agent, for example SnCl2-The resulting compound of structure 16 is useful as a key intermediate for several series of compounds. In the case highlighted in Scheme 3 this 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 temperature environment to give a compound of formula 17. Compound 17 can be a compound of the invention depending on the nature of R or can be converted into a compound of the invention with an appropriate hydrolysis process, for example in the case where R is lower alkyl, by hydrolysis by treatment with excess alkali metal hydroxide, such as lithium hydroxide in an aqueous alcohol. When R represents an appropriate resin for solid phase synthesis the appropriate hydrolysis conditions will depend on the choice 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 the formula 18.

T he burning of Re a c t ion 3 14 15 In a particularly well-suited method for solid phase synthesis a phenylalanine derivative N '-Al 1 protected oc-amino-Na-Fmoc of formula 19 can be coupled to a resin suitable for solid phase synthesis, for example, a resin of Wang using standard coupling procedures, for example, by forming a mixed anhydride with 2,6-dichlorobenzoyl chloride and carrying out the coupling reaction in a polar aprotic solvent, such as N-methyl pyr rolidinone to give a compound of structure 20 where R * represents the resin. The Alloc group can be separated with ordinary methods, for example by treatment with a reducing agent such as nBusSnH in the presence of a catalyst which is a source of Pd °, for example, Pd (Ph3P) 2Cl2 to give an amino derivative of structure 21. This compound can be coupled with a carboxylic acid of the 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 22. The Fmoc protecting group can be separated from 22 using standard base treatment well known to those practicing peptide chemistry, for example with piperidine in DMF, to offer an amine of formula 23. The resulting compound 23 can coupling 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 dissociated from the resin under conditions dependent on the particular choice of resin. For example, in the case of a Wang resin, treatment of acid with trifluoroacetic acid in dichloromethane in the presence of sequestrants as necessary will provide a compound of formula 18.

Depending on the particular synthetic objective the order of separation of the protecting groups of 19 may be altered so that the Fmoc group is first removed, the coupling of the resulting amine is carried out with an acid of the formula 11 followed by separation of the Alloc group. and coupling the product with an acid of the formula 8 and a dissociation of the resin. Also the choice of protecting groups can be modified to reflect the reactivities of the resin or choice of R7 'and the nature of any functional group incorporated into R5 and R6.

Reaction Scheme 4 21 22 23 24 18 Compounds derived from 3- or 4- (alkylamino) phenylalanine derivatives can be prepared as set forth in Reaction Scheme 5. A compound of formula 16 or 7 can be treated with diazomethane in an appropriate solvent, for example ether ethyl to give products of formulas 25 and 26 respectively wherein 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 is subjected to hydrogenation or catalytic reduction with cyanbor or hydride or sodium in the presence of an organic acid, for example acetic acid to give a compound of the formula 25 or 26 wherein R8 is lower alkyl other than methyl. The conversion of compounds 25 or 26 to prodrug esters 27 or 28 or to the corresponding acids 29 or 30 respectively, can be carried out as described above in Reaction Schemes 2 and 3.

Reaction Scheme 5 26 29 30 For the preparation of 3-o-sulphon-1-amino-phenylalanine derivatives, the compounds of the formula 7, 16, 25 or 26 can be reacted with a sulfonyl chloride of the formula 31, wherein R9 is a substituted aryl fraction or heteroaryl, in an inert solvent, for example dichloromethane in the presence of a non-nucleophilic base, for example triethylamine or pyridine between about 0 ° C and room temperature to give compounds of structure 32 or 33 respectively as illustrated in the Reaction Scheme 6 for compounds 7 and 26. These can be further converted to compounds of formulas 34 and 35 if desired using the general methods described above in Reaction Schemes 2 and 3.

For the preparation of compounds derived from 3- or 4-ami nome ti 1-phenylalanine, the procedure shown in Reaction Scheme 7 can be used. A benzoate of 3- or 4-idr oxime ti 1 or Formula 36, wherein R 10 is lower alkyl, which are known compounds, or can be prepared by known methods, is treated with a silylating agent wherein R 11 -R 13 are lower alkyl or phenyl, for example t erbutyl chloride i 1 Si 1 ilo in an inert solvent, for example dimethylformamide in the presence of imidazole at about 0 ° C to give a protected silyl compound of formula 37. The reduction of 37 can be carried out using a variety of appropriate reducing agents, by example, lithium aluminum hydride in an inert solvent such as ether or tetrahydrofuran at a temperature of about 0 ° C followed by aqueous work up to give an intermediate alcohol which can be oxidized with any of several oxidizing agents. They are used to oxidize benzyl alcohols to the corresponding aldehydes, for example activated manganese dioxide, to give an aldehyde of the formula 38. The protected monosilyl diols are available, alternatively, from 3- or 4-hydrox ideneben 1 to 1 coh or 1 is by monkeys i 1 i 1 aci ón and separation of byproducts. Alternatively an ester of formula 37 can be reduced directly to 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 wherein R3 is lower alkyl and R4 is an alkoxy group, for example benzyloxy- or tert-butoxy- or represents a portion of one of the acyl groups of the compounds of the invention, for example aryl ortho-substituted or heteroaryl. For example, the treatment of 38 with trimethyl ester of (±) -N- (benzyloxycarbonyl) -a-phosphonoglycine in the presence of an appropriate base, for example tetramethyl guanidine leads directly to a dehydroamino acid of formula 39, R3 = methyl and R4 = benzyloxy. The enantioselective reduction from 39 to L-amino acid 40 can be effected with the use of one of a series of reducing agents suitable for the purpose, for example, the recently described rhodium ethyl-DuPHOS reagent. It will be readily apparent to the person skilled in the art that the optimum procedure for the subsequent conversion of compounds to the invention will depend on the choices of R and R3. For the case where R3 is inner alkyl and R4 is benzyloxy, the conversion to an amine of formula 41 can be conveniently effected by hydrogenation of catalytic transfer of 4 to Pd in an appropriate solvent, for example, methanol in the presence of ammonic format as the reducing agent. The acylation of 41 with a carboxylic acid of the formula 11 can be carried out as described above in Reaction Scheme 2 to give a compound of the formula 42. The conditions for the separation of the silyl protecting group will depend on the choice particular of Rp-Rp- In the case of Ru, R12 = methyl and R13 = tert-butyl, this group is easily separated by treatment with a strong acid, for example hydrochloric acid in an appropriate solvent for the choice of R3, for example wherein R3 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 the formula 43 can be converted to a leaving group, for example a mesylate by treatment with methanesulfonyl chloride in the presence of a proton acceptor, for example pyridine, followed by displacement with an alkali metal azide, by example, sodium azide in a polar aprotic solvent such as dimethylformamide. Alternatively, the transformation of 43 to an azide of formula 44 can be carried out directly by treatment with phosphorus diphenyl phosphide as described in: Thompson, A.S .; Humphrey, G.R .; DeMarco, A.M .; Mathre, D.J .; Grabowski, E. J.J. J. Or g. Ch em. 1993, 58, 5886-5888. The reduction of azide 44 to an amine of formula 45 can be carried out with a series of means suitable for the conversion of azides to amines, for example by treatment with a phosphine, for example triphenyl phosphine in an inert solvent such as dichloromethane or THF followed by an aqueous preparation or by catalytic hydrogenation over a suitable catalyst, for example Pd® 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 using the procedures applicable to free amines described in the other reaction schemes. For example, the coupling of 45 with a carboxylic acid of formula 8 under the conditions described in 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 base as described in Reaction Scheme 2.

Reaction Scheme 6 R9- SC ^ CI 31 Reaction Scheme 7 For the synthesis of urea derivatives a compound of the formula 26 can be treated with an isocyanate of the formula 49, wherein R 14 is substituted aryl, substituted heteroaryl or lower alkyl substituted with potentially reactive substituents protected as appropriate using conventional protecting group strategies , in a suitable inert solvent, for example dichloromethane, to give a urea of the formula 50. More generally a compound of the formula 26 can be treated with an equivalent phosgene, for example, triphosgene in an inert solvent such as dichloromethane in the presence of a proton acceptor non-core fi i i co, 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 wherein R15 and RIÓ are independently hydrogen, substituted lower alkyl, substituted aryl, substituted heteroaryl or taken together they form a ring of 5, 6 or 7 members leading to a compound of formula 52. Further conversion, if necessary, of 50 or 51 to compounds of the invention can be carried out as described in the Reaction Scheme. 5.

Reaction Scheme 8 For the synthesis of imides, an aminophen-lalanin derivative of structure 53 wherein Ri is H or lower alkyl, R6 is as previously defined and R "is H or an easily dissociable group such as substituted benzyl, terbutyl, allyl, or the like, or in the case that a prodrug ester is desired as the final product, ie the ester group, ethyl is used, for example, The compounds of the formula 53 can be obtained easily from the intermediates. described above in 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 structure involved by 54 includes bicyclic molecules that can incorporate aromatic rings or have them fused together, instead of 54 it is also possible to use dicarboxylic acids that are capable of forming cyclic imides. In the same case, a condensation agent can be used in the first stage, for example carbonyl diimidazole. Treatment of the compound of formula 55 with a reagent such as carbonyl diimidazole capable of carrying out the cyclodehydration leads to an imide of formula 56. Further manipulation of functional groups that were present on the anhydride of formula 54 and modification of R7 ~ can carried out on the compound 56 as desired to obtain additional analogs using standard chemistry that is compatible with the presence of the functional functionality.

For the synthesis of compounds of the invention wherein Ri is halogen, preferably chlorine, the appropriate halogen atom can be inserted at various points during the course of the synthesis depending on the nature of the additional functionality in the molecule. For example, a compound of the formula 6 in which R 1 is hydrogen can be treated with a mild chlorinating agent, for example N-c 1 or rosy imine in the presence of a proton acceptor, for example sodium acetate to give the corresponding compound of formula 6 where R \ is chlorine. In the case where 6 is derived from 3-amino-L-phenylalanine, a mixture of materials can be followed which can be separated at a convenient point in the overall synthesis. Other intermediates described in the above schemes may be more appropriate starting materials for halogenation for a particular target molecule. The particular merits of individual candidate starting materials will be apparent to those skilled in the art.

Reaction Scheme 9 53 33 56 For the synthesis of the idol tolols of the formula 62 described in the Scheme of Reaction 10, an aminophenylalanine derivative of structure 16 may be used, wherein R6 and R7 are as previously defined. The reaction of 16 with an a-mercapto carboxylic acid of the formula 59 wherein R 20 can be hydrogen, lower alkyl or aryl, for example a-mercapto acetic acid, and an aldehyde of the formula 60 wherein R 21 can be alkyl, hydroxyalkyl 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 4Á molecular sieves at 60-80 ° C provides a compound of formula 61. 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 with an appropriate hydrolysis process, for example in the case where R7 is lower alkyl, by treatment with hydroxide. of excess alkali metal, such as sodium hydroxide in an aqueous alcohol. When R represents an appropriate resin for solid phase synthesis, the appropriate hydrolysis conditions will depend on the choice of resin. In the case of Wang resin, treatment with trifluoroacetic acid in the presence of appropriate sequestrants will lead to an acid of formula 62. The sequence can be initiated with related anilines, for example a compound of formula 7 wherein Ri is lower alkyl or halogen to give the corresponding thiazolidinones.

Reaction Scheme 10 For the synthesis of imidazole idinones of the formula 67 shown in the Scheme of Reaction 11 can be used a amine niphen derivative of structure 16 wherein R6 and R are as previously defined. Compound 16 can be readily obtained by the synthesis described in Reaction Scheme 3. This compound can be coupled with an N-protected a-amino acid of formula 63, wherein R22 can be a lower alkyl or an aryl group, R23 can a side chain of D- or La-amino acid natural or unnatural or R22 and R23 together can form a ring, for example a proline or pipicolinic acid ring and R24 can be a suitable amine protecting group suitable for the particular selection of Rβ, R7, R22, and R23 for example ter-butoxy carboni lo. 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 the formula 64. Depending on the of the nature of the protecting group R24 / a suitable deprotection method is used to give a compound of the formula 65. In case the protective group R24 is a Boc group the deprotection can be carried out by reaction of 64 with HCl in dioxane at room temperature. The reaction of compound 65 with an aldehyde of formula 60, wherein R2? is as defined above, in the presence of a water scavenger such as molecular sieves of 4Á at 60-80 ° C in an appropriate solvent, for example THF, provides a compound of formula 66. Compound 66 can be a compound of the invention depending on the nature of R7 or can be converted into a compound of the invention with an appropriate hydrolysis process, for example in the case where R is lower alkyl by hydrolysis and treatment with an alkali metal hydroxide, such as sodium hydroxide in aqueous alcohol to give a carboxylic acid of the formula 67.

Reaction Scheme 11 For the synthesis of imide zo 1 and dinones of formula 68 described in Reaction Scheme 12, a 1 to 1 an aminophen derivative of structure 16 is used wherein Rg and R are as previously defined. Compound 16 can be easily obtained by the synthesis described in Reaction Scheme 3 in the case that R7 is lower alkyl. This compound can be coupled with an N-protected a-amino acid of the formula 69, wherein R25 can be a side chain of natural or unnatural Do-amino acid and R26 is a nitrogen protecting group of the type conventionally used in the chemistry of the peptides, for example an Fmoc group, 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 the formula 70. Depending on the nature of the protecting group R26 an appropriate deprotection method is used to give the compound of the formula 71. In the case where the protecting group R26 is the Fmoc group, this can be separated from 70 using standard base treatment well known to those who practice the chemistry of peptides, for example with piperidine in DMF, to give an amine of formula 71. Compound 71 can then react with an aldehyde 60, wherein R21 is as previously defined, in the presence of a water scavenger such as 4A molecular sieves in an appropriate solvent such as dichloromethane or THF at 25-60 ° C to give an imine of the formula The imine 72 can then be treated with an acylating agent such as the acyl chloride of formula 74 wherein R 27 can be an alkyl or aryl group in the presence of a base such as DIPEA or DBU in an appropriate solvent such as dichloromethane or THF at 25-60 ° C to give an acyl imide zo-1-one of the formula 73. Alternatively another reactive acylating group such as acid anhydrides or mixed anhydrides may be used in this reaction. The compound 73 can be a compound of the invention, or depending on the nature of R 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 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 wherein R? is lower alkyl or halogen to give the corresponding 3-acyl imidazole nones.

Reaction Scheme 12 Ortho-substituted benzoic acid derivatives which are not commercially available can be prepared by conventional means. For example, ortho-substituted aryl iodides or triflates can be carbonylated in the presence of carbon monoxide and an appropriate palladium catalyst. The preparation of these iodide or triflate intermediates depends on the particular substitution pattern desired and can be obtained by iodination or diazotization of an aniline followed by treatment with an iodine source, for example, potassium iodide. The triflates can be derived from the corresponding phenols with conventional means such as treatment with sulfuric acid anhydride in the presence of a base such as triethylamine or diisopropylethylamine in an inert solvent. Other means of obtaining ortho-substituted benzoic acids involves treatment of a 2-me t-oxy-phenol-1-oxazo derivative such as 75 with an alkyl Grignard reagent followed by hydrolysis of the oxazoline ring following the general procedure described by Meyers, AI, Gabel, R., Mihelick, ED, J. Org. Chem. 1978, .43_, 1372-1379, to give an acid of the formula 76. The benzonitriles 2- or 2,6-diols thereof also serve as suitable precursors for the corresponding benzoic acids. In the case of highly hindered nitriles, for example 2-chloro-6-me t-thiombenzoni tri, conventional hydrolysis under acidic or basic conditions is difficult and better results are obtained by DIBAL reduction to the corresponding benzaldehyde followed by oxidation using an oxidizing reagent of chrome.

Reaction Scheme 13 75 76 General Melting Points were taken on a Thoma s-Hoover apparatus and are polarimeter 241. The spectra of ^? - NMR were collected with Varian XL-200 spectrometers and Unityplus 400 MHz, using tet ramet i 1 s i tin (TMS) as internal standard. The impact of electrons (El, 70 ev) fast bombardment mass spectra (FAB) on mass spectrometers VG Autospec or VG 70E-HF was taken. The silica gel used for column chromatography was silica gel Mallinkrodt SiliCar 230-400 mesh for flash chromatography; the columns operated under a head of 0-5 psi of nitrogen to assist the flow. Thin-film chromatograms were developed on thin uncorrected glass. Optical rotations were determined with Perkin-Elmer model layer plates coated with gel. silica as supplied by E. Merck (E. Merck No. 1.05719) and visualized by observation under UV light of 254 nm in an observation box, by exposure to I2 vapor, or by spraying with phosphorus acid 1 bd ico (PMA) in aqueous ethanol, or after exposure to CI2, with a reagent of 4,4'-tet ramethyl 1 di ami no-di-phenylene prepared in accordance with E. Von Arx, M. Faupel and M. Brugger, J Ch roma t o graphy, 1976, 1 20, 224-228.

An inverted phase high pressure liquid chromatography (RP-HPLC) was carried out using a Waters Delta Prep 4000 using a Delta Pak 15 μM C-18 30 x 30 cm column at a flow of 40 mL / mm using a gradient of acetonite rilo: water (each containing 0.75% TFA) typically from 5 to 95% acetonitrile for 35-40 min or a Rainin HPLC using a Dynamax ™ C-18 column of 41.4 x 300 mm, 8 μM, to a flow of 49 mL / min and a similar gradient of ace t on itri 1 o: water as indicated above. HPLC conditions are typically described in the format (5-95-35-214); this refers to a linear gradient of 5% to 95% acetonitrile in water for 35 min while controlling the effluent with a UV detector at a wavelength of 214 nM.

Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, ether and methanol were Fisher's reagent grades and were used without further purification except as indicated, acetonitrile was grade of Fisher hplc and was used as is.

Definitions: THF is tetrahydrofuran, DMF is N, N-dimet i 1 formamide, HOBT is 1-hydroxybenzo triazol, BOP is [(benz otri azo 1 - 1 -yl) oxy] tris- (dimethylamino) phosphonium hexafluorophosphate , HATU is 0- (7-zabenzo-triazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate, HBTU is 0-benzot-azot-N, N ', N'-tet hexafluorophosphate rame ti 1 ur on io, DIPEA is diisopropylethylamine, DMAP is 4 - (N, -dime ti 1 ami o) pir idi na, DPPA is di fen i 1 fos for i 1 azide DPPP is 1, 3 -bi s (i fen i 1 fos f ino) propane DBU is 1, 8 -di azabi ci c 1 or [5.4.0] undec- 7 -no NaH is sodium hydride brine is satu- rated aqueous sodium chloride solution TLC is thin layer chromatography LDA is di is op r op i 1 lytic amide BOP-Cl is bis (2-oxo-3-oxa zo 1 idini 1) -phosphinic chloride NMP is N-methyl pyr rol idinone EXAMPLES Example 1. Synthesis of 4 [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(1,1-di-ethylethoxy) carbonyl] -L-phenylalanine methyl ester To a solution of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenyl-alanine methyl ester (2.6 g, 8.6 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.3 L, 13 L). mmol) followed by 2,6-dichlorobenzoyl chloride (1.99 g, 9.5 mmol) at ambient temperature. The mixture was stirred for 15 hours at which time a white precipitate formed. The mixture was diluted with 30 mL of dichloromethane and 50 mL of water. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the solvent gave 4.03 g (quant) of methyl 4- [(2,6-chloro-phenylcarbonyl) amino] -N- [1,1-dimethylethoxy) -carbonyl ester 1] -L- f in i 1 to 1 an i na - in the form of a white solid: melting point 148-151 ° C.

Example 2. Synthesis of the hydrochloride salt of 4 - [[(2,6-di chloropheni 1) -carbonyl] amino] -L-phenylalanine methyl ester The methyl ester of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(1,1-dimethyl-e t-oxy) carbon] 1-L-phenin on the 1 year (1.86 g) was treated. , 40 mmol) with 10 mL of 4 N hydrochloric acid in dioxane at room temperature. After 5 minutes the solid came into solution and the mixture was stirred for 1 hour and 25 mL of ethyl ether was added to precipitate the product. The solids were collected by filtration and washed with hexane. The resulting copious and rubbery solid solids were dissolved in 50 mL of methanol and concentrated. After drying under high vacuum, the hydrochloride salt of the methyl ester of 4 - [[(2, 6-dic 1 or ro fe ni 1) ca rb oni 1] -amino] -L-phenylalanine (1.64 g, 97%) in the form of a light yellow solid, melting point 158-161 ° C.

Example 3. Synthesis of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) -carbonyl] amino] -L-phenylalanine methyl ester A solution of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester hydrochloride (1.23 g, 3.05 mmol), 2-chloro-6-acid was stirred 15 hours at room temperature. I am lben z oí co (0.50 g, 2.93 mmol), HBTU (1.16 g, 3.05 mmol) and DIPEA (1.33 mL, 7.6 mmol) in DMF (12 mL). The mixture was diluted with ethyl acetate (250 mL) and washed with 0.5 N HCl (2 x 80 mL), saturated sodium bicarbonate. (2 x 80 mL) and brine (2 x 80 L) and dried (a2S0). The solution was filtered and concentrated to a yellow gum which was crystallized from ethyl acetate-hexane to give N- (2-c 1 or o-6-me ti lben zoi 1) - 4 - [(2,6) methyl ester). -dichlorophenyl) carbonyl) amino) -L-phenyl-alanine (0.75 g), suitable for use in the next stage. The mother liquor was concentrated and purified by silica gel chromatography eluting with 1: 1 ethyl acetate: hexane to give 0.625 g more.

Examples 4 to 12. The compounds shown below were prepared from 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester hydrochloride and the appropriate benzoic acid derivatives in accordance with method described in E j emp 1 or 3.

Example 13. Synthesis of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] -amino] -L-phenylalanine A solution of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichloro-phenyl) 1) carboni 1] amino] -L- pheny1 alanine methyl ester was stirred overnight at room temperature. (1.31 g, 2.6 mmol) in ethanol (45 mL) and 1.0 N sodium hydroxide (45 mL, 45 mmol) to give a clear solution. The mixture was neutralized with 1N hydrochloric acid to precipitate 1.28 g of a white solid. The mother liquors were extracted with ethyl acetate (2 x 50 L) and the combined extracts were washed with saturated brine, dried (Na S0) and evaporated, which gave 0.56 g. The reaction of the first crop in ethyl acetate gave N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] -amino] -L- phenylalkyl. aniña (0.77 g). Recrystallization of the second crop in ethyl acetate gave 0.20 g more. FAB HRMS: obs mass 505.0483. Mass cale., 505.0488 (M + H).

Example 14. Synthesis of the sodium salt of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) -carbonyl] amino] -L-phenylalanine A solution of N- (2-c-loro-6-me ti lbenzoi 1) -4 - [(2,6-dichlorophenyl) carbonyl] -amino] -L-phenylalanine (0.15 g) in 1.0 N NaOH (0.3 mL) to an open column of 2 x 20 cm inverted phase silica gel (40-63 μM, RP Silica Gel60, as supplied by EM Separations, Cat. 10167) eluting with water, then with 40-50% methanol in water to give sodium salt of N- (2-c-loro-6-me ti Ibe n zo i 1) - 4 - [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine (147 mg) in the form of an amorphous white solid after lyophilization.

Examples 15-30. The compounds set out below were prepared from the corresponding methyl esters using the method described in Example 13. 1. The performance is for the two stages following the procedure described in E js p 3 and 4. 2. Isolated as the sodium salt as described in Example 14.

Example 29. Synthesis of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[2- (methylthio] phenyl] carbonyl] -L-phenylalanine methyl ester A solution of 4- [(2,6-dichlorophenyl) carbonyl] amino] -N- [[2- (methylthio) phenyl] carbonyl] -L-phenylalanine methyl ester (0.25 g, 0.48 mmol) and oxone (147 mg) , 0.24 mmol) in ethyl acetate (12 mL) and water (6 L) was stirred at room temperature for 2 hours and a second portion of oxone (147 mg, 0.24 mmol) was added. The mixture was stirred overnight at which time the TLC (d i c 1 orome t a n o: me t ano 1 20: 1) suggested the presence of starting material and sulfone in addition to two sulfoxides. The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined extracts were washed with saturated brine and dried (Na 2 SO 4). The residue, after concentration, was chromatographed on silica gel, elution being carried out with dichloromethane: et anol 20: 1 to give methyl ester of 4 - [[(2,6-di c 1 oropheni 1) carbon i] -amino] -N- [[2- (methylsulfinyl) phenyl] carbonyl] -L-phenylalanine (218 mg) in the form of a mixture of diastereomers Example 30. Synthesis of 4- [[(2, 6-chloro-phenyl) carbonyl] amino] -N- [[2- (methylsulfinyl) -pheni]] carboni 1] -L- phenylalanine The hydrolysis was carried out as described in Example 13. From methyl ester of 4 - [(2,6-di c 1 oro fen i 1) ca rbon i 1] -amino] -N- [[ 2- (Methylsulfinyl) phenyl] carbonyl] -L-phenylalanine (214 mg, 0.41 mmol) and isolation of the product by RP HPLC, elution with ace t oni tr 1 or: water followed by lyophilization gave the ter mole day more polar 4 - [[(2,6-dichlorophenyl) carbonyl] amino] - [[(N- (2-methyl-sulfinyl) phenyl] carbonyl] -L-phenylalanine (63.6 mg) in the form of an amorphous solid, HR MS: Mass obs., 541.0385, Mass Cale, 541.0368 (M + Na) followed by the di erectomer or less polar (74.2 mg), HR MS: Mass Obs., 541.0351. Mass Cale, 541.0368 (M + Na).

Example 31. Synthesis of 4 - [(2,6-di c 1 or ro phenyl 1 carbonyl] amino] -N- [[(2-phenylmethyl) phenyl] -carboni 1] -L-phenylalanine to. A solution of 4- [[(2-propenyloxy) carbonyl] amino] -L-phenylalanine methyl ester (935 mg, 3.54 mmol), HOAT (658 mg, 5.31 mmol), methanol, was stirred overnight at room temperature. -benc i lben z oi co (1.13 g, 5.31 mmol) and DCC (1.09 g, 5.31 mmol) in DMF (20 mL). The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried (Na 2 SO), filtered and evaporated. The residue was recrystallized from ethyl acetate containing small amounts of dichloromethane and methanol, which gave 4 - [[(2-propenyloxy) carbonyl] amino] -N- [[(2-phenyl-me ti 1) fei 1] ca rbon i 1] -L-pheni 1 to 1 an i na (1.21 g, 74%) suitable for use in the next stage. b. Argon was passed through a solution of methyl ester of 4 - [[(2 -prope or 1-oxy) -carbonyl] amino] -N- [[(2-phenylmethyl) phenyl] -carbon i 1] -L- phen i 1 to 1 an i na (1.21 g, 2.63 mmol) ytet ra ki s - (t ri fen i 1 fos fi na) pa 1 adió (61 mg, 0.053 mmol) in 45 mL dichloromethane for 5 minutes and added tributyl hydride t year (800 mL, 2.9 mmol). After 1 hour and a half at room temperature the mixture was diluted with dichloromethane (50 L) and washed with saturated NaHCO 3 and brine, dried (Na 2 SO 4) and concentrated. The residue was dissolved in dichloromethane and ether and hexane was added to precipitate 99 mg of a white solid. The filtrate was concentrated and the residue was recrystallized from dichloromethane, which gave 4-amino-N- [[(2-phenylmethyl) phenyl] carbonyl] -L-phenylalanine methyl ester (594 mg). c. A mixture of 4-amino-N- [[(2-phenylmethyl) phenyl] carbonyl] -L-phenylalanine ethyl ester (20.0 mg, 0.52 mmol), 2,6-di chloride, was stirred 6 hours at room temperature. orobe zoi (131 mg, 0.62 mmol) and triethylamine (108 μL, 0. 78 mmol) in 5 mL of dichloroethane. The mixture was diluted with dichloromethane (10 mL) and washed with water and saturated brine. The organic phase was dried (Na 2 SO 4) and the residue was chromatographed on silica gel, eluting with 20-60% ethyl acetate in hexane, which gave 4 - [[(2,6-dichloropheni 1) carbonyl) methyl ester. 1] -amino] -N- [[(2-phenylmethyl) phenyl] carbonyl] -L-phenylalanine (195 mg) as an off-white solid. d. A solution of methyl ester of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N [[(2-phenyl-me ti 1) phen i 1] carbon i 1] -L-pheni 1 to 1 an Na (195 mg, 1.4 mmol) and lithium hydroxide (33.5 mg, 1.4 mmol) in TH F: MeOH 1: water (6 mL, 3: 1: 1) was stirred overnight at room temperature and concentrated. The residue was triturated with 1 N aqueous HCl for 10 minutes and the solids were collected by centrifugation, washing with water and ether to give 4 - [[(2,6-di c 1 oro-phenyl) carbonyl] amino] -N- [[(2-phenylmethyl) -fen i 1] carbon i 1] -L-phen i 1 to 1 an (165 mg) in the form of a white powder having a purity of 97% according to the hplc analysis. FAB MS 569 (M + Na) (1 Cl), 547 (M + H) (1 Cl).

Example 32. Synthesis of 4 - [[(2,6-di-chloro-phenyl) carbonyl] amino] -N- [[(2-chloro-4 - [[[(3-hydroxythenyl) methyl] amino] carbonyl] phenyl ] -carbonyl] -L-phenylalanine to. In an inert atmosphere, a solution of 3-chloro-4-methoxycarbonyl-1-benzoic acid (1.13 g, 5.27 mmol), 3-hydroxybenzyl chloride hydrochloride (0.85 g, 5.35 mmol) and HBTU (2.08 g) was stirred. 5,485 mol) in dimethylformamide (15 mL), while DIPEA (3.54 mL, 26.33 mmol) was added. The reaction mixture was stirred overnight at room temperature, then the volatiles were removed. The amber oily residue was partitioned between ethyl acetate (50 L) and 0.5 N HCl (30 mL) and the organic extract was washed in turn with brine (30 mL), saturated NaHCO3 solution (30 mL) and brine (30 mL). mL). The aqueous phases were in turn treated with ethyl acetate (30 mL). The evaporation of the combined and dried organic phases (MgSO4) gave 1.7 g of crude product. The material was chromatographed (silica gel, 50 g) and eluted with ethyl acetate-hexane (2: 3) to give the amide as a colorless oil (1.3 g). Crystallization from ether-hexane dro 1.12 g of 2-chloro-4- [[(3-hydroxyphenyl) amino] carbonyl] -benzoic acid methyl ester as a colorless solid. FAB HRMS: (C16H? ClN0) Mass obs. 320.0681. Mass cale. 320.0689 (M + H). b. A solution of 2-chloro-4- [[(3-hydroxyphenyl) amino] carbonyl] -benzoic acid methyl ester (900 mg, 2.82 mmol) in an aqueous solution of 0.5 N sodium hydroxide was stirred at room temperature under argon. After 2 hours the solution was acidified with 1 N HCl (11 mL) and the resulting colorless solid was filtered, washed with water, and dried in vacuo, which gave 840 mg of 2-c 1 gold - 4 - [[(3 - hrrrr i i -pheni 1) ami no] carbon i 1] benzoic. FAB HRMS: (C? 5H? 2ClN04) Mass obs. 306.0548 Mass Cale. 306.0533 (M + H). c. In an argon atmosphere, to a stirred solution of 2-chloro- or 4 - [[3-hydroxy-phenyl-1-yl] -carbonyl] 1-benzoic acid (45 mg, 0.1472 mmol), methyl ester of 4 - (2,6-di-chlorobenzyl-1-amino) -L-phenylalanine (60 mg, 0.1488 mmol) and HBTU (59 mg, 0.16 mmol) in ethylformamide were added DIPEA (0.102 mL, 0.585 mmol). The reaction mixture was stirred for 18 hours at room temperature, then concentrated to dryness and partitioned between dichloromethane (25 mL) and 0.5 N HCl (10 mL). The organic phase was washed with water and the aqueous phases were in turn treated with dichloromethane. The organic extracts were dried (Na 2 SO) and evaporated, which gave 80 mg of crude material which was crystallized from methanol-ethyl acetate, which gave 38 mg of N- [2-] methyl ester. chloro- 4 - [[(3-hydroxyphenyl) amino] carbonyl] phenyl] carbonyl] -4 - [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine, melting point 230-232 ° C. FAB HRMS: (C32H26CI3 3O6) Mass obs. 654.0952 Mass cale. 654.0965 (M + H). d. A solution of N - [[2-chloro-4- [[(3-hydroxyphenyl) amino] carbonyl] -phenyl] carbonyl] -4- [[(2,6-dichlorofenyl) -carbonyl] amino] methyl ester ] -L-feni lalanine (35 mg, 0.053 mmol) in methanol (0.35 mL) and tetrahydrofuran (0.35 mL) was treated with an aqueous 1N lithium hydroxide solution (0.16 mL) and the mixture was stirred at room temperature under argon for 90 minutes. The solution was concentrated under reduced pressure, then diluted with water (5 L) and extracted with diethyl ether (2 x 5 mL). The separated aqueous phase was acidified with 1N HCl (0.18 mL) and the resulting colorless solid was filtered off with water, and dried, which gave 29 mg of N- [[2- chloro- 4 - [[2-hydroxy] feni 1) amino] -carbonyl] phenyl] carbonyl] -4- [[(2,6-dichloro-phenyl) carbonyl] amino] -L-phenylalanine. FAB HRMS: (C3iH2 Cl3N3? 5) Mass obs. 640.0821 Masa Cale. 640.0809 (M + H).

Example 33. Synthesis of 4 - [[(2,6-di chloro fen i 1) carbonyl] amino] -N- [[2-chloro-4- [5- [t (3-hydroxyphenyl) methyl] amino] - lH-tetrazol-1-yl] phenyl] carbonyl] -L-phenylalanine to. A stirred suspension of 3-hydroxy phenylacetic acid (10.2 g, 67 mmol) in acetic anhydride (100 L, 1.06 mol) under anhydrous conditions was treated with pyridine (0.5 mL). In the mild exothermic reaction the solids were dissolved within several minutes and the mixture was kept at 40 ° C for five hours. The reaction was concentrated to about half the volume then water (30 g) was added in the form of ice chips in a proportion such that the temperature was maintained at < 45 ° C. When the exotherm subsided, a second portion of water (200 mL) was added slowly and the mixture was stirred for another 30 minutes. The precipitated solid was filtered, washed with water and dried to constant weight in vacuo over P2O5 to give 3-ace t-oxy-phenolic acid (11.7 g) which was used without further purification.

In an inert atmosphere, a solution of the above 3-ace t-oxy-phenolic acid (1.942 g) was stirred at room temperature for 1 hour.; 10 mmol), di-phenylphosphoryl azide (2.8 g, 10.17 mmol) and DIPEA (1.92 mL, 11 mmol) in benzene (25 mL), then the reaction temperature was raised slowly to 70 ° C. The evolution of gas began to be evident as the reaction temperature reached about 55 ° C and became much more vigorous when the reaction temperature approached 70 ° C. Within 30 minutes at said temperature the evolution of gas was stopped and the reaction solution containing the 3-ace t-oxybenzyl-1-isocyanate formed was cooled to 40 ° C. Another portion of DIPEA (3.84 mL, 22 mmol) was added, followed by the salt of 4-amino-2-c-lorobenzoic acid methyl ester hydrochloride salt (2.95 g, 13.3 mmol) and the brownish purple solution was stirred and dried. heated under reflux under argon overnight. The reaction mixture was cooled, diluted with benzene (50 L) and washed in turn with 1N HCl (50 mL) and dilute brine. The aqueous phases were back-extracted with benzene, the combined and dried organic extracts were evaporated (MgSO) and the crude residue was purified by HPLC (silica gel, ethyl acetate, hexane-2: 3). Evaporation of the appropriate fractions gave 3.24 g of the solid urea which was then crystallized from ethyl acetate to give methyl 4- [3- (3-acetyl oxybenzyl) ureido] - 2-Chlorobenzoic acid (2.71 g) as a colorless solid, melting point 11-114 ° C. FAB HRMS: (C18H17CIN2O5) Mass obs. 377.0898 Mass cale. 377.0905 (M + H). b) In a dry argon atmosphere, a solution of fine t rifenilfos (1644 g, 6.42 mmol), diethyl azodicarboxylate (1.13 g, 6.42 mmol) and methyl 4- [3- (3-a oxib-e-nc i 1) ureido] -2-c 1 or robe nzoi co (1.21 g, 3.21 mmol) in dry THF (30 mL) with trimethylsilyl azide (0.86 mL, 6.48 mmol) and stirred at room temperature environment for 24 hours. Examination of the reaction mixture by TLC suggested the presence of considerable starting material, so that additional amounts of t ri fen i 1 fos f i na were added. (0.842 g, 3.21 mmo 1), diethyl azodicarboxylate (0.565 g, 3.21 mmol) and triethyl azide were 1 i i 1 (0.43 mL, 3.21 mmol). The reaction was stirred at room temperature for a further 40 hours. After the solvents were removed under reduced pressure, the residue was taken up in dichloromethane (100 mL) and washed with water (2 x 50 mL). The aqueous extracts were in turn treated with dichloromethane (50 mL) and the combined and dried extracts were evaporated (MgSO4). From a previous experiment, it had been established that the reaction would give a complex mixture, hardly separable, of several products, some of which were deacetylated and / or deserfied. Thus, in this experiment the residue was dissolved in a mixture of methanol (30 mL) and 1N lithium hydroxide (15 mL) and the mixture was stirred at room temperature for 2 hours to complete the hydrolysis of both the ester and acetate phenol co. Most of the volatiles were removed under reduced pressure, then the basic solution was diluted with water (20 mL) and washed with dichloromethane (2 x 30 mL). Then the aqueous phase was acidified with 1N HCl (16 L) and extracted with ethyl acetate (2 x 50 mL). The dried ethyl acetate extracts were evaporated (MgSO) and the residual solid crystallized (810 mg), approximately a 4: 1 mixture of the desired amino tertrazole 1 and its positional isomer, in ether, to give 560 mg of 2-chloro-4- [5- [(3-hydroxyphenyl) amino] tetrazol-1-yl] -benzoic acid co-focus of a colorless solid FAB HRMS: (C? 5Hi2ClN503) Mass obs. 345.0624 Mass Cale. 345.0629 (M + H). c. In an argon atmosphere, DIPEA (0.102 mL, 0.585 mmol) was added to a stirred solution of 2-chloro-4 - [5- [[(3-hydroxy-phenyl) -met-il-amino] -1H-1] et razol- 1 -i 1] benzoi co (51 mg, 0.15 mmol), 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester (60 mg, 0.15 mmol) and HBTU (59 mg, 0.1555 mmol) in dimethylformamide (3 mL). The reaction mixture was stirred for 17 hours at room temperature, then concentrated under reduced pressure. The residual oil was taken up in dichloromethane (25 mL) and washed in turn. with 0.5 N HCl (10 L) and water (10 mL). The aqueous phases were in turn treated with dichloromethane. The combined organic phases were dried (Na2 = 04) and evaporated to give 85 mg of crude product. This material was crystallized from diethyl ether to give 79 mg of 4 - [[(2,6-di-c-phenyl) carbonyl] amino] -N- [[2- (2-methyl)] methyl ester. chloro-4- [5- [[(3-hydroxyphenyl) methyl] amino] -lH-tetrazol-1-yl] phen i 1] carboni 1] -L- phen i laine in the form of a colorless solid, of fusion 155-158 ° C. FAB HRMS: C32H26C13N705 Mass obs. 694.1158 Mass cale. 694.1139 (M + H). d. An aqueous solution of 1N lithium hydroxide was added to a solution of methyl 4 - [[(2,6-dichloropheni-1) carboni-1] -amino] -N- [[2-chloro-4- [5- [[ (3-hydroxyphenyl) -methyl] amino] -lH-tetrazo-1-yl] phenyl] carbonyl] -L-phenylalanine (75 mg, 0.108 mmol) in methanol (0.66 mL) and THF (0.66 mL) and the Mix at room temperature for 90 minutes. After the solvents were dissociated under reduced pressure, the residue was dissolved in water (20 mL) and extracted with diethyl ether. (3 x 5 mL). The aqueous phase was filtered through Celite, then acidified with 1N HCl (0.35 mL). The resulting colorless solid was filtered off through Celite, then acidified with 1N HCl (0.35 L). The resulting colorless solid was filtered off, washed with water, and dried in vacuo to give 57 mg of 4 - [[(2,6-di c 1 or ro phen i 1) -carbon i] - amino] -N- [[2-chloro-4- [5- [[(3-hydroxyphenyl) methyl] amino] -lH-tetrazol-1-yl] -phenyl] carbonyl] -L-phenylalanine. FAB HRMS (C3iH24Cl3N7? 5) Mass obs. 680.0981 Mass Cale 680.0983 (M + H).

Example 34. Synthesis of 4- [[(2,6-dichloro-phenyl) carbonyl] amino] -N- [[2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] sulfonyl] phenyl] -carbonyl] -L-phenylalanine to. At room temperature, a stirred solution of 4-amino-2-chlorobenzoic acid methyl ester hydrochloride (1.11 g, 5 mmol) in conc. (10 L) with Na 2 (0.42 g, 6.09 mmol) in water (3 mL). After 15 minutes the resulting suspension was added for 2 minutes to a saturated and rapidly stirred solution of S02 in acetic acid (15 mL) containing CuCl2 (0.15 g) in water (1 mL). There was an immediate vigorous evolution of gas that remitted after 20 minutes, after which the reaction mixture was diluted with ice-water (200 mL). The resulting purple solid was filtered off, washed with water, then dissolved in dichloromethane. The dried solution (Na2SO4) was evaporated in vacuo and the residual material was chromatographed on silica gel (50 g). The appropriate fractions, eluted with 30-40% diethyl ether in hexane, were concentrated to dryness under reduced pressure, to give 1.1 g of 3-chloro chloride or 4-methoxycarbonylbenzene sulfonyl in the form of a colorless solid.

The chloride of 3-c 1 oro-4-methoxycarbonyl 1-benzenesulfonyl above (0.14 g, 0.52 mmol) in dichloromethane or (0.5 mL) was added in one portion to a stirred solution of 3- hydrochloride. acetoxybenzylamine (0.105 g, 0.52 mmol) and triethylamine (0.2 mL, 1.42 mmol) in dichloromethane (0.2 L). The reaction was allowed to proceed for 90 minutes at room temperature, then diluted with dichloromethane (20 mL) and washed sequentially with 0.5 N HCl (10 mL). The aqueous phases were in turn quenched with dichloromethane (10 mL). The combined and dried organic phases were concentrated (Na2SO), which gave 0.2 g of an oil which was chromatographed (silica gel, 15 g). The product was diluted on the column with diethyl ether 1-hexane (4: 1) and diethyl ether, which gave, after evaporation of the appropriate fractions, 165 mg of methyl ester of 4 - [(3 -acet oxybenzyl lamino) -sul foni 1] - 2 - c loroben zoi co as a colorless solid. FAB HRMS: { C? 7H 16C1N065) Mass obs. 398.0469 Mass cale. 398.0465 (M + H). b. A stirred solution of 4- [(3-acetoxybenzylamino) sulfonyl] -2-chlorobenzoic acid methyl ester (163 mg, 0.41 mmol) in methanol (3 L) and tetrahydrofuran (3 mL) was treated at room temperature with an aqueous 1 N lithium hydroxide solution (1.65 mL). After 2 hours the volatiles were removed under reduced pressure and the residual material was dissolved in water (15 mL) and the solution was filtered through Celite. The filtrate was acidified with 1N HCl (2 mL) and extracted with ethyl acetate (3 x 10 L). After the extracts were re-washed with brine, they were combined, dried (Na 2 SO 4) and evaporated in vacuo to give 140 mg of 2-chloro-4 - [(3-1-droxib in 1: 1 ami) its 1 ph. ni 1] be nzoi co. A small sample of the product was crystallized from ethyl acetate-hexane to give a colorless solid, melting point 167-169 ° C. FAB LRMS: (C? 4H? 2ClN05S) Mass obs. 342 Masa Cale. 342 (M + H). c. A solution of 2-chloro-4 - [3-hydroxy-benzylamino) sulphonyl] benzoic acid (50 mg, 0.146 mmol), methyl ester of 4 - [[(2,6-di chlorophenyl) carbonyl] amino] -L-phenylalanine (60 mg, 0.1486 mmol), HBTU (5 mg, 0.15 mmol) and DIPEA (0.102 mL, 0.585 mmol) in dimethylformamide (3 mL) was stirred for 17 hours under argon at room temperature, then concentrated to dryness under reduced pressure. The residue was partitioned between dichloromethane (25 L) and 0.5 N HCl (25 mL). The separated aqueous phase was re-extracted with dichloromethane (10 mL), then the organic extracts were washed in turn with water (2 x 25 mL). The combined dichloromethane phases were dried (Na 2 SO) and evaporated to give 90 mg of the crude product as a dark oil. Chromatography of the oil on silica gel (9 g, ethyl acetate-hexane 4: 1) gave 55 mg of methyl 4- [[(2,6-dichlorophenyl) carbonyl] -amino] -N- [[2 -chloro-4- [[[(3-hydroxyphenyl) -methyl] mino] sulfonyl] phenyl] carbonyl] -L-phenylalanine, in the form of a colorless solid. FAB HRMS: (C31 H26CI3N3O75) Mass obs. 690.0639 Mass cale. 690.0635 (M + H). d. A 1N aqueous lithium hydroxide solution (0.25 mL) was added to a solution of methyl 4 - [[(2,6-di c 1 or ro fen i 1) -carbonyl] amino] -N- [[2- chloro-4- [[1- (3-hydroxy-phenylmethyl] amino] sulfonyl] phenyl] carbonyl] -L-phenylalanine (51 mg, 0.0738 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.35 mL). reaction at room temperature for 90 minutes, the solvents were removed under reduced pressure, then the crude product was applied in the minimum amount of methanol to a column of silica gel (5 g) formed in a mixture of chloroform, methanol, acetic acid and water (15: 3: 1: 0.6) .The column was eluted with the same solvent mixture and the appropriate fractions were combined and evaporated.The residue was lyophilized in deionized water to give 36 mg of 4- [[(2, 6-dichlorophenyl) carbonyl] amino] -N- [[2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -sulfonyl] phenyl] carbonyl] -L-phenylalanine in the form of a white solid thereof FAB HRMS gone. (C3 H24Cl3 75?) Obs. 676.0482 Mass cale. 676.0479 (M + H).

Example 35. Coupling of N- [(9H-f luoren-9-ylmethoxy) carbonyl] -4- [[(2-propenyloxy) -carbonyl]] ami no] -L- phen i 1 to 1 an a resin from Wang.

A cylindrical glass container 250 mL equipped with a coarse glass frit was charged with 10 g of Wang resin, (loading factor: 1.15 mmol / 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-chloride. 6-dichloro-benzoyl (8.06 mL, 57.5 mmol) in N-met i lp rol idona (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. Substitution was found at 0.75 mmol of N [(9 H -f 1 u or re n- 9 - i Ime t ox i) -carbonyl] -4- [[(2-propenyloxy) carbonyl] amino] -L-phen i 1 to 1 ani na per gram of resin by quantitative UV measurement of the Fmoc present in the resin.

Example 36. Synthesis of 4-ami non-N- [(9 H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine on Wang resin.

A cylindrical glass container 500 mL equipped with a coarse glass frit was charged with 10 g of N- [(9H-fluoren-9-ylmethoxy) carbonyl] -4- [[(2-propenyloxy) -carbon i 1] ami no] -L- 1 to 1 anion, substituted Wang resin (10 g) obtained from Example 35 and a solution prepared from Pd (Ph3P) 2 Cl2 (1.6 g, 2.3 mmol) and acetic acid (5 L, 83 mmol) in dry dichloromethane (150 mL). The resulting mixture was stirred for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 L, 74.3 mmol). The resulting mixture was stirred for 1 hour. To the mixture was added tri-n-butyl tin hydride (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 Pd (Ph3P) 2Cl2 (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dry dichloromethane (150 L). The mixture was stirred for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was stirred 1 hour. To the mixture was added additional tri-n-butyl tin hydride (10 L, 37.15 mmol). Stirring was continued for 1 hour. After the second cycle of sprouting, the mixture was washed with dichloromethane (2 x 100 mL), methanol (2 x 100 mL) and dimethylformamide (2 x 100 L) to give 4-amino-N- [(9H -fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine on Wang resin suitable for use in subsequent steps.

Example 37. Synthesis of 4 - [[(-quinol ini 1) -carboni 1] amino] -L- phenylalanine on Wang resin A 250 mL cylindrical glass vessel equipped with a coarse glass frit was charged with 4-ami not -N- [(9H-f 1 uo ren - 9 -i lme t oxi) ca rboni 1] -L- fen i the lan on Wang resin (10 g) obtained in Example 36 and a solution prepared from quinoline-4-carboxylic acid (5.2 g), 30 mmol), BOP (13.75 g, 30 mmol) and diisopropylethylamine (6.8 mL) in 70 mL of NMP. The suspension was stirred for 4 hours. 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 NMP (80 mL), the mixture was stirred at room temperature for 20 minutes and filtered. The procedure was repeated and the resulting suspension was filtered and washed with dichloromethane (2 x 100 mL), methanol (2 x 200 mL) and dimethylformamide (2 x 100 mL).

The filtration gave 4 - [[(4 -qu ino 1 i n i 1) ca rboni 1] -amino] -L-phenylalanine on Wang resin suitable for use in the next step.

Example 38. Synthesis of N- [(2,6-dime t i 1 pheni 1) -carbonyl] -4- [[(4-quinolinyl) carbonyl] amino] -L-phenylalanine 4- '[[(4-Quinolinyl) carbonyl] -amino] -L-phen i 1 to 1 ani on Wang resin was washed (300 mg, 0.20 mmol) 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 2,6-dimethyl-benzoic acid (150 mg, 1.0 mol), BOP (450 mg, 1.02 mmol) and diisopropylethylamine (0.23 mL) in 4 ml of N-me ti lp. I donate 1 at room temperature. The resulting mixture was stirred for 2 hours. The reaction mixture was then filtered and washed with dichloromethane (2 x 10 L), methanol (2 x 10 mL) and dichloromethane (2 x 10 mL). Dissociation was effected by treatment 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) resulted in the precipitation of N- [(2,6-dimethyl-1-phenyl) -carbonyl] -4- [[(4-quinolinyl) carbonyl) amino] -L-phenylalanine (0.16 g) .

Examples 39-49. Using the procedure described in Example 38, the compounds shown below were prepared from 4- [[(4-quinolinyl) carbonyl] amino] -L-phenylalanine and the appropriate benzoic acid derivatives.

Examples 50 to 61. Using the method described in Examples 37 to 38 the following compounds were prepared from 4-amino-N- [(9H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine on Wang resin and the appropriate carboxylic acids: Example 62. Synthesis of N- [(2,6-dimethylphenyl) carbonyl] -4- [[(2,4,6-trimethylphenyl) sulfonyl] -amino]] -L- fe n i 1 a lan i na The Wang resin added with 4-amino-N- [(9H-fluoren-9-ylmethoxy) carbonyl] -L-phenylalanine (3.0 g, 2.28 mmol) in pyridine (15 mL) was cooled to 0 ° C and was add 2,4,6-benzenesulfonyl chloride (2.49 g, 11.4 mmo 1) and stir the mixture overnight at room temperature. The mixture was filtered and the resin was washed with methanol and dichloromethane. The coupling procedure was repeated. To the washed resin was added a solution of 25% piperidine in N-methyl iodide (10 mL), the mixture was stirred at room temperature for 20 minutes and filtered. The procedure was repeated and the resulting suspension was filtered and washed with dichloromethane (2 x 10 mL), methanol (2 x 10 mL) and dimethylformamide (2 x 10 mL). Filtration gave 4- [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine on Wang resin suitable for use in the next step.

A sample of the above resin (0.3 g, 0.28 mmol) was suspended in N-methyl-pyrrolidone (3 mL) and treated with 2,6-dimethylbenzoic acid (171 mg, 1.14 mmol), BOP (0.50 g, 1.14 mmol) and DIPEA (0.26 mL, 1.4 mmol). The mixture was stirred at room temperature for 3 hours, filtered and washed with dichloromethane (2 x 10 mL), methanol (2 x 10 mL) and dichloromethane (2 x 10 mL). The dissociation 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 L) carried out the precipitation of N- [(2,6-dimethyl ti lf eni 1) -carbonyl] -4- [[(2,4,6-trimethylphenyl) sulfonyl] -amino]] - L-phenylalanine.

Example 63. N- (2-bromobenzoi 1) -4 - [[(2,4,6-trimethylphenyl) sulfonyl] amino] -L-phenylalanine was prepared from 4 - [[(2, 4, 6-tr ime ti 1-phenyl) sulfonyl] amino] -L-phenylalanine on Wang resin and 2-b-romobe nzoic acid using the general method described in Example 62.

Example 64. Synthesis of 4 - [[(4-ci ano-4-f e n i 1 -1-piperidinyl) carbonyl] amino] -N- (2,6-dimethyl-phenyl) carbonyl] -L-phenylalanine In a vessel equipped with a glass frit was placed 4-ami non-N- [(9H-f 1 uor en-9-imethoxy) carboni 1] -L- phenylalanine on Wang resin (3.0 g, 2.04 mmol) and was suspended in dichloromethane (50 mL) and DIPEA (0.98 mL, 5.6 mmol). The mixture was shaken for 15 minutes and triphosgene (1.1 g, 3.7 mmol) was added in one portion. The mixture was stirred for 2 hours at room temperature. The mixture was then filtered and washed with dichloromethane (3 x 25 mL). The resin was suspended in dichloromethane (50 L) and DIPEA (1.0 L, 5.6 mmol) and 4-cyano-4-phene hydrochloride Ipipe r idina were added. (2.73 g, 12.2 mmol). The resulting mixture was stirred for 4 hours. Then the reaction mixture was filtered and washed with dichloromethane (2 x 50 mL), methanol (2 x 50 mL), dimethylformamide (2 x 50 mL) and methanol (2 x 10 mL). The cleavage of the Fmoc group was effected by treatment with 25% piperidine in N-me t i lp i r r o 1 i d i n ona (2 x 15 min).

The above resin (0.3 g, 0.20 mmol), 2,6-dimethylbenzoic acid (0.15 g, 1 mmol) was suspended in N-me ti lp irro 1 idi nona (3 mL) and treated with BOP-Cl (0.26 g, 1.0 mmol) and DIPEA (0.23 mL, 1.3 mmol). The mixture was stirred at room temperature for 3 hours and filtered. 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 dissociation was carried out with 90% trifluoroacetic acid (TFA) in dichloromethane for 3 minutes. The mixture was filtered and the TFA was removed under high vacuum. The addition of ether (25 mL) carried out the precipitation of 4- [[(4-cyano-4-phenyl-1-piperidinyl) carbonyl] -amino] -N- [(2,6-dimethylphenyl) carbonyl] -L- phenylalanine Examples 65-66. Using the procedure described in example 64 the following compounds were prepared: Example 67. Synthesis of the N- (2-chloro-6-methylbenzoyl) -4-nitro-L-phenyl-alanine methyl ester To a solution of methyl ester hydrochloride of 4-nitro-L-phenylalanine (1527 g, 5.86 mmol), 2-c 1 oro-6-methyl thiobenzoic acid (1.0 g, 5.86 mmol) and DIPEA (3.2 mL, 2.3 g, 18 mmol) in DMF (10 L) was added HBTU (2.22 g, 5.86 mol) at room temperature. After 4 hours at room temperature the reaction mixture was diluted with ethyl acetate (200 mL) and the organic phase was washed with water (20 mL), 1 N HCl, NaHCO 3 and brine (2 x 30 mL for each solvent) and dried over Na2SO4. After removal of the solvent, the residue was purified by chromatography on silica gel, eluting with ethyl acetate: hexane (1: 2) to give N- (2-chloro-6-methylbenzoyl) -4-nitro-methyl ester. L-phenyl-alanine (1.71 g, 4.50 mmol, 77.6%), mp 123-4 ° C. Analysis (C 18 H 17 Cl 2? 5) calculated ": C, 57.38, H, 4.55, N, 7.43, Found: C, 57.11, H, 4.58, N, 7.27.

Example 68. Synthesis of 4-amino-N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester N - [(2-Chloro-6-methylphenyl) carbonyl] -4-nitro-L-phenyl-alanine methyl ester (1.51 g, 4.0 mmol) and SnCl2 »H20 (4.5 g, 20 mmol) in 30 mL were suspended. of ethanol. The suspension was stirred at a bath temperature of 97 ° C for 1 hour. Then it was cooled to room temperature, the solvent was evaporated and the residue was dissolved in 15 mL of water. Then the aqueous solution was made alkaline by the addition of solid K2CO3 at pH > 10 and extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried over K2CO3 and concentrated, which gave 4-amino-N- (2-chloro-6-methylbenzoyl) -L-phenylalanine methyl ester as a light yellow foam (1.37 g).

Example 69. Synthesis of (S) -N- (2-chloro-6-methylbe? Zoyl) -4- [[[[1- (1,1-dimethylethoxy) carbonyl] -2-piperidinyl] -carbonyl methyl ester ] amino] -L-phenylalanine A solution of 4-amino-N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester (347 mg, 1.0 mmol) in DMF (2.0 mL) with ester 1 - (1, 1-d ime ti 1) et í 1 i co of acid (S) -p ipe r idi n-1, 2-di carboxy 1 i co (347 g, 1.0 mmol), HBTU (380 mg, 1.0 mmol) and DIPEA (0.54 L, 3.0 mmol) at room temperature for 6 hours . The reaction mixture was diluted to 6 mL with water and the white precipitate was collected by filtration and washed with water (2 x 2 mL). After drying under vacuum, the light yellow powder was recrystallized from ethyl acetate-hexane, which gave methyl ester of (S) -N- (2-chloro-6-methylbenzoyl) -4- [[[[(1: 1)] -dimethyl-ethoxy) carbonyl] -2-piperidinyl] carbonyl] amino] -L-phenylalanine (507 mg, 0.82 mmol, 82%) as a white solid, melting point: 87-91 ° C. HRMS: calculated 558.2371. Obs. 558.2359 (M + H).

Example 70. Synthesis of methyl ester hydrochloride of (S) -N- (2-chloro-6-me t i lben zo i 1) - 4 - [[(2-piperidinyl) carbonyl] amino] -L-phenylalanine A solution of methyl ester of (S) -N- (2-chloro-6-methylbenzoyl) -4 - [[[1- (1,1-dimethylethoxy) carbonyl] -2-piperidinyl] -carboni 1] was treated. ami no] -L- phen i 1 a lan i na (475 mg, 0.85 mmol) in 2 mL of dichloromethane with 4N HCl in dioxane (2 mL). The solution was stirred at room temperature for 4 hours and then the solvent was removed under vacuum. The residue was then treated with 50 L of ether and the light yellow precipitate was collected and dried under vacuum, which gave methyl ester hydrochloride of (S) -N- (2-cl or o- 6-me ti 1 - benzoyl) -4- [[(2-piperidinyl) carbonyl] amino] -L-phenylalanine (440 mg, 0.89 mmol,> 100% as a light yellow powder) MS: 458 (100%) (M + H) NMR (DMSO-d6, d, ppm): 10.26 (s, 1H), 9.30 (bd, 1 H), 9.00 (d, 1H, J = 9 Hz), 8.80 (bt, 1H), 7.65 ( d, 2H, J = 7.8 Hz), 7.24 (m, 5H), 4.70 (m, 1H), 3.90 (m, 1H), 3.67 (s, 3H), 3.32 (m, 2H), 3.05 (m, 2H) ), 2.25 (m, 1H), 2.05 (s, 3H), 1.70 (, 5H).

Example 71. Synthesis of N- [(2-c 1 or o -6-methylphenyl) carbonyl] -4- [(8aS) -hexahydro-3- (4-hydroxy-phenyl) -1-oxoimidazole [1, 5-a] pyridin-2-yl] -L-phenylalanine To a suspension of activated 3 A molecular sieves (100 mg) in THF (1.45 mL) was added (S) -N- (2-chloro-6-methylbenzoyl) -4- [(2-piperidinyl) methyl ester hydrochloride. ) -carbonyl] ami no] -L- phen i la 1 aniña (100 mg, 0.2 mmol), DIPEA (0.10 mL, 0.54 mmol) and 4-h idr ox ibe nza 1 deh í do. The resulting mixture was stirred at room temperature overnight and at 60 ° C for 3 hours. It was then cooled to room temperature, the mixture was transferred to a column of silica gel and eluted with ethyl acetate: hexane (2: 1) to give N- [(2-chloro-6-methylphenyl) carbonyl] methyl ester] -4- [(8aS) -hexahydro-3- (4-hydroxyphenyl) -1-oxoimidazo [1, 5-a] pyridin-2-yl] -L-phenylalanine (17.5 mg, 0.031 mmol) in the form of a foam . The methyl ester (17.5 mg, 0.031 mmol) was hydrolyzed with 1N NaOH (0.1 mL, 0.1 mmol) in 0.5 mL of ethanol at room temperature for 6 hours. The reaction mixture was acidified to pH < 2 with TFA and purified over RP-HPLC to give N- [(2-chloro-6-methyl-phenyl) carbonyl] -4- [(8aS) -hexa-idro-3- (4-hydroxy-phenyl) -1- oxo-imidazo- [1, 5-a] pyridin-2-y1] -L-fe or 1 to 1 an i na (8.3 mg, 0.015 mmol) in 7.5% yield. HRMS: calculated, 548.1952. Obs. 548.1938 (M + H).

Example 72-74. Using the procedure described in Example 71, the compounds shown below were prepared.

, Example R Mass cale Obs mass, (M + H) (M + H) Example 75. Synthesis of N- (2-chloro-6-methyl-benzoyl) -4- [[(2R) -2-amino-4-methyl-1-oxopentyl] amino] -L-phenylalanine methyl ester A solution of 4-amino-N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester (561 mg, 1.61 mmol), prepared using the procedure described in Example 68, in DMF (4.5 mL) was treated with N-Boc-D-leucine (393.2 mg, 1.7 mmol), HBTU (644.3 mg, 1.7 mmol) and DIPEA (0.62 mL, 3.50 mmol) at room temperature for 6 hours. The reaction mixture was diluted to 30 mL with water - and the white precipitate was collected by filtration and washed with water (2 x 2 mL). After drying under vacuum, the light yellow powder was recrystallized from ethyl acetate-hexane to give N- (2-chloro-6-methyl ester Ibenzoi 1) - 4 - [[(2R) -2- [( 1, 1-dimethylethoxy) carbonyl] amino-4-methyl-1-oxopentyl] amino] -L-phenylalanine (920 mg) as a white solid. MS 560 (M + H, l Cl). This solid was dissolved in 4N HC1 in dioxane (5 'mL). The solution was stirred at room temperature overnight. After dilution with ether, the white suspension was allowed to stand at -5 ° C for 1 hour. The white solid was collected by filtration and dried under vacuum for 5 hours. The above solid was then dissolved in 20 L of water and the solution was treated with sodium bicarbonate followed by K2C03 at pH > 9. The mixture was then extracted with dichloromethane (2 x 25 mL) and dried over sodium sulfate. After removal of the solvent, the residue was then dried under vacuum at -50 ° C overnight to give white solid (520 mg, 1.1 mmol) in total yield of 70%. HRMS: Obs. 460.1997, Cale. 460.2003 (M + H).

Example 76-77. 4 - [(25, 4 R) -3-ace ti 1-2-phen i 1-4 (2-methylpropyl) -5-oxo-imidazolidin-1-yl] -N- (2-chloro-6-me ti lben zoi 1) -L- feni lalani na and 4 [(2R, 4R) -3-acetyl-2-phenyl-4- (2-methylpropyl) -5-oxo-imidazolidin-1-yl] -N- ( 2-chloro-6-methyl-benzoyl) -L-phenylalanine Methyl ester of (S) -N- (2-chloro-6-methylbenzoyl) -4 - [((2R) -2-amino-4-methyl-1-oxopentyl) amino] -L-phenylalanine (100 mg) was dissolved. , 0.2 mmol) in THF / CH (OMe) 3 mixture (1/1, 1.0 mL). To the solution was then added benzaldehyde (21.2 mg, 0.2 mmol) and the solution was stirred at room temperature. After 24 hours the reaction mixture was heated to 95 ° C, acetic anhydride (0.1 mL, 1.0 mmol) was introduced via a syringe and the solution was stirred at 110 ° C for 3 hours. After evaporation of the solvent, the residue was diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution.

After removal of the solvent, the residue was dissolved in 3 L of mixed solvent (THF / ethanol / H20 = 2/2/1) and treated with 1N sodium hydroxide (0.2 mL, 0.2 mmol). After 4 hours at room temperature, the reaction was cooled with 0.5 mL of acetic acid and the crude product was purified on RP-HPLC (C18, 5-95-35-214) to give the trans isomer, 4 - [(2S, 4R) -3-acetyl-2-phenyl-4- (2-methylpropyl) -5-oxoimidazolidin-1-yl] -N- (2-chloro-6-methyl-ben zoi 1) -L-phen i 1 to 1 an i na (27 mg, 46 μmol), HRMS (M + H) obs. 576.2251, cale. 576.2265. The corresponding cis-isomer, 4 - [(2 R, 4 R) -3- a ce ti 1 -2-phenyl-4- (2-methylpropyl) -5-oxoimidazolidin-1-yl] -N- (2- chloro-6-methylbenzoyl) -L-phenylalanine (50.1 mg, 86 μmol) HRMS (M + H). Cale. 576.2265, obs. 576.2250.

Example 78. Synthesis of N- [(2-c 1 oro-6-methylphenyl) carbonyl] -4- [(S) -hexahydro-1,3-dioxoimidazo [1, 5-a] pyridin-2-yl]] -L-phenylalanine To a solution of N- (2-chloro-6-me thienbenzoi) - 4 - [[(S) - (2-piperidinyl) carbonyl] amino] -L-phenylalanine methyl ester hydrochloride (50 mg , 0.1 mmol) and DIPEA (0.020 mL, 0.1 mmol) in 0.2 mL of dichloromethane was added Charcoal and Idi imida zo 1 (16.2 mg, 0.1 mmol) at room temperature. The solution was then stirred at this temperature for 6 hours. The reaction mixture was diluted with ethyl acetate to 5 mL and the organic phase was washed with 1N HCl, sat. NaHC 3. and brine (2 x 1 L for each solvent) and dried over Na2SO4. The solvent was then removed under vacuum to give a light yellow solid (53.4 mg, 0.11 mmol). The above solid was then dissolved in ethanol (1 mL) and stirred with 1N NaOH (0.1 mL, 0.1 mmol) at room temperature for 6 hours. The reaction mixture was acidified to pH < 2 with TFA and purified on RP-HPLC to give N- [(2-C-loro-6-methylphenyl) carbonyl] -4- [(S) -hexahydro-1,3-dioxo-imide zo [1, 5-a] ] pir id n-2-i 1)] -L-phen i 1 -alanine (27.0 mg, 0.057 mmol) with an overall yield of 57%. HRMS: obs. 470.1465. Cale. 470.1483 (N + H).

Examples 79-84. Using the procedures described in Examples 69, 70 and 78, the following compounds were prepared from methyl ester of 4-amino-N- [(2-chloro-6-met i 1 phen i 1) carbon i 1] - L - faith not 1 to 1 an i na and the appropriate amino acid derivatives: Example 85. Synthesis of 4-Nitro-N- [(2,6-dimethylphenyl) carbonyl] -L-phenyl-alanine methyl ester A solution of nitrophenol lalanin methyl ester (5.21 g, 20 mmol) in 20 L of dichloromethane and of DIPEA (15 mL) was treated with 2,6-dimethyl and Ibenzoyl chloride. After 4 hours the mixture was concentrated, the residue was taken up in ethyl acetate (200 mL) and washed with 1 N HCl (50 mL), sat. NaHCO 3. (50 mL) and brine sat. (30 mL), and dried (MgSO4). Filtration and concentration gave 8.0 g of a solid which was purified by HPLC (Waters Prep 500 - double silica gel cartridges, ethyl acetate-hexane 1: 1), which gave methyl ester of 4-n-t-ro-N - [(2, 6-dime ti 1 f eni 1) -carboni 1] -L- phen i 1 a lani na (5.26 g, 74%).

Example 86. 4-Amino-N- [(2,6-dimethylphenyl) carbonyl] -L-phenylalanine methyl ester was prepared using the procedure described in Example 68; 4-Nitro-N- (2,6-dimethylphenyl) carbonyl] -L-phenylalanine methyl ester (5.2 g, 14.6 mmol) was obtained from 4-amino-N- [(2,6-) methyl ester. tell me 1 faith or 1) ca rb on i 1] -L- phen i 1 to 1 an i na (4.6 g, 97%) in the form of a light yellow glass.

Example 87. Synthesis of 4 - [[(4-carboxy-3-pyridinyl) carbonyl] amino] -N- [(2,6-dimethyl-phenyl) carbonyl] -L-phenylalanine and 4- [[(3-carboxy)] 4-pyridinyl) carbonyl] amino] -N- [(2,6-d-imephenyl) carbonyl] -L-phenylalanine A solution of 4-amino-N- [(2,6-dimethylphenyl) carbonyl] -L-phenylalanine methyl ester (530 mg, 1162 mmol) and 3,4-pyridine hydrocarboxylic acid anhydride in dichloromethane (30 L) was allowed to stir overnight and the precipitate was collected. The solids were dissolved in THF (100 mL), filtered and concentrated, which gave 1.1 g of a mixture of isomeric carboxylic acids. This material was dissolved in ethanol (50 mL) and treated with 1 N NaOH (15 L, 15 mmol) and stirred for 2.5 hours. The mixture was acidified with excess acetic acid and purified in 3 batches on Rainin RP-HPLC to give 0.60 g of a white solid in the form of a mixture of dicarboxylic acids.

Example 88. Synthesis of 4- (2,3-dihydro-1,3-dioxo-lH-pyrrolo- [3, 4-c] pyridin-2-yl) -N- (2,6-dimethylbenzoyl) -L- phenylalanine A solution of the acid mixture of Example 87 (272 mg, 0.59 mmol) in DMF (10 mL) was treated with carbonyl diimidazole (385 mg, 2.4 mmol) and allowed to stir overnight. The mixture was filtered and purified directly by HPLC on the Rainin instrument to provide, after lyophilization of the product fraction, 4- (2,3-dihydro-1,3-dioxo-lH-pyrrolo [3, 4-c ] pyridin-2-yl) -N- (2,6-dimet ilben zoi 1) -L-phenylalanine (108 mg, 41%), FAB HRMS: obs., 444.1548. Calculated 444.1559 (M + H).

Example 89. Synthesis of N- [(2,6-dimethylphenyl) -carbonyl] -4- [(R, S) -2, 3, 5, 6, 7, 7a-hexahydro-l, 3-dioxo-lH- pyrrolo [3, 4-c] pyridin-2-yl] -L-phenylalanine A solution of 4 - (2,3-dihydro-1,3-dioxo-lH-pyrrolo [3,4-c] pyridin-2-yl) -N- (2,6-di et i lbenzoi 1) -L-phenylalanine (108 mg, 0.24 mmol) in ethanol: THF (25 mL, 1: 1) was hydrogen on 10% Pd / C (20 mg) for 4 hours. The mixture was filtered, concentrated and purified by RP-HPLC on a Rainin HPLC. The first product to elute was lyophilized to give N- [(2,6-dimethylphenyl) carbonyl] -4- [(R, S) -2, 3, 5, 6, 7, 7a-hexahydro-l, 3-dioxo -lH-pyrrolo- [3, 4-c] pi ri di n-2-i 1] - L-phen i 1 to 1 an i na (29 mg, 27%), FAB HRMS: obs., 448.1862. Calculated 448.1873 (M + H). The second product to elute was lyophilized to give recovered starting material (47 mg, 43%).

Examples 90-96. The compounds shown below were prepared using the methods described in Example 13 by hydrolysis of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N-aroyl-L-phenylalanine methyl ester.

Example 96. N- (2-chloro-6-methylbenzoyl) - [(R) -2,5-dioxo-3-methyl-4- (1-methylethyl) -1-imidazolininyl] -L- methyl ester was prepared. phenylalanine from 4-amino-N- (2-chloro-6-me t-ylbenzoyl) -L-phenylalanine methyl ester and N- [(1,1-dimethyl-ethoxy) carbonyl] -N-methyl-D -valina using the procedure described in Examples 69, 70 and 78.

Example 97-102. Using the procedures described in Examples 75, 76 and 77, the following compounds were prepared from methyl ester of -ami no-N- (2-c 1 or ro-6-me ti lben zoi 1) -L-phenylalanine and the amino acids Bo c-pro t eg es.

Example 103. Preparation of 2-bromo-6-methylbenzoic acid.

CaHgNOz CaH7Bf02 Weight Mol. : 151.18 Weight Mol ..: 215.04 Cuprous bromide was prepared by heating an intense purple solution of CuS04.5H2? (33 mmol, 8.25 g) and NaBr (66 mol, 6.75 g) in HBr (33 mL, 48%) and adding Cu p-olvo (66 mmol, 4.2 g) in portions until the purple solution became a colorless solution. This solution was then added in portions to a hot solution (about 90 ° C) of 2-ami-non-6-methyl-1-benzoic acid (33 mmol, 5 g) in H20 (80 mL) and HBr (11.54 mL). ). This was followed by dropwise addition of a solution of NaN02 (99 mmol, 6.85 g) in H20 (20 L) to this stirred stirred solution over a period of 25 minutes. The dark brownish mixture was heated at about 90 ° C for 1 hour and then refluxed for another 30 minutes before cooling to room temperature and stirred for 2 hours. The mixture was then poured onto ice (-500 g), 5% NaOH solution was added until pH 14 was reached and the resulting dark suspension was filtered through celite. The yellow filtrate was acidified with concentrated HCl to pH 1. Extractive work up (Et20, 3 x 150 mL) gave a dark residue which was dissolved in Et20 (100 mL), charcoal was added and the resulting solution was heated to reflux. Filtration and concentration gave a material that was recrystallized from Et2? / Petroleum ether in hexane (100 mL) to give 2-bromo-6-methylbenzoic acid (3.5 g, 49%, HR MS: Mass obs 213.9633. 213.9629, M +) in form-a of a crystalline light pink solid; melting point 104-106 ° C.

Example 104. Preparation of 2-ethyl-6-methylbenzoic acid.

CH3C, H2O, NEt3, 83"C, 15 h C9H11I C10H12 2 Weight Mol24S.09 Weight Mol; 164.20 A 250 mL pressure bottle with 2 -et i 1 - 6-met i 1 iodob in ce no (30.07 mmol, 7.4 g), Pd (0Ac) 2 (1.43 mmol, 334 mg) and dppp (1.43 mmol) was charged. 620 mg). The flask was closed with a septum and evacuated three times with argon. Then it was added successively with the syringe aid acetonitrile (96 mL), triethylamine (189 mmol, 19.0 g, 26.25 mL) and water (19.1 mL). Then the rubber septum was replaced by a Teflon-lined plug connected to a source of carbon monoxide. The flask was now pressurized with carbon monoxide (40 psi) and the excess pressure was released. This procedure was repeated three times and finally the mixture was stirred for 5 minutes under 40 psi carbon monoxide pressure. The flask was then disconnected from the carbon monoxide cylinder and immersed in a preheated oil bath (83-85 ° C). The reaction mixture turned black in 1 hour and was stirred for another 14 hours at this temperature. The reaction mixture was then cooled to room temperature and the pressure was released. The resulting mixture was diluted with ether (200 mL) and 1N NaOH (20 L). The formed acid was extracted in water (2 x 100 mL). The combined aqueous extracts were neutralized with 1N HCl and the acid was extracted into dichloromethane (3 x 100 mL). The combined dichloromethane extracts were washed with brine solution and dried over MgSO4. Filtration of the drying agent and removal of the solvent under vacuum gave 3.58 g (72.5%) of a viscous brown oil that solidified slowly overnight. HR MS: obs. Mass, 164.0833. Mass cale, 164.0837 (M +).

Example 105. Preparation of 2-chloro-6'-acetylbenzoic acid. to) . Preparation of 1 -acet i 1 -3-chloro-2 [[(trifluoromethyl) sulfonyl] oxy] benzene.

To a solution of 1 -acetyl-6-c-parol phenol (2.9 mmol, 0.5 g) in dichloromethane (33 mL) was added 4- (N, N-dimethylamino) pyridine (6.54 mmol, 0.8 g) a- 70 ° C followed by triflic anhydride (4.33 mmol, 1.22 g, 0.73 mL) at -70 ° C. After the addition the suspension was stirred for 30 minutes at this temperature and then warmed to room temperature and stirred for another 3 hours, at which time the TLC of the reaction mixture indicated the absence of starting material. The mixture was diluted with H2O (50 mL) and the two phases were separated. The aqueous phase was extracted with dichloromethane (50 mL). The combined dichloromethane extracts were washed with brine solution and dried over MgSO4. Filtration of the drying agent and removal of the solvent under vacuum gave a yellow oil which was purified by silica gel column chromatography to obtain 0.76 g (86%) of a colorless oil. HR MS: Obs. Mass, 301.9617. Masa cale, 301.9627 (M +).

Preparation of l-acetyl-3-chlorobenzoic acid A 100 L pressure bottle was charged with 1-ace ti 1 -3-c 1 or o- 2 - [[(trif 1 uor ome ti 1) -sul-fonyl] oxy] benzene (2.41 mmol, 0.73 g), Pd (0Ac) 2 (0.2 mmol, 47 mg) and dppp (0.2 mmol, 87 mg). Then the flask was closed with a septum and evacuated three times with argon. Then, with the aid of a syringe, acetonitrile (96 mL), triethylamine (188.7 mmol, 19.0 g, 26.25 mL) and water (19.1 mL) were added successively. Then the rubber septum was replaced by a Teflon-lined lid connected to a source of carbon monoxide. The flask was now pressurized with carbon monoxide (40 psi) and the excess pressure was released. This procedure was repeated three times and finally the mixture was stirred for 5 minutes under 40 psi carbon monoxide pressure. The flask was then disconnected from the carbon monoxide cylinder and immersed in a preheated oil bath (83-85 ° C) and stirred for 3 hours. The reaction mixture was cooled to room temperature and the pressure was released and the mixture diluted with ether (200 mL) and lOH NaOH (20 L). The acid was extracted in water (2 x 100 mL). The combined aqueous extracts were neutralized with 1N HCl and the acid was again extracted into dichloromethane (3 x 100 L). The combined dichloromethane extracts were washed with brine solution and dried over MgSO4. Filtration of the drying agent and removal of the solvent under vacuum gave a crude residue which was recrystallized from dichloromethane (-10 L) and hexane (-8 mL) and stored in the refrigerator overnight. The precipitated solid was collected by filtration and dried under high vacuum to give 330 mg (69%) of a colorless solid: melting point 128-129 ° C. HR MS: Obs mass, 195.0090. Masa cale, 195.0084 (M +).

Example 106. Preparation of 2-is? propyl-6-methylbenzoic acid. a) Preparation of 2- (1-met ilet i 1) - 6-methylodobenzene To a suspension of 2- (1-methyl-1-ethyl) -6-methylaniline (15.57 mmol, 14.9 g), in concentrated HCl (50 mL) and 30 g of ice, a solution of NaN.sub.2 (110) was added dropwise. mmol, 8 g) in H20 (35 mL) at -5 ° C to 5 ° C for 30 minutes. Then a solution of KI (200 mmol, 33.2 g) in H20 (50 L) was added dropwise during 20 minutes at 0-5 ° C. After the addition, the mixture was allowed to warm to room temperature during which time an exothermic reaction with evolution of gas occurred. The resulting red solution was stirred for 18 hours. The mixture was then extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with sodium thiosulfate solution (200 mL), brine solution and dried over MgSO4. Filtration of the drying agent and concentration of the solvent under vacuum gave a colored compound which was purified by silica gel column chromatography to obtain pure 2- (1-methylethyl) -6-methylodobenzene (17.8 g, 68%) of a yellow oil HR MS: Obs. Mass, 260.0063. Masa cale, 260.0062 (M +). b) Preparation of 2 - (1 -me t i e t i 1) - 6 -methylbenzoic acid.

A pressure bottle of 250 mL was loaded with 2- (1-me t i let i 1) - 6-me t i lyodobenzene (25.2 mmol, 6.55 g), Pd (OAc) 2 (1.2 mmol, 280 mg) and dppp (1.2 mmol, 520 mg). Then the flask was closed with a septum and evacuated three times with argon. Then it was added successively with the help of syringe, acetonitrile (96 L), triethylamine (188.7 mmol, 19.0 g, 26.25 L) and water (19.1 mL). Then the rubber septum was replaced by a Teflon-lined plug connected to a source of carbon monoxide. The flask was now pressurized with carbon monoxide (40 psi) and the excess pressure was released. This procedure was repeated three times and finally the mixture was stirred for 5 minutes under 40 psi carbon monoxide pressure. The flask was then disconnected from the carbon monoxide cylinder and immersed in a preheated oil bath (83-85 ° C). The reaction mixture turned black in 1 hour and was stirred for another 4 hours at this temperature. The reaction mixture was then cooled to room temperature, the pressure was released and the mixture was diluted with ether (200 mL) and 1N NaOH (10 mL). The acid was extracted in water (2 x 100 mL). The combined organic extracts were washed with brine solution and dried over MgSO4. Filtration of the drying agent and removal of the solvent under vacuum gave 2.8 g (62%) of a viscous yellow oil. HR MS: Obs. Mass, 178.0996. Mass cale, 178.0994 (M +).

Example 107. N- (2-c 1 oro- 6-me t i lben z or i 1) -4 [(2,4-dimethyl-3-pyridinyl) carbonyl] amino] -L-phenylalanine. to. Preparation of methyl ester hydrochloride of [[(2,4-dimime t i 1-3 -p i r idi 1) -carbonyl] amino] -L-phenylalanine To a solution of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester (1.4 g, 4.8 mmol) in DMF (12 mL) was added 2,4-dimethyl hydrochloride. -3-pir idincarboxy 1 ico (919 mg, 4.9 mmol), HBTU (1900 mg, 5 mmol) and diisopropylethylamine (2.7 mL, 15 mmol) at room temperature. The mixture was stirred for 15 hours and diluted with 10 mL of ethyl acetate and 10 mL of water. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the solvent gave a crude product which was purified on silica gel eluting with ethyl acetate: hexane (2: 1 to 4: 1) to give 4 - [(2,4-dimethyl) 1- methyl ester 3-pi ridi 1) -carbonyl) amino] -N- [(1,1-dimethylethoxyl) -carbonyl] -L-phenylalanine (226 mg). This compound (220 mg) was treated with 6 mL of 4N hydrochloric acid in dioxane at room temperature. After 5 minutes, the solid was passed to solution and the mixture was stirred for 18 hours and concentrated to give white solid (210 mg). This intermediate was used in the next stage synthesis without further purification. b. Preparation of N- (2-c 1 or ro-6 -me t i 1 ben z or i 1) -4- [(2,4-dimethyl-3-pyridyl) carbonyl] amino] -L-phenylalani a.

A solution of 4- [(2,4-dimethyl-3-pyridyl) carbonyl] amino] -L-phenylalanine methyl ester hydrochloride (50 mg, 0.125 mmol), 2-chloro-2-chlorohydrate, was stirred 15 hours at room temperature. 6-me ti Iben zoico (34 mg, 0.2 mmol), HBTU (76 mg, 0.2 mmol) and DIPEA (0.071 mL, 0.4 mmol) in DMF (0.5 mL). The mixture was diluted with ethyl acetate (10 mL) and washed with 0.5 N HCl (2 x 8 mL), saturated sodium bicarbonate (2 x 8 mL) and brine (2 x 8 mL) and dried (Na 2 SO). The solution was filtered and concentrated to a yellow gum which was hydrolyzed by treatment with 1N NaOH (0.5 mL) in MeOH (3 mL) and room temperature for 4 hours. The reaction mixture was then acidified with acetic acid and purified by HPLC using conditions described in Example 76-77 to give a white solid (23.3 mg). MS (M + H): 466 (1 Cl).

Example 108. N- (2-boron-5-methoxybenzoi-1) -4 - [(2,4-dimethyl-3-pyridinyl) carbonyl] amino] -L-phenylalanine was prepared from hydrochloride 4- [(2,4-Dimethyl-3-pyridyl) carbonyl] amino] -L-phenylalanine methyl ester and 2-boron-5-methyl methoxybenzoic acid using the general method described in Example 107 MS (M + H) 526 (lBr).

Example 109. Preparation of the methyl ester of 4- [[(2-chloro-5-cyanophenyl) carbonyl] amino] -L-phenylalanine to) . Preparation of 4 - [(2-chloro-5-bromo-phenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine.

To a mixture of 4-amino-N- [(1,1-dimethyethoxy) carbonyl] -L-phenylalanine methyl ester (20 mmol, 5.88 g), 2-chloro-5-bromobenzoic acid (22 mmol, 5.18 g) and HBTU (22 mmol, 8.34 g) in DMF (70 mL) was added diisopropylethylamine (50 mmol, 8.7 mL) at room temperature. The suspension was stirred for 48 hours at which time the TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water (100 mL) and the solids were collected by filtration and washed with water (150 mL). After air drying, the crude product was purified by silica gel column chromatography to obtain 1.02 g (10%) of a white solid: melting point 158-161 ° C. HR MS: Obs. Mass, 533.0442. Mass cale 533.0455 (M + Na). b) Preparation of 4 - [[(2-chloro-5-cyanophenyl) carbonyl] amino] -N- [(1,1-dimethyl ethoxy) carbonyl] -L-phenylalanine methyl ester.

To a mixture of methyl ester of 4 - [(2-chloro-5-bromophenylcarbonyl) amino] -N- [(1,1-dimethyl ti 1 et ox i) ca rbon i 1] -L-fe ni 1 to 1 an Na (2 mmol, 1.02 g), zinc cyanide (1.3 mmol, 152 mg) and Pd (PPh3) (0.2 mmol, 231 mg) were added with distilled and deoxygenated DMF (8 mL) at room temperature. The suspension was heated to 80-85 ° C and stirred for 15 hours at which time the TLC analysis of the mixture indicated the absence of starting material. 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 over 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 555 mg (61%) of a white solid: m.p. 185-187 ° C. HR MS: Obs. Mass, 480.1301. Calculated mass, 480.1302 (M + Na). c) Preparation of TFA Salt of 4- [(2-chloro-5-cyanophenylcarbonyl) amino] -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 L) ) trifluoroacetic acid (3 mL) was added at room temperature. The reaction mixture was stirred for 15 hours at room temperature at which time the TLC analysis of the mixture indicated the absence of starting material. The solvent was removed under vacuum and the residue was azeotroped with toluene (2 x 10 mL) and dried under high vacuum to give 0.43 g. (100%) of a yellow solid. HR MS: obs. Mass, 358.0963. Mass cale, 358.0959 (M + H).

Example 110. Preparation of 4 - [[(2-chloro-5-cyanophenyl) carbonyl] amino] -N- [1- (2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine. a) Preparation of 4 - [(2-chloro-5-cyano-phenylcarbonyl) amino] -N- [1- (2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester.

Using the procedure described in Example 3, 3, 4- [(2-chloro-5-cyanophenyl-carbonyl) amino] -N- [1- (2-chloro-6-methylphenyl) carbonyl] methyl ester was prepared. -L-phenylalanine with an overall yield of 61% in the form of a white solid. HR MS: Obs. Mass, 510.1003. Mass cale, 510.0988, M + H. b) Preparation of 4 - [(2-c 1 or ro-5-ci ano fen i 1 -carbonyl) amino] -N- [1- (2-chloro-6-methylphenyl) -carbonyl] -L-phenylalanine.

To a mixture of 4 - [(2-chloro-5-cyanophenylcarbonyl) amino] -N- [1- (2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester (0.146 mmol, 75 mg) and Lithium iodide (1.5 mmol, 200 mg) was added pyridine (3 mL) at room temperature. The solution was refluxed for 15 hours at which time the TLC analysis of the mixture indicated the absence of the starting material. It was then cooled to room temperature and diluted with water (15 mL). The pyridine was removed under reduced pressure on a rotary evaporator and the residue extracted with ether (2 x 15 mL) to remove any neutral impurities. The aqueous phase was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 20 mL of water and 20 mL of hexane. After air drying, the crude product was dissolved in ethyl acetate-hexane and stored in the refrigerator overnight. Only traces of solid were formed and the solvent was decanted and separated under vacuum to give 55 mg (76%) of a white solid. HR MS: Obs. Mass, 496.0850. Mass cale., 496.0831 (M + H).

Example 111. Preparation of 4- [(2-chloro-6-methylphenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester.

Using the procedure described in Example 1, 1,4- [(2-chloro-6-methylphenylcarbonyl) amino] -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester was prepared from 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester and 2-c 1 or ro-6-methyl-1 or nzoi-1-chloride or in overall yield of 83% form of a white solid, melting point 154-157 ° C. HR MS: Obs. Mass, 469.1513. Masa cale, 469.1507 (M + Na).

Example 112. Preparation of 4 - [(2-c 1 oro-6-me t i 1 -phenyl-1 -carbonyl) amino] -L-phenylalanine methyl ester hydrochloride salt Using the procedure described in Example 2, hydrochloride salt of 4 - [(2-chloro-6-methyl-1-phenylcarbonyl) amino] -L-phenylalanine methyl ester was prepared in overall yield of 99% from the product of the Example 111 in the form of a white solid. HR MS: Obs. Mass, 347.1165. Mass cale. 347.1162 (M + H).

Example 113. 4- [(2-Chloro-6-methylphenylcarbonyl) amino] -N- [1- (2-methyl-6-ethylphenyl] carbonyl] -L-phenylalanine methyl ester was prepared using the procedure described in the Example 3, to give an overall yield of 70% of a white solid HR MS: Obs. Mass, 515.1690. Mass cale, 515.1714 (M + Na).

Example 114. N- [1 - (2-c 1 or ro-6-methylphenyl) carbonyl] -4- [[(2,6-difluorophenyl) -carbonyl]] ami no] -L-phenylalanine was prepared from of methyl ester of 4-amino-N- [(2-c 1 or ro- 6-me ti 1 feni 1) carbon i 1] -L- phen i 1 a lan i na and acid 2, 6-dif luoraben zoi co using the procedures described in Examples 109 and 13. HR MS: Obs mass 473.1094. Mass cale 473.1079 (M + H).

Example 115. N- [1 - (2-C-loro-6-methylphenyl) carbonyl] -4- [[(2, 3, 4, 5, 6-penta-fluorophenyl) carbonyl] amino] -L-phenylalanine was prepared from methyl ester of 4-amino-N- [(2-c 1 oro- 6-me ti 1-pheni 1) ca rbon i 1] -L- phen i 1 to 1 an i n a and acid pen taf 1 uorobe nzoi co using the procedure described in examples 109 and 13. HR MS: Obs. mass, 527.0798. Mass cale 527.0797 (M + H).

Example 116. Preparation of (Z) -3- [- [[(1,1-dimethylethoxy) carbonyl] -amino] -3-methylphenyl] -2- [[(phenylmethoxy) -carbonyl] amino] -methyl ester - 2-propenoic to. Preparation of 4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -3-methyl-benzyl alcohol. A solution of 3-methyl-1-4-nitro-robinyl alcohol (7.0 g, 42 mmol) in ethyl acetate (175 mL) and Boc anhydride (9.1 g, 42.7 mmol) over 10% palladium on carbon was hydrogenated. % (0.33 g) for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from ether-hexane, which gave a white crystalline solid (6.73 g, (68%), melting point 73-74 ° C. Anal. (C? 3 H19N03): C, 65.80; H, 8.07; N, 5.90, Found: C, 65.74; H, 7.80; N, 5.80. b. Preparation of 4 - [(1, 1 - dime t i 1 e t oxy) -carbon i 1] ami no] - 3 -me t i Iben za ldehí do. A solution of 4- [[(1,1-dimethylethoxy) carbonyl] amino] -3-methylbenzyl alcohol (7.2 g, 30.4 mmol) in dichloromethane (60 mL) was treated with manganese dioxide (4 x 7 g) at two hours and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through a pad of Celite washing with dichloromethane and the filtrate was concentrated. The residue was recrystallized from ether-hexane, which gave a white crystalline solid (6.3 g, 87%), melting point 109-111 ° C. Anal. (C13H17N03): Calculated: C, 66.36, H, 7.28; N, 5.95. Found: C, 66.14; H, 7.14; N, 5.85. c. Preparation of (Z) -3- [4- [[(1,1-dimethylethoxy) carbonyl] amino] -3-methylphenyl] -2- [[(phenylmethoxy) carbonyl] -amino] -2-propenoic acid methyl ester A solution of N- [(phenylmethoxy) carbonyl] -2-phosphonoglycine trimethyl ester (11.9 g, 36 mmol) in dichloromethane (60 mL) was treated with tetramethylguanidine (4.5 L, 36 mmol). After 1 hour the mixture was cooled to an internal temperature of -3 ° C and treated with a solution of 4 - [[(1,1-dimethyl-1-oxo) -carbonyl] amino] -3-met i 1-benzaldehyde (7.02 g, 29.8 mmol) in dichloromethane (25 mL) at a rate such that no rise in temperature was reached. The reaction mixture was stirred at -30 ° C for 30 minutes and allowed to warm to room temperature over the night. The mixture was diluted with ether (150 mL) and washed successively with 0.5 N HCl (2 x 50 mL) and saturated NaHCO 3 (1 x 50 mL) and dried over MgSO 4. The solution was concentrated and the residue was purified by chromatography on a Biotage Kilo Prep HPLC using a silica gel cartridge and eluting with ethyl acetate: hexane (1: 2). The fractions containing the Z-isomer were combined and concentrated, finally under high vacuum to give a colorless glass (11.48 g, 86%). Anal. (C2 H28N2? 6): Calculated: C, 65.44; H, 6.41; N, 6.36. Found: C, 64.81; H, 6.43; N, 6.04. HR MS: Obs. Mass, 440.1933. Mass cale, 440.1947 (M + H).

Example 117. Preparation of 4- [[(1,1-dimethylethoxy) carbonyl] amino] -3-methyl-N- [[(phenylmethoxy) carbonyl] -L-phenylalanine methyl ester.

A solution of acid methyl ester (Z) -3- [4- [[(1,1-Dimethylethoxy) carbonyl] amino] -3-methylphenyl] -2- [[(phenylmethoxy) carbonyl] -amino] -2-propylene (10 g, 22.7 mmol) of Example 116 in methanol (50 mL) and THF (20 mL) was placed in a pressure bottle and a stream of Ar was passed through the mixture overnight. Trifluoromethane (+) - 1, 2-bis ((2S, 5S) -2,5-dimethylphospholane) benzene (ci c 1 octadiene) rhodium sulfonate was added and the bottle was pressurized at 50 psi with hydrogen 3. times and the mixture was stirred overnight at room temperature under 50 psi of hydrogen. The pressure was released and the solution was concentrated. The residue was treated with activated carbon and recrystallized from ethyl acetate-hexane, which gave 6.72 g (67%), mp 120-121 ° C. [a] 589-5.9 ° (c = 1%, methanol).

HR MS (C2 H3oN2? 6): Obs. 442.2113. Mass cale. 442.2104 (M +).

Example 118. Preparation of 4- [[(1,1-dimethylethoxy) carbonyl] amino] -3-methyl-N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester. to. A solution of methyl 4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -3-methyl-N- [[(phenemethyl) ca rbon i 1] - L- f in i 1 a 1 an a Na (3.0 g, 6.8 mmol) in ethanol (40 mL) and cyclohexene (14 mL, 140 mmol) was treated with 10% palladium on charcoal (1.5 g) and the mixture was heated to reflux for 20 minutes and allowed to cool. The mixture was filtered through a pad of celite being washed with ethanol and the filtrate was concentrated to give methyl 4 - [[(1,1-dimethyl t-oxy oxy) carboni 1] -amino] -3-met i 1 methyl ester. -L-phenylalanine (2.24 g) in the form of a light yellow oil. HR MS (C? 6H24N20): Obs. 309.1819. Mass cale. 309.1815 (M + H). b. A solution of 4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -3-methyl-L-phenyl-alanine methyl ester (1.0 g, 3.24 mol) and 2-chloro-6-methylbenzoic acid (0.66 g) 3.86 mmol) in DMF (8 mL) was treated with HBTU (1.72 g, 4.53 mmol) and DIPEA (3 mL), 17 mmol) and the mixture was stirred overnight. The solution was concentrated. The residue was dissolved in ethyl acetate. (30 mL) and washed with saturated NaHC 3 (10 mL), 0.1 N HCl (10 mL) and brine (10 L) and dried over MgSO4. The residue obtained after filtration and evaporation was purified by silica gel chromatography on 140 g of silica gel, eluting with ethyl acetate: 1: 9 dichloromethane to give 1.16 g (78%) of a gum. HR MS (C24H29N205C1): Obs. 461.1858. Mass cale 461.1844 (M + H).

Example 119. Preparation of the hydrochloride salt of the 4-amino-3-methyl-N- [[(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester.

The methyl ester of 4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -3-methyl-N- [[(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine (1-1 g, 2.17 mmol) of Example 118 was treated with 4 N HCl in dioxane (20 mL) for 4 hours and concentrated to dryness. The residue was triturated with ether and filtered to give 0.83 g, 96% as a white solid. HR MS (C19H22 2O3C12): Obs. 361.1309. Mass cale. 361.1320 (M + H).

Example 120. Preparation of N- [1 - (2-C 1 -O-6-methylphenyl) carbonyl] -4- [[(3- (3-hydroxyphenyl)) -1-oxopropyl] amino] -3-methyl-L -phenylalanine. to. A solution of methyl ester hydrochloride salt of 4-ami-non-3-methyl-1 - N- [[(2-chloro-6-ethyl-1-phenol) carbon] 1 -L- phen i 1 alanine ( 79.5 mg, 0.20 mmol) of Example 119, 3- (3-hydroxyphenyl) propanoic acid (33.2 mg, 0.20 mmol) and DIPEA (120 mL, 0.69 mmol) in dichloromethane (3 mL) was cooled to 10 ° C and treated with BOP-Cl (51 mg, 0.20 mmol). The mixture was stirred for 4 hours and concentrated. The residue was dissolved in dichloromethane (15 mL) and washed with 5 mL portions of 0.5 N NaC03, 0.5 N HCl and saturated brine and dried (MgSO4). The residue obtained after filtration and concentration was purified by chromatography on 25 g of silica gel, eluting with 7: 3 ethyl acetate: hexane to give 47 mg of a colorless glass. HR MS: Obs mass 509.1849. Mass cale. 509.1844 (M + H). b. A solution of the N- [1- (2-chloro-6-methylphenyl) carbonyl] -4- [[3- (3-hydroxy-phenyl)) -1-oxopropyl] amino] -3-methyl-L methyl ester phenyl-alamin (45 mg, 0.088 mmol) in THF (30 mL) was treated with a solution of LioH »H20 (20 mg, 0.47 mmol) in water (1.0 mL). Methanol was added (0.5 mL) for solubility and the mixture was stirred at room temperature for 18 hours. The mixture was acidified with 0.5 mL of acetic acid and purified directly by RP-HPLC (5-95-35-214) to give, after lyophilization, 34.3 mg of a white powder. HR MS (C27H27N2O5CI): Obs. 495.1697. Masa Cale 495.1687 (M + H).

Example 121. N- [1- (2-C 1 -O-6-methylphenyl) carbonyl] -4- [[2- (3-hydroxyphenyl)) -1-oxoethyl] amino] -3-methyl-L- was prepared phenylalanine using the general procedure described in Example 120 from methyl ester of 4-amino-3-methyl-N- [[(2-chloro-6-methylphenyl) -carbon i 1] -L-fe ni 1 a lan Na (79.5 mg) and 2- (3-hydroxy-phenyl) -acetic acid (30 mg 0.2 mmol) to give 23 mg of a colorless glass. HR MS (C26H25N2O5CI): Obs. 481.1527. Mass cale 481.1530 (M + H).

Example 122. N- [1- (2-C 1 -O-6-methylphenyl) carbonyl] -4- [[2- (3-nitrophenyl)) -1-oxoe ti 1] amino] -3-met i was prepared 1-L-phenylalanine from methyl ester of 4-ai non-3-me ti 1-N - [[(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine (52 mg) and 3-n i t ro-be n z o i co acid (32 mg, 0.19 mmol) using the procedure described in Example 120 to give 15 mg of white powder.

HR MS (C 5 H 22 N 3 O 6 Cl): Obs. 496.1288. Mass cale. 496.1288 (M + H).

Example 123. N- [1- (2-Chloro-6-methylphenyl) carbonyl] -4- [[2,6-dichlorophenyl) -carbonyl] amino] -3-met i 1 -L-phenylalanine was prepared from 4-amino-3-methyl-1 - N - [[(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester (87.4 mg, 0.22 mmol) and 2,6-di c 1 orobe chloride nzoi 1 or using the procedures described in Examples 1 and 120 to give 56 mg of a white powder. HR MS (C25H2i 20 Cl3): Obs. 519.0656. Mass cale 519.0645 (M + H).

Example 124. Preparation of N- [(4-amino-2-chlorophenyl) carbonyl] -4- [[(2,6-dichlorophenyl) -carbonyl] amino] -L-phenylalanine A solution of 4-amino-2-chlorobenzoic acid (43 mg, 0.25 mmol) and 4 - [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester hydrochloride (100 mg, 0.25 mmol) and HBTU (100 mg, 0.27 mmol) in DMF (3 L) was treated with DIPEA (0.20 L) and the mixture was stirred 2 hours at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCOl and dried (MgSO4). The residue after filtration and concentration was chromatographed on 16 g of silica gel, eluting with 4: 1 ethyl acetate: hexane, to give N- [(4-amino-2-chlorophenyl) carbonyl] -4- methyl ester. [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine (66 mg, 51%) of a white foam. HR MS (C2 H2oCl3 304): Mass obs. 520.0589. Mass cale. 520.0597 (M + H). b. A solution of N - [(4-amino-2-chlorophenyl) carbonyl] -4- [(2,6-dichloro-fe-n-1) ca rbo ni 1] ami no] - L - fe ni 1 a 1 anina (66 mg, 0. 126 mmol) in THF (3 mL) was treated with a solution of LiOH * H2? (20 mg, 0.48 mmol) in water (0.5 mL) and the mixture was stirred overnight at room temperature. Acetic acid (0.5 mL) was added and the mixture was purified directly by RP-HPLC (5-95-35-214) to give 40 mg of a white solid. HRMS: (C23H18C13N30): Obs. 506.0461. Mass cale 506.0441 (M + H).

Example 125. Preparation of 4- (4-cyan-1, 3 dioxo-2H-isoindol-2-yl) -N- [1,2-chloro-6-methyl-phenyl) carbonyl] -L-phenylalanine a) Preparation of 4- (4-cyano-1,3-dioxo-2H-isoindol-2-yl) -N- [1- (2-chloro-6-methyl-ethenyl) carbonyl] -L-phenylalanine methyl ester Using the procedure described in Example 3, 4- (4-cyano-l, 3-dioxo-2H-isoindol-2-yl) -N- [1- (2-chloro-6-methylphenyl) methyl ester was prepared carbonyl] -L-phenylalanine with 63% overall yield in the form of a white solid: melting point 200-202 ° C. HR MS: Obs. Mass, 502.1173. Mass cale, 502.1169, M + H. b) Preparation of 4- (4-cyano-1,3-dioxo-2H-isoindol-2-yl) -N- [1- (2-chloro-6-methylphenyl) -carbonyl] -L-phenylalanine.

Using the procedure described in Example 110, 4 - (- cyano- 1, 3-dioxo-2H-isoindol-2-yl) -N- [1 (2-chloro-6-methyl-pheny1) carbon i was prepared. ] -L- phen i 1 alan i na with overall yield of 26% in the form of a white solid: melting point 170-175 ° C. HR MS: Obs. Mass, 488.1004. Mass cale, 488.1013, M + H.

Example 126. Synthesis of N- (2-chloro-6-methyl-benzoyl) -4- [(2,6-dichloro-phenyl) carbonyl] amino] -L-phenylalanine ethyl ester To a solution of sodium salt of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) -carbon i 1] ami no] -L-phenylaine (1,583 g, 3.0 mmol) ) in DMF (75 mL) was added iodoethane in excess (3.27 g, 21 mmol) at room temperature. The resulting solution was stirred for 124 hours. TLC analysis of the mixture indicated the absence of starting material and excess iodoethane and certain DMF were removed on a rotary evaporator under vacuum. The residue was diluted with 100 mL of ethyl acetate and washed successively with water (2 x 100 mL).brine solution (100 L) and dried over MgSO4. Filtration of the drying agent and removal of the solvent gave a white solid which was purified by silica gel column chromatography eluting with ethyl acetate: hexane (1: 1) to obtain 1.4 g (87%) of ethyl ester in the form of a white solid, melting point 230-235 ° C. HR MS: Obs mass 533.0817. Mass cale 533.0801 (M + H).

Example 127. Synthesis of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichloro-phenyl) carbonyl] amino] -L-phenylalanine ethyl ester To a suspension of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] -ami no] -L- phenylalanine (7.0 g, 13.84 mmol) and sodium bicarbonate in Dust (5.88 g, 70 mmol) in DMF (100 mL) was added with excess of iodoethane (10.91 g, 70 mmol) at room temperature. The resulting suspension was stirred for 20 hours at which time the TLC analysis of the mixture indicated the absence of starting material and the excess of iodoethane and certain DMF was removed on a rotary evaporator under vacuum. The remaining residue was diluted with 150 mL of ethyl acetate and washed successively with water (2 x 100 L), brine solution (100 mL) and dried over MgSO4. Filtration of the drying agent and removal of the solvent gave a white solid which was crystallized from acetonitrile. The resulting crystalline solid was collected by filtration and dried under high vacuum to give 5.58 g (77%) of N- (2-c-loro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl ethyl ester. ] -ami no] - L - faith nor 1 to 1 an ina in the form of a white solid, melting point 230-235 ° C.

Example 128. Synthesis of 2-morpholino ethyl ester of N- (2-c 1 or r o -6 -me t i 1 be z or i 1) -4 - [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine.

To a solution of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] -amino] -L-phenylalanine (0.505 g, 1.0 mmol) and 2- (4-morpholino) Ethanol (0.262 g, 2.0 mmol) in THF (13 mL) was added di ci clohexylcarbodimide (0.309 g, ~ 1.5 mmol) in THF (13 m) was added - dicyclohexylcarbodimide (0.309 g, 1.5 mmol) and 4-dimethyl ilaminopyr idine (61 mg, 0.5 mmol) at room temperature. The resulting cloudy solution was stirred for 4 hours at which time the TLC analysis of the reaction mixture indicated the absence of acid. The mixture was then diluted with water (50 L) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water (2 x 100 mL) and brine solution (100 mL) and dried over MgSO4. Filtration of the drying agent and removal of the solvent gave a white solid which was purified by silica gel column chromatography using di-1-omene-1-methoxy (15: 1) as eluent to obtain 0.428 g (69%). %) of N- (2-chloro-6-me thi-1-benzoyl) -4- [(2,6-dichlorophenyl) carbonyl] amino] -L ester of 2 - (4-morpholine) and 1-yl ester phenylalanine in the form of a white solid, melting point 109-118 ° C. HRMS: Obs. Mass, 618.1311. Mass cale, 618.1329 (M + H).

Example 129. Synthesis of 2- (4-morpholine) ester and 1-co-ester of N- (2-C 1 oro-6-me ti 1-benzoyl) -4- [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine Weight Moi: «05.78 weight > Mol ..; 618.93 To a solution of 'N- (2-c 1 oro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] -amino] -L- phen i 1-yl (0.253 g, 0.5 mmol) and 2- (4-morpholino) ethanol (0.131 g, 1.0 mmol) in THF (5 mL) was added diisop rop i 1 ca rbodimi da (94.6 mg, 0.75 mmol) and 4-dime ti 1 ami nop iri di na ( 30.5 mg 0.25 mmol) at room temperature. The resulting mixture was stirred for 15 hours at room temperature at which time the TLC analysis of the reaction mixture indicated the absence of acid. The mixture was then diluted with water (50 mL) and the THF was removed under vacuum 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 L) and dried over MgSO4. Filtration of the drying agent and concentration of the solvent gave a white solid which was purified by silica gel column chromatography using dichloromethane and ethyl acetate (5: 1 to 1: 1) and pure ethyl acetate as eluent to obtain 0.2 g. (65%) of a white solid, melting point 109-118 ° C.

Example 130-132. Using the procedure described in Example 129 the following ester derivatives were prepared.

EXAMPLE 133. Synthesis of 1-methyl ester 1 - 2 - (4-mor folino) eti 1 i co of N- (2-c loro-6-me ti 1-benzoyl) -4- [(2,6 -dichlorophenyl) carbonyl] -amino] -L-phenylalanine was prepared in 32% yield in accordance with the procedure described in Example 129. Calculated HRMS 632.1484 Observed: 632.1486 (M + H) Example 134. The N- (2-c 1 oro-6-met i lben zoi 1) -4 - [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine 1-methyl ethyl ester was prepared in the yield of 60% with the procedure described in Example 127. HRMS m / z Cale, 569.0778. Obs., 569.0774 (M + Na).

Example 135. The ester 2-me ti lp rop i 1 co of N- (2-c 1 oro- 6-me ti Iben zoi 1) -4- [(2,6-dichloro-phenyl) carbonyl was prepared. ] amino] -L-phenylalanine with the method described in Example 127. HRMS m / z Cale., 561.1114. Obs., 561.1125 (M + H).

Example 136. L-methyl-4-piperidinyl ester of N- (2-c 1 oro-6-me ti lben zoi 1) - 4 - [(2,6-dichlorophenyl) carbonyl] amino] -L- was prepared phenylalanine with 65% yield and with the method described in Example 128. HR MS C3? H3oCl3N304): Obs., 602.1386. Cale: 602.1380 (M + H).

Example 137. Butyl N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichloro-phenyl) carbonyl] ami no] -L-phenyl alanyl butyl ester was prepared in 75% yield with the procedure described in Example 127. HR MS (C28H27C13N204): Obs., 561.1115. Cale, 561.1114 (M + H).

Example 138. N- (2-Chloro-6-methylbenzoyl) -4- [(2,6-dichloro-) -2- [(1, 1-dimethylethoxy) carbonyl] -1-piperazinyl] ethyl ester was prepared. phenyl) carbonyl] amino] -L-phenylalanine with 78% yield from N- (2-c-loro-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] -amino] -L- phen i la lan ina and 2 - [4 - [(1,1-dimethy1-ethoxy) carbonyl] -1-piperazinyl] ethanol using the procedure described in Example 129. HR MS: Obs. Mass, 717.1995. Mass cale., 717.2013 (M +).

Example 139. Ester 2 - (1-pipe razini 1) et i 1 co of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichloro-phenyl) carbonyl] amino] -L- phenylalanine To a solution of N- (2-chloro-6-methylbenzoyl) -4- [(2,6-dichloro-) ethyl ester 2- [4-E (1, 1-di etyletoxy) carbonyl] -1-piperazinyl] ethyl] phenyl) ca boni l] amino] -L-phenylalanine (1.0 mmol, 0.72 g) in dioxane (4 mL) was added a solution of HCl in dioxane (3.0 mmol, 0.75 mL, 4N) at room temperature. The resulting solution was stirred for 2 hours at room temperature at which time the TLC analysis of the reaction mixture indicated the absence of starting material. The dioxane was then removed under vacuum and the solid was triturated with ether (15 mL). The ether was decanted and the solid was dried under high vacuum to obtain 0.68 g (90%) as a white solid. HR MS (C30H31 C 13N4C4): Obs. Mass, 617.1464. Mass cale, 617.1489 (M + H).

Example 140. Preparation of 2- (4-methyl-1-p ipe razini 1) ester and N- (2-c loro-6-me ti 1-benzoyl) -4- [(2, 6) ester -dichlorophenyl) carbonyl] amino] -L-phenylalanine To a suspension of N- (2-c 1 or R-6-methylbenzoyl) -4- [(2,6-dichlorophenyl) carbonyl] - 2- (1-p ipe razini 1) ester dichloride. amino] -L-phen i 1 lani na (1.0 mmol, 0.617 g) of Example 139 and K2C03 (8.0 mmol, 1.1 g) in NMP (10 mL) was added methyl iodide (3.0 mmol, 0.43 g) at room temperature . The resulting mixture was stirred for 48 hours at room temperature at which time the TLC analysis of the reaction mixture indicated the absence of starting material. The mixture was then diluted with water (100 mL) and the precipitated solid was collected by filtration and dried under high vacuum. This solid was purified by Reverse Phase HPLC to obtain 0.35 g (5%) of a white solid. HR MS (C31 H33 C 13N40): Obs. Mass, 631.9208. Mass cale 631.9193 (M + H).

Example 141. Preparation of N-methyl-N- [1- (2-chloro-6-methylphenyl) carbonyl] -4-nitro-L-phenylalanine methyl ester To a suspension of N- [1- (2-chloro-6-methylphenyl) carbonyl] -4-nitro-phenylalanine methyl ester (0.375 mmol, 142 mmol) and silver oxide (1.5 mmol, 340 mg) in DMF (2 mL) was added methyl iodide (28 mmol, 1.75 mL) at room temperature. The suspension was stirred for 2 days at room temperature, at which time the TLC analysis of the mixture indicated the absence of starting material and the solid was filtered. The solution was concentrated and diluted with ethyl acetate (30 L) and washed with water (20 L), brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave 99 mg (67%) of a light brown oil. HR MS (C 19 H] 9 C 1 N 205): 390 (M + H).

EXAMPLE 142 Preparation of this methyl 4-amino-N-methyl-N- [1- (2-chloro-6-methylphenyl) -cabore n i 1] - L - fe n i 1 to 1 an i na To a mixture of N-methyl-N- [2- (2-chloro-6-methylphenyl) carbonyl] -4-n-t-L-phenol 1-methyl ester (0.5 mmol, 192 mg) of Example 141 , zinc powder (~ 325 meshes, 5.0 mmol, 0-33 g, 10 equivalents) and ammonium chloride (7.5 mmol, 0.4 g, 15 equiv.) were added methanol (4 mL) and water (2 mL) at room temperature. ambient. After the addition of water the reaction was exothermic. The suspension was stirred for 2 hours at room temperature, at which time the TLC analysis of the mixture indicated the absence of starting material, and the reaction mixture was filtered through celite. The filter cake was washed with methanol (30 mL) and water (20 mL). The filtrate was concentrated to remove methanol and the residue was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solvent gave 148 mg (82%) of a yellow oil. LR MS (C 19 H 21 C 1 N 203): 361 (M + H).

Example 143. Preparation of 4- (2,6-dichloro-phenylcarbonyl) amino] -N-methyl-N- [1- (2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester.

Using the procedure described in Example 1, 4 - [[(2,6-di-chloro-phenyl) carbonyl] amino] -N- [1- (2-chloro-6-methyl-phenyl) 1) carboni 1] - L-Methyl phenylalanine with 68% overall yield in the form of an amorphous solid. HR MS (C 26 H 23 Cl 3 N 20 4): 534 (M + H).

Example 144. Preparation of 4 - [(2,6-dichloro-phenylcarbonyl) amino] -N-methyl-N- [1- (2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine Using the procedure described in Example 13, N- [1- (2-chloro-6-methylphenyl) carbonyl] -N-methyl-4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine was prepared from the product of Example 143 with overall yield of 59% as a white solid. HR MS: Obs. Mass, 519.0631. Masa Cale. 519.0645 (M + H).

Example 145. Preparation of 2-chloro-6-methylbenzoic acid. to. Preparation of 2-cl oro- 6-me t i lben z a ldeh í do A round-bottom, three-neck, 500 mL flask, equipped with a magnetic stirrer, thermometer, additional funnel, and argon admission was charged with 75 g (494 mmol) of 2-chloro-6-me t ylbenzoni tri lo and 400 mL of toluene (stored on 4 Á molecular sieves). The mixture was cooled to -2 ° C (ice + acetone) and added dropwise, during a period of 30 minutes, while maintaining the temperature below 0 ° C, a solution of DIBAL-H (593 mmol, 593 mL, l.ON). After the addition, the reaction mixture was stirred for 1 hour at 0 ° C and then allowed to warm to room temperature. After 2 hours at room temperature the TLC analysis indicated the absence of starting material (hexane: ether 4: 1, pulverization of phosphorus-1-ibidic acid, since the analysis by means of UV fluorescence led to erroneous results). The reaction mixture was poured into ice (2000 g) and concentrated sulfuric acid (50 mL) -and stirred overnight. The precipitated solids were collected by filtration and the filtrate was extracted with ether (2 x 200 mL). The combined extracts were washed with brine solution and dried over MgSO4. Filtration of drying agent and concentration of the solution gave the crude aldehyde which was combined with the above solid to give 71.31 g (93%) of light yellow solid suitable for use in the next step. b. Preparation of 2-c 1 or o-6-me t i 1 -benzoic acid.

A round-bottom, three-neck, 1000 mL flask equipped with a magnetic stirrer, thermometer, additional funnel, and argon admission was charged with 71.31 g (461 mmol, crude obtained from the previous experiment) of 2-chloro-6-me t. ilbenzaldehyde and 750 mL acetonitrile. To this suspension was added a solution of sodium phosphate monobasic (115 mmol, 15.9 g, 0.25 eq.) In water 240 L) followed by hydrogen peroxide (50 mL, 30%) at room temperature. Then a solution of sodium chlorite (73.5 g, 811 mmol, 1.76 eq.) In water (700 mL) was added dropwise at 0 ° C while maintaining the temperature below 3 ° C. After the addition, the yellow suspension was stirred for 15 hours at 0 ° C at room temperature, at which time the TLC analysis of the mixture indicated the absence of aldehyde. Then a solution of sodium bisulfite (73 g, 701 mmol, 1.52 eq.) In water (200 mL) was added dropwise at 0 ° C until the disappearance of the yellow color (Kl-positive paper). Cooling is essential for the control of the exothermic reaction. The solvent was removed under vacuum to give a white solid. The solid was collected by filtration and the filtrate was extracted with ether (200 mL). The above solid was also dissolved in this ether solution and washed with 10% NaOH solution (2 x 200 mL). The basic aqueous solution was neutralized with 10% HCl to pH ~ 1. The precipitated white solid was collected by filtration and dried in air to give 54.88 g (65%, overall in two steps) of 2-cl or o-6-methyl-1-benzoic acid as a white solid.

Example 146. Preparation of 4- [(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester. to. Preparation of 4-Nitro-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester.

To a suspension of 4-n-n-t-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) were added. add methyl iodide (1.13 mmol, 70.4 mL) at room temperature. The suspension was stirred for 15 hours at room temperature at which time the TLC analysis of the mixture indicated the absence of starting acid and the excess of methyl iodide and some DMF were removed under high vacuum. The mixture was poured into water (2 L) and stirred at room temperature in the form of a precipitate formed slowly over the weekend. The precipitated solids were collected by filtration and washed with water (2 L). After drying in air and vacuum, 72 g (98%) of 4-nitro-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester was isolated as a light yellow solid. fusion 95-96 ° C. l E NMR, DMSO-d6 (400 MHz) delta 8.16 (d, 2H, J = 20 Hz), 7.53 (d, 2H, J = 20 Hz), 7.39 (d, 1H, J = 22 Hz), 4.26- 4.28 (m, 1H), 3.6 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H). 13C NMR, CDC13 (100Mhz) 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: Obs. Mass, 325.1404. Mass cale, 325.1400 (M + H). b. Preparation of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester To a mixture of methyl ester of 4-nitro-N- (1,1-dimethylethoxy) carbonyl] -L-phenyl-alanine (222 mmol, 72 g.), Zinc powder (-32.5 mesh, 2.2 mol, 145.2 g, 10 equiv.) and ammonium chloride (3.3 mol, 178.1 g, 15 equiv.) methanol (1 L) and water (500 L) were added at room temperature After the addition of water the reaction mixture exothermed and the temperature was raised to 45-50 ° C. The suspension was stirred for 1 hour at room temperature at which time the TLC analysis of the mixture indicated the absence of starting material and the reaction mixture was filtered through celite, washing the filter cake with methanol (1 L) and water (500 mL) The concentration to remove methanol and certain water resulted in the formation of a white solid which was collected by filtration and washed with water. air was obtained 65.5 g (quant) of a white solid, melting point 86.89 ° C.? NMR, DMSO-d6 (400 MHz) delta 6.9 (d, 2H, J -20 Hz ), 6.62 (d, 2H, J = 20 Hz), 7.39 (d, 1H, J = 22 Hz), 4.26-4.28 (m, 1H), 3.68 (s, 3H), 2.96-3.19 (m, 2H) , 1.25 (s, 9H). HR MS: Obs. Mass, 284.1614. Mass cale., 294.1621. c. Preparation of 4 - [(2,6-dichlorophenylcarbonyl) amino] -N- [(1,1-dimethyl-ethoxy) carbonyl] -L-phenylalanine methyl ester.

To a solution of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenyl-alanine methyl ester (127.6 mol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 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, which gave a white suspension. At this time the TLC analysis of the mixture indicated the absence of starting material. The solids were collected by filtration and washed with dichloromethane (150 mL) and dried in air to obtain 52.75 g (88.4%) of a white solid, melting point 148-151 ° C. * H NMR, DMSO-d6 (400 MHz) delta 10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.27 (m, 1H), 3.62 (s, 3H), 2.79-2.99 (n, 2H), 1.33 (s, 9H). 13C NMR, CDC13 (100 MHz) 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. HR MS. Obs. , 466. 1069. Mass cale, 466.1062 (M + H). d. Preparation of hydrochloride salt of 4 - [(2,6-dichlorophenyl carboni 1) -amino] -L-phenylalanine methyl ester.

Methyl ester of 4 - [(2,6-dichlorophenylcarbonyl) amino] -N- [(1,1-dimethyl-ethoxy) carboni 1] -L-phenylalan (92.97 mmol) was treated., 43.45 g) in dioxane (90 mL) with 166 mL of 4N hydrochloric acid in dioxane at room temperature. After 5 minutes solids came into solution and the mixture was stirred for 2 hours. Part of the dioxane was removed under vacuum to give 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 g (100%) of the hydrochloride salt as a white solid H NMR, DMSO-dβ (400 MHz) delta 10.81 (s, 1H), 7.76 (d, 2H, J = 22 Hz), 7.58 (d, 2H), J = 18 Hz), 7.51 (t, 1H, J = 15 Hz), 7.24 (d, 2H, J = 22 Hz), 4.23-4.26 (m, 1H), 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: Obs. Mass, 367.0611. Masa Cale. , 367.0616 (M +).

Example 147. Preparation of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester.

To a solution of the hydrochloride salt of the methyl ester of 4 - [[(2,6-di coro-feni-1) -carboni-1] amino] -L-phenylalanine (272.5 mmol, 105 g) of Example 146 and acid 2-C 1 or o-6-methylbenzoic acid (276 mmol, 47.15 g) in DMF (600 mL) was added HBTU (276 mmol, 105 g) and diisopropylethylamine (1.24 mol, 119 mL) at room temperature. The clear solution was stirred 48 hours at room temperature at which time the TLC analysis of the reaction mixture indicated the absence of the starting material. The reaction mixture was poured slowly into 5 L of water which contained some ice to lower the temperature. The white precipitated solid was allowed to settle and the solid was collected by filtration. The solid cake was washed with water (1 L) and hexane (1 L) and air dried to obtain 150 g of a crude product. This solid product was dissolved in hot acetonitrile (1 L) and cooled in the refrigerator. The solid was collected by filtration and washed with hexane (500 mL) and air dried to obtain 101.1 g. The mother liquors were concentrated and the residue purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate (15: 1) to obtain another 17.07 g (total = 118.17 g, 83%), melting point 244- 245 ° C. H NMR, DMSO-d6 (400 MHz) delta 10.66 (s, 1H), 8.83 (d, 1H, J = 19 Hz), 7.47-7.6 (m, 5H), 7.15-7.29 (m, 5H), 4.58- 4.68 (m, 1H), 3.65 (s, 3H), 3.12 (dd, 1H, J = 17, 13 Hz), 2.87 (dd, 1H, J = 17, 11 Hz), 2.09 (s, 3H). HR MS: Obs. Mass, 518.0652. Masa Cale, 518.0641.

Example 148. Preparation of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine.

To a suspension of the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine (166 mmol, 86.2 g) of Example In ethanol (350 mL), aqueous 1.0 N sodium hydroxide (250 mL) was added at room temperature. The mixture was heated to 40-45 ° C and the resulting clear solution was stirred for 3-4 hours. The mixture was then cooled to room temperature and the ethanol was separated on a rotary evaporator. The residue was diluted with 100 mL of water. Neutral impurities were extracted in ether (2 x 100 mL) and the basic aqueous phase was neutralized with 1 N HCl. The precipitated solid was collected by filtration and the solid cake was washed with water (1 L) and dried in air during the weekend. The crude solid was dissolved in hot acetonitrile (2 L) and the resulting solution was stored in the refrigerator for 15 hours. The white crystalline solids were collected by filtration and washed with cold acetonitrile (100 L). After drying in air, 79.76 g (95%) of a white solid were obtained, melting point 212-215 ° C. JH NMR, DMS0-d6 (400 MHz) delta 10.66 (s, 1H), 8.85 (d, 1H, J = 19 Hz), 7.47-7.6 (m, 5H), 7.15-7.29 (m, 5H), 4.58- 4.68 (, 1H), 3.12 (dd, 1H, J = 17, 13 Hz), 2.87 (dd, 1H, J = 17.11 Hz), 2.09 (s, 3H). HR MS: Obs. Mass, 505.0483. Masa Cale, 505.0488 (M +).

Example 149. Preparation of 2,6-dimethyl-4-trifluoromethyl-3-pyridinecarboxylic acid.

A solution of 2,6-dimethyl-4-trifluoromethyl-3-pyridinecarboxylic acid ethyl ester in 40 mL of THF and 10 mL of 1N sodium hydroxide solution was heated to reflux for 48 hours. The TLC of the mixture (me t a no 1: di c 1 or rome t a n o 3: 7) indicated that the starting material had been 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 indicated by NMR. This material was combined with the product of a similar experiment and chromatographed on silica gel, eluting with me t anol: di c 1 oreóme taño (3: 7) 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 to give, after drying under high vacuum, 0.9 g of a white foam. LR-ES-MS (C9H6F3N02): 218 (M-H).

Example 150. Preparation of N- [(2-chloro-6-methylphenyl) carbonyl] -4- [(2,6-dimethyl-4-trifluoromethyl-3-pyridinyl) carbonyl] amino] -L-phenylalanine. to. To a solution of 2, 6-dimetyl 1-4-t-fluorome thiol pyridine carboxylic acid (102 mg, 0.6 mmol) of Example 149 in dichloromethane (3 mL) was added a drop of DMF and oxalyl chloride ( 0.78 mmol, 99 mg) at 0 ° C (ice bath). The solution was stirred at this temperature for 3 0 min., Warmed to room temperature and stirred for a further 1 hour. The solvent and excess oxalyl chloride were then removed under vacuum and the residue was dried under high vacuum. To this was added methyl ester of 4-amino-N- [(2-c 1 oro-6-me ti 1-pheny1) ca rbon i 1] -L-phen i 1 to 1 ani na (0.5 mmol, 212 mg ) and in dichloromethane (5 mL) was dissolved. To this clear solution was added DIPEA (2.0 mmol, 0.258 g) at room temperature. The mixture was stirred for 15 hours at which time the TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with dichloromethane (20 mL) and water (100 mL). The two layers were separated and the organic phase was washed with saturated sodium bicarbonate solution (20 mL), brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtering the drying agent and removing the solvent gave a crude product which was used directly in the next step.

Examples 151-155. N- [(2-Chloro-6-methylphenyl) carbonyl] -4 - [(heteroaryl) carbonyl] amino] -L-phenylalanine derivatives subsequently prepared by the treatment of equimolar amounts of the 4-amino acid methyl ester were prepared N- [(2 - c 1 oro- 6-me ti 1 phen i 1) ca rb on i 1] - L - faith ni 1 to 1 an i na and the appropriate carboxylic acids are teroaromatics using the coupling procedure described in Example 109 and the hydrolysis process of the ester described in Example 13 Examples 156-160. The 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(heteroaryl) carbonyl] -L-phenylalanine derivatives set forth below were prepared by coupling methyl ester of 4 - [[(2, 6 -di cl orofeni 1) -carboni 1] ami no] -L- phen i 1 a lan i na and the appropriate heteroaromatic carboxylic acid using the general procedure described in Example 3, followed by ester hydrolysis using the general procedure described in Example 13.

Example 161. The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(1-na ft i 1) carbon i] -L- phen i the 1 anna was prepared with 77% yield from 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester and 1-naphthoic acid using the general procedure described in Example 3. HR MS: Obs mass. , 521.1024. Masa Cale, 521.1053 (M + H Example 162. N- [(2 -acetyl-1-6-methylphenyl) carbonyl] -4- [[(2,6-dichlorophenyl) -carbonyl]] ami no] -L-pheni 1 to 1 aine was prepared in yield 38% from methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine and 2-acetyl-6-methybenzoic acid using the general procedure described in Example 3 HR MS: Obs. Mass, 547.0579. Masa Cale., 547.0594 (M + Na).

Example 163. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N- [[2- (1, 1-dimethylethyl) phenyl] carbonyl] -L-phenylalanine methyl ester was prepared from the methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine and 2 - (1, 1 -dime ti 1 eti 1) benzoic acid using the general procedure described in Example 3. HR MS: Obs. Mass, 527.1523. Mass cale, 527.1573 (M + H).

Example 164. 2,6-Bis- (1-me tetyl 1) ben zoic acid was prepared in two steps from 2,6-bis (1-methyl-1-phenyl) 1 using the general procedure of two stages described in Example 105. HR MS: Mass obs., 206.0325. Mass cale, 206.0342 (+) f Example 165. The methyl ester of 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -N- [[(2,6-bis- (1-methylethyl) phenyl] was prepared ] carbonyl] -L-phenylalanine from 4 - [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine methyl ester and 2,6-bis- (l-methylethyl) benzoic acid methyl ester using the procedure general described in Example 3. LR MS: 555 (M +).

Example 166. The methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(2-me toxifeni 1) carboni 1] -L-phenylalanine was prepared from the methyl ester of 4 - [[(2,6-dichlorophenyl) -carboni 1] amino] -L-phenylalanine and 2-me t oxiben zoic acid using the general procedure described in Example 3. HR MS: Obs. Mass, 501.0984. Mass cale, 501.0984 (M + H).

Example 167. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N - [(2-chloro-4-methylsulfonylphenyl) carbonyl] -L-phenyl-alanine methyl ester was prepared in 73% yield from methyl ester of 4 - [[(2,6-di c 1 or ro faith or 1) -carboni 1] amino] -L-phenylalanine and 2-chloro-4-methyl-1-its-1-fonyl-benzoic acid co using the general procedure described in Example 3. HR MS: Obs. Mass, 583.0263. Mass cale, 583.0264 (M + H).

Example 168. The N- [(2,6-dichlorophenyl) carbonyl] -4- [[(2-chloro-6-methylphenyl) carbonyl] amino] -L-phenylalanine methyl ester was prepared from methyl ester of 4-methyl-4-chlorocarbonyl ester. - [[(2-chloro-6-methylphenyl) carbonyl] amino] -L-phenylalanine and 2,6-dichlorobenzoic acid using the general procedure described in Example 3.

Example 169. N- [(2,6-di-chloro-phene-1) -carbonyl] -4- [[(2-chloro-6-methylphenyl) carbonyl] -amino] -L-phenylalanine was prepared by ester hydrolysis N- [(2,6-di chloropheni-1) -carbonyl] -4- [[(2-chloro-6-methylphenyl) carbonyl] -amino] -L-fe-1-amino acid methyl ester of the anna of Example 168 using the general procedure described in Example 13.

Example 170. Preparation of 4 - [(2 S, 4 R) -3-acetyl-2-phenyl-4- (phenylmethyl) -5-oxo-l-imidazolinyl] -N- [(2-chloro-6-methylphenyl) ) -carboni 1] -L- feni lalan ina and 4 - [(2 R, 4 R) -3-acetyl-2-phenyl-4- (phenylmethyl) -5-oxo-l-imidazolinyl] -N- [( 2-chloro-6-methylphenyl) -carbonyl] -L-phenylalanine. to. Synthesis of N - [(1,1-dimethylethoxy) carbonyl] -4- [[(2 R) -2-amino-1-oxo-3-phenylpropyl] amino] -L-phenylalanine methyl ester To a solution of 4-amino-N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine methyl ester (5.09 g, 17 mmol) in DMF (60 mL) was added Fmoc-D-phen i 1 to 1 ani na (8.70 g, 22.5 mmol); DIPEA (12 mL, 69 mmol) and HBTU (8.50 g, 22.5 mmol). The mixture was then stirred at room temperature for 4 hours. The reaction mixture was diluted with water (150 mL) and the pale yellow solid which precipitated was collected by filtration. This solid was then redissolved in 60 mL of acetone and the solution was treated with 100 mL of water. The solid was collected by filtration and washed with 1N HCl, H20. After drying at 60CC under vacuum overnight a light yellow solid (13.2 g) was obtained. A portion of this solid (2.51 g, 3.78 mmol) 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 min. After removal of the solvent, the residue was recrystallized from ethyl acetate-hexane to give the N- [(1,1-dimethylethoxy) carbonyl] -4- [[(2R) -2-amino-1-oxo methyl ester -3-phenylpropyl] amino] -L-phenylalanine (1.36 g, 3.0 mmol) with yield of 81.5%. LR MS 442 (M + H). b. Synthesis of 4- (3-acetyl 5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine 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. Then the reaction flask was heated to 90 ° C and acetic anhydride (net, 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 4- (3-a-thi-5-oxo-2-phenyl) methyl ester. 4-phenylmethyl-1-imidazolidinyl) -N- [(1, 1 -dimet i let oxy) carbonyl] -L-phenylalanine, erythromycin 1 (4 1 1 mg) and triethromycin days 2 (1.25 g). These compounds are tereomeric days at the # 2 position of the idolimide zolimide ring. Both diastereomers gave LR MS (C33H37N3O6): 572 (M + H) c. Preparation of 4 [(2S, R) -3-acetyl-2-phenyl-4- (phenylmethyl) -5-oxo-1-imidazolinyl] -N- [(2-chloro-6-methylphenyl) -carbonyl methyl ester ] -L-phenylalanine.

The methyl ester of 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N- [(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (Di aster eme ro 1) (415 mg, 0.7 mmol) with 10 mL of 4N HCl in dioxane at room temperature for 2 hours. After removal of 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 2-cl or o-6-me thienobenzoic acid (105 mg, 0.617 mmol), HBTU (234 mg, 0.617). mmol) and DIPEA (246 μL, 1.42 mmol) at room temperature for 4 hours. The mixture was diluted with 30 mL of ethyl acetate, the mixture was washed with 1N HCl, water and brine (8 mL each). It was then dried over MgSO4, the solvent was removed and the residue was filtered through silica gel eluting with ethylhexane acetate (4: 1) to give methyl 4- (3-a) thi-5-oxo-1-methyl ester. 2-phenyl-4-phenylmethyl-1-ylamidazolidinyl) -N- [(2-chloro-6-methyl-1-phenyl) carbonyl] -L-phenylalanine diastereomer 1. d. Preparation of 4- (3-α-Cι-1 -5-oxo-2-phenyl-1-4-phenylmethyl-1-imidazolidinyl) -N- [(2-chloro-6-ethyl-phenyl) carbonyl] -L-phenylalanine di aste re omero 1.

Methyl ester of 4- (3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl) -N - [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine di aster was treated. ero 1 (90 mg, 0.128 mmol) in EtOH 3 mL) with NaOH (1N, 0.3 mL) at room temperature for 30 minutes. The resulting solution was acidified with 1 drop of HOAc and purified by HPLC (C-18, linear gradient of 5% 95% acetonitrile in water for 30 minutes) to give a white solid after lyophilization. MS: Obs. Mass, 609.9 (M + H).

Example 171. 4 - [(2 S, 4 R) -3- a -acetyl-2-phenyl-4- (3-pyridinium-lime-yl) -5-oxo-l-imidazolinyl] -N- [( 2-Chloro-6-methylphenyl) carbonyl] -L-phenylalanine and 4- [(2R, 4R) -3- a ce ti 1-2-phenyl-4- (3-pyridinylmethyl) -5-oxo-l-imidazolinyl ] -N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine from 4-amino-N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester and Fmoc -D-3-1-to-1-pyridine using the general procedure described in Example 170. The two diastereomers at the 2-position of the imidazoline ring were not easily separated by C-18 RP-HPLC and the compounds were isolated. they rehearsed as a mixture. HR MS: obs. 611.2070, cale 611.2061 (M + H).

Example 172. 4- [[(2,6-Dichloro-phenyl) carbonyl] amino] -N - [(2-chloro-4-hydroxyphenyl) carbonyl] -L-phenylalanine methyl ester was prepared in 35% yield at Starting from methyl ester of 4 - [[(2,6-di c 1 oro feni 1) carbon i 1] -amino] -L-phenylalanine and 2-chloro-4-hydroxybenzoic acid using the general procedure described in Example 3. IR MS: Mass obs 521.0433. Mass cale 521.0438 (M + H Example 173. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N - [(2-methylsulfonylphenyl) carbonyl] -L-phenylalanine methyl ester was prepared in 99% yield from 4-methyl ester. - [[(2,6-dichloropheni 1) carboni 1] -amino] -L-phenylalanine and 2-met i 1 sulfoni 1-benzoic acid using the general procedure described in Example 3. LR MS: 548 (M +).

Example 174. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N- [(2- (1-methyl) ethyl-6-methylphenyl) carbonyl] -L-phenyl-alanine methyl ester was prepared with 35% yield from methyl ester of 4 - [[(2,6-di-c-chloro-1) -carbon i 1] ami no] -L- phen i lalanin and 2- (l-me ti 1 ) eti 1 - 6 -meltigene zoi co using the general procedure described in Example 3. HR MS: Obs. mass, 526.1417. Mass cale, 526.1426 (M +).

Example 175. 4- [[(2,6-Dichlorophenyl) carbonyl] amino] -N- [(2-bromo-6-methylphenyl) carbonyl] -L-phenylalanine methyl ester was prepared in 64% yield from methyl ester of 4 - [[(2,6-di-chloro-phenyl-1-carbon) 1] -amino] -L-phenylalanine y. 2-bromo-6-methylbenzoic acid using the general procedure described in Example 3. HR MS: Obs. Mass, 563.0138. Mass cale, 563.0140 (M + H).

Example 176. Methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(2-ethyl-1-6-me ti-1-phenyl-1) ca rbon i 1] -L- phen was prepared 1 to 1 year with 46% yield from methyl ester of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -L-phenylalanine and 2-ethyl-1-6-me thiolben zoi acid co using the general procedure described in Example 3. HR MS: Obs. Mass, 513.1359. Mass cale, 513.1348 (M + H).

Example 177. N- [(2,6-Dichlorophenyl) -carbonyl] -4- [(2,4-dimethyl-3-pyridinyl) -carbonyl] amino] -L-phenylalanine was prepared from the hydrochloride of the methyl ester of 4 - [[(2,4-dimethyl) -3-pyridyl) carbonyl] amino] -L-phenylalanine and 2,6-dichloroben zoi co acid using the general method described in Example 107. MS (M + H ) 486 (2C1).

Example 178. Preparation of the sodium salt of 4- [[(2,6-dichlorophenyl) carbonyl] amino] -N- [(2-chloro-6-methylphenyl) carbonyl] -L-phenylalanine.

A suspension of 4- [[(2,6-dichloro-phenyl) carbonyl] amino] -N- [(2-chloro-6-methyl-phenyl) carboni 1] -L- phenylalanine (127.13 mmol, 64.3 g) in water (500 mL) was titrated with aqueous 1.0 N sodium hydroxide (120 mL) at room temperature until the pH of the solution became neutral. In order to ct complete dissolution, the mixture was heated to 40-45 ° C during the course of the titration. Some of the water was removed to an approximate volume of 300-350 mL under vacuum and the clear solution was lyophilized under high vacuum for 2 days to obtain 67 g (100%) as a white amorphous solid. Analysis (C24H? 8Cl3NaO4 »0.70H20): Calculated: C, 54.62; H, 3. 44; N, 5.31; Cl, 20.15; Na, 4.36; H20, 2.33. Found: C, 54.37; H, 3.49; N, 5.18; Cl, 20.11; Na, 4.25; H20, 2.54.

Example 179. VL & -4 / VACM-1 Scan Test The antagonist activity of VLA-4, defined as the ability to compete for binding to VCAM-1 i nmun ib i 1 i ada, was quantified using dual-antibody solid-phase ELISA. VLA-4 (integrin a4bl) linked to VCAM-1 is detected by a complex of anti-i-i n bl antibody antibody: HRP-conjugated anti-mouse IgG: chromogenic substrate (K-Blue). Initially this involves coating 96 well plates (Nunc Maxisorp) with recombinant human VCAM-1 (0.4 μg in 100 μl PBS), sealing each plate and then letting the plates stand at 4 ° C for 18 hours. The VCAM-coated plates were subsequently blocked with 250 μl of 1% BSA / 0.02% NaN3 to reduce non-specific binding. On the day of the assay, all plates were washed twice with VCAM assay buffer (200 μl / well of 50 mM Tris-HCl, 100 mM NaCl, 1 mM MnCl, 0.05% Tween, pH 7.4). The test compounds are dissolved in 100% DMSO and then diluted 1:20 in VCAM Assay Buffer supplemented with 1 mg / mL BSA (ie, final DMSO = 5%). A series of 1: 4 dilutions was carried out to obtain a concentration range of 0.005 nM - 1563 μM for each test compound. 100 μl per well of each dilution is added to the plates coated with VCAM, followed by 10 μl of VLA-4 derived from Ramos cell. These plates are mixed sequentially on a platform shaker for 1 minute, incubated for 2 hours at 37 ° C and then washed four times with 200 μl / well of VCAM assay buffer. Mouse anti-human integrin bl antibody is added to each well (0.6 μg / mL in VCAM Assay Buffer + 1 mg / mL BSA) and allowed to incubate for 1 hour at 37 ° C. At the end of this incubation period, all plates are washed four times with VCAM assay buffer. (220 μl / well). Then a corresponding second antibody is added to each well, goat anti-mouse IgG HRP-IgG (100 μl per well: 1: 800 dilution in VCAM Assay Buffer + 1 mg / mL BSA), followed by an incubation of 1 hour at room temperature and -conclusions through three washes (200 μl / well) with VCAM Assay Buffer. The color development begins with the addition of 100 μl of K-Blue per well (15 min incubation, room temperature) and ends with the addition of 100 μl of Red Stop Buffer per well. Then all the plates are read in a UV / Vis rofotome specimen at 650 nM. The results are calculated as inhibition% of the total binding (ie, VLA-4 + VCAM-1 in the absence of the test compound). In the following table, selected data for compounds of this invention are shown: E j emp 1 or 180. Cell-based scanning assay protocol (VLA-4) / VCAM-1 Ramos Ma fair: Soluble recombinant human VCAM-1 (mixture of domain 5- and 7-Ig) was purified from CHO cell culture medium by immunoaffinity chromatography and kept in a solution containing 0.1 M Tris-glycine (pH 7.5), NaCl 0.1 M, 5 M EDTA, 1 mM PMSF, 0.02% NaN3 and 10 μg / mL leupeptin. Calcein-AM was purchased from Molecular Probes Inc.

Methods: The antagonist activity of VLA-4 (integrin a4bl), defined as the ability to compete with surface cell VLA-4 for binding to immobilized VCAM-1, was quantified using the Ramos-VCAM-1 cell admission assay. Ramos cells comprising VLA-4 from surface cells were indicated with a fluorescent color (Calcein-AM) and allowed to bind to VCAM-1 in the presence or absence of test compounds. A reduction in fluorescence intensity associated with adherent cells (% inhibition) reflected the competitive inhibition of cell adhesion mediated by VLA-4 by the test compound.

Initially this involved coating 96 well plates (Nunc Maxisorp) with recombinant human VCAM-1 (100 ng in 100 μg PBS), sealing each plate and letting the plates stand at 4 ° C for 18 hours. The VCAM-coated plates were subsequently washed two times with 0.05% Tween-20 in PBS, and then blocked for 1 hour (room temperature) with 200 μl blocking buffer (1% BSA / 0.02% interanal). ) to reduce non-specific binding. After incubation with blocking buffer the plates were inverted, absorbed and the remaining buffer was aspirated. Then each plate was washed with 300 μl of PBS, inverted and the remaining PBS was aspirated.

The test compounds were dissolved in 100% DMSO and then diluted 1:25 in VCAM cell adhesion assay buffer (4 mM CaCl2, 4 mM MgCl2 50 M TRIS-HC1, pH 7.5) (final DMSO = 4% ). A series of eight 1: 4 dilutions was carried out for each compound (general concentration range of 1 nM - 12,500 nM). 100 μl / well of each dilution was added to the plates coated with VCAM, followed by 100 μl of Ramos cells (200,000 cells / well in 1% BSA / PBS). The plates containing the test compounds and Ramos cells were incubated for 45 minutes at room temperature, after which 165 μl / well of PBS was added. The plates were inverted to separate the non-adherent cells, absorbed and 300 μl / was added. PBS well. The plates were inverted again, absorbed and the remaining buffer gently aspirated. 100 μl of lysis buffer (0.1% SDS in 50 mM TRIS-HC1, pH 8.5) was added to each well and stirred for 2 minutes on a rotating shaking platform, then the plates were read for fluorescence intensity. on a Cytofluor 2300 fluorescence measurement system (Millipore) (excitation = 485 nm, emission = 530 nm).

The results are shown in the table s i gu i en t e: Table Example 181. Oral dosage form Preparation procedure: 1. Mix products 1, 2, 3 in an appropriate mixer for 15 minutes. 2. The powder mixture of Step 1 is granulated with 20% PVP K30 solution. 3. The granulate from Step 2 is dried at 50 ° C. 4. The granulate of Step 3 is passed through an appropriate grinding equipment. 5. The product 5 is added to the ground granulate of Step 4 and mixed for 3 minutes. 6. Combine the granulate from Step 5 in an appropriate press.

E j emp 1 or 182 Admi ssm onm ation Ae ol * Depending on the activity of the compound The pH is adjusted with sodium hydroxide solution (1 N) or HCl solution (10% w / v) Process : 1 The drug substance is dissolved in the t ampon. 2. The solution is filtered through a 0.22 micron filter.

The particle size distribution after nebulization of the previous solution (measured using Malvern Mastersizer X) is in the range of 1-6 mi eras It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is what is clear from the present description of the invention - Having described the invention as above, it is claimed as property what is contained in the following

Claims (43)

1. - A compue.sto of the formula

characterized in that: one of X and X 'is hydrogen, halogen, or lower alkyl, the other is a group of the formula ":

wherein: Ri is hydrogen or lower alkyl, Rt 5 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, -OH, lower alkoxy-, to 1 coxy carbon and the lower, carboxy, lower alkyl aminosulfonyl, perfluoro lower alkyl, lower alkylthio-, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkyl halo, lower alkylthio lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryloxy or a group of the formula R17-C = C-, Ri6 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluoro lower alkyl or lower alkylthio, R17 is hydrogen, aryl, heteroaryl or lower alkyl which is unsubstituted or substituted by O'H, aryl or heteroaryl, it is already 0 or 1; or one of X y1 X 'is a group of the formula:

wherein Het is a 5 or 6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms chosen from N, O, and S;

of 9 or 10 member-s containing I, 2, 3 or heteroatoms chosen from O, S and N, a, Ri, R15 'and Rie are as indicated ant is, and R30 is hydrogen or lower alkyl, or is absent; or one of X and Xt is a group of the formula:

wherein: R 8 is lower alkyl, aryl, heteroaryl, arylalkyl, ethereal alkyl, R 19 is lower alkyl, which is unsubstituted or substituted by no or more than halogen, hydroxy, lower alkoxy, ryl, hetero to ri 1 or,? i? iitio, or 19 is aiiio ± iateroarixo, and R20 is to the lower uilo or lower aioio, or

R19 and R20 taken together are tet ramet i leño;

And it's a group of the formula

wherein: R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, coxy 1 to qui 1 or lower, lower alkylamino, aryl, arylalkyl, nitro, cyano, lower alkylthio, to lower sulphide, alkyl lower sulfonyl, lower alkanoyl, halogen, or perfluoroalkyl and at least one of R22 and R23 is other than hydrogen, and R24 is hydrogen, hydroxy, lower alkyl, lower alkoxy, al -ui lsu-tf ^ eí + il-O- inferiox, amino, aryl, nitro, cyano, halogen, or is a group of the formula:

where R25 is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkoxy alkyl, and -R26 is hydrogen or lower alkyl, or R22 and R24 taken together are a fused benzene ring; or Y is a g po Y - 2 qe »is a five or six member monocyclic heteroaromatic group containing 1, 2 or 3 heteroatoms chosen from N, 0, and S, or a bicyclic heteroaromatic group of 9 or 10 members containing 1, 2 *, 3 or 4 heteroatoms chosen from O, S, and N, where said heteroaromatic group is linked via a carbon atom to the amide carbonyl and one or two carbon tones of said heteroaromatic group are (t) their titers (a) by lower alkyl, allogen, cyano, perfluoroalkyl or aryl and at least one of said substituted carbon atoms is adjacent to the carbon atom bonded to the amide carbonyl; and 2 is hydrogen or lower alkenyl; and its pharmaceutically acceptable salts and esters.

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

3. - A compound according to the rei indication 1 6 2, characterized in that X 'is hydrogen.

4. - A compound according to any of claims 1-3, characterized in that: R-22 and R23 are independently hydrogen, lower alkyl, nitro, lower alkylthio, lower alkoxy, lower alkylamino, lower alkyl, lower alkyl sulfonyl , lower alkanoyl, halogen, or perfluoroalkyl wherein at least one of

R22 and R23 is not hydrogen, and R2 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, amino, nitro, halogen or a group of the fmumu 1 a:

wherein R25 is aryl lower alkyl and R26 is hydrogen or lower alkyl, or R22 and R24 taken together, are a fused benzene ring.

5. - A compound according to claim 4, characterized in that R22 is hydrogen (when R23 is other than hydrogen), lower alkyl or halogen.

6. - A compound according to claim 4 or rei indication 5, characterized in that R 2 is hydrogen, hydroxy, lower alkylsulfonyl, lower alkyl, halogen, nitro or lower alkoxy or a group of the f rmu 1 a:

wherein R25 is phenyl unsubstituted or unsaturated hydroxy-unsaturated alkyl, and R26 is hydrogen, or R22 and R24 taken together are a fused phenyl ring.

7. - A compound according to claim 6, characterized in that R24 is hydrogen, hydroxy, amino, methyl, chlorine, bromine, nitro, -OCH3, -SO2CK3 and R26 is H and R55 is

HO ^ ^

8. - A compound according to any of claims 4-7, characterized in that R23 is hydrogen (when R22 is other than hydrogen), lower alkyl, lower alkylamino, halogen, nitro, perfluoro lower alkyl, lower alkoxy, lower alkanoyl, i ls u 1 fini 1 or lower or lower alkyl sulfonyl.

9. - A compound according to claim 8, characterized in that R23 is methyl, ethyl, isopropyl, tertbutyl, trifluoromethyl chloro bromo or n ro

-COCH3, -SCH3, -SOCH3, -SO2CH3, -NHCH3 or -OCH3

10. - A compound according to any of the above indications 4-9, characterized in that Y-1 is selected from the group consisting of:

11. - A compound according to any of the rei indications 1-3, characterized in that in Y-2 the monocyclic heterocyclic groups or bicyclic ethers of 9 or 10 members are chosen from the group of:

< r < vtT CTsO?

12. - A compound according to claim 11, characterized in that the groups Y-2 have the formula:

13. - A compound according to any of claims 1-3, characterized in that in X-6 the groups R15 and Ri6 are independently hydrogen, lower alkyl, nitro, halogen, perfluoroalkyl, cyano or aryloxy.

14. - A compound according to claim 13, characterized in that R15 or Ri6 is H, methyl, nitro, chloro, fluoro, trifluoromethyl, cyano or phenoxy.

15. - A compound according to claim 13 or claim 14, characterized in that the group X-6 has the formula:

16. - A compound according to any of claims 1-3, characterized in that in X-7 Het is 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 o.xigen

17. - A compound according to claim 16, characterized in that the heteroaromatic ring is

• (* -VS, '< N-N tSyr eSxr

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

19. - A compound according to claim 18, characterized in that the bicyclic heteroaromatic ring is

4 - . 4-quinol in i 1 o, 1 - i s oqu i no 1 i n i 1 o o o?

20. - A compound according to any of claims 1-3, characterized in that in X-7 Rj5 is hydrogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluoro lower alkyl, lower alkylthio, lower alkanoyl or aryl.

21. - A compound according to claim 20, characterized in that R15 is isopropyl, methyl or phenyl.

22. - A compound according to any of claims 1-3, characterized in that R 6 in X-7 is hydrogen, halogen, nitro, cyano, lower alkyl or perfluoro lower alkyl.

23. - A compound according to claim 22, characterized in that Rie is methyl or trifluoromethyl.

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

25. - A compound according to any of claims 1-3, characterized in that the groups X-7 have the formula 1 a:

26. - A compound according to any of claims 1-3, characterized in that in X-6 or X-7 Ri is hydrogen.

27. - A compound according to any of claims 1-3, characterized in that in X-6 or X-7 a is 0.

28. - A compound according to any of claims 1-3, characterized in that in X-10 R? 8 is lower alkyl or phenyl in which the phenyl ring is unsubstituted or monosubstituted by halogen, hydroxyl or is phenyl lower alkyl.

29. - A compound according to claim 28, characterized in that R 8 is terbutyl, phenyl, phenoxy, chlorophenyl or phenylethyl.

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

31. - A compound according to claim 30, characterized in that R19 is methyl, isobutyl, benzyl, 4-c 1 or stearic acid, 4-me t oxiben c i 1 or 2-p i r i di lme t i 1.

32. - A compound according to any of claims 1-3, characterized in that en.X-10 R2o is lower alkanoyl.

33. - A compound according to the rei indication 32, characterized in that R20 is acetyl.

34. - A compound according to any of claims 1-3, characterized in that the groups X-10 have the formula:

35. A compound selected from the group:

rrr "Tl

36. - Compounds according to any of claims 1-35, for their use as a medicament.

37. - Compounds according to any of claims 1-35 for its use as a medicament in the treatment of rheumatoid tritis, multiple sclerosis, intestinal disease inflates to oria or asthma.

medicamen or containing a compound according to any of claims 1-35 and a vehicle and apreceic te vehicle in te.

39. - An edicament for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma, containing a compound of non-limiting nature with any of claims 1-35 and a therapeutically inert carrier material.

40. - A method for the production of a medicament, especially for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma, whose method comprises giving a galenical dosage form to a compound according to any of the claims. 1-35 together with a therapeutically inert carrier material and, if desired, one or more additional therapeutically active substances.

41. - The use of a compound according to any of claims 1-35 in the treatment of diseases, especially in the treatment of rheumatoid arthritis, multiple sclerosis, Inflammatory bowel disease or asthma.

42. - Use of a compound according to any of claims 1-35 in the preparation of a medicament for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease or asthma.

43. - The new compounds, intermediates, procedures, medications and methods as described above.

D E R I V D Y N D 'N -'? ROTrJ? Np.AT.ANTN?

SUMMARY OF THE INVENTION

The compounds of the formula are described

as was their salts and esters wherein X, X ', Z and Y are as described in the description and which have activity as inhibitors of binding between VCAM-1 and c expressing VLA-4. These compounds are useful for the treatment of diseases whose symptoms and / or injury are related to the binding of VCAM-1 to c expressing VLA-4.