MXPA01003284A

MXPA01003284A - Diaminopropionic acid derivatives

Info

Publication number: MXPA01003284A
Application number: MXPA/A/2001/003284A
Authority: MX
Inventors: Robert William Guthrie; Nader Fotouhi; Paul Gillespie; Sherrie Lynn Pietranicocole; Weiya Yun
Original assignee: F Hoffmannla Roche Ag
Priority date: 1998-10-13
Filing date: 2001-03-29
Publication date: 2002-02-26

Abstract

Compounds of the formula (1a), wherein R1 is a group of the formula (2) where R1, R2, A, B, U, V, W, X, Y, Z, k and n have the significance given in the specification, are useful to treat rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, ulcerative colitis, artherosclerosis, restenosis, pancreatitis, transplant rejection, delayed graft function and diseases of ischemia reperfusion injury, including acute myocardial infarction and stoke.

Description

DERIVATIVES OF DIAMINOPROPIONIC ACID Field of the Invention Inflammation occurs when the leukocytes migrate to the site of injury in the tissue, eg, injured tissue as a result of acute myocardial infarction, cardiopulmonary bypass or stroke. In myocardial infarction, the interruption of blood flow to cardiac tissue causes lesions due mainly to lack of oxygen (ischemia). When the blood flow is restored (reperfusion), additional damage to the ischemic tissue can occur. This reperfusion injury is of significant importance mainly due to neutrophils migrating from blood vessels to damaged tissue by interaction with adhesion molecules on the surface of blood vessels. Neutrophils mediate inflammation, tissue necrosis and filling of microvessels. An effective approach to the reduction of reperfusion injuries is to block the interaction between neutrophils and adhesion molecules in the walls of blood vessels. REF .: 127727 One of said adhesion molecules is the intracellular adhesion molecule 1 (ICAM-1), a member of the superfamily of immunoglobulin (Ig) genes that is expressed in activated endothelial cells in the blood vessel wall. , activated T cells, activated B cells and monocytes. ICAM-1 binds to receptors known as β2 integrins that are found in B and T lymphocytes, monocytes and neutrophils. The binding of ICAM-1 expressed in endothelial cells to β2 integrins Mac-1 (macrophage differentiation antigen, also known as CDllb / CD18, CR3, and ctMß2) and / or LFA-1 (antigen associated with the function lymphocytic - 1, also known as CDlla / CD18 and aLß2) expressed in neutrophils activated by mediators of inflammation such as platelet activation factor (PAF) and interleukin 8 (IL-8), mediates the firm adhesion required before extravasation of neutrophils at points of inflammation. The extravasated and activated neutrophils adhere to the tissue bed, causing tissue necrosis and microvascular obturation. In vitro studies have shown that the binding of neutrophils to activated cardiac myocytes depends on β2 integrins (Entman et al., J Clin Invest, 1990, 85, 1497-1506). Mac-1 also binds to fibrinogen, the plasma protein that mediates platelet aggregation in the presence of platelet activation factor. The platelets bind to damaged tissue, which results in the deposition of fibrinogen in the blood vessel wall. The interaction of fibrinogen and Mac-1 L [o / Grn 13.9.99 can therefore contribute to the adhesion of neutrophils and monocytes to endothelial cells. The murine antibody 7E3, directed against the interin anbß3, binds also to integrins av ß3 and Mac-1, and also inhibits the interaction of neutrophils with immobilized fibrinogen (Plescia et al., J. Biol. Chem., 1998, 273, 20372-20377). The humanized Fab fragment of 7E3 is approved for the prevention of ischemic complications in patients undergoing percutaneous cardiac coronary intervention. In humans, the expression of beta-2 integrin Mac-1 is positively regulated during cardiopulmonary bypass (Gillinov et al., Ann Thorac Surg., 1993, 56, 847-853) and in the acute phase of heart attack. myocardium (Meisel et al., J. Am. Coil, Card., 1998, 31, 120-125). Soluble ICAM-1 concentrations are also elevated in acute myocardial infarction in humans (Kaikita et al., Japanese Cir. Journal, 1997, 61, 741-748). The reduction of the interaction between ICAM-1 and its receptor decreases neutrophil migration and the corresponding inflammation, and consequently reduces reperfusion injury caused by inflammation after acute myocardial infarction. For example, mice deficient in ICAM-1 show decreased neutrophil migration in response to chemical peritonitis (Sligh et al., Proc. Nati, Acad. Sci. USA, 1993, 90, 8529-33), and were protected from reperfusion injury in models of stroke and renal failure (Soriano et al., Ann Neurol., 1996, 39, 618-624); Kelly et al., J. Clin. Invest. 1996, 97, 1056-63). Antibodies against ICA-1 are protective in models in cats, dogs and rabbits, as well as in various primate models of cardiac reperfusion injuries (Ma et al., Circulation, 1992, 86, 937-946; Lefer et al., Am. J. Physiol., 1996, 271, H2421-H2429, Zhao et al., J. Leukocyte Biol., 1997, 62, 292-300, Lefer et al Circulation 1993, 88, 1779-1787). Biological molecules that block ICAM-1 activity, for example antibodies against ICAM-1, CDllb and CD18 have also been shown to reduce inflammatory lesions in stroke models (Zhang et al., Stroke, 1995, 26, 1438-43; Chen et al., Ann Neurol., 1994, 35, 458-63; Zhang et al., Brain Res. 1995, 698, 79-85; Bowes et al., Exp. Neurol., 1993, 119, 215-219). Antibodies to CDllb are effective in attenuating neointima growth in a rabbit model of restenosis (Rogers et al., Proc.Nat.Acid.Sci.USA, 1998, 95, 10134-10137). Antibodies that block ICAM-1 activity are subject to International Patent Applications Nos. 9302191, 9402175, 9404188, 9408620, 9412214, 9726912, and U.S. Patent No. 5,695,760. Antisense oligonucleotides against murine ICAM-1 have been shown to attenuate reperfusion injury and renal failure in rats (Stepkowski et al., J. Immunol., 1994, 153, 5336-46; Haller et al., Kidney Int., 1996, 50, 473-480). Molecules of this type have been patented (U.S. Patent Nos. 5,591,623 and 5, 580, 969). However, compounds such as small molecule (ie, low molecular weight) antagonists of the interaction between ICAM-1 and its ligands offer advantages over antibodies and antisense oligonucleotides for the treatment of reperfusion injury because the molecules They have smaller tissue penetration, lack immunogenicity, have shorter half-lives, lower cost and generally have less risk of serious adverse effects. Accordingly, compounds other than these biological molecules that block ICAM-1 activity are desirable as therapeutic agents for the treatment of acute inflammatory conditions such as ischemia-reperfusion injury. A certain number of patents and applications refer to compounds that block ICAM-1 activity, for example, US Pat. 5,288,854, 5,530,157, 5,489,598, 5,464,855, 5,709,141, 5,707,985, International Patent Applications Nos. 9640641 and 9807423.

This invention relates to compounds which are capable of blocking ICAM activity and which are consequently particularly useful in the treatment of reperfusion injury after acute myocardial infarction. More particularly, this invention relates to compounds of the formula: where Rl is a group of formula where A is hydrogen, hydroxy, amino or halogen, and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl or lower alkoxy, R2 is a group of the formula: H-CH2-N? H -CH-CH = CH- -CH2-CH2-CH- -C-NH-CH- wherein R3 is hydrogen, carboxy or lower alkyl; n is 0 or 1; U, V and are independently hydrogen, halogen or lower alkyl, with the proviso that U and V are not both hydrogen; X is carbonyl, lower alkylene substituted with phenyl, or sulfonyl; Y is lower alkylene which may be substituted with one or more of amino, substituted amino or cycloalkyl, or Y is lower alkenylene or lower alkylenethi; Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) -amino] carbonyl] pyrazin-2-yl, hydroxy, phenylmethoxy, -chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] phenyl, [(2,6-dichlorophenyl) methoxy] -phenyl or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, and may be any of the unsubstituted rings or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy , lower alkyl or lower alkyl that is substituted with halogen, amino or lower alkoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH, or -CONH2, as well as pharmaceutically acceptable salts and esters thereof. The term halogen means bromine in general, chlorine, fluorine or iodine. In the case of U, V and, the preferred halogens are bromine, chlorine and fluorine. By "lower alkyl" is meant saturated hydrocarbon chains such as methyl, ethyl, propyl, and the like. The length of the chains is preferably from 1 to 10 carbon atoms, and more preferably from 1 to 4 atoms, including any branched carbon such as defined in this paragraph. A lower alkyl substituent of this invention may be branched, which means a lower alkyl having one or more lower alkyl groups attached to one or more of its carbons, such as isobutyl or 2-ethyl-4-methylpentyl, A lower alkyl substituent it may also be unbranched, which means that it is a linear chain without alkyl substituents. Examples of various lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tere-butyl, n-pentyl, n-hexyl. The lower alkyl groups may be substituted with another group, preferably halogen, or lower alkoxy as defined below. Examples of substituted lower alkyl groups include 2-hydroxyethyl, 2-methoxypropyl, 3-oxobutyl, cyanoethyl, trifluoromethyl, 2-nitropropyl, benzyl, including p-chlorobenzyl and p-methoxybenzyl, and 2-phenylethyl. By "lower alkoxy" is meant a lower alkyl as defined above which may be branched or unbranched as also defined above, and which is linked by an oxygen to another group (ie, alkyl ethers). Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. Said groups may be substituted, preferably by halogen or lower alkyl as defined above. By "lower alkylene" is meant a hydrocarbon chain linking two other groups, for example it is attached to another group at either end thereof, for example methylene, ethylene, butylene and the like. Said substituent preferably has from 1 to 10 carbon atoms, and more preferably from 1 to 5 carbons. Said groups may be substituted, preferably with an amino, acetylamino (an alkylcarbonyl group linked through a nitrogen atom), or a lower cycloalkyl group. By the latter, it is meant a saturated hydrocarbon ring, preferably with a total of 3 to 10 methylenes (including the linking carbons), more preferably from 3 to 6. Examples are cyclopropyl, cyclobutyl and cyclohexyl. By "lower alkenylene" is meant a hydrocarbon chain containing a double bond and linking two other groups, that is, it is joined to another group at either of its two ends. Said substituent is preferably chosen from 1 to 10 carbons, and more preferably from 2 to 6 carbons including branched carbons, and may be branched or unbranched as defined above with respect to the alkyl groups. Examples are -CH = CH-, -CH = CH-CH2-CH2-CH2-, -CH2-CH2- and -CH = CH-CH2-. By "lower alkylthio" is meant a lower alkyl group linked through a divalent sulfur atom, for example a methylmercapto group or an isopropylmercapto. By cycloalkyl containing 0 to 3 heteroatoms which may be the same or different is meant a non-aromatic ring with from 3 to 10, preferably from 3 to 6, atoms in the ring. For the purposes of this invention, cycloalkyl includes heterocycloalkyl. As defined above, said ring may consist solely of hydrocarbon residues (that is, methylene groups), or may include one or more heteroatoms, preferably nitrogen, sulfur or oxygen alone or in any combination, instead of one or more methylenes. Said ring may contain a double bond. Said rings may be unsubstituted or substituted with at least one of several possible substituents. By * at least one of "it means that the ring may be substituted by one of the possible substituents, or by more than one of the same substituent, or by any combination of several possible substituents. Preferably the substitution occurs on a carbon and not on a heteroatom. Examples of rings of this type are cyclohexyl, ethylcyclopentel, piperidyl, pyrrolidinyl, morpholinyl, and the like. When specific rings such as cyclohexyl and the like are mentioned, unless otherwise specified these rings are not substituted. Thus, cyclohexyl means "unsubstituted cyclohexyl", while substituted cyclohexyl means cyclohexyl with one or more substituents.

By "aryl" is meant containing from 0 to 3 heteroatoms which may be the same or different from an aromatic ring with from 5 to 6 ring atoms. For purposes of this definition, aryl includes heteroaryl. Thus as defined above, said ring may consist solely of carbon, or may include one or more heteroatoms, preferably nitrogen, sulfur or oxygen, alone or in any combination, in substitution of one or more of the carbons. Said rings may be unsubstituted or substituted as previously described by cycloalkyls. Examples of such rings are phenyl, thiophene (used herein as a synonym of thienyl), methyl thiophene, pyridine (pyridyl), m- or o-nitrophenyl, p-tolyl, m- or p-methoxyphenyl, 3,4-dimethoxy- phenyl, p-chlorophenyl, p-cyanophenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, perfluorophenyl and the like. When specific rings such as phenyl, thiophene, pyridine and the like are mentioned, unless otherwise indicated these rings are not replaced. Thus, "thiophene" means unsubstituted thiophene, while substituted thiophene means a thiophene with one or more substituents. By "aryl-lower alkyl" is meant an aryl ring with a lower alkyl substituent, which is attached through the substituent to another group In this context, aryl means an aromatic ring with five or six ring atoms, preferably all of which are carbon atoms, and preferably the ring is not substituted in any other way.Phenyl-lower alkyl is intended to mean a phenyl ring with a lower alkyl substituent, which is attached through the substituent to another group Examples are benzyl (phenylmethyl), phenylethyl and the like A fused ring system containing two or three rings which are independently cycloalkyl or aryl as defined above two or three fused rings, in any combination of aromatic and non-aromatic co, which may be unsubstituted or substituted by halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl which may be unsubstituted or substituted by halogen or lower alkoxy, lower alkoxy, alkanesulfonyl lower, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, alkoxycarbonyl or acetoxy as defined above. Examples of rings of this type are naphthalene, indole, indoline, benzimidazole, oxindole, benzotriazole and the like. Amino lower alkyl means a lower alkyl group which is substituted by an amino group and which is attached to another group via a carbon of the lower alkyl group. This is different from a substituted amino, which is linked to another group through nitrogen. "Substituted amino" means an amino group which is mono- or di-substituted with another group, preferably a lower alkyl (for example methyl) or a lower acyl group (for example acetyl). By "lower acyl" is meant a group derived from an alkyl lower carboxylic acid or an aryl carboxylic acid. Examples are acetyl, propionyl, butyryl, pivaloyl, benzoyl or the like. By "aryloxy" is meant an aryl group that is bonded through an oxygen atom to another group. An example is phenoxy.

A lower alkane (or alkyl) sulfonyl is an alkyl group attached to a sulfonyl group, which is attached to another group, such as methylsulfonyl and the like. By "lower alkoxycarbonyl" is meant an inner alkoxy group linked through a carbonyl group to another group. Examples of internal alkoxy groups are carbonyl methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like. When W is hydrogen, then U and V are symmetric in that U and V are equivalent positions, and the U and V identifications can be used interchangeably. Therefore, for the purposes of this application, a compound wherein W is hydrogen and U is a first substituent and wherein V is a second substituent, is effectively the same compound if V is identified as the first substituent and U is identified as the second substituent For example, a compound in which U is chlorine and V is hydrogen is equivalent to a compound in which V is chlorine and U is hydrogen. Accordingly, the description of one of said compounds also describes its equivalent. This does not mean in general that U and V must be the same. In any compound of this invention, U and V are independent of one another, and consequently may be the same or different. By 'substituted with at least one of' followed by a list of several possible substituents is meant substitution with one or more of a type of substituent or by a combination of more than one type of substituent, for example substituted by at least one of halogen, methyl or hydroxy includes substitution by two bromines, or a chlorine, a bromine and an iodine, or a chlorine and a methyl, or a fluorine, a methyl and a hydroxy, or two hydroxys, or two methyls and a hydroxy , or a methyl or a bromine, etc. The selection of the substituents available in any of these claims is limited to the specific substituents listed in claim 1. Thus, a claim referred to a group substituted by at least one of methyl or hydroxy will not include substituted groups, for example, with a methyl and a bromine, or a methyl, a hydroxy and a nitro.The pharmaceutically acceptable salts and esters are well known in the field and can be prepared by conventional methods taking into account the chemical nature of the compound. Examples of pharmaceutically acceptable salts of alkali metal or alkaline earth metal compounds such as sodium, potassium, calcium, magnesium, basic amines or basic amino acids, ammonia or alkylammonium salts. Particularly desirable salts for compounds of this invention are sodium salts. The sodium salt of any compound of this invention is easily obtained from the acid by treatment with sodium hydroxide. Examples of said sodium salts are 3-benzoylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -benzoyl] -L-alanine, sodium salt, and 3-benzoylamino- N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine, sodium salt. As for the basic compounds, the examples are salts of inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, citric, formic, fumaric, maleic, acetic, succinic, tartaric, methanesulfonic and p-toluenesulfonic acids. Examples of pharmaceutically acceptable esters include unbranched lower alkyl esters such as methyl, ethyl, n-propyl and the like.

This invention includes the following compounds: Compounds of the formula wherein Rl is : R2 is -CH-NH-c_, or -CH2-CH2-C- f 0) 0 -O-CH2-C- R i 3 -CH2-CH2-CH-Q -CH-CH = C-j 0 -CH = CH-CH- > 0 - C-NH-CH- f 0 , _ and R2 e £ rCH-NH-C-, 0-CH2-CH2-C- > 0 > 0 -O-CH.-C- or - CH = CH-CH- c - CH-CH = CH- 0 • - CH2-CH2-CH- 0 -C-NH-CH- - ° " - CH2-CH - f 0 -r CuH2-rCuH OR R3 OO or I3 II "II H and R2-CH-NH-C-> C-CH2-CH2-C-> c-0-CH2-C -? 3 R3? HO R3 - CH = CH-CH-> 0 - CH-CH = CH-% 0 - CH, -CH, -CH- _ c -_C_NH-CH- ^ Q - CH, - "N -, or - CH2-C -CH = CH- (H - CH2 - N R ^, _, A, "i | 3 X N", - 'N compounds in the -CH2-CH2-CH- C -c-NH-CH-, or N. ^ J ^ es OR II - C-NH-CH - or "X N * N_ -, and ccppuestos in B Cl and R2 is that Rl is - CH-NH-C-, or - CH2-CH2-C- 0? HO • R, A "n i3 ^ -, N - C - NH - CH - 0 i In one aspect, the invention includes compounds of the formula wherein Y is lower alkylene which may be substituted by amino, acetylamino or lower cycloalkyl , lower alkenylene, lower alkylenethio, X is carbonyl or sulfonyl, Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3- [[(5-chloropyridin-2-yl) amino] carbonyl ] pyrazin-2-yl, cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be same or different and in which the rings they represent, Z may be unsubstituted or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl, which may be be unsubstituted or substituted by halogen or lower coxy, lower alkylsulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl or acetoxy; and wherein R1, R2, U, V,, X, n and k are as above. In another aspect, the invention includes compounds of the formula lb wherein U is chlorine or bromine; X is carbonyl, lower alkylene substituted with phenyl or sulfonyl; Y is lower alkylene which may be substituted with one or more of amino, substituted amino or lower alkyl cycloalkyl, or Y is lower alkylene or lower alkylenethio; Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) amino) carbonyl] pyrazin-2-yl, hydroxy, phenylmethoxy, or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms , which may be the same or different, any of the rings may be unsubstituted or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl , lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl which is substituted by halogen, amino or lower alkoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH, or -CONH2; compounds of formula where U, X, Y, Z and k are as in the formula lb; compounds of formula ld in which any or all of U, V and W are halogen, hydrogen or methyl, with the proviso that U and V are not both hydrogen; X is carbonyl or sulfonyl; k is 0 or Y is methylene, R3 is hydrogen, carboxy or lower alkyl; and Z is like in the formula lb; with the proviso that Y is methylene when Z is hydrogen, lower alkylthio, amino, -COOH or -CONH2. Compounds of the formula le where Rl is a group of formula wherein at least one of U and V are chlorine, bromine or methyl; k is 0 or Y is butylene; X is carbonyl, phenyl-lower alkyl, or sulfonyl; and Z is hydrogen, phenyl, thiazole or thiophene, or Z is phenyl, thiazole or thiophene substituted with at least one of methyl or acetylamino; with the proviso that Y is butylene when Z is hydrogen, lower alkylthio, amino, -COOH or -CONH2; Compounds of formula lf wherein U, V and are independently hydrogen, halogen, or lower alkyl with the proviso that U and V are not both hydrogen; X is carbonyl, phenyl-lower alkylene or sulfonyl; Y is lower alkylene which may be substituted by amino, substituted amino, cyclo lower alkyl, lower alkenylene or lower alkylenethio, and k and z are as in formula lb.

Among the compounds of the formula, those in which R 1 is naphthalenyl are preferred. Preferred compounds of formula I are those in which one of U or V is chlorine or methyl, while the other is hydrogen, chlorine or methyl; W is hydrogen; and X is carbonyl and k is 0, especially those in which one of U or V is chlorine, while the other is hydrogen, W is hydrogen and R3 is hydrogen. Of all the mentioned compounds, those in which Z is thienyl, furyl, thiazolyl, cyclopentyl, cyclohexyl, piperidyl, pyridyl, naphthalenyl, benzothienyl, benzothiazolyl, 1,4-dioxa-8-thiaspiro- [4, 5] - are preferred. decyl, phenyl or phenyl substituted with one or more of lower alkoxy, lower alkyl, chloro, bromo, fluoro, hydroxy, nitro, cyano, amino, substituted amino, aminosulfonyl, alkoxycarbonyl, trifluoromethyl, or carboxy. Also preferred are those in which A when present, is hydroxy, hydrogen or amino and B is hydrogen or hydroxy; is hydrogen and at least one of U and V are methyl or halogen; k is 1 and Y is lower alkylene; or k is 0; Z is hydrogen phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl or isoxazolyl or a six-membered aromatic ring with one to three nitrogens, said ring systems being unsubstituted or substituted with at least one of: halogen , hydroxy, lower alkoxy, nitro, amino, substituted amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl, or lower alkoxycarbonyl. Examples of said compounds especially Preferred are: N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (diphenylacetyl) amino-L-alanine; 3 (1-adamantylcarbonyl) amino-N ~ [2-chloro-4- [[[(3-hydroxy-phenyl) -methyl] amino] -carbonyl] benzoyl] -L- N- [2-chloro-4] - [[[3- (3-hydroxyphenyl) methyl] amino] - - c? -bonyl] bsnzoyl] -3 - [(2S) -5-oxotetrahydrofuran-2-C * rbonyl] amino-L-alanine; N [2-chloro-4- [[[3-hydroxyphenyl) methyl] amino] carbonyl] > 3-bcnzoyl] -3- (1, 4-dioxa-8-thiapiro [4.5] decane-6-carbonyl) -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (2-phenoxybenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (furan-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (5-nitrofuran-2-carbonyl) amino-L-alanine; N- [2-cyoro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (5-bromofuran-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(3,5-dimethylisoxazol-4-yl) carbonyl] amino -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (piperidine-4-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-prolyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (1, 2, 3-thiadiazole-4-carbonyl) amino-L-dlaniíic .:. N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzo.i l] -3- (4-methyl-l, 2,3-thiadiazol-5-carbqnil) amino -L-alani na; N- [2-chloro-4 [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -be.'zo.i 1] -3- (isoxazole-5-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-chloro-2-nitrobenzoyl) amino-L-alanine; N - [--- clo? O-4-_ [[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2,4-dimethylthiazole-5-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3 - [[2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] ] carbonyl] -benzoyl] amino] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -benzoyl] -3 - [[[(3S) -2,3,4,9-tetrahydro-1H-pyrido] [3, 4-b] -indol-3-yl] carbonyl] amino] -L-alanine. Examples of such especially preferred compounds in which Z is cycloalkyl are the following: N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (cyclopropylcarbonyl) amino -L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3 - [(2,2-dichloro-l-methylcyclopropyl) -carbonyl] araino-alaniia; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3-- [(1-phenylcyclopropyl) carbonyl] am (ino-L-alanine; N- [ 2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (cyclobutylcarbonyl) amino-L-alanine; N [2-chloro-4 - [[[(3-hydroxy phenyl) ethyl] amino] carbonyl] benzoyl] -3- (cyclopentylcarbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxy-phenyl) -phenyl] -amino] -carbonyl] -benzoyl] -3- [1- (2-methoxyethyl) cyclopentylcarbonyl] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] aminocarbonyl] -benzoyl] -3- [(1- phenyl-cyclopentyl) carbonyl] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (1-methylcyclohexylcarbonyl) amino-L- alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- [1-aminocyclopentyl) carbonyl] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- [cis-4-aminocciohexyl) carbonyl] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [trans-6-ap? J not -3- cyclohexcno- l-cscsbon.il] -amino-L-alanine; 3- [[trans-4- (aminomethyl) ciciohexyl] carbonyl]; amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- [(l-a -cyclohexy-1) carbonyl] amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) -ethyl] -amino] -carbonyl] -benzoyl] -L-alanine; 3- [(3-aminociclo exil) carbonil] iuino-W- [2-chloro-4- [[[(3-hydroxy-phenyl) ethyl] -amino] carbonyl] benzoyl] -L-alanine. Further preferred compounds of this invention are compounds of formula Id in which Z is thiophene or Z is phenyl, or Z is thiophene substituted with at least one of halogen or methyl, or Z is phenyl substituted with at least one of halogen, hydrogen, cyano, lower alkyl, lower alkoxy, amino, substituted amino, aminocarbonyl, nitro, aminosulphonyl, acetoxy or substituted lower alkyl, or Z is a five or six member ring with 0 to 3 heteroatoms selected from O, N and S which they may be the same or different, said ring may be unsubstituted or substituted with hydroxy, or Z is a fused ring system containing at least one benzene anion and quoj contains one or two additional rings which are independently cycloalkyl or aryl of 5 or 6 members with 0 to 3 heteroatoms selected from O, N and S, which may be the same or different, any of which may be unsubstituted or substituted with at least one of alco? i lower, halogen, oxo or hydroxy. Examples of such preferred compounds are: 3- (3-amino-5-nitrobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] -amino] carbonyl] benzoyl] -L -to the girl; 3- (3-bromo-5-nitrobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine; 3- (3-bromo-5-nitrobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3-nitro-5-trifluoromethylbenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3-methyl-5-nitrobenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hyd or ifeni.l) methyl] amino] carbonyl] -benzoyl] -3- (3-methyl-4-nitrobe zoil) amino-L-alanine; 3- (4-amino-3-methylbenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] -amino] carbonyl] benzoyl] -L-alanine; 3- (-b omo-3-methylbenzoyl) amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-methoxy-4-nitrobenzoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-hydroxy-4-methoxybenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2-methyl-3-nitrobenzoyl) amino-L-alanine; 3- (1H-benzotriazole-5-carbonyl) amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] -amino] carbonyl] benzoyl] -L-alanine; 3- (3-aminocarbonylbenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -be zoyl] -3- (furan-3-carboni1) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -ben-oil] -3 (3-fluoro-5-trifluoromethylbenzoyl) aroino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] arbonyl] -benzoyl] -3-- [(4R) -thiazolidine-4-carbonyl) amino-L-alanine? N- [2-cioro-4- [[[(3-hydroxy phenyl) ethyl] amino] carbonyl] benzoyl] -3 - [(4R) -4-hydroxy-L-prolyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2,3-dihydro-l-indol-2-carbonyl) amino-L-alanine .

In the above-described compound of formula Id, those in which Z is thiophene (that is, unsubstituted thiophene as defined above) or thiophene substituted with at least one of halogen or methyl (as defined above, are especially preferred; this use means a halogen or a methyl or two or more halogens or two or more methyl or any combination of halogen and methyl Examples of such compounds are: N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] ] -amino] carbonyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; 3- (3-bromothiophene-2-carbonyl) amino-N- [2-chloro-4- [[[ (3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -L-alanyl; 3- (5-bromo-thiophene-2-carbonyl) amino-N- [2-chloro-4- [[[(3 -hydroxyphenyl) methyl] amino] carbpnil] -benzoyl] -L-alanma; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carboryl] benzoyl] -3 - [(3 -chlorothiophene-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- [(5-chlorothiophene-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- [(4,5-diborothiophene-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3 - [(3-methylthiophene-2-carbonyl)] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3 - [(5-methylthiophene-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- [(thiophene-3-carbonyl)] -amino-L-alanine. In the above-described compounds of formula Id, Z may be a five or six membered ring with one to three nitrogens, that is, a heterocycle with one to three nitrogens included among the ring atoms, for example: N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (pyrrolo-2-carbonyl)] amino-L-alanine; N-. { 2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3 - [(5-nitropyrazole-3-carbonyl)] amino-L-alanine; N- [2-chloro-4-L [[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [(pyridine-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [(6-methylpyridine-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- [5- (3,4-dibromobutyl) pyridine-2-carbonyl)] amino-L- to the girl; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [(pyridine-3-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3 - [(2-chloropyridine-3-carbonyl)] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(6-chloropyridyl-3-carbonyl)] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxypheni.l) methyl] amino] carbonyl] -benzoyl] -3 - [(2,6-dimethoxypyridine-3-carbonyl)] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) -retyl] -roino] carbonyl] -benzoyl] -3- [(2-hydroxy? Iridine-3-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [(pyrazine-2-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] mino] caiboni 1] -benzoyl] -3- [3- [[(5-chloro-2-pyridinyl) amino] carbonyl] - pyrazine-2-carbonyl] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(2,4-dihydroxypyrimidine-5-carbonyl)] - amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(2,4-dihydroxypyrimidine-6-carboni 1)] - amino-L-alanine. In the above-described compounds of formula Id, Z can be phenyl (i.e., unsubstituted phenyl as defined above) or phenyl substituted with at least one of hydroxy, cyano, lower alkyl or substituted lower alkyl, e.g. : 3-benzoylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -a a] carbonyl] benzoyl] -L-alaninn; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-cyanobenzoyl) amino-L-alanine;, N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-hydroxybenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] araino] carbonyl] -benzoyl] -3- (2-methylbenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-methylbenzoyl) amino-L-ianiña; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-methylbenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [3- (trifluoromethyl) benzoyl] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3, 5-dimethylbenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (3,4-dimethylbenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -. 10 -. 10-benzoyl] -3- (3-hydroxy-4-methylbenzoyl) amino-L-alanine; and N- [2-chloro-4 [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2-hydroxy-4-methylbenzoyl) amino-L-alanine. i-. In the above-described compounds of formula Id, Z can be phenyl substituted with at least one hydroxy. Examples of such especially preferred compounds are: 0 N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (3-hydroxybenzoyl) amino-L-alanine and N - [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonii] -benzoyl] -3- (3,5-dihydroxybenzoyl) -amino-L-alanin.

In the above-described compounds of formula Id, Z can be phenyl substituted with at least one of lower alkoxy, -0-C (0) -CH3 or -C (0) -0-CH3, for example: 5 N- [2 -chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-methoxybenzoyl) amino-L-alanine; 3- (2-acetoxybenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-ethoxybenzoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (2-methoxybenzoyl) -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-methoxybenzoyl) amino-L-alanine; l 'W [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] ar .-. ino] carbonyl] -benzoyl] -3- [3- (methoxycarbonyl) benzoyl] amino-L-alanine; , N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -ben / yoyl] -3- (4-pentyloxybenzoyl) amino-L-alanine and 0 N- [2 -chloro-4 - [[H 3 -hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [(pyridine-2-carbonyl)] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3,4,5-trimethoxybenzoyl) amino-L-alanine. In the above-described compounds of formula Id, Z can be phenyl substituted with at least one of halogen, for example 3- (2-bromobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] ] amino] carbonyl] benzoyl] -L-alanine; 3- (3-bromobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- (2-chlorobenzoyl) amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- (3-chlorobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- (4-chlorobenzoyl) amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; , N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-fluorobenzoyl) amino L-alanine; N-- [2-chloro-4 - [[[(3-'-hydroxy-phenyl) -lo-ethyl] -amino] carbonyl] -benzoyl] -3- (3-iodobenzoyl) amino-L- to the girl; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino], carbonyl] -benzoyl] -3- (3, 5-difluorobenzoyl) to ino-J.-alanine; 3- (3-chloro-5-fluorobenzoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] ami.no] cr.rbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (3,5-dichlorobenzoyl)] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxy phenyl) ethyl] amino] carbonyl] -benzoyl] -3- (3,5-dibromb-benzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (2,4,5-trifluorobenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3,5-dimethoxybenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3,4-dimethoxybenzoyl) amino-L-alanine. In the above-described compounds of formula Id, Z can be phenyl substituted with at least one of amino, substituted amino, nitro or aminosulfonyl, for example 3- (3-aminobenzoyl) amino-N- [2-chloro-4- [[ [(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- (4-aminosulfonylbenzoyl) amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alaiAn ..; N- [2-chloro-4- [[[(3-hydroxyphenyl) eti]] -amino] carbonyl] benzoyl] -3- (3-dimethylaminoben, zo.l) -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (4-dimethylaminobenzoyl) -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- (3, 5-dinitrobenzoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hyd oxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (2-nitrobenzoyl) mino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -5-amino] carbonyl] benzoyl] -3- (3-nitrobenzoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] -benzoyl] -3- (4-nitrobenzoyl) amino-L-alanine; 3- (3-aminobenzoyl) amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] benzoyl] -L-alanine.

Additionally, in the above-described compounds of formula Id, Z may be I-. a fused ring system containing at least one benzene ring and containing one or two additional rings which are independently aryl or cycloalkyl of 5 or 6 members with 0 to 2 heteroatoms selected from O, N and S, which 0 may be the same or different, either of which may be unsubstituted or substituted by at least one of lower alkoxy, halogen, oxo or hydroxy, for example: N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] ] amino] carbonyl] benzoyl] -3 - [(1,2,3,4-tetrahydronaphthalene-2-carbonyl)] -amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(DL-7-methoxy-1,2,4,4,4 aß, 9, 10, 10 aβ-octahydro-2β-phenanthrenecarbonyl)] amino-L-alanine; 3- (6-Bromo-2-oxo-l, 2,3,4-tetrahydroquinoline-4-carbonyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl ] benzoyl] -L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (benzofuran-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (benzothiophene-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (benzimidazole-5-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (benzothiazole-6-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (naphthalene-1-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (naphthalene-2-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (isoquinoline-1-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (quinoline-2-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (-methoxyquinoline-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (quinoline-3-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (quinoline-4-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (cinnoline-4-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2-hydroxyquinolaline-3-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -bcnzoyl] -3- (4-oxo-4H-1-benzopyran-2-carbonyl) aminoL-alanini; N [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3- (2-oxo-2H-l-benzopyran-3-carbonyl) amino-L-alanine; 3- (anthracene-9-carbonyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (1,2,3,4-tetrahydroacridine-9-carbonyl)] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2-methoxy-l-oxo-lH-pyrido [2,1] quinazo-lina- 8-carbonyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (9-oxo-9H-thioxanthene-3-carbonyl) amino-L-alanine; Examples of compounds of the formula wherein Y is methylene are the following: 3-acetylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (cyclopentylacetyl) amino-L-alanine; N- [2-chloro-4 - [[[3-Hydrcxyphenyl] methyl] -amino] carbonyl] benzoyl] -3- (cyclohexylacetyl) amino-L-alanine; , N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- (phenyl acetyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (4-methoxyphenylacetyl) -aiaino-L-alanine; N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- (-nitrophenylacetyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (3-trifluoromethyl-phenylacetyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- (3, 5-dinitrophenylacetyl) -amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (2-thienylacetyl) -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (3-pyridylacetyl) -amino-L-alanine; N- [2-chloro-4- [[[(3-hyd or ifanyl) -helyl] -amino] carbonyl] benzoyl] -3- (2-naphthylacetyl) -amino-L-alanine; (N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- (9H-fluoren-9-ylacetyl) -amino-L-alanine; [(2S) -2-carboxy-2- [2-chloro-4- [(3-hydroxyphenyl) methyl] amino] carbonyl) benzoylamino] -ethylaminocarbonyl] ethyl] -benzothiazol-3-yl salt; N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] -2-acetyl] amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] ] -amino] carbonyl] benzoyl] -L-alanine; Also compounds of this invention are those in which Y is -CH2-CH2-CH2- in a compound of formula ld, such as for example: 3- (4-aminobutanoyl) amino-N- [2-chloro-4- [[ [(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; and N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (4-carboxy-1-oxobutyl) -amino-L-alanine. This invention includes compounds of formula ld wherein Y is -CH2-CH2- or -C (CH3) 2CH2- / o -CH (CH3) CH2-, or -CH2CH (CH3) CH2- or -CH2CII (CH3) -O as for example: N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl ] -benzoyl] -3- (3-phenylpropanoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(3,5-dimethylisoxazol-4-yl) propanoyl] -amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] iuino] carbonyl] -benzoyl] -3- [3- (piperidin-1-yl) propanoyl] -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(3RS) -3-phenylbutanoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(3-cyclohexyl- (2S) -2- (1-pyrrolyl) -propanoyl)] -amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (trimethylacetyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (2-methylpropanoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-methylbutanoyl) amino-L-alanine. Also part of this invention are compounds of formula Id in which Y is -CH = CH-, -CII = CH CH2 - or -CH2S-, co or for example: N- [2-Cl? Ro 4 - [[[ (3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-pyridylthioacetyl) amino-L-alanine; N [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [(pyrimidin-2-ylthio) acetyl] amino-L-alanine. Also part of this invention are compounds of formula ld in which Y is -CH = CH-, -CH = CH-CH2- 'or -CH2S-, as for example: N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- (4-pyridylthioacetyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3 - [(pyrimidin-2-ylthio) acetyl] -amino-L-alanine; 3- (but-2-enoyl) amino-N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] -amino] carbonyl] benzoyl] -3- [3- (4-methoxy phenyl) prop-2-enoyl] amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -3- [3- (pyridin-3-yl) prop-2-enoyl] amino-L-alanine; and N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl) -3- [3- (2-thienyl) prop-2-enoyl] -amino-L-alanine. Also included in this invention are compounds of formula ld in which Y is lower alkylene substituted by an amino group. In this last compound, And it can be • • • • • • • • • • • • • • • • • • 2 • Ni 2 NH 2 -CH-CH 2 -CH 2 CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -H 2 -CH, -CH, -CH- for example: N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-methionyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-lysyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-phenylalanyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-asparaginyl) amino-L-alanine; N- [2-chloro 4 - [[[(3-hydroxyphenyl) methyl] mino] carbonyl] -benzoyl] -3- (L- tryptopyl) amino-L-alanine or N- [2-chloro-4 - [[ [(3-hydroxyphenyl) methyl] amino], carboni1] -benzoyl] -3-- (L -? - glutamyl) amino-L-alanine. In this regard, compounds of formula I in which Y is lower alkylene substituted by amino, lower alkyl, lower alkylamino or trifluoromethyl are also part of this invention. Examples of such compounds are the above compounds together with the following compounds: N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (N-methyl-L-alanyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (N-methyl glycyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-leucyl) amino-L-alanine; 3- (2-amino-2-methylpropanoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- (3-amino-4,4,4-trifluorobutanoyl) amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- (3-amino-2-methylpropanoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro -4 - [[[(3-hydroxife-11) methyl] amino] c-rbonyl] -benzoyl J -3- [4- (2,6-dichlorophenyl) methoxy-L-phenylalanyl) amino-L-alanine; , N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-seryl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- [O- (phenylmethyl) -L-seryl] amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-phenylglycyl) amino-L-alanine; 3- (3-aminobutanoyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] enzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-nitro-L-phenylalanyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-fluoro-D, L-phenylalanyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (D-tyrosyl) amino-L-alanine; 3- (D-aspartyl) amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (D-triptophyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (L-alane) amino-L-alanine and N- [2- chloro-4- [ [[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (D-alane) amino-L-alanine. Also forming part of this invention are compounds of the formula wherein R 1 is a group Formula R2 is a group of formula R3 or -CH-NH-C- • 'w is hydrogen and one of U or V is chloro, fluoro, bromo, or methyl, while the other is hydrogen, X is carbonyl; Y is -CH = CH- or k is 0; and Z is thiophene or phenyl, or thiophene or phenyl substituted by one or more of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl. Preferably said compound is a compound of formula ld wherein X is carbonyl, k is 0, Z is thiophene or phenyl or thiophene or phenyl substituted by one or more of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl , cyano or lower alkoxycarbonyl (which differs from the above compound in that preferably Y is absent). In any case, it is preferred that Z is thiophene or phenyl or thiophene or fsnyl substituted by methyl, methoxy, chloro, bromo, fluoro, hydroxy or nitro. Examples of such compounds are: N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -benzoyl] -3- (4-methoxy thiophene-3-carbonyl) amino-L- to the girl; and N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl) amino] carbonyl] benzoyl] -3- (5-chloro-4-methoxythiophene-3-carbonyl) amino-L-alanine. Also part of this invention are compounds of the formula wherein R 1 is a group of for hydrogen, and one of U or V is chlorine or bromine, while the other is hydrogen, or one of U or V is methyl and the other is chlorine or bromine; X is carbonyl; Y is inner alkylene substituted with cycloalkyl (preferably cyclohexyl), lower alkylenethio, unbranched lower alkylene or alkenylene, ok is 0 and Z is thiophene, furan, cyclopentyl, cyclohexyl, piperidine, pyridine, naphthalene, benzothiophene, bonzothiazole, 1, 4- dioxa ~ 8-thiapiro [4,5] decyl, or phenyl or phenyl substituted with one or more of lower alkoxy, lower alkyl, chloro, bromo, fluoro, hydroxy, nitro, cyano, amino, substituted amino, methyl, aminosulfonyl, trifluoromethyl , alkoxycarbonyl or carboxy. Another compound of this invention is a compound of the formula wherein U, V and W are independently chloro, bromo or fluoro. Still another compound of this invention is a compound of the formula wherein Z is thiophene, furan, thiazole, cyclopentyl, cyclohexyl, piperidine, pyridine, naphthalene, benzothiophene, benzothiazol, 1, -dioxa-8-thiaspiro [4, 5] decyl or phenyl or phenyl substituted with one or more of lower alkoxy, lower alkyl, chloro, bromo, fluoro, hydroxy, nitro, cyano, amino, substituted amino, methyl, aminosulfonyl, trifluoromethyl or carboxy. A compound of this invention is a compound of the formula wherein R 1 is a group formula, and A is hydroxy, hydrogen or amino, and B is hydrogen or hydroxy, or Rl is a group of f and B is hydrogen or hydroxy; R2 is a group of formula H -CH2-í ?! • u_ Rj R3 OH OR, CH-CH-CH-, -CH-CH = CH-, -CH2-CH2-H- -C-NH-CH- VN W is hydrogen and at least one of U and V is methyl or halogen; X is carbonyl, sulfonyl or phenyl lower alkyl; k is 0 or Y is lower alkylene; Z is hydrogen, phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole. As explained above, these specific rings are not replaced unless otherwise indicated. Z may also be a six-membered aromatic ring with one to three nitrogens, which may be substituted or unsubstituted. Any of these rings (phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole, isoxazole, or a six-membered aromatic ring with one to three nitrogens) may be unsubstituted or substituted by at least one halogen, hydroxy, lower alkoxy, jiitro, amino, substituted amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl or lower alkoxycarbonyl, for example: N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl]] amino] carbonyl] -benzoyl] -3- (phenylsulfonyl) -amino-L-alanine; N- [2-fluoro-4- [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] enzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] benzoyl] -3- (phenylmethyl) amino-L-alanine; 3- (3-carboxybenzoyl) amino-N- [2-chloro-4 - [[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; N- [4- [[[(3-aminophenyl) methylamino] carbonyl] -2-bromobenzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; 3- (benzoylamino) -N- [2-chloro-4 - [[(3,5-dihydroxybenzoyl) amino] methyl] -benzoyl] -L-alanine; 3- (benzoylamino) -N- [2-chloro-4- [[(2-hydroxybenzoyl) -amino] methyl] benzoyl] -L-alanine; 3- (benzoylamino) -N- [2-chloro-4- [[(3-hydroxybenzoyl) -amino] methyl] benzoyl] -L-alanine; N- [4- [[(3-aminobenzoyl) amino] methyl] -2-chlorobenzoyl] -3- (benzoyl) amino-L-alanine; N • [2-bromo-4- [[[(3-hyd oxyphenyl) methy1] amino] -carbonyl] ben-7-oyl] -3- (thiophene-2-carbonyl) amino-L-alanine); and N- [2-chloro-4- [[[(3,5-dihydroxyphenyl) methyl] amino] -carbonyl) benzo] -3- [thiophene-2-carbonyl] amino-L-alanine. In this way the compound is as shown in the formula la, except that A, when present, is hydroxy, hydrogen or amino and B is hydrogen or hydroxy; W is hydrogen and at least one of U and V is methyl or halogen, k is 0 or Y is lower alkylene; and Z is hydrogen, phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole or a six-membered aromatic ring with one to three nitrogens, which may be substituted or unsubstituted. Any of these rings may be unsubstituted or substituted by at least one of halogen, hydroxy, lower alkoxy, nitro, amino, substituted amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl or lower alkoxycarbonyl, or additionally by substituted amino. In a more preferred compound, one of U or V is chloro or bromo, and the other is hydrogen and X is carbonyl and Y is methylene ok ec 0 and Z is thiophene or phenyl, or thiophene or phenyl substituted by at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl. In any of these preferred compounds, R1 can be a group of formula The above compound is preferred when X is carbonyl, for example: N- [2-chloro-4- [5- [(3-hydroxy) phenylmethylamino] tetrazol-1-yl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [l-oxo-3- (3-hydroxy-phenyl) -propyl] -benzoyl] -3- (thiophene-2-carbonyl) -amino-L-alanine; N- [2-chloro-4- [l-hydroxy-3- (3-hydroxy phenyl) propyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-chloro-4- (l-oxo-3-phenylpropyl) benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine. The above compound is also preferred when X is carbonyl and Rl is a group of formula for example when A is hydroxy and B is hydrogen, especially when W is hydrogen and one of U or V is chlorine or bromine and the other is hydrogen (or when U is chlorine or bromine, which as defined above has the same meaning), and in particular when k is 0 or when Y is methylene. Even more preferably wherein the compound k is 0 when Z is phenyl or thiophene or phenyl or thiophene substituted with at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl. When Z is phenyl or thiophene, as described above in a compound preferred R2 is a group of formula for example: N- [2-chloro-4- (2-phenyl-trans-cyclopropyl) carbonyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine). In another preferred compound of this type R2 or is a group of formula O-CH2-C-I for example: N- [2-chloro-4- (phenoxyacetyl) ben7oyl] -3- (thiophene-2-carbonyl) amino-L-alanine. In another preferred compound of this type, R2 is a group of formula -CH-CH "CH- especially in which R3 is hydrogen, for example: N- [2-chloro-4- (3-phenyl-1-propenyl) benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine) are examples of compounds of the formula le in which R3 is hydrogen: 3 (benzoylamino) -N- [2-chloro-4- [[(2,3-dihydro-2-oxo-lH-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine; 3- (benzoylamino) -N- [2-chloro-4- [[(lH-indol-4-ylmethyl) 5-amino] carbonyl] benzoyl] -L-alanine; N- [2-chloro-4 - [[(lH-benzimidazol-4-ylmethyl) amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[(lH-indol-4-ylmethyl) amino] carbonyl] -10-benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-chloro-4- [[(2,3-dihydro-lH-indol-4-ylmethyl) -amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-bromo-4- [[(IH-indol-4-ylmethyl) amino] carbonyl] -l'-benzoyl] -3- (thiophene-2-carbonyl) -mine-L-alanine; N- [2-chloro-4 - [[(lH-indol-4-ylmethyl) amino] carbonyl] -benzoyl] -3- (thiophene-3-carbonyl) amino-L-alanine; N- [2-chloro-4 - [[(lH-indol-4-ylmethyl) amino] carbonyl] -benzoyl] -3 - [(5-methylthiophene-2-carboni1) amino-L-0 alanine, and N- [2-chloro-4 - [[[(lH-indazol-4-yl-) methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; Examples of compounds of formula le in which R3 is methyl are the following: 3- (1-butanesulfonyl) amino-N- [2-chloro-4- [[[(IR) -l- (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -L-alanine; 3- [(2-Acetamido-4-methylthiazol-5-yl) sulfonyl] amino-N- [2-chloro- - [[[(IR) -1- (1-naphthalenyl) ethyl] amino] -carbonyl] benzoyl ] -L-alanine; N- [2,6-dimethyl) -4 - [[[(1 R) -l- (1-naphthalenyl) ethyl] -amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; N- [2-bromo) -4 - [[[(1 R) -l- (1-naphthalenyl) ethyl] -amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine, and N- [2,6-dichloro) -4 - [[[(1R) -1- (1 -naphthalenyl) ethyl] -amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-T, - to the girl; N- [2-methyl) -4 - [[[(1 R) -l- (1-naphthalenyl) ethyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine; 3- (benzoylamino) -N- [2-methyl) -4 - [[[(lR) -l- (l-naphthalenyl) -ethyl] amino] carbonyl] benzoyl] -L-alanine, and 3- (benzoi lamino ) -N- [2,6-dichloro) -4- [[[(1 R) -l- (1-naphthalenyl) -ethyl] amino] carbonyl] benzoyl] -L-alanine. These last four compounds are particularly preferred.

Another compound of this invention is a compound of the formula wherein R 1 is a group of formula and A is hydroxy or amino and B is R3 or I J II hydrogen; R2 is a group of formula - CH-NH-C - W is hydrogen and at least one of U and V are methyl or halogen; X is carbonyl, sulfonyl or phenyl lower alkyl; k is 0 or Y is lower alkylene; and Z is hydrogen, phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole or a six-membered aromatic ring with one to three nitrogens, either of which may be unsubstituted or substituted with at least one halogen , hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl or lower alkoxycarbonyl. In any of said compounds, Rl can be a group of formula.

Another compound of this invention that is preferred is a compound of the formula wherein Rl is a group of formula and A is hydroxy or amino and B is hydrogen; R2 is a group of formula R3 or -CH-NH-C-; is hydrogen and at least one of U and V is methyl or halogen; X is carbonyl; k is 0 or Y is methylene; and Z is thiophene or phenyl, or thiophene or phenyl substituted with at least one of methyl, methoxy, hydroxy, chloro, bromo, fluoro or nitro. In a preferred compound of this type R3 is hydrogen and k is 0, and this compound is even more preferred when Z is thiophene or tri-phene substituted with at least one of methyl, methoxy, hydroxy, chloro, bromo, fluoro or nitro. In another preferred compound one of U or V is chlorine or bromine and the other is hydrogen. In any preferred compound of this type Rl can be a group of formula It is also part of this invention a compound of the formula wherein R 1 is a group of formula A is amino or hydroxy and B is hydrogen; R2 is a group of formula -CH-NH-C-; any or all of U, V and W are hydrogen, halogen or methyl, with the proviso that U and V are not both hydrogen; X is carbonyl or sulfonyl; and k is 0 or Y is methylene, in particular when one of U or V is chlorine or methyl, while the other is hydrogen, chlorine or methyl; W is hydrogen; and X is carbonyl, and k is 0; and further, when R3 is hydrogen and Z is thiophene or phenyl or thiophene or phenyl substituted with at least one of lower carboxy or lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl, especially phenyl or phenyl independently substituted by fluorine or hydroxy; or thienyl. In another preferred compound of this type, R3 is hydrogen; one of U or V is halogen (especially bromine, chlorine or fluorine) and the other is hydrogen; X is sulfonyl; and k is 0. In a preferred compound is hydrogen and one of U or V is chlorine or bromine and the other is hydrogen; X is carbonyl; And it is methylene or k is 0; Z is thiophene or phenyl or thiophene or phenyl substituted by at least one of methyl, methoxy, hydroxy, chloro, bromo, fluoro or nitro. Still another preferred compound in which the halogen is bromine, chlorine or fluorine, W is hydrogen and U and V are halogen or methyl (independently of one another, for example in any combination of any halogen and any methyl such as two chlorines, or a bromine or a methyl, and the like). In a preferred compound of this type, X is carbonyl. Z may additionally be thiophene or phenyl, or thiophene or phenyl which may be substituted by at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl. In another preferred compound Z is thiophene or phenyl, or thiophene or phenyl which may be substituted by at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano, or lower alkoxycarbonyl. Preferably Z is thiophene. In an especially preferred compound of this type, W is hydrogen, U and V are halogen or methyl, X is carbonyl, and Z is thiophene. In any compound of this type Rl It can be a formula group.

In particular, this invention includes compounds of formula ld as defined above. Preferred compounds of formula Id are those in which R3 is hydrogen, one of U or V is halogen and the other is hydrogen (or equivalently U is halogen and V is hydrogen), X is sulfonyl and k is 0, especially when W is hydrogen. Also preferred is a compound having the formula ld wherein W is hydrogen and Z is hydrogen or Z is one of the following: cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a ring system fused containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, such that any of said cycloalkyl, aryl or fused rings may be unsubstituted or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl which may be unsubstituted or substituted by halogen or lower alkoxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio , acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, or acetoxy. In the particularly preferred compounds U is methyl and V is hydrogen. Examples of such compounds are: N- [4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -2-methyl-benzoyl] -3- [(thiophene-2-carbonyl) -amino] -L- alanine, 3- (benzoylamino) -N- [4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -2-yl-benzoyl] -L-alanine. - The above compound is also preferred in which U and V are independently bromine, chlorine, fluorine or methyl, especially when Z is phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole, or a six-membered aromatic ring with one to three nitrogens, any of which may be unsubstituted or substituted by at least one of halogen, hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl or lower alkoxycarbonyl. This compound is preferred when Z is substituted by at least one of methyl, methoxy, hydroxy, chloro, bromo, fluoro or nitro. This compound is also preferred when Z is thiophene, or phenyl, or thiophene or phenyl substituted by at least one of methyl, halogen, methoxy or hydroxy. The above compound in which U and V are independently bromo, chloro, fluoro or methyl is also preterred when X is carbonyl. The compound wherein X is carbonyl is particularly preferred when Z is thiophene or phenyl, or thiophene or phenyl substituted by at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl. The latter compound is preferred in those cases in which U and V are independently chloro or methyl, and especially when Z is substituted thiophene. Examples of such compounds include: 3- [(3-bromothiophene-2-carbonyl) amino] -N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] - L-alanine; 3- [(5-Bromothiophene-2-carbonyl) amino] -N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; 3- [(3-chlorothiophene-2-carbonyl) amino] -N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) methyl] mino] carbonyl] benzoyl] -L-alanine; 3- [(4,5-dibromothiophene-2-carbonyl) amino] -N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) met yl] amino] -carbonyl] benzoyl) -3 - [(3-methylthiophene-2-carbonyl) -amino] -L-alanine; and N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl) -5 - [(3-methylthiophene-2-carbonyl) -amino] -L-alanine. Examples of this type in which Z is substituted phenyl include: 3- (3,5-difluorobenzoylamino) -N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] ap.ino] carbonyl] -benzoyl] -L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3 - [(3,5-difluorobenzoyl) -amino] -L-alanine; N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- (3,5-dihydroxybenzoyl-amino) -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3,5-dihydroxybenzoylamino) -L-alanine; 3- [(3-chlorobenzoyl) amino] -N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine; N- [2,6-di-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(3-fluorobenzoyl) amino] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(3-hydroxybenzoyl) amino] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) ethyl] amino] -carbonyl] benzoyl] -3 - [(3-hydroxy-4-methoxybenzoyl) -amino] -L-alanine; and N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) ethyl] amino] -carbonyl] benzoyl] -3 - [(3-methylbenzoyl) amino] -L-alenine. Especially preferred are: N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (3-hydroxybenzoyl) amino-L-alanine; N- [2-chloro-4- [[[(3-hydroxyphenyl) ethyl] amino] -carbonyl] benzoyl] -3- (3,5-dihydroxybenzoyl) amino-L-alanine; N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- (3,5-dihydroxybenzoyl-amino) -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) ethyl] amino] -carbonyl] benzoyl] -3- (3,5-dihydroxybenzoylamino) -L-alanine; and N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(3-hydroxybenzoyl) amino] -L-alanine. When Z is thienyl, the especially preferred compounds are: N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- [(thiophene-2-carbonyl ) -amino] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [(thiophene-2-carbonyl) -amino] -L-alanine; N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benoyl] -3- [(thiophene-3-carbonyl) -amino] -L-alanine; and N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3- [(thiophene-3-carbonyl) -amino] -L-alanine. N- [2,6-dimethyl] -4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carboni1) -amino] -L-alanine and N- [ 2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (thiophene-3-carbonyl) -amino] -L-alanine. In a preferred compound of formula la, Rl is a group of formula 'A is amino ° hydroxy and B is hydrogen; R2 is a group of or formula -Ci-NH 8 -; R3 is hydrogen or methyl; one of U or V is chlorine, bromine or fluorine and the other is hydrogen, and W is hydrogen, X is carbonyl; k is 0, or Y is methylene, and Z is phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole, or a six-membered aromatic ring with from one to three nitrogens, any of which may be unsubstituted or substituted with at least one of halogen, hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl or lower alkoxycarbonyl, especially at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro , aminosulfonyl, cyano or lower alkoxycarbonyl, in particular at least one of methyl, methoxy, hydroxy, chloro, bromo, fluoro or nitro. In a preferred compound of this type, Z is thiophene or phenyl, or thiophene or phenyl substituted with at least one of methyl, halogen or hydroxy. In any of the preferred compounds of this type Rl it can be a formula group In another preferred coxtipuecto of formula la, Rl is a group of the formula is amino or hydroxy and B is hydrogen; R2 is a group of ? 3 p formula -CH-NH-C-; R3 is hydrogen; one of U or V is chlorine, bromine or methyl and the other is hydrogen, and is hydrogen, X is carbonyl; k is 0 or Y is methylene, and Z is phenyl, thiophene, furano, pyrrole, pyrazole, imidazole, thiazole or isoxazole, or a six-membered aromatic ring with one to three nitrogens, any of which may be unsubstituted or substituted with at least one of halogen, hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl or lower alkoxycarbonyl. In any of the preferred compounds of this type Rl can be a formula group Still in another preferred compound of formula the Rl is a group of formula A is amino or hydroxy and - B is hydrogen; R2 is a group of formula -CF3H-NH-Cf? -; R3 is hydrogen or methyl; one of U or V is chlorine, bromine or methyl and the other is hydrogen and W is hydrogen, X is carbonyl; k is 0 or Y is methylene, and Z is phenyl, or Z is phenyl substituted with at least one of halogen, hydroxy, meioxy, nitro, amino, cyano, carboxy or trifluoromethyl, or Z is thiophene, or Z is thiophene substituted with at least one of halogen, methyl, methoxy or nitro, or Z is selected from the group of furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole (which may be substituted as defined above by phenyl, thiophene, and others), or Z is selected from the group of furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole substituted by at least one of halogen, methyl, methoxy or nitro, or Z is pyridine, which may be substituted by at least one of methyl, methoxy, halogen or hydroxy, or Z is a six-membered aromatic ring with two nitrogens, which may be substituted with at least one of methyl, methoxy, halogen or hydroxy, or Z is a six-membered aromatic ring with three nitrogens, which may be substituted with at least one of methyl, methoxy, halogen or hydroxy. Said compound wherein Z can be any of the groups mentioned above is likewise part of this invention. In any of the compounds of this type R1 can be a group of formula I XW.

Preferred compounds of formula I are further those in which R 1 is 1-naphthalenyl, R 3 is methyl, X is carbonyl, k is 0, and Z is thienyl. An example of a compound of this type is N- [2,6-dichloro-4- [[[(IR) -1 (1-naphthalenyl) -ethyl] amino] carbonyl] benzoyl] -3- [(thiophene-2 -carboni1) amino] -L-alanine. Preferred compounds of formula I are those in which U is chlorine, V is chlorine or fluorine and is hydrogen; and X is carbonyl, in particular when Y is methylene, -CH2CH2-, -CH = CH-, or -CH2CH (CH3) -for example: N- (2,6-di-chlorobenzoyl) -3- [3- (2 -thienyl) prop-2-enoyl] -amino-L-alanine; N- (2,6-dichlorobenzoyl) -3- (phenylacetyl) amino-L-alanine; N-- (2,6-dichlorobenzoyl) -3- [(4-nitrophenylacetyl)] amino-L-alanine; N- (2,6-dichlorobenzyl) -3- [(4-nitrophenylacetyl)] amino-L-alanine}; N- (2,6-dichlorobenzoyl) -3- [(3-RS) -3-phenyl-butaoyl] -amino-L-alanine; N- (2-chloro-6-fluorobenzoyl) -3- [(3RS) -3-phenylbutanoyl] amino-L-alanine) or k is 0, as per. Example: N- (2,6-dichlorobenzoyl) -3- [(2S) -5-oxotetrahydrofuran-2-carbonyl] amino-L-alanine; N- (2-chloro-6-fluorobenzoyl) -3- [(2S) -5-oxotetrahydrofuran-2-carbonyl] amino-L-alanine; 3- (6-bromo-2-oxo-l, 2, 3, 4-tetrahydroquinoline-4-carbonyl) amino-N- (2,6-dichlorobenzoyl) -L-alanine; 3- (benzoylamino) -N- (2,6-dichlorobenzoyl) -L-alanine. 3- (benzoylamino) -N- (2-chloro-6-fluorobenzoyl) -L-alanine. N- (2,6-dichlorobenzoyl) -3- [(3-methoxybenzoyl)] amino-L-alanine; N- (2-chloro-6-fluorobenzoyl) -3- [(3-methoxybenzoyl)] -amino-L alanine; N- (2,6-dichlorobenzoyl) -3- [(5-brornothiophene-2-carbonyl)] amino] -alanine; N- (2-chloro-6-fluorobenzoyl) -3 - [(5-bromothiophene-2-carbonyl)] amino-L-alanine; N- (2,6-dichlorobenzoyl) -3- [(indo-1-5-carbonyl)] amino] -L-alanine; N- (2,6-dichlorobenzoyl) -3- [(6-methylpyridine-2-carbonyl)] mino-L-alanine; and 3- (lH-benzotriazole-5-carbonyl) amino] -N- (2-chloro-6-fluorobenzoyl) -L-alanine. In the latter compounds Z is preferably lower cycloalkyl, for example: N- (2,6-dichlorobenzoyl) -3- (cyclopropycarbonyl) amino-L-alanine; N- (2-chloro-6-fluorobenzoyl) -3- (cyclopropylcarbonyl) -amino-L-alanine; N- (2,6-dichlorobenzoyl) -3- (cyclobutylcarbonyl) amino-L-alanine; N- (2,6-dichlorobenzoyl) -3- (cyclopentylcarbonyl) amino-L-alanine; N- (2-chloro-6-fluorobenzoyl) -3- (cyclopentylcarbonyl) -amino-L-alanine; N- (2,6-dichlorobenzoyl) -3- (cyclohexylcarbonyl) amino-L-alanine; and N- (2-chloro-6-fluorobenzoyl) -3- (cyclohexylcarbonyl) -amino-L-alanine; or Z is phenyl, or phenyl substituted by at least one of methyl, hydroxy, alkoxy, or halogen. Also part of this invention are compounds of formula 1 wherein n is 0, W is hydrogen, chlorine, bromine or fluorine and at least one of U and V are methyl, chlorine, bromine or fluorine; X is carbonyl or sulfonyl; k is 0 or Y is methylene; Z is phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole, or a six-membered aromatic ring with one to three nitrogens, any of which may be unsubstituted or substituted by at least one of halogen, hydroxy , lower alkoxy, nitro, amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl, NHC (0) CH3 or lower alkoxycarbonyl, preferably when Z is substituted by at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl, especially when Z is substituted by at least one of methyl, methoxy, hydroxy, chloro, bromo, fluoro or nitro. Also preferred are compounds of formula I in which U is fluorine or chlorine, V is chlorine, W is hydrogen, Y is methylene or k is 0; and Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, and any of which may be unsubstituted or substituted by at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl which may be being unsubstituted or substituted by halogen or lower alkoxy, lower alkoxy, lower alkanesulfañilo, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl or acetoxy. Another compound of this invention is a compound of formula I wherein X is carbonyl, Y is lower alkylene or lower alkenylene or k is 0; and Z is a 3 to 6 membered cycloalkyl; aryl or heteroaryl, which may be substituted with lower alkyl, lower alkoxy, halogen or nitro; heterocycloalkyl substituted with oxo, indole, indazole, benzimidazole, benzotriazole or dihydro-quinolone substituted with halogen, and U and V are independently halogen or methyl. In another preferred compound of formula I, V is bromine, chlorine or fluorine, especially bromine or chlorine. In yet another preferred compound of formula the one of U or V is halogen or methyl and the other is hydrogen. In another preferred compound U and V are independently halogen or methyl (for example U is halogen and V is methyl, or U and V are both methyl, or U and V are both halogen) especially when halogen is chlorine, fluorine or bromine.

In another compound of formula lf, especially when U and V are independently halogen or methyl, X is carbonyl or sulfonyl, k is 0 or Y is methylene and Z is phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole, or an aromatic ring of six. members with one to three nitrogens, any of which may be unsubstituted or substituted by at least one of halogen, hydroxy, lower alkoxy, nitro, amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl, NHC (0) CH3 or lower alkoxycarbonyl, preferably when Z is substituted by at least one of lower alkyl, lower alkoxy, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl, especially when Z is substituted by at least one of methyl, methoxy, hydroxy , chlorine, bromine, fluorine or nitro. The compound described in the previous paragraph is also preferred when Z is phenyl or when Z is phenyl substituted by at least one of halogen, hydroxy, methoxy, nitro, amino, cyano, carboxy, or trifluoromethyl, or when Z is thiophene, or when Z is thiophene substituted by at least one of halogen, methoxy, methyl or nitro, or when Z is selected from the group consisting of furan, pyrrole, pyrazole, imidazole, thiazole or isoxazole, or when Z is selected from the group of furan, pyrrole , pyrazole, imidazole, thiazole or isoxazole substituted by at least one of halogen, methyl or nitro, or when Z is pyridine, especially when the pyridine is substituted by at least one of methyl, methoxy, halogen or hydroxy, or when Z is a A six-membered aromatic ring with two nitrogens, especially when the six-membered aromatic ring with two nitrogens is replaced by at least one of methyl, methoxy, halogen, or hydroxy, or when Z is a six-membered aromatic ring with three nit rhogens, especially when the six-membered aromatic ring with three nitrogens is substituted by at least one of methyl, methoxy, halogen or hydroxy. Also part of this invention are compounds of the formula: where R12 is a group of the formula R32 is hydrogen, carboxy or lower alkyl; U2, V2 and 2 are independently hydrogen, halogen to lower alkyl with the proviso that U2 and V2 are not both hydrogen; R42 is hydrogen; X is carbonyl, phenyl-lower alkyl or sulfonyl; Y 2 is lower alkenyl, lower alkylthio or lower alkylene which may be substituted by amino, acetylamino or lower cycloalkyl, and k2 is 0 or 1; Z2 is hydrogen, lower alkylthio, -COOH, -C0NH2, 1-adamantyl, diphenylmethyl, 3- [[[(5-chloropyridin-2-yl) amino] -carbonyl] pyrazin-2-yl or Z2 is one of the following : cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms, which may be the same or different, any of which may be unsubstituted or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl, which may be unsubstituted to substituted by halogen or lower alkoxy, carboxy, alkoxycarbonyl or acetoxy; and pharmaceutically acceptable salts and esters thereof. Examples of such compounds are: 3- (benzoylamino) -N- [2-chloro-4- [[[(quinoline-3-carbonyl) -amino] methyl] benzoyl] -L-alanine; 3- (benzoylamino) -N- [2-chloro-4- [[[(1 H -indodo-6-carbonyl) amino] methyl] benzoyl] -L-alanine and 3- (benzoylamino) -N- [2-chloro] -4- [[(lH-indol-5-carbonyl) amino] methyl] benzoyl] -L-alanine. Also part of this invention are compounds of formula 2 wherein A3 is hydrogen, hydroxy, amino or halogen and B3 is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl or lower alkoxy; R23 is a group of formula - CH-NH-C -, - CH2-CH2- CH ~ CH- - H-CH = CH-. -CH2-CH2- wherein R33 is hydrogen, carboxy, or lower alkyl; U3, V3 and W3 are independently hydrogen, halogen or lower alkyl, with the proviso that U3 and V3 are not both hydrogen; R 4 is hydrogen, lower alkyl or aryl-lower alkyl, which may be unsubstituted or substituted by at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, hydroxy, aryl, aryloxy, lower alkyl which may not be substituted or substituted by halogen or lower alkoxy, lower alkoxy, carboxy, lower alkoxycarbonyl or acetoxy; and pharmaceutically acceptable salts and esters thereof. An example of a compound of this type of N- [2-chloro-4- [[[3-hydroxyphenyl) ethyl] amino] carbonyl] benzoyl] -3 - [(aminoiminomethyl)] amino-L-alanine. Also part of this invention are compounds of formula 3 which are prodrugs. By "prodrugs" is meant a metabolic precursor of a drug that when administered to a patient becomes the drug and acceptable by-products. In the prodrug of this invention, the hydrogen R4 is replaced by other groups, which when administered produce a hydrogen and reconstitute the resulting carboxy group. Any single compound of this invention can be obtained in the form of a prodrug as described below. wherein R 1, R 2, n, U, V,, X, Y, k and Z are as in formula 1, for example R 1 is a group of formula wherein A is hydrogen, hydroxy, amino to halogen and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl or lower alkoxy; R2 is a group of formula wherein R3 is hydrogen, carboxy or lower alkyl; n is 0 or 1, U, V and W are independently hydrogen, halogen or lower alkyl, with the proviso that U and V are not both hydrogen; R6 is lower alkyl (preferably unbranched) or -CH2CH2-R7 where R7 is -N (CH3) 2 / -N ~) I -CH-O-C (0) O-R9 NH-O I wherein R8 R8 is hydrogen or methyl and R9 is lower alkyl or lower cycloalkyl; X is carbonyl, phenyl-lower alkyl, or sulfonyl; And it is lower alkenylene, or lower alkylenethio; Z is hydrogen, lower alkylthio, amino, -COOH, -CONH2, 1-adamantyl, diphenylmethyl, 3- [[(5-clorapyridin-2-yl) amino] carbonyl] pyrazin-2-yl, or further hydroxyl, phenylmethoxy, 2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] phenyl, [(2,6-dichlorophenyl) methoxy] phenyl or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, any of which may be unsubstituted or substituted by at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxyl, aryl, aryloxy, lower alkyl which may be unsubstituted or substituted by halogen or lower alkoxy, lower alkoxy, carboxyl, alkoxycarbonylor to acetoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH or -CONH2; and pharmaceutically acceptable salts and esters thereof.

In a compound of this preterm type R6 is unbranched lower alkyl, in particular ethyl. In another compound of this preferred type R6 is CH2CH2-R7. It is this last compound that is preferred than R7 sea -N (CH3) 2, -N NH -N O -CH-O-C (0) 0-R9 I In another of these compounds R6 is Rβ In this compound it is preferred that R8 is hydrogen or methyl and R9 is ethyl or cyclohexyl. The compounds of the present invention and their pharmaceutically acceptable salts inhibit the binding of beta-2-integrins LFA-1 and Mac-1, expressed in activated lymphocytes, monocytes and neutrophils, to the immunoglobulin ICAM-1 which is expressed in endothelial cells. activated, epithelial cells, synovial cells, myocytes, glial cells and neurons, as well as lymphocytes and antigen-presenting cells. The compounds of this invention can therefore be used in the treatment of disorders involving the binding of beta-2 integrins LFA-1 and Mac-1 with ICAM-1. Examples of these disorders include, but are not limited to, rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, ulcerative colitis, atherosclerosis, restenosis, pancreatitis, rejection of transplants, functional graft retardation, and reperfusion injury diseases. ischemia, including acute myocardial infarction and stroke. The compounds of the invention are preferably used in the treatment of reperfusion injury of ischemias. The inflammatory response in reperfusion injury requires the binding and extravasation of neutrophils to activated endothelium that is mediated by the interaction of LFA-1 with ICAM-1. The binding of Mac-1 with ICAM-1 activates the release by neutrophils of inflammatory cytokines, for example, IL-1, IL-6, IL-8, TNF-alpha and by the endothelial cells of chemotactic agents eg factor platelet activator. The result of the interaction is the generation of superoxide and free hydroxyl radicals that cause tissue destruction. Any compound of Formula 1 having the pharmaceutical activity described is part of this invention. In the following Examples, in vitro tests are provided to determine the desired pharmaceutical activity. Another indicator of pharmaceutical activity is the ability to inhibit a biological activity associated with LFA-1, such as the proliferation of T lymphocytes in a mixed lymphocyte reaction or the adhesion of Mac-1 to fibrinogen. Competitive binding assays, for example from ICAM1 by Mac-1, also indicate pharmaceutical activity. Trials of the pharmaceutical activity are also provided. The compounds of this invention inhibit the swelling induced in claws and ears in rats. The activities within the ranges exemplified in the Examples are indicative of the desired pharmaceutical activity. Accordingly, part of this invention is pharmaceutical compositions comprising a compound of formula 1 or any other compound of this invention, and a pharmaceutically acceptable excipient. The pharmaceutical compositions can be manufactured in any conventional form, including solid forms for oral administration such as tablets, capsules, pills, powders, granules, and the like. The pharmaceutical compositions can be sterilized and / or can contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure, and / or buffers. Another active compound can be added. Typical preparations for administration by injection would be sterile aqueous solutions of the compounds of this invention including buffered aqueous solutions. The injection can be by any conventional mode, for example, intravenous, intramuscular, subcutaneous or intraperitoneal. The pharmaceutically acceptable carriers or excipients may include fluids such as water, replenishers of nutrients and electrolytes, sugars such as sucrose., glucose, invert sugar. Preservatives and other additives such as antibiotics and antioxidants may also be present. Adjuvants that may be present include alcohol, polyols, glycerol, vegetable oil. The pharmaceutically acceptable excipients typically used in these preparations can be added to control properties such as pH, viscosity, sterility, stability, and dissolution rate. Typical preparations for oral administration contain compounds of this invention in association with a pharmaceutically acceptable compatible excipient material. Any compatible conventional pharmaceutically acceptable excipient can be used. Any conventional oral dosage form such as tablets, capsules, pills, powders, granules and the like can be used. The pharmaceutically acceptable excipient may be an inert organic or inorganic excipient material suitable for oral administration. Suitable excipients include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, water, vegetable oils, fats, liquid or semi-solid polyols, and the like. In addition, the pharmaceutical composition may contain other pharmaceutically active agents. Other additives such as flavoring agents, preservatives, stabilizers, antioxidants, emulsifying agents, masking agents, buffers and the like can be added according to the accepted practices of the pharmaceutical composition. Administration by suppository is also possible. The excipients for this purpose include oils, waxes, fats, polyols. Also part of this invention is the use of a compound of formula la in the preparation of a medicament for attenuating tissue damage resulting from reperfusion following an acute myocardial infarction. The compounds of the invention can be administered orally, rectally, or parenterally, for example, intravenously, intramuscularly, infusion, subcutaneously, intrathecally or transdermally.; or by sublingual route, or as ophthalmological 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, injectable solutions, eye drops, ointments or aerosol solutions. The compounds of the invention are preferably administered parenterally, for example by intravenous injection or infusion (although other routes such as oral, subcutaneous, intramuscular, topical or rectal are also contemplated). Thus, a preferred excipient is saline, although other pharmaceutically acceptable excipients such as those described above can be used. The dosages in which the compounds of the invention are administered in effective amounts depend on the nature, the specific active ingredient, the age and requirements of the patient and the mode of administration. The dosage for a given person can be determined by a qualified person based on the information provided herein. The dosages can be determined by any conventional means. However, in the methods of this invention, it is preferred that the amount of the compound is between about 1.0 and about 100 mg / kg / day. The compound can be administered by a qualified person to create a preselected circulating concentration, preferably a plasma level of about 5.0 mg / ml in plasma in a patient to whom the compound is administered. These plasma levels can be determined by conventional methods. Doses of about 1.0 to about 100 mg / kg of body weight per day are preferred, with doses of about 1 to about 25 mg / kg per day, and especially preferred doses of about 1.0 to about 10 being particularly preferred. mg / kg of body weight per day. The dosages are preferably administered by intravenous infusion, but may alternatively be given in equal doses, for example about 4 to about 15 times a day. Higher doses may be administered if necessary. The compounds of this invention can be prepared by a qualified person with the information provided. The following Examples are illustrative below and are not intended to limit the invention in any way.

General route for the DAPA compounds Synthesis of the compounds of structure I (R4 = H) (Note: there are two ways to obtain the compounds of structure I (R4 = alkyl optional) The other route is shown on the next page .) (a) acid or o, CH, -NH X-Y [kJ.2 (b) alkali, or COOR i (c) hydrogenation Structure B4 - M (g) acylation or sulfonylation Eli-Tiinc-r the protective group Rl Coupling Eliminate the generally known protecting group R1 or C6, or analogs of known compounds, CH1 -NH RIO or which can be prepared in the manner R1-NH-CH COOR * similar to known compounds, or in the manner described in the Examples or by analogy to the same synthesis of the compounds of structure I (R4 = optionally substituted alkyl) (Note: there are two ways to obtain compounds of structure I (R4 = alkyl opt. sust ). The other route is shown on the previous page. ) Coupling R4 = optionally substituted alyl ^. < -n-? ~ t Remove the protective group Rll aiJX H, COCO. Structure 6 Structure 7 equation or co-sulfonylation Structure 11 Esterification Structure 12 R4 = optionally substituted alkoxy ^ CHj-NM, generally known compounds, or analogues of known compounds, or which can be prepared in a manner similar to known compounds, or R4 = H the form described in the Examples, or by analogy to the same Synthesis of the compounds of structure 7 Structure 7 Structure 13 Structure 14 Synthesis of compounds of structure 13 (Note: eight ways of obtaining different compounds of structure 13 are shown) Structure 13 The starting products of structure 15, 19, 20, 22, 24 and 28 are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples which follow, or by analogy thereto. Synthesis of the compounds of structure 16 Structure 16 Structure 30 (t) carboxylate Structure 27 Some of the compounds of structure 30 are known compounds. The rest can be prepared according to the following Scheme Structure 30 Structure 32 Structure 33 structure 34 Structure 35 Structure 36 Structure 37 Syntheses of structure compounds 18 Rearrangement of Curtius RH-CH: -N «C« 0 - RH-CH, -C-CH Structure 18 Structure 31 Synthesis of structure compounds 21 Structure 43 Structure 16 Synthesis of structure compounds 23 Structure 23 Structure 44 Structure 45 Structure 16 The compounds of the present invention can be prepared by any conventional means. For example, the compounds of structure 1 can be manufactured by (a) for the preparation of a compound of structure 1 in which R 4 is hydrogen from a compound of structure 1 in which R 4 is an optionally substituted alkyl group which can be cleaved in acidic conditions, such as tert-butyl or aralkyl (for example Wang resin) and the like, by treatment with a strong acid, (b) for the preparation of a compound of structure 1 wherein R4 is hydrogen from a compound of structure 1 in which R4 is a lower alkyl or aralkyl group, unbranched at the carbon adjacent to oxygen, for example, methyl, ethyl, n-propyl, n-butyl, benzyl groups and the like, by treatment with dissolution of an alkali metal hydroxide, or (c) for the preparation of a compound of structure 1 in which R 4 is hydrogen from a composed of structure 1 in which R 4 represents a portion that can be removed hydrogenologically, such as benzyl, and in which the rest of the molecule is stable to hydrogenolysis, by catalytic hydrogenation, and / or (d) if desired , separating a mixture of diastereoisomers in the optically pure diastereomers and / or (e) if desiredconverting a compound of structure 1 having a basic nitrogen into a pharmaceutically acceptable addition salt; and / or (f) if desired, converting a compound of structure 1 in which R4 is hydrogen into a pharmaceutically acceptable alkali metal salt. The breakage of a labile portion against the acid according to process (a) can be carried out according to methods that are known per se. For example, the ester can be treated with a strong inorganic acid, for example, a hydrohalic acid such as hydrogen chloride or hydrogen bromide, or a strong organic acid, for example a halogenated carboxylic abano acid such as trifluoroacetic acid and Similar. The reaction is conveniently carried out in the presence of an inert organic solvent (such as dichloromethane) and at a temperature between about 0 degrees and about room temperature, preferably about room temperature. The breaking of a labile portion against the alkali according to process (b) can be carried out according to known procedures. For example, the ester can be treated with an alkali metal hydroxide, for example lithium hydroxide, in a suitable inert solvent system, for example a mixture of methanol, tetrahydrofuran and water. The reaction is carried out at a temperature between about 0 degrees and about room temperature. The breakage of a hydroquinolytically labile ester portion by catalytic hydrogenation according to process (c) can be carried out in a known manner. The reaction can be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium on carbon in the presence of an inert solvent (for example, an alcohol such as ethanol) at room temperature around room temperature and at atmospheric pressure. The optional separation according to process (d) can be carried out according to known methods such as column chromatography, thin layer chromatography, high pressure liquid chromatography, etc. The optional conversion of a compound of structure 1 to a pharmaceutically acceptable addition salt according to process (e) can be carried out by conventional means. For example the compound can be treated with an inorganic acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., or with an appropriate organic acid such as acetic acid, trifluoroacetic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluensulonic acid, or the like. The optional conversion of a compound of structure 1 to a pharmaceutically acceptable alkali metal salt according to process (f) can be carried out by conventional means. For example, the compound can be treated with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like. Compounds of structure 1 in which R4 represents an optionally substituted alkyl moiety can be prepared by means which are well known to someone with normal qualification in the field. For example, they can be prepared by Structure 5 Structure 6 Structure 7 (g) treating a compound of structure 5 with an agent that provides a carboxamide or a sulfonamide or, (h) coupling a compound of structure 6 with a compound of structure 7. Acylation or sulfonylation of compounds of structure 5 according to the process (g) can be carried out using methods that are known per se. For example, compounds of structure 1 in which X represents a sulfonyl group can be prepared by reacting compounds of structure 5 with a sulfonyl chloride in the presence of an appropriate base, for example pyridine, which can also be used as a solvent. The reaction can also be carried out using a tertiary amine as a base, in the presence of an inert solvent such as tetrahydrofuran or dichloromethane; or in aqueous solution using an alkali metal hydroxide such as sodium hydroxide as a base. The reaction is conveniently carried out at a temperature between about room temperature and about 80 degrees, preferably at a temperature around the room. Compounds of structure 1 can be prepared in which X represents a carbonyl group by reaction of compounds of structure 5 with carboxylic acids in the presence of a coupling agent, of which many examples are known per se in peptide chemistry, and in the presence optionally of a substance which increases the speed of the reaction, such as 1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole; or by the reaction of compounds of structure 5 with reactive derivatives of carboxylic acids such as the corresponding acid halides (for example, acid chlorides), acid anhydrides, mixed anhydrides, activated esters etc. The reaction is conveniently carried out by treating the compound of structure 5 with a carboxylic acid and l-hydroxy-7-azabenzotriazole in an inert solvent such as N, N-dimethylformamide or N-methylpyrrolidinone at a temperature between about 0 degrees and around room temperature, preferably around room temperature. The carboxylic acids and the reactive derivatives thereof used for the acylation of the compounds of structure 5 and the compounds of structure 12, and the sulfonyl chlorides used for the sulfonylation of the compounds of structure 5 and the compounds of structure 12, are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples that follow, or by analogy thereto. Examples of reactions which can be used for the preparation of such acids are: saponification of known carboxylic esters, alkylation of known carboxylic esters followed by carboxylation, conversion of the amino group of an α-amino acid to pyrrole, protection of amino acids known from the group ( 9H-fluoren-9-ylmethoxy) carbonyl, oxidation of known aldehydes, and reaction of the known halofor or methyl ketones. The coupling of structure compounds 6 with compounds of structure 7 according to process (h) can be achieved using methods well known to someone with normal qualification in the field. For example, the transformation can be carried out by reacting carboxylic acids of structure 7 or the appropriate derivatives thereof such as activated esters, with amines of structure 6 or their corresponding acid addition salts (for example, hydrochlorides) in presence, if necessary, of a coupling agent, of which many examples are known per se in peptide chemistry. The reaction is conveniently carried out by treatment of the carboxylic acid of structure 7 with the hydrochloride of the amine of structure 6 in the presence of an appropriate base, such as diisopropylether ielamine, a coupling agent such as O- (benzotr) hexafluorophosphate iazol-1-il) -1, 1, 3, 3-tetramethyluronium, and in the optional additional presence of a substance that increases the rate of the reaction, such as 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole, in an inert solvent such as a halogenated hydrocarbon ( for example, dichloromethane) or N, N-dimethyl-formamide or N-methylpyrrolidinone, at a temperature between about 0 degrees and around room temperature, preferably around room temperature.

Structure Structure 9 The compounds of structure 5 can be prepared by methods that are well known in the art, such as the removal of the RIO protecting group from a compound of structure 8, in which RIO represents one of several amine protecting groups commonly used in the field of peptide chemistry, for example a carbamate such as tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 9H-fluoren-9-ylmethoxycarbonyl or the like, using the appropriate conditions which are used in conventional manner for the removal of one of these protecting groups . For example, compounds of structure 5 can be prepared from compounds of structure 8 in which RIO represents the allyloxycarbonyl group by treatment with a source of palladium (0), for example bi-2-chloride (triphenylphosphine) palladium (II), and an agent reducing, for example, tri-n-butyltin hydride. The reaction is conveniently carried out in an inert solvent such as a halogenated hydrocarbon (eg, dichloromethane) around room temperature. The compounds of structure 8 can be prepared by conventional means by coupling a carboxylic acid of structure 7, or an activated derivative thereof such as an activated ester (for example, the N-hydroxysuccinimide ester), with an amine of structure 9, or a salt of it. This coupling can be carried out analogously to that described above in connection with the coupling of the carboxylic acids of structure 7 with amines of structure 6 or salts thereof , CH, -NH R10, CH; -NH X-YW-Z R11-NH-CH and / R1 t-NH-CH COOR4 CO OR4 Structure 10 Structure 11 The compounds of structure 9 can be prepared from compounds of structure 10 in which RIO and Rll each represent one of several amine protecting groups commonly used in the field of peptide chemistry, for example a carbamate such as tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 9H-fluoren-9-ylmethoxycarbonyl or the like, with the proviso that the protecting group represented by Rll is not the same as the protecting group represented by RIO, by methods known to someone with a qualification normal in the field. For example, in the case of a compound of structure 10 in which Rll represents a tert-butoxycarbonyl group and RIO represents an allyloxycarbonyl group, the compound of structure 9 can be conveniently obtained by treatment with a strong acid, for example an acid halogenated alkanecarboxylic acid such as trifluoroacetic acid. The reaction can be carried out in an inert organic solvent (such as dichloromethane) at a temperature between about 0 degrees and about room temperature, preferably around room temperature. Compounds of structure in which R 4 represents an optionally substituted alkyl group, for example, lower alkyl (for example, methyl or ethyl), aralkyl (for example benzyl), or a resin commonly used in solid phase synthesis (for example, Wang resin), can be obtained by any conventional method. For example, they can conveniently be obtained from the corresponding carboXylic acid of structure in which R4 represents hydrogen by any esterification reaction, many of which are well known to someone with normal qualification in the field. For example, compounds of structure in which R 4 represents methyl can be prepared from compounds of structure in which R 4 represents hydrogen by treatment with an ether solution of diazomethane. The reaction is conveniently carried out in an inert solvent such as an ether (e.g., diethyl ether or tetrahydrofuran) or an alcohol (e.g., methanol), at a temperature between about 0 degrees and about room temperature, preferably around 0 degrees. The starting materials of structure 10 in which R 4 represents hydrogen are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples that follow, or by analogy thereto. The compounds of structure 6 can be prepared by methods that are well known in the field of peptide chemistry for the removal of amine protecting groups from compounds of structure 11, in which Rll represents one of several commonly used amine protecting groups in the field of peptide chemistry, for example a carbamate such as tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 9H-fluoren-9-ylmethoxycarbonyl or the like. For example, in the case of a compound of structure 11 in which Rll is a tert-butoxycarbonyl group, the compound of structure 6 can conveniently be obtained in a manner analogous to that described above in connection with the elimination of the tert-butoxycarbonyl group from a compound of structure 10 in which Rll represents a tert-butoxycarbonyl group. The compound of structure 11 in which R 4 represents an alkyl group, an aralkyl group or a ream such as those commonly used in solid phase synthesis (for example, Wang resin), is prepared from a compound of structure 11 in which R4 represents hydrogen and X represents carbonyl, by conventional methods. For example, the compound of structure 11 in which R 4 represents hydrogen and X represents carbonyl can be converted to a compound of structure 11 in which R 4 represents methyl and X represents carbonyl by treatment with an ether solution of diazomethane. The reaction is conveniently carried out under conditions analogous to those described above for the preparation of compounds of structure in which R 4 represents methyl.

Structure 12 Structure 13 The compounds of structure 11, in which R 4 represents hydrogen, can be conveniently prepared by acylation or sulfonylation of compounds of structure 12, in which R 4 represents hydrogen, by conventional methods. For example, in case R4 represents hydrogen and X represents sulfonyl, the compound of structure 11 can be conveniently prepared by treatment of the compound of structure 12 wherein R4 represents hydrogen with a sulfonyl chloride in the presence of an appropriate base, such as pyridine or a tertiary amine (eg, diisopropylethylamine) and optionally in the presence of an inert solvent such as tetrahydrofuran. The reaction can conveniently be carried out at a temperature between about 0 degrees and about room temperature, preferably around room temperature. As a further example, in case R4 represents hydrogen and X represents carbonyl, the compound of structure 11 can be obtained by treatment of a compound of structure 12, in which R4 represents hydrogen, with reactive derivatives of carboxylic acids such as the corresponding ones acid halides (eg, acid chlorides), acid anhydrides, mixed anhydrides, activated esters etc. The reaction is conveniently carried out in a mixture of water and an ether such as dioxane, at a temperature between about 0 degrees and about room temperature, preferably around room temperature. The starting materials 12 in which R 4 represents hydrogen and R 1 represents one of several amine protecting groups commonly used in the field of peptide chemistry, are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples that follow, or by analogy thereto.

The starting products of structure 7 in which n represents zero are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a similar manner to known compounds. The compounds of structure 7 in which n represents 1 are prepared by methods that are well known in the field of organic chemistry. For example, they can be prepared by: (i) by removing carboxylic acid protecting groups from compounds of structure 13, wherein R 17 represents for example an unbranched lower alkyl group (e.g., methyl or ethyl), an aralkyl group , or a tert-butyl group or the like. (j) by carboxylation of compounds of structure 14, in which R16 represents a group that can be carboxylated with catalysis by a noble metal, and in which the rest of the molecule is stable against this treatment. For the deprotection of ester-type protecting groups according to process (i), any conventional means can be used. For example, in the case where R17 represents an unbranched lower alkyl group (e.g., methyl), the reaction can be carried out by treatment of the compound of structure 13 with an alkali metal hydroxide, such as potassium hydroxide, Sodium hydroxide or lithium hydroxide, preferably lithium hydroxide, in an appropriate solvent, such as a mixture of tetrahydrofuran, methanol and water. The reaction is conveniently carried out at a temperature between about 0 degrees and about room temperature, preferably around room temperature. For the carboxylation of compounds of structure 14, in which Rlβ represents a group which can be carboxylated with catalysis by a noble metal, according to process (j), various methods can be used. For example, the reaction can be carried out by reacting the compound of structure 14 with water under carbon monoxide gas at a pressure between about 14 pounds per square inch and about 50 pounds per square inch., preferably at about 40 pounds per square inch, in the presence of a base, for example a tertiary amine, such as triethylamine, in an inert solvent, such as N, N-dimethyl formamide, dimethyl sulfoxide, acetonitrile or the like. The reaction can be carried out at a temperature between about 40 degrees and about 100 degrees, preferably about 80 degrees. Compounds of structure 14 can be obtained by routes similar to those described below for the preparation of compounds of structure 13. Compounds of structure 13, in which R 17 represents for example an unbranched lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, can be prepared by any conventional means. They can be prepared, for example, by Structure 15 Structure 16 Structure 17 Structure l: Structure 19 Structure 20 Structure 21 Structure 22 Structure 23 R13 -CHZCH2 Structure 24 Structure 25 Structure 26 Structure 27 Structure 28 Structure 29 k) for the preparation of a structure compound Wherein R2 represents, -CH-NH-C-, by reacting a compound of structure 15 or a salt thereof with a compound of structure 16 or a reactive derivative thereof, or (1) for the preparation of a compound of structure . R3 or 13 in which R2 represents, -CH-NH-C-, by reacting a compound of structure 17 with a reactive derivative of a compound of structure 16 under reducing conditions, or (m) for the preparation of a compound of structure H Wherein R2 represents, '-N, by reacting an isocyanate of structure 18 with an aniline of structure 19 and converting the resulting urea into an aminotetrazole, or (n) for the preparation of a compound of structure Wherein R2 represents -CH2-CH2-C-0-CH2-CH2-CH- by reacting an aldehyde of structure 20 with a phosphorane of structure 21, and reducing the resulting chalcone, or (o) for the preparation of a compound of structure 13 in which R2 represents, -C-NH-CH- by reacting a compound of structure 22 or a reactive derivative thereof with a compound of structure 23 or a salt thereof. (p) for the preparation of a compound of structure 13 in which R2 represents -CH, -CH, -C- or -O-CH2-C-, by reacting a compound of structure 24, in which R13 and carbonyl represent in set R1-R2-, with a compound of structure 25. (q) for the preparation of a structure compound 13 wherein R2 represents, -CH-CH = CH-, by reacting a compound of structure 26 with a compound of structure 27, wherein R15 represents a group that can be substituted under the conditions of the Heck reaction. (r) for the preparation of a structure compound R3 in which R2 represents, -CH = CH-CH-, by reacting a compound of structure 28 with a compound of structure 29, in which R15 represents a group that can be substituted under the conditions of the Heck reaction. The acylation of compounds of structure 15 to give compounds of structure 13, wherein R2 represents, -CR3H-NH-fC? - according to process (k) can be carried out in a manner analogous to that described above in connection with the coupling of a compound of structure 6 with a compound of structure 7. The coupling of structure compounds 17 with reactive derivatives of compounds of structure 16 according to process (1) can be carried out under conditions that are known per se. Examples of reactive derivatives of the compounds of structure 16 which can be used in the reaction are acid anhydrides, mixed anhydrides, and activated esters (for example, the N-hydroxysuccinimidyl ester), preferably activated esters. The reaction can be conveniently carried out using palladium on carbon as a reduction catalyst in the presence of hydrogen at a pressure between about 14 pounds per square inch and about 50 pounds per square inch, preferably about 14 pounds per square inch. . The reaction can be carried out in the presence of an inert solvent such as ethyl acetate, or an aromatic hydrocarbon (for example, benzene), or an alcohol (for example, methanol), or in a mixture of these solvents. The reaction can be carried out conveniently at a temperature around room temperature. The coupling of the isocyanates of structure 18 with the anilines of structure 19 to give ureas, according to process (m), can be carried out by methods known per se. For example, the reaction can be carried out by reacting the isocyanate of structure 18 with the aniline of structure 19 in the presence of a suitable base, such as a tertiary amine (for example diisopropylethylamine), in an inert solvent such as an aromatic hydrocarbon (for example, benzene). The reaction can conveniently be carried out at a temperature of about 80 degrees and about 110 degrees, preferably at about 80 degrees. The resulting urea can be converted to the amino tetrazole using any conventional means to effect such transformation, such as by treatment with trimethylsilazaide under dehydration conditions. For example, the reaction can be conveniently carried out by treating the urea with trimethylsilyl azide, diethylazodicarboxylate, and triphenylphosphine in an inert solvent, such as tetrahydrofuran, at a temperature between about 0 degrees and about room temperature, preferably about the room temperature. The coupling of the aldehydes of structure 20 with the phosphorans of structure 21 to give the chalcones, according to process (n), can be carried out by methods that are well known in the field of organic chemistry. For example, the phosphorane can be treated with the aldehyde in a solvent such as an aromatic hydrocarbon (for example benzene) at a temperature between about 80 degrees and about 110 degrees, preferably about 80 degrees. The resulting chalcones can be reduced by catalytic hydrogenation to give a compound of structure 13, in which R2 represents -CH2-CH2-C- 0 -CH2-CH2-CH- The reaction can be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium on carbon in the presence of an inert solvent (eg, ethyl acetate) or an alcohol such as ethanol) at about room temperature and under a hydrogen atmosphere. The coupling of a carboxylic acid of structure 22, or a reactive derivative thereof, such as the acid halide (eg, acid chloride), acid anhydride, mixed anhydride, or activated ester, with an amine of the structure 23 or the salt thereof, according to the procedure (o), can be carried out using one of a variety of conditions that are well known in the field of peptide chemistry. For example, the reaction can be carried out in a manner analogous to that described at the beginning in connection with the coupling of a compound of structure 6 with a compound of structure 7. The coupling of a compound of structure 24 with a Composite of structure 25 according to process (p) can be carried out under conditions that are well known to those skilled in organic chemistry. For example, the reaction can be carried out in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylidenacetone) dipalladium (0), or transbenzyl (chloro) bis (triphenylphosphine) palladium (11), preferably tris (di-benzylidene ketone) dipalladium (0), and in the additional and optional presence of bases such as potassium carbonate, diisopropylethylamine and / or triethylamine, in an inert solvent, such as an aromatic hydrocarbon (for example, benzene or toluene), dichloroethane, or an ether such as dioxane or tetrahydrofuran, preferably tetrahydrofuran, at a temperature between about room temperature and about 100 degrees, preferably at about room temperature. The coupling of a compound of structure 26 with a compound of structure 27, in which R15 represents a group that can be substituted under conditions of the Heck reaction, according to procedure (q), can be carried out by methods that are known to a person with average skill in the art. For example, the reaction can be carried out by treating the compound of structure 26 with the compound of structure 27 in the presence of a source of palladium (0) such as palladium (II) acetate, in the optional presence of a phosphine such as (tributyl phosphine), (triphenylphosphine) or tri-ortho-tolylphosphine preferably triphenylphosphine, in the optional presence of tetrabutylammonium chloride, in the presence of a base which may be organic (for example, triethylamine) or inorganic (for example carbonate potassium, sodium acid carbonate, thallium (I) acetate or silver acetate), in an inert solvent (for example N, N-dimethyl formamide or N, N-dimethylacetamide) at a temperature between about room temperature and about 110 degrees, preferably at approximately 100 degrees. The coupling of a compound of structure 28 with a compound of structure 29, in which R15 represents a group which can be substituted under the conditions of the Heck reaction, according to process (r) can be carried out by methods which are well known . For example, the reaction can be carried out analogously to that described in connection with the coupling of a compound of structure 26 with a compound of structure 27. The starting materials of structure 15, 19, 20, 22, 24 and 28 they are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples that follow, or by analogy thereto.

Structure 30 The compounds of structure 16 can be obtained by any conventional means. For example, can be prepared by: (s) hydrolysis of a compound of structure in which R17 and R14 represent separately an unbranched lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or similar, or (t) the carboxymethylation of a compound of structure 27, in which R15 is a group which can be substituted by catalysis by a noble metal, such as iodide, bromide or trifluoromethanesulfonate. The hydrolysis of a compound of structure 30 according to the process (s) can be carried out by any conventional means. For example, in the case of a compound of structure 30 in which R14 is a group that can be cleaved by basic hydrolysis, the reaction can be conveniently carried out by treating the compound with one equivalent of an alkali metal hydroxide, such as hydroxide potassium, sodium hydroxide, or lithium hydroxide, preferably lithium hydroxide, in a suitable solvent such as a mixture of tetrahydrofuran, methanol and water. The reaction can be carried out at a temperature between about 0 degrees and about room temperature, preferably around room temperature. The carboxylation of compounds of structure 27, in which R15 is a group which can be substituted by catalysis by a noble metal, such as iodide, bromide or trifluoromethanesulfonate, according to process (t) can be carried out using conventional methods. For example, the reaction can be carried out by reacting the compound of structure 27 with water under carbon monoxide gas at a pressure between about 14 pounds per square inch and about 50 pounds per square inch, preferably at about 40 pounds per square inch. square inch, in the presence of a base, for example a tertiary amine, such as triethylamine, in an inert solvent, such as N, N-dimethylformamide, dimethylsulphoxide, acetonitrile or the like. The reaction can be carried out at a temperature between about 40 degrees and about 100 degrees, preferably about 80 degrees. The compounds of structure 17 can be prepared by any conventional means. For example, in case R3 is hydrogen, they can be prepared from compounds of structure 38 by substitution of bromine. The reaction can be carried out by treating the compound of structure 38 with an alkali metal salt of azide, preferably sodium azide, in the presence optionally of an agent that increases the reaction rate, such as potassium iodide. The reaction can be carried out in the presence of an inert solvent such as acetone or N, N-dimethylformamide at a temperature between about room temperature and about 60 degrees, preferably about 60 degrees. In the case that R3 is a lower alkyl group, the compounds of structure 17 can be prepared by reacting an alcohol of structure 39 with a reagent such as diphenyl phosphoryl azide. The reaction is conveniently carried out in the presence of a base such as 1,8-diazabicyclo [5 .0] undec-7-ene and in an inert solvent such as tetrahydrofuran at a temperature around room temperature. or Rt-CH2-C-OH Structure 31 The compounds of structure 18 can be prepared by reactions known per se. For example, they can be prepared by rearranging Curtius of compounds of structure 31. The reaction can be conveniently carried out by treating the compound of structure 31 with a reagent such as diphenyl tosphorylazide and one such as a tertiary amine (eg, diisopropylethylamine). ) in an inert solvent such as an aromatic hydrocarbon (for example, benzene). The reaction can be carried out conveniently at a temperature of about 70 degrees. The compounds of structure 21 can be prepared by various methods well known in the field of organic chemistry. For example, they can be prepared by deprotonation of the corresponding phosphonium salts by treatment with a base, for example sodium carbonate, in an inert solvent, such as a mixture of an aromatic hydrocarbon (for example, benzene) and water. The reaction can be carried out conveniently at room temperature. The phosphonium salts can be prepared by any conventional means. For example, they can be prepared by a substitution reaction of the compounds of structure 41. The reaction can be conveniently carried out by treating the compound of structure 41 with triphenylphosphine in the presence optionally of a catalytic amount of pyridine in an inert solvent such as acetonitrile. . The reaction can be carried out at a temperature between about ambient and about 80 degrees, preferably around room temperature. The compounds of structure 23 can be obtained by methods that are known per se in the field of organic chemistry. For example, they can be obtained by reducing azides of structure 44 by any of various methods, including catalytic hydrogenation using a noble metal catalyst, treatment with triphenylphosphine and water, or treatment with sodium borohydride. For example, in the case that the compound of structure 23 is prepared by catalytic hydrogenation, a noble metal catalyst such as palladium on carbon can be used, and the reaction can be carried out in the presence of an inert solvent (for example an alcohol). as ethanol) at room temperature and under 1 atmosphere of hydrogen. The structure compounds can be obtained by methods that are well known. For example, they can be prepared by coupling a compound of structure 27 in which R15 represents iodide, bromide or trifluoromethanesulfonate, with hexabutyldistannan in the presence of a noble metal catalyst such as tetrakis (triphenylphosphane) palladium (0), allyl palladium (II) chloride dimer, or dichlorobis- (triphenylphosphine) palladium (II), in a solvent such as an aromatic hydrocarbon (e.g., toluene), and ether (e.g., tetrahydrofuran, dioxane, or dimethoxymethane) or an amine (e.g., triethylamine) The reaction is conveniently carried out at a temperature between about 60 degrees and about 100 degrees, preferably about 80 degrees. The compounds of structure 26 are either known compounds or can be prepared by methods known per se. For example, they can be prepared by reaction of tannanal allyls with compounds of structure 28 with palladium catalysis. This reaction can be conveniently carried out by treatment of the compound of structure 28 with the tannin alkyl in the presence of catalysts such as tetrakis- (triphenylphosphine) palladium (0), dichlorobis- (triphenylphosphine) palladium (II), tris (dibenzylidene ketone) dipalladium (O) or trans-benzyl- (chloro) bis (triphenylphosphine) palladium (II), preferably tetrakis (tri-phenylphosphoro) palladium (0), optionally in the presence in addition to lithium chloride, in a solvent inert such as an aromatic hydrocarbon (for example, benzene) or a polar aprotic solvent such as • N-methylformamide. { or N-methylpyrrolidinone, at a temperature between about room temperature and about 150 degrees, preferably about 100 degrees. The compounds of structure 27 can be obtained by reactions that are well known in the field of organic chemistry. They can be obtained by (u) for the preparation of compounds of structure 27, wherein R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, the termination of a carboxylic acid of structure 27, in which R17 represents hydrogen, or (v) for the preparation of compounds of structure 27, in which R17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or similar and R15 represents iodide, the diazotization of an aniline of structure 19 in which R17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, and the treatment of the resulting diazonium salt with iodine, or (w) for the preparation of compounds of structure 27, wherein R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like and R15 represents trifluoromethanesulfonate, the reaction of a phenol of structure 27, in which R17 represents a lower alkyl group (for example, methyl or ethyl) ), an aralkyl group, or a tert-butyl group or the like and R 15 represents hydroxyl, with a reactive derivative of trifluoromethanesulfonic acid. The carboxylic acids of structure 27 in which R.sub.17 represents hydrogen can be converted into the corresponding esters, for example those in which R.sub.17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like , according to the procedure (u) using various procedures that are familiar to someone with a normal qualification in the field. For example, a compound of structure 27 in which R17 presents methyl can be prepared by reacting a carboxylic acid of structure 27 in which R 17 represents a hydrogen with an ethereal diazonetane solution. The reaction is conveniently carried out in an inert solvent such as an ether (e.g., diethyl ether or tetrahydrofuran) or an alcohol (e.g., methanol), at a temperature between about 0 degrees and around the room temperature, preferably around 0 degrees. The anilines of structure 19, in which R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, can be converted to the corresponding aryl iodides of structure 27, wherein R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, and R 15 represents iodide, according to process (v), by reactions that are well known per se . For example, the transformation can be carried out by converting the aniline of structure 19, wherein R17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, into the corresponding diazonium salt by treatment with an aqueous solution of sodium nitrite. The reaction is conveniently carried out in aqueous acid solution, such as aqueous hydrochloric acid, at a temperature between about -10 degrees and about 10 degrees, preferably about 0 degrees. The resulting diazonium salt solution can then be converted to the iodide in a form that is well known in the art. For example, it can be treated with an aqueous solution of potassium iodide. The reaction is conveniently carried out at a temperature between about 0 degrees and about room temperature, preferably about 0 degrees. The phenols of structure 27, in which R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, and R 15 represents hydroxyl can be converted into the corresponding structure tri-fluoromethanesulfonates 27, in which R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like and R 15 represents trifluoromethanesulfonate, according to process (w), by any conventional means. For example, the transformation can be carried out by reacting the phenol of structure 27, wherein R 17 represents a lower alkyl group (for example, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, and R 15 represents hydroxyl, in a manner analogous to that described above in connection with the preparation of the compounds of structure 33 from compounds of structure 3. The compounds of structure 27, wherein R17 represents a lower alkyl group (eg, methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, and R15 represents amino or hydroxyl, can be prepared by any conventional means. For example, structural compounds. 27, in which R17 represents hydrogen, and R15 represents amino or hydroxyl, can conveniently be prepared by treating the carboxylic acid of structure 27, wherein R17 represents hydrogen, and R15 represents amino or hydroxyl, with a solution of methanol containing an inorganic acid strong, for example sulfuric acid or a hydrohalic acid such as hydrogen chloride. The reaction is conveniently carried out at a temperature between about room temperature and about 65 degrees, preferably around room temperature. The carboxylic acids of structure 27, in which R 17 represents hydrogen, and R 15 represent bromo, amino or hydroxyl are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples that follow, or by analogy thereto. The compounds of structure 29 can conveniently be prepared from the compounds of structure 27 by methods that are known in the field of organic synthesis. For example, the reaction can be carried out in a manner analogous to that described in connection with the coupling of a compound of structure 28 with an allylantan to give a compound of structure 26. The compounds of structure 30 are generally known compounds or, in case if not, they can be prepared by any conventional means. For example, the compounds of structure 30 can be prepared by esterification of compounds of structure 32. This reaction can be carried out by methods that are well known to someone with a normal qualification in the field. For example, a compound of structure 30, in which R17 represents methyl, can be prepared from a compound of structure 32 by reaction with an ether solution of diazamethane. The reaction is conveniently carried out in an inert solvent such as an ether (e.g., diethyl ether or tetrahydrofuran) or an alcohol (e.g., methanol), at a temperature between about 0 degrees and about room temperature , preferably around 0 degrees. Compounds of structure in which U and V represent both chlorine can be prepared from compounds of structure 47 by reactions which are well known. For example, in the case where U and V represent both chlorine, and W represents hydrogen, the compounds of structure 30 can be prepared by reaction of compounds of structure 47 with a diazotization reagent, preferably an alkyl nitrite, more preferably nitrite of isoamyl, in a suitable solvent which can also act as a hydrogen donor, for example N, N-dimethylformamide or preferably tetrahydrofuran, at a suitable temperature, for example at around 65 degrees. The compounds of structure in which U and V represent both chlorine and W represent halogen can be prepared from the compounds of structure 47 by reactions which are well known, such as for example Sandmeyer or Schiemann reactions. The compounds of structure in which U and V represent both chlorine and W represent lower alkyl can be prepared from compounds of structure in which U and V represent both chlorine and W represents iodine, by reaction with an organostannic reagent with palladium as a catalyst . For example, compounds of structure in which U and V represent both chlorine and W represent methyl can be prepared from compounds of structure in which U and V represent both chlorine and W represents iodine by reaction with tetramethyl urea in the presence of tetrakis (triphenyl fos) palladium (0), and in the presence optionally of lithium chloride, in a suitable solvent such as a polar aprotic solvent such as N, N-dimethylformamide or N-methylpyrrolidinone at a suitable temperature as about 100 degrees.

E s tuctu re 32 Stru ctu re 33 Structure 34 Structure 35 Structure 47 The compounds of structure 32 can be prepared by reactions that are well known. For example, they can be obtained from the trifluoromethanesulfonate derivatives of structure 33 by reaction with carbon monoxide and water with a noble metal as a catalyst. This reaction can be carried out analogously to that described above in connection with the carboxylation of compounds of structure 27.

The compounds of structure 33 can be prepared by reactions that are known per se. For example, they can be prepared by reacting compounds of structure 34 with a reactive derivative of trifluoromethanesulphonic acid, such as trifluoromethanesulphonic anhydride or N-phenyl tri-fluorometanesulfonimide, preferably trifluoromethanesulfonic anhydride, in the presence of a base, such as a tertiary amine ( for example, diisopropylethylamine) in an inert solvent, such as a halogenated hydrocarbon (for example, dichloromethane). The reaction can conveniently be carried out at a temperature between about -78 degrees and about room temperature, preferably about -40 degrees. The compounds of structure 34 can be prepared by any conventional means. For example, they can be prepared by esterification of compounds of structure 35 by various reactions, such as those conventionally used to prepare esters of carboxylic acids, preferably by reactions that allow the esterification of the carboxylic acid in the presence of the phenolic hydroxyl group. For example, compounds of structure 34, in which R 14 represents methyl, can be prepared by treating compounds of structure 35 with a solution of methanol containing a strong inorganic acid, for example sulfuric acid or a hydrohalic acid such as hydrogen chloride. The reaction is conveniently carried out at a temperature between about room temperature and about 65 degrees, preferably around room temperature.

Structure 36 Structure 37 The compounds of structure 35 can be prepared by various methods that are known in the field of organic chemistry. For example, they can be prepared by oxidation of compounds of structure 36. This oxidation can be conveniently carried out by treating the compound of structure 36 with an oxidizing agent such as sodium chlorite, in the presence optionally of a chlorine dioxide sequestrant such or sulfamic acid. The reaction is conveniently carried out in an inert solvent system such as a mixture of water and tert-but anol, at a temperature between about 0 degrees and about 50 degrees, preferably at room temperature. The compounds of structure 36 can be prepared by any conventional means. For example, they can be prepared from the compounds of structure 37 by various methods, such as the treatment of compound 37 with hexamethylenetetramine under acidic conditions, for example by carrying out the reaction in an acidic solvent such as trifluoroacetic acid. The reaction is carried out conveniently at about 70 degrees.

R3 RT-CH-Br R3 R1-CH-0H R1-CH3 Structure 3 Structure 39 Structure 40 Structure compounds 38 can be obtained by any conventional means. For example, in case R3 represents hydrogen, they can be obtained by bromination of compounds of structure 40 where R1 can contain the suitable protecting groups that will be obvious to someone with a normal application in the field of organic synthesis. This bromination can be carried out by treating a compound of structure 40 with a brominating agent such as N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or bromine, preferably N-bromosuccinimide. The reaction can be carried out in the presence of an agent that increases the reaction rate such as a zodi i sobut ironi tri lo or benzoyl peroxide, and / or under irradiation with a light source such as a low pressure mercury lamp. The reaction can be carried out in the presence of an inert solvent such as carbon tetrachloride, at a suitable temperature such as about 76 degrees. The compounds of structure 40 are generally known compounds. As long as they are not known compounds or analogs of known compounds, they can be prepared in a manner similar to known compounds, or in the manner described in the Examples that follow, or by analogy thereto.

Structure 1 Structure 42 Structure 43 The compounds of structure 41 can be obtained by any conventional means. For example, these compounds can be obtained by reacting a diazoketone of structure 42 with hydrogen bromide. The reaction can be carried out conveniently by bubbling hydrogen bromide gas through a suspension of the compound of structure 42 in an inert solvent such as diethyl ether. The reaction can conveniently be carried out at a temperature between about 0 degrees and about room temperature, preferably around room temperature. The structure compounds 42 can be obtained by any conventional means. For example, they can be obtained by treating compounds of structure 43 with diazomethane. The reaction is conveniently carried out in the presence of a base, such as a tertiary amine (e.g., triethylamine) in an inert solvent such as ether at a temperature between -10 degrees and around room temperature, preferably around of 0 degrees. The compounds of structure 43 can be obtained by various methods familiar to someone with a normal qualification in the field. For example, they can be obtained by reacting a compound of structure 16 with a reagent that is commonly used for the conversion of carboxylic acids to acid chlorides such as thionyl chloride or oxalyl chloride in the presence or absence of an inert solvent such as an aromatic hydrocarbon (for example, benzene) or dichloromethane. In the case that thionyl chloride is used, the reaction can be carried out at a temperature of about 80 degrees.

Structure 44 Structure 45 The compounds of structure 44 can be obtained by various means. For example, they can be obtained by replacing the hydroxyl group of compounds of structure 45 with azide. This can be conveniently achieved by reaction of the compound of structure 44 with a reagent such as di-phenylphosphoryl azide. The reaction is conveniently carried out in the presence of a base such as 1,8-diazabicyclo [5 .0] undec-7-ene and in an inert solvent such as tetrahydrofuran at a temperature around room temperature. The structure compounds 45 can be obtained by various means. For example, in the case that R3 represents hydrogen, they can be obtained by reducing compounds of structure 16 by treatment with a reducing agent that effects the reduction of the carboxylic acid while leaving the carboxylate ester intact. An example of a reagent of this type is the complex of borane and methyl sulfide. The reaction can be conveniently carried out in the presence of an inert solvent such as tetrahydrofuran at a temperature between about room temperature and about 65 degrees, preferably about 65 degrees. The compounds of structure 2 can be prepared by methods analogous to those described above for the synthesis of compounds of structure 1 in which R2 represents Structure 46 Structure 48 The compounds of structure 47 can be obtained by any conventional means. For example, the compounds of structure 47 can be obtained by chlorination of compounds of structure 48, for example by treatment with a chlorinating agent such as N-chlorosuccinimide in a polar solvent such as acetonitrile at a suitable temperature, such as about 65. degrees. The compounds of structure 48 are generally known compounds, or can be prepared in a similar manner to known compounds. The compounds of structure 3 can be prepared by any conventional means. For example, they can be prepared by reacting compounds of structure 5 where Rl represents By "with structure compounds 46. The reaction is conveniently carried out in an inert solvent such as methanol or acetonitrile at a temperature between about room temperature and about 80 degrees., preferably around room temperature. The compounds of structure 46 are known compounds, a can be prepared in a similar manner to known compounds, using for example the procedure of Maryanoff, C.A. et al. J. Org. Chem. 1986, 51, 1882-1884. The compounds of structure 4 can be prepared by various methods. For example, they can be prepared from compounds of structure 1 wherein R4 represents hydrogen by reaction with an alkylating agent of structure R6-R16 wherein R16 represents iodo, bromo, or chloro. The reaction is conveniently carried out in the presence of a base, such as potassium carbonate, optionally in the presence of a catalyst such as potassium iodide, in an inert solvent such as N, N-dimethyl-formamide at a temperature between about from room temperature and around 80 degrees, preferably around 60 degrees. The compounds of structure R6-R16 are generally known compounds or can be prepared in a similar manner to known compounds In vitro inhibition of the interaction of ICAM-1 with LFA-1 and with Mac-1 by compounds of the present invention can be demonstrated by means of of the following assays: (a) Screening assay of LFA-1 / ICAM-1: The antagonist activity LFA-1 / ICAM-1 was quantified, defined as the ability of the compounds of the invention to block the binding of LFA- 1 to ICAM-1 Immobilized, using a solid phase ELISA. Typically, 96-well microtiter plates were coated overnight at 4 ° C with a fusion protein consisting of the complete extracellular domain of human ICAM-1 and the Fc domain of human IgG (5dICAM-Ig) (0.15μ in 100 μL of PBS). The plates were then blocked with 150 μL of 1% BSA / 1 mM MnCl2 / 0.14 M NaCl / 20 mM HEPES, pH 7.2 for 1 h at 37 ° C and washed 3 times (150 μL each time) with Wash Buffer ( 50 M Tris, pH 7.4 / 100 mM NaCl / 1 mM MnCl2 / 0.05% Tween 20). The stock solutions (100 μM in 100% DMSO) of the tested compounds were diluted 50 times with 150 μL of Binding Buffer (0.05% BSA / 0.05% Tween 20/1 mM MnCl2 / 0.14M NaCl / 20 mM HEPES pH 7.2) plus 10% DMSO. Series of 1: 4 dilutions were made to reach a range of 0.12 nM concentrations. - 2 μM. Fifty μL of each dilution per well was added to the ICAM-1 coated plates, followed by 50 μL per well of membrane-bound LFA-1 (280 ng / mL in Binding Buffer), obtained from transfected 293 cells. The plates were shaken vigorously for 1 minute (room temperature) and gently for 2 h (37 ° C). After incubation, the plates were washed 3 times (150 μL each time) with TAMP Washed. Human antiintegrin mouse monoclonal antibody 2 (100 μL / well, 1 μg / mL in Binding Buffer) was added and allowed to incubate for 1 h (37 ° C) with gentle agitation. The plates were then washed 3 times with Wash Buffer. Goat anti-IgG mouse HRP conjugate was added to each well (100 μL / well, dilution 1: 1500 in Binding Buffer), followed by incubation for 1 h (37 ° C), and finalized with three washes (150 μL). μL each) with Wash Buffer. TMB solution (100 μL per well) was added for color development (10 min). The reaction was stopped by adding 100 μL of 1M H3P04 to each well. The plates were then read at 450 nm. The inhibitory activities of the compounds tested were determined by the (b) Mac-1 / ICAM-1 screening assay: Mac-1 / ICAM-1 antagonist activity, defined as the ability to compete with the binding of ICAM-1 to immobilized Mac-1, was quantified by an ELISA. of solid phase. Microtiter plates were coated 96 wells overnight at 4 ° C with membrane bound Mac-1 obtained from transfected 293 cells (50 μL / well, 3 mg / mL Mac-1 in 20 mM Hepes, pH 7.2 / 0.14 M NaCl / 1 mM MnCl2). The plates were blocked with 100 μL / well of 0.5% BSA in 20 mM Hepes pH 7.2 / 0.14 M NaCl / 1 mM MnCl2 at 37 ° C for 1 h and washed 3 times (120 μL each time) with Binding Buffer (20 μL). mM Hepes pH 7.2 / 0.14 M NaCl / 1 mM MnCl2 /0.05% Tween 20). The tested compounds were dissolved in 100% DMSO and diluted 1:50 in Binding Buffer plus 10% DMSO. Series of 1: 4 dilutions were made for each compound (concentration range 0.12 nM 20 μM). (25 μL / well) of each dilution was added to the plates, followed by 25 μL / well of 5dICAM-Ig (40 μg / mL in Binding Buffer). The plates were shaken vigorously for 1 minute (room temperature) and then gently for 2 h (37 ° C), and washed with Binding Buffer (3 times, 120 μL each time). To each well (50 μL / well), conjugate HRP-goat anti-human IgG antibody (specific for FC) (0.125 μg / mL in Binding Buffer plus 0.05% BSA) was added, followed by incubation for 1 h (37 μL / well). ° C) The plates were then washed 3 times with Binding Buffer (120 μL each). TMB solution (100 μL / well) was added to each well for color development for 10 min.

The reaction was stopped with 1M H3P04 (100 μL / well) and the plates were read at 450 nm. The inhibitory activities of the compounds tested were determined by the IC50S. The results obtained in the cited tests using representative compunds of structure 1 as test compound are compiled in the following Table. LEA-1 / ICAM Mac-1 / ICAM Composite to IC5o (nM IC50 (nM) A 1.2 43.4 B 0.9 31.2 C 6.4 101.3 D 0.5 6.4 E 15.2 520.8 F 6.4 81.7 G 1.3 22.4 H 1.4 43.4 I 2.6 75.5 J 11.9 1413 Compound A: N- [2-chloro- - [[[(3-hydroxy-phenyl-1) -methyl]] -amino] carbonyl] enzoyl] -3- (3-methoxybenzoyl) amino-L-alanine Compound B: 3-benzoylamino -N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine Compound C: N- [2-chloro-4- [[[(3-hydroxy phenyl)] ) methyl] amino] carbonyl] benzoyl] -3- (5-nitropyrazole-3-carbonyl) amino-L-alanine Compound D: N- (2-chloro-4- [[[(3-hydroxy phenyl) methyl] - amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine Compound E: N- [2-chloro-4- [[[(3-hydroxy phenyl) met yl] -amino] carbonyl-benzoyl] -3- (4-methoxy quinoline-2-carbonyl) amino-L-alanine Compound F: 3- (5-bromothiophene-2-carbonyl) amino-N- (2,6-dichlorobenzoyl) -L-alanine Compound G : N- [2-chloro-4 - [[(lH-indol-4-ylmethyl) -amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine Compound H: N- [ 2-chloro-4- [l-oxo-3- (3-hydroxy phenyl) -propyl] benzayl] -3- (thiophene-2-carbonyl) amino-L-alanine Compound I: N- [2-chloro-4 - [5- [[(3-hydroxy-phenyl-1) -methyl] -amino] -tetrazol-1-yl] -enzoyl] -3 (thiophene-2-carbonyl) amino-L-alanine Compound J : 3- (phenylmethyl) amino-N- [2-chloro-4 - [[(1 H -indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine.

General The electron impact (El, 70ev) and fast atom bombardment (FAB) mass spectra were performed on a VG Autoespea or VG 70E-HF mass spectrometer. High-pressure reverse phase chromatography (RP-HPLC) was carried out using a Waters Delta Prep 3000 instrument with a Waters 484 detector, using a YMC ODS-A C-18 2.0 x 5cm column and using a linear gradient of acetonitrile: water (both containing 0.1% TFA), or a Rainin Dynamax HPLC system using a Dynamax 60A preparative column of 41.4 mm x 250 mm using a linear gradient of acetonitrile: water (both containing 0.075-0.1% TFA). Definitions: Alloc is allyloxycarbonyl, BSA is bovine serum albumin, DCC is dicyclohexylcarbodiimide, DCU is N, N'-dicyclohexylurea, DICI is diisopropylcarbodiimide, DMF is N, N-dimethylformamide, DMSO is dimethyl sulfoxide, ELISA is a linked immunosorbent assay to enzyme, Fc is the crystallizable fragment of an antibody, Fmoc is (9H-fluoren-9-ylmethoxy) carbonyl, HATU is 0- (7- azabenzotriazol-1-yl) -1, 1, 3, 3- tetramethexafluorophosphate i luronium, HEPES is 4- (2-hydroxy et il) piperazin-1-ethanesulphonic acid, HOAT is l-hydroxy-7-azabenzotriazole, HBTU is 0- (benzo triazol- 1 - i 1) - 1 hexafluorophosphate , 1,3,3-tetramet-illuronium, HOBT is hydroxybenzotriazole, HPLC is high-pressure liquid chromatography, HRP is horseradish peroxidase, ICAM-1 is the cell-1 adhesion molecule, IgG is immunoglobulin G, IMDM is medium. Dulbecco modified according to Iscove, LFA-1 is the antigen associated with the function of lymphocyte-1 (CDlla / CD18, DL D2), LSM is Lymphocyte separation medium, Mac-1 is the antigen of differentiation of macrophages associated with the receptor of type three complement (CDllb / CD18; DMD2), PBS is phosphate buffered saline, PVP is polyvinylpyrrolidone TBS is buffered saline with tris (hydroxymethyl) aminomethane hydrochloride, TMB is 3, 3 ', 5, 5' tetramethylbenzidine Examples 1 Preparation of 1-methyl ester of 2-chloro-1,4-benzenedicarboxylic acid 2-Chloro-1,4-benzenedicarboxylic acid, dimethyl ester (25.15 g, 0.11 mol), methanol (300 mL) and tetrahydrofuran (300 mL) were introduced into a 2-L round bottom flask equipped with a mechanical stirrer. . A solution of lithium hydroxide monohydrate (4.62 g, 0.11 mol) in deionized water (200 mL) was added over 10 min. After allowing the reaction to proceed at room temperature overnight, the solution was concentrated in vacuo to about 150 mL and then diluted with deionized water (200 mL). The precipitated solid was filtered and washed with deionized water (2 x 20 L) to give the acid 2-chloro-1, -benzenedicarboxylic acid, starting dimethyl ester (1.8 g) as bright plates. The combined filtrates were stirred while IN hydrochloric acid (112 mL, 0.112 mol) was added. The resulting solid was filtered, washed with deionized water (2 x 50 mL) and air dried. The solid was dissolved in methanol (300 mL) and heated to about 45 ° C. Then deionized water was added to the stirred solution until just before the cloud point. The solution was left at room temperature overnight. The resulting colorless solid was filtered, washed in turn with a cold mixture of deionized methanol (1: 2, 30 mL) and cold deionized water (30 mL). The solid was recrystallized once more from methanol-deionized water in the manner described above and dried, to give 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (13.1 g, 55.5%) as colorless needles . Example 2 Preparation of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester Potassium hydroxide (2.87 g, 51 mmol) was added to a solution of 2-bromo-1,4-benzenedicarboxylic acid, dimethyl ester (14 g, 51 mmol) in methanol (50 mL) at 25 ° C. The reaction mixture was stirred at 25 ° C for 24 h, and then at 50 ° C for 3 h. The solvent was concentrated under reduced pressure and the residue was diluted with water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The aqueous phase was acidified to pH 2 with 2M HCl and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with brine (100 L), dried (MgSO4), filtered, and concentrated. The resulting solid was boiled in toluene (100 mL) and the insolubles were filtered. The filtrate was concentrated and the resulting solid was subjected to flash chromatography (silica, 50% ethyl acetate in petroleum ether with 1% acetic acid) to give 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (3.28 g, 24%) as a white solid.

EXAMPLE 3 Preparation of 2-met i l-benzene-1,4-dicarboxylic acid, 1-methyl ester A. 4-Bromo-2-methylbenzoic acid, methyl ester A mixture of 4-bromo-2-methyl-ylbenzoic acid (14.77 g, 68. 7 mmol) and sulfuric acid (5 mL) in methanol (200 mL) was heato reflux for 3 h. The solvent was evaporaand dichloromethane (200 mL) was added. The solution was washed with water, 1M NaOH, and brine (200 L each), dried (MgSO), filtered and evaporato give 4-bromo-2-methyl-ylbenzoic acid, methyl ester (12.21 g, 78%). %) in the form of a colorless liquid. B. 2-Methylbenzene-1,4-dicarboxylic acid, 1-methyl ester A mixture of 4-bromo-2-methylbenzoic acid, methyl ester (22.59 g, 98.6 mmol), triethylamine (32.00 g, 316.2 mmol), acetate of palladium (II) (0.56g, 2.5 mmol), bi s (di-pheni-1-phosphine) -propane (1.04 g, 2.5 mmol) and water (32 mL, 1776.3 mmol) in acetonitrile (80 mL) was pressurized to 40 psi with carbon monoxide and the pressure was released. After six of these cycles, the bottle was pressurized again and the contents were stirred at 83 ° C for 3 h. The reaction mixture was cooled to room temperature and depressurized. Ethyl acetate (200 mL) was added. The solution was filtered and then extracwith water (2 x 300 mL). The combined aqueous phases were acidified with 12 M HCl to pH 0. The resulting mixture was extracwith ethyl acetate (2 x 300 mL). The combined organic phases were dried (MgSO.sub.4), filtered and evaporato give 2-meth ilbenzene-1,4-dicarboxylic acid, 1-methyl ester (16.57 g, 87%), as a white solid, mp 134 -136 ° C Example 4 Preparation of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester N-chlorosuccinimide was added carefully (60.00 g, 449.3 mmol) was added to a solution of 2-aminoterephthalic acid, dimethyl ester (50.00 g, 239 mmol) at -60 ° C and the solution was then heaat 80 ° C for 6 h. The reaction mixture was left at room temperature for 4 days and then the solvent was evapora Ether (500 mL) was added and the mixture was washed with 1M NaOH (200 mL). The aqueous phase was extracwith ether (100 mL) and the combined ether phases were dried (MgSO 4), filtered and evaporato give a red oil. This was extracwith boiling hexanes (4 x 300 mL) and the hexane was evaporato give a red oil (67.77 g). Tetrahydrofuran (300 mL) was added, followed by isoamyl nitrite (70 g, 597.5 mmol) (CAUTION: this reaction is exothermic and the isoamyl nitrite should be added cautiously) and the solution heato reflux for 2 h. The reaction mixture was left at room temperature for 2 days, then the solvent was evapora(using initially the pressure of the aspirator, and then 0.5 mm Hg). The residue was chromatographed (3% ethyl acetate / hexanes) to give a light yellow liquid (27.56 g). Tetrahydrofuran (100 mL) was added, followed by a solution of sodium hydroxide (4.20 g, 105 mmol) in water (100 mL). The solution was stirred at room temperature for 2 days and then the solvent was evapora Water (80 L) was added and the mixture was stirred at ~50 ° C for 10 minutes to give a light yellow-orange solution. 1M HCl (120 mL) was added with stirring and the mixture was stirred for a further 15 minutes. The solid was filtered and recrystallized from methanol / water twice to give 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (18.85 g, 32%) as a white solid.

Example 5 Preparation of 1- [[3-chloro-4- (methoxycarbonyl) benzoi 1] -oxi] -2,5-pyrrolidinedione In a three-neck 1 L round-bottom flask equipped with a magnetic stirrer, an ice bath, a thermometer and an argon inlet tube, 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl, was introduced. ester (Example 1; 21.5 g, 0.1 mol) in tetrahydrofuran (250 mL). The solution was cooled to 10 ° C under argon and treated sequentially with N-hydroxysuccinimide (12.66 g, O.llmol) and 1,3-dicyclohexylcarbodiimide (21.66 g, 0.105 mol). These reagents were finished by washing with more tetrahydrofuran (100 mL). A precipitate began to form immediately. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight, and then diluted with diethyl ether (400 mL) and stirred for a further 30 minutes. The precipitate was collected by filtration, and the filtered mass was washed with diethyl ether (3 x 50 mL) The dried solid (DCU) weighed 22.2 g (> 99% of theory) The combined filtrates were diluted with hexane (100 mL ), were then transferred to a 2 L separatory funnel and washed in turn with saturated cold sodium bicarbonate solution (150 mL) and brine (150 L), each aqueous phase was then extracted with diethyl ether. (200 mL), and then the combined organic extracts were dried (MgSO 4), and evaporated to give crude l- [[3-chloro-4- (methoxy carbonyl) benzoyl] oxy] -2,5-pyrrolidinedione (~ 35g). ) as a colorless solid This product was used directly in the next step without further purification.

It was also prepared by this procedure Example 7 Preparation of (3-hydroxyphenyl) methylamine hydrochloride In a 250 mL Parr flask, methanol (100 mL) and 10% palladium on carbon (2 g) were introduced followed by 3-cyanophenol (19.0 g, 0.1595 mol) and concentrated HCl (16.66 mL, 0.2 mol). The mixture was hydrogenated at room temperature and 50 psi until the hydrogen consumption was stopped (about 10 h). The reaction was filtered through a pad of Celite and the filtered mass was washed with methanol (3 x 25 mL). The combined filtrates were evaporated under reduced pressure. The volatiles still present were removed by evaporating the residue twice from 50 ml portions of absolute ethanol. The crude amine hydrochloride, essentially free of residual HCl, was dissolved with heating in a minimum amount of absolute ethanol (~80 mL) and the stirred solution was diluted with anhydrous diethyl ether (500 mL). The mixture was stirred in an ice bath for 1 h and then the colorless crystalline product was filtered, washed with anhydrous diethyl ether (3 x 50 mL) and dried under vacuum to give (3-hydroxyphenyl) -methylamine hydrochloride (20.6 g) 80.9%), mp 146-148 ° C. EXAMPLE 8 Preparation of 3- [[(1,1-dimethylethyl) dimethyl-silyl] oxy] -benzenemethanamine A. 3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] benzonitrile To a solution of 3-cyanophenol (5 g, 42 mmol) and imidazole (6.3 g, 92 mmol) in N, N-dimethylformamide (85 mL) ) at 0 ° C tert-butyldimethylsilyl chloride (7.6 g, 50 mmol) was added. After 10 min, the reaction was warmed to room temperature and stirred for 24 h. The solvent was removed in vacuo. The residual oil was diluted with water (100 mL) and extracted with ether (300 mL). The ether phase was extracted with water (3 x 100 mL) and brine (100 mL), dried (MgSO 4) and filtered. Concentration and flash chromatography (silica, 50% ethyl acetate in petroleum ether) gave 3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] benzonitrile (9 g, 92%) as an oil. B. 3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] benzene-methanamine 10% palladium on carbon (250 mg) was added under a nitrogen atmosphere to a solution of 3- [[(1, 1- dimethylethyl) dimethylsilyl] oxy] benzonitrile (1 g, 4.3 mmol) in methanol (25 mL) at 25 ° C. The reaction mixture was hydrogenated at 50 psi on a Parr shaker for 3 h. The reaction mixture was then filtered through Celite and the filtered mass was washed abundantly with methanol (50 mL). The solvents were concentrated under reduced pressure and the residue was dried under vacuum for 1 h to give 3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -benzenemethanamine (950 mg, 95%) as an oil. Example 9 Preparation of 2,3-dihydro-2-oxo-lH-indole-4-methanamine hydrochloride A. 4-Cyano-3, 3-dibromo-l, 3-dihydro-lH-indol-2-one lH-indole-4-carbonitrile was dissolved (prepared according to Clark, Robin D., Repke, David B. J.

Heterocycl. Chem. 1985, 22, 121-5; 3.26 g, 22.9 mmol) in a 3: 1 mixture of tBuOH / H20 (100 mL). Pyridinium perbromide (25.6 g, 80.1 mmol) was added portionwise over 30 mm to the stirred mixture in portions. The mixture was stirred for 1 h and then neutralized by the addition of aq NaHCO 3. sat The mixture was stirred for a further 2 h and the product was filtered. An additional portion of pyridinium perbromide (7.3 g, 22.9 mmol) was added to the filtrate, the resulting mixture was stirred overnight, and an additional amount of product was filtered. The filtrate was concentrated and the black residue partially dissolved in CHC13. It was filtered through a plug of silica gel which was washed several times with hot chloroform. The solids collected in the filtrations were combined and purified in the same way. 4-Cyano-3,3-dibromo-1,3-dihydro-1H-indol-2-one was obtained as light brown solid (5.20 g, 72%). B. 4-cyano-l, 3-dihydro-lH-indol-2-one Suspend in AcOH (50 mL) 4-cyano-3, 3-dibromo-1,3-dihydro-1H-indole-2 -one (2.5 g, 7. 9 mmol). The mixture was heated to 80 ° C and zinc powder (5.20 g, 79 mmol) was added in portions over 15 min. The solution was stirred for 20 minutes, and then filtered hot. The filtrate was concentrated to give a light yellow solid. Water was added and the mixture was filtered and washed with water to give -cyano- 1,3-dihydro-2H-indol-2 -one (1.12 g, 90%). C. 2,3-Dihydro-2-oxo-1H-indol-4-methanamine hydrochloride Palladium on carbon (10%, 0.10 g) and concentrated HCl (a few drops) were added to a solution of 4-cyano-1, 3-dihydro-lH-indol-2 -one (0.10 g, 0.63 mmol) in methanol (10 L). The mixture was hydrogenated for 36 h at 65 psi and then filtered. The filtrate was concentrated to give 2,3-dihydro-2-oxo-lH-indole-4-methanamine hydrochloride (0.120 g, 95%). Example 10 Preparation of lH-indole-4-methanamine Lithium aluminum hydride (3.80 g, 100.0 mmol) was added in portions of 0.5 g over 30 min to a solution of lH-indole-4-carbonitrile (prepared according to Clark, Robin D., Repke, David BJ He t erocycl, Ch., 1985, 22, 121-5, 7.50 g, 52.8 mmol) in tetrahydrofuran (250 mL). The mixture was refluxed for 30 min. A solution of 1M sodium hydroxide was added to neutralize the excess of lithium aluminum hydride. The mixture was filtered and the filtered mass was washed with water. The filtrate was first acidified with 1M HCl and then basified again by the addition of saturated aqueous NaHCO3. The aqueous phase was then extracted with nBuOH. By evaporation of nBuOH, and drying under vacuum, lH-indole-4-methanamine (6.24 g, 80%) was obtained as a beige solid. Example 11 Preparation of lH-indol-4-methanamine hydrochloride A. IH-indole-4-carboxylic acid, methyl ester To a mixture of lH-indole-4-carboxylic acid (100 mg, 0.62 mmol), 1- (3-dimethylaminopropyl) -3-ethexcarbodi imide hydrochloride (131 mg, 0.68 mmol), and methanol (1 mL, 24.7 mmol) in dichloromethane (2 mL) was added N, N-dimethyl-amino-pyridine (7.6 mg, 0.06 mmol). The mixture was allowed to stir at room temperature overnight, then the solvent was evaporated and ethyl acetate (20 L) was added. The solution was washed with 1M HCl (2 x 15 mL), saturated sodium hydrogencarbonate (15 mL) and brine (10 L), dried (MgSO 4), filtered and evaporated to give lH-indole-4-carboxylic acid, methyl ester (85.4 mg, 79%) as a light yellow solid.

B. lH-indol-4-methanol To a solution of lH-indole-4-carboxylic acid, methyl ester (85 mg, 0.49 mmol) in ether (1.6 mL) at -70 ° C, diisobutylaluminum hydride (1M) was added. in toluene, 1.3 mL, 1.3 mmol). The solution was allowed to stir at -70 ° C for 1 h, and then at room temperature for 1 h. Ethyl acetate (20 mL) was added, and the solution was stirred with an aqueous solution of potassium sodium tartrate (30% w / v; 20 mL) for 30 min. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO), filtered, evaporated, and dried under high vacuum to give 4H-indole-4-methanol (73.2 mg, quantitative yield) which was used in the next step without further purification. . C. 4- (azido ethyl) -lH-indole To a solution of lH-indole-4-methanol (71 mg, 0.48 mmol) in tetrahydroturan (1 mL) at 0 ° C was added di-phenyl-1-phosphoryl azide ( 156 μL, 0.72 mmol) followed by 1,8-diaza [5, 4, 0] undec-7-ene (87.4 μL, 0.58 mmol). The cooling bath was removed and the solution was allowed to stir for 5 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 1M HCl and brine, dried (MgSO 4), filtered, concentrated and chromatographed (12% ethyl acetate / hexanes) to give 4- (azidomethyl) -lH-indole (1496 g, 88% ) in the form of oil. D. IH-indol-4-methanamine hydrochloride To a solution of 4 - (azidomet i 1) -IH-indole (628 mg, 3.65 mmol) in tetrahydrofuran (10 mL) a ° C was added triphenylphosphine (1.05 g, 3.65 mmol) and the reaction was stirred for 24 h. Water was added (1.0 mL) and the reaction was stirred at 25 ° C for 24 h.

The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (20 mL) and washed with 0.5 M HCl (8 mL). The acid phase was lyophilized to give 1H-indole-methanamine hydrochloride. (510 mg, 77%) as a whitish solid.

Example 12 Preparation of 4-aminomethyl-1- (te-trahydro-2H-pyran-2-yl) -IH-indazole A. L-acetyl-lH-indazole-4-methanol acetate Acetic anhydride (1.68 mL, 17.8 mmol) was added to a suspension of 3-amino-2-methylbenzyl alcohol (0.82 g, 5.98 mmol) in chloroform (25 g). mL). Potassium acetate was added and the resulting mixture was stirred at room temperature for 3 h, refluxed for 2 h, and then at room temperature overnight. Amyl nitrite (1.82 mL, 13.7 mmol) and 18-crown-6 (79 mg, 0.3 mmol) were added and the turbid light yellow mixture was heated to reflux overnight, then allowed to cool to room temperature and Stir for 5 h. The reaction mixture was poured into acetic anhydride (5 mL) and stirred at room temperature overnight. Dichloromethane (20 mL) was added and the solution was washed with sodium hydrogencarbonate solution, water, and brine (10 L of each), dried (Na 2 SO 4), filtered, concentrated, and chromatographed (10-40%). ethyl acetate / petroleum ether) to give l-acetyl-lH-indazol-4-methanol acetate (1.19 g, 86%) as a light yellow solid. B. IH-indazole-methanol hydrobromide A solution of 1-acetyl-lH-indazole-4-methanol acetate (0.5 g, 2.15 mmol) and 48% HBr in water (2.5 mL) was stirred overnight at room temperature. ambient. The solid was filtered, washed with 48% HBr and dried under high vacuum to give 61 mg of brown solid. This procedure was repeated to give 39.8 mg of light brown solid. The mother liquors of both reactions were combined, concentrated, and kept under high vacuum overnight to give lH-indazol-4-methanol hydrobromide (0.918 g) as an orange solid. Overall yield: 1019 g (103%). C. Hydrobromide of 4-bromomethyl-lH-indazole A mixture of lH-indazole-4-methanol hydrobromide (0.60 g, 2.6 mmol) and 48% HBr in water (6 mL) was heated in an 80 ° oil bath. C for 4.75 h. The heating was then stopped and the reaction mixture was allowed to stir for 15 min. The solid was filtered, washed with cold water and dried under high vacuum overnight to give 5-bromomethyl-lH-indazole hydrobromide (0.609 g, 80%) as a brown solid. D. 4 -Brush me tii-1- (tetrahydro-2H-pyran-2-yl) -lH-indazole A hydrobromide solution of 5-bromomethyl-lH-indazole (194 mg, 0.665 mmol) and 3,4-dihydro- 2H-pyran (0.118 mL, 1.29 mmol) in tetrahydrofuran (4.7 mL) was heated to reflux for 2 h and then stirred overnight at room temperature. Dichloromethane was added (12 mL) and the solution was washed with aqueous sodium hydrogencarbonate, water, and brine. (10 mL of each), dried (MgSO <), concentrated, and chromatographed (5-60% ethyl acetate / petroleum ether) to give 4-bromomet-1 - (tetrahydro-2H-) pyran-2-yl) -lH-indazole (153 mg, 78%) as an off-white solid. E. 4-Azidomethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole A mixture of 4-bromome-t-1- (tetrahydro-2H-pyran-2-yl) -lH-indazole (150 mg , 0.508 mmol) and sodium azide (132 mg, 2.0 mmol) in N, N-dimethyl formamide (1.5 L) was heated in an oil bath at 90 ° C for 30 min, then allowed to cool, and poured over water (5 L). The mixture was extracted with ether (2 x 10 mL), dried (MgSO.sub.4), filtered, evaporated, and dried under high vacuum overnight to give 4-azido and 1- 1 - (tetr ahydro-2H -piran-2-yl) -lH-indazole (124 mg, 95%) as a yellow oil. F. 4 -Aminomet i 1-1- (tetrahydro-2H-pyran-2-yl) -lH-indazole A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 0.51 mL, 0. 51 mmol) was added dropwise over 12 min to a cooled (0 ° C) solution of 4-zidome ti 1- 1 - (tetrahydro-2H-pyran-2-yl) -lH-indazole (130 mg, 0.505 mmol) in dry tetrahydrofuran (1.5 mL). The solution was stirred at ~ 0 ° C for 1 h and then neutralized with 1 M sodium hydroxide (75 μL) for approximately 1 min. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was diluted with ethyl acetate (3 mL), dried (Na2SO4), filtered through Celite (which was washed with ethyl acetate), and concentrated to give 4-aminomethyl-1- (tetrahydro-2H) -piran-2-yl) -lH-indazole (106 mg, 91%) as a yellow solid. Example 13 Preparation of 4- (azidomet i 1) benzimidazole-1-carboxylic acid, 1,1-dimethyl-ilet-1-ester A. 4-Methylbenzimidazole A solution of 3-methyl-1,2-diaminobenzene (5.00 g, 40.9 mmol) in formic acid (25 mL) was heated at 105 ° C for 2 h. The reaction mixture was allowed to cool and then concentrated ammonium hydroxide (50 mL) was added dropwise. The mixture was extracted with dichloromethane (2 x 100 mL). The extracts were washed with brine, dried (Na2SO4), treated with activated charcoal, filtered, and evaporated to dryness. The residue was triturated with cold ether, filtered, and washed with cold ether, ether / hexane (1: 1), and hexane to give 4-methylbenzimidazole (3.85 g, 71%) as a yellow solid. B. 4-Methylbenzimidazole-l-carboxylic acid, 1,1-dimethylethyl ester A solution of 4-methybenzimidazole (810 mg, 6.1 mmol), N, N-dimethylaminopyridine (75 mg, 0.6 mmol) and di-tert-bicarbonate -butyl (1.54 g, 7.1 mmol) in acetonitrile (20 mL) was stirred at room temperature for 15 min. The solvent was evaporated and the residue was chromatographed (10% ethyl acetate / hexanes) to give 4-methyl-benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (1.35 g, 95%).

C. 4- (Bromomethyl) benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester A mixture of 4-methylbenzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (6.50 g, 28.0 mmol) and N-bromosuccinimide (5.50 g, 30.9 mmol) in carbon tetrachloride (75 mmol) was stirred and irradiated with a 250 w lamp for 1 h. The reaction mixture was allowed to cool and the solid was filtered and discarded. The filtrate was evaporated and purified by HPLC (20% ethyl acetate / hexanes) to give 4- (bromomethyl) benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (3.69 g, 42%). D. 4- (Azidomethyl) benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester. A mixture of 4 - (bromomethyl) -benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (1.08 g, 3.5 mmol), sodium azide (240 mg, 3.7 mmol), and sodium iodide (5 mg) in acetone (10 mL) was heated to reflux for 66 h. The solvent was evaporated and dichloromethane was added. The solution was washed with dilute aqueous sodium hydrogencarbonate, dried (Na 2 SO 4), filtered and evaporated to give 4- (azidomethyl) benzimidazole-1-carboxylic acid, 1,1-dimethyl ethyl ester (800 mg, 84%).

Example 1 Preparation of 2-bromo-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoic acid, methyl ester . Diisopropylethylamine (8.4 mL, 48.2 mmol) was added dropwise to a cooled (~ 0 ° C) solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2, 5.00 g, 19.3 mmol) , HBTU (7.31 g, 19.3 mmol), 3-hydroxybenzyl sheet, HCl salt (Example 7, 3.37 g, 21.2 mmol), and HOBT (2.6 g, 19.2 mmol) in N, N-dimethylformamide (50 mL). The solution was allowed to stir at ~ 0 ° C for 1 h, then at room temperature for 4 h, and then concentrated to remove most of the N, N-dimethyl formamide. The residue was partitioned between ethyl acetate and 1 M HCl (200 mL each). The ethyl acetate phase was washed with 1M HCl (2 x 100 mL) and the combined aqueous phases were extracted with ethyl acetate (50 L). The combined ethyl acetate phases were washed with saturated sodium hydrogencarbonate solution (2 x 100 mL), and brine, then dried (MgSO 4), filtered, evaporated and recrystallized from hot ethyl acetate (~60 mL ) and hexanes (15 mL) to give 2-bromo-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoic acid, methyl ester (5.15 g, 73%) as white crystals. Example 15 Preparation of 2-bromo-4- [[[(lH-indol-4-yl) methyl] -amino] carbonyl] benzoic acid, methyl ester . Diisopropylethylamine (2.3 mL, 13.2 mmol) was added dropwise to an acid solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2, 861 mg, 3.32 mmol), HBTU (1.39 g). 3.65 mmol), lH-indole-4-methanamine hydrochloride (Example 11; 528 mg, 3.98 mmol), and HOBT (493 mg, 3.65 mmol) in N, N-dimethyl formamide (6.5 mL) at 0 ° C. The solution was warmed to room temperature and stirred for 24 h. The solvent was concentrated in vacuo to remove most of the N, N-dimethyl formamide. The residue was diluted with ethyl acetate (50 mL) and washed with 1 M HCl (10 mL), water (10 mL), saturated aqueous NaHCO 3 (10 L) and brine (10 mL). The organic phase was dried (MgSO 4), filtered, evaporated and subjected to flash chromatography (silica, 25-35% ethyl acetate / petroleum ether) to give 2-bromo-4- [[[(1H)] acid. -indol-4-yl) methyl] -amino] carbonyl] benzoic acid, methyl ester (900 mg, 70%) as a whitish solid. The following products were also prepared by this route, with the indicated modifications: Reaction time: 6 h. The product is a white solid. The eluent used for the chromatography was 30-% ethyl acetate / petroleum ether d The eluent used for the chromatography was 25% ethyl acetate / petroleum ether The eluent used for the chromatography was 20% ethyl acetate / ether petroleum Example 19 Preparation of 2-chloro-4- [l-oxo-3- (3-hydroxy phenyl) -propyl] benzoic acid, methyl ester and 2-chloro-4- [l-hydroxy-3- (3- hydroxy phenyl) propyl] benzoic, methyl ester A. 2-Chloro-4- (diazoacetyl) benzoic acid, methyl ester. To a cooled (-10 ° C) suspension of 2-chlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 1, 430 mg, 2.0 mmol) in benzene (15 mL), oxalyl chloride ( 0.25 mL, 2.9 mmol). A drop of N, N-dimethyl formamide was added and the solution was stirred at room temperature for 3 h. The solvent was evaporated and the residue was evaporated from toluene (2 x 25 mL) to give the acid chloride as a colorless waxy solid. Ether (20 mL) was added, followed by excess diazomethane in ether. The reaction mixture was left overnight at room temperature, and then concentrated. By addition of hexanes, followed by filtration, 2-chloro-4- (diazoacetyl) benzoic acid, methyl ester (410 mg, 86%) was obtained in the form of bright yellow crystals B. 4- (Bromoacetyl) -2-chlorobenzoic acid , methyl ester Hydrogen bromide gas was bubbled through a suspension of 2-chloro-4- (diazoacetyl) benzoic acid, methyl ester (400 mg, 1.7 mmol) in ether (30 mL) for 10 min. The solvent was evaporated and the residue was triturated with ether / hexane and filtered to give 4- (bromoacetyl) -2-chlorobenzoic acid, methyl ester (385 mg, 79%) as a colorless solid. C. (2-Oxo-2- [2-chloro-4- (methoxycarbonyl) -phenyl) ethyl] triphenylphosphonium bromide A mixture of 4- (bromoacetyl) -2-chlorobenzoic acid, methyl ester (372 mg, 13 mmol ), triphenylphosphine (336 mg, 1.3 mmol) and pyridine (1 drop) in acetonitrile (5 mL) was stirred at room temperature for 3 h. The solvent was evaporated and the residue was triturated with tetrahydrofuran. Ether was added, and then the mixture was filtered and the residue was washed with ether to give [2-oxo-2- [2-chloro-4- (methoxycarbonyl) phenyl] ethyl] -triphenyl-phosphonium bromide (641 mg, 90%) as a colorless solid. D. 2-Chloro-4- [l-oxo-3- (3-hydroxyphenyl) -2-propenyl] benzoic acid, methyl ester Sodium carbonate (215 mg, 2. 0 mmol) to [2-oxo-2- [2-chloro-4- (methoxycarbonyl) phenyl] ethyl] -triphenylphosphonium bromide (620 mg, 1. 1 mmol), benzene (5 mL) and water (5 mL) in a separatory funnel. The mixture was stirred until the solids dissolved (about 10 min). The aqueous phase was separated and extracted with benzene. The organic phases were washed with brine, combined, dried (MgSO 4) and concentrated to dryness. Benzene (4 mL) was added, followed by 3-hydroxy-benzaldehyde (137 mg, 1.1 mmol), and the solution was heated to reflux for 35 h. The solution was allowed to enter, hexane (3 Ml) was added, and the solid was filtered, washed with benzene / hexane, and then hexane to give 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) acid) -2-propenyl] benzoic acid, methyl ester (260 mg, 73%) as a yellow solid. E. 2-Chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] -benzoic acid, methyl ester and 2-chloro-4- [l-hydroxy-3- (3-hydroxyphenyl) propyl] benzoic, methyl ester A mixture of 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) -2-propenyl] benzoic acid, methyl ester (250 mg, 0.8 mmol) and 10% palladium on carbon (25 mg) in ethyl acetate (5 mL) was hydrogenated at atmospheric pressure for 90 min. The reaction mixture was filtered through Celite and the filtered mass was washed with ethyl acetate. The solvent was evaporated and the residue was chromatographed (20-50% ethyl acetate / hexanes) to give 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] -benzoic acid, methyl ester (160 mg, 64%) and 2-chloro-4- [l-hydroxy-3- (3-hydroxyphenyl) propyl] benzoic acid, methyl ester (65 mg, 26%). The alcohol was obtained as a racemic mixture and was not resolved. Example 20 Preparation of 2-bromo-4- [[[3- [[(1,1-dimethylethoxy) -carbonyl] aminophenyl] methyl] amino] -carbonyl] benzoic acid, methyl ester A. 4- [[[(3-Aminophenyl) methyl] amino] carbonyl] -2-bromobenzoic acid, methyl ester Powdered iron (135 mg, 2.4 mmol) was added to a suspension of 2-bromo-4- [-] acid. [[(3-nitrophenyl) methyl] -amino] carbonyl] benzoic, methyl ester (Example 16; 125 mg, 3.18 mmol) in water (530 μL) and acetic acid (111 μL) at 25 ° C. The reaction was refluxed for 30 min and then cooled to 25 ° C. The suspension was diluted with water (20 mL), stirred for 15 min, and filtered through Celite. The filtered mass was washed well with water (100 mL). The filtrate was extracted with ethyl acetate (50 mL) followed by ethyl acetate containing 2% methanol (50 mL). The organic phases were combined, dried (MgSO 4), filtered, and concentrated. The residue was diluted with 10% methanol in dichloromethane and stirred with Celite. After 1 h, the suspension was filtered and washed well with 10% methanol in dichloromethane. The concentration of the filtrate gave 4 - [[[(3-amino phenyl) -methyl] amino] carbonyl] -2-bromo-benzoic acid, methyl ester (100 mg, 87%) as an off-white solid. B. 2-bromo-4- [[[3- [[(1, 1-dimet i le toxi) carbonyl] aminopheni 1] e th 1] amino] carbonyl] enzoic acid, methyl ester To a solution of 4 - [[[(3-amino phenyl) methyl] amino] carbonyl] -2-bromobenzoic acid, methyl ester (420 mg, 1.16 mmol) in 1,4 dioxane (6.5 mL) at 25 ° C was added a solution of sodium carbonate (135 mg, 1.3 mmol) in water (2.1 mL) followed by di-tert-butyl bicarbonate (304 mg, 1.39 mmol).

After stirring 24 h, the reaction mixture was diluted with water (200 L) and washed with dichloromethane (300 mL). The organic phase was separated and washed with 10% acetic acid in water (100 mL), water (50 mL), and brine (50 L). The organic phase was dried (MgSO 4), filtered, evaporated and subjected to flash chromatography (silica, 25-35% ethyl acetate in petroleum ether) to give 2-bromo-4- [[3- [3- [[(1, 1-dimethylethoxy) carbonyl] aminophenyl] methyl] amino] carboni 1] benzoic, methyl ester (499 mg, 93%) as a white foam.

Example 21 Preparation of N- [3- [[[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] -3,5-dimethyl-1-4-hydroxybenzamide To a solution of 4-hydroxy-3,5-dimethybenzoic acid (1.53 g, 9.2 mmol) in dichloromethane (30 mL) at 0 ° C was slowly added dropwise benzotriazol-1-yloxy-tris- (dimethylamino) hexafluorophosphate. ) -phosphonium (BOP reagent, 4.45 g, 10 mmol) and 3- [[(1,1-dimethylethyl) dimethylsilyl] -oxy] benzenemethanamine (Example 8, 3.28 g, 13.8 mmol), followed by diisopropylethylamine (4.9 mL, 27.6) mmol). After 1 h, the reaction was heated to 25 ° C and stirred for 1 h. The solvent was removed under reduced pressure and the oily residue was diluted with ethyl acetate (100 mL) and washed with IN HCl (2 x 25 mL), saturated aqueous sodium bicarbonate (2 x 25 mL), water (25 mL) , and brine (25 mL). The organic phase was dried (MgSO 4), filtered, evaporated and subjected to flash chromatography (silica, 20-30% ethyl acetate in petroleum ether) to give N- [3- [[[(1.1)]. -dimethylethyl) -dimethylsilyl] oxy] phenyl] -methyl] -3,5-dimethyl-4-hydroxybenzamide (3.1 g, 87%) as a whitish foam. It was also prepared by this route: a The reaction time was 4 h at 25 ° C; The eluent used for the chromatography was 30-35% ethyl acetate / petroleum ether; The product was obtained in the form of whitish foam. EXAMPLE 23 Preparation of acid trifluoromethanesulfonic acid, 2,6-dimethyl-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -phenyl] methyl] amino] carbonyl] phenyl ester To a solution of N- [3- [[[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] -3,5-dimethyl-4-hydroxybenzamide (Example 21; 0.5 g, 1.3 mmol) in dichloromethane ( 9 mL) at -78 ° C was slowly added dropwise triethylamine (0.72 mL, 5.2 mmol) followed by tri fluoromethane sulfonic anhydride (0.26 mL, 1.56 mmol). After stirring for 2 h, the reaction was quenched with saturated aqueous ammonium chloride (1 mL). The mixture was warmed to 25 ° C, diluted with ethyl acetate (70 mL) and washed with 1N HCl (25 mL), saturated aqueous sodium bicarbonate (25 mL), water (25 mL), and brine (25 mL). ). The organic phase was dried (MgSO 4), filtered, evaporated and rapidly passed through a plug of silica (20% ethyl acetate in petroleum ether) to give trifluoromethane sulfonic acid, 2,6-dimethyl-4- [[[[[3- [[(1, 1-dimethylethe) dimethylsilyl] oxy] phenyl] methyl] -amino] carbonyl] phenyl ester (577 mg, 86%) as an oil. The following compounds were also prepared by this route: a The eluent used for the chromatography was 10-25% ethyl acetate / petroleum ether; The product was obtained as a solid. b The eluent used for the chromatography was 10-15% ethyl acetate / petroleum ether; The product was obtained as a light yellow oil.

Example 26 Preparation of 2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoic acid Into a 1 L round bottom flask equipped with a magnetic stirrer, ice cooling bath and an argon inlet tube, 1- [[3-chloro-4- (methoxy-carbonyl) benzoyl] oxy] -2 was introduced. , Crude 5-pyrrolidinedione (Example 5; ~ 35g, ~ 0.1 mol), using dimethylformamide (350 mL) to complete the transfer. The mixture was cooled to about 10 ° C, and (3-hydroxy-phenyl-1) methylamine hydrochloride (18.35 g, 0.115 mol) and triethylamine (35 mL, were added in rapid succession, with stirring and under an argon atmosphere). 0.25 mol). A precipitate started to form immediately. After stirring the reaction at room temperature overnight, the volatiles were removed under reduced pressure (< 0.5 mm). The oily residue was dissolved in ethyl acetate (600 mL) and washed in turn with 0.5N hydrochloric acid (400 mL), brine (300 mL), saturated sodium bicarbonate solution (2 x 300 mL) and brine (300 mL). Each aqueous phase was extracted in turn with ethyl acetate (2 x 300 mL), then the combined organic extracts were dried (MgSO4), and evaporated to give 2-chloro-4- [[[(3-hydroxy)] acid. phenyl) -methyl] amino] carbonyl] benzoic, crude methyl ester (~ 32g) as a whitish solid. In a 2 L round bottom flask equipped with a magnetic stirrer, a suspension of crude 2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoic methyl ester (~ 32 g, ~ 0.10 mol) in deionized water (300 mL) was treated with 1 N sodium hydroxide solution (300 mL, 0.3 mol). Most of the solids dissolved rapidly, and the solution was stirred at room temperature overnight. The mixture was filtered through Celite to remove undissolved solids (residual DCU) and the filtered mass was washed with deionized water (2 x 30 mL). The combined filtrates were transferred to a separatory funnel and extracted with diethyl ether (2 x 300 mL). Each ether extract was washed in turn with brine (50 mL). The combined aqueous phases were stirred while acidifying by the addition of 6N hydrochloric acid (55 mL, 0.33 mol). The resulting mixture was stirred overnight at room temperature, then the precipitated solid was collected by filtration and the filtered mass was washed with deionized water (2 x 60 mL). The slightly off-white solid was dried in vacuo over P2Os, then dissolved in hot ethyl acetate (400 mL), and the solution was treated with activated charcoal (4 g) and filtered through a pad of Celite. The filtered mass was washed with ethyl acetate (2 x 40 mL). The combined filtrates were concentrated to about 250 mL and then sufficient hexane was added to the hot stirred solution to produce a permanent cloud point. The mixture was cooled to room temperature and then stored at -20 ° C overnight. The solids were collected by filtration and washed with hexane (2 x 50 mL) to give 2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoic acid, mp 167-169 ° C (27.1 g, 88.6% from 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester) Example 27 Preparation of 4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -2-methylbenzoic acid A. 4- [[[(3-Hydroxyphenyl) methyl] amino] carbonyl] -2-methylbenzoic acid, methyl ester A solution of l - [[4- (methoxycarbonyl) -3-methylbenzoyl] oxy] -2, 5- pyrrolidine-dione (Example 6, 6.00 g, 20.6 mmol), 3-hydroxy-benzylamine (2.92 g, 23.7 mmol) and triethylamine (2.61 g, 25.8 mmol) in N, N-dimethyl formamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40 ° C) and ethyl acetate (200 mL) was added. The solution was washed with 0.5N hydrochloric acid (200 mL), brine (200 mL), saturated sodium bicarbonate solution (2 x 150 mL) and brine (200 mL). Each of the aqueous phases was extracted in turn with ethyl acetate (100 mL). The combined organic phases were dried (MgSO 4), filtered, and evaporated to give acid - [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -2-methylbenzoic acid, methyl ester (5.63 g, 91%) as of an orange liquid that solidified on standing, mp 100-103 ° C. B. 4- [[[(3-Hydroxyphenyl) methyl] amino] carbonyl] -2-methylbenzoic acid A solution of 4 - [[[(3-hydroxy phenyl] methyl] amino] carbonyl] -2-methylbenzoic acid (5.63) g, 18.8 mmol) in water (60 mL) was treated with aqueous sodium hydroxide (1 M, 60 mL, 60 mmol) and the solution was stirred at room temperature overnight.The solution was acidified with 1 M HCl (100 mL). ), and extracted with ethyl acetate (2 x 100 mL) The combined extracts were washed with brine (100 mL), the solution was dried (MgSO), filtered, and evaporated to give 4- [[[ (3-hydroxyphenyl) -methyl] amino] carbonyl] -2-meth ilbenzoic acid (5.22 g, 97%) as an orange oil.

EXAMPLE 29 Preparation of 2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoic acid A solution of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 4, 18.75 g, 75.3 mmol), dicyclohexylcarbodiimide (16.46 g, 79.8 mmol), and N-hydroxysuccinimide (9.59 83.3 mmol in tetrahydrofuran (200 mL) was stirred at room temperature overnight The solid was filtered and discarded, and the solvent in the filtrate was evaporated to give a white solid (29.13 g) DMF was added. (100 mL), followed by 3-me toxibenzylamine (14.20 g, 103. 5 mmol) and triethylamine (14.20 g, 140.3 mmol). The solution was stirred at room temperature overnight, then the solvent was evaporated (0.5 mm Hg, ~ 50 ° C), and 1 M HCl (200 mL) and dichloromethane (200 mL) were added. The mixture was stirred during min and then allowed to stand until the phases separated. A white precipitate formed in the dichloromethane phase. Most of the aqueous phase was decanted and the remaining material was heated until the solid dissolved. The remaining water was removed using a separatory funnel, the dichloromethane solution was allowed to cool, and the precipitate was filtered and air dried to give 2,6-dichloro-4- [[((3-methoxy-phenyl)] acid. methy] amino] carbonyl] benzoic acid, methyl ester (23.67 g, 85%) as a white solid. A suspension of this material (11.83 g, 32.1 mmol) in dichloromethane (400 mL) was cooled to ~ -78 ° C (acetone bath dry ice) and boron tribromide (1 M in dichloromethane; 100 mL, 100 mmol) was added. ). The mixture was stirred in the cooling bath for 3 h, and then allowed to stand at room temperature for 72 h. The supernatant was decanted and water (300 mL) was added to the supernatant and to the residue. The mixtures were stirred at ~40 ° C for 1 h and then combined, filtered and air dried to give 2,6-dichloro-4- [[[(3-hydroxy phenyl) -methyl] amino] carbonyl] benzoic acid (8.73 g, 80%) as a cream-colored solid.

Example 30 Preparation of 2,6-dimethyl-4 - [[[[3- [[(1,1-dimethyl-ethyl) dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] benzoic acid To a solution of trifluoromethanesulfonic acid, 2,6-dimethyl-4- [[[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] phenyl ester (Example 23; 3.02 g, 5.83 mmol) in acetonitrile (49 mL) and water (7 mL) at 25 ° C was added palladium (II) acetate (196 mg, 0.874 mmol), 1,3-bis (diphenyl phosphino) propane (360 mg , 0.873 mmol), followed by triethylamine (2.03 mL, 14.5 mmol). The reaction was then pressurized at 40 psi with carbon monoxide and heated at 80 ° C for 4 h. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL) containing 1 mL of triethylamine. The aqueous phase was reextracted with ethyl acetate (2 x 50 mL) and the combined ethyl acetate phases were discarded. The aqueous phase was acidified with 1 N HCl to pH 2, and extracted with ethyl acetate (200 mL). The ethyl acetate phase was washed with water (50 mL) and brine (50 mL), dried (MgSO 4), filtered and concentrated yielding 2, 6-dimeti1-4- [[[[3- [[ (1,1-dimethylethyl) dimethylsilyl] -oxy] phenyl] methyl] amino] carbonyl] benzoic acid (1.7 g, 71%) as a white solid. The following compounds were also prepared by this route: Example 33 Preparation of 2-chloro-4- [[[[[3- [[(1,1-dimethyl-lethyl) -dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] -6-methylbenzoic acid A. 3-Chloro-4-hydroxy-5-methylbenzaldehyde To a solution of 2-chloro-6-methyl phenol (20.00 g, 117.2 mmol) in trifluoroacetic acid (200 mL) hexamethyl traminine was added in portions (19.60 g, 139.8 mmol). There was a slight exotherm and effervescence was observed. The reaction mixture was heated in an oil bath at 84-86 ° C for 5 h, then cooled and evaporated (~ 50 ° C, 0.2 min).

The residue was evaporated from hexane, then water with ice (500 mL) was added and the mixture was stirred for 20 min. Ether (100 mL) was added and the reaction was brought to about pH 5 by careful addition in portions of solid sodium hydrogen carbonate. (49 g). The resulting mixture was extracted with ether (2 x 250 mL), and the ether phases were washed with brine, dried (MgSO 4), filtered and concentrated to about 100 mL. The mixture was allowed to crystallize over the weekend to give a solid which was filtered and washed with ice-cold ether to give 3-chloro-4-hydroxy-5-methyl-ylbenzaldehyde (6.9 g, %) in the form of a yellow solid. The mother liquors were evaporated and dichloromethane (30 mL) was added. The yellow solid was filtered (2.9 g, 14%). The remaining solution was purified by HPLC (7% ethyl acetate / hexanes) to give a yellow solid (7: 8 g, 39%). The overall yield was 17.6 g (88%). B. 3-Chloro-4-hydroxy-5-methylbenzoic acid A solution of sulfamic acid (11.8 g, 121.5 mmol) in water (25 mL) was added with vigorous stirring to 3-chloro-4-hydroxy-5-methyl-methylbenzaldehyde (16.00 g, 93.8 mmol) in tert-butanol (100 mL). The mixture was cooled (~ 12 ° C) and a solution of sodium chlorite (12.00 g, 106.1 mmol) in water was added. (25 mL) in 5 mL portions with vigorous shaking.

The reaction was exothermic and the temperature at the end of the addition was about 50 ° C. The two phases were separated and the aqueous phase was extracted with ether (2 x 50 mL). The organic phases were washed with brine and evaporated to dryness. Water was added, and the mixture was stirred and filtered. The solid was dissolved in hot ether (250 mL), and the solution was dried, filtered, concentrated to 100 mL, and cooled in the freezer (approximately -20 ° C). After filtering and washing with cold ether, 3-chloro-4-hydroxy-5-methylbenzoic acid (9.10 g, 52%) was obtained as a yellow solid, mp 242-244 ° C. C. 2-Chloro-4 - [[[[3 - [[(1,1-dimethylethyl) dimethylsilyl] -oxy] phenyl] methyl] amino] carbonyl] -6-methyl phenol A suspension of 3-chloro-4-acid -hydroxy-5-methylbenzoic acid (4.7 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0 ° C and BOP reagent was added (12.3 g, 27.8 mmol), followed by diisopropylethylamine (13.2 mL, 75.6 mmol). A solution of 3 - [[(1, 1-dimethylethyl) dimethylsilyl] oxy] benzenemethanamine (Example 8, 6.59 g, 27.8 mmol) in dry dichloromethane was added via syringe. (10 mL) and the resulting solution was stirred at ~ 0 ° C for 3 h. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (2 x 50 mL), aqueous sodium hydrogencarbonate (100 mL), brine (100 mL), and water (100 mL), dried (MgSO 4), filtered, evaporated, and chromatographed (30% acetate ethyl / hexanes) to give 2-chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] -methyl] amino] carbonyl] -6-methylphenol (6.03 g, 59 %) in the form of a pink solid. D. Trifluoromethanesulfonic acid, 2-chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] -amino] carbonyl] -6-methylphenyl ester. Tri-fluoromethane-anhydride was added. sulfonic acid (3 mL, 17.7 mmol) to a cooled solution (-78 ° C) of 2-chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl 1] amino ] -carbonyl] -6-methylphenol (6.00 g, 14.8 mmol) and triethylamine (8.24 mL, 59.1 mmol) in dichloromethane (60 mL). After stirring for 2 h at -78 ° C, the reaction was quenched with solid ammonium chloride (4 g). The mixture was diluted with ethyl acetate (200 mL) and washed with IN HCl (100 mL), saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO), filtered, evaporated and chromatographed (20-30% ethyl acetate / hexanes) to give trifluoromethanesulfonic acid, 2-chloro-4 - [[[[3 - [[ (1, 1-dimethylethyl) -dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] -6-methylphenyl ester (5.00 g, 63%) as an orange oil. E. 2-Chloro-4- [[[[3- [[(1,1-dimethylethyl) -dimethylsilyl] oxy] phenylmethyl] amino] carbonyl] -6-methylbenzoic acid A mixture of trifluoromethanesulonic acid, 2-chloro -4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy) phenyl] methyl] amino] -carbonyl] -6-methylphenyl ester (4.00 g, 7.4 mmol), water (10 mL), triethylamine (2.6 mL18.6 mmol), palladium (II) acetate (0.25 g, 1.1 mmol), and bis (diphenylphosphino) propane (0.46 g, 1.1 mmol) in acetonitrile (70 mL) was pressurized to 40 psi 'with carbon monoxide and released the pressure. After four of these cycles, the bottle was pressurized again and the contents were stirred at 80 ° C for 3.5 h. The reaction mixture was cooled to room temperature and depressurized. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was extracted three times with aqueous sodium hydrogencarbonate. Water was then added to the organic phase, followed by triethylamine (3 mL), and the mixture was extracted with ethyl acetate. The aqueous phase was acidified with 2M HCl and extracted three times with ethyl acetate. The combined ethyl acetate phases of this extraction were washed with brine, dried (MgSO 4), filtered, concentrated, and dried overnight under high vacuum to give 2-chloro-4- [[[[3]] acid. - [[(1, 1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] -6-methybenzoic acid (2.30 g, 71%) as a yellow solid. Example 34 Preparation of 2,6-dichloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] benzoic acid A. 2,6-Dichloro-4 - [[[[3 - [[(1,1-dimethylethyl) -dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl] phenol A solution of 3- [[(1, 1)] -dimethylethyl) dimethylsilyl] oxy] benzenemethamine (Example 8; 5.80g, 24.5 mmol) in dry dichloromethane (20 mL) was added to a cooled (0 ° C) suspension of 3,5-dichloro-4-hydroxybenzoic acid (4.2 g, 20.4 mmol) and BOP reagent (9.80 g, 22.3 mmol) in dry dichloromethane (50 mL). Diisopropylethylamine (10.6 mL, 60.9 mmol) was added slowly, and the cooling bath was removed. The solution was stirred at room temperature for 5 h, then the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 1 M HCl (2 x 100 mL), saturated aqueous sodium hydrogencarbonate (100 mL), and brine (100 mL), dried (MgSO 4), filtered, evaporated, and chromatographed (30% ethyl acetate). ethyl / hexanes) to give 2,6-dichloro-4 - [[[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] -carbonyl] phenol (7.50 g, 87%) in the form of a white solid. B. Trifluoromethanesulonic acid, 2,6-chloro-4 - [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] -amino] carboni 1] phenyl ester Trifluoromethane anhydride was added -sulfonic (3.55 mL, 21.1 mmol) to a cooled solution (-75 ° C) of 2,6-dichloro-4 - [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl ] amino] -carbonyl] phenol (7.50 g, 17.6 mmol) and triethylamine (9.8 mL, 70.4 mmol) in dry dichloromethane (70 mL).

After stirring for 3 h at ~ -70 ° C, the reaction was quenched with solid ammonium chloride (6 g). The solvent was evaporated and ethyl acetate was added. The solution was washed with IN HCl, saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO 4), filtered, evaporated and dried under high vacuum to give trifluoromethanesulonic acid, 2,6-dichloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] ] oxy] -phenyl] methyl] amino] carbonyl] phenyl ester (9.46 g, 97%) as an orange oil. C. 2,6-Dichloro-4- [[[[3- [[(1,1-dimethylethyl) -dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl] benzoic acid A mixture of tri fluoromethanesulonic acid, 2, 6-Dichloro-4- [[[[3- [[(1,1-dimethylethyl) -dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl] phenyl ester (3.33 g, 6.0 mmol), water (7 mL), triethylamine (1.7 mL, 11.9 mmol), palladium (II) acetate (0.20 g, 0.9 mmol), and bis (diphenylphosphino) propane (0.37 g, 0.9 mmol) in acetonitrile (80 mL) was pressurized to 40 psi with monoxide. carbon and the pressure was released. After three of these cycles, the bottle was pressurized again and the contents were stirred at 80 ° C for 5 h. The reaction mixture was cooled to room temperature and depressurized. The solvent was evaporated and ethyl acetate was added. The mixture was acidified with 1 M HCl and then the phases were separated. The organic solution was washed with brine, dried (MgSO 4), filtered, evaporated and chromatographed (70-100% ethyl acetate / hexanes followed by 10% methanol / ethyl acetate) to give 2,6-dichloroic acid. -4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -phenyl] methyl] amino] carbonyl] benzoic acid (1.23 g, 45%) as a white solid. Example 35 Preparation of 2-chloro-4- [[(2,3-dihydro-2-oxo-lH-indol-4-methyl) amino] carbonyl] benzoic acid To a solution of 2-chloro-l, 4-benzenedicarboxylic acid, 1-methyl ester (Example 1, 0.129 g, 0.60 mmol) and 2,3-dihydro-2-oxo-lH-indole-4-methanamine hydrochloride ( Example 9; 0-.120 g, 0.60 mmol) in DMF (6 mL) were added successively DCC (0.124 g, 0.60 mmol), HOBT (0.081 g, 0.60 mmol) and triethylamine (0.060 g, 0.060 mmol). The mixture was stirred at room temperature for 13 h and then filtered and diluted with water. The aqueous phase was extracted several times with ethyl acetate. The combined organic extracts were washed with water, concentrated and chromatographed (45% ethyl acetate / hexanes) to give 2-chloro-4- [[(2, 3-dihydro-2-oxo-1H-indole-4) acid. -methyl) amino] carbonyl] -benzoic acid, methyl ester (0.11 g, 50%). A solution of lithium hydroxide monohydrate (39 mg, 0.93 mmol) in water (1 mL) was added to a solution of the ester (0.11 g, 0.31 mmol) in tetrahydrofuran / methanol / water (3: 1: 1).; 4 mL). The mixture was stirred for 3 h at room temperature and then acidified with 6N HCl and diluted with water. The mixture was extracted several times with ethyl acetate and the combined organic phases were dried (Na2SO) and concentrated to give 2-chloro-4 - [[(2,3-dihydro-2-oxo-1H-indole-4) acid. -methyl) amino] -carbonyl] benzoic acid in the form of a brown solid (0.080 g, 75%). They were also prepared by this procedure: Example 38 Preparation of 2,6-dichloro-4 - [[[(IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl] benzoic acid A. 2, 6-Dichloro-4- [[[(IR) -l- (1-naphthalenyl) ethyl] amino] carbonyl] benzoic acid, methyl ester A solution of 2,6-di-chlorobenzene-1, 4 acid -dicarboxylic acid, 1-methyl ester (Example 4, 3.00 g, 12.0 mmol), (R) - (+) - 1- (1-naphthyl) ethylamine (2.00 g, 11.7 mmol), HBTU (5.68 g, 15.0 mmol) ), HOBT (2.04 g, 15.1 mmol), and, diisopropylethylamine (6.20 g, 48.0 mmol) in N, N-dimethylformamide (50 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (150 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous phase was extracted in turn with ethyl acetate (100 mL). The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate and brine (200 mL each), and then dried (MgSO 4), filtered, evaporated and chromatographed (30% ethyl acetate / hexanes) to give anhydrous acid. , 6-dichloro-4- [[[(IR) -1- (1-naphthalenyl) ethyl] amino] -carbonyl] benzoic, methyl ester (4.52 g, 96%) as a white foam. B. 2,6-dichloro-4- [[[(IR) -1- (1-naphthalenyl) ethyl] -amino] carbonyl] benzoic acid To a solution of 2,6-dichloro-4- [[[( lR) -l- (1-naphthalenyl) ethyl] amino] carbonyl] -benzoic acid, methyl ester (5.62 g, 14.0 mmol) in tetrahydrofuran (100 mL) was added a solution of sodium hydroxide (0.62 g, 15.5 mmol) in water (100 mL). The solution was stirred overnight at room temperature. A CCF indicated that the reaction had not been completed. 1 M NaOH (20 mL) was added and the mixture was heated to reflux for 6 h. Methanol (100 mL) was added and the mixture was stirred overnight at room temperature. Again, a CCF indicated that the reaction had not been completed so the reaction mixture was heated to reflux for 2 h, 1 M NaOH (100 mL) was added and the solution was heated to reflux for a further 4 h. The reaction mixture was left overnight at room temperature, and then the solvent was evaporated, and water (100 mL) and 1 M HCl (200 mL) were added. The mixture was stirred for 20 min and then the white solid was filtered and dried overnight in a vacuum oven (25 mm Hg, 60 ° C) to give acid 2,6-dichloro-4- [[((IR)] -1- (1-naphthalenyl) ethyl] amino] carbonyl] benzoic acid (4.84 g, 89%) as a white solid, mp 213-215 ° C (dec.). Example 39 Preparation of 2-chloro-4- [[[[1- (tetrahydro-2H-pyran-2-yl) -lH-indazol-4-yl] methyl] amino] carbonyl] -benzoic acid A. 2-Chloro-4- [[[[1- (tetrahydro-2H-pyran-2-yl) -lH-indazol-4-yl] methyl] amino] carbonyl] benzoic acid, methyl ester A suspension of 2-Chloro-1,4-benzene-dicarboxylic acid, 1-methyl ester (Example 1; 84.3 mg, 0.393 mmol) in dichloromethane (1.5 L) and the mixture was cooled to 0 ° C. BOP reagent (191 mg, 0.432 mmol) was added in one portion, followed by 4-aminomet-il-1- (tetrahydro-2H-pyran-2-yl) -lH-indazole (Example 12, 91 mg, 0.393 mmol) with a wash of 2 x 0.25 mL of dichloromethane. Diisopropylethylamine (0.21 g, 1.62 mmol) was added over 1 min. The mixture was stirred for 30 min and then at room temperature for 3.5 h. The mixture was concentrated to remove dichloromethane, and ethyl acetate (60 mL) was added. The solution was washed with 1 M HCl, sodium hydrogencarbonate solution, and brine (10 mL each), and then dried (MgSO 4), filtered, and concentrated. Ethyl acetate / petroleum ether was added and the insoluble material was filtered to give 2-chloro-4- [[[[1- (tetrahydro-2 H -pyran-2-yl) -lH-indazol-4-yl] acid] -methyl] amino] carbonyl] benzoic acid, methyl ester (93 mg, 55%) as a white solid. B. 2-Chloro-4- [[[[1- (tetrahydro-2H-pyran-2-yl) -lH-indazol-4-yl] methyl) amino] carbonyl] benzoic acid A suspension of 2-chloro- 4- [[[[1- (tetrahydro-2 H -pyran-2-yl) -lH-indazol-4-yl] -methyl] amino] carbonyl] benzoic acid, methyl ester (87.8 mg, 0.206 mmol) in methanol (1 mL) was cooled to ~ -0 ° C and 1 M sodium hydroxide (0.206 mL, 0.206 mmol) was added. The cooling bath was removed and the reaction mixture was allowed to stir overnight. An additional portion of sodium hydroxide was added (1 M; 0.2 mL, 0.2 mmol) and the mixture was stirred at room temperature for 7 h. The solvent was evaporated and the residue dissolved in water (25 mL) and washed with ethyl acetate (2 x 10 mL). The aqueous phase was acidified with 1 M HCl and extracted with ethyl acetate (2 x 20 mL). These extracts were combined, washed with brine (10 mL), dried (MgSO4), filtered, and concentrated to give 2-chloro-4 - [[[[1- (tetrahydro-2H-pyran-2-acid]] il) -lH-indazol-4-yl] tyl] -amino] carbonyl] benzoic acid (77.3 mg, 91%) as a white solid. Example 40 Preparation of 2-chloro-4- [[[(benzimidazol-4-yl) methyl] amino] carbonyl] benzoic acid A mixture of 4- (azidomethyl) -benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13, 1.40, 5.1 mmol), 1- [[3-chloro-4- (methoxycarbonyl) benzoyl] oxy] -2,5-pyrrolidinedione (Example 5, 1.62 g, 5.2 mmol), and 10% palladium on carbon. % (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite.

A CCF indicated that the reaction had not been completed so 10% palladium on carbon was added (210 mg) and the mixture was hydrogenated at atmospheric pressure for 3 h and then stirred at 50 psi of hydrogen for 3 h. The reaction mixture was left under hydrogen for 12 h, filtered through Celite, evaporated, and chromatographed (20-100% ethyl acetate / hexanes) to give 2-chloro-4- [[[[1]] acid. - [(1,1-dimethylethoxy) -carbonyl] benzimidazol-4-yl] methyl] amino] carbonyl] -benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4- [[[(benzimidazol-4-yl) methyl] amino] carbonyl] benzoic acid (925) mg, 86%). Example 41 Preparation of 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] benzoic acid A mixture of 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] benzoic acid, methyl ester (Example 19, 2.1 g, 6.6 mmol) and 1 M sodium hydroxide solution was stirred for 4 h room temperature. The solution was filtered through Celite and the filtered mass was washed with water (5 mL). 1 M HCl (22 mL) was added to the stirred filtrate and the resulting mixture was stirred for 2 h and then filtered. The solid was washed with water, dried and recrystallized from ether / hexane to give 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] benzoic acid (1.59 g, 79%) as whitish solid. Example 42 Preparation of 2-chloro-4- [l-hydroxy-3- (3-hydroxyphenyl) propyl] benzoic acid This compound was prepared in a 90% yield from 2-chloro-4- [l-hydroxy-3- (3-hydroxyphenyl) -propyl] benzoic acid, methyl ester (Example 19) by the procedure described for the acid 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) -propyl] benzoic acid (Example 41). The product was a racemic mixture and it was not resolved. Example 43 Preparation of 2-chloro-4- [5- [(3-hydroxy) phenylmethylamino] tetrazol-1-yl] benzoic acid A. 4- [[[[(3-Acetoxy) phenyl] methyl] amino] -carbonyl] amino-2-chlorobenzoic acid, methyl ester A stirred suspension of 3-hydroxyphenylacetic acid (10.2 g, 67 mmol) in acetic anhydride ( 100 mL, 1.06 mol) under anhydrous conditions was treated with pyridine (0.5 mL). In the mildly exothermic reaction, the solids dissolved after several minutes and the mixture was maintained at 40 ° C for 5 h. The reaction was concentrated in vacuo to about half the volume, then water (30 g) was added in the form of crushed ice at a rate such that the temperature would be maintained < 45 ° C. When the exotherm ceased, a second portion of water (200 mL) was added slowly and the mixture was stirred for a further 30 min. The precipitated solid was filtered, washed with water and dried in vacuo over P205 to constant weight to give 3-acetoxy-phenylacetic acid (11.7 g, 90%) which was used without any further purification. A solution of this 3-acetoxyphenylacetic acid (1942 g, 10 mmol), diphenylphosphoryl azide (2.8 g, 10.17 mmol) and diisopropylethylamine (1.92 mL, 11 mmol) in benzene (25 mL) under inert atmosphere was stirred at room temperature for 1 hour. h, then the reaction temperature was slowly raised to 70 ° C. When the temperature of the reaction reached 55 ° C, the gas evolution became evident and became much more vigorous when the temperature of the reaction approached 70 ° C. After 30 minutes at this temperature the gas evolution had ceased and the reaction solution containing 3-acetoxybenzylisocyanate was cooled to 40 ° C. Another portion of DIPEA (3.84 mL) was added., 22 mmol), followed by 4-amino-2-chlorobenzoic acid hydrochloride, methyl ester (2.95 g, 13.3 mmol) and the brownish purple solution was stirred and refluxed under argon overnight. The reaction mixture was cooled, diluted with benzene (50 mL) and washed in turn with IN HCl (50 mL) and dilute brine. The aqueous phases were backextracted with benzene, and the combined extracts were dried (MgSO 4), evaporated, and purified by HPLC (silica gel; 40% ethyl acetate / hexane). Evaporation of the appropriate fractions gave 3.24 g of the solid urea which was then crystallized from dichloromethane-ethyl acetate to give 4- [[[[(3-acetoxy) phenyl] methyl] amino] carbonyl] amino-2- acid chlorobenzoic acid, methyl ester (2.71 g, 72%) as a colorless solid, mp 113-114 ° C. B. 2-Chloro-4- [5- [[[(3-hydroxy) phenyl] methyl] -amino] tetrazol-1-yl] benzoic acid In an atmosphere of dry argon, a solution of triphenylphosphine (1684 g, 6.42 g. mmol), diethyl azodicarboxylate (1.13 g, 6.42 mmol), 4 - [[[[(3-acetoxy) phenyl] methyl] amino] carbonyl] -amino-2-chlorobenzoic acid, methyl ester (1.21 g, '3.21 mmol) in dry THF (30 mL) was treated with trimethylsilyl azide (0.86 mL, 6.48 mmol) and stirred at room temperature for 24 hr. Analysis of the reaction mixture by TLC suggested the presence of a considerable amount of the starting material, whereby additional amounts of triphenylphosphine (0.842 g, 3.21 mmol), diethylazodicarboxylate (0.565 g, 3.21 mmol) and trimethylsilyl were added. azide (0.43 mL, 3.21 mmol). The reaction was stirred at room temperature for 40 hr more. The solvents were removed under reduced pressure and the residue redissolved in dichloromethane (100 mL) and washed with water (2 x 50 mL). The aqueous phases were extracted in turn with dichloromethane (50 mL) and the combined organic phases were dried (MgSO 4), filtered and evaporated in vacuo. The residue was dissolved in a mixture of methanol (30 mL) and 1 N lithium hydroxide (15 mL) and the mixture was stirred at room temperature for 2 hr to complete the hydrolysis of both ester and phenolic acetate groups. 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). The aqueous phase was then acidified with IN HCl (16 mL) and extracted with ethyl acetate (2 x 50 mL). The dried extracts (MgSO4) of ethyl acetate were evaporated and the residual solid (810 mg), a mixture approximately 4: 1 of the desired aminotetrazole and its positional isomer, was crystallized from ether to give 2-chloro-4- [5] acid. - [[[(3-hydroxy) phenyl] methyl] amino] tetrazol-1-yl] benzoic acid (560 mg, 46%) as a colorless solid. Example 4 Preparation of 2-bromo-4 - [[[3- [[(1,1-dimethylethoxy) carbonyl] aminophenyl] methyl] amino] carbonyl] benzoic acid To a solution of 2-bromo-4- [[[3- [[(1,1-dimethylethoxy) carbonyl] aminophenyl] methyl] amino] carbonyl] benzoic acid, methyl ester (Example 20; 495 mg, 1. 07 mmol) in methanol (5 mL) at 0 ° C was added 1 M NaOH (1.07 mL, 1.07 mmol). The reaction mixture was heated to 25 ° C and stirred for 24 h. TLC (10% methanol in dichloromethane) revealed that the starting product was still present. NaOH IN was added (0.5 mL) at room temperature and the reaction was heated to 50 ° C. After stirring for 3 h, the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The aqueous phase was separated, acidified to pH 4 with 1N HCl, and extracted with ethyl acetate (2 x 100mL). The organic phases were combined, washed with brine (50 mL), dried with MgSO 4, filtered, and concentrated to yield 2-bromo-4- [[[3- [[(1,1-dimethylethoxy) carbonyl] acid. ] - aminophenyl] methyl] amino] carbonyl] benzoic (474 mg, 99%) in the form of white foam. The following compounds were also prepared by this procedure, except that the reaction was allowed to proceed for 48 h at 25 ° C instead of 24 h: Example 47 Preparation of 2-bromo-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoic acid A solution of lithium hydroxide monohydrate (4.41 g, 105.1 mmol) in water (15 mL) was added to a solution of 2-bromo-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoic acid, methyl. ester (Example 14; 15.30 g, 42.0 mmol) in tetrahydrofuran / methanol (2: 1, 21 mL). The solution was stirred at room temperature for 1 h, and then concentrated to remove tetrahydrofuran and methanol. The remaining aqueous solution was extracted with ethyl acetate (15 mL) and the ethyl acetate extract was discarded. The aqueous phase was acidified with 1 M HCl (75 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine (15 mL), dried (MgSO 4), filtered, and evaporated to give 2-bromo-4- [[[(3-hydroxy phenyl) methyl] amino] -carbonyl acid] benzoic (15.1 g, quantitative yield) that was used in the next step without further purification.

Example 48 Preparation of 1- (2-methoxyethyl) cyclopentane-carboxylic acid Into a 3-L round bottom flask equipped with a thermometer and addition funnel, diisopropylamine (136 mL, 0.98 mol) and tetrahydrofuran (750 mL) were added. The solution was stirred under nitrogen and cooled in an ice bath. It was added through the n-butyllithium addition funnel (2.5 M in hexanes, 376 mL, 0.94 mol), and the solution was allowed to stir at 0 ° C for 30 min and then cooled to -70 ° C. A solution of cyclopentanecarboxylic acid, methyl ester (83.04 g, 0.65 mol) in tetrahydrofuran (135 mL) was added through the addition funnel. The solution was stirred at -70 ° C for 1 h and then a solution of 2-bromoethyl methyl ether (55.5 mL, 0.59 mol) in tetrahydrofuran (135 mL) was added. The solution was stirred at -70 ° C for 1 h and then the cooling bath was removed. The solution was stirred at room temperature overnight, then poured into saturated ammonium chloride solution (2 L) and extracted with ether (3 x 500 mL). The combined ether extracts were washed with saturated brine (6 x 400 mL), dried (Na2SO4), filtered, evaporated, and distilled in vacuo to give 1- (2-methoxyethyl) -cyclopentanecarboxylic acid, methyl ester (71.39). g, 59%) in the form of a light yellow liquid (eg 94-102 ° C to 8 mm). This was dissolved in a mixture of tetrahydrofuran (340 mL), methanol (340 mL) and 1 M sodium hydroxide solution (425 mL). The mixture was stirred and heated at 55-60 ° C for 24 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. Water (400 mL) was added and the solution was extracted with ether (2 x 200 mL). The aqueous phase was acidified to pH 1 with HCl 1 N (500 L), and extracted with ether (300 mL, followed by 2 x 200 mL). The combined ether extracts were washed with saturated brine (2 x 200 mL), dried (Na 2 SO 4), filtered, and evaporated to give 1- (2-methoxyethyl) -cyclopenti-carboxylic acid (63.68 g, 97% ) in the form of yellow liquid.

Example 49 Preparation of 1,4-dioxa-8-thiazide [4, 5] decane-6-carboxylic acid A solution of l, 4-dioxa-8-t iaspiro [4, 5] decane-6-carboxylic acid, methyl ester (prepared according to Baldwin, JJ et al., US 4803286; 30.00 g, 0.137 mol) in ethanol (500 mL) and a solution of potassium hydroxide (16.80 g, 0.299 mol) in ethanol (300 mL) were combined and heated to reflux for 7 h. The solution was concentrated in vacuo and water was added. The mixture was extracted with ether, and the ether phase was discarded. The aqueous phase was acidified and extracted with ether. The ether phases were washed, dried, and evaporated, and the residue was recrystallized from benzene / hexane to give 1,4-dioxa-8-thiaspiro [4,5] decane-6-carboxylic acid (17.8 g, 63% ) in the form of white crystals, mp 99-101 ° C. Example 50 Preparation of (2S) -3-cyclohexyl-2- (pyrrol-1-yl) -propanoic acid By analogy with the literature procedure (Ceccherelli, P. et al., J. Org. Ch., 1994, 59, 2882-4), to a reflux solution of anhydrous sodium acetate (71.86 g, 0.876 mol) in acetic acid ( 609 mL) was added [3-cyclohexyl-L-alanine (25.00 g, 0.146 mol) followed by 2,5-dimethoxy tetrahydrofuran (18.9 mL, 0.146 mol). The solution was heated for 1 min and then concentrated. Saturated brine (250 mL) was added and the solution was extracted with ethyl acetate (2 x 400 mL). The combined extracts were washed with brine (250 mL), dried (MgSO 4), filtered, concentrated to dryness, and the residue co-evaporated with toluene to remove traces of acetic acid. The dark residue (36.99 g) was dissolved in ethanol (125 mL) and activated charcoal (10 g) was added. The solution was stirred and filtered through Celite® and the filtered mass was washed with ethanol (150 mL). Dicyclohexylamine (29.1 mL, 0.146 mol) was added to the filtrate and the brown precipitate was filtered and washed with cold ethanol (2 x 18 mL) and ether (30 mL). The solid (40.22 g) was suspended in ethyl acetate (300 mL) and washed with 1 N citric acid (2 x 200 mL). The aqueous phase was extracted in turn with ethyl acetate (300 mL) and the combined ethyl acetate phases were washed with saturated brine (200 mL), dried (MgSO 4), filtered and concentrated to give a dark liquid. (26.1 g). An impurity (1.6 g) was removed by crystallization from ether / petroleum ether (1: 1, 20 mL). Concentration of the filtrate gave (2S) -3-cyclohexyl-2- (pyrrol-1-yl) propionic acid (21.48 g, 66%) as a dark brown oil which solidified upon standing, mp 78-80 ° c. Example 51 Preparation of N- [(9H-Fluoren-9-ylmethoxy) carbonyl] -piperidin-4-carboxylic acid Piperidine-4-carboxylic acid was added (15.00 g, 116 mmol) was added to a solution of sodium hydrogencarbonate (12.7 g, 151 mmol) in water (200 mL) and the mixture was stirred. { or for 10 min. A solution of 1- [[(9H-fluoren-9-ylmethoxy) carbonyl] oxy-2,5-pyrrolidinedione (Fmoc-Osu; 46.9 g, 139 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature for 20 h and then acidified to pH 1 with 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (200 mL and then 100 mL) and the combined organic phases were washed with saturated brine (3 x 100 mL), dried (Na2SO4), filtered and concentrated to about 100 mL. When concentrating, crystallization took place. The mixture was left for 2 h, then the solid was filtered, washed with ethyl acetate and dried in a vacuum oven at 60 ° C to give N- [(9H-fluoren-9-ylmethoxy) carbonyl] piperidine-4-carboxylic acid (34.51 g, 85%) as a white solid, mp 187-189 ° C. The following compounds can also be prepared by this procedure: Example 57 Preparation of 3- [N- [(9H-f-luoren-9-ylmethoxy) carbonyl] amino] butanoic acid DL-3-aminobutyric acid (15 g, 145 mmol) was added to a solution of sodium hydrogencarbonate (15.9 g, 188.5 mmol) in water (200 mL). A solution of 1- [[(9H-fluoren-9-ylmethoxy) carbonyl] oxy-2,5-pyrrolidinedione (Fmoc-OSu; 58.7 g, 174 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature for 20 h and then acidified to pH 1 with 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (250 mL followed by 100 mL) and the combined organic phases were washed with saturated brine (3 x 100 mL), dried (Na2SO4), filtered and concentrated to dryness to give a white solid (56.22 g). This was triturated with boiling ether (500 mL), and allowed to cool. The mixture was filtered and the solid was washed with ether, and then dried in a vacuum oven at room temperature to give 3- [N- [(9H-fluoren-9-ylmethoxy) carbonyl] amino] -butanoic acid (35.33) g, 75%) as a white solid, mp 135-143 ° C. Example 58 Preparation of 3- [N- [(9H-Fluoren-9-ylme-toxy) -carbonyl] amino] -4,4,4-trifluorobutyric acid 3-Amino-4,4,4-trifluorobutyric acid (10 g, 63.7 mmol) was added to a solution of sodium hydrogencarbonate (6.95 g, 82.8 mmol) in water (100 mL). A solution of 1 - [[(9H-fluoren-9-ylmethoxy) carbonyl] oxy-2,5-pyrrolidinedione was added.

(Fmoc-OSu; 25.78 g, 76.4 mmol) in tetrahydrofuran (200 mL). The solution was stirred at room temperature for 19 h and then acidified to pH 1 with 3 M HCl (250 mL). The mixture was extracted with ethyl acetate (250 mL followed by 100 mL) and the combined organic phases were washed with saturated brine (3 x 100 mL), dried (Na2SO4), filtered and concentrated to approximately 200 mL. When concentrating, crystallization occurred. The mixture was left for 10 min, then the solid was filtered, washed with ethyl acetate and dried in a vacuum oven at 50 ° C to give 3- [N - [(9H-fluoren-9-ylmethoxy) acid. ) carbonyl] amino] -4,4,4-trifluoro-butyric (11.47 g) as a white solid, mp 187-189 ° C. The mother liquors were concentrated to 80 mL. When concentrating, crystallization occurred. The solid was filtered, washed with ethyl acetate and dried in a vacuum oven at 50 ° C to give a second batch of product (4.69 g). The overall yield was 16.16 g (67%). Example 59 Preparation of 3- [N- [(9H-Fluoren-9-ylmethoxy) -carbonyl] amino] cyclohexanecarboxylic acid A. 3-aminocyclohexanecarboxylic acid A mixture of 3-aminobenzoic acid (66.12 g, 0.48 mol) and 10% palladium on carbon (13.2 g) in 30% aqueous ethanol (1200 mL) was introduced into a high pressure reactor. 4 L stainless steel and reduced to 50 ° C and 500 psi of hydrogen for 30 h. The mixture was filtered through Celite and the filtered mass was washed with ethanol. The solvent was evaporated, boiling ethanol was added (1 L) and the mixture was left for 8 days at room temperature. The mixture was filtered and the product was washed with ethanol and then dried in a 50 ° C vacuum oven, to give acid 3-aminocyclohexanecarboxylic acid (39.30 g, 57%) as a white solid. B. 3- [N - [(9H-Fluoren-9-ylmethoxy) carbonylamino] cyclohexanecarboxylic acid 3-Aminocyclohexane-carboxylic acid (10 g, 70 mmol) was added to a solution of sodium hydrogencarbonate (7.6 g, 91 mmol) in Water (100 mL). A solution of 1 - [[(9H-fluoren-9-ylmethoxy) carbonyl] oxy-2, 5-pyrrolidinedione was added.

(Fmoc-OSu; 28.3 g, 84 mmol) in tetrahydrofuran (200 mL). The solution was stirred at room temperature overnight and then poured into 3 M HCl (200 mL). The mixture was extracted with ethyl acetate (100 mL followed by 50 mL) and the combined organic phases were washed with saturated brine (3 x 100 mL), dried (Na 2 SO 4), filtered, and concentrated to approximately, 200 mL. When concentrating, crystallization occurred. The mixture was left overnight, then the solid was filtered, washed with ethyl acetate and dried in a vacuum oven at 55 ° C to give 3- [N- [(9H-fluoren-9-i) acid. lme tox i) carbonyl] amino] cyclohexanecarboxylic (14.66, 57%) as a white solid. EXAMPLE 60 Preparation of 4- [N - [(9H-Fluoren-9-ylme-toxy) -carbonyl] amino] -1,3,4-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic acid A. 4-amino-1, 3, 4, 5-tet rahydro-3-oxo-2H-2-benzazepin-2-acetic acid. Hydrazine monohydrate (36 mL, 0.742 mol) was added to an acid solution (4S) ) -4- (1, 3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1, 3, 4, 5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic (prepared according to the procedure of Tourwe, D. et al., Bioorg, Med Chem. Lett, 1992, 2, 1305-1308; 90.99 g, 0.245 mol) in ethanol (2.6 L) under argon, with mechanical agitation. The solution was heated to reflux for 1 h, and then cooled in a water and ice bath for 30 min. The white solid was filtered and washed with cold ethanol (800 mL), and then air dried for 1 h, and at 0.3 mm Hg at 60 ° C for 1.5 h to give a white solid (139 g). 3 N HCl (245 mL) was added and the mixture was mechanically stirred for 40 min and then allowed to stand overnight. The solid was filtered and washed with water (2 x 180 mL). The aqueous phase was concentrated, water (300 mL) was added and the mixture was stirred for 1.5 h and filtered. The filtrate was concentrated, first at the pressure of the aspirator and then at 0.2 mm Hg at 50 ° C for 6 h to give a beige solid (80 g). Ethanol (300 mL) was added and the mixture was stirred for 30 min and filtered. The solid was washed with ethanol (50 mL), and dried (0.15 mm Hg, 50 ° C for 3 h) to give a white solid (73 g). Ethanol (300 mL) was added and the mixture was stirred for 1 h and filtered. The solid was washed with ethanol (50 mL), dried (0.2 mm Hg, 50 C overnight) to give a white solid (69.21 g). Water (50 mL) and ethanol (20 mL) were added and the mixture was heated in a steam bath for 30 min. The supernatant was decanted and placed in the refrigerator overnight. The mixture was filtered and the filtrate was concentrated to give 60 g of solid. Water (50 mL) was added and the mixture was heated in a water bath for 1.5 h and then allowed to stand overnight at room temperature. The solid was filtered, stored in the filter in the refrigerator for 4 h, washed with cold water (50 mL), and then dried (0.25 mm Hg, 50 ° C overnight) to give 4-amino acid. 1, 3, 4, 5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic (34.57 g, 52%) as a white solid, mp 266-268 ° C. B. 4- [N- [(9H-Fluoren-9-ylmexy) carbonyl-amino] -1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic acid. 4-amino-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic acid (15 g, 55 mmol) was added to a solution of sodium hydrogencarbonate (12 g, 143 mmol) in water (200 mL). A solution of 1- [[(9H-f-luoren-9-ylmethoxy) carbonyl] oxy-2,5-pyrrolidinedione (Fmoc-OSu; 22.3 g, 66 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature overnight and then poured into 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (250 mL followed by 100 mL) and the combined organic phases were washed with saturated brine (3 x 100 mL), dried (Na2SO4), filtered and evaporated to give white foam (29.62). g). This was dissolved in ethanol (150 mL), and the solution was left at room temperature for 4 h. The white solid was filtered, washed with ethanol and dried in a vacuum oven at 60 ° C to give 4- [N - [(9H-fluoren-9-ylmethoxy) carbonyl] amino acid] -1, 3, 4 , 5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic acid (25.19 g, 100%) as a white solid, mp 117-120 ° C. Example 61 Preparation of 3- [[(9H-fluoren-9-ylmethoxy) -carbonyl] amino] hexahydro-2-oxo-lH-azepin-1-acetic acid 3-Aminohexahydro-2-oxo-1H-azepine-1-acetic acid (which can be prepared by the method of Thorsett, ED et al., J. Med. Chem., 1986, 29, 251-260; 9.3 g, 50 mmol) was added to a solution of sodium hydrogencarbonate (5 g, 60 mmol) in water (100 mL). A solution of 1 - [[(9H-fluoren-9-ylmethoxy) carbonyl] -oxi-2, 5-pyrrolidinedione (Fmoc-OSu; 18.6 g, 55 mmol) in tetrahydrofuran (110 mL) was added. The solution was stirred at room temperature overnight and then ether (200 mL) was added. The phases were separated and the organic phase was extracted with saturated sodium hydrogen carbonate: water (1: 1).; 60 mL). The combined aqueous phases were acidified with 1 M HCl (110 mL). The solid was filtered, washed with water (4 x 20 mL), and dried under vacuum to give 3- [[(9H-fluoren-9-ylmethoxy) -carbonyl] amino] hexahydro-2-oxo-lH- acid. azepine-1-acetic (20.1 g, 98%) as a white solid, mp 118 ° C (dec.) Example 62 Preparation of N- [(1,1-dimethyletoxy) carbonyl] -3- [(9H-) fluoren-9-ylmethoxy) carbonyl] amino-L-alanine, methyl ester, A. N- [(1,1-Dimethylethoxy) carbonyl] -3- [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine To a solution of N- [(1,1-dimethylethoxy) -carbonyl] ] -L-asparagine (Boc-Asn; 20.00 g, 86.1 mmol) in N, N-dimethylformamide / water (2: 1; 300 mL), bis (trifluoroacetoxy) iodobenzene (44.4 g, 103.2 mmol) was added. The solution was stirred at room temperature for 30 min and then pyridine (10 mL, 123.6 mmol) was added. The solution was stirred at room temperature for 4.5 h and then the solvent was evaporated (45 ° C, ~ 0.5 mm Hg). The residue was dissolved in acetone / water (1: 1, 400 mL) and sodium hydrogencarbonate (31.8 g, 378.5 mmol) and 1- [[(9H-fluoren-9-ylmethoxy) carbonyl] oxy] -2.5 were added. pyrrolidinedione (Fmoc-OSu, 34.74 g, 103.0 mmol). The mixture was stirred at room temperature overnight, then the acetone was evaporated and the mixture was acidified to pH 1 with 1 M HCl and extracted with ethyl acetate (200 mL, followed by 100 mL). The combined organic phases were washed with brine (3 x 50 mL), dried (Na 2 SO 4), filtered, evaporated (45 ° C, ~ 0.5 mm Hg), and chromatographed (50-60% ethyl acetate / hexanes ) to give N- [(1,1-dimethyl-ethoxy) carbonyl] -3 - [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine (32.33 g, 88%) as a white solid. B. N- [(1,1-Dime thioethoxy) carbonyl] -3 - [(9H-fluoren-9-yl methoxy) carbonyl] amino-L-alanine, methyl ester. A solution of N - [(1,1-dimethylethoxy) -carbonyl] -3 - [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine (5.00 g, 11.7 mmol) in N, N-dimethylformamide ( 10 mL) was treated with potassium hydrogen carbonate (1.4 g, 14.1 mmol) and iodomethane (0.8 mL, 12.9 mmol). The reaction mixture was stirred at room temperature for 2 h. Then water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried (Na 2 SO 4), concentrated and chromatographed (10-40% ethyl acetate / hexanes) to give N - [(1,1-dimethyl-ethoxy) -carbonyl] - 3- [(9H-Fluoren-9-ylmethoxy) carbonyl] amino-L-alanine, methyl ester (4.20 g, 81%) as a white solid.

Example 63 Preparation of 3-carboxybenzamide A. 3-Iodobenzamide A solution of 3-iodobenzoic acid (5.00 g, 20.2 mmol) and thionyl chloride (5.00 g, 42 mmol) in benzene (100 mL) was heated to reflux for 1 h. The solvent was evaporated and the residue azeotropically distilled with toluene. Ethyl ether (200 mL) was added and ammonia gas was bubbled through the solution for 10 min. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The mixture was filtered to give 3-iodobenzamide (0.88 g) as a cream-colored solid. The ethyl acetate phase was dried (MgSO 4), filtered and evaporated to give 3-iodobenzamide (3.40 g) as a cream colored solid. B. 3-Carboxybenzamide A mixture of 3-iodobenzamide (4.28 g, 17.3 mmol), water (25.00 g, 1387.7 mmol), triethylamine (8.00 g, 79.1 mmol), palladium (II) acetate (0.28 g, 1.2 mmol) , and bis.diphenylphosphino) propane (0.52 g, 1.3 mmol) in acetonitrile (50 mL) was pressurized to 40 psi with carbon monoxide and the pressure was released. After six of these cycles the bottle was pressurized again and the contents were stirred at 85 ° C for 3 h. The reaction mixture was cooled to room temperature and depressurized. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was filtered and then extracted with water (2 x 200 mL). The combined aqueous phases were acidified with 12 M HCl to pH 0. The solid was filtered and dried. air to give 3-carboxybenzamide (1.93 g, 87%) as a yellow solid. Example 64 Coupling of N- [(9H-fluoren-9-ylmethoxy) carbonyl] -3- [(2-propenyloxy) carbonyl] amino-L-alanine to Wang resin.

In a cylindrical glass vessel equipped with a sintered glass filter of coarse pore, 30 g of Wang resin was introduced. (load factor: 1.1 mmol / g, 300 mesh). The resin was washed with dichloromethane, methanol and dimethylformamide. To the inflated resin was added N - [(9H-fluoren-9-ylmethoxy) carbonyl] -3 - [(2-propenyloxy) -carbonylamino-L-alanine (20.4 g, 4 9.7 mmol) and 2-6-chloro dichlorobenzoyl (23.6 mL, 163 mmol) in N-methylpyrrolidone (300 mL) and the mixture was stirred for 30 min. Pyridine (18.6 mL, 230 mmol) was added and the resulting mixture was stirred for 4 hr. The resin was filtered and washed abundantly with dimethylformamide, dichloromethane and methanol and dried in vacuo. The substitution which was found to be 0.92 mmol of N- [(9H-fluoren-9-ylmethoxy) -carbonyl] -3 - [(2-propenyloxy) carbonyl] amino-L-alanine per gram of resin was determined by quantitative measurement in the UV of the Fmoc group present in the resin.

Example 65 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3 - [(2-propenyloxy) carbonyl] amino-L-alanine in Wang resin A N- [(9H-fluoren-9-ylmethoxy) carbonyl] -3 - [(2-propenyloxy) carbonyl] amino-L-alanine resin was introduced into a cylindrical glass vessel equipped with a sintered glass filter of coarse pore. (Example 64; 5 g) and 25% piperidine in N-methylpyrrolidinone (50 mL). The mixture was stirred at room temperature for 30 min. The resin was filtered and re-treated with more 25% piperidine in N-methylpyrrolidinone (50 mL) at room temperature for 30 min. After filtration, the resin was washed with dichloromethane and methanol. A solution prepared from 2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] benzoic acid (Example 26, 2.5 g, 8.2 mmol), HOAT (3.7 g) was added to the resin. , 27.2 mmol) and DICI (4.3 L, 27.5 mmol) in N-methylpyrrolidinone (50 mL). The reaction mixture was stirred at room temperature for 1 h, and then filtered. The resin was washed with dichloromethane and methanol, and dried under vacuum to give N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl) -3 - [(2-propenyloxy) carbonyl] amino-L-alanine bound to resin. Example 66 Preparation of 3-amino-N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine in Wang resin To the Wang resin substituted with N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [(2-propenyloxy) carbonyl] amino-L-alanine obtained from Example 65 a solution prepared from bis (triphenylphosphine) palladium dichloride (0.8 g, 1.15 mmol) and acetic acid (2.5 mL, 42.0 mmol) in dry dichloromethane (40 mL) was added. The suspension was stirred at room temperature for 30 min and then tri-n-butyltin hydride (10 mL, 37 mmol) was added. After 1 h, more tri-n-butyltin hydride (5 mL) was added to the mixture. Stirring was continued for 1 h. The resin was filtered and the procedure repeated. After the second deprotection cycle, the resin was washed with dimethylformamide, dichloromethane and methanol to give Wang resin substituted with 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl ] benzoyl-L-alanine. They were also prepared by this procedure Example 72 Preparation of 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine, methyl ester A. N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(9H-fluoren-9-ylmethoxy) -carbonyl] amino-L-alanine , methyl ester A solution of N- [(1,1-dimethylethoxy) -carbonyl] -3 - [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine, methyl ester (Example 62; 1.50 g, 3.4 mmol) was converted to 3- [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine, crude methyl ester (1.30 g, 112% of theory) by treatment with trifluoroacetic acid / dichloromethane (1: 1). ). A portion of this material (0.50 g) was combined with 2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoic acid (449 mg, 1.5 mmol), HOAT (219 mg, 1.6 mmol ) and dicyclohexylcarbodiimide (363 mg, 1.8 mmol) in N, N-dimethylformamide (5 L) and the reaction mixture was stirred at room temperature over the weekend. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried, filtered, evaporated, and chromatographed (2-10% methanol / dichloroethane) to give N- [2-chloro-4 - [[[(3- hydroxyphenyl) ethyl] amino] -carbonyl] benzoyl] -3 - [(9H-fluoren-9-ylmethoxy) -carbonyl] amino-L-alanine, methyl ester (0.57 g, 62%) as a white solid. B. 3-Amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -L-alanine, methyl ester A solution of N- [2-chloro-4] - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -3 - [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine, methyl ester (1.17 g, 1.9 mmol) in dichloromethane / methanol (2: 1) was added to piperidine (1.1 mL, 11.2 mmol) The reaction mixture was stirred for 4 h at room temperature and then more piperidine was added ( 1.1 mL, 11.2 mmol) The solution was stirred at room temperature overnight, then concentrated and the residue was chromatographed (0-40% methanol / dichloromethane) to give 3-amino-N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -L-alanine, methyl ester (760 mg, 100%) as a light yellow solid.

Example 73 Preparation of 3-amino-N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine, methyl ester A. N- [2,6-Dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [[1,1-dimethylethoxy) carbonyl] -amino] -L-alanine , methyl ester Diisopropylethylamine (0.211 mL, 1.21 mmol) was added to a solution of 2,6-dimethyl-4 - [[[[3 - [[(1, 1-di-aethylethyl) dimethylsilyl] oxy] phenyl] - useful] amino] carbonyl] benzoic acid (Example 30, 100 mg, 0.242 mmol), HOBT (39 mg, 0.29 mmol), and HBTU (110 g, 0.29 mmol) in N, N-dimethylformamide (1 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate (50 mL) was added. The solution was washed with 1 M HCl (25 mL), saturated aqueous sodium hydrogencarbonate (25 mL), and brine (25 mL), dried (MgSO 4) / filtered, and evaporated to give N- [2,6- dimethyl-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] enzoyl] -3 - [[(1,1-dimethylethoxy) carbonyl] amino] -L-alanine, crude methyl ester (144 jng, 97% This was used without any further purification B. 3-amino-N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine, methyl ester A solution of N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] enzoyl] -3 - [[(1,1-dimethylethoxy) carbonyl] amino] -L- alanine, crude methyl ester (144 mg, 0.235 mmol) in trifluoroacetic acid (2 L) and dichloromethane (2 L) was stirred at room temperature for 1 h.The reaction mixture was concentrated and ethyl acetate was added. washed with saturated aqueous sodium hydrogencarbonate, and the aqueous phase was extracted in turn seven times with ethyl acetate The combined organic phases were dried (MgSO 4), filtered, and evaporated to give 3-amino-N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine, crude methyl ester (104 mg, 110% of the theoretical amount). Example 74 Preparation of 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -L-alanine, methyl ester A. N- [2-chloro-4- [[[[3- [[(1,1-dimethylethyl) -dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl] -6-ethylbenzoyl] -3- [[( 1, 1-dimethylethoxy) carbonyl] amino] -L-alanine, methyl ester Diisopropylethylamine (2.11 L, 12. 1 mmol) to a solution of 2-chloro-4- [[[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] -methyl] amino] carbonyl] -6-methyl-benzoic acid (Example 33; 1. 32 g, 3.04 mmol) and 3 - [[(1, 1-dimethylethoxy) carbonyl] amino] -L-alanine hydrochloride, methyl ester, (1.54 g, 6.05 mmol) in dichloromethane (15 mL). Benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophostat (Reagent BOP, 1.48 g, 3. 35 mmol) and the mixture was stirred at room temperature for 4 h. The solution was diluted with ethyl acetate, washed with 1 M HCl, water, saturated aqueous sodium hydrogencarbonate, and water. The solution was then dried (MgSO 4), filtered, evaporated, and chromatographed (40% ethyl acetate / petroleum ether) to give N- [2-chloro-4- [[[[(3 - [[ (1, 1-dimethylethyl) dimethylsilyl] oxy] phenyl] -methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [[(1, 1-dimethylethoxy) carbonyl] amino] -L-alanine, methyl ester (1.57 g, 81%) in the form of a white foam B. N- [2-Chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- [[(1, 1-dimethylethoxy) carbonyl] amino] -L-alanine, methyl ester A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 M, 1.78 raL, 1.78 mmol) was added in two portions to a solution of N- [2 -chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [[(1,1-dimethylethoxy) carbonyl] ] amino] -L-alanine, methyl ester (1.03 g, 1.62 mmol) in dry tetrahydrofuran (20 mL) The solution was stirred at room temperature for 30 min, then diluted with water. The reaction was carried out with ethyl acetate (100 mL) and washed with water (25 mL) and brine (25 mL). The solution was dried (MgSO4), filtered, evaporated, maintained at high vacuum for 2.5 h, and then chromatographed (60-70% ethyl acetate / petroleum ether) to give N- [2-chloro-4- [[[(3- hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [[(1,1-dimethylethoxy) carbonyl] amino] -L-alanine, methyl ester (0.82 g, 97%) as a white foam. C. 3-amino-N- [2-chloro-4 [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -L-alanine hydrochloride, methyl ester. Trifluoroacetic acid (20 mL) was added. to a solution of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -6-methylbenzoyl-3- [[(1,1-dimethylethoxy) carbonyl] amino] -L -alanine, methyl ester (800 mg, 1.54 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, azeotropically distilled three times with dichloromethane / hexanes, and then kept at high vacuum for 35 min. 1 M HCl was added (4.6 mL, 4.6 mmol), together with acetonitrile (4 mL) and the mixture was lyophilized overnight, to give 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] hydrochloride ] amino] carbonyl-6-methylbenzoyl] -L-alanine, crude methyl ester (0.85 g, 120% of theory). Example 75 Preparation 3-amino-N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine hydrochloride, methyl ester A. N- [2,6-dichloro-4 - [[[(3-hydroxy phenyl) methyl] aminocarbonyl] benzoyl] -3 - [[(1,1-dimethylethoxy) carbonylamino] -L-alanine, methyl ester added diisopropylethylamine (14 mL, 80. 6 mmol) to a cooled solution (~ 0 ° C) of 2,6-dichloro-4 - [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] benzoic acid (Example 29; 7.44 a, 21.9 mmol) , 3- [[(1,1-dimethylethoxy) carbonyl] -amino] -L-alanine hydrochloride, methyl ester, (6.15 g, 24.1 mmol), HOBT (3.12 g, 22.8 mmol), and HBTU (8.64 g, 22.8 mmol) in NN-dimethylformamide (200 L). The mixture was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (200 L) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous phase was extracted with ethyl acetate (100 L). The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate, and brine (200 mL each), dried (MgSO 4), filtered, evaporated, and chromatographed (70% ethyl acetate / hexanes) to give N- [2,6-dichloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3 - [[(1, 1-dimethylethoxy) carbonyl) amino] -L-alanine, methyl ester ( 8.64 g, 73%) in the form of white foam. B. 3-amino-N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine hydrochloride, methyl ester An acid methanol solution was prepared by addition of acetyl chloride (25 mL, 351.6 mmol) to methanol (200 mL) cooled (~ 0 ° C) and stirring for 10 min. This solution was added to N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] -3 - [[(1, 1-dimethylethoxy) carbonyl] amino] - L-alanine, methyl ester (8.64 g, 16.0 mmol) and the resulting solution was stirred at room temperature for 16 h. The solvent was evaporated to give 3-amino-N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine hydrochloride, methyl ester (7.40 g, 97%) in the form of cream-colored foam.

Example 76 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] enzoyl] -3- (3-methoxybenzoyl-amino) alanine, A suspension of Wang resin substituted with 3-amino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine was prepared (Example 66; mg) in a solution prepared from HOAT (75 mg, 0.55 mmol), DICI (86 μl, 0.55 mmol) and 3-methoxybenzoic acid (700 mg, 4.6 mmol) in N-methylpyrrolidinone (1 ml) and stirred for 2 h until the ninhydrin test was negative. The resin was then filtered and washed extensively with N-methylpyrrolidinone, dichloromethane and methanol. Cleavage of the product was carried out with 50% trifluoroacetic acid in dichloromethane for 30 min. The cleavage solution was collected by filtration and the solvent was evaporated under high vacuum. The residue was purified by reverse phase HPLC chromatography to yield N- [2-chloro-4- [[[[3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (3-metho-benzoylamino) -L -to the girl. The procedures used to prepare Example 76 were also used to prepare Examples 77-227 (see Tables 1 and 2). Table 1. Derivatives of [[[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] (Examples 77-203) \ 180 1-isoquinoline-carboxylic acid 181 quinoline-2-carboxylic acid 182 4-methoxyquinoline-2-carboxylic acid 183 Or quinoline-3-carboxylic acid 184 quinoline-4-carboxylic acid 185 cinnoline-4-carboxylic acid 186 3-hydroxyquinoline- XX lina-2-carboxylic acid 187 chromone-2-carboxylic acid 188 XO cup? Arin-3-carboxylic acid 189 anthracene-9-carboxylic acid 190 1,2,3,4-tetrahydro-acridine-9-carboxylic acid dihydrate 191 methoxy-11-oxo-HH-pyrido [2, 1-b] quinazoline-8-carboxylic acid, which can be prepared according to the pro- cedure of Kierstead, R.W. and cois., US 4348396 192 9-oxo-9H-thioxanthene-3-carboxylic acid 10,10-dioxide 193, -CH, acetic acid 194 isobutyric acid 195 isovaleric acid 196 BOC-L-proline a The starting material of this substance is racemic. The diastereomeric products did not separate. Table 2. Truncated compounds (Examples 204-227) a The starting material of this substance is racemic. The diastereomeric products did not separate. Example 228 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl) amino] carbonyl] enzoyl] -3 (3,5-dibromobenzoyl) amino-L-alanine Diisopropylamine (0.4 mL, 2.47 mmol) was added to a cooled solution (approximately 0 ° C) of 3-amino-N- [2-chloro-4 - [[[3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -L-alanine, methyl ester (Example 72, 200 mg, 0.49 mmol), 3,5-dibromobenzoic acid (125 mg, 0.45 mmol), HBTU (187 mg, 0.49 mmol) and HOBT (66.5 mg, 0.49 mmol) in N, N-dimethylformamide (3 ml). The solution was stirred at about 0 ° C for 10 min and then the cold bath was removed and the solution was stirred overnight at room temperature. The solvent was evaporated. Ethyl acetate (20 ml) was added and the solution was washed with 0.5 M HCl (5 ml), sodium hydrogen carbonate solution (5 ml) and saline (10 ml). The ethyl acetate solution was dried (MgSO 4) and evaporated to yield a brown oil (237 mg). This was dissolved in tetrahydrofuran / methanol (1: 1, 2 ml) and the solution was added to a solution of lithium hydroxide monohydrate (100 mg, 2.38 mmol) in water (1 ml). The resulting solution was allowed to stir at room temperature over the weekend, and was then concentrated. Water was added and the solution was acidified to pH 2 with 1 M HCl. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate solution was washed with saline, dried (MgSO4), filtered, evaporated and purified by HPLC to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] -carbonyl] benzoyl] -3- (3, 5 -dibromobenzoyl) amino-L-alanine (94.2 mg, 40%) as a white solid. The following compounds were prepared by the same procedure: Example 252 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl) amino] carbonyl] benzoyl] -3 (3,5-difluorobenzoyl) -amino-L-alanine To a suspension of Wang resin substituted with N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine (Example 66, 100 mg, 0.111 mmol) in DMF (3 mL) was added 3,5-difluorobenzoic acid (26 mg, 0.166 mmol), HOAT (44 mg, 0.333 mmol) and then DICI (26 μl, 0.166 mmol). The reaction mixture was stirred for 1 hour. The solvent was removed by air pressure with filtration and the resin was washed with dichloromethane (3 times) followed by methanol (once), and this was repeated a total of five times. The ninhydrin test was negative. Cleavage of the product was carried out by stirring the resin with 50% trifluoroacetic acid in dichloromethane (3 ml) for 30 min. The cleavage solution was collected by filtration and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile, water, 0.075% TFA) to yield N- [2-chloro-4 - [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] benzoyl] -3- (3 , 5-difluorobenzoyl) amino-L-alanine (11 mg, 19%) as a white solid. The following compounds were prepared according to the same procedure. All of them were obtained in. white solid form.

Example 258 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- (5-chloro-4-methoxythiophene-3-carbonyl) amino-L- to the girl To a suspension of Wang resin substituted with N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine (Example 66; 100 mg, 0.111 mmol) in DMF (3 ml) was added 2-chloro-3-methoxythiophene-4-carboxylic acid (32 mg, 0.166 mmol), HOAT (44 mg, 0.333 mmol) and then DICI (26 μl, 0.166). mmol). The reaction mixture was stirred for 1 hour. The solvent was removed by air under pressure with filtration and the resin was filtered with dichloromethane (3 times) followed by methanol (once), and this process was repeated a total of five times. The ninhydrin test was positive, so DMF (3 ml), HBTU (84 mg, 0.222 mmol) and 2-chloro-3-methoxythiophene-4-carboxylic acid (32 mg, 0.166 mmol) were added, followed by DIPEA (0.44 mmol, 77 μl), stirring the reaction mixture for 1.5 hours. The solvent was removed by air under pressure with filtration and the resin was washed with dichloromethane (3 times) followed by methanol (once) repeating the process five times. The ninhydrin test was negative. Cleavage of the product was carried out by stirring the resin with 50% trifluoroacetic acid in dichloromethane (3 ml) for 30 min. The cleavage solution was collected by filtration and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile, water, 0.075% TFA) to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- ( 5-chloro-methoxythio-pheno-3-carbonyl) amino-L-alanine (9 mg, 15%) as a white solid.

Example 259 Preparation of N- [2-chloro-4- [[[(3-hydroxy phenyl) ethyl] amino] carbonyl] benzoyl) -3- (furan-3-carbonyl) amino-L-alanine A suspension of Wang resin substituted with N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine (Example 66, 100 mg, 0. 111 mmol) was washed three times with DMF and then suspended in DMF and 3-furoic acid was added. (14.0 mg, 0.13 mmol), HBTU (55 mg, 0.15 mmol) and diisopropylethylamine (77 μl, 0.44 mmol). The reaction mixture was stirred for 3 hours. The solvent was removed by pressurized air with filtration and > the resin was washed with dichloromethane (3 times) followed by methanol (once) and this process was repeated a total of five times. The ninhydrin test was positive, so DMF, - 3-furoic acid, was added (14.9 mg, 0.13 mmol), HBTU (55 mg, 0.15 mmol) and diisopropylethylamine (77 μl, 0.44 mmol), stirring the reaction mixture for 2 hours. The solvent was removed by air under pressure and the resin was washed with dichloromethane (3 times) followed by methanol (once), repeating this process a total of five times. The ninhydrin test was finally negative. The product was cleaved by stirring the resin with 50% trifluoroacetic acid in dichloromethane (3 ml) for 1 hour. The reaction solution was collected by filtration and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile, water, 0.075% TFA) and then lyophilized to yield N- [2-chloro-4- [[[[[(furan-3-carbonyl) oxy] phenyl] methyl ] -amino] carbonyl) benzoyl] -3- [(furan-3-carbonyl) amino-L-alanine. This product was dissolved in methanol (1 ml) and treated with 2 equivalents of 1 M NaOH. The solution was stirred for 8 h, then concentrated and purified by HPLC and frozen to yield N- [2-chloro-4 - [[[(3-hydroxyphenyl) ethyl] amino] -carbonyl] benzoyl] -3- (furan-3-carbonyl) amino-L-alanine (3 mg, 5.5%) as a white solid. The following compound was also prepared from Example 66 and 3-fluoro-3- (trifluoromethyl) benzoic acid by the following procedure: Example 261 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl)] methyl] amino] carbonyl] benzoyl] -3- (4-aminobutanoyl) amino-L-alanine A suspension of Wang resin substituted with 3-amino-2- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] benzoyl] -L-aianine (Example 66, 100 mg) was stirred in a solution prepared from HOAT (68 mg, 0.5 mmol), DICI (78 μl, 0.5 mmol) and 4- [(9H-fluoren-9-ylmethoxy) carbonyl] -amino] butanoic acid (163 mg, 0.5 mmol) ) in N-methylpyrrolidinone (1 ml) and stirred for 1 hour. The resin was filtered and washed extensively with dichloromethane and methanol. The resin was then treated with a solution of piperidine in N-methylpyrrolidone (1: 3, 2 ml) and the mixture was stirred for 1 hour. The resin was then filtered and washed extensively with dichloromethane and methanol. The product was cleaved with 50% trifluoroacetic acid in dichloromethane (1: 1, 2 ml) for 30 min. The cleavage solution was collected by filtration and the solvent was evaporated under high vacuum. The residue was purified by reverse phase HPLC to yield 2- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino) carbonyl] benzoyl] -3- (4-amino-butanoyl) amino- L-alanine. The following compounds were prepared according to the same procedure: a The carboxylic acid was racemic and the diastereomeric products were not separated b The diastereomeric products were not separated Example 297 Preparation of 3- (3-carboxybenzoyl) amino-N, - [2-chloro-4- [[(3-hydroxyphenyl)] ethyl] amino] carbonyl] benzoyl-L-alanine Lithium hydroxide monohydrate (2 mg, 0.048 mmol) was added to a solution of 3- [3- (methoxycarbonyl) benzoyl] amino-N- [2-chloro-4- [[(3-hydroxyphenyl) ethyl] amino] carbonyl ] benzoyl] -L-alanine (Example 136, 7 mg, 0.012 mmol) in tetrahydrofuran / methanol / water (3: 1: 1, 0.5 ml). The solution was stirred at room temperature for 3 h and then purified by HPLC to yield 3- (3-carboxybenzoyl) amino-N- [2-chloro-4- [[(3-hydroxy-phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine (5.6 mg, 82%) in the form of a white powder. The following product was also prepared by this procedure from Example 203: Example 299 Preparation of 3- (benzoylamino) -L-alanine methyl ester Bromine (10 ml, 194.1 mmol) was added to a solution of sodium hydroxide (40.00 g, 1000 mmol) in water (330 ml) cooled in a bath at -10 ° C. The pale yellow solution was stirred for 15 min and then 2- [(1,1-dimethylethoxy) -carbonyl] -L-asparagine (Boc-Asn; 39.50 g, 170.1 mmol) was added as a solid. The resulting solution was heated to about 70 ° C for 1 h. After cooling, a solution of benzoyl chloride (25.30 g, 180.0 mmol) in ether (50 ml) was added and the reaction mixture was allowed to stir at room temperature overnight. The pH of the solution was adjusted to about 10 with 1 M NaOH solution and the solution was extracted with ethyl acetate (200 ml). The organic phase was discarded and the aqueous phase acidified to pH about 2 with 1 M HCl solution. The resulting solution was extracted with ethyl acetate (2 x 200 ml), washed with saline (200 ml), dried (MgSO 4), filtered, and evaporated to yield a white solid (31.5 g). The white solid was dissolved in dichloromethane (200 ml) and ethereal diazomethane was added until the yellow color persisted, acetic acid (approximately 2 ml) was added to quench the excess diazomethane and the solution was washed with water and saline (200 ml). ml of each), dried (MgSO 4), filtered, evaporated, and chromatographed (30-50% ethyl acetate / hexanes) to yield methyl benzoate (13.86 g, Rf 0.75 in HCl). % ethyl acetate / hexanes) and 3- (benzoylamino) -N- [(1,1-dimethylethoxy) carbonyl] -L-alanine methyl ester (Rf 0.12 in 30% ethyl acetate / hexanes) in the form of a colorless oil (6.39 g, 11.5%) that solidified at rest together with 3.54 g of less pure fractions (6.5%). A solution of pure 3- (benzoylamino) -N- [(1,1-dimethylethoxy) carbonyl] -L-alanine methyl ester (200 mg, 0.62 mmol) in dichloromethane / trifluoroacetic acid (1: 1, 2.5 ml) it was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. Ethyl acetate (10 ml) was added and the solution was washed with saturated aqueous solution of NaHCO 3 (10 ml), dried (Na 2 SO 4), filtered, concentrated and then dried under high vacuum to yield 3- (benzoylamino) -L-alanine methyl ester (77 mg, 56%). EXAMPLE 300 Preparation of 3- (benzoylamino) -L-alanine methyl ester hydrochloride Bromine (20 ml, 388.2 mmol) was added to a solution of sodium hydroxide (80.00 g, 2000 mmol) in water (660 ml) cooled in a bath at -10 ° C. The pale yellow solution was stirred for 15 min and then 2- [(1,1-dimethylethoxy) carbonyl] -L-asparagine (Boc-Asn, 79.00 g, 340.2 mmol) was added as a solid. The resulting solution was heated to about 70 ° C for 1 h. After cooling to about 0 ° C, a solution of benzoyl chloride (50.80 g, 361.6 mmol) in ether (100 ml) was added and the reaction mixture was allowed to stir at room temperature for 48 h. The pH of the solution was adjusted to approximately 10 with 3 M NaOH solution and the solution was extracted with ethyl acetate (200 ml). The organic phase was discarded and the aqueous phase was acidified to pH about 2 with 3 M HCl solution. The resulting solution was extracted with ethyl acetate (2 x 300 ml), washed with saline, dried (MgSO 4), filtered, and evaporated to yield a white solid (64.87 g). To this was added a solution prepared by adding acetyl chloride (50 g) dropwise to a cooled solution (~ 0 ° C) of methanol, stirring for 10 min. The resulting solution was stirred at room temperature for 24 h, then the solvents were evaporated and water (250 ml) was added. The mixture was extracted with ethyl acetate (300 ml) and the organic extract was discarded. A white precipitate formed in the aqueous phase after concentration. This was filtered to yield 3- (benzoylamino) -L-alanine methyl ester hydrochloride (11.62 g, 15%) as a white solid.

Example 301 Preparation of 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester hydrochloride Bromine (25.25 ml, 0.49 mol) was added to a solution of sodium hydroxide (100.8 g, 2.52 mol) in water (830 ml) cooled in an ice bath and acetone at -10 ° C. The pale yellow solution was stirred for 15 min and then 2- [(1,1-dimethyl-ethoxy) -carbonyl] -L-asparagine (Boc Asn; 100.0 g, 0.43 mol mmol) was added as a solid. The resulting solution was heated to about 15 ° C for 1.5 h. After cooling, a solution of thiophene-2-carbonyl chloride (66.7 g, 0.455 mol) in ether (125 ml) was added and the reaction mixture was allowed to stir at room temperature for 3 days. The pH of the solution was adjusted to -10 with 3 M NaOH solution and the solution was extracted with ethyl acetate (500 ml). The organic phase was discarded and the aqueous phase was acidified to pH about 2 with 6 M HCl solution. The resulting solution was extracted with ethyl acetate (2 x 500 ml), washed with saline (200 ml), dried (MgSO), and filtered to yield 1400 ml of solution. From this solution, 1100 ml were evaporated to dryness and dissolved in methanolic HCl (prepared by the addition of acetyl chloride (45 ml) to methanol (600 ml)). The mixture was stirred at 50 ° C overnight, then cooled and evaporated. The residue was evaporated twice from ethyl acetate (200 ml). Water (150 ml) was added, and the solution was extracted with ethyl acetate (3 x 250 ml). The organic extracts were washed again with water (50 ml). The combined aqueous phases were concentrated in vacuo to about 150 ml to yield 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester hydrochloride (21.7 g, 24%) as a colorless solid. Example 302 Preparation of 3-benzoylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine A. 3-Benzoyl-amino-N- [2-chloro-4- [[[. { 3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine methyl ester Diisopropylethylamine was added dropwise (27 mL, 147.2 mmol) was added to a cooled solution of 2-chloro-4- [[[(((3-hydroxyphenyl) methyl] amino] carbonyl] -benzoic acid (Example 26, 9.00 g, 29.4 mmol), hydrochloride of 3 -benzoylamino-L-alanine methyl ester (Example 300; 11.4 g, 44.2 mmol), HTBU (13.4 g, 35.3 mmol and HOBT (4.8 g, 35.3 mmol) in N, N-dimethylformamide (125 mL) .The reaction was allowed to warm to room temperature and was left stirring for 18 h The solvent was concentrated in vacuo to remove most of the N, N-dimethylformamide Ethyl acetate was added and the solution was washed with water (2 x 150 ml), 1 M HCl (3 x 100) ml) and saline solution The solution was dried (MgSO 4), filtered, evaporated, and chromatographed (0-50% acetone / dichloromethane) to yield 3-benzoylamino-N- [2-chloro-4- [[[( 3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -L-alanine methyl ester (10.7 g, 71%) B. 3-Benzoylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl)] -methyl] amino] carbonyl] benzoyl] -L-alanine A solution of 3-benzoylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -L-alanine Methyl ester (10.7 g, 21.0 mmol) in tetrahydrofuran / methanol (3: 1, 80 ml) was added to a stirred solution of water. Lithium dioxide monohydrate (2.65 g, 63.0 mmol) in water (40 ml) at room temperature. The reaction was stirred at room temperature overnight and then concentrated to remove methanol and tetrahydroturan. Water (150 ml) was added and the mixture was cooled to between 0 and -5 ° C. The mixture was acidified to pH 3 with concentrated HCl and stirred for 10 min. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with saline, dried (MgSO 4), filtered and evaporated to yield 3-benzoyl amino-N- [2-chloro-4- [ [[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine (7.1 g). The drying reagent was extracted with ethyl acetate / methanol (50: 3; 2 x 106 ml) to yield an additional amount of the product (3.3 g). Overall yield: 10.4 g (quantitative). Example 303 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine A. N- [2-Chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl] amino-L-alanine methyl ester Diisopropylethylamine was added, (7.00 g, 64. 2 mmol) to a solution of 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester hydrochloride (Example 301; 7.00 g, 26.4 mmol), 2-chloro-4- [[[(3-hydroxyphenyl)] ) methyl] amino] carbonyl] benzoic acid (Example 26; 7.00g, 22.9 mmol), and HBTU (13.00 g, 34. 3 mmol) in DMF (75 ml). The solution was allowed to stir at room temperature for 4 days, and then concentrated to remove most of the DMF. Ethyl acetate (200 ml) was added, followed by water (200 ml) and 1 M HCl solution (100 ml). The phases were separated; the ethyl acetate phase was evaporated, and the residue was chromatographed (50-100% ethyl acetate / hexanes) to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (8.30 g, 70%) as a white solid. B. N- [2-Chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl) -3- (thiophene-2-carbonyl) amino-L-alanine A solution of N- [2 -chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carboni 1] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (8.30 g, 16.1 mmol) and lithium hydroxide monohydrate (2.05 g, 48.9 mmol) in tetrahydrofuran (60 ml), methanol (20 ml), and water (40 ml) was stirred at room temperature overnight. The solution was concentrated to remove tetrahydrofuran and methanol, and ethyl acetate (200 ml) and 1 M HCl solution (100 ml) were added. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic phases were washed with saline (200 ml), dried (MgSO 4), filtered, and evaporated to yield N- [2-chloro-4 - [[[(3-hydroxyphenyl) methyl) amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (7.75 g, 96%) as a white solid. Example 304 Preparation of 3-benzoylamino-N- [2-chloro-4- [[[(3-hydroxy-phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine, sodium salt A solution of sodium hydroxide (1 M; 13. 5 ml, 13.5 mmol) was added to a suspension of 3-benzoyl-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine (Example 302; 6.68 g, 13.5 mmol) in water (200 ml). The reaction mixture was stirred at room temperature during min and it was filtered. The filtrate was lyophilized. The lyophilized material was re-lyophilized twice more and then dissolved in HPLC-grade water (200 ml) to yield 3-benzoylamino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine, sodium salt (5.78 g, 83%) in shape of a white solid. EXAMPLE 305 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine, sodium salt A solution of sodium hydroxide (1M, 25 ml, 25 mmol) was added to a suspension of N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (Example 303; 12.53 g, 25.0 mmol) in water (200 ml). The reaction mixture was stirred at room temperature for 2 h, and filtered. The filtrate was lyophilized. The lyophilized material was re-lyophilized twice more and then dissolved in HPLC-grade water (100 ml) to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] - 3- (thio-pheno-2-carbonyl) amino-L-alanine, sodium salt (12.43 g, 957) as a white solid. Example 306 Preparation of N- [2-bromo-4- [[[(3-hydroxyphenylmethyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester Diisopropylethylamine (305 μL, 1.71 mmol) was added dropwise to a solution of 2-bromo-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoic acid (Example 47, 150 mg, 0.428 mmol) , HBTU (179 mg, 0.471 mmol), 3- (thiophene-2-cat: rbonyl) amino-L-alanine methyl ester hydrochloride salt (Example 301; 125 mg, 0.471 mmol), and HOBT (64 mg, 0.71 mmol) in N, N-dimethylformamide (6.5 mL) at 25 ° C. The solution was stirred for 6 h. The solvent was concentrated in vacuo to remove most of the N, N-dimethylformamide. The residue was diluted with ethyl acetate (60 ml) and washed with 1 N HCl (10 ml), water (10 ml), saturated aqueous NaHCO 3 (10 ml) and saline (10 ml). The organic phase was dried (MgSO 4), filtered, evaporated and subjected to flash chromatography (silica, 60-75% ethyl acetate in petroleum ether) to yield N- [2-bromo-4- [[[( 3-hydroxy-phenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (198 mg, 83%) as a whitish foam. The following compounds were also prepared by this same route: a The reaction time was 4 h at 25 ° C; The diluent used during the chromatography was 60-70% ethyl acetate / petroleum ether; the product was obtained as a white solid. b The reaction time was 2 h at 25 ° C; the diluent used during the chromatography was 60-70% ethyl acetate / petroleum ether; the product was obtained in the form of a white foam. c The reaction time was 6 h at 25 ° C; the diluent used during the chromatography was 60-70% ethyl acetate / petroleum ether; the product was obtained in the form of a whitish foam. d The reaction time was 24 h at 25 ° C; the diluent used during the chromatography was 2% methanol / dichloromethane; the product was obtained in the form of a yellow oil. e The reaction time was 24 h at 25 ° C; the product was obtained in the form of a white foam, and was used without chromatography. Example 312 Preparation of N- [2,6-dimet-il-4- [[[(IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino- L-alanine methyl ester < To a solution of 2,6-dimeti 1-4 - [[[(IR) -1- (1-naphthalenyl) -ethyl] amino] carbonyl] benzoic acid (Example 31, 100 mg, 0.29 mmol) in dichloromethane (1 ml) at 25 ° C was added benzotriazol-1-yloxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP reagent, 140 mg, 0.32 mmol), hydrochloride salt of 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (Example 301; 114 mg, 0.43 mmol), followed by diisopropylethylamine (250 μL, 1.4 mmol), dropwise slowly. After stirring for 2 h, the reaction was diluted with ethyl acetate (50 ml) and washed with HCl (10 ml), saturated aqueous sodium bicarbonate (10 ml) and saline (15 ml). The organic phase was dried (MgSO 4), filtered, evaporated and subjected to flash chromatography (silica, 50% ethyl acetate in petroleum ether) to yield N- [2,6-dimethyl-4- [[[( IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (88 mg, 54%) as an off-white solid.

Example 313 Preparation of N- [2-chloro-4- [[(2,3-dihydro-2-oxo-lH-indol-4-methyl) amino] carbonyl] benzoyl] -3- (3-methoxy-benzoylamino) -L-alanine DCC (0.072 g, 0.352 mmol) and HOAT (0.087 g, 0.64 mmol) were added to a solution of 2-chloro-4- [[(2, 3-dihydro-2-oxo-lH-indole-4-methyl) ) -amino] carbonyl] benzoic acid (Example 35; O.lllg, 0.32 mmol) and 3- (benzoylamino) -L-alanine methyl ester (Example 299; 0.142 g, 0.64 mmol) in DMF (5 ml). The solution was stirred at room temperature for 48 h, then filtered and diluted with ethyl acetate. The resulting solution was washed with water several times, evaporated, and chromatographed (70% ethyl acetate / hexanes to elute the DCC, then 10% methanol / dichloromethane and then 100% ethanol) to yield N- [2-chloro- 4- [[(2,3-dihydro-2-oxo-lH-indole-4-methyl) amino] carbonyl] -benzoyl] -3- (3-methoxybenzoylamino) -L-alanine methyl ester in the form of a brown solid (27 mg, 15%). A solution of lithium hydroxide monohydrate (5 mg, 0.1 mmol) was added to a solution of the ester (27 mg, 0.05 mmol) in tetrahydrofuran / methanol / water (3: 1: 1, 3 mL). The mixture was stirred for 5 h at room temperature and then acidified with 6 N HCl. The solvent was evaporated and the residue was resuspended in water. The product was filtered, washed with diethyl ether and water, and purified by HPLC to yield N- [2-chloro-4- [[(2,3-dihydro-2-oxo-lH-indole-4-methyl)] amino] -carbonyl] benzoyl] -3- (3-methoxybenzoi lamino) -L-alanine (10.7 mg, 42%).

Example 314 Preparation of 3- (benzoylamino) -N- [2-chloro-4- [[(1 H -indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine 3- (Benzoylamino) -L-alanine methyl ester (Example 299, 77 mg, 0.35 mmol) was mixed with 2-chloro-4- [[(lH-indol-4-yl-1-methyl) amino] carbonyl] benzoic acid (Example 36, 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCI (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (approximately 20 ml). The solution was extracted with ethyl acetate (3 x 10 ml) and the ethyl acetate phase was washed with dilute aqueous sodium chloride solution and then saline., dried (Na 2 SO 4), concentrated, and chromatographed (40-80% ethyl acetate / hexanes) to yield 3- (benzoylamino) -N- (2-chloro-4- [[(4H-indole-4 ylmethyl) amino] -carbonyl] benzoyl] -L-alanine methyl ester (88 mg, 47%) A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran / methanol / water (3: 1: 1; 2 ml) was stirred at room temperature for 3 h. The solvent was removed and the product was purified > HPLC to yield 3- (benzoylamino) -N- [2-chloro-4- [[(1H-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine (37 mg, 75%) as a a spongy white powder. EXAMPLE 315 Preparation of 3- (thiophene-2-carbonyl) amino-N- [2-chloro-4 [[lH-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine A. 3- [9H-Fluoren-9-ylmethoxy) carbonyl] amino-N- [2-chloro-4 - [[(IH-indol-methylmethyl) amino] carbonyl] -benzoyl] "- L-alanine methyl ester A solution of N- [(1,1-dimethyletoxy) -carbonyl] -3- [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine methyl ester (Example 62; 200 mg, 0.45 mmol) in trifluoroacetic acid / dichloromethane (1: 1, 2 ml) was stirred at room temperature for 40 min.The solvent was evaporated and ethyl acetate was added (10 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and evaporated to yield 3- [(9H-fluoren-9-ylmethoxy) carbonyl] amino-L-alanine methyl ester. HOAT (73 mg, 0.45 mmol), DCC (111 mg, 0.45 mmol), 2-chloro-4- [(1H-indol-4-ylmethyl) amino] -carbonyl] benzoic acid (Example 36, 148 mg, 0.45 mmol) and N, N-dimethyl formamide (5 ml) and the solution was stirred at room temperature for 1.5 h. Water was added and the solution was extracted three times with ethyl acetate. The combined extracts were washed with saline, dried (Na2SO4), filtered, evaporated, and chromatographed (40-80% ethyl acetate / hexanes) to yield 3- [(9H-fluoren-9-ylmethoxy) carbonyl. ] -amino-N- [2-chloro-4- [[(lH-indol-4-ylmethyl) -amino] carbonyl] -benzoyl] -L-alanine methyl ester (116 mg, 40%). B. 3- (Thiophene-2-carbonyl) amino-N- [2-chloro-4- [[(1 H -indol-4-lmethyl) amino] carbonyl] benzoyl] -L-alanine Piperidine (88 μl, 0.89 mmol) was added to a solution of 3- [(9H-fluoren-9-ylmethoxy) carbonyl] -amino-N- [2-chloro-4- [[(H-indol-4-lmethyl) amino] carbonyl] benzoyl. ] -L-alanine methyl ester (116 mg, 0.18 mmol) in N, N-dimethylformamide (5 ml). The solution was stirred at room temperature for 30 min and then the solvent was evaporated. The resulting white solid was triturated with ether five times and dried under vacuum to yield 3-amino-N- [2-chloro-4 - [[(lH-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L- alanine methyl ester as an off-white solid (59 mg, 81%). N, N-dimethylformamide (5 ml) was added, followed by HOAT (23 mg, 0.17 mmol), l- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (32 mg, 0.17 mmol), and thiophene- 2-carboxylic acid (18 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with saline, dried (Na2SO), filtered, evaporated, and chromatographed (40-80% ethyl acetate / hexanes) to yield 3- [(thiophene-2-carbonyl) amino) - N- [2-chloro-4 - [[(lH-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine methyl ester (58 mg, 78%). A solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in tetrahydrofuran / methanol / water (3: 1: 1) was added, and the solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified by HPLC to yield 3- (thiophene-2-carbonyl) amino-N- [2-chloro-4- [[(lH-indol-4-ylmethyl) amino] carbonyl] benzoyl- L-alanine (45 mg, 80% from the ester, 48% during three stages) in the form of a white powder. The following compounds were also prepared by this process: Example 318 Preparation of 3- (thiophene-2-carbonyl) amino-N- [2-chloro-4 [[(2,3-dihydro-lH-indol-4-ylmethyl) amino] -carbonyl] benzoyl] -L-alanine It was added to 3-amino-N- [2-chloro-4- [[(1H-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine in Wang resin (Example 69, 100 mg) a solution of HOAT (70 mg, 0.51 mmol), diisopropylcarbodiimide (80 μL, 0.51 mmol), and thiophene-2-carboxylic acid (70 mg, 0.55 mmol) in 1-met il-2-pyrrolidinone (1 mL). The mixture was stirred for 2 h and then the resin was filtered and washed extensively with dichloromethane and methanol. The cleavage of the product was carried out with triethylsilane / trifluoroacetic acid / dichloromethane (2: 1: 1; 1 ml) at room temperature for 30 min. The solvent was evaporated and the residue was purified by HPLC to yield 3- (thiophene-2-carbonyl) amino-N- [2-chloro-4 - [[(2,3-dihydro-lH-indol-4-ylmethyl) amino] carbonyl] -benzoyl] -L-alanine (10.7 mg). Example 319 Preparation of N- [2-chloro-4 - [l-oxo-3- (3-hydroxyphenyl) propyl] benzoyl] -3- (thiophene-2-carboni 1) -amino-L-alanine A. N- [2-chloro-4- [l-hydroxy-3- (3-hydroxyphenyl) -propyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester A solution of acid 2 -chloro-4- [l-oxo-3- (3-hydroxy-phenyl) -propyl] -benzoic acid (Example 41; 75.8 mg, 0.25 mmol), 3- (thiophene-2-carbonyl) amino-L-alanine hydrochloride methyl ester (Example 301; 73 mg, 0.28 mmol), HBTU (113 mg, 0.30 mmol), HOBT (41 mg, 0.27 mmol) and diisopropylethylamine (0.22 mL, 1.26 mmol) in N, N-dimethylformamide (6 mL) were added. stirred overnight at room temperature. The solvent was evaporated. Ethyl acetate (30 ml) was added and the solution was washed with sodium hydrogen carbonate solution and 0.5 M HCl. Each of the aqueous phases was extracted with ethyl acetate (10 ml) and the combined organic phases were dried (Na2SO4), filtered, evaporated, and chromatographed (10-100% ethyl acetate / hexanes) yield N- [2-chloro-4- [l-hydroxy-3- (3-hydroxyphenyl) propyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (125 mg, 98%) . B. N- [2-chloro-4- [1-hydroxy-3- (3-hydroxy phenyl) propyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine A solution of N-. { 2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (120 mg, 0. 23 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) in tetrahydrofuran / methanol / water (2: 2: 1, 2.5 ml) was stirred at room temperature for 90 min. The solvent was evaporated, then water was added, followed by 1 M HCl (1.1 ml). The resulting solid was filtered, washed with water, dried, and purified by HPLC to yield N- [2-chloro-4- [l-oxo-3- (3-hydroxyphenyl) propyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (95mg, 81%). The following compounds were also prepared by this process: a This product was a mixture of diastereomers, which were not separated. Example 327 Preparation-of-N- [2-chloro-4- [[[(lH-indazol-4-yl) methyl] amino] carbonyl] benzoyl] -3 - (thiophene-2-carbonyl) -amino-L-alanine A. N- [2-chloro-4- [[[[1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl] methyl] amino] carbonyl] benzoyl] -3- (thiophene -2-carbonyl) amino-L-alanine methyl ester Diisopropylethylamine (0.147 ml, 0. 84 mmol) was added to a solution of 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester hydrochloride (Example 301, 58 mg, 0.22 mmol), 2-chloro-4- [[[[1- ( tetrahydro-2 H -pyran-2-yl) -lH-indazol-4-yl] -methyl] amino] carbonyl] -benzoic acid (Example 39; 70 mg, 0.169 mmol), HBTU (78 mg, 0.21 mmol), and HOBT (27 mg, 0.20 mmol) in DMF (2 ml). The solution was allowed to stir at room temperature overnight, and then concentrated to remove most of the DMF. Ethyl acetate was added, and the solution was washed with saturated aqueous sodium hydrogen carbonate (twice), di acid, and saline, dried (MgSO 4), filtered, evaporated and chromatographed (2% methanol / dichloromethane) to yield N- [2-chloro-4 - [[[[1- (tetrahydro-2 H -pyran-2-yl) -lH-indazol-4-yl] methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (108 mg, 102%) as a brown solid.

B. N- [2-Chloro-4- [[[[1- (tetrahydro-2 H -pyran-2-yl) -lH-indazol-4-yl] methyl] amino] carbonyl] benzoyl] -3- (thiophene -2-carbonyl) amino-L-alanine A solution of sodium hydroxide (1 M, 190 pL, 0.19 mmol) was added to a solution of N- [2-chloro-4- [[[[1- (tetrahydro-2H -piran-2-yl) -lH-indazol-4-yl] methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (108 mg, approximately 0.169 mmol) in methanol (1 ml). The solution was left stirring at room temperature for 2 days, then it was concentrated and kept under high vacuum for 1 h to yield N- [2-chloro-4 - [[[1- (tetrahydro-2H-pyran-2- il) -lH-indazol-4-yl] methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (100 mg, 97%) as a yellow solid. C. N- [2-Chloro-4 - [[[(lH-indazol-4-y1) met yl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine A solution of N- [2-chloro-4- [[[[1- (tetrahydro-2 H -pyran-2-yl) -lH-indazol-4-yl] methyl] -amino] carbonyl] benzoyl] -3- ( thiophene-2-carbonyl) amino-L-alanine (35 mg, 0.057 mmol) in 2 M HCl (2 mL) and methanol (2 mL) was hd to reflux for 3 h. The solution was concentrated, diluted with aqueous acetic acid and purified by HPLC to yield N [2-chloro-4- [[[(1H-indazol-4-yl) ethyl] amino] carbonyl] -benzoyl) -3 - (thiophene-2-carbonyl) amino-L-alanine (8 mg, 26%) together with N- [2-chloro-4- [[[(lH-indazol-4-yl) methyl] amino] carbonyl] benzoyl ] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (13 mg, 42%). Example 328 Preparation of N- [2-bromo-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine To a solution of N- [2-bromo-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine methyl ester (Example 306; 195 mg, 0.348 mmol) in methanol (2 ml) at 25 ° C was added 1 N NaOH (350 μl, 0.348 mmol). The reaction mixture was stirred for 24 h and TLC (10% methanol in dichloromethane) revealed that the starting material was still present. 1 N NaOH (350 μL) was added at room temperature and the reaction was stirred for 24 h. The solvent was evaporated under reduced pressure, the residue was subjected to vacuum for 1 h, and then purified by HPLC (gradient of acetonitrile, water, 0.075% TFA). The pure fractions were combined, concentrated in vacuo and then lyophilized for 24 h to yield N- [2-bromo-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl) -benzoyl] -3- (thiophene -2-carbonyl) amino-L-alanine (144 mg, 76%) as a white solid. The following compounds were prepared according to the same procedure. In each case the product was a white solid.

Example 311 54% 331 Example 310 79% 332 Example 309 73% 333 Example 312 67% Example 334 Preparation-of-N- [4- [[[(3-amino phenyl) methyl] amino] carbonyl] -2- bromobenzoyl] -3- (thiophene-2-carboni 1) - amino-L-alanine A. N- [2-bromo-4- [[[3- [[(1,1-dimethylethoxy) carbonyl] -aminophenyl] methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino- L-alanine To a solution of N- [2-bromo-4- [[[3- [[(1,1-dimethylethoxy) carbonyl] aminophenyl] methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2 carbonyl) amino-L-alanine methyl ester (Example 308, 320 mg, 0.485 mmol) in methanol (2.5 ml) at 0 ° C was added 1 N NaOH (534 μl, 0.533 mmol). The reaction mixture was heated to 25 ° C and stirred for 24 h. The solvent was evaporated under reduced pressure, the residue was diluted with ethyl acetate (50 ml) and washed with water (100 ml). The aqueous phase was separated, acidified to pH 4 with 1 N HCl, and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saline (50 ml), dried with MgSO 4, filtered, and concentrated to yield N- [2-bromo-4- [[[3- [[(1, 1- dimethyl-ethoxy) carbonyl] -aminophenyl] methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (260 mg, 83%) in the form of a white foam. B. N- [4- [[[(3-aminophenyl) methyl] amino] carbonyl) -2-bromobenzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine, trifluoroacetate salt To a solution of N - [2-Bromo-4- [[[3- [[(1,1-dimethylethoxy) carbonyl] aminophenyl] methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine ( 260 mg, 0.40 mmol) in dichloromethane (2 ml) at 25 ° C was added trifluoroacetic acid (2 ml). The reaction mixture was stirred for 1.5 h. The solvent was evaporated under reduced pressure, the residue was subjected to vacuum for 1 h, and then purified by HPLC (gradient of acetonitrile, water, 0.075% TFA). The pure fractions were combined, concentrated in vacuo and then lyophilized for 24 h to yield TFA salt of N- [4 - [[[(3-aminophenyl) -methyl] amino] -carbonyl] -2-bromobenzoyl] - 3- (thiophene-2-carbonone 1) -amino-L-alanine (182 mg, 69%) as a white solid. Example 335 Synthesis of N- [2-chloro-4- [[[(3,5-dihydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- [thiophene-2-carbonyl] -amino-L-alanine A. 2-Chloro-4- [[(3,5-dimethoxybenzi-1) amino] -carbonyl] benzoic acid methyl ester A solution of 1- [[3-chloro-4- (methoxycarbonyl) benzoyl] oxy] -2, 5-pyrrolidinedione (Example 5, 2.00 g, 6.4 mmol), 3,5-dimethoxybenzyl-amine (1.25 g, 7.5 mmol) and triethylamine • (1.00 g, 9.9 mmol) in N, N-dimethylformamide (100 ml) was stirred at room temperature throughout the night. The solvent was evaporated (< 0.5 mm Hg, 40 ° C), ethyl acetate (200 ml) was added, and the solution was allowed to stand for a weekend at room temperature. A white solid was filtered and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (30-50% ethyl acetate / hexanes) to yield 2-chloro-4- [[((3,5-dimethoxyphenyl) -methyl] amino] carbonyl] benzoic acid methyl ester (1.69 g, 72%) in the form of a white solid, mp 101-103 ° C. B. 2-Chloro-4- [[[(3,5-dihydroxyphenyl) methyl] -amino] carbonyl] benzoic acid methyl ester A solution of 2-chloro-4- [[(3,5-dimethoxybenzyl) -amino acid] ] carbonyl] benzoic methyl ester (0.50 g, 1.4 mmol) in dry dichloromethane (20 ml) was cooled to -78 ° C a solution of boron tribromide (1 M in dichloromethane) was added; 10 ml, 10 mmol) and the solution was allowed to warm to room temperature and stir overnight. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with saline < (200 ml), dried (MgSO 4), filtered, and evaporated to yield 2-chloro-4- [[[(3,5-dihydroxyphenyl) -methyl] amino] carbonyl] benzoic methyl ester (400 mg, 90%) in the form of a white solid, mp 152-155 ° C. C. N- [2-Chloro-4 - [[[(3,5-dihydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [thiophene-2-carbonyl] amino-L-alanine methyl ester Diisopropylethylamine was added (0.40 g, 3.09 mmol) on an ice-cold ice solution of 3- (thiophene-2-carbonyl) -L-alanine methyl ester hydrochloride (Example XX, 0.33 g, 1.25 mmol), 2-chloro-4 acid - [[[(3,5-dihydroxy) -phenyl] -methyl] amino] carbonylbenzoic acid (0.40 g, 1.24 mmol), HBTU (500 mg, 1.3 mmol), and HOBT (180 mg, 1.3 mmol) in N, N dimethylformamide (10 ml). The solution was allowed to stir at room temperature overnight. It was then concentrated to remove most of the N, N-dimethylformamide. Ethyl acetate was added (200 ml), followed by water (200 ml) and 1 M HCl (100 ml). The phases separated; the ethyl acetate phase was washed with saline (200 ml), dried (MgSO 4), and evaporated to yield N- [2-chloro-4 - [[[(3,5-dihydroxyphenyl) methyl] amino] carbonyl] • benzoyl] -3- [thiophene-2-carbonyl] amino-L-alanine methyl ester in the form of a white solid (270 mg, 41%), mp 120-123 ° C. D. N- [2-Chloro-4 - [[[(3,5-dihydroxy phenyl) methyl] amino] -carbonyl] benzoyl] -3- [thiophene-2-carbonyl] amino-L-alanine A solution of N - (2-chloro-4- [[[(3,5-dihydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- [thiophene-2-carbonyl] amino-L-alanine methyl ester (250 mg, 0.47 mmol) , and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in tetrahydrofuran (30 ml), methanol (10 ml), and water (10 ml) were stirred at room temperature overnight. The solution was concentrated to remove methanol and tetrahydrofuran, and then water was added (50 ml) and 1 M HCl (20 ml). The mixture was extracted with ethyl acetate (2 x 30 ml), and the solvent was evaporated from the extracts. The residue was dissolved in methanol (30 ml) and 10 ml of this solution was purified by HPLC to yield N- [2-chloro-4- [[[(3,5-dihydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl] amino-L-alanine (21.2 mg, 26%) as an off-white solid Example 336 Preparation of N- [2,6-dimethyl-4- [[[(3- hydroxy-phenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-3-carbonyl) amino-L-alanine To a cooled solution (~ 0 ° C) of crude N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3-amino-L-alanine methyl ester (Example 73, 50 mg, approximately 0.125 mmol) in N, N-dimethylformamide (1 ml) were added HBTU (57 mg, 0.150 mmol), HOBT (20 mg, 0.148 mmol), diisopropylethylamine (109 μl, 0.626 mmol), and finally thiophene-3-carboxylic acid (18 mg, 0.140 mmol). The solution was stirred for 1 h at 0 ° C and then for 5 h at room temperature. The N, N-dimethylformamide was evaporated. The residue was diluted with ethyl acetate and the solution was washed with 1 M HCl (twice) and sodium hydrogen carbonate (twice). The solution was dried (MgSO4), filtered and concentrated to yield a yellow oil (52 mg). This contained two main components: N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- (thiophene-3-carbonyl) amino-L-alanine methyl ester and N- [2,6-dimeti 1-4- [[[[3- (t -pheno-3-carbonyl) -oxyphenyl] methyl] amino] carbonyl] benzoyl] -3- (thiophene-3-carbonyl) amino -L-alanine methyl ester. A solution of sodium hydroxide (1 M, 196 μL, 0.196 mmol) was added to a solution of this yellow oil (50 mg) in methanol (1 mL). The reaction mixture was stirred at room temperature overnight. This indicated the presence of some of the starting material, so that an additional 50 μl (0.05 mmol) of sodium hydroxide was added and the solution was stirred overnight again. The solvent was evaporated (using a rotary evaporator and then a vacuum pump) and the residue was purified by HPLC and lyophilized to yield N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-3-carbonyl) amino-L-alanine (3.7 mg, 6% as a whole from 2,6-dimethyl-4- [[[[3- [[(1, 1-dimethylethyl) -dimethyl-silyl] oxy] phenyl] methyl] -amino] carbonyl] benzoic acid) in the form of a white solid.

Example 337 Preparation of N- [2,6-dimet i 1-4 - [[[(3-hydroxy phenyl) -methyl] amino] carbonyl] benzoyl] -3- (3, 5-difluorobenzoyl-amino) -L- to the girl To a cooled solution (~ 0 ° C) of N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3-amino-L-alanine methyl ester crude (Example 73, 50 mg, approximately 0.125 mmol) in N, N-dimethylformamide (1 ml) were added HBTU (57 mg, 0.150 mmol), HOBT (20 mg, 0.148 mmol), diisopropylethylamine (109 μL, 0.626 mmol), and finally 3,5-difluorobenzoic acid (22 mg, 0.14 mmol). The solution was stirred for 1 h at 0 ° C and then for 5 h at room temperature. The N, N-dimethylformamide was evaporated. The residue was diluted with ethyl acetate and the solution was washed with 1 M HCl (twice) and sodium hydrogen carbonate (twice). The solution was dried (MgSO4), filtered, and concentrated to yield a yellow oil (48 mg). This was dissolved in methanol (1 ml), and an aqueous solution of sodium hydroxide (1 M) was added.; 117 μL, 117 μmol). The solution was stirred at room temperature overnight and then the solvents were evaporated. The residue was purified by HPLC and lyophilized to yield N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3, 5-difluorobenzoylamino) -L -alanine (4 mg, 6%).

Example 338 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylenbenzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine A. N- [2-Chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl] -6-methylbenzoyl) -3- [(thiophene- 2 -carboni 1) amino] -L-alanine methyl ester Diisopropylethylamine (4.6 ml, 26.5 mmol) was added to a solution of 2-chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] ] oxy] phenyl] -methyl] amino] carbonyl] -6-methyl-benzoic acid (Example 33, 2.30 g, 5.3 mmol), 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester hydrochloride (Example 301; 1.80 g, 6.9 mmol), HOBT (0.80 g, 6.4 mmol), and HBTU (2.40 g, 6.4 mmol) in N, N-dimethylformamide (10 mL). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated (< 0.5 mm Hg, 40 ° C), and ethyl acetate was added. The solution was washed with 1 M HCl, saturated sodium hydrogen carbonate and saline, dried (MgSO 4), filtered, evaporated and chromatographed (50-100% ethyl acetate / hexanes then 5% methanol / ethyl acetate) to yield N- (2-chloro-4 - [[[[3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl ] methyl] amino] carbonyl] -6-methyl-l-benzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (2.00 g, 59% of the theoretical amount) and N- [2-chlor , o-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (850 mg, 30% of the theoretical amount) B. N- [2-Chloro-4 - [[[(3-hydroxy-phenyl-1) -methyl] -amino] -carbonyl] -6-methybenzoyl] -3- [(thiophene-2-carbonyl) -amino] -L-alanine methyl ester Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 3.4 ml, 3.4 mmol) was added to a solution of N- [2-chloro-4- [[[[3- [[(1,1-dimethylethyl-dimethylsilyl] oxy) phenyl] methyl] amino] carbonyl] -6-methylbenzoyl) -3- [(thiophene-2-carbonyl) -amino] -L-alanine (2.0 g, 3.1 mmol ) in tetrahydrofuran (10 ml). The solution was stirred at room temperature for 20 min, then diluted with ethyl acetate and washed with water and then saline. The solution was dried (MgSO), filtered, evaporated, concentrated, evaporated, dried overnight under high vacuum and then crystallized from methanol to yield N- [2-chloro-4- [[ [(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3 - [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (1.06 g) as a solid. The mother liquors were concentrated and chromatographed (70% ethyl acetate / hexanes then methanol / ethyl acetate / hexanes 10: 133: 57) to yield an additional portion of the product (0.16 g). The overall yield was 1.22 g (74 g. %). C N- (2-Chloro-4 ~ [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methyl-ylbenzoyl] -3- [(thiophene-2-carbonyl) -amino] -L-alanine Una mixture of N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl) -6-methylbenzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (2.06 g, 3.9 mmol) in methanol (100 ml) and sodium hydroxide (0.31 g, 7.8 mmol) in water (2 ml) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate phase was discarded. The aqueous phase was poured into 2 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with saline, concentrated, and dried under high vacuum to yield N [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [(thiophene-2-carbonyl) amino] -L-alanine (1.50 g, 75%) as a white solid. EXAMPLE 339 Preparation of N- (2-chloro-4 - [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -6-methybenzoyl] -3- [(thiophene-3-carbonyl) amino] -L- to the girl A. N- [2-Chloro-4 - [[[[3- [(thiophene-3-carbonyl) oxy] -phenyl] methyl] amino] carbonyl] -6-methylbenzoyl] -3- [(thiophene-3- carbonyl) amino] -L-alanine methyl ester Diisopropylethylamine (0.286 ml, 1. 64 mmol) was added to a cooled solution (approximately 0 ° C) of 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -L hydrochloride. - alanine methyl ester (Example 74; 150 mg, 0.329 mmol), thiophene-3-carboxylic acid (92.7 mg, 0. 72 mmol), HOBT (97.8 mg, 0.72 mmol), and HBTU (275 mg, 0.73 mmol) in N, N-dimethylformamide (3 ml).

The reaction mixture was allowed to stir at room temperature over the weekend. The solvent was evaporated. Ethyl acetate (100 ml) was added and the solution was washed with 1 M HCl, saturated aqueous sodium hydrogen carbonate, and saline (25 ml each). The solution was dried (MgSO.sub.4), filtered, evaporated and chromatographed (60% ethyl acetate / petroleum ether) to yield N- (2-chloro-4- [[[[3- [(thiophene-3- carbonyl) oxy] phenyl] methyl] amino] carbonyl] -6-methybenzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine methyl ester (170 mg, 81%) in the form of an orange foam .

B. N- [2-Chloro-4 - [[[(3-hydroxyphenyl) methyl] -amino] carbonyl] -6-methylbenzoyl] -3- [(thiophene-3-carbonyl) -amino] -L-alanine Una Aqueous sodium hydroxide solution (1M, 0.5 ml, 0.5 mmol) was added to a solution of N- [2-chloro-4 - [[[[3- [(thiophene-3-carbonyl] oxy] -phenyl] ethyl ] amino] carbonyl] -6-methylbenzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine methyl ester (160 mg, 0.25 mmol) in methanol (2 ml) The solution was allowed to stir throughout overnight and then concentrated The residue was purified by HPLC and lyophilized to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl) -3- [ (thiophene-3-carbonyl) amino] -L-alanine (76.5 mg, 59%) as a white solid. Example 340 Preparation of N- [2-chloro-4 - [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [(3,5-difluorobenzoyl) -amino] -L- to the girl AN- [2-Chloro-4- [[[[3- [(3,5-di-fluorobenzoi-1) oxy] phenyl] methyl] aminolcarbonyl] -6-methybenzoyl] -3- [(3,5-difluoro- benzoyl) amino] -L-alanine methyl ester and N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3- [(3,5-difluorobenzoyl) amino] -L-alanine methyl ester Diisopropylethylamine (0.287 ml, 1.65 mmol) was added to a cooled solution (approximately 0 ° C) of 3-amino-N- [2-chloro-4- [[[(3-) hydrochloride] hydroxy phenyl) methyl] amino] carbonyl] -6-methybenzoyl] -L-alanine methyl ester (Example 74; 150 mg, 0.329 mmol), 3,5-di-fluorobenzoic acid (114 mg, 0.72 mmol), HOBT (98 mg, 0.73 mmol), and HBTIU (275 mg, 0.73 mmol) in N, N-dimeti-1 formamide (3 ml). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated. Ethyl acetate (100 ml) was added and the solution was washed with 1 M HCl, saturated aqueous sodium hydrogen carbonate, and saline (25 ml each). The solution was dried (MgSO 4), filtered, evaporated and chromatographed (40-60% ethyl acetate / petroleum ether) to yield N- [2-chloro-4- [[[[3- [(3, 5-difluorobenzoyl) oxy] phenyl] methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-alanine methyl ester (48.9 mg, 21%) as a solid whitish, and N- [2-chloro-4 - [[[(3-hydroxy phenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [(3,5-difluorobenzoyl) -amino] -L-alanine methyl ester (44.6 mg, 24%) as an off-white solid. B. N- [2-Chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- [(3,5-difluorobenzoyl) amino] -L-alanine A solution aqueous sodium hydroxide (1 M, 0.123 ml, 0.123 mmol) was added to a solution of N- [2-chloro-4 - [[[[3 - [(3,5-di-fluorobenzoyl) oxy] phenyl] methyl] amino] carbonyl] -6-methybenzoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-alanine methyl ester (43 mg, 0.0614 mmol) in methanol (1 ml). The solution was left stirring overnight and then concentrated. The residue was purified by HPLC and lyophilized to yield N- [2-chloro-4 - [[[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3- [(3, 5- difluorobenzoyl) amino] -L-alanine (14.6 mg, 43%) as a white solid. Example 341 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] -6-methylbenzoyl] -3- (3,5-dihydroxybenzoyl-amino) -L-alanine A. N- [2-Chloro-4- [[[(3-hydroxyphenyl) methyl) amino] -carbonyl] -6-methylbenzoyl] -3- (3,5-dihydroxybenzoylamino) -L-alanine methyl ester Diisopropylethylamine was added (0.68 ml, 3.9 mmol) was added to a cooled (approximately 0 ° C) solution of 2-chloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amino] carbonyl ] -6-methylbenzoic acid (Example 33, 400 mg, 0.92 mmol), 3- [[(1,1-dimethyletoxy) carbonyl] amino] -L-alanine methyl ester hydrochloride methyl ester, (259 mg, 1.02 mmol), HOBT (138 mg, 1.02 mmol), and HBTU (380 mg, 1.02 mmol) in N, N-dimethylformamide (6 mL). The reaction mixture was allowed to warm to room temperature and stir overnight. The solvent evaporated (< 0.5 mm Hg, 40 ° C), and ethyl acetate were added (10 ml), water (10 ml) and 1 M HCl (4 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate and saline, dried (MgSO 4), filtered, evaporated and chromatographed (0-66% ethyl acetate / hexanes) to yield N- [2-chloro] -4 - [[[[3 - [[(1, 1-dimethylethyl) dimethylsilyl] oxy] -phenyl] methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [[(1, 1-dimethylethoxy) carbonyl] amino] -L-alanine methyl ester (299 mg, 51% of theory) and N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methylbenzoyl] -3 - [[(1, 1-dimethyletoxy) carbonyl] amino] -L-alanine methyl ester (242 mg, 51% of theoretical amount). The two products were combined. A portion (510 mg) of the resulting material was dissolved in dichloromethane (5 ml) and the solution was cooled to 0 ° C. A solution of trifluoroacetic acid (3.5 ml) in dichloromethane (3 ml) was added dropwise. The cooling bath was removed and the solution was allowed to stir at room temperature for 2 h. The sol-vent was evaporated and the residue was removed by azeotropy three times with hexanes / dichloromethane (1: 1) and then kept under high vacuum to yield the unprotected amine (466 mg). This material was dissolved in N, N-dimet and formamide (10 ml) and 3,5-dihydroxybenzoic acid was added. (284 mg, 1.84 mmol), HOBT (248 mg, 1.84 mmol), and HBTU (383 mg, 1.84 mmol). The solution was cooled to about 0 ° C and diisopropylethylamine (1.4 ml, 7.4 mmol) was added. The solution was allowed to stir overnight at room temperature and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 ml) and tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 5 ml, 5 mmol) was added. The mixture was stirred at room temperature for 3 h and then the solvent was evaporated. Water (10 ml) and ethyl acetate (10 ml) were added and the mixture was acidified with 1 M HCl. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 15 ml). The combined ethyl acetate phases were washed with saturated aqueous sodium hydrogen carbonate and saline, and then dried (MgSO4). A precipitate was formed on the magnesium sulfate, so that methanol was added, the mixture was filtered and the filter cake was washed with 10% methanol / ethyl acetate. The filtrate was evaporated to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methybenzoyl] -3- (3,5-dihydroxybenzoyl-amino) -L -alanine methyl ester (790 mg). B. N- [2-Chloro-4 - [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- (3,5-dihydroxybenzoi lamino) -L-alanine A solution of N - [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -6-methyl-benzyl] -3- (3,5-dihydroxybenzoylamino) -L-alanine methyl ester (790 mg, 0.87 mmol ) in tetrahydrofuran / methanol (1: 1, 8 ml) was added to a solution of lithium hydroxide monohydrate (183 mg, 4.4 mmol) in water (4 ml). The solution was stirred at room temperature overnight and then the solvents were evaporated. Water (15 ml) was added and the solution was acidified with 3 M HCl. The mixture was extracted with ethyl acetate (3 x 20 ml) and the combined extracts were washed with saline and evaporated. The residue was dissolved in methanol (14 ml) and purified in two portions by HPLC to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] - 3- (3, 5-dihydroxybenzoyl-amino) -L-alanine (65 mg, 14%). Example 342 Preparation of N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) -methyl] amino] carbonyl] benzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine A. N- [2,6-Dichloro-4 - [[[[3 - [[(1,1-dimethylethyl) -dimethylsilyl) oxy] phenyl] methyl] amino] carbonyl] benzoyl] -3- [(thiophene- 2-carbonyl] amino] -L-alanine, methyl ester Diisopropylethylamine (3.49 ml, 20.0 mmol) was added to a solution of 2,6-dichloro-4- [[[[3- [[1,1-dimethylethyl]) dimethylsilyl] oxy] phenyl] -methyl] amino] carbonyl] benzoic acid (Example 34, 1.82 g, 4.0 mmol), 3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester hydrochloride (Example 301; 1. 27 g, 4.8 mmol), HOBT (0.65 g, 4.8 mmol), and HBTU (1.82 g, 4.8 mmol) in N, N-dimethyl formamide (10 ml) The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated (< 0.5 mm Hg, 40 ° C), and ethyl acetate was added. The solution was washed with 1 M HCl, saturated sodium hydrogen carbonate and saline, dried (MgSO 4), filtered, evaporated and chromatographed ("50-100% ethyl acetate / hexanes then 5% methanol / acetate ethyl) to yield N- [2,6-dichloro-4- [[[[3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -phenyl] methyl] amino] carbonyl] benzoyl] -3- [ (thiophene-2-carbonyl) amino] -L-alanine methyl ester (1.09 g, 42%) as a white solid, and N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] ] amino] carbonyl] -benzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (510 mg, 23%) as a white solid B. N- [2, 6 Dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoi 11-3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester Tetra-n-butylammonium fluoride ( 1 M in tetrahydrofuran, 3.94 mL, 3.94 mmol) to a solution of N- [2,6-dichloro-4- [[[[3- [[1,1-dimethylethyl) dimethylsilyl] oxy] phenyl] methyl] amin. or] -carbonyl] benzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine (2.38 g, 3.6 mmol) in tetrahydrofuran (30 ml). The solution was stirred at room temperature for 3 h, then diluted with ethyl acetate and concentrated. The residue was chromatographed (50-100% ethyl acetate / hexanes then 10% methanol / ethyl acetate) to yield N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] -benzoyl] - 3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (1.68 g, 85%) as a white solid. C. N- [2,6-Dichloro-4- [[[(3-hydroxyphenyl) methyl] -amino] -carbonyl] benzoyl] -3- [(thiophene-2-carbonyl) -amino] -L-alanine Una mixture of N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (2.41 g, 4.4 mmol) in methanol (100 ml) and sodium hydroxide (0.35 g, 8.8 mmol) in water (2 ml) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate phase was discarded. The aqueous phase was acidified with 1 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with saline, and the product began to precipitate. The solvent was evaporated from the organic phase, and dichloromethane / hexanes was added to the residue. The solid was filtered, dried overnight under high vacuum, and recovered again in dichloromethane / hexanes. The solid was filtered, and then dried overnight under high vacuum to yield N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [ (thiophene-2-carbonyl) amino] -L-alanine (2.10 g, 89%) as a white solid. EXAMPLE 343 Preparation of N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) -methyl] amino] carbonyl] benzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine A. N- [2,6-Dichloro-4 - [[[[3- [(thiophene-3-carboni 1) oxy] -phenyl] methyl] amino] carbonyl] benzoyl] -3- [(thiophene-3- carboni 1) amino] -L-alanine methyl ester and N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(thiophene-3-carbonyl ) amino] -L-alanine methyl ester Diisopropylethylamine (0.274 ml, 1.57 mmol) was added to a solution of 3-amino-N- [2,6-dichloro-4- [[((3-hydroxyphenyl) methyl] hydrochloride] amino] -carbonyl] benzoyl] -L-alanine methyl ester (Example 75; 150 mg, 0.315 mmol), thiophene-3-carboxylic acid (85 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol), and HBTU (251 mg, 0.66 mmol) in N, N-dimeti-1 formamide (2 ml). The reaction mixture was allowed to stir at room temperature overnight. TLC indicated that the reaction had not been completed, so that two additional equivalents of thiophene-3-carboxylic acid, HOBT, and HBTU, and 2 equivalents of diisopropylethylamine were added and the reaction was allowed to stir overnight. The solvent was evaporated. Ethyl acetate was added and the solution was washed with 1 M HCl, saline, saturated aqueous sodium hydrogen carbonate, and saline. The solution was dried (MgSO 4), filtered, evaporated and chromatographed (40-60% ethyl acetate / petroleum ether) to yield N- [2,6-dichloro-4- [[[[3- [( thiophene-3-carbonyl) oxy] phenyl] methyl] amino] -carbonyl] benzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine methyl ester (101 mg, 49%) and N- [2 , 6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine methyl ester (58 mg, 33%). B. N- [2,6-Di-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine A solution Aqueous sodium hydroxide (1M, 0.305 ml, 0.305 mmol) was added to a solution of N- [2,6-dichloro-4- [[[[3- [(thiophene-3-carboni 1) oxy] -phenyl] ] methyl] amino] carbonyl] benzoyl] -3 - [(thiophene-3-carbonyl) amino] -L-alanine methyl ester (101 mg, 0.153 mmol) in methanol (2 ml). The solution was left stirring overnight and then concentrated. An aqueous solution of sodium hydroxide (1 M, 0.210 mL, 0.210 mmol) was added to a solution of N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- [(thiophene-3-carbonyl) amino] -L-alanine methyl ester (58 mg, 0.105 mmol) in methanol (2 ml). The solution was left stirring overnight and then concentrated. The residues produced by the two reactions were purified by HPLC and lyophilized to yield N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3- [(thiophene - 3-carbonyl) amino] -L-alanine (107 mg, 78%) as a white solid. Example 344 Preparation of N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) -methyl] amino] carbonyl] benzoyl] -3 - [(3, 5-difluorobenzoyl) amino] -L-alanine A. N- [2,6-Dichloro-4- [[[[3- [(3,5-difluorobenzoyl) oxy] -phenyl] methyl] amino] carbonyl] benzoyl] -3- [(3,5-difluorobenzoyl) ) amino] -L-alanine methyl ester and N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -3 - [(3,5-difluorobenzoyl) amino ] -L-alanine methyl ester Diisopropylethylamine (0.343 ml, 1.97 mmol) was added to a cooled solution (about 0.degree. C. of 3-amino-N- [2,6-dichloro-4- [[(3 -hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine methyl ester (Example 75, 188 mg, 0.394 mmol), 3,5-di-fluorobenzoic acid (137 mg, 0.87 mmol), HOBT (117 mg, 0.87 mmol ), HBTU (328 mg, 0.86 mmol) in N, N-dimethyl formamide (3.5 ml), the cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight.The solvent was evaporated. added ethyl acetate (100 ml) and the solution was washed with 1 M HCl, saturated aqueous sodium hydrogen carbonate, and solutions. alina (25 ml each). The solution was dried (MgSO 4), filtered, evaporated and chromatographed (40-60% ethyl acetate / petroleum ether) to yield N- [2,6-dichloro-4- [[[[3- [( 3, 5-difluorobenzoyl) oxy] phenyl] methyl] amino] carbonyl] ben-zoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-alanine methyl ester (54.8 mg, 19%) and N- [ 2,6-dichloro-4 - [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- [(3,5-di-fluorobenzoyl) amino] -L-alanine methyl ester (121 mg, 53 %).

B. N- [2,6-Dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-aianine An aqueous solution of sodium hydroxide (1 M; 0.386 ml, 0.386 mmol) was added to a solution of N- [2,6-dichloro-4- [[[(3-hydroxy phenyl] -methyl] amino] carbonyl] benzoyl] -3- [(3,5- difluoro-benzoyl) amino] -L-alanine methyl ester (112 mg, 0.193 mmol) in methanol (2 ml) The solution was allowed to stir overnight and then concentrated.The residue was purified by HPLC and lyophilized yield N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3 - [(3,5-difluorobenzoyl) amino] -L-alanine (43 mg, 39 %) in the form of a white solid Example 345 Preparation of N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) -methyl] amino] carbonyl] benzoyl] -3- (3, 5- dihydroxybenzoylamino) -L-alanine A. 3, 5-bis [(tetrahydro-2H-pyran-2-y1) oxy] -benzoic acid A mixture of methyl 3,5-dihydroxybenzoate (10.00 g, 59.5 mmol), 3,4-dihydro-2H -pirano (15.00 g, 178.3 mmol), and pyridinium p-toluenesulfonate (1.50 g, 6.0 mmol) in dichloromethane / tetrahydrofuran (1: 1, 60 mL) was stirred at room temperature overnight. The solution was washed with 0.5 M sodium hydroxide solution (200 ml) and the aqueous wash was back extracted with dichloromethane (200 ml). The combined organic phases were washed with saline (200 ml), dried (MgSO 4), filtered, and evaporated to yield 3,5-bis [(tetrahydro-2H-pyran-2-yl) oxy] benzoic acid methyl. crude ester (19.53 g) as a yellow oil. Tetrahydrofuran (100 ml) was added, followed by a solution of sodium hydroxide (3.00 g, 75 mmol) in water (100 ml). The mixture was stirred at room temperature overnight and the solvent was evaporated. Ethyl acetate was added (200 ml). The solution was washed with 0.5 M HCl (200 ml) and the aqueous wash was reextracted with ethyl acetate (100 ml). The combined organic phases were washed with saline (200 ml), dried (MgSO 4), filtered, and evaporated to yield 3, 5-bi s [(tetrahydro-2H-pyran-2-yl) oxy] benzoic acid. (15.62 g, 84%) in the form of a pale yellow solid. B. l - [[3,5-Bis [(tetrahydro-2 H -pyran-2-yl) oxy] -benzoyl] oxy] -2,5-pyrrolidinedione A mixture of 3,5-bis [(tetrahydro- 2H-pyran-2-yl) oxy] benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexyl-carbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydroturan (100 ml. ) was stirred at room temperature for 40 h. Ether (100 ml) was added and the mixture was stirred for 20 min. The white solid was filtered and discarded. The solvent was evaporated from the filtrate and the residue was coated on silica gel and chromatographed (50-75% ethyl acetate / hexanes) to yield l - [[3,5-bis [(tetrahydro-2H-pyran-2 -yl) oxy] benzoyl] oxy] -2,5-pyrrolidinedione (5.84 g, 90%) as a white solid. C. 3 - [[3,5-Bis [(tetrahydro-2 H -pyran-2-yl) oxy] -benzoyl] amino] -N- [2,6-dichloro-4- [[[(3-hydroxyphenyl)] -met-il] amino] carbonyl] benzoyl] -L-alanine methyl ester A solution of 1- [[3,5-bis [(tetrahydro-2 H -pyran-2-yl) oxy] benzoyl] oxy] -2,5 -pyrrolidinedione (2.10 g, 5.0 mmol), 3-amino-N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -L-alanine methyl ester hydrochloride (Example 75, 2.00 g, 4.2 mmol), and triethylamine (500 mg, 4.9 mmol) in N, N-dimethyl-formamide (20 ml) was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate (125 mmol) was added. The solution was washed with 0.2 M HCl (125 mL) and the aqueous wash was reextracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate and saline (30 ml each), evaporated, and chromatographed (50-100% ethyl acetate / hexanes) to yield 3- [[3, 5 bis [(Tetrahydro-2H-pyran-2-yl) oxy] benzoyl] amino] -N- [2,6-dichloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L -alanine methyl ester (1.61 g, 52%) in the form of a white foam. D. N- [2,6-Dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (3,5-dihydroxybenzoyl amino) -L-alanine methyl ester A solution of HCl in methanol was prepared by adding acetyl chloride (10 ml) to methanol at about 0 ° C. The solution was left stirring for 10 min and then it was added to 3- [[3,5-bis [(tetrahydro-2 H -pyran-2-yl) oxy] benzoyl] amino] -N- [2,6-dichloro- 4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine methyl ester (1.60 g, 2.1 mmol). The resulting solution was allowed to stir overnight at room temperature and then the volatiles were evaporated to yield N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] - 3- (3, 5-dihydroxy-benzoyl-amino) -L-alanine methyl ester (1.26 g, quantitative yield) in the form of an off-white solid. E. N- [2,6-Dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (3,5-dihydroxybenzoylamino) -L-alanine A solution of lithium hydroxide Monohydrate (160 mg, 3.8 mmol) in water (10 mL) was added to a solution of N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3,5-dihydroxybenzoylamino) -L-alanine methyl ester (490 mg, 0.85 mmol) in tetrahydrofuran / methanol (3: 1); 40 ml). The solution was stirred at room temperature overnight and then the solvent was evaporated. Tetrahydrofuran and water (75 ml each) were added followed by 1 M HCl (10 ml). The milky solution was heated to about 50 ° C for 10 min and then allowed to stand overnight at room temperature. The solvent was evaporated and the residue was dissolved in methanol / water (1: 4, 60 ml) and purified by HPLC in 10 ml portions. The homogeneous fractions were combined for the product and lyophilized to yield N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3,5-dihydroxybenzoyl) amino) -L-alanine (308.5 mg, 65%) as a white solid. Example 346 Preparation of N- [2,6-dichloro-4- [[[(IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -3- [(thiophene-2-carbonyl) amino] -L-alanine A. N- [2,6-Dichloro-4 - [[[(1 R) -l- (1-naphthalenyl) ethyl] -amino] carbonyl] benzoyl] -3 - [(thiophene-2-carbonyl) -amino] -L-alanine methyl ester A solution of 2,6-dichloro-4- [[[(IR) -1 - (1-naphthalenyl) -ethyl] amino] carbonyl] benzoic acid (Example 38, 1.00 g, 2.6 mmol) , 3- (thiophene-2-carbonyl) amino-L-alanine methyl ester hydrochloride (Example 301; 680 mg, 2.6 mmol), HBTU (1.27 g, 3.35 mmol), HOBT (450 mg, 3.3 mmol), and diisopropylethylamine (1.33 g, 10.3 mmol) in N, N-dimet and formamide (2.0 ml) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (200 ml) was added. The solution was washed with 1 M HCl (100 ml), saturated aqueous sodium hydrogen carbonate (Note: some material was lost due to effervescence at this stage) and saline (200 ml each), then dried (MgSO4). ), filtered, evaporated and chromatographed (70% ethyl acetate / hexanes) to yield N- [2,6-dichloro- - [[1 (IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl ] benzoyl] - -3- [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (260 mg, 17%) as a white solid. B. N- [2,6-Dichloro-4 - [[[(1 R) -l- (1-naphthalenyl) ethyl] -amino] carbonyl) benzoyl) -3 - [(thiophene-2-carbonyl) -amino] -L-alanine A solution of lithium hydroxide monohydrate (100 mg, 2.38 mmol) in water (5 ml) was added to a solution of N- [2,6-dichloro-4- [[[(IR) -1 - (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -3 - [(thiophene-2-carbonyl) amino] -L-alanine methyl ester (260 mg, 0.434 mmol) in tetrahydrofuran (15 ml) and methanol (5 ml). ml), and the resulting mixture was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between ethyl acetate (40 ml) and 1 M HCl (10 ml). The organic phase was evaporated and the residue was dissolved in methane-1 (~1 ml), purified by HPLC, and lyophilized to yield N- [2,6-dichloro-4- [[(IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -3 - [(thiophene-2-carbonyl) amino] -L-alanine (170 mg, 67%). The following compounds were also prepared by this route: Example 348 Preparation of 3- [(3-chlorobenzoyl) amino] -N- [2,6-dichloro-4 - [[[(3-hydroxy-phenylmethyl] amino] carbonyl] -benzoyl] -L-alanine Diisopropylethylamine (220 mg, 1.7 mmol) was added to a cooled solution (approximately 0 ° C) of 3-amino-N- [2,6-dichloro-4- [[((3-hydroxyphenyl) methyl] amino] hydrochloride] carbonyl] benzoyl] -L-alanine, methyl ester (Example 75; 135 mg, 0.28 mmol), 3-chlorobenzoic acid (53 mg, 0.34 mmol), HBTU (136 mg, 0.36 mmol), and HOBT (49 mg, 0.36 mmol) in N, N-dimethylformamide (2 ml). The solution was left stirring at room temperature for 4 days, and then the solvent was evaporated. Ethyl acetate (50 ml) was added, and the solution was washed with 1 M HCl, saturated aqueous sodium hydrogen carbonate, and saline (10 ml each), and evaporated. Tetrahydrofuran / methanol (3: 1; 4 ml), followed by 10% aqueous lithium hydroxide monohydrate (1 ml, 2.38 mmol). The solution was stirred at room temperature overnight, then the solvent was evaporated and the residue was partitioned between ethyl acetate (30 ml) and 1 M HCl. (10 ml). The ethyl acetate layer was evaporated and the residue was dissolved in methanol (~1 ml), purified by HPLC, and lyophilized to yield 3 - [(3-chlorobenzoyl) amino] -N- [2,6-dichloro] -4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine (81.1 mg, 51%) as a white solid. The following compounds were prepared by this route, by reacting 3-amino-N- [2,6-dichloro-4 - [[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -L-alanine hydrochloride. methyl ester (Example 75) with the indicated carboxylic acids: fifteen twenty Example 359 Preparation of 3- (phenylmethyl) amino-N- [2-chloro-4- [[(lH-indol-4-ylmethyl) amino] carbonyl] benzoyl] -L-alanine It was added to Wang resin substituted with 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine- (Example 66; 1.00 g) a solution of benzaldehyde (1.16 g, 10.9 mmol) and benzotriazole (0.20 g, 1.7 mmol) in tetrahydrofuran / trimethyl ortofarmata (1: 1, 10 ml). The mixture was stirred at room temperature for 18 h and then washed twice briefly with dichloromethane. 100 mg of this resin was treated with a solution of sodium cyanoborohydride (80 mg, 1.3 mmol) in acetic acid / N, N-dimethylacetamide (9: 1, I ml), and the mixture was stirred at room temperature for 5 h. The resin was filtered and washed extensively with dichloromethane and methanol. The cleavage of the product was carried out with trifluoroacetic acid / dichloromethane (1: 1, 1 ml) at room temperature for 30 min. The solvent was evaporated and the residue was purified by HPLC to yield 3- (phenylmethyl) amino-N- [2-chloro-4- [[(lH-indol-4-ylmethyl) -amino] carbonyl] benzoyl] - L-alanine (15 mg). EXAMPLE 360 Preparation of 3- (phenylsulfonylamino) -N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -L-alanine Wang resin substituted with 3-Amino-N- [2-chloro-4- [[[(3-hydrphenyl) methyl] amino] -carbonyl] benzoyl] -L-alanine was stirred (Example 66, 100 mg, 1.1 mmol / g) in pyridine (1 ml), and benzenesulfonyl chloride (0.12 g, 0.67 mmol) was added. The mixture was stirred at room temperature for 1 h. The resin was then filtered and washed extensively with dichloromethane and methanol. Cleavage of the product was carried out with 50% trifluoroacetic acid in dichloromethane for 30 min. The cleavage solution was recovered by filtration and the solvent was evaporated under high vacuum. The compound was purified by reverse phase HPLC to yield 3- (phenylsulfonylamino) -N- [2-chloro-4- [[[(3-hydrhenyl) -methyl] amino] carbonyl] benzoyl] -L-alanine. Example 361 Preparation of 3- (1-butanesulfonylamino) -N- [2-chloro-4 - [[[(IR) -1- (1-naphthalenyl) ethyl] amino] carbonyl] -benzoyl] -L-alanine Wang resin substituted with 3-amino-N- [2-chloro-4- [[[(1 R) -l- (1-naphthalenyl) ethyl] amino] carbonyl] benzoyl] -L-alanine (Example 70, 100 mg, 1.1 mmol / g) was stirred in pyridine (1 ml), and 1-butanesulfonyl chloride (0.10 g, 0.66 mmol) was added. The mixture was stirred at room temperature for 1 h. The resin was then filtered and washed extensively with dichloromethane and methanol. Cleavage of the product was carried out with 50% trifluoroacetic acid in dichloromethane for 30 min. The cleavage solution was collected by filtration and the solvent was evaporated under high vacuum. Purification by reverse phase HPLC yielded 3- (1-butanesulfonylamino) -N- [2-chloro-4 - [[[(1 R) -l- (1-naphthalenyl) ethyl] amino] -carbonyl] benzoyl] -L -to the girl. The following compound was also prepared by the same route: Example 363 Preparation of N- [4- (aminomethyl) -2-chlorobenzoyl] -3- (benzoyl) amino-L-alanine methyl ester A. 2-Chloro-4- (hydrethyl) benzoic acid, methyl ester. Boron-methyl sulfide complex (10 M: 10 mL, 100 mmol) was added to a solution of 2-chloro-1,4-benzenedicarbic acid, 1-methyl ester (Example 1, 11.98 g, 55.8 mmol) in tetrahydrofuran (100 ml). The solution was refluxed for 2 h and then allowed to stand at room temperature overnight. It was poured into water and ethyl acetate (200 ml each). The phases were separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with saline (200 ml), dried (MgSO 4), filtered, and evaporated to yield 2-chloro-4- (hydrethyl) benzoic acid methyl ester (11.09 g, 99%) as of a colorless oil. B. 4- (Azidomethyl) -2-chlorobenzoic acid methyl ester A solution of 2-chloro-4- (hydrethyl) benzoic acid, methyl ester (11.09 g, 55. 3 mmol), diphenylphosphoryl azide (22.58 g, 82.0 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (8.57 g, 56.3 mmol) in tetrahydrofuran was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. The residue was chromatographed (10% ethyl acetate / hexanes) to yield 4- (azidomethyl) -2-chlorobenzoic acid methyl ester (12.17 g, 98%) as a white solid. C. 4- (Azidomethyl) -2-chlorobenzoic acid A solution of lithium hydroxide monohydrate (7.00 g, 166.9 mmol) in water (100 ml) was added to a solution of 4- (azidomethyl) -2-chlorobenzoic acid methyl ester (12.17 g, 53.9 mmol) in tetrahydrofuran (100 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated to remove a little tetrahydrofuran. The solution was extracted with ethyl acetate (200 ml) and the extract discarded. 1 M HCl (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic phases were dried (MgSO 4), filtered, and evaporated to yield 4- (azidomethyl) -2-chlorobenzoic acid (6.82 g, 60%) as a white solid, e.g. F. 87-88 ° C. D. 1- [[4- (Azidomethyl) -2-chlorobenzoyl] -2,5-pyrrolidinedione A solution of 4- (azidomethyl) -2-chlorobenzoic acid (6.82 g, 32.2 mmol), N-hydruccinimide (5.19) g, 45.1 mmol) and dicyclohexylcarbodiimide (9.31 g, 45.1 mmol) in tetrahydrofuran (250 mL) was stirred overnight at room temperature. Dicyclohexylurea (7.70 g, 76%) was filtered and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (40-60% ethyl acetate / hexanes) to yield 1- [[4- (azidomethyl) -2-chlorobenzoyl] -oxy] -2,5-pyrrolidinedione (9.64) g, 97%) in the form of a white solid. E. N- [4- (Azidomethyl) -2-chlorobenzoyl] -3- (benzoyl) -amino-L-alanine methyl ester A solution of 1- [[4- (azidomethyl) -2-chlorobenzoyl] oxy] -2,5 -pyrrolidinedione (4.64 g, 15.0 mmol), 3- (benzoyl) amino-L-alanine methyl ester hydrochloride (4.00 g, 15.5 mmol), and triethylamine (4.00 g, 39.5 mmol) in N, N-dimethylformamide (50 ml) ) was stirred at room temperature for 3 h. The solvent was evaporated, and 1 M HCl (100 ml) was added. The mixture was extracted with ethyl acetate (2 x 100 ml), washed with saline (100 ml), dried (MgSO 4), filtered, evaporated, and chromatographed (50-75% ethyl acetate / hexanes ) to yield N- [4- (azidomethyl) -2-chlorobenzoyl] -3- (benzoyl) amino-L-alanine methyl ester (4.34 g, 69%) as a colorless oil which solidified on standing, mp 112-114 ° C. F. N- [4- (Aminomethyl) -2-chlorobenzoyl] -3- (benzoyl) -amino-L-alanine methyl ester A mixture of N- [4- (azidomethyl) -2-chlorobenzoyl] -3- (benzoyl) -amino) -L-alanine methyl ester (4.34 g, 10.4 mmol) and 10% palladium on carbon (0.20 g, 0.2 mmol) in ethanol (200 ml) was hydrogenated at atmospheric pressure for 1 hour. The mixture was filtered through Celite and the filter cake was washed with ethanol (100 ml). The combined filtrates were evaporated to yield N- [4- (aminomethyl) -2-chlorobenzoyl] -3-benzoylamino-L-alanine methyl ester (3.65 g, 90%) as a colorless foam.

Example 364 Preparation of N- [2-chloro-4- [[(3-hydroxyphenyl) carbonyl] amino-methyl] benzoyl] -3-benzoyl amino-L-alanine A mixture of N- [4- (aminomethyl) -2-chlorobenzoyl] -3-benzoyl-amino-L-alanine (Example 363, 100 mg, 0.26 mmol), 3-hydroxybenzoic acid (40 mg, 0.29 mmol) and dicyclohexylcarbodiimide (60 mg, 0.29 mmol) in tetrahydrofuran / DMF (4: 1, 2.5 ml) was stirred at room temperature overnight. Methanol (1 ml) and a solution of lithium hydroxide monohydrate (100 mg, 2.4 mmol) in water (1 ml) were added and the solution was stirred at room temperature overnight. The solution was acidified with 1 M HCl and extracted with ethyl acetate. The ethyl acetate was evaporated and the residue was purified by HPLC to yield N- [2-chloro-4- [[(3-hydroxy phenyl) carbonyl] aminomethyl] benzoyl] -3-benzoylamino-L-alanine (12.2 mg, 9%) in the form of a white solid.

EXAMPLE 371 Preparation of N- [2-chloro-4- [[[(3-hydroxy-enyl) -methyl] -amino] -carbonyl] -benzoyl] -3- (amino imi nome t il) -amino-L-alanine To a solution of 3-amino-N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] -benzoyl] -L-alanine methyl ester (Example 72, 50 mg, 0.123 mmol) in methanol (2 ml) were added triethylamine (3 drops) and aminoiminomethane sulphonic acid (prepared according to Kim, K. et al, Tetrahedron Lett, 1988, 29, 3183-3186, 37 mg, 0.30 mmol). The reaction was stirred at room temperature overnight, and then the solvent was evaporated. The residue was resuspended in tetrahydrofuran / methanol / water (3: 1: 1, 2 ml) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was purified by HPLC of reverse phase to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] -carbonyl] benzoyl] -3- (aminoiminomethyl) amino-L-alanine (17 mg, 33%) in shape of a white powder. Example 372 Preparation of N- (4-bromo-2-chlorobenzoyl) -3- (thiophene-2-carbonyl) amino-L-alanine in Wang resin Wang resin substituted with 3-amino-N- (4-bromo-2-chlorobenzoyl) -L-alanine (Example 71, 15 g) was stirred in a solution prepared from HOAT (11.22 g, 82.4 mmol), DICI (12.9 mL, 82.4 mmol) and thiotene-2-carboxylic acid (10.6 g, 82.7 mmol) in N-methylpyrrolidinone and the mixture was stirred for 2 h. The resin was then filtered and washed extensively with N-methylpyrrolidinone, dichloromethane and methanol to yield N- (4-bromo-2-chlorobenzoyl) -3- (thiophene-2-carbonyl) amino-L-alanine in Wang resin. Example 373 Preparation of N- [2-chloro-4- (3-phenyl-1-propenyl) -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine A mixture of N- (4-bromo-2-chlorobenzoyl) -3- (thiophene-2-carbonyl) amino-L-alanine in Wang resin (Example 372, 100 mg), allylbenzene (73 μL, 0.55 mmol), palladium (II) acetate (12 mg, 0.05 mmol), triphenylphosphine (58 mg, 0.22 mmol) and tetra-n-butylammonium chloride (61 mg, 0.22 mmol) in N, N-dimethylacetamide was stirred overnight. The resin was then filtered and washed extensively with dichloromethane and methanol. The product was cleaved from the resin using 50% trifluoroacetic acid in dichloromethane. The cleavage solution was collected by filtration and the solvent was evaporated under high vacuum. The residue was purified by reverse phase HPLC to yield N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] -amino] - carbonyl] -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine.

Example 374 Preparation of 1- [[2-chloro-4- (tributylstannyl) benzoyl] oxy] -2,5-pyrrolidinedione A.1- [(4-Bromo-2-chlorobenzoyl) oxy] -2,5-pyrrolidinedione A solution of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.5 mmol), N-hydroxysuccinimide (1.07 g, 9.3 mmol) and EDCI (1.79 g, 9.3 mmol) in tetrahydrofuran / N, N-dimethylformamide (3: 1, 40 ml) was stirred at room temperature for 18 h. The reaction was concentrated and water (50 ml) was added. The mixture was extracted with ethyl acetate (3 x 50 ml) and the combined organic phases were washed with saline, dried (Na 2 SO 4), concentrated, and dried in vacuo to give 1- [(4-bromo-2 -chlorobenzoyl) oxy] -2,5-pyrrolidinedione (2.59 g, 92%) as an off-white solid which was used directly in the next step without further purification.

B l - [[2-Chloro-4- (tributylstannyl) benzoyloxy] -2,5-pyrrolidinedione hexabutyldistannan (3.9 ml, 7.7 mmol) and tetrakis (triphenylphosphine) palladium (0) (103 mg, 0.09 mmol) were added to a solution of l - [(4-bromo-2-chlorobenzoyl) oxy] -2,5-pyrrolidinedione (1.78 g, 5.4 mmol) in toluene (50 ml), and the solution was stirred at reflux for 6 h. The solvent was removed under reduced pressure and the oily residue was loaded onto a short pad of Si02, washed with hexane, and then eluted with 30% ethyl acetate in hexanes. The solvent was evaporated and the residue was chromatographed (30% ethyl acetate in hexanes) to yield 1- [[2-chloro-4- (tributylstannyl) benzoyl] -oxy] -2,5-pyrrolidinedione (1.74 g, 60%) in the form of a colorless oil. Example 375 Preparation of N- [2-chloro-4- (tri-n-butylstannyl) -benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine in Wang resin.

A. 3-Amino-N- [(9H-Fluoren-9-ylmethoxy) carbonyl] -L-alanine in Wang resin A mixture of N- [(9H-fluoren-9-ylmethoxy) -carbonyl] -3 resin - [(2-propenyloxy) carbonyl] -amino-L-alanine Example 64; 2 g), tetrakis (triphenylphosphine) palladium (0) (509 mg, 0.45 mmol), and phenylsilane (21.9 mmol) in dichloromethane (20 ml) was stirred for 35 min. The resin was washed with dichloromethane and methanol, then stirred with dimethylformamide / water (1: 1) at room temperature for 10 min and washed again with dichloromethane and methanol to yield 3-amino-N- [(9H-fluoren- 9-ylmethoxy) -carbonyl] -L-alanine in Wang resin. B. 3- (Thiophene-2-carbonyl) amino-L-alanine in Wang resin A mixture of 3-amino-N- [(9H-fluoren-9 -ylmethoxy) carbonyl] -L-alanine in Wang resin (2 g), thiophene-2-carboxylic acid (1.41 g, 11.0 mmol), HOAT (1.50 g, 11.0 mmol) and diisopropylcarbodiimide (1.68 ml, 10.7 mmol) in N -methyl-pyrrolidinone (20 ml) was stirred for 3 h and then washed with dichloromethane and methanol to yield N - [(9H-fluoren-9-ylmethoxy) carbonyl] -3- (thiophene-2-carboni 1) -amino- L-alanine in Wang resin. The FMOC group was cleaved by treatment with 25% piperidine in N-methylpyrrolidinone, followed by stirring for 1 h. The resin was washed with dichloromethane and methanol to yield 3- (thiophene-2-carbonyl) amino-L-alanine in Wang resin. The resin was washed with dichloromethane and methanol to yield 3- (thiophene-2-carbonyl) amino-L -alanine in Wang resin. C. N- [2-Chloro-4- (tri-n-butylstannyl) benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine in Wang resin A mixture of 3- ( thiophene-2-carbonyl) amino-L-alanine in Wang resin (2.00 g) and l - [[2-chloro-4- (tributylstannyl) benzoyl] oxy] -2,5-pyrrolidinedione (Example 374); -2.50 g, 4.6 mmol) in N, N-dimethylformamide was stirred for 72 h. The resin was washed with dichloromethane and methanol to yield N- [2-chloro-4- (tri-n-butylstannyl) benzoyl] -3- (thiophene-2-carbon-1) -amino-L-alanine in Wang resin. Example 376 Preparation of N- [2-chloro-4- (phenoxyacetyl) benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine A mixture of N- [2-chloro-4- (tri-n-butyl-stannyl) benzoyl] -3- (thiophene-2-carboni 1) amino-L-alanine in Wang resin (Example 375, 100 mg), acetyl phenoxychloride (100 pL, 0.72 mmol), tris (dibenzylideneacetone) dipalladium (0) (18 mg, 0.02 mmol), potassium carbonate (50 mg, 0.36 mmol) and diisopropylethylamine (100 pL, 0.57 mmol) in tetrahydrofuran (2 ml) was stirred for 2 h, then washed with water, dichloromethane and methanol. The cleavage was carried out by treatment with trifluoroacetic acid / dichloromethane (1: 1, 4 ml) and stirring for one hour. The cleavage solution was collected by filtration and the solvent was evaporated. The residue was purified by reverse phase HPLC to yield N- [2-chloro-4- (phenoxyacetyl) benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine. The following products were also prepared by this process: The carboxylic acid was racemic and the diastereoisomeric products were not separated Example 379 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine, 2- (dimethylamino) ethyl ester A mixture of N- [2-chloro-4- [[[(3-hydroxy phenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (Example 303; 1 mmol ), potassium carbonate (2.1 mmol), potassium iodide (0.2 mmol), and (2-chloroethyl) -dimethylamine hydrochloride (1.1 mmol) in N, N-dimethylformamide (10 mL) was heated to 60 ° C. for 3 h. The reaction mixture was concentrated to remove the N, N-dimethylformamide. Water (50 ml) was added and the pH adjusted to 9. The mixture was extracted with ethyl acetate (3 x 50 ml). The combined layers of ethyl acetate were washed with saline (100 ml), dried (MgSO 4), filtered, evaporated and chromatographed to yield N- [2-chloro-4- [[[(3-hydroxyphenyl)] -methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine, 2- (dimethylamino) ethyl ester.

Example 380 Preparation of N- [2-chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carboni1) -amino-L-alanine, [(ethoxycarbonyl ) oxy] -methyl ester A mixture of N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (thiophene-2-carbonyl) amino-L-alanine (Example 303; 1 mmol) , potassium carbonate (1.1 mmol), potassium iodide (0.2 mmol), and chloromethyl ethyl carbonate (which was prepared according to Boehme, H. et al., Synthesis 1971, 588-590, 1.1 mmol) in N, N dimethylformamide (10 ml) was heated at 60 ° C for 3 h. The reaction mixture was concentrated to remove N, N-dimethylformamide. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined layers of ethyl acetate were washed with saline (100 ml), dried (MgSO 4), filtered, evaporated and chromatographed to yield N- [2-chloro-4 - [[[(3-hydroxy phenyl)] ) methyl] amino] -carbonyl] benzoyl] -3- (thiophene-2-carboni1) amino-L-alanine, [(ethoxycarbonyl) oxy] -methyl ester Example 381 Protein-protein assay with LFA-1 / ICAM-1 LFA-1 / ICAM-1 antagonist activity, defined as the ability to block the binding of LFA-1 to immobilized ICAM-1 was quantified using solid-phase ELISA. Typically, the fusion protein consisted of the complete extracellular domain of human ICAM-1 and the human Fc domain of IgG (5dICAM-Ig), and was coated onto 96-well microtiter plates (0.15 μg in 100 μl of PBS). ) overnight at 4 ° C. The plates were then blocked with 150 μl of 1% BSA / 1 mM MnCl 2 / 0.14 M NaCl / 20 mM HEPES, pH 7.2 for 1 h at 37 ° C, and washed 3 times (150 μl each time) with Wash Buffer ( 50 mM Tris-HCl pH 7.4 / 100 mM NaCl / 1 mM MnCl2 / 0.05% Tween 20). The stock solutions of the test compounds (100 μl in 100% DMSO) were diluted 50 times with 150 μl of Binding Buffer (0.05% BSA / 0.05% Tween 20/1 mM MnCl 2 / 0.14 M NaCl / 20 mM HEPES, pH 7.2) plus 10% DMSO. Series of 1: 4 dilutions were made to achieve a concentration range of 0.12 nM to 2 μM. 50 μl per well of each dilution was added to the ICAM-1 coated plates, followed by 50 μl per well of membrane-bound LFA-1 (280 ng / ml in Binding Buffer) derived from transfected 293 cells. The plates were shaken vigorously for 1 minute (room temperature) and gently for 2 hours (37 ° C). After incubation, the plates were washed three times (150 μl each) in wash buffer. Human monoclonal antibody against human a2 integrin (100 μl / well, 1 μg / ml in Binding Buffer) was added and allowed to incubate for 1 h (37 ° C) with gentle agitation. The plates were then washed three times with Wash Buffer. Goat IgG anti-mouse IgG conjugated with HRP (100 μL / well, dilution 1: 1500 in Binding Buffer) was added, followed by incubation for 1 h (37 ° C) and finally three washes (150 μL each) with Wash Buffer. The TMB solution (100 μl per well) was added for color development (10 min). The reaction was stopped by the addition of 100 μl of 1 M H3P04 to each well. The plates were then read at 450 nm. The inhibitory activities of the test compounds were determined by the CI5o and are presented in Table 4.

Example 382 Mixed Lymphocyte Reaction (MLR) The mixture of mouse spleen cells from two inbred strains of mice induces the proliferation of T lymphocytes. The magnitude of T cell proliferation depends on the level of disparity in the antigens. greater histocompatibility between the two strains. The spleen T lymphocytes of both strains proliferate thanks to the recognition of alloantigens, a process for which the interaction of ICAM-1 in antigen-presenting cells with LFA-1 on lymphocytes is necessary. The ability of antagonists to inhibit T lymphocyte proliferation after recognition of alloantigens was assessed by a one-way MLR, in which the cells of one strain were irradiated to allow measurement of the cell proliferative response of the other strain Spleen cells were washed three times in tissue culture medium (TCM, see below). 50 μl of spleen cell suspension (prepared at a concentration of 10 x 10 6 cells / ml TCM) obtained from C57B1 / 6 mice was added to an equal amount of lethal irradiated spleen cells (2000 rads) obtained from BALB / mice. c in a U-shaped tissue culture plate (Costar, 3799). 100 μl of serial dilutions of antagonists or TCM were added to the spleen cell mixture. The total volume in each well was 200 μl. TCM consisted of RPMI1640 containing 10% heat-inactivated fetal bovine serum, 200 mM L-glutamine, 100 units / ml of penicillin and streptomycin and 5 x 10"5 M of 2-mercaptoethanol.Antibody dilutions were prepared in TCM. The plates were incubated in C02 5% for 3 days.On the third day, 0.5 μCi of tritiated thymidine (10 μCi / ml) was added to all the wells, the cells recovered 6 h later and the amount of incorporated tritiated thymidine was added. evaluated in a liquid scintillation counter The IC50's were calculated, which are presented in Table 4. The IC50's for anti-LFA-1 (M17) and anti-CD18 (HB226) antibodies are 0.138 nM and 3.35 nM respectively. The anti-Mac-1 antibody (Ml / 70) was not found to inhibit the mixed lymphocyte reaction.

EXAMPLE 383 Mac-1 / ICAM-1 Screening Assay The Mac-1 / ICAM-1 antagonist activity, defined as the ability to compete with the binding of ICAM-1 to immobilized Mac-1 was quantified in a solid-phase ELISA. Mac-1 bound to membranes derived from transfected 293 cells was coated onto 96-well microtiter plates (50 μl / well, 3 μg / ml Mac-1 1 mM MnCl 2 / 0.14 M NaCl / 20 mM HEPES, pH 7.2) throughout the night at 4 ° C. Plates were blocked with 0.5% BSA / 1 mM MnCl 2 / 0.14 M NaCl / 20 mM HEPES, pH 7.2 at 37 ° C for 1 h and washed three times (120 μl each) with Binding Buffer (1 mM MnCl 2 / NaCl 0.14.M / 20 mM HEPES, 0.05% Tween 20 pH 7.2). The test compounds were dissolved in 100 μl of DMSO and diluted 1:50 in Binding Buffer plus 10% DMSO. A series of 1: 4 dilutions was made for each compound (concentration range, 0.12 nM to 20 μM). Each dilution (25 μl / well) was added to the plates, followed by 25 μl / well of 5dICAM-Ig (40 mg / ml in Binding Buffer). The plates were shaken vigorously for 1 minute (room temperature), followed by gentle shaking for 2 h at 37 ° C, and then washed with Binding Buffer (3 times, 120 μL each). Goat anti-human IgG antibody conjugated with HRP (specific for Fc) (0.125 μg / ml in Binding Buffer plus BSA 0.05%, 50 μl / well) was added, followed by incubation for 1 h (37 C) and then three washes (150 μl each) with Wash Buffer. The TMB solution (100 μl per well) was added for color development (10 min). The reaction was stopped by the addition of 100 μl of 1 M H3P04 to each well. The plates were then read at 450 nm. The inhibitory activities of the test compounds are determined by the IC50 and are presented in Table 4. Example 384 Mac-1 / Fibrinogen cell-based screen assay Mac-1 / Fibrinogen cell antagonist activity, defined as the capacity of inhibiting the adhesion of Mac-1 on cell surface to immobilized fibrinogen was quantified by a cell-based assay. Human fibrinogen was coated on 96-well microtiter plates (1 μg in 100 μl of TBS) overnight at 4 ° C.

The plates were blocked with 150 μl of 10% polyvinylpyrrolidone (PVP) in TBS for 1 h at 37 ° C. The plates were washed three times (150 μl each) with TBS. HL-60 cells (8 x 106 / ml) differentiated for 62-72 h with DMSO 1.5% were fluorescently labeled with 6-carboxy-fluorescein (a stock solution of 5 mg / ml in acetone was added to the cells for a final concentration of 100 μg / ml) for 40 min in IMDM / 1 Mm MgCl2 / 1.2 mM CaCl2. Ten times more excess of the same buffer was added and the cells were centrifuged. The medium was decanted and the cells were resuspended at a concentration of 2 x 106 cells / ml in RPMI / 0.05% BSA / 0.2 mM MnCl2. The stock solutions of the test compounds (10 mM in DMSO) were diluted to 2.5 mM with DMSO. A series of 1: 4 dilutions in DM50 was performed to achieve a final concentration range of 38.2 nM - 2.5 nM. Each sample was then diluted 50 times with RPMI / 0.05% BSA / 0.2 mM MnCl2. Equal volumes of labeled cells were added to the test tubes containing the diluted compounds. The final concentration of the compounds tested ranged from 0.38 nM to 25 μM with cell concentrations of 1 x 106 per ml. Cells were incubated for 10 min at 37 ° C with gentle shaking, and then dispensed (100 μl per well) onto fibrinogen coated plates and incubated for 30 min at 37 ° C / 5% C02. Unbound cells were gently washed with TBS twice. The plates were read on a Cytofluor ™ (Millipore) at an excitation wavelength of 485 nm and an emission wavelength of .530 nm. The inhibitory activities of the test compounds were determined by the IC50 and are presented in Table 4. Example 385 Neutrophil cell-based screening assay (Mac-1 and LFA-1) / ICAM-1 Both Mac-1 and LFA-1 are expressed on the surface of neutrophils. The ability of the antagonists to inhibit neutrophil binding mediated by Mac-1 and LFA-1 to immobilized ICAM-1 was quantified in a cell-based assay. Typically, the fusion protein consisted of the complete extracellular domain of human ICAM-1 and the Fc domain of human IgG (5dICAM-Ig). The fusion protein was coated on 9-well microtiter plates (1 μg in 100 μl TBS) overnight at 4 ° C. The plates were then blocked with 150 μl of 10% PVP in TBS for 1 h at 37 ° C. The plates were washed three times (150 μl each) with TBS. Human neutrophils were purified from whole blood of healthy volunteers using LSM (ICN). Cells (8 x 10 6 / ml) were fluorescently labeled with 6-carboxyfluorescein (100 μg / ml) for 40 min in IMDM / 1 mM MgCl 2 / 1.2 mM CaCl 2, as described in Example 287. Cells (8 x 10 6 / ml) were stimulated with f-Met-Leu-Phe (10 μg / ml). μM) for 5 min at room temperature just before use in the assay, and diluted to 2 x 106 cells / ml with RPMI / 0.05% BSA / 0.2 mM MnCl2. The preservation solutions (10 mM) of the test compounds were diluted to 2.5 mM with DMSO. A series of 1: 4 dilutions in DMSO was performed to achieve a concentration range of 38.2 nM - 2.5 mM. Each sample was subsequently diluted 50 times with RPMI / 0.05% BSA / 0.2 mM MnCl2. Equal volumes of labeled cells were then added to the test tubes containing the diluted compound. The final concentrations of the compound tested were in the range of 0.38 nM to 25 μM, with a final cell concentration of 1 x 106 per ml. Cells were incubated for 10 min at 37 ° C with gentle shaking, and then dispensed (100 μl per well) onto plates coated with ICAM-1 and incubated for 30 min at 37 ° C / 5% C02. The unbound cells were washed and the plates were read in a Cytbfluortm 2300 (Millipore) as described in Example 384. The inhibitory activities of the compounds tested were determined by the IC50 and are presented in Table 4. Table 4: Results of assays based on protein-protein interaction cells Example 386 Delayed hypersensitivity in mice Sensitization: On day 0, adult female C57B1 / 6 mice (20-25g) each received 50 μl of a 1: 1 mixture of 10 mg / ml of methylated bovine serum albumin (mBSA) in solution phosphate buffered saline (PBS) and complete Freund's adjuvant (CFA) intradermally at two points in the shaved abdomen (total volume = 100 μl per mouse). The control mice received an equal volume of a PBS / CFA mixture (non-sensitized). Challenge: On day 7 the mice received 200 μl of 5 mg / ml mBSA in PBS injected into the right hind paw. The contralateral left claw of each mouse was injected with an identical volume of PBS. After 24 hours the inflammation of both rear claws of all mice was measured with micropinzas. To determine the inflammation response of the claws, the measurement of the left claw of the right claw was subtracted for each particular mouse. At the time of the challenge, Alzet osmotic minipumps were implanted in the back of the mice, which administered subcutaneously a constant volume per hour of the inhibitors (for example Example 226). The pumps administered a volume of 200 μl for a period of 1 day. Different doses of the compounds were tested with 850, 250 and 85 mg / kg / day. The inhibitors were formulated in distilled water. Control mice received pumps containing distilled water. For the antibody treatment groups the mice received 200 μg of anti-mouse LFA-1 (M17), Mac-1 antirathon (Ml / 70) or rat control IgG intraperitoneally on the day of challenge. The results show that Mac-l / LFA-1 inhibitors inhibit the paw inflammation response in a dose-dependent manner in this model of DTH. The measurement of serum circulating drug concentrations shows that the inhibitor is effective at 9 μM and at 3 μM (850 mg / kg / day and 250 mg / kg / day, respectively). In parallel studies, it was also found that anti-LFA-1 and anti-Mac-1 antibodies were effective in inhibiting the response. In table 10 the inflammation response in animals treated with antibodies is compared with the inflammation response in animals treated with IgG. The inflammation response in animals treated with compound is compared to the inflammation response in mice that have received pumps containing distilled water.

Table 5: Percentage of inhibition of claw inflammation in response to challenge with methylated bovine serum albumin Example 387 Croton oil induced dermatitis Adult female Balb / c mice (20 25 g) received 10 μl of croton oil in 80% acetone: 20% olive oil vehicle on each side of the right ear (20 μl) total per mouse). All mice received a similar volume of the acetone / olive oil vehicle in the contralateral left ear. The negative control mice received vehicle in both ears. Six hours later the inflammation of both ears was measured with micropinzas. The inflammation response of the ear was determined by subtracting the measurements of inflammation of the left ear from those of the right ear for each individual mouse. Inhibitors were administered to the mice by Alzet osmotic minipumps. Pumps containing different concentrations of the inhibitors were implanted in the back of anesthetized mice 2 days before the croton oil application. Additional mice received an equal volume of distilled water in pumps. For mice that received antibodies, anti-CD18 antibody (HB226) or rat Igc control i.p. at 200 μg per mouse 18 hours before oil application. The results demonstrate that Mac-1 / LFA-1 antagonists inhibit the inflammation response of the ear in a dose-dependent manner in this acute inflammation model. Measurements of circulating blood drug concentrations show that the inhibitors are effective at 4 μM and at 2 μM (250 mg / kg / day and 64 mg / kg / day, respectively). In parallel studies it was also found that the anti-CD18 antibody was also effective in inhibiting the inflammation response of the ear. In Table 11 the inflammation response in animals treated with antibody is compared to the inflammation response in animals treated with IgG. The inflammation response in animals treated with compound is compared to the inflammation response in mice that have received sneakers containing distilled water. Table 6: Percentage of inhibition of inflammation of the ear in response to the application of croton oil It is noted that in relation to this date, the best method known to the applicant, to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

R E I V I N D I C A C I O N S Having described the invention as above, property is claimed as contained in the following:

1. A compound of formula: characterized in that Rl is a group of formula where A is hydrogen, hydroxy, amino or halogen, and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl or lower alkoxy; R2 is a group of formula wherein R3 is hydrogen, carboxy or lower alkyl; n is 0 or 1; U, V and W are independently hydrogen, halogen or lower alkyl, with the proviso that U and V are not both hydrogen; X is carbonyl, lower alkylene substituted with phenyl, or sulfonyl; Y is lower alkylene which may be substituted with one or more of amino, substituted amino or cyclo lower alkyl, or Y is lower alkenylene or lower alkylenethio; Z is hydrogen, lower alkylthio, -COOH,

-CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) -amino] carbonyl] pyrazin-2-yl, hydroxy, phenylmethoxy, 2-chloro-4- [[[(3 -hydroxyphenyl) -methyl] amino] carbonyl] phenyl, [(2,6-dichlorophenyl) -methoxy] -phenyl or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, any of the rings may be unsubstituted or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl which is substituted with halogen, amino or lower alkoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH, or -CONH2, as well as pharmaceutically acceptable salts and esters thereof. 2. A compound of claim 1, characterized in that Y is lower alkylene which may be substituted by amino, acetylamino or lower cycloalkyl, lower alkenylene, lower alkylenethio; X is carbonyl or sulfonyl; Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3- [[(5-chloropyridin-2-yl) amino] carbonyl] pyrazin-2-yl, cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different and in which the rings representing Z may be unsubstituted or substituted by at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl, which may be unsubstituted or substituted by halogen or lower alkoxy, lower alkylsulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl or acetoxy; and wherein R 1, R 2, U, V, W, X, n and k are as in claim 1, as well as pharmaceutically acceptable salts and esters thereof.

3. A compound of claim 1 or claim 2, characterized in that Z is thienyl, furyl, thiazolyl, cyclopentyl, cyclohexyl, piperidyl, pyridyl, naphthalenyl, benzothienyl, benzothiazolyl, 1,4-dioxa-8-thiaspiro- [4, 5] -decyl, phenyl or phenyl substituted with one or more of lower alkoxy, lower alkyl, chloro, bromo, fluoro, hydroxy, nitro, cyano, amino, substituted amino, aminosulfonyl, alkoxycarbonyl, trifluoromethyl, or carboxy.

4. A compound of any of claims 1 to 3, characterized in that A when present, is hydroxy, hydrogen or amino and B is hydrogen or hydroxy; W is hydrogen and at least one of U and V are methyl or halogen; k is 1 and Y is lower alkylene; or k is 0; Z is hydrogen phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl or isoxazolyl or a six-membered aromatic ring with one to three nitrogens, said ring systems being unsubstituted or substituted with at least one of: halogen, hydroxy, lower alkoxy, nitro, amino, substituted amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl, or lower alkoxycarbonyl.

5. A compound of any of claims 1 to 4, characterized in that R1 is a group of formula A is hydroxy and B is hydrogen.

6. A compound of claim 5, having the formula: characterized in that U is chlorine or bromine; X is carbonyl, lower alkylene substituted with phenyl or sulfonyl; Y is lower alkylene which may be substituted with one or more of amino, substituted amino or lower alkyl cycloalkyl, or Y is lower alkylene or lower alkylenethio; Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) amino] carbonyl] pyrazin-2-yl, hydroxy, phenylmethoxy, or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, wherein either of the rings may be unsubstituted or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl which is substituted by halogen, amino or lower alkoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH, or -CONH2.

7. A compound of claim 5 having the formula: characterized in that U is chlorine or bromine; X is carbonyl, lower alkylene substituted with phenyl or sulfonyl; Y is lower alkylene which may be substituted with one or more of amino, substituted amino or lower alkyl cycloalkyl, or Y is lower alkylene or lower alkylenethio; Z is hydrogen, lower alkylthio, -COOH,

-CONH2, amino, 1-adamantyl, diphenylmetyl, 3 - [[(5-chloropyridin-2-yl) amino] carbonyl] pyrazin-2-yl, hydroxy, phenylmethoxy, or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms that may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, and may be any of the rings unsubstituted or substituted by at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl which is substituted by halogen, amino or lower alkoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH, or -CONH2. 8. A compound of the rei indication 5 having the formula: characterized in that any or all of U, V and W are halogen, hydrogen or methyl, with the proviso that U and V are not both hydrogen; X is carbonyl or sulfonyl; k is 0 or Y is methylene, R3 is hydrogen, carboxy or lower alkyl;

Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) -amino] carbonyl] pyrazin-2-yl, or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be same or different, wherein either of the rings may be unsubstituted or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl that is substituted by halogen, amino or lower alkoxy; with the proviso that Y is methylene when Z is hydrogen, lower alkylthio, amino, -COOH or -CONH2. 9. A compound of claim 8 characterized in that one of U or V is chlorine or methyl, while the other is hydrogen, chlorine or methyl; W is hydrogen, X is carbonyl and k is 0.

10. A compound as in claim 9, characterized in that R3 is hydrogen and Z is thiophene or phenyl or thiophene or phenyl substituted with at least one of lower carboxy, or lower alkyl, alkoxy lower, hydroxy, halogen, carboxy, nitro, aminosulfonyl, cyano or lower alkoxycarbonyl.

11. A compound as in claim 9, characterized in that Z is phenyl or phenyl independently substituted by one or two fluoro or hydroxy.

12. A compound as in claim 9, characterized in that Z is thienyl.

13. A compound of claim 11, characterized in that it is N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- [(3, 5- dihydroxybenzoyl amino) -L-alanine.

14. A compound of claim 11, characterized in that it is N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [(3,5-difluorobenzoyl) amino] -L-alanine.

15. A compound of claim 11, characterized in that it is N- [2,6-dichloro-4 - [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- (3,5-dihydroxybenzoylamino) -L - to the girl.

16. A compound of claim 11, characterized in that it is N- [2-chloro-4 - [[[(3-hydroxy phenyl) ethyl] amino] -carbonyl] benzoyl] -3- (3-hydroxybenzoyl) amino-L -to the girl.

17. A compound of claim 11, characterized in that it is N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- (3,5-dihydroxybenzoyl) amino- L-alanine.

18. A compound of claim 11, characterized in that it is N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [(3-hydroxybenzoyl) amino ] -L-alanine.

19. A compound of claim 12, characterized in that it is N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- [(thiophene-2- carboni 1) - amino] -L-alanine.

20. A compound of claim 12, characterized in that it is N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) ethyl] amino] carbonyl] benzoyl] -3- [(thiophene-2-carboni 1) -amino] -L-alanine.

21. A compound of claim 12, characterized in that it is N- [2,6-dichloro-4- [[[(3-hydroxyphenyl) methyl] amino] carbonyl] benzoyl] -3- [(thiophene-3-carbonyl ) amino] -L-alanine.

22. A compound of claim 12, characterized in that it is N- [2-chloro-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] -6-methylbenzoyl] -3- [(thiophene-3) carbonyl) -amino] -L-alanine.

23. A compound of claim 12, characterized in that it is N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] benzoyl] -3- [(thiophene-2-carbonyl ) -amino] -L-alanine.

24. A compound of claim 12, characterized in that it is N- [2,6-dimethyl-4- [[[(3-hydroxyphenyl) methyl] amino] -carbonyl] enzoyl] -3- [(thiophene-3-carbonyl amino] -L-alanine.

25. A compound of claim 1 having the formula: characterized in that Rl is a group of formula wherein at least one of U and V are chlorine, bromine or methyl; k is 0 or Y is butylene; X is carbonyl, lower alkylene substituted with phenyl, or sulfonyl; and Z is phenyl, thiazolyl or thienyl, or Z is phenyl, thiazolyl or thienyl substituted with at least one of methyl or acetylamino.

26. A compound of claim 25, characterized in that R1 is naphthalenyl, R3 is methyl, X is carbonyl, K is 0 and Z is thienyl.

27. A compound of claim 26, characterized in that it is N- [2,6-dichloro-4- [[[(IR) -1- (1-naphthalenyl) ethyl] amino] -carbonyl] benzoyl] -3- [(thiophene -2-carbonyl) amino] -L-alanine.

28. A compound of claim 1 having the formula: characterized in that U, V and W are independently hydrogen, halogen, or lower alkyl with the proviso that U and V are not both hydrogen; X is carbonyl, phenyl-lower alkylene or sulfonyl; Y is lower alkylene which may be substituted by amino, substituted amino, cyclo lower alkyl, or Y is lower alkenylene or lower alkylenethio, Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) amino] carbonyl] pyrazin-2-yl, one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, any of the rings may be unsubstituted or substituted with at least one of: halogen, cyano, amino , substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl which is t substituted with halogen, amino or lower alkoxy; k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH, or -CONH2.

29. A compound of claim 28, characterized in that U is fluorine or chlorine, Y is methylene or k is 0; Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms , which may be the same or different, and any of which may be unsubstituted or substituted by at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl , lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, lower alkyl or lower alkyl which is substituted by halogen, amino or lower alkoxy.

30. A compound of the formula characterized in that A3 is hydrogen, hydroxy, amino or halogen and B3 is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl or lower alkoxy; R23 is a group of formula wherein R33 is hydrogen, carboxy, or lower alkyl; U3, V3 and W3 are independently hydrogen, halogen or lower alkyl, with the proviso that U3 and V3 are not both hydrogen; R 4 is hydrogen, lower alkyl or aryl-lower alkyl, which may be unsubstituted or substituted by at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, hydroxy, aryl, aryloxy, lower alkoxy, carboxy, alkoxy lower carbonyl, acetoxy, lower alkyl or lower alkyl which is substituted with halogen, amino or lower alkoxy; and pharmaceutically acceptable salts and esters thereof.

31. A compound of the formula: characterized in that R1 is a group of the formula: where A is hydrogen, hydroxy, amino or halogen, and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl or lower alkoxy; R2 is a group of formula: H-CH2-N R3 < ? H OR R3 ii l J - CH-CH = CH- - CH2-CH2-CH- -C-NH-CH- V " wherein R3 is hydrogen, carboxy or lower alkyl; n is 0 or 1; U, V and W are independently hydrogen, halogen or lower alkyl, with the proviso that U and V are not both hydrogen; X is carbonyl, lower alkylene substituted with phenyl, or sulfonyl; Y is lower alkylene which may be substituted with one or more of amino, substituted amino or cyclo lower alkyl, or Y is lower alkenylene or lower alkylenethio; Z is hydrogen, lower alkylthio, -COOH, -CONH2, amino, 1-adamantyl, diphenylmethyl, 3 - [[(5-chloropyridin-2-yl) -amino] carbonyl] pyrazin-2-yl, hydroxy, phenylmethoxy, -chloro-4- [[[(3-hydroxyphenyl) -methyl] amino] carbonyl] phenyl, [(2,6-dichlorophenyl) -methoxy] -phenyl or Z is one of the following: cycloalkyl or aryl containing from 0 to 3 heteroatoms that may be the same or different, or a fused ring system containing two or three rings, which rings are independently cycloalkyl or aryl containing from 0 to 3 heteroatoms, which may be the same or different, and may be any of the rings unsubstituted or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl , acetoxy, lower alkyl or lower alkyl which is substituted with halogen eno, amino or lower alkoxy; R6 is inner alkyl or • CH2CH2-R7 wherein R7 is -N (CH3) 2, -NJ? J ^ NH- * _ -CH-O-C (0) 0-R9 R? Where R8 is hydrogen or methyl R9 is lower alkyl or lower cycloalkyl; and pharmaceutically acceptable salts and esters thereof, k is 0 or 1, with the proviso that k is 1 when Z is hydrogen, lower alkylthio, amino, -COOH or -CONH2.

32. A pharmaceutical composition comprising a compound of any of claims 1 to 31 and a pharmaceutically acceptable carrier.

33. The compounds of any of claims 1 to 31 for use as medicaments.

34. The use of a compound of any one of claims 1 to 31 in the preparation of a medicament for the treatment of rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, ulcerative colitis, arteriosclerosis, restenosis, pancreatitis, rejection of transplantation, delayed graft function and diseases caused by ischaemia reperfusion injuries, including acute myocardial infarction and stroke.