MXPA99003730A

MXPA99003730A - Heteroaryl succinamides and their use as metalloproteinase inhibitors

Info

Publication number: MXPA99003730A
Application number: MXPA/A/1999/003730A
Authority: MX
Inventors: A Abreo Melwyn; L Castelhano Arlindo; L Bender Steven; Jeffrey Chen Jian; Km Chong Wesley; J Billedeau Roland; G Deal Judith
Original assignee: Agouron Pharmaceuticals Inc Syntex
Priority date: 1996-10-24
Filing date: 1999-04-22
Publication date: 2000-04-24

Abstract

The present invention is directed to compound of formula (I), wherein R1, R2, R3, R4, R5, X, Y and (Ia) are as defined herein. These compounds are useful for inhibiting the activity of a metalloproteinase by contacting the metalloproteinase with an effective amount of the inventive compounds.

Description

SUCCINAMIDAS DE HETEROARILO AND ITS USE AS INHIBITORS OF METALOPROTE INASA The matrix metalloproteinases ("MMPs") are a family of proteases (enzymes) involved in the degradation and remodeling of connective or conjunctive tissues. Members of this family of endopeptidase enzymes are secreted as proenzymes from various cell types that reside in or associate with the connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells and invasive tumor cells or tatic targets. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade the protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous extracellular matrix components are present in the coatings of joints, interstitial connective tissues, basal membranes and cartilage. MMPs share several of the properties, which include zinc and calcium dependence, secretion as zymogens and 40-50% amino acid sequence homology. Eleven enzymes have been well characterized as MMP 's in humans, including three collagenases, three stromelysins, two gelatinases, matrilysin, metalloelae rate and membrane type MMP, as discussed in more detail below. The interstitial collagenases catalyze the initial decomposition or splitting and limiting ratio of types I, II and III of natural collagen. Collagen, the main structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon and skin. Interstitial collagenases are very specific matrix metalloproteases that break down these collagens to provide two agents that spontaneously denature at physiological temperatures and thus become susceptible to decomposition by fewer specific enzymes. Decomposition by collagenases results in the loss of structural integrity of the target tissue, an essentially irreversible process. Currently there are three known human collagenases, the first two are relatively well characterized (FASEB J., 5, 2145-54 (1991)). Fibroblast-like collagenase from human (HFC, MMP-1, or collagenase-1) is produced by a wide variety of cells including fibroblasts and macrophages. Human neutrophil type collagenase (HNC, MMP-8, or collagenase-2) has so far only been shown to be produced by neutrophils. Human collagenase-3 (MMP-13) is the most recently discovered member of this group of MMPs, which was originally found in breast or breast carcinomas (J. Bi ol. Ch em., 269, 16,766-16,773). (1994)), although it has already been shown to be produced by chondrocytes (J. Cl in. In ve st., 97, 761-768, 1996). Gelatinases include two distinct but highly related enzymes: a 72-kD enzyme (gelatinase A, HFG, MMP-2) secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme (gelatinase B, HNG , MMP-9) released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), types IV of collagen (basement membrane) and V, fibronectin and insoluble elastin. Esterlysins 1 and 2 have been shown to decompose a wide range of matrix substrates, including laminin, fibronectin, proteoglycans, and collagen types IV and IX in their non-helical domains. Matrilysin (MMP-7, PUMP-1) has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin and laminin. Its expression has been documented in mononuclear phagocytes, explantations of uterine tissue in rats and sporadically in tumors. Other less characterized MMPs include metaloelas macrophage rate (MME), MMP-12), membrane type MMP (MMP-14) and stromelysin-3 (MMP-11). Excessive degradation of the extracellular matrix by MMPs is implicated in the pathogenesis of many diseases of both chronic and acute nature. For example, many studies, such as those reviewed in Exp. Opi n. In ves t. Drugs, 5, 323-335, (1996), have established that the expression and activation of MMPs are critical events in the growth, invasion and tumor metastasis. In addition, it has been shown that MMP activity is required for angiogenesis, which is necessary for tumor growth as well as for other pathological conditions such as macular degeneration. MMPs, especially stromelysin-1, collagenase-1 and collagenase-3, have been strongly implicated in the destruction of articular cartilage that is the hallmark of rheumatoid arthritis and osteoarthritis. See, for example, J. Clin. Invest., 97, 761-768 (1996). In addition, it is believed that tissue destruction associated with gingivitis and periodontal disease is mediated by overexpression of MMPs in response to proinflammatory cytokines. See Molecular Pathogenesis of Periodontal Say, Chapter 17, 191-202 (1994). Other diseases in which critical performances have been identified for MMPs include multiple sclerosis (J. Neuroimmunol., 41, 29-34 (1992)), corneal ulceration (Invest. Opthalmol and Visual Sci., 32, 1569-1575 ( 1989), apoplectic attack (Brain Research, 703, 151-155 (1995) and J. Cereb. Blood Flow Metab., 16, 360-366 (1996)), aging of the skin induced by the sun (Nature, 379 , 335-339 (1996)), chronic obstructive pulmonary disease such as emphysema (Am. J. Respir, Cell, Mol. Biol. 7, 5160-5165 (1994)), chronic ulceration (J. Clin. Invest., 94, 79-88 (1994)), cardiac arrhythmia and endometriosis. Finally, performances for MMP-mediated degradation of basal membranes have been proposed in the rupture of atherosclerotic plaques (Basic Res. Cardiol., 89 (SUPPL.l), 59-70, (1994)) and in the development of glomerular disease (J. Cl in. In ves t., 97, 1094-1101 (1996)). It is expected that the MMPs inhibitors provide useful treatments for the diseases described above in which the degradation of the extracellular matrix by MMPs contributes to the pathogenesis of the disease. In general, selective MMP inhibitors of particular subsets of MMPs may offer therapeutic advantages, as has been typically observed, that limited number of members of the MMP family is involved in any of the disease states listed above. For example, the involvement of individual collagenases in the degradation of tissue collagens is likely to be strongly dependent on the tissue. The tissue distribution of human collagenases suggests that collagenase-3 is the major contributor to the degradation of the cartilage collagen matrix, whereas collagenase-1 is more likely to be involved in tissue remodeling of the collagenase. skin and other soft tissues. In addition, stromelysin-1 appears to be largely responsible for the excessive loss of proteoglycan from cartilage. Thus, the inventive compounds described herein that are selective inhibitors for collagenase-3 and is thromelysin on collagenase-1, are preferred for the treatment of diseases associated with erosion of cartilage, such as rheumatoid arthritis and osteoarthritis. . Similarly, among MMPs, metalloelastase has been specifically implicated in the pathology of pulmonary emphysema. See J. Biol. Chem. 270, 14568-14575 (1995). The design and uses of MMP inhibitors were reviewed, for example, in J. Enzime Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 5, 1287-1296 (1995); and in Drug Discovery Today, 1, 16-26 (1996). MMP inhibitors are also the subject of many patents and patent applications. In most of these publications, the preferred inventive compounds are hydroxamic acids, just as it has also been established that hydroxamate function is the optimal functionality for the coordination of zinc to bind the active site of the MMPs. For example, the hydroxamate inhibitors described in the literature are generally 100 to 1000 times more potent than the corresponding inhibitors, wherein the functionality of the hydroxamic acid is replaced by a carboxylic acid functionality. Despite this, hydroxamic acids tend to exhibit relatively poor bioavailability. The preferred compounds described herein are carboxylic acid inhibitors that possess inhibitory potency against MMPs that is comparable to the potency of the hydroxamic acid inhibitors that have been reported in the literature. The following patents and patent applications describe carboxylic acid inhibitors which are like the inventive carboxylic acid inhibitors described herein, substituted succinic acid monoamine derivatives: Celltech Ltd .: EP-A-0489577 (WO 92/099565), EP-A-0489579, WO 93/24475, WO 93/244449; British Biotech Pharmaceuticals Ltd .: WO 95/32944, WO 95/19961; Sterling Winthrop, Inc .: US 5,256,657; Sanofi Winthrop, Inc .: WO 95/22966; and Syntex (U.S.A.) Inc. WO 94/04735, WO 95/12603, and WO 96/16027.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to the compounds of the formula I: wherein X is a single bond or a saturated or unsaturated, linear or branched chain containing from 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with 0, or S, and wherein one or more of the hydrogen atoms is optionally replaced with F; And it is a simple bond, -CH (OH) -, or -C (0) -; Ri is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C (O) R? Or wherein R-i0 is H, an alkyl group, an aryl group, a group heteroaryl, a cycloalkyl group, a heterocycloalkyl group, a 0-aryl group, an O-alkyl group, or NRnR? 2; wherein R n is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R 2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R p and Ri 2 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and R is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NRuR? , or ORn, wherein Rn and Ri2 are as defined above, or R2 and R3, together with the atom or atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R is H or any suitable organic portion; R5 is C (0) NH0H, C (0) 0R? 3, SH, N (OH) CHO, SC (0) R? 4, P (O) (OH) R? 5, or P (O) (OH ) OR13; Ri3 is H, an alkyl group, or an aryl group, Ri4 is an alkyl group or an aryl group, and Rlb is an alkyl group; and is a heteroaryl group having five ring atoms, including 1, 2 or 3 heteroatoms selected from 0, S and N; and the pharmaceutically acceptable salts and solvates thereof, and the pharmaceutically acceptable prodrugs thereof, the prodrugs are different from the compounds of the formula (I); with the proviso that the compound of the formula (I) is: wherein Ri, R4 and R5 are as defined above, W is H, OH, a halo group, an alkyl group, or an O-alkyl group, and furthermore where when m is 2, 3 or 4, n be 1, 2, 3 6 4, and A CH2, 0, NH, or N-alkyl; and when m is 4, 5 or 6, n is 0, and A is -CHJ-, wherein J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I); then it is pyrrolyl.

The present invention is further directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a composed of the formula (I). The present invention is further directed to methods for using the compounds of the formula (I), and pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, the prodrug is different from a compound of the formula (I). ).

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the compounds of the formula I: wherein X is a single bond or a saturated or unsaturated, linear or branched chain containing from 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with 0, or S, and wherein one or more of the hydrogen atoms is optionally replaced with F; And it is a Simple link, -CH (OH) -, or -C (0) -; Ri is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; R 2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C (0) R 0 wherein Rio is H, an O-alkyl group, an alkyl group, a group aryl, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NRuRi2; wherein Rn is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein Ri2 is H, an alkyl group, an aryl group, a group heteroaryl, a cycloalkyl group, or a heterocycloalkyl group, or wherein R p and Ri 2 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and R3 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NRnR? 2, or ORn, wherein Rn and Ri2 are as defined above, or R2 and R3, together with the atom or atoms to which they are attached, they form a cycloalkyl group or a heterocycloalkyl group; R4 is H or any suitable organic portion; R5 is C (0) NHOH, C (0) OR? 3, SH, N (OH) CHO, SC (0) Rn, P (O) (OH) R? S, OP (O) (0H) 0R? 3; Ri3 is H, an alkyl group, or an aryl group, Ri4 is a group at which or an aryl group, and R15 is a group at which; and is a heteroaryl group having five ring atoms, including 1, 2 or 3 heteroatoms selected from 0, S and N; and the pharmaceutically acceptable salts and solvates thereof, and the pharmaceutically acceptable prodrugs thereof, the prodrugs are different from the compounds of the formula (I); with the proviso that the compound of the formula (I) is: wherein Ri, R4 and R5 are as defined above, W is H, OH, a halo group, an alkyl group, or an O-alkyl group, and furthermore where when m is 2, 3 or 4, n be 1, 2, 3 or 4, and A CH2, 0, NH, or N-alkyl; or when m is 4, 5 or 6, n is 0, and A is -CHJ-, where J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I); then it is pyrrolyl.

More preferably, the compounds of the present invention are selected from the compounds of the formula I wherein X is a single bond; And it is a simple bond, -CH (OH) - or -C (O) -; Ri is an aryl group or a heteroaryl group; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C (O) R? 0, wherein Rio is as defined above; R3 is H, an alkyl group, a heteroaryl group, NR11R2 or OR11, wherein Rn and R12 are as defined above or R2 and 3, together with the atoms to which they are attached, form a cycloalkyl group or heterocycloalkyl group; R 4 is H, an alkyl group, OH, an O-alkyl group, NH 2, NH-alkyl, or a cycloalkyl group; R5 is C (0) NHOH, C (0) 0Ri3, SH, or SC (0) R? 4, wherein Ri3 is H, an alkyl group, or an aryl group, and R? 4 is an alkyl group or an aryl group; Y # is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I). In the compounds of the present invention, and the pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, preferably X is a single bond. In particularly preferred embodiments, when Y is -CH (OH) -, preferably R3 is H or an alkyl group or together with R2 and the atom or atoms to which R2 and R3 are attached forms a cycloalkyl group or a heterocycloalkyl group, and more preferably R3 is H. When Y is -C (0) - preferably, R3 is an alkyl group, NRn and R12, or ORn, wherein Rn and Ri2, are as defined above, or together with R2 and the atoms to which R3 and R2 are attached form a cycloalkyl group or a heterocycloalkyl group. When Y is a simple bond, preferably R3 is a heteroaryl group, more preferably the heteroaryl group: H wherein R2i and R22 are independently any suitable organic portion or together with the carbon atoms to which they are attached form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group. Preferably, R2? and R22 are selected from hydrogen, an alkyl group, an aryl group, a heteroaryl group, a halo group, a C (O) 0-alkyl group, a carbamoyl group, a cycloalkyl group, or a heterocycloalkyl group. Preferably Ri is an aryl group or a heteroaryl group. More preferably, Ri is an aryl group of the formula: wherein Z is H, halogen, an alkyl group, an O-alkyl group, a cyano group, a hydroxy group, an aryl group, a heteroaryl group, or a Heterocycloalkyl group. Preferably R4 is H, an alkyl group, or OH. Most preferably R4 is H or an alkyl group selected from CHR? 6OH and CH (NHR? 7) Rie, wherein Ri6 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group , and Ri7 is C (0) R? 8, S02Ri8, H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or Rie and R17, together with the atoms to which they are united, they form a heterocycloalkyl group; wherein Ri8 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or R19R20; wherein R? 9 and R2o independently are H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or Ri9 and R2o together with the nitrogen atom to which they are attached, form a group heterocycloalkyl. Preferably it is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl, more preferably pyrrolyl, furyl or thienyl, and more preferably is pyrrolyl. Preferably R5 is C (0) NH0H or C (0) 0R? 3, wherein R13 is hydrogen. Particularly preferred compounds according to the invention include: N- [2, 2-Dimeti 1-1 (S) - (methy learbamoi 1) -propyl] -3 (R) - (3-phenyl-1 H -pyrrol- I-il) succinamic; N- (8-0xo-4-oxa-l, 7-diazatricyclo- [9.6.1.012'17] octadeca-ll (18), 12, 14, 16-tetraen-9 (S) -yl) -3 ( R) - (3-phenyl-lH-pyrrol-1-yl) succinamic; N- [2, 2-Dimeti 1-1 (S) - (met i learbamoi 1) -propyl] -3 (R) - [3- (pyridin-4-yl) -lH-pyrrol-1-yl] acid succinamic; 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-1- (S) - (methylcarbamoyl) propyl] succinamic acid; Acid 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2-hydroxy-1 (S) - [(1H-imidazol-4-yl) et il ] ethyl] -succinnamic; N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (R) - [3- (4-propyl-phenyl) -lH-pyrrol-1-yl] -succinamic acid; 3 (R) - [3- (4-Cyano-phenyl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-1-1 (S) - (methylcarbamoyl) -propyl] -succinamic acid; N- [2, 2-Dimethyl-l (S) - (hydroxymethyl) -propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl acid ] succinamic; N- (2-Hydroxy-l (S) -phelethyl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid; 3 (R) - [3- (4'-Cyanobiphenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] succinamic acid; 3 (R) - [3- (4'-Cyanobiphenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) acid -propyl] succinamic; Acid 3 (R) - [3- (4 '-Carbar oil i feni 1-4-yl) -1H-pyrrol-l-yl] -N- [2,2-di ethyl-l (S) - (methylcarbamoyl) ) -propyl] succinamic; Acid 3 (R) - [3- (4'-Carbamoyl ifeni 1-4-yl) -1H-pyrrol-l-yl] -N- [2, 2-dimethyl-l (S) - (pyridine-4- il-carbamoyl) propyl] succinamic; Acid 3 (R) - [3- (4'-Cyanobi-phenyl-1-4-yl) -1H-pyrrol-1-yl] -N- [2,2-dimethyl-l (S) - (hydroxymethyl) propyl] succinamic; N- (2 (R) -Hydroxyindan-1 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid; N- (2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl) -3 (R) - [3- (4- (pyridin-phenyl) -lH-pyrrol-1-yl) acid) succinamic; N- (4, 4-Dimethyl) acid 1-2-oxo-tetrahydrofuran-3 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol- 1-yl] succinamic; N- (8-Oxo-4-oxa-l, 7-diazatricyclo- [9.6.1, O12'17] -octadeca-11 (18), 12, 14, 16-tetraen- 9 (S) -il) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-y1] succinnamic; N- [2, 2-Dimethyl-l (S) -pyridin-4-ylcarbamoyl) -propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-p acid. Irolol-1-yl] succinámico; N- [1 (S) - (lH-Imidazol-2-yl) -3-methylbutyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1 acid -yl] succinamic; N1- [2, 2-Dimethyl-l (S) - (hydroxymethyl) propyl] -N4-hydroxy-2 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1 -yl] succinamide; N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (S) - [1- (4-fluorophenyl) -lH-pyrrol-3-yl] succinamic acid; 3 (S) - [1- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-3-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] acid succinamic; Acid 3 (S) - [1- (4'-Cyano and phenyl-4-yl) -1H-pyrro1-3-yl] -N- [1 (S) - (1H-imide zol- 2i) -3-met ilbutyl] -succinnamic; Acid 3 (S) - [1- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-3-yl] -N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3 (S) - il) succinic; Acid 3 (R) - [3- ('-Cianobi-phenyl-1-4-yl) -1H-pyrrol-1-yl] -N- [1 (S) - (lH-imidazol-2-yl) -3- methylbutyl] -succinnamic; 3 (R) - [3- (4-Cyanophenyl) -lH-pyrrol-1-yl] -N- [1 (S) - (1H-imidazol-2-yl) -3-methylbutyl] succinnamic acid; N- [2, 2-Dimethyl-l (S) - (hydroxymethyl) propyl] -3 (S) - [1- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-3-yl] succinamic; Acid 3 (R) -. { 3- [2- (4-Cyanophenyl) ethynyl] -1H-pyrrol-1-yl} -N- [2, 2-dimethyl-l (S) (methylcarbamoyl) -propyl] succinnamic; Acid 3 (R) -. { 3- [2- (4-Cyano-phenyl) -ethyl] -1H-pyrrol-1-yl} -N- [2, 2-dimethyl-l (S) (methylcarbamoyl) -propyl] succinnamic; N ^ Hydroxy-N'-methyl-S (R) - [3- (4- (pyridin-4-yl) phenyl) -lH-pyrrol-1-yl] succinamide; Acid 3 (R) - [3- (4 »-Cianobi phenyl-4-yl) -1H-pyrrol-1-yl] -2 (S) -cyclopropyl-N- (2, 2-dimethyl-1 (S) (methylcarbamoyl) propyl) succinamic; 3 (S) - [2- (Cyanobi-phenyl-4-yl) furan-4-yl] -N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] -succinnamic acid; 3 (S) - [1- (4 * -Cianobiphenyl-4-yl) -1H-pyrrol-3-yl] -N- acid. { 2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) -2 (R) - (hydroxymethyl) succinnamic; 3 (S) - [1- (4'-Cyanobifeni-4-yl) -1H-pyrrol-3-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) acid -2 (S) - (hydroxy) succinamic; Acid 3 (R) - [3- (4'-Cyanobiphenyl-4-yl) -1H-pyrrol-1-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) - 2 (S) - (hydroxy) succinamic; and the pharmaceutically acceptable salts and solvates thereof, and the pharmaceutically acceptable prodrugs thereof. As used in the present application, the following definitions apply: An "alkyl group" is intended to refer to a monovalent chain radical, linear or branched carbon atoms and saturated and / or unsaturated hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentinyl, hexynyl and the like, which may be unsubstituted or substituted (ie, containing only carbon and hydrogen) by one or more suitable substituents as defined below. An "O-alkyl group" is intended to refer to an oxygen atom attached to an alkyl group, wherein the alkyl group is as defined above. A "cycloalkyl group" is intended to refer to a monocyclic, bicyclic or tricyclic, monovalent, non-aromatic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms in the ring, each of which may be saturated or unsaturated and may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which one or more heterocycloalkyl groups may be fused, aryl, or heteroaryl groups, which by themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1.] Heptyl, bicyclo [2.2.1. ] hept-2-en-5-yl, bicyclo [2.2.2) octyl, bicyclo [3.2.1.] nonyl, bicyclo [4.3.0] nonyl, bicyclo [4.4.0] decyl, indan-1-yl, indan-2-yl, tetralin-1-yl, tetralin-2-yl, adamantyl and the like. A "heterocycloalkyl group" is intended to refer to a monocyclic, bicyclic, or tricyclic, monovalent, non-aromatic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 atoms in the ring and which include 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below and to which one or more cycloalkyl groups, aryl groups or heteroaryl groups may be fused, which by themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of the heterocycloalkyl groups include, but are not limited to: azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1, 4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, , 3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathyanyl, 1,3-di-thienyl, azabicyclo [3.2.1] octyl, azabicyclo [3.3.1] onyl, azabicyclo [4.3. 0] Nonyl, oxabicyclo [2.2.1] heptyl, 1, 5, 9-triazacyclododecyl and the like. An "aryl group" is intended to refer to a monocyclic, bicyclic or tricyclic, monovalent, aromatic radical containing 6, 10, 14 or 18 carbon atoms in the ring, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which one or more cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups may be fused, which by themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like. A "heteroaryl group" is intended to refer to a monovalent monocyclic, monocyclic or aromatic tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 atoms in the ring, including 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which they may be fused one or more cycloalkyl groups, heterocycloalkyl groups or aryl groups, which by themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of the heteroaryl groups include, but are not limited to: pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl , benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl and the like. An "acyl group" is intended to refer to a radical -C (0) -R-, wherein R is any suitable substituent as defined below. A "sulfonyl group" is intended to refer to a radical -S (O) (O) -R-, wherein R is any suitable substituent as defined below. The term "suitable substituent" is intended to refer to any of the recognizable substituents for those skilled in the art that do not adversely affect the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to: oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, groups of the formula (A) HE. wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, groups of the formula (B) wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, groups of the formula (C) wherein Rb and Rc are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, groups of the formula (D) R < ti (D) A e wherein Rd is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dyalkylamino group or an acylamino group; and Re is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group or a dialkylamino group, groups of the formula (E) wherein Rf is a group alkyl, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, groups of the formula (F) wherein Rg and Rh are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, groups of the formula (G) wherein Ri is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a group of the formula (A), formula (B), formula (C), formula (H), or formula (K), groups of the formula (H) wherein R-, is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of the formula (A), formula (B), formula (C) or formula (D); and wherein Rk is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a group of the formula (A), formula (B), formula (C), formula (D) , formula (E) or formula (F), groups of the formula (J) > * (? wherein Ri is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a group of the formula (C), and groups of the formula (K) wherein Rm and Rn are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group. The term "suitable organic portion" is intended to refer to any organic portion recognizable to those skilled in the art that does not adversely affect the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to: oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, alkyl cyclo groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups and the formulas (A), (B), (C), (D), (E), (F), (G), (H), (J) and (K), as defined in the above. A "hydroxy group" is intended to refer to the -OH radical.

An "oxo group" is meant to refer to the divalent radical = 0. A "halo group" is meant to refer to any of the radicals -F, -Cl, -Br or -I. A "cyano group" is meant to refer to the radical -C = N. A "nitro group" is meant to refer to the radical -N02. A "trialkylsilyl group" is intended to refer to the radical -SiRpRqRs, wherein Rp, Rq and Rs are each independently an alkyl group. A "carboxy group" is intended to refer to a group of the formula (B) wherein Rt is hydrogen. An "alkoxycarbonyl group" is intended to refer to a group of the formula (B) wherein Rt is an alkyl group as defined above. A "carbamoyl group" is intended to refer to a group of the formula (C) wherein Rt and Rt are both hydrogen. An "amino group" is intended to refer to the -NH2 radical. An "alkylamino group" is intended to refer to the radical -NHRU, wherein Ru is an alkyl group as defined above.

A "dialkylamino group" is intended to refer to the radical -NRURV, wherein Ru and Rv, which are the same or different, are each an alkyl group as defined above. A "pharmaceutically acceptable prodrug" is intended to refer to a compound that can be converted, under physiological conditions or by solvolysis, to a compound of formula I. A "pharmaceutically acceptable solvate" is intended to refer to a solvate that is the effectiveness and biological properties of the biologically active components of the compounds of formula I. Examples of pharmaceutically acceptable solvates include, but are not limited to: the compounds of formula I in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine. In the case of solid formulations it should be understood that the inventive compounds can exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.

A "pharmaceutically acceptable salt" is intended to refer to those salts that preserve the effectiveness and biological properties of free acids and bases and that are not biological or otherwise undesirable. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulphites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates. , formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1, -dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, Methoxbenzoates, phthalates, sulfonates, xylensulphates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,? -hydroxybutyrates, glycolates, tartrates, methanesulfonates, propansulphonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates. If the inventive compound is a base, the desired salt can be prepared by any suitable method known in the art, which includes treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid or the like. If the inventive compound is an acid, the desired salt can be prepared by any suitable method known in the art, which includes treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), a alkali metal hydroxide or alkaline earth metal or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. The inventive compounds can exist as simple stereoisomers, racemates and / or mixtures of enantiomers and / or diastereomers. All simple stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the compounds of the present invention are used in a form containing at least 90% of a simple isomer (80% enantiomeric or diastereomeric excess), more preferably at least 95% (90% ee or de), even more preferred at least 97.5% (95% of ee or de), and even more preferred by at least 99% (98% of ee or de). The compounds identified herein as simple stereoisomers are intended to describe the compounds used in a form that contains at least 90% of a single isomer. The present invention is further directed to methods for inhibiting the activity of the matrix metalloproteinase comprising contacting the protease with an effective amount of a compound of the formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate of the same. For example, one can inhibit the activity of the matrix metalloproteinase in mammalian tissue by administering a compound of the formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof. The activity of the inventive compounds, as inhibitors of the activity of the matrix metalloproteinase, can be measured by any of the methods available to those skilled in the art, including the in vi and the vi vi tests. Examples of suitable assays for activity measurements include the fluorometric determination of the rate of hydrolysis of a fluorescently labeled peptide substrate, which is described herein. The administration of the compounds of the formula I, or their pharmaceutically acceptable prodrugs, or pharmaceutically acceptable salts or solvates, can be carried out according to any of accepted modes of administration, available to those skilled in the art. Illustrative examples of suitable modes of administration include, but are not limited to, oral, nasal, intraocular, parenteral, topical, transdermal and rectal. The inventive compounds of formula I, and their pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts and solvates, can be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable dosage forms include, but are not limited to, the forms: solid, semisolid, liquid or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions and aerosols. The pharmaceutical composition may also include suitable excipients, diluents, carriers and carriers, as well as other pharmaceutically active agents, depending on the intended use. Acceptable methods for preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations can be prepared following conventional techniques of the pharmaceutical chemist, involving steps such as mixing, granulating and compressing, when necessary, for the tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to provide the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, infraocular, intraural and / or 1T T C L ci -L • Pharmaceutically acceptable diluents, carriers or excipients, solid or liquid, can be used in pharmaceutical compositions. Exemplary solid carriers include starch, lactose, calcium sulfate dihydrate, kaolin or magnesia, sucrose, talc, gelatin, pectin, acacia, magnesium stearate and stearic acid. Illustrative liquid carriers may include syrup, peanut oil, olive oil, saline and water. The carrier or diluent may include a suitable prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (eg, solution), or a non-aqueous or aqueous liquid suspension.

A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (ie, a compound of the formula I or a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable salt or solvate thereof) and is preferably made from a or more pharmaceutical dosage units. The selected dose can be administered to a mammal, for example, a human patient, in need of treatment mediated by the inhibition of matrix metalloproteinase activity, by any known method for administering the dose including the topical method, for example as a ointment or cream; orally, rectally, for example as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or infraocular infusion. A "therapeutically effective amount" is intended to refer to the amount of a compound of formula I or II which, when administered to a mammal in need thereof, is sufficient to effect treatment for the disease conditions alleviated by the inhibition of the activity of one or more matrix metalloproteinases, such as tumor growth, invasion or metastasis, osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, gingivitis, chronic dermal wounds, corneal ulcerations, degenerative skin disorders, multiple sclerosis, apoplectic attack, diabetic retinopathy, macular degeneration, angiofibromas, hemangiomas; obstructive, chronic lung disease, such as emphysema, atherosclerosis, glomerular disease, cardiac arrhythmia, endometriosis or disease conditions characterized by unwanted angiogenesis. The amount of a given compound of formula I that will correspond to a "therapeutically effective amount" will vary depending on factors such as the particular compound, the disease condition and the severity thereof, and the identity of the mammal in need thereof, however, it can be easily determined by someone skilled in the art. "Treat" or "treatment" is intended to refer to at least mitigating a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more matrix metalloproteinases, such as tumor growth, invasion or metastasis, osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, gingivitis, chronic dermal wounds, corneal ulcerations, degenerative skin disorders, multiple sclerosis, apoplectic attack, diabetic retinopathy, macular degeneration, angiofibromas, hemangiomas, or conditions of disease characterized by unwanted angiogenesis, and includes: (a) prophylactic treatment in a mammal, particularly when the mammal is found to be predisposed to have the disease condition, but has not yet been diagnosed as having it; (b) inhibit the disease condition; and / or (c) alleviate, in whole or in part, the disease condition. The inventive compounds, and their salts, solvates and prodrugs, can be prepared by employing techniques available in the art using readily available starting materials. Certain novel and eminent methods for preparing the inventive compounds are described in the following.

METHODS FOR PREPARING THE INHIBITORS OF METALOPROTEINASE CARBOXYLATE MATRIX VXX PREPARATION OF COMPOUNDS OF FORMULA I The methods for preparing compounds of Formula I, wherein R5 is carboxyl, culminate in the deprotection of the esters (1) to the corresponding carboxylates as illustrated in Scheme Reaction I in the following. Suitable types of esters (1) and decomposition of R5 are described, for example, in Greene, T; Wuts, P.G.M. "Protective Groups in Organic Synthesis", Wiley: 1991 and Kocienski, P.J. "Protecting Groups", Thieme: 1994, which are incorporated herein by reference. Some examples and conditions found here are given in the following.

REACTION SCHEME I (1) As an example of the decomposition of the typical ester, an ester of Formula (1), where Re is benzyl, is placed in a suspension with solvent, for example, ethyl acetate also containing metal catalyst, preferably palladium (0) in a source of hydrogen such as hydrogen gas at one atmosphere or higher, at room temperature for 30 minutes to three days, preferably four hours. The carboxylates of the formula I, where R 5 is -COOH, are subject to the usual isolation and purification. For the esters of the formula (1) wherein R6 is t-butyl, the ester (1) is deprotected in a solution of solvent, preferably chloroform or dichloromethane, with trifluoroacetic acid in excess, at room temperature for 15 minutes at 12 hours to obtain a carboxylate of Formula I. For the esters of the formula (1) wherein R6 is allyl, the ester (1) is subjected to decomposition in an inert solvent, preferably acetonitrile, with a catalytic amount of palladium catalyst, such as tetrakis (triphenylphosphine) -palladium (0), with an excess of secondary amine, such as morpholine, for 15 minutes at 12 hours at room temperature. Other protective strategies can be used where the above conditions are incompatible with the functional groups contained in either R4 or R5. For example, the simultaneous protection where R is olefinic and R5 is carboxylate can occur through its connection as in a halolactone of Formula (2) where X is halogen, as shown in Scheme Reaction II below. The halolactone (2) is subjected to reductive opening for the compounds of the formula I, wherein R 4 is allyl and Rs is carboxylate.

REACTION SCHEME II Preparation of the Compounds of Formula I, wherein R "is Allyl and Rs is Carboxylate A solution of halolactone (2) is exposed to a reductive environment, preferably zinc dust in excess zinc in acetic acid. The resulting carboxylate of Formula I, wherein R is allyl, is isolated and purified by conventional methods.

The compounds (5) of the Formula I wherein R5 is hydroxamic acid (-C (O) NHOH) can be obtained from the compounds (3) of the Formula I wherein R5 is carboxyl. Any of the many commercially available coupling reagents can be used for conversion to either a protected version of a compound of the formula (4) wherein R7 is alkyl or directly to hydroxamate (5), as indicated by the following Reaction Scheme III: REACTION SCHEME lll Step 1 - Preparation of the Compounds of the Formula (4) or (5) The carboxylic acids of the formula (3) and the hydroxylamine or its O-alkyl derivatives in inert solvent, preferably dimethylformamide (DMF), are coupled with any of the many available coupling reagents, preferably benzotriazol-1-yloxy tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), at room temperature for one to 24 hours to provide either the hydroxamates (5) or O-alkyl hydroxamates (4), respectively. The products are subject to the usual handling and purification.

Step 2 - Preparation of the Compounds of the Formula (5) from the Compounds of the Formula (4) The protected hydroxamates of the Formula (4) are deprotected as determined by the nature of the protecting group R7. Where R7 is a trialkylsilyl, hydrolysis with mild acid or decomposition with fluoride in protic or aprotic solvent at room temperature or lower for one to 12 hours is sufficient. Where R7 is benzyl, selective deprotection without decomposition of the N-O bond proceeds in the presence of palladium on carbon, with a source of hydrogen, such as hydrogen gas at atmospheric pressure, in a suitable solvent such as dimethylformamide or methanol.

DS PREPARATION COMPOUNDS OF FORMULA II The pyrrole compounds of Formula II can be prepared from the cyclocondensation of the amines of Formula (6) with the tetrahydrofurans of formula (7), as shown in the following Reaction Scheme IV: REACTION SCHEME IV (6) (7) Preparation of the Compounds of the Formula II The condensation of the amine salts of the Formula (6) and 2,5-dimethoxytetrahydrofurans of the Formula (7) can be carried out in acetic acid for a period of from one to 24 hours at temperatures from 40 ° to 90 ° C. Another effective set of conditions includes heating a solution of the compounds (6) and (7) in an inert organic solvent, for example, 1,2-dichloroethane, with or without acid, such as trifluoroacetic acid, and with or without stoichiometric amounts. of water, for a period of one to 48 hours at 40 ° -90 ° C. The product of Formula II is isolated and purified by conventional means.

ALTERNA PREPARATION OF COMPOUNDS OF FORMULA II Another method for the preparation of the pyrrole compounds of Formula II involves the premature formation of a ring. The cyclocondensation of the amino acids D of the Formula (8) with the tetrahydrofurans of the Formula (7) and the subsequent coupling are shown below in Reaction Scheme V: ESQUEMADE REACTIONV Stage 1 (Y (ß) t (7) (9) (10) Step II - Preparation of the Compounds of the Formula (9) The amino acids of the Formula (8) and the 2,5-dimethoxytetrahydrofurans of the Formula (7) are dissolved or suspended in solution in an inert organic solvent , for example, 1,2-dichloroethane, with chlorotrimethylsilane, with or without acid, such as trifluoroacetic acid, and with or without a base, such as pyridine, for a period of from one to 48 hours at room temperature at 80 ° C, preferably the last one. The product (9) is isolated and purified by conventional means.

Step 2 - Preparation of the Compounds of the Formula II from the Compounds of the Formulas (9) and (10) The carboxylates of the Formula (9) and the amines of the Formula (10) are coupled under typical coupling conditions . The acids of Formula (9) can first be converted to a corresponding activated ester (ie, acid fluoride) or used with a reagent, for example BOP, together with the amine (10) in an inert solvent such as chloroform, and with or without a base such as N-methylmorpholine (NMM), for a period of one to 48 hours at 0 ° C at room temperature, preferably the latter. The product II is isolated and purified by conventional means.

PREPARATION OF THE STARTING MATERIALS Preparation of the Amines of the Formula (6) The amines of the Formula (6), wherein R4 is hydrogen and R is an ester (-COOR6) are available after two steps as shown in the Scheme of Reaction VI: the coupling of the commercially available aspartate D derivatives (11) and the various amines (10) of commercial or synthetic origin. Subsequent deprotection of the protected amines (12) provides the amine salts (6).

REACTION SCHEME VI Step 1 - Preparation of the Compounds of the Formula (12) The carboxylates of the Formula (11) and the amines (10) are condensed as described above for the preparation of a compound of the Formula II according to the Scheme Reaction V.

Typical coupling reagents, for example BOP, are used in an inert solvent such as chloroform, and with or without a base such as N-methyl orpholine, from 0 ° C to room temperature, preferably the latter, for a period of one to 48 hours to provide the product of Formula (12), which is isolated and purified by conventional means.

Step 2 - Preparation of the Amines of the Formula (6) The t-Butoxycarbonylamines of the Formula (12) are traditionally deprotected, for example, in an inert solvent, preferably dichloromethane or chloroform, with an excess of trifluoroacetic acid, of 0. ° C at room temperature, preferably the first, for 30 minutes to 18 hours to obtain the amine salts (6), which can be used immediately without further purification although they are subject to the usual handling and purification.

Preparation of the Compounds of the Formula (18) The aspartates of the Formula (8), wherein R4 is hydrogen are available for acquisition, or from synthesis according to methods known to those skilled in the art, such as those described in Literature. However, the aspartates of the Formula (8), where R4 is alkyl, they must be synthesized. An example of this synthesis is shown in the following Reaction Scheme VII. Aspartate D (13) is converted to aspartate (15) by means of diallyl ester (14), which undergoes rearrangement Iréland-Claisen from β-ester to allyl compound (16). The appropriate processing provides the carboxylates of the Formula (18), wherein R is allyl, which are suitable for subsequent conversion to lower alkyls, for example, reduction where R4 is propyl.

REACTION SCHEME Vil stage 3 Step 1- Preparation of the Compounds of the Formula (14) The dual esters of aspartate D can be produced in a wide variety of ways. For example, aspartate D (13) is esterified with an excess of allylic alcohol, preferably in inert solvent such as benzene with stoichiometric amounts of acid, such as p-toluenesulfonic acid, for one to 12 hours, under reflux under conditions for eliminate the water in an azeotropic manner. The salt (14) is precipitated or otherwise isolated and purified by conventional means.

Step 2 - Preparation of the Compounds of the Formula (15) The protection of an amine is well documented and is well known to those skilled in the art. For example, the amine salt (14) is treated with excess di-butyl dicarbonate in an appropriate solvent, preferably dichloromethane, in the presence of a base, preferably triethylamine for one to 24 hours at room temperature. The product (15) is isolated and purified by conventional means.

Step 3 - Preparation of the Compound of Formula (16) The esters of Formula (15) are treated with a specified stoichiometric amount of an obstructed lithium amide base, preferably two equivalents of lithium hexamethyldisilazide, in an inert aprotic solvent , preferably tetrahydrofuran, at -78 ° C for 15 to 45 minutes, after which two or more equivalents of trialkylsilyl chloride, preferably chlorotrimethylsilane, are preferably added, and the reaction solution is subsequently heated from 50 to 70 ° C. Reflux for 30 minutes to 4 hours, then allow to cool, and stop with methanol. The usual aqueous preparation leads to the isolation of the allyl compound (16), which is purified by conventional means.

Step 4 - Preparation of the Compounds of the Formula (17) The acids of the Formula (16) are esterified to be classified in the carboxyl terms. This esterification can be carried out by any of several means known to those skilled in the art, preferably with an appropriate isourea to prevent racemisation, for example, with O-benzyl-N, N'-diisopropylurea in inert solvent such as chloroform, at reflux for 3 to 6 hours. The diester (17) is isolated and purified by conventional means.

Step 5 - Preparation of the Compounds of the Formula (18) The selective mono-deprotection of the diesters of the Formula (17) is preferably carried out by means of the usual allyl ether decomposition conditions, as discussed above for the Reaction Scheme I. A solution of the diester (17) is placed in polar aprotic solvent, preferably acetonitrile, with palladium catalyst, for example with tetrakis- (triphenylphosphine) -palladium (0) and an excess secondary amine base, preferably morpholine at room temperature for 15 minutes to four hours, preferably 30 minutes. The acid product of Formula (18) is isolated and purified in the usual manner.

Preparation of the Compounds Formula (2) For the simultaneous protection of the functionality of R4 and Rs for certain compounds of Formula I, for example, where R is allyl and R5 is carboxyl, the halolactone-amide of the formula is prepared (2) . The synthesis of these compounds of Formula (2) uses the methods described for Formula II in Reaction Scheme V, as shown in the following Reaction Schemes VIII and IX. In Reaction Scheme VIII, the monoacid (19) is subjected to conventional coupling (as described for Reaction Scheme V) with the amine of Formula (10) to provide the amide of Formula (20), which is deprotected for the amine of the Formula (20). twenty-one) . The pyrrole ring is formed (as in the preparation of the pyrroles of Reaction Scheme V) in the amine (21) with dimethoxy-furan (7) to obtain the products of the Formula (2).

REACTION SCHEME VIII Step 1 - Preparation of the Compounds of the Formula (20). The coupling of the acid (19) and the amine (10) is carried out under the usual peptide amide formation conditions as described above in Reaction Scheme V, Step 2.

Step 2 - Preparation of the Compounds of the Formula (21) The deprotection of the amine (20) for the amine salt (21) is carried out as described above for the preparation of the amines of the Formula (6). ) in Reaction Scheme VI, Stage 2.

Step 3 - Preparation of the Compounds of Formula (2) The formation of pyrroles of Formula (2) from (21) and (7) can be carried out as described above in Reaction Scheme V , Step 1. An alternate route for the compounds of Formula (2) proceeds through the formation of pyrrole (23) prior to coupling, as illustrated by the following Reaction Scheme IX: REACTION SCHEME IX Step 1 - Preparation of the Compounds of the Formula (22) The deprotection of the monoacid (19) for the amine salt (22) is as described above for the preparation of the amines of the Formula (6) in the Scheme of Reaction VI, Stage 2.

Step 2 - Preparation of the Compounds of the Formula (23) The condensation and cyclization of the compounds (22) and (7) provides the pyrroles of the Formula (23) in the same manner as discussed above for the Scheme of Reaction V, Stage 1.

Step 3 - Alternate Preparation of the Compounds of the Formula (2) The coupling of the acid (23) and the amine (10) is carried out with the usual peptide amide formation conditions described above for Reaction Scheme V, Step 2. For the preparation of the intermediates of the last step of the Formula (2), they need the aspartate derivatives of the Formula (19). As shown in the following Reaction Scheme X, intermediate (16) is cyclized alternately to produce the halolactones (25), which protect the carboxylate completely and the final olefin is R5 of R4 in a previous step. .

X REACTION SCHEME Step 1: Preparation of the Compounds of the Formula (25) The carboxy-olefins of the Formula (16) in an inert solvent suspension, for example tetrahydrofuran or acetonitrile, and excess aqueous alkali, preferably sodium bicarbonate, are exposed to excess halogen, preferably iodine, initially at -10 to 0 ° C, then left to warm and equilibrate at room temperature for a period of 2 to 24 hours. The halolactone product (25) is isolated and purified according to customary methods.

Step 2: Preparation of the Compounds of the Formula (19) The compound (19) is prepared from the compound of the Formula (25) in a manner identical to that described above for the preparation of the compounds of the Formula ( 18) in Reaction Scheme VII, Step 5.

Preparation of Tetrahydrofurans of Formula (7) Tetrahydrofuran of Formula (7), where Ri is hydrogen and X is a single bond, is commercially available. Frequently, most of the 3-substituted furans (26) are treated with bromine in methanol to provide 2,5-dimethoxy-dihydrofurans (27), which in turn are hydrogenated to produce tetrahydrofurans (7). The total approach is illustrated in the following Reaction Scheme XI: XI REACTION SCHEME (26) Step 1 - Preparation of the Compounds of the Formula (27) The furans of the Formula (26) are treated with stoichiometric amounts of bromine in methanol as solvent or in mixtures with fewer polar solvents, at temperatures of -20 ° C to room temperature , preferably -10 ° C, for 10 minutes to 8 hours, preferably for 90 minutes. The products (27) are isolated and purified by conventional means.

Step 2 - Preparation of the Compounds of the Formula (7) The olefins of the Formula (27) are reduced in a suitable protic or aprotic solvent under hydrogen at one atmosphere or higher in the presence of a metal catalyst, preferably rhodium on alumina or palladium on carbon, in the temperature range of about 0 ° C to 40 ° C, for about 1 to 8 hours, preferably 3 hours. The compounds (7) are isolated and purified by conventional means. The tetrahydrofuran (7a) of Formula (7), wherein X is a single bond and Ri is formyl (-CHO) is commercially available. The construction of the various combinations of X and Ri is possible through the elaboration of carboxaldehyde. A possible sketch is shown in the following Reaction Scheme XII.

REACTION SCHEME XII (7b) Step 1 - Preparation of the Compound of Formula (28) As an example, the aldehyde of Formula (7a) is added to a mixture with at least two equivalents of the reagent formed from carbon tetrabromide, triphenylphosphine and zinc powder in dichloromethane for 24 hours at room temperature. After 60 minutes at room temperature, the desired 1,1-dibromo-olefin intermediate can be isolated and purified in a conventional manner. The alkyne product of Formula (28) is produced from the treatment of 1,1-dibromo-olefin with alkyl lithium, preferably n-butyllithium, in inert aprotic solvent, preferably tetrahydrofuran, at a low temperature of -78. ° C at 0 ° C after 60 minutes, and subsequent coronation with trialkylstannyl halide, such as chlorotributyl-tin (IV). The product (28) can be handled and purified by customary methods.

Step 2 - Preparation of the Compounds of the Formula (29) The alkyne (28) is worked through an alkylation with the corresponding anion for the compounds of the Formula (7) wherein X is -C = C- and Ri is alkyl , or the alkyne (28) is coupled in a Stille reaction to a compound of the Formula (7) where X is a -C = C- and Ri is aryl. For the above compounds of Formula (29) where Ra is alkyl, a solution of the alkyne (28) in inert solvent at low, ambient or lower temperature, is subjected to metal exchange with a suitable alkyl lithium, and subsequently it is alkylated with a suitable alkylating reagent, for example primary alkyl halides. For the compounds of Formula (29), where Ri is vinyl or aryl, the alkyne (28) and the vinyl halide or aryl are coupled in the presence of palladium catalyst, such as tetrakis- (triphenylphosphine) palladium (0), with aprotic solvent at lower or higher temperature than room temperature. The products of Formula (29) are isolatable and can be purified by conventional techniques.

Step 3 - Preparation of the Compounds of the Formula (7b) The alkyne (29) can be hydrogenated in a suitable solvent, with a source of hydrogen, such as hydrogen gas at atmospheric pressure, in the presence of a catalyst, such as palladium on carbon, to provide, for example, the compounds (7b) of Formula (7) wherein X is -CH2CH2-. The products of Formula (7b) can be subjected to the usual handling and purification. Other tetrahydrofurans of the Formula (7), where X is a single bond and Ri is vinyl or aryl are available from the corresponding furans. Adequately functionalized furans arise from the production of the substitute by coupling the appropriate vinyl or aryl pairs: sequential Suzuki, Heck, or Stille couplings, carefully choreographed with olefins, haloaryls, arylboronic acids, aryltriflates and / or tanoalkyl arils can be used to prepare the arylfurans (22), as exemplified in the following Reaction Schemes XIII, XIV, XV and XVI.

An example of a Suzuki-style coupling to develop Rx is shown in the following Reaction Scheme XIII.- REACTION SCHEME XIII Preparation of the Compounds of Formula (32) 3-Bromofuran (30) and the boronic acids of Formula (31), wherein R 8 is aryl or vinyl, in a mixture of inert solvent, for example benzene and aqueous alkali, preferably sodium carbonate, in the presence of a suitable metallic catalyst, are heated at 30 ° to reflux temperature for one to 24 hours. Suitable metal catalysts include tetrakis (tri-phenyl-fos) -palladium (0) or palladium (II) acetate as examples. The product (32) is isolable and can be processed in the usual manner. Alternatively, the performances of the reaction partners can be reversed, for example as shown in the following Scheme XIV where the furan-3-yl-boronic acid (33) and the unsaturated halides of the Formula (34), where X is bromide, iodide, or triflate and R8 is vinyl or aryl, are coupled to result in the compounds (32).

XIV REACTION SCHEME (33) (34) 32) Preparation of the Compounds of the Formula (32) The furan-3-ylboronic acid (33) and the vinyl or aryl halides of the Formula (34) are reacted under conditions similar to those described above for the Reaction Scheme XIII. The Heck coupling represents the additional useful methodology for introducing and processing substituents on unsaturated systems as shown in Reaction Scheme XV which follows: SCHEME 06 REACTION W (M) (35) (32) Alternate Preparation of the Compounds of the Formula (32) The 3-Bromofuran (30) and the olefinic compounds of the Formula (35), wherein R 8 is aryl or vinyl, are placed in an inert solvent suspension, in the presence of a metal catalyst , preferably tetrakis (triphenylphosphine) -palladium (0) or palladium (II) acetate with catalytic tertiary phosphine, preferably tri (o-tolyl) phosphine or tri (o-tolyl) arsine, at room temperature at reflux during a 24 hours. The product (32) is isolable and can be processed in the usual manner. For the larger Ri groups, further processing of the smaller Ri groups can be obtained from different coupling conditions, in a manner complementary to those reactions1 represented in Reaction Schemes XIII, XIV, and XV above. For example, once the above methods are used to prepare a furan of Formula (36), this in turn can be manipulated to join an additional vinyl or aryl group as shown in the following Reaction Scheme XVI: SCHEME OF REACTION XVI Step 1: Preparation of the Compounds of the Formula (37) The phenol of the Formula (36) in an inert solvent solution, for example chloroform, in the presence of amine base, preferably 2,6-lutidine, at a temperature of -10 ° C or higher, preferably 0 ° C, is treated with a stoichiometric amount of trifluoromethanesulfonic anhydride. The triflate product (37) is potentially reactive; It can be isolated and purified under anhydrous conditions in an inert atmosphere and must be used quickly.

Step 2: Alternate Preparation of the Compounds of the Formula (32b) Either the triflate of the Formula (37) or the vinyl halide of the Formula (37a) is coupled with trialkyl-vinyl or aryl-tin (IV) of the Formula (38) in an inert solvent solution, such as benzene, in the presence of a metal catalyst, such as palladium (II) acetate, with a stoichiometric amount of lithium chloride at room temperature or higher. The coupled product (32b) is subjected to conventional isolation and purification. The components constituting the furan in Reaction Schemes XIII, XIV, XV, and XVI are readily available. 3-Bromofuran (30) can be purchased from Aldrich. Furan-3-yl-boronic acid can be prepared, for example, as described in Thompson, W. J; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243. The furans of Formula (36) can be synthesized using the methodology indicated in the foregoing for Reaction Schemes XIII, XIV, XV and XVI. The boronic acids of the formula (31) are known in the literature or can be synthesized. The organotin compounds (IV) of the Formula (38) are also known in the literature or can be synthesized.

PREPARATION OF THE COMPOUNDS OF FORMULAS III, IV, V, VI, VII AND VIII All the compounds of Formulas III, IV, V, VI, VII and VIII, where R5 is carboxyl can be produced from the corresponding esters as described above for Formula I in Reaction Scheme I. The compounds of Formulas III, IV, V, VI , VII and VIII, where R5 is N-hydroxy-carbamoyl (-C (O) NHOH) can be produced by the method described above for Reaction Scheme 11. The heterocyclic acetic acid derivatives of the Formula (40) , wherein Rg is alkoxy, alkylamino, or oxazolidin-3-yl, are alkylated with a-haloesters of Formula (39) wherein X is chloride, bromide, iodide, or triflate for the objective esters of Formula (41) as it shows immediately in the Reaction Scheme XVII. The Rg group of the compounds of Formula (40) can serve as a chiral auxiliary to help establish the absolute stereochemistry of the compounds of Formula (41).

REACTION SCHEME XVII Solutions of the compounds of Formula (40) in inert solvent, preferably tetrahydrofuran, are added to solutions with stoichiometric and / or defined amounts of a suitable base, for example, sodium hexamethyldisilazane or lithium diisopropylamide, in inert solvent , preferably tetrahydrofuran, at low temperature, preferably from -78 to -15 ° C, for five minutes to one hour, are suitable to effect the formation of the corresponding anion. Then the a-haloesters of Formula (39) are added alone or in an inert solvent solution. The reaction mixture is allowed to stir for 30 minutes to 24 hours, preferably one hour, to form the objective esters (41), which are isolated and purified by customary methods. For an example of the alkylation process indicated by Reaction Scheme XVII, where R9 is a chiral auxiliary, see Reaction Scheme XVIII below. According to this Scheme, the amides of Formula (40), wherein R9 are chiral oxazolidines (see the following Formula (42)) can be subjected to stereoselective alkylation to provide the products of Formula (43), which at their they may again provide hydroxyethylamines of the Formula (44) (Formula I, where R5 is an ester, Y is -CH (OH) -).

REACTION SCHEME XVIII (44) Step 1 - Preparation of the Compounds of the Formula (43) The compounds of the Formula (43) are prepared from the compounds of the Formula (40) wherein R9 is a chiral oxazolidine under conditions identical to those described in the above for the preparation of the compounds of Formula (41) from the compounds of Formulas (39) and (40) in Reaction Scheme XVII, except that the compounds of Formula (42) are replaced by compounds of the Formula (40). The product of Formula (43) is subject to conventional isolation and purification.

Step 2 - Preparation of the Compounds of the Formula (44) The compounds of the Formula (43) in solvent, such as tetrahydrofuran, are treated with excess acid, preferably diluted, 0.5 molar aqueous hydrochloric acid, from room temperature to reflux , preferably the first one. The product of Formula (44) is isolated and purified by customary methods. The disubstituted heterocycles of the Formula (41) can also be joined in a variation of the order of execution shown in the above in Reaction Scheme XVIII. The alkylations in Schemes XVII and XVIII above may precede the installation or processing of the portion containing X and Ri. The last stages use appropriate sequences of the coupling methods analyzed in Reaction Schemes XIII, XIV, XV and XVI. For example, in the following Reaction Scheme XIX, the monosubstituted heterocycle of Formula (46) could be halogenated to an appropriately disubstituted heterocycle of Formula (47), which in turn is a coupling partner for the methodology outlined in US Pat. Reaction Schemes XIII, XIV, XV and XVI. In this example, a Suzuki coupling with boronic acid of Formula (31) is used to provide a compound of Formula (48).

REACTION SCHEME XIX 01) PREPARATION OF STARTING MATERIALS The a-haloesters of Formula (39), where R is hydrogen, are commercially available. When R4 is alkyl, many compounds of the Formula (39) can be prepared by the synthesis described in the literature. For example, many amino acids can be converted to optically active compounds of Formula (39), where R is alkyl, as described in Coppola, G.M., Schuster, H. F. Asymmetric Synthesis: Construction of chiral molecules using amino acids; J. Wiley & Sons: New York, 1987.

Certain heterocyclic acetic acid derivatives of Formula (40) are commercially available in certain cases (eg, 2- or 3-thiophene acetic acid), although usually they must be synthesized in various ways, as described in the following. The direct alkylation on the nitrogen of an appropriate heterocycle of Formula (49), wherein T, U and V are each independently carbon or nitrogen, by the a-haloacetic acid derivatives of Formula (50), wherein X is halogen or triflate, produces the desired intermediates of Formula (51), as shown in the following Reaction Scheme XX: ESQUEMADE REACTION XX (49) (50) (51) Step 1 - Preparation of the Compounds of the Formula (51) The nitrogen-containing heterocycles of the Formula (49) (for example, pyrazole) are placed in aprotic solvent such as N, -dimethylformamide , and if warranted, are deprotonated with a base such as sodium hydride and treated with a-haloacetamides of Formula (50) wherein X is halogen or triflate, at room temperature or higher for one to 24 hours. The products of the Formula (51) are subject to usual isolation and purification techniques. A direct, analogous substitution of the heterocyclic ring involves the alkylation of an organometallic derivative of the Formula (53) wherein M is, for example, lithium, magnesium, or copper, with an a-haloacetic acid derivative of the Formula (50) , as shown in the following Reaction Scheme: REACTION SCHEME XXI (50) (40) Step 1 - Preparation of the Compounds of the Formula (53) The heterocyclic metallo derivatives of the Formula (53) are available in the usual manner from a heterocycle of the Formula (52). The main methods include deprotonation of the matrix of Formula (52) wherein W is hydrogen, or from the halogen-metal exchange of the corresponding halo-heterocycle of Formula (52) wherein W is halogen. These reactions are typically carried out in inert aprotic solvent such as tetrahydrofuran, at room temperature or below, from 15 minutes to 24 hours. The organometallics of the Formula (53) are usually unstable in contact with the atmosphere and humidity. They are formed in the usual way i n if t u and are used immediately without isolation.

Step 2 - Alternate Preparation of the Compounds of the Formula (40) The organometallics of the Formula (53) are alkylated by stoichiometric or excess amounts of acetate or acetamide of the Formula (50) in inert solvent, preferably tetrahydrofuran, at low temperature from -78 to 0 ° C, for ten to 90 minutes. The product of Formula (40) is isolated and purified by customary methods. As another alternative, an acylation can be carried out with oxalates or oxamates of the Formula (54), where Rio is, for example, halogen, alkoxy, or imidazol-1-yl, for the ketoesters or ketoamines of the Formula (55). ), which are subsequently deoxygenated in various stages for the ester or amides of Formula (40), as shown in the following Reaction Scheme XXII.

REACTION SCHEME XXII Step 1 - Preparation of the Compounds of the Formula (55) The heterocyclic organometallic derivatives of the Formula (53), wherein M is lithium, can be prepared as shown in Reaction Scheme XII above and can be acylated by an oxalate or oxamate of Formula (54) wherein Ri0 is typically halogen, alkoxy, or imidazol-1-yl in inert solvent, preferably tetrahydrofuran, at low temperatures of -78 to 0 ° C, for ten to 90 minutes. The product of Formula (55) is isolated and purified by customary methods.

Step 2 - Preparation of the Compounds of the Formula (56) The ketoester or amide of the Formula (55) in solvent, preferably ethanol, at temperatures of -15 to 0 ° C, is treated with a hydride reducing agent, sodium borohydride preference, for five minutes to four hours to provide the products of Formula (56), which are isolatable and purified by conventional techniques.

Step 3 - Preparation of the Compounds of the Formula (57) The alcohols of the Formula (56) can be processed for deoxygenation by conversion to the various portions designated Q, preferably where Q is an ester or halide. Typically they are acylated in aprotic solution, for example, chloroform, with the excess acylating agent, for example acetic anhydride or acetyl chloride in the presence of an excess amine base, preferably pyridine, with or without catalytic amounts of (4) -dimethylamino) pyridine to provide the acetates of Formula (57) where Q is acetoxy, which are manipulated and purified in the usual manner.

Step 4 - Preparation of the Compounds of the Formula (40) The α-halides or acetates of the Formula (57) wherein Q is halogen or acetoxy, respectively, are reduced to the products of the Formula (40) with a metal catalyst, preferably palladium on carbon, and a source of hydrogen, preferably ammonium formate. The products (40) are handled and purified in a conventional manner. The disubstituted heterocycles of the Formula (40) can also be constructed in a differently ordered sequence: recent formation of the portion containing X and Ri by using the appropriate sequences of the coupling methods discussed in Reaction Schemes XIII, XIV, XV, and XVI. Many of the monosurbed heterocycles which are commercially available carry only one carbon in the substituent, and further processing is necessary to prepare the disubstituted heterocycles of Formula (40), as shown in the following Scheme of 'Reaction XIII. The commercially available mono-substituted heterocycles of the Formula (58), where Ru is hydrogen, hydroxy, or alkoxy (eg, 3-furan carboxaldehyde or 3-furfural, where Rn is hydrogen) can be homologated through any of several suitable methods known to those skilled in the art, for example, as described in Martin, SF Syn the si s 1979, 633-665, to provide the 2-heterocyclic acetic acid derivatives (59), which are they can be substituted additionally, for example as a halide of the Formula (60). Alternatively, the heterocycles of Formula (58) are substituted as halides of Formula (61), then homologated to the derivatives of Formula (60). Subsequent binding of a compound of Formula (60) with an appropriate coupling partner such as a compound of Formula (31) provides the esters or amides of Formula (62). As recognized by those skilled in the art, the versatility of the methods of Reaction Scheme XXIII allows the interchangeability of the stages. For example, substitution of the halides of Formula (61) with the boronic acids of Formula (31) may precede a homologation to the desired intermediates of Formula (62) (not shown).

REACTION SCHEME XXIII Step 1 - Preparation of the Compounds of the Formulas (59) and (60) The heterocycles of the Formulas (58) and (61) are homologous to the compounds of the Formulas (59) and (60), respectively, depending on the nature of Ru and R9. See, for example, Martin, S. F. Syn th esi s 1979, 633-665. As an example, for compounds (58) and (61), when Rn is hydrogen, the anion of 2-trimethylsilyl-3, 3-dithiane in inert aprotic solvent, preferably tetrahydrofuran at low temperature, from 0 ° to -78 ° C for 30 minutes at several hours, to obtain the corresponding ditian adduct, which is subsequently converted through any of a variety of methods to the derivatives of the Formula (59). An example of dithian elimination uses mercuric chloride in water and alcohol to produce an ester of the Formula (59) where R9 is alkoxy. The products of Formula (59) are subject to conventional handling and purification.

Stage 2 - Preparations of the Compounds of the Formulas (60) and (61) As an example of the introduction of the second heteroaromatic substituents, the compounds of Formulas (59) and (58) are halogenated in an inert solvent, for example, with a bromine source, such as bromine. or N-bromosuccinimide, at room temperature or lower, for one hour to one day. The resulting heteroaryl halides of Formulas (60) and (61), respectively, are subjected to customary purification and handling.

Step 3- Preparations of the Compounds of the Formula (62) The coupling of the heteroaryls of the Formula (60) is carried out analogously to that described for Reaction Schemes XIII, XV, or XVI to obtain the compounds of the Formula (62). Amides with the generic Formula (40), where R9 is alkylamino, are often available from the corresponding carboxylic acid or corresponding activated esters of Formula (40) wherein R9 is alkoxy or hydroxy, as exemplified in the following Reaction Scheme XXIV: SSQUEMADE REACTIONXXIV The formation of the amides (64) (ie, the Formula (40) wherein R9 is alkylamine) results from the acids of the Formula (63) which are coupled with the amines of the Formula (10) under the same conditions described above for Reaction Scheme V, Step 2. The products of Formula (64) are isolated and purified by conventional methods. The oxazolidines of Formula (42) can be made from the acetamides of Formula (65) where Y, in the terms of Formula I, is -CH (OH) -, as shown in the following Reaction Scheme XXV: REACTION SCHEME XXV The hydroxyamides of Formula (65) are placed in a solution containing acetone or its equivalent, preferably 2-methoxypropene, with a catalytic amount of acid, such as p-toluenesulfonic acid, under dehydration conditions, such as entrapment of water. with a Dean-Stark apparatus, at room temperature at reflux, for an adequate amount of time to convert the starting materials (65). The product (42) is subject to the usual processing for isolation and purification.

A preferable way to reach the oxazolidines of Formula (42) involves the coupling of the oxazolidines of Formula (67) with the acetic acids of Formula (63), as shown in the following Reaction Scheme XXVI. The oxazolidines (67) in turn originate from amino-alcohols of the Formula (66) of commercial and synthetic origin.

REACTION SCHEME XXVI Step 1 - Preparation of the Compounds of the Formula (67) The compounds of the Formula (67) are prepared from the compounds of the Formula (66) using a method similar to that described above for the preparation of the compounds of Formula (42) of Reaction Scheme XXV, except that lower temperatures are preferred. The products of Formula (67) may be somewhat unstable and are used in the usual way i n if t u or immediately in the next reaction without purification.

Step 2 - Alternative Preparation of the Compounds of the Formula (42) Conditions for the formation of amides with typical coupling reagents as discussed above for Reaction Scheme V, Step 2, are applied for the preparation of the compounds of the Formula (42). Rings can be constructed for mono-substituted heterocycles that are not commercially available. For example, for the compounds of Formula III, as shown below in Reaction Scheme XXVII, the tetrahydrofurans of Formula (68), where Ri2 is hydrogen or alkyl, are condensed with the amines of Formula (69) to provide the pyrroles of the Formula (70).

Depending on the nature of X and Ri, R12 of the pyrrole (70) can be converted from hydrogen to a halogen and subsequently an alkyl (as in Reaction Scheme XXII, for example).

OE REACTION XXVII SCHEME Preparation of the Compounds of the Formula (70) The compounds of the Formula (70) can be prepared from the compounds of the Formulas (68) and (69) using the conditions identical to those described for the preparation of the pyrroles of Formula II in Reaction Scheme IV.

EXAMPLES The following examples are merely illustrative of the invention and should not be construed as limiting the invention. Examples include preferred embodiments of the inventive compounds. Someone with experience in the art can make, without undue experimentation, various substitutions and variations.

Example 1 (a). N- (1 (S) -Benzy-2-hydroxyethyl) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -synatamic acid A suspension of 10% Pd / C (type DeGussa humid, 15 mg) and benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (biphenyl-4- il) -1H-pyrrol-1-yl] succinnamic acid (68 mg, 0.12 mmol) in EtOAc (5 mL) is stirred under H2 for 20 hours. The catalyst is filtered over Celite and rinsed with MeOH. The filtrate is concentrated under reduced pressure to provide a yellow oil, which is purified by flash column chromatography with a stepwise elution gradient with 1% HOAc / 2-5% MeOH / CH2Cl2 to give 47 mg ( 82%) of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] succinnamic acid as a soft solid . NMR ^ (CDCIS): d 7.66-7.48 (m, 3H), 7.42 (t, 2H, J = 7.2 Hz), 7.34-7.28 (, 1H), 7.21-7.12 (m, 2H), 7.04-6.96 (m , 1H), 6.94 (broad s, 1H), 6.68 (dd, 1H, J = 2.5, 2.5 Hz), 6.55 (dd, 1H, J = 1.6, 1.6 Hz), 5.78 (broad d, 1H, J = 7.5 Hz), 4.90 (t, 1H, J = 7.2 Hz), 4. 36-4.02 (m, 1H), 3.68 (dd, 1H, J = 3.4, 11.2 Hz), 3.50 (dd, 1H, J = 5.3, 9.0 Hz), 3.31 (dd, J = 5.9, 7.4 Hz), 3. 12 (dd, 1H, J = 7.2, 17.1 Hz), 2.74 (ddd, 1H, J = 6.2, 14.3, 14.3 Hz), 2.68 (ddd, J = 8.7, 14.0, 14.3 Hz). GO (film): 3387, 3028, 2931, 1715, 1660, 1532, 1494, 1204, 702, 698 cm "1. EMARFAB: Calculated for C29H28 204Cs (M + CsA: 643.1209. Found: 643.1185.

Anal, calculated for C29H28N204 • 0.1 CHC13 • 0.35 H20: C, 71.80; H, 5.96; N, 5.75. Found: C, 71.92; H, 5.87; N, 5.77. The starting material, N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] succinamic acid benzyl ester, It is prepared as follows: Benzyl Ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (t-butoxycarbonylamino) succinamic acid To a solution of ß-benzyl ester of Nt-butoxycarbonyl-D-aspartic acid (2.00 g, 6.20 mmol) in CHCl3 (80 mL) at 0 ° C is added in succession 1- (3-dimethylaminopropyl) -3- hydrochloride. ethyl carbodiimide (EDC, 1.30 g, 6.82 mmol) and N-hydroxybenzotriazole hydrate (HOBt • H20, 1.04 g, 6.82 mmol). After 10 minutes at 0 ° C, 2S-amino-3-phenyl-1-propanol (936 mg, 6.20 mmol) is added and the resulting mixture is allowed to warm to room temperature overnight. After 20 hours, the mixture is stirred with 10% aqueous HCl (5 mL) and saturated aqueous NH 4 Cl (25 mL). The separated aqueous layer is extracted with more CHC13 (2 x 10 mL). The combined organic extracts are washed with saturated aqueous NaHCO3: H20 (25:25 mL) twice, dried over Na2SO4 and concentrated in vacuo with a yellow foam, 2.84 g, which is recrystallized from EtOAc / hex in crops. successively to yield 2.34 g (83%) of benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (t-butoxycarbonylamine) succinnamic acid as white micro-needles, mp 94-95 ° C. XH NMR (CDC13): d 7.40-7.10 (m, 10H), 6.81 (d, 1H, J = 10.8 Hz), 5.55 (d, 1H, J = 7.2 Hz), 5.11 (ddd, 2H, J = 1.2, 6.9, 7.4 Hz), 4.50-4.32 (broad m, 1H), 4.21-4.04 (m, 1H), 3.68 (dd, 1H, J = 3.4, 11.2 Hz), 3.52 (dd, 1H, J = 5.3, 11.5 Hz), 3.03 (dd, 1H, J = 4.7, 17.1 Hz), 2.86 (dd, 1H, J = 7.2, 13.7 Hz), 2.83 (dd, 1 H, J = 7.2, 13.7 Hz), 2.64 (dd, 1H, J = 5.9, 17.1 Hz), 1.43 (s, 9H). IR (KBr): 3442, 3381, 3307, 1729, 1676, 1656, 1554, 1522, 1300, 1164, 1041, 701 cm. "1 Anal." Calculated for C25H32 206: C, 65.77; H, 7.07; N, 6.14 Found: C, 65.74; H, 7.10; N, 6.20. 4-biphenylboronic acid 4-biphenylboronic acid is prepared in a different way from that described in the literature (see Yabroff, D. L .; Branch, G. E .; Bettman, B. J. Am.

Ch em. Soc. 1934, 56, 1850-1857). To a solution of 4-bromobiphenyl (2.00 g, 8.58 mmol) in THF (20 mL) a -78 ° C n-butyllithium (4.0 mL of 2.5 M in hexanes) is added in a slow stream via syringe.

After 15 minutes, triisopropylborate is added (3.0 mL, 13 mmol) in a slow stream via syringe. After 10 minutes, the resulting homogeneous solution is allowed to warm to room temperature for 45 minutes and divided between EtOAc (50 mL) and 10% aqueous HCl (50 mL). The aqueous layer is separated and extracted with more EtOAc. The combined organic layers are washed with brine, dried over NaSO4 and concentrated to give an unpurified product which is triturated with hexanes to yield 1.53 g (90%) of 4-biphenylboronic acid as a white solid. NMR I (DMS0-d6): d 8.05 (s, 2H), 7.83 (d, 2H, J = 8.5 Hz), 7.65 (d, 2H, J = 7.0 HZ), 7.60 (d, 2H, J = 8.1 Hz ), 7.43 (t, 2H, J = 7.4 Hz), 7.33 (t, 1H, J = 7.2 HZ). Anal. C? 2 HnB02: C, 72.78; H, 5.60. Found: C, 72.51; H, 5.62. 3- (Biphenyl-4-yl) furan A biphasic mixture of 3-bromofuran (2.90 L, 32.1 mmol), benzene (70 mL) and aqueous 2N Na2CO3 (50 mL) is degassed and purged with argon. Sequentially, tetrakis (triphenylphosphine) -palladium (O) (3.7 g, 3.2 mmoles) and a solution of 4-biphenylboronic acid (6.36 g, 32.1 mmoles) in EtOH are added. (50 mL). The mixture is heated at 80 ° C for 18 hours, allowed to cool and divided between CH2C12 and H20. The aqueous layer is separated and extracted with CH2C12 twice. The combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated to an unpurified product, which is dissolved in a minimum amount of CH 2 Cl 2 and applied to a flash chromatography column packed with hexanes. Elution with 10% CH2Cl2 / hex leads to some mixed fractions, which are re-chromatographed. A total of 5.37 g (76%) of 3- (biphenyl-4-yl) furan is obtained as a pale yellow oil. XH NMR: d 8.28 (s, 1H), 7.64-7.55 (m, 6H), 7.50 (s, 1H), 7.45 (t, 2H, J = 7.35 Hz), 7.40 (t, 1H, J = 7.35 Hz) , 6.75 (s, 1H). Anal. calculated for C? 6H? 20: C, 87.25; H, 5.49. Found: C, 87.15; H, 5.52. 3- (Biphenyl-4-yl) -2-5-dihydro-2, 5-dimethoxy furan To a suspension of 3- (biphenyl-4-yl) furan (100 mg, 0.450 mmol) and Na2CO3 (48 mg, 0.45 mmol) in benzene (1 L) and MeOH (1 mL) at -10 ° C is added bromine (22 μL, 0.43 mmol) per drip via syringe. After 30 minutes at -10 ° C, the mixture is diluted with EtOAc and filtered twice. The filtrate is concentrated to give an unpurified solid which is purified by flash column chromatography with an elution gradient of 0-1% EtOAc / CH2Cl2 to give 90 mg (74%) of a diastereomer mixture of 3- ( biphenyl-4-yl) -2,5-dihydro-2, 5-dimethoxy furan as a colorless oil. 1B-NMR (CDC13): d 7.70-7.28 (m, 9H), 6.35 (dd, 0.75H, major isomer, J = 0.9, 0.9 Hz), 6.30 (d, 0.25H, minor isomer, J = 6.0 Hz), 6.04-6.03 (m, 1H, major + minor isomer), 5.71 (d, 0.75H, major isomer, J = 0.9 Hz), 3.60-3.40 (m, 6H). Anal. Calculated for C? 8H? 803: C, 76.57; H, 6.43. Found: C, 76.52; H, 6.38. 3- (Biphenyl-4-yl) -2,5-dimethoxytetrahydrofuran A mixture of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran (1.00 g, 3.55 mmol) and 5% Pd / C (300 mg) in EtOH: EtOAc (1: 2) stir under H2 atmosphere for 1.75 hours. The catalyst is filtered over Celite. The filtrate is concentrated to give 0.97 g (97%) of a tereomeric 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran as a colorless oil which is typically used without purification. NMR 1] l: d 7.60-7.53 (m, 4H), 7.45-7.28 (m, 5H), 5.26 (t, 1H, J = 5.5 Hz), 5.02 (d, 1H, J = 4.4 Hz), 3.54 ( s, 3H), 3.36 (s, 3H), 2.63-2.53 (m, 1H), 2.41-2.30 (m, 1H). Anal, calculated for C? 8H2o03: C, 76.03; H, 7.09. Found: C, 75.74; H, 6.92.

Benzyl Ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -synatamic acid To a solution of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (t-butoxycarbonylamino) succinamic acid benzyl ester (389 mg, 0.851 mmol) in CH2C12 (5 mL) is added acid trifluoroacetic (1 mL). After 2.5 hours at room temperature, the solvent is removed in vacuo to provide 3 (R) -amino-N- (1 (S) -benzyl-2-hydroxyethyl) succinnamic acid benzyl ester trifluoroacetate salt as a foam yellow that is placed with 3- (biphenyl-4-yl-) 2, 5-dimethoxytetrahydrofuran (182 mg, 0.641 mmol) in HOAc (1 mL) and heated to 50 ° C. After 2 hours, the mixture is allowed to cool, stirred carefully with saturated aqueous NaHCO3 (25 mL), and extracted into CHC13 (3 * 15 mL). The combined organic layers are dried over Na 2 SO and evaporated to give a brown oil, 685 mg. Flash column chromatography with 10% MeOH / CH2Cl2 as eluent affords 276 mg (64%) of benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (3- ( biphenyl- -yl) -1H-pyrrol-1-yl) succinnamic acid as a yellow solid. RMN 1ñ (CDCA): d 7.70-7.48 (m, 10H), 7.44 (dd, 2H, J = 7.2, 7.8 Hz), 7.38-7.12 (m, 5H), 7.08-6.98 (m, 2H), 6.89 (m wide) , 1H), 6.63 (dd, 1H, J = 2.5, 2.5 Hz), 6.54 (dd, 1H, J = 1.2, 1.2 Hz), 5.76 (d, 1H, J = 7.5 Hz), 5.10 (dd, 2H, J = 12.1, 15.9 Hz), 4.95 (dd, 1H, J = 5.0, 8.7 Hz), 4.34-4.00 (broad m, 1H), 3.66 (dd, 1H, J = 3.7, 11.2 Hz), 3.49 (dd, 1H, J = 5.3, 11.2 Hz), 3.37 (dd, 1H, J = 5.0, 16.8 Hz), 3.18 (dd, 1H, J 8.7, 16.8 Hz), 2.74 (ddd, 2H, J = 6.5, 13.7, 15.9 Hz). IR (KBr): 3314, 3029, 2925, 1731, 1658, 1548, 1495, 1355, 1196, 1165, 361.698 cm "1; Anal, calculated for C36H34N204 • 0.5 H20: C, 76.17; H, 6.22; N, 4.94 Found: C, 76.24; H, 6.18; N, 4.97.

The following was prepared in a similar way: Example 1 (b). N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (R) - (3-phenyl-lH-pyrrol-1-yl) -synatamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -3 (R) - (3-phenyl-1H) -pyrrol-1-yl) succinamic acid (371 mg, 0.781 mmol) in MeOH (15 mL) is hydrogenated to provide 301 mg (100%) of N- [2,2-dimethyl-l (S) - (methylcarbamoyl) acid) -propyl] -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinnamic acid as a yellow foam. AH NMR (CDC13): d 7.50-7.20 (m, 4H), 7.15 (tt, 1H, J = 1.2, 7.3 Hz), 7.06 (dd, 1H, J = 2.0, 2.0 Hz), 6.78 (dd, 1H, J = 2.5, 2.5 Hz), 6.48 (dd, 1H, J = 1.6, 2.8 Hz), 5.20 (t, 1H, J = 6.9Hz), 4.20 (d, 1H, J = 9.3 Hz), 3.34 (dd, 1H, J = 6.9, 17.4 Hz), 3.06 (dd, 1H, J = 7.2, 17.4 Hz), 2.69 (d, 3H, J = 4.7 Hz), 0.93 (s, 9H); IR (KBr): 3318, 2966, 1718, 1654, 1559, 1542, 1202, 745 cm "1. EMARFAB: Calculated for C2iH27N30Cs (M + Cs +): 518.1056. Found: 518.1037.Analyzed Calculated for C2? H27N304 • 0.3 CHC13: C, 60.73; H, 6.53; N, 9.97, Found: C, 60.70; H, 6.58; N, 9.64, The starting material, benzyl ester of N- [2,2-dimethyl-l (S)] - (Methylcarbamoyl) propyl] -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic, is given as follows: Benzyl Ester of 3 (R) -t-Butoxycarbonylamino- N- (2-2-dimethyl-l (S) - (methylcarbamoyl) propyl) -succinamic acid To a solution of β-benzyl ester of N-t-butoxycarbonyl-D-aspartic acid (2.19 g, 6.77 mmol) in DMF (40 mL) is added in succession 4-methylmorpholine (NMM, 13.5 mmol, 1.49 mL), 2- (1-H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU, 2.17 g, 6.77 mmoles) and a solution of N-methylamide of L-t-leucine (see Malón, P .; Pancoska, P .; Budesinsky, M .; Hlavacek, JX; Pospisek, J.; Blaha, K. Coll. Czech Chem. Commun. 1983, 48, 2844-2861; 886 mg, 6.15 mmol) in DMF (10 mL). After 3 hours at room temperature, the mixture is stirred with 10% aqueous KHSO4 (25 mL) and water (100 mL) and extracted with CHC13 (100 mL) three times. The extracts of CHC13 are washed with 10% KHS04: H20 aqueous (10: 250 mL)NaHC03: saturated aqueous H20 (100: 200 L), and water (200 mL) three times, dried over Na2SO4, and evaporated to give 2.49 g (90%) of benzyl ester of 3 (R) -t- acid. butoxycarbonylamino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinnamic as a yellow foam, typically used without further purification. Flash column chromatography with 3% MeOH / CHCl 3 as eluent produces an amorphous, analytically pure solid. 1H-NMR: d 7.40-7.30 (m, 5H), 7.03 (d, 1H, J = 9.0 Hz), 5.90 (broad d, 1H, J = 4.7 Hz), 5.56 (broad d, 1H, J = 8.5 Hz) , 5.13 (dd, 2H, J = 2.5, 17.4 Hz), 4.56 (broad d, 1H, J = 7.5 HZ), 4.11 (d, 1H, J = 9.0 Hz), 3.00 (dd, 2H, J = 4.0, 16.2 Hz), 2.85 (d, 3H, J = 4.7 Hz), 1.00 (s, 9H). Anal. Calculated for C23H35N3O6: C, 61.45; H, 7.85; N, 9.35. Found: C, 61.56; H, 7.83; N, 9.27. 2, 5-Dihydro-2, 5-dimethoxy-3-phenyl-furan According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-2, 5-dihydro-2,5-dimethoxifuran, 3-phenylfuran (see Pridgen, LN; Jones, SSJ Org. Chem. 1982, 47, 1590-1592 and Yang, Y., Wohg, HNC Tetrahedron 1994, 32, 9583-9608; 848 mg, 5.89 mmoles) is provided 1.00 g (82%) of 2,5-dihydro- 2,5-dimethoxy-3-phenylfuran as a yellow oil, which is a mixture of about 80:20 diastereoisomers by NMR aH and is used without further purification. XH NMR (CDC13): d 7.64-7.52 (m, 2H), 7.44-7.30 (m, 3H), 6.36-6.30 (m, 0.9H, major + minor isomer), 6.28 (dd, 0.1H, minor isomer, J = 1.2, 3.7 Hz), 6.04-6.00 (m, 0.9H, major + minor isomer), 5.70 (d, 0.8 H, major isomer, J = 1.2 Hz), 3.52 (s, 2. 2H, major isomer), 3.46 (s, 0.60H, minor isomer), 3.43 (s, 2.2H, major isomer), 3.40 (s, 0.60H, minor isomer); Anal. Calculated for C? 2H? 403? 0.04 Br2: C, 67.78; H, 6.64. Found: C, 67.79; H, 6.45. 2, 5-Dimethoxy-3-phenyl-tetrahydrofuran A mixture of 2,5-dihydro-2,5-dimethoxy-3-phenylfuran (590 mg, 2.86 mmol) and 10% Rh / Al203 (110 mg) in EtOAc (10 L) is stirred under H 2 O for 24 h. hours. The catalyst is filtered over Celite and rinsed with EtOAc. The filtrate is concentrated in vacuo to yield 583 mg (98%) of 2,5-dimethoxy-3-phenyl-tetrahydrofuran as a colorless oil which is typically used without further purification. NMR aH: d 7.40-7.18 (m, 5H), 5.30-4.80 (m, 2H), 3.70-3.40 (, 6H), 2.78-2.43 (m, 1.2H), 2.34 (ddd, 0.75H, J = 5.6.12.7, 18.3 Hz), 2.17 (dd, 0.1H, J = 8.4, 12.8 Hz). Anal. Calculated for C? 2H? 60j? 0.2 H20: C, 68.03; H, 7.80. Found: C, 68.11; H, 7.60.

Benzyl Ester Trifluoroacetate salt of Acid 3 (R) -Amino -N- (2, 2-dimethyl-l (S) - (met i Icarbamoi 1) - propyl) succinámico To a solution of 3 (R) -butoxycarbonyl-amino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) succinamic acid benzyl ester (2.05 g, 4.57 mmol) in CHC13 (15 mL ) add trifluoroacetic acid (3 mL). After 2.5 hours at room temperature, more trifluoroacetic acid (3 L) is added, and after 90 minutes, the solvent is removed in vacuo to provide trifluoroacetate salt of benzyl ester of 3 (R) -amino-N acid without purification. - [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinamic as a yellow oil which is used without further purification. NMR ^ U d 7.50-7.20 (, 5H), 5.14 (dd, 2H, J = 12.1, 15.6 Hz), 4.57 (t, 1H, J = 6.2 Hz), 4.33 (d, 1H, J = 8.7 Hz), 3.13 (d, 1H, J = 6.2 Hz), 2.74 (d, 3H, J = 4.7 Hz), 0.93 (s, 9H).

Benzyl Ester of N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) propyl] -3 (R) - (3-phenyl-lH-pyrrol-l-yl) -succinamic acid A 3 (R) -amino-N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -succinnamic acid trifluoroacetate salt solution without purification (2.33 mmoles), 2,5-dimethoxy-3-phenyl-tetrahydrofuran (583 mg, 2.80 mmol), trifluoroacetic acid (216 μL, 2. 80 mmoles) and water (50 μL, 2.8 mmoles) in 1,2-dichloroethane (1 mL) is heated to 70 ° C. After 20 hours, the mixture is allowed to cool and concentrated in vacuo to provide a brown oil, which is purified by flash column chromatography with 0.5% HOAc / 35% EtOAc / hex as eluent to yield 407 mg (37%) N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) -3 (R) - (3-phenyl-1H-pyrrol-1-yl) succinamic acid benzyl ester as a yellow foam. 1E NMR: d 7.52.7.44 (m, 2H), 7.38-7.15 (m, 3H), 7.04 (dd, 1H, J = 1.8, 1.8 Hz), 6.78 (t, 1H, J = 2.5 Hz), 6.56 ( dd, 1H, J = 1.6, 2.5 Hz), 6.42 (d, 1H, J = 9.0 Hz), 5.95 (broad d, J = 4.0 Hz), 5.18-5.04 (m, 3H), 4.30 (d.1H, J = 9.0 Hz), 3.38 (dd, 1H, J = 5.9, 16.8 Hz), 3.10 (dd, 1H, J = 8.4, 16.8 Hz), 2.72 (d, 3H, J = 5.0 Hz), 0.93 (s, 9H). IR: 3301, 2960, 1736, 1645, 1542, 1166, 752, 695 cm. "1 EMARFAB: Calculated for C28H33N3? 4CS (M + CS +): 608.1525. Found: 608.1549. Anal. Calculated for C28H33N3O4 • 0.2 H20: C. , 70.18; H, 7.03, N, 8.77, Found: C, 70.45; H, 6.99; N, 8.84.

Example 1 (c). N- (8-Oxo-4-oxa-l, 7-diazatricyclo- [9.6.1.012 17] -octadeca-ll (18), 12, 1, 16-tetraen-9 (S) -yl) -3 ( R) - (3-phenyl-lH-pyrrol-1-yl) succinnamic According to the procedure described in Example 1 (a), the benzyl ester of N- (8-oxo-4-oxa-1, 7-diazatricyclo [9.6.1, O12'17] octadeca-ll (18) , 12,14,16-tetraen-9S-yl) -3 (R) - (3-phenyl-1H-pyrrol-1-yl) succinnamic acid is hydrogenated to yield, in 94% yield, the N- (8 -oxo-4-oxa-l, 7-diazatricyclo [9.6.1, O12'17] octadeca-11 (18), 12, 14, 16-tetraen-9 (S) -yl) -3 (R) - ( 3-phenyl-lH-pyrrol-1-yl) succinnamic as an amorphous solid. XH NMR (CD3CN): d 7.65 (d, 1H, J = 7.4 Hz), 7.48 (d, 2H, J = 7.7 Hz), 7.39 (d, 1H, J = 8.1 Hz), 7.33 (t, 2H, J = 7.7 Hz), 7.23-7.13 (m, 3H), 7.11 (s, 1H), 6.97 (s, 1H), 6.78-6.71 (m, 2H), 6.43 (t, 1H, J = 2.0 Hz) , 5.46-5.43 (broad m, 1H), 5.11 (t, 1H, J = 7.2 Hz), 4.42-4.34 (m, 1H), 4.28-4.10 (, 2H), 3.45-3.24 (m, 5H), 3.07 -2.76 (m, 5H). Anal. Calculated for C29H3oN405 • 0.35 H20 • 0.1 MTBE: C, 66.89; H, 6.07; N, 10.58. Found: C, 66.99; H, 6.06; N, 10.33. The starting material, benzyl ester of N- (8-oxo-4-oxa-l, 7-diazatricyclo [9.6.1, O12'17] -octadeca-11 (18), 12, 14, 16- tetra- 9S-1) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic, was available as follows: Benzyl Ester of 3 (R) -t-Butoxycarbonylamino- N- (8 -Oxo-4-oxa- l, 7 -dia ztrictric acid [9 .6.1.112,17] octadeca- 11 (18), 12 , 14, 16-tetraen-9S-yl) succinámico According to the procedure described in Example 1 (b) for the preparation of the trifluoroacetate salt of benzyl ester of 3 (R) -amino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) -succinnamic, 9S-t-butoxycarbonylamino-4-oxa-l, 7-diazatricyclo- [9.6.1.012'17] -octadeca-11 (18), 12, 14,16-tetraen-8-one (see Castelhano, AL; Liak, TJ; Home, S .; Yuan, Z .; Krantz, A. Int. Patent Appl. WO95 / 04735-A1, February 16, 1995) is deprotected with trifluoroacetic acid. In accordance with the procedure described in Example 1 (b) for the preparation of N- (2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl) -3 (R) -t-butoxycarbonylaminosuccinamic acid benzyl ester, the unpurified amine salt and the β-benzyl ester of Nt-butoxycarbonyl-D-aspartic acid are coupled with TBTU to produce, in 70% yield, the benzyl ester of 3 (R) -t-butoxycarbonylamino-N- (8-oxo-4-oxa-l, 7-diaza-tricyclo- [9.6.1.012'17] -octadecali (18), 12, 14, 16-tetraen-9S-yl) succinamic. Trituration with MTBE provides an off-white amorphous solid which is suitable for further use without further purification. XH NMR (DMSO-d6): d 7.76 (d, 1H, J = 8.1 Hz), 7.49-7.28 (m, 8H), 7.14 (d, 1H, J = 8.1 Hz), 7.08 (s, 1H), 7.04 (d, 1H, J = 7.7 Hz), 6.98 (t, 1H, J = 7.0 Hz), 5.07 (s, 2H), 4.38-4.15 (m, 4H), 3.47-3.38 (m, 2H), 2.96- 2.75 (m, 5H), 2.65-2.53 (m, 2H), 1.34 (s, 9H). Anal. Calculated for C3? H38N40: C, 64.34; H, 6.62; N, 9.68. Found: C, 64.24; H, 6.65; N, 9.61.

Benzyl Ester of N- (8-Oxo-4-oxa-1, 7-diazatricyclo [9.6.1.012'17] octadeca-11 (18), 12, 14, 16-tetraen-9S-Í1) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinnamic According to the procedure described in Example 1 (b) for the preparation of the trifluoroacetate salt of benzyl ester of 3 (R) -amino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) -succinamic, the benzyl ester of 3 (R) -t-butoxycarbonylamino-N- (8-oxo-4-oxa-l, 7-diaza-tricyclo- [9.6.1, O12'17] -octadeca- 11 (18), 12, 14, 16-tetraen-9S-yl) succinamic acid (157 mg, 0.27 mmol) is deprotected with trifluoroacetic acid. An unpurified, dry amine salt solution and 2,5-dimethoxy-3-phenyl-tetrahydrofuran (67 mg, 0.32 mmol, from Example 1 (b)) in anhydrous 1,2-dichloroethane (2 mL) is heated to ~ 75 ° C for 17 hours, allowed to cool and partitioned between EtOAc / phosphate buffer with pH7. The combined organic layers are dried over Na2SO4 and concentrated to provide a residue that is purified by flash column chromatography with 0-25% elution gradient EtOAc / CH2Cl2 and triturated with MTBE to provide 70 mg (43%) of N- (8-oxo-4-oxa-1) benzyl ester, 7-diaza-tricycle [9.6.1. O12.17] -octadeca-11 (18), 12, 14, 16-tetraen-9S-yl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinnamic as an off-white solid, m.p. 163-6 ° C. AH NMR (CDC13): d 7.68 (d, 1H, J = 6.6 Hz), 7.37-7.13 (m, 12H), 6.95 (s, 1H), 6.64 (s, 1H), 6.45 (t, 1H, J = 2.2 Hz), 6.32 (s, 1H), 6.17 (d, 1H, J = 7.7 Hz), 5.14 (s, 2H), 4.96 (t, 1H, J = 7.2 Hz), 4.62-4.56 (m, 1H) , 4.44-4.40 (m, 1H), 4.12 (t, 2H, J = 4.4 Hz), 3.49-3.40 (m, 3H), 3.35-3.26 (m, 1H), 3.09-2.96 (m, 3H), 2.92-2.85 (m, 2H), 2.77-2.69 (m, 1H). Anal.

Calculated for C36H36N4? 5 • 0.4 H20: C, 70.66; H, 6.06; N, 9.16. Found: C, 70.69; H, 6.11; N, 8.99.

Example 1 (d). N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (R) - [3- (pyridin-4-yl) -lH-pyrrol-1-yl] -synatamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -3 (R) - [3- (pyridine- 4-yl) -IH-pyrrol-1-yl] succinnamic acid is hydrogenated in MeOH to give 60 mg (95%) of N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -3 ( R) - [3- (pyridin-4-yl-lH-pyrrol-1-yl)] succinnamic as a yellow powder, mp 145-8 ° C: XH NMR (CD3OD): d 8.48 (d, 2H, J = 6.2 Hz), 7.62 (d, 2H, J = 6.2 Hz), 7.58 (s, 1H), 6.94 (t, 1H, J = 2.5 Hz), 6.64 (t, 1H, J = 2.2 Hz), 5.30 (t, 1H, J = 7.3 Hz), 2.98 (dd, 1H, J = 7.2, 16.5 Hz), 2.64 (d, 3H, J = 3.7 Hz), 1.00 (s, 9H). IR (KBr): 3315, 2959, 1710, 1654, 1545, 1400, 1206 cm "1. EMARFAB: Calculated for C2oH26N404Cs (M + CS) +: 519.1008. Found: 519.1026.Anal.Calcd for C20H26N4O4 • 0.1 EtOAc • 0.2. CHC13: C, 59.03; H, 6.49; N, 13.37, Found: C, 59.24; H, 6.75; N, 13.10 The starting materials are prepared as follows: 4-Furan-3-yl-pyridine According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromopyridine hydrochloride (500 mg, 2.57 mmol) is coupled with freshly prepared 3-furanboronic acid (see Thompson, W. J .; Gaudino, GJ Org. Ch., 1984, 49, 5237-5243) to provide 373 mg (100%) of 4-furan-3-yl-pyridine without purification as an unstable solid which is used immediately. NMR and IR are similar in the literature (see Ribereau, P .; Queguiner, G. Can. J. Ch., 1983, 61, 334-342 and Ishikura, M .; Ohta, T .; Terashima, M. Ch em Farm, B ul l 1985, 33, 4755-4763). 4- (2,5-Dimethoxy-2,5-dihydro-furan-3-yl) pyridine According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-2, 5-dihydro-2, 5-dimethoxy furan, 4-furan-3-yl-pyridine without purification (2.57 mmol) is treated with bromine in MeOH at -15 ° C in the presence of Na 2 CO 3 to provide 450 mg (85%) of a mixture of diastereomers of 4- (2,5-dimethoxy-2,5-dihydro-furan- 3-yl) pyridine as a yellow oil, which is used without further purification: NMR: H (CDC13): d 8.62 (d, 2H, J = 5.0 Hz), 7.44-7.38 (m, 2H), 6.52 (d , 1H, J = 0.9 Hz), 6.02 (dd, 0.5H, J = 0.9, 3.7 Hz), 6.00 (dd, 0.5H, J = 0.9, 3.7 Hz), 5.98 (s, 0.5H), 5.71 (d, 0.5H, J = 1.2 Hz), 3.48-3.40 (m, 6H). IR: 2933, 1597, 1547, 1438, 1369, 1193, 1118, 1039, 974, 918, 889, 821 cm. "1 EMARFAB: Calculated for CnH? 4N03 (M + H +): 208.0974. Found: 208.0968. 4- (2,5-Dimethoxy-tetrahydro-furan-3-yl) pyridine According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran, a mixture of 4- (2,5-dimethoxy-2,5-dihydro-furan-3-yl) pyridine (500 mg, 2.41 mmol) is hydrogenated in MeOH (2 mL) and EtOAc (8 mL) for 2 hours to provide 500 mg (100%) of a mixture of diastereomers by NMR of 4- (2,5-dimethoxy) -tetrahydro-furan-3-yl) pyridine as a yellow oil. AH NMR (CDC13): d 8.52-8.48 (, 2H), 5.34-4.98 (m, 2H), 3.60-3.20 (m, 6H), 2.76-1.94 (, 3H). GO (KBr): 2920, 1601, 1120, 988, 860 cm "1. EMARFAB: Calculated for CuH16N03 (M + H +): 2101130. Found: 210.1137.

Benzyl Ester of N- (2, 2-Dimethyl-l (S) -methylcarbamoylpropyl] -3 (R) - (3-pyridin-4-yl-lH-pyrrol-1-yl) succinamic acid A solution of 3 (R) -amino-N- (2,2-dimethyl-1 (S) -methylcarbamoylpropyl) succinamic acid benzyl ester trifluoroacetate salt (0.44 mmol), 4- (2,5-dimethoxy-) tetrahydro-furan-3-yl) pyridine (101 mg, 0.482 mmol), pyridine (156 μL, 1.92 mmol), and chlorotrimethylsilane (366 μL, 2.88 mmol) in 1,2-dichloroethane (5 mL) is heated to 90 °. C. After 3 days, the mixture is allowed to cool and concentrated in vacuo to provide a brown oil which is purified by means of flash column chromatography with 0.5% HOAc / 10% MeOH / CH2Cl2 as eluent to yield 90 mg (43%) N- (2, 2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-pyridin-4-yl-1H-pyrrol-1-yl) succinic acid benzyl ester a pale yellow powder, mp 130-3 ° C. NMR XH (CD3OD): d 8.36 (s broad, 2H), 7.98 (d, 2H, J = 4.4 Hz), 7.51 (d, 2H, J = 5.0 Hz), 7.48 (t, 1H, J = l.8 Hz), 6.93 (t, 1H , J = 2.5 Hz), 6.61 (dd, 1H, J = 1.7.3.0 Hz), 5.34 (t, 1H, J = 7.6 Hz), 5.10 (dd, 2H, J = 2.5, 14.3 Hz), 4.16 (s, 1H), 3.14 (dd, 1H, J = 7.8 Hz, 16.5 Hz), 2.60 (d, 3H, J = 3.4 Hz), 0. 92 (s, 9H). IR (KBr): 3314, 2965, 1734, 1648, 1604, 1543, 1400, 1167 cm "1. EMARFAB: Calculated for C27H32N404Cs (M + CsA: 609.1478. Found: 609.1499. Anal. Calculated for C27H32N404 • 0.1 CH2C12 • MeOH : C, 65.27; H, 7.06; N, 10.83, Found C, 65.52; H, 6.89; N, 10.52.

Example l (e). Acid 3 (R) - [3- (Biphenyl-4-yl) -lH ^ pyrrol l-yl] -N- [2, 2-dimeti 1-1 (S) - (methylcarbamoyl) propyl] -succinámico According to the procedure described in Example 1 (a), the benzyl ester of 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2 dimethyl-1 (S) - (methylcarbamoyl) propyl] succinnamic is hydrogenated to give 310 mg (95%) of 33 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] acid] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinnamic as an amorphous solid. 1 K NMR (CDC1): d 7.56 (d, 2H, J = 7.4 Hz), 7.51 (s, 4H), 7.40 (t, 2H, J = 7.4 Hz), 7.32-7.26 (m, 2H), 7.11 ( s, 1H), 6.81 (s, 1H), 6.51 (s, 1H), 5.96-5.93 (broad m, 1H), 5.23 (t, 1H, J = 6.8 Hz), 4.17 (d, 1H, J = 9.6 Hz), 3.34 (dd, 1H, J = 6.4, 17.1 Hz), 3.09 (dd, 1H, J = 7.6, 17.5 Hz), 2.71 (d, 3H, J = 4.8 Hz), 0.90 (s, 9H); Anal. Calculated for C27H3? N304 • 0.3 MTBE • 0.1 H20: C, 69.89; H, 7.16; N, 8.58. Found: C, 70.02; H, 7.33; N, 8.25. The starting material is prepared as follows: Benzyl Ester of 3 (R) - [3- (Biphenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] succinnamic acid ester According to the procedure described in Example 1 (c) for the preparation of benzyl ester of N- (8-oxo-4-oxa-1, 7-diaza-tricyclo- [9.6.1, O12'17] - octa-deca-11 (18), 12, 14, 16-tetraen-9S-yl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic, the benzyl ester of acid 3 (R ) -amino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic (prepared as described in Example 1 (b)) is condensed with 3-biphenyl-4-yl-2, 5-dimethoxy-tetrahydrofuran (prepared as described in Example 1 (a)) in 1,2-dichloroethane with trifluoroacetic acid to provide, in 35% yield, the benzyl ester of 3 (R) - [3- ( biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl] -succinnamic acid as an amorphous solid. XH NMR (CDC13): d 7.63-7.57 (m, 6H), 7.44 (t, 2H, J = 7.6 Hz), 7.35-7.25 (m, 6H), 7.09 (s, 1H), 6.80 (t, 1H, J = 2.4 Hz), 6.61 (t, 1H, J = 2.0 Hz), 6.28 (d, 1H, J = 8.8 Hz), 5.99-5.71 (broad m, 1H), 5.17-5.08 (m, 3H), 4.02 (d, 1H, J = 8.0 Hz), 3.40 (dd, 1H, J = 5.7, 16.7 Hz), 3.12 (dd, 1H, J = 8.5, 16.9 Hz), 2.76 (d, 3H, J = 4.8 Hz), 0.87 (s, 9H) . Anal. Calculated for C34H37N304: C, 74.02; H, 6.76; N, 7.62. Found: C, 73.87; H, 6.93; N, 7.39.

Example 1 (f). N- (1 (S) -Benzy-2-methoxyethyl) -3 (R) - [3- (bi phenyl-4-yl) -lH-pyrrol-1-yl] -synatamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - [3- (bifeni 1-4-yl) -lH-pyrrol-1-yl] succinamic acid is hydrogenated, in 90% yield, for N- (1 (S) -benzyl-2-methoxy-ethyl) -3 (R) - [3- (bifeni 1 -4-yl) -lH-pyrrol-1-yl] succinnamic as an amorphous solid, mp 247 ° C. 1H-NMR (CDC13): d 7.64-7.53 (, 6H), 7.44 (t, 2H, J = 7.5 Hz), 7.34 (t, 1H, J = 7.4 Hz), 7.25-7.19 (m, 3H) 7.10 (d , 2H, J = 8.1 Hz), 6.98 (s, 1H), 6.70 (s, 1H), 6.59 (s, 1H), 5.83 (d, 1H, J = 7.7 Hz), 4.97 (t, 1H, J = 7.0 Hz), 4.22-4.15 (m, 1H), 3.43 (dd, 1H, J-6.6, 16.5 Hz), 3.29-3.16 (, 5H), 3.00 (dd, 1H, J = 7.4, 16.9 Hz), 2.78 (d, 2H, J = 7.0 Hz). Anal. Calculated for C3oH3oN20 • 0.25 H20: C, 73.97; H, 6.31; N, 5.75. Found: C, 73.99; H, 6.59; N, 5.45. The starting materials are prepared as follows: Benzyl Ester of N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - (t-butoxycarbonylamino) succinamic acid A mixture of β-benzyl ester of Nt-butoxycarbonyl-D-aspartic acid (480 mg, 1.50 mmol), 2S-amino-1-methoxy-3-phenylpropane hydrochloride (300 mg, 1.50 mmol), benzotriazole-1 hexafluorophosphate -loxitris (dimethylamino) phosphonium (BOP, 663 mg, 1.50 mmol) and triethylamine (0.5 mL, 3.6 mmol) in DMF (5 mL) is stirred at room temperature for 4 hours. The mixture is poured into H20 (75 L) and extracted with EtOAc: hex (3: 1; 2 x 50 L). The combined organic extracts are washed with aqueous NaHS04 (2 * 25 mL), saturated aqueous NaHCO3 (25 mL) twice and brine (25 mL), dried over NaSO4, and evaporated to provide with trituration with hexane 545 mg (76 mL). %) of N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - (t-butoxycarbonylamino) succinnamic acid benzyl ester as a solid, mp. 60-3 ° C. NMR ^ (CDCls): d 7.37-7.16 (m, 10H), 6.74 (broad s, 1H), 5.64 (broad d, 1H, J = 6.6 Hz), 5.12 (dd, 2H, J = 12.1, 17.7 Hz) , 4.48-4.46 (m, 1H), 4.25-4.20 (m, 1H), 3.34 (s, 3H), 3.31-3.23 (m, 2H), 2.98 (dd, 1H, J = 4.4, 16.9 Hz), 2.82 (d, 2H, J = 7.4 Hz), 2.62-2.57 (m, 1H), 1.44 (s, 9H). Anal. Calculated for C26H33N206 • 0.25 H20: C, 65.87; H, 7.12; N, 5.91. Found: C, 65.73; H, 7.29; N, 5.89.

Benzyl Ester of N- (1 (S) -Benzyl-2-methoxyethyl) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -synatamic acid According to the procedure described in Example 1 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (biphenyl-4-yl) benzyl ester ) -lH-pyrrol-1-yl] succinamic acid, the benzyl ester of N- (1 (S) -benzyl-2-methoxy-yl) -3 (R) - (t-butoxycarbonylamino) succinamic acid is deprotected and the Unpurified salt is condensed in HOAc with 3- (biphenyl-4-yl) -2,5-dimethoxy tetrahydrofuran (prepared as described in Example 1 (a)) to provide, in 54% yield, benzyl ester of the acid N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] succinnamic acid as an oil, which is used without purification additional. XH NMR (CDC13): d 7.65-7.62 (m, 6H), 7.57 (t, 2H, J = 7.4 Hz), 7.48-7.16 (, 9H), 7.10 (d, 2H, J = 7.7 Hz), 6.98 ( s, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 5.78 (d, 1H, J = 8.5 Hz), 5.10 (s, 2H), 5.01 (dd, 1H, J = 5.5, 9.2 Hz ), 4.20-4.16 (, 1H), 3.43 (dd, 1H, J = 5.3, 16.7 Hz), 3. 28-3.15 (m, 5H), 3.02 (dd, 1H, J = 9.2, 16.6 Hz), 2.76 (d, 2H, J = 7.4 Hz); IR: 3315, 3063, 3030, 2930, 2891, 1738, 1682, 1526, 1495, 1204, 1167, 764, 737. 698 cm "1.

EMARFAB: Calculated for C37H36N204 (M + H +): 572.2675. Found: 572.2674.

Example 1 (g). Trifluoroacetate salt of Acid 3 (R) (3- (Bifeni1-4-yl) -lH-pyrrol-1-yl] -N- [2-hydroxy-1 (S) - [(1H-imidazole -4-yl) ) methyl] ethyl] succinámiso HO? - YGN > ,, O ° H 9 According to the procedure described in Example 1 (a), the benzyl ester of 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2-hydroxy] -hydroxy ester -1 (S) - [(1H-imidazol-4-yl) ethyl] ethyl] succinamic acid is hydrogenated and, after purification by reverse phase CLAP, (12%) of the acid trifluoroacetate salt is obtained 3 (R) - [3- (2-phenyl-4-yl) -1H-pyrrol-1-yl] -N- [2-hydroxy-1 (S) - [(1H-imide zol-4-yl) methyl) ] ethyl] succinamic as a reddish amorphous solid. XH NMR (CD30D): d 8.74 (s, 1H), 7.61-7.51 (m, 6H), 7.41 (t, 2H, J = 7.5 Hz), 7.34-7.27 (m, 2H), 7.19 (s, 1H) , 6.81 (t, 1H, J = 2.2 Hz), 6.48 (s, 1H), 5.00 (dd, 1H, J = 5.9, 8.8 Hz), 4.17-4.12 (m, 1H), 3.58-3.46 (m, 2H ), 3.30-3.21 (m, 1H), 3.06 (dd, 1H, J = 4.8, 15.1 Hz), 2.95-2.87 (m, 2H). Anal. Calculated for C26H26N404 • 1.0 TFA • 1.4 H20 • 0.15 C6H • 4: C, 56.84; H, 5.27; N, 9.17. Found: C, 57.04; H, 5.00; N, 8.94. The starting material is prepared as follows: Benzyl Ester of Acid 3 (R) - (t-Butoxycarbonylamino) -N- [2-hydroxy-l (S) - [(lH-imidazol-4-yl) methyl] ethyl] succinámico According to the procedure described in Example 1 (b) for the preparation of 3 (R) -t-butoxycarbonylamino-N- (2, 2-dimethyl-1 (S) - (methylcarbamoyl) propyl) succinnamic acid benzyl ester , the N-butoxycarbonyl-D-aspartic acid β-benzyl ester and the L-histidinol dihydrochloride are coupled with TBTU to provide 410 mg (92%) of 3 (R) - (t-butoxycarbonylamino) - benzyl ester N- [2-hydroxy-l (S) - [(1H-imidazol-4-y1) methyl] ethyl] succinnamic acid as a solid which is used without further purification.

Benzyl Ester of Acid 3 (R) - [3- (Biphenyl-4-yl) -1H-pyrrol-l-yl] -N- [2-hydroxy-l (5) - [(1H-imidazole-4-yl) ) methyl] ethyl] succinámico According to the procedure described in Example 1 (c) for the preparation of benzyl ester of N- (8-oxo-4-oxa-1, 7-diaza-tricyclo- [9.6.1, O12'17] - octadeca-11 (18), 12, 14, 16-tetraen-9S-yl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic acid, the benzyl ester of acid 3 (R) - (t-butoxycarbonylamino) -N- [2-hydroxy-1 (S) - [(1H-imidazol-4-yl) methyl] ethyl] succinamic acid is deprotected, and the resulting unpurified amine salt is condensed with 3- (bi-phenyl-4-yl) -2,5-dimethoxy-tetrahydrofuran (produced as described in Example 1 (a)) in 1,2-dichloroethane in the presence of trifluoroacetic acid to provide, in 37% yield, benzyl ester of 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2-hydroxy-l (S) - [(1H-imidazole-4) benzyl ester il) methyl] ethyl] succinamic acid as a yellow solid. 1 K NMR (CDC13): d 7.65-7.59 (m, 4H), 7.53 (d, 2H, J = 8.5 Hz), 7.45 (t, 2H, J = 7.4 Hz), 7.37-7.26 (m, 7H), 6.95 (s, 1H), 6.70 (t, 1H, J = 2.2 Hz), 6.65 (s, 1H), 6.52 (s, 1H), 6.45 (s broad, 1H), 5.10 (s, 2H), 5.06- 5.02 (m, 1H), 4.13-4.11 (m, 1H), 3.69 (dd, 1H, J = 3.9, 11.6 Hz), 3.56 (dd, 1H, J = 4.8, 11.8 Hz), 3.42 (dd, 1H, J = 5.5, 16.9 Hz), 3.06 (dd, 1H, J = 8.8, 16.9 Hz), 2.84 (t, 2H, J = 4.8 Hz). Anal. Calculated for C33H32N4O4 • 0.8 H20 • 0.15 MTBE: C, 70.34; H, 6.19; N, 9.72. Found: C, 70.51; H, 6.05; N, 10.15.

Example l (h). 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -N- (2 (R) -hydroxycyclohex-1 (R) -yl) -synynamic acid According to the procedure described in Example 1 (a), the benzyl ester of 3 (R) - [3- (bifeni-4-yl) -lH-pyrrol-1-yl] -N- (2 ( R) -hydroxycyclohex-1 (R) -yl) succinamic acid is hydrogenated to obtain, in 81% yield, 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrole-1-yl] -N- (2 (R) -hydroxycyclohex-1 (R) -yl) succinnamic as an amorphous solid. XH NMR (CD3OD): d 8.00 (d, 1H, J = 8.9 Hz), 7.61 (d, 2H, J = 7.4 Hz), 7.56 (s, 4H), 7.40 (t, 2H, J = 7.5 Hz), 7.28 (t, 1H, J = 7.5 Hz), 7.23 (s, 1H), 6.86 (t, 1H, J = 2.6 Hz), 6.48 (t, 1H, J = 2.2 Hz), 5.07 (t, 1H, J = 7.4 Hz), 3.59-3.53 (m, 1H), 2.98 (dd, 1H, J = 7.7, 16.9 Hz), 2.01-1.95 (m, 1H), 1.83-1.78 (m, 1H), 1.72-1.61 ( m, 2H), 1.34-1.11 (m, 4H). Anal. Calculated for C26H28N204 • 0.5 H20: C, 70.73; H, 6.62; N, 6.35. Found: C, 70.79; H, 6.61; N, 6.26. The starting material is prepared as follows: Benzyl Ester of 3 (R) -t-Butoxycarbonylamino- N- (2 (R) -hydroxycyclohex-lR-yl) succinamic acid According to the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) -t-butoxycarbonyl-amino-succinamic acid benzyl ester, the β-Benzyl ester of Nt-butoxycarbonyl-D-aspartic acid and racemic trans-2-aminocyclohexanol are coupled with BOP to provide an unpurified solid that is triturated with MTBE / hex, and then successively recrystallized from MTBE / isooctane and MTBE / cyclohexanes / isooctane to provide 260 mg (20%) of the simple diastereomer of 3 (R) -t-butoxycarbonylamino-N- (2 (R) -hydroxy-cyclohex-lR-yl) succinnamic acid benzyl ester as a whitish solid, mp 124-5 ° C. XH NMR (DMS0-d6): d 7.52 (d, 1H, J = 7.0 Hz), 7.36-7.31 (m, 5H), 7.09 (d, 1H, J = 9.2 Hz), 5.08, 5.05 (AB quartet, 2H , J = 12.1 Hz), 4.48 (d, 1H, J = 5.2 Hz), 4.34-4.27 (m, 1H), 3.26-3.18 (m, 1H), 2.76 (dd, 1H, J = 4.4, 16.2 Hz) , 2.56 (dd, 1H, J = 9.2, 16.2 Hz), 1.82-1.70 (m, 2H), 1.60-1.50 (m, 2H), 1.36 (s, 9H), 1.20-1.08 (m, 4H). Anal. Calculated for C22H32N206: C, 62.84; H, 7.67; N, 6.66. Found: C, 63.10; H, 7.69; N, 6.60.

Benzyl Ester of Acid 3 (R) - [3- (Bifenyl-4-yl) -1H-pyrrol-l-yl] -N- (2 (R) -hydroxycyclohex-l (R) -yl) succinnamic acid As described in Example 1 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (3- (biphenyl-4-yl) -lH-benzyl ester -pyrrol-1-yl) succinámico, the benzyl ester of 3 (R) -t-butoxycarbonylamino-N- (2 (R) -hydroxycyclohex-1 (R) -yl) succinamic acid and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1 (a)) are condensed in acetic acid to provide, in 41% yield, the benzyl ester of 3 (R) - [3- (biphenyl-4-yl) -lH- pyrrol-1-yl] -N- (2 (R) -hydroxycyclohex-1 (R) -yl) succinnamic acid as an off-white amorphous solid. XH NMR (CDC13): d 7.63-7.54 (m, 6H), 7.45 (t, 2H, J = 7.5 Hz), 7.36-7.26 (m, 6H), 7.06 (s, 1H), 6.76 (t, 1H, J = 2.4 Hz), 6.58 (s, 1H), 5.46 (d, 1H, J = 7.0 Hz), 5.15-5.10 (m, 3H), 3.61-3.55 (m, 1H), 3.49 (dd, 1H, J = 5.5, 16.6 Hz), 3.27-3.21 (m, 1H), 3.06 (dd, 1H, J = 8.3, 16.7 Hz), 2.04-1.98 (m, 1H), 1.85-1.78 (m, 1H), 1.71- 1.51 (, 2H), 1.32-1.02 (m, 4H). Anal. Calculated for C33H34N204 • H 0: C, 73.31; H, 6.71; N, 5.18. Found: C, 72.93; H, 6.72; N, 4.93.

Example l (i). 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2-hydroxy-1 (S) - (hydroxymethyl) -2-methylpropyl] succinnamic acid H0J ^ YrNH- > k OH- ^ OH According to the procedure described in Example 1 (a), a mixture of the benzyl ester of 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrole-1-benzyl ester il] -N- [2-hydroxy-l (S) - (hydroxymethyl) -2-methylpropyl] succinamic acid (137 mg, 0.26 mmol) in ETOH (2.5 mL) and EtOAc (2.5 mL) is hydrogenated after 110 minutes for provide a white solid, which is triturated with CH2Cl2 / hex to give 85 mg (75%) of 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl] -N- acid [2-hydroxy-1 (S) - (hydroxymethyl) -2-methylpropyl] succinnamic as a white solid, mp 150-2 ° C. NMR XH (acetone-d6): d 7.67-7.61 (m, 6H), 7.46-7.39 (m, 3H), 7.33 (t, 1H, J = 7.4 Hz), 7.09 (broad d, 1H, J = 8.5 Hz ), 6.97 (t, 1H, J = 2.4 Hz), 6.53 (t, 1H, J = 2.2 Hz), 5.28 (t, 1H, J = 7.2 Hz), 3.81-3.67 (m, 3H), 3.35 (dd) , 1H, J = 7.4, 16.9 Hz), 3.02 (dd, 1H, J = 7.4, 16.9 Hz), 1.24 (s, 3H), 1.12 (s, 3H). Anal. Calculated for C25H28 2? 5: C, 68.79; H, 6.47; N, 6.42. Found: C, 68.54; H, 6.50; N, 6.39. The starting material is prepared as follows: 3-Benzyloxycarbonyl-2, 2-dimethyl-4R- (1-hydroxy-1-methylethyl) oxazolidine To a solution of methyl 2- (3-benzyloxycarbonyl-2, 2-dimethyloxazolidin-4R-yl) acetate (see Delacotte, J.-M .; Galons, H., Schott, D .; Morgat, J. -LJ Label l ed Comp. Ra di oph a rm 1991, 29, 1141-1146; 500 mg, 1.70 mmoles) in dry THF (10 L) at -78 ° C is added dropwise, by syringe, a solution of bromide methylmagnesium (1.5 mL of 3M in ether). After 15 minutes, the reaction vessel is placed in a bath with ice at 0 ° C. After 2 hours, the mixture is cooled to -78 ° C and more methylmagnesium bromide (0.5 mL of 3M in ether) is added. The mixture is allowed to warm to 0 ° C for 2 hours, then quenched with acetone (1 L) and partitioned between EtOAc (50 mL) and 1M phosphate buffer with pH7 (50 mL). The separated organic layer is washed with 1M phosphate buffer with pH7 (50 mL) and brine (25 mL), dried over Na2SO4 and concentrated to a residue which is purified by means of flash column chromatography with 0-12% EtOAc / CH2Cl2 elution gradient to give 280 mg (56%) of 3-benzyloxycarbonyl-2,2-dimethyl-4R- (1-hydroxy-1-methylethyl) -oxazolidine as a colorless oil. 1E NMR (CD3CN): d 7.52-7.45 (m, 5H), 5.35-5.2 (broad m, 2H), 4.68 (broad s, 1H), 4.15-3.95 (broad m, 3H), 1.67 (s, 3H) , 1.57 (s, 3H), 1.21 (s, 6H). Anal. Calculated for C? 6H23N? 4 • 0.3 H20: C, 64.32; H, 7.96; N, 4.69. Found: C, 64.48; H, 7.87; N, 4.67.

Benzyl Ester of 3 (R) -t-Butoxycarbonylamino- N- [2-hydroxy-l (S) - (hydroxymethyl) -2-methylpropyl] succinamic acid 3-Benzyloxycarbonyl-2,2-dimethyl-4R- (1-hydroxy-1-methyl-ethyl) -oxazolidine is hydrogenated in the presence of HCl according to the conditions described in Example 1 (a) to give hydrochloride 2 ( R) -amino-3-methyl-butane-l, 3-diol without purification. In accordance with the procedure described in Example 1 (b) for the preparation of 3 (R) -t-butoxycarbonylamido-N- (2, 2-dimethyl-1 (S) - (methylcarbamoyl) propyl) succinnamic acid benzyl ester , the unpurified amine salt is coupled with β-benzyl ester of Nt-butoxycarbonyl-D-aspartic acid with TBTU. Purification by column chromatography with EtOAc / CH2Cl2 (1: 1) for elution gradient of 10% MeOH / CH2Cl2 leads to the isolation, in 52% yield, of benzyl ester of 3 (R) -t- acid butoxycarbonylamino-N- [2-hydroxy-l (S) - (hydroxymethyl) -2-methylpropyl] succinamic, which is used without further purification. XH NMR (CD3CN): d 7.51 (s, 5H), 6.99 (broad s, 1H), 5.99 (broad s, 1H), 5.25 (s, 2H), 4.57-4.50 (, 1H), 3.83-3.76 (m , 3H), 3.00 (dd, 1H, J = 5.7, 16.4 Hz), 2.87 (dd, 1H, J = 7.2, 16.6 Hz), 1.55 (s, 9H), 1.34 (s, 2H), 1.22 (s, 3H). Anal. Calculated for C2? H32N20 • 0.5 H20 • 0.1 0 = C [N (CH3) 2] 2: C, 58.02; H, 7.74; N, 6.92. Found: C, 58.29; H, 7.75; N, 6.82.

Benzyl Ester of Acid 3 (R) - [3- (Biphenyl-4-yl) -1H-pyrrol-1-yl] -N- [2-hydroxy-l (S) - (hydroxymethyl) -2-methylpropyl] succinnamic acid According to the procedure described in Example 1 (c) for the benzyl ester of N- (8-oxo-4-oxa-l, 7-diaza-tricyclo- [9.6.1, O12, 17] -octake deca-ll (18), 12,14,16-tetraen-9S-yl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic acid, the benzyl ester of 3 (R) - t-Butoxycarbonylamino-N- (2-hydroxy-l (S) -hydroxymethyl-2-methyl-propyl) succinamic acid is deprotected with trifluoroacetic acid. The unpurified amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1 (a)) are condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide , in 11% yield, the benzyl ester of 3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-l-yl] -N- [2-hydroxy-1 (S) -hydroxymethyl ester ) -2-met ilpropyl] succinamic as an amorphous solid. NMR XH (acetone-d6): d 7.67-7.61 (, 6H, 7.48) (t, 2H, J = 7.7 Hz), 7.39 (t, 1H, J = l.8 Hz), 7.37-7.27 (m, 6H), 7.09 (broad d, 1H, J = 9.2 Hz), 6.96 (t, 1H, J = 2.6 Hz), 6.53 (dd, 1H, J = 1.7, 2.8 Hz), 5.35 (t, 1H, J = 7.4 Hz), 5:11 (s, 2H), 3.81-3.62 (m, 3H), 3.39 (dd, 1H, J = 6.8, 16.4 Hz), 3.12 (dd, 1H, J = 7.7, 16.6 Hz ), 1. 24 (s, 3H), 1.21 (s, 3H). Anal. Calculated for C32H3 N205: C, 72.98; H, 6.51; N, 5.32. Found: C, 72. 83; H, 6.60; N, 5.24.

Example l (j). N- [2, 2-Dimethyl-l (S) (methylcarbamoyl) propyl] -3 (R) - [3- (4-propylphenyl) -1H-pyrrol-1-yl] succinamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -3 (R) - [3- (4- propylphenyl) -lH-pyrrol-1-yl] succinamic acid in MeOH and EtOAc is hydrogenated to give 30 mg (91%) of N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -3 ( R) - [3- (4-propyl enyl) -lH-pyrrol-1-yl] succinnamic as a yellow powder, mp 104-6 ° C. NMR I (CD3OD): d 7.95 (broad s, 1H), 7.60 (broad s, 1H), 7.48 (d, 2H, J = 7.5 Hz), 7.16 (broad s, 1H), 7.08 (d, 2H, J = 7.5 Hz), 6.86 (broad s, 1H), 6.42 (broad s, 1H), 5.34 (t, 1H, J = 7.0 Hz), 4.15 (broad d, 1H, J = 5.9 Hz), 2.83 (dd, 1H, J = 6.2, 16.0 Hz), 2.62 (s, 3H), 2.60-2.50 (m, 2H), 1.7-1.58 (m, 2H), 0.95 (s, 9H). IR (KBr): 3300, 2960, 1642, 1560, 1195, 775 cm "1. EMARFAB: Calculated for C24H33N304Cs (M + Cs +): 560.1525. Found: 560.1509.Anal.Calcd for C24H33N304 • 0.3 EtOAc: C, 66.67; H, 7.86; N, 9.26. Found: C, 66.93; H, 7.78; N, 8.89. The starting materials are prepared as follows: 3- (4-Propylphenyl) -furan A ^ As described in Example 1 (d) for the preparation of 4-furan-3-yl-pyridine, l-iodo-4-propylbenzene (500 mg, 2.03 mmol) is coupled with 3-furanboronic acid to provide high yield 3- (4-propylphenyl) -furan as a light brown oil which is unstable and used immediately without further purification. RMN 1E (CDCA): d 7.69 (t, 1H, J = 0.9 Hz), 7.46 (t, 1H, J = l .7 Hz), 7.40 (d, 2H, J = 8.1 Hz), 7.18 (d, 2H, J = 7.8 Hz), 6. 68 (t, 1H, J = 0.9 Hz), 2.59 (t, 2H, J = 7.5 Hz), 1.66- 1.60 (, 2H), 0.95 (t, 3H, J = 7.5 Hz). 2, 5-Dimethoxy-3- (4-propyl phenyl) -2,5-dihydro-furan As described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-2, 5-dihydro-2, 5-dimethoxy-tetrahydrofuran, the unpurified 3- (4-propylphenyl) -furan becomes to 490 mg (98% from l-iodo-4-propylbenzene) of 2,5-dimethoxy-3- (4-propylphenyl) -2,5-dihydro-furan as a light brown oil which is unstable and is used immediately without further purification. NMR ^ (C Cls): d 7.47 (dd, 2H, J = 1.4, 8.1 Hz), 7.17 (d, 2H, J = 8.1 Hz), 6.25, (dd, 1H, J = 0.6, 1.2 Hz), 6.00 (d, 1H, J = 0.6 Hz), 5.69 (d, 1H, J = 1.6 Hz), 3.49 (s, 2H), 3.43 (s, 1H), 3.40 (s, 2H), 3.38 (s, 1H) , 2.59 (t, 2H, J = 7.5 Hz), 1.64 (c, 2H, J = 7.5 Hz), 0.94 (t, 3H, J = 7.5 Hz). IR: 2930, 1514, 1464, 1192, 1105 cm "1. 2, 5-Dimethoxy-3- (4-propylphenyl) -tetrahydrofuran As described in Example 1 (b) for the preparation of 2,5-dimethoxy-3-phenyl-tetrahydrofuran, the 2,5-Dihydro-2,5-dlmethoxy-3- (4-propylphenyl) -furan (320 mg, 1.29 mmol) is hydrogenated to provide 322 mg (100%) of a diastereomeric mixture of 2,5-dimethoxy-3-metho-isomeric mixture. - (4-propylphenyl) -tetrahydrofuran as a viscous colorless oil which is unstable and used immediately without further purification. NMR tE (CDC13): d 7.24 (d, 2H, J = 8.1 Hz), 7.12 (d, 2H, J = 8.1 Hz), 5.24 (t, 1H, J = 5.9 Hz), 3.60-3.30 (m, 6H ), 2.59 (d, 1H, J = 7.5 Hz), 2.52 (d, 1H, J = 8.1 Hz), 2.32 (broad s, 3H), 1.62 (c, 2H, J = 7.5 Hz), 0.92 (t, 3H, J = 7.5 Hz).

Benzyl Ester of N- [2, 2-Dimethyl-l (S) -methylcarbamoyl) ropil] -3 (R) - (4-propyl-3-phenyl-4-yl-lH-pyrrol-1-yl) succinnamic acid As described in Example l (d) for the preparation of N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-pyridin-4-yl-lH) benzyl ester -pyrrol-1-yl) succinamic acid, the trifluoroacetate salt of 3 (R) -amino-N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl] -succinnamic acid benzyl ester (prepared as described in Example 1 (b): 522 mg, 1.16 mmol) is condensed with unpurified 2,5-dimethoxy-3- (4-propylphenyl) -tetrahydrofuran (1.29 mmol) in 1,2-dichloroethane with 90 ° chlorotrimethylsilane. C for 3 days. Unpurified dark oil is purified by flash column chromatography with 1% HOAc / 10% MeOH / CH2Cl2 as eluent to provide 40 mg (7%) of benzyl ester of the acid N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] -3 (R) - [3- (4-propylphenyl) -lH-pyrrol-1-yl] succinnamic acid as a solid, m.p. 63.5 ° C: 1H-NMR (CDC13): d 7.40 (d, 2H, J = 8.1 Hz), 7.34-7.20 (m, 5H), 7.14 (d, 2H, J = 8.1 Hz), 7. 00 (t, 1H, J = 1.9 Hz), 6.78 (t, 1H, J = 2.5 Hz), 6.56 (t, 1H, J = 1.9 Hz), 6.24 (d, 1H, J = 8.7 Hz), 5.70 (d, 1H, J = 4.7 Hz), 5.16-4.96 (, 3H), 4.00 (d, 1H, J = 9.0 Hz), 3.38 (dd, 1H, J = 5.6, 16.8 Hz), 3.10 (dd, 1H, J = 8.7, 16.8 Hz), 2.76 (d, 3H, J-5.0 Hz), 2.59 (d, 1H, J = 7.2 Hz), 2.56 (d, 1H, J = 7.8 Hz), 1.65 (c, 2H, J = 7.5 Hz), 0.96 (t, 3H, J = 7.5 Hz), 0.86 (s, 9H). IR (KBr): 3314, 2959, 1736, 1648, 1560, 1165, 697 cm "1. EMARFAB: Calculated for C3? H39N304Cs (M + Cs +): 650.1995. Found: 650.1977.Analyzed Calculated for C3? H39N304 • 0.3 C6H? 4: C, 72.33; H, 7.62; N, 7.71 Found: C, 72.36; H, 7.77; N, 7.38.

Example l (k). Methyl ester of the acid 4- [2S- [2 (R) [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -3-carboxy-propionylamino] - -methyl-pentanoi lamino] benzoic acid In accordance with the procedure described in Example 1 (a), the methyl ester of 4-acid. { 2S- [2 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -3-carbobenzyloxy-propionyl-amino] -4-methyl-pentanoylamino} -benzoic acid is hydrogenolyzed in quantitative yield to provide the methyl ester of 4- acid. { 2S- [2 (R) - (3-Biphenyl-4-yl-lH-pyrrol-1-yl) -3-carbobenzyloxy-propionyl-amino] -4-methyl-pentanoylamino} -benzoic acid as a solid, m.p. 209 -11 ° C. NMR I (CD30D): d 7.81 (d, 2H, J = 8.8 Hz), 7.60-7.50 (m, 8H), 7.40 (t, 2H, J = 7.4 Hz), 7.28 (t, 1H, J = 7.4 Hz ), 7.20 (s, 1H), 6.88 (s, 1H), 6.48 (s, 1H), 5.16 (t, 1H, J = 7.2 Hz), 4.54 (t, 1H, J = 7.2 Hz), 3.77 (s) , 3H), 2.98 (dd, 1H, J = 6.4, 17.1 Hz) 1.75-1.64 (m, 3H), 0.95 (t, 6H, J = 5.9 Hz). Anal. Calculated for C34H35N306 • 0.6 H20: C, 68.92; H, 6.16; N, 7.09. Found: C, 68.98; H, 6.20; N, 6.98. The starting material is available as follows: Methyl Ester of 4- [2S- (3-Benzyloxycarbonyl-2 (R) -t-butoxycarbonylamino-propionylamino) -4-methyl-pentanoylamino] -benzoic acid As described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - (t-butoxycarbonylamino) -succinnamic acid benzyl ester, the β- ester benzyl of Nt-butoxycarbonyl-D-aspartate and 4- (2S-amino-4-methyl-pentanoylamino) benzoic acid methyl ester (Castelhano, A. L .; Yuan, Z .; Horne, S.; Liak, T. J.

WO95 / 12603-A1, May 11, 1995) are coupled with BOP to provide, in 91% yield, 4- [2S- (3-Benzyloxycarbonyl-2 (R) -t-butoxycarbonylamino-propionylamino) -4-methyl-pentanoylamino] -benzoic acid methyl ester, which is used without purify, without any purification. XH NMR (CDC13): d 8.62 (s, 1H), 7.98 (d, 2H, J = 8.8 Hz), 7.73 (d, 2H, J = 8.8 Hz), 7.38-7.26 (m, 5H), 6.68 (d broad, 1H, J = 8.5 Hz), 5.45 (broad m, 1H), 5.09 (dd, 2H, J = 12.1, 29 Hz), 4.60-4.51 (m, 2H), 3.89 (s, 3H), 3.34-3.26 (m, 1H), 2.82 (dd, 1H, J = 4.8, 18.0 Hz), 2.01-1.95 (m, 1H), 1.70-1.53 (m, 2H), 1.45 (s, 9H), 0.98- 0.93 (m, 6H); Anal. Calculated for C3oH39N309 • 0.4 H20: C, 62.46; H, 6.95; N, 7.28. Found: C, 62.47; H, 6.98; N, 7.36.

Estf 2r Metílic of 1 Acid 4--. { 2S - [3-Benzylloxycarbonyl-2 (R) - (3-biphenyl-4-i-lH-p-1-i-D-propionylamino] -4-methyl-pentanoylamino] -benzoic acid As described in Example 1 (b) for the preparation of benzyl ester of 3 (R) -amino-N- (2,2-dimethyl-l-S-methyl-1-carbanoyl-propyl) succinamic acid ester, the methyl ester of acid 4 - [2S- (3-Benzyloxycarbonyl-2 (R) -t-butoxycarbonylamino-propionylamino) -4-methylpentanoylamino] -benzoic acid is deprotected with trifluoroacetic acid.

As described in Example 1 (b) for the preparation of N- (2,2-dimethyl-1 (S) -methylcarbamoylpropyl) -3 (R) - (3-phenyl-1H-pyrrole-1) benzyl ester -yl) succinamic, the trifluoroacetate salt of 4- [2S- (2 (R) -amino-3-benzyloxycarbonyl-propionylamino) -4-methyl-pentanoyl-amino] -benzoic acid methyl ester without purification and 3- biphenyl-4-yl-2, 5-dimethoxy-tetrahydrofuran (prepared as described in Example 1 (a)) are condensed in 1,2-dichloroethane with trifluoroacetic acid and water to provide, in 27% yield, the ester acid methyl 4-. { 2S- [3-Benzyloxycarboni 1-2 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -propionylamino] -4-methyl-pentanoylamino} -benzoic as a solid, m.p. 186-8 ° C. NMR I (CDC13): d 8.49 (s, 1H), 7.95 (d, 2H, J = 8.8 Hz), 7.69-7.26 (m, 16H), 6.78 (s, 1H), 6.61 (s, 1H), 5.80 (s, 1H), 5.25-5.05 (m, 3H), 4.54-4.50 (m, 1H), 3.88 (s, 3H), 3.38-3.35 (m, 2H), 1.89-1.80 (m, 1H), 1.54 -1.40 (m, 2H), 0.89 (d, 6H, J = 6.3 Hz). Anal. Calculated for C4? H4? N306: C, 73.30; H, 6.15; N, 6.26. Found: C, 73.21; H, 6.16; N, 6.25.

Example 1 (1). 3 (R) - (3-Biphenyl-4-yl-lH-pyrrol-1-yl) -N- [1 (S) - (N-methoxy-methylcarbamoyl) -3-methylbutyl] succinamide acid According to the procedure described in Example 1 (a), the benzyl ester of 3 (R) - [3- (bifeni-4-yl) -lH-pyrrol-1-yl) -N- [1 ( S) - (N-methoxy-N-methylcarbamoyl) -3-methyl-butyl] succinnamic acid is hydrogenated to yield, in 97% yield, 3 (R) - (3-biphenyl-4-yl-lH-pyrrole) -1-yl) -N- [1 (S) - (N-methoxy-N-methylcarbamoyl) -3-methyl-butyl] succinnamic acid as an amorphous solid. 1H-NMR (CDC13): d 7.59-7.53 (m, 6H), 7.40 (t, 2H, J = 7.2 Hz), 7.33-7.26 (m, 1H), 7.10 (s, 1H), 6.88 (broad d, 1H , J = 9.2 Hz), 6.80 (s, 1H), 6.54 (s, 1H), 5.13 (t, 1H, J = 6.8 Hz), 5.03-5.00 (m, 1H), 3.76 (s, 3H), 3.39 (dd, 1H, J = 6.4, 17.5 Hz), 3.16 (s, 3H), 3.00 (dd, 1H, J = 7.2, 17.1 Hz), 1.60-1.42 (m, 3H), 0.92 (d, 3H, J = 6.6 Hz), 0.89 (d, 3H, J = 6.6 Hz). Anal. Calculated for C28H33N305 • 0.25 H20 • 0.20 C6H14: C, 68.32; H, 7.13; N, 8.19. Found: C, 68.28; H, 7.08; N, 7.93. The starting material is available as follows: Benzyl Ester of 3 (R) -t-Butoxycarbonylamino- N- [1 (S) - (N-methoxy-N-methylcarbamoyl) -3-methyl-butyl] succinamic acid As described in Example 1 (b) for the preparation of benzyl ester of N- (2,2-dimethyl-1 (S) -methylcarbamoylpropyl) -3 (R) - (3-phenyl-1H-pyrrol-1) -yl) succinamic, the 2-S-butoxycarboni lamino-N-methoxy-4-methyl-pentanoylamide is deprotected with trifluoroacetic acid. The resulting amine salt and the β-benzyl ester of Nt-butoxycarbonyl-D-aspartic acid are coupled with TBTU to provide, in 89% yield, the benzyl ester of 3 (R) -t-butoxycarbonylamino-N- [ 1 (S) - (N-methoxy-N-methylcarbamoyl) -3-methyl-butyl] succinnamic acid as an oil, which is used without further purification.

XH NMR (CDCl3): d 7.34 (s, 5H), 6.90 (d, 1H, J = 8.5 Hz), 5.61 (d, 1H, J = 7.4 Hz), 5.13, 5.11 (quartet AB, 2H, J = 12.3 Hz), 5.04-4.98 (, 1H), 4.61-4.54 (m, 1H), 3.76 (s, 3H), 3.19 (s, 3H), 3.02 (dd, 1H, J = 4.4, 16.6 Hz), 2.74 ( dd, 1H, J = 5.2, 16.6 Hz), 0.93 (d, 3H, J = 6.4 Hz), 0.90 (d, 3H, J = 6.4 Hz). Anal. Calculated for C24H37 307 • 0.3 H20: C, 59.44; H, 7.82; N, 8.66. Found: C, 59.41; H, 7.69; N, 8.63.

Ester Benzyl 1 ico of Acid 3 (R) - (3-Biphenyl-4-yl-1H-pyrrole-1-yl) - N- [1 (S) - (N - me toxi - N -methylcarbamoyl) -3-methyl-butyl] succinámico As described in Example 1 (c) for the preparation of benzyl ester of N- (8-oxo-4-oxa-1, 7-diaza-tricyclo- [9.6.1. O12'17] -octadeca-ll (18), 12,14,16-tetraen-9-yl) -3- (3-phenyl-lH-pyrrol-1-yl) succinamic, the benzyl ester of 3 (R) -amino-N- (1 (S) - (N-methoxy-N-methylcarbamoyl) -3-methyl-butyl) succinnamic is deprotected. The unpurified amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1 (a)) are condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide , in 48% yield, the benzyl ester of the acid 3 (R) - (3-biphenyl-4-yl-lH-pyrrol-l-yl) -N- [1 (S) - (N-methoxy-N- methylcarbamoyl) -3-methyl-butyl] succinnamic acid as an amorphous solid. XH NMR (CDC13): d 7.62 (d, 2H, J = 7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J = 7.7 Hz), 7.35-7.21 (m, 7H), 7. 10 (s, 1H), 6.80 (t, 1H, J = 2.2 Hz), 6.60 (s broad, 1H), 5.17-1.13 (, 1H), 5.10 (s, 2H), 4.97-4.92 (, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J = 5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J = 8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J = 6.25 Hz), 0.87 (d, 3H, J = 6.3 Hz). Anal. Calculated for C35H39N305: C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.

Example 1 (m). 3 (R) - [3- (Cyanophenyl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) (methylcarbamoyl) propyl] -syncinnamic acid In accordance with the procedure described in Example 1 (a), the benzyl ester of 3 (R) - [3- (4-cyanophenyl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) ) propyl] succinamic in MeOH and EtOAc is hydrogenated to provide 1.2 g (90%) of the acid 3 (R) - [3- (4-cyanophenyl) -lH-pyrrol-1-yl] -N- [2, 2- dimethyl-l (S) - (methylcarbamoyl) propyl] succinnamic as a yellow powder, mp 138-40 ° C. XH NMR (CD30D): d 7.98 (broad s, 1H), 7.82 (broad d, 1H, J = 8.4 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.50 (d, 2H, J = 8.4 Hz ), 7.38 (t, 1H, J = l.6 Hz), 6.92 (t, 1H, J = 2.5 Hz), 6.55 (t, 1H, J = 2.2 Hz), 5.28 (t, 1H, J == 7.5 Hz), 4.19 (d, 1H, J = 9.0 Hz), 2.98 (dd, 1H, J = 6.9, 16.5 Hz), 2.64 (d, 3H, J = 4.7 Hz), 0.98 (s, 9H). IR (KBr): 3317, 2963, 2225, 1648, 1550, 1410, 1180 cm. "1 EMARFAB: Calculated for C22H26N404Cs (M + Cs +): 543.1008. Found 543.1021. Anal. Calculated for C22H26N404 • 0.4 EtOAc: C, 63.60.; H, 6.60; N, 12.57, Found: C, 63.80; H, 6.77; N, 12.57.

The starting material was available as follows: 3- (4-Cyanophenyl) -furan CN As described in Example l (d) for the preparation of 3- (pyridin-4-yl) furan, 4-bromobenzonitrile (4.00 g, 22.0 mmol) is coupled with 3-furanboronic acid to provide, in high yield without purification, 3- (4-cyanophenyl) -furan as a brown solid, mp 55-7 ° C, which is used immediately without further purification. XH NMR (CDC13): d 7.82 (broad s, 1H), 7.67 (d, 2H, J = 8.4 Hz), 7.59 (d, 2H, J = 8.4 Hz), 7.52 (t, 1H, J = l .9 Hz), 6.72 (broad s, 1H). IR (KBr): 2214, 1608, 1160, 796 c -1 Anal. Calculated for CnH7N0 0.1 C6Hí C, 78. 72; H, 4.33; N, 7.91 Found: C, 78.32; H, 4.60; N, 7.65. 3- (4-Cyanophenyl) -2,5-dihydro-2, 5-dimethoxy furan As described in Example 1 (a) for the preparation of 3-bi phenyl-2,5-dihydro-2,5-dimethoxy-tetrahydrofuran, 3- (4-cyanophenyl) furan is converted without purification. Flash column chromatography with EtOAc: hex (30:70) as eluent afforded 3.8 g (73% from 4-bromobenzonitrile) of 3- (4-cyanophenyl) -2,5-dihydro-2,5-dimethoxyfuran as a yellow solid, mp 71-2 ° C XH NMR (CDC13): d 7.62 (s, 4H), 6.46 (d, 1H, J = 0.9 Hz), 6.22 (dd, 0.5H, 5 = 0.9, 3.7 Hz), 6.00 (dd, 0.5H, J = 0.9, 3.7 Hz), 5.97 (d, 0.5H, J = 0.6 Hz), 5.71 (d, 0.5H, J = 1.3 Hz), 3.48-3.40 (m, 6H). IR: 2933, 2832, 2227, 1607, 1505, 1369 cm. "Anal." Calculated for C? 3H? 3N03: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.39; H, 5.71; N , 6.14. 3- (4-Cyanophenyl) -2,5-dimethoxy-tetrahydrofuran As described in Example 1 (a) for the preparation of 3- (biphenyl-4-yl) -2,5-dimethoxy-tetrahydrofuran, 3- (4-cyano-phenyl) -2,5-dihydroxy-2 , 5-dimethoxy furan (3.8 g, 16.43 mmol) is reduced to provide 3.70 g (97%) of a diastereomeric mixture of 3- (4-cyanophenyl) -2,5-dimethoxy-tetrahydrofuran as an oily white solid, which it is used without further purification. XH NMR (CDC13): d 7.60 (d, 2H J = 7.8 Hz), 7.42 (d, 2H, J = 8.1 Hz), 5.30-4.94 (m, 2H), 3.60-3.20 (m, 6H), 2.78- 1.92 (m, 3H! IR: 2912, 2833, 2227, 1607, 1511 cm "1.

Benzyl Ester of Acid 3 (R) - [-3- (4-Cyanophenyl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcabamoyl) -propyl] succinnamic acid According to the procedure described in Example 1 (c) for the preparation of benzyl ester of N- (1,7-diaza-4-oxa-8-oxo-tricyclo- [9.6.1.012'17] -octadeca- 11 (18), 12,14, 16-tetraen-9S-yl) -3 (R) - (-3-phenyl-1H-pyrrol-1-yl) -succinnamic acid, the trifluoroacetate salt of benzyl ester of 3 (R) -amino-N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -succinnamic acid without purification (prepared as described in Example 1 (b)) and 3- (4-cyanophenyl) -2 , 5-dimethoxy-tetrahydrofuran is condensed. Drying the product without purification by means of azeotrope with benzene gives 1.70 g (41%) of 3 (R) - [-3- (4-cyanophenyl) -lH-pyrrol-1-yl] -N- benzyl ester [2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinnamic as a yellow solid, mp 102-4 ° C. NMR I (CDCI3): d 7.60-7.55 (m, 4H), 7.30-7.25 (m, 5H), 7.12 (t, 1H, J = 2.2 Hz), 6.80 (t, 1H, J = 2.5 Hz), 6.56 (t, 1H, J = 2.8 Hz), 6.32 (d, 1H, J = 8.7 Hz), 5.60 (d, 1H, J = 5.0 Hz), 5.18-5.05 (m, 3H), 4.05 (d, 1H, J = 9.0 Hz), 3.38 (dd, 1H, J = 5.9, 17.0 Hz), 3.08 (dd, 1H, J = 8.7, 16.8 Hz), 2.76 (d, 3H, J = 5.0 Hz), 0.92 (s, 9H). IR: 3310, 2958, 2227, 1736, 1648, 1547 cm "1. EMARFAB: Calculated for C29H32N404Cs (MH + Cs +): 633.1478. Found: 6333.1452.Analyzed Calculated for C29H32N 04 • 0.4 C6H6: C, 70.91; H, 6.52; N, 10.53, Found: C, 70.97; H, 6.15; N, 10.26.

Example 1 (n). Ethyl Ester of Acid 4- [2S- (3-Carboxy-2 (R) -lH-pyrrol-1-yl-propionylamido) -4-methyl-pentanoylamino] benzoic acid According to the procedure described in Example 1 (a), the ethyl ester of 4- [2S- (3-carbobenzyloxy-2 (R) -lH-pyrrol-1-yl-propionylamido) -4-methyl-pentanoylamino ] -benzoic acid in ETOH and THF is hydrogenated. The unpurified product is successively purified by means of flash column chromatography with a step gradient of 20-40% EtOAc / hex-5% MeOH / CH2Cl2 and preparative RPCLAP (C18) with 50% CH3CN / aqueous NH4OAc 1 M to provide 45 mg of 4- [2S- (3-carboxy-2 (R) -lH-pyrrol-1-yl-propionyl-amido) -4-methyl-pentanoylamino] -benzoic acid ethyl ester fluffy crystals, mp 111-4 ° C. EMFAB: 444.1 (C23H3oN306; M + H +). The starting materials were available as follows: Ethyl Ester of 4- [2S- (3-Benzyloxycarbonyl-2 (R) -t-butoxycarbonylamino-propionylamino) -4-methyl-pentanoylamino] -benzoic acid According to the procedure described in Example 1 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) -t-butoxycarbonylamino-succinamic acid benzyl ester, the ethyl ester of Nt-butoxycarbonyl-D-aspartate acid and 4- (2S-amino-4-methyl-pentanoylamino) benzoic acid ethyl ester (Castelhano, AL; Yuan, Z .; Horne, S.; Liak, TJ W095 / 12603 -A1, May 1, 1995) were coupled with EDC to provide 2.4 g (67%) of 4- [2S- (3-benzyloxycarbonyl-2 (R) -t-butoxycarbonylamino-propionylamino) -4- ethyl ester. methyl-pentanoylamino] -benzoic acid as a glassy solid, which is used without further purification.

Ethyl Ester of 4- [2S- (2 (R) -A? T? Ino-3-benzyloxycarbonyl-propionylamino) -4-methyl-pentanoylamino] benzoic acid As described in Example 1 (b) for the preparation of trifluoroacetate salt of benzyl ester of 3 (R) amino-N- (2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl) succinamic acid, the 4- [2S- (3-Benzyloxycarbonyl-2 (R) -t-butoxycarbonylamino-propionylamino) -4-methyl-pentanoylamino] -benzoic acid ethyl ester is deprotected with trifuoroacetic acid, except that a solution of the resulting salt it is neutralized by washing a CH2C12 solution with aqueous IN NaOH. Removal of the solvent under reduced pressure yields 2.00 g (100%) of 4- [2S- (2 (R) -amino-3-benzyloxycarbonyl-propionyl-amino) -4-methyl-pentanoyl-amino acid ethyl ester - benzoic as a viscous yellow oil, which is used without further purification.

Ethyl Ester of 4- [2S- (3-Carbobenzyloxy-2 (R) -lH-pyrrol-1-yl-propionylamido) -4-methyl-pentanoylamino] -benzoic acid ester A mixture of 4- [2S- (2 (R) -amino-3-benzyloxycarbonyl-propionyl-amino) -4-methyl-pentanoyl-amino] -benzoic acid ethyl ester (150 mg, 0.310 mmol), 2, 5-dimethoxy tetrahydrofuran (43 mg, 0.33 mmol), sodium acetate (153 mg, 1.86 mmol), and glacial HOAc (3 mL) is heated at reflux for 30 minutes. The mixture is allowed to cool, is emptied on ice, diluted with H20 (30 mL), and extracted with EtOAc (2 x 50 mL). The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. Flash column chromatography with a stepwise gradient of 15-20-25-30% EtOAc / hex yields 107 mg (65%) of ethyl 4- [2 S- (3-carbobenzyloxy-2 (R)) ethyl ester - 1 H -pyrrol-1-yl-propionylamido) -4-met i 1 -pentane i lamino] -benzoic acid.

Example 1 (o). N- (9-Oxo-l, 8-diaza-tricyclo [10.6.1. O13'18] nonadeca-12 (19), 13,15,17-tetraen-lOS-il) -3 (R) -lH acid -pyrrol- 1-il -succinámico According to the procedure described in Example 1 (a), the benzyl ester of N- (9-oxo-1, 8-diaza-tricyclo [10.6.1.013'18] nonadeca-12 (19), 13, 15 , 17-tetraen-10S-yl) -3 (R) -lH-pyrrol-1-ylsuccinnamic acid is hydrogenated in EtOH and THF. Crystallization from CH2C12 provides 120 mg (36%) of N- (9-oxo-l, 8-diaza-tricyclo- [10.6.1.013'19] nonadeca-12 (19), 13,15, 17- tetraen-lOS-yl) -3 (R) -lH-pyrrol-1-yl-succinnamic as colorless, spongy crystals, mp 139-44 ° C EMFAB: 451 (C25H3? N404; M + HA.

Example 1 (p). 3 (R) - [3- [(4-Cyanophenyl) acetyl] -1H-pyrrole-1-i1] -N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinamic acid The usual allyl ester decomposition conditions were previously described by Friedrich-Bochni t schek, S .; Waldmann, H.; Kunz, H.

J. Org. Chem. 1989, 54, 751-756. To a solution of 3 (R) - [3 - [(4-cyanophenyl) acetyl] -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-1 (S) - (met ilcarbamoyl) -propyl] succinamic (247 mg, 0. 501 mmoles) in acetonitrile (2 mL) is added in succession Pd (PPh3) (29 mg, 0.026 mmol) and morpholine (226 μL, 2.60 mmol). The resulting mixture is carefully purged with argon. After 30 minutes, the resulting green mixture is stirred with 10% aqueous KHS04 (20 mL) and extracted with CHC13 (35 mL). The organic layer is washed with 10% aqueous KHS04 (20 mL), dried over Na2SO4 and concentrated. Flash column chromatography with 1% HOAc / 3% MeOH / CHCl 3 and drying by azeotrope with n-heptane provides 243 mg (94%) of 3 (R) - [3- [(4-cyanophenyl) acid acetyl] -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl] -succinnamic acid as a yellow solid. NMR I (CD3OD): d 8.09 (d, 1H, J = 8.7 Hz), 8.05 (dd, 1H, J = 2.8, 6.9 Hz), 7.78 (dd, 1H, J = 1.9, 1.9 Hz), 7.66 (d , 2H, J = 8.4 Hz), 7.46 (d, 2H, J = 8.4 Hz), 6.90 (dd, 1H, J = 2.2, 2.2 Hz), 6.59 (dd, J = 1.9, 3.1 Hz), 5.33 (t , 1H, J = 7.5 Hz), 4.22-4.15 (, 3H), 3.24 (t, 1H, J = 8.7 Hz), 2.98 (dd, 1H, J = 5.3, 17.4 Hz), 2.66 (d, 3H, J = 4.7 Hz), 0.99 (s, 9H). IR (KBr): 3332, 2696, 2230, 1719, 1654, 1532, 1412, 1177 c "1. EMARFAB: Calculated for C24H29N405 (M + H +): 453.2125. Found: 453.2125.Analyzed Calculated for C24H28N405 • 0.5 HOAc • 0.3 CHC13: C, 58.62; H, 5.89; N, 10.81 Found: C, 58.41; H, 5.72; N, 10.50 The starting materials were available as follows: Allyl Ester of Acid 3 (R) - (t-Butoxycarbonylamino) - N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic acid According to Example 1 (b) for benzyl ester of 3 (R) -t-butyloxycarbonylamino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic acid, β-allyl-Nt -butoxycarbonyl-D-aspartate (Belshaw, P .; Mzengeza, S .; Lajoie, G. Syn Commun 1990, 20, 3157-3160; 2.00 g, 7.32 mmol) and Lt-leucine N-methylamide (Malon, P .; Pancoska, P .; Budesinsky, M .; Hlavacek, J .; Pospisek, J .; Blaha, K. Coi. Chem Comm A. 1983, 48, 2844-286 1; 1.05 g, 7.32 mmol) are coupled with TBTU. The resulting yellow oil is used in the usual manner without further purification. Flash column chromatography with 2% MeOH / CH2Cl2 provides 2.44 g (84%) 3 (R) - (t-Butoxycarbonyl amino) -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic acid allyl ester as a pale yellow oil. AH NMR (CDC13): d 7.05 (d, 1H, J = 9.0 Hz), 5.98 (d, 1H, J = 4.4 Hz), 5.77 (ddt, 1H, J = 5.6, 10.3, 16.2 Hz), 5.29 (ddd) , 1H, J = 1.5, 2.8, 15.6 Hz), 5.23 (dd, 1H, J = 1.3, 10.5 Hz), 4.57 (dddd, 2H, J = 1.6, 3.1, 5.6, 12.1 Hz), 4.11 (d, 1H , J = 9.4 Hz), 2.77 (d, 3H, J = 5.0 Hz), 1.46 (s, 9H), 0.99 (s, 9H).

Salt of Alllic Ester Trifluoroacetate of Acid 3 (R) -Amino-N- (2-2-dimethyl-l (S) - (methylcarbamoyl) -propyl) succinamic As described in Example 1 (b) for the preparation of trifluoroacetate salt of benzyl ester of 3 (R) -amino-N- (2,2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic acid, the 3 (R) - (t-butoxycarbonylamino) -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic acid allyl ester without purification is deprotected after 2 hours. Flash column chromatography with 0.5% TFA / 7% MeOH / CHCl3 provides 2.46 g (87%) of 3 (R) -amino-N- (2, 2-dimethyl-1) allyl ester trifluoroacetate salt (S) - (Methylcarbamoyl) -propyl) succinnamic as a colorless foam. XH NMR (CD30D): d 5.96 (ddt, 1H, J = 5.6, 10.6, 17.1 Hz), 5.35 (ddd, 1H, J = 1.6, 3.1, 17.1 Hz), 5.25 (ddd, 1H, J-1.2, 2.5 , 10.3 Hz), 4.66 (ddd, 2H, J = 1.2, 1.3, 5.9 Hz), 4.34 (dd, 1H, J = 5.6, 7.8 Hz), 4.21 (s, 1H), 3.03 (dd, 1H, J = 5.6, 17.4 Hz), 2.94 (dd, 1H, J = 7.5, 17.4 Hz), 2.71 (d, 3H, J = 5.0 Hz), 1.46 (s, 9H), 0.99 (s, 9H). IR (KBr): 3413, 2966, 1672, 1656, 1207, 1143 cm "1. EMARFAB: Calculated for C? 4H25N304Na (M + Na +): 322. 1743. Found: 322.1747. Anal. Calculated for C? 4H25N304 • 2.5 F3COOH • 0.5 CHC13: C, 36.36; H, 4.38; N, 6.52. Found: C, 36.34; H, 4.25; N, 6.51. 3- (2, 2-Dibromoethenyl) -2-5-dimethoxy-tetrahydrofuran A mixture of Zn powder (1.65 g, 25.0 mmol), triphenylphosphine (6.54 g, 25.0 mmol) and CBr4 (8.30 g, 25.0 mmol) in dry CH2C12 (40 mL) is stirred at room temperature. After 24 hours, 2,5-dimethoxy-tetrahydrofuran-3-carboxaldehyde (2.00 g, 12.5 mmol) is added and an exothermic reaction results. After 30 minutes, special ether (100 L) is added and the resulting top layer is separated. The lower layer is diluted twice with CH2C12 (50 mL) and special ether (50 mL), and the upper layer is reserved. The combined top layers are combined, passed through a pad of Si02, and concentrated under reduced pressure at 30 ° C or lower to provide 2.18 g (55%) of 3- (2,2-dibromoethenyl) -2 , 5-dimethoxy-tetrahydrofuran as a volatile colorless oil, which is a mixture of diastereoisomers by 1 E NMR and is used immediately without further purification. 2, 5-Dimethoxy-3 - (S ^ - t ributyl e stani i et ini l) - tetrahydro furan To the solution of unpurified 3- (2, 2-dibromoethenyl) -2,5-dimethoxy-tetrahydrofuran (1.78g, 5.64 mmol) in ether (30 mL) at -78 ° C is added n-butyllithium (9.02 mL of 1.25 M in hex). After 1 hour at -78 ° C, tributyltin chloride (1.68 mL, 6.20 'mmoles) is added and the mixture is allowed to warm to room temperature. After 16 hours, ether (35 L) and saturated aqueous NH 4 Cl (30 mL) are added. The organic layer is separated, washed with saturated aqueous NH4C1 (30 mL), H20 (25 mL), and saturated aqueous NaHCO3 (25 mL), dried over K2C03 and evaporated to give an orange oil, which was purified by means of flash column chromatography with 2% MTBE / hex to provide 1.92 g (77%) of 2,5-dimethoxy-3- (2-tributyltin-lenyl) -tetrahydrofuran as a colorless oil. A mixture of diastereomers is observed in the NMR spectrum aH, which is used immediately without further purification. IR: 2923, 1456, 1374, 1215, 1105, 1017, 967 cm. "1 Anal. Calculated for C2oH3803Sn: C, 53.96; H, 8.60 Found: C, 54.21; H, 8.66. 3- [2- (4-Cyanophenyl) -etinyl] -2,5-dimethoxy-tetrahydrofuran A mixture of 2, 5-dimethoxy-3- (2-tributylstannyltinyl) -tetrahydrofuran (1.86 g, 4.18 mmol), 4-iodobenzonitrile (1.15 g, 5.02 mmol) and tetrakis (triphenylphosphine) -palladium (0) (145 mg, 0.125 mmol) in Toluene (25 L) is heated to 100 ° C. After 5.5 hours, the resulting red solution is allowed to cool and the solvent is removed under reduced pressure. By flash chromatography twice with 10% EtOAc / hex, 1.10 g (100%) of 3- [2- (4-cyanophenyl) -etinyl] -2,5-dimethoxy-tetrahydrofuran is provided as a color oil. orange. A mixture of diastereoisomers is observed by XH NMR, which is used without further purification. NMR * H (CDC13): 3.12 (ddd, J = 2.8, 6.6, 9.0 Hz), 2.57 (ddd, J = 5.6, 9.3, 13.4 Hz), 2.08 (dd, J = 2.5, 4.7 Hz), 2.04 (dd) , J = 3.1, 4.3 Hz). IR: 2227, 1603, 1216, 1102, 1012, 841 cm "Anal." Calculated for C15H5NO • 0.1 EtOAc: C, 69.51; H, 5.98; N, 5.26 Found: C, 69.52; H, 5.76; N, 5.32.

Allyl Ester of Acid 3 (R) - [3 - [(4-Cyanophenyl) acetyl] -lH-pyrrol-1-yl] -N- [2, 2 -dimeti 1- (S) - (methylcarbamoyl) propyl] succinámico As described in Example 1 (c) for the preparation of benzyl ester of N- (8-oxo-4-oxa-l, 7-diaza-tricyclo [9.6.1.01, 17] octadeca-11 (18), 12, 14, 16-tetraen-9-yl) -3- (3-phenyl-1H-pyrrol-1-yl) succinamic acid, the trifluoroacetate salt of allyl ester of 3 (R) -amino-N- ( 2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic acid and 3- [2- (4-cyanophenyl) -etinyl] -2,5-dimethoxy-tetrahydrofuran are heated with trifluoroacetic acid (1 equiv) to 70 ° C for 4 hours. It is subjected to flash column chromatography twice with 0.5% HOAc / 15% EtOAc / CH2Cl2 as eluent and azeotroped with n-heptane yields 800 mg (36%, 43% based on the recovered furan) of the allyl ester of the acid 3 (R) - [3 - [(4-Cyanophenyl) acetyl] -lH-pyrrol-1-yl] -N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] succinamic acid as a brown oil . XH NMR (CDC13): d 7.58 (d, 2H, J = 8.1 Hz), 7.47 (dd, 1H, J = 1.9, 1.9 Hz), 7.36 (d, 2H, J = 8.1 Hz), 6.84 (d, 1H , J = 9.0 Hz), 6.74 (dd, 1H, J = 2.8, 2.8 Hz), 6.63 (dd, 1H, J = 1.6, 2.8 Hz), 6.08 (dd, J = 2.8, 6.8 Hz) ,. 5.82 (ddt, 1H, J-5.9, 10.3, 17.1 Hz), 5.26 (ddd, 1H, J = 1.2, 2.8, 17.1 Hz), 5.19 (c, 1H, J = 7.2 Hz), 4.56 (dddd, 2H, J = 1.6, 2.8, 4.4, 15.9 Hz), 4.18 (d, 1H, J = 9.0 Hz), 4.05 (s, 2H), 3.34 (dd, 1H, J = 7.2, 16.8 Hz), 2.99 (dd, 1H , J = 7.2, 16.8 Hz), 2.72 (d, 3H, J = 5.0 Hz), 0.90 (s, 9H). 13 C NMR (CDC13): d 191.2, 170.2, 169.4, 168.0, 140.6, 132.2, 131.3, 130.3, 125.7, 125.7, 122.0, 119.0, 118.9, 110.5, 110.4, 66.0, 61.0, 59.4, 46.1, 37.5, 34.8, 31.9 , 29.0, 26.5, 26.0. IR (KBr): 3320, 2965, 229, 1736, 1648, 1531, 1173 c "1.

EMARFAB: Calculated for C27H33N4? 5 (M + H +): 493.2451.

Found 493.2462. Anal. Calculated for C27H32N4? 5 • 0. 2 H20 • 0.2 CH2C12: C, 63.66; H, 6.44; N, 10.92. Found: C, 63.86; H, 6.56; N, 10.58.

Example 2. N- (1 (S) -acetyl-3-methylbutyl) -3 (R) - [3- (bipheni-4-yl) -lH-pyrrol-1-yl) -synatamic acid To a solution of 3 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -N- [1 (S) - (N-methoxy-N-methylcarbamoyl) -3-methyl- acid butyl] succinnamic (prepared as described in Example 1 (1)) (209 mg, 0.425 mmol) in THF (5 mL) was added at -78 ° C methylmagnesium bromide (3 M in ether, 0.7 mL) per drop After 15 minutes at -70 ° C and 2 hours at 0 ° C, the mixture is quenched with acetone (50 μL), and then added to EtOAc / NaHS04 IN.The aqueous phase is extracted with EtOAc The combined organic layers are dried over Na 2 SO 4 and concentrated.After 3 days at room temperature, the dark residue begins to crystallize and trituration with MTBE / hexanes gives 90 mg (46%) of N- (1 (S)) acid. -acetyl-3-met ilbut i 1) -3 (R) - [3- (biphenyl-4-yl) -lH-pyrrol-1-yl) succinnamic acid pure as an off-white solid. XH NMR (CDC13): d 7.62-7.55 (m, 6H), 7.44 (t, 2H, J = 7.5 Hz), 7.33 (t, 1H, J = 7.0 Hz), 7.11 (s, 1H), 6.81 (t , 1H, J = 2.4 Hz), 6.62 (dd, 1H, J = 1.3, 2.4 Hz), 6.07 (d, 1H, J = 8.5 Hz), 5.12 (t, 1H, J = 6.8 Hz), 4.61-4.54 (m, 1H), 3.46 (dd, 1H, J = 6.4, 16.7 Hz), 3.01 (dd, 1H, J = 7.4.16.9 Hz), 2.16 (s, 3H), 1.58-1.51 (m, 2H), 1.33 (d, 1H, J = 7.4 Hz), 0.92 (d, 3H, J = 6.3 Hz), 0.87 (d, 3H, J = 6.3 Hz). Anal. Calculated for C27H30N2O4 • 0.5 H20: C, 71.18; H. 6.86; N, 6.15. Found: C, 71.01; H, 6.78; N, 6.40.

Example 3. 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] N- [1 (S) - (1 (RS) -hydroxy-ethyl) -3-methylbutyl acid ] -Succinic To a solution of N- (1 (S) -acetyl-3-methylbutyl) -3 (R) - (biphenyl-4-yl-lH-pyrrol-1-yl) succinamic acid (prepared as described in Example 2 45 mg, 0.10 mmol) in THF (2 mL) and ETOH (1 mL) at -78 ° C is added a solution of NaBH 4 (19 Mg, 0.50 mmol) in EtOH (1 mL). After 2 hours at -78 ° C, the reaction is stopped with acetone (0.5 mL) and concentrated in vacuo to yield a residue that is partitioned with EtOAc and citrate buffer pH 4.5. The aqueous phase is further extracted with EtOAc. The combined organic layers are dried over Na2SO4 and evaporated to give a solid which is dissolved in MTBE and precipitated with hexanes to provide 30 mg (67%) of 3 (R) - [3- (bi-phenyl-4-yl) acid. ) -lH-pyrrol-1-yl) -N- [1 (S) - (1-RS-hydroxy-ethyl) -3-met-1-butyl] -succinnamic acid as an amorphous solid. H NMR (CDC13): d 7.60-7.56 (m, 6H), 7.44 (t, 2H, J = 7.4 Hz), 7.33 (t, 1H, J = 6.8 Hz), 7.11 (s, 1H), 6.82 (s, 1H), 6.61 (s, 1H), 5.70 (m, 1H, minor isomer), 5.49 (d, 1H, J = 8.1 Hz, major isomer), 5.05 (t, 1H, J = 6.3 Hz), 4.04-4.01 (m, 1H, major isomer), 3.86-3.82 (m, 1H), 3.76-3.74 (, 1H, minor isomer), 3.41 (dd, 1H, J = 5.9, 16.9 Hz), 3.16 (dd, 1H, J = 6.6, 10.7 Hz), 1.75-1.42 (m, 1H), 1. 28-1.13 (m, 2H), 1.08 (d, 3H, J = 6.3 Hz, minor isomer), 1.01 (d, 3H, J = 6.3 Hz, major isomer), 0.87 (d, 6H, J = 6.6 Hz). Anal. Calculated for C27H32N204 • 0. 8 H20: C, 70.04; H, 7.32; N, 6.05. Found: C, 69.89; H, 7.33; N, 5.97.

Example (a). N- (1 (S) -Benzy-2-hydroxyethyl) -3 (R) [3- ('-cyanobiphenyl-4-yl) -lH-pyrrol-1-yl] succinamide acid In accordance with the procedure described in Example 1 (a), the benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-cyanobiphenyl-4-yl) -IH-pyrrole-l -yl] succinamic (50 mg, 0.070 mmol) is hydrogenated in MeOH: EtOAc (2: 3 mL) to give after 2 hours a yellow powder, which is washed with CHC13 and hexane to provide 35 mg (100%) of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-cyclobiphenyl) -4-yl) -lH-pyrrol-1-yl] succinnamic acid as a yellow powder, mp 189-92 ° C: NMR? E (DMSO-ds): d 8.82-8.78 (broad m, 1H), 7.90 (s, 4H), 7.72 (d, 2H, J = 8.1 Hz), 7.50 (d, 2H, J = 8.1 Hz), 7.20 ( m, 6H), 6.82 (s, 1H), 6.45 (s, 1H), 4.95 (t, 1H, J = 7.2 Hz), 3.88-3.78 (m, 1H), 2.84 (d, 1H, J = 5.9 Hz ), 2.75-2.60 (m, 3H). IR (KBr): 3396, 3029, 2925, 2229, 1654, 1602, 1560, 1495 cm. "1 EMARFAB: Calculated for C3oH? 7N304Na (MH + Na +): 516.1899. Found: 516.1912. Anal. Calculated for C3oH27N304 • 0.81. CHC13: C, 62.69; H, 4.75; N, 7.12, Found: C, 62.64; H, 4.89; N, 7.23 The starting material is prepared as follows: 4'-Bromo-biphenyl-4-carbonitrile As described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromobenzonitrile (9.42 g, 51.8 mmol) and 4-bromophenylboronic acid (5.20 g, 25.9 mmol) are coupled in EtOH to yield 4.50 g (67%) of 4'-bromo-biphenyl-4-carbonitrile as a gray powder, mp 147-8 ° C (lit 153-5 ° C; McNamara, J .; Gleason, W.B. J. Org. Chem. 1976, 41, 1071). The material had an NMR spectrum that fits the literature (see Amatore, C; Juland, A.; Negri, S. J. Organomet, Chem. 1990, 390, 389-398) and is normally used without further purification. 4 '- (Furan-3-yl) -biphenyl-4-carbonitrile As described in Example 1 (a) for the preparation of 3-bi phenyl-4-yl-furan, the unpurified 4'-bromo-bi phenyl-4-carbonitrile (200 mg, 0.775 mmole) and the 3 - furanboronic (see Thompson, W.

J .; Gaudino, G. J. Org. Ch em. 1984, 49, 5237-5243; 105 mg, 0.937 mmol) in MeOH (2 mL) are coupled to give a yellow solid, which is purified by preparative TLC. Elution with EtOAc-benzene (1:99) gives 100 mg (53%) of 4'-furan-3-yl-biphenyl-4-carbonitrile as a gray powder, m.p. 199-203 ° C. AH NMR (CDC13): d 7.81 (broad s, 1H), 7.72 (d, 4H, J = 1.9 Hz), 7.61 (s, 4H), 7.51 (broad s, 1H), 6.75 (s, 1H). IR (KBr): 2225, 1604, 1503, 1396, 1162, 1102, 1058 cm "Anal, calculated for C? 7HX? NO 0. 3 EtOAc • 0.2 C6H6: C, 80.78; H, 5.05; N, 5.01 Found: C, 80.96; H, 4.88; N, 5.00. 4 '- (2,5-Dimethoxy-2,5-dihydro-furan-3-yl) -biphenyl-4- carbonyl According to the process for the preparation of 3-bi-phenyl-4-yl-furan described in Example 1 (a), 4'-furan-3-yl-biphenyl-4-carbonitrile (1.29 g, 5.26 mmol) is converted to 4 '- (2,5-dimethoxy-2,5-dihydro-furan-3-yl) -biphenyl-4-carbonitrile.

The crude product is recrystallized from EtOAc / hex to provide 1.03 g (64%) of a mixture of diastereomers by NMR as a pale white powder, m.p. 136-7 ° C. XH NMR (CDC13): d 7.80-7.58 (, 8H), 6.40 (s, 1H), 6.30 (d, 0.5H, J = 3.7 Hz), 6.06 (s, 0.5H), 6.01 (d, 0.5H, J = 3.7 Hz), 5.72 (d, 0.5H, J = 1.6 Hz), 3.55 (s, 1.5H), 3.48 (s, 1.5H), 3.44 (s, 1.5H), 3.02 (s, 1.5 H). IR (KBr): 2933, 2831, 2229, 1654, 1604 1560, 1498 cm -1 EMARFAB: Calculated for C? 9H? 8N03 (M + H +): 308.1287. Found: 308.1275. Anal. Calculated for d9H? 7N03: C, 74.25; H, 5.58; N, 4.56. Found: C, 74.11; H, 5.63; N, 4.49. 4'- (2,5-Dimethoxy-tetrahydrofuran-3-yl) -biphenyl-4-carbonyl trile As described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-2, 5-dimethoxy-tetrahydrofuran, 4 '- (2,5-dimethoxy-2,5-dihydro-furan-3) -yl) -biphenyl-4-carbonitrile (260 mg, 0.846 mmol) is reduced in 2 hours to provide 260 mg (99%) of 4 '- (2,5-dimethoxy-tetrahydro furan-3-yl) -biphenyl- 4-carbonitrile as a white solid, mp 149-50 ° C, which is used without further purification. XH NMR (CDC13): d 7.78-7.26 (m, 8H), 5.30-5.00 (m, 2H), 3.52-3.22 (m, 6H), 2.78-2.00 (m, 3H). IR (KBr): 2910, 2220, 1606, 1498, 1448, 1380, 1224, 11 90 cm "Anal Calcium for 9H? 9N03 • 0 .3 H20: C, 72. 28; H, 6.28; N, 4.45 Found: C, 72.2: H, 6.19; N, 4.11.

Benzyl Ester of N- (1 (S) -Benzyl-2-hydroxyethyl) -3 (R) - [3- (4 '-cyanobi-phenyl-4-yl] -lH-pyrrol-1-yl] -synatamic acid Co or described in Example 1 (b) for the preparation of trifluoroacetate salt of benzyl ester of 3 (R) -amino-N- (2, 2-dimethyl-l (S) -. {Methylcarbamoyl) propyl) ) succinamic, the trifluoroacetate salt of 3 (R) -amino-N- (1 (S) -benzyl-2-hydroxyethyl) succinnamic acid benzylester without purification (prepared as described in Example 1 (a); 0.876 mmoles) is condensed with 4 '- (2,5-dimethoxy-tetrahydrofuran-3-yl) -biphenyl-4-carbonitrile (326 mg, 1.05 mmol) in 1,2-dichloroethane (5 mL). The solution is heated at 85-90 ° C for 5 hours, allowed to cool and evaporated to give a brown oil which is purified by flash column chromatography with 1% HOAc / 30% EtOAc / hex as eluent. The HOAc is removed by azeotrope with layers of n-heptane to provide 200 mg (39%) of benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-cyanobi-phenyl-1-4-yl) -lH-urea-1-yl] -syntamic acid as a pale yellow powder, mp 149-50 ° C. NMR I (CDC13):? 7.74 (s, 4H), 7.59 (d, 4H, J = 4.1 Hz), 7.32-7.18 (m, 10H), 7.05 (broad, 2H), 6.94 (t, 1H, J = 2.2 Hz), 6.64 (t , 1H, 2.5 Hz), 6.58 (broad m, 1H), 5.48 (d, 1H, J = 7.8 Hz), 5.10 (d, 2H, J = 3.1 Hz), 5.00 (dd, 1H, J = 5.0, 9.3 Hz), 4.46-4.32 (, 2H), 4.22-4.12 (m, 1H), 3.41 (dd, 1H, J = 5.3, 17.1 Hz), 3.04 (dd, 1H, J = 9.1, 17.1 Hz), 2.70- 2.63 (m, 2H). IR: 3389, 3030, 2948, 2225, 1735, 1665, 1603, 1528, 1495 cm "1. EMARFAB: Calculated for C37H33N304Cs (MH + Cs +): 716.1525. Found: 716.1503 Anal.Calpha for C37H33N304 • 0.4 CH2C12: C , 72.73; H, 5.52; N, 6.80, Found: C, 72.67, H, 5.53; N, 6.81 The following compounds are prepared in a similar manner: Example 4 (b). N- (l-Benzyl-2-hydroxyethyl) -3 (R) [3- ('-carbamoylbiphenyl-4-yl) -lH-pyrrol-1-yl] -synatamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-carbamoylbifeni 1-4 -yl) -lH-pyrrol-1-yl] succinamic acid is hydrogenolyzed with N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-carbamoylbiphenyl-4-yl) acid) -lH-pyrrol-l-yl] succinamic in 95% yield, mp 218-20 ° C. XH NMR (DMS0-d6): d 8.12 (d, 1H, J = 8.5 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J = 8.5 Hz), 7.72 (d, 2H, J = 8.5 Hz ), 7.57 (d, 2H, J = 8.1 Hz), 7.33 (broad s, 1H), 7.24 (s, 1H), 7.22-7.11 (m, 6H), 6.80 (s broad, 1H), 6.42 (s broad) , 1H), 4.98-4.90 (broad m, 1H), 4.80-4.72 (m, 1H), 3.82-3.76 (m, 1H), 2.82-2.70 (m, 2H), 2.62-2.50 (m, 1H). IR (KBr): 3402, 2925, 1658, 1601, 1400, 1202, 825, 782, 702, 633 cm -1 EMARFAB: Calculated for C3oH29N3OsCs (M + Cs + 644.1162. Found: 644.1147.Analyzed Calculated for C3oH29N305 • 0.3 CHC13 : C, 66.49; H, 5.40; N, 7.68 Found: C, 66.30; H, 5.50; N, 7.50 The starting material is prepared as follows 3- (4 '-Carboxamidobifeni 1-4-yl) -2,5- dimethoxytetrahydrofuran To a solution of 4 '- (2,5-dimethoxy-tetrahydrofuran-3-yl) -bifeni 1-4-carbonitrile (100 mg, 0. 32 mmoles) in 95% EtOH (1.5 mL) is added 30% hydrogen peroxide (114 μL, 1.12 mmol) and 6N aqueous NaOH (13 μL, 0.08 mmol). The resulting mixture is heated at 50 ° C for 5 hours, allowed to cool, neutralized to? H7 by paper with pH 5% H2SO4, diluted with water (10 mL) and extracted with CHC13 (2 x 30 mL). The organic layers are dried over MgSO4 and evaporated under reduced pressure to provide a solid, which is precipitated from EtOAc / hex to provide 1.04 g (100%) of 3- (4'-carboxamidobiphenyl-4-yl) - 2, 5-dimethoxytetrahydrofuran as a white powder, mp 184-6 ° C. NMR 1 (CDC13): d 7.87 (d, 2H, J = 8.1 Hz), 7.66 (d, 2H, J = 8.1 Hz), 7.56 (d, 2H, J = 8.1 Hz), 7.42 (d, 2H, J = 8.1 Hz), 5.26-5.00 (m, 2H), 3.54-3.29 (, 6H), 2.78-2.00 (m, 3H); IR (KBr): 3383, 3191, 2908, 1654, 1612, 1400, 1116, 983, 857, 779 cm. "1 EMARFAB: Calculated for C? 9H22N304 (M + H +): 328.1549. Found: 328.1560 Anal. for C? 9H2XN0: C, 69.69; H, 6.47; N, 4.28, Found: C, 69.68, H, 6.43; N, 4.19.

Benzyl Ester of N- (l-Benzyl-2-hydroxyethyl 3- [4'-carbamoylbifeni1-4-yl] -IH-pyrrol-1-yl] succinnamic acid As described in Example 4 (a) for the preparation of benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-cyano-biphenyl-4 -yl) -lH-pyrrol-1-yl] succinamic acid, the benzyl ester of N- (l (S) -benzyl-2-hydroxyethyl) -3 (R) -butoxycarbonyl-amino-succinnamic acid (0.320 mmol) is deprotected . A solution of the benzyl ester trifluoroacetate salt of the N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) -a ino-succinamic acid without purifying and 3- (4 '-carboxamidobiphenyl) 4- il) -2.5-dimethoxytetrahydrofuran (110 mg, 0.330 mmol) in 1,2-dichloroethane is condensed for 18 hours to give a brown solid, which is purified by flash column chromatography with 5% MeOH / CH2Cl2 as eluent to provide 60 mg (31%) of N- (1-benzyl-2-hydroxyethyl) -3- [3- (4'-carbamoyl-phenyl-4-yl) -lH benzyl ester -pyrrol-1-yl] succinamic as a pale yellow solid, mp 192-4 ° C. XR NMR CDMSO-d6): d 8.18 (d, 1H, J = 8.5 Hz), 8.00 (s, 1H), 7.94 (d, 2H, J = 8.1 Hz), 7.76 (d, 2H, J = 8.5 Hz) , 7.68 (d, 2H, J = 8.5 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.36-7.14 (broad m, 7H), 6.84 (t, 1H, J = 2.2 Hz), 6.47 (s) , 1H), 5.10-4.95 (m, 3H), 4.81 (t, 1H, J = 5.1 Hz), 3.88-3.75 (, 1H), 3.00 (d, 2H, J = 7.4 Hz), 2.80 (dd, 1H) , J = 5.5, 13.2 Hz), 2.67 -2.60 (m, 1H). IR (KBr): 3330, 2962, 1729, 1655, 1606, 1560, 1498, 1261, 1092 cm "1. EMFAB: 602 (M + H +) Anal.Calcd for C 37 H 35 N 3 5 5 • 0.4 CH 2 Cl 12: C, 70.67; H, 5.68; N, 6.61, Found: C, 70.78; H, 5.86; N, 6.98.

Example 4 (c). 3 (R) - [3- (4'-Carbamoylbiphenyl-4-yl) -lH-pyrrol-1-yl] -N- (1 (S) -hydroxymethyl-2, -dimethyl-propyl) -synnamic acid In accordance with the procedures described in Example 1 (a), the benzyl ester of 3 (R) - [3- (4 '-carbamoyl-phenyl-4-yl) -lH-pyrrol-1-yl] -N- (1 (S) -hydroxy-methyl-2,2-dimethyl-propyl) -succinamic acid in MeOH and EtOAc is hydrogenated to yield, in 88% yield, 3 (R) - [3- ('-carbamoylbi phenyl- 4-yl) -lH-pyrrol-1-yl] -N- (1 (S) -hydroxymethyl-2, 2-dimethyl-yl-propyl) -succinic acid as a white powder, mp 192-4 ° C. XH NMR (CD3OD): d 7.95 (d, 2H, J = 8.4 Hz), 7.72 (d, 2H, J = 8.1 Hz), 7.60 (s, 4H), 7.32 (d, 1H, J = 1.6 Hz) ), 6.92 (t, 1H, J = 2.5 Hz), 6.51 (s, 1H), 5.20 (t, 1H, J = 7.5) Hz 3.85-3.75 m, 2H! 3.02 (dd, 1H, J = 7.2, 17.0 Hz), 0.92 (s, 9H). IR (KBr): 3360, 2961, 1710, 1658, 1404, 1201, 770 cm "1; EMARFAB: Calculated for C27H32N305 (M + H) +: 478.2342. Found: 478.2360.

Calculated for C27H3iN3? 5 • 0.25 CH2C12: C, 65.62; H, 6. 37; N, 8.42. Found: C, 65.86, H, 6.69; N, 8.30. The starting materials were available as follows: Benzyl Ester of Acid 3 (R) - (t-Butoxycarbonylamino) -N- (1 (S) -hydroxymethyl-2, 2-dimethyl-propyl) succinnamic acid As described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - (t-butoxy-carbonyl-lamino) -succinnamic acid benzyl ester, the β-benzyl ester of Nt-butoxycarbonyl-D-aspartic acid (1.00 g, 3.10 mmol) and Lt-leucinol (400 mg, 3.40 mmol) are coupled with BOP to produce 1.20 g (90%) of the benzyl ester of 3 (R) - (t-Butoxycarbonylamino) -N- (1 (S) -hydroxymethyl-2, 2-dimethyl-propyl) succinnamic acid as a white powder, mp 186-7 ° C. AH NMR (CDC13): d 7.22 (s, 5H), 6.52 (d, 1H, J = 9.3 Hz), 5.62-5.52 (m, 1H), 5.25 (dd, 2H, J = 12.1, 18.7 Hz), 4.58 -4.48 (m, 1H), 3.90-3.78 (, 2H), 3.58-3.50 (m, 1H), 3.22-3.10 (m, 1H), 2.78 (dd, 1H, J = 5.9, 17.7 Hz), 2.52- 2.45 (m, 1H), 1.22 (s, 9H), 0.98 (s, 9H). IR: 3322, 2960, 1730, 1664 1528, 1367, 1249, 1165, 1050 cm. "1 Anal. Calculated for C22H34N2? 6: C, 62.52; H, 8.12; N, 6.63. Found: C, 62.20; H, 8.13; N, 6.62.

Benzyl Ester of Acid 3 (R) - [3- (4'-Carbamoyl-phenyl-4-yl) -lH-pyrrol-1-yl] -N- (1 (S) -hydroxymethyl-2, 2-dimethyl-propyl succinámico As described for Example 4 (a) for the preparation of benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-cyano-biphenyl-4 -yl) -lH-pyrrol-1-yl] succinamic acid, 3- (4 '-carboxamidobiphenyl) -2,5-dimethoxy-tetrahydrofuran without purification and the trifluoroacetate salt of benzyl ester of 3 (R) -amino-N - (1-hydroxymethyl-2,2-dimethyl-propyl) succinnamic are condensed in 1,2-dichloroethane to give 110 mg (41%) of 3 (R) - [3- (4'-carbamoylbiphenyl) benzyl ester 4-yl) -lH-pyrrol-1-yl] -N- (1 (S) -hydroxymethyl-2, 2-dimethyl-propyl) succinnamic acid as a solid, mp. 201-3 ° C. NMR * H (CDC13): d 7.88 (d, 2H, J = 8.1 Hz), 7.69 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.7 Hz), 7.36-7.26 (m, 5H), 7.10 (d, 1H, J = l, 9 Hz), 6.81 (d, 1H, J = 2.5 Hz), 6.61 (t, 1H, J = l .6 Hz), 5.60-5.56 (m, 1H), 5.10-5.02 (m, 3H), 3.80-3.70 (, 2H), 3.50-3.38 (m, 3H), 3.24 (dd, 1H, J = 4.0, 17.0 Hz), 0.80 (s, 9H). IR (KBr): 3356, 2961, 1735, 1655, 1606, 1560, 1542, 1406, 1200 cm. "1 Anal. Calculated for C34H37N3O5 • 0.25 CH2C12: C, 69.85; H, 6.42; N, 7.14 Found: C , 69.82, H, 6.67; N, 7.12.

Example 5 (a). N- [2, 2-Dimethyl-l (S) - (hydroxymethyl) propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinámico A mixture of N- (1-benzyloxycarbonyloxy-3, 3-dimethylbut-2 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH benzyl ester -pyrrol-1-yl] succinámico (140 mg, 0.212 mmol) and Pd (OH) 2 (60 mg of 20% Pd per content) in MeOH (1 mL) and EtOAc (9 mL) are shaken under.

H2 atmosphere for 3 hours. The catalyst is filtered on Celite and rinsed with 10% MeOH / CHCl3 (75 mL). The filtrate is concentrated in va c uo to provide a yellow solid, which is precipitated from a hot CHC13 solution with hexane to provide 68 mg (95%) of N- [2,2-dimethyl-1 (S)] - (hydroxymethyl) propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic acid as a yellow solid, mp 192-4 ° C. NMR: H (CD3OD): d 8.56 (d, 1H, J = 5.9 Hz), 7.78-7.60 (m, 7H), 7.37 (t, 1H, J = 1 .9 Hz), 6. 96 (t, 1H, J = 2.5 Hz), 6.54 (t, 1H, J = 1.6 Hz), 5.22 (dd, 1H, J = 2.5 Hz), 3.83-3.70 (m, 2H), 3.45-3.40 (m, 1H), 3.22 (d, 1H, J = 7.5 Hz), 3.02 (dd, 1H, J = 7.2, 16.8 Hz), 0.90 (s, 9H). IR (KBr): 3405, 2960, 1718, 1656, 1602, 1560, 1408, 1364, 1203, 922, 818, 783 cm "1. EMARFAB: Calculated for C25H29N3O4CS (M + Cs +): 568.1212. Found: 568.1189. Calculated for C25H29 304 • 0.10 CHC13: C, 67.38; H, 6.55; N, 9.39 Found: C, 67.69, H, 6.90; N, 9.65 The starting material is prepared as follows: 4- (4-Bromo-phenyl) -pyridine fH According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromopyridine (700 mg, 3.00 mmol) is subjected to coupling with 4-bromophenylboronic acid to provide 2.38 g (100%) of 4- (4-bromo-phenyl) -pyridine as a yellow solid, which has an MRI that fits with the literature (Boy, P .; Combellas, C., Tiebault, A .; Amatore, C .; Jutand, A. Te trahedron Le tt. 1992, 33, 491-494) and used without further purification. IR (KBr): 1593, 1474, 1412, 1075, 1006, 807, 756, 693, 498 c "1. 3- (4'-Pyridylphenyl-4-yl) furan According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-furan, 4- (4-bromophenyl) pyridine (700 mg, 3.00 mmol) is subjected to coupling with 3-biphenyl-4-yl-furan. -furanboronic (see Thompson, WJ, Gaudino, GJ Org. Chem. 1984, 49, 5237-5243). Purification by means of flash column chromatography with 2% MeOH / CH2Cl2 as eluent leads to the obtainment of 640 mg (97%) of 3- (4'-pyridylphenyl-4-yl) furan as a yellow solid, which It is used in the next reaction. XH NMR (CDC13): d 8.68 (d, 2H, J = 5.9 Hz), 7.82 (dd, 1H, J = 0.6, 1.6 Hz), 7.76-7.43 (m, 7H), 6.76 (dd, 1H, J = 0.9, 1.8 Hz). Apál. Calculated for CisHuNO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.32, H, 5.08; N, 6.28. 2, 5-Dihydro-2, 5-diptetoxy-3- (4- (pyridin-4-yl) phenyl) furan According to the procedure described in Example 1 (a) for the preparation or 3-biphenyl-4-yl-2, 5-dihydro-2, 5-dimethoxyfuran, 3- (4'-pyridylphenyl-4-yl) Furan (470 mg, 2.12 mmol) is converted and purified by means of flash column chromatography with 2% MeOH / CH2Cl2 as eluent to yield 600 mg (100%) of 2,5-dihydro-2,5-dimethoxy- 3- (4- (pyridin-4-yl) phenyl) furan as a tan solid. XH NMR (CDC13): d 8.68 (d, 2H, J = 4.0 Hz), 7.68 (s, 4H), 7.52 (d, 2H, J = 5.9 Hz), 6.40 (s, 1H), 6.30 (d, 0.5 H, J = 3.7 Hz), 6.05 (s, ^ 0.5H), 6.02 (d, 0.5H, J = 3.7 Hz), 5.72 (s, 0.5H), 3.52 (s, 1.5H), 3.48 (s, 1.5H), 3.45 (s, 1.5H), 3.43 (s, 1.5H). EMARFAB: Calculated for C? 7H? 8N03: (M + H +): 284.1287. Found: 284.1294. Anal. Calculated for C? 7H17N03: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.97, H, 6.05; N, 4.95. 2, 5-Dimethoxy-3- (4- (pyridin-4-jl) phenyl) tetrahydrofuran According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-2, 5-dimethoxy-tetrahydrofuran, 2,5-dihydro-2,5-dimethoxy-3- (4 - (pyridin-4-yl) phenyl) furan (300 mg, 1.06 mmol) is hydrogenated in MeOH after 6 hours to give 300 mg (100%) of 2,5-dimethoxy-3- (4- (pyridine-4) -yl) phenyl) tetrahydrofuran as a yellow oil, which is a mixture of diastereomers by NMR, and that is used without further purification. H-NMR (CDC13): d 8.68 (broad s, 2H), 7.76-7.36 (m, 6H), . 34-4.94 (m, 2H), 3.72-3.20 (m, 7H), 2.75 (ddd, 0.15H, minor isomer, J = 5.9, 10.0, 13.7 Hz), 2.35 (ddd, 0.74H, major isomer, J = * 5.6.12.8, 12.8 Hz), 2.20 (dd, 0.0.19H, minor isomer, J = 6.9.12.0 Hz), 2.12 (ddd, 0.16H, minor isomer, J = 3.7, 5.9, 13.7 Hz); Anal. Calculated for Cx7H? GN03 • 0.2 H20: C, 70.66; H, 6.77; N, 4.85. Found: C, 70.49; H, 6.74; N, 4.76.

Benzyl Ester of N- (1 (S) -Benzyloxycarbonyloxymethyl-2,2-dimethylpropyl) -3 (R) - (t-butoxycarbonylamino) succinamic acid To a solution of 3 (R) - (t-butoxycarbonylamino) -N- (2, 2-dimethyl-l (S) -hydroxymethyl-propyl) -sycinnamic acid benzyl ester (1.27 g, 3.01 mmol, prepared as described in Example 4 (c)) and DMAP (920 mg, 7.51 mmol) in CHC13 (5 mL) is added benzyl chloroformate (1.07 mL, 7.51 mmol). After 2 hours, 10% aqueous KHS04 (15 mL) is added. The aqueous layer is extracted with more CHCl3 (15 mL) twice. The combined CHC13 layers are washed with % aqueous KHS04 (10 mL), saturated aqueous NaHCO3 (10 mL), and H20 (10 mL), dried over Na2SO4 and evaporated to give an unpurified solid, which is purified by flash column chromatography to yield 1.42 g (85%) of benzyl ester of the acid. N- (1 (S) -benzyloxycarbonyl-oxymethyl-2,2-dimethyl-propyl) -3 (R) - (t-butoxycarbonylamino) -succinnamic as a white solid, mp 69-71 ° C. XH NMR (CDC13): d 7.37-7.27 (broad m, 10H), 6.63 (d, 1H, J = 9.3 Hz), 5.61 (d, 1H, J = 7.5 Hz), 5.16 (s, 2H), 5.15 ( d, 1H, J = 12.3 Hz), 4.97 (d, 1H, J = 12.3 Hz), 4.51 (d, 1H, J = 5.6 Hz), 4.29 (dd, 1H, J = 3.7, 11.2 Hz), 4.15 ( dd, 1H, 7.8, 11.2 Hz), 4.05 (ddd, 1H, J = 3.7, 7.8, 9.6 Hz), 3.01 (dd, 1H, J = 4.7, 17.1 Hz), 2.72 (dd, 1H, J = 6.5, 17.1 Hz), 1.44 (s, 9H), 0.93 (s, 9H). IR: 3340, 2951, 1753, 1707, 1671, 1533, 1507, 1456, 1364, 1272, 1175, 790, 734 cm. "1 EMARLSI: Calculated for C3oH4oN208Cs (M + Cs +): 689.1839. Found: 689.1826. Calculated for C3oH40N208: C, 64.72; H, 7.24; N, 5.03, Found: C, 64.82; H, 7.25; N, 4.98.

Benzyl Ester of N- (1-Benzyloxycarbonyloxy-3, 3-dimethylbut-2 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole- 1-il] succinámico According to the procedure described in Example 1 (b) for the preparation of 3 (R) -t-butoxycarbonylamino-N- (2, 2-dimethyl-1 (S) -methylcarbamoylpropyl) succinamic acid benzyl ester, the ester Benzyl of N (lR-benzyloxycarbonyloxymethyl-2 acid, 2-dimethyl-propyl) -3 (R) - (t-butoxycarbonyl amino) -succinic acid is deprotected. The corresponding amine salt and 2,5-dimethoxy-3- (4'-pyridylphenyl-4-yl) -tetrahydrofuran are condensed in wet 1,2-dichloroethane at 80-90 ° C after 18 hours to provide a product unpurified, which is purified by flash column chromatography with 1% HOAc / 5% MeOH / CH2Cl2 as eluent to give 160 mg (54%) of N- (1-benzyloxycarbonyloxy-3-benzyl ester, 3-dimethylbut-2 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic acid as a yellow solid, mp 74-6 ° C. XH NMR (CDC13): d 8.65 (d, 2H, J = 5.9 Hz), 7.58 (d, 5H, J = 2.2 Hz), 7.55-7.43 (m, 4H), 7.34-7.22 (m, 7H), 7.08 (t, 1H, J = 1.9 Hz), 6.74 (t, 1H, J = 2.5 Hz), 6.54 (dd, 1H, J = 1.9, 2.8 Hz), 5.46 (d, 1H, 9.3 Hz), 5.18-5.05 (m, 4H), 5.03 (s, 2H), 4.30 (dd, 1H, J = 2.5, 12.0 Hz), 4.00 (m, 2H), 3.46 (dd, 1H, J = 5.3, 15.0 Hz), 3.00 ( dd, 1H, J = 9.3, 15.0 Hz), 0.83 (s, 9H). IR (KBr): 2961, 1748, 1666, 1600, 1560, 1263, 1118, 815, 783, 737, 695, 541 cm "1. EMARFAB: Calculated for C4oH4? N306Cs (M + Cs +): 792.2050 Found: 792.2034 Anal, calculated for C4oH41N3? 6 • 0.2 CHCli • 0.3 C6H? 4: C, 71.10; H, 6.45; N, 5.92. Found: C, 71.01, H, 6.36; N, 5.59. The following compounds are prepared in a similar manner: Example 5 (b). N- (2-Hydroxy-l (S) -phenylethyl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-l-yl] -synatamic acid According to the procedure described in Example 5 (a), the benzyl ester of N- (2-benzyloxycarbonyloxy-1 (S) -phenylethyl) -3 (R) - [3- [4- (pyridine-4- il) phenyl] -lH-pyrrol-1-yl] succinamic acid is hydrogenated to yield 60 mg (68%) of N- (2-hydroxy-1 (S) -phenylethyl) -3 (R) -3 (R) acid - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid. 1 E NMR (CD3OD): d 8.56 (d, 2H, J = 5.9 Hz), 7.78-7.60 (m, 7H), 7.38 (t, 1H, J = 1.9 Hz), 6.95 (t, 1H, J = 2.5 Hz), 6.55 (dd, 1H, J = 1.6, 2.8 Hz), 5.22 (dd, 1H, J = 7.2, 7.4 Hz), 3.76-3.64 (broad m, 2H), 3.02 (dd, 1H, J = 7.2 , 16.8 Hz). IR (KBr): 3315, 1718, 1670, 1654, 1602, 1560, 1491, 1406, 1202 cm "1. EMARFAB: Calculated for C27H2sN304Cs (M + Cs +): 588.0899. Found: 588.0914.

Calculated for C27H25N304 • 0.2 CHC13: C, 68.15; H, 5.30; N, 8.77. Found: C, 68.19, H, 5.63; N, 8.38. The starting materials are prepared as follows: Benzyl Ester of Acid 3 (R) - (t-Butoxycarbonylamino) -N- (2-hydroxy-l (S) -phenyl-ethyl) succinamic acid According to the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxy-yl) -3 (R) -1-butoxycarbonyl-amino acid benzyl ester succinamic acid, the benzyl ester of Nt-butoxycarbonyl-D-aspartic acid and 2S-phenylglycinol are coupled with BOP to provide 290 mg (85%) of benzyl ester of 3 (R) - (t-butoxycarbonylamino) -N - (2-hydroxy-l (S) -phenyl-ethyl) succinamic, mp 117-8 ° C. XH NMR (CDC13): d 7.40-7.22 (, 10H), 7.10 (broad d, 1H, J = 9.3 Hz), 5.66 (broad d, 1H, J = 9.3 Hz), 5.14 (dd, 2H, J = 12.1) , 18.4 Hz), 5.08-5.02 (m, 1H), 4.58-4.50 (m, 1H), 3.94-3.80 (m, 2H), 3.12 (dd, 1H, J = 4.4, 17.1 Hz), 2.75 (dd, 1H, J = 5.9, 17.4 HZ), 2.42-2.36 (m, 1H), 1.20 (s, 9H). IR: 3322, 2965, 1730, 1660, 1367, 1166 cm. "1 Anal. Calculated for C24H3oN206 • 0.25H20: C, 64.49; H, 6.88; N, 6.27. Found: C, 64.34; H, 6.73; N, 6.29.

Benzyl Ester of N- (2-Benzyloxycarbonyloxy-1 (S) -phenylethyl) -3 (R) -t- (butoxycarbonylamino) -succinamic acid According to the procedure described in Example 5 (a) for the preparation of N- (lR-benzyloxycarbonyloxymethyl-2,2-dimethyl-propyl) -3 (R) - (-butoxycarbonylamino) succinamic acid benzyl ester, the ester N- (2-hydroxy-l (S) -phenylethyl) -3 (R) - (t-butoxycarbonylamino) succinnamic acid benzyl ester is acylated to provide an unpurified product, which is purified by means of flash column chromatography with 30% EtOAc / hex as eluent to give 333 mg (96%) of N- (2-benzyloxycarbonyloxy-1 (S) -phenyl-ethyl) -3 (R) - (t-butoxycarbonylamino) succinamic acid benzyl ester as a white solid, mp 105-6 ° C. XH NMR (CDC13): d 7.40-7.18 (m, 15H), 5.63 (broad s, 1H), 5.24 (c, 1H, J = 6.6 Hz), 5.12 (s, 2H), 5.06 (c, 2H, J = 10.3 Hz), 4.50 (broad s, 1H), 4.55 (ddd, 2H, J = 5.0, 6.8, 11.2 Hz), 2.99 (dd, 1H, J = 4.4, 17.0 Hz), 2.66 (dd, 1H, J = 6.2, 17.0 Hz), 2.42-2.36 (m, 1H), 1.40 (s, 9H). IR: 3320, 2981, 1742, 1692, 1657, 1518, 1458, 1394, 1313, 1277, 1171 cm. "Anal." Calculated for C32H36N208: C, 66.65; H, 6.29; N, 4.86 Found: C, 66.57; H, 6.31; N, 4.88.

Benzyl Ester of N- (2-Benzyloxycarbonyloxy- (S) -phenylethyl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -1H-pyrrol-1-yl] -synatamic acid benzyl ester In accordance with the procedure described in Example 1 (b) for the preparation of acid benzyl ester N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic acid, the benzyl ester of N- (2-benzyloxycarbonyloxy-1) (S) -phenyl-ethyl) -3 (R) - (t-butoxycarbonylamino) succinamic acid and 2,5-dimethoxy-3- (4-pyridin-4-yl-phenyl) -tetrahydrofuran (prepared as described in Example 5 (a)) are condensed in wet 1,2-dichloroethane at 80-90 ° C after 18 hours. Flash column chromatography with 4% MeOH / CH2Cl2 as eluent afforded 140 mg (56%) of benzyl ester of N- (2-benzyloxycarbonyloxy-1 (S) -phenylethyl) -3 (R) - (3- [ 4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic acid as a yellow solid, p.f. 138-40 ° C. AH NMR (CDC13): d 8.66 (broad s, 2H), 7.60 (s, 5H), 7.50 (d, 3H, J = 5.3 Hz), 7.34-7.22 (m, 10H), 7.19 (d, 1H, J = 2.2 Hz), 7.17 (d, 1H, J = 1.9 Hz), 7.09 (t, 1H, J = 1.9 Hz), 6.77 (dd, 1H, J = 2.5, 2.8 Hz), 6.57 (broad t, 1H, J = 1.9, 2.5 Hz), 6.24 (d, 1H, J = 7.8 Hz), 5.26 (m, 1H), 4.25 (dd, 1H, J = 7.2, 11.5 Hz), 3.44 (dd, 1H, J = 7.2 , 16.8 Hz), 3.00 (dd, 1H, 8.7, 16.8 Hz). IR (KBr): 2985, 1738, 1657, 1598, 1560, 1495, 1202, 815, 697 cm "1. EMARFAB: Calculated for C42H37N306Cs (M + Cs +): 812.1737. Found: 812.1712.Analyzed Calculated for C42H37N3O6 • 0.25 CHC13: C, 71.51; H, 5.29. Found: C, 71.72; H, 5.60.

Example 5 (c). Acid 3 (R) - [3- (4'-Cyanobi-enyl-1-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-1 (S) - (methylcarbamoyl) - succinamic] According to the procedure described in Example 1 (a), the benzyl ester of 3 (R) - [3- (4 '-cyanobi phenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimeti 1-1 (S) - (methylcarbamoyl) propyl] succinamic (58 mg, 0.101 mmol) is hydrogenated to yield 31 mg (63%) of 3 (R) - [3- (4f-cyanobi phenyl-4-yl) -lH-pyrrol-1-ylJ- N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinnamic acid as a solid, mp 142-4 ° C. XH NMR (CDC13): d 7.61 (dd, 4H, J = 8.4, 15.2 Hz), 7.45 (dd, 4H, J = 8.2, 16.6 Hz), 7.12 (s, 1H), 6.77 (s, 1H), 6.44 (s, 1H), 6.31 ( s broad, 1H), 5.26 (t, 1H, J = 6.8 Hz), 4.29 (d, 1H, J = 9.3 Hz), 4.03 (broad s, 1H), 3.32 (dd, 1H, J = 6.5, 17.1 Hz ), 3.07 (dd, 1H, J = 7.6, 17.3 Hz), 2.66 (d, 3H, J = 4.05 Hz), 0.92 (s, 9H). IR (KBr): 3354, 2955, 2367, 1737, 1719, 1655, 1561 cm. "1 EMARFAB: Calculated for C28H3? N404 (M + H +): 487.2345. Found: 487.2356.Analyzed Calculated for C28H3oN4? 4 • 1.2 EtOAc: C, 66.51; H, 6.74; N, 9.46 Found: C, 66.57, H, 6.54; N, 9.28 The starting material was available as follows: Benzyl Ester of Acid 3 (R) - [3- (4 '-Cianobifenil-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcabamoyl) propyl] succinámico According to the procedure as described in Example 1 (c) for the benzyl ester of N- (1, 7-diaza-4-oxa-8-oxo-tricyclo- [9.6.1, O12, 17] - octadeca-11 (18), 12, 14, 16-tetraen-9S-yl) -3 (R) - (3-pheny1-lH-pyrrol-1-yl) -succinnamic, the trifluoroacetate salt of the benzyl ester of the acid 3 (R) -amino-N- (2,2-dimethyl-1 (S) -methylcarbamoylpropyl) -succinnamic acid without purification (prepared as described in Example 1 (b)) and 4 '- (2, 5) dimethoxy-tetrahydrofuran-3-yl) -biphenyl-4-carbonitrile (prepared as described in Example 4 (a)) were condensed to provide 84 mg (48%) of benzyl ester of 3 (R) - [3- (4'-cyclobiphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] succinnamic acid as a yellow solid, mp 120 ° C. NMR? E (CDC13): d 7.72 (s, 4H), 7.59 (s, 4H), 7.32-7.28 (m, 2H), 7.26 (s, 3H), 7.12 (t, 1H, J = 2.1 Hz), 6.82 (t, 1H, J = 2.7 Hz), 6.61 (dd, 1H, J = 1.8, 3.0 Hz), 6.27 (d, 1H, J = 9.0 Hz), 5.58 (m, 1H), 5.13 (s, 2H) ), 5.12 (m, 1H), 4.01 (d, 2H, 8.7 Hz), 3.41 (dd, 1H, J = 5.8, 16.7 Hz), 3.11 (dd, 1H, 8.7, 16.8 Hz), 2.78 (d, 3H) , J = 5.0 Hz), 0.87 (s, 9H). IR (KBr): 2960, 2221, 1736, 1685, 1654, 1562, 1542 cm. "1 EMARFAB: Calculated for C35H37N4O4 (M + H +): 577.2815. Found: 577.2832. Anal. Calculated for C35H36N4O4 • 0.2 DMF 0.5 H20: C, 71.23; H, 6.45; N, 9.80, Found: C, 71.14, H, 6.23; N, 10.19.

Example 5 (d). Acid Formate Salt 3 (R) - [3- (4 'Cyano-phenyl-4-yl) -lH-pyrrol-yl] -N- [2, 2-dimethyl-l (S) - (pyridin-4 - i1carbamoyl) propyl] succinámico .HO? - NH 'NH1 ^ A mixture of palladium on carbon and benzyl ester of 3 (R) - [3- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-1-yl] -N- [ 2, 2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) propyl] succinamic acid (72 mg, 0.112 mmol) in MeOH with formic acid provides 30 mg (49%) of formate salt of 3 (R) acid - [3- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-lyl] -N- [2, 2-dimethyl-l (S) pyridin-4-ylcarbamoyl) propyl] succinamic acid as a solid, mp 134-6 ° C. NMR I (DMSO-d6): d 8.39-8.35 (m, 3H), 7.81 (d, 2H, J = 5.9 Hz), 7.63 (s, 2H), 7.34-7.23 (m, 4H), 7. 28 (d, 2H, J = 10.3 Hz), 7.24 (s, 1H), 6.96-6.92 (m, 1H), 6.52 (dddd, 1H, J = 1.8, 2.9, 4.8, 7.4 Hz), 5.35- 5.29 ( , 1H), 3.39-3.18 (broad m, lH), 3.09-2.91 (broad m, 1H), 1.06 (s, 9H). IR (KBr): 2966, 2225, 1719, 1654, 1594, 1560, 1507, 1396, 1196 c "1.

EMARFAB: Calculated for C28H3? N4? 4 (M + H +): 550.2454.

Found: 550.2450. Anal. Calculated for C32H31N5? 4 • 1. 0 HC02H • 2.5 CH3OH: C, 63.10; H, 6.41; N, 10.36.

Found: C, 63.03, H, 6.75; N, 10.38. The starting material was available as follows: 2S-t-Butoxycarbonylamino-3,3-dimethyl-N-pyridin-4-yl-butanamide To a mixture of Nt-butoxycarbonyl-L-t-leucine (produced according to Shiosaki, K .; Tasker, AS; Opgenorth, TJ WO 92/13545, November 8, 1991 and adapted with the data from Pospisek, J. Blaha, K. Coil, Czech, Chem. Commun. 1977, 42, 1069-1076, 200 mg, 0.860 mmol) and 4-aminopyridine (356 mg, 1.72 mmol) in anhydrous DMF are added morpholine (284 μL, 2.58 mmoles). After cooling to 0 ° C, tetrafluoroformamidinium hexafluorophosphate (TFFH) is added (see Carpino, L.A., El-Faha, A.J. Am. Chem. Soc., 1995, 217, 5401-5402, 340mg, 1.29mmol). The mixture is allowed to warm to room temperature and is stirred overnight. The resulting mixture is diluted with CH2C12 (50 mL), washed with saturated aqueous NH4C1 (25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4 and concentrated under reduced pressure to provide a yellow solid, which is purified by flash column chromatography to provide 167 mg (67%) of 2S-t-butoxycarbonylamino-3, 3-dimethyl-N-pyridin-4-yl-butanamide as a white solid. NMR aH: d 8.60 (broad s, 1H), 8.42 (broad s, 2H), 7.34 (broad s, 2H), 5.34 (broad d, 1H, J = 8.7 Hz), 4.08 (broad s, 1H, J = 8.7 Hz), 1.42 (s, 9H), 1.02 (s, 9H). IR (KBr): 3286, 2971, 1682, 1594, 1518, 1367, 1169 cm "1. EMARFAB: Calculated for C 16 H 26 N 303 (M + H +): 308.1974. Found: 308.1967 Anal. Calculated for C? 6H25N303 • 0.37 H20: C, 61.19; H, 8.26; N, 13.38. Found: C, 61.52; H, 8.18; N, 12.99. 2S-Amino-3-3-dimethyl-N-4-pyridinyl-butanamide To a solution of 2S-t-butoxycarbonylamino-3, 3-dimethyl-N-pyridin-4-yl-butanamide (3.00 g, 9.75 mmol) in CH2C12 (10 mL) is added trifluoroacetic acid (3 mL). After 3 hours at room temperature, the solvent is removed in vacuo and azeotropically dried with hexane twice to provide a colorless foam, which is dissolved in MeOH (50 mL) and neutralized by stirring with anion exchange resin with IRA-400 (in the form of HC03; 3 g) for 3 hours. The resin is removed by filtration and the solution is concentrated in vacuo to give a white solid, which is recrystallized from hexanes to provide 1.18 g (90%) of 2S-amino-3, 3-dimethyl-N-4 pyridinyl butanamide as a white powder (cited in Chapman, KT, Hagmann, WK, Durette, PL, Esser, CK, Kopka, IE, Caldwell, CG WO 9412169, November 18, 1995). NMR 2H d 9.40 (broad s, 1H), 8.50 (d, 1H, J = 4.7 Hz), 7.50 (d, 2H, J = 4.7 Hz), 3.15 (s, 3H), 1.02 (s, 9H). IR (KBr): 3250, 2962, 1686, 1592, 1517, 1418 cm "1. Anal.Calcd for CnH17N30: C, 63.74; H, 8.27; N, 20.27. Found: C, 63.79; H, 8.23; N, 20.35.

Benzyl Ester of 3 (R) -t-Butoxycarbonylamino- N - [2, 2-dimethyl- • 1 (S) - (N-pyridin-4-ylcarbamoyl) propyl] succinamic acid To a solution of 2S-amino-3, 3-dimethyl-N-4-pyridinyl-butanamide (100 mg, 0.482 mmol) and β-benzyl ester of Nt-butoxycarbonyl-L-aspartate (156 mg, 0.482 mmol) in DMF dry (3 mL) at 0 ° C diethylcyanophosphonate is added sequentially (81 μL, 0.482 mmol) and triethylamine (200 μL, 1.46 mmol). After 30 minutes at 0 ° C, the mixture is allowed to warm to room temperature. After 4, the resulting orange mixture is stirred with saturated aqueous NaHCO 3 and extracted with EtOAc three times. The combined organic layers are washed with 5% citric acid, H20 and brine, dried over Na2SO4 and evaporated to give a viscous yellow oil, which is purified by flash column chromatography with EtOAc as eluent to produce 150 mg (61%) of benzyl ester of 3 (R) t-butoxycarbonylamino-N- [2, 2-dimethyl-1 (S) - (N-pyridin-4-yl-carbamoyl) -propyl] succinamic acid ester as an oil yellow. NMR 1E: d 9.11 (broad s, 1H), 8.37 (d, 2H, J = 5.0 Hz), 7.43 (d, 2H, 4.7 Hz), 7.28 (m, 5H), 5.90 (broad s, 1H), 5.09 (d, 1H, J = 12.1 Hz), 5.01 (d, 1H, J = 12.1 Hz), 4.60 (dd, 1H, J = 5.5, 12.6 Hz), 4.35 (d, 1H, 8.1 Hz), 3.03 (ddd) , 1H, J = 4.6, 4.6, 17.1 Hz), 2.83 (dd, 1H, 5.6, 17.1 Hz), 1.47 (s, 9H), 1.05 (s, 9H). IR (KBr): 3319, 2966, 1737, 1719, 1701, 1666, 1596, 1525, 1420, 1367, 1290 cm. "1 EMARFAB: Calculated for C27H37N4? 6 (M + H +): 513.2713. Found: 513.2726. Calculated for C27H36N4? 6: C, 63.26; H, 7.09; N, 10.92, Found: C, 63.11; H, 7.12; N, 10.89.

Benzyl Ester of Acid 3 (R) - [3- (4'-Cyanobiphenyl-4-yl) -lH-pyrrol-lyl] -N- [2, 2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) propyl] succinámico In accordance with the procedure described in Example 1 (c) for the preparation of benzyl ester of N- (1,7-diaza-4-oxa-8-oxo-tricyclo- [9.6.1, O12, 17] - octadeca-11 (18), 12, 14, 16-tetraen-9S-yl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) -succinnamic, the trifluoroacetate salt of the benzyl ester of the acid 3 (R) -amino-N- [2,2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) -propyl] succinamic acid without purification and the 4'- (2,5-dimethoxy-tetrahydrofuran-3-) il) -biphenyl-4-carbonitrile is condensed to provide 75 mg (42%) of benzyl ester of 3 (R) - [3- ('-cyanobiphenyl-4-yl) -lH-pyrrol-lyl] -N- [2,2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) propyl] succinnamic acid or an off-white powder, mp. 115-6 ° C. 1 H NMR. d 8.42 (d, 2H, J = 5.6 Hz), 7.72 (s, 2H), 7.58 (s, 2H), 7.50 (d, 2H, J = 5.0 Hz), 7.31 (s, 2H), 7.26 (s, 7H), 7.12 (m, 1H), 6.85 (dd, 1H, J = 2.5, 2.5 Hz), 6.64 (dd, 1H, J = 1.6, 2.8 Hz), 6.25 (m, 1H), 5.20, 5.10 (m , 3H), 4.15 (d, 1H, J = 8.1 Hz), 3.39 (dd, 1H, J = 5.5, 17.3 Hz), 3.25 (dd, 1H, J = 7.9, 17.3 Hz), 0.94 (s, 9H) . IR (KBr): 3331, 2959, 2225, 1735, 1687, 1655, 1602, 1559, 1511, 1288, 1203, 825 c "1. EMARFAB: Calculated for C35H37N404 (M + H +): 640.2924. Found: 640.2908. Calculated for C39H37N504 • 1.1 EtOAc: C, 70.76; H, 6.27; N, 9.51, Found: C, 70.73; H, 6.19; N, 9.16.

Example 5 (e). 3 (R) - [3- (4'-Carbamoylbifenyl-4-yl) -lH-pyrrol-1-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) acid succinámico In accordance with the procedure described in Example 5 (a), the benzyl ester of 3 (R) - [3- (4 '-carbamoyl-phenyl-4-yl) -lH-pyrrol-1-yl acid} -N- (2,2-Dimethyl-1 (S) - (methylcarbamoyl) propyl) succinnamic is hydrogenated to give 45 mg (90%) of 3 (R) - [3- (4'-carbamoylbifeni 1-4- il) -lH-pyrrol-1-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinnamic acid as a yellow solid. 2 H NMR (CD3OD): d 7.98 (d, 2H, J = 8.1 Hz), 7.78 (d, 2H, J = 8.1 Hz), 7.62 (s, 4H), 7.30 (broad s, 1H), 6.92 (broad s) , 1H), 6.54 (broad s, 1H), 5.98 (1H, J = 2.8 Hz), 5.39 (t, 1H, J = 6.5 Hz), 4.19 (d, 1H, J = 9.3 Hz), 3.02 (dd, 1H, J = 7.2, 16.5 Hz), 2.60 (s, 3H), 0.98 (s, 9H). IR (KBr): 3332, 2915, 1658, 1547, 1408 cm. "1 Anal. Calculated for C28H32N4? 5 • 0.7 H20: C, 65.03; H, 6.51; N, 10.83 Found: C, 65.10, H, 6.74; N, 10.43 The starting material is prepared as follows: Benzyl Ester of Acid 3 (R) - [3- (4'-Carbamoylbi phenyl-4-yl) -lH-pyrrol-1-yl] -N- (2, 2 -dimeti 1- (S) - (methylcarbamoyl) propyl) succinámico According to the procedure described in Example 1 (b) for the preparation of N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-phenyl-1H-) benzyl ester pyrrol-1-yl) succinamic acid, the benzyl ester of 3 (R) -t-butoxycarbonylamino-N- (2, 2-dimethyl-1 (S) -methylcarbamoylpropyl) succinamic acid is deprotected. The unpurified amine salt and the 3-. { 4 '-carboxamidobiphenyl-4-yl) -2,5-dimethoxy-tetrahydrofuran without purification (prepared as described in Example 4 (b)) are condensed in humid 1,2-dichloroethane at 90-100 ° C to produce 180 mg (55%) of 3 (R) - [3- (4 '-carbamoylbiphenyl-4-yl) -lH-pyrrol-1-yl] -N- (2, 2-dimethyl-l (S) benzyl ester ) - (methylcarbamoyl) propyl) succinamic. 1H NMR: 7.90 (d, 2H, J = 8.4 Hz), 7.70 (d, 2H, J = 8.7 Hz), 7.60 (dd, 3H, J = 8.7, 11.5 Hz), 7.38-7.22 (m, 8H) , 7.10 (t, 1H, J = 2.2 Hz), 6.82 (t, 1H, J = 2.5 Hz), 6.62 (t, 1H, J = 3.0 Hz), 6.32 (d, 1H, J = 9.0 Hz), 5.63 (d, 1H, J = 4.70 Hz), 5.14 (d, 3H, J = 3.7 Hz), 4.00 (d, 1H, J = 8.7 Hz), 3.48 (dd, 1H, J = 7.2, 13.1 Hz), 3.39 (d, 1H, J = 5.9 Hz), 3.14 (dd, 1H, J = 8.7, 16.8 Hz), 2.78 (d, 3H, J = 4.7 Hz), 0.92 (s, 9H). IR (KBr): 3356, 2929, 1735, 1657.1402 cm "1. Anal. Calculated for C35H39N405 • 0.5 H20: C. 69. 63; H, 6.51; N, 9.28. Found: C, 69.85, H, 6.46; N, 9.14.

Example 5 (f). Acid 3 (R) - (3- (4'-Carbamoylbiphenyl-yl) -lH-pyrrol-l-yl] -N- [2, 2-dimethyl-l (S) - (N- (pyridin-4-yl ) carbamoyl) propyl] succinámico According to the procedure described in Example 5 (a), the benzyl ester of 3 (R) - [3- (4'-carbamoylbifeni-4-yl) -lH-pyrrol-1-yl] -N- [2,2-Dimeti 1-1 (S) - (N- (pyridin-4-yl) carbamoyl) propyl] -succinnamic is hydrogenated in MeOH / EtOAc to give 35 mg (81%) of 3 (R) - [3- (4'-carbamoyl-phenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-1 (S) - (N- (pyridin-4-yl) carbamoyl) propyl] succinamic as a yellow solid, mp 194-6 ° C. 2 H NMR (CD30D): 88.35 (d, 2H, J = 6.5 Hz), 7.95 (d, 2H, J = 8.4 Hz), 7.75 (d, 3H, J = 8.4 Hz), 7.70-7.52 (m, 6H) , 7.28 (t, 1H, J = 2.0 Hz), 6.90 (t, 1H, J = 2.8 Hz), 6.52 (dd, 1H, J = 6.9, 16.8 Hz), 1.20 (s, 9H). IR (KBr): 3400, 2962, 1665, 1606, 1511, 1402 cm "1. EMARFAB: Calculated for C32H34N5O5 (M + H +): 568.2560. Found: 568.2575.Analyzed Calculated for C32H33N5O5 • 0.7 HOAc * 0.5 CHC13: C, 60.83; H, 5.47; N, 10.46. Found: C, 60.93, H, 5.88; N, 10.19. The starting materials are prepared as follows: Esther; Benzyl of Acid 3 (R) - [3- (4'-Carbamoylbiphenyl-4-yl) -1H-pyrrol-1-yl] - N- [2, 2-dimethyl-1 (S) - ( N- (pyridin-4-yl) carbamoyl) propi 1] succinámico According to the procedure described in Example 1 (b) for the preparation of N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-phenyl-1H-) benzyl ester pyrrol-1-yl) succinamic acid, the benzyl ester of 3 (R) -t-butoxycarbonyl amino-N- [2, 2-dimethyl-l (S) - (pyridin-4-yl) carbamoylpropyl] succinamic acid is deprotected. Unpurified amine salt and unpurified 3- (4'-carboxamidobi phenyl-4-yl) -2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 4 (b)) are condensed in 1.2 -hydrous dichloroethane at 90-100 ° C to produce 130 mg (36%) of 3 (R) - [3- (4'-carbamoylbifeni-4-yl) -lH-pyrrol-1-yl benzyl ester] -N- [2,2-dimethyl-1 (S) - (N- (pyridin-4-yl) carbamoyl) propyl] succinamic acid. NMR I E (CD3OD): d 8.35 (broad s, 2H), 7.95 (d, 2H, J = 8.4 Hz), 7.72 (d, 2H, J = 8.7 Hz), 7.60 (dd, 6H), J = 8.7 , 13.4 Hz), 7.28 (s, 5H), 6.90 (t, 1H, ZJ = 2.8 Hz), 6.52 (dd, 1H, 1.6, 2.8 Hz), 5.38 (t, 1H, J = 7.5 Hz), 5.12 ( d, 2H, J = 1.9 Hz), 4.40 (s, 1H), 1.00 (s, 9H). IR (KBr): 2725, 1735, 1664, 1510 cm. "1 Anal. Calculated for C39H39N5? 5 • 1.0 HOAc: C, 68.38; H, 6.05; N, 9.76 Found: C. 68.38, H, 6.05; N , 9.38.

Example 5 (g). Triethylammonium salt of Acid 3 (R) - [3- (4'-Cyanobiphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-1 (S) - (hydroxymethyl) propyl] According to the procedure described in Example 1 (a), a mixture of N- (2-benzyloxycarboxymethyl-1 (S) -dimethylpropyl) -3 (R) - [3- (4'-cyanobi phenyl) benzyl ester - 4-yl) -lH-pyrrol-1-yl] succinamic acid and the benzyl ester of N- (2-benzyloxycarboxymethyl-1 (S) -dimethylpropyl) -3 (R) - [3- (4-cyanophenyl) - lH-pyrrol-l-yl] succinamic acid is hydrogenated to provide a mixture which is separated by means of preparative RPCLAP (C18) with HOAc / Et3N / MeOH / CH2Cl2 as eluent to provide 50 mg of 3 (R) - [3- (4'-cyclobiphenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (hydroxymethyl) -propyl) succinnamic acid as a solid, mp 110-2 ° C: XH NMR (CD3OD): d 7.82 (d, 2H, J = 8.3 Hz), 7.77 (d, 2H, J = 8.3 Hz), 7.65-7.60 (broad m, 4H), 7.34 (s) , 1H), 6.93 (s, 1H), 6.50 (s, 1H), 5.19 (dd, 1H, J = 3.6, 3.6 Hz), 3.45 (dd, 1H, J = 8.2, 12.1 Hz), 3.16 (c, 6H, J = 7.4 Hz), 1.28 (t, 9H, J = 7.4 Hz), 0.91 (s, 9H). IR (KBr): 3389, 2955, 2226, 1655, 1601, 1561, 1396, 1367, 1202, 920, 826, 779 cm. "1 EMARFAB: Calculated for C2 H29N3O4CS (MH + CS +): 592.1212 Found: 592.1230. Anal Calc'd for C27H29N3O4 • Et3N • 2.5 H20: C, 65.42; H, 7.87; N, 9.11 Found: C, 65.43; H, 8.15; N, 9.25.

Example 5 (h). Triethylammonium salt of 3 (R) - [3 (4-Cyanophenyl) -lH-pyrrol-1-yl] -N- (2, 2-dimethyl-l (S) - (hydroxymethyl) propyl) succinamic acid Separation by preparative CLAP of the mixture obtained as described in Example 5 (g) yields 50 rag of 3 (R) - [3- (4-cyanophen-1) -1H-pyrrol-1-yl] - acid. N- [2, 2-dimethyl-l (S) - (hydroxymethyl) propyl] succinamic: NMR l: d 7.66 (d, 2H, J = 8.1 Hz), 7.60 (d, 2H, J = 8.1 Hz), 7.42 (s, 1H ), 6.94 (s, 1H), 6.51 (s, 1H), 5.18 (broad s, 1H), 3.45 (dd, 1H, J = 9.2, 12.1 Hz), 3.16 (c, 6H, J = 7.4 Hz), 1.96 (s broad, 1H), 1.28 (t, 9H, J = 7.4 Hz), 0.91 (s, 9H), IR (KBr): 3378, 2955, 2214, 1655, 1602, 1561, 1489, 1396, 1172, 1094, 920, 838, 785 c "1. EMFAB: 516. Anal. Calculated for C21H25N304 • Et3N • HOAc • 1.7H20: C, 60.70; H, 8.05; N, 9.51. Found: C, 60.54; H, 8.30; N, 9.74.

Example 6 (a). N- (2 (R) -Hydroxyindan-1 (R) -yl) 3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1-yl] -synatamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- (2 (R) -hydroxyindan-1 (R) -yl) -3 (R) - [3- [4- (pyridine -4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid is hydrogenated to obtain, in 61% yield, N- (2 (R) -hydroxyindan-1 (R) -yl) -3 ( R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic acid as a yellow amorphous solid. NMR K (DMS0-d6): d_12.52 (broad s, 1H), 8.59 (d, 2H, J = 5.9 Hz), 8.24 (d, 1H, J = 8.5 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.71 (d, 2H, J = 6.3 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.45 (s, 1H), 7.30-7.15 (m, 4H), 6.97 (t, 1H, J = 2.4 Hz), 6.51 (s, 1H), 5.34 (t, 1H, J = 7.5 Hz), 5.17 (dd, 1H, J = 5.0, 8.7 Hz), 5.11 (d, 1H, J = 3.7 Hz) , 4.35 (d, 1H, J = 3.3 Hz), 3.27-2.94 (m, 2H), 2.76 (d, 1 H, J = 1 6, 0 H z). Ana l. Calcd for C28H2sN304 • 0.2 EtOAc: C, 71.30; H, 5.53; N, 8.66. Found: C, 71. 24; H, 5.59; N, 8.52. The starting material was available as follows: 4-Benzyl Ester Hydrochloride Acid 2 (R) - [3- [4 Pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinic According to the procedure as described in Example 1 (d) for the preparation of benzyl ester of N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-pyridine) 4-yl-lH-pyrrol-1-yl) succinamic acid, to a solution of β-benzyl ester of D-aspartate (223 mg, 1.00 mmol) and 2,5-dimethoxy-3- (4- (pyridine-4- il) phenyl) tetrahydrofuran (350 mg, 1.20 mmol;) prepared as described in Example (a)) in 1,2-dichloroethane is sequentially added pyridine (0.16 mL, 2.0 mmol), trifluoroacetic acid (0.08 L, 1 mmol), and chlorotrimethylsilane (0.38 mL, 3.0 mmol). After 17 hours at 80 ° C, the mixture is allowed to cool to room temperature. Filtration leads to the isolation of 408 mg (87%) of 2 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1-yl-4-benzyl ester hydrochloride. ] succinic as a yellow solid, mp 203-5 ° C (d). Al NMR (DMSO-d6): d 8.86 (d, 2H, J = 6.3 Hz), 8.38 (d, 2H, J = 6.6 Hz), 8.02 (d, 2H, J = 8.5 Hz), 7.74 (d, 2H , J = 8.5 Hz), 7.58 (s, 1H), 7.31-7.24 (m, 5H), 6.96 (t, 1H, J = 2.4 Hz), 6.58 (s, 1H), 5.23 (t, 1H, J = 7.4 Hz), 5.10 (s, 2H), 3.36 (dd, 1H, J = 6.6, 16.6 Hz), 3.21 (dd, 1H, J = 7.7, 16.9 Hz). Anal. Calculated for C26H22N204 • HCl • 0.3 H20: C, 66.68; H, 5.08; N, 5.98; Cl, 7.57. Found: C, 66.56; H, 5.01; N, 5.98; Cl, 7.80.

Benzyl Ester of N- (2 (R) -Hydroxyindan-1 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl ] succinámico According to the procedure as described in Example 1 (f) for the benzyl ester of 3 (R) -t-butoxycarbonylamino-N- (1 (S) -benzyl-2-methoxy-et i 1) succinamic acid, 2 (R) - [3- (4'-pyridin-4-yl-phenyl) -lH-pyrrol-1-yl] succinic acid 4-benzyl hydrochloride and 1 (S) -amino-2 ( R) -hydroxy-indane are coupled with BOP to produce, in 60% yield, the benzyl ether of N- (2 (R) -hydroxyindan-1 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic acid as an off-white solid, m.p. 199-202 ° C (d). XH NMR (DMSO-d6): d_8.66 (d, 2H, J = 5.9 Hz), 8.34 (d, 1H, J = 8.8 Hz), 7.84 (d, 2H, J = 8.5 Hz), 7.79 (d, 2H, J = 6.3 Hz), 7.73 (d, 2H, J = 6.3 Hz), 7.69 (s, 1H), 7.36 (s, 5H), 7.29-7.21 (m, 4H), 7.04 (t, 1H, J = 2.2 Hz), 6.58 (s, 1H), 5.49 (t, 1H, J = 7.2 Hz), 5.25-5.12 (, 4H), 4.43-4.39 (m, 1H), 3.48 (dd, 1H, J = 7.5 , 16.5 Hz), 3.26 (dd, 1H, J = 7.7, 16.5 Hz), 3.09 (dd, 1H, J = 4.6, 15.6 Hz), 2.83 (d, 1H, J = 16.2 Hz). Anal. Calculated for C3sH3? N304 • 0.6 H20: C, 73.95; H, 5.71; N, 7.39. Found: C, 73.70; H, 5.61; N, 7.26. The following is prepared in a similar way: Example 6 (b). N- (2, 2-Dimethyl-l (S) - (methylcarbamoyl) propyl) -3 (R) - [3- (4- (pyridin-4-yl) phenyl) -lH-pyrrol-1-yl] acid] succinámico According to the procedure described in Example 1 (a), the benzyl ester of N- (2,2-dimethyl-1 (?) - (methylcarbamoyl) propyl) -3 (R) - [3- (4- (pyridin-4-yl) phenyl) -lH-pyrrol-1-yl] succinnamic acid is hydrogenated in MeOH after 20 hours. Purification by means of flash column chromatography with 1% HOAc / 10% MeOH / CHCl3 as eluent and azeotrope with n-heptane provides 24 mg (32%) of N- (2, 2-dimeti t-1 (S) - (methylcarbamoyl) -propyl) -3 (R) - [3- (4- (pyridin-4-yl) phenyl) -lH acid -pyrrol-1-yl] succinámico like yellow crystals. NMR I (CD3OD): d 8.54 (d, 2H, J = 5.6 Hz), 7.99 (broad d, 1H, J = 4.4 Hz), 7.80-7.59 (, 6H), 7.34 (t, 1H, J = 1.9 Hz ), 6.92 (t, 1H, J = 2.5 Hz), 6.55 (dd, 1H, J = 1.9, 2.8 Hz), 5.28 (t, 1H, J = 7.2 Hz), 4.17 (s, 1H), 3.23 (dd) , 1H, J = 7.5, 16.7 Hz), 3.01 (dd, 1H, J = 7.2, 16.7 Hz), 2.66 (d, 3H, J = 3.5 Hz), 0.95 (s, 9H). IR (KBr): 3422, 1654, 1598, 1562, 1535 cm. "1 EMARFAB: Calculated for C26H3? N404 (M + H +): 463.2345. Found: 463.2356. Anal. Calculated for C26H30N4O4 • 1.15 H20 • 0.1 CHC13: C , 63.30; H, 6.59; N, 11.31, Found: C, 63.28; H, 6.58; N, 11.08, The starting material was available as follows: Benzyl Ester of N- (2, 2-Dimethyl-l (S) - (methylcarbyl) propyl) -3 (R) - [3- (4- (pyridin-4-yl) phenyl) -lH-pyrrole- 1-ilch succinámico According to the procedure described in Example 1 (b) for the preparation of benzyl ester of N- (2,2-dimethyl-l (S) - (methylcarbamoyl) propyl) -3 (R) -t-butoxycarbonylamino- succinamic, 2 (R) - [3- (4'-pyridin-4-yl-phenyl) -1H-pyrrol-1-yl] succinic acid 4-benzyl hydrochloride and the trifluoroacetate salt of Lt-leucin -N-methylamide (prepared as described in Example 5 (d)) is coupled with TBTU to provide, in 86% yield, the benzyl ester of N- (2,2-dimethyl-1 (S) - ( methylcarbamoyl) propyl) -3 (R) - [3- (4-pyridin-4-yl) phenyl) -lH-pyrrol-1-yl] succinnamic acid. XH NMR: d 8.80-8.57 (broad s, 2H), 7.76-7.50 (m, 6H), 7.36-7.22 (m, 5H), 7.12 (d, 1H, J = 1.6 Hz), 6.82 (t, 1H, J = l.9 Hz), 6.60 (dd, 1H, J = 1.2, 1.2 Hz), 5.20-5.15 (m, 3H), 4.09 (dd, 1H, J = 2.8, 9.0 Hz), 3.41 (dd, 1H , J = 5.3, 16.5 Hz), 3.10 (dd, 1H, J = 8.4, 16.5 Hz), 2.76 (dd, 3H, J = 2.5, 4.4 Hz), 0.90 (s, 9H). IR (KBr): 3314, 2959, 1736, 1652, 1598, 1560, 1550, 1409, 1166 cm "1. LSIEM: 553 (MH *) Anal. Calculated for C33H3fcN404 • 0.5 H20: C, 70.56; H, 6.64; N, 9.98, Found: C, 70.70; H, 6.62; N, 9.78.

Example 6 (c). N- (, 4-Dimethyl-2-oxo-tetrahydrofuran-3 (S) -yl) -3 (R) - [3- [4- (pyridin-phenyl) -lH-pyrrol-1-yl) acid ] succinámico According to the procedure described in Example 1 (a), the benzyl ester of N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3 (S) -yl) -3 (R) - [3- [4- (Pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid is hydrogenated to obtain, in 70% yield, N- (4,4-dimethyl-2-oxo-tetrahydrofuran- 3 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -IH-pyrrol-1-yl] succinnamic acid as an amorphous solid.

NMR ^ (DMSO-ds): d 12.60 (broad s, 1H), 8.82 (d, 1H, J = 8.8 Hz), 8.59 (d, 2H, J = 5.9 Hz), 7.77 (d, 2H, J = 8.1 Hz), 7.71 (d, 2H, J = 5.9 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.41 (s, 1H), 6. 92 (s, 1H), 6.52 (s, 1H), 5.16-5.11 (m, 1H), 4.75 (d, 1H, J = 8.8 Hz), 4.08, 4.00 (quartet, 2H, 2H, J-8.3 Hz), 3.22 (dd, 1H, J = 9.2, 16.6 Hz), 2.93 (dd, 1H, J = 5.9, 16.9 Hz), 1.05 (s, 3H), 0.96 (s, 3H). Anal. Calculated for C2bH2sN3O • 0.2 MTBE • 0.2 H? 0: C, 66.62; H, 5.98; N, 8.97.

Found: C, 66.55; H, 5.90; N, 8.98. The starting material was available as follows: Benzyl Ester of N- (4, -Dimet-2-oxo-tetrahydrofuran-3 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH- acid pyrrol-1-yl] succinámico (Y °) According to the procedure described in Example 1 (f) for the preparation of 3 (R) -t-butoxycarbonylamino-N- (1 (S) -benzyl-2-methoxy-ethyl) succinnamic acid benzyl ester , 2 (R) - [3- (4 * -pyridin-4-yl) -1H-pyrrol-1-yl] succinic acid 2-benzyl hydrochloride and 3 (R) -amino-4, 2 -dimethyl-2-oxo-tetrahydrofuran (see Freskos, JN Syn, Commun, 1994, 24, 557-563) are coupled using BOP reagent to provide, in 55% yield, benzyl ester of N- (4, 4) acid. -dimet il-2-oxo-tetrahydrofuran-3 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic as a solid white, mp 175-7 ° C. NMR: 8.64 d (d, 2H, J = 6.3 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 6.3 Hz), 7.32-7.26 (m, 5H), 7.13 (s, 1H), 6.83 (t, 1H, J = 2.4 Hz), 6.61 (dd, 1H, J ^ 1.7, 2.8 Hz), 5.23 (dd, 1H, J = 5.9, 8.5 Hz), 5.13 (s, 2H), 4.59 (d, 1H, J = 8.1 Hz), 4.01 (s, 2H), 3.50 (dd, 1H, J = 5.9, 16. 9 Hz), 3.09 (dd, 1H, J = 8.5, 16.9 Hz), 1.20 (s, 3H), 0.86 (s, 3H). Anal. Calculated for C 2H3: N30s: C, 71. 49; H, 5.81; N, 7.82. Found: C, 71.57; H, . 84; N, 7.77.

Example 7 (a). N- (8-Oxo-4-oxa-l, 7 diazatricyclo [9.6.1, O12'17] octadeca-ll (18), 12,14, 16-tetraen-9 (S) -yl) -3 ( R) - [3- [4- (pyridin-4-yl) phenyl] -1H-pyrrol-1-yl] succinnamic To a solution of benzyl ester of N- (8-oxo-4-oxa-l, 7-diazatricyclo [9.6.1, O12, 17] octadeca-11 (18), 12, 14, 16-tetraen-9 ( S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic acid (185 mg, 0.280 mmol) in EtOAc / EtOH / THF was add in succession 10% palladium on carbon (50 mg) and 88% formic acid (0.1 mL). After 1.5 hours, HOAc (1 L) is added. After 16 hours, add 10% of additional carbon palladium (25 mg), 88% formic acid (0.1 mL), and HOAc (1 mL). At 24 hours, 10% additional palladium on carbon (25 mg) is added. After 25 hours of elapsed time, the catalyst is removed by filtration. The filtrate is concentrated to an unpurified solid. The product dissolved in a minimum amount of MeOH / EtOAc, and the inorganic particulates are removed by filtration. The filtrate is concentrated to a solid which is triturated with CH2Cl2 / hex to give 76 mg (46%) of N- (S-oxo-4-oxa-l, 7-diazatricyclo [9.6.1, O12.1 ']] octadeca-11 (18), 12,14, 16-tetraen-9 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1- il] succinámico like a yellow solid, pf > 172 ° C (d). XH NMR (CD3COOD): d 8.91 (d, 2H, J = 6.6 Hz), 8.23 (d, 2H, J = 6.6 Hz), 7.93 (d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J = 8.5 HZ), 7.62 (d, 1H, J = 7.4 Hz), 7.40-7.33 (m, 2H), 7.17 (t, 1H, J = 7.5 Hz), 7.10 (t, 1H, J = 7.4 Hz), 7.04 (s, 1H), 6.93 (t, 1H, J = 2.6 Hz), 6.79 (broad m, 1H, partially exchanged), 6.58 (s, 1H), 5.34 (t, 1H, J ^ 7.5 Hz), 4.72 (dd, 1H, j = 4.6, 11.2 Hz), 4.35-4.30 (m, 1H), 4.23-4.15 (, 1H), 3.74-3.65 (, 2H), 3.56-3.42 (, 2H), 3.31-3.00 ( m, 4H), 2.91-2.85 (m, 1H), 2.74-2.67 (m, 1H). Anal. Calculated for C34H33N50s • 0.4 H20: C, 68.19; H, 5.69; N, 11.70. Found: C, 68.13; H, 5.77; N, 11.81. The starting material was available as follows: Benzyl Ester d < ! N- (8-Oxo-4-oxa-1,7-diazatricyclo [9 .6. 1. 0l2'l7] oc1tadeca -11 (18), 12, 14, 16-tetraen-9 (S) - ) -3 (R) - [3- [4- i] pyridin-4-yl) phenyl] -1H-pyrrol-1-yl] succinnamic According to the procedure described in Example 1 (b) for the preparation of benzyl ester of N- (2,2-dimethyl-l (S) - (methylcarbamoyl) propyl) -3 (R) - (t-butoxycarbonylamino) ) succinamic acid, 2 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinic acid 4-benzyl hydrochloride (prepared as described in Example 6 (a)) and 9S-t-butoxycarboni lamino-4-oxa-1, 7-diaza-tricyclo- [9.6.1. O12'17] -octadeca-11 (18), 12, 14, 16-tetraen-8 -one (see Castelhano, AL; Liak, TJ; Horne, S.; Yuan, Z .; Krantz, A. Int. Patent Appl. WO95 / 04735-Al, February 16, 1995) are coupled with TBTU to provide, at 77 % yield, after purification by means of column chromatography with 5% MeOH / EtOAc and trituration with MTBE / hex, N- (8-oxo-4-oxa-l, 7-diazatricicio [9.6.1.012 '17] -octadeca-11 (18), 12, 14, 16-tetraen-9 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH- pyrrol-1-yl] succinnamic acid as a pale yellow amorphous solid. XH NMR: d 8. 91 (d, 2H, J = 6.6 Hz), 8.23 (d, 2H, J = 6.6 Hz), 7.93 (d, 2H, J = 8.5 Hz), 7.74 (d, 2H, J = 8.5 Hz), 7.59 (d, 1H, J = 7.4 Hz), 7.37-7.25 (m, 7H), 7.17 (t, 1H, J = 7.4 Hz), 7.10 (t, 1H, J = 7.4 Hz), 7.03 (s, 1H), 6.90 (t, 1H, J = 2.2 Hz), 7.79 (broad d, 1H, partially exchanged), 6.57 (s, 1H ), 5.37 (t, 1H, J = 7.5 Hz), . 18 (s, 2H), 4.70 (dd, 1H, J = 5.0, 11.2 Hz), 4.35-4.30 (m, 1H), 4.23-4.15 (m, 1H), 3.70-3.65 (, 2H), 3.56-3.43 (m, 2H), 3.31-3.15 (m, 3H), 3.02 (t, 1H, J = 12.7 Hz), 2.91-2.84 (m, 1H), 2.72-2.67 (m, 1H). Anal. Calculated for C4? H38N5Ob • 0.5 H20: C, 71.39; H, 5.70; N, 10.15. Found: C, 71.47; H, 5.82; N, 10.26. The following was available in a similar way: Example 7 (b). N- [2, 2-Dimethyl-l (S) - (pyridin-4 i1carbamoyl) propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1 acid -yl] succinámico According to the procedure described in Example 7 (a), the benzyl ester of N- [2,2-dimethyl-1 (S) - (pyridin-4-ylcarbamoyl) propyl] -3 (R) - [ 3- [4- (Pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid (185 mg, 0.280 mmol) is hydrogenated in EtOH (10 L) and HOAc (1 mL) and a solid is provided which is triturated with EtOAc to give 60 rag (41%) of N- [2, 2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) -propyl] -3 (R) - [3- [4 - (pyridin-4-yl) phenyl] -lH-pyrrol-1-y] succinnamic acid as a yellow solid. XR NMR (CD3OD): d 8.54 (d, 2H, J = 6.6 Hz), 8.33 (d, 2H, J = 6.6 Hz), 7.73-7.68 (m, 4H), 7.64-7.59 (m, 4H), 7.32 (s, 1H), 6.91 (t, 1H J = 2.4 Hz), 6.52 (dd, 1H), J = l-8, 2.9 Hz), 5.31 (t, 1H, J = 7.5 Hz), 4.41 (s, 1H), 2.99 (dd, 1H, J = 6.8, 16.7 Hz), 1.03 (2, 9H). Anal. Calculated for C30H31N5? 4 • 0.6 H? 0 • 0.2 EtOAc: C, 66.77; H, 6.15; N, 12.64. Found: C, 66.72; H, 5.99; N, 12.62.

The starting material was available as follows Benzyl Ester of N- [2, 2-Dimethyl-l (S) -pyridin-4-yl carbamoyl) propyl] -3 (R) - [3- [4- (pyridin-4 'yl) phenyl] -lH acid -pyrrol-1-yl] succinámico According to the procedure described in Example 1 (b) for the preparation of benzyl ester of N- (2,2-dimethyl-l (S) - (methylcarbamoyl) propyl) -3 (R) -t-butoxycarbonylamino- succinamic acid, 2S-t-butoxycarbonylamino-3, 3-dimethyl-N- (pyridin-4-yl) -butanamide (prepared as described in Example 5 (d)) is deprotected with trifluoroacetic acid. Unpurified amine salt and ester hydrochloride 4-Benzyl acid of 2 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinic acid (prepared as described in Example 6 (a)) are coupled with TBTU to provide, after purification by means of column chromatography with 5% MeOH / CH? Cl2 and trituration with MTBE / hex, in 76% yield, the benzyl ester of N- [2, 2- dimethyl-l (S) - (pyridin-4-yl carbamoyl) propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl) succinamic as a Pale yellow amorphous solid, which is used without further purification. 1H-NMR: 8.65 d (d, 2H, J = 5.9 Hz), 8.43 (d, 2H, J = 6.3 Hz), 8.26 (s, 1H), 7.64 (d, 2H, J = 8.5 Hz), 7.58 (d , 2H, J = 8.5 Hz), 7.53 (d, 2H, J = 6.3 Hz), 7.40 (d, 2H, J = 6.3 Hz), 7.32-7.24 (m, 5H), 7.12 (s, 1H), 6.85 (t, 1H, J = 2.4 Hz), 6.64 (dd, 1H, J = 1.8, 2.9 Hz), 6.23 (d, 1H, J = 8.1 Hz), 5.19-5.08 (m, 3H), 4.19 (d, 1H, J = 8.1 Hz), 3.39 (dd, 1H, J = 5.2, 16.9 Hz), 3.23 (dd, 1H, J = 8.1, 17.3 Hz), 0.93 (s, 9H). Anal. Calculated for C37H37N5O4 • 0.9 H20: C, 70.32; H, 6.19; N, 11.08. Found: C, 70.37; H, 6.11; N, 10.94.

Example 7 (c). N- (1 (S) - (1H-Imidazol-2-yl) -3-methylbutyl] -3 (R) - (3- [4- (pyridin-4-yl) phenyl] -lH acid formate. -pyrrol-1-yl] succinámico According to the procedure described in Example 7 (a), the benzyl ester of N- [1 (S) - (lH-imidazol-2-yl) -3-methylbutyl] -3 (R) - [3- [4-pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid is hydrogenated in EtOH: THF (1: 1) to yield, in 81% yield, the salt of forniate of N- [ 1 (S) - (1H-imidazol-2-yl) -3-methylbutyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -IH-pyrrol-1-yl] succinnamic as a yellow amorphous solid. XH NMR (DMSO-d6): d 12.30 (broad s, 1H), 8.65 (d, 1H, J = 8.1 Hz), 8.59 (d, 2H, J = 4.4 Hz), 8.13 (s, 1H), 7.75 ( d, 2H, J = 8.5 Hz), 7.71 (d, 2H, J = 4.4 Hz), 7.60 (d, 2H, J = 8.5 Hz), 7.34 (s, 1H), 6.91-6.83 (m, 3H), 6.44 (s, 1H), 5.08 (t, 1H, J = 7.5 Hz), 4.97 (dd, 1H, J = 8.1, 16.2 Hz), 3.10 (dd, 1H, J = 8.1, 16.6 Hz), 2.90 (dd) , 1H, J = 7.2, 16.7 Hz), 1.68 (t, 2H, J = 7.2 Hz), 1.52-1.45 (m, 1H), 0.86 (d, 3H, J = 7.0 Hz), 0.83 (d, 3H, J = 6.6 Hz). Anal. Calculated for C27H29NsO, • HC0H • 0.5 EtOAc: C, 64.15; H, 6.28; N, 12.47. Found: C, 64.21, H, 6.40; N, 12.60. The starting material is prepared as follows: Benzyl Ester of N- [1 (S) - (lH-Imidazol-2-yl) -3-methylbutyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH- acid pyrrol-1-yl] succinámico According to the procedure described in Example 1 (b) for the preparation of benzyl ether of 3 (R) -t-butyloxycarbonylamino-N- (2, 2-dimethyl-1 (S) - (methylcarbamoyl) propyl) 2- (l (S) -amino-3-methyl-butyl) -imidazole (See Chen, JJ; Zhang, Y .; Hammond, S.; Dewdney, N .: Ho, T .; Browner, MF Castelhano, AL, submitted for publication, and Abel-Meguid, SS, Metcalf BW, Caw, TJ, DeMarsh, P., Des Jariais, RL, Fisher, S., Green, D., et al., Bi ochemi s try, 1994, 33, 11671-11677) and 2 (R) - [3- [4-pyridin-4-yl] phenyl] -lH-pyrrol-1-yl] succinic acid 4-benzyl hydrochloride ( prepared as described in Example 7 (a)) are coupled with TBTU. Flash column chromatography with 0-5% elution gradient MeOH / CH2Cl2 and recrystallization from EtOAc gives, in 41% yield, the benzyl ester of N- [1 (S) - (1H-imidazole-2 -yl) -3-methylbutyl] -3 (R) - [3- [4 (pyridin-4-yl) phenyl-lH-pyrrol-1-yl] succinnamic as white crystals, mp 179-81 ° C (d). NMR I (DMSO-de): d 11.84 (broad s, 1H), 8.68 (d, 1H, J = 8.5 Hz), 8.59 (d, 2H, J = 4.4 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.71 (d, 2H, J = 6.3 Hz), 7.60 (d, 2H, J = 8.5 Hz), 7.36 (s, 1H), 7.30 (s, 5H), 6.94-6.80 (m, H), 6.46 (s, 1H), 5.17 (t, 1H, J = 7.5 Hz), 5.11, 5.05 (quartet AB, 2H, J = 12.7 Hz), 4.97 (dd, 1H, J = 7.7, . 4 Hz), 3.24 (dd, 1H, J = 7.4, 12.9 Hz), 3.11 (dd, 1H, J = 7.7, 16.6 Hz), 1.67 (t, 2H, J = 7.7 Hz), 1.48-1.40 (m, 1H), 0.85 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.6 Hz).

Ana l. Calcium for C34H3 bN503: C, 72. 70; H, 6 28; N, 12. 47. Found: C, 72.43, H, 6.33; N, 12.34.

Example 7 (d). N-Methyl-3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] -synatamic acid According to the procedure described in Example 7 (a), the benzyl ester of N-methyl-3 (R) - [3- [4- (pyridin-4-yl) phenyl-1H-pyrrone acid 1- il) succinámico is hydrogenolyzed in acetic acid to produce, in 90% yield, the acid N-methyl-3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-l- il] succinamic as a yellow amorphous solid. XH NMR (DMSO-d6): d 8.58 (d, 2H, J = 5.9 Hz), 7.75 (d, 2H, J = 8.1 Hz), 7.71 (d, 2H, J = 6.2 Hz), 7.61 (d, 2H) , J = 8.4 Hz), 7.29 (s, 1H), 6.77 (t, 1H, J = 2.2 Hz), 6.42 (t, 1H, J = 2.2 Hz), 4.80 (d, 1H, J = 10.7 Hz), 3.16 (dd, 1H, J = 15.8, 11.0 Hz), 2.36 (s, 3H). Anal. Calculated for C20H? 9N3O3 • 1.0 H20 • 0.33 AcOH: C, 64.08; H, 5.81; N, 10.85. Found: C, 64.23, 64.16; H, 5.66, 5.67; N, 10.83, 10.78. The starting materials are prepared as follows: Benzyl Ester of N-Met il-3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] -synatamic acid c According to the procedure described in Example 1 (b) for the preparation of benzyl ester of 3 (R) -t-butyloxycarbonyl-N- (2, 2-dimethyl-1 (S) - (methylcarbamoyl) benzyl ester) propyl) succinamic ester, 4-benzyl ester hydrochloride 2 (R) - [3- [- (pyridin-4-yl) phenyl] -lH-pi rrol-1-y1] succinic (prepared as described in Example 7 (a)) and 40% excess aqueous methylamine are coupled with TBTU. The solid that is precipitated from the reaction mixture is washed with water and, after drying with ethyl acetate, provides 51% benzyl ester of N-methyl-3 (R) - [3- [4- ( pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid as a yellow solid: XH NMR (DMSO-de,): d_8.58 (d, 2H, J = 4.4 Hz), 7.84 (broad s , 1H), 7.76-7.70 (m, 4H), 7.60 (d, 2H, J = 8.5 Hz), 7.29-7.25 (m, 6H), 6.76 (s, 1H), 6.40 (s, 1H), 5.03 ( s, 2H), 4.67 (t, 1H, J = 6.2 Hz), 3.20 (dd, 1H, J = 15.8, 6.2 Hz), 2.86 (dd, 1H, J = 16.0, 8.6 Hz), 2.32 (s, 3H ); Anal. Calculated for • 1.3 H20: C, 70.05; H, 6.01; N, 9.08. Found: C, 69.98, 69.97; H, 5.98, 6.00; N, 9.01, 9.00.

Example 8 (a). N1- (1 (S) -Benzyl-2-hydroxyethyl) -3 (R) - [3- (bi phenyl-4-yl) -lH-pyrrol-1-yl) -hydroxysuccinamide To a solution of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (3- (biphenyl-4-yl) -lH-pyrrol-1-yl) succinamic acid (prepared as described in Example 1 (a): 61 mg, 0.130 mmol) in CHCl 3 (2 mL) is added in succession NMM (44 μL, 0.39 mmol), benzotriazol-1-yloxy-tris-1 H-pyrrolidino-phosphonium hexafluorophosphate (PyBOP , 203 mg, 0.390 mmol), and hydroxylamine hydrochloride (27 mg, 0.390 mmol). After 20 hours at room temperature, 10% aqueous HCl (2 mL) and saturated aqueous NH C1 (10 mL) are added, and the resulting mixture is extracted with CHC13 (15 mL) three times. The combined organic layers are washed with saturated aqueous NH 4 Cl (10 mL), dried over Na 2 SO 4 and evaporated to give a yellow solid, which is purified by flash column chromatography with 1% HOAc / 10% MeOH / CHCl.3 as eluent. Subsequent radial chromatography with a stepwise elution gradient of 1% HOAc / 10% MeOH / CH2Cl2 and the azeotropic removal of HOAc with n-heptane provides 9 mg (14%) of N1- (1 (S) -benzyl) -2-hydroxyethyl) -3 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -N 4 -hydroxysuccinamide as a yellow solid. RMN lE (CD3OD): d 6.90-6.79 (m, 1H), 6.58-6.76 (m, 1H), 5.18- 5.02 (m, 1H), 4.19-4.01 (m, 1H), 3.00-2.84 (m, 1H), 2.84-2.70 (m, 3H). IR (CHCI3): 3244, 3018, 1659, 1208, 1201 cm "1. EMARFAB: Calculated for C29H3oN30 (M + H): 483.2158. Found: 483.2139. Anal.

Calculated for C29H30N3O4 • NH20H, • 0.2 CHC13 • 0.25 H20: C, 64.35; H, 6.05; N, 10.28. Found: C, 64.13; H, 5.69; N, 1056. The following was prepared in a similar manner: Example 8 (b). N1- (1 (S) -Benzy-2-methoxyethyl) -3 (R) - [3- (bif eni-4-yl) -lH-pyrrol-l-yl-N4-hydroxysuccinamide In accordance with the procedure described in Example 8 (a), N- (1 (S) -benzyl-2-methoxyethyl) -3 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) succinamic acid (prepared as described in Example l (f)) and hydroxylamine hydrochloride are coupled with BOP and triturated with MTBE / CH2Cl2 / hex to provide, in 62% yield, N1- (1 (S) -benzyl-2-methoxyethyl ) -3 (R) - [3- (biphenyl-4-yl) -1H-pyrrol-1-yl) -N4-hydroxysuccinamide as a solid, mp 180-2 ° C (d). 2 H NMR (DMSO-dβ): d 8.80 (s, 1H), 8.26 (d, 1H, J = 8.5 Hz), 7.65-7.49 (m, 6H), 7.41 (t, 2H, J = 7.4 Hz), 7.31 -7.12 (m, 7H), 6.73 (s, 1H), 6.40 (s, 1H), 5.06-5.01 (m, 1H), 4.00-3.95 (m, 1H), 3.19 (d, 2H, J = 5.2 Hz ), 3.14 (s, 3H), 2.81-2.29 (m, 4H). Anal. Calculated for C30H3? N3O4: C, 72.41, H, 6.28; N, 8.44. Found: C. 72.24; H, 6.29; N, 8.39.

E xemployment 8 (c). N4-Hydroxy-N1- (9-oxoyl, 8 -diazatrici clo- [10.6.1.0 13, 18] nonadeca-12 (19) 13.15, 17-tetraen-10S-il) -3 (R ) -lH- (pyrrol-l-yl) succinamide A mixture of N1-benzyloxy-N'1- (9-oxo-l, 8-diaza-tricyclo [10.6.1.01318] nonadeca-12 (19), 13, 15, 17-tetraen-lOS-il) -3 ( R) -lH-pyrrol-1-yl-succindyamide (180 mg, 0.324 mmol) and 10% Pd / C (40 mg) in THF (250 mL) with a minimum amount of EtOH is stirred under H 2 atmosphere. After 3.5 hours, the catalyst is removed by filtration and rinsed with THF and EtOH. The filtrate is concentrated to approximately 40 mL, after which the product is precipitated. Filtration provides N ^ hydroxy-N1- (9-oxo-l, 8-diaza-tricyclo [10.6.1. O13 '18] nonadeca- 12 (19), 13, 15, 17-tetraen-lOS-il) - 3 (R) -1 H- (pyrrol-1-yl) succinamide as a solid, mp 158-65 ° C. EMFAB: 466.1 (C? BH32Nb04; M + H.

Example 9. N1- [2,2-Dimethyl-1 (S) - (hydroxymethyl) propyl] N4-hydroxy-2 (R) - [3- [4 - (pyridin-4-yl) phenyl] -lH-pyrrole -1-yl] succinamide WJM N * VOH To a solution of N4-t-butyldi phenylsiloxy-N1- [2, 2-Dimethyl-l (S) - (hydroxymethyl) propi 1] -2 (R) - [3- [4- (pyridine-4- il) pheny1] - lH-pyrrol-1-y1] succinamide (112 mg, 0.160 mmol) in THF (5 mL) is added a solution of tetra-n-butylammonium fluoride (0.20 mL of 1M in THF). After 1.25 hours at room temperature, the mixture is added dropwise to 1M phosphate buffer at pH7 (40 mL). The resulting precipitate is collected by filtration and washed with H20. A solution of CHCl2 / MeOH is passed through a 0.45 μ syringe filter and the filtrate is concentrated to give a solid which is triturated with EtOH to yield 30 mg (42%) of N1- [2, 2 - Dimet i 1-1 (S) - (hydroxymethyl) propyl] -N 4 -hydroxy-2 (R) - [3- [4- (pyridin-4-y1) pheny1] -lH-pyrrol-1 -i 1 ] succinamide as an amorphous solid, which decomposes to >200 ° C. H NMR (CD3COD): d 8.91 (d, 2H, J = 6.6 Hz), 8.23 (d, 2H, J = 7.0 Hz), 7.93 (d, 2H, J = 8.8 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.42 (s, 1H), 6.95 (s, 1H), 6.60 (s, 1H), 5.44 (t, 1H, J = 7.4 Hz), 3.92-3.88 (m, 2H), 3.63-3.55 (m, 1H), 3.21 (dd, 1H, J = 6.4, 14.5 Hz), 3.03 (dd, 1H, J = 8.1, 15.1 Hz), 0.93 (s, 9H). Anal. Calculated for C2sH3oN404 • 0.4 H? 0: C, 66.08; H, 6.96; N, 11.95. Found: C, 65.92; H, 6.79; N, 11.86. The starting material was available as follows: N ^ t-butyldiphenylsiloxy-N 1 - [2 -2-Dimethyl-l (S) -hydroxymethyl) propyl] -2 (R) - [3- [4- (pyridin-4-yl) phenyl 1 H -pyr rol- 1 -yl] succinamide According to the procedure described in Example 1 (b) for the preparation of 3 (R) -t-butyloxycarbonylamino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinnamic acid benzyl ester , N- (2, 2-dimethyl-1 (S) -hydroxymethyl-propyl) -3 (R) - [3- [4-pyridin-4-yl] phenyl] -1H-pyrrol-1-yl] -sycinnamic acid ( prepared as described in the Example 5 (a)) and t-butyldiphenylsiloxyamine are coupled with TBTU. Flash column chromatography with 0-5% elution gradient of MeOH / CH2Cl2 provides, in 43% yield, Nt-butyldiphenylsiloxy-N1- [2, 2-Dimethyl-1 (S) - (hydroxymethyl) propyl] -2 (R) - [3- [4- (pyridin-4-yl) phenyl] -1H-pyrrol-1-yl] succinamide as an amorphous solid. NMR JH (DMSO-d6): d 10.73 (s, 1H), 8.59 (d, 2H, J = 6.3 Hz), 7.85-7.70 (ra, 5H), 7.65-7.56 (m, 6H), 7.45-7.34 (m, 6H), 7.29 (s, 1H), 6.79 (s, 1H), 6.43 (s, 1H), 5.20-5.14 (m, 1H) , 4.38-4.36 (ra, 1H), 3. 54-3.50 (m, 2H), 2.82-2.70 (m, 1H), 0.99 (s, 9H), 0.84 (s, 9H). Anal Calculated for C4 H48N4? 4Si • 0. 4 H20: C, 70. 74; H, 7. 07; N, 8.05. Found: C, 70.83; H, 7.04; N, 8.33.

Example 10 (a). 2S- [IR- (1 (S) -Benzyl-2-hydroxyethyl carbamoyl) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -methyl] -pentanoic acid In accordance with the procedure described in Example 1 (a), the benzyl ester of 2S- [IR- (1 (S) -benzyl-2-hydroxyethylcarbamoyl) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -methyl] - pent-4-enoic (50 mg, 0.08 mmol) is hydrogenated in EtOAc (1 mL) and MeOH (1 mL). Radial chromatographic purification with 1% gradient of HOAc / 1-2% elution of MEOH / CH2Cl? provides 24 mg (55%) of 2S- [1R- (1 (S) -benzyl-2-hydroxyethylcarbamoyl) - (3-bipheni-l4-yl-lH-pyrrol-1-yl) -methyl] -pentanoic acid as a slightly pink powder, mp 179-81 ° C (d). XH NMR: d 7.64-7.54 (m, 5H), 7.47-7.42 (m, 2H), 7.36-7.06 (, 3H), 6.83 (s broad, 1H), 6.54 (broad s, 1H), 4.56 (d, 1H, J = 8.4 Hz), 4.27-4.10 (broad m, 1H), 3.74-3.61 (broad m, 1H), 3.50-3.39 (broad m, 2H), 2.83 (dd, 1H, J = 6.2, 13.4 Hz ), 2.70 (dd, 1H, J = 8.7.13.4 Hz), 1.69-1.52 (broad m, 1H), 0.87 (t, 3H, J = 7.1 Hz). HRLSIEM: Calculated for C33H34N204Cs (M + Cs "): 643.1573, Found: 643.1594, Anal.Calpha for C." H34N2? 4 • 0.5H2O: C, 73.96; H, 6.79; N, 5.39. Found: C, 74.02; H, 6.79; N, 5.41 The starting materials are prepared as follows: Salt of p-Toluensul fonate D-Dialyl Aspartate A mixture of D-aspartic acid (4.00 g, 30.1 mmol), allylic alcohol (12.4 mL, 181 mmol), p-toluensufonic acid hydrate (7.15 g, 37.6 mmol) and benzene (35 mL) is brought to reflux with elimination of water through a Dean-Stark trap. After 4 hours, the resulting yellow solution is allowed to cool and then concentrated to a yellow solid, which is dissolved in a minimum amount of hot MeOH (~15 mL). The solution is diluted with Et20 (200 mL), and with gradual addition of hexanes (-100 mL), pale yellow crystals are obtained. Filtration provides 10.00 g (86% yield) of diallyl p-toluenesulfonate salt D-aspartate as analytically pure crystals, m.p. 60-61 ° C. 3 H NMR: d 8.40-8.10 (broad m, 3H), 7.72 (d, 2H, J = 8.1 Hz), 7.12 (d, 2H, J = 8.1 Hz), 5.76 (dddd, 2H, J = 2.5, 2.5, 8.7, 13.1 Hz), 5.23 (ddd, 2H, J = 2.8, 8.7, 13.1 Hz), 5.18 (dd, 2H, J = 2.8, 13.1 Hz), 4.58 (ddd, 1H, J = 5.6, 13.1, 13.1 Hz ), 4.49 (dd, 2H, J = 1.6, 4.4 Hz), 3.15 (ddd, 2H, J = 5.0, 18.1, 18.1 Hz), 3.09 (ddd, 2H, J = 5.2, 18.1, 18.1 Hz), 2.17 ( s, 3H). IR (KBr): 3436, 2923, 1734, 1215, 1126, 1035, 1011, 685, 569 cm "A Anal, calculated for C1 H2JN07S • 0.5 H20: C, 51.76; H, 6.13; N, 3.55; S, 8.13 , Found: C, 51.61; H, 6.06; N, 3.60; S, 8.04.

N-t-Butoxicarbonil-D-Dialyl Aspartate To a solution of diallyl-D-aspartate p-toluenesulfonate salt (5.00 g, 13.0 mmol) in CH2C12 (50 mL) is added triethylamine (1.99 mL), 14.3 mmoles) and di-t-butyl dicarbonate (3.12 g, 14.3 mmoles). After 20 hours at room temperature, the resulting mixture is stirred with 10% aqueous HCl (5 mL) and H20 (25 mL). The organic layer is separated, washed with saturated aqueous NaHCO3: H20 (2 x 25:25 mL), dried over Na2SO4 and evaporated to give a yellow oil, which is fractionally distilled under vacuum to remove the t-BuOH as a prefraction and provide 3.33 g (82%) of diallyl DNt-butoxycarbonyl-aspartate as a colorless oil, mp 160-170 ° C (1 mm Hg). NMR: H: d 5.90 (dddd, 2H, J = 4.7, 10.5, 10.6, 17.1 Hz), 5.51 (broad d, 1H, J = 8.7 Hz), 5.31 (dddd, 2H, J = 1.6, 1.6, 5.9, 17.1 Hz), 5.24, (dd, 2H, J = 1.3, 10.3 Hz), 4.68-4.55 (m, 5H), 3.05 (dd, 1H, J = 4.7, 17.1 Hz), 2.87 (dd, 1H, J = 4.7, 17.1 Hz), 1.45 (s, 9H). IR: 1736, 1719, 1501, 1368, 1166 cm. "1 Anal. Calculated for C? 5H23N06: C, 57.50; H, 7.40; N, 4.47, Found: C, 57.35; H, 7.39; N, 4.44. 3 (R) -Alyl-N-t-butoxycarbonyl-D-aspartate of α-Allyl To a solution of diallyl Nt-butoxycarbonyl-D-aspartate (15.00 g, 47.9 mmol) in THF (300 mL) at -78 ° C is added a solution of lithium hexamethyldisilazide (96.0 mL of 1.0 M in THF) by drip by means of an addition funnel for 10 minutes. After 30 minutes at -78 ° C, trimethylsilyl chloride (12.2 mL, 96.0 mmol) is added dropwise by means of an addition funnel for 7 minutes, and the resulting golden solution is allowed to slowly warm for 1 hour at room temperature . The solution is then heated to 55-65 ° C. After 1 hour, the mixture is allowed to cool and MeOH (105 mL) is added, after which a yellow suspension results. After 5 minutes, the solvent is removed by evaporation under reduced pressure to give a yellow solid, which is stirred with 10% aqueous KHS04 (100 mL), H ?0 (100 mL) and extracted with CHC14 ( 100 mL) three times. The combined organic layers are washed with NH4C1: saturated aqueous H20 (100: 100 mL), dried over Na2SO4 and evaporated to give 16.2 g of yellow oil, which is purified by flash column chromatography with silica gel. Elution with 1% HOAc / 3% MeOH / CH2Cl? provides 14.94 g (100%) of a mixture of epimers (80:20) by NMR of 3 (R) -alyl-N-t-butoxycarbonyl-α-allyl-aspartate as a light brown oil. This material is usually used without further purification. 1 H NMR: d 9.00-8.24 (broad s, 1H), 5.99-5.72 (m, 2H), 5.53-5.08 (m, 4H), 4.71-4.55 (m, 2H), 3.25 (ddd, 0.2H, minor isomer, J = 3.4, 6.2, 7.5 Hz), 2.97 (ddd, 0.8H, major isomer, J = 4.7, 7.2 , 11.8 Hz), 2.68-2.51 (m, 1H), 2.47-2.30 (m, 1H), 1.42 (s, 9H). IR: 3330, 3082, 2980, 1737, 1715, 1369, 1251, 1163 cm "1. Anal.Calpha for C? BH23N06? 0.15 H20: C, 57.00; H, 7.43; N, 4.43. Found: C, 56.94; H. 7.45; N, 4.31. 3 (R) -Alyl-t-butoxycarbonyl-D-aspartate-benzyl, α- Allyl O HN ^ O ^ * cr 0 To a solution of 3 (R) -alyl-Nt-butoxycarbonyl-D-aspartate α-allylic acid (213 mg, 0.681 mmol) in CHC13 (2 mL) is added O-benzyl-N, N '-di isopropylisourea (see Mathias, LJ Syn th esi s 1979, 561-576, 165 μL, 1.02 mmol). The resulting solution is heated to reflux for 5.5 hours, allowed to cool, filtered to remove the by-product of urea and evaporated to provide a suspension, which is purified by passing it through a pad of silica gel with 10% of EtOAc / hex as eluent to provide 270 mg (100%) of 3 (R) -alyl-t-butoxycarbonyl-D-aspartate-benzyl, α-allylic as a colorless oil. 1 H NMR: d 7.36 (broad s, 5H), 5.86 (ddt, 1H, J = 5.9, 10.6, 16.2 Hz), 5.76 (ddt, 1H, 6.9, 10.0, 17.1 Hz), 5.30 (ddd, 1H, J = 1.2, 2.8, 17.1 Hz), 5.31 (s broad, 1H), 5.24 (ddd, 1H, J = 0.9, 1.2, 10.4 Hz), 5.11 (s, 2H), 5.07 (quintet, 1H, J = 1.6 Hz) , 5.04 (broad s, 1H), 4.66 (dd, 1H, J = 4.9, 8.9 Hz), 4.57 (d, 2H, J = 5.6 Hz), 3.00 (broad c, 1H, J = 7.5 Hz), 2.59 ( ddd, 1H, J = 7.5, 8.1, 14.6 Hz), 2.37 (ddd, 1H, J = 6.9, 13.7, 14.0 Hz), 1.43 (s, 9H). IR: 3374, 2979, 1730, 1504, 1368, 1163, 989 cm. "Anal." Calculated for C;> 2H29N06: C, 65.49; H, 7.24; N, 3.47. Found: C, 65.46; H, 7.25; N, 3.45. 3 (R) -Alyl-N-t-butoxycarbonyl-D-aspartate-Benzyl As in Example l (p), 3 (R) -alyl-t-butoxycarbonyl-α-allyl, β-benzyl (216 mg, 0.535 mmol) is deprotected. Flash column chromatography with 1% HOAc / 30% EtOAc / hex as eluent affords 154 mg (79%) of 3 (R) -alyl-N-t-butoxycarbonyl-D-aspartate-benzyl as a yellow oil. 1 H-NMR (CDCA): d 7.40-7.20 (m, 5H), 6.75 (broad s, 1H), 5.68 (dddd, 1H, 3 = 1.2, 10.0, 10.0, 16.5 Hz), 5.98 (d, 1H, J = 9.7 Hz), 5.18-4.95 (m, 2H), 4.47 (dd, 1H, J = 3.4, 10.0 Hz), 3.15 (ddd, 1H, J = 3.4, 5.9, 8.4 Hz), 2.45 (ddd, 1H , J = 6.3, 7.1, 13.5 Hz), 2.26 (ddd, 1H, J = 7.8, 8.7, 13.5 Hz), 1.38 (s, 9H). IR: 3425, 2978, 1722, 1499, 1164 cm "1; Anal. Calculated for C19H2bN06 • 0.15 C6H14: C, 63.51; H, 7.26; N, 3.72, Found: C, 63.50; H, 693; N, 3.44.

Benzyl Ester of 2S- [IR- (1 (S) -Benzyl-2-hydroxyethylcarbamoyl-t-butoxycarbonyl-lamino) methyl] pent-4-eic acid In accordance with the procedure described in Example 1 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) -t-butoxycarbonyl-amino-succinamic acid benzyl ester, the 3 (R) -alyl-Nt-butoxycarbonyl-D-aspartate-benzyl is coupled with EDC to 2S-amino-3-phenyl-1-propanol to provide 2. 30 g (67%) of 2S- [1R- (1 (S) -benzyl-2-hydroxyethylcarbamoyl) -1- (t-butoxycarbonylamino) methyl] -pent-4-enoic acid benzyl ester as a white solid. NMR aH: d 7.31 (m, 5H), 7.20 (m, 5H), 6.59 (d, 1H, J = 8.1 Hz), 5.78 (d, 1H, J = 9.0 Hz), 5.71 (ddd, 1H, J = 6.9, 9.7, 16.5 Hz), 5.09 (m, 4H). 4.31 (dd, 1H, J = 4.2, 9.0 Hz), 4.10 (ra, 1H), 3.63 (d, 1H, J = 11.8 Hz), 3.48 (d, 1H, J = 11.8 Hz), 3.28 (dd, 1H , J = 7.8, 10.9 Hz), 2.83 (ddd, 2H, J = 7.3, 13.9, 21.6 Hz), 2.46 (s, 1H), 2.39 (ddd, 1H, J = 6.5, 6.9, 13.7 Hz), 2.20 ( ddd, 1H, J = 7.8, 8.1, 15.0 Hz), 1.44 (s, 9H). IR (KBr): 3319, 1735, 1686, 1654, 1560, 1542, 1522, 1297 cm. "1. HRLSIEM: Calculated for C? 8H36N206Cs (M + Csf): 629.1628. Found: 629.1603. Anal. Calculated for C28H36N20 (, : C, 67.71; H, 7.32; N, 5.64, Found: C, 67.68; H, 7.37; N, 5.64.

Benzyl Ester of Acid 2S- [IR- (1 (S) -Benzyl-2-hydroxiet i learbamoi 1) - (3-biphenyl-4-yl-lH-pyrrol-l-yl) -methyl] -pent-4- eonic According to the procedure described in Example 1 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - (3-biphenyl-4-yl) benzyl ester lH-pyrrol-1-yl) succinámico, the benzyl ester of acid 2S- [IR- (1 (S) -benzyl-2-hydroxyethylcarbamoyl), -1- (t-butoxycarbonylamino) -methyl] -pent-4-enoic it is deprotected and the unpurified amine salt is condensed with 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran in HOAc. Radial chromatography with 1% MeOH / CHCl2) eluant gives 77 rag (30%) of benzyl ester of 2S- [IR- (1 (S) -benzyl-2-hydroxyethylcarbamoyl) - (3-biphenyl-4- il-lH-pyrrol-l-yl) -methyl] -pentanoic, mp 166-7 ° C. NMR * H: d 7.68-6.97 (m, 20H), 6.69 (dd, 1H, J = 2.5, 2.8 Hz), 6.53 (dd, 1H, J = 1.6, 2.8 Hz), 5.79 (d, 1H, J = 7.5 Hz), 5.69 (dddd, 1H, J = 6.5, 8.2, 10.0, 16.9 Hz), 5.15-4.94 (m, 4H), 4.57 (d, 1H, J = 7.2 Hz), 4.28-4.19 (broad m, 1H), 3.73-3.63 (broad m, 2H), 3.50 (ddd, 1H, J = 5.3, 5.3, 11.5 Hz), 2.81 (dd, 1H, J = 6.2, 13.8 Hz), 2.68 (dd, 1H, J = 8.2, 13.8 Hz), 2.59-2.44 (m, 2H), 2.10 (ddd, 1H, J = 7.1, 7.1, 14.3 Hz). HRLSIEM: Calculated for C39H38N204Cs (M + Cst): 731.1886. Found: 731.1853. Anal. Calculated for C39H39N204: C, 78.29; H, 6.42; N, 4.68. Found: C, 78.17, H, 6.43; N, 4.63. The following compounds were prepared in a similar manner: Example 10 (b). Acid 2 (RS) -. { IR- [1 (S) -Benzyl-2-hydroxyethylcarbamoyl] - [3- (4'-cyano-bipheni-4-y1) -1H-pyrrol-1-yl] -methyl} -pentanoic Ho According to the procedure described in Example 1 (a), the benzyl ester of acid 2 (RS) -. { IR- [1 (S) -benzyl-1-2-hydroxyethylcarbamoyl] - [3- (4'-cyanobyl-phenyl-4-yl) -lH-pyrrol-1-yl] -methyl-pent-4-enoic is hydrogenated in EtOAc and MeOH. Flash column chromatography with 1% HOAc / 1% MeOH / CH2Cl2 as eluent affords 29 mg (69%) of 2 (RS) - acid. { IR- [1 (S) -benzyl-1-hydroxyethylcarbamoyl-1] - [3- (4'-cyano-biphenyl-4-yl) -lH-pyrrol-1-yl] -methyl} - Pentanoic as a yellow powder. NMR JH: d 7.72 (s, 4H), 7.60 (s, 5H), 7.21-6.99 (broad m, 6H), 6.70 (s, 1H), 6.58 (s, 1H), 4.70 (d, 0.67H, isomer greater, J = 10.3 Hz), 4.62 (d, 0.33H, minor isomer, J = 6.5 Hz.), 4.19 (broad s, 0.33H, minor isomer), 4.02 (broad s, 0.67H, major isomer) , 3.25-3.14 (broad m, 1H), 2.78 (d, 2H, J = 7.0 Hz). IR (KBr): 3334, 2226, 1652, 1604, 1558, 1496, 1200, 824 cm "1. EMARFAB: Calculated for C3 H34 304 (M + H4): 536.2549. Found: 536.2555; Anal. Calculated for Ci3H, 3N304 • 0.8 HOAc: C, 71.20; H, 6.25; N 7.20, Found: C, 71.21, H, 6 49; N, 7.25.The starting material was available as follows: Benzyl Ester of Acid 2 (RS) - [1 (R) - [1 (S) -Benzyl-2- (hydroxyethyl) carbamoyl] -1- [3- (4'-cyanobiphenyl-4-yl) - lH-pyrrole - 1-yl] methyl] pent-4-enoic According to the procedure described in Example 1 (c) for the preparation of benzyl ester of N- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1, O12'17] -octadeca -11 (18), 12, 14, 16-tetraen-9S-yl) -3 (R) - (3-phenyl-lH-pyrrol-1-yl) succinamic, 3 (R) -alyl-Nt-butoxycarbonyl -D-benzyl aspartate is deprotected. The amine salt and the corresponding 4 '- (2, 5-dimethoxy-tetrahydrofuran-3-yl) -biphenyl-4-carbonitrile are condensed in 1,2-dichloroethane with trifluoroacetic acid under anhydrous conditions and purified by chromatography. radial with step gradient of 0-20-30-40% EtOAc / hex to provide 168 mg (51%) of benzyl ester of acid 2 (RS) - [1 (R) - [1 (S) -Benzyl- 2- (hydroxyethyl) carbamoyl] -1- [3- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-1-yl] methyl] pent-4-enoic as a golden powder, m.p. 84 ° C, which is used without further purification. XH NMR: d 7.72 (d, 2H, J = 3.1 Hz), 7.64-7.50 (m, 3H), 7.41-6.96 (m, 4H), 6.72 (t, 0.33H, minor isomer, J = 2.5 Hz), 6.68 (t, 0.67H, major isomer, J = 2.5 Hz), 6.57 (dd, 0.67H, major isomer, J = 1.8, 2.8 Hz), 6.52 (dd, 0.33H, minor isomer, J = 1.6, 2.8 Hz ), 5.83 (d, 1H, J = 7.8 Hz), 5.62 (dddd, 1H, J = 6.5, 7.8, 10.3, 16.8 Hz), 5.18 (d, 2H, J = 1.2 Hz), 4.73 (d, 0.67H) , major isomer, J = 10.6 Hz), 4.57 (d, 0.33H, minor isomer, J = 7.8 Hz), 4.15 (broad m, 1H), 3.99 (dddd, 1H, J = 5.0, 7.5, 7.5, 10.9 Hz ), 3.75-3.48 (m, 2H), 3.38 (dddd, 1H, J = 5.3, 5.3, 5.3, 7.8 Hz), 2.93-2.64 (m, 2H). IR: 3406, 2226, 1731, 1660, 1605 cm "1. EMARFAB: Calculated for C cH37N304 (M + H): 624.2862. Found: 624.2875.Anal.C. Calculated for C40H37N3O4 • 0.25 EtOAc • 0.5 H20: C, 75.21; , 6.16; N, 6.42, Found: C, 75.29; H, 5.97; N, 6.42.

Example 10 (c). 2S- (IR- (3- ('-Cianobifenyl-4-yl) -lH-pyrrol-1-yl) -1- (2, 2-dimethyl-l (S) - (hydroxymethyl) -propylcarbamoyl) - methyl] -pentanoic In accordance with the procedure described in Example 1 (a), the benzyl ester of 2S- [IR- (3- ('-cyano-biphenyl-4-yl) -lH-pyrrol-1-yl) -N- (2, 2-dimethyl-l) (S) -hydroxymethylpropyl-1-carbamoyl) -methyl)] -pentanoic acid is debenzylated in MeOH: EtOAc (2: 3) after 18 hours to give 30 mg (36%) of 2S- [IR- (3- (4 '-cyanobi phenyl-yl) -lH-pyrrol-1-yl) -1- (2, 2-dimethyl-l (S) - (hydroxymethyl) propylcarbamoyl) methyl)] -pentanoic acid as a white solid, mp 130-2 ° C. NMR aH: d 7.70 (m, 4H), 7.60 (m, 4H), 7.15 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.72 (d, 1H, J = 8.7 Hz) , 4.86 (d, 1H, J = 9.7 Hz), 3.90-3.82 (m, 2H), 3.45-3.38 (m, 1H), 3.30-3.20 (m, 1H), 1.45-1.10 (m, 4H), 0.95 (s, 3H), 0.90 (s, 9H). IR (KBr): 3406, 2962, 2227, 1719, 1664, 1604, 1560, 1497, 1367, 1200 cm "1. EMFAB: 502 (M + H *) Anal. Calculated for C3oH3bN304 • 0.15 CHC13: C, 69.70; H, 6.82; N, 8.09, Found: C, 69.71; H, 6.83; N, 8.01, The starting material is prepared as follows: Benzyl Ester of Acid 2S- [lR- (t-Butoxycarboni-lamino- (2, 2-dimethyl-l (S) (hydroxymethyl) propi learbamoi 1) methyl] -pent-4-enoic Following the procedure described in Example 1 (f) for the preparation of benzyl ester of N- (1 (S) -benzyl-2-methyl-1 -3 (R) -t-butoxycarbonylamino-succinamic acid, (R) -alyl-Nt-butoxycarbonyl-β-benzyl-D-aspartate (154 mg, 0.424 mmol) is coupled with BOP to Lt-leucinol (55 mg, 0.466 mmol). Flash column chromatography with 5% MeOH / CH ?Cl 2 as eluent affords 176 mg (90% yield) of 2S- [IR- (t-butoxycarbonyl amino- (2, 2-dimetit-1) benzyl ester. S) - (hydroxymethyl) propylcarbamoyl) -methyl] -pent-4-enoic as waxy plates, mp 75-7 ° C. NMR 'H: d 7.43-7.20 (broad s, 5H), 6.38 (d, 1H, J = 9.7 Hz), 5.73 (dddd, 1H, J = 7.2, 10.0, 10.3, 16.8 Hz), 5.60 (broad m, 1H), 5.20-4.95 (m, 4H), 4.40 (dd, 1H, J = 7.2, 8.4 Hz), 3.78 (ddd, 2H, J = 3.4, 9.3, 9.3 Hz), 3.50 (ddd, 1H, J = 0.9, 8.7, 11.2 Hz), 2.98 (c, 1H, J = 6.5 Hz), 2.55 ( ddd, 2H, J = 7.2, 14.6, 14.6 Hz), 2.48 (ddd, 2H, J = 7.2, 14.6, 14.6 Hz), 2.18 (s broad, 1H), 1.42 (s, 9H), 0.95 (s, 9H ); IR (KBr): 3363, 2996, 1734, 1708, 1654, 1508, 1367, 1253, 1173, 1055 cm "A Anal, calculated for C2bH38N206: C, 64.91; H, 8.28; N, 6.06. Found: C , 65.02; H, 8.33; N, 6.11.

Benzyl Ester of Acid 2S-. { IR- [3- (4'-Cyanobi phenyl-4-yl) -lH-pyrrol-1-yl] - (2,2-dimethyl-l (S) - (hydroxymethyl) propyl-carbamoi 1) -methyl} -pent- 4-e oico According to the procedure described in Example 4 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [3- (4'-cyano-biphenyl) benzyl ester -4-yl) -lH-pyrrol-1-yl] succinamic acid, the benzyl ester of 2S- [IR- (t-butoxycarbonylamino- (2, 2-dimethyl-1 (S) -hydroxymethyl-propylcarbamoyl) - methyl] -pent-4-enoic is deprotected The unpurified amine salt and the corresponding 4 '- (2, 5-dimethoxy-tetrahydrofuran-3-yl) bi-phenyl-4-carbonyl t are condensed in 1, 2-dichloroethane.Short column chromatography with 1% HOAc / 20% EtOAc / hex as eluent afforded 160 mg (63%) of benzyl ester of 2S- (IR- [3- (4 '- cyanobiphenyl-4-yl) -lH-pyrrol-1-yl] - (2,2-dimethyl-l (S) -hydroxymethyl) propyl-carbamoyl) -methyl) -pent-4-ene as a yellow foam, mp 74-6 ° C. XH NMR: 7.70 (s, 4H), 7.50 (s, 4H), 7.20 (s, 5H), 7.05 (s, 1H), 6.80 (s, 1H), 6.60 (s, 1H), 5.60 (d, 1H, J = 8.1 Hz), 5.20 (d, 2H, J = 4.0 Hz), 5.05-4.82 (m, 3H), 3.86-3.68 (m, 2H), 3.30-3.10 (m, 2H), 2.30-2.20 (m, 1H), 1.70-1.50 (m, 2H), 0.90 (s, 9H). IR (KBr): 3358, 3067, 2962, 2226, 1732, 1682, 1604, 1557, 1496, 1360 cm. "1 Anal. Calculated for C37H39N3? 4 • 0.35 CHC13: C, 70.69; H, 6.25; N, 6.62 Found: C, 70.81; H, 6.20; N, 6.70.

Example 11. 2S- [IR- (3- (Biphenyl-4-yl) -lH-pyrrol-1-yl) -l- (l (S) -hydroxymethyl-2-, -dimethyl-propylcarbamoyl) -methyl acid] -5-hydroxypentanoic A suspension of palladium hydroxide (II) (20% Pd carbon content, 30 mg) and 2S- [IR- (3- (bi-phenyl-4-yl) -1H-pyrrol-1-yl) -1- (1 (S) benzyl ester ) -hydroxymethyl-2, 2-dimethyl-il-propylcarbamoyl) -methyl] -5-hydroxypentanoic acid (120 mg, 0.141 mmol) in MeOH (20 mL) is stirred under an atmosphere of H2 for 2 hours. The catalyst is filtered over Ceiite and rinsed with MeOH (20 mL). The filtrate is concentrated to yield 70 mg (100%) of 2S- [lR- (3- (bi-phenyl-4-yl) -lH-pyrrol-1-yl) -1- (1 (S) -hydroxyme) til-2, 2-dimethyl-il-propyl carbamoyl) -methyl] -5-hydroxypentanoic acid as white crystals. 1H-NMR (CD3OD): d 7.70-7.55 (m, 6H), 7.43 (t, 2H, J = 7.4 Hz), 7.38-7.27 (m, 2H), 6.93 (dd, 1H, J = 2.2, 2.2 Hz) , 6.53 (broad m, 1H), 3.80-3.77 (m, 3H), 2.75-1.23 (m, 4H), 0.97 (s, 9H). IR (KBr): 3406, 2958, 1719, 1656, 1200, 763 cm "1. EMFAB: 493 (M + H +), 515 (MH + Na +) Anal.Calcd for C29H36N20s • 0.2 CHC13: C, 67.90; 7.06; N, 5.42 Found: C, 67.85; H, 7.11; N, 5.41 The starting materials are prepared as follows: Benzyl Ester of 2S- [lR-t-Butoxy carboni lamino- (2, 2-dimeti 1-1 (S) -hydroxymethyl-propylcarbamoi 1) -methyl] -5-hydroxy-pent-4-enoic acid ester To a solution of BH3 • THF (6.93 mL of 1M in THF) at 0 ° C is added cyclohexene (1.40 mL, 13.9 mmol) by drip via syringe. After 5 minutes, the white suspension is diluted with dry THF (5 mL). After 15 minutes at 0 ° C, the dicyclohexylborane suspension is carefully added by means of a cannula to a solution of 2S- [lR-t-butoxycarbonyl amino- (2, 2-dimethyl-l (S) - benzyl ester. hydroxymethyl-propyl-carbamoyl) -methyl] -pent-4-enoic acid (1.07 g, 2.31 mmol) in dry THF (10 mL) at 0 ° C and a vigorous gas emission is observed. After 10 minutes at 0 ° C, the resulting suspension is allowed to warm to room temperature. After 90 minutes, the mixture is treated in succession with phosphate buffer to pH7 (50 mL), EtOH (20 mL), and 30% aqueous H202 (10 mL), and then allowed to stir overnight. After 20 hours at room temperature, the mixture is cooled to 0 ° C and stirred with 10% freshly prepared aqueous S203 Na (100 mL). The mixture is allowed to warm to room temperature and is extracted with CHC1; (75 mL) three times. The combined organic layers are stirred with p-TsOH »H20 (100 mg) for 15 minutes, then washed with NaHC? H20 saturated aqueous (100: 100 mL), dried over Na2SO4 and evaporated to give 1.96 g of yellow oil, which was purified by flash column chromatography with 5% MeOH / CHCl3 as eluent to yield 500 mg (45%) 2S- [lR-t-Butoxycarbonyl amino- (2, 2-dimethyl-l (S) -hydroxymethyl-propylcarbamoyl) -methyl] -5-hydroxy-pent-4-enoic acid benzyl ester as a white foam. RMN lE. d 7.45-7.20 (broad s, 5H), 6.56 (d, 1H, J = 9.7 Hz), 5.87 (d, 1H, J = 7.8 Hz), 5.23-5.05 (m, 2H), 4.56 (dd, 1H, J = 5.9, 8.4 Hz), 3.82 (ddd, 2H, J = 3.4, 9.3, 11.8 Hz), 3.70-3.39 (m, 4H), 3.06 (ddd, 1H, J = 5.9, 10.3, 10.3 Hz), 1.90 -1.38 (m, 4H), 0.98 (s, 9H), 0.95 (s, 9H). IR: 3342, 2955, 1718, 1696, 1682, 1661, 1522, 1367, 1249, 1166 cm "1. Anal." Calculated for C25H 0N O-7 • 0.4 CHC13: C, 57.74; H, 7.71; N, 5.30. Found: C, 57.74; H, 7.85; N, 5.42.

Benzyl Ester of 5-Benzyloxy-carboxy-2 S- [1R-t-butoxycarbonylamino- (2, 2-dimethyl-l (S) -hydroxymethi-propyl-carbaraoyl) -raeti 1] -pentanoic acid ester CX 0 * 0 According to the procedure described in Example 5 (a) for the preparation of carbonic acid of benzyl ester of N- (1 (S) -benzyloxycarbonyloxymethyl-2,2-dimethyl-propyl) -3 ( R) - (t-butoxycarbonylamino) succinamic acid, the benzyl ester of 2S- [IR- t -butoxycarboni lamino- (2, 2-dimethyl-1 (S) - (hydroxymethyl) propylcarbamoyl) methyl] -5-hydroxy-pent -4-enoic as was initially acylated with benzyl chloroformate to provide a yellow oil, which is purified by means of flash column chromatography with 4% MeOH / CHCA as eluent to provide 172 mg (46%) benzyl ester of 5-benzyloxycarboxy-2S- [IR-t-butoxycarboni-lamino- (2, 2-dimethyl-l (S) - (hydroxymethyl) propi Icarbamoi 1) met il] -pentanoic acid as an oil colorless and 67 mg (17%) of 5-benzyloxycarboxy-2S- [(1 (S) -benzyloxycarboxymethi 1-2, 2-dimethyl-propylcarbamoyl) -t-butoxycarbonyl-amino-methyl] -pentanoic acid benzyl ester. NMR Al: d 7.45-7.20 (m, 10H), 6.38 (d, 1H, J = 9.7 Hz), 5.48-5.32 (broad m, 1H), 5.23-5.05 (m, 4H), 4.45-4.30 (m, 1H), 4.20-3.95 (m, 2H), 3.80-3.72 (m, 2H), 3.55-3.40 (m, 1H), 3.00-2.89 (m, 1H), 2.08-1.55 (m, 4H), 1.42 ( s, 9H), 0.95 (s, 9H). IR (KBr): 3322, 2964, 1741, 1664, 1264, 1169 cm "1. EMFAB: (M + Cs +) 747.

Benzyl Ester of 5-Benzyloxycarboxy-2S- [(1 (S) -bezyloxycarboxymethyl-2, 2-dimethylpropylcarbamoy 1) -t-butoxycarbonyl-lamino-methyl] -pentanoic acid ester To a solution of 5-benzyloxycarboxy-2S- [IR-t-butoxycarbonylamino- (2,2-dimethyl-1 (S) -hydroxymethyl-propylcarbamoyl) methyl] -pentanoic acid benzyl ester (170 mg, 0.277 mmol) in CHC13 (3 mL) is added DMAP (68 mg, 0.692 mmol) and Benzyloxychloroformate (100 μL, 0.692 mmol). After 2.5 hours, the mixture is stirred with 10% KHS0 (15 mL) and extracted with CHC13 (10 mL twice). The CHCA layers are washed with 10% aqueous KHS04 (10 mL) and saturated NaHC0i: H20 aqueous (10:10 mL), dried over Na2SO4 and evaporated to give a yellow oil, which is purified by chromatography in an instantaneous column with step gradient of 10-20-30% EtOAc / hex. Thus, 135 mg (65%) of benzyl ester of 5-benzyloxycarboxy-2S- [(1 (S) -benzyloxycarboxymethyl 1-2, 2-dimet i 1 -prop i learbamoyl) -t-butoxycarbonylamino-methyl benzyl ester ] -pentanoic are isolated as radial plates. JH NMR: d 7.35-7.25 (m, 15H), 6.40 (broad d, 1H, J = 8.4 Hz), 5.22-5.04 (m, 6H), 4.48 (dd, 1H, J = 6.9, 8.7 Hz), 4.33 (c, 1H, J = 7.3 Hz), 4.16-3.95 (m, 4H), 3.67 (broad m, 1H), 3.51 (dd, 1H, J = 4.4, 5.3 Hz), 2.91 (ddd, 1H, J = 3.7, 7.2, 10.3 Hz), 1.80-1.50 (m, 4H), 1.41 (s 9H), 0.93 (s, 9H). IR: 3330, 2964, 1743, 1263, 1170 cm. "1 EMARFAB: Calculated for C41Hb N20n Cs (M + Cs'): 881.2625. Found: 881.2631.

Benzyl Ester of Acid 2S-. { IR- [(3-Bi-phenyl-4-yl) -lH-pyrrol-1-yl- (1 (S) hydroxymethi 1-2, 2-dimethyl-1-propylcarbamoyl) -methyl]} -5-hydroxypentanoic To a solution of benzyl ester of 5-benzyloxycarboxy-2S- [(1 (S) -benzyloxycarboxymethyl-2,2-dimethyl-propyl-1-carbamoyl) -t-butoxy-carbonyl-1-aminomethyl] -pentanoic acid ester (135 mg, 0.180 mmol) ) in CHC13 (2 mL) is added trifluoroacetic acid (0.5 mL). After 4 hours at room temperature, the solvent is removed in vacuo to give a yellow oil which is placed with 3-bi phenyl-4-yl-2, 5-dimethoxy tetrahydrofuran (66 mg, 0.23 mmole), acid trifluoroacetic (20 μL), and H20 (20 μL) in C1CH2CH2C1 (1 mL). The mixture is heated at 70 ° C for 90 minutes, allowed to cool and evaporated to provide a brown oil. Flash column chromatography with 1% HOAc / 20% EtOAc / hex as eluent and removal of HOAc by azeotrope of n-heptane provides 126 mg (82%) of benzyl ester of 2S- acid. { l R - [(3-bi-phenyl-4-yl) -lH-pyrrol-1-yl- (l (S) -hydroxymethyl-2, 2-dimethyl-yl-propylcarbamoyl) -methyl]} -5-hydroxypentanoic acid as a yellow solid. NMR lE: d 7.59-7.50 (m, 9H), 7.44 (t, 2H, J = 7.4 Hz), 7.38-7.20 (m, 13H), 7.04 (broad m, 1H), 6.70 (dd, 1H, J = 2.5, 2.5 Hz), 6.49 (broad m, 1H), 5.57 (d, 1H, J = 9.6 Hz), 5.22 (d, 1H, J = 12.1 Hz), 5.14 (d, 1H, J = 12.1 Hz), 5.05 (s, 2H), 4.97 (dd, 2H, J = 12.1, 15.5 Hz), 4.84 (d, 1H, J = 10.3 Hz), 4.26 (dd, 1H, J = 2.9, 11.0 Hz), 4.10-3.88 (m, 4H), 3.32-3.20 (m, 1H), 1.70-1.15 (m, 4H), 0.87 (s, 9H). IR (KBr): 2961, 1743, 1687, 1453, 1398, 1263, 1167, 763, 697 cm "3. SEA FAB: Calculated for Cb2Hb N209Cs (M + Cs +): 983.2884. Found: 983.2861. Anal. Calculated for C52Hb4N209 • 0.15 CHC13: C, 72.02; H, 6.28; N, 3.22. Found: C, 72.03; H, 6.43; N, 3.26.

Example 12. 2S acid, 2 (IS) - [[3- (Bifenyl-4-yl) -1H-pyrrol-lR-yl] - [2, 2-dimethyl-l (S) - (hydroxymethyl) -propylcarbamoyl ] methyl] pent-4-enoic To a solution of 2, 2, 2-trichloroethyl carbonate of 2R- [2 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -2- (5R-iodomethyl-2-oxo- tetrahydrofuran-3 (S) -yl) acetylamino] -3,3-dimethylbutyl (100 mg, 0.129 mmol) in HOAc (2 mL) was added zinc powder (86 mg, 1.3 mmol). After 24 hours at room temperature, the resulting mixture is partitioned with H20 (25 mL) and CHC13 (15 mL). The aqueous layer is adjusted to pH5 with saturated aqueous NaHCO3 and extracted with CHC13 (10 mL) twice. The CHCI3 layers are dried over Na2SO4 and evaporated to give a white solid, which is purified by radial chromatography with a step gradient of 0.5% HOAc / 5-10% MeOH / CHCl3 to provide 32 mg ( 50%) of 2S, 2 (lS) - [[3- (ifenyl-4-yl) -lH-pyrrol-lR-yl] - [2, 2-dimeti1-1 (S) - (hydroxymethyl) propylcarbamoyl] methyl] pent--enoic acid as a pale yellow solid. NMR JH (DMSO-d6): d 7.89 (d, 1H, J = 9.3 Hz), 7.80-7.50 (m, 6H), 7.44 (t, 2H, J = 7.8 Hz), 7.36-7.23 (m, 2H) , 6.88 (broad m, 1H), 6.49 (wide m, 1H), 5.68 (ddd, 1H, J = 7.5, 9.3, 16.8 Hz), 5.03-4.78 (m, 2H), 2.09-1.85 (m, 2H) 0.83 (s, 9H). IR (KBr): 3384, 3240, 2960, 2916, 1743, 1717, 1651, 1562, 1456, 1362, 1240, 1196, 758 cm "EMARFAB: Calculated for C29H33N204Cs (M + Cs'): 607.1573.

Found: 607.1555. Anal. Calculated for C29H34N204 • 0.17 CHC13: C, 70.80; H, 6.96; N, 5.66. Found: C, 70.76; H, 7.03; N, 5.55. The starting material is prepared as follows: Allyl Ester of Acid 2 (R) - t-Butoxycarboni lamino-2- 5R-iodomethyl-2-oxo-tetrahydro-furan-3 (S) -yl) acetic acid TO HN ^ O > JvIvc To a solution of 4-allyl ester of 2S-allyl-3 (R) -t-butoxycarbonylamino-succinic acid (230 mg, 0.734 mmole) in THF (10 mL) is added saturated aqueous NaHCO3 (10 mL). After 20 minutes, the mixture is cooled to 0 ° C, and iodine (742 mg, 2.94 mmol) is added. The resulting mixture is allowed to warm slowly to room temperature overnight. After 20 hours, 10% freshly prepared aqueous NaS203 (20 mL) is added and the mixture is extracted with EtOAc (15 mL) three times. The combined organic layers are washed with 10% Na2S20? aqueous (25 mL), dried over MgSO 4 and evaporated to provide 322 mg (100%) of 2 (R) -t-butoxycarbonylamino-2- (5R-iodomethyl-2-oxo-tetrahydro-furan-3 (S) -yl) acetic acid allyl ester as a yellow oil, which is saturated without further purification. 1E NMR: d 5.80 (dddd, 1H, J = 6.3, 6.8, 11.1, 12.0 Hz), 5.58 (broad s, 1H), 5.27-5.15 (m, 2H), 4.64-4.47 (m, 3H), 4.40 ( dddd, 1H, J = 5.0, 6.1, 8.6, 10.8 Hz), 3.41-3.04 (m, 3H), 2.65-2.47 (m, 1H), 2.02-1.45 (m, 2H), 1.32 (s, 9H). IR: 3374, 2976, 1774, 1714, 1507, 1367, 1161 cm. "1 Anal. Calculated for C, bH22N06I • 0.25 EtOAc: C, 41.66; H, 5.24; N, 3.04; I, 27.51. Found: C, 41.93; H, 5.00; N, 3.04. 2 (R) -t-Butoxycarbonylamino-2- (5R-yodomet il-2-oxo-tetrahydrofuran-3 (S) yl) acetic acid According to the procedure described in Example 10 (a) for the preparation of β-benzyl ester of 3 (R) -al i 1-N- t-butoxycarboni 1 -D-aspartate, the allyl ester of acid 2 (R) ) -t-butoxycarboni laraino-2- (5R-iodomethyl-2-oxo-tetrahydrofuran-3 (S) -yl) acetic acid (322 mg, 0.734 mmol) is deprotected to provide 293 mg (100%) of 2 (R) -t-butoxycarbonyl lamino-2- (5R-iodomethyl-2-oxo-tetrahydrofuran-3 (S) -yl) acetic acid as a yellow oil, which is used without purification additional. The analytical sample provides by flash column chromatography with gradient elution of 1% HOAc / 3-5% of MeOH / CH2Cl2 and azeotrope with n-heptane. RMN ^ -H: d 9.30 (s broad, 1H), 5.40 (d, 1H, J = 8.7 Hz), 4.84-4.36 (m, 3H), .3.64 (broad t, 1H, J = 9.5 Hz), 3.56-3.15 (m, 4H), 2.67 (ddd, 1H, J = 4.1, 9.0, 13.1 Hz), 1.25 (s, 9H). IR: 3395, 2978, 1772, 1708, 1511, 1366, 1251, 1160 cm "1.

EMFAB: 532 (M + Cs4). Anal. Calculated for C12H18N06I • 0.12 C, Hlb: C, 37.50, H, 4.88, N, 3.41; I, 30.86. Found: C, 37.51; H, 4.78; N, 3.52; I, 30.94. 2 (R) -t-Butoxycarbonyl amino-N- (3, 3-diraet i 1- 1 -hydrox i -but-2 (R) -yl) -2- (5R-iodo-methyl-2-oxo-tetrahydrofuran - 3 (S) -yl) acetamide In accordance with the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxy-ethyl) -3 (R) -t-butoxycarbonylamino-succinamic acid benzyl ester, the acid 2 (R) -t- butoxycarbonylamino-2- (5R-iodomethyl-2-oxo-tetrahydro-furan-3 (S) -yl) acetic acid (293 mg, 0.734 mmol) is coupled with Lt-leucinol. (55 mg, 0.466 mmol) with BOP. After chromatography on silica gel and l% / HOAc / 5% MeOH / CHCA as eluent, azeotropic removal of HOAc with n-heptane, and crystallization from EtOAc / hex, 184 mg (50%) are obtained yield) of 2 (R) -t-butoxycarbonylamino-N- (3, 3-dimethyl-l-hydroxy-but-2 (R) -yl) -2- (5R-iodo-methyl-2-oxo-tetrahydrofuran -3 (S) -yl) acetamide as a white powder, mp 142-3 ° C. NMR] H: d 6.78 (broad d, 1H, J = 8.2 Hz), 6.23 (broad d, 1H, J = 8.2 Hz), 3.88-3.68 (m, 2H), 3.60-3.40 (m, 2H), 3.40 -3.25 (m, 2H), 3.15-2.99 (broad m, 1H), 2.63 (ddd, 1H, J = 7.1, 10.5, 13.4 Hz), 2.37 (broad s, 2H), 2.00 (c, 1H, J = 11.0 Hz), 1.44 (s, 9H), 0.94 (s, 9H). IR: 3319, 2965, 1774, 1665, 1530, 1367, 1153, 755 was "1. Anal, calculated for C, 43.38, H. 6.27, N, 5.62, I, 25.46, Found: C, 43.13; H, 6.34.; N, 5.54; I, 25.31.

Carbonate of 2 (R) - [2 (R) - t-Butoxy-carboni laraino-2- (5R-iodomethyl-2-oxo-tetrahydrofuran-3 (S) -yl) acetylamino] - 3,3-dimethyl 2 , 2, 2-Trichloroetyl To a solution of 2 (R) -t-butoxycarbonylamino-N- (3, 3-dimeti 1-1 -hydroxy-but-2 (R) -yl) -2- (5R-yodomet i 1-2-oxo- tetrahydrofran-3 (S) -yl) acetamide (155 mg, 0.311 mmol) in CHC1 (5 mL) was added DMAP (84 mg, 0.68 mmol) and 2, 2, 2-1-chloro-chloro-ethylchloride (86 μL, 0.62 μL). mmoles). After 2 hours at room temperature, the resulting mixture is stirred with 10% aqueous HCl (10 mL). The organic layer is separated, washed with 10% aqueous HCl (10 mL) and saturated NaHCO 3: H20 aqueous (10:10 mL), dried over Na S04 and evaporated to give a yellow oil, which is purified by means of flash column chromatography with % EtOAc / hex as eluent to produce 138 mg (66%) of 2, 2, 2- trichloroet i 1 carbonate of 2 (R) - [2 (R) -t-butoxycarbonylamino-2- (5R-iodomethyl-2-oxo-tetrahydrofuran-3 (S) - il) acetyl amino] -3,3-dimethylbutyl as a yellow oil. NMR Al: d 6.82 (broad d, 1H, J = 9.0 Hz), 6.17 (broad d, 1H, J = 7.8 Hz), 4.77 (s, 2H), 4.60 (quintet, 1H), 4.49 (dd, 1H, J = 4.7, 8.7 Hz), 4.42 (dd, 1H, J = 3.1, 10.9 Hz), 4.20-4.00 (m, 2H), 3.48 (dd, 1H, J = 5.3, 10.0 Hz), 3.33 (c, 1H , J = 9.3 Hz), 3.04-2.90 (broad m, 1H), 2.64 (ddd, 1H, J = 6.5, 10.0, 12.8 Hz), 1.99 (c, 1H, J = 12.2 Hz), 1.82-1.72 (m broad, 1H), 1.46 (s, 9H), 0.97 (s, 9H). IR (KBr): 3386, 2966, 1764, 1703, 1683, 1676, 1521, 1369, 1244, 1165 cm. "1 Anal. Calculated for C21H32N208C13I • 0.25 C6H14: C, 38.87; H, 5.15; N, 4.03; Cl. 15.30, I, 18.25 Found: C, 39.04; H, 5.13; N, 4.12; Cl, 15.64; I, 18.65. 2, 2, 2-Trichloroethyl Carbonate of 2 (R) - [2 (R) - (3-Biphenyl-4-yl-lH-pyrrol-1-yl) -2- (5R-iodomethyl- -2-oxo-tetrahydrofuran-3 (S) -i 1) acetyl-amino] - • 3, 3- dimethyl ilbut i lo According to the procedure described in Example 1 (b) for the preparation of N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -3 (R) - (3-phenyl-1H-) benzyl ester pyrrol-1-yl) succinamic, 2, 2, 2-trichloroethyl carbonate of 2 (R) - [2 (R) -t-butoxycarbonylamino-2- (5R-iodomethyl-2-oxo-tetrahydrofuran-3 (S) -yl) acetylamino] -3,3-dimethylbutyl (105 mg, 0.156 mmol) is deprotected with trifluoroacetic acid and then condensed with 3-biphenyl-4-yl-2,5-dimethoxytetrahydrofuran (prepared as described in Example 1 (a)) in 1,2-dichloroethane with H ?0 and tifluoroacetic acid. Flash column chromatography with 0.5% HOAc / 20% EtOAc / hex as eluent afforded 120 mg (99%) of 2, 2, 2-trichloroethyl carbonate of 2 (R) - [2 (R) - (3-biphenyl-4-yl-lH-pyrrol-1-yl) -2- (5R-iodomethyl-2-oxo-tetrahydrofuran- 3 (S) -yl) acetylamino] -3,3-dimethylbutyl as a yellow solid, which is used in the next reaction. NMR] E: d 7.74-7.54 (m, 5H), 7.48-7.19 (m, 4H), 7.16 (dd, 1H, J = 1.9, 1.9 Hz), 6.86 (dd, 1H, J = 2.5, 2.5 Hz) , 6.59 (dd, 1H, J = 1.9, 2.5 Hz), 5.80 (d, 1H, J = 10.0 Hz), 5.20 (d, 1H, J = 3.4 Hz), 4.63 (dd, 2H, J = 12.1, 18.0 Hz), 4.53-4.35 (m, 2H), 4.21 (ddd, 1H, J = 3.4, 9.0, 9.0 Hz), 4.05 (dd, 1H, J = 9.0, 11.2 Hz), 3.73 (ddd, 1H, J = 3.1, 9.0, 12.1 Hz), 3.27 (dd, 1H, J = 4.7, 10.3 Hz), 3.02 (dd, 1H, J = 7.5, 9.3 Hz), 2.70 (ddd, 1H, J = 6.2, 9.3, 12.8 Hz ), 1.74 (ddd, 1H, J = 9.7, 12.1, 12.8 Hz), 0.97 (s, 9H). IR (KBr): 1763, 1686, 1242, 1166, 819, 764 cm "1.

Example 13. N- (1 (S) -Benzyl-2-hydroxyethyl) -3 (S) [3- (bifeni-4-yl) -lH-pyrrol-3-yl] -synatamic acid To a solution of t-butyl acid ester N- (4 (S) -benzyl 1-2, 2-dimet i 1-oxazole idin-3-yl) -3 (S) - [3- (biphenyl-4-yl) -lH-pyrrol-3-yl ] succinamic acid (80 mg, 0.14 mmol) in THF (5 mL) was added aqueous 2M LiOH (5 mL).

EtOH (few drops) and H20 are added until a homogeneous solution is obtained. The resulting solution is heated to 50 ° C. After 12 hours, the mixture is acidified with 6N HCl to pHl. After a further 5.5 hours at 50 ° C, the mixture is partitioned between EtOAc and 1M phosphate buffer at pH7. The aqueous phase is separated and extracted with EtOAc twice. The combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated to a residue which, by trituration with CH 2 Cl 2 / hex, gives 32 mg (49%) of N- (1 (S) -benzyl-2-hydroxyethyl ) -3 (S) - [3- (bifeni-l4-yl) -lH-pyrrol-3-yl] -succinnamic acid as a white solid, mp 151-4 ° C. NMR] H: (DMS0-d6) d 7.83 (d, 1H, J = 8.5 Hz), 7.74 (d, 2H, J = 8.8 Hz), 7.69 (d, 2H, J = 7.4 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.46 (t, 2H, J = 7.4 Hz), 7.38-7.31 (m, 2H), 7.28-7.13 (m, 6H), 6.22 (s, 1H), 4.81-4.70 (m , 1H), 3.89-3.78 (m, 2H), 2.85-2.69 (m, 2H). Anal. Calculated for C29H28N204 • 0.4 H20: C, 73.21; H, 6.10; N, 5.89. Found: C, 73.39; H, 6.09; N, 5.93. The starting material is prepared as follows: N-Biphenyl-4-yl-lH-pyrrole To a solution of 4-aminobi phenyl (1.0 g, 5.9 mmol) in 1,2-dichloroethane (20 mL) is added TFA (0.46 mL, 5.9 mmol). To the resulting suspension of the TFA salt is added 2,5-dimethoxy-tetrahydrofuran (0.92 mL, 7.1 mmol). The suspension is heated at 75 ° C for 17 hours. The mixture is allowed to cool, partitioned between EtOAc and 1M phosphate buffer at pH7, and the aqueous layer is extracted again with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated to an unpurified residue, which is purified by flash column chromatography with elution gradient of 10-25% CH2Cl2 / hex. The purified material is triturated with MTBE / hex to provide 800 mg (62%) of N-biphenyl-4-yl-lH-pyrrole as an off-white solid, m.p. 190-2 ° C. NMR: H: d 7.65 (d, 2H, J = 8.5 Hz), 7.61 (d, 2H, J = 7.0 Hz), 7.48-7.43 (m, 4H), 7.36 (t, 1H, J = 7.0 Hz), 7.14 (t, 2H, J = 2.0 Hz), 6.37 (t, 2H, J = 2.0 Hz). Anal. Calculated for C 16 H] 3 N: C, 87.63; H, 5.98; N, 6.39. Found: C, 87.48; H, 6.01; N, 6.30.

N- (Biphenyl-4-yl) -3-bromo-lH-pyrrole To a mixture of N-biphenyl-4-yl-lH-pyrrole (500 mg, 2.28 mmol), dimethyl sulfide (0.25 mL, 3.4 mmol), CH2C1? (30 mL), and acetonitrile (10 mL) at -10 ° C is added dropwise a solution of bromine in CH? C12 (5 mL) for 15 minutes. The mixture is allowed to warm to 10 ° C for 2 hours. The resulting mixture is washed with 1M phosphate buffer to pH7 (50 mL) and extracted with CH2C1 (25 mL). The combined organic layers are dried over Na 2 SO 4 and concentrated to an unpurified residue which is purified by flash column chromatography with elution gradient of 0-10% CH 2 Cl 2 / hex to provide 240 mg (40%) of N- (biphenyl-4-y1) -3-bromo-lH-pyrrole as a white solid, mp 141-3 ° C. NMR Al: d 7.65 (d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 8.1 Hz), 7.49-7.34 (m, 5H), 7.12 (s, 1H), 7.02 (t, 1H, J = 2.6 Hz), 6.36 (dd, 1H, J = 3.2, 1.7 Hz). Anal. Calculated for C16HJ2NBr: C, 64.45; H, 4.06; N, 4.70; Br, 26.80. Found: C, 64.37; H, 4.10; N, 4.64; Br, 26.69.

Ethyl Ester of N- (4 (S) -Benzyl-2, 2-dimethyl-oxazolidin-3-yl) -oxamic acid MgSO4 (4 g) is added to a solution of 2S-amino-3-phenyl-1-propanol (2.0 g, 3.12 mmol) in CH2C1 (30 mL) and acetone (1 5 mL). After 17 hours at room temperature, triethylamine is added (2 mL, 14.3 mmol) and the mixture was opened at -75 ° C. Ethyl-oxalyl chloride (1-5 mL) is added dropwise via syringe and the mixture is allowed to warm to room temperature for 4 hours. The mixture is filtered and the filtrate is washed with 1M phosphate buffer at pH7 (50 mL). The aqueous layer is extracted with CH? C12 (25 mL). The combined CH2C12 layers are washed with brine, they are dried over Na? S0 and concentrated to a minimum volume, which is diluted with MTBE and filtered. The filtrate is concentrated to an oily residue, which is dissolved in MTBE / hex / iso-octane and results in a viscous or sticky residue which is removed by decanting. The supernatant is concentrated to an oil which is passed through a short column of silica gel with elution gradient of 0-25% EtOAc / hex to provide 3.1 g (83%) of N- (N-) ethyl ester ( 4 (S) -benzyl-2, 2-dimethylyloxazolidin-3-yl) -oxamic acid as a colorless oil. NMR lE: d 7.35-7.22 (m, 3H), 7.19 (d, 2H, J = 7.4 Hz), 4.53-4.47 (m, 1H), 4.37-4.25 (m, 2H), 3.89 (m, 2H), 3.00 (dd, 1H, J = 4.4, 13.2 Hz), 2. 82 (dd, 1H, J = 10.5, 13.1 Hz), 1.76 (s, 3H), 1.59 (s) 3H), 1.38 (t, 3H, J = 7.0 Hz). Anal. Calculated for C16H21N04: C, 65.96; H, 7.26; N, 4.81. Found: C, 65.96; H, 7.26; N, 4.84. 1- (4 (S) -Benci 1-2, 2-dirad yl-oxazole idin-3-i 1) -2- [1- (biphenyl-4-yl) -lH-pyrrol-3-yl] ethan- l-2-dione To a solution of N-bi phenyl-4-yl-3-bromo-1H-pyrrole (0.45 g, 1.5 mmol) in dry THF (10 mL) at -78 ° C is added dropwise via a n-but syringe i-thio (0.7 mL of 2.5M in hexanes). After 15 minutes at -78 ° C, the resulting mixture is transferred via cannula to a solution of N- (4 (S) -benzyl-2,2,2-dimethyl-oxazolidin-3-yl) - ethyl ester. oxamic (714 mg, 2.4 mmol) in dry THF at -90 ° C. The mixture is heated at -59 ° C for 15 minutes and then cooled to -78 ° C for 45 minutes before stopping with saturated aqueous NH 4 Cl (25 mL) and allowing to stir at room temperature. After 16 hours, the brine layer is separated and extracted with EtOAc (15 mL). The combined organic layers are washed with brine, dried over Na 2 SO 4 and evaporated to provide a residue which is purified by flash column chromatography with elution gradient of 0-1% EtOAc / CH 2 Cl 2. . The purified product is triturated from MTBE / hex to obtain 300 mg (43%) of l- (4 (S) -benzyl-2, 2-dimeti-1-oxa zol idin-3-i 1) -2- [ 1- (biphenyl-4-yl) -lH-pyrrol-3-yl) ethane-1,2-dione as an off-white solid, mp 150-2 ° C. XH NMR: d 7.86 (s, 1H), 7.70 (d, 2H, J = 8.8 Hz), 7.61 (d, 2H, J = 7.0 Hz), 7.51-7.45 (m, 4H), 7.39 (t, 1H, J = 7.4 Hz), 7.32-7.23 (m, 2H), 7.17-7.13 (m, 3H), 7.10 (dd, 1H, J = 2.2, 2.9 Hz), 6.91 (dd, 1H, J = 1.7, 3.1 Hz ), 4.53-4.48 (m, 1H), 3.87 (s, 2H), 3.00 (dd, 1H, J = 3.9, 12.7 Hz), 2.76 (dd, 1H, J = 10.7, 13.2 Hz), 1.85 (s, 3H), 1.67 (s, 3H). Anal. Calculated for C3oH28N20- !: C, 77.56; H, 6.07; N, 6.03. Found: C, 77.61; H, 6.11; N, 6.05. l- (4 (S) -Benzyl-2, 2-dimeti-1-oxazole idin-3-i 1) -2- [1- (biphenyl-4-yl) lH-pyrrol-3-yl] -2-hydroxy -etanone To a solution of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- [1- (biphenyl-4-yl) -lH-pyrrol-3-yl) ethano- 1,2-dione (250 mg, 0.54 mmol) in EtOAc (6 mL) and MeOH (2 mL) at 0 ° C is added NaBH4 (20 mg, 0.54 mmol). After 2.75 hours at 0 ° C, more NaBH4 (20 mg, 0.54 mmol) is added. After 1.25 hours at 0 ° C, the reaction is stopped with a few drops of HOAc) and H20 (2 mL). The pH is adjusted to 5 (by pH paper) with HOAc and divided between H20 (25 mL) and EtOAc (25 mL). The organic layers are dried over Na2SO4 and concentrated to provide 0.25 g (99%) of 1- (4 (S) -benzyl-2,2-dimethyl-xazolidin-3-yl) -2- [1- (bi-phenyl). 1-4-yl) lH-pyrrol-3-yl] -2-hydroxy-ethanone as a brittle foam. NMR: H: d 7.65 (d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 7.4 Hz), 7.48-7.19 (m, 10H), 7.14 (t, 1H, J = 2.0 Hz), 7.06 (t, 1H, J = 2.6 Hz), 6.31 (t, 1H, J = 2.4 Hz), 5.11 (d, 1H, J = 7.4 Hz), 4.29 (d, 1H, J = 6.6 Hz), 3.99- 3.95 (m, 1H), 3.76 (d, 1H, J = 9.2 Hz), 3.60 (dd, 1H, J = 5.0, 8.6 Hz), 3.08-3.02 (m, 1H), 2.90 (dd, 1H, J = 10.5, 13.4 Hz), 1.82 (s, 3H), 1.60 (s, 3H). Anal. Calculated for C3oH3oN203 • 0.4 H20: C, 76.05; H, 6.55; N, 5.91. Found: C, 76.17; H, 6.66; N, 5.74. 2-Acetoxy-l- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) 2- [l-biphenyl-4-yl) -lH-pyrrol-3-yl] ethanone To a solution of 1- (4 (S) -benzyl-2, 2-dimethyl-1-oxazolidin-3-yl) -2- [l- (biphenyl-4-yl) lH-pyrrol-3-yl] -2 -hydroxy-ethanone (867 mg, 1.86 mmol) in dry pyridine (5 mL) was added acetic anhydride (0.42 mL, 4.5 mmol). After 4.5 hours at room temperature, the mixture is partitioned between aqueous NaHS04 IN (25 mL) and EtOAc (25 mL). The EtOAc layer is washed with IN phosphate buffer at pH7 (25 mL) twice, H20 (25 mL) and brine (25 mL), dried over Na2SO4, and evaporated to give 0.91 g (100%) of 2%. -acetoxy-1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- [1- (biphenyl-4-yl) -lH-pyrrol-3-yl] -ethanone as an amorphous solid that is used without further purification. An analytical sample is obtained by subjecting to flash column chromatography with gradient elution of 0-2% EtOAc / CH2Cl2. NMR aH: d 7.65 (d, 2H, J = 8.5 Hz), 7.62 (d, 2H, J = 7.0 Hz), 7.48-7.24 (m, 1H), 7.10 (4 1H, J = 2.6 Hz), 6.46 (dd, 1H, J = 1.7 , 2.8 Hz), 6.25 (s, 1H), 3.98-3.93 (m, 1H), 3.81 (d, 1H, J = 9.2 Hz), 3.64-3.60 (m, 1H), 3.42 (d, 1H, J = 13.6 Hz), 2.96 (dd, 1H, J = 11.6, 13.8 Hz), 2.22 (s 3H), 1.78 (s, 3H), 1.55 (s, 3H). Anal. Calculated for CJ2H32N2? 4: C, 75.57; H, 6.34; N, 5.51. Found: C, 75.47; H, 6.37; N, 5.45. 1- (4 (S) -benzyl-2-, 2-dimethyl-1-oxazolidin-3-yl) -2- [1- 'biphenyl-4-yl) -lH-pyrrol-3-yl] -ethanone To a mixture of 2-acetoxy-l- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- [l- (biphenyl-4-yl) -lH-pyrrole-3- il] -etanone without purification (1.82 mmoles) and 10% palladium on carbon (120 mg) in EtOAc (4.5 mL) and EtOH (4.5 mL) was added ammonium formate (0.58 g, 9.2 mmol). After 40 hours at room temperature, the resulting mixture is filtered and the filtrate is concentrated to a residue which is dissolved in EtOAc, washed with 1M phosphate buffer at pH7, dried over Na2SO and evaporated under reduced pressure to provide an Unpurified product. Flash column chromatography with gradient elution of 0-4% EtOAc / CH2Cl2 gives 220 mg (43%) of 1- (4 (S) -benzyl-2,2-dimethyl-yl-oxazolidin-3-yl) -2- [1- (biphenyl-4-yl) -lH-ironol-3-yl] -ethanone as a pale yellow amorphous solid. 1E NMR: 7.62 (t, 4H, J = 9.4 Hz), 7.47 (d, 2H, J = 7.4 Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.35 (t, 2H, J = 6.6 Hz), 7.30-7.21 (m, 4H), 7.08 (t, 1H, J = 2.6 Hz), 7.05 (s, 1H), 6.28 (t, 1H, J = 2.21 Hz), 4.16-4.10 (m, 1H), 3.82 (m, 2H), 3.62, 3.54 (Quartet AB, 2H, J = 15.5 Hz), 3.07 (dd, 1H, J = 3.9, 13.8 Hz), 2.91 (dd, 1H, J = 9.9, 13.6 Hz), 1.78 (s, 3H), 1.59 (s) , 3H). Anal. Calculated for C3üH3oN202 • 0.25 H20: C, 79.18; H, 6.76; N, 6.16. Found: C, 79. 24; H, 6.79; N, 6.12.

T-Butyl Ester of N- (4 (S) -Benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2 (S) - (biphenyl-4-yl-lH-pyrrol-3-yl) succinamic acid To a solution of 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol-3-yl) -ethanone (226 mg, 0.500 mmol) in dry THF (5 mL) at -78 ° C a solution of sodium hexamethyldisilazide (0.60 mL of 1M in THF) is added dropwise by syringe. After 15 minutes at -78 ° C, to the resulting dark red mixture is added t-butyl bromoacetate (1000 μL, 0.68 mmol). The mixture is heated at -50 ° C for 1 hour, then stopped with 1M phosphate buffer at pH7 and allowed to warm to room temperature. The aqueous layer is separated and extracted with EtOAc. The combined organic layers are washed with brine, dried over NaSO4, and concentrated to provide a residue that is purified by flash column chromatography with gradient elution of 0-25% EtOAc / hex to yield 108 mg. 38%) of N- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2 (R) - (biphenyl-4-yl-lH-pyrrole-3-t-butyl ester) -yl) succinamic as a colorless amorphous solid. XE-NMR: d 7.60 (t, 4H, J = 8.3 Hz), 7.46 (d, 2H, J = 7.4 Hz), 7.41 (d, 2H, J = 4.8 Hz), 7.36 (d, 2H, J = 8.1 Hz ), 7.31 (d, 2H, J = 7.4 Hz), 7.21 (d, 2H, J = 8.1 Hz), 7.11 (t, 1H, J = 2.0 Hz), 7.03 (t, 1H, J = 2.6 Hz), 6.35 (dd, 1H, J = 1.7, 2.8 Hz), 4.56-4.50 (m, 1H), 4.33 (dd, 1H, J = 4.0, 10.3 Hz), 3.93-3.88 (m, 1H), 3.82 (d, 1H, J = 9.2 Hz), 3.18 (dd, 1H, J = 10.5, 16.7 Hz), 2.96 (broad d, 1H, J = 12.5 Hz), 2.73-2.63 (m, 2H), 1.71 (s, 3H) , 1.57 (s, 3H), 1.44 (s, 9H). Anal. Calculated for C36H40N2O4: C, 76.57; H, 7.14; N, 4.96. Found: C, 76.31; H, 7.16; N, 4.93.

Example 14 (a). N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (S) - [1- (4-fluorophenyl) -lH-pyrrol-3-yl] -synatamic acid As described in Example 1 (a), the benzyl ester of N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] -3 (S) - [1- (4-fluorophenyl) - 1H-pyrrol-3-yl] succinamic acid is hydrogenated in EtOH after 1.5 hours. The trituration with MTBE / hex provides, in quantitative yield, the acid N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] -3 (S) - [1- (4-fluorophenyl) -lH- pyrrol-3-yl] succinnamic acid as a colorless amorphous solid. NMR lH: d 7.27-7.23 (m, 2H), 7.07 (t, 2H, J = 8.6 Hz), 6.90-6.89 (m, 2H), 6.21 (t, 1H, J = 2.2 Hz), 6.13-6.10 ( m, 1H), 4.24 (d, 1H, J = 9.6 Hz), 4.03 (dd, 1H, J = 5.2, 8.5 Hz), 3.14 (dd, 1H, J = 8.5, 16.6 Hz), 2.80 (dd, 1H , J = 5.7, 16.7 Hz), 2.72 (d, 3H, J = 4.8 Hz), 0.94 (s, 9H). Anal. Calculated for C21H2ßN304F: C, 63.17; H, 6.80; N, 10.09. Found: C, 62.89; H, 6.93; N, 9.81. The starting material is prepared in the following way: 2- (2,5-Dimethoxy-tetrahydrofuran-3-yl-methylidene) -1,3-dithiane According to a procedure described in Boger, D.L .; Brotherton, CE. J. Org. Ch em. 1984, 49, 4050-4055, to a solution of 2-trimethylsilyl-1,3-dithiane (1.2 mL, 6.3 mmol) in dry THF (40 mL) at 0 ° C is added n-butyllithium (4 mL of 1.6 M in hexanes). After 15 minutes at 0 ° C and 20 minutes in 4 mL of 1.6M at room temperature, a solution of 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde (1.00 g, 6.00 mmol) in dry THF (10 mL) is added by drip. After 17 hours at room temperature, the resulting mixture is treated with saturated aqueous NH 4 Cl (10 mL) and partitioned between EtOAc and H 20. The layers are separated and the aqueous phase is extracted with EtOAc: hex (1: 1) twice. The combined organic layers are washed with brine, dried over Na2S? and concentrating to produce a residue that is purified by flash column chromatography with 10% EtOAc / hex as eluent to yield 1.06g (70%) of a mixture of 2- (2,5-dimethoxytetrahydrofuran-3) -il-met i lideno) -1, 3-diastereoisomeric dithiane as a yellow oil, which is used without any additional purification. 1H-NMR: d 6.00 (d, 1H, J = 9.6 Hz), 5.93 (d, 1H, J = 9.6 Hz), 5.77 (d, 1H, J = 9.6 Hz). Anal. Calculated for C ??H10O3S2: C, 50.35; H, 6.92; S, 24.44. Found: C, 50.07; H, 7.00; S, 24.33. 2- (2,5-Dimethoxy-tetrahydrofuran-3-yl) -methyl acetate Agree also with a procedure of Boger, D.L .; Brotherton, CE. J. Org. Ch em. 1984, 49, 4050-4055, to a solution of 2- (2,5-dimethoxy-tetrahydrofuran-3-yl-methyladide) -1,3-dithiane (200 mg, 0.76 mmol) in a mixture of MeOH: THF H20 (8: 1: 1, 10 mL) is added mercuric chloride (450 mg, 1.66 mmol). Upon heating to 80 ° C, a white precipitate forms, and after 5 hours at 80 ° C, the mixture is filtered through Celite. The collected solid is washed with EtOAc followed by aqueous NH 4 Cl. The filtrate is combined and the biphasic mixture is separated. The aqueous layer is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated to yield 120 mg (77%) of methyl 2- (2, 5-dimethoxy-tetrahydrofuran-3-yl) -acetate as an oil, which it was a mixture of diastereoisomers as evident by NMR, and which is used without further purification. An analytical sample is obtained by flash column chromatography with 0-20% EtOAc / hex as the elution gradient. 1 E NMR: d 3.68 (s, 3 H), 3.67 (s, 3 H). Anal. Calculated for CgH160: C, 53.27; H, 7.90. Found: C, 53.11; H, 7.96.

Methyl Ester of 2- [1- (4-Fluorophenyl) -1H-pyrrol-3-yl] -acetic acid According to the procedure described in Example 1 (c) for the preparation of benzyl ester of N- (8-oxo-4-oxa-1, 7-diazatricyclo- [9.6.1.012'17] octadeca-ll (18), 12, 14, 16-tetraen-9-yl) -3- (3-phenyl-lH-pyrrol-1-yl) -succinamic, to a mixture of 2- (2,5-dimethoxy-tetrahydrofuran-3) -yl) -methyl acetate without purification (120 mg, ~ 0.58 mmole) and 4-fluoroaniline (50 μL, 0.53 mmole) in 1,2-dichloroethane (10 mL) add trifluoroacetic acid (0.2 mL, 0.26 mmol). After 16 hours at 80 ° C, the resulting mixture is partitioned between EtOAc and 1M phosphate buffer at pH7. The separated aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over NaS? 4 and concentrated to an oil without purification, which is purified by means of flash column chromatography with elution gradient of 0-15% EtOAc / hex to produce 100 mg (77%) of 2- [1- (4-fluorophenyl) -lH-pyrrol-3-yl] -acetic acid methyl ester as an oil. 3H-NMR: d 7.34-7.30 (m, 2H), 7.10 (t, 2H, J = 8.6 Hz), 6.96-6.94 (m, 2H), 6.28 (t, 1H, J = 2.2 Hz), 3.72 (s, 3H), 3.56 (s, 2H). Anal. Calculated for C? 3H2? N02F • 0.6 H20: C, 63.98; H, 5.45; N, 5.74. Found: C, 64.01; H, 5.04-, N, 5.65. 2- [1- (4-Fluorophenyl) -lH-pyrrol-3-yl] -acetic acid To a solution of 2- [1- (4-fluorophenyl) -lH-pyrrol-3-yl] -acetic acid methyl ester (100 mg, 0.43 mmol) in THF (1 mL) at 0 ° C is added by dropping aqueous 2N LIOH (0.5 mL). After warming to room temperature for 4 hours, the mixture is added dropwise to aqueous 0.5N HCl (10 mL). The resulting light brown solid is collected by filtration, washed with H20 and dried in vacuo over P20b to yield 700 mg (74%) of 2- [1- (4-fluorophenyl) -lH-pyrrole- 3-yl] -acetic analytically pure as a solid, mp 100-2 ° C. H NMR: d 7.34-7.30 (m, 2H), 7.10 (t, 2H, J = 8.6 Hz), 6.97-6.95 (m, 2H), 6.29 (t, 1H, J = 2.2 Hz), 3.60 (s, 2H). Anal. Calculated for C: 2H10No2F • 0.15 H20: C, 64.95; H, 4.68; N, 6.31. Found: C, 65.03; H, 4.71; N, 6.25. 1- (4 (S) -Benzl-oxazolidin-2-on-3-yl) -2- [1- (4-fluorophenyl) -lH-pyrrol-3-yl] -ethanone To a solution of (S) - (-) -4-benzyl-2-oxazolidinone (710 mg, 4 mmol) in dry THF (10 mL) at -78 ° C is added n-butyllithium (2.5 mL of 1.6 M in hexanes). In a separate reaction vessel, to a solution of 2- [1- (4-fluorophenyl) -1H-pyrrol-3-yl] -acetic acid (920 mg, 4.2 mmol) and triethylamine (0.7 mL, 5 mmol) in dry THF (20 mL) at -78 ° C pivaloyl chloride (0.5 mL, 4 mmol) is added dropwise. After stirring from -78 ° to 0 ° C for 1 hour, after collecting at -78 ° C, the above solution is added via cannula. The resulting mixture is allowed to warm to room temperature for 17 hours, then it is partitioned with EtOAc and aqueous NH 4 Cl. The separated aqueous phase is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated to an oil, which is purified by flash column chromatography with elution gradient of 15-20% EtOAc / hex. The oily product is crystallized from benzene to provide 1.04 g (69%) of 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) -2- [1- (4-fluorophenyl) - 1H-pyrrol-3-yl] -ethanone as a solid, mp 106-8 ° C. NMR] H: d 7.36-7.25 (m, 5H), 7.17-7.07 (m, 4H), 7.04 (s, 1H), 6.98 (t, 1H, J = 2.6 Hz), 6.35 (dd, 1H, J = 1.8, 2.6 Hz), 4.72-4.67 (m, 1H), 4.28-4.14 (m, 4H), 3.28 (dd, 1H, J = 3.3, 3.6 Hz), 2.79 (dd, 1H, J = 9.4, 13.4 Hz ). Anal. Calculated for C, 69.83; H, 5.06; N, 7.40. Found: C, 69.80; H, 5.07; N, 7.30.

Benzyl Ester of 1- (4 (S) -Benzyl-oxazolidin-2-yn-3-yl) -3 (S) - [1- (4-fluorophenyl) -lH-pyrrol-3-yl] succinamic acid According to the procedure described in Example 13 for the preparation of ester 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -3 (S) - (1-biphenyl-4) il-lH-pyrrol-3-yl) succinamic t-butyl ester, 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) -2- [l- (4-fluoro-phenyl) - lH-pyrrol-3-y1] -ethanone is alkylated with benzyl bromoacetate to give 550 mg (50%) of benzyl ester of 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) benzyl ester -3 (S) - [1- (4-fluorophenyl) -lH-pyrrol-3-yl] succinnamic acid as an amorphous solid. NMR? E: d 7.35-7.20 (m, 12H), 7.09 (t, 2H, J = 8.6 Hz), 7.02 (t, 1H, J = 2.0 Hz), 6.91 (t, 1H, J = 2.6 Hz), 6.30 (dd, 1H, J = 1.8, 2.9 Hz), 5.54 (dd, 1H, J = 4.0, 11.4 Hz), 5.13 (s, 2H), 4.59-4.53 (m, 1H), 4.06 (d, 2H, J = 4.8 Hz), 3.49 (dd, 1H, J = 11.4, 17.3 Hz), 3.25 (dd, 1H, J = 2.8.13.1 Hz), 2.79 (dd, 1H, J = 4.1, 17.3 Hz), 2.51 ( dd, 1H, J = 10.1, 13.4 Hz). Anal. Calculated for C? H27N2ObF: C, 70.71; H, 5.17; N, 532. Found: C 70.83; H, 5.27; N, 5.30.

Benzyl Ester of Acid 2 (S) - [1- (4-Fluorophenyl) -1H-pyrrol-3-yl] -succinic acid To the benzyl ester solution of 1- (4 (S) -benzyl-o to zolidin-2-on-3-yl) -3 (S) - [l- (4-fluorophenyl) -lH-pi rrol- 3-i 1] succinamic acid (900 mg, 1.7 mmol) in THF (15 mL) at 0 ° C is added 30% H70? aqueous (0.8 mL, 6.8 mmol), followed by the dropwise addition of aqueous 2N LiOH (1.7 mL). After stirring at 0 ° C for 1 hour, 30% aqueous H202 (0.04 mL) and additional aqueous 2N LiOH (0.08 mL) are added. After 45 minutes at 0 ° C, the mixture is treated with a mixture of saturated aqueous NaHCO3 (10 mL) and aqueous 2N Na2SO3 (5 mL). After 10 minutes at 0 ° C, the mixture is partitioned with EtOAc and 1M phosphate buffer at pH7. The aqueous phase is separated and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over NaSO4 and concentrated to an oil which is purified by flash column chromatography with an elution gradient of 1-5% MeOH / CH2Cl2 to yield 320 mg. (51%) of 2 (S) - [1- (4-fluorophenyl) -lH-pyrrol-3-yl] succinic acid 4-benzyl ester as an oil. 1E NMR: d 7.36-7.26 (m, 7H), 7.10 (t, 2H, J = 8.6 Hz), 6.93-6.92 (m, 2H), 6.27 (t, 1H, J = 2.4 Hz), 5.14 (s, 2H), 4.14 (dd, 1H, J = 5.7, 9.4 Hz), 3.19 (dd, 1H, J = 9.6, 16.9 Hz), 2.81 (dd, 1H, J = 5.9, 16.9 Hz). Anal. Calculated for C2? H] 0NO4F • 0.5 H20: C, 67.01, H, 5.09; N, 3.72. Found: C, 66.96; H, 4.95; N, 3.63.

Benzyl Ester of N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) propyl] -3 (S) - [1- (4-fluorophenyl] -1H-pyrrol-3-yl] succinamic acid According to the procedure described in Example 1 (b) for the preparation of 3 (R) -t-butoxycarbonylamino-N- (2, 2-dimethyl-1 (S) - (methylcarbamoyl) propyl) succinnamic acid benzyl ester , the 1-benzyl ester of 2 (S) - [1- (4-fluorof nyl) -lH-pyrrol-3-yl] -succinic acid and the Lt-leucine N-methylamide (see Malón, P .; Pancoska, P .; Budesinsky, M .; Hlavacek, J .; Pospisek, J .; Blaha, K. Coi., Czech, Chem Commun., 1983, 48, 2844-2861) are coupled with TBTU. Flash column chromatography with 0-5% MeOH / CH2Cl? as elution gradient provides, in 82% yield, the benzyl ester of the acid N- (2,2-dimethyl-l (S) - (methylcarbamoyl) propyl) -3 (S) - [1- (4-f luoropheni 1) -lH-pyrrol-3-yl] succinamic acid as a brittle foam. NMR] H: d 7.34-7.26 (m, 7H), 7.10 (t, 2H, J = 8.6 Hz), 6.95 (t, 1H, J = 2.4 Hz), 6.89 (t, 1H, J = 2.0 Hz), 6.49 (d, 1H, J = 8.8 Hz), 6.23 (dd) , 1H, J = 1.8, 3.0 Hz), 5.76-5.74 (m, 1H), 5.11 (s, 2H), 4.12 (d, 1H, J = 9.2 Hz), 4.00 (t, 1H, J = 7.2 Hz) , 3.20 (dd, 1H, J = 7.7, 16.5 Hz), 2.84 (dd, 1H, J = 6.6, 16.6 Hz), 2.75 (d, 3H, J = 4.8 Hz), 0.95 (s, 9H). Anal. Calculated for C28H32N3? 4F: C, 67.89; H, 6.55; N, 8.48. Found: C, 67.78; H, 6.52; N, 8.50. The following compound is prepared in a similar way: Example 14 (b). Acid 3 (S) - [1- ('-Cianobiphenyl-4-yl) lH-pyrrol -3-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] succinnamic acid According to the procedure described in Example 1 (a), benzyl ester of 3 (S) - [1- (4'-cyclobiphenyl-4-yl) -lH-pi ro 1-3-yl] -N - [2, 2-dimeti 1-1 (S) - (methylcarbamoyl) propyl] succinamic is hydrogenated in EtOH / EtOAc after 6 hours to give, in 87% yield, 3 (S) - [1- ( 4'-Cyanobi phenyl-4-yl) -lH-pyrrol-3-yl] -N- [2, 2-dimethyl-1- (S) - (meth ilcarbamoyl) propyl] succinnamic acid as a colorless amorphous solid. NMR] H: d 7.74 (d, 2H, 8.5 Hz), 7.68 (d, 2H, 8.5 Hz), 7.63 (d, 2H, J = 8.5 Hz), 7.45 (d, 2H, J = 8.5 Hz), 7.08 (t, 1H, J = 2.4 Hz), 6.89-6.83 (m, 1H), 6.29 (t, 1H, J = 1.8 Hz), 5.77-5.71 (m, 1H), 4.17 (d, 1H, J = 9.2 Hz), 4.06-4.01 (m, 1H), 3.19 (dd, 1H, J = 8.6, 16.4 Hz), 2.85 (dd, 1H, J = 4.6, 16.4 Hz), 2.78 (d, 3H, J = 4.8 Hz ), 0.96 (s, 9H). Anal. Calculated for C20H30N4O4 • 0.25 EtOAc • 0.2 C6H14: C, 68.98; H, 6.67; N, 10.66. Found: C, 68.91; H, 6.79; N, 10.64. The starting materials are prepared in the following way: Methyl ester of 2- [1- (4'-Cyanobi phenyl-4-yl) lH-pyrrol-3-yl] -acetic acid According to the procedure described in Exarnple 14 (a) for the preparation of 2- [1- (4-fluorophenyl) -lH-pyrrol-3-yl] -acetic acid methyl ester, 4-amino-4-cyano-biphenyl (commercially available from of TCI) and methyl 2- (2, 5-dimethoxy-tetrahydrofuran-3-yl) acetate are condensed for 6 hours at 80 ° C to provide an unpurified product. Successive flash column chromatography with EtOAc / CH2Cl2 / hex affords, in 60% yield, 2- [1- (4'-cyanobi phenyl-4-yl) -lH-pyrrole-3-yl] methyl ester. -Acetic as an amorphous solid. XR-NMR: d 7.75 (d, 2H, J = 8.8 Hz), 7.69 (d, 2H, J = 8.8 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.48 (d, 2H, J = 8.8 Hz) ), 7.10-7.09 (m, 2H), 6.33 (t, 1H, J = 2.2 Hz), 3.73 (s, 3H), 3.58 (s, 2H). Anal. Calculated for C20H16N202: C, 75.93; H, 5.10; N, 8.86. Found: C, 75.86; H, 5.14; N, 8.90. 2- [1- (4'-Cyanobi phenyl-4-yl) -lH-pyrro 1-3-yl] -acetic acid In accordance with the procedure described in Example 14 (a) for the preparation of 2- [l- (4-fluorophenyl) -lH-pyrrol-3-yl] -acetic acid, 2- [1- (4'-cyanobiphenyl-4-methyl) methyl ester il) -lH-pyrrol-3-yl] -acetic is hydrolyzed in 86% yield to provide 2- [1- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] -acetic acid as a solid, mp 201-4 ° C (d).

X H NMR (DMSO-dβ): d 12.20 (broad s, 1H), 7.92 (s, 4H), 7. 84 (d, 2H, J = 8.8 Hz), 7.68 (d, 2H, J = 8.5 Hz), 7.40 (s, 1H), 7.35 (s, 1H), 6.22 (s, 1H), 3.41 (s, 2H). Anal. Calculated for C? 9Hi4N202: C, 74.81; H, 4.73; N, 9.18. Found: C, 74.90; H, 4.92; N, 9.12. 1- (4 (S) -Benzy-1-oxazolidin-2-on-3-yl] -2- [1- (4'-cyanobiphenyl-4-yl) -lH-pyrro1-3-yl] -ethanone As in Example 14 (a) for 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) -2- [1- (4-fluorophenyl) -lH-pyrrol-3-yl] -etanone, 2- [1- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -acetic acid and 4 (S) -benzyl-2-oxazolidinone are coupled. Flash column chromatography with 10-25% EtOAc / hex with stepwise CH2C1 elution gradient and subsequent trituration with EtOAc / MTBE / hex provides, in 59% yield, 1- (4 (S) -benzyl- oxazolidin-2-on-3-yl) -2- [1- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -ethanone as an amorphous solid. XH NMR: d 7.75 (d, 2H, J = 8.8 Hz), 7.70 (d, 2H, J = 8.5 Hz), 7.65 (d, 2H, J = 8.8 Hz), 7.49 (d, 2H, J = 8.8 Hz ), 7.32-7.25 (m, 3H), 7.17-7.15 (m, 3H), 7.12 (t, 1H, J = 2.8 Hz), 6.40 (dd, 1H, J = 1.7, 2.8 Hz), 4.74-4.68 ( m, 1H), 4.31-4.16 (m, 4H), 3.29 (dd, 1H, J = 2.9, 13.6 Hz), 2.80 (dd, 1H, J = 9.4, 13.4 Hz). Anal. Calculated for C 29 H 23 N 3 O 3: C, 75.47; H, 5.02; N, 9.11. Found: C, 75.36; H, 5.08; N, 9.15.

Benzyl Ester of l- (4 (S) -Benzyl-oxazolidin-2-yl) -3- (S) - [l- (4'-cyanobi phenyl-4-yl) -lH-pyrrole-3-acid il] succinámico According to the procedure described in Example 1 (a) for the preparation of benzyl ester of 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) -3 (S) - [1-] benzyl ester (4-fluorophenyl) -lH-pyrrol-3-yl] succinamic, 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) -2- [1- (4'-cyanobiphenyl-4 -yl) -1H-pyrrol-3-yl] -ethanone is alkylated with benzyl bromoacetate. Flash column chromatography with 25% EtOAc / hex and CH? C1 as a stepwise elution gradient provides, in 60% yield, the benzyl ester of 1- (4 (S) -benzyl-oxazolidin-2-on -3-yl) -3 (S) - [1- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] succinnamic acid as an amorphous solid. RMN lE. d 7.74 (d, 2H, J = 8.5 Hz), 7.68 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H, J = 8.8 Hz), 7.45 (d, 2H, J = 8.5 Hz), 7.35 -7.21 (m, 10H), 7.16 (t, 1H, J = 2.2 Hz), 7.05 (t, 1H, J = 2.8 Hz), 6.35 (dd, 1H, J = 1.8, 2.9 Hz), 5.57 (dd, 1H, J = 4.2, 11.2 Hz), 5.14 (s, 2H), 4.61-4.56 (m, 1H), 4.07 (d, 2H, J = 5.2 Hz), 3.51 (dd, 1H, J = 11.4, 17.3 Hz ), 3.26 (dd, 1H, J = 2.9.13.6 Hz), 2.81 (dd, 1H, J = 4.2,17.1 Hz), 2.53 (dd, 1H, J = 10.1, 13.4 Hz). Anal. Calculated for C30H31N3O5O.4 H20: C, 73.98; H, 5.20; N, 6.81. Found: C, 73.87; H, 5.53; N, 6.63. 4-Benzyl Ester of Acid 2 (S) - [1- (4'-Cyanobi-phenyl-1-4-yl) -lH-pyrrol-3-yl] -succinic acid According to the procedure described in Example 14 (a) for the preparation of 2 (S) - [1- (4-fluorophenyl) -lH-pyrrol-3-yl] succinic acid 4-benzyl ester, the benzyl ester of 1- (4 (S) -benzyl-oxazolidin-2-on-3-yl) -3 (S) [1- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -synatamic acid hydrolyzed and purified by flash column chromatography with 25-75% EtOAc / hex with elution gradient of 5% MeOH / CH2Cl2 to provide, in 55% yield, the 4-benzyl ester of acid 2 ( S) - [1- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] succinic acid as an oil, which has some residual 4 (S) -benzyl-2-oxazolidinone by NMR, and it is used without further purification. The analyzes were performed on pure chromatography fractions. 3 H NMR: d 7. 74 (d, 2H, J = 8.5 Hz), 7.68 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H, J = 8.5 Hz), 7.43 (d, 2H, J = 8.8 Hz), 7.32 (s, 5H), 7.07 (s, 1H), 7.06 (s, 1H), 6.33 (t, 1H, J = 2.4 Hz), 5.14 (s, 2H), 4.16 (dd, 1H, J = 5.7, 9.4 Hz), 3.21 (dd, 1H, J = 9.6, 16.9 Hz), 2.83 (dd, 1H, J = 5.9, 16.9 Hz). Anal. Calculated for C20H22N2O4 • 0.4 H20: C, 73. 48; H, 5.02; N, 6.12. Found: C, 73.38; H, . 17; N, 6.00.

Benzyl Ester of Acid 3 (S) - [1- (4'-Cyanobi-phenyl-1-4-yl) -lH-pyrro-1-3-yl] -N- (2, 2-dimethyl-l (S) - ( methylcarbamoyl) succinámico According to the procedure described in Example 1 (b) for the preparation of 3 (R) -t-butoxycarbonylamino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinnamic acid benzyl ester , the 4-benzyl ester of 2 (S) - [1- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] succinic acid and the Lt-leucine N-methylamide (see Malon, P.; Pancoska, P .; Budesinsky, M .; Hlavacek, J .; Pospisek, J .; Blaha, K. Coil, Czech, Chem Commun., 1983, 48, 2844-2861) are coupled with TBTU. Successive flash column chromatography with 0-30% EtOAc / CH2Cl2 and elution gradient of 2-5% MeOH / CH2Cl2, respectively, and radial chromatography with elution gradient of 0-40% EtOAc / hex provide, in 66% yield, the benzyl ester of 3 (S) - [1- ('-cyanobiphenyl-4-yl) -1H-pyrro1-3-yl] -N- (2, 2-dimethyl-l (S ) - (methylcarbamoyl) propyl) -succinnamic as a brittle foam. H NMR: d 7.75 (d, 2H, J = 8.5 Hz), 7.69 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.5 Hz ), 7.31 (s, 5H), 7.09 (t, 1H, J = 2.6 Hz), 7.04 (t, 1H, J = l.8 Hz), 6.50 (broad d, 1H, J = 9.6 Hz), 6.28 ( dd, 1H, J = 1.7, 2.8 Hz), 5.70-5.67 (m, 1H), 5.12 (s, 2H), 4.13 (d, 1H, J = 9.2 Hz), 4.02 (t, 1H, J = 7.4 Hz ), 3.23 (dd, 1H, J = 7.5, 16.7 Hz), 2.85 (dd, 1H, J = 6.8, 16.7 Hz), 2.76 (d, 3H, J = 4.8 Hz), 0.96 (s, 9H). Anal. Calculated for CbH36N404 • 0.5 H20: C, 71.77; H, 6.37; N, 9.57. Found: C, 71.73; H, 6.35; N, 9.54.

Example 14 (c). Acid 3 (S) - [1- (4 • -Cianobifenil-4-yl) lH-pyr rol -3-yl] -N- [1 (S) - (1 H -imidazole -2 -i 1) 3 -methylbutyl] succinámico According to the procedure described in Example 1 (a), the benzyl ester of 3 (S) - [l- (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -N- [ 1 (S) - (1H-imidazol-2-yl) -3-methylbutyl] succinamic acid is hydrogenated in EtOH / THF for 3 hours to provide, in 54% yield, 3 (S) - [1- (4 '-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -N- [1 (S) - (lH-imidazol-2-yl) -3-methylbutyl] succinamic: mp 206-210 ° C (dec); NMR lE ~ (DMSO-dfi): d_12.0 (broad s, 1H), 8.31 (d, 1H, J = 8.45 Hz), 7.93 (s, 4H), 7.86 (d, 2H, J = 8.5 Hz), 7.63 (d, 2H, J = 8.8 Hz), 7.33-7.30 (m, 2H), 6.81 (s, 2H), 6.18 (s, 1H), 5.02 (dd, 1H, J = 15.8, 8.8 Hz), 3.86 (dd, 1H, J = 9.6, 4.8 Hz), 2.87 (dd, 1H, J = 16.9, 10.3 Hz), 2.60 (dd, 1H, J = 16.5, 4.8 Hz), 1.7-1..5 (m, 3H), 0.87 (d, 3H, J = 6.6 Hz), 0.84 (d, 3H, J = 5.9 Hz); EMARFAB: Calculated for C29H29Nb03Cs (M + Cs): 628.1325 Found: 628.1335.

The starting material is prepared in the following way: Benzyl Ester of 3 (S) - [1- (4'-Cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -N- [1 (S) - (1H-iraidazole-2-yl) acid -3- methylbutyl] succinamic In accordance with the procedure described in Example 1 (b) for the preparation of acid benzyl ester 3 (R) -t-Butoxycarbonylamino-N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl) succinamic, the 4-benzyl ester of 2 (S) - [1- (4'-cyanobiphenyl) -4-yl) -lH-pyrrol-3-yl] succinic (prepared as described in Example 14 (b)) and 2- (1 (S) -amino-3-methyl-butyl) -imidazole (see Chen, J.J .; Zhang, Y.; Hammond, S .; Dewdney, N.: Ho, T .; Browner, M.F .; Castelhano, A.L., submitted for publication; and Abel-Meguid, H.H.; Metcalf B.W .; Caw, T.J .; DeMarsh, P .; Des Jaríais, R.L .; Fisher, S .; Green, D.W .; et al. Biochemistry, 1994, 33, 11671-11677) are coupled with TBTU to provide, in 49% yield, the benzyl ester of 3 (S) - [l- (4'-cyanobiphenyl-4-yl) -lH-pyrrole -3-yl] -N- [1 (S) - (lH-imidazol-2-yl) -3-methylbutyl] succinamic: mp 186-188 ° C (dec); NMR] H (DMSO-dc) d 11.79 (s, 1H), 8.40 (d, 1H, J = 8.5 Hz), 7.92 (s, 4H), 7.85 (d, 2H, J = 8.5 Hz), 7.62 (d , 2H, J = 8.8 Hz), 7.34 (s, 5H), 6.97 (s, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 5.13-5.00 (m, 3H), 3.96 (dd, 1H, J = 9.9, 5.5 Hz), 2.99 (dd, 1H, J = 16.4, 10.8 Hz), 2.78 (dd, 1H, J = 16.4, 5.0 Hz), 1.67-1.60 (m, 2H), 1.55-1.45 (m, 1H), 0.85 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.3 Hz); Anal. Calculated for • H20: C, 71.62; H, 6.18; N, 11.60. Found: C, 71.50, 71.45; H, 5.97, 6.01; N, 11.51, 11.48.

Example 14 (d). 3 (S) - [1- (4'-Cyanobifenyl-4-yl) -lH-pyrrol-3-yl] -N- (4, 4 -dimethyl-2-oxo-tetrahydrofuran -3 (S) - acid il) succinámico According to the procedure described in Example 1 (a), the benzyl ester of 3 (S) - [1 - (4'-cyanobiphenyl-4-yl) -lH-pyrrol-3-yl] -N- ( 4, 4-dimethyl-2-oxo-tetrahydrofuran-3 (S) -yl) succinamic acid is hydrogenated in EtOH / EtOAc for 3 hours to provide, in 81% yield, 3 (S) - [1- (4 '-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] -N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3 (S) -yl) succinnamic acid: NMR: H (DMSO-d6) : d 12.2 (s broad, 1H), 8.48 (d, 1H, J = 8.8 HZ), 7.92 (s, 4H), 7.86 (d, 2H, J = 8.5 Hz), 7.67 (d, 2H, J = 8.5 Hz), 7.40 (s, 1H), 7.37 (s, 1H), 6.33 (s, 1H), 4.75 (d, 1H, J = 8.8 Hz), 4.08, 4.00 (quartet AB, 2H, J = 8.6 Hz) , 3.97-3.92 (m, 1H), 3.01-2.92 (m, 1H), 2.64 (dd, 1H, J = 16.54, 4.0 Hz), 1.05 (s, 3H), 0.97 (s, 3H); Anal. Calculated for C27H2sN3Ob • C5H120 (MTBE): C, 68.67; H, 6.66; N, 7.51. Found: 69.00.68.91; H, 6.37, 6.42; N, 7.60, 7.52. The starting material is prepared in the following way: Benzyl Ester of Acid 3 (S) - [1- (4'-Cyanobifeni 1-4-yl) -lH-pyrro 1-3-yl] -N- (4, 4-dimet i 1-2-oxo-tetrahydrofuran -3 (S) -yl) succinámico In accordance with the procedure described in Example 1 (b) for the preparation of 3 (R) -t-Butoxycarbonylamino-N- (2, 2-dimethyl-1 (S) - (methylcarbamoyl) propyl) succinnamic acid benzyl ester , the 4-benzyl ester of 2 (S) - [1- (4-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] succinic acid (prepared as described in Example 14 (b)) and 3 (R) -amino-4,4-dimethyl-2-oxo-tetrahydrofuran (see Freskos, JN Syn Commum 1994, 24, 557-563) are coupled using TBTU with N-methylmorpholine as the base to provide a mixture of diastereoisomers that are separated by using silica gel column chromatography with a gradient of 0 to 5% MeOH in CH2C12. The mixed fraction is re-purified in a chromatotron using 0-2.5% MeOH / CH2Cl2, then 0-1.25% MeOH / CH2Cl2 as eluent to obtain the benzyl ester of 3 (S) - [1- (4 '- cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] -N- (4, 4 -dimet i 1-2 -oxo-tetrahydrofuran-3 (S) -yl) succinamic, in 29% yield, as a Amorphous solid: NMR] H (CDC13): d 7.75 (d, 2H, 8.1 Hz), 7. 69 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.46 (d, 2H, J = 8.5 Hz), 7.32 (s, 5H), 7.13 (s, 1H), 7.09 (t, 1H, J = 2.2 Hz), 6.32 (s, 1H), 6.06 (d, 1H, J = 7.7 Hz), 5.13 (s, 2H), 4.67 (d, 1H, J = 7.7 Hz), 4.08-4.01 (m, 3H), 3.31 (dd, 1H, J = 16.9, 8.5 Hz), 2.82 (dd, 1H , J = 16.7, 6.1 Hz), 1.23 (s, 3H), 0.98 (s, 3H); Anal. Calculated for C34H ,, 3Ob • 0.2 H20: C, 72.25; H, . 60; N, 7.43. Found: 72.32, 72.26; H, 5.88, 5.91; N, 7.07, 7.02.

Example 15 (a). N- (1 (S) -Benzy-2-hydroxyethyl) -3 (S) - (2- (biphenyl-4-yl) furan-5-yl) -synatamic acid To a solution of t-butyl acid ester N- (4 (S) -benzyl 1-2, 2-dimethyl-1-oxa-zol-idin-3-yl) -3 (S) - (2-biphenyl-4-yl-furan-5-yl) -sycinnamic acid (240 mg, 0.42 mmol) in CH2C12 (6 mL) was added trifluoroacetic acid (3 mL). After 30 minutes at room temperature, the mixture is divided between phosphate buffer CH2Cl2 / pH7. The organic layer is washed with phosphate buffer to pH7 and brine, dried over Na2SO4 and evaporated to give a residue which is purified by means of flash column chromatography with elution gradient of 0 -9 HOAc / 10% MeOH / CH2Cl2. The purified product is triturated with CH? Cl / hex to obtain 40 mg (20%) of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (S) - (2- (bi phenyl) -4- il) furan-5-yl) succinamic as a pale yellow solid. XH NMR (DMSO-d6): d 8.12 (broad m, 1H), 7.74-7.68 (m, 6H), 7.46 (t, 2H, J = 7.5 Hz), 7.35 (t, 1H, J = 7.4 Hz), 7.25-7.12 (m, 5H), 6.86 (d, 1H, J = 3.3 Hz), 6.26 (d, 1H, J = 3.0 Hz), 4.04 (t, 1H, J = 7.5 Hz), 3.89-3.84 (m , 1H), 2.83 (dd, 1H, J = 5.7, 13.8 Hz), 2.71-2.59 (m, 3H). Anal. Calculated for C 9H2, NOb, • H, 0: C, 71.44; H, 6.00; N, 2.87. Found: C, 71.51; R, 5.78; N, 2.92. The starting material is prepared in the following way: 2-Biphenyl-4-yl-furan To a mixture of 4-bromobi phenyl (1.00 g, 4.80 mmol) and bis (triphenylphosphine) -palladium (II) chloride (0.3 g, 0.4 mmol) in THF (10 mL) is added 2-tributyl tani 1 furan (1.6 mL, 5.0 mmol). After heating to reflux for 1 hour, the resulting mixture is concentrated to a residue which is dissolved in minimal CH2C12 and applied to a flash chromatography column. Elution with 10% CH? Cl2 / hex leads to the isolation of a mixture, which, by successive triturations with hexanes or pentane, provides the pure product. The mother liquor is divided with acetonitrile and hexanes. The separated acetonitrile layer is evaporated to obtain more pure product. A total of 0.55 g (58%) of pure 2-biphenyl-4-ylfuran is prepared as a pale yellow solid, m.p. 155-7 ° C (d). NMR lE: d 7.75 (d, 2H, J = 8.1 Hz), 7.63 (d, 4H, J = 8.5 Hz), 7.49-7.43 (m, 3H), 7.35 (t, 1H, J = 7.0 Hz), 6.69 (d, 1H, J = 3.3 Hz), 6.50 (dd, 1H, J = 1.5, 3.3 Hz). Anal. Calculated for C? -, H120: C, 87.25; H, 5.49. Found: C, 87.16; H, 5.49. 1- (4 (S) -Benci 1-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-phenyl-4-yl) ethane-1,2-dione According to the procedure described in Example 13 for the preparation of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol- 3-yl) ethane-1,2-dione, 2-biphenyl-4-yl-furan is deprotonated and alkylated with N- (4 (S) -benzyl-2,2,2-dimethyl-oxazolidinyl) ethyl ester. 3-yl) -oxamic to provide, in 57% yield, 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl- furan-5-yl) ethane-1,2-dione as yellow amorphous solid. XH NMR: d 7.91 (d, 2H, J = 8.1 Hz), 7.69 (d, 2H, J = 8.1 Hz), 7.64 (d, 2H, J = 8.1 Hz), 7.49-7.36 (m, 4H), 7.25 -7.10 (m, 5H), 6.85 (d, 1H, J = 4.0 Hz), 4.62-4.57 (m, 1H), 3.91 (m, 2H), 3.00 (dd, 1H, J = 5.0, 13.0 Hz), 3.82 (dd, 1H, J = 10.1, 13.2 Hz), 1.86 (s, 3H), 1.68 (s, 3H). Anal. Calculated for C30H27N04: C, 77.40; H, 5.85; N, 3.01. Found: C, 77.43; H, 5.88; N, 3.06. 1- (4 (S) -Benzy1-2, 2-dimethyl-1-oxazolidin-3-yl) -2- (2-phenyl-4-yl-furan-5-yl) -2-hydroxy-ethanone In accordance with the procedure described in Example 13 for the preparation of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol-3-yl) -2-hydroxy -etanone, 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan-5-yl) ethane-2, 2- dione is reduced with NaBH to provide, in quantitative yield, 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan-5) -yl) -2-hydroxy-ethanone. XH NMR: d 7.70 (d, 2H, J = 7.7 Hz), 7.61 (d, 4H, J = 8.5 Hz), 7.45 (t, 2H, J = 7.4 Hz), 7.38-7.19 (m, 6H), 6.64 (d, 1H, J = 2.9 Hz), 6.43 (d, 1H, J = 3.3 Hz), 5.08 (d, 1H, J = 6.6 Hz), 4.45 (d, 1H, J = 7.0 Hz), 3.88-3.85 (m, 1H), 3.78 (d, 1H, J = 8.8 Hz), 3.63 (dd, 1H, J = 5.2, 8.8 Hz), 3.03 (dd, 1H, J = 4.2, 13.1 Hz), 2.89 (dd, 1H, J = 9.8, 13.4 Hz), 1.83 (s, 3H), 1.58 (s, 3H). Anal. Calculated for C30H29N04 • 0.5 H20: C, 75.61; H, 6.34; N, 2.94. Found: C, 75.62; H, 6.32; N, 2.88. 2 - . 2-Acetoxy-1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl-2-biphenyl-4-yl-furan-5-yl) -ethanone In accordance with the procedure described in Example 13 for the preparation of 2-acetoxy-1- (4 (S) -benzyl-2-, 2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol-3-yl) -etanone, 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan-5-yl) -2-hydroxy-ethanone it is acylated to provide, in quantitative yield, 2-acetoxy-1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan- 5-yl) -ethanone as an off-white solid, mp 120-8 ° C, which is used without further purification. XH NMR: d 7.75 (d, 2H, J = 8.5 Hz), 7.66-7.62 (m, 4H), 7.46 (t, 2H, J = 7.4 Hz), 7.39-7.22 (m, 6H), 6.70 (d, 1H, J = 3.7 Hz), 6.62 (d, 1H, J = 3.3 Hz), 6.39 (s, 1H), 3.86-3.79 (m, 2H), 3.64-3.60 (m, 1H), 3.39 (d, 1H , J = 14.0 Hz), 2.96 (dd, 1H, J = 11.4, 14.0 Hz), 2.25 (s, 3H), 1.78 (s, 3H). Anal. Calculated for C32H3i 05: C, 75.42, H, 6.13; N, 2.75. Found: C, 75.27; H, 6.22; N, 2.65. 1-4 (S) -Benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan-5-yl) -ethanone In accordance with the procedure described in Example 13 for the preparation of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol-3-yl) -ethanone, the 2-Acetoxy-1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan-5-yl) -ethanone is hydrogenated to provide , in 42% yield, 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-yl-furan-5-yl) -ethanone as an amorphous solid. 2H-NMR: d 7.68 (d, 2H, J = 8.1 Hz), 7.62-7.58 (m, 4H), 7.44 (t, 2H, J = 7.5 Hz), 7.37-7.25 (m, 6H), 6.64 (d, 1H, J = 3.3 Hz), 6.32 (d, 1H, J = 2.9 Hz), 4. 17-4.14 (m, 1H), 3.87 (m, 2H), 3.77, 3.65 (quartet AB, 2H, J = 15.8 Hz), 3.09 (dd, 1H, J = 4.8, 13.6 Hz), 2.94 (dd, 1H, J = 9.6, 13.6 Hz), 1.78 (s, 3H), 1.59 (s, 3H).

Anal. Calculated for C30H29NO3: C, 79.80; H, 6.47; N, 3.10. Found: C, 79.72; H, 6.49; N, 3.03.

T-Butyl Ester of N- (4 (S) -Benzyl-2, 2-dimethyl-oxazolidin-3-yl) -3 (R) - (2-biphenyl-4-yl-furan-5-yl) succinamic acid In accordance with the procedure described in Example 13 for the preparation of N- (4 (S) -benzyl-2,2,2-dimethyl-oxazolidin-3-yl) -3 (R) - (1) t-butyl ester -biphenyl-4-yl-lH-pyrrol-3-yl) succinamic acid, 1- (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (2-biphenyl-4-) il-furan-5-yl) -ethanone is deprotonated with sodium hexamethyldisilazide and alkylated to provide, in 74% yield, the t-butyl ester of N- (4 (S) -benzyl-2,2-dimethyl -oxazolidin-3-yl) -3 (R) - (2-biphenyl-4-yl-furan-4-yl) succinamic acid. NMR 1E: d 7.65 (d, 2H, J = 8.5 Hz), 7.57 (t, 4H, J = 8.3 Hz), 7.43 (t, 2H, J = 7.4 Hz), 7.35-7.22 (m, 6H), 6.63 (d, 1H, J = 3.3 Hz), 6.36 (d, 1H, J = 3.3 Hz), 4.88-4.52 (m, 2H), 3.96-3.87 (m, 2H), 3.24 (dd, 1H, J = 10.9 , 17.1 Hz), 3.04 (d, 1H, J = 11.4 Hz), 2.88-2.81 (m, 2H), 1.72 (s, 3H), 1.44 (s, 3H). Anal. Calculated for C36H39N? 5 • 0.25 H20: C, 75.83; H, 6.98; N, 2.46. Found: C, 75.83; H, 6.97; N, 2.46.

Example 15 (b). N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) propyl] -3- (2 - (bi-phenyl-4-yl) -furan-5-l) succinamic acid According to the procedure described in Example 15 (a) for the preparation of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (S) - (2-biphenyl-4-yl-furan-5) acid -yl) succinamic acid, the t-butyl ester of N- [2,2-dimethyl-1 (S) - (methylcarbamoyl) propyl] -3- (2- (biphenyl-4-yl) -furan-5-yl) ) succinamic acid is deprotected with trifluoroacetic acid in CH2C12 after 1 hour. The trituration, without purification, with MTBE / hex provides, in 48% yield, N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] -3- (2- (biphenyl-4- il) -furan-5-yl) succinámico like a reddish amorphous solid.

NMR 1E (CD3CN): d 7.75 (d, 2H, J = 8.5 Hz), 7.69-7.66 (m, 4H), 7.47 (t, 2H, J = 7.2 Hz), 7.37 (t, 1H, J = 7.2 Hz), 6.91 (d, 1H, J = 7.7 Hz), 6.77 (d, 1H, J = 3.3 Hz), 6. 56 (s broad, 1H), 6.39 (d, 1H, J = 3.3 Hz), 4.24-4.19 (m, 1H), 4.12 (d, 1H, J = 9.2 Hz), 3.17-3.08 (m, 1H), 2.82 (dd, 1H, J = 5.0, 17.1 Hz), 2.67 (d, 3H, J = .8 Hz), 0.86 (s, 9H). EMARFAB: Calculated for C2 H3? N205 (M + H +) 463.2233. Found: 463.2236. The starting material is prepared in the following way: Ethyl ester of 2- (2-Biphenyl-4-yl-furan-5-yl) -2-oxoacetic acid According to the procedure described in Example 13 for the preparation of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol- 3-yl) ethane-1,2-dione, 2-biphenyl-4-yl-furan is deprotonated and alkylated with diethyl oxalate to provide, in 74% yield, 2- (2-ethyl) ethyl ester biphenyl-4-yl-furan-5-yl) -2-oxoacetic acid as a yellow solid, mp 91-94 ° C 1 H NMR: d 7.94 (d, 2H, J = 8.5 Hz), 7.83 (d, 1H, J = 4.1 Hz), 7.69 (d, 2H, J = 8.1 Hz), 7.64 (d, 2H, J = 7.7 Hz), 7.47 (t, 2H, J = 7.4 Hz), 7.39 (t, 1H, J = 7.2 Hz), 6.90 (d, 1H, J = 4.2 Hz), 4.44 (c, 2H, J = 7.0 Hz), 1.45 (t, 3H, J = 7.2 Hz). Anal. Calculated for C20H? 604: C, 74.99; H, 5.03. Found: C, 75.11; H, 5.07.

Ethyl ester of 2- (2-Biphenyl-4-yl-furan-5-yl) -2-hydroxy-acetic acid According to the procedure described in Example 13 for the preparation of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrol- 3-yl) -2-hydroxy-ethanone, the 2- (2-biphenyl-4-yl-furan-5-yl) -2-oxoacetic acid ethyl ester is reduced with NaBH4 to provide, in quantitative yield, the ester Ethyl 2- (2-biphenyl-4-yl-furan-5-yl) -2-hydroxy-acetic acid ethyl ester as a yellow solid, mp 75-80 ° C (d), which is used crude without purification. 1H-NMR: d 7.73 (d, 2H, J = 8.5 Hz), 7.62 (d, 4H, J = 8.1 Hz), 7.45 (t, 2H, J = 7.4 Hz), 7.35 (t, 1H, J = 7.4 Hz ), 6.66 (d, 1H, J = 3.3 Hz), 6.48 (d, 1H, J = 3.3 Hz), 5.24 (d, 1H, J = 5.9 Hz), 4.36-4.28 (m, 2H), 3.42 (d , 1H, J = 6.3 Hz), 1.30 (t, 3H, J = 7.2 Hz).

Ethyl Ester of 2-Acetoxy-2- (2-biphenyl-4-yl-furan-5-yl) -acetic acid According to the procedure described in Example 13 for the preparation of 2-acetoxy-1- (4 (S) -benzyl 1-2, 2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl) -lH-pyrrol-3-yl) -ethanone, the 2- (2-biphenyl-4-yl-furan-5-yl) -2-hydroxy-acetic acid ethyl ester is acylated to provide, in 83% yield , the ethyl ester of 2-acetoxy-2- (2-biphenyl-4-yl-furan-5-yl) -acetic acid which is used without purification. Flash column chromatography with 0-20% EtOAc / hex as eluent affords an analytically pure pink solid, m.p. 136-140 ° C. XH NMR: d 7.74 (d, 2H, J = 8.5 Hz), 7.63 (d, 4H, J = 8.5 Hz), 7.46 (t, 2H, = 7.4 Hz), 7.36 (t, 1H, J = 7.2 Hz) , 6.68 (d, 1H, J = 3.7 Hz), 6.58 (d, 1H, J = 3.3 Hz), 6.57 (s, 1H), 4.29 (c, 2H, J = 7.0 Hz), 2.21 (s, 3H) , 1.29 (t, 3H, J = 7.2 Hz). Anal. Calculated for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.61; H, 5.63.

Ethyl Ester of 2- (2-Biphenyl-4-yl-furan-5-yl) -acetic acid According to the procedure described in Example 13 for the preparation of (4 (S) -benzyl-2, 2-dimethyl-oxazolidin-3-yl) -2- (biphenyl-4-yl-lH-pyrrole-3-) il) -ethanone, the ethyl ester of 2-acetoxy-2- (2-biphenyl-4-yl-furan-5-yl) -acetic acid is hydrogenated to provide, in 61% yield, the ethyl ester of 2-acetoxy-2- (2-biphenyl-4-yl-furan-5-yl) -acetic acid. - (2-biphenyl-4-yl-furan-5-yl) -acetic acid as a white solid, mp 77-78 ° C. 1H-NMR: d 7.71 (d, 2H, J = 8.5 Hz), 7.63-7.59 (m, 4H), 7.45 (t, 2H, J = 7.4 Hz), 7.35 (t, 1H, J = 7.4 Hz), 6.64 (d, 1H, J = 2.9 Hz), 6.34 (d, 1H, J = 3.3 Hz), 4.22 (c, 2H, J = 7.2 Hz), 3.76 (s, 2H), 1.30 (t, 3H, J = 7.2 Hz). Anal. Calculated for C20H? 8O3: C, 78.41; H, 5.92. Found: C, 78.16; H, 5.92. 2- (2-Biphenyl-4-yl-furan-5-yl) -acetic acid To a solution of 2- (2-biphenyl-4-yl-furan-5-yl) -acetic acid ethyl ester (0.465 g, 1.44 mmol) in THF (10 mL) at 0 ° C is added 2M aqueous LiOH ( 2 mL). The mixture is allowed to warm for 4 hours at room temperature and then it is poured into 0.5M aqueous HCl (50 mL). The resulting pale orange precipitate is filtered off, rinsed with water and dried under vacuum over P205 to provide 400 mg (100%) of 2- (2-biphenyl-4-yl-furan-5-yl) acid. -acetic as a light orange solid, mp 196-210 ° C, which is used without further purification. NMR XH (acetone-d6): d 7.78 (d, 2H, J = 8.1 Hz), 7.72-7.67 (m, 4H), 7.46 (t, 2H, J = 7.4 Hz), 7.35 (t, 1H, J = 7.4 Hz), 6.84 (d, 1H, J = 3.3 Hz), 6.41 (d, 1H, J = 3.3 Hz), 3.81 (s, 2H). Anal. Calculated for C? 8H? 403: C, 77.68; H, 5.07. Found: C, 77.44; H, 5.16.

N- [2, 2-Dimethyl-l (S) - (N-met i 1-carbamoi 1) -propyl] -2- (2-biphenyl-4-yl-furan-5-yl) -acetamide According to the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxy-ethyl) -3 (R) -t-butoxycarbonyl-amino-succinamic acid benzyl ester , 2- (2-biphenyl-4-yl-furan-5-yl) -acetic acid is coupled with trifluoroacetic acid salt of Lt-leucine N-methylamide with BOP. Flash column chromatography with gradient elution of 0-5% MeOH / CH2Cl2 provides, in 58% yield, N- [2,2-dimethyl-1 (S) - (N-methyl-carbamoyl) -propyl ] -2- (2-biphenyl-4-yl-furan-5-yl) -acetamide as an orange foam, which decomposes to >75 ° C and used without further purification. XH NMR (acetone-d: d 7.72 (d, 2H, J = 8.5 Hz), 7.61 (d, 4H, J = 7.7 Hz), 7.45 (t, 2H, J = 7.5 Hz), 7.35 (t, 1H, J = 7.4 Hz), 6.65 (d, 1H, J = 3.3 Hz), 6.56 (d, 1H, J = 9.2 Hz), 6.36 (d, 1H, J = 3.3 Hz), 5.93 (s broad, 1H), 4.22 (d, 1H, J = 9.2 Hz), 3.71 (s, 2H), 2.79 (d, 3H, J = 4.5 Hz), 0.94 (s, 9H), Anal. Calculated for C25H28N203 • 0.6 H20 • 0.1 MTBE: C, 72.21; H, 7.23; N, 6.61, Found: C, 72.10; H, 6.97; N, 6.39.

T-Butyl Ester of N- [2, 2-Dimethyl-l (S) -methylcarbamoyl) propyl] -3- (2-biphenyl-4-yl) -furan-5-yl) succinamic acid In accordance with the procedure described in Example 13 for the preparation of N- (4 (S) -benzyl-2,2-dimethyl-oxazole idin-3-yl) -2 (R) - (t) -butyl ester ( biphenyl-4-yl-lH-pyrrol-3-yl) succinamic, but rather N- (2, 2-dimethyl-l (S) - (N-methylcarbamoi 1) -propyl) -2- (2-biphenyl) -4-yl-furan-5-yl) -acetamide is deprotonated with n-butyl-thiol (3.1 equiv) and alkylated to give 17 mg (7%) of t-butyl ester of N- [2, 2-Dimethyl-l (S) - (methylcarbainoyl) propyl] -3- (2- (biphenyl-4-yl) -furan-5-yl) succinnamic acid as an amorphous solid. NMR tE: d 7.70 (d, 2H, J = 8.1 Hz), 7.62-7.59 (m, 4H), 7.45 (t, 2H, J = 7.5 Hz), 7.35 (t, 1H, J = 7.4 Hz), 6.63 (d, 1H, J = 3.3 Hz), 6.50 (d, 1H, J = 9.6 Hz), 6.33 (d, 1H, J = 3.3 Hz), 5.09 (broad m, 1H), 4.19-4.10 (m, 2H ), 3.15 (dd, 1H, J = 8.5, 16.6 Hz), 2.86-2.73 (m, 4H), 1.41 (s, 9H), 0.89 (s, 9H). HRMS: Calculated for C31H39 2O5 (M + H +): 519.2859. Found: 519.2865.

Example 16. N- (1 (S) -Benzy-2-hydroxyethyl) -3 (R) - [4- (bipheni-4-yl) -pyrazol-1-yl] -synatamic acid According to the procedure described in Example 1 (a), the benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [4- (biphenyl-4-yl) pyrazole -l-yl] succinamic acid is hydrogenated to obtain, in 74% yield, N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [4-biphenyl-4-yl] pyrazole- l-il] succinámico like a white solid, pf 154-9 ° C NMR? E (D3COD): d 8.17 (s, 1H), 8.06 (s, 1H), 7.64-7.67 (m, 6H), 7.49 (t, 2H, J = 7.5 Hz), 7.38 ( t, 1H, J = 7.0 Hz), 7.29-7.16 (m, 5H), 5.60 (t, 1H, J = 7.2 Hz), 4.32-4.28 (m, 1H), 3.79-3.65 (m, 2H), 3.35 (d, 2H, J = 6.6 Hz), 2.96-2.83 (m, 2H). Anal. Calculated for C28H27N304 • 0.25 H20 • 0.25 C6H? 4: C, 71.49; H, 6.31; N, 8.48. Found: C, 71.54; H, 6.30; N, 8.40. The starting material is prepared in the following way: 2-Bromo-N- (1 (S) -hydroxymethyl-2-phenylethyl) acetamide To a solution of (S) -2-amino-3-phenyl-1-propanol (1.00 g, 6.61 mmol) and triethylamine (1 mL, 7.17 mmol) in THF (70 mL) at -78 ° C is added dropwise bromoacetyl bromide (0.60 mL, 6.9 mmol). After 1.25 hours at -78 ° C, the resulting mixture is partitioned between 1M phosphate buffer at pH7 (100 mL) and hexanes (100 mL). The aqueous layer is extracted with EtOAc: hex (2: 1, 50 mL). The combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated to provide 1.59 g (85%) of 2-bromo-N- (1 (S) -hydroxymethyl-2-phenylethyl) acetamide as a solid, m.p. 83-5 ° C. NMR? E (DMSO-d6): d 8.15 (d, 1H, J = 8.1 Hz), 7.32-7.11 (m, 5H), 4.82 (t, 1H, J = 5.3 Hz), 3.83-3.74 (m, 3H ), 2.80 (dd, 1H, J = 5.9, 13.6 Hz), 2.59 (dd, 1H, 1 = 8.9, 13.6 Hz). Anal. Calculated for CnH14N02Br: C, 48.55; H, 5.19; N, 5.15; Br, 29.36. Found: C, 48.69; H, 5.13; N, 5.13; Br, 29.30. 3- (2-Bromoacetyl) -2, 2-dimeti 1-4 (S) -phenylmethyl-oxazolidine To a mixture of 2-bromo-N- (1 (S) -hydroxymethyl-2-phenylethyl) acetamide (1.55 g, 5.45 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in CH2C12 (50 mL) is added 2-methoxypropene (1.50 mL, 15.7 mmol) by drip via a syringe. After 15 minutes at room temperature, the resulting mixture is washed with 1M phosphate buffer at pH7 (25 mL) and brine (25 mL), dried over Na2SO and concentrated to give a dark solid, which is triturated with MTBE. / hex to provide 1.46 g (86%) of 3- (2-bromoacet-yl) -2,2-dimethyl-4 (S) -phenylmethyl-1-oxazolidine as a pale yellow solid. XH NMR (DMSO-d6): d 7.33-7.17 (m, 5H), 4.21-4.15 (m, 1H), 4.04, 3.86 (quartet AB, 2H, J = 12.1 Hz), 3.79 (dd, 1H, J = 4.8, 9.2 Hz), 3.71 (d, 1H, J = 9.2 Hz), 2.99 (dd, 1H, J = 5.0, 13.4 Hz), 2.70 (dd, 1H, J = 9.2, 13.2 Hz), 1.55 (s, 3H), 1.38 (s, 3H). Anal. Calculated for C? 4H ?? N02Br: C, 53.86; H, 5.81; N, 4.49; Br, 25.59. Found: C, 53.91; H, 5.82; N, 4.47; Br, 25.58. l- (4 (S) -Benzyl-2, 2-dimethyl-yl-oxazolidinyl) -2- (4-iodopyrazol-1-yl) -ethanone To a suspension of sodium hydride washed with hexane (from 15 mg of 60% dispersion in oil, 0.38 mmol) in THF (2 mL) at 0 ° C is added a solution of pyrazole (62 mg, 0.32 mmol) in THF (1 mL) by drip via cannula. After 15 minutes at 0 ° C, a solution of 3- (2-bromoacetyl) -2,2-dimethyl-4 (S) -phenylmethyl-oxazolidine (100 mg, 0.320 mmol) in THF (1 mL) is added by cannula means After 5 minutes at 0 ° C, the mixture is allowed to stir at room temperature for 30 minutes. The resulting mixture is partitioned between EtOAc and phosphate buffer at pH7. The aqueous layer is extracted with more EtOAc. The combined organic layers are dried over Na 2 SO and concentrated to an oily residue, which crystallizes spontaneously. The crystals are triturated with MTBE / hex to obtain a white solid. The filtrate gives another crop and 100 mg in total (75%) of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidinyl) -2- (4-iodopyrazol-1-yl) -ethanone is obtained as white crystals, mp 117-20 ° C. NMR aH (DMSO-d6): d 7.76 (s, 1H), 7.51 (s, 1H), 7.37-7.24 (m, 5H), 5.25, 4.87 (quartet AB, 2H, J = 16.6 Hz), 4.35-4.30 (m, 1H), 3.86-3.81 (m, 1H), 3.76 (d, 1H, J = 8.8 Hz), 3.06 (dd, 1H, J = 4.0, 13.6Hz), 2.80 (dd, 1H, J = 9.9 , 13.6 Hz), 1.55 (s, 3H), 1.41 (s, 3H). Anal. Calculated for C17H20N3O2I: C, 48.01; H, 4.74; N, 9.88. Found: C, 48.28; H, 4.78; N, 9.79. 1- (4 (S) -Benzyl-2, 2-dimethyl-t-oxazolidinyl) -2- (4-biphenyl-4-yl-pyrazol-1-yl) -ethanone According to the procedure described in Example 1 (a) for the preparation of 3-biphenyl-4-yl-furan, 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidinyl) -2- ( 4-iodopyrazol-1-yl) -ethanone is coupled to 4-biphenylboronic acid to provide, in 39% yield, 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidinyl) -2- (4 -biphenyl-4-yl-pyrazol-1-yl) -ethanone as a white solid, mp 150-1 ° C. NMR? E: d 7.83 (s, 1H), 7.68 (s, 1H), 7.62-7.52 (m, 6H), 7.47-7.28 (m, 8H), 4.83, 4.38 (quartet AB, 2H, J = 15.6 Hz), 4.22-4.18 (m, 1H), 3.94 (m, 2H), 3.09 (dd, 1H, J = 6.4, 13. 0 Hz), 2.97 (dd, 1H, J = 8.5, 13.2 Hz), 1.79 (s, 3H), 1. 55 (s, 3H). Anal. Calculated for C29H29 3? 2: C, 77. 14; H, 6.47; N, 9.31. Found: C, 77.04; H, 6. 52; N, 9.37. 4- (4 (S) -Benci 1-2, 2-dimethyl-oxazl idin-3-yl) -3 (R) - (4-biphenyl-4-yl-pyrazol-1-yl) succinnamic To a solution of diisopropylamine (0.10 mL, 0.76 mmol) in THF (2 mL) at 0 ° C is added n-butyllithium (0.4 mL of 2.5M in hexanes). After 30 minutes at 0 ° C, the solution is added dropwise to a solution of 1- (4 (S) -benzyl-2,2-dimethyl-oxazolidinyl) -2- (4-biphenyl-4-yl-pyrazole -l-yl) -ethanone (325 mg, 0.720 mmol) in THF (8 mL) at -78 ° C. After 15 minutes at -78 ° C, the light yellow solution is cooled to -100 ° C and benzyl 2-bromoacetate (freshly passed through A1203, 0.16 mL, 1.0 mmol) is added. After 1 hour at -100 to -70 ° C, the mixture is partitioned between EtOAc and water and the aqueous layer is extracted with more EtOAc. The combined organic layers are dried over Na2SO4 and concentrated to provide an unpurified oil which is purified by flash column chromatography with elution gradient of 0-5% EtOAc / CH2Cl2 to provide 150 mg (35%) of 4- (4 (S) -benzyl-2-, 2-dimethyl-1-oxazolidin-3-yl) -3 (R) - (4-biphenyl-4-yl-pyrazol-1-yl) -synalamic acid benzyl ester as a oil, which is used without further purification. An analytical sample is obtained after trituration with MTBE / hex and dried to an amorphous solid. XH NMR. d 8.01 (s, 1H), 7.82 (s, 1H), 7. 62-7.53 (m, 7H), 7.44 (t, 2H, J = 7.7 Hz), 7.36-7.30 (m, 10H), 5.83 (dd, 1H, J = 4.2, 10.5 Hz), 4.14 (s, 2H), 4.44-4.39 (m, 1H), 3.85 (d, 1H, J = 9.2 Hz), 3.79-3.74 (m , 1H), 3.57 (dd, 1H, J = 10.3,16.9 Hz), 3.08 (dd, 1H, J = 3.1, 15.6 Hz), 2.79-2.64 (m, 2H), 1.67 (s, 3H), 1.50 (s, 3H). Anal.

Calculated for C38H37N304 • 0. 2 H20: C, 75. 65; H, 6 25; N, 6. 97. Found: C, 75.74; H, 6.56; N, 6.90.

Benzyl Ester of N- (1 (S) -Benzy-2-hydroxyethyl) -3 (R) - (4-biphenyl-4-yl-pyrazol-1-yl) -synatamic acid To a solution of 4- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -3 (R) - (4-biphenyl-4-yl-pyrazol-1-yl) benzyl ester. ) succinamic (174 mg, 0.290 mmol) in THF (3 mL) was added 0.5M aqueous HCl (1 mL). After 1 hour at room temperature without apparent reaction, 6N HCl (4 drops) is added and the mixture is heated to 45 ° C. After 17 hours, the mixture is partitioned between EtOAc and saturated aqueous NaHC03 and the aqueous layer is extracted with CH2C12. The combined organic layers are washed with water, dried over Na 2 SO and concentrated to provide 70 mg (43%) of benzyl ester of N- (1 (S) -benzyl-2-hydroxyethyl) -3 (R) - [4- (biphenyl-4-yl) pyrazol-1-yl] succinnamic as colorless crystals, m.p. 116-7 ° C. NMR? E: d 7.88 (s, 1H), 7.65 (d, 5H, J = 8.1 Hz), 7.53 (d, 2H, J = 8.1 Hz), 7.47 (t, 2H, J = 7.5 Hz), 7.37 ( t, 1H, J = 7.5 Hz), 7.34-7.23 (m, 5H), 7.19-7.13 (m, 3H), 7.01 (d, 2H, J = 7.7 Hz), 6.54 (d, 1H, J = 6.6 Hz ), 5.22 (t, 1H, J = 6.8 Hz), 5.11, 5.06 (AB quartet, 2H, J = 12.1 Hz), 4.20-4.10 (m, 1H), 3.72 (dd, 1H, J = 3.7, 11.0 Hz) ), 3.56 (dd, 1H, J = 5.2, 11.4 Hz), 3.34-3.31 (m, 2H), 2.82 (dd, 1H, J = 6.6, 13.6 Hz), 2.70 (dd, 1H, J = 8.3, 13.8 Hz). Anal. Calculated for C35H33N304 • 0.3 H20: C, 74.39; H, 5.99; N, 7.44. Found: C, 74.49; H, 6.02; N, 7.44.

Example 17 (a). Methyl ester of Acid 4- [2 (S) - (2 (R) Carboxymethyl-2- (thien-2-yl) acetylamino] -4-methyl-valeryl] -aminobenzoic acid According to the procedure described in Example 15 (a), the methyl ester of 4- [2S- (2 (R) -t-butoxycarbonylmethyl 1-2-thien-2-ylathylamino) -4-methyl- valeroyl] -aminobenzoic acid is hydrolysed with trifluoroacetic acid, apart from doing so in CH2C12: anisole (1: 1) as a solvent, to provide, in 88% yield, the methyl ester of 4- [2S- (2 (R) - carboxymethyl-2-thien-2-ylacetylamino) -4-methyl-valeroyl] -aminobenzoic acid as a white solid, mp 197-200 ° C NMR: H (DMSO-d6): d 12.25 (s, 1H), 10.32 (s, 1H), 8.52 (d, 1H, J = 7.7 Hz), 7.88 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.33 (d, 1H, J = 5.0 Hz), 6.96-6.90 (m, 2H), 4.49-4.45 (m, 1H), 4.31 (dd, 1H , J = 5.4, 9.8 Hz), 3.80 (s, 3H), 2.92 (dd, 1H, J = 9.8, 16.5 Hz), 2.61 (dd, 1H, J = 5.4, 16.6 Hz), 1.74-1.46 (m, 3H), 0.90 (d, 3H, J = 6.6 Hz), 0.86 (d, 3H, J = 6.5 Hz). Anal. Calculated for C22H26N2? 6S: C, 59.18; H, 5.87; N, 6.27; S, 7.18. Found: C, 59.28; H, 5.92; N, 6.29; S, 7.27. The starting materials were available as follows: 4 (S) -Benzyl-3- (2-thien-2-yl-acetyl) -2-oxazolidinone To a solution of (S) - (-) -4-benzyl-2-oxazolidinone (350 mg, 2.00 mmol) in dry THF (10 mL) at -30 ° C n-butyl 1-1 is added dropwise ( 2.59 M in hexanes, 0.8 mL). The mixture is cooled to -78 ° C and treated with 2-thiopheneacetyl chloride (0.25 mL, 2 mmol). After stirring at -78 ° C for 45 minutes, the mixture is allowed to warm to room temperature and stir for 1 hour. The mixture is diluted with hexanes (10 mL), quenched with 1M phosphate buffer at pH7, and stirred for 45 minutes. The layers of the resulting biphasic mixture are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with 0.5N aqueous HCl twice, with NaHCO 3 saturated twice and brine, dried over Na 2 SO 4 and concentrated to give an unpurified residue which was purified by flash column chromatography with 20% EtOAc / hex as eluent to give 319 mg (53%) of (S) -benzyl-3- (2-thien-2-yl-acetyl) -2-oxazolidinone as a tan solid, mp 56-9 ° C. 1H-NMR: d 7.34-7.26 (m, 5H), 7.17-7.14 (m, 2H), 7.02-6.98 (m, 1H), 4.72-4.67 (m, 1H), 4.57, 4.48 (quartet AB, 2H, J = 16.8 Hz), 4.26-4.17 (m, 2H), 3.29 (dd, 1H, J = 3.2, 13.4 Hz), 2.78 (dd, 1H, J = 9.5, 13.4 Hz). Anal. Calculated for C16H? 5N03S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.87; H, 5.04; N, 4.71; S, 10.74.

T-Butyl ester of 4- (4 (S) -Benzyloxazole idin-2-on-3-yl) -3 (R) -thien-2-ylsuccinamic acid In accordance with the procedure described in Example 13 for the preparation of N- (4 (S) -benzyl-2,2-dimethyl-l-oxazolidin-3-yl) -3 (R) - t-butyl ester ( biphenyl-4-yl-lH-pyrrol-3-yl) succinamic acid, the corresponding anion of 4 (S) -benzyl-3- (2-lien-2-yl-acetyl) -2-oxazolidinone is alkylated with 2- t-butyl bromoacetate. Flash column chromatography with 10% EtOAc / hex as the eluent affords, in 65% yield, the 4- (4 (S) -benzyloxazolidin-2-on-3-yl) -3-t-butyl ester ( R) -thien-2-ylsuccinamic as a white solid, mp 109-11 ° C. XH NMR: d 7.36-7.26 (m, 5 H), 7.22 (d, 1H, J = 5.0 Hz), 7.06 (d, 1H, J = 3.5 Hz), 6.93 (dd, 1H, J = 3.9, 5.2 Hz ), 5.85 (dd, 1H, J = 4.2, 11.4 Hz), 4.62-4.57 (m, 1H), 4.14-4.09 (m, 2H), 3.42-3.33 (m, 2H), 2.82-2.70 (m, 2H) ), 1.43 (s, 9H). Anal. Calculated for C22H25N05S: C, 63.60; H, 6.06; N, 3.37; S, 7.72. Found: C, 63.37; H, 6.07; N, 3.31; S, 7.69.

T-Butyl ester of Acid 2 (R) -Tien-2-yl-succinic acid To a solution of 4- (4 (S) -benzloxazolidin-2-on-3-yl) -3 (R) -thien-2-yl-succinamic acid t-butyl ester (630 mg, 1.52 mmol) in THF (15 mL) at 0 ° C is added 2N aqueous LiOH (1.14 mL). H20 is added periodically to maintain homogeneity. After 5.75 hours at 0 ° C, saturated aqueous NaHCO3 (5 mL) is added. The THF is removed under reduced pressure and the mixture is extracted with CH2C12 (5 mL) three times. The combined organic layers are extracted with saturated aqueous NaHCO 3. The combined aqueous layers are acidified to ~ pH2 using 2N aqueous HCl and extracted with CH2C12 (5 mL) three times. These extracts are dried over Na 2 SO 4 and concentrated to yield 350 mg (90%) of the 2 (R) -thien-2-yl-succinic acid 4-t-butyl ester as an oil, which is pure and is used without additional purification. 1H-NMR: d 7.22 (d, 1H, J = 5.1 Hz), 6.99 (m, 2H), 4.33 (dd, 1H, J = 5.4, 9.9 Hz), 3.11 (dd, 1H, J = 9.9, 16.7 Hz) , 2.74 (dd, 1H, J = 5.4, 16.7 Hz), 1.41 (s, 9H). IR: 2980, 2934, 1732, 1715, 1370, 1285, 1256, 1152, 843, 702 cm. "Anal." Calculated for C2H16N04S: C, 56.23; H, 6.29; S, 12.51 Found: C, 56.24; 6.35; S, 12.45.

Methyl Ester of Acid 4- [2S- (2 (R) - t-Butoxycarbonyl-2-ethyl-2-thien-2-ylacetylaraine) -4-methylvaleroyl] -aminobenzoic acid According to the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxy-yl) -3 (R) -t-butoxycarbonyl-amino acid benzyl ester succinamic acid, the 2- (R) -thien-2-yl-succinamic acid 4-t-butyl ester and the 4- (2S-amino-4-methyl-pentanoylamino) benzoic acid methyl ester methyl acid (see Castelhano, AL; Yuan, Z .; Horne, S .; Liak, TJ W095 / 12603-AI, May 11, 1995) are coupled with BOP to provide a mixture of diastereoisomers which are separated by means of flash column chromatography with a Elution gradient of 10-25% EtOAc / hex. The mixed fractions are purified by radial chromatography with MTBE / CH2Cl2 / hex (1: 5: 5) as eluent. In this way a total yield of 51% of 4- [2S- (2 (R) -t-butoxycarbonylmethyl-2-thien-2-ylacetylamino) -4-methylvaleroyl] -aminobenzoic acid methyl ester is obtained as a solid white, mp 80-l ° C 1 H NMR: d 8.72 (s, 1H), 7-95 (d, 2H, J = 8.6 Hz), 7.61 (d, 2H, J = 8.6 Hz), 6.99-6.96 ( m, 2H), 6.02 (d, 1H, J = 8.0 Hz), 4.64-4.56 (m, 1H), 4.20 (t, 1H, J = 6.2 Hz), 3.89 (s., 3H), 3.04 (d, 2H, 1 = 6.2 Hz), 1.89-1.83, (m, 1H), 1.44 (s, 9H), 0.91 (t, 6H, J = 6.2 Hz). Anal. Calculated for C26H34N206S: C, 62.13; H, 6.82; N, 5.57; S. 6.38 Found: C, 62.13; H, 6.83; N, 5.54; S, 6.46.

Example 17 (b). Acyclic Methyl Ester 4- [2 (S) - [2 (R) Carboxymethyl-2- (thien-3-yl) acetylamino] -4-methyl-valeroyl] -aminobenzoic acid According to the procedure described in Example 17 (a), the methyl ester of 4- [2S- (2 (R) -t-butoxycarbonylmethyl-2-thien-3-ylacetylamino) -4-mctyl- methyl ester valeroyl] -aminobenzoic acid is hydrolyzed with trifluoroacetic acid in CH2C12: anisole (1: 1) to provide, in 88% yield, the methyl ester of 4- [2S- (2 (R) -carboxymethyl-2-t- 2-ylacetylamino) -4-methyl-yl-valeroyl] -aminobenzoic acid as a white solid, mp 199-201 ° C NMR IE (DMS0-d6): d 12. 15 (s, 1H), 10.31 (s, 1H), 8.43 (d, 1H, j = 7.5 Hz), 7. 89 (d, 2H, J = 8.6 Hz), 7.68 (d, H), J = 8.7 Hz), 7.44-7.41 (m, 1H), 7.25 (d, 1H, J = 2.5 Hz), 7.09 ( d, 1H, J = 4.1 Hz), 4.48-4.45 (m, 1H), 4.08 (dd, 1H, J = 4.8, 10.2 Hz), 3.80 (s, 3H), 2.89 (dd, 1H, J = 10.3, 16.5 Hz), 2.61 (dd, 1H, J = 5.0, 16.6 Hz), 1.75-1.44 (m, 3H), 0.90 (d, 3H, J = 6.6 Hz), 0.86 (d, 3H, J = 6.5 Hz). Anal.

Calculated for C22H26N206S: C, 59.18; H, 5.87; N, 6.27; S, 7.18. Found: C, 59.21; H, 5.92; N, 6.21; S, 7.25. The starting materials were available as follows: 4 (S) -Benzyl-3- (2-thien-3-yl-acetyl) -2-oxazolidinone According to the procedure described in Example 17 (a) for the preparation of 4 (S) -benzyl-3- (2-thien-2-yl-acetyl) -2-oxazolidinone, the 3-thiopheneacetyl chloride and the (S) - (-) -4-benzyl-2-oxazolidinone provides, in 68% yield, 4 (S) -benzyl-3- (2-thien-3-yl-acetyl) -2-oxazolidinone as a solid , pf 80- c. NMR? E: d 7.33-7.24 (m, 5H), 7.15-7.09 (m, 3H), 4.72-4.65 (m, 1H), 4.39, 4.28 (quartet AB, 2H, J = 15.9 Hz), 4.22-4.15 (m, 2H), 3.26 (dd, 1H, J = 3.2, 13.4 Hz), 2.77 (dd, 1H, J = 9.4, 13.4 Hz). Anal.

Calculated for d6H15N03S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.80; H, 5.04; N, 4.69; S, 10.70. 4- (4 (S) -Bezyloxazolidin-2-yn-3-yl) -3 (R) -thien-3-ylsuccinamic acid t-Butyl ester According to the procedure described in Example 13 for the preparation of N- (4 (S) -benzyl-2,2-dimethyl-oxazolidin-3-yl) -3 (R) - (biphenyl) t-butyl ester -4-yl-lH-pyrrol-3-yl) succinamic acid, the corresponding anion of 4 (S) -benzyl-3- (2-thien-3-yl-acetyl) -2-oxazolidinone is alkylated with 2-bromoacetate of t-butyl. Flash column chromatography with 10% EtOAc / hex as eluent affords, in 77% yield, the 4- (4 (S) -benzyloxazolidin-2-on-3-yl) -3-t-butyl ester ( R) -thien-2-ylsuccinamic as a white solid, mp 103-4 ° C 1 H NMR: d 7.36-7.25 (m, 7H), 7.10 (t, 1H, J = 3.2 Hz), 5.64 (dd, 1H, J = 4.4, 11.2 Hz), 4.62- 4.57 (m, 1H), 4.14-4.04 (m, 2H), 3.39-3.27 (m, 2H), 2.78 (dd, 1H, J = 10.0, 13.4 Hz), 2.63 (dd, 1H, J = 4.4, 17.1 Hz), 1.43 (s, 9H). Anal. Calculated for C22H24N05S: C, 63.60; H, 6.06; N, 3.37; S, 7.72. Found: C, 63.44; H. 6.09; N, 3.33; S, 7.78. 4-t-Butyl ester of 2 (R) -Tien-3-yl-succinic acid According to the procedure described in Example 17 (a) for the preparation of 2 (R) -thien-2-yl-succinic acid 4-t-butyl ester, the 4- (4 S) -benzyloxazolidin-2-on-3-yl) -3 (R) -thien-3-yl-succinamic acid is hydrolyzed, to provide in 70% yield, the t-butyl ester of acid 2 (R) -t ien-3-yl-succinic as an oil, which is used without further purification.

NMR tE: d 7.29 (dd, 1H, J = 3.0, 4.9 Hz), 7.17 (dL 1H, J = 2.7 Hz), 7.05 (d, 1H, J = 5.0 Hz), 4.18 (dd, 1H, J = 5.5, 9.8 Hz), 3.06 (dd, 1H, J = 9.9, 16.7 Hz), 2.66 (dd, 1H, J = 5.6, 16.7 Hz), 1.40 (s 9H). IR: 3104, 2978, 2934, 1728, 1715, 1370, 1258, 1154, 855, 774 cm "1.

Anal. Calculated for Ci2H? 6N04S: C, 56.23; H, 6.29; S, 12. 51. Found: C, 56.29; H, 6.35; S, 12.42.

Methyl Ester of 4- [2S- (2 (R) -t-Butoxycarbonyl-2-thien-3-ylacetylamino) -4-methylvaleroyl] -aminobenzoic acid In accordance with the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxy-ethyl) -3 (R) -t-butoxycarbonyl-anino-succinamic acid 4-t-butyl ester, the ester 4 2 (R) -thien-3-yl-succinamic acid t-butyl ester and 4- (2S-amino-4-methyl-pentanoylamino) benzoic acid methyl ester (see Castellano, AL; Yuan, Z; Horne, S .; Liak, TJ W095 / 12603-A1, May 11, 1995) are coupled with BOP. Precipitation with H20 and recrystallization from toluene provide, in 55% yield, the methyl ester of 4- [2S- (2 (R) -t-butoxy-carbonylmethyl-2-thien-3-ylacetylamino) -4- methylvaleroyl] -aminobenzoic acid as a white solid, mp 168-70 ° C. NMR? E: d 8.62 (s, 1H), 7.96 (d, 2H, J = 8.6 Hz), 7.56 (d, 2H, J = 8.8 Hz), 7.33 (dd, 1H, J = 3.0, 4.8 Hz), 7.19 (s, 1H), 7.02 (d, 1H, J = 5.1 Hz), 5.86 (broad d, 1H, J = 6.7 Hz), 4.57-4.51 (m, 1H), 4.04 (t, 1H, J = 6.6 Hz), 3.89 (s, 3H), 3.04 (dd, 1H, J = 7.4.16.9 Hz), 2.88 (dd, 1H, J = 5.6, 16.9 Hz), 1.88-1.81 (m, 1H), 1.42 (s, 9H), 0.92 (t, 6H, J = 6.5 Hz). Anal. Calculated for C26H34N206S: C, 62.13; H, 6.82; N, 5.57; S, 6.38 Found: C, 62.08; H, 6.79; N, 5.64; S, 6.46.

Example 17 (c). N- [2, 2-Dimethyl-1 (S) - (pyridin-4 i 1 carbamoyl) -propyl] -3 (R) -ti acid in -3-yl-succinic acid According to the procedure described in Example 17 (a), the t-butyl ester of N- [2, 2-dimethyl-1 (S) - (pyridin-4-ylcarbamoyl) -propyl] -3 (RS) -tien-3-yl-succinámico is deprotected. Flash column chromatography with 1% HOAc / 5% MeOH / CH2Cl2 as eluent leads to isolation of the major isomer; 15 mg (21%) of N- [2,2-dimethyl-l (S) -pridin-4-ylcarbamoyl) -propyl] -3 (R) -thien-3-yl-succinnamic acid as a white solid, m.p. 205 ° C (d). 2 H NMR (DMSO-de): d 8.30 (d, 2H, J = 6.0 Hz), 7.45 (dd, 2H, J = 1.5, 6.0 Hz), 7.26 (dd, 1H, J = 3.0, 5.0 Hz), 7.21 -7.18 (m, 1H), 7.04 (dd, 1H, J = 1.0, 5.0 Hz), 4.38 (s, 1H), 4.26 (dd, 1H, J = 5.0, 10.0 Hz), 3.04 (dd, 1H, J = 10.0, 16.5 Hz), 2.65 (dd, 1H, J = 5.0, 16.5 Hz), 1.01 (s, 9H). Anal. Calculated for C? 9H23N304S • 0.6 HOAc: C, 57.02; H, 6.02; N, 9.88; S, 7.54. Found: C, 56.99; H, 6.06; N, 9.88; S, 7.55.

The starting material is prepared as follows T-Butyl Ester of N- [2, 2-Dimethyl-l (S) - (pyridin-4-ylcarbamoyl) -propyl] -3 (RS) -thien-3-ylsuccinamic acid According to the procedure described in Example 1 (f) for the preparation of N- (1 (S) -benzyl-2-methoxy-ethyl) -3 (R) -t-butoxycarbonylamino-succinamic acid benzyl ester, the 4-t-butyl ester of 2 (R) -thien-3-yl-succinamic acid (prepared as described in Example 17 (b)) and 2S-amino-3, 3-dimethyl-N-4- pyridinyl-butanamide (prepared as described in Example 5 (d)) are coupled with BOP for 48 hours at room temperature. Flash column chromatography with 10% MeOH in CH C12 provides 718 mg (39%) of N- [2,2-dimethyl-l (S) - (pyridin-4-yl-carbamoyl) t-butyl ester -propyl] -3 (RS) -thien-3-ylsuccinamic as a white solid, mp 205 ° C (d), which is an inseparable mixture of isomers by NMR (3 (R): S; 87:13, respectively) and used without further purification. XH NMR (DMSO-d6): d 8.48 (d, 1.74H, J = 5.5 Hz, major isomer), 8.38 (d, 0.87H, J = 9.0 Hz, major isomer), 7.65 (d, 1.74H, J = 5.5 HZ, major isomer), 7.59 (d, 0.26H, J = 5.0 Hz, minor isomer), 7.49 (dd, 0.87H, J = 3.0, 4.0 HZ, major isomer), 7.43 (m, 0.87H, major isomer) ), 7.30 (m, 0.13H, minor isomer), 7.23 (d, 0.87H, J = 5.0 Hz, major isomer), 7.12 (d, 0.13H, J = 5.0 Hz, minor isomer), 4.52 (d, 0.87) H, J = 9.0 Hz, major isomer), 4.37 (dd, 0.87H, J = 5.0, 10.0 Hz, major isomer), 4.08 (dd, 0.13H, J = 7.0, 15.5 Hz, minor isomer), 3.00 (dd) , 0.87H, J = 10.0, 16.0 Hz, major isomer), 1.40 (s, 1.17H, minor isomer), 1.29 (s, 7.83H, major isomer), 1.03 (s, 0.13H, minor isomer), 0.84 ( s, 7.83H, major isomer).

Example 18 (a). Acid 3 (RS) - (3-Biphenyl-4-yl-lH-imidazol-1-yl) -N- (hexahydroazepin-2-on-3 (S) -yl) succinamic acid According to the procedure described in Example 1 (a), a suspension of 3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N- (hexahydroazepin-2) benzyl ester -on-3 (S) -yl) succinamic in EtOH is hydrogenated after 90 minutes to give 779 mg (94%) of 3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) acid ) -N- (hexahydroazepin-2-on-3 (S) -yl) succinamic as a solid. EMFAB: 447 (C 25 H 27 N 404; M + H +). The starting material is prepared as follows: Dibenzyl Ester of Acid 2 (RS) - (3-Bifenyl-4-yl-lH-imidazol-1-yl) -succinic ester A mixture of dibenzyl fumarate (5.30 g, 18.0 mmol) and 4-biphenyl-4-yl-lH-midazole (see Ellis, et al.

Pharm. Pharmacol. 1964, 400-3; 3.94 g, 18.0 mmol) is heated to 110-5 ° C. After 4 hours, the mixture is allowed to cool, is diluted with ether, washed with 0.05% aqueous HCl, Aqueous 0.01N NaOH and brine, dried over Na2SO and concentrated under reduced pressure to provide 5.75 g (62%) of 2 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -succinic acid dibenzyl ester. EMFAB: 517.3 (C33H29N20,; M + H +). 4-Benzyl Ester of Acid 2 (RS) - (3-Bifenyl-4-yl-1H-imidazol-1-yl) -succinic ester A suspension of 2 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -succinic acid dibenzyl ester (551 mg, 1.07 mmol) in H20 (0.5 mL) is brought to reflux during the night. Once it is allowed to cool to room temperature, the resulting precipitate is collected and dried in vacuo to provide 436 mg (96%) of 2 (RS) - (3-biphenyl-4-yl-1H-imidazole benzyl ester -l-il) -succinic. EMFAB: 427 (C 26 H 23 N 204; M + H +).

Benzyl Ester of Acid 3 (RS) - (3-Bifenyl-4-yl-lH-iraidazol-1-yl) -N- (hexahydroazepin-2-on-3 (S) -yl) succinámico According to the procedure described in Example 8 (a), the 4-benzyl ester of 2 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -succinic acid (1.20 g, 2.82 mmoles) and La-amino-e-caprolactam (469 mg, 3.67 mmol) are coupled in DMF with pyBOP to provide 1.02 g (67%) of 3 (RS) - (3-biphenyl-4-yl) benzyl ester -lH-imidazol-1-yl) -N- (hexahydroazepin-2-on-3 (S) -yl) succinamic acid. EMFAB: 537.5 (C 32 H 33 N 404; M + H +). The following is prepared in a similar way: Example 18 (b). Acid 3 (RS) - (3-Biphenyl-4-yl-lH-imidazol-1-yl) -N- (2, 2-dimethyl-l (S) -hydroxymethylpropyl) -succinnamic acid In accordance with the procedure described in Example 1 (a), a suspension of 3 (RS) - (3-bi phenyl-4-yl-lH-imidazol-1-yl) -N- (2) benzyl ester , 2-dimethyl-1 (S) -hydroxymethylpropyl) succinnamic acid in EtOH is hydrogenated to give the acid 3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N- (2, 2 -dimethyl-l (S) -hydroxymethylpropyl) -succinnamic acid as a solid, mp 145-50 ° C. EMFAB: 436.1 (C2sH33N304; + H +).

Example 18 (c). Acid 3 (RS) - (3-Bifenyl-4-yl-lH-imidazol-1-i]) -N- (2,2-dimethyl-l (S) -methylcarbamoylpropyl) -succinic acid According to the procedure described in Example 1 (a), a suspension of 3 (RS) - (3-bi phenyl-4-yl-lH-imidazol-1-yl) -N- (2, benzyl) benzyl ester 2-Dimethyl-1 (S) -methylcarbamoylpropyl) succinamic in ETOH is hydrogenated to give 3 (RS) - (3-biphenyl-4-yl-lH-inudazol-1-yl) -N- (2, 2-dimethyl) acid -l (S) -met ilcarbamoylpropyl) succinnamic as a solid, mp 187.0-8.2 ° C EMFAB: 463.2 (C26H3? N404; M + H +).

Example 19 (a). 3 (RS) - (3-Biphenyl-4-yl-lH-imidazol-1-yl) -N 4 - (2, 2-dimethyl-l (S) -hydroxymethylpropyl) -N 1 -hydroxy-succindyamide A suspension of N1-benzyloxy-3 (RS) - (3-biphenyl-4-yl-lH-imidazol-l-yl) -N4- (hexahydroazepin-2-on-3 (S) -yl) -succindyamide without purification (800 mg, 1.45 mmol) and 10% Pd / C (800 mg) in ETOH (100 mL) are stirred under H2 atmosphere. After 6 hours, more catalyst (300 mg) is added. After 2 hours, the catalyst is filtered over Celite and rinsed. The filtrate is concentrated to provide 301 mg (45%) of 3 (RS) - (3-bi-phenyl-1-4-y1-lH-imidazol-1-y1) -N- (hexahydroazepin-2-on-3 (S) -yl) -N-hydroxy-succindyamide as a solid, which enters effervescence at 180.5 ° C EMFAB: 462.2 (C2sH28N504; M + H +). The starting materials are prepared as follows: N ^ Benzyloxy-S (RS) - (3-biphenyl-4-yl-lH-imidazol-1 -i 1 N4 hexahydro a z epin-2-on-3 (S) -i l) - succ indi amide According to the procedures described in Example 8 (a), the acid 3 (RS) - (3-bi phenyl-4-i 1- 1 H-imidazol-1-yl) -N- (hexahydroazepin-2-on- 3 (S) -yl) succinamic acid (prepared as described in Example 18 (a): 779 mg, 1.74 mmol) and benzyloxyamine hydrochloride (334 mg, 2.09 mmol) are coupled with pyBOP to provide 800 mg (83%) ) of N 1 -benzyloxy-3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N 4 - (hexahydroazepin-2-on-3 (S) -yl) -succindyamide. EMFAB: 552.2 (C 32 H 34 N 504; M + H +). The following is prepared in a similar way: Example 19 (b). 3 (RS) - (3-Biphenyl-4-yl-lH-imidazol-1-yl) -N4- (2, 2-dimethyl-l (S) -hydroxymethylpropyl) -N1-hydroxy-succindyamide According to the procedure described in Example 19 (a), N-benzyloxy-S (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N4- (2, 2-dimethyl) -l (S) -hydroxymethylpropyl) -succidiamide is selectively hydrogenated to provide 3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N4- (2, 2-dimethyl- l (S) -hydroxymethylpropyl) -N-hydroxy-succindyamide EMFAB 451.3 (C25H31N4O4; M + H +).

Example 19 (c). 3 (R) - (3-Biphenyl-yl-lH-imidazol-1-yl) N4- (2, 2-dimethyl-l (S) -hydroxymethylpropyl) -N1-hydroxy -succindyamide The diastereoisomeric mixture of N 1 -benzyloxy-3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N 4 - (2, 2-dimethyl-1 (S) -hydroxymethylpropyl) -succindyamide ( Example 19 (b)) is purified by means of preparative RPCLAP (C18) to provide 3 (R) - (3-biphenyl-4-yl-lH-imide zol-1-yl) -N- (2,2-dimethyl) -l (S) -hydroxymethylpropyl) -N1-hydroxy-succindyamide as a solid, mp 157.5-60 ° C EMFAB: 451.2 (C25H31N4O4; M + H +).

Example 19 (d). 3 (S) - (3-Biphenyl-4-yl-lH-imidazol-1-yl) N 4 - (2, 2-dimethyl-l (S) -hydroxymethylpropyl) -N 1 -hydroxy -succindyamide The separation of Example 19 (b), described in Example 19 (c), also provides 3 (S) - (3-bi phenyl-4-yl-lH-imidazol-1-yl) -N- (2, 2 -dimethyl-l (S) -hydroxymethylpropyl) -N-hydroxysuccinamide as a solid, mp 134.5-6.5 ° C. EMFAB: 451.1 (C25H3iN4? 4; M + M.

Example 19 (e). 3 (RS) - (3-Biphenyl-4-yl-lH-imidazol-1-yl) N4- (2, 2-dimethyl-l (S) -methylcarbamoylpropyl) -N1-hydroxy-succindyamide According to the procedure described in Example 19 (a), N1-benzyloxy-3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N4- (2, 2-dimethyl-l (S) -methylcarbamoylpropyl) -succindyamide to give 3 (RS) - (3-biphenyl-4-yl-lH-imidazol-1-yl) -N4- (2, 2-dimethyl-l ( S) -methylcarbamoylpropyl) -Ni-hydroxy-succindiamide as a solid, which enters effervescence at 169 ° C EMFAB: 478.2 (C26H32 5O4; M + H +). The results obtained during the biological testing of some preferred embodiments of the inventive compounds are described below.

BIOLOGICAL DATA Isolation of MMPs for Analysis The catalytic domain of human collagenase-1 is expressed as a fusion protein with ubiquitin in E. col i (see Gehring, E.R., J Biol. Ch em., 1995, 270, 22507). After purification of the fusion protein, the catalytic domain of fibroblast collagenase-1 (HFC) is released either by treatment with active, purified-1 (1:50 ratio w / w), which generates almost 100% N-terminal Phel, or by self-processing the concentrated collagenase-1 fusion and then incubating at 37 ° C for 1 hour. The final purification is completed by using zinc chelate chromatography. The propeptide and the catalytic domain of human collagenase-3 (Coll3) is expressed in E. col i as an N-terminal fusion protein with ubiquitin. After purification of the fusion from the inclusion bodies, the catalytic domain is released by treatment with 2mM APMA at room temperature overnight. The final purification is completed by using copper chelate chromatography. The catalytic domain of human thromelysin (Hsln) is obtained by the expression and purification of a prostromelysin-1 terminally truncated with C from host BL21 of E. col i (see Marcy et al. Bi och em, 1991, 30, 6476). Subsequent activation of the mature form (Hsln) is completed with 2mM APMA for 1 hour at 37 ° C, followed by separation using a sizing column. Human matrilysin (Matr) is expressed in E. col i as a fusion protein with ubiquitin. After purification of the matrilysin / ubiquitin fusion from the inclusion bodies, the catalytic domain is released by treatment with 2mM APMA at 37 ° C for 2 hours. The final purification is completed by using copper chelate chromatography. The catalytic and fibronectin-like portion of human progelatinase A (GelA) is expressed as a fusion protein with ubiquitin in E. Col i. The analyzes are carried out in autocatalytically activated material. The compounds of Formula I exhibit the ability to inhibit MMPs when tested in the following analysis.

In Viral Analysis Procedure The analyzes are performed in analysis buffer (50 mM Tricine at pH 7.5, 200 mM sodium chloride, 10 mM calcium chloride, 0.5 mM zinc acetate, containing 2% dimethyl sulfoxide (DMSO) once the substrate and the inhibitor are diluted therein. The stock solutions of the inhibitors are prepared in 100% DMSO. The stock solutions of the substrate are prepared in 100% DMSO at a concentration of 6 mM. The method of analysis is based on the hydrolysis of MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2 (American Peptide Co.) at 37 ° C (see Knight, CG et al., FEBS, 1992, 296, 263-266). Fluorescence changes are monitored with a Perkin-Elmer LS-50B fluorimeter that uses an excitation wavelength of 328 nm and an emission wavelength of 393 nm. The substrate concentration used in the analyzes is 10 μM. The inhibitor is diluted in the analysis of a solution in 100% DMSO and the controls replace an equal volume of DMSO in such a way that the final concentration of DMSO, from the inhibitor and the dilution of the substrate in all the analyzes, is of 2%. The concentration of the enzyme in the analysis ranges from 60 pM for the gelatinase A to 1.5 nM for the thromelysin and is a function of the respective kcat / Km enzymes for the MCA peptide substrate. The proper determination of the steady state velocities of the substrate decomposition requires 60 minute analysis periods to allow complete equalization of the enzyme inhibitor complex. The Km for the peptide substrate of MCA with the matrix metalloproteinases is quite high and exceeds its solubility under analysis conditions. Therefore, the Kx (Ki, apparent app is determined to describe the inhibiting resistance.) However, in this case, K1 / app would be essentially equal to Kx after [S] «Km. For the determination of Kirapp, the concentration The inhibitor is varied to a constant and the low concentration of the substrate and the steady state rates of fluorescence change are determined.In the majority of cases no abrupt absorbent cooling is observed due to the presence of ligand. At low fixation, the inhibition initiation curves are ordered for at least 45 minutes in such a way that equilibrium is established.The steady state velocities of the fluorescence change are obtained by fitting a curve to an equation for a simple exponential decay that contains a linear phase.The adjusted value of the linear phase is taken as the steady-state velocity.The steady-state velocities are adjusted to the Michaelis equation that describes competitive inhibition by non-linear methods. The data resulting from the inhibition of tight fixation are analyzed and the Ki, app is determined by fitting the data to Morrison's narrow fixation equation (Bi och em Bi ophys. Ac ta, vol 185, p. 269-286 (1969)) by non-linear methods. The results of the tests described above are presented in the following Table 1.

TABLE 1 Determination of the Inhibitory Concentration in Plasma after Oral Dosing The dosing solution consists of the dissolved inhibitor in either a molar equivalent of HCl in water (vehicle A), in 60% propylene glycol ac. (vehicle B), or in 2.8 mg / mL of sodium bicarbonate in 60% aqueous propylene glycol (vehicle C), producing a final concentration ranging from 10-15 mg / ml. Sprague Dawley rats (Hilltop Lab Animáis, Scottsdale, PA) were dosed as a drug function in weight per body weight, usually 50 mg per kg. Blood is drawn from the rats and centrifuged, and the plasma is stored in the freezer. The drug is extracted from about 50 μl of aliquot of plasma to add 1 ml of acetonitrile, stirring for 2 minutes, centrifuging for 15 minutes at 4000 rpm, collecting the supernatant and then evaporating to dryness under a stream of nitrogen. The samples are reconstituted with 130 μl of mobile phase, shaken for 2 minutes and centrifuged for 15 minutes at 4000 rpm. the supernatant is collected and the samples are analyzed by injecting 100 μl of supernatant into CLAP.

The quantification of drug levels is carried out by generating a standard curve of known amounts of drug that are extracted from the aggregated plasma. Drug levels are plotted as a function of time and analyzed to provide the area under the curve (AUC) and the concentration values (Cmax). The results are shown in Table 2.

TABLE 2 * dosed as the benzyl ester prodrug

Claims

CLAIMS A compound of Formula I characterized in that X is a single bond or a saturated or unsaturated, linear or branched chain containing from 1 to 6 carbon atoms, wherein one or more of the carbon atoms is optionally independently replaced with O, or S, and wherein one or more of the hydrogen atoms are optionally replaced with F; And it is a simple bond, -CH (OH) -, or -C (O) -; Ri is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; R 2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C (O) R 0 wherein Rio is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR? Ri2; where Rn is H, an alkyl group, a group

O-alkyl, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R 12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein Rn and Ri2 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and R3 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NRnR? 2, or ORU wherein Rn and R12 are as defined above, or R2 and R3, together with the atom or atoms to which they are attached, they form a cycloalkyl group or a heterocycloalkyl group; R4 is H or any suitable organic portion; R5 is C (0) NHOH, C (0) 0Ri3, SH, N (0H) CH0, SC (0) R? 4, P (0) (0H) R? 5, or P (0) (0H) 0R13; R 13 is H, an alkyl group, or an aryl group, R 14 is an alkyl group or an aryl group, and Ris is an alkyl group; y / ÍMT V is a heterohydro 9ruP that has five atoms ^^ in the ring, which include 1, 2 or 3 heteroatoms selected from 0, S and N; or a pharmaceutically acceptable salt and solvate thereof, the prodrugs are different from a compound of the formula (I); with the proviso that the compound of the formula (I) is: wherein Ri, R4 and Rs are as defined above, W is H, OH, a halo group, an alkyl group, or an O-alkyl group, and also wherein when m is 2, 3 or 4, n be 1, 2, 3 6 4, and A is CH2, 0, NH, or N-alkyl; or when m is 4, 5 or 6, n is 0, and A is -CHJ-, where J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I); then it is pyrrolyl.
2. A compound according to claim 1, characterized in that X is a single bond; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
3. A compound according to claim 1, characterized in that Y is -CH (OH) - or C (O) -; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
4. A compound according to claim 3, characterized in that Y is -CH (OH) - and R3 is H or an alkyl group or together with R2 and the atom or atoms to which R2 and R3 are attached forms a cycloalkyl group or a Heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
5. A compound according to claim 4, characterized in that Y is -CH (OH) - and R3 is H; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I).
6. A compound according to claim 3, characterized in that Y is -C (O) - and R3 is an alkyl group, NRuR? 2, or ORn, wherein Rn is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, an cycloalkyl group, or a heterocycloalkyl group, and wherein Ri2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein Ri and Ri2 form, together with the nitrogen to which are attached, a heteroaryl group or a heterocycloalkyl group; or wherein Y is -C (O) - and R2 and R3, together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
7. A compound according to claim 1, characterized in that R is an aryl group or a heteroaryl group; or an acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
8. A compound according to claim 7, characterized in that R is an aryl group of the formula: wherein Z is H, halogen, an alkyl group, an O-alkyl group, a cyano group, a hydroxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
9. A compound according to claim 1, characterized in that R2 is an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
10. A compound according to claim 1, characterized in that R4 is H, an alkyl group, OH, O-alkyl, NH2, NH-alkyl, or a cycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
11. A compound according to claim 10, characterized in that R4 is an alkyl group selected from CHR? 6OH and CH (NHRi7) R16, wherein Ri6 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group and Ri7 is C (0) R? 8, S02R? 8, h, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or Rie and Ri7, together with the atoms to which they are attached, forms a heterocycloalkyl group; wherein R a is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, a 0-alkyl group, or NR? 9 R 20; wherein Ri9 and R20 independently are H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or Ri9 and R20, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
12. A compound according to claim 1, characterized in that is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
13. A compound according to claim 12, characterized in that is pyrrolyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the Formula (I)
14. A compound according to claim 1, characterized in that R5 is C (0) NHOH or C (0) OR? 3, wherein Ri3 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
15. A compound according to claim 1, characterized in that Y is a single bond and R 3 is a heteroaryl group.
16. A compound according to claim 15, characterized in that R3 is the heteroaryl group: where R2? and R22 are independently any suitable organic moiety or together with the carbon atoms to which they are attached form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I) •
17. A compound according to claim 16, characterized in that R2i and R22 are independently selected from hydrogen, an alkyl group, an aryl group, a heteroaryl group, a halo group, a C (O) O-alkyl group, a carbamoyl group, a cycloalkyl group, or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (I).
A compound of Formula I characterized in that X is a simple bond; And it is a simple bond, -CH (OH) -, or -C (0) -; Ri is an aryl group or a heteroaryl group; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C (O) R? 0, wherein Rio is H, an alkyl group, an aryl group, a heteroaryl group , a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NRnR? 2; wherein R p is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein Ri 2 is H, an alkyl group, an aryl group, a group heteroaryl, a cycloalkyl group, or a heterocycloalkyl group, or wherein Rn and Ri2 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and R3 is H, an alkyl group, a heteroaryl group, wherein Rn and R12 are as defined above, or R2 and R3, together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R 4 is H, an alkyl group, or OH; R5 is C (0) NH0H, C (0) OR? 3, SH, or SC (0) R? 4; where R13 is H, an alkyl group, or an aryl group, and R14 is an alkyl group or an aryl group, and is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of Formula (III); with the proviso that the compound of the formula (I) is: wherein Ri, R4 and R5 are as defined above, W is H, OH, a halogen atom, an alkyl group, or an O-alkyl group, and furthermore where when m is 2, 3 or 4, n is 1, 2, 3 or 4, A is CH2, O, NH, or N-alkyl; or when m is 4, 5 or 6, n is 0, and A is -CHJ-, where J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I); then it is pyrrolyl.
19. A compound selected from the group: N- [2, 2-Dimethyl-1 (S) - (methylcarbamoyl) -propyl] -3 (R) - (3-phenyl-1H-pyrrol-1-yl) -succinamic acid; N- (8-Oxo-4-oxa-l, 7-diazatricyclo- [9.6.1.012'17] octadeca-ll (18), 12, 14, 16-tetraen-9 (S) -yl) -3 ( R) - (3-phenyl-lH-pyrrol-1-yl) succinamic; N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (R) - [3- (pyridin-4-yl) -lH-pyrrol-1-yl] succinamic acid; 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinamic acid; Acid 3 (R) - [3- (Biphenyl-4-yl) -lH-pyrrol-1-yl] -N- [2-hydroxy-1 (S) - [(1H-imidazole-4-yl) methyl) ] ethyl] -succinnamic; N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (R) - [3- (4-propylphenyl) -lH-pyrrol-1-yl] -succinamic acid; 3 (R) - [3- (4-Cyano-phenyl) -lH-pyrrol-1-yl] -N- [2,2-dimethyl-l (S) - (methylcarbamoyl) propyl] succinamic acid; N- [2, 2-Dimethyl-l (S) - (hydroxymethyl) -propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl acid ] succinamic; N- (2-Hydroxy-1 (S) -phenylethyl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] -sycinnamic acid; 3 (R) - [3- (4'-Cyanobifeni-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] acid succinamic; 3 (R) - [3- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (pyridin-4-ylcarbamoyl) acid ) -propyl] succinámico; Acid 3 (R) - [3- (4 '-Carbarmoylbi phenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] succinamic; 3 (R) - [3- (4'-Carbamoylbifeni-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (pyridin-4-yl) acid carbamoyl) propyl] succinamic; 3 (R) - [3- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-1-yl] -N- [2, 2-dimethyl-l (S) - (hydroxymethyl) propyl] succinamic acid; N- (2 (R) -Hydroxyindan-1 (R) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinamic acid; N- (2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl) -3 (R) - [3- (4- (pyridin-4-yl) phenyl) -lH-pyrrol-l-yl acid ) succinamic; N- (4,4-Dimethyl-2-oxo-tetrahydrofuran-3 (S) -yl) -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1 acid -yl] succinamic; N- (8-Oxo-4-oxa-l, 7-diazatricyclo- [9.6.1.012'17] octadeca-ll (18), 12, 14, 16-tetraen-9 (S) -yl) -3 ( R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol-1-yl] succinnamic; N- [2, 2-Dimethyl-l (S) -pyridin-4-ylcarbamoyl) -propyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrol- acid 1-yl] succinamic; N- [1 (S) - (1H- Imidazo 1-2 -i 1) -3-methylbutyl] -3 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole acid -1-yl] succinamic; N1- [2, 2-Dimethyl-l (S) - (hydroxymethyl) propyl] -N4-hydroxy-2 (R) - [3- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-1 -yl] succinamide; N- [2, 2-Dimethyl-l (S) - (methylcarbamoyl) -propyl] -3 (S) - [1- (4-fluoro-phenyl) -lH-pyrro-1-3-yl] -sycinnamic acid; 3 (S) - [1- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-3-yl] -N- [2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl] acid succinamic; 3 (S) - [1- (4'-Cyanobiphenyl-4-yl) -1H-pyrro1-3-yl] -N- [1 (S) - (lH-imidazol-2-yl) -3-methylbutyl acid ] -succinámico; Acid 3 (S) - [1- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-3-yl] -N- (4, 4 -dimethyl-2-oxo-tetrahydro furan-3 (S) -yl) succinamic; Acid 3 (R) - [3- (4'-Cyanobifeni 1-4-yl) -1H-pyrrol-1-yl] -N- [1 (S) - (lH-imidazol-2-yl) -3- methylbutyl] -succinnamic; 3 (R) - [3- (4-Cyano-phenyl) -lH-pyrrol-1-yl] -N- [l (S) - (1H-imidazol-2-yl) -3-methyl-butyl] -succinamic acid; N- [2, 2-Dimethyl-l (S) - (hydroxymethyl) -propyl] -3 (S) - [l- [4- (pyridin-4-yl) phenyl] -lH-pyrrole-3-yl acid ] succinamic; Acid 3 (R) -. { 3- [2- (4-Cyanopheni 1) ethynyl] -1H-pyrrol-1-yl} -N- [2, 2-dimethyl-l (S) (methylcarbamoyl) -propyl] succinnamic; Acid 3 (R) -. { 3- [2- (4-Cyanophenyl) ethyl] -1H-pyrrol-1-yl} -N- [2, 2-dimethyl-l (S) (methylcarbamoyl) -propyl] succinnamic; N 1 -hydroxy-N 4 -methyl-3 (R) - [3- (4- (pyridin-4-yl) phenyl) -IH-pyrrol-1-yl] succinamide; Acid 3 (R) - [3- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-1-yl] -2 (S) -cyclopropyl-N- (2, 2-dimethyl-1 (S) (methylcarbamoyl) propyl) succinamic; 3 (S) - [2- (4'-Cyanobi phenyl-4-yl) furan-4-yl] -N- [2, 2-dimeti-1 (S) - (methylcarbamoyl) propyl] -succinnamic acid; 3 (S) - [1- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-3-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) acid -2 (R) - (hydroxymethyl) succinamic; 3 (S) - [1- (4 »-Cianobiphenyl-4-yl) -1H-pyrrol-3-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) - acid 2 (S) - (hydroxy) succinamic; 3 (R) - [3- (4'-Cyanobi phenyl-4-yl) -1H-pyrrol-1-yl] -N- (2, 2-dimethyl-l (S) - (methylcarbamoyl) -propyl) acid -2 (S) - (hydroxy) succinamic; and the pharmaceutically acceptable salts and solvates thereof, and the pharmaceutically acceptable prodrugs thereof.
20. A pharmaceutical composition, characterized in that it comprises: (a) a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I); and (b) a pharmaceutically acceptable carrier, diluent, carrier, or excipient.
21. A method for treating a disease condition of a mammal, mediated by metalloproteinase activity, characterized in that it comprises administering, to a mammal in need thereof, a therapeutically effective amount of a compound as defined in claim 1 or a salt pharmaceutically acceptable or solvate thereof, or a pharmaceutically acceptable prodrug thereof, the prodrug is different from a compound of the formula (I).
22. A method according to claim 21, characterized in that the disease condition of the mammal is growth, invasion or tumor metastasis.
23. A method, according to claim 21, characterized in that the disease condition of the mammal is osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis or gingivitis.
24. A method according to claim 21, characterized in that the disease condition of the mammal is chronic dermal lesions, corneal ulceration, or degenerative skin disorders.
25. A method according to claim 21, characterized in that the disease condition of the mammal is multiple sclerosis or apoplectic attack.
26. A method according to claim 21, characterized in that the disease condition of the mammal is atherosclerosis, glomerular disease, or Alzheimer's disease.
27. A method according to claim 21, wherein the disease condition of the mammal is characterized by undesirable angiogenesis.
28. A method according to claim 27, characterized in that the disease condition of the mammal is diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas.
29. A method for inhibiting the activity of a metalloproteinase characterized in that it comprises contacting the metalloproteinase with an effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug of the same, the prodrug is different from a compound of the Formula (I).