MXPA00009162A

MXPA00009162A - Inhibitors of caspases

Info

Publication number: MXPA00009162A
Application number: MXPA/A/2000/009162A
Authority: MX
Inventors: Marion W Wannamaker; Guy W Bemis; Paul S Charifson; David J Lauffer; Michael D Mullican; Amurcko Mark; Keith P Wilson; James W Janetka; Robert J Davies; Annelaure Grillot; Zhan Shi; Cornelia J Forster
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 1998-03-19
Filing date: 2000-09-19
Publication date: 2001-07-31

Abstract

The present invention relates to novel classes of compounds which are caspase inhibitors, in particular interleukin-1&bgr;converting enzyme ("ICE") inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting caspase activity and consequently, may be advantageously used as agents against interleukin-1- ("IL-1"), apoptosis-, interferon-&ggr;inducing factor- (IGIF), or interferon-&ggr;- ("IFN-&ggr;") mediated diseases, including inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, and degenerative diseases. This invention also relates to methods for inhibiting caspase activity and decreasing IGIF production and IFN-&ggr;production and methods for treating interleukin-1, apoptosis-, and interferon-&ggr;- mediated diseases using the compounds and compositions of this invention. This invention also relates to methods of preparing the compounds of this invention.

Description

INHIBITORS OF CASPASAS TECHNICAL FIELD OF THE INVENTION The present invention relates to novel classes of compounds that are caspase inhibitors, in particular inhibitors of the interleukin-1β (ECI) conversion enzyme (also known as interleukin-1β). This invention is also related to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly suitable for the inhibition of caspase activity and, consequently, they can be used, advantageously as agents against diseases mediated by interleukin-1 (IL-1), apoptosis-, interferon-gamma induction factor (FIIG), or interferon-gamma (IFN-?), including inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases and degenerative diseases. This invention is also related to methods for inhibiting the activity of caspase and decreasing the production of FIIG and the production of IF? -? and methods for the treatment of diseases mediated by interleukin-1, apoptosis and interferon-gamma using the compounds and compositions of this invention. This invention is also related to methods of preparing the compounds of this invention.

BACKGROUND OF THE INVENTION Interleukin-1 (IL-1) is a major pro-inflammatory and immuno-regulatory protein that stimulates the differentiation and proliferation of fibroblasts, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, degranulation of basophils and eosinophils and activation of neutrophils. J.H. Oppenheim, et al., Immunolocfy Today, 7, pp. 45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. For example, in rheumatoid arthritis, IL-1 is a mediator of both inflammatory symptoms and the destruction of cartilage proteoglycan in affected joints. D.D. Wood, et al., Arthritis Rheum. 26, 975, (1983); E.J. Pettipher, et al., Proc. Nati Acad. Sci. USA, 71, 295 (1986); W.P. Arend and J.W. Dayer, Arthritis Hheum. , 38, 151 (1995). IL-1 is also a highly potent bone resorption agent. J.J. Jandiski, J. Oral Path. , 17, 145 (1988), F.E. Dewhirst, et al., L. Immunol. 8, 2562, 1985). Alternatively referred to as "osteoclast activation factor" in destructive bone diseases such as osteoarthritis and multiple myeloma. R. Bataille, et al., Int. J. Clin. Lab. Res. 21 (4), 283, (1992). In certain proliferative disorders, such as acute myelogenous leukemia and multiple myeloma, IL-1 can promote the growth and adhesion of tumor cells. M. R. Bani, J. Nati. Cancer Inst. 83, 123, (1991); F. Vidal -Vanaclocha, Cancer Res. 54, 2667 (1994).

In these disorders, IL-1 also stimulates the production of other cytokines (also known as cytokines) such as IL-6, which can modulate tumor growth (Tartour, et al., Cancer Res. 54, p.6243 (1994)). IL-1 is produced predominantly by peripheral blood monocytes as part of the inflammatory response and exists in two distinct agonist forms, IL-la and IL-lβ. B.S. Mosely, et al., Proc. Nat. Acad. Sci., 84, pp. 4572-4576 (1987); G. Lonnemann, et al., Eur. J. Immunol. , 19, pp. 1531-1536 (1989). IL-1β is synthesized as a biologically inactive precursor, pIL-lβ. PIL-1 ß lacks a conventional guide sequence and is not processed by a signal peptidase. C.J. March, Nature, 315, pp. 641-647 (1985). In contrast, pIL-1β is divided by the enzyme that converts interleukin-1β (EIC) between Asp-116 and Ala-117 to produce the biologically active termination fragment C found in human serum and synovial fluid. P.R. Sleath, et al., J. Biol. Chem., 265, pp. 14526-14528 (1992), A.D. Howard et al., J. Immunol. 147, pp. 2964-2969 (1991). The ECI is a cysteine protease located mainly in monocytes. This converts the precursor of IL-1β to the mature form. R.A. Black et al., FEBS Lett. 247, pp. 386-390 (1989); M.J. Kostura et al., Proc. Nati Acad. Sci. USA, 86, pp. 5227-5231 (1989). It is also necessary to process the ECI for the transport of mature IL-1β through the cell membrane. The ECI (or caspase-1) is a member of a family of homologous enzymes called caspases. These homologs have sequence similarities in the active site regions of the enzymes. Such homologs (caspases) include TX (or ECIrei-n or ICH-2) (caspase-4) (Faucheu et al., EMBO J., 14, p.1914 (1995); J. Kamens, et al., J. Biol. Chem., 270 pp. 15250 (1995);? Icholson et al., J. Biol. Chem., 270, 15870 (1995)), TY (or ECIre? -n?) (Caspase-5) ( icholson et al., J. Biol. Chem., 270, p. 15870 (1995), ICH-1 (or? edd-2) (caspase-2) (L. Wang. et al., Cell, 78, P. 739 (1994)), MCH-2 (caspase-6), (T. Fernandes-Alnemri, et al., Cancer Res., 55, p. 2737 (1995)), CPP32 (or YAMA or apopaina) (caspasa-3). (T. Fernandes-Alnemri, et al., J. Biol.

Chem., 269, p, 30761 (1994); D.W. ? icholson et al.,? ature, 376, p. 37 (1995)), CMH-1 (or MCH-3) (caspase-7) (Lippke, et al., J. Biol. Chem, 271 (4), pp. 1825-1828 (1996)); T.

Fernandes-Alnemri, et al., Cancer Res. (1995), Mch5 (caspase-8) (Muzio, M. et al., Cell, 85 (6), 817-827, (1996)), MCH-6 (caspase-9) (Duan, H. et al., J. Biol. Chem. 271 (34), p 16720-16724 (1996)), Mch4 (caspase-10) ( Vincenz C. et al., J. Biol. Chem., 272, p. 6578-6583 (1997); T.

Fernandes-Alnemri, et al., Proc. Nati Acad. Sci., 93, p. 7464-7469 (1996)), Ich-3 (caspase-11) (S. Wang, et al., J.

Biol. Chem. 271, p. 20580-20587 (1996)), mCASP-12 (caspase-12), (M. Van de Craen, et al., FEBS Lett, 403, pp. 61-69 (1997); Y. Yuan and Miura, PCT Publication WO95 / 00160 (1995)), ERICE (caspase-13), (E. W. Humke, et al., J. Biol.

Chem. 273, (25) p. 15702-15707 (1998)), and MICE (caspasa-14) (S. Hu, et al., J. Biol. Chem .. 273 (45) pp. 29648-29653 (1998) .Each of these homologs of the ECI, as well as the same ECI, is capable of inducing apoptosis when it is overexpressed in transfected cell lines The inhibition of one or more of these homologs with the Tyr-Val-Ala-Asp-chloromethyl ketone inhibitor peptidyl-ECI results in the inhibition of apoptosis in primary cells or cell lines Lazebnik et al., Nature, 371, p.346 (1994). Caspases also appear to be involved in the regulation of cell death or apoptosis.

P1123 programmed. J. Yuan et al., Cell, 75, pp. 641-652 (1993), M. Miura, et al., Cell, 75, p. 653-660 (1993), M.A. Nett-Fiordalisi, et al., J. Cell Biochem, 17B, p. 117 (1993). In particular, the ECI or ECI homologs are thought to be associated with the regulation of apoptosis in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. J. Marx and M. Baringa, Science, 259, pp. 760-762 (1993), V. Gagliardini et al., Science, 263, pp. 826-828 (1994). Therapeutic applications for the inhibition of apoptosis may include the treatment of Alzheimer's disease, Parkinson's disease, seizures, myocardial infarction, spinal atrophy, and aging. It has been shown that ICE mediates apoptosis (programmed cell death) in certain tissue types H. Steller, Science, 267, p. 1445 (1995); M. Whyte and G. Evans, Nature, 376, p. 17 (1995); S.J. Martin and D.R. Green, Cell, 82, p. 349 (1995); IS. Alnemri, et al., J. Biol. Chem., 270, p. 4312 (1995); J. Yuan, Curr. Opin. Cell Biol., 7, p. 211. (1995). A transgenic mouse with an interruption of the ICE gene has a deficiency in Fas-mediated apoptosis (K. Kuida et al., Science, 267, 2000 (1995)). This activity of the ECI is different from its role as the processing enzyme for pro-IL-lβ. It is conceivable that in certain tissue types, the inhibition of IHD may not affect the secretion of mature IL-1β, but may inhibit P1123 apoptosis. The ECI enzymatically has previously been described as a heterodimer composed of two subunits, p20 and plO (molecular weights of 20kDa and 10kDa, respectively). These subunits are derived from a 45 kDa pro-enzyme (p45) via a p30 form, through an activation mechanism that is autocatalytic. N.A. Thornberry, al., Nature. 356, pp. 768-774 (1992). The pro-enzyme of the ECI has been divided into several functional domains: a pro-domain (pl4), a p22 / 20 subunit, a polypeptide binding agent and a plO subunit, Thornberry, et al., Cited above; Casano, et al., Genomics, 20, pp. 474-481. (1994). The full-length p45 has been characterized by its cDNA and amino acid sequences, PCT Patent Applications WO 91/15577 and WO 94/00154. The cDNA and amino acid sequences of p20 and plO are also known. Thornberry, et al., Previous citation. The murine and rat ECI has also been sequenced and cloned. These have high homology in the sequence of amino acids and nucleic acid with respect to human ECI. D.K. Miller et al., Ann. N.Y. Acad. Sci., 696, pp. 113-148 (1993); YE.

Molineaux, et al., Proc. Nat. Acad. Sci., 90, pp. 1809-1813 (1993). The three-dimensional structure of the ECI has been determined in atomic resolution by crystallography of P1123 X-rays. K.P. Wilson, et al., Nature, 370, pp. 270-275 (1994). The active enzyme exists, as a tetramer of two p20 subunits and two plO. Recently, the ECI and other members of the ECI / CED-3 family have been linked to the conversion of pro-FIIG into FIIG or to the production of IFN-? in vivo (application PCT / US96 / 20843, publication No. WO 97/22619, which is incorporated herein by reference). FIIG is synthesized in vivo as the "pro-FIIG" precursor protein. The induction factor of interferon-gamma (FIIG) is a polypeptide of approximately 18 kDa that stimulates the production of T cells of interferon-gamma (IFN-γ). FIIG is produced by activated Kupffer cells and macrophages in vivo and is sent out of such cells during endotoxin stimulation. Therefore, a compound that decreases FIIG production could be useful as an inhibitor of such T cell stimulation which in turn would reduce the levels of IFN-α production. through those cells. The IFN-? is a cytokine with immuno-modular effects on a variety of immune cells. In particular, the IFN-? it is involved in the activation of macrophages and the selection of Thl cells (F. Belardelli, APMIS, 103, p.161 (1995)). The IFN-? exerts its effects in part by modulating the expression of genes to P1123 through the STAT and IRF pathways (C. Schindler and JE Darnell, Ann. Rev. Biochem., 64, p.621 (1995); T. Taniguchi, J. Cancer Res. Clin. Oncol., 121, p. 516 (1995)). Mice lacking IFN-α? or its receptor have multiple defects in immune cell function and are resistant to endotoxic shock. (S. Huang, et al., Science, 259, p.1742 (1993), D. Dalton, et al., Science, 259, p.1739 (1993); BD Car et al., J. Exp. Med. ., 179, p.1437 (1994)). Together with IL-12, FIIG appears to be a potent inducer of IFN-α production. by T cells (H. Okamura et al, Infection and Immunity, 63, p 3966 (1995), H. Okamura et al, Nature, 378, p.88 (1995), S. Ushio et al., J. Immunol., 156, p.4274 (1996)). The IFN-? has been shown to contribute to the pathology associated with a variety of inflammatory, infectious and autoimmune disorders and diseases. Therefore, compounds capable of decreasing the production of IFN-? could be useful to improve the effects of pathologies related to IFN- ?. Accordingly, the compositions and methods capable of regulating the conversion of pro-FIIG to FIIG could be useful for the decrease of the production of FIIG and IFN-? in vivo, and therefore, produce an improvement over the harmful effects of these proteins that contribute to P1123 human diseases and disorders. Caspase inhibitors represent a class of compounds useful for the control of inflammation or apoptosis or both. Peptide and peptidyl inhibitors of the ECI have been described (PCT patent applications WO 91/15577, WO 93/05071, WO 93/09135, WO 93/12076, WO 93/14777, WO 93/16710, WO 95/35308 , WO 96/30395, WO 96/33209 and WO 98/01133; European Patent Applications 503 561, 547 699, 618 223, 623 592, and 623 606; U.S. Patent Nos. 5,434,248, 5,710,153, 5,716,929; 5,744,451). It has been observed that such peptide inhibitors of ECI block the production of mature IL-lß in a mouse inflammation model (see above reference) and suppress the growth of cells with leukemia in vi tro (Estrov et al., Blood, 84 , 380a (1994)). However, due to their peptide nature, such inhibitors are typically characterized by undesirable pharmacological properties, such as cellular penetration and poor cellular activity, poor oral absorption, instability and rapid metabolism. J.J. Plattner and D.W. Norbeck, in Druq Discovery Technolocries, C.R. Clark and W.H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. These properties have impeded their development towards effective drugs. It has also been reported that peptidyl-free compounds inhibit ICE in vivo. The PCT Patent application WO 95/26958; U.S. Patent No. 5,552,400, to Dolle et al., J. Med. Chem., 39, pp. 2438-2440 (1996). However, this does not clarify whether these compounds have appropriate pharmacological profiles to be useful therapeutically. Accordingly, there is a need for compounds that can effectively inhibit caspases and have favorable in vivo activity, to be used as agents for the prevention and treatment of acute and chronic forms of IL-1, apoptosis, FIIG, or IFN-α mediated diseases. as well as inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases and degenerative diseases.

SUMMARY OF THE INVENTION The present invention provides novel classes of compounds and pharmaceutically acceptable derivatives thereof, which are useful as caspase inhibitors, particularly inhibitors of ECI. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immuno-modulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by IL-1, apoptosis, FIIG or IFN-α. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of a caspase and inhibiting activity of that enzyme. A principal objective of this invention is to provide novel classes of compounds represented by formula I, which has favorable in vivo profiles: the different substituents are described herein. It is a further objective of this invention to provide pharmaceutical compositions, including compositions with multiple components. This invention also provides methods for the use and preparation of the compounds of this invention and related compounds.

DETAILED DESCRIPTION OF A NATION In order to understand the invention more fully, the following detailed description is presented. The following abbreviations and definitions are used through the application. Abbreviations The term "caspase" refers to an enzyme that is a member of the family of enzymes that includes ICS (see H. Hará, Nati, Acad. Sci., 94, pp. 2007-2012 (1997)). The terms "HBV", "HCV" and "VHG" refer to hepatitis B virus, hepatitis C virus and hepatitis G virus, respectively. The term "Ki" refers to a numerical measure of the effectiveness of a compound in inhibiting the activity of a target enzyme or target enzyme, such as ECI. The lower the value of the i, the greater its effectiveness. The Ki value is derived by fitting experimentally determined velocity data for the kinetic equations of the standard enzyme (see I.H. Segel, Enzyme Kinetics, Wiley-Interscience, 1975). The term "interferon-gamma induction factor" or FIIG refers to a factor that is capable of stimulating endogenous IFN-α production. The term "caspase inhibitor" refers to a compound that is capable of demonstrating the detectable inhibition of one or more caspases. The term "ECI inhibitor" refers to a compound that is capable of demonstrating detectable inhibition of ICE and optionally one or more additional caspases. The inhibition of these enzymes can be determined using the methods described and incorporated herein by reference. The skilled practitioner understands that an enzyme inhibitor in vivo is not necessarily an inhibitor of P1123 enzyme in vi tro. For example, a prodrug form of a compound typically shows little or no activity in in vitro trials. Such prodrug forms can be altered by metabolic processes or other biochemical processes in the patient to provide an ICI inhibitor in vivo. The term "cytokine" (also known as cytokine) refers to a molecule that mediates interactions between cells. The term "condition" refers to any disease, disorder or effect that produces consequences of biological deterioration in a subject. The term "subject" refers to an animal or to one or more cells derived from an animal. Preferably, the animal is a mammal, more preferably it is a human being. The cells may be in any form, including, but not limited to: cells retained in tissue, cell groups, immortalized cells, transfected or transformed cells and cells derived from an animal that has been physically or phenotypically altered. The term "patient" as used in this application refers to any mammal, preferably human. The term "alkyl" refers to a saturated aliphatic hydrocarbon, straight or branched chain containing 1 to 6 carbon atoms. The term "alkenyl" refers to an unsaturated, straight-chain or branched hydrocarbon containing from 2 to 6 carbon atoms and at least one double bond. The term "alkynyl" refers to an unsaturated, straight-chain or branched hydrocarbon containing from 2 to 6 carbon atoms and at least one triple bond. The term "cycloalkyl" refers to a hydrocarbon ring system, mono or polycyclic, non-aromatic, which may optionally contain unsaturated bonds in the ring system. Examples include cyclohexyl, adamantyl, norbornyl and spirocyclopentyl. The term "aryl" refers to a mono- or polycyclic ring system containing 6, 10, 12 or 14 carbons in which at least one ring of the ring system is aromatic. The aryl groups of this invention are optionally substituted in single or multiple form with R 11. Examples of these ring systems include phenyl, naphthyl and tetrahydronaphthyl. The term "heteroaryl" refers to a mono- or polycyclic ring system containing 1 to 15 carbon atoms and 1 to 4 heteroatoms, and in which at least one ring of the ring system is aromatic. The heteroatoms are sulfur, nitrogen or oxygen. The heteroaryl groups of this invention are optionally substi tuted in single or multiple form with R11. The term "heterocyclic" refers to a mono- or polycyclic ring system containing 1 to 15 carbon atoms and 1 to 4 heteroatoms, in which the mono- or polycyclic ring system may optionally contain unsaturated but non-aromatic bonds. The heteroatoms are independently sulfur, nitrogen or oxygen. The term "alkylaryl" refers to an alkyl group, wherein a hydrogen atom of the alkyl group is replaced with an aryl radical. The term "alkyl-heteroaryl" refers to an alkyl group, wherein a hydrogen atom of the alkyl group is replaced with a heteroaryl radical. The term "amino acid side chain" refers to any group attached to the carbon a of a natural amino acid or not. The term "substitute" refers to the replacement of a hydrogen atom in a compound with a substituent group. The term "straight chain" refers to a continuous unbranched chain of covalently bonded atoms.

P1123 The straight chain may be substituted, but these substituents are not part of the straight chain. In chemical formulas, parentheses are used here to denote connectivity in molecules or groups. In particular, parentheses are used to indicate: 1) that more than one atom or group is bound to a particular atom; or 2) a branching point (ie, the atom immediately before the opening of the parentheses is attached to both the atom or group in the parenthesis and to the atom or group immediately after the closure of parentheses). An example of the first use is "- (alkyl) 2", indicating two alkyl groups attached to an N atom. An example of the second use is "-C (0) NH2, indicating that both the carbonyl group and the amino group" NH2"They are attached to the indicated carbon atom A group" -C (0) NH2"can be represented in other forms, including the following structure: The substituents can be represented in various forms. These different forms are known to the practicing expert and can be used by exchanging them. For example, a methyl substituent or a P1123 Phenyl ring can be represented in any of the following ways: Various forms of substituents, such as methyl, are used interchangeably. Where necessary, other definitions will be presented in this specification.

Compounds of this Invention The compounds of one embodiment A of this invention are those of the formula 1: where: Y is: (a) P1123 provided that when R7 is -OH then Y may also be: X is -C (R3) 2- or -N (R3) -; m is 0 or 1; R1 is H, -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, -S (0) R8, -C (0) 0R8, -C (0) N (H) R8, -S (0) 2N (H) -R8, -S (O) N (H) -R8, -C (0) C (0 ) N (H) R8, -C (0) CH = CHR8, -C (0) CH2OR8, -C (O) CH2N (H) R8, -C (0) N (R8) 2, -S (0) 2N (R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, -C (0) CH2N (R8) 2, -CH2R8, -CH2-alkenyl-R8, or -CH2-alkynyl-R8; R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl-R9, or alkynyl-R9, or R2 and an R3 together with the atoms to which these are attached, form a system of cyclic or heterocyclic ring of 3 to 7 members, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with -R10, an atom P1123 of hydrogen bonded to any aryl or heteroaryl carbon atom is optionally replaced with -R1, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; R4 is -H and each R5 is independently -H, an amino acid side chain, -R8, -alkenyl-R9, or alkynyl-R9, or R4 and an R5 together with the atoms to which these are attached, form a cyclic or heterocyclic ring of 3 to 7 members, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of aryl or heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with R1; R6 is -H; R7 is -OH; -OR8 OR -N (H) OH; each R8 is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, alkylcycloalkyl, -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom P1123 bound to any nitrogen atom is optionally replaced with R1; each R9 is independently -aryl, -heteroaryl, -cycloalkyl, or -heterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any hydrogen atom. -aril or -heteroaryl carbon is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R10 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH 2, -perfluoroalkyl, -0-alkyl, -0-aryl, -0-alkylaryl, -N (H) alkyl, -N (H) -aryl, -N (H ) alkylaryl, -N (alkyl) 2. -C (O) N (H) alkyl, -C (O) (alkyl) 2, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl) 2, -S-alkyl, -S-aryl , -S-alkylaryl, -S (0) 2alkyl, -S (O) alkyl, -C (O) -alkyl, -CH2NH2, -CH2N (H) alkyl, or -CH2N (alkyl) 2, -alkyl, - cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkylcycloalkyl, -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11 and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R11 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (O) NH 2, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -O-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) - aryl, -N (H) alkylaryl, -N (alkyl) 2, -C (O) N (H) alkyl, -C (0) N (alkyl) 2, -N (H) C (O) alkyl, - N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl) 2. -S-alkyl, -S-aryl, -S-alkylaryl, -S (0) 2alkyl , -S (O) alkyl, -C (O) -alkyl, -CH2NH2, -CH2N (H) alkyl, or -CH2N (alkyl) 2.

In an alternative form of the A mode: R1 is H, -R8, -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, -S (0) R8, -C (0) OR8, -C (0) N (H) R8, -S (O) 2N (H) -R8, -S (O) N (H) -R8, -C (0) C (0) N (H) R8, -C (0) CH = CHR8, -C (0) CH2OR8, -C (O) CH2N (H) R8, -C (0) N (R8) 2, -S (0) 2N ( R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, -C (0) CH2N (R8) 2, -CH2R8, -CH2-alkenyl-R8 , or -CH2-alkynyl-R8; R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl-R9, or alkynyl -R9, or each R3 together with the atoms to which these are attached, form a cyclic ring system or 3- to 7-membered heterocyclic, or R2 and an R3 together with the atoms to which these are attached, form a 3- to 7-membered cyclic or heterocyclic ring system, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with P1123 -R1-0 a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with -R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; each R10 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH 2, -perfluoroalkyl, -0-alkyl, -O-aryl, -0-alkylaryl, -N (H) alkyl, -N (H) -aryl, -N (H alkylaryl, -N (alkyl) 2, -C (O) N (H) alkyl, -C (O) N (alkyl) 2, -N (H) C (O) alkyl, - (H) C (O) Oalkyl, -N (H) C (O) Oaryl, -N (H) C (O) O-alkylaryl, -N (H) C (O) O-heteroaryl, - (H) C (O) O-alkylheteroaryl, -N (H) C (O) Occycloalkyl, -N (H) C (O) N (H) alkyl, -N (H) C (0) N (alkyl) 2, -N (H) C (0) N (H) aryl, -N (H) C (O) N (H) alkylaryl, -N (H) C (0) N (H) heteroaryl, - (H) C (O) N (H) alkylheteroaryl, -N (H) C (O) N (H) cycloalkyl, -S-alkyl, -S-aryl, -S-alkylaryl, -S (O) 2alkyl, -S (O) alkyl, -C (O) - rent, -CH2NH2, -CH2N (H) alkyl, or -CH2N (alkyl) 2 / -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkylcycloalkyl, -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11 and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; and the other substituents are as defined above. Preferably, in any of the above modalities: m is 0; R2 is -H; one R3 is -H and the other R3 is -R8, -alkenyl -R9, or -alkynyl-R9, or R4 and an R5 together with the atoms to which they are attached form a cyclic or heterocyclic ring system of 3 to 7 members , wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of aryl or heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with R1, wherein the ring system is: P1123 In an alternative preferred embodiment, X is C (R3) 2 or R3 is an amino acid side chain, -R8, alkenyl-R9, or alkynyl -R9. More preferably, one R3 is -H and the other R3 is -alkyl; or R4 and an R5 together with the atoms to which they are attached form a cyclic or heterocyclic ring system of 3 to 7 members, wherein any hydrogen atom attached to any carbon atom of the ring system is optionally replaced with R10, and any hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with R1, selected from: P1123 More preferably, one R3 is -H and the other R3 is -C (H) (CH3) 2 or -C (CH) 3; and R4 and an R5 together with the atoms to which they are attached form a 3- to 7-membered cyclic or heterocyclic ring system, wherein any hydrogen atom attached to any carbon atom of the ring system is optionally replaced with R10, and any hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with R1, selected from; P1123 It is an alternative modality of greater preference, one R3 is -H and the other R3 is -CH3, -C (H) (CH3) 2 or -C (CH3) 3 and R4 and R5 are as defined in the previous paragraph. According to another embodiment B, the present invention provides a compound of formula I, wherein Y is: provided that when Re is not hydrogen, R6 and Y, together with the nitrogen to which they are attached, form a ring (g): P1123 R 12 is -C (O) alkyl, -C (O) cycloalkyl, -C (O) alkenyl, -C (O) alkylaryl, -C (O) alkylheteroaryl, -C (O) eterocyclyl or -C (O) alkylheterocyclyl . R 13 is -H, -alkyl, -aryl, -alkylaryl or -alkylheteroaryl-, and the other substituents are as described above. Preferably, in (c), (d), (e), or (f), R8 is methyl, ethyl, n-propyl, isopropyl, cyclopentyl, phenethyl, or benzyl. The preferred definitions for the other individual components of the B-modality are the same as those presented above for the A-modality. A preferred embodiment C of this invention provides compounds of the formula I: P1123 where Y is: (a) (b) m is 0 or 1; X is -C (R3) 2- R-1 is H, -R ° -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, -S (0) R8, -C (0) 0R8, -C (0) N (H) R8, -S (O) 2N (H) -R8, -S (O) N (H) -R8, - C (0) C (0) N (H) R8, -C (0) CH = CHR8, -C (0) CH2OR8, -C (O) CH2N (H) R8, -C (0) N (R8) 2, -S (0) 2N (R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, -C (0) CH2N (R8) 2, -CH2R8, -CH2-alkenyl-R8, or -CH2-alkynyl-R8; R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl-R9, or alkynyl-R9, or each R3 together with the atoms to which these are attached, form a cyclic ring system or 3-7 membered heterocyclic, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with -R10, a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with -R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; R4 is -H and each R5 is independently -H, an amino acid side chain, -R8, -alkenyl-R9, or alkynyl-R9, or R4 and an R5 together with the atoms to which these are attached, form a cyclic or heterocyclic ring of 3 to 7 members, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of aryl or heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with R1; Rs is -H; R7 is -OH; -OR8 or -N (H) OH or -N (H) S (O) 2R8; each R8 is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, alkylcycloalkyl, -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, an atom of hydrogen P1123 bound to any aryl or heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R9 is independently -aryl, -heteroaryl, -cycloalkyl, or -heterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any hydrogen atom. -aril or -heteroaryl carbon is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1, - each R10 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, -perfluoroalkyl, -0- alkyl, -0-aryl, -0-alkylaryl, -N (H) alkyl, -N (H) -aryl, -N (H) alkylaryl, -N (alkyl) 2, -C (O) N (H) alkyl, -C (O) N (alkyl) 2, -N (H) C (0) alkyl, -N (H) C (O) Oalkyl, -N (H) C (O) Oaryl, -N (H) C (O) O-alkylaryl, -N (H) C (O) O-heteroaryl, - (H) C (0) O-alkylheteroaryl, -N (H) C (0) Occycloalkyl, -N (H) C (O) N (H) alkyl, -N (H) C (0) N (alkyl) 2, -N (H) C (0) N (H) aryl, -N (H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) heteroaryl, -N (H) C (O) N (H) alkylheteroaryl, -N (H) C (O) N (H) cycloalkyl, -S-alkyl, -S-aryl, -S-alkylaryl, -S (O) 2alkyl, -S (O) alkyl, -C (O) - rent, P1123-CH2NH2, -CH2N (H) alkyl, or -CH2N (alkyl) 2, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkylcycloalkyl, -alkylaryl, -alkylheteroaryl, or -alkylheterocyclyl, wherein a hydrogen atom bonded to any aryl or heteroaryl carbon atom is optionally replaced with R11 and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; and each R11 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) ) H, -N (H) C (O) H2, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -0-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) -aryl, -N (H) alkylaryl, -N (alkyl) 2, -C (O) N (H) alkyl, -C (0) N (alkyl) 2, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (0) N (alkyl) 2 / -S-alkyl, -S-aryl, -S-alkylaryl, -S (0) 2alkyl, -S (O) alkyl, -C (O) alkyl, -CH2NH2, -CH2N (H) alkyl, or -CH2N (alkyl) 2. Provided that if one R3 is -H, then the other R3 is not -H Another preferred embodiment D of the present invention provides a compound of formula I, and wherein Y is: P1123 (c) (d) (e) (f) R12 is -C (O) alkyl, -C (O) cycloalkyl, -C (O) alkenyl, -C (0) alkylaryl, -C (O) alkylheteroaryl, -C (O) heterocyclyl, or -C (O) alkylheterocyclyl; and the other substituents are as described above except that both R3 groups can be -H. In any of the A-D modalities, the preferred compounds are those wherein: R 1 is -C (0) R 8 or -C (0) (O) R 8; R2 and R3 are -H and the other R3 is an amino acid side chain, R8, alkenyl -R9, or alkynyl-R9; or R4 and R? together with the atoms to which they are attached form a ring system selected from: Pll 3 provided that each of the ring systems is optionally substituted with one or more R10 groups. Alternatively, the most preferred compounds of the A-D modalities are those wherein R3 is -H and the other R3 is methyl, isopropyl, tert-butyl, -CH2SR8, -CH2S02R8, -CH2CH2SR8, -CH2CH2S02R8.

Pll 3 The most preferred compounds of the A-D configurations are those wherein R4 and R5 together with the atoms to which they are attached form the ring system: and the other R5 is H; or one R3 is -H and the other R3 is methyl. Alternatively, the most preferred compounds of the A-D modalities are those wherein R4 and R5 together with the atoms to which they are attached form the ring system: and the other R 5 is H. In the above alternative embodiment, R 10 is preferably 4-fluoro or 4,4-difluoro. The most preferred compounds of this invention are those wherein R3 is methyl; and R4 and R5 together with the atoms to which they are attached form the ring system: P1123 and the other R5 is H. Alternatively, the most preferred compounds of the A-D modalities are those wherein R3 is methyl; and R4 and R5 together with the atoms to which they are attached form the ring system: and the other R is H; and R10 is 4-fluoro or 4, 4, -difluoro. The compounds the preferred modalities (B) (D) are those where Y is: where Z represents -OR and Z is: CH30, P1123 3 Specific compounds of this invention include, by way of example: Examples 5a-5bd, 7a-7at, 9a-9g, I5a-15f, 16a-16b, 17a-17e, 18a-18f, 20a-20t, 23a-23i, 24a -24e, 25a-25e, 26a-26h, 27a-27n, 28a-28c, 29a-29s, 32a-32e, 34, Gl, G2, 41, 42, 45, 46, 51, 52, 56, 57, P1123 60, 61, 64, 65, 68, 69, 72, 73, 76-93, 98a-z, aa-az, and ba-bb, 101, 102a, 102b, 108a-d, 110, 111, 116a- h, 120a and b, 121, 122 av, and 123 ac. The compounds of this invention may contain one or more "asymmetric" carbon atoms and, therefore, may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Each stereogenic carbon can be of R- or S-configuration. Although specific compounds and structures exemplified in this application can be represented in a particular stereochemical configuration, compounds and structures having the opposite stereochemistry at any given chiral center or mixtures of these are also considered. . All such isomeric forms of these compounds are expressly included in the present invention, as well as pharmaceutically acceptable derivatives thereof. The term "pharmaceutically acceptable derivative" denotes any salt, ester, or salt of such an ester, the compound of this invention or any another compound which, during administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof. The pharmaceutically acceptable salts of P1123 compounds of this invention include, for example, those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzene-sulfonic. Other acids, such as oxalic, although by themselves are not pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (C? 4-alkyl) 4+ salts. This invention also considers the "quaternization" of any basic nitrogen-containing group of the compounds disclosed herein. The basic nitrogen may be quaternized with any agent known to those skilled in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl sulphates, P1123 dibutyl and diamyl; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Products soluble or dispersible in water or oil can be obtained by such quaternization. When there are multiple substituents, each substituent can be selected independently from any other substituent as long as the combination of substituents results in the formation of a stable compound. The combinations of substituents and variables considered by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds that possess sufficient stability to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least one week. The preferred compounds of this invention can be readily absorbed by the bloodstream of patients during oral administration. This oral availability makes such compounds excellent agents for treatment and prevention regimens administered orally against diseases mediated by IL-1, apoptosis, FIIG, or interferon-gamma. It should be understood that the compounds of this invention can exist in various forms of equilibrium, depending on the conditions that include the selection of the solvent, pH, and others known to the skilled artisan. All such forms of these compounds are expressly included in the present invention. In particular, many of the compounds of this invention, especially those containing aldehyde or ketone groups and Y carboxylic acid groups, can have hemiacetal or hydrated forms. For example, compounds of mode A are in a hemiacetal form when Y is: Depending on the selection of the solvent and other conditions known to the skilled artisan, the compounds of this invention can also take the hydrated, acyloxy-acetal, acetal or enol forms. For example, compounds of this invention are in hydrated forms when Y is: P1123 the acyloxy-acetal forms when Y is acetal forms when Y is R8 is different from H, and Y is and enol forms when Y is Furthermore, it should be understood that the equilibrium forms of the compounds of this invention can P1123 include tautomeric forms. All such forms of these compounds are expressly included in the present invention. The compounds of formula 1 can be synthesized using conventional techniques.

Advantageously, these compounds are conveniently synthesized from readily available starting materials. The compounds of this invention can be prepared using the processes described herein. As can be appreciated by the skilled practitioner, these processes are not the only means by which the compounds described and claimed in this application can be synthesized. Additional methods will be apparent to those skilled in the art. Additionally, the different synthetic passes described herein can be performed in an alternating sequence to give the desired compounds. It should be understood that the compounds of this invention can be modified with appropriate functionalities to improve the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological system (eg, blood, lymphatic system, central nervous system), increase in P1123 oral availability, increased solubility to allow administration by injection, modified metabolism and modified excretion rate. In addition, the compounds can be altered to the prodrug form in such a way that the desired compound is created in the patient's body as the result of the action of metabolic or other biochemical processes on the prodrug. Such forms of prodrug typically show little or no activity in in vitro trials. Some examples of prodrug forms include ketal, acetal, oxime, imine and hydrazone forms of compounds containing ketone or aldehyde groups, especially where these occur in the Y group of the compounds of this invention. Other examples of prodrug forms include the hemi-ketal, hemiacetal, acyloxy-ketal, acyloxy-acetal, ketal, acetal and enol forms that are described herein.

Compositions and Methods The compounds of this invention are caspase inhibitors, and in particular ECI inhibitors. Accordingly, these compounds are capable of targeting and inhibition functions in diseases mediated by IL-1, apoptosis, FIIG or interferon-gamma, and, therefore, the final activity of that protein in inflammatory diseases, autoimmune diseases, disorders P1123 destructive bites, proliferative disorders, infectious diseases and degenerative diseases. For example, the compounds of this invention inhibit the conversion of the IL-1β precursor to mature IL-1β by inhibition of ECI. Because IHD is essential for the production of mature IL-1, inhibition of that enzyme effectively blocks the onset of IL-1-mediated physiological effects and symptoms, such as inflammation, by inhibiting the production of mature IL-1. Thus, by inhibiting the activity of the IL-1β precursor, the compounds of this invention effectively function as inhibitors of IL-1. The compounds of this invention also inhibit the conversion of pro-FIIG to its active form, mature FIIG by inhibition of ECI. Because IHD is essential for the production of mature FIIG, inhibition of ICE effectively blocks the onset of physiological effects and symptoms mediated by FIIG, inhibiting the production of mature FIIG. The FIIG is in turn essential for the production of IFN- ?. Consequently, the ECI effectively blocks the onset of physiological effects and symptoms mediated by IFN- ?, inhibiting the production of the mature FIIG and, therefore, producing it of IFN- ?. The compounds of this invention are surprisingly bioavailable when compared to P1123 peptidyl inhibitors, such as those described in, for example, EP 618 223, EP 623 592, WO 93/09135, WO 93/16710, US Patent No. 5,434,248, WO 95/35308 or WO 96/33209. Therefore, the pharmaceutical compositions and methods of this invention will be useful for the control of caspase activity in vivo. The compositions and methods of this invention will be useful for the control of the levels of IL-1, FIIG, or IFN-? in vivo and for the treatment or reduction of the advance, severity or effects of conditions mediated by IL-1, apoptosis, FIIG, or interferon-gamma, including diseases, disorders or effects. The pharmaceutical compositions of this invention comprise a compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Such compositions may optionally comprise an additional therapeutic agent. Such agents include, but are not limited to: an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immuno-modulator, a prostaglandin or an anti-vascular hyperproliferation compound. The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be P1123 administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to: ion exchangers, alumina, alumina stearate, lecithin, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, acid sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, sodium dibasic phosphate, potassium monobasic phosphate, sodium chloride, zinc salts, colloidal silica, trisilicate magnesium, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool grease and self-emulsifying drug delivery systems (SSDAE) such as alpha-tocopherol, polyethylene glycol succinate 1000 , or other similar polymeric delivery matrices. In the pharmaceutical composition comprising embodiments a compound of the A-D modalities as the active component, the methods for the administration of these compositions may additionally comprise the P1123 administration step to the subject of an additional agent. Such agents include, but are not limited to: an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immuno-modulator, a prostaglandin or an anti-vascular hyperproliferation compound. The term "pharmaceutically effective amount" refers to an effective amount in treatment or improvement of a disease mediated by IL-1, apoptosis, FIIG or IFN-? in a patient. The term "prophylactically effective amount" refers to an effective amount for the prevention or substantial decrease of a disease mediated by IL-1, apoptosis, FIIG or interferon-gamma in a patient. The compounds of this invention can be employed in a conventional manner to control the levels of FIIG and IFN-? in vivo and for the treatment of diseases or reduction of the advance or severity of effects that are mediated by IL-1, apoptosis, FIIG or IFN- ?. Such treatment methods, their dosage levels and requirements can be selected by those skilled in the art from available methods and techniques.

For example, a compound of this invention can be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from an IL-1 mediated disease., apoptosis, FIIG or IFN-? in a pharmaceutically acceptable form and in an amount effective to decrease the severity of that disease. Alternatively, the compounds of this invention can be used in compositions and methods for the treatment or protection of individuals against diseases mediated by IL-1, apoptosis, FIIG, or interferon-gamma for extended periods of time. The compounds may be employed in such compositions alone or together with other compounds of this invention in a manner consistent with the conventional use of enzyme inhibitors in pharmaceutical compositions. For example, a compound of this invention can be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals for a prolonged period of time against diseases mediated by IL-1, apoptosis, FIIG, or interferon- gamma. The compounds of the formula I can also be co-administered with other inhibitors of ECI or caspases to increase the effect of therapy or prophylaxis against diseases mediated by IL-1, apoptosis, FIIG, or IFN- P1123 In addition, the compounds of this invention can be used in combination with conventional anti-inflammatory agents or with matrix metalloprotease inhibitors, lipoxygenase inhibitors and cytokine antagonists other than IL-1β. The compounds of this invention can also be administered in combination with immuno-modulators (e.g., biririmin, alpha-interferon anti-human antibody, IL-2, GM-CSF, methionine encephalomyelum, interferon-alpha, diethyl-dithiocarbamate, tumor necrosis, naltrexone and EPO), with protaglandins, or with antiviral agents (eg, 3TC, polysulphated polysaccharides, ganiclovir, ribavirin, acyclovir, alpha-interferon, trimethotrexate and fanciclovir) or prodrugs of these or related compounds to prevent or combat symptoms of disease mediated by IL-1, such as inflammation. When the compounds of this invention are administered in combination of therapies with other agents, they can be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention comprise a combination of a compound of formula I and another therapeutic or prophylactic agent.

P1123 The pharmaceutical compositions of this invention can be administered orally, parenterally, by inhalation, topical, rectal, nasal, buccal, vaginal spray or via an implanted reservoir. We prefer oral administration. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffer solutions to improve the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intra-sternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-solvent or solvent.

P1123 toxic parenterally acceptable, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are in mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectable products, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These solutions or suspensions in oil may also contain a long chain alcohol diluent or dispersant, such as those described in the Helvetic Pharmacopoeia, or a similar alcohol. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to: capsules, tablets, suspensions and aqueous solutions. In the case of tablets for oral use, the carriers that are commonly used include lactose to corn starch. Lubricating agents, such as magnesium stearate, are also typically added.

P1123 For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When suspensions and aqueous solutions and propylene glycol are orally administered, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will consequently melt in the rectum to release the active components. Such materials include, but are not limited to: cocoa butter, beeswax and polyethylene glycols. Topical administration of pharmaceutical compositions of this invention is especially useful when the desired treatment involves easily accessible areas or organs by topical application. For topical application to the skin, the pharmaceutical composition must be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the pharmaceutical compositions of this invention include, but are not limited to: mineral oil, liquid petrolatum, white oil, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Altexatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldocanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically to the lower intestinal tract by a rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in this invention. The pharmaceutical compositions of this invention can be administered by aerosol or nasal inhalation. Such compositions are prepared according to techniques well known in the art of pharmacological formulation and can be prepared as solutions in saline, employing benzyl alcohol or other preservatives, absorption promoters suitable for improving bioavailability, fluorocarbons and / or other preservative agents. solubilization or dispersion known in the art.

P1123 Dosage levels of between about 0.01 and about 100 mgM body weight per day, preferably between 0.5 and about 75 mg / kg body weight per day and more preferably between about 1 to 50 mg / kg body weight per day of compound of active ingredient are useful in a monotherapy for the prevention and treatment of diseases mediated by IL-1, apoptosis, FIIG or interferon-gamma, including, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, degenerative diseases, necrotic diseases, inflammatory peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, respiratory pain syndrome in adults, glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia unitary, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, host reaction disease against grafting, osteoporosis, bone disorder related to multiple myeloma, leukemia and related disorders , myelodysplastic syndrome, acute myelogenous leukemia, P1123 chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic attack, shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, encephalitis related to HIV aging, alopecia, neurological damage due to cerebral vascular accident, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary cirrhosis, uveitis, Behcet's disease, atopic skin disease, aplasia red blood cells, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome and systemic diseases or diseases with localized effects on the liver or other organs, which has an inflammatory or apoptotic component, caused by excess ingestion of alcohol or by viruses, such as HBV, HCV , VHG, yellow fever virus, dengue fever virus, and Japanese virus s of encephalitis. Typically, the pharmaceutical compositions of this invention will be administered approximately 1 to 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a simple dosage form will vary P1123 depending on the treated host and the particular mode of administration. A typical preparation will contain about 5% to about 95% active compound (w / w). Preferably, such preparations contain about 20% to about 80% active compound. When the pharmaceutical compositions of this invention comprise a combination of a compound of the formula I and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent must be present at dosage levels of between about 10% to 80% of the dosage normally administered in a monotherapy regimen. Upon improvement of the condition of a patient, if necessary, a maintenance dosage of a compound, composition or combination of this invention can be administered. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, and treatment should cease. However, patients may require intermittent treatment or long-term treatment during any symptom of recurrence or disease. As can be appreciated by an expert in P1123 art, lower or higher doses than those indicated above may be required. The specific dosage and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration, rate of excretion, combination of drugs, the severity and course of the disease, and the patient's disposition to the disease and the judgment of the attending physician. Diseases mediated by IL-1 or apoptosis that can be treated or prevented by the compounds of this invention include, but are not limited to: inflammatory diseases, autoimmune diseases, proliferative disorders, infectious diseases and degenerative diseases. The apoptosis-mediated diseases that can be treated or prevented with the compounds of this invention include degenerative diseases. Inflammatory diseases mediated by IL-1 or apoptosis that can be treated or prevented include, but are not limited to: osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, and adult respiratory distress syndrome. Preferably the inflammatory disease is osteoarthritis or acute pancreatitis.

P1123 Autoimmune diseases mediated by IL-1 or apoptosis that can be treated or prevented include, but are not limited to: glomulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus ( type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, severe myasthenia, multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis and host reaction disease against the graft. Preferably the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriasis or atopic dermatitis. Destructive bone disorders mediated by IL-1 or apoptosis that can be treated or prevented includes, but is not limited to: osteoporosis and multiple myeloma related to bone disorders. IL-1-mediated proliferative disorders or apoptosis that can be treated or prevented include, but are not limited to: leukemias and related disorders, such as myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma and multiple myeloma . Infectious diseases mediated by IL-1 or apoptosis that can be treated or prevented include, but are not limited to: sepsis, septic attack and Shigellosis. Necrotic or degenerative diseases mediated by IL-1 or apoptosis that can be treated or prevented by the compounds of this invention include, but are not limited to: Alzheimer's disease, Parkinson's disease, cerebral ischemia and myocardial ischemia. Preferably, the degenerative disease is Alzheimer's disease. Degenerative diseases mediated by IL-1 or apoptosis that can be treated or prevented by the compounds of this invention include, but are not limited to: Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, encephalitis related to AIDS, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke. Other diseases that have an inflammatory or apoptotic component can be treated or prevented by compounds of this invention. Such diseases can be systemic diseases or diseases with localized effects in the liver or other organs and can be caused by excess ingestion of alcohol or by viruses, such as HBV, HCV, VHG, yellow fever virus, dengue fever virus, and Japanese encephalitis virus.

P1123 Diseases mediated by FIIG or IFN-? which can be treated or prevented by the compound of this invention include, enunciatively: inflammatory, infectious, autoimmune, proliferative, neurodegenerative and necrotic conditions. Inflammatory diseases mediated by FIIG or IFN-? which can be treated or prevented include, but are not limited to, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cerebral ischemia, myocardial ischemia, and respiratory distress syndrome. adult. Preferably the inflammatory disease is rheumatoid arthritis, ulcerative colitis, Crohn's disease, hepatitis or respiratory pain syndrome in adults. Infectious diseases mediated by FIIG or IFN-? which can be treated or prevented include, but are not limited to: infectious hepatitis, sepsis, septic attack and Shigellosis. Autoimmune diseases mediated by FIIG or IFN-? which can be treated or prevented include, but are not limited to: glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), juvenile diabetes, hemolytic anemia Autoimmune P1123, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple sclerosis, psoriasis, lichen planus, host-graft reaction disease, acute dermatomyositis, eczema, primary cirrhosis, hepatitis, uveitis, Behect's disease, atopic skin disease, aplasia of red blood cells, aplastic anemia, amyotrophic lateral sclerosis and nephrotic syndrome. Preferably, the autoimmune disease is glomerulonephritis, insulin dependent diabetes mellitus (type I), juvenile diabetes, psoriasis, host reaction disease against grafting or hepatitis. The diseases most preferred for treatment or prevention include rheumatoid arthritis, inflammatory bowel disease, including Crohn's disease, and ulcerative colitis, inflammatory peritonitis, septic attack, pancreatitis, traumatic brain injury, rejection of organ transplantation, osteoarthritis, asthma , psoriasis, Alzheimer's disease, atopic dermatitis, or leukemias and related disorders, such as myelodysplastic syndrome or multiple myeloma. Accordingly, one embodiment of this invention is to provide a method for the treatment or prevention of a disease mediated by IL-1 or apoptosis in a subject, comprising the step of administering to the subject any compound, pharmaceutical composition or combination P1123 described herein and a pharmaceutically acceptable carrier. Another embodiment of this invention is to provide a method for decreasing the production of FIIG in a subject, comprising the step of administering to the subject any compound, pharmaceutical composition or combination described herein and a pharmaceutically acceptable carrier. Yet another embodiment of this invention is to provide a method for decreasing the production of IFN-? in a subject, comprising the step of administration to the subject of any compound, pharmaceutical composition or combination described herein and a pharmaceutically acceptable carrier. Although this invention focuses on the use of the compounds disclosed herein for the prevention and treatment of diseases mediated by IL-1, apoptosis, FIIG, or interferon-gamma, the compounds of this invention can also be used as inhibitory agents for other cysteine proteases. The compounds of this invention are also useful as commercial reagents that effectively bind to caspases or other cysteine proteases including, but not limited to, ECI. As commercial reagents, the compounds of this invention, and their derivatives, can be used to block the proteolysis of a white peptide in P1123 biochemical or cellular tests for ECI or ECI homologs or can be derived to bind to a stable resin as a connected substrate for affinity chromatography applications. These and other uses that characterize commercial cysteine protease inhibitors will be apparent to those skilled in the art. To more fully understand this invention, the following examples are presented. These examples are for the sole purpose of illustrating the invention and in no way limit the scope thereof.

GENERAL METHODS HPLC analytical conditions Column: C-18, Particle size: 5μ, Pore size: 100Á, Column size: 4.6 x 150 mm. Solvent A: 0.1% TFA / 1% MeCN / 98.9% water Solvent B: 0.1% TFA / 99.9% MeCN Gradient: A to B in 20 min. at a flow rate of 1 mL / min.

Column: Ciano, Particle size: 5μ, Pore size: 100Á, Column size: 4.6 x 150 mm Solvent A: 0.1% TFA / l% MeCN / 98.9% water Solvent B: 0.1% TFA / 99.9% MeCN Gradient : A / B = 99% / l% at 50% / 50% for 20 min. at a flow rate of 1 mL / min.

P1123 Analysis of the mass spectrum coupled with HPLC. Mass spectrum analysis: All mass spectrum data were collected using a triple quadrupole mass spectrometer Micromass Quattro II (Beverly, MA) equipped with a cross-flow electroaspertion ionization source. The mass spectrometer was coupled to an HPLC system manufactured by Hewlett Packard (HP1100). The automatic sampling device for the system was a Gilson 215 liquid control device (Middleton, Wl). The entire equipment was controlled by a MassLynx software package purchased from Micromass. The mass spectrum analysis was performed by EM in liquid chromatography to determine the purity and confirm the molecular weight simultaneously. In cases where the purity of the sample has been determined by other means, a flow injection analysis (AIF) was used instead of the complete chromatography analysis. In any case, both positive and negative ion spectra were collected. Conditions for obtaining the mass spectrum: For all experiments, the mass spectrometer was confirmed in the electrospray mode with the cross flow counter electrode. A flow divider was P1123 used to reduce the flow from HPLC to 40% of the original flow. The inlet temperature was adjusted to 140 ° C and the drying of the gas flow was adjusted to maximize the signal. The resolution of the mass spectrometer was adjusted to 0.65 urn FWHM and the data were collected in the centroid mode. In the positive ion mode, the cone voltage was adjusted to 25V, the capillary voltage was 3.8kV. In the negative ion mode, the cone voltage was adjusted to 25V and the capillary voltage was adjusted to 3.5 kV. In both the positive ion and negative ion modes, the time to obtain a full spectrum was 1 s with a changeover time of 0.25 seconds between sweeps. The range of mass swept for molecules with an expected molecular weight of less than 350 urn was 70-500 m / z while for molecules with an expected mass of more than 350 urn the mass to load swept ratio was 200- 1000 m / z. Chromatography conditions: Liquid chromatography was performed using a YMC AQ C18 column (150 mm x 3 mm with 5 μm particles and a pore size of 120 A). For all analyzes, MeCN with 0.2% formic acid was combined with water with 0.2% formic acid to form the gradient of the eluent. The gradient profile consisted of a start with 15% MeCN: water, increasing the amount of MeCN linearly for ten minutes or 90%. That P1123 concentration was kept constant for 2 minutes before returning to the initial conditions. During the complete analysis, the flow rate was 0.9 mL / min. Flow injection conditions: A 1: 1 mixture of water to MeCN (both with 0.2% added formic acid) was used to obtain the AIF data. The flow rate was adjusted to 0.3 mL / min.

H1 NMR All H1 NMR spectra were obtained using an AMX-500 NMR spectrometer from Bruker Instruments in the given solvent.

METHODS OF SYNTHESIS General procedure for the preparation of the compounds of Formula I Form C (Schemes I-VI).

Procedure for the preparation of the analogs 5a-5bd.

Scheme I.

Step 4 R, -C02H In Schemes 1-VIII, the variable LR refers to the linker-resin agent and is defined as shown above in Scheme I. Step 1. A portion of 6.7 g (0.8 mmoles / gram of filler, 5.36 mmoles) of hydrochloride salt P1123 4-methyl benzhydrylamine (Scheme I) was washed with DMF (3 X 50 mL), 10% DIEA / DMF (3 x 50 mL) and N-methylpyrrolidinone (NMP) (3 x 50 mL). To a suspension of the resin washed in 25 mL of NMP was added successively Compound 1 (1.1 eq, 3.5 g, 5.90 mmol) DIEA eq, 3.1 mL, 17.70 mmol) 1-hydroxybenzotriazole hydrate (HOBt) (1.1 eq, 797 mg, 5.90 mmol), and O-benzotriazole-N hexafluorophosphate, N, N, N '-tetramethyl-uronium (HBTU) (1.1 eq, 2.24 g, 5.90 mmol). Compound 1 was prepared according to the literature procedure of A.M. Murphy et al, J. Am Chem. Soc. , 114, pp. 3156-3157, (1992). The mixture was kept stirring overnight at room temperature using an articulated arm stirrer. The resulting mixture was filtered, and the resin was rinsed with DMF then treated with 12 mL of 20% acetic anhydride solution in DMF for 30 minutes at room temperature. The mixture was filtered, and the resin was washed successively with DMF (2 x 50 mL), CH 3 OH (50 mL), DMF / CH 2 C 12 1: 1 (2 x 50 mL), CH 30 H (50 mL) and CH 2 Cl 2 (3 x 50 mL). After drying under vacuum, 9.0 grams of resin 2 were obtained (0.48 mmoles / gram of charge). Step 2: To 4.5 g of resin 2 (0.48 mmole / gram, 2.16 mmole) was added 25 mL of a 20% piperidine solution in DMF. The suspension was stirred at room temperature for 5 minutes and drained. He P1123 procedure was repeated for 20 minutes. The resin was then washed successively with DMF (2 x 40 mL), CH3OH (40 mL), CH2C12 (2 x 40 mL), CH3OH (40 mL) and NMP (40 mL). To a suspension of resin in 40 mL of NMP was added 2.92 g of N-Fmoc-Proline (4 eq, 8.64 mmol), 3.0 mL of DIEA (8 eq, 17.28 mmol), 1.17 g of HOBt (4 eq. 8.64 mmoles) and 3.27 g of HBTU (4 eq, 8.64 mmoles). The mixture was kept stirring overnight and drained. This coupling procedure was repeated for 3 hours. Then the resin was washed successively with DMF (2 x 40 mL), CH3OH (40 mL), DMF / CH2C12 1: 1 (2 x 40 mL), CH3OH (40 mL) and CH2C12,, (3 x 40 mL), and briefly dried under vacuum to obtain resin 3. Step 3: A suspension of resin 3 in 25 mL of a 20% piperidine solution in DMF was stirred at room temperature for 5 minutes. The suspension was drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 x 40 mL), CH3OH (40 mL), CH2C12 (2 x 40 mL), CH3OH (40 mL) and NMP (2 x 40 mL). To a suspension of resin in 40 mL of NMP was added 2.93 g of N-Fmoc-valine (4 eq, 8.64 mmol), 3.0 mL of DIEA (8 eq, 17.28 mmol), 1.17 g of HOBt (4 eq. 8.64 mmoles) and 3.27 g of HBTU (4 eq, 8.64 mmoles). The mixture was kept stirring overnight and drained. This coupling procedure was P1123 repeated for 3 hours. Then the resin was washed successively with DMF (2 x 40 mL), CH3OH (40 mL), DMF / CH2C12 1: 1 (2 x 40 mL), CH30H (40 mL) and CH2C12 (3 x 40 mL), and dried under vacuum to obtain resin 4 (0.45 mmole / gram). Step 4. To a portion of 0.05 mmole of resin 4 was added 2 mL of a 20% solution of piperidine in DMF. The suspension was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resulting resin was washed successively with DMF (3 x 5 mL), CH30H (5 mL), and NMP (3 x 5 mL). Then the desired carboxylic acid (4 eq, 0.2 mmol) was added, followed by 0.8 mL of a 0.25M solution of HOBt in NMP, 0.14 mL of DIEA (8 eq, 0.4 mmol) and 0.8 mL of a 0.25M solution of HBTU in NMP. The mixture was stirred at room temperature overnight and drained. The resin was washed successively with DMF (2 x 5 mL), CH3OH (5 mL), DMF / CH2C12 1: 1 (2 5 mL), CH30H (5 mL) and CH2C12 (3 x 5 mL), and dried under empty. A 2 mL portion of a 95% solution of TFA in water was then added to the resin. The mixture was stirred at room temperature for one hour, and filtered. The filtrate was evaporated and the residue was reconstituted in acetonitrile-water and purified by preparative HPLC to yield compounds 5a-5bd. Product performance, conditions Analytical HPLC P1123, HPLC retention time, product purity, and mass spectrum data are "obtained by the examples: 5a-5bd, 7a-7at, 9a-g, 15a-15f, 16a -16b, 17a-17e, 18a-18f, 20a-20t, 23a-23i, 24a-24e, 25a-25e, 26a-26h, 27a-27n, 28a-28c, 29a-29s, 32a-32e provided in the Table 1, unless otherwise noted.

Table 1. Physical data for the selected examples.

P1123 P1123 Pll23 P1123 P1123 P1123 123 P1123 Procedure for the preparation of the 7a-7at analogues, Scheme II Step 4 RTCO? H The 7a-7at analogs were prepared as described above in Scheme I only that P1123 substituting Fmoc-valine for Fmoc-alanine in step 3 (scheme II). Step 3. A suspension of resin 3 (3.5 g, 1.75 mmol) in 20 mL of a 20% piperidine solution in DMF was stirred at room temperature for 5 minutes. The suspension was drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 x 30 ml), CH 3 OH (30 ml), CH 2 Cl 2 (2 x 30 ml), CH 30 H (30 ml) and NMP (2 x 30 ml). To a suspension of resin in 30 mL of NMP was added successively 1.44 g of N-Fmoc-alanine (4 eq., 7.0 mmoles), 2.4 mL of DIEA (8 eq, 14.0 mmol), 0.95 g of HOBt (4 eq, 7.0 mmol) and 2.66 g of HBTU (4 eq, 7.0 mmol). The mixture was kept stirring overnight at room temperature and drained. This coupling procedure was repeated for 3 hours. Then the resin was washed successively with DMF (2 x 30 mL), CH3OH (30 mL), DMF / CH2C12 1: 1 (2 x 30 mL), CH3OH (30 mL) and CH2C12, (3 x 30 mL), and dried under vacuum to obtain resin 6. (0.5 mmole / gram). Step 4: To a portion of 0.125 mmoles of resin 6 was added 5 mL of a 20% solution of piperidine in DMF. The suspension was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resulting resin was washed successively with DMF (3 x 5 mL), CH 3 OH (5 mL), and NMP (3 x 5 mL). Then it was P1123 added the desired carboxylic acid (4 eq, 0.6 mmol), followed by 2.0 mL of a 0.25 M solution of HOBt in NMP, 0.35 mL of DIEA (8 eq, 1.0 mmol) and 2.0 mL of a 0.25 M solution of HBTU in NMP The mixture was stirred at room temperature overnight and drained. The resin was washed successively with DMF (3 x 5 mL), CH30H (5 mL), DMF / CH2C12 1: 1 (2 x 5 mL), CH3OH (5 mL) and CH2C12 (3 x 5 mL), and dried under vacuum. Then a 5 mL portion of a 95% solution of TFA in water was added to the resin. The mixture was stirred at room temperature for one hour, and filtered. The filtrate was evaporated and the residue was dissolved in acetonitrile-water and purified by preparative HPLC to yield the compounds 7a-7at.

P1123 123 2. 3 Procedure for the preparation of analogs 9a-9g.

P1123 Scheme III Step 1: A portion of 10.0 g (0.75 mmoles / gram of charge, 7.5 mmoles) of AgroPore aminomethyl resin (Catalog number 800047) was washed with DMF (3 x 40 mL), DIEA 10% / DMF (3 x 40 mL), DMF and NMP (3 x 40 mL). To the previous resin was added successively the compound 1 P1123 (0.87 eq, 3.88 g, 6.55 mmoles) HBTU (1.14 eq, 3.13 g, 8.25 mmole), HOBt (1.14 eq, 1.26 g, 8.25 mmole), and NMP (40 mL). Then the reagents were mixed by bubbling nitrogen through the bottom of the flask for two minutes at room temperature. N, N-diisopropyl-ethylamine (3.33 eq., 4.35 mL, 25 mmol) was added and the resulting suspension was mixed at room temperature overnight, filtered, then washed successively with NMP (3 x 40 mL) and DMF ( 3 x 40 mL). Then the resin was treated with 50 mL of 20% acetic anhydride solution in DMF for 38 minutes at room temperature. The mixture was filtered, and the resin was washed successively with NMP (3 x 40 mL), CH2Cl2 (3 x 40 mL) CH30H / CH2C12 1: 1 (3 x 40 mL) and CH3OH (3 x 40 mL). After drying under vacuum, 13.76 grams of resin 2 (0.35 mmoles / gram of charge) were obtained. Step 2: Seven reaction vessels were each charged with 181 mg of resin 2 (0.48 mmole / gram, 0.063 mmole), then washed with CH2C12 (3 x 1 mL) and NMP (3 x 1 mL). Then each container was treated with 1 mL of a 25% piperidine solution in DMF and mixed (vortexing) at room temperature for 15 minutes. This procedure was repeated in triplicate. Each vessel was then washed three times with NMP (3 x 1 mL). The containers were treated with 500 μl of a solution of (2S, 4R) -Fmoc-4-amino-1-Boc acid.

Pll 3 pyrrolidin-2-carboxylic acid 0.4 M / HOBt 0.4 M / NMP, 500 μl of a 0.4 M HBN / NMP solution, and 250 μl of a 1.6 M DIAM / NMP solution, and mixed for 3 hours at room temperature . After mixing, the vessels were drained and the procedure repeated. Step 3: The resulting resin was washed with NMP (3 x 1 mL) and then treated with 1 mL of a 25% piperidine solution in DMF and mixed (vortexing) at room temperature for 15 minutes. This procedure was repeated in triplicate. The resulting resin was washed with NMP (3 x 1 mL) then treated with acetic anhydride, or isopropyl isocyanate, or methane-sulfonyl chloride, or methyl chloroformate. For acetic anhydride: 300 μl of 1.6 M DIEA / NMP solution and 1 ml of 0.5 M acetic anhydride solution / 0.125 M DIEA / 0.015 M HOBt in NMP are added. For isopropyl isocyanate: 300 μl of a 1.6 M DIEA / NMP solution and 1 ml of a 1 M isopropyl isocyanate solution in NMP are added. For methane sulfonyl chloride: 600 μl of a solution of 1 M pyridine in CH 2 C 12 and 600 μl of a solution of 1 M methanesulfonyl chloride in CH 2 C 12 is added. For methyl chloroformate: 500 μl of a 1.6 M DIEA / NMP solution and 1 ml of a 0.7 M methyl chloroformate solution in CH2C12 are added. The resulting suspensions were mixed for 6 hours at room temperature, the solvent was drained and the P1123 repeated the coupling procedure. Step 4: The resulting resin was washed with NMP (3 x 1 mL) then treated with a 1: 1 mixture of TFA / CH2C12 at room temperature for 30 minutes. The resulting resin was then washed with CH2C12 (2 x 1 mL) and NMP (3 x 1 mL). Then the resin was treated with 500 μl of a solution of Fmoc-valine-0.4 M carboxylic acid / 0.4 M HBOt / NMP, 500 μl of a 0.4 M HBN / NMP solution and 250 μl of a 1.6 M DIAM / NMP solution and mixed for 3 hours at room temperature. After mixing, the vessels were drained and the coupling procedure was repeated. Step 5: The resulting resin was washed with NMP (3 x 1 mL) then treated with 1 mL of a 25% piperidine solution in DMF and mixed (until vortex formation) at room temperature for 15 minutes. This procedure was repeated in triplicate. The resulting resin was washed with NMP (3 x 1 mL), then treated with 500 μL of a solution of 1-isoquinoline-0.4 M carboxylic acid / 0.4 M HBOt NMP or 500 μL of 0.4 M p-anisic acid solution / HBOt 0.4 M / NMP. The resulting mixtures were treated with 500 μl of a 0.4 M HBN / NMP solution and 250 μl of a 1.6 M DIAM / NMP solution and then mixed for 3 hours at room temperature, the solvent was drained and the procedure was repeated. The resulting resin was treated with 1.5 mL of a 95% solution of TFA in water and stirred P1123 at room temperature for one hour then was filtered. The filtrate was evaporated, and the residue was reconstituted in a 2: 1: 2 DMF / acetonitrile / water mixture and purified by preparative HPLC to yield compounds 9a-9g.

P1123 Procedure for the synthesis of analogues 15-18 Scheme IV , R3 = C H (CH3) 2 17, R3 = CH (CH3) 2 16, R3 = C H3 18, R3 = CH3 P1123 Preparation of analogous compounds 15 and 16 (Scheme IV): Synthesis of 1- (9H-fluoren-9-ylmethyl) 4-tert-butyl ester of 2- (S) -piperazin-1,2 acid, 4-tricarboxylic. To a solution of 2 - (S) -piperazine-carboxylic acid (Lonza) (3 g, 15 mmol) in H20: dioxane 1: 1 (30 mL) was added a solution of (Boc) 20 in dioxane (3.3 g). , 15 mmoles, in 5 mL of dioxane) while maintaining the pH in 11 with NaOH IN. The pH was maintained for 3 hours at room temperature. The solution was adjusted to 9.5 pH with IN HCl, cooled to 0 ° C and treated with Fmoc-Cl (3.87 g, 15 mmol). The pH was maintained at 9.5 for 1 hour and the mixture was stirred at room temperature overnight. The resulting suspension was filtered and the filtrate treated with KHS04 IN at pH 2 was then extracted with ethyl acetate (2 x 75 mL). The organic layer was dried with brine and filtered through MgSO, and concentrated to give a colorless oil. The oil was dissolved in ethyl acetate and added to hexane to give 3.5 g (51% yield) of a white solid after separation. MRN H1 (500 MHz, DMSO-ds) d 1.55 (s, 9H), 2.80-3.5 (m, 3H), 3.8-4.9 (m, 5H), 5.7 (bs, 1H), 7.3 (m, 2H), 7.3-7.9 ppm (m, 8H), LC / MS (ES +) m / e 451.3 (MH). Step 1: To 5 g of resin 2 (0.375 mmole / gram, P1123 1.82 mmole) was added 25 mL of a 20% piperidine solution in DMF. The suspension was stirred at room temperature for 5 minutes and drained. The procedure was repeated for 20 minutes. The resin was then washed successively with DMF (2 x 50 mL), CH 3 OH (50 mL) and CH 2 Cl 2 (2 x 50 mL), CH 3 OH (50 mL) and NMP (50 mL). To a resin suspension was 25 mL of NMP was added successively 3.5 g of N-Fmoc-Boc-piperazine-carboxylic acid (4 eq., 7.48 mmol), 1.0 mL of DIEA (8 eq., 14.96 mmol), 1.01 g of HOBt (4 eq., 7.48 mmoles) and 2.83 g of HBTU (4 eq., 7.48 mmoles). The mixture was stirred overnight at room temperature and then drained. This coupling procedure was repeated for 3 hours. Then the resin was washed successively with DMF (2 x 50 mL), CH3OH (50 mL), DMF / CH2C12 1: 1 (2 x 50 mL), CH30H (1 x 50 mL) and CH2Cl2 (3 x 50 mL), and dried briefly under vacuum to produce the resin 10. Step 2: To 5 grams (0.335 mmol / gram of filler, 1675 mmol) of resin 10 was added 25 mL of a 20% solution of piperidine in DMF. The suspension was stirred at room temperature for 5 minutes and drained. The resin was then washed successively with DMF (2 x 50 mL), CH3OH (50 mL), CH2C12 (2 x 50 mL), CH3OH (50 mL) and NMP (2 x 50 mL). To a resin suspension in 25 mL of NMP was added 2.08 g of N-Fmoc-valine or N-Fmoc successively.

P1123 alanine (4 eq, 6.7 mmoles), 1.17 mL of DIEA (4 eq, 6.7 mmoles), 0.905 g of HOBt (4 eq, 6.7 mmoles) and 1.38 g of HBTU (4 eq, 3.66 mmoles). The mixture was stirred overnight at room temperature and drained This coupling procedure was repeated for 3 hours, Then the resin was washed successively with DMF (2 x 50 mL), CH 3 OH (50 mL), DMF / CH 2 C 12 1: 1 (2 x 50 mL), CH 3 OH (50 mL) and CHC 1 (3 x 50 mL), and dried under vacuum to produce resin 11 or 12, respectively. (0.35 mmoles / gram, 5 g). Step 3: To a portion of 1.5 g (0.165 mmoles) of resin 11 or 12 was added 2 mL of a 20% solution of piperidine in DMF. The suspension was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resulting resin was washed successively with DMF (3 x 15 mL), CH 3 OH (15 mL) and NMP (3 x 15 mL) Then the desired carboxylic acid was added (4 eq., 0.66 mmol), followed by 0.25 g HBOt ( 0.6 mmoles), 0.12 mL of DIEA (4 eq, 0.66 mmoles) and 0.89 g (0.66 mmoles) of HBTU in NMP. The mixture was stirred overnight at room temperature and then drained. The resin was washed successively with DMF (2 x 15 mL), CH3OH (15 mL), DMF / CH2C12, 1: 1 (2 x 15 mL), CH30H (15 mL) and CH2C12 (3 x 15 mL), dried under vacuum to produce 13 or 14. - Step 4: A 2 mL portion of a solution to P1123 95% TFA in water was added to the resin. The mixture was stirred at room temperature for one hour, and filtered. The filtrate was evaporated, and the residue was reconstituted in acetonitrile-water and purified by preparative HPLC to yield compounds 15 and 16.

P1123 Procedure for the synthesis of analogous compounds 17 and 18 (see scheme IV): Step 5: Resin 13 or 14 was treated with 2 ml of 25% TFA / CH2Cl2 for 30 minutes and washed with DMF (2 x 5 mL), DIEA 10% / CH2C12 (2 x 5 mL), DMF / CH2C12 (2 x 5 mL), CH3OH (5 mL) and CH2C12 (3 x 5 mL) and dried for five minutes. The resulting resin was washed with NMP (3 x 1 ml) then treated with acetic anhydride, or methoxacetic acid, or 2-propane-sulfonyl chloride, or isopropyl isocyanate, or methane-sulfonyl chloride, or methyl chloroformate. according to the procedure used to prepare the analogous compounds 9 (scheme III). Compounds 17, 18 were obtained as described in step 4 for compounds 15 and 16. Compounds 17a and 17b were prepared by reductive amination using Na (OAc) 3BH and HCHO (38% in water, 0.2 mL) and CH3C00H (0.02 mL) prior to step 4 and compound 18c was prepared by the treatment with Phosgene followed by ammonia prior to step 4.

P1123 P1123 Process for the Preparation of Analogs 20. Compounds 20a-20t were prepared according to the procedure described for compounds 5 (Scheme I) only by substituting the Fmoc-valine with the appropriate Fmoc-amino acid in Step 3 (Scheme V) ). Scheme V Step 4 R? -CQH Preparation of 3- (. {1-l- [2- (4-amino-3-chloro-benzoyl-amino) -3-methyl-sulfonyl-propionyl] -pyrrolidin-2-carbonyl} -animo) -4 -oxo-butyric (20i). A suspension of 0.132 mmol of resin 3 in 4 ml of 20% piperidine in DMF was stirred at room temperature for 5 minutes, and the mixture was drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times) CH30H (one time), CH2C12 P1123 (2 times), CH3OH (once), NMP (2 times). To a suspension of the resin in 4 ml of NMP was added successively 189 mg of N-Fmoc-methyl-cysteine (4 q, 0.528 mmole), 0.185 ml of DIEA (8 eq., 1.056 mmole), 71 mg of HOBt (4 eq., 0.528 mmole) and 200 mg of HBTU ~~ (4 eq., 0.528 mmole). The mixture was stirred overnight at room temperature and then drained. This coupling procedure was repeated for 3 hours. Then the resin was washed successively with DMF (2 times) CH3OH (once), and DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CHC12 (3 times), and dried under vacuum. A suspension of 100 mg of this resin in 2 mL of 20% piperidine in DMF was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times), CH3OH (once), CH2C12 / (2 times), CH3OH (once) and NMP (2 times). To a suspension of the resin in 2 ml of NMP was added successively 38 mg of 4-amino-3-chlorobenzoic acid (4 eq., 0.2 mmoles), 0.140 ml of DIEA (8 eq., 0.4 mmoles), 27 mg of HOBt (4 eq., 0.2 mmoles) and 76 mg of HBTU (4 eq., 0.4 mmoles). The mixture was stirred overnight at room temperature and then drained. Then the resin was washed successively "with DMF (2 times) CH3OH (once) and DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CH2C12 (3 times) and dried under vacuum. HE P1123 treated with 2 mL of 95% TFA in water for 1 hour. The suspension was filtered, the filtrate was concentrated under vacuum and purified by preparative HPLC to yield the title compound (20i).

Preparation of 3- (. {1 L- [2- (3, 5-dichloro-4-hydroxy-benzoyl-amino) -4-methanesulfonyl-butyryl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric (20p). Compound 20p was prepared according to the procedure used for the preparation of 20i using N-Fmoc-methionine as the first component coupled to resin 3, and 3,5-dichloro-4-hydroxybenzoic acid as the second component.

Preparation of 3 [(1 - {2- [(Isocyanin-1-carbonyl) -amino] -methane-sulfonyl-propionyl} -pyrrolidin-2-carbonyl) -amino] -4-oxo- butyric (20r). The N-Fmoc-methyl-cysteine was oxidized to the corresponding sulfone using the method of B.M. Trost and D.P. Curran, Tetrahedron Lett .. 22, pp. 1287-190 (1981). A solution of 0.714 g (2 mmoles) of N-Fmoc-methyl-cysteine in 24 ml of a 1: 1 solution of CH3OH-water stirred at 0 ° C was added 3.68 g (3 eq., 6 mmoles) of Oxone ™. The mixture was stirred at room temperature for 48 hours, diluted with water, acidified to a pH of 2 using 6N HCl, and extracted P1123 with three 100 ml portions of ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to yield 0.700 g (89% yield) of sulfone: H-NMR (DMSO-dg 500 MHz) d 2.97 (s, 3H), 3.49-3.59 (m, 2H), 4.25 (m, 1H), 4.30-4.38 (m, 2H), 4.46 (m, 1H), 7.33 (t, 2H), 7.42 (t, 2H), 7.70-8.00 (m, 4H) ); the exact mass for C? 9H? 9NOeS m / e 389.09 was calculated, m / e 390.2 was found. A suspension of 0.250 mmole of resin 3 in 10 ml of the 20% piperidine solution in DMF was stirred at room temperature for 5 minutes, and the mixture was drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times) CH30H (once), CH2C12 (2 times), CH3OH (once) and NMP (2 times). To a suspension of the resin in 6 ml of NMP was added successively 200 mg of N-Fmoc-methyl-cysteine-sulfone (4 eq., 0.50 mmol), 0.175 ml of DIEA (8 eq., 1.00 mmol), 70 mg of HOBt (4 eq., 0.50 mmol) and 188 mg of HBTU (4 eq., 0.50 mmol). The mixture was stirred overnight at room temperature and then drained. This coupling procedure was repeated for 3 hours. Then the resin was washed successively with DMF (2 times) CH3OH (once), and DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CH2C12 (3 times), and dried under vacuum. A suspension of 150 mg of this resin in 4 ml P1123 of the 20% piperidine solution in DMF was stirred at room temperature for 5 minutes and drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times) CH3OH (once), CH2C12 (2 times), CH3OH (once) and NMP (2 times). To a suspension of the resin in 3 ml of NMP was added successively 52 mg of 1-isoquinoline-carboxylic acid (4 eq., 0.3 mmol), 0.104 ml of DIEA (8 eq., 0.6 mmol 37 mg of HOBt (4 eq., 0.3 mmol) 104 mg of HBTU (4 eq., 0.3 mmol) The mixture was stirred overnight at room temperature and then drained The resin was washed successively with DMF (2 times) CH3OH (once ), and DMF / CH2C12 1: 1 (2 times), CH2C12 (3 times), and dried under vacuum, then the resin was treated with 2 m 1 of TFA-95% solution in water for 1 hour. The suspension was filtered, the filtrate was concentrated under vacuum and purified by preparative HPLC to yield the title compound (20r).

Preparation of 3- (. {1 L- [2- (3, 5-dichloro-4-hydroxy-benzoyl-amino) -4-methanesulfonyl-propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric (20s). Compound 2Os was prepared according to the procedure used for the preparation of 20i, using 3,5-dichloro-4-hydroxybenzoic acid instead of 1-isoquinolinecarboxylic acid.

P1123 Process for the preparation of analogous compounds 23. The compounds 23a-23i were prepared according to the procedure described for the compounds 7 (Scheme 11) only by substituting the Fmoc-proline with the appropriate Fmoc-amino acid in step 2 (Scheme VI).

P1123 Scheme VI Step 4 R-i-CO? H Preparation of 3- (. {2- [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -4-methyl-3,4-dihydro-2H-pyrazole-3-carbonyl acid} . amino) -4 -oxo-butyric (23g). The compound 23g was prepared according to the procedure described for the compounds 7 only by substituting the Fmoc-proline with the 1- (9H-f luoren-9-il- P1123 methyl) 4-methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid ester (Scheme II) in step 2.

Preparation of 4-methyl-4,5-dihydro-pyrazol-1,5-dicarboxylic acid 1- (9H-fluoren-9-yl-methyl) -ester ester. To a solution of 650 mg (2 mmol) of (10,10-dimethyl-3, 3-dioxo-? 6-thia-4-aza-tricyclo [5.2.1 .O0.0] dec-4-yl) - (4-methyl-3, 4-dihydro-2H-pyrazol-3-yl) -methanone (J. Am. Chem. Soc. 119, pp. 8379-8380 (1997)) in 6 ml of water and 14 ml of THF stirred at 0 ° C was added 420 mg (10 mmol, 5 eq) of lithium hydroxide. The mixture was stirred at 0 ° C for 2 hours and at room temperature for 30 minutes it was diluted with 20 ml of water and washed with ether (20 ml). The pH of the solution was then adjusted to 9, and a solution of 519 mg (2 mmoles, 1 eq) of Fmoc-Cl in 3 ml of dioxane was added. The mixture was stirred overnight at room temperature, washed with ether, acidified to a pH of 2-3 and extracted with three 40 ml portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO) and concentrated in vacuo to yield 690 mg (98% yield) of a colorless foam that was identified as the title compound: H1-NMR (DMSO-d6, 500 MHz) d 1.2 (d, 3 H), 3.2 (m, 1 H), 4.2-4.6 (m, 3 H), 7.1 (s, 1H), 7.2-7.5 (m, 5H), 7.7-8.0 (m , 4H). The exact mass was calculated for C2oH? 8N204 m / e 350.13, m / e 351.3 was found Preparation of 3- (. {1 - l- [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -4-methoxy-pyrrolidin-2-carbonyl} -amino) -4-oxo acid -butyric (23i). Compound 23i was prepared according to the procedure described for compounds 7 only by substituting Fmoc-proline with N-Fmoc-4-methoxy-proline (scheme II) in step 2. Preparation of N-Fmoc-4- methoxy proline: To a solution of 735 mg (3 mmol) of N-Boc-4-hydroxyproline methyl ester in 20 mL of THF stirred at 0 ° C was added 79 mg (1.1 q, 3.3 mmol) of hydride of sodium at 60% in mineral oil. The mixture was stirred at 0 ° C for 1 hour, and methyl iodide (0.56 mL, 3 eq, 9 mmol) was added. The mixture was stirred overnight at room temperature, quenched with the addition of saturated aqueous ammonium chloride, diluted with water, and extracted with three 80 ml portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under vacuum to yield a pale yellow oil. The oil was recovered in 9 mL of CH3OH and 3 mL of water, and 378 mg (3 eq, 9 mmol) of lithium hydroxide was added. The mixture was stirred overnight at room temperature, diluted with water, acidified to a P1123 pH of 3 and extracted three times with 80 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO) and concentrated in vacuo. The residual oil was taken up in 10 ml of TFA and the solution was stirred at room temperature for 2 hours, and concentrated in vacuo. The residual oil was diluted with 6 ml of 10% aqueous sodium carbonate solution and 3 ml of dioxane, and a solution of 9-fluorenyl-methyl chloroformate (779 mg, 1 eq, 3 mmol) in 5 mL was added. of dioxane. The mixture was stirred overnight at room temperature, diluted with water, acidified to a pH of 3 and extracted with three 80 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield an oil, which was purified by column chromatography on silica gel eluted with CH2Cl2 / CH3OH 20: 1, to yield 600 mg ( 55%) of N-Fmoc-4-methoxy-proline: The exact mass was calculated for C2? H23N05 m / e 367.14, m / e 368.4 was found. To a portion of 0.125 mmole of resin 2 was added 4 mL of 20% piperidine in DMF. The mixture was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times), CH3OH (once), CH2Cl2, (2 times), CH3OH (once) and? MP (2 times). To a suspension of the resin in 4 mL of NMP, 184 mg of N-Fmoc-4-methoxy-proline (4 eq., 0.50 mmole), 0.175 mL of DIEA (8 eq., 1.00 mmole), 70 mg of HOBt (4 eq., 0.50 mmole) and 188 mg of HBTU (4 eq., 0.50 mmole). The mixture was stirred overnight at room temperature and drained. This coupling procedure was repeated for 3 hours. The resin was washed successively with DMF (2 times) CH3OH (once), and DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CH2C12 (3 times), and dried under vacuum. To the resin was added 4 ml of 20% piperidine in DMF. The mixture was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times) CH3OH (once), CH2C12 (2 times), CH3OH (once) and NMP (2 times). To a suspension of the resin in 4 mL of NMP was added successively 156 mg of N-Fmoc-alanine (4 eq., 0.50 mmol), 0.175 mL of DIEA (8 eq., 1.00 mmol), 70 mg of HOBt ( 4 eq., 0.50 mmole) and 188 mg of HBTU (4 eq., 0.50 mmole). The mixture was stirred overnight at room temperature and drained. This coupling procedure was repeated for 3 hours. Then the resin was washed successively with DMF (2 times) CH3OH (once), and DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CH2C12 (3 times), and dried under vacuum.

P1123 To the resin was added 4 mL of the 20% piperidine solution in DMF. The mixture was stirred at room temperature for 5 minutes, and drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times) CH3OH (once), CH2C12 (2 times), CH30H (once) and NMP (2 times). To a suspension of the resin in 4 mL of NMP was added successively 80 mg of 4-amino-3-chlorobenzoic acid (4 eq., 0.50 mmol), 0.175 mL of DIEA (8 eq., 1.00 mmol), 70 mg. of HOBt (4 eq., 0.50 mmoles) and 188 mg of HBTU (4 eq., 0.50 mmoles). The mixture was stirred overnight at room temperature and drained. Then the resin was washed successively with DMF (2 times) CH3OH (once), and DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CH2C12 (3 times), and dried under vacuum. The resin was treated with 4 mL of 95% TFA solution in water for 1 hour. The mixture was filtered. The filtrate was concentrated under vacuum to produce an oil, which was purified by HPLC to yield the title compound (23i).

P1123 P1123 Process for the preparation of analogous compounds 24a-e. Compounds 24a-24e were prepared according to the procedure described for compounds 5 (Scheme I) only by substituting Fmoc-proline with Fmoc-azetidine-carboxylic acid or trans-2-phenyl-Fmoc-azetidine-carboxylic acid in Step 2 24c Process for the preparation of analogous compounds 25. Compounds 25a-25e were prepared from P1123 according to the procedure described for compounds 5 and 7 (scheme I and scheme II) only replacing the Fmoc-proline with the Fmoc-2 (S) -pipecolic acid in step 2 and coupling the Fmoc-valine or Fmoc- alanine or Fmoc-ter-leucine in step 3.

Procedure for the preparation of analogs 26a-h. The compounds 26a-26h. were prepared according to the procedure described for compounds 23 (scheme VI) only by substituting Fmoc-alanine with Fmoc-valine in step 3.

P11.23 Procedure for the preparation of analogues 27. Compounds 27a-27n were prepared according to the procedure described for compounds 7 (scheme II) only by substituting Fmoc-proline with Fmoc-4, 4-difluoro-proline in step 2.

Preparation of N-Boc-4, 4-difluoro-proline-methyl ester: To a solution of 9.63 mL (7.2 mmol) of oxalyl chloride in 10.6 mL of CHC12 stirred at -78 ° C was added a solution of 0.94. mL (13.2 mmol) of methyl sulfoxide in 15 mL of CH2C12. The solution was stirred at -78 ° C for 30 minutes. Then a solution of 1.47 g (6 mmol) of N-Boc-4-hydroxy-proline methyl ester in 19 mL of CH2C12 was added dropwise. The mixture was stirred at -78 ° C for 1.5 hours, and 3.34 mL (24 mmol) of triethylamine was added. The solution was allowed to warm to room temperature and stirred overnight. Then it was diluted with 100 ml of CH2C12, washed successively with 100 ml of water, 100 ml of IN HCl, and 100 ml of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with ethyl acetate / hexanes, 1: 3), to produce 1. 294 g (89% yield) of N-Boc-4-oxo-proline methyl ester, H-NMR (500 MHz, CDC13) d 1.45 (m, 9 H), 2.60 (m, 1 H), 2.95 ( m, 1 H), 3.75 (m, 3 H), 3.90 (m, 2 H), 4.80 (m, 1 H). To a solution of 808 mg (3.33 mmoles) of N-Boc-4-oxo-proline methyl ester in 13 mL of CH2C12 stirred at 0 ° C was added 0.88 mL (7.19 mmole, 2.2 eq) of DAST. Mix P1123 was stirred at 0 ° C for 2 hours, at room temperature for 16 hours, and poured into ice-water. The mixture was stirred at room temperature for 2 hours. The organic phase was separated, washed with water, dried (MgSO 4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with ethyl acetate / hexanes, 1: 8), to yield 754 mg (79% yield) of difluorinated derivative as a pale yellow oil. NMR H1 (500 MHz, CDC13) d 1.50 (m, 9H), 2.45 (m, 1 H), 2.70 (m, 1 H), 3.75 (m, 3H), 3.80 (m, 2H), 4.50 ( m, 1H).

Preparation of N-Fmoc-4, 4-difluoro-proline: To a solution of 754 mg (2.85 mmol) of N-Boc-4, 4-difluoro-proline methyl ester in 5 mL of THF stirred at 0 ° C a solution of 179 mg (4.27 mmoles) of lithium hydroxide in 5 mL of water was added. The solution was stirred at 0 ° C for 3 hours, at room temperature for 1 hour, diluted with water, extracted with ether, acidified to pH 2-3, and extracted with two 30 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield 652 mg (91%) of acid as a pale yellow solid. A solution of 652 mg (2 mmoles) of N-Boc-4,4-difluoro-proline in 10 mL of 1: 1 TFA / CHCl2 was stirred at 0 ° C for 45 minutes, and concentrated in vacuo. The residue P1123 was absorbed in 3 mL of dioxane, and 5 mL of 10% aqueous sodium carbonate was added, followed by a solution of 675 mg (1 eq) of Fmoc-Cl in 5 mL of dioxane. The mixture was stirred at room temperature for 16 hours, diluted with 20 mL of water, extracted with 2 portions of 20 L of diethyl ether, acidified to a pH of 2 and extracted with three 30 mL portions of ethyl acetate. ethyl. The combined organic extracts were washed with 50 mL of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2 / CH3OH 10: 1), to yield 850 mg (88%) of N-Fmoc-4,4-difluoroproline as a brown solid. NMR H1 (500 MHz, CDC13) d 2.55 (m, 1H), 2.95 (m, 1H), 3.80 (m, 2H), 4.20 (m, 1H), 4.30 (m, 2H), 4.55 (m, 1H) , 7.32 (m.2H), 7.45 (m, 2H), 7.70 (m, 2H), 7.90 (m, 2H). The exact mass for C20H? 7F2NO4 m / e 373.11 was calculated, m / e 374.4 was found.

The compounds 28a-28c were prepared according to the procedure described for compounds 5 and 7 (scheme I and scheme II) only by replacing the Fmoc-proline with Fmoc-dimethyl-thio-proline in step 2.

GENERAL PROCEDURES FOR A PREPARATION OF COMPOUNDS OF MODICITY A OF FORMULA 1 (SCHEME VI -VIIL). The compounds of Modality A of Formula I where R4 = H and R5 = H: Process for the Preparation of Analogs 29. Compounds 29a-29s were prepared according to the procedure described for compounds 5 (Scheme I) only by substituting Fmoc-proline with Fmoc-alanine in step 2 and using Fmoc-valine or Fmoc-alanine or Fmoc-ter-leucine in step 3. 29th 29g 29f 291 P1123 Procedure for the preparation of analogues 32. The compounds 32a-32e were prepared according to the procedure described for the compounds (Scheme I) only replacing Fmoc-proline with 2 - (3-tert-butoxy-carbonyl-amino-2-oxo-pyrrolidin-1-yl) -4-methyl-pentanoic acid (30) (catalog number from Neosystem BB02101) in step 2 followed by step 4 (Scheme VII). P1123 The compounds of the mode A Formula I wherein R2 and R3 together with the atoms to which they are attached form a 5-membered ring.

Scheme VII P1123 Compound of Modality A of Formula I where X = N-CH3.

P1123 Scheme VIII Step 3 Preparation of 3- (. {L- [N- (isoquinoline-1-carbonyl) -N-methyl-hydrazin-carbonyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (34 ). A suspension of 0.250 mmole of resin 3 (Scheme VIII) in 10 mL of the 20% piperidine solution in DMF was stirred at room temperature for 5 minutes and drained. The procedure was repeated for 20 minutes. The resin was washed successively with DMF (2 times) CH3OH (one time), DMF / CH2C12 1: 1 (2 times), CH3OH (one time) and CH2C12 (3 times), and dried briefly. To the resin was added P1123 5 mL of dry CH2C1, 0.128 mL of DIEA (3 eq, 0.75 mmol) and 0.400 mL of a 20% solution of phosgene in toluene (3 eq, 0.75 mmol). The suspension was stirred at room temperature for 1.5 hours. The mixture was drained, and the resin was washed several times with CH2C12. To a resin suspension in 5 mL of CH2C12 was added 0.133 mL of methyl hydrazine (10 eq., 2.5 mmol). The mixture was stirred overnight-at room temperature and drained. The resin was washed successively with DMF (2 times) CH3OH (one time), DMF / CH2C12 1: 1 (2 times), CH3OH (one time) and CH2C12 (3 times), and dried under vacuum. To a 0.075 mmole portion of the resin in 3 mL of NMP was added successively .52 mg of 1-isoquinoline-carboxylic acid (4 eq, 0.3 mmol), 0.19 ml of DIEA (8 eq, 0.6 mmol), 37 mg of HBOt (4 eq, 0.3 mmoles) and 104 mg of HBU / 4 eq, 0.3 mmoles). The mixture was stirred overnight at room temperature and drained. Then the resin was washed successively with DMF (2 times) CH30H (once), DMF / CH2C12 1: 1 (2 times), CH3OH (once) and CH2C12 (3 times), and dried under vacuum. The resin was treated with 4 mL of 95% TFA solution in water for 1 hour. The mixture was filtered. The filtrate was concentrated under vacuum to produce an oil which was purified by HPLC to yield the title compound (34).

Compound of Modality A Formula I where R3 = R3 = H: 3- ( { 1 - [4-amino-3-chloro-benzoyl-amino) -acetyl] -pyrrolidin-2 -carbonyl acid} amino) -4-oxo-butomer (Gl). Prepared as described for compounds 7 only by substituting Fmoc-alanine with Fmoc-glycine in Step 3 (Scheme II) to yield 4.3 mg of the title compound. LC-MS (ES +) m / e = 425.2 (M + H). 3- ( { 1 - [4-amino-3-chloro-benzoyl-amino) -acetyl] -4,4-difluoro-pyrrolidine-2-carbonyl acid} -amino) -4-oxo-butyric acid (G2). Prepared as described for compounds 7 and 27 only by substituting Fmoc-alanine with Fmoc-glycine in Step 3 (Scheme II) to produce 10.0 mg of the P1123 composed of the title. LC-MS (ES +) m / e = 461.2 (M + H).

GENERAL PROCEDURES FOR THE PREPARATION OF COMPOUNDS OF MODALITY C OF FORMULA I AND MODALITY D OF FORMULA I WHERE Y = C (SCHEMES IX-XXII) Scheme IX ROUTE A TFA P1123 ROUTE Sources for the selected ring systems.

P1123 Scheme X P1123 5-tert-Butyl-3- [2- (9H-fluoren-9-yl-methoxy-carbonyl-amino) -3-methyl-butyryl] -2-, 3-dihydroxy, ethyl ester, 3,4 ] -thiadiazole-2-carboxylic acid (37). A stirred suspension of polyvinylpyridine (2.63 g, 25 mmol) in a solution of the ethyl ester of the acid -tert-butyl-2,3-dihydro- [1,3,4] -thiadiazole-2-carboxylic acid (36), (J. Med. Chem. 34, pp439, (1991)), (2.16 g, 10 mmol) in dry toluene was treated by dropwise addition of 9H-fluoren-9-yl-methyl-acid ester ( 1-chloro-carbonyl-2-methyl-propyl) -carbamic acid (4.76 g, 12.1 mmol) in 20 mL of anhydrous toluene. After stirring for 16 hours, the suspension was filtered and the filtrate was washed with saturated sodium bicarbonate solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and evaporated to give a yellow oil. Purification by flash chromatography eluting with hexane / ethyl acetate 9/1 gave 2.66 g (49% yield) of the title compound (37) as a clear, viscous oil. NMR H1 (500 MHz, CD3OD) d 0.89 (d, 1.5H), 0.93 (d, 1.5H), 1.00 (d, 1.5H), 1.06 (d, 1.5H), 1.22 (t, 3H), 1.28 (d, 1.5H) s, 9H), 2.12-2.22 (m, 0.5H), 2.32-2.42 (m, 0.5H), 4.18-4.28 (m, 2H), 4.31-4.45 (m, 2H), 4.96-5.01 (m, 0.5 H), 5.02-5.10 (m, 0.5H), 5.52 (d, 0.5H), 5.61 (d, 0.5H), 6.10 (s, 0.5H), 6.13 (s, 0.5H), 7.27-7.34 (m , 2H), 7.35-7.42 (m, 2H), 7.56-7.64 (m, 2H), 7.73-7.78 (m, 2H).

P1123 3- (2-Acetylamino-3-methyl-butyryl) -5-tert-bu-2, 3-dihydro- [1,2,4] -thia-diazole-2-carboxylic acid ethyl ester ( 38). To a solution of (37) (Scheme IX) (0.508 g, 0.94 mmol) in CH3CN (10 mL) was added diethylamine (1 mL). The solution was stirred at room temperature for 2 hours, the solvent was removed under vacuum and the resulting oil was azeotroped with CH2C12 (4X). The crude oil was dissolved in CH2C12 (5 L) and triethylamine (0.26 mL, 1.86 mmol) and acetyl chloride (80 μL, 1.1 mmol) were added. The solution was stirred at room temperature under N2 atmosphere for 2 hours. The solvent was evaporated, and the crude material was dissolved in EtOAc and washed with 0.5 N NaHS0 (2 X), saturated NaHCO3 (2 X) and brine and dried over anhydrous Na2SO4, filtered and evaporated to give a yellow oil. Purification by flash column chromatography on silica gel using hexanes / EtOAc (95/5 to 90/10%) yielded as a yellow oil (0.301 g, 89% yield). NMR H1 (500 MHz, CDC13) d 0.88 (dd, 3H), 0.99 (dd, 3H), 1.16-1.45 (m, 12H), 2.02 (s, 3H), 2.09-2.19 (m, 0.5H), 2.30 -2.40 (m, 0.5H), 4.12-4.29 (m, 2H), 5.20-5.27 (m, 0.5H), 5.30-5.36 (m, 0.5H), 6.60 (s, 0.5H), 6.90 (s, 0.5H), 6.20-6.31 (m, 1H). Analytical HPLC (column C18), (mixture of diastereomers) 7.77, 7.98 min. LC-ME (ES +) m / e = 358.3 (M + H).

P1123 3- (2-Acetylamino-3-methyl-butyryl) -5-tert-butyl-2,3-dihydro- [1,2,4] -thiadiazole-2-carboxylic acid (39). To a solution of 38 (0.301 g, 0.84 mmol) in MeOH (10 mL) was added a solution of NaOH 1? (1.7 mL, 1.7 mmol). The reaction was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was dissolved in EtOAc and washed with? AHS04 0.5? (2 X) and brine and dried over anhydrous? A2SO4, filtered and evaporated to give the title compound as a yellow solid (0.277 g, quantitative).

Preparation of 2- (benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester (40). Compound 40 was prepared from the tert-butyl ester of 3-allyloxycarbonyl-amino-4-hydroxybutyric acid by a modification of the procedure described in Bioorcr. Med. Chem. Lett. vol. 2,? O. 6, pp. 613-618, (1992). To a solution of DMSO (27.52 g, 352 mmol) in CH2C12 (240 mL) at -78 ° C was added oxalyl chloride (24.4 g, 192 mmol). After 15 minutes, a solution of 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid tert-butyl ester (41.44 g, 160 mmol) in CH2C12 (100 mL) was added slowly and the mixture was stirred at - 78 ° C for 1.5 additional hours. DIEA (62.0 g, 480 mmol) was added and P1123 The mixture was allowed to warm to room temperature for 15 minutes. The resulting solution was diluted with CH2C12 (300 L), washed with 0.5 N NaHS04 (500 mL x 2), water (300 mL x 2), and brine (400 mL x 2). The organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum at 200 mL volume. To this solution was added benzyl alcohol (48 g, 444 mmol), followed by 3 molecular sieves of 3 Á (30 g) and p-toluene sulfonic acid (0.8 g). The reaction mixture was allowed to stir for 4 days and TFA (96 mL) was added. The resulting suspension was stirred for one hour then evaporated under vacuum. Ethyl acetate (500 mL) was added and the mixture was filtered through Celite. The filtrate was washed with saturated NaHCO 3 (500 mL x 2), water (400 ml x 2) and brine (300 ml x 2). The organic solution was dried over anhydrous Na 2 SO 4, filtered and evaporated under vacuum to give 90 g of a pale yellow oil, which was stirred with hexane (400 mL x 2) to give 31 g of the crude product from the residue of the product. lower layer. Chromatography using ethyl acetate / hexane (4/96 to 22/78) afforded 6.97 g of anti-2- (benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester (Rf greater), 4.53 g of diastereomer without and 12.97 g of the mixture of the diastereomers (total yield of 53%).

NMR H1 (500 MHz, CDC13) d for anti diastereomer: d 2.41- 2.45 (m, H), 3.02-3.07 (m, H), 4.28 (br, H), 4.50-4.80 (, P1123 3H), 4.80-5.15 (m, 2H), 5.24-5.32 (m, 2H), 5.48 (s, H), 5.88-6.00 (m, H), 7.31-7.56 (M, 5H); for diastereomer without: d 2.49-2.53 (m, 14), 2.83-2.89 (m, H), 4.57-4.65 (m, 4H), 4.87-4.90 (m, H), 5.12-5.30 (m, 3H), 5.52-5.53 (d, H), 5.88-6.00 (m, H), 7.31-7.39 (m, 5H); retention time in analytical HPLC: 10.49 min for anti diastereomer and 10.37 min for diastereomer without; LC-MS: m / z = 292 (M + H +). 3- (2-Acetylamino-3-methyl-butyryl) -5-tert-butyl-2,3-dihydro (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl) -amide. , 4] -thiadiazole-2-carboxylic acid (41). To a solution of 2- (benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester (40) (0.385 g, 1.32 mmol) in DMF (2 mL) and CH2C12 (2 mL) were added. added DMBA (0.456 g, 2.92 mmol) and Pd (PPh3) 4 (0.136 g, 0. 12 mmol) and the solution was stirred at room temperature for 15 minutes. A solution of (39) in CH2C12 was added (4.5 mL) and DMF (0.5 mL), followed by HBOT (0.168 g, 1.24 mmol) and EDC (0.256 g, 1.33 mmol). The reaction was stirred at room temperature for 18 hours under N2. The solvent was evaporated. The crude material was dissolved in EtOAc and washed with NaHS04 0.5? (2 X), saturated aHC03 (2 X) and brine and dried over anhydrous? 2SO4, filtered and evaporated to give a yellow solid. Purification by flash column chromatography gave the title compound (41) P1123 as a mixture of diastereomers (374 mg, yield 88%). NMR H1 (500 MHz, CDC13) d 0.75-1.05 (m, 6H), 1.19- 1.34 (m, 9H), 1.93-2.08 (m, 3H), 2.19-2.50 (m, 2H), 2.80- 3.03 (m , 1H), 4.56-4.93 (m, 3H), 5.02-5.20 (m, 1H), 5.46-5.56 (m, 1H), 5.95-6.16 (m, 2H), 6.86-6.95 (m, 1H), 7.20 - 7.43 (m, 5H). Analytical HPLC (column C18), (mixture of diastereomers) 8.58 min. LC-MS (ES +) m / e-519.2 (M + H).

Preparation of the acid 3-. { [3- (2-Acetylamino-3-methyl-butyryl) -5-tert-butyl-2,3-dihydro- [1,3,4] -thiadiazole-2-carbonyl] -amino} -4-oxo-butyric (42). A sample of 45 mg (0.087 mmol) of 41 was hydrolyzed according to method A (see scheme XXIII) to give 17 mg (45% yield) of the title compound. Analytical HPLC (column C18): 5.15 min. LC-MS (ES +) m / e = 429.3 (M + H). -tert-Butyl-3- [2- (4-methoxy-benzoylamino) -3-methyl-butyryl] -2,3-dihydro [1,3,4] -thiadiazole-2-carboxylic acid ethyl ester (43 ). This compound was prepared by the method indicated for compound 38 using anisoyl chloride to give 216 mg (50%) of the title compound as an amorphous solid. NMR H1 (500 MHz, CDC13) d 0.92 (d, 1.5R), 0.98 (d, 1.5H), 1.03 (d, 1.5H), 1.07 (d, 1.5H), 1.21 (t, 3H), 1.28 P1123 (s, (H), 2.21 - 2.28 (m, 0.5H), 2.41-2.48 (m, 0.5H), 3.83 (s, 3H), 4.15-4.28 (m, 2H), 5.41-5.46 (m, O.5H), 5.48-5.53 (m, 0.5H), 6.08 (s, 0.5H), 6.13 (s, 0.5H), 6.75 (d, 0.5H), 6.85 (d, 0.5H), 6.91 (d , 2H), 7.59 (d, 2H). -tert-Butyl-3- [2- (-methoxy-benzoyl-amino) -3-methyl-butyryl] -2,3-dihydro- [1,4-] thiadiazole-2-carboxylic acid (44). Prepared by the procedure described for 39 to give 180 mg (quantitative) of the title compound as a white solid. NMR H1 (500 MHz, CDC13) d 0.92 (d, 1.5H), 0.96 (d, 1.5H), 1.03 (d, 1.5H), 1.07 (d, 1.5H), 2.22-2.30 (m, 0.5H) , 2.37-2.45 (m, 0.5H), 3.83 (s, 1.5H) 3.84 (s, 1.5H), 5.41-5.48 (m, 1H), 6.14 (s, 0.5H), 6.15 (s, 0.5H) , 6.87-6.95 (m, 2H), 7.75-7.83 (m, 3H). -tert-Butyl-3- [2- (4-methoxy-benzoyl-amino) -3-methyl-butyryl] -2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide , 3-dihydro [1, 3,4] -thiadiazole-2-carboxylic acid (45a and 45b). They were prepared by the procedure indicated for compound 41 to give the title compound as 4 diastereomers. The crude material was purified by flash chromatography, eluting with a gradient of CH2C12 to CH2Cl2 / ethyl acetate (6/4) to give 31 mg of the major Rf component as a diastereomer (45a). Analytical HPLC (C18 Microsorb column): 19.87 min. H1 NMR (500 P1123 MHz, CDCI3) (one diastereomer) d 1.04 (d, 3H), 1.14 (d, 3H), 1.28 (s, 9H), 2.77 (d, 0.5H), 2.81 (d, 0.5H), 2.90 (d , 0.5H), 2.95 (d, 0.5H), 3.84 (s, 3H), 4.44-4.49 (m, 1H), 4.53 (d, 1H), 4.85 (d, 1H), 5.02-5.08 (m, IR ), 6.37 (s, 1H), 6.41 (d, 1H), 6.93 (d, 2H), 7.26-7.40 (m, 5H), 7.75 (d, 2H), 7.92-7.96 (m, 1H).

The interior Rf fraction contained 185 mg of a solid as a 3: 1: 2 mixture of diastereomers (45b). Analytical HPLC: C18 Microsorb column: 19.00, 19.26, 20.02 min, H1-NMR (500 MHz, CDC13) (3: 1: 2 mixture of 3 diastereomers) d 0.89 (d, 2.25 H), 0.98 (d, 0.75H), 1.02 (d, 0. * 5H), 1.03 (d, 1.5H), 1.08 (d, 0.25H), 1.10 (d, 0.75H), 1.16 (s, 0.75H), 1.17 (s, 2.25H), 1.23 (s, 0.375H), 1.24 (s, 1.125H), 1.28 (s, 1.125 H), 1.29 (s, 3.375H), 2.12-2.18 (m, 0.33H), 2.32- 2.42 (m, 0.67H) ), 2.43-2.51 (m, 0.5H), 2.61-2.67 (m, 0.5H), 2. 84-2.92 (m, 0.5H), 2.96-3.07 (m, 0.5H), 3.85 (s, 3H), 4. 58-4.71 (m, 2H), 4.81 (d, 0.16H), 4.86 (d, 0.32H), 4.91 (d, 0.52H), 5.09-5.13 (m, 0.33H), 5.14-5.18 (m, 0.67H), 5.35 (dd, 1H), 5.46 (s, 0.16H), 5.53 (d, 0.32H), 5.58-5.62 (d, 0.52H), 6.17 (s, 0.52H), 6.20 (s, 0.16H), 6.34 (s, 0.32H), 6.50 (d, 0.32H), 6.62 (d, 0.16H), 6.67 (d, 0.52H) 6.86 (d, 0.33H), 6.91 (d, 0.67H), 6.94 (d, 1. OH) 7.24-7.43 (m, 5H), 7.61 (d, 1H) 7.70 (d, 0.33H), 7.71 (d, 0.67H, 7.76 (d, 1H).

P1123 Preparation of 3- (. {5-tert-Butyl-3- [2- (4-methoxy-benzoyl-amino) -3-methyl-butyryl-2 acid, 3-dihydro- [1,3,4] -thiadiazol-2-carbonyl} -amino) -4-oxo-butyric acid (46a). A 45a sample of 30 mg was hydrolyzed according to method B (see Scheme XXIII) to give 8 mg (30% yield) of the desired product. Analytical HPLC (column C18 Microsorb, acetonitrile / water, with TFA buffer) 12.85 min, H1-NMR (500 MHz, CD30D) d 0.98-1.1 (m, 6H), 1.28 (s 9H), 2.20-2.31 (m, 1H ), 2.40-2.48 (m, 1H), 2.6-2.72 (m, 1H), 3.84 (s, 3H), 4.18-4.26 (m, 1H), 4.56-4.62 (m, 1H), 5.25-5.32 (m , 1H), 6.24-6.28 (m, IR), 6.98 (d, 2H), 7.85 (d, 2H).

Preparation of 3- (. {5-tert-Butyl-3- [2- (4-methoxy-benzoyl-amino) -3-methyl-butyryl] -2, 3-dihydro- [1,3,4] -thiadiazole-2-carbonyl].). -amino) -4-oxo-butyric acid (46b). A sample of 45b of 30 mg (mixture of 3 diastereomers) was hydrolyzed according to method B (see scheme XXIII) to give 22 mg (84% yield) of the desired product as a 3: 2 mixture of diastereomers.

Analytical HPLC (cyano Microsorb column) 7.08, 7.78 min.

NMR H1 (500 MHz, CD30D) d 0.98-1.08 (m, 4H), 1.09-1.12 (m, 2H), 1.29 and 1.31 (2 singles, 9H), 2.23-2.30 (m, 0.5H), 2. 36-2.55 (m, 1.5H), 2.62-2.72 (m, 1H), 3.85 (s, 3H), 4.18-4.27 (m, 1H), 4.58-4.65 (m, 1H), 5.27-5.33 (m, 1H), 6.23- P1123 6.27 (m, 1H), 7.00 (d, 2 H), 7.70-7.88 (m, 2H) Scheme XI 47 48 49 51 50 1- (2-Benzyl-oxy-carbonylamino-2-methyl-propionyl) -pyrrolidine-2-carboxylic acid tert-butyl ester (49). To a solution of proline-tert-butyl ester (47) (2.00 g, 12 mmol) in CH2C12 (15 ml) was added N-carbobenzyloxy-2-methyl-alanine (3.05 g, 13 mmol), HOBT (2.36 g, 17 mmol) and EDC (3.43 g, 18 mmoles) and the solution was stirred at room temperature under N2, for 48 hours. The solvent was evaporated, the crude material was dissolved in EtOAc and washed with 0.5 N NaHS04 (2 X), saturated NaHCO3 (2 X) and brine and dried over anhydrous Na2SO4, filtered and evaporated to give a white solid (4.68). g, 100%). NMR H1 (500 MHz, CDC13) d 1.20-2.15 (m, 4H), 1.43 (s, 9H), 1.59 (d, 6H), 3.21-3.79 (m, 2H), 4.35 (br s, 1H), 4.82 -5.19 (m, 3H), 5.74 (br s, 1H), 7.17-7.49 (m, 5H). Analytical HPLC (C18 column) 10.66 min. LC-MS (ES +) m / e = 391.3 (M + H). [1- (2- (4-methoxy-benzoyl-amino) -2-methyl-propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester (50). To a solution of compound 49 (1.00 g, 2.56 mmol) in MeOH (20 ml) was added 10% Pd / C (200 mg) and the mixture was stirred under H2 for 2 hours. The mixture was filtered through a 0.45 μm PTFE filter and the solvent was removed under vacuum to yield a colorless oil. This oil was dissolved in CH2C12 (25 mL) and DIEA (660 μL, 3.79 mmol) and p-anisoyl chloride (480 mg, 2.8 mmol) were added. The solution was stirred at room temperature under N2 for 18 hours. The solvent was removed under vacuum and the oil was dissolved in EtOAc. The organic phase was washed with 0.5 N NaHS04 (2 X), water, saturated NaHCO3 (2 X) and brine. The organic phase was dried over Na 2 SO 4, filtered and evaporated to give a white solid which was purified by P1123 Flash column chromatography eluting with CH2Cl2 / MeOH (99/1 to 98/2%) to give the title compound as a white solid (655 mg, 65% yield). NMR H1 (500 MHz, CDC13) d 1.47 (s, 9H), 1.68-2.24 (m, 5H), 1.80 (d, 6H), 3.55-3.68 (m, 1H), 3.72 -3.93 (m, 1H), 3.84 (s, 3H), 4.43-4.55 (m, 1H), 6.90 (d, 2H), 7.60 (br s, 1H), 7.77 (d, 2H). Analytical HPLC (C18 column) 8.98 min. (1- (2- (4-methoxy-benzoyl-amino) -2-methyl-propionyl] -pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (51) . To a solution of compound 50 (325 mg, 0.83 mmole) in dioxane (5 mL) was added triethylamine (463 μL, 3.32 mmol) and TMS-triflate (642 μL, 3.32 mmol) and the solution. It was stirred at 100 ° C for 5 hours, then at room temperature for 18 hours. The reaction was diluted with water, the pH adjusted to 8 with saturated NaHCO3 and extracted with Et20, dried over Na2SO, filtered and evaporated to give a white solid (230 mg, 83% yield) which was used directly. in the next step. To a solution of 2- (benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester (40) (1.027 g, 3.5 mmol) in CH2C12 (20 mL) was added DMBA (543 mg, 3.48 mmol) and Pd (PPh3) 4 (280 mg, 0.24 mmol) and the solution was stirred at room temperature under N2 for 20 minutes.

P1123 minutes A solution of 1- [2- (4-methoxy-benzoyl-amino) -2-methyl-propionyl] -pyrrolidin-2-carboxylic acid was added. (818 mg, 2.45 mmol) in CH2C12 (5 ml), followed by HBOT (0.534 3.95 mmoles) and EDC (738 mg, 3.84 mmoles). The reaction was stirred at room temperature for 18 hours under N2 The solvent was evaporated, the crude material was dissolved in EtOAc and washed with 0.5 N NaHS04 (2 X), saturated NaHCO3 (2 X) and brine and dried over anhydrous Na2SO4, filtered and evaporated to give a yellow solid. Purification by flash column chromatography eluting with ethyl acetate / hexanes (20/80 to 50/50%), gave the product as a pale yellow solid (760 mg, 61% yield). RJMN H1 (500 MHz, CD3OD) d 1.53 (d, 6H), 1.65-1.93 (m, 3H), 1.96-2.14 (m, 1H), 2.60 (dd, 0.1H), 2.77 (dd, 0.85H), 2.94 ( dd, 0.85H), 3.04-3.11 (m, 0.2H), 3.42-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.84 (s, 3H), 4.38-4.76 (m, 3H), 4.84 (d, 1H), 5.64-5.70 (m, 1H), 6.96-7.03 (m, 2H), 7.23-7.43 (m, 5H), 7.78-7.97 (m, 2H). Analytical HPLC (column C18) 13.32, 14.37 min. LC-MS (ES +) m / e = 524.3 (M + H).

Preparation of 3- (. {1 L- [2- (4-methoxy-benzoyl-amino) -2-methyl-propionyl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (52 ). A sample of 51 of 61 mg (0.14 mmol) was hydrolysed according to method C (see scheme XXIII) to give 30 mg (yield 60%) of the title compound: analytical HPLC (column C18): 6.79 min. LC-MS (ES +) m / e = 434.3 (M + H).

Scheme XII 58, X = CI.Y = NH2 56, X = H, Y = MeO 55, X = H, Y = MeO 60, X = CI, Y = NH2 59, X = CI.Y = NH2 61, X = C1, Y = NH2 P1123 1- [2- (4-Methoxy-benzoyl-amino) -3-methyl-butyryl] -pyrrolidine-2-carboxylic acid tert-butyl ester (54). To a suspension of H-val-pro-OtBu-HCl (53) (2.011 g, 7.44 mmoles) in CH2C12 (20 mL) DIEA was added (3.2 mL, 18.4 mmol) followed by a solution of 4-methoxy-benzoyl chloride (1.26 g, 7.4 mmol) in CH2C12 (5 mL).

The solution was stirred at room temperature under nitrogen for 1 hour and then concentrated. The resulting oil was dissolved in EtOAc and washed with 0.5 N KHS04 (2 X), saturated NaHCO3 (2 X) and brine, then concentrated in vacuo to give the title compound as a white solid. (2.814 g, 94% yield). H1 NMR (500 MHz, CDC13) d 1.05 (dd, 6H), 1.46 (s, 9H), 1.88-2.29 (m, 5H), 3.65-3.74 (m, 1H), 3.81-3.92 (m, 1H), 3.85 (s, 3H), 4.32-4.42 (m, 1H), 4. 81-4.91 (m, 1H), 6.79-6.86 (m, 1H), 6.91 (d, 2H,), 7.78 (d, 2H). Analytical HPLC (cyano column) 10.18 min. [1- (2- (4-methoxy-benzoyl-amino) -3-methyl-butyryl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide ( 56). A sample of 54 of 1079 g (2.67 mmol) was dissolved in 15% TFA in CH2Cl2, (40 mL) and stirred at room temperature for 4 hours. The solvent was concentrated under vacuum to give compound 55 as a white solid (0.93 g, 100%) which was used in the P1123 next step. To a solution of compound 40 (1796 g, 6.17 mmol) in CH2C12 (20 mL) was added DMBA (1119 g, 7.17 mmol) and Pd (PPh3) 4 (0.683 g, 0.59 mmol) and the solution was stirred at room temperature. environment for 20 minutes. A solution of compound 55 (0.928 g, 2.67 mmol) in CH2C12 (17 mL) and DMF (2 mL) was added, followed by HBOT (0.811 g, 6.01 mmol) and EDC (1.16 g, 6.04 mmol). The reaction was stirred at room temperature for 18 hours under N2. The solvent was evaporated, the crude material was dissolved in EtOAc and washed with 0.5 N NaHS04 (2 X), saturated NaHCO3 (2 X) and brine and dried over anhydrous Na2SO4, filtered and evaporated to give a yellow solid. Purification by flash chromatography eluting with ethyl acetate / CH2Cl2 (10/90 to 40/60%), gave the title compound as a pale yellow solid (910 mg, 63% yield). H1 NMR (500 MHz, CDC13) d 0.96 (dd, 6H), 1.84-2.19 (m, 4H), 2.25-2.38 (m, 1H), 2.45 (dd, 1H), 2.80-2.98 (m, 1H), 3.60-3.72 (m, 1H), 3.82-3.95 (m, 1H), 3.86 (s, 3H), 4.26-4.95 (m, 6H), 5.41 (s, 0.2H), 5.53 (d, 0.8H), 6.67-6.77 (m, 1H), 6.88-6.99 (d, 2H), 7.22-7.57 (m, 5H), 7.71-7.82 (d, 2H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 9.21 min. LC-MS (ES +) m / e = 538.3 (M + H).

P1123 3- (. {1-l- [2- (4-methoxy-benzoyl-amino) -3-methyl-butyryl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (57) . A sample of 56 of 125 mg (0.23 mmol) was hydrolyzed according to method A (see scheme XXIII) to give 60 mg (58% yield) of the title compound: analytical HPLC: 5.71 min. LC-MS (ES +) m / e = 448.2 (M + H). Preparation of 4-ammonium-3-chloro-benzoic acid: A suspension of 4-amino-3-chlorobenzonitrile (4.82 g, 31.58 mmol) was heated to reflux in 6N HCl (140 ml). The precipitate dissolved upon heating to give a colorless solution. Upon further heating the solution became cloudy. After 9 hours the reaction was cooled to room temperature. The resulting precipitate was filtered, then dissolved in THF and the solvent was evaporated. The residue was repeatedly concentrated from toluene to give a white solid (3.18 g, 58% yield). H1 NMR (500 MHz, CD30D: CDC13 1: 4) d 6.80 (d, 1H), 7.75 (dd, 1H), 7.94 (* d, 1H). Analytical HPLC (cyano column): 8.73 min. [1- (2- (4-amino-3-chloro-benzoyl-amino) -3-methyl-butyryl] -pyrrolidine-2-carboxylic acid tert-butyl ester (58). To a suspension of 53 (1707 g, 0.31 mmol in CH2C12 (25 ml) at 0 ° C was added DIEA (3.2 ml, 18.4 mmol) P1123 followed by a solution of 4-amino-3-chloro-benzoic acid (1298 g, 7.56 mmoles) HBOT (1,005 g, 7.44 mmol) and EDC (1456 g, 7.58 mmoles). The resulting mixture was stirred at 0 ° C for 15 minutes then allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated and the resulting oil was dissolved in EtOAc, washed with 0.5 N NaHS04 (2 X), saturated NaHCO3 (2 X) and brine to give a white solid 2.68 g). Flash chromatography using MeOH / CH2Cl2 (1/99 to 2/98%) gave 2.04 g (76% yield) of 58 as a white solid. NMR H1 (500 MHz, CDCl3) d 1.05 (dd, 6H), 1.47 (s, 9H), 1.86-2.29 (m, 5H), 3.62-3.78 (m, 1H), 3.78-3.94 (m, 1H), 4.39 (dd, 1H), 4.79-4.89 (dd, 1H), 6.73 (d, 1H), 6.78 (d, 1H), 7.52 (dd, 1H), 7.75 (d, 1H). Analytical HPLC (cyano column): 16.18 min. LC-MS (ES +) m / e = 424.3 (M + H). (1- (2- (4-amino-3-chloro-benzoyl-amino) -3-methyl-butyryl] -pyrrolidin-2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. -carboxylic (60). A sample of compound 59 of 0.632 g (1.49 mmol) was dissolved in 50% TFA in CH2C12 (20 ml) and the solution was stirred at room temperature for 2 hours. The residual TFA was removed by repeated concentration of CH2C12 (3 times) to give the product as a white solid. A sample of 385 mg (1.04 mmol) was allowed to react with compound 40 by the method used for compound 56. The title compound (60) was isolated as a yellow solid (265 mg, 45% yield). NMR H1 (500 MHz, CD3OD) d 0.89-1.12 (m, 6H), 1.72-2.26 (m, 5H), 2.49 (dd, 0.25H), 2.60 (dd, 0.7H), 2.80 (dd, 0.75H) , 2.96-3.09 (m, 0.3H), 3.64-3.77 (m, 1H), 3.94-4.10 (m, 1H), 4.20-4.74 (m, 4H), 4.76-4.95 (m, 1H) 5.51 (s, 0.5H), 5.61-5.70 (m, 1.5H), 6.79 (dd, 1H), 7.23-7.43 (m, 5H), 7.48-7.61 (m, 1.4H), 7.68-7.81 (m, 1H) 7.99- 8.12 (m, 0.6H). Analytical HPLC (cyano column) (mixture of 2 diastereomers): 14.90, 15.20 min. LC-MS (ES +) m / e = 557.2 (M + H). 3- ( { 1 - [2- (4-Amino-chloro-benzoyl-amino) -3-methyl-butyryl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid. (61) A 60 sample of 45 mg (0.08 mmol) was hydrolysed according to method A (see scheme XXIII) to yield 30 mg (80% yield) of the title compound. NMR H1 (500 MHz, CD3OD) d 1.06 (dd, 6H), 1.78-2.38 (m, 5H), 2.38-2.86 (m, 2H), 3.62-3.83 (m, 1H), 4.12-4.76 (m, 4H), 7.04-7.21 (m, 1H), 7.58-8.01 (m, 2H); Analytical HPLC: 8.16 min. LC-MS (ES +) m / e = 467.3 (M + H).

P1123 Scheme XIII [1- (2- (4-Hydroxy-3,5-dimethyl-benzoyl-ammonium) -3-methyl-butyryl] -pyrrolidin-2-carboxylic acid tert-butyl ester. (63). To a solution of 62 (prepared from 53 and Fmoc-Cl) (600 mg, 1.22 mmol) in anhydrous DMF (10 ml) was added diethylamine (3 ml). The solution was stirred at room temperature under N2 for 3 hours and the solvent was evaporated. The resulting oil was dissolved in CH2C12 (8 ml), 3,5-dimethyl-hydroxy-benzoic acid was added (0.302 g, 1.82 mmol), HOBT (338 mg, 2.5 mmol) and EDC (0.456 g, 2.43 mmol) and the solution was stirred at room temperature under N2 for 18 hours. The solvent was concentrated under vacuum and the resulting oil was dissolved in EtOAc, washed with 0.5 N NaHS04 (2 X), saturated NaHCO3 (2 X) and brine.

P1123 to give the crude product as a white solid (0.80 g).

Flash chromatography eluting with MeOH / CH2Cl2 (1/99 to 2/98%) gave 380 mg (75% yield) of a white solid.

NMR H1 (500 MHz, CDCl3) d 1.06 (dd, 6H), 1.47 (s, 9H), 1.90-2.32 (m, 5H), 2.24 (s, 6H), 3.65-3.75 (m, 1H), 3.84- 3.92 (m, 1H), 4.36-4.42 (m, 1H), 4.82-4.88 (m, 1H), 5.53-5.61 (m, 1H), 6.77-6.85 (m, 1H), 7.42 (s, 2H) analytical HPLC (cyan column) 17.53 min. LC-MS (ES +) m / e = 419.3 (M + H). (2- (4-Hydroxy-3,5-dimethyl-benzoyl-amino) -3-methyl-butyryl] -pyrrolidine (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl) -amide. -2 -carboxylic (64). Prepared from 63 and 40 by the method used to prepare 56 to give the title compound (64) as a pale yellow solid (325 mg, 72% yield). RM? H1 (500 MHz, CD3OD) d 0.83-1.28 (m, 6H), 1.66-2.37 (m, 3H), 2. 23 s, 6H), 2.48-2.54 (m, 0.2H), 2.61 (ddd, 0.8H), 2.72 (ddd, 0.9H), 3.01-3.09 (m, 1H), 3.66-3.76 (m, 1H), 3.95- 4.07 (m, 1H), 4.48-4.73 (m, 3H), 4.75-4.92 (m, 1H) ), 5.45-5.48 (m, 0.1H), 5.61-5.64 (m, 0.1H), 5.64-5.70 (m, 0.8H), 7. 21-7.62 (m, 6H), 7.88-8.04 (m, 1H). Analytical HPLC (cyano column) • (mixture of two diastereomers) 17.73 min.

LC-MS (ES +) m / e = 552.3 (M + H).

P1123 3- ( { 1- [2- (4-hydroxy-3,5-dimethyl-benzoyl-amino) -3-methyl-butyryl] -pyrrolidin-2-carbonyl} -amino) -4- oxo-butyric (65). A sample of 64 of 160 mg (0.29 mmol) was hydrolyzed according to method A (see scheme XXIII) to give 13.1 mg (10% yield) of the title compound: analytical HPLC (cyano column): 10.28 min. LC-MS (ES +) m / e = 462.2 (M + H).

Scheme XIV 66 67 P1123 1- [2- (2-9H-Fluoren-9-yl-acetylamino) -3,3-dimethyl-butyryl] -Pyrrolidine-2-carboxylic acid tert-butyl ester. { 66). To a solution of H-pro-Boc (53) (1.033 g, 6.0 mmol, II, Scheme 5) in CH2C12 (20 ml) and DMF (5 ml) was added Fmoc-tLeu-OH (2.337 g, 6.60 mmol , 1, scheme 5), HBOT (1.63 g, 12.1 mmol) and EDC (2.30 g, 12.0 mmol) and the solution was stirred at room temperature under N2 for 18 hours. The solvent was removed under vacuum and the residue was dissolved in EtOAc, then washed with 0.5 N NaHS04 (2 X), saturated NaHCO3 (2 X) and brine. The organic layer was dried over anhydrous NaHSO 4 and evaporated to give a pale yellow solid (3.65 g). Flash chromatography using EtOAc / hexanes (10/90 to 20/80%) gave the title compound (66) (2.25 g, 74% yield). NMR H1 (500 MHz, CDC13) d 1.09 (5.9H), 1.47 (s, 9H), 1.79-2.28 (m, 3H), 3.62-3.72 (m, 1H), 3.76-3.83 (m, 1H), 4.18-4.43 (m, 4H), 5.48-5.67 (m, 1H), 7.28-7.44 (m, 4H), 7.55-7.64 (m, 2H), 7.72-7.82 (m, 2H). Analytical HPLC (cyano column) 11.95 min. LC-MS (ES +) m / e = 507.3 (M + H). [1- (2- (4-methoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine-2-carboxylic acid tert-butyl ester. (67). To a solution of 66 (0.503 g, 0.99 mmol) in DMF (8 ml) was added diethylamine (2.5 ml) and the solution was stirred at room temperature for 1 hour and the solvent was evaporated. The resulting residue was repeatedly concentrated from CH2C12 (3 X). The resulting oil was dissolved in CH2C12 (9 mL) and DIEA (260 μL, 149 mmol) and 4-methoxy-benzoyl chloride (190 mg, 1.05 mmol) were added. The solution was stirred under N2 for 18 hours and the solvent was concentrated under vacuum. The residue was dissolved in EtOAe and washed with 0.5 N NaHS0 (2 X), saturated NaHCO3 (2 X) and brine and dried over anhydrous Na2SO4 and evaporated to give a white solid (0.529 g). Flash chromatography on silica gel using MeOH / CH2Cl2 (1/99 to 2/98%) gave the title compound (2.25 g, yield 74%). NMR H1 (500 MHz, CD3OD) d 1.01 (s, 1.4H), 1.11 (s, 7.6H), 1.73-2.25 (m, 4H), 2.47-2.77 (m, 1H), 2.81 (dd, 0.7H) , 2.91-3.11 (m, 0.3H), 3.61-4.03 (m, 3H), 3.84 (s, 3H), 4.29-4.49 (m, 1H), 4.49-5.00 (m, 5H), 5.46 (s, 0.15) H), 5.58-5.73 (m, 0.85H), 6.94-7.04 (m, 2H), 7.27-7.41 (m, 4H), 7.61-7.73 (m, 1H), 7.74-7.84 (m, 2H). Analytical HPLC (cyano column): 13.10 min. (1- (2- (4-me-oxy-benzoyl-amino-3, 3-dimethyl-butyryl) -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide) (68) To a solution of 67 (0.90 g, 1.74 mmol) in CH2C12 (25 mL) was added 2,6-lutidine (2.1 mL, 18.0 mmol) and TMS-triflate (2.3 mL, 11.9 mmol) and the reaction P1123 was stirred at room temperature under N2 for 1.5 hours. The resulting mixture was diluted with CH2C12, washed with 10% NaHCO3 (2 X) and brine and dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2C12 and then treated with DIEA (0.6 ml, 3.5 mmol) and 4-methoxy-benzoyl chloride (0.355 g, 2.09 mmol) and stirring was allowed under N2 for 18 hours at room temperature. The crude product was purified by flash chromatography, eluting with CH2Cl2 / MeOH, (99/1) to yield the title compound (274 mg, 28% yield). RM1 H1 (500 MHz, CD3OD) d 1.01, (s, 1.4H), 1.11, (s, 7.6H), 1.73-2.25 (m, 4H), 2.47-2.77 (m, 1H), 2.81 (dd, 0.7H) , 2.91-3.11 (m, 0.3H), 3.61-4.03 (m, 3H), 3.84 (s, 3H), 4.29-4.49 (m, 1H), 4.49-5.00 (m, 5H), 5.46 (s, 0.15H), 5.58 -5.73 (m, 0.85H), 6.94-7.04 (m, 2H), 7.27-7.41 (m, 4H), 7.61-7.73 (m, 1H), 7.74-7.84 (m, 2H). Analytical HPLC (cyano column) (mixture of 2 diastereomers): 17.03, 17.39 min. LC-MS (ES +) m / e = 552.3 (M + H). 3- ( { 1 - [2- (4-methoxy-benzoyl-amino) -3,3-dimethyl-butyryl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid ( 69). A 68 sample of 117 mg (0.21 mmol) was hydrolyzed according to method C (see Scheme XXIII) to give 40 mg (41% yield) of the title compound: analytical HPLC 7.16 min. LC-MS (ES +) m / e = 462.3 P1123 (M + H) Scheme XV 1- (2-tert-Butoxy-carbonyl-amino-3,3-dimethyl-butyryl) -pyrrolidine-2-carboxylic acid benzyl ester (70). To a suspension of H-pro-OBzl-HCl (2.00 g, 8.66 mmol) in CHC12 (20 mL) was added DIEA (2.25 mL, 12.92 mmol) to give a colorless solution. Boc-tLeu-OH (1.95 g, 9.52 mmol), HBOT (1.76 g, 13.03 mmol) and EDC (2.49 g, 12.95 mmol) were added and the solution was stirred at room temperature under N2 for 18 hours. The solvent was removed under vacuum and dissolved in EtOAc, and water was washed, P1123 NaHS04 0.5N (2 X), NaHCO3 (2 times) and brine. Dry over anhydrous Na2SO and evaporate to give the title compound (3.57 g, 99% yield). NMR H1 (500 MHz, CDC13) d 0.99 (s, 9H), 1.40 (s, 9H), 1.88-2.33 (m, 4H), 3.58-3.90 (m, 2H), 4.21-4.35 (d, 1H), 4.53-4.66 (m, 1H), 5.04-5.38 (m, 3H), 7.14-7.42 (m, 5H). LC-MS (ES +) m / e = 419.4 (M + H).

Ter-butyl acid ester. { l- [2- (2-Benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-carbonyl] -2,2-dimethyl-propyl} -carbámico (71). A sample of 871 mg (2.08 mmol) of compound 70 was dissolved in MeOH (15 ml) and 10% Pd / C (200 mg) was added. The suspension was stirred under H2 for 1 hour and then filtered through Celite and the solvent was evaporated. This resulting residue was reacted with compound 40 according to the procedure used to prepare compound 56 to give 889 mg (71% yield) of the title compound (71). H1 NMR (500 MHz, CDC13) d 0.93 (s, 9H), 1.44 (s, 9H), 1.78-2.18 (m, 4H), 2.29-2.49 (m, 2H), 2.76-3.04 (m, 1H), 3.50-3.70 (m, 1H), 3.70 -3.85 (m, 1H), 4.20-4.37 (m, 1H), 4.49-4.78 (m, 3H), 4.78-4.98 (m, 1H), 5.12-5.26 (m, 1H), 5.40-5.59 (m, 1H), 7.10-7.78 (m, 5H). Analytical HPLC (cyano column) 11.17 min. LC-MS (ES +) m / e 518.3 (M + H).

P1123 1- [2- (4-amino-3-chloro-benzoyl-amino) -3,3-dimethyl-butyryl] -2- benzyl-5-oxo-tetrahydro-furan-3-yl) -amide] - pyrrolidin-2-carboxylic acid (72). To a solution of 456 mg (0.088 mmol) of compound 71 in CH2C12 (20 mL) was treated with anhydrous TFA (5 mL) then stirred at room temperature under N2 for 1 hour and evaporated to dryness. The residue was concentrated with several repetitions from CH2C12 (3 X) then dried under vacuum. The resulting residue was dissolved in CH2C12 (20 mL), cooled to 0 ° C, then treated with DIEA (1.3 mL, 8 eq, 2.46 mmol) followed by 4-amino-3-chloro-benzoic acid (202 mg, 1.17 mmole), HOBT (183 mg, 1.35 mmole), and EDC (279 mg, 1.45 mmole). The resulting mixture was allowed to warm to room temperature and was stirred for 18 hours. The solvent was removed under vacuum and the residue dissolved in EtOAc then washed with distilled water (3 X), with NaHS04 0.5N (2 X), saturated NaHC03 (2 X) and brine. The organic layer was dried over Na2S04, filtered and evaporated to give a residue which was purified by flash chromatography eluting with CH2Cl2 / MeOH (99/1 to 97/3%) to yield 285 mg (57% yield) of compound of title (72) as a yellow solid. NMR H1 (500 MHz, CD3OD) d 0.91-1.24 (m, 9H), 1.70-2.27 (m, 4H), 2.47-2.85 (m, 1.5H), 2.99-3.13 (m, 0.5H), 3.39-3.53 (m, 0.5H), 3.60-3.78 (m, 1.5H), 3.85-4.04 (m, 1H), 4.24-4.47 P1123 (m, 2H), 4.53-4.97 (m, 4H), 5.46 (s 0.3H), 3.88-4.02 (m, 0.1H), 5.60-5.69 (m, 0.6H), 6.80 (d, 1H), 7.22-7.77 (m, 7H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 15.90, 16.23 min. LC-MS (ES +) m / e = 571.2 (M + H). 3- ( { L- [2- (4-amino-3-chloro-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (73). A 72 sample of 40 mg (0.07 mmol) was hydrolyzed according to method A (see scheme XXIII) to yield 25 mg (74% yield) of the title compound: analytical HPLC (cyano column) 10.66 min. LC-MS (ES +) m / e = 481.3 (M + H).

Scheme XVI P1123 ter-butyl acid ester. { 2- [2- (2-Benzyloxy-5-oxo-tetrahydro-furan-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -carbámico (75). To a solution of 40 (6.69 g, 23.0 mmol) in anhydrous CH2C12 was added 1,3-dimethylbarbituric acid.

(DMBA) (3.97 g, 25.4 mmoles) and Pd (PPh3) 4 (1.12 g, 0.97 mmoles). The solution was stirred at room temperature under N2 for 15 minutes, cooled to 0 ° C, followed by the addition of Boc-ala-pro-OH (BaChem) (5.087 g, 17.8 mmol), HBOT (3.60 g, 26.7 mmol) and EDC (5.12 g, 26.7 mmoles). The resulting solution was allowed to warm to room temperature and was stirred for 18 hours under N2. The solvent was concentrated under vacuum and the residue dissolved in EtOAc and washed with NaHS04 0.5? (2 X), saturated aHC03 (2 times) and brine. The organic layer was dried over anhydrous? 2SO.sub.4, evaporated to give an orange oil (12.23 g). Flash column chromatography on silica gel using CH2Cl2 / EtOAc (80/20 to 60/40%), gave the title compound 75 as a yellow solid (7.28 g, 86% yield). RM? H1 (500 MHz, CD30D) d 1.19-1.31 (m, 3H), 1.42 (s, 9H), 1.69-2.29 (m, 4H), 2.45-2.67 (m, 0.9H), 2.71-2.86 (m, 0.5 H), 2.99-3.10 (m, 0.6H), 3.49-3.84 (m, 2H), 4.24-4.45 (m, 2.5H), 4.57-4.73 (m, 1.5H), 4.76-4.92 (m, 1H) , 5.45 (s, 0.45H), 5.63-5.68 (m, 0.55H), 7.25-7.40 (m, 5H). Analytical HPLC (cyano column): 15.99, 16.33 min. LC-MS (ES +) P1123 m / e, = 476.3 (M + H) [1- [2- (4-amino-3-chloro-benzoyl-ammonium) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide ( 76). A sample of 75 of 1899 g (3.99 mmol) in CH2C12 (20 mL) was treated with anhydrous TFA (5 mL) then stirred at room temperature under N2 for 1 hour and evaporated to dryness. The residue was repeatedly concentrated in CHC12 (3 X) and then dried under vacuum. The resulting residue was dissolved in CH2C12 (20 mL), cooled to 0 ° C, then treated with DIEA (5.6 mL, 8 eq. 32.1 mmol), 4-amino-3-chloro-benzoic acid (0.910 g, 5.3 mmoles), HOBT (0.824 g, 6.1 mmol), and EDC (1197 g, 6.23 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed under vacuum and the residue was dissolved in EtOAc then washed with distilled water (3X), 0.5N NaHS04 (2X), saturated NaHCO3 (2X) and brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated to give a residue which is P1123 purified by flash chromatography using CH2Cl2 / MeOH (99/1 to 197/3%). The title compound was obtained as a white solid (1221 g, 58% yield). RM1 H1 (500 MHz, CD30D) d 1.15 (d, 0.25H), 1.29-1.60 (m, 2.75H), 2. 41-2.54 (m, 0.5H) 2.55-2.70 (m, 0.5H), 2.77 (dd, 0.5H), 3. 03 (ddd, 0.5H) 3.59-3.75 (m, 1H), 3.75-3.98 (m, 1H), 4. 26-5.01 (m, 5H), 5.41-5.57 (m, 1H), 5.60-5.76 (m, 0.5H), 6. 70-6.92 (m, 0.5H), 7.15-7.48 (m, 5H), 7.48-7.68 (m, 1H), 7. 68-7.88 (m, 1H), 8.15-8.34 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 14.44, 14.89 min. LC-MS (ES +) m / e = 529.3 (M + H). [1- [2- (4-Methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidin-2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. carboxylic (77). It was synthesized from compound 75 and acid 3,5-dimethyl-4-methoxy-benzoic acid according to the procedure used to prepare compound 76 to produce the title compound (1.18 g, 44% yield).

P1123 NMR H1 (500 MHz, CD3OD) d 1.40 (m, 3H), 1.67-2.41 (m, 4H), 2.28 (s, 6H), 2.48 (ddd, 0.5H), 2.62 (dd, 0.5H), 2.78 (ddd, 0.5H), 3.04 (ddd, 0.5H,) 3.62-3.94 (m, 3H), 3.71 (s, 3H), 4.21-4.51, (m, 2H), 4.59-4.85 (m, 4H), 5.46 (s, 0.25H), 5.52 (s, 0.25H), 5.63 (d, 0.4H), 5.67 (d, 0.1H), 7.17-7.45 (m, 5H), 7.45-7.65 (M, 2H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 15.06, 15.39 min. LC-MS (ES +) m / e = 538 (M + H).

Preparation of 4-acetyl-amino-3-chloro-benzoic acid To a solution of 4-amino-3-chloro-benzoic acid (10.0 g, 58.3 mmol) in anhydrous THF (100 mL) was added acetyl chloride (20.7 g). mL, 291.1 mmol) and the solution was stirred at room temperature for 48 hours. The solvent was evaporated and the precipitated hexanes product was then filtered and dried to yield a white solid (11.73 g, 94% yield). NMR H1 (500 MHz, CD30D) d 2.28 (s, 3 H =, 7.92 (dd, lH) 7.99-8.16 (m, 2H) Analytical HPLC (cyano column) 7.84 min.

P1123 1- [2- (4-Acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-benzyl-2-oxo-etrahydrofuran-3-yl-amide carboxylic (78). Prepared from compound 75 and 4-acetyl-amino-3-chloro-benzoic acid according to the procedure used to prepare compound 76 to produce the title compound (146 mg, yield 19%). NMR H1 (500 MHz, CD30D) d 1.28-1.52 (m, 3H), 1.68-2.38 (M, 4H), 2.20 (s, 3H), 2.41-2.88 (m, 1.5H), 2.96-3.10 (m, 0.5H), 2.96-3.10 (m, 0.5H), 3.43-3.75 (m, 1H), 3.80-3.96 (m, 1H), 4.25-5.00 (m,% H), 5.42-5.54 (m, 0.5H) ), 5.63-5.78 (m, 0.5H), 7.13-7.48 (m, 0.5H), 7.79-8.14 (m, 2.5H), 8.56-8.70 (m, 0.5H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 8.64 min. LC-MS (ES +) m / e = 571.2 (M + H). (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of propionyl] -pyrrolidin-2-carboxylic acid (79). Prepared from compound 75 and acid 3- P1123 isopropoxy-benzoic according to the procedure used to prepare compound 76 to produce the title compound (120 mg, 58% yield). NMR H1 (500 MHz, CD3OD) d 1.27 (d, 6H), 1.33-1.52 (m, 3H), 1.69-2.31 (m, 4H), 2.49 (dd, 0.3H), 2.63 (dd, 0.7H), 2.78 (dd, 0.7H), 3.03 (dd, 0.3H) 3.43-3.73 (m, 1H), 3.78-3.94 (m, 1H), 4.27-4.47 (m, 2H), 4.47-4.87 (m, 4H) , 5.47 (s, 0.7H), 5.53 (d, 0.3H), 5.64 (d, 0.8H), 5.72 (d, 0.2H), 6.98-7.12 (m, 1H), 7.19-7.47 (m, 9H) . Analytical HPLC (cyano column): (mixture of 2 diastereomers) 14.54, 14.85 min. LC-MS (ES +) m / e = 538 (M + H). (2- [2- (2-Benzyloxy-5-oxo-tetrahydrofuran-3-yl-carbamoyl) pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -amide of quinoxalin-2-acid carboxylic acid (80) Prepared from compound 75 and 2-chenoxaline carboxylic acid according to the procedure used to prepare compound 76 to produce the title compound (122 mg, 60% yield).

P1123 (500 MHz, CD3OD) d 1.12-1.67 (m, 3H), 1.68-2.34 (m, 4H), 2.35-2.70 (m, 0.85H), 2.70-2.95 (m, 0.75H), 3.06 (dd, 0.4H), 3.41-3.49 (m, 2H), 4.18-5.03 (m, 6H), 5.47 (d, 0.5H), 5.55 (d, 2H), 5.67 (dd, 1H), 5.71 (dd, 0.3H ), 7.03-7.53 (m, 5H), 7.80-8.06 (m, 2H), 8.06-8.34 (m, 2H), 9.43-9.48 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers 9.06 min LC-MS (ES +) m / e = 532.3 (M + H). (1- [2- (3-Benzyloxy-4-methoxy-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (81 ). Prepared from compound 75 and 2-benzyloxy-4-methoxy-benzoic acid according to the procedure used to prepare compound 76 to produce the title compound (142 mg, 58% yield). NMR H1 (500 MHz, CD30D) d 1.14 (d, 0.3H), 1.27-1.52 (m, 2.7H), 1.66-2.30 (m, 4H), 2.47 (dd, 0.4H), 2.59 (dd, 0.6H) ), 2.77 P1123 (dd, 0.6H), 3.02 (dd, 0.4H), 3.41-3.72 (m, 1H), 3.72-3.99 (m, 2H), 3.86 (s, 3H), 4.19-4.86 (m, 5H), 4.99-5.15 (m, 2H), 5.45 (m, 0.8H), 5.65 (m, 1.2 H), 6.98 (dd, 1H), 7.11-7.63 (m, 12H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 12.28, 12.44 min. LC-MS (ES +) m / e = 616.3 (M + H). 4-allyloxy-3,5-dimethyl-benzoic acid A mixture of 4-hydroxy-3,5-dimethyl-benzoic acid (3.32 g, 20 mmol), allyl bromide (7.26 g, 60 mmol), benzyl chloride triethylammonium (455 mg, 2 mmol) and K2CO3 (6.9 g, 50 mmol) in DMF (50 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated under vacuum to give 5.3 g of the ester as an oil. The ester was brought to reflux with NaOH (5g, 125 mmol) in water / methanol (50 mL / 50 mL) for 6 hours. The mixture was evaporated under vacuum to remove the methanol and the resulting solution was diluted with water (200 ml), washed with ethyl acetate / bexane (30 ml / 70 ml). The aqueous layer was acidified at 0 ° C with concentrated HCl solution to a pH of 2. The resulting precipitate was collected by filtration and washed with water, dried under high vacuum to yield 3.86 g (94% yield) of the compound of the P1--23 title. NMR H1 (500 MHz, CDC13) d 2.33 (s, 6H), 4.35-4.37 (m, 2H), 5.28-5.30 (m, H), 5.42-5.46 (m, H), 6.07-6.15 (m, H ), 7.79 (S, 2H); retention time in analytical HPLC: 11.28 min. LC-MS m / z = 205 (M-H +). (1- [2- (4-Allyloxy-3,5-dichloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. (82). It was prepared from compound 75 and 4-allyloxy-3,5-dichloro-benzoic acid according to the procedure used to prepare compound 76 to produce the title compound (208 mg, 47% yield). NMR H1 (500 MHz, CDC13) d 1.05-1.58 (m, 3H), 1.68-3.21 (m, 7H), 3.39-3.90 (m, 3H), 4.05-5.01 (m, 6H), 5.22-5.62 (m , 3H), 6.04-6.25 (m, 1H), 6.94-7.63 (m, 8H). Analytical HPLC (cyano column) (mixture of 2 diastereomers): 9.69, 9.89 min. LC-MS (ES +) m / e = 604.2 (M + H).

P1123 (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of 1- [2- (3,5-disloro-4-hydroxy-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (83). To a sample 140 mg of 82 (0.23 mmol) was dissolved in CH2C12 (4 mL) and treated with ADMB (35.4 mg, 0.26 mmol) and Pd (PPh3) (32 mg, 0.028 mmol). The solution was stirred at 0 ° C for 15 minutes, warmed to room temperature for 2 hours, then diluted with CH 2 Cl and washed with water (2 X) and brine. The solvent was concentrated under vacuum and the residue was purified by flash chromatography on silica gel using MeOH / CH2Cl2 (1/99 to 3/97) to give the title compound (93.2 mg, 71% yield). NMR H1 (500 MHz, CD30D) d 1.16 (d, 0.25H), 1.28-1.49 (m, 2.75H), 1.63-2.33 (m, 4H), 2.48 (dd, 0.4H), 3.39-3.59 (m, 0.2H), 3.60-3.73 (m, 0.8H), 3.73-3.96 (m, 1H), 4.24-4.48 (m, 2H), 4.57-4.92 (m, 7H), 5.44 (s, 0.4H), 5.50 (d, 0.4H), 5.64 (d, 0.8H), 5.75 (d, 0.5H), 7.6-7.43 (m, 5H), 7.78-7.89 (m, 1.6H), 8.40-8.63 (m, 0.4H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 11.57, 11.82 min. LC-MS (ES +) m / e = 564.1 (M + H). 1- (2-Benzoyl-amino-propionyl) -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (84). It was prepared from compound 75 and benzoyl chloride according to the procedure used to prepare compound 76 to produce the title compound as a colorless oil (8 mg, 38% yield). NMR H1 (500 MHz, CD30D) d 1.35-1.54 (m, 3H), 1.72-2.30 (m, 4H), 2.42-2.70 (m, 1.3H), 2.74-2.84 (m, 0.5H), 3.03 (dd) , 0.2H), 3.41-3.75 (m, 2H), 3.81-3.96 (m, 1H), 4.22-4.86 (m, 4H), 5.46 (s, 0.3H), 5.51-5.54 (m, 0.1H), 5.66 (d, 0.5H), 5.72 (d, 0.1H), 7.20-7.57 (m, 7H), 7.77-7.89 (m, 2H), 8.42- 8.67 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 15.23, 15.67 min. LC-MS (ES +) m / e = 481.2 (M + H).

P1123 . { 2- (2-Benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -aminoquinoline-1-carboxylic acid amide (85). It was prepared from compound 75 and 1-isoquinoline carboxylic acid according to the procedure used to prepare compound 76 to produce the title compound (732 mg, 53% yield). NMR H1 (500 MHz, CD30D) d 1.22-1.56 (m, 3H), 1.70-2.34 (M, 4H), 2.43-2.71 (m, 0.9H) 2.73-2.89 (m, 0.5H), 3.06 (ddd, 0.6H), 3.42-3.81 (m, 2H), 3.84-4.01 (m, 1H), 4.29-5.00 (m, 5H), 5.47 (d, 0.65H), 5.55 (s, 0.3H), 5.67 (d , 0.8H), 5.72 (d, 0.25H), 7.21-7.43 (m, 5H), 7.49-7.83 (m, 2.8H), 7.88-8.04 (m, 1.8H), 8.45-8.54 (m, 0.8H) ), 8.97-9.06 (m, 0.6H). Analytical HPLC (mixture of 2 diastereomers): 15.71, 16.04 min. LC-MS (ES +) m / e = 531.2 (M + H). (1- (2- (4-amino-5-sloro-2-methoxy-benzoyl-amino) -propionyl] -pyrrolidin-2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. -carboxylic (86). It was prepared from compound 75 and 4-amino-5-chloro-2-methoxy-benzoic acid according to the procedure used to prepare compound 76 to yield the title compound (330 mg, 61% yield). NMR H1 (500 MHz, CD3OD) d 1.22 (d, 0.25H), 1.29-1.50 (m, 0. 75H), 1.68-2.36 (m, 4H), 2.38-2.89 (m, 1.5H), 2.94-3.14 (m, 0.5H), 3.37-3.98 (m, 6H), 4.27-4.98 (m, 6H), 5.44-5.50 (m, 0.4H), 5.53-5.56 (s, 0.1H), 5.60-5.75 (m, 0.5H), 6.50 (s, 1H), 7.17-7.45 (m, 4H), 7.73-7.90 (m, 1H), 8.49-8.70 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 16.39, 16.82 min. LC-MS (ES + m / e = 559.2 (M + H).

P1123 1- [2- (4-Acetylamino-5-chloro-2-methoxy-benzoyl-amino) -propionyl] -2- benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide pyrrolidine-2-carboxylic acid (87) «. It was prepared from compound 75 and 4-acetylamino-5-chloro-2-methoxy-benzoic acid according to the procedure used for compound 76 to produce the title compound (364 mg, 64% yield). RM1 H1 (500 MHz, CD3OD) d 1.20-1.27 (m, 0.25), 1.35-1.49 (m, 0.75H) 1.72-2.30 (m, 4H), 2.23 (s, 3H), 2.42-2.58 (m, 0.6H) , 2.59-2.68 (m, 0.5H), 2.73-2.86 (m, 0.7H), 2.99-3.11 (m, 0.7H), 3.41-4.07 (m, 5H), 4.29-4.97 (m, 5H), 4.79-5.56 0.5H), 5.65-5.73 (m, 0.5H), 7.18-7.44 (m, 4.3H) ), 7.90-8.09 (m, 2H), 8.71-8.85 (m, 0.7H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 15.61, 16.01 min. LC-MS (? S +) m / e = 601.1 (M + H). . { 2- [2- (2-bnzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} pyridine-2-carboxylic acid amide (88). It was prepared from compound 75 and acid P1123 pyridine-2-carboxylic acid according to the procedure used to prepare compound 76 to produce the title compound (233 mg, 42% yield). H1 NMR (500 MHz, CD3OD) d 1.30-1.59 (m, 3H), 1.68-2.36 (m, 4H), 2.39-2.57 (m, 0.6H), 2.57-2.69 (m, 0.35H), 2.71-2.87 (m, 0.4H), 3.05 (dd, 0.65H), 3.39-3.93 (m, 3H), 4.24-4.99 (m, 5H), 5.49- 5.55 (m, 0.8H), 5.63-5.77 (m, 1.2H), 7.17-7.46 (m , 5H), 7. 49-7.60 (m, 1H), 7.89-7.99 (m, 1H), 8.03-8.12 (m, 1H), 8. 58-8.67 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 8.63 min. LC-MS (ES +) m / e = 481.3 (M + H). [2- (4-Amino-3,5-dichloro-benzoyl-amino) -propionyl] -pyrrolidin-2 (2-benzyloxy-5-oxo-etrahydrofuran-3-yl) -amide] -carboxylic (89). It was prepared from compound 75 and 3,5-dichloro-4-amino-benzoic acid according to the procedure used to prepare compound 76 to produce the title compound (162 mg, yield 70%).

P1123 (500 MHz, CD3OD) d 1.21-1.58 (m, 3H), 1.58-2.37 (m, 4H), 2.37-3.13 (m, 2H), 3.43-3.74 (m, 1.5H), 3.77-3.94 (m , 1H), 4.28-4.51 (m, 1.5H), 4.50-5.01 (m, 3H), 5.41-5.77 (m, 1H), 7.15-7.49 (m, 5H), 7.66-7.88 (m, 2H). Analytical HPLC (cyano column) (mixture of 2 diastereomers): 8.36 min. LC-MS (ES +) m / e 563.2 (M + H). 1- [2- (4-Methoxy-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-xl) -amide. (90). It was prepared from compound 75 and 4-methoxy-benzoyl chloride according to the procedure used for compound 76 to produce the title compound (404 mg, 50% yield). NMR H1 (500 MHz, CD3OD) d 1.19 (d, 0.3H), 1.29-1.58 (m, 2.7H), 1.58-2.38 (m, 4H), 2.43-2.69 (m, 1H) 2.74-2.86 (m, 0.6H), 2.99-3.11 (m, 0.4H), 3.39-3.75 (m, 1.5H), 3.77-3.94 (m, 1H), 3.84 (s, 3H), 4.29-4.94 (m, 4.5H), 5.45-5.55 (m, 4.5H), 5.63-5.71 (m, 0.5H), 5.73 (d, 0.1H), 6.85-7.09 (m, 2H), 7.19-7.44 (m, 4H), 7.73- 7.92 ( m, 2H), 8.26-8.44 (m, 1H). Analytical HPLC (column P1123 cyano) (mixture of 2 diastereomers): 15.18, 15.65 min. LC-MS (ES +) m / e = 510.2 (M + H). 91 (2-benzyloxy-5-oxo-tetrahydro-furan-3-xl) -amide of l- acid. { 2- [(9-oxo-9H-fluoren-4-carbonyl) -amino] -propionyl} -pyrrolidine-2-carboxylic acid (91). Prepared from compound 75 and 9-oxo-9H-fluoren-carboxylic acid according to the procedure used to prepare compound 76 to yield the title compound (403 mg, 44% yield) H NMR (500 MHz, CDC13 ) d 1.38-1.59 (m, 3H), 1.75-2.37 (m, 4H), 2.43-2.59 (m, 0.65H), 2.59-2.72 (m, 0.35H), 2.79-2.89 (m, 0.35), 3.01 -3.11 (m, 0.65H), 3.68-3.86 (m, 1H), 3.92-4.09 (m, 1H), 44.35-5.03 (m, 7H), 5.45-5.90 (m, 1H,), 7.06-8.00 ( m, 12H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 12.30 min. LC-MS (ES +) m / e = 582.1 (M + H).

P1123 92 (2- (3,5-Dichloro-4-methoxy-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. (92). It was prepared from compound 75 and 3,5-dichloro-4-methoxy-benzoic acid according to the procedure used for compound 76 to yield the title compound (364 mg, 46% yield). NMR H1 (500 MHz, CD3OD) d 1.17 (d, 0.25H), 1.28-1.53 (m, 2.75H), 1.64-2.33 (m, 4H), 2.39-2.94 (m, 1.5H), 2.94-3.12 ( m, 0.5H), 3.41-3.74 (m, 2H), 3.74-4.00 (M, 1H), 3.91 (s, 3H), 4.26-5.02 (m, 5H), 5.42-5.81 (m, 1H), 7.08 (d, 0.4H), 7.21-7.43 (m, 4.6H), 7.53-7.69 (m, 0.8H), 7.85-7.97 (m, 1.2H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 10.79 min. LC-MS (ES +) m / e = 578.2 (M + H).

P1123 93 . { 2- (2-Benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} quinilin-6-carboxylic acid amide (93) Prepared from compound 75 and 6-quinoline-carboxylic acid according to the procedure used for compound 76 to produce the title compound (344 mg, yield 71%) . NMR H1 (500 MHz, CD3OD) d 1.11-1.58 (m, 3H), 1.69-2.40 (m, 4H), 2.42-3.15 (m, 2H), 3.80-4.01 (m, 1H), 4.29-4.99 (m , 5H), 5.44-5.54 (m, 0.5H), 5.63-5.73 (d, 0.4H), 5.73-5.79 (d, 0.1H), 7.18-7.43 (m, 5H), 7.56-7.67 (m, 1H) ), 8.08 (d, 1H), 8.13-8.25 (m, 1H), 8.40-8.56 (m, 2H), 8.88-8.99 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 10.27, 10.50 min. LC-MS (ES +) m / e = 531.2 (M + H).

P1123 Scheme XVI I Ter-butyl ester of 1- (2-benzyloxycarbonyl-amino-propionyl) -pyrrolidine-2-carboxylic acid (95). Prepared according to the method described by Pierre Chevallet, Patrick Garrouste, Barbara Malawaska and Jean Martinez in Tetrahedro Letters, Vol. 34, pp. 7409-7412, (1993). A mixture of Cbz-ala-pro-OH (10.0 g, 31.2 mmol), tert-butyl bromide (180 g, 1.31 mmol), benzyltriethylammonium chloride (7.11 g, 31.2 mmol) and K2C03 (180 g , 1.30 mmole) in N, N-dimethylacetamide (DMA) P1123 (225 mL) was stirred at 55 ° C for 24 hours. The reaction mixture was cooled to room temperature and diluted with one liter of ice-water, extracted with ethyl acetate (200 mL x 3). The organic layer was dried over anhydrous Na 2 SO, filtered and evaporated in vacuo to give 14 g of oil, which was purified by flash chromatography using hexane / ethyl acetate (95/5 to 50/50) to yield 11.73 g (yield 99.7%) of the title compound as a clear oil. NMR H1 (500 MHz, CDC13): d 1.25-1.50 (m, 12H), 1.85-2.25 (m, 4H), 3.42-3.70 (m, 2H), 4.25-4.57 (m, 2H), 5.07-5.11 ( m, 2H), 5.69 (d, H), 7.28-7.38 (m, 5H); retention time in analytical HPLC: 11.07 min .; LC-MS: m / z = 377 (M + H +). 96c, X = CI, Y = AcNH, Z = CH30 97c, X = CI. Y = AcNH, Z = CH3? 1- [2- (4-Ammon-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid ter-butyl carboxylic ester (96a) To a solution of compound 95 (10.50 g, 27.9 mmol) in MeOH (100 mL) was added a suspension of Pd P1123 10% / C (5.00 g) in EtOAc (50 mL). The mixture was stirred under H 2 for 48 hours, filtered through Celite and the solvent was evaporated to produce a waxy solid. This was dissolved in CH2C12 (100 mL) and DMF (50 mL) and the solution was cooled to 0 ° C. 4-Amino-3-chloro-benzoic acid (5.82 g) was added, 27.2 mmoles), DIEA (14.58 mL, 83.7 mmol, HOBT (3.77 g, 27.9 mmol) and EDC (6.68, 34.8 mmol) and the solution was stirred at 0 ° C for 15 minutes and then at room temperature for 24 hours. The reaction mixture was diluted with EtOAc, washed with NaHS04 (2 X), 10% NaHCO3 (2 X) and brine and dried over Na2SO, filtered and evaporated.The crude product was purified by flash column chromatography, using CH2Cl2 / MeOH (99/1 to 97/3%) to afford the title compound as a white solid (7.75 g, 70% yield) RgMN H1 (500 MHz, CD3OD) d 1.27-1.67 (m, 12H), 1.82-2.14 (m, 4H), 3.48-3.85 (m, 2H), 4.26-4.53 (m, 3H), 4.81-4.98 (m, 1H), 6.71 (d, 1H), 7.15 (m, 1H), 7.50 (dd, 1H), 7.75 (d, 1H) Analytical HPLC: 10.83 min LC-MS (ES +) m / e = 396.3 (MH +). 1- [2- (4-Amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (97a). Prepared from compound 96a by treatment with TFA / CH2C12. After completing the reaction, this solvent is removed under vacuum and the residue P1123 was repeatedly concentrated in toluene. The resulting residue was dried under vacuum to constant weight. 1- [2- (4-Acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid tert-butyl ester (96b). It was prepared from compound 95 and 4-acetylamino-3-chloro-benzoic acid according to the method used for compound 96a to yield the title compound as a white solid (9.18 g, 77% yield). NMR H1 (500 MHz, CD3OD) d 1.30-1.62 (m, 12H), 1.85-2.16 (m, 3H), 2.16-2.44 (m, 1H), 2.27 (s, 3H), 3.47-3.83 (m, 2H) ), 4.34-4.54 (m, 1H), 4.89 (m, 1H), 7.27-7.39 (m, 1H), 7.59-7.71 (m, 2H), 7.83-7.97 (m, 1H), 8.47 (d, 1H) ). Analytical HPLC: 9.43 min. 1- [2- (4-Acetyl-α-ino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (97b). Prepared from compound 96b by treatment with TFA / CH2C12. After completion of the reaction, this solvent is removed under vacuum and the residue is repeatedly concentrated in toluene. The resulting residue was dried under vacuum to constant weight. 4-Acetyl-amino-5-chloro-2-methoxy-benzoic acid 4-acetyl-amino-5-chloro-4-methyl ester P1123 2-methoxy-benzoic acid (2.09 g, 8.11 mmol) was dissolved in MeOH (110 mL) and a solution of LiOH (25.48 mmol in 30 mL, MeOH: H20 1: 1) was added, said solution was stirred at room temperature for 6 hours. The solvent was concentrated under vacuum, EtOAc was added and the organic phase was washed with 0.5N HCl and then extracted with saturated NaHCO3 (2X). The aqueous phase was acidified with 12N HCl to a pH of 1 and the resulting precipitate was extracted into CH2C12. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound as a white solid (0.933 g, 50% yield). RM1 H1 (500 MHz, CDC13) d 2.31 (s, 3H), 4.10 (s, 3H), 7.78-7.92 (br s, 1H), 8.17 (s, 1H), 8.45 (s, 1H). Analytical HPLC . 62 min. 1- [2- (4-Acetylamino-5-chloro-2-methoxy-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid tert-butyl ester (96c). To a solution of compound 95 (1534 g, 4.07 mmol) in MeOH (40 mL) was added 10% Pd / C (650 mg) and the mixture was stirred under H2 for 2 hours. The suspension was filtered through Celite and evaporated to give a yellow oil. This was allowed to react with 4-acetyl-5-chloro-2-methoxy-benzoic acid following the procedure used for the preparation of compound 96a to give the P1123 composed of the title (497 mg, yield 52%). NMR H1 (500 MHz, CD3OD) d 1.46 (d, 3H), 1.49 (s, 9H), 1.80-2.01 (m, 3H), 2.19-2.40 (m, 1H), 2.22 (s, 3H), 3.58- 3.72 (m, 1H), 3.78-3.89 (m, 1H), 3.98-4.09 (s, 3H), 4.31-4.45 (s, 1H), 4.78-4.95 (m, 1H), 7.89-8.10 (m, 2H). Analytical HPLC 11. 31 min. 1- [2- (4-Acetylamino-5-chloro-2-methoxy-benzoyl-amino) -prop-onyl] -pyrrolidine-2-carboxylic acid (97c). Prepared from compound 96c by treatment with TFA / CH2C12. After completion of the reaction, this solvent is removed under vacuum and the residue is repeatedly concentrated in toluene. The resulting residue was dried under vacuum to constant weight. (1- (2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (5-oxo-2-phenethyloxy-tetrahydro-furan-3-yl) -amide (98a) ). To a solution of the (5- oxo-2-phenethyloxy-tetrahydro-furan-3-yl) -carbamic acid allyl ester (194 mg, P1123 0.54 mmole) (prepared as described for compound (40) using phenethyl alcohol) in anhydrous CH2C12 (5 ml) was added ADMB (196 mg, 1.26 mmole) and Pd (PPh3) 4 (32 mg, 0.03 mmole) . The solution was stirred for 15 minutes, and a solution of compound 97a (prepared from 96a by treatment with TFA in CH2C12) (166 mg, 0.49 mmol) and DIEA (680 μl)., 3.90 mmol,) in CHC12 (2 mL) was added, followed by HBOT (98 mg, 0.73 mmol) and EDC (122 mg, 0.63 mmol). The solution was stirred at 0 ° C for 15 minutes and then at room temperature for 18 hours. The solvent was removed under vacuum and the residue was dissolved in EtOAc and washed with 0.5 N NaHS0 (2 X), saturated NaHCO3 (2 X) and brine. Dry over anhydrous Na2SO4, evaporate to give an orange solid which was purified by flash column chromatography using CH2Cl2 / MeOH (99/1 to 97/3%), to yield the title compound as a white solid (190 mg, 73% yield). NMR H1 (500 MHz, CD3OD) d 1.29 (d, 0.6H), 1.41 (d, 2.4H), 1.78 (m, 1H), 2.08 (m, 3H) 2.56 (m, 1H), 2. 77 (dd, 1H), 2.94 (t, 2H), 3.53 (m, 0.3H), 3.67 (m, 0.8H), 3.85 (m, 2H), 3.96-4.08 (m, 1H), 4.40 (m, 2H), 4.62 (m, 1H), 4.67-4.79 (m, 1H), 5.57 (d, 0.7H), 5.60 (d, 0.3H) 6 78 (dd, 1H), 7. 21 (m, 5H), 7. 58 (m, 1H), 7. 79 (m, 1H), 8. 26 (d, 1H). Analytical HPLC 14. 52 min. LC-MS (ES +) m / e = 543. 2 (MH +).

P1123 [1- (2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide ( 98b). It was prepared from the diastereomer without the (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (40) allyl ester and the compound 97a following the method used for the compound 98a. The title compound was separated as a pale yellow solid (720 mg, 51% yield). NMR H1 (500 MHz, CD3OD) d 1.16 (d, 0.5H), 1.40 (d, 2.5H), 1.64-2.25 (m, 4H), 2.61 (dd, 1H), 2.79 (dd, 1H), 3.37- 3.59 (m, 1H), 3.59-3.74 (m, 1H), 3.77-3.92 (m, 1H), 4.29-4.47 (m, 1H), 4.47-5.02 (m, 4H), 5.48 (s, 0.5H) , 5.66 (d, 1H), 5.68 (d, 0.5H), 6.79 (d, 1H), 7.17-7.52 (m, 5H), 7.48-7.62 (m, 1H), 7.68-7.83 (m, 1H). Analytical HPLC 15.98 min. LC-MS (ES +) m / e = 529.2 (MH +).

P1123 98c [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-etrahydro-furan-3-yl) -amide (98c) ). It was prepared from the allylic acid ester (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic (40) anti and compound 97a following the method used for compound 98a. The title compound was separated as a white solid (186.6 mg, 46% yield). H1 NMR (500 MHz, CD3OD) d 1.30-1.52 (m, 3H), 1.76-2.33 (m, 4H), 2.41- 2.59 (m, 1H), 2.90 (dd, 0.15H), 3.04 (dd, 0.85H), 3.44- 3.75 (m, 1.5H), 3.82-3.95 (m, 1H), 4.27-4.42 (m, 2H), 4.42-4.56 (m, 0.5H), 4.56-4.86 (m, 4H), 5.42-5.55 (m, 1H), 6.79 (d, 1H), 7.21-7.42 (m, 4.6H), 7.54-7.63 (m, 1.4H) ), 7.76-7.83 (m, 0.65H) 8.60-8.68 (m, 0.35H). Analytical HPLC 15.19 min.

LC-MS (ES +) m / e = 529. 3 (MH +).

P1123 98d 2- (Ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester. It was prepared from the 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described for compound (40) using ethanol. Chromatography using hexane / ethyl acetate (95/5 to 80/20) gave 0.94 grams of 2- (ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester (major Rf), 1.96 g of diasteromer without (lower Rf) and 8.08 g of the mixture of the diastereomers (total yield 60%). NMR H1 (500 MHz, CDC13) for the anti diastereomer: d 1.13-1.31 (m, 3H), 2.31-2.45 (m, 1H), 2.92-3.08 (m, 1H), 3.52-3.72 (m, 1H), 3.78-3.92 (m, 1H), 4.10-4.25 (m, 1H), 4.45-4.70 (m, 2H), 5.00 (bs, 1H), 5.12-5.45 (m, 3H), 5.80-5.95 (m, 1H) ); for the diastereomer without 1.13-1.35 (m, 3H), 2.38-2.50 (m, 1H), 2.75-2.92 (m, 1H), 3.60-3.73 (m, 1H), 3.82-3.95 (m, 1H), 4.40 -4.70 (m, 3H), 5.10-5.52 (m, 4H), 5.80-5.94 (m, 1H); LC-MS: m / z = 230 (M + H +) for both diastereomers.

P1123 1- [2- (4-amino-3-chloro-benzoyl-amino) -propionxl] -pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide ( 98d). It was prepared from the allyl ester of (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid and compound 97a following the method used for compound 98a. The title compound was separated as a white solid (175 mg, 77% yield). NMR H1 (500 MHz, CD3OD) d 1.13 (t, 0.5H), 1.23 (t, 2.5H), 1.36 (d, 0.5H), 1.44 (d, 2.5H), 1.75-2.38 (m, 4H), 2.56 (dd, 1H), 2.76 (dd, 1H), 3.45-3.97 (m, 5H), 4.47 (dd, 1H), 4.59-4.67 (m, 1H), 4.74 (q, 1H), 5.55 (d, 0.2H), 5.56 (d, 0.8H), 6.75-6.82 (m, 1H), 7.56 (dd, 1H), 7.77 (d, 1H), 8.39 (d, 1H). Analytical HPLC 8.17 min. LC-MS (ES +) m / e = 467.4 (MH +). allyl ester (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid. It was prepared from the tert-butyl ester of 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid as described for compound 40 using cyclopenanol for P1123 produce the title compound as a mixture of diastereomers. Flash column chromatography using hexane / EtOAe (90/10 to 80/20) gave the diastereomer without the title compound: diastereomer without, H-NMR (500 MHz, CDC13) d 1.5-2.0 (m, 8H), 2.45 (dd, 1H), 2.81 (dd, 0.9H), 3.0 (dd, 0.1H), 4.31 (m, 1H), 4.59 (m, 4H), 5.23 (m, 1H), 5.32 (m, 1H), 5.45 (s, 0.1H) , 5.51 (s, 0.9H), 5.92, (m, 1H) ppm; anti diastereomer, H1-NMR (500 MHz, CDCl3) d 1.50 (m, 2H) 1.67 (m, 6H), 2.36 (d, 1H), 2.8 (dd, 0.08H) 2.96 (dd, 0.92H), 4.13 (m , 1H), 4.25 (m, 1H), 4.55 (br, 2H), 5.20 (d, 1H), 5.30 (m, 2H), 5.43 (s, 0.92H), 5.5 (d, 0.08H), 5.89 (s, 1H) ppm. (1- (2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98e) ). It was prepared from the (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester and compound 97a following the method used for compound 98a to give the title compound (280 mg, 51% yield). NMR H1 (500 MHz, CD3OD) d 1.38 (d, 0.5H), 1. 44 (d, 2.5H), 1.49-2.35 (m, 12H), 2.47 (dd, 0.7H), 2.56 (dd, 0.3H), 2.75 (dd, 0.3H), 2.81-2.88 (m, 0.1H), 2.97 (dd, 0. 6H), 3.47-3.76 (m, 0.2H), 3.82-3.96 (m, 1H), 4.10-4.40 (m, 2H), 4.40-4.46 (m, 1H), 5.44 (d, 0.5H), 3.50 ( d, 0.2H), P1123 5.65 (d, 0.3H), 6.79 (d, 1H), 7.54-7.64 (m, 1H), 7.78 (d, 1H), 8.21-8.31 (m, 1H). Analytical HPLC, 15.02, 15.34 min. LC-MS (ES +) m / e = 507.3 (MH +).

Allyl ester of (2-cydohexyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid. It was prepared from the 3-allyloxycarbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using cyclohexanol to produce the title compound as a mixture of diastereomers (pale yellow oil) ( 4.62 g, 85% yield). Flash column chromatography using hexane / EtOAc (90/10 to 80/20) gave 394 mg (7% yield) of the diastereomer without the title compound. NMR H1 (500 MHz, CDC13) d 1.11-2.09 (m, 10H), 2.35-2.61 (dd, 1H), 2.72-2.98 (dd, 1H), 3.60-3.83 (m, 1H), 4.32-4.72 (m , 3H), 5.06-5.43 (m, 2H), 5.60 (d, 1H), 5.82-6.03 (m, 1H).

P1123 1- [2- (4-Acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl) -amide carboxylic (98f). Prepared from the allyl ester of (2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid and compound 97b following the method used for compound 98a to give the title compound (121 mg , 33% yield). NMR H1 (500 MHz, CD30D) d 1.06-1.61 (m, 9H), 1.61-2.37 (m, 7H), 2.22 (s, 3H), 2.52-2.81 (m, 2H), 3.49-3.78 (m, 2H) ), 3.84-3.97 (m, 1H), 4.42-4.57 (m, 1H), 4.57-4.69 (m, 1H), 5.67-5.81 (m, 1H), 7.72-7.89 (m, 1H), 7.89-8.12 (m, 2H). Analytical HPLC, 9.84 min. LC-MS (ES +) m / e = 563.3 (MH +). [1- (2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid (2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98g) ). It was prepared from the allylic acid ester (2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic without P1123 and compound 97a following the method used for compound 98a to give the title compound (153 mg, 47% yield). NMR H1 (500 MHz, CD30D) d 1.06-2.38 (m, 14H), 1.42 (d, 3H), 2.50-2.66 (m, 1H), 2.69-2.82 (dd, 1H), 3.06-3.75 (m, 2H) ), 3.80-3.94 (m, 1H), 4.40-4.52 (, 1H), 4.57-4.65 (m, 1H), 4.70-4.80 (m, 1H), 5.72 (d, 1H), 6.71 (m, 1H) , 7.50-7.63 (m, 1H), 7.78 (d, 0.6H), 8.42 (d, 0.4H). Analytical HPLC: 10.30 min. LC-MS (ES +) m / e = 521.2 (MH +). 98h 1- [2- (4-Amino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (98h). It was prepared from the allylic acid ester (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid and compound 97a following the method used for compound 98a. The title compound was separated as a white solid (195 mg, 82% yield). NMR H1 (500 MHz, CD3OD) d 1.32-1.55 (m, 3H), 1.58-1.77 (m, 3H), 1.98-2.54 (m, 4H), 2.68-2.76 (d, 0.3H), 2.79-2.89 ( m, 0.7H.), 2.96-3.10 (m, P1123 0.7H), 3.18-3.27 (dd, 0.3H), 3.72-4.18 (m, 4H), 4.46-5.12 (m, 3H), 5.60 (s, 0.4H), 5.74-5.84 (m, 0.6H) , 7.03 (d, 0.8H), 7.75-7.86 (m, 1H), 8.01 (d, 0.7H), 8.35 (d, 0.3H), 8.74 (d, 0.2H). Analytical HPLC: 8.31 min. LC-MS (ES +) m / e = 467.3 (NH +). [5-Oxo-2- (tricyclo [3.3.1.1 °] dec-2-yloxy) -tetrahydro-furan-3-yl] -carbamic acid allyl ester Prepared from the tert-butyl ester of the acid -alloyloxycarbonyl-amino-4-hydroxy-butyric as described for compound 40 using 2-adamantanol (6.21 g, 5 eq) to afford the title compound as a pale yellow oil (1.52 g, 61% yield). NMR H1 (500 MHz, CDC13) d 1.38-2.33 (m, 14H), 2.40 (d, 0.2 H), 2.53 (dd, 0.7H), 2.87 (dd, 0.7H), 2.87 (dd, 0.8H), 3.00-3.12 (m, 0.3H), 3.84-3.97 (m, 1H), 4.40-4.71 (, 3H), 5.18-5.44 (m, 2H), 5.53-5.69 (m, 1H), 5.82-6.02 (m , 1 HOUR) .

P1123 [5-OXO-2- (tricyclo [3.3.1.1 °]] dec-2-yloxy) -tetrahydrof ran-3-yl] -amide of 1- [2- (4-amino-3-chloro- benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (98i). It was prepared from the [5-OXO-2- (tricyclo [3.3.1. Io '] dec-2-yloxy) -tetrahydrofuran-3-yl) -carbamic acid ester and the compound 97a following the method used for compound 98a. The title compound was separated as a white solid. (76 mg, yield 13%). NMR H1 (500 MHz, CD3OD) d 1.38-2.22 (m, 14H), 2.40 (d, 0.2H), 2.53 (dd, 0.7H), 2.87 (dd, 0.8H), 3.00-3.12 (m, 0.3H) ), 3.84-3.97 (m, 1H), 4.40-4.71 (m, 3H), 5.18-5.44 (m, 2H), 5.53-5.69 (m, 1H), 5.82-6.02 (m, 1H). Analytical HPLC. 11.89 min. LC-MS (ES +) m / e = 573.2 (MH +). 98j [1- (2- (4-acetylamino-5-chloro-2-methoxy-benzoyl-amino) -propionyl] -pyrrolidine (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide] -2-carboxylic acid (98j). It was prepared from the tert-butyl ester of the acid. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl- P1123 carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -carbamic-sin and compound 97a following the method used for compound 98a to produce the title compound (222 mg, 82% yield). NMR H1 (500 MHz, CD3OD) d 1.23 (d, 0.6H), 1.42 (d, 2.4H), 1.72-2.27 (m, 4H), 2.23 (s, 3H), 2.63 (dd, 1H) 2.77-2.88 (m, 1H), 3.43-3.52 (m, 0.5H), 3.56-3.71 (m, 1.5H), 3.74-3.85 (M, 1H), 3.98 (s, 3H), 4.38-4.50 (m, 1.5H), 4.51-4.92 (m, 4.5H), 5.63-5.76 (m, 1H), 7.23-7.40 (m, 5H), 7.97 (s, 1H), 8.45 (d, 1 H), 8.69-8.80 (m, 1H). Analytical HPLC: 11.63 min. LC-MS (ES +) m / e = 601.2 (MH +). 98k Synthesis of 1- [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2 (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide carboxylic (98k). It was prepared from the allylic acid ester Anti (2-ethoxy-5-oxo-tetrahydrofuran-3-yl) -carbamic acid and compound 97a following the method used for the compound 98a to yield 175 mg of the title compound (59%).

NMR H1 (500 MHz, CDC13: CD3OD 1: 1) d 1.10-1.28 (m, 3H), 1.42 P1123 (d, 0.6H), 1.46 (d, 2.4H), 1.75-2.45 (m, 4H), 2.45-2.70 (m, 1H), 2.80-3.05 (m, 1H), 3.50-3.95 (m, 4H) ), 4.20-4.75 (m, 3H), 4.75-4.90 (m, 1H), 5.32 (s, 0.8H), 5.38 (s, 0.2H), 6.80 (d, 1H), 7.55-7.84 (m, 2H) ). Analytical HPLC: 10.47 min. LC-MS (ES +): m / e = 467.3 (M + H +).

Synthesis of 1- [2- (4-amino-3,5-dichloro-benzoyl-amino) -propionyl] -pyrrolidin- (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide 2-carboxylic acid (981). They were prepared from the allyl ester of (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid and the ter-butyl ester of the acid 1- [2- (4-amino-3, 5- dichloro-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid according to the method used for compound 98a to yield 158 mg of the title compound (54% yield).

NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.08-1.30 (m, 3H), 1.32-1.52 (m, 3H), 1.72-2.44 (m, 4H), 2.40-3.05 (m, 2H), 3.50-3.97 (m, 4H), 4.25-4.70 (m, 3H), 4.70-4.86 (m, 1H), 5.33 (s, 0.4H), 5.47 (s, 0.1H), 5.56 (d, 0.4H), 5.62 (d, 0.1H), 7. 50 (s, 1H), 7.80 (s, 1H). Analytical HPLC. 10.84 min.

LC -EM (ES +): m / e = 501. 2 (M + H +). (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide 1- [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (98m .). It was prepared according to the procedure used to prepare compound 98a using Cbz-Ala-D-pro-OH to yield 230 mg of the title compound (69% yield). 1H NMR (500 MHz, CDC13: CD3OD 1: 1) d 1.30 (d, 1.2H), 1.45 (d, 1.8H), 1.62-2.40 (m, 4H), 2.40-3.10 (m, 2H), 3.30- 3.97 (m, 2H), 4.33-4.95 (m, 5H), 5.30 (s, 0.5H), 5.68 (d, 0.5H), 6.80 (d, 1H), 7.25-7.95 (m, 7H). Analytical HPLC: 11.56, 11.91 min. LC-MS (ES +): m / e = 529.2 (M + H +).

P1123 1- [2- (4-Acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-benzyl-2-oxo-tetrahydro-furan-3-yl) -amide carboxylic (98n). It was prepared from compound 97b and the (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester according to the procedure used to prepare compound 98a to produce 210 mg of the compound of title (64% yield). NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.33 (d, 0.6H) 1.44 (d, 2.4H), 1.68-2.40 (m, 4H), 2.26 (s, 3H), 2.55-3.05 (m, 2H), 3.40-3.90 (m, 2H), 4.20-4.95 (m, 5H), 5.68 (d, 0.8H), 5.84 ( d, 0.2H), 7.15-8.30 (m, 8H). Analytical HPLC: 15.67 min. LC-MS (ES +): m / e = 571.1 (M + H +).

Allyl ester of (2-isopropoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid. Prepared as described for compound 40 using isopropanol to yield 3.80 grams (81% yield) of the title compound as a colorless oil. NMR H1 (500 MHz, CDC13) d 1.10-1.35 (m, 6H), 2.32-2.60 (m, 1H), P1123 2.82 (dd, 0.5H), 3.02 (dd, 0.5H), 3.82-4.11 (m, 1H), 4.48-4.66 (m, 3H), 5.20-5.36, (m, 2H), 5.54 (dd, 1H ), 5.82-6.05 (m, 1H). LC-MS (ES +) m / e = 244.2 (M + H +). (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of 1- [2- (-amino-3-chloro-benzoyl-ammonium) -propionyl] -pyrrolidin-2-carboxylic acid (98o) . allyl ester -carbamic acid (2-isopropoxy-5-oxo-tetrahydro-furan-3-yl) according to the procedure used to prepare compound 98a to afford 200 mg of the compound was prepared from 97a compound and title (66% yield). NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.05-1.35 (m, 6H), 1.35-1.50 (m, 3H), 1.70-2.45 (m, 4H), 2.45-3.05 (m, 2 H) , 3.55-4.10 (m, 3H), 4.15-4.88 (m, 4H), 5.48 (s, 0.4H) 5.58 (s, 0.1H), 5.64 (d, 0.4H.), 5.70 (d, 0.1H) , 6.78 (d, 1H), 7.58 (d, 1H), 7.80 (S, 1H). Analytical HPLC: 12.19, 12.40 min. LC-MS (ES +): m / e = 581.2 (M + H +).

P1123 1- [2- (4-Acetylamino-3,5-dichloro-benzoyl-amino) -propionyl] -pyrrolidin- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. 2-carboxylic acid (98p). was prepared from tert-butyl ester 1- [2- (4-acetylamino-3, 5-Dichloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid and the allyl ester of (2 -benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid-sin according to the procedure used to prepare compound 98a to yield 230 mg of the title compound (yield 72%). NMR H1 (500 MHz, CDCl3: CD3OD 1: 1) d 1.36 (d, 0.6H), 1.47 (d, 2.4H), 1.68-2.47 (m, 4H), 2.23 (s, 3H), 2.60- 3.15 (m, 2H), 3.40-3.90 (m, 2H), 4.15-4.95 (m, 5H), 5.68 (d, 0.8H), 5.84 (d, 0.2H), 7.20-7.98 (m, 7H). Analytical HPLC: 13.07 min. LC-MS (ES +): m / e = 605.1 (M + H +). (1- (2- (4-acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2- (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. carboxylic acid (98q). allyl ester -carbamic acid (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) according to the procedure used to prepare compound 98a was prepared from compound 97b and to produce 215 mg of the compound title (69% yield). NMR H1 (500 MHz, CDCl3: CD3OD 1: 1) d 1.35-1.90 (m, 11H), 1.90-2.35 (m, 4H), 2.24 (s, 3H), 2.40-3.10 (m, 2H), 3.50- 3.95 (m, 3H), 4.15-4.90 (m, 3H), 5.44 (s, 0.55H), 5.56 (s, 0.15H), 5.64 (d, 0.22H), 5.71 (d, 0.08H), 7.70 -8.25 (m, 3H). Analytical HPLC: 12.13 min. LC-MS (ES +): m / e = 549.2 (M + H +).

Synthesis of 1- [2- (4-acetylamino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl] -amide ( 98r) It was prepared from compound 97b and the (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester without according to the procedure used to prepare compound 98a to produce 68 mg of the title compound (24%) .1 H NMR (500 MHz, CDC13: CD30D 1: 1) d 1.13 (t, 0.6H), 1.28 (t, 2.4H), 1.38 (d, 0.6H), 1.48 ( d, 2.4H), 1.75-2.40 (m, 4H), 2.22 (s, 3H), 2.55-2.88 (m, 2H), 3.50- 3.92 (m, 4H), 4.40-4.90 (m, 3H), 5.57 (d, 0.8H), 5.61 (d, P1123 0.2H), 7.60-8.20 (m, 3H). Analytical HPLC: 8.64 min. LC-MS (ES +): m / e = 509.2 (M + H +).

Preparation of the allyl ester of the acid (2-cyclopentyl-methoxy-5-oxo-e-rahydro-furan-3-y1) -carbamic acid. It was prepared from the 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using cyclopentyl-methanol (6.5 mL, 60 mmol) to yield 2.98 grams (total yield 52 %) of the title compound as a mixture of epimers. Purification afforded 0.97 grams (17% yield) of 4 (S), 5 (R) as a colorless oil. RgMN H1 (500 MHz, CDC13) d 1.19 (m, 2H), 1.54 (m, 4H), 1.71 (m, 2H), 2.16 (m, 1H), 2.44 (dd, J = 17.2, 10.4Hz, 1H) , 2.82 (dd, J = 17.2, 8.4Hz, 1H), 3.44 (dd, J = 9.3, 7.2Hz, 1H), 3.71 (dd, J = 9.3, 7.2Hz, 1H), 4.57 (m, 3H), 5.32 (m, 3H), 5.41 (d, J = 5.2Hz, 1H), 5.91 (ddt, J = 17.1, 10.4, 5Hz, 1H) ppm. LC-MS. (ES +): m / e = 284. A mixture of epimers (0.66 grams, 11% yield) and epimer 4 (S), 5 (S) (1.35 grams, 24% yield) was also separated as a waxy solid. NMR H1 (500 MHz, CDC13) d 1.20 (m, 2H), 1.54 (m, 4H), 1.69 (m, 2H), 2.10 (m, 1H), 2.37 (d, J = 8, 1Hz, 1H), 2.97 (d, J = 18.0, 7.6Hz, 1H), 3.42 (dd, J = 7.3, 1.7Hz, 1H), 3.49 (m, 2H), 3.64 (dd, J = 9.0, 7.3Hz, 1H), 4.19 (br, 1H) ), 4.55 (m, 2H), 5.25 (m, 2?), 5.36 (s, 1H), 5.87 (m, 1H) ppm. LC-MS (ES +): m / e = 284 (M + H). 1- [2- (4-Amino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-cyclopentylmethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (98s). It was prepared from compound 97b and the (2-cyclopentylmethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester according to the procedure used to prepare compound 98a to produce 195 mg of the compound of title (51% yield). RgM? H1 (500 MHz, CDC13: CD30D 1: 1) d 1.15-1.90 (m, 11H, 1.90-2.40 (m, 5H), 2.55-2.78 (m, 2H), 3.50-3.90 (m, 4H), 4.38- 4.92 (m, 3H), 5.53 (d, 0.8 H), 5.57 (d, 0.2H), 6.78 (d, 1H), 7.50-8.15 (m, 2H) Analytical HPLC: 10.48 min LC-MS (ES + ): m / e = 521.2 (M + H +).

P1123 Alkyl ester of the acid (5-oxo-2- (3-phenyl-propoxy) -tetrahydro-furan-3-yl) -carbamic acid. It was prepared from the 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using 3-phenylpropanol to yield 1.15 grams (32% yield) of the title compound as a colorless oil. NMR H1 (500 MHz, CDC13) d 1.82-2.05 (m, 2H), 2.38 (dd, 1H), 2.68 (m, 2H), 2.82 (dd, 1H), 3.55-3.65 (m, 1H), 3.82- 3.92 (m, 1H), 4.48-4.72 (m, 3H), 5.12-5.59 (m, 3H), 5.82-6.03 (m, 1H), 7.11-7.45 (m, 5H). Analytical HPLC: 9.08 min. LC-MS (ES +): m / e = 320.2 (M + H +). (1- (2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-5-oxo-2- (3-phenyl-propoxyl) -tetrahydro-furan-3-yl) -amide. -2-carboxylic acid (98t). It was prepared from compound 97b and the (5-oxo-2- (3-phenyl-propoxy1) -tetrahydrofuran-3-yl) -carbamic acid allylic ester without according to the procedure used to prepare compound 98a to produce 200 mg P1123 of the title compound (57% yield) 1H-NMR (500 MHz, CDC13: CD30D 1: 1) d 1.34 (d 0.6H), 1.44 (d, 2.4H), 1.75-2.40 (m, 6H), 2.50- 2.95 (m, 4H), 3.47-3.95 (m, 4H), 4.38-4.82 (m, 3H), 5.52 (d, 0.8H), 5.56 (d, 0.2H), 6.75- 8.25 (m, 8H). Analytical HPLC: 10.79 min. LC-MS (ES +) m / e = 557.2 (M + H +).

Synthesis of 1- [2- (4-acetylamino-3-chloro-benzoyl-amino) -propionyl] (2-cyclopentyl-methoxy-5-oxo-tetrahydro-furan-3-yl) -amide] - pyrrolidin-2-carboxylic acid (98u). It was prepared from compound 97b and the syn- (2-cyylpentylmethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester according to the procedure used to prepare compound 98a to produce 215 mg of the composed of the title (67% yield). H1 NMR (500 MHz, CDC13: CD30D 1: 1) d 1.38 (d, 0.6H), 1.47 (d, 2.4H), 1.11-1.88 (m, 8H), 1.92-2.40 (m, 5H), 2.24 (s, 3H), 2.53-2.86 (m, 2H), 3.30-3.90 (m, 4H), 4.38-4.89 (m, 3H), 5.53 (d, 0.8H), 5.60 (d, 0.2H), 7.68-8.22 (m, 3H). Analytical HPLC 9.90 min. LC-MS (ES +) m / e = 563.3 (M + H +). 1- [2- (4-Acetylamino-3-chloro-benzoyl-amino) -propionyl] -5-oxo-2- (3-phenyl-propoxyl) -tetrahydro-furan-3-yl) -amide] -pyrrolidine-2-carboxylic acid (98v). It was prepared from the 1- [2- (4-acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and the allyl ester of the acid- (2- (4-acetylamino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid ester. -oxo-2- (3-phenyl-propoxyl) -tetrahydro-furan-3-yl) -carbamic acid according to the procedure used to prepare compound 98a to yield 238 mg of the title compound (75% yield). NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.33 (d, 0.6H), 1.56 (d, 2.4H), 1.78-2.45 (m, 6H), 2.27 (s, 3H), 2.53-2.97 ( m, 4H), 3.53-3.94 (m, 4H), 4.47-4.86 (m, 3H), 5.53 (d, 0.8H), 5.62 (d, 0.2H), 7.11-8.26 (m, 8H). Analytical HPLC: 10.27 min. LC-MS (ES +) m / e = 599.2 (M + H +).

P1123 4 213 (1- (2- (4-amino-3-trifluoromethyl-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98w). It was prepared from the tert-butyl ester of the acid. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -carbamic acid and 4-amino-3-trifluoromethyl-benzoic acid according to the procedure used to prepare compound 98a to yield 56 mg of the title compound (48% yield). NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.20-1.55 (m, 3H), 1.75-2.50 (m, 4H), 2.50-3.10 (m, 2H), 3.50-4.00 (m, 2H), 4.30-5.00 (m, 5H), 5.42 (s, 0.4H), 5.51 (s, 0.2H), 5.62 (d, 0.3H), 5.78 (d, 0.1H), 6.84 (d, 1H), 7.20- 8.15 (m, 7H). Analytical HPLC: 14.90, 15.20 min. LC-MS (ES +) m / e = 563.2 (M + H +). (2- (3-Chloro-4-dimethylamino-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98x) ). It was prepared from the tert-butyl ester of P1123 acid. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -carbamic acid and 3-chloro-4-dimethyl-amino-benzoic acid according to the procedure used to prepare compound 98a to yield 82 mg of the title compound (44% yield). NMR H1 (500 MHz, CDCl3: CD3OD 1: 1) d 1.18-1.53 (m, 3H), 1.70-2.40 (m, 4H), 2.55-3.10 (m, 2H), 2.84 (s, 6H), 3.45- 3.94 (m, 2H), 4.25-4.95 (m, 5H), 5.46 (s, 0.3 H), 5.51 (s, 0.2H), 5.63 (d, 0.4H), 5.73 (d, 0.1H), 7.05 (d , 1H), 7.15-7.95 (m, 7H). Analytical HPLC: 11.85, 12.19 min. LC-MS (ES +): m / e = 557. 3 (M + H +). (2- (4-Dimethyl-amino-3,5-difluoro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. (98y). It was prepared from the tert-butyl ester of the acid. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} -carbamic acid and 4-dimethyl-amino-3,5-dichloro-benzoic acid according to the procedure used to prepare compound 98a P1123 to yield 106 mg of the title compound (65% yield). NMR H1 (500 MHz, CDC13: CD3OD 1: 1) d 1.10-1.55 (m, 3H), 1.75-2.30 (m, 4H), 2.45-3.15 (m, 2H), 2.84 (s, 6H), 3.40- 3.95 (m, 2H), 4.15-4.95 (m, 5H), 5.47 (s, 0.35H), 5.54 (s, 0.15H), 5.67 (d, 0.4H), 5.77 (d, 0.1H), 7.20- 7.70 (m, 7H). Analytical HPLC: 12.21, 12.51 min. LC-MS (ES +): m / e = 559.2 (M + H +). (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of 1- [2- (4-amino-2,3,5,6,6-tetrafluoro-benzoylamino) -propionyl] -pyrrolidine-2 -amide -carboxylic (98z). It was prepared from the tert-butyl ester of the acid. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl] -carbamic acid and 4-amino -2, 3, 5, 6-tetrafluoro-benzoic acid according to the procedure used to prepare compound 98a to yield 58 mg of the title compound (73% yield). NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.30-1.50 (m, 3H), 1.62-2.35 (m, 4H), 2.45-3.12 (m, 2H,) 3.50-3.90 (m, 2H), 4.20-4.95 (m, 5H), 5.42 (s, 0.4H), 5.52 (s, 0.1H), 5.64 (d, 0.4H), 5.82 (d, 0.1H), 7.25-7.65 (m, 5H) . Analytical HPLC: 16.56, 16.90 min. LC-MS (ES +): m / e = 567.2 (M + H +). (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of l- acid. { 2- [3-chloro-4- (2, 2-dimethylpropionylamino) -benzoylamino] -propionyl} -pyrrolidine-2-carboxylic acid (98aa). To a suspension of 98b (100 mg, 0.19 mmol) and poly (4-vinylpyridine) (200 mg) was added pivaloyl chloride (70 μL, 0.57 mmol). The resulting suspension was stirred overnight at room temperature, filtered and diluted with EtOAc (25 mL). The organic layer was washed with 10% NaHCO 3 (2 x 25 mL), saturated NaCl (1 x 25 mL), dried (MgSO 4), and evaporated to dryness to yield 98 mg of the title compound (yield 85%) after of chromatography. NMR H1 (500 MHz, CDC13: CD3OD 1: 1) d 1.10-1.55 (m, 3H), 1.38 (s, 9H), 1.65-2.40 (m, 4H), 2.60-3.10 (m, 2H), 3.46- 3.88 (m, 2H), 4.20-4.95 (m, 5H), 5.62 (d, 0.8H), 5.78 (d, 0.2H), 7.15-8.30 (m, 8H). Analytical HPLC: P1123 11. 82 min. LC-MS (ES +) m / e = 613. 2 (M + H +) (2- (3-Chloro-4-propionylamino) -benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98ab) . It was prepared from compound 98b and propionyl chloride according to the procedure used to prepare compound 98aa to yield 104 mg of the title compound (95% yield). NMR H1 (500 MHz, CDC13: CD30D 1: 1) d 1.16 (t, 0.6H), 1.18 (d, 0.6H), 1.27 (t, 2.4H), 1.38 (d, 2.4H), 1.72-2.35 ( m, 4H), 2.45-2.58 (m, 2H), 2.58-3.05 (m, 2H), 3.45-3.85 (m, 2H), 4.20-4.88 (m, 5H), 5.64 (d, 0.8H), 5.76 (d, 0.2H), 7.20-8.35 (m, 8H). Analytical HPLC: 9.89 min. LC-MS (ES +) m / e = 585.2 (M + H +).

P1123 1- [2- (3-Chloro-4-phenyl-acetylamino) -benzoyl-amino) -propionyl] -pyrrolidine acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide -2-carboxylic acid (98ac) Prepared from compound 98b and phenylacetyl chloride according to the procedure used to prepare compound 98aa to produce 85 mg of the title compound (77% yield). NMR H1 (500 MHz, CDCl3: CD3OD 1: 1) d 1.18 (d, 0.6H), 1.40 (d, 2.4H), 1.72-2.38 (m, 4H), 2.58-3.05 (m, 2H), 3.46-3.78 (m, 2H), 3.85 (s, 2H), 4.18-4.92 (m, 5H), 5.63 (d, 0.8H), 5.75 ( d, 0.2H), 7.15-8.34 (m, 13H). Analytical HPLC: 11.63 min. LC-MS (ES +): m / e = 647. 2 (M + H +). (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of 1- [2- (3-chloro-4-methyl-butyryl-amino) -benzoyl-amino) -propionyl] -pyrrolidin- 2-carboxylic acid (98ad). It was prepared from compound 98b and isovaleryl chloride according to the procedure used to prepare compound 98aa to yield 60 mg of the title compound (58% yield). H1 NMR (500 MHz, P1123 CDC13: CD30D 1: 1) d 1.07 (d, 5H), 1.15 (d, 0.8H), 1.27 (d, 1H), 1.45 (d, 2.2H), 1.67-2.30 (m, 5H), 2.34 ( d, 2H), 2.58-3.05 (m, 2H), 3.48-3.88 (m, 2H), 4.10-4.98 (m, 5H), 5.68 (d, 0.7H), 5.78 (m, 0.3H), 7.18- 8.33 (m, 8H). Analytical HPLC: 10.74 min. LC-MS (ES +) m / e = 613.2 (M + H +). (1- [2- (4-methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide. (98ae). It was prepared from the 1- [2- (4-methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid tert-butyl ester and the allyl ester of the non-2- (4-methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid ester. -ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid according to the procedure used to prepare compound 98a to yield 174 mg (81% yield) of the title compound. H1 NMR (500 MHz, CDC13) d 1.04 (t, 0.45H), 1.27 (t, 2.55H), 1.34-1.45 (m, 3H), 1.95-2.45 (m, 10H), 2.78-2.84 (m, H), 3.60-3.90 (m, 8H), 4.50-4.70 (m, 2H), 4.90-4.94 (m, H), 5.45 (d, 0.85H), 5.61 (d, 0.15H), 6.99 (d, H), 7.15 (d , H), 7.45 (s, 2H); retention time on analytical HPLC: P1123 10.09 min ..; LC-MS m / z = 476 (M + H +) [2- (4-Methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide. (98af). It was prepared from the 1- [2- (4-methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and the (2-ethoxy) allyl ester -5-oxo-tetrahydro-furan-3-yl) -carbamic acid (anti) according to the procedure used to prepare compound 98a to yield 168 mg (77% yield) of the title compound. NMR H1 (500 MHz, CDC13): d 1.10-1.35 (m, 3H), 1.35-1.60 (m, 3H), 1.90-2.45 (m, 10H), 2.60-3.00 (m, H), 3.55-3.95 ( m, 8H), 4.15-4.60 (m, 2H), 4.83-5.00 (m, H), 5.29 (s, H), 6.95-7.06 (m, H), 7.50 (s, 2H), 7.92 (d, H); retention time on analytical HPLC: 10.14 min; LC-MS: m / z = 476 (M + H +).

P1123 (1- [2- (4-methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. (98ag). It was prepared from the 1- [2- (4-methoxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and the alkylester of sirz- (2) -benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (40) according to the procedure used to prepare compound 98a to yield 406 mg (71% yield) of the title compound. NMR H1 (500 MHz, CDC13): d 1.09 (d, 0.6H), 1.35 (m, 2.4H), 1.90-2.20 (m, 3H,), 2.22-2.50 (m, 10H), 2.84-2.90 (m , H), 3.52-3.62 (m, 1.6H), 3.65-3.80 (m, 3.4H), 4.10-4.40 (m, H), 4.50-4.75 (m, 3H), 4.82-4.95 (m, 2H) , 5.54 (d, 0.8H), 5.80 (d, 0.2H), 6.87 (d, H), 7.10-7.40 (m, 6H), 7.45 (s, 2H); retention time in analytical HPLC: 16.71 min1; LC-MS: m / z = 538 (M + H +).

P1123 (1- (2- (Allyloxy-3,5-dimethyl-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98ah). It was prepared from the 1- [2- (4-allyloxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid tert-butyl ester and compound 40 according to the procedure used to prepare compound 98a to yield 264 mg (46% yield) of the title compound. H1 NMR (500 MHz, CDC13) d 1.09-1.43 (m, 3H), 1.90-2.20 (m, 3H) 2.20-2.38 (m, 7H), 2.38-2.52 (m, H), 2.80-2.95 (m, H), 3.52-3.67 (m, H), 3.70-3.80 (m, H), 4. 10-4.40 (m, 2H), 4.40-4.95 (m, 5H), 5.26-5.55 (m, 3H), 6.00-6.14 (m, H), 6.87 (d, H), 7.10-7.70 (m, 8H ); retention time in analytical HPLC: 18.56 and 18.92 min1. LC-MS m / z = 564 (M + H +).

P1123 Allyl ester of acid. { 2- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -carbámico It was prepared from the 3-allyloxycarbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described in compound 40 using (IR, 2S, 5R) - (-) -mentol to yield 0.32 g of the diastereomer without (lower Rf) of the title compound and 4.25 g of the anti / sin diastereomer mixture (total yield 67%). NMR H1 (500 MHz, CDC13) mixture: d 0.70-1.05 (m, 13H), 1.20-1.47 (m, 2H), 1.60-1.80 (m, 2H), 1.94-2.20 (m, 2H), 2.35-2.50 (m, H), 2.82-3.04 (m, H), 3.40-3.61 (m, H), 4.43-4.70 (m, 3H), 5.15-5.35 (m, 2H), 5.48-5.61 (m, H) 5.90-5.94 (m, H); for the diastereomer without; 0.70-1.05 (m, 13H), 1.20-1.47 (m, 2H), 1.60-1.80 (m, 2H), 1.94-2.18, (m, 2H), 2.40-2.50 (m, H), 2.82-2.92 ( m, H), 3.54-3.61 (m, H), 4.45-4.70 (m, 3H), 5.18-5.35 (m, 2H), 5.58-5.61 (m, H), 5.90-5.93 (m, H); LC-MS: m / z = 340 (M + H +) for the mixture of anti / sin diastereomers.

P1123 4-Benzyloxy-3,5-dimethyl-benzoic acid Prepared by the method used to synthesize 4-allyloxy-3,5-dimethyl-benzoic acid to yield 2.43 g (56% yield) of the title compound. 1 H-NMR (500 MHz, CDC13) d 4.87 (s, 2H) 7.36-7.48 (m, 5H), 7.92 (s, 2H); LC-MS: m / z = 255 (M + H +). . { 2- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -amide of 1- [2- (4-benzyloxy-3) acid, 5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid (98ai). It was prepared from the 1- [2- (4-benzyloxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and the allyl ester of the acid. { 2- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -carbamic according to the procedure used to prepare compound 98a to produce 130 mg (39% yield) of the title compound. NMR H1 (500 MHz, CDC13) d 0.45-1.10 (m, 12H), 1.15-1.90 (m, 8H), 1.90-2.45 (m, 12H), 2.80-2.84 (m, H), 3.50-3.85 (m , 3H), 4.45-4.70 (m, 2H), 4.80-4.95 (m, 3H), 5.62 (d, H), 7.05 (d, H), 7.17 (d, H), 7.30-7.60 (m, 7H ), 7.62-7.75 (m, H); retention time on analytical HPLC: 15.90 and 16.08 min .; LC-MS: m / z 662. (M + H +).

P1123 . { 2- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} 1- [2- (4-Hydroxy-3,5-dimethyl-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid amide (98aj). A solution . { 2- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} 1- [2- (4-Benzyloxy-3,5-dimethyl-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid amine (110 mg, 0.17 mmol) in ethyl acetate (2 mL) was stirred with 10% palladium on carbon (20 mg) under a hydrogen atmosphere for 24 hours then it was filtered through Celite and evaporated under vacuum. The resulting residue was purified by chromatography using CH2Cl2 / methanol (99/1 to 96/4) to yield 58 mg of the title compound. H1 NMR (500 MHz, CDC13) d 0.70-1.00 (m, 10H), 1.20-1.80 (m, 10H), 1.90-2.40 (m, 11H), 2.82-2.86 (m,?), 3.57-3.78 (m, 3H), 4.55-4.67 (m, 2H), 4.90-4.94 (m, H), 5.29 (s, H), 5.62 (d, H), 6.90 (d, H), 7.14 (d, H), 7.42 (s, 2H); retention time in analytical HPLC: 12.84 and 13.05 min .; LC-MS: m / z = 572 (M + H +). (2- (4-Hydroxy-3,5-dimethyl-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98a) ). A solution of 98ah (230 mg, 0.41 mmol) in CH2C12 (10 mL) was treated with ADMB (65 mg, 0.42 mmol) and Pd (PPh3) (50 mg) at room temperature for 20 hours. The mixture was concentrated to dryness under vacuum and purified by flash chromatography using CH2Cl2 / methanol (99.5 / 0.5 to 97/3) to yield 181 mg of the title compound. NMR H1 (500 MHz, CDC13) d 1.08 (d, 0.75H), 1.20-1.35 (m, 2.25H), 1.70-2.50 (m, 12H) 2.80-2.90 (m, H), 3.50-3.65 (m, H). 3.70-3.80 (m, H), 4.10-4.25 (m, H), 4.35-4.98 (m, 3H), 5.53 (d, 0.75H), 5.85 (d, 0.25H), 6.81 (d, H), 7.13-7.60 (m, 8H); retention time in analytical HPLC: 10.38 and 10.56 min. LC-MS: m / z = 524 (M + H +). (1- [2- (4-Dimethyl-amino-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98al). It was prepared from the 1- [2- (4-dimethyl-amino-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and the sin- (2-benzyloxy-5) allyl ester -oxo-2-tetrahydro-furan-3-yl) -carbamic acid according to the procedure used to prepare compound 98a to yield 60 mg (45% yield). 1 H-NMR (500 MHz, CDCl 3) d 1.04 (d, 0.75H), 1.35 (d, 2.25H), 1.80-2.50 (m, 5H), 2.75-3.20, (m, 8H), 3.45-3.75 (m, 2H), 4.05-4.20 (m, 0.5H), 4.30-4.80 (m, 3.5H), 4.80-4.95 (m, 1.5H), 5.52 (d, H), 5.75-6.00 (m, 0.5H), 6.60-6.90 (m, 3H), 7.10-7.50 (m, 4H), 7.50-7.80 (m, 2H), retention time in analytical HPLC: 10.46 min; LC-MS: m / z = 523 (M + H +).

P1123 . { R- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} 1- [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidine-2-carboxylic acid amide (98am). It was prepared from the 1- [2- (4-amino-3-chloro-benzoyl-amino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and the allyl ester of the acid. { R- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} carbamic without (97a) according to the procedure used to prepare compound 98a to yield 103 mg (67% yield) of the title compound. NMR H1 (500 MHz, CDC13) d 0.70-1.10 (m, 12H), 1.20-1.50 (m, 5H), 1.50-1.85 (m, 2H), 1.90-2.30 (m, 5H), 2.75-2.85 (m , H), 3.50-3.70 (m, 2H), 3.70-3.82 (m, H), 4.20-4.65 (m, 4H), 4.80-4.95 (m, H), 5.61 (d, H), 6.70-6.73 (m, H) 6.95 (d, H), 7.15 (d, H), 7.49-7.51 (m, H), 7.73 (s, H); retention time in analytical HPLC: 12.88 min; LC-MS m / z = 577 (M + H +).

P1123 Acyl ester of acid. { 2- [SS- (2R-isopropyl-5S-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -carbámico Prepared from the 3-allyloxy-carbonyl-yl-amino-4-hydroxy-butyric acid tert-butyl ester was described for compound 40 using (SS, 2R, 5S) - (+) -mentol to produce 855 mg of the anti diasteromer (upper Rf) of the title compound and 503 mg of the diastereomer without (lower Rf) and 459 mg of the mixture of anti / sin diasteromers (total yield 66%) 1 H NMR (500 MHz, CDC13) diastereomer anti d 0.74-1.00 (m, 12H), 1. 20-1.45 (m, 2H), 1.58-1.72 (m, 2H), 1.98-2.12 (m, 2H), 2. 18-2.40 (m, H) 2.98-3.03 (m, H), 3.49-3.54 (m, H), 4.17 (br, H), 4.59 (br, 2H), 4.97 (br, H), 5.22-5.33 (m, 2H), 5.58 (s, H), 5.87-5.93 (m, H); for diastereomer without: 0.75-1.02 (m, 12H), 1.25-1.45 (m, 2H), 1.57-1.70 (m, 2H), 2.00-2.16 (m, 2H), 2.40-2.52 (m, H), 2.78 -2.90 (m, H), 3.40-3.50 (m, H), 4.58 (br, 2H), 5.24-5.35 (m, 2H), 5.51-5.52 (d, H), 5.85-5.98 (m, H); LC-MS: m / z = 340 (M + H +) for both diastereomers.

P1123 { 2R- [IS- (2R-isopropyl-5S-methyl-cyclohexyloxy)} -5-oxo-tetrahydro-furan-3-yl} 1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid amide (98an).

It was prepared from compound 97a and the allyl ester of the acid. { 2- [IR- (2S-isopropyl-5S-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -carbamic according to the procedure used to prepare compound 98a to yield 88 mg (50% yield) of the title compound. H1 NMR (500 MHz, CDC13): d 0.70-1.10 (m, 12H), 1.20-1.50 (ra, 14H), 1.50-1.70 (br, 2H), 1.90-2.25 (m, 4H), 2.27-2.37 (m, H), 2.40-2.50 (m, H), 2.75-2.79 (m, H), 3.35-3.80 (m, 3H), 4.20-4.57 (m, 3H), 4.60-4.70 (m, H), 4. 88-4.92 (m, H), 5.53 (d, H), 6.71-6.75 (m, H), 6.90 (d, H), 7.20 (d, H), 7.50-7.53 (m, H), 7.75 (d, H); Time of: m / z = 577 Allyl ester of (2-c-tetrahydro-furan-3-yl) -carbamic acid. It was prepared from the tert-butyl ester of P1123 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid as described for compound 40 using cyclohexyl-methanol to yield 1.04 g (upper Rf) (35% yield) of the anti diastereomer of the title compound and 1295 g of the diastereomer without (lower Rf) (44% yield). H1 NMR (500 MHz, CDC13) for the anti-diastereomer d: 0.90-0.96 (m, 2H), 1.10-1.30 (m, 3H), 1.55-1.85 (m, 6H), 2.37-2.41 (d, H), 2.97-3.03 (m, H), 3.34-3.38 (m, H), 3.58-3.62 (m, H), 4.55-4.70 (m, 2H), 4.70-4.73 (m, H), 5.03 (bs, H ), 5.22-5.37 (m, 3H), 5.87-5.93 (m, H); for diastereomer without 0.91-0.97 (m, 2H), 1.10-1.31 (m, 3H), 1.56-1.90 (m, 7H), 2.44-2.48 (m, H), 2.81-2.87 (m, H), 3.35- 3.39 (m, H), 3.63-3.67 (m, H), 4.53-4.70 (m, 3H), 5.20-5.50 (m, 3H), 5.89-5.95 (m, H); LC-MS: m / z = 298 (M + H +) for both diastereomers. [2- (4-Asethylamino-3-chloro-benzoylamino) -propionyl] pyrrolidin-2-carboxylic acid (2-cyclohexylmethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (98ao). Prepared from compound 97b and (2-cyclohexylmethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (sin) allyl ester according to the procedure used to prepare compound 98a to produce 212 mg (64% yield) of the title compound. 1 H-NMR (500 MHz, CDCl 3): d 0.70-1.30 (m, 5H), 1.30-1.85 (m, 9H), 1.85-2.60 (m, 8H), 2.75-3.00 (m, H) 3.10-3.80 (m , 4H), 4.30-4.95 (m, 3H), 5.42 (d, 0.85H), 5.62 (d, 0.15H), 6.87 (d, 0.15H), 7.08 (d, 0.85H) 7.25 (d, H) 7.60-7.90 (m, 3H), 8.08 (d, 0.15H), 8.50 (d, 0.85H); retention time in analytical HPLC: 11.81 min; LC-MS: m / z = 577 (M + H +). . { 2R- [IS- (2R-isopropyl-5S-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} 1- [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid amide (98ap). It was prepared from compound 97b and allylic acid ester. { 2- [SS- (2R-isopropyl-5S-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -carbamic (sin) according to the procedure used to prepare compound 98a to yield 223 mg (63% yield) of the title compound. NMR H1 (500 MHz, CDC13): d 0.70-1.15 (m, 12H), 1.20-1.85 (m, 8H), 1.85-2.60 (m, 9H), 2.74-2.88 (m, H), 3.35-3.85 ( m, 3H), 4.40-4.55 (m, H), 4.65-4.78 (m, H), 4.88-4.91 (m, H), 5.53 (d, H), 7.00-7.25 (m, 2H), 7.60- P1123 7.90 (m, 3H), 8.50 (d, H); retention time in analytical HPLC: 13.31 min; LC-MS: m / z = 619 (M + H +). [1- (2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid (2-cyclohexylmethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (98aq). Prepared from compound 97a and (2-cyclohexylmethoxy-5-oxo-tetrahydrofuran-3-yl) -carbamic acid (sin) allyl ester according to the procedure used to prepare compound 98a to produce 113 mg ( 56% yield) of the title compound. 1 H-NMR (500 MHz, CDCl 3): d 0.70-1.35 (m, 5H), 1.35-1.90 (m, 8H), 1.90-2.20 (m, 3H), 2.30-2.60 (m, H), 2.80-3.00 ( m, H), 3.15-3.80 (m, 4H), 4.28-4.75 (m, 4H), 4.89-4.93 (m, H), 5.42 (d, H), 6.74 (d, H), 6.87 (d, H), 7.30 (d, H), 7.51-7.53 (m, H), 7.74 (d, H); retention time in analytical HPLC: 12.02 P1123 (2-Butoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester. It was prepared from the 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using n-butanol to yield 878 mg (29% yield) of the title compound ( 313 mg of the anti diastereomer, 260 mg of the diastereomer without and 305 mg of the mixture). 1 H-NMR (500 MHz, CDCl 3) for the anti diastereomer: d (upper Rf) 0.89-0.96 (t, 3H), 1.32-1.40 (m, 2H), 1.54-1.63 (m, 2H), 2.37-2.41 (d , H), 2.98-3.04 (q, H), 3.55-3.60 (m, H), 3.77-3.82 (m, H), 4.19-4.22 (m, H), 4.58 (br, 2H), 5.03 (br, H), 5.23-5.40 (m, 3H), 5.87-5.93 (M, H), for diastereomer without (Lower Rf) 0.91-0.95 (t, 3H), 1.34-1.39 (m, 2H), 1.56-1.63 (m, 2H), 2.42-2.50 (m, H), 2.83-2.87 (m, H), 4.07 -4.11 (t, H), 4.45-4.50 (m, 0.5H), 4.51-4.70 (m, 2.5H), 5.23-5.35 (m, 2H), 5.42-5.43 (d, H), 5.80-5.95 (m, H); LC-MS: m / z = 258 (M + H +) for both diastereomers. [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-butoxy-5-oxo-tetrahydro-furan-3-yl) -amide (98ar). It was prepared from compound 97a and (2-butoxy-5-oxo-tetrahydrofuran-3-yl) -carbamic acid allyl ester (without) according to the procedure used for P1123 prepare compound 98a to yield 118 mg (48% yield) of the title compound as a diastereomer without. NMR.H1 (500 MHz, CDC13): d 0.80-1.02 (m, 2H), 1.35-1.51 (m, 5H), 1.51-1.70 (m, 2H), 1.90-2.27 (m, 3H), 2.30-2.46 (m, H), 2.80-2.90 (m, H), 3.55-3.94 (m, 4H), 4.30-4.75 (m, 4H), 4.90-5.00 (m, H), 5.44-5.46 (m, H) , 6.73-6.80 (m, H), 6.80-6.93 (m, H), 7.16-7.25 (m, H), 7.49-1.60 (m, H), 7.70-7.84 (m, H); retention time in analytical HPLC: 9.71 min; LC-MS: m / z = 495 (M + H +).

Allyl ester of (2-isobutoxy-5-oxo-etrahydro-furan-3-yl) -carbamic acid. It was prepared from the 3-allyloxy-carbonyl-amino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using isobutanol to yield 190 mg (7.3% yield) of the title compound as a diastereomer anti and 290 mg (11% yield) of the diastereomer without. NMR H1 (500 MHz, CDC13) for the anti diastereomer: d (upper Rf) 0.85-1.05 (m, 6H), 1.82-1.98 (m, H), 2.37-2.42 (d, H), 2.98-3.04 (m , H), 3.31-3.35 (m, H), 3.55-3.58 (m, H), 4.20-4.30 (t, H), 4.58 (br, P1123 2H), 5.07 (br, H), 5.22-5.43 (m, 3H), 5.84-5.96 (m, H), for diastereomer sin (lower Rf) 0.85-1.05 (m, 6H), 1.88-1.95 (m , H), 2.40-2.51 (m, H), 2.83-2.90 (m, H), 3.33-3.36 (m, H), 3.61-3.65 (m, H), 3.87-3.88 (d, H), 4.40 -4.68 (m, 3H), 5.20-5.40 (m, 2H), 5.42-5.43 (d, H), 6.80-5.97 (m, H); LC-MS: m / z = 258 (M + H +) for both diastereomers. (98-) 1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-isobutoxy-5-oxo-tetrahydro-furan-3-yl) -amide. It was prepared from compound 97a and the allyl ester of (2-isobutoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (sin) according to the procedure used to prepare compound 98a to yield 93 mg (yield 38%) of the title compound. H1 NMR (500 MHz, CDC13): d 0.74-0.76 (t, 0.6H), 0.80-1.00 (m, 5.4H), 1. 40-1.50 (m, 3H), 1.90-2.22 (m, 3H), 2.33-2.45 (m, H), 2. 80-2.90 (m, H), 3.32-3.38 (m, H), 3.55-3.80 (m, 3H), 4.38 (br, H), 4.50-4.60 (m, H), 4.70-4.80 (m, H), 4.90-5.00 (m, H), 5.42-5.45 (m, H), 6.74-6.76 (d, H) , 6.86-6.88 (d, H), 7.31-7.33 (d, H), 7.51-7.53 (m, H), 7.74-7.75 (d, H); retention time in analytical HPLC: 9.63 and 9.80 min; LC-MS: m / z = 495 (M + H +).

P1123 [2- (Indan-2-yl) oxy-5-oxo-tetrahydro-furan-3-yl] -carbamic acid allyl ester. It was prepared from the 3-allyloxycarbonyl-amino-4-hydroxy-butyric acid tert-butyl ester (5.2 grams, 20 mmol) as described for compound 40 using 2-indanol (8.05 grams, 60 mmol) to yield 4.10. grams (65% yield) of the title compound as a mixture of epimers. Upon carrying out the purification, 1.76 grams (yield 28%) of the epimer 4 (S), S (R) were obtained as a yellow oil. NMR H1 (500 MHz, CDC13) d 2.42 (dd, J = 17.2, 10.5Hz, 1H), 2.79 (dd, J = 17.2, 8.4Hz, 1H), 2.99 (dd, J = 16.7, 4.1Hz, 1H) , 3.04 (dd, J = 16.7, 4.1Hz, 1H), 3.22 (dd, J = 17.2, 6.6Hz, 1H), 3.26 (dd, J = 17.2, 6.6Hz, 1H), 4.53 (m, 3H), 4.70 (m, 1H), 5.20 (m, 2H), 5.60 (d, J = 5.3Hz, 1H), 5.87 (m, 1H), 7.17 (m, 4H) ppm. LC-MS (ES +): m / e = 318 (M + H). Analytical HPLC (column C18): 17.094 min. A mixture of epimers (0.75 grams, yield 12%), and epimer 4 (S), 5 (S) (1.59 grams, 25%) was also separated as a white solid. NMR H1 (500MHZ, CDC13) d 2.38 (d, J = 17.9Hz, 1H), 3.0 (m, 3H), 3.22 (m, 2H), 4.13 (m, 1H), 4.58 (m, 2H), 4.68 ( m, 2H), 4.98 (br s, 1H), 5.26 (m, 1H), 5.57 (s, 1H), 5.88 (ddt, J = 18.0, 11.1, 5.4Hz, 1H), 7.20 (m, 4H) ppm . LC-MS (ES +): m / e = 318 (M + H). Analytical HPLC (column C18): 17.025 (5.5%), 17.325 (94.5%) min. [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2 [2- (indan-2-yloxy) -5-oxo-tetrahydro-furan-3-yl] -amide. -carboxylic (98at). It was prepared from compound 97a and [2- (indanol-2-yl] oxy-5-oxo-tetrahydrofuran-3-yl) -carbamic acid allyl ester according to the procedure used to prepare compound 98a to produce the compound of the title as a 71:29 mixture of epimers as a blaquecino solid (0.20g, 58% yield). RgMN H1 (500 MHz, CDC13) d 1.0-1.5 (m, 3H), 1.6-2.3 (m, 4H), 2.42 (m, 1H), 2. 6-3.4 (m, 6H), 3.5-4.1 (m, 3H), 4.2-4.9 (m, 4H), 5.65 (d, J = 5.0Hz, 0.80H), 5.8 (m, 0.07H), 5.85 (d, J = 5.0Hz, 0.13H), 6. 8-7.3 (m, 6H), 7.4-7.9 (m, 3H) ppm. Analytical HPLC (column C18) 16,035 (71.4%), 16,476 (28.6%) min. LC-MS (ES +): m / e = 555 (M + H).

P1123 1- [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -pyrrolidin- [2- (indan-2-yloxy) -5-oxo-tetrahydro-furan-3-yl] -amide. 2 -carboxylic (98au). Prepared from compound 97b and [2- (indanol-2-yl] oxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester according to the procedure used to prepare compound 98a for produce the title compound as a 76:24 mixture of epimers as an off-white solid (0.22g, 57% yield). NMR H1 (500 MHz, CDC13) d 1-08 (d, J = 6.9Hz, 0.4H), 1.26 (d, J = 6.9Hz, 0.6H), 1.35 (d, J = 6.9Hz, 2H), 1.8 -2.3 (m, 3H), 2.28 (s, 2H), 2.29 (s, 1H), 2.4 (m, 1H), 2.8 (M, 1H), 3.10 (m, 2H), 3.27 (m, 2H), 3.58 (m, 2H), 3.69 (m, 1H), 4.5-4.9 (m, 4H), 5.65 (d, J = 5.3Hz, 0.68H), 5.84 (d, J = 5.3Hz, 0.18 H), 6.38 (br, 0, 14H), 6.9-7.7 (m, 6H), 7.6-7.9 (m, 3H), 8.33 (br d, J = 6.8Hz, 0.18H), 8.51 (br d, J = 8.0Hz, 0.82H) ppm. Analytical HPLC (column C18) 15.596 (76.2%), 15.932 (23.8%) min. LC-MS (ES +): m / e = 597 (M + H).

P1123 1- [2- (4-Amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98av) . It was prepared from compound 97a and (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (sin) allyl ester according to the procedure used to prepare compound 98a to produce the compound of title as a whitish solid (0.19g, yield 59%). H1 NMR (500 MHz, CDC13) d 1.2-2.4 (m, 15H), 2.4-3.1 (m, 2H), 3.6-3.9 (m, 2H), 4.2-4.4 (m, 2H), 4.5-5.0 (m, 4H), 5.40 (d, J = 5.0Hz, 0.35H), 5.55 (d, J = 5.0Hz, 0.65H), 6.8-8.2 (m, 5H) ppm. Analytical HPLC (column C18) 14.065 min. LC-MS (ES +): m / e = 507 (M + H). (2- (3,5-Dichloro-4-hydroxy-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98a) ). It was prepared from the 1- [2- (4-allyloxy-3,5-dimethyl-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid tert-butyl ester and compound 40 (without) of agreement P1123 with the procedure used to prepare compound 98a to afford the title compound as a pale yellow solid (1.087g, 64% yield) 1 H-NMR (500MHZ, CDCl3) dl.09 (d, J = 6.9Hz, 0.6H) , 1.33 (d, J = 6.9Hz, 2.4H), 1.96 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H), 2.28 (m, 0.8H), 2.40 (dd, J = 17.3 , 10.2Hz, 0.8H), 2.56 (m, 0.2H), 2.85 (dd, J = 17.3, 8.5Hz, 0.8H), 3.09 (dd, J = 17.7, 10.2Hz, 0.2H), 3.57 (m, 1H), 3.73 (dt, J = 9.2, 7.9Hz, 0.8H), 4.09 (m, 0.2H), 4.21 (d, J = 7.9Hz, 0.2H), 4.44 (d, J = 9.8Hz , 0.2H), 4.55 (dd, J = 8.0, 3.0Hz, 0.8H), 4.62 (d, J = 11.6Hz, 1H), 4.70 (m, 1H), 4.80 (m, 1H), 4.89 (d, J = 11.6Hz, 0.8H), 5.52 (d, J = 5.2Hz, 0.8H), 5.82 (d, J = 5.2Hz, 0.2H), 6.51 (br, 0.2H), 6.62 (br, 0.8H) , 7.0-7.4 (m, 7H), 7.43 (s, 0.4H), 7.66 (d, J = 1.0Hz, 1.6H) ppm. Analytical HPLC (C18 column) 10,135 min. LC-MS (ES +): m / e = 564, 566 (6: 4) (M + H). (1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (98ax). Prepared according to the procedure used to prepare the compound (98av) using the anti- (2-cyclopentyloxy-5-oxo-tetrahydrofuran-3-yl) -amide for P1123 yield the title compound as an off-white solid (0.24 g, 74% yield). NMR H1 (500MHz, CDC13) d 1.41 (d, J = 6.5Hz, 3H), 1.7 (m, 7H), 1.98 (br, 2H), 2.13 (br, 2H), 2.27 (m, 1H), 2.69 ( m, 1H), 2.86 (dd, J = 18.0, 6.8Hz, 0.7H), 2.98 (dd, J = 18.3, 8.2Hz, 0.3H), 3.60 (br, 1.4H), 3.77 (br, 0.6H) , 4.1-4.6 (m, 5H), 4.82 (m, 1H), 5.27 (m, 0.65H), 5.51 (d, J = 5.3Hz, 0.05H), 5.59 (br s, 0.3H), 6.76 (br , 1H), 7.00 (br, 1H), 7.49 (br, 1H), 7.74 (br, 1H), 7.89 (br, 1H) ppm. Analytical HPLC (column C18) 9756 min. LC-MS (ES +): m / e = 507 (M + H). 98ay [1- (2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (98a). It was prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester and compound 97b following the method used to prepare compound 98a. The title compound was separated as a white solid (51 mg, 18% yield). H1 NMR (500MHZ, 1: 1 CDC13: CD30D) d 1.08-1.35 (m, 3H), 1.35-1.55 (m, 3H), Pll23 1.75-2.44 (m, 4H), 2.26 (s, 3H), 2.44-3.07 (m, 2H), 3.48-3.97 (m, 2H), 4.18-4.92 (m, 5H), 5.32 (d, 0.4H) ), 5.47 (d, 0.1H), 5.58 (d, 0.4H), 5.64 (d, 0.1H), 7.70-8.35 (m, 3H). Analytical HPLC 10.37, 10.54 min. LC-MS (ES +) m / e = 509.2 (M + H +). [2- (2-Chloro-ethoxy) -5-oxo-tetrahydro-furan-3-yl] -carbamic acid allyl ester. It was prepared from the 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester (5.2 g, 20 mmol) as described for the preparation of the compound 40 using chloroethanol (4.05mL, 60mmol) to yield 1.84g (35% yield) of the title compound as a mixture of epimers. For the anti diastereomer: H1 NMR (500 MHz, CDC13) d2.42 (dd, J = 18.1Hz, 1H), 3.00 (dd, J = 18.1, 7. 8Hz, 1H), 3.63 (m, 2H), 3.85 (m, 1H), 4.02 (m, 1H), 4.23 (m, 1H), 4.57 (br s, 2H), 5.17 (br s, 1H), 5.22 (d, H = 11.5Hz, 1H), 5.29 (d, J = 16.8Hz, 1H), 5.44 (s, 1H), 5.89 (m, 1H) ppm; LC-MS (ES +) m / e = 264 (M + H). for him P1123 diastereomer without: H1 NMR (500 MHz, CDCl3) d2.47 (dd, J = 17.3, 10.7Hz, 1H), 2.83 (d, J = 17.3, 8.4Hz, 1H), 3.65 (m, 2H), 3.83 (m, 1H), 4.11 (m, 1H), 4.57 (m, 3H), 5.22 (d, H = 10.4Hz, 1H), 5.30 (d, J = 17.2Hz, 1H), 5.33, (m, 1H) ), 5.47 (d, J = 5.2Hz, 1H), 5.89 (ddt, J = 17.1, 11.0, 5.4Hz, 1H) ppm; LC-MS (ES +) m / e = 264 (M + H). [2- (2-morpholin-4-yl-ethoxy) -5-oxo-tetrahydro-furan-3-yl] -carbamic acid allyl ester. It was prepared from the allylic acid ester [2- (2-Chloro-ethoxy) -5-oxo-tetrahydrofuran-3-yl] -carbamic acid by reaction with morpholine (2 eq) and Kl (1 eq) in DMF. 1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] 2- [2 (morpholin-4-yl-ethoxy) -5-oxo-tetrahydro-furan-3-yl] -amide] -pyrrolidin-2-carboxylic acid (98az). It was prepared from compound 97a and [2- (2-morpholin-4-yl-ethoxy) -5-oxo-tetrahydro-furan-3-yl] -carbamic acid (sin) allyl ester following the method used for prepare compound 98a.

P1123 98ba [2- (4-Chloro-benzyloxy) -5-oxo-tetrahydro-furan-3-yl] -carbamic acid allyl ester. It was prepared from the 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using 4-chlorobenzyl alcohol to obtain the title compound as a white solid. Anti diastereomer: HPLC (C18 column) 10.924 min; NMR H1 (500 MHz, CDCl3) d 2.41 (d, J = 8.0 Hz, 1 H), 3.02 (dd, J = 18.1, 7.8 Hz, 1 H), 4.25 (br, 1 H), 4.56 (m, 2 H) 4.58 ( d, J = 11.7Hz, 1H), 4.79 (d, J = 11.7Hz, 1H), 4.99 (br, 1H), 5.22 (dd, J = 10.4, 1.1Hz, 1H), 5.28 (dd, J = 17.2) , 1.3Hz, 1H), 5.44 (s, 1H), 5.86 (m, 1H), 7.25 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4Hz, 2H) ppm; LC-MS (ES +) m / e = 326 (M + H); For diastereomer without: HPLC (C18 column) 10,780 min; NMR H1 (500 MHz, CDC13) d2.47 (dd, J = 17.3, 10.5Hz, 1H), 2.85 (dd, J = 17.3, 8.4Hz, 1H), 4.55 (m, 3.H), 4.58 (d) , J = 11.7Hz, 1H), 4.84 (d, J = 11.7Hz, 1H), 5.23 (dd, H = 10.4, 1.1Hz, 1H), 5.30 (d, J = 16.6Hz, 1H), 5.49 (d , J = 5.0Hz, 1H), 5.89 (ddt, J = 17.1, 11.0, 5.4Hz, 1H), 7.23 (d, J = 8.3HZ, 2H), 7.31 (d, P1123 J = 8.3Hz, 2H) ppm; LC-MS (ES +) m / e = 326 (M + H). [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2 [2- (4-chloro-benzyloxy) -5-oxo-tetrahydro-furan-3-yl] -amide. -carboxylic (98ba). Prepared from compound 97a and [2- (4-chloro-benzyloxy) -5-oxo-tetrahydro-furan-3-yl] -carbamic acid (sin) allyl ester following the method used for compound 98a for yield 154 mg (yield 65%) of the title compound as a pale pink solid. HPLC (column C18) 10.597 min; NMR H1 (500 MHz, CDC13) d 1.14 (d, J = 6.8Hz, 0.75H), 1.34, (d, J = 6.8Hz, 2.25H), 1.6 (br, 0.25H), 1.91 (m, 1H) , 2.03 (m, 1H), 2.10 (m, 1H), 2.29 (m, 0.75H), 2.40 (dd, J = 17.3, 10.3Hz, 0.75H), 2.51 (m, 0.25H), 2.82 (dd, J = 17.3, 8.5Hz, 0.75H), 3.08 (dd, J = 17.9, 10.9Hz, 0.25H), 3.58 (m, 1H), 3.72 (dd, J = 16.5, 8.7Hz, 0.75H), 4.10 ( m, 0.25H), 4.22 (d, J = 8.0Hz, 0.25H), 4.39 (d, J = 10.8Hz, 0.25H), 4.54 (dd, J = 9.1, 2.9Hz, 0.75H), 4.60 (d , J = 11.9Hz, 0.75H), 4.68 (m, 1H), 4.85 (d, J = 11.7Hz, 0.75H), 4.86 (m, 1H), 5.49 (d, J = 5.2Hz, 0.75H), 5.81 (d, J = 5.2Hz, 0.25H), 6.2 (br, 0.25H), 6.74 (m, 2H), 7.05 (d, J = 8.5Hz, 0.5H), 7.17 (d, J = 8.4Hz, 0.5H), 7.30 (m, 3.25H), 7.48 (dd, J = 8.4, 2.0Hz, 0.75H), 7.56 (d, J = 1.9Hz, 0.25H), 7.73 (d, J = 1.9Hz, 0.75) H), 8.42 (d, J = 5.7Hz, 0.25H) ppm; LC-MS (ES +) m / e = 563, 565 (M + H).

P1123 98bb [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2 [2- (4-chloro-benzyloxy) -5-oxo-tetrahydro-furan-3-yl] -amide. -carboxylic (98bb). Prepared from compound 97b and [2- (4-chloro-benzyloxy) -5-oxo-tetrahydrofuran-3-yl] -carbamic acid (sin) allyl ester according to the procedure used for compound 98a for yield 165mg (64% yield) of the title compound as a pale yellow solid. HPLC (column C18) 10.491 min; PJMN H1 (500 MHz, CDC13) d 1.16 (d, J = 6.8Hz, 0.6H), 1.35, (d, J = 6.8Hz, 2.4H), 1.94 (m, 1H), 2.04 (m, 1H), 2.10 (m, 1H), 2.25 (s, 3H), 2.28 (m, 1H), 2.40 (dd, J = 17.3, 10.4Hz, 0. 8H), 2.53 (m, 0.2H), 2.84 (dd, J = 17.3, 8.5Hz, 0.8H), 3.02 (dd, J = 17.5, 10.5Hz, 0.2H.), 3.58 (m, 1H), 3.72 (ddd, J = 17.2, 8.3, 8.3Hz, 0.8H), 4.13 (m, 0.2H), 4.22 (d, J = 8.2Hz, 0.2H), 4.40 (d, J = 10.9Hz, 0.2H), 4.54 (d, J = 8.1, 3.0Hz, 0.8H), 4.60 (d, J = 11.8Hz, 0.8H), 4.69 (m, 1H), 4.85 (d, J = 11.8Hz, 0.8H), 4.87 (m, 1H), 5.49 (d, J = 5.2Hz, 0.8H), P1123 5.80 (d, J = 5.2Hz, 0.2H), 6.47 (br, 0.2H), 6.95 (d, J = 8.3Hz, 0.8H), 7.05 (d, J = 8.3Hz, 0.4H), 7.18 ( d, J = 8.3Hz, 0.4H), 7.29 (ra, 3.2H), 7.49 (dd, J = 8.6, 1.9Hz, 0.2H), 7.63 (dd, J = 8.6, 1.9Hz, 0.8H), 7.74 (d, J = 1.9Hz, 1H), 7.85 (d, J = 1.9Hz, 0.8H), 8.25 (d, J = 6.4Hz, 0.2H), 8.51 (m, 0.8H) ppm; LC-MS (ES +) m / e = 605, 607 (M + H).

Scheme XVIII 102a, Y = AcNH 101 102b, Y = NH2 2- (2-Benzyloxy-5-oxo-tetrahydro-furan-3-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester (100). It was prepared from the 1-terbutyl ester of piperidin-1,2-dicarboxylic acid 99 and the compound 40 following the method used in the preparation of the compound P1123 75 to give the title compound as a yellow solid (2.63g, 57% yield). NMR H1 (500MHZ, CDC13) d 1.15-1.79 (m, 15H), 2.12-2.50 (m, 2H), 2.56-2.83 (m, 1H), 2.89 (dd, 0.5H), 3.05 (dd, 0.5H) , 3.81-4.15 (br s, 1H), 4.36-4.97 (m, 3H), 5.37-5.61 (m, 1H), 6.42-6.89 (br s, 1H), 7.17-7.51 (m, 5H). LC-MS (ES +) m / e = 419.4 (MH +).

Ter-butyl acid ester. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-carbamoyl) -piperidin-1-yl] -l-methyl-2-oxo-ethyl} -carbámico (101). The 2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) piperidine-1-carboxylic acid (100) tert -butyl ester was dissolved in 20% TFA in CH2Cl2 (25mL) and stirred at room temperature for 50min. The solvent was evaporated and the residual acid formed an azeotrope with CH2C1 (4x). The resulting oil was dissolved in CH2C12 (20mL) and DMF (5mL), cooled to 0 ° C and treated with DIEA (4.7mL, 27.0mmol), Boc-alanine (970mg, 5.1mmol), HOBT (924mg, 6.8 mmoles) and EDC (1.31g, 6.8mmol) and the solution was stirred under N2 for 18 hours. The solvent was concentrated under vacuum then dissolved in EtOAc and washed with 0.5 N NaH0 (2 times), saturated NaHCO3 (2 times) and brine. The organic layer was dried over Na2S04 anhydride and evaporated to give an orange solid which was dissolved in CH2C12 and added drop-wise to diethyl ether to afford a white precipitate. SE afforded the title compound as a white solid (1.21g, 73% yield). NMR H1 (500MHZ, CDCI3) dl.10-1.79 (m, 18H), 1.98-2.19 (m, 0.5H), 2.28-2.88 (m, 3H), 2.89-3.13 (m, 0.5H), 3.78-3.95 (m, 0.5H), 4.21-5.16 (m, 5.5H), 5.38-5.59 (m, 0.3H), 5.66 (d, 0.4H), 5.80 (d, 0.3H), 7.24-7.40 (m, 5H ). LC-MS (ES +) m / e = 490.3 (MH +). 1- [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -piperidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) amide (102a). It was prepared from the tert-butyl ester of the acid. { 2- [2- (2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -piperidin-1-yl] -l-methyl-2-oxo-ethyl} -carbamic acid and 4-acetylamino-3-chlorobenzoic acid by the procedure used in the preparation of compound 98a to give the title compound (71mg, 47% yield). NMR H1 (500MHZ, CDCl3) d 1.10 -1.97 (m, 10H), 2.10-2.68 (m, 5H), 2.73-3.24 (m, 2H), 3.62-3.92 (m, 1H), 4.24-5.27 (m, 5H), 5.48-5.59 (m, 0.5H), 5.75-5.85 (m, 0.5H), 6.51-6.61 (d, 1H), 7.05-7.45 (m, 4H), 7.52-8.12 (m, 4H). Analytical HPLC 8.30min. LC-MS (ES +) m / e = 585.3 (MH +).

P1123 1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -piperidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (102b) . Prepared as in the previous case for compound 102a to give the title compound (0.06g, yield 27%) as a yellow solid. 1H NMR (500MHz, CDC13) d 1.2-1.8 (m, 7H) 2.1-2.6 (m, 2H), 2.7-3.2 (m, 4H), 3.6-4.0 (m, 1H), 4.3-4.9 (m, 7H ), 5.0-5.8 (m, 2H), 6.5-7.0 (m, 2H), 7.2-7.8 (m, 8H) ppm. Analytical HPLC (cyano column) 14.559 (39.6%), 15.198 (60.4%). LC-MS (ES +): m / e = 543 (M + H) Scheme XIX P1123 2-tert-butyl ester 1-benzyl ester of 4-hydroxy-pyrrolidin-1,2-dicarboxylic acid (104). Compound 104 was prepared according to the procedure used to prepare compound 95. A suspension of Cbz-Hyp-OH (4,854g, 18mmol) in DMA (135ml), benzyltriethylammonium chloride (4.105g), 18 mmol), KC03 (64 g, 46 mmol) and 2-bromo-2-methylpropane (99 ml, 859 mmol) was stirred at 55 ° C for 18 hours. The mixture was diluted with ice-water and extracted with EtOAc (3x). The organic phase was washed with water, 0.5N NaHS0 solution and brine, the solvent was dried under vacuum to yield the title compound as a yellow oil (5.368g, 98% yield). NMR H1 (500MHz, CDC13) d 1.33 (s, 5H), 1.4 7 (s, 4H), 2.01-2.14 (m, 1H), 2.22-2.38 (m, 1H), 3.50-3.72 (m, 2H), 4.34-4.45 (m, 1H), 4.45-4.53 (m, 1H), 5.04-5.20 (m, 2H), 7.22-7.42 (m, 5H) analytical HPLC 10.14min. LC-MS (ES +) m / e = 322.2 (MH +). 2-ester-butyl ester 1-benzyl ester of 4-fluoro-pyrrolidin-1,2-dicarboxylic acid (105). A solution of compound 104 (4.262, 13. 96 mmol) in CH2Cl2 (100 ml) at -78 ° C was treated with DAST (1.80ml, 13.6mmol), stirred for 10 minutes then warmed to room temperature and stirred for 60 hours under N2. The mixture was poured into NaHC03 on ice ( P1123 10%, 350ml) and extracted with CH2C12 (2x). The organic phase was washed with water, brine, dried over anhydrous Na 2 SO and concentrated to give a brown oil (4299g) which was purified by flash column chromatography on silica gel using hexanes / EtOAc (90/10 to 80 /twenty%) . The title compound was obtained as a yellow oil (2.805g, 64% yield). NMR H1 (500MHZ, CDCl3) d 1.37 (s, 4.5H), 1.45 (s, 4.5H), 2.20-2.55 (m, 2H), 3.61-3.93 (m, 2H), 4.41 (d, 0.5H), 4.49 (d, 0.5H), 5.03-5.21 (m, 3H), 7.23-7.44 (m, 5H). Analytical HPLC 12.15min. LC-MS (ES +) m / e = 324.2 (MH +). 2-tert-butyl ester 1-benzyl ester of l- (2-benzyloxyarbonyl-amino-propionyl) -4-fluoro-pyrrolidin-1,2-dicarboxylic acid (106). A solution of compound 105 (2.72g, 8.42 mmol) in MEOH (50ml) and Pd 10% / C (1.27g) was stirred under H2 for 2 hours then was filtered through Celite and the solvent was evaporated to give a yellow oil (1.526g).

This oil was dissolved in CH2C12 (30ml) and treated with DIEA (1.5ml, 8.6mmol), Cbz-ala-OR (2.34g, 10.5mmol) and EDC (2.32g, 12mmol) at 0 ° C. The mixture was further stirred 10 minutes at 0 ° C then allowed to warm to room temperature and stirred for 18 hours. The solvent was concentrated under vacuum and the residue was dissolved in EtOAc then washed with 0.5 N NaH0 (2 times), saturated NaHCO 3 (2 times) and brine. The organic layer was dried over anhydrous Na2SO4 and Pll23 was evaporated to give a white solid which was purified by flash column chromatography, eluting with hexanes / EtOAc (80/20 to 60/40%). The title compound was separated as a white solid (286g, 86% from the 2-ester-butyl ester-benzyl ester of 4-fluoro-pyrrolidin-1,2-dicarboxylic acid.) RMN H1 (500MHz, CD3OD) dl. 26-1.59 (m, 12H), 2.20-2.67 (m, 2H), 3.45-4.13 (m, 2H), 4.25-4.47 (m, 1H), 4.58-4.71 (m, 1H), 4.96-5.17 (m , 2H), 5.19-5.45 (m, 1H), 7.23-7.48 (m, 5H) Analytical HPLC 16.36min LC-MS (ES +) m / e = 395.3 (MH +) 1- [2- (4-Amino-3-chloro-benzoylamino) -propionyl] -4-fluoro-pyrrolidine-2-carboxylic acid tert-butyl ether (107). A suspension of compound 106 (2.65 g, 6. 72 mmol) in MEOH (40 ml) and 10% Pd / C (1.32 g) was stirred under H 2 atmosphere for 1.5 hours, filtered through Celite and concentrated to give a waxy solid (1694 g). The solid was dissolved in CH2C12 (25ml) and treated with DIEA (3.4ml, 19.5mmol), 4-amino-3-chlorobenzoic acid (1362g, 7.9mmol), HOBT (1164g, 8.62mmol) and EDC (1645). g, 8.57 mmol) at 0 ° C under N2. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was concentrated under vacuum. The residue was dissolved in EtOAc, washed with water (4 times), NaHS04 0.5N (2 P1123 times), saturated NaHC03 (2 times) and brine. The organic layer was dried over anhydrous Na 2 SO and evaporated to give a white solid which was purified by flash column chromatography, using CH 2 Cl 2 / MeOH (99/1 to 98/2%). The product was obtained as a white solid (2.705g, 97%). NMR H1 (500MHz, CD3OD) dl.33 (s, 9H), 1.48 (d, 3H), 2.31-2.55 (m, 2H), 3.93 (d, d, 1H), 4.02-4.21 (m, 1H), 4.59-4.76 (m, 1H), 5.31 (br s, 0.5H), 5.41 (br s, 0.5H), 6.78 (d, 1H), 7.57 (d, d, 1H), 7.78 (s, 1H), 8.31 (d, 1H). Analytical HPLC 14.14min. LC-MS (ES +) m / e = 414.2 (MH +). 108a (2- (4-amino-3-chloro-benzoylamino) -propionyl] -4-fluoro-pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. (108a). It was prepared from the allylic acid ester (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (sin) and compound 107a following the method used for the synthesis of compound 98a. The title compound was isolated as a white solid (41mg, 15% yield). H1 NMR (500MHZ, CD3OD) d 0. 94 (d, 0. 3H), 1. 07 (d, 1H), 1. 40 (m, P1123 1.7H), 2.21-2.65 (m, 2.2H), 2.70-2.85 (m, 1.4H), 2.96-3.08 (m, 1.4H), 2.96-3.08 (dd, 0.4H), 3.57-4.24 (m , 3H), 4.41-4.93 (m, 4H) ^, 5.14-5.45 (m, 1H), 5.60-5.67 (m, 0.6H), 5.77 (d, 0.4H), 6.77 (dd, 1H), 7.15-7.41 (m, 5H), 7.51-7.62 (m, 1H), 7.77 (dd, 1H). Analytical HPLC 12.83min. LC-MS (ES +) m / e = 547.1 (MH +). 108b (2- (4-amino-3-chloro-benzoylamino) -propionyl] -4-fluoro-pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. (108b). It was prepared from the allylic acid ester (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid 107a following the method used for the synthesis of compound 98a. The title compound was isolated as a white solid (654mg, 54% yield). H1 NMR (500MHZ, CD3OD) dl.07 (d, 0.5H), 1.25-1.56 (m, 2.5H), 2.21-2.65 (m, 2. 3H), 2.68-2.89 (m, 1H), 2.91-3.10 (m, 0.7H), 3.57-4.23 (m, 2H), 4.32-4.95 (m, 5H), 5.16-5.52 (m, 1H), 5.45-5.50 (m, 0.3H), 5.54-5.58 (m, 0.2H), 5.61-5.67 (m, 0.3H), 5.77 (d, 0.2H), 6.72-6.84 (m, 1H), 7.16-7.41 (m, 5H), 7.50-7.65 P1123 (m, 1H), 7.71-7.87 (m, 1H). Analytical HPLC 12.83 min. LC-MS (ES +) m / e = 547.1 (MH +). 108c [1- (2- (4-amino-3-chloro-benzoylamino) -propionyl] -4-fluoro-pyrrolidin-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide. (108c). It was prepared from the allylic acid ester (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (sin) and compound 107a following the method used for the synthesis of compound 98a to give the title compound (100.3mg, 38% yield). H1 NMR (500MHZ, CD30D) 1.09 (t, 1.2H), 1.25 (t, 1.8H), 1.40 (d, 1H), 1.49 (d, 2H), 2. 33-2.61 (m, 2H), 2.65-2.95 (m, 2H), 3.44-4.30 (m, 4H), 4. 47-4.79 (m, 3H), 5.18-5.25 (m, 0.2H), 5.27-5.36 (m, 0. 5H), 5.39-5.46 (m, 0.3H), 5.56 (m, 1H), 6.72-6.94 (m, 0. 8H), 7.54-7.69 (m, 0.8H), 7.79 (d, 0.55H), 8.06 (d, 0 55H), 9. 00 (d, 0, 3H). Analytical HPLC 8. 46 min. LC-MS (ES +) m / e = 485. 2 (MH +).

P1123 1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] 2- (2-isopropyl-5-methyl-cyclohexyl) -5-oxo-etrahydro-furan-3-yl] -amide] -4-fluoro-pyrrolidine-2-carboxylic acid (108d). It was prepared from the allyl ester of the acid. { 2- [IR- (2S-isopropyl-5R-methyl-cyclohexyloxy)] -5-oxo-tetrahydro-furan-3-yl} -carbamic and compound 107a following the method used for the synthesis of compound 98a to give the title compound (95 mg, 31% yield). NMR H1 (500MHZ, CD3OD) d0.42 (d, 2H), 0.57 (d, 2H), 0.60-1.10 (m, 10H), 1.22-1.76 (m, 6H), 1.96-2.17 (m, 1H), 2.29-2.60 (m, 2H), 2.61-2.88 (m, 1.5H), 3.02-3.23 (dd, 0.5H), 3.37-3.47 (m, 0.5H), 3.50-3.61 (m, 0.5H), 3.63 -4.24 (m, 2H), 4.48-4.62 (m, 3H), 5.18-5.48 (m, 1H), 5.72 (d, 0.4H), 5.82 (d, 0.6H), 6.77-6.84 (m, 1H) , 7.53-7.67 (, 1H), 7.78 (d, 0.4H), 7.84 (d, 1H) Analytical HPLC 8.34min. LC-MS (ES +) m / e = 595 (MH +) P1123 Scheme XX 110 111 Ter-butyl ester of acid. { 2- [2- (2-ethoxy-5-oxo-tetrahydro-furan-3-carbamoyl) -pyrrolidin-1-yl] -l-methyl-2-oxo-ethyl} carbamic (109). It was prepared from the allyl ester of (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid 74 following the method used for the synthesis of compound 75 to give the title compound as a pale yellow solid. (660mg, 73% yield). H1 NMR (500MHZ, CD30D) d 1.14-1.36 (m, 6H), 1.42 (s, 9H), 1.75-2.29 (m, 4H), 2. 48 (dd, 0.5H), 2.58 (dd, 0.5H), 2.72-2.85 (m, 0.5H), 2.99 (dd, 0.5H), 3.43-3.91 (m, 4H), 4.07-4.52 (m, 2.5H), 4.53- 4.72 (m, 0.5H), 5.37 (s, 0.5H), 5.57 (d, 0.5H) ). Analytical HPLC (mixture of 2 diastereomers) 7.92, 8.14 min. LC- P1123 EM (ES +) ra / e = 414.3 (MH +) [1- (2- (4-Allyloxy-3,5-dichloro-benzoylamino) -propionyl] -pyrrolidin-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (110 ). It was prepared from compound 109 and 4-allyloxy-3,5-dichloro-benzoic acid following the method used for the synthesis of compound 82 to give the title compound as a white solid (228mg, 65%). RgMN H1 (500MHZ, CD30D) d 1.10-1.30 (m, 4H), 1.32-1.52 (m, 3H), 1.63-2.31 (m, 4H), 2.41-2.50 (d, 0.5H), 2.52-2.61 (dd, 0.5H), 2.67-2.81 (m, 0.5H), 2.94-3.05 (dd, 0.5H), 3.47-3.96 ( m, 4H), 4.21-4.81 (m, 5H), 5.22-5.32 (m, 1H), 5.35-5.49 (m, 1.5H), 5.55-5.63 (m, 0.5H), 6.06-6.21 (m, 1H) ), 7.90 (s, 2H). Analytical HPLC (mixture of 2 diastereomers) 12.56 min. LC-MS (ES +) m / e = 542.3 (MH +).

L- [2- (3,5-dichloro-4-hydroxy-benzoylamino) -propionyl] -pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide (111 ). To a solution of compound 110 (194Mg, 0. 36mmol) in CH2C12 (5ml) was added ADMB (70.7mg, 0. 45mmol) and Pd (PPh3) 4 (50.3mg, 0.044mmol) at 0 ° C. The solution was warmed to room temperature, after 15 minutes it was stirred for 2 hours, diluted with CH2Cl2 then P1123 was washed with water (2 times) and brine. The organic layer was dried over anhydrous Na 2 SO and evaporated to give the crude product. Flash chromatography using CH2Cl2 / MeOH (99/1 to 95/5%) afforded the title compound (138.6mg, 77% yield). NMR H1 (500MHZ, CD3OD) d 1.13-1.31 (m, 3H), 1.35-1.49 (m, 3H), 1.84-2.35 (m, 4H), 2.43-3.05 (m, 2H), 3.48-3.93 (m, 4H), 4.22-4.80 (m, 3H), 5.38 (d, 0.4H), 5.46 (s, 0.1H), 5.55-5.61 (m, 0.5H), 7.76-7.94 (m, 2H). Analytical HPLC 8.70min. LC-MS (ES +) m / e = 502.2 (MH +).

Scheme XXI 114 113 115a, X = Cl, Y = NH2. Z = H 116a- 116h 15b, X = Cl, Y = AcNH, Z = H 115c, X = CI. Y = AcNH, Z = CHaO Compounds 116a-116h were prepared as described above for compounds 98 only by substituting the l- (2-benzyloxycarbonyl-amino-propionyl) -pyrrolidine-2-carboxylic acid tert-butyl ester ( 95) by the 1- (2-benzyloxycarbonyl-amino-propionyl) -4,4-difluoro-pyrrolidin-2-carboxylic acid tert-butyl ester (114).

Preparation of 1- (2-benzyloxycarbonyl-α-n-propionyl) -4,4-difluoro-pyrrolidine-2-carboxylic acid tert-butyl ester (114). A solution of 4,4-difluoro-pyrrolidin-1,2-dicarboxylic acid 2-butyl ester ester 1-benzyl (113) (Karanewsky, et al., Med. Chem. 33, pp. 1459- 1469 (1990)) (0.42 9, 1.23 mmoles) and 10% palladium on carbon (0.22g) in methanol (6 mL) was stirred under a hydrogen pressure atmosphere for 3 hours. The mixture was filtered through Celite and evaporated. The residue was dissolved in CH2C12 (4 mL) and DMF (2 mL) and cooled to 0 ° C. 2-Benzyloxycarbonylamino-propionic acid was added (0.30 g, 1.35 mmol), EDC (0.30, 1.54 mmol), DIEA (0.65 mL) and HOBt (0.17 9, 1.23 mmol) and the reaction was stirred by 0. 5 hours at 0 ° C, then 16 hours at room temperature under nitrogen. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate, then washed with P1123 10% sodium bisulfate, saturated sodium bicarbonate, water and brine, dried over sodium sulfate and evaporated. Purification by flash chromatography on silica, eluted with 25:75 ethyl acetate: hexanes provided the l- (2-benzyloxycarbonyl-aminopropionyl) -4,4-difluoro-pyrrolidine-2-carboxylic acid tert-butyl ester (0.39 9 , yield 77%) as a colorless oil. NMR H1 (500 MHz, CDC13) d 1.3-1.6 (m, 12H), 2.5 (m, 0.8H), 2.7 (m, 1.2H), 3.9 (m, 1H), 4.1 (m, 1H), 4.4 ( m, 1H), 4.7 (m, 1H), 5.1 (m, 2H), 5.59 (br d, J = 7.7Hz 0.8H), 5.7 (br d, J = 7.7Hz, 0.2H), 7.35 (m, 5H) ppm. Analytical HPLC (cyano column) 17.069 min. LC-MS (ES +): m / e = 413 (M + H), 357 (M + H-tert-butyl), 313 [M + H- (C02ter-butyl)].

Acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide 1- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -4,4-difluoro-pyrrolidine-2-carboxylic acid (116a). It was prepared from compound 115a and P1123 compound 40-without to produce the title compound as an off-white solid (0.14g, 73% yield) 1 H-NMR (500 MHz, CD3OD) d 1.0-1.5 (m, 3H), 2.0-3.5 (m, 4H + CH30H ), 3.5-5.5 (M, 6H + H20), 5.6-5.8 (m, 1H), 6.7-6.8 (m, 1H), 7.1-7.8 (m, 8H), 8.2-8.6 (m, 1H) ppm. Analytical HPLC (cyano column) 13,744 min. LC-MS (ES +) m / e = 565 (M + H). 1- [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide., 4-difluoro-pyrrolidin-2-carboxylic acid (116b) Prepared from compound 115b and compound 40 -sin to produce the title compound as an off-white solid (0.08 g, 38% yield). NMR H1 (500 MHz, CDCl3) dl.03 (d, J = 6.9Hz, 0.4H), 1.30 (d, J = 6.9Hz, 0.6H), 2.25 (d, J = 2.9Hz, 3H), 2.4- 3.2 (m, 4H), 3.6-4.4 (m, 4H), 4.6-4.9 (m 3H), 5.52 (d, J = 5.2Hz, 0.6H), 5.78 (d, J = 5.2Hz, 0.4H), 6.6 (br s, 1H), 6.9-7.9 (m, 5H), 8.39 (d, J = 8.1 Hz, 0.4H), 8.44 (d, J = 8.3Hz, 0.6H), 8.74 (d, J = 6.8 Hz, 1H) ppm. Analytical HPLC (cyano column) 11.830 min. LC-MS (ES +): m / e = 607 (M + H).

P1123 (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide of 1- [2- (4-acetylamino-5-chloro-2-methoxy-benzoylamino) -propionyl] -4,4-difluoro -pyrrolidine-2-carboxylic acid (116c). Prepared from compound 115c and compound 40-sin to produce the title compound as an off-white solid (0.07 g, 29% yield). NMR H1 (500MHz, CDCl3) d0.99 (d, J = 6.9Hz, 1.35H), 1.32 (d, J = 6.9Hz, 1.65H), 2.25 (s, 1.5H), 2.26 (s, 1.5H), 2.3-3.2 (m, 4H), 3.95 (s, 0.55H), 3.98 (s, 0.45H), 3.7-4.1 (m, 2. 5H), 4.2-4.5 (m, 1.5H), 4.6-4.9 (m, 3H), 5.52 (d, J = 5.3Hz, 0.55H), 5.80 (d, J = 5.3Hz, 0.45H), 7.0-7.4 (m, 4H), 7.7-7.9 (m, 2H), 8.0-8.4 (m, 2H), 8.49 (d, J = 6.5Hz, 1H), 8.93 (d, J = 6.7Hz, 1H) ppm. Analytical HPLC (cyano column) 12,959 min. LC-MS (ES +): m / e = 637 (M + H). (1- (2- (4-acetylamino-3-chloro-benzoylamino) -propionyl] -4,4-difluoro-pyrrolidin-2-ethoxy-2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide. carboxylic (116d). Prepared from compound 115b and (2-ethoxy-5-oxo-tetrahydrofuran-3-yl) -carbamic acid (sin) allyl ester to produce the title compound as a 92: 8 mixture of epimers. Whitish solid (0.27g, 66% yield), H1-NMR (500 MHz, CDC13) d 1.0-1.5 (m, 6H), 2.25 (s, 1.8H), 2.26 (s, 1.2H), 2-3-3.1 (m, 4H), 3.3-4.3 (m, 4H), 4.5-4.9 (m, 3H), 5.45 (d, J = 5.3Hz, 0.75H), 5.59 (d, J = 5.2Hz, 0.25H), 6.7-7.1 (m, 2H), 7.62 (dd, J = 8.7, 2. OHZ, 1H), 7.76 (m, 1H), 7.85 (d, J = 2.0Hz, 1H), 8.48 (m, 1H) ppm . Analytical HPLC (column C18) 13.300 (91.8%), 14.046 (8.2%) min. LC-MS (ES +): m / e 545 (M + H). (1- (2- (4-acetylamino-3-chloro-benzoylamino) -propionyl] -4,4-difluoro-pyrrolidin-2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl) -amide. -carboxylic (116e). Prepared from compound 115b and ester Allyl p1123 (2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (without) to produce the title compound as a 93: 7 mixture of epimers. NMR H1 (500 MHz, CDC13) d 1.0-2.0 (m, 13H), 2.25 (s, 2H), 2.26 (s, IR), 2.40 (dd, J = 17.3, 10.1Hz, 1H), 2.84 (dd, J = 17.3, 8.5Hz, 1H), 2.5-3.0 (m, 2H), 3.5-4.3 (m, 3.5H), 4.5-4.9 ( m, 2.5H), 5.59 (d, J = 5.3Hz, 0.75H), 5.76 (d, J = 5.2Hz, 0.25 H), 6.74 (br d, J = 5.7HZ, 0.25H), 6.93 (br d, J = 7.1Hz, 1H), 7.06 (br d, J = 7.8Hz, 0.75H), 7.62 (dd, J = 8.6, 2.0Hz , 1H), 7.78 (m, 1H), 7.85 (d, J = 2.0Hz, 1H), 8.35 (br d, J = 6.6Hz, 0.25H), 8.50 (br d, J = 8.2Hz, 0.75H) ppm. Analytical HPLC (column C18) 17,112 (93%), 17,433 (7%) min. LC-MS (ES +): m / e = 599 (M + H). [2- (4-acetylamino-3-chloro-benzoylamino) -propionyl] -4- [2- (indanol-2-yl) oxy-5-oxo-tetrahydro-furan-3-yl] -amide], 4-difluoro-pyrrolidine-2-carboxylyl (116f). Prepared from compound 115b and [2- (indanol-2-yl] oxy-5-oxo-tetrahydroxy] allyl ester P1123 furan-3-yl) -carbamic acid to produce the title compound as a 62:38 mixture of epimers. Whitish solid (0.34g, yield 71%). NMR H1 (500 MHz, CDC13) d 1.09 (d, J = 6.9Hz, 0.6H), 1.21 (d, J = 6.9Hz, 0.9H), 1.33 (d, J = 6.9Hz, 0.9H), 1.42 ( d, J = 6.9Hz, 0.6H), 2.28 (s, 2H), 2.29 (s, 1H), 2.40 (d, J = 17.4, 10.3Hz, 1H), 2.4-3.3 (m, 7H), 3.6- 4.2 (m, 2H), 4.5-4.8 (m, 4H), 5.66 (m, 0.6H), 5.84 (d, J = 4.3Hz, 0.2H), 6.22 (m, 0.2H), 6.7-7.0 (m , 2H), 7.2-7.3 (m, 4H), 7.5-7.7 (m, 1H), 7.8-8.0 (m, 2H), 8.52 (m, 0.6H), 8.62 (br d, J = 6.5Hz, 0.4 H) ppm. Analytical HPLC (column C18) 16.556 (62.0%), 16.824 (38.0%) min. LC-MS (ES +): m / e = 633 (M + H). (1- (2- (4-acetylamino-3-chloro-benzoylamino) -propionyl] -4,4-difluoro-pyrrolidin-2-cyclopentylmethoxy-5-oxo-tetrahydro-furan-3-yl) -amide. -carboxylic (116g). Prepared from compound 115b and (2-cyclopentylmethoxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid (sin) allyl ester to produce the title compound as an off-white solid (0.20g, yield 44%).

P1123 NMR H1 (500 MHz, CDCl3) d 1.0-1.8 (m, 11H) 1.9-3.0 (m, 5H), 2.26 (s, 3H), 3.29 (m, 0.25H), 3.47 (m, 0.75H), 3.58 (m, 0.25H), 3.74 (m, 0.75H), 3.8 (m, 0.75H), 4.1 (m, 0.25H), 4.25 (m, 1H), 4.4-4.8 (m, 3H), 5.44 ( d, J = 5.2Hz, 0.75H), . 62 (d, J = 5.2Hz, 0.25H), 6.7 (br, 0.25H), 6.91 (d, J = 7.1Hz, 1H), 7.1 (m, 0.75H), 7.59 (d, J = 8.5Hz, 0.25H), 7. 63 (dd, J = 8.5, 2.5Hz, 0.75H), 7.75 (m, 1H), 7.86 (d, J = 1.8Hz, 1H), 8.33 (br d, J = 6.5Hz, 0.25H), 8.49 ( br d, J = 8.4Hz, 0.75H) ppm. Analytical HPLC (C18 column) 17.705 min. LC-MS (ES +) m / e = 599 (M + H). [1- (2- (4-acetylamino-3-chloro-benzoylamino) -propionyl] -4,4-difluoro-pyrrolidin-2-phenylethoxy-5-oxo-tetrahydro-furan-3-yl) -amide. -carboxylic (116h). Prepared from compound 115b and the allyl ester of (5-oxo-2-phenethyloxy-tetrahydro-furan-3-yl) -carbamic acid (without) to produce the title compound as an off-white solid (0.15g, yield) 24%). NMR H1 (500MHZ, CDCl3) dl.29 (d, J = 6.9Hz, 0.75H), 1.40 (d, P1123 J = 6.9Hz, 2.25H), 2.25 (s, 2.25H), 2.26 (s, 0.75H), 2.3-3.0 (m, 6H), 3.7-4.8 (m, 7H), 5.38 (d, J = 5.3Hz, 0.75H), 5.67 (d, J = 5.1Hz, 0.25H), 6.65 (m, 1H), 6.90 (d, J = 7.0Hz, 0.75H), 7.06 (d, J = 7.6Hz) , 0.25H), 7.1-7.3 (m, 5H), 7.57 (d, J = 8.6HZ, 0.25H), 7.63 (d, J = 8.6Hz, 0.75H), 7.75 (m, 1H), 7.86 (d , J = 1.8Hz, 1H), 8.35 (d, J = 6.2 Hz, 0.25H), 8.49 (d, J = 8.3Hz, 0.75H) ppm. Analytical HPLC (C18 column) 17.265 min. LC-MS (ES +): m / e = 621 (M + H). SCHEME XXII 40 118 121 120a = anti 120b = syn 2- (2-Benzyloxy-5-oxo-tetrahydro-furan-3-carbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ether (118). Prepared from compound 40 (1.16 g, 4.0 mmol) and Boc-Pro-OH according to the procedure used to prepare compound 100 (Scheme XVIII) to yield 1.53 g (94% yield) of the title compound as a solid white. NMR H1 (500 MHz, CDC13): 1.61 (br, 9H), 1.88 (br, 2H), 2.00-2.50 (m, 3H), 2.80-3.10 (m, H), 3.20-3.60 (m, 2H), 4.05-4.45 (m, 1.5H), 4.58-4.80 (m, 1.5H), 4.83-4.98 (m, H), 5.43-5.53 (m, H), 7.26-7.45 (m, 5H), 7.60-7.80 (d, H); Analytical HPLC: 11.32 min; LC-MS: m / e = 405 (M + H +). 2-phenylaminopropionic acid (119). A mixture of alanine (356 mg, 4.0 mmol), iodobenzene (816 mg, 4.0 mmol), trans-dichlorobis (tri-o-tolylphosphine) palladium (II). { Pd [P (o-Tol) 3] 2C12} (160 mg, 0.2 nimol), copper iodide (I) (40 mg, 0.2 mmol) K2C03 (552 mg, 4.0 mmol), benzyltriethylammonium chloride (160 mg, 0.8 mmol), triethylamine (1.6 mL), and water (0.8 mL) in DMF (8 mL) was stirred under a nitrogen atmosphere at 100 ° C for 20 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), acidified with 6N HCl to a pH of 2 to 3. The aqueous layer was extracted with ethyl acetate (50 mL x 4). The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and evaporated under vacuum to give a red oil. Flash chromatography using hexane / ethyl acetate / acetic acid (95/5 / 0.5 to 80/20 / 0.5) yielded 300 mg (yield 45%) of the P1123 composed of the title as a pink solid. NMR H1 (500 MHz, CDCl3 / CD3OD = 0.5 ml / 3 drops) dl.45 (d, 3H), 4.02-4.15 (m, H), 6.57-6.70 (m, 3H), 7.11-7.25 (m, 2H) ); Analytical HPLC: 6.10 min. LC-MS: m / e = 166 (M + H +). 1- (2-phenylamino-propionyl) -pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide (120a and 120b). A solution of compound 118 (405 mg, 1.0 mmol) was treated with TFA (2 ML) in CH2C12 (2 mL) for one hour. The reaction solution was evaporated under vacuum and an azeotrope was formed with CH2C12 four times to give the pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide as a yellow solid. pale. RM? H1 (500 MHZ, CDCl3): d 1.87-2.15 (m, 4H), 2.30-2.70 (m, 2H), 2.80-3.08 (m, H), 3.45 (br, 2H), 4.35-4.98 (m, 3H ), 5.30-5.56 (m, H), 7.10-7.60 (m, 5H); Analytical HPLC: 7.78 / 8.20 min; LC-MS: m / e 305 (M + H +). 2-phenylaminopropionic acid (119) (300 mg, 1.8 mmol) in CH2C12 (10 mL) was treated with HOBT (270 mg, 2.0 mmol) and EDC (2.1 g, 11 mmol) at 0 ° C for 10 min. Diisopropylethylamine (2 mL) was added followed by a solution of pyrrolidin-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -amide in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 4 hours, diluted with P1123 CH2C12 (40 mL), washed with water, then with brine. The organic layer was dried over anhydrous Na 2 SO 4, filtered and evaporated under vacuum to give a pale yellow solid. Flash chromatography using CH2Cl2 / methanol (99/1 to 98/2) yielded 151 mg (33% yield) of the anti diastereomer of the title compound (120a) and 129 mg (29% yield) of diastereomer without (120b) as a solid white. NMR H1 (500 MHz, CDC13) for the anti diastereomer: d 1.37-1.41 (m, 3H), 1.50-2.45 (m, 4H), 2.60-2.70 (m, 0.3H), 2.89-2.94 (m, 0.7H ), 3.40-3.80 (m, 2H), 4.10-4.50 (m, 3H), 4.50-4.90 (m, 3H), 5.26 (s, 0.3H), 5.38 (s, 0.7H), 6.45-6.60 (m , 2.3H), 6.65-6.80 (m, H), 7.10-7.20 (m, 2.5H), 7.25-7.50 (m, 4.5H), 7.53-7.70 (m, 0.7H), 7.82 (d, H) . For the diastereomer without: d 0.86-0.89 (m, H), 1.20-1.40 (m, 4H), 1.80-2.45 (m, 4H), 2.80-2.86 (m, H), 3.58-3.65 (m, 2H) , 4.20-4.40 (m, H), 4.50-4.75 (m, 2H), 4.90 (d, H), 5.52 (d, H), 6.45-6.70 (m, 3H), 6.75-6.85 (m, H) , 7.10-7.20 (m, 2.3H), 7.30-7.50 (m, 5.7H); Analytical HPLC: 10.55 min for the anti diastereomer and 10.62 min for the diastereomer without; LCMS: m / e = 452 (M + H +) for both diastereomers. 4-Oxo-3- acid. { [1- (2-phenylamino-propionyl) -pyrrolidine-2-carbonyl] -amino} -butyric (121). Prepared from compound 120 (151 mg, 0.33 mmol) using hydrolysis method A to produce P1123 101 mg (83% yield) of the title compound as a white solid. NMR H1 (500 MHz, CDC13 / CD30D = l / l): dl.20-1.65 (m, 2H), 1.65-2.35 (m, 3H), 2.40-3.00 (m, H), 3.20-3.80 (m, 2H), 3.90-4.90 (m, 7H), 7.25-7.80 (m, 5H); Analytical HPLC: 6.38 min; LC-MS: m / e = 362 (M + H +).

GENERAL PROCEDURES FOR THE PREPARATION OF COMPOUNDS OF THE CONFIGURATION C OF FORMULA I (SCHEMES XXIII-XXV) Scheme XXIII Hydrolysis, Method A: A sample of 0.005-50 mmol of alkylhemiacetal was dissolved in 2.5 N HCl / CH3CN (10/1) and stirred at room temperature until the reaction was complete. The resulting aqueous layer was washed with diethyl ether (2 x 20 mL) and lyophilized to obtain the product.

P1123 Hydrolysis, Method B: A sample of 0.005-50 mmol of alkylhemiacetal was diluted in pure formic acid and stirred overnight at room temperature. The mixture was triturated with a 3: 1 mixture of hexane / diethyl ether to give a precipitate. The solvent was decanted and the precipitate was washed with diethyl ether to obtain the product.

Hydrolysis, Method C: A sample of 0.005-50 mmol of alkylhemiacetal was dissolved in CH30H and Pd (0H) 2 / C 20% and stirred under H2 until the reaction was complete. The resulting suspension was filtered and the solution was concentrated under vacuum, then triturated with a 3: 1 mixture of hexane / diethyl ether to give a precipitate. The solvent was decanted and the precipitate was washed with diethyl ether to obtain the product.

Hydrolysis, Method D: A sample of 0.005-50 mmol of alkylhemiacetal in CH3CN / water (1/2) was stirred vigorously with acid resin (Dowex type 50w x 2, H +) until the reaction was complete. The solution was filtered and the resin was washed with P1123 CH3CN / water (1/4). The resulting aqueous layer was washed with diethyl ether, concentrated to a smaller volume under vacuum, then lyophilized to obtain the product.

Scheme XXIV 122a 4-Oxo-3- [(1 -. {2- [9-oxo-9H-fluoren-4-carbonyl) -amino] -propionyl acid} -pyrrolidin-2-carbonyl) -amino] -butyric acid (122a). A sample of 109. Omg (0.19 mmol) of compound 91 was hydrolyzed according to method A to yield 88 mg (96% yield) of the title compound: analytical HPLC 7.15 min. LC-MS (ES +) m / e = 492.2 (M + H).

P1123 3- ( { L- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (122b). A sample of 51.0mg (0.096mmol) of compound 76 was hydrolyzed according to method A to yield 43.0mg (100% yield) of the title compound: H1-NMR (500 MHz, CD3OD / D20: 0.5mL / 10 drops ): d 1.37-1.52 (m, 3H), 1.80-2.20 (m, 3H), 2.20-2.37 (m, H), 2.49-2.60 (m, H), 2.60-2.75 (m, H), 3.70- 3.80 (m, H), 3.80-3.95 (m, H), 4.20-4.35 (m, H), 4.40-4.50 (m, H), 4.50-4.70 (m, H), 4.70-4.85 (m, H ), 6.85-6.87 (d, H), 7.58-7.60 (m, H), 7.77 (s, H); retention time in analytical HPLC: 6.54 min; LC-MS: m / z = 439 (M + H +). 122c 3- ( { 1 - [2- (3,5-Dichloro-4-methoxy-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122c). A sample of 51.0mg (0.088mmol) of compound 92 was hydrolyzed according to method A to yield 24.0mg (56% yield) of the title compound: analytical HPLC 6.4lmin. LC-MS (ES +) m / e = 488.3 (M + H).

P1123 122 3- ( { 1 - [2- (4-Methoxy-3,5-dimethyl-benzoylamino) propionyl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (122d). A sample of 55. Omg (0.102 mmol) of the compound 77 was hydrolyzed according to method A to produce 44. Omg (96% yield) of the title compound: analytical HPLC (C18) 8.70min, 1H-NMR (CDC13, 500Mhz) d 1.23-1.70 (m, 3H), 1.80-2.70 (m, 10H), 2.70-3.15 ( m, 2H), 3.58-4.20 (m, 5H), 4.32-5.50 (m, 3H), 5.60-6.00 (m, H), 6.80-7.90 (m, 4H); LC-MS (ES +) m / e = 448.2 (M + H). 122e 4-Oxo-3- [(1 -. {2- [pyridine-2-carbonyl) -anino) -propionyl acid} -pyrrolidine-2-carbonyl) -amino] -butyric acid (122e). A sample of 55.Omg (0.114 mmol) of compound 88 was hydrolyzed according to method A to yield 30. Omg (67% yield) of the title compound: HPLC Analytical P1123 4. 60min LC-MS (ES +) m / e = 391. 3 (M + H) 12 » 3- ( { L- [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122f) . A sample of 52 mg (0.091 mmol) of compound 78 was hydrolyzed according to method A to yield 40 mg (91% yield) of the title compound: H1-NMR (500MHZ, CD3OD) d 1.08-1.61 (m, 3H), 1.77-2.41 (m, 3H), 2.21 (s, 3H), 2.41-2.77 (m, 2H), 3.43-3.63 (m, 0.3H), 3.65-3.76 (m, 1H), 3.81-3.94 (m, 1H), 4.18-4.34 (m, 1H), 4.42-4.64 (m, 1.7H), 4.77 (q, 1H), 7.79 (dd, 1H); Analytical HPLC 4.97min. LC-MS (ES +) m / e = 481.3 (M + H). 122g 3- ( { L- [2- (4-e? Mino-3,5-dichloro-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl}. -amino) -4-oxo-butyric acid (122g) ). A sample of 44. 3mg (0.079mmol) of the compound P1123 89 was hydrolyzed according to method A to yield 3Omg (81% yield) of the title compound: analytical HPLC 5.40min. LC-MS (ES +) m / e = 473.2 (M + H). 3 - ( { 1 - [2- (3-isopropoxy-benzoylamino) -propionyl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (122h). A sample of 52.Omg (0.097 mmol) of compound 79 was hydrolyzed according to method A to yield 30. Omg (69% yield) of the title compound: analytical HPLC 8.92min. LC-MS (ES +) m / e = 448.3 (M + H). 3- ( { 1 - [2- (3-Bensyloxy-4-methoxy-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122i). A sample of 50.8mg (0.082mmol) of the compound P1123 81 was hydrolyzed according to method A to yield 22.4mg (52% yield) of the title compound: analytical HPLC 6.72min. LC-MS (ES +) m / e = 526.3 (M + H). 4-Oxo-3- [(1 -. {2- [(quinoxalin-2-carbonyl) -amino] -propionyl} -pyrrolidin-2-carbonyl) -amino] -butyric acid (122j). A sample of 38.Omg (0.072 mmol) of compound 80 was hydrolyzed according to method A to yield 32. Omg (100% yield) of the title compound: analytical HPLC 5.95min. LC-MS (ES +) m / e = 442.3 (M + H). 122k 3- ( { 1 - [2- (3,5-Dichloro-4-hydroxy-benzoylamino) -propionyl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (122k). A sample of 35mg (0.060mmol) of compound 83 was hydrolyzed according to method A to produce P1123 29.4mg (75% yield) of the title compound: analytical HPLC 7.91min. NMR H1 (500 MHz, CD3OD) dl.47 (m, 3H), 1.8-2.3 (m, 4H), 2.49 (m, 1H), 2.61 (m, 1H), 3.5 (br m, 0. 2H), 3.69 (brm, 0.9H), 3.84 (brm, 0.9H), 4.27 (m, 1H), 4. 46 (m, 1H), 4.57 (m, 1H), 4.73 (m, 1H), 7.83 (m, 2H) ppm, LC-MS (ES +) m / e = 474.1 (M + H). 1221 3- ( { 1- [2- (4-amino-3-trifluoromethyl-benzoylamino) -propionyl] -pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (1221). A sample of lOmg (0.021 mmol) of compound 98 was hydrolyzed according to method A to yield 7.9mg (94% yield) of the title compound: analytical HPLC 6.64min. LC-MS (ES +) m / e = 473.3 (M + H). 122rn P1123 3- (. {L- [2- (3-Chloro-4-dimethylamino-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122m). A sample of 10. Omg (0.021 mmol) of compound 98x was hydrolyzed according to method A to yield 7. Omg (yield 84%) of the title compound: analytical HPLC 5.15min. LC-MS (ES +) m / e = 467.3 (M + H). 122n 3- ( { 1 - [2- (4-Dimethylamino-3, 5-difluoro-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyryrene (122n). A sample of 20. Omg (0.043 mmol) of compound 98y was hydrolyzed according to method A to yield 16.8 mg (100% yield) of the title compound: analytical HPLC 5.86 min. LC-MS (ES +) m / e = 469.3 (M + H). 122o P1123 3- ( { L- [2- (4-amino-3-chloro-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122o). A sample of 20. Omg (0.046 mmol) of compound 98m was hydrolyzed according to method A to yield 16.7mg (100% yield) of the title compound: analytical HPLC 8.47min. LC-MS (ES +) m / e = 439.2 (M + H). 122p 3- ( { L- [2- (4-Amino-2, 3,5,6-tetrafluoro-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122p). A sample of 20. Omg (0.042 mmol) of compound 98z was hydrolyzed according to method A to yield 15.3 mg (91% yield) of the title compound: analytical HPLC 7.90 min. LC-MS (ES +) m / e = 477.2 (M + H). 122q P1123 -oxo-3- [(1- {2- [(gjuinolin-6-carbonyl) -amino) -propionyl acid} -pyrrolidin-2 -carbonyl) -amino] -butyric acid (122q). A sample of 44mg (0.080 mmoles) of compound 93 was hydrolyzed according to method A to yield 4lmg (100% yield) of the title compound: 1H NMR (5Ó0MHZ, CD30D) d 1.24-1.69 (m, 3H), 1.75-2.37 (m, 4H), 2.39-2.87 (m, 2H), 3.46-4.04 (m, 2H), 4.11-4.77 (m, 3H), 8.19 (dd, 1H), 8.33 (d, 1H), 8.56-8.58 (m, 1H), 8.85 (s, 1H), 9.27-9.39 (m, 2H); Analytical HPLC 4.91min. LC-MS (ES +) m / e = 441.2 (M + H). 122r 3- ( { L- [2- (4-Acetylamino-5-chloro-2-methoxybenzoylamino) propionyl] -pyrrolidine-2-carbonyl}. Amino) -4-oxo-butyric acid (122r). A sample of 44.5mg (0.074mmol) of the compound 87 was hydrolyzed according to method A to yield 34.5mg (91% yield) of the title compound: analytical HPLC 6.88min. LC-MS (ES +) m / e = 511.2 (M + H).

P1123 3- [(L- { 2- [3-Chloro-4- (2,2-dimethyl-propionylamino) -benzoylamino) -propionyl acid} -pyrrolidine-2-carbonyl) -amino] -4-oxo-butyric acid (122s). A sample of 19. Omg (0.036 mmol) of compound 98aa was hydrolyzed according to method A to yield 14.5 mg (90% yield) of the title compound: analytical HPLC 7.28 min. LC-MS (ES +) m / e = 523.3 (M + H). 122t 3- ( { 1- [2- (3-Chloro-4-propionylamino-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122t). A sample of 21. Omg (0.042 mmol) of compound 8ab was hydrolyzed according to method A to yield 17.5 mg (97% yield) of the title compound: HPLC Analytical P11Z3 5.72min. LC-MS (ES +) m / e = 495.2 (M + H) 122u 3- ( { L- [2- (3-Chloro-4-phenylacetylamino-benzoylamino) -propionyl] -pyrrolidine-2-carbonyl} -amino) -4-oxo-butyric acid (122u). A sample of 10. Omg (0.17 mmol) of compound 8ac was hydrolyzed according to method A to yield 7.9 mg (85% yield) of the title compound: analytical HPLC 7.52 min. LC-MS (ES +) m / e = 557.2 (M + H). 122v P1123 3- [(L-. {2- [3-Chloro-4- (3-methyl-butyrylamino) -benzoylamino] -propionyl} -pyrrolidin-2-carbonyl} -amino] -4- acid oxo-butyric (122v) A sample of 8. Omg (0.015 mmol) of compound 98ad was hydrolyzed according to method A to yield 6.5 mg (96% yield) of the title compound: analytical HPLC 6.92 min. MS (ES +) m / e = 523.2 (M + H).

Scheme XXV 108a, X = CI, Y = NH2, 2 = H, Q -? = F, Q2 = H 123a, X = CÍ, Y = NH2, Z = H, Q? = F. Q2 = H 116b, X = CI. Y = AcNH, Z = H, Q? = Cb = F 123b, X = CI, Y = AcNH, Z = H. Q? = Q2 = F 116c, X = CI, Y = AcNH, 2 = CH3?, Q? = Q2 = F 123c, X = C !, Y = AcNH, Z = CH30, Q? = Q2 = F 3- ( { 1 - [2- (4-Amino-3-chloro-benzoylamino) -propionyl] -4-fluoro-pyrrolidin-2-carbonyl} -amino) -4-oxo-butyric acid (123a) ). A sample of 12.4mg (0.022mmol) of compound 108b was hydrolyzed according to method A to yield 9.6mg (93% yield) of the title compound: analytical HPLC 6.99min. LC-MS (ES +) m / e = 473.2 (M + H).

P1123 3- ( { L- [2- (4-Acetylamino-3-chloro-benzoylamino) -propionyl] -4,4-difluoro-pyrrolidine-2-carbonyl} -amino) -4-oxo- butyric (123b). A sample of 26.2mg (0.043mmol) of compound 116b was hydrolyzed according to method A to yield 10.8mg (49% yield) of the title compound: analytical HPLC 9.89min. LC-MS (ES +) m / e = 517.2. 3- ( { 1 - [2- (4-Acetylamino-3-chloro-2-methoxybenzoylamino) -propionyl] -4,4-difluoro-pyrrolidine-2-carbonyl} -amino) -4-oxo acid -butyric (123c). A sample of 23.1mg (0.036mmol) of compound 116c was hydrolyzed according to method A to yield 1.8mg (yield 9%) of the title compound: analytical HPLC 11.87 min. LC-MS (ES +) m / e = 547.1 (M + H).

BIOLOGICAL METHODS We obtained in vi tro, ex vivo, and in vivo data for the selected compounds of this invention using the methods described below. The results are shown in Tables 2-8. The designation "ND" indicates that the compound was not tested in the described test. In the caspase ICE tests, the category "A" indicates an inhibition < 10nM Category "B" indicates an inhibition of 10-1000 nM. Category "C" indicates a P1123 inhibition > 1000 nM. See Tables 2 and 3. In the CMSP trial, the category "A" indicates an inhibition < 500 nM. Category "B" indicates an inhibition of 500-1000 nM. Category "C" indicates an inhibition of 1001-2000 nM. Category "D" indicates an inhibition > 2000 nM. See Table 4. In the whole blood test, the category "A" indicates an inhibition < 2500 nM. Category "B" indicates an inhibition of 2500-7500 nM. Category "C" indicates an inhibition > 7500 nM. See Table 5. In the on-site metabolism test, the values of [f (g) x f (h)] are classified as follows: category "A" indicates < 0.25. Category "B" indicates 0.25-0.49. The category "C" indicates 0.5-0.75. Category "D" indicates > 0.75. In the measurement of biliary excretion, category "A" indicates < 5%. Category "B" indicates 5-10%. Category "C" indicates > 10% See Table 6. In the i.v. clearance test, the reported values are as follows: category "A" indicates < 50. Category "B" indicates 50-80. Category "C" indicates > 80. See Table 7. In the bioavailability test, the values Cmax (μg / ml) are classified as follows: category "A" indicates < 2.5. Category "B" indicates 2.5-5.0. Category "C" indicates > 5.0. The .ABC values (μg x hr / ml) are P1123 2§1 classified as follows: category "A" indicates < 2.5. Category "B" indicates 2.5-5.0. Category "C" indicates > 5.0. The half-life ranges (hours) are classified as follows: category "A" indicates < 1.5. Category "B" indicates 1.5-2.0. Category "C" indicates > 2.0. The F (%) values are classified as follows: the category "A" indicates < 33. Category "B" indicates < 33-67. Category "C" indicates > 67. See Table 8.

IN VITRO TESTS Inhibition of Enzyme Ki values for the test compounds with the different layers were obtained by the method of Margolin et al. (J. Biol. Chem., 272 pp, 7223-7228 (1997)). Tests were performed on 10 mM Tris (Sigma Corp, St. Louis MO) pH 7.5, 1 mM Dithiothreitol (DTT, Research Organic Inc., Cleveland, OH) and 0.1% CHAPS (Pierce, Rockford IL) at 37 ° C. For caspase 3, an 8% glycerol solution was added to the test buffer to improve the stability of the enzyme. An aliquot of 65 μL of the test buffer and an aliquose of 5 μL of appropriate dilutions of the inhibitor in DMSO were pipetted into 96-well plates, treated with 10 μL of caspase, then diluted in test buffer (active protein 0.5-40 nM by active site titration). A control containing DMSO but without the compound was included for each determination. Then the plates were incubated for 15 minutes at 37 ° C, before the addition of the appropriate substrate (20 μl, with final concentration 1-4 x KM, final assay volume 100 μL) to start the reaction. Reaction rates were measured at 37 ° C either following time with respect to the increase in absorbance at 405 nM (for pNA substrates) or fluorescence (Ex 390, Em 460) (for substrates VMC). The velocities obtained were plotted against the concentration of the inhibitor and the datas were adjusted to the Morrison approximation equation for competitive inhibitors (Morrison, J.F., Biochem. Biophys. Acta, 185 pp, 269-286 (1969)). The substrates used "for the individual tests were the following: Caspase-1 Suc-YVAD-pNA (Bachem, King of Prussia, PA) (final concentration in the 80 μM test), Caspase-3 Ac-DEVD-pNA (Bachem, King of Prussia, PA) (final concentration in the test, 60 μM) Caspasa-4 Ac-EHD-AMC (Synpep, Dublin, CA) (final concentration in the 20 μM test), Caspasa-7 Ac-DEVD-AMC (Bachem, King of Prussia, PA) (final concentration in the 50 μM test), Caspasa-8 Ac-DEVD-pNA (Bachem, King of Prussia, PA) (final concentration in the 80 μM test), Table 2. Inhibition data of caspase-1 P1123 P1123 255 P1123 P1123 P1123 P1123 P1123 P1123 P1123 122i 122j B 122k 1221 B 122m B 122n B 122o 122p 122q B 122r B 122s B 122t B 122u 122V B 123a B 123b 123C B Table 3. Inhibition data of caspase-3, caspase-4, and caspase-8 CMSP cellular test The IL-lβ test with a mixed population of human peripheral blood mononuclear cells (PBMC) or enriched adherent mononuclear cells. The processing of pre-IL-lβ by the ECI can be measured in a cell culture using a variety of cellular sources. Human PBMCs obtained from donors P1123 provide a mixed population of lymphocyte subtypes and mononuclear cells that produce a spectrum of interleukins and cytokines in response to many classes of physiological stimulators. The adherent mononuclear cells of PBMC provide an enriched source of normal monocytes for selective studies of cytosine production by activated cells.

Experimental Procedure .- A series of initial dilutions of the test compound in DMSO or ethanol is prepared, with a subsequent dilution in RPMI-10% FBS media (containing '2 mM -glutamine, 10 mM, 50 U HEPES and 50 μg / ml pen / strep.) respectively to produce drugs at 4 times the final test concentration containing 0.4% DMSO or 0.4% ethanol. The final concentration of DMSO is 0.1% for all dilutions of the drug. A titration of the concentration that supports the apparent Ki for a test compound determined in an ECI inhibition test is generally used for the classification of the primary compound. Generally 5-6 dilutions of compound are tested and the cellular component of the test is performed in duplicate, with the ELISA determinations in duplicate in each cell culture supernatant.

P1123 Isolation of PBMC and IL-1 test: Cleaning cells isolated from a pint of human blood (which produce plasma-positive cells with a final volume of 40-45 ml) are diluted with media up to 80 ml and separation tubes LeukoPREP (Becton Dickinson) are each covered with 10 ml of cell suspension. After 15 minutes of centrifugation at 1500-1800 xg, the plasma / media layer is aspirated and then the mononuclear cell layer is collected with a Pasteur pipette and transferred to a 15 ml conical centrifuge tube.

(Corning) The medium is added to bring the volume to 15 ml, by gently mixing the cells by inversion and centrifuging at 300 xg for 15 minutes. The PBMC pellet is resuspended in a small volume on average, the cells are counted and adjusted to 6 x 106 / ml. For the cell assay, 1.0 ml of the cell suspension is added to each well of a 24-well flat-bottom tissue culture dish (Corning), 0.5 ml of compound dilution and 0.5 ml of LPS solution (Sigma #L -3012 solution 20 ng / ml solution prepared in complete RPMI media, final concentration LPS of 5 ng / ml). Additions of 0.5 ml of the test compound and LPS are generally sufficient to mix the contents of the cavities. Three mixtures are made per experiment, already P1123 either with LPS alone, solvent vehicle control, and / or additional means to adjust the final culture volume to 2.0 ml. The cell cultures are incubated for 16-18 hours at 37 ° C in the presence of C02 5%. At the end of the incubation period, the cells are harvested and transferred to 15 ml conical shaped tubes. After centrifuging for 10 minutes at 200 xg, the supernatants are harvested and transmffered to 1.5 ml Eppendorf tubes. It can be noted that the cell pellet can be used for a biochemical evaluation of the content of pre-IL-1-β and / or mature IL-1-β in extracts of cytosol by Western staining or ELISA with specific antisera pre-IL- 1-ß.

Isolation of adherent mononuclear cells: PBMC are isolated and prepared as described above. The media (1.0 ml) is first added to cavities followed by 0.5 ml of CMSP suspension. After one hour incubation, the plates are gently shaken and the non-adherent cells are aspirated from each cavity. The cavities are then gently washed three times with 1.0 ml of medium and finally suspended in 1.0 ml of medium. The enrichment of adherent cells generally produces 2.5-3.0 x 105 cells per well. The addition of test compounds, LPS, conditions of P1123 cell incubation and processing of supernatants proceed as described above.

ELISA: Quantikine equipment (R &D Systems) can be used for the measurement of mature IL-l-β. The tests are carried out according to the manufacturer's instructions.

Mature IL-1-β levels of approximately 1-3 ng / ml in both PBMC and positive mononuclear cell controls. ELISA assays are performed in 1: 5, 1:10 and 1:20 dilutions of supernatants in the test panel. The inhibitory potency of the compounds can be represented by an IC 50 value which is the concentration of the inhibitor in which 50% of the mature IL-1-β is detected in the supernatant compared to the positive controls. The experienced practitioner is aware that the values obtained in cellular assays may depend on multiple factors. Values can not necessarily represent accurate quantitative results.

Table 4. Data of the CMSP cellular test P1123 P1123 7a 7b B 7c 7d A 7e D 7f D 7g A 7h B 7k B 71 B 7m B 7n B 7o A 7p 7q 7s B 7t D 7u 7v D 7w 7x D 7y 7z 9a B P1123 9b B 9c 9d B 9e 9f B sg 15a D 15b 15c B 15d 15e D 15f D 16a A 16b 17b 17c 17d D 17e B 18a B 18b B 18c B 18d B 18e 18f P1123 P1123 23e B 23f 23g 23h 23i 24a B 24b D 24c A 24d B 24e 25a 25b B 25c B 26a 26b B 26c B 26d B 26e A 26f 26g 26h A 27a 28a B 28b B P1123 P1123 Whole blood assay for the production of IL-1-β The IC50 values of whole blood test for compounds of this invention were obtained using the method described below: Purpose: The whole blood test is a method for measuring the production of IL-1β (or other cytokines) and the activity of potential inhibitors. The complexity of this assay system, with its full complement of lymphoid and inflammatory cell types, spectrum of plasma proteins and red blood cells is an ideal representation of human physiological conditions in vivo. materials P1123 Pyrogen-free syringes (approx 30 cc) Sterile, pyrogen-free vacuum tubes containing lyophilized Na2EDTA (4.5 mg / lOml tube). Sample of human whole blood (approx 30-50 ce) Eppendorf tubes 1.5 ml. Reservation solutions of test compound (approximately 25mM in DMSO or other solvent). Endotoxin-free sodium chloride solution (0.9%) and HBSS. Reserve solution of lipopolysaccharide (Sigma, Cat. # L-3012) in 1 mg / ml of HBSS. ELISA IL-l-ß kit (R &D Systems; Cat DLB50) ELISA TNF-a kit (R & D Systems; Cat DTA50) Water bath or incubator.

Experimental procedure of whole blood test: The incubator or water bath is adjusted to 30 ° C. An aliquot of 0.25ml of blood was taken in 1.5 ml eppendorf tubes. Note: Be sure to invert the whole blood sample tubes after every two aliquots. Differences in duplicates may result if the cells settle and are not suspended uniformly. The use of a positive displacement pipette will also minimize the differences between aliquots in duplicate. Drug dilutions are prepared in solution P1123 sterile pyrogen-free saline by serial dilution. A serial dilution covering the apparent Ki for a test compound determined in an ECI inhibition test is generally used for the classification of the primary compound. For extremely hydrophobic compounds, dilutions of compound are prepared in fresh plasma obtained from the same blood donor or in 5% DMSO containing PBS to improve solubility. 25 μl of dilution of test compound or control vehicle is added and the sample is gently mixed. Then add 5.0 μl of LPS solution (reserved 250 ng / ml prepared fresh: LPS with a final concentration of 5.0 ng / ml), and mix again. The tubes are incubated at 30 ° C in a water bath for 16 to 18 hours with occasional mixing. Alternatively, the tubes can be placed in a rotation device setting at 4 rpm for the same incubation period. This test must be prepared in duplicate or triplicate with the following controls: negative control - without LPS; positive control - without test inhibitor; control vehicle - the highest concentration of DMSO or compound solvent used in the experiment. Additional saline is added to all control tubes to normalize the volumes for both control and experimental whole blood test samples.

After the incubation period, the whole blood samples are centrifuged for 10 minutes at 2,000 rpm in microcentrifugation, the plasma is transferred to a fresh microcentrifuge tube and centrifuged at 1000 xg for residual pellet platelets if necessary. Plasma samples can be stored with freezing at -70 ° C prior to testing for cytokine levels by ELISA.

ELISA: Quantikine R & D Systems (614 McKinley Place N.E. Minneapolis, MN 55413) can be used for the measurement of IL-1-β and TNF-α. The tests are carried out according to the manufacturer's instructions. IL-l-β levels of approx. 1-5 ng / ml in positive controls among a group of individuals. A 1: 200 dilution of plasma for all samples is generally sufficient for the results of ELISA experiments to fall within the linear range of standard ELISA curves. It may be necessary to optimize standard dilutions if you notice differences in the whole blood test. Nerad, J.L. et al., J. Leukocyte Biol. 52, pp, 687-692 (1992).

Table 5. Complete blood test data P1123 P1123 P1123 P1123 P1123 P1123 P1123 P1123 122b 122c B 122d A 122e B 122f 122g 122h A 122i A 122j B 122k A 1221 122m B 122p B 122q B 122r 122S B 123a A 123b B EX VIVO TESTS Metabolism and Excretion One-step perfusion studies in rats were performed to evaluate gastrointestinal wall metabolism (Gl) (f (g)), liver metabolism (f (h)), and excretion Biliary P1123. The method used has been described in J. Pharmacol Exp. Therapeutics, 333, p. 788-798 (1984). Table 6. Metabolism and Excretion Data IN VIVO TESTING In vivo rat clearance test - Clearance rate The clearance rate in rats (ml / min / kg) for the compounds of this invention can be obtained P1123 using the method described below: Representative Procedure: Cannulations of the jugular and carotid veins of rats were performed under anesthesia one day prior to the pharmacokinetic study. M.J. Free, R.A. Jaffee; "Cannulation techniques for the collection of blood and other bodily fluids" in: Animal Models; p. 480-495; N.J. Alexander, Ed .; Academic Press; (1978). A drug (10 mg / ml) was administered via the jugular vein in a vehicle usually consisting of: propylene glycol / saline, containing 100 mM sodium bicarbonate in a 1: 1 ratio. The animals are dosed with 10-20 mg drug / kg and blood samples are drawn at 0, 2, 5, 7, 10, 15, 20, 30, 60, and 90 minutes from a resident carotid catheter. The blood was centrifuged to plasma stored at -20 ° C until analysis. The pharmacokinetic analysis of data was performed by non-linear regression using standard software such as RStrip (MicroMath Software, UT) and / or Pcnonlin (SCI Software, NC) to obtain clearance values.

Representative analytical: Rat plasma was extracted with an equal volume of acetonitrile (containing 0.1% TFA). Then samples are centrifuged at approximately 1,000 xg and the supernatant P1123 analyzed by HPLC with gradient. A typical test procedure is described below. 200 μL of plasma was precipitated with 200 μL of 0.1% trifluoroacetic acid (TFA) in acetonitrile and 10 μL of 50% aqueous zinc chloride solution, vortexed and centrifuged at approximately 1,000 xg and the supernatant was collected and analyzed by HPLC.

HPLC procedure: Column: Zorbax SB-CN (4.6 x 150 mm) (particle size 5 μ) Column temperature 50 ° C Flow rate: 1.0 mL / min Injection volume: 75 μL. Mobile phase: A = TFA 0.1% in water and B = 100% Acetonitrile Gradient used: A 100% a A 30% in 15.5 min A 0% at 16 min A 100% at 19.2 min Wavelength: 214 nm A standard curve is run at concentrations of 20, 10, 5, 2 and 1 μg / mL.

Table 7. Clarification data P1123 AVAILABILITY Oral pharmacokinetic studies Spraque-Dawley male rats (Harian, Indianapolis, IN, 300-350 g) were anesthetized by intramuscular injection of ketamine / rompum mixture. A PESO cannula was inserted into the right carotid artery for arterial blood sampling. The rats were allowed to recover from surgery overnight (. >; 16 hours) prior to being used in the study. The test compounds were administered orally in EL / water Cremophorus 25% (w / w) or 100% propylene glycol (PG) in a dose volume of 10 mL / kg. The blood samples (-0.30 mL) were P1123 removed at 0.25, 0.50, 1.0, 1.5, 2, 3, 4, 6, and 8 hours post-dose, the plate was separated by centrifugation and stored at -20 ° C pending analysis. The quantification of the plasma samples was conducted using an HPLC / MS / MS gradient or an enzymatic method that is detailed in the following: HPLC / MS / MS method for the quantification of EIC inhibitors in rat plasma Sample preparation • 50μl aliquots were made in Eppendorf centrifuge vials. • An equal volume of acetonitrile was added to the plasma to precipitate plasma proteins. • The samples were placed in a Vortex for 5 minutes, and centrifuged at 14,000 rpms for 5 minutes. • 75μl of the supernatant was loaded into liquid sampling vials by 12mm HPLC. • 50μl of the sample was injected for analysis via the mass spectrometer.

HPLC Instrumental Parameters HPLC: Hewlett Packard HP1100 Binary Solvent Delivery System.

P1123 HPLC Gradient Conditions A = H20 in 0.2% Formic Acid B = Acetonitrile in 0.2% Formic Acid Mobile Phase Time% A% B 0 100 0 2 100 0 5 0 100 11 0 100 11.5 100 0 17 100 0 Column. HPLC analysis: Keystone Phenyl -2 Hypersil 2.0xl00mm, pore size 5μ 120Á, P / N # 105-39-2 Injection volume 50μl Flow rate: 0.20 mL / min.

Instrumental Parameters of Mass Spectrometry Instrument: Tandem Mass Spectrometer P E Sciex API-365 Ionization Technique: Turbo-Ionspray (ESI) Polarity: Positive Residence time: 300msec P1123 Pause Time: 5mse Scan Time: 0.9sec Scan Mode: MRM (Multiple Reaction Monitoring) ECI ENZYMATIC TEST FOR THE QUANTIFICATION OF INHIBITORS ECI IN RAT PLASMA 50 μL of plasma were extracted with 150 μL of acetonitrile, sonicated, placed in Vortex, centrifuged at 10,000 xg and 180 μL of the supernatant was dried in a Vortex Sorvall evaporator at room temperature. Samples were reconstituted in 100 μL of buffer (10 mM tris-HCl, pH 7.5 with 0.1% CHAPS, 1 mM DTT) with sonication, 10 μL of each sample was mixed with 10 μL ICE (1.1 mg / mL) in a microtitre plate, with 60 μL of buffer. The samples were incubated for 15 minutes at room temperature, then 20 μL of Succ YVAD-pNA (400 μM, preheated at 37 ° C) was added, and the plate was monitored at 405 nm for 20 minutes at 37 ° C using a reader SpectraMax The data was adjusted using a parametric adjustment of 4 with the SpectraMax software using a standard curve obtained. The test was linear from 0.15 to 2.0-3.0 μg / mL of aldehyde.

Pharmacokinetic parameters P1123 The pharmacokinetic analysis of this concentration data was conducted using non-division methods. The area under the curve (AUC (0-t)) was estimated from the zero point to the last point of time measured using the trapezoidal rule. The elimination rate (ke) was estimated by linear regression from the terminal phase of the plasma concentration-time curves. The area under the col of the curve was estimated as the ratio of the last measured concentration to ke. The area under the curve from time zero to infinity (ABC (O-8)) was obtained by adding the area under the tail to ABC (0-t). The elimination of half-life was estimated as 0.693 / ke. The observed values for the peak plasma concentration (Cmax) were recorded. For prodrug studies: the bioavailability of aldehyde was calculated as: (C12a? D / prodrug po) / (C12a? D / ald iv) x (dose ald, iv ald / dose prodrug, prodrug po) x (PM prodrug / PM aldehyde).

Table 8. Bioavailability data P1123 TESTS? N? TVTRKLES The efficacy of the compounds of this invention in the treatment or prevention of diseases, disorders or related antiviral conditions can be evaluated in several tests in vi tro and in vivo. For example, tests can be performed to determine the ability of these compounds to inhibit the inflammatory responses associated with viral infections. In vi tro tests may employ complete cells or separate cellular components. In vivo tests include animal models for viral diseases. Examples of such animal models include, but are not limited to, rodent models for HBV or HCV infection, the Woodchuck model for HBV infection, and the chimpanzee model for infection.

VHC. The compounds of this invention can also be evaluated in animal models for disease induced by ingestion of alcohol. Other tests that can be used to evaluate the compounds of this invention are disclosed in PCT / US96 / 20843, published on June 26, 1997, under publication No. WO 97/22619. These tests include in vivo pharmacokinetic studies in mice, inhibition of ICD homologs, inhibition of apoptosis, acute in vivo test for anti-inflammatory efficacy, measurement of blood levels of drugs, IGIF tests, carrageenan peritoneal inflammation test in mouse and arthritis induced type II collagen. As far as the compounds of this invention are capable of inhibiting caspases, particularly ICC, in vi tro and additionally, can be administered orally to mammals, these are of obvious clinical utility for the treatment of diseases mediated by IL-1. , apoptosis-, IGIF-, and IFN -? -. Although a number of embodiments of this invention have been described, it is appreciated that our basic constructions can be altered to provide other embodiments using the products and processes of this invention.

P1123

Claims

CLAIMS; 1. A compound represented by the formula I where Y is (a) provided that when R7 is -OH, then Y may also be: (b) X is -C (R3) 2- or -N (R3) -; m is 0 or 1; R1 is H, -R8, -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, P1123 S (0) R8, -C (0) OR8, -C (0) N (H) R8, -S (O) 2N (H) -R8, -S (O) N (H) -R8, - C (0) C (0) N (H) R8, -C (0) CH = CHR8, -C (0) CH2OR8, -C (O) CH2N (H) R8 -C (0) N (R8) 2 , -S (0) 2N (R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, C (O) CH2N (R8) 2, -CH2R8 , -CH2-alkenyl-R8, or -CH2-alkynyl-R8; R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl -R9, or alkynyl -R9, or each R3, together with the atom to which they are attached, form a cyclic ring system or 3 to 7 membered heterocyclics, or R2 and an R3 together with the atoms to which these are attached, form a cyclic or heterocyclic ring system of 3 to 7 members, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with -R10, a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; R4 is -H and each R5 is independently -H, an amino acid side chain, -R8, -alkenyl -R9, or alkynyl -R9, or R4 and an R5 together with the atoms to which these are attached, form a system of ring selected from: P1123 wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and an atom of hydrogen attached to any nitrogen atom of the ring system is optionally replaced with R1 or R4 and an R5 together with the atoms to which they are attached to form a ring system: P1123 R6 is -H, R7 is -OH, -OR8 or -N (H) OH; each R8 is independently -alkyl-, cycloalkyl-, -aryl, -heteroaryl, -heterocyclyl, alkylcycloalkyl, -alkylaryl, -alkylheteroaryl or alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R3 is independently -aryl-, heteroaryl, -cycloalkyl or -heterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of aryl or heteroaryl is optionally replaced with R 11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R 1; each R10 is independently -OH, -SH, -F, -Cl, P1123 -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, -perfluoroalkyl , -O-alkyl, -O-aryl, -0-alkylaryl, -N (H) alkyl, -N (H) aryl, - (H) -alkylaryl, N (alkyl) 2, -C (0) N ( H) alkyl, -C (O) N (alkyl) 2, N (H) C (O) alkyl, -N (H) C (O) O-alkyl, -N (H) C (O) O-aryl , N (H) C (0) 0-Alkylaryl, -N (H) C (O) O-heteroaryl, -N (H) C (0) 0-alkyl-heteroaryl, -N (H) C (0) O -cycloalkyl, N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl) 2, -N (H) C (O) N (H) aryl, -N ( H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) -heteroaryl, N (H) C (0) N (H) -alkyl-heteroaryl, -N (H) C (O) N (H) -cycloalkyl, -S-alkyl, -S-aryl, -S-alkylaryl, -S (O) 2alkyl, S (O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or CH 2 N (alkyl) 2 -alkyl, -cycloalkyl, -aryl, heteroaryl, heterocyclyl, -alkyl-cycloalkyl, -alkylaryl, alkylheteroaryl or -alkylheterocyclyl, wherein a hydrogen atom attached to any aryl carbon atom or heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1, and each R11 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, alkyl, cycloalkyl , -perfluoroalkyl, -0-alkyl, -O-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) aryl, N (H) -alkylaryl, -N (alkyl) 2, -C ( O) (H) alkyl, C (0) N (alkyl) 2, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, P1123 N (H) C (0) N (alkyl) 2, -S-alkyl, -S-aryl, -S-alkylaryl, S (0) 2alkyl, -S (O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or -CH2N (alkyl) 2.
2. A compound represented by the formula I: where: Y is provided that when R6 is not hydrogen, R6 and Y, together with the nitrogen to which they are attached, form a ring Cg) = (g) X is -C (R3) 2- or -N (R3) -; m is 0 or 1; R1 is H, -R8, -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, -S (0) R8, -C (0) 0R8, -C (0) ) N (H) R8, -S (O) 2N (H) -R8, -S (O) N (H) -R8, -C (0) C (0) N (H) R8, -C (0 CH = CHR8, -C (0) CH2OR8, -C (O) CH2N (H) R8 -C (0) N (R8) 2, -S (0) 2N (R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, C (0) CH2N (R8) 2, -CH2R8, -CH2-alkenyl-R8, or -CH2-alkynyl-R8; R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl -R9, or alkynyl -R9, or each R3, together with the atom to which they are attached, form a cyclic ring system or 3 to 7 membered heterocyclics, or R2 and an R3 together with the atoms to which these are attached, form a cyclic or heterocyclic ring system of 3 to 7 members, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with -R10, a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; R4 is -H and each R5 is independently -H, an amino acid side chain, -R8, -alkenyl-R9, or alkynyl -R9, or R4 and an R5 together with the atoms to which these are attached, form a system of ring selected from: P1123 wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and an hydrogen attached to any nitrogen atom of the ring system is optionally replaced with R1 or R4 and an R5 together with the atoms to which they are bound form a ring system: Rb is -H, each R8 is independently -alkyl-, cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, alkylcycloalkyl, -alkylaryl, -alkylheteroaryl or alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R 10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R 11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R 1; each R9 is independently -aryl-, heteroaryl, -cycloalkyl or -heterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of aryl or heteroaryl is optionally replaced with R 11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R 1; each R10 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, - P1123 N (H) C (0) NH2, -perfluoro-alkyl, -O-alkyl, -O-aryl, -0-alkylaryl, -N (H) alkyl, -N (H) aryl, -N (H) -alkylaryl, N (alkyl) 2, -C (O) N (H) alkyl, -C (O) N (alkyl) 2, N (H) C (O) alkyl, - (H) C (O) O -alkyl, - (H) C (O) O-aryl, N (H) C (0) 0-alkylaryl, -N (H) C (O) O-heteroaryl, -N (H) C (0) 0 -alkyl-heteroaryl, -N (H) C (O) O-cycloalkyl, N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl) 2, -N ( H) C (O) N (H) aryl, -N (H) C (O) N (H) alkylaryl, -N (H) C (O) (H) -heteroaryl, N (H) C (O) N (H) -alkyl-heteroaryl, -N (H) C (O) N (H) -cycloalkyl, -S-alkyl, -S-aryl, -S-alkylaryl, -S (O) 2alkyl, S (O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or CHN (alkyl) 2 , -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkyl-cycloalkyl, -alkylaryl, alkylheteroaryl or alkylheterocyclyl, wherein a hydrogen atom attached to any -aryl or -heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1, and each R11 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2 , -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, - O-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) aryl, N (H) alkylaryl, -N (alkyl) 2, -C (O) N (H) alkyl, C (O) ) N (alkyl) 2, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, N (H) C (O) N (alkyl) 2, -S- alkyl, -S-aryl, -S-alkylaryl, P1123 S (0) 2alkyl, -S (O) alkyl, • C (O) alkyl, -CH2NH2, CH2N (H) alkyl or -CH2N (alkyl) 2; R12 is -C (O) alkyl, -C (O) cycloalkyl, C (O) alkenyl, -C (O) alkylaryl, -C (O) alkylheteroaryl, C (O) heterocyclyl, or -C (O) alkyl- heterocyclyl; and R 13 is -H, -alkyl, -aryl, -alkylaryl or alkylheteroaryl.
3. A compound represented by formula I: where: Y is: (a) (b) m is 0 or 1; P1123 X is -C (R3) 2- R1 is H, -R8, -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, -S (0) R8, - C (0) OR8, -C (0) N (H) R8, -S (O) 2N (H) -R8, -S (O) N (H) -R8, -C (0) C (0) N (H) R8, -C (0) CH = CHR8, -C (0) CH2OR8, -C (O) CH2N (H) R8 -C (0) N (R8) 2, -S (0) 2N ( R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, C (0) CH2N (R8) 2, -CH2R8, -CH2-alkenyl-R8, or -CH2-alkynyl-R8; R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl-R9, or alkynyl-R9, or each R3, together with the atom to which they are attached, form a cyclic ring system or 3 to 7 membered heterocyclic, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with -R10, a nitrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; R4 is -H and each R5 is independently -H, an amino acid side chain, -R8, -alkenyl-R9, or alkynyl-R9, or R4 and an R5 together with the atoms to which these are attached, form a system of ring selected from: P1123 wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and an atom of hydrogen attached to any nitrogen atom of the ring system is optionally replaced with R1, or R4 and an R5 together with the atoms to which they join to form a ring system: P1123 Re is -H, R7 is -OH, -OR8 or -N (H) OH or N (H) S (0) 2R8; each R8 is independently -alkyl-, cycloalkyl-, -aryl, -heteroaryl, -heterocyclyl, alkylcycloalkyl, -alkylaryl, -alkylheteroaryl or alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any aryl or heteroaryl carbon atom is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R9 is independently -aryl, -heteroaryl, -cycloalkyl or -heterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R10 is independently -OH, -SH, -F, -Cl, Pll23 -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, -perfluoro -alkyl, -O-alkyl, -O-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) aryl, -N (H) -alkylaryl, N (alkyl) 2, -C (0 ) N (H) alkyl, -C (O) N (alkyl) 2, N (H) C (O) alkyl, -N (H) C (O) O-alkyl, -N (H) C (O) O-aril, N (H) C (0) 0-Alkylaryl, -N (H) C (O) O-heteroaryl, -N (H) C (0) 0-alkyl-heteroaryl, -N (H) C (O) O -cycloalkyl, N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl) 2, -N (H) C (O) N (H) aryl, -N ( H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) heteroaryl, N (H) C (O) N (H) alkyl-heteroaryl, -N (H) C ( O) N (H) cycloalkyl, -S-alkyl, -S-aryl, -S-alkylaryl, -S (O) 2alkyl, S (O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or CH 2 N (alkyl) 2, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkyl-cycloalkyl, -alkylaryl, alkylheteroaryl or -alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of - aryl or -heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1, and each R11 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, -alkyl, -cycloalkyl, -perfluoro-alkyl, -O-alkyl, -O-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) aryl, N (H) alkylaryl, -N (alkyl) 2 / -C (O) N (H) alkyl, C (0) N (alkyl) 2, -N (H) C (0) alkyl, - (H) C (0) N (H) alkyl, P1123 N (H) C (O) N (alkyl) 2, -S-alkyl, -S-aryl, -S-alkylaryl, S (0) 2alkyl, -S (O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or -CH2N (alkyl) 2; provided that if one R3 is -H, then the other R is not -H.
A compound represented by formula I where Y is m is 0 or 1; X is -C (R3) 2- R1 is H, -R8, -C (0) R8, -C (0) C (0) R8, -S (0) 2R8, S (0) R8, -C (0) 0R8, -C (0) N (H) R8, -S (0) 2N (H) -R8, -S (0) N (H) -R8, C ( 0) C (0) N (H) R8, -C (O) CH = CHR8, -C (0) CH20R8, -C (O) CH2N (H) R8 C (0) N (R8) 2, -S (0) 2N (R8) 2, -S (0) N (R8) 2, -C (O) C (O) N (R8) 2, C (0) CH2N (R8) 2, -CH2R8, -CH2 -alkenyl-R8, or -CH2- to quiñi 1 -R8; P1123 R2 is -H and each R3 is independently -H, an amino acid side chain, -R8, alkenyl-R9, or alkynyl -R9, or each R3, together with the atom to which they are attached, form a cyclic ring system or 3-7 membered heterocyclic, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with -R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom of the ring system is optionally replaced with -R1; R4 is -H and each R5 is independently -H, an amino acid side chain, -R8, -alkenyl-R9, or alkynyl -R9, or R4 and an R5 together with the atoms to which these are attached, form a system of ring selected from: P1123 wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and an hydrogen attached to any nitrogen atom of the ring system is optionally replaced with R1 or R4 and an R5 together with the atoms to which they are bound form a ring system: Rb is -H, P1123 each R8 is independently -alkyl-, cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, alkylcycloalkyl, -alkylaryl, -alkylheteroaryl or alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R9 is independently -aryl-, heteroaryl, -cycloalkyl or -heterocyclyl, wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10, a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1; each R10 is independently -OH, -SH, -F, -Cl, -Br, -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N (H) C (0) H, -N (H) C (0) NH2, -perfluoro-alkyl, -O-alkyl, -O-aryl, -0-alkylaryl, -N (H) alkyl, -N (H) aryl, -N ( H) -alkylaryl, N (alkyl) 2, -C (O) N (H) alkyl, -C (O) N (alkyl) 2, N (H) C (0) alkyl, -N (H) C ( 0) O-alkyl, -N (H) C (0) O-aryl, N (H) C (0) 0-alkylaryl, -N (H) C (O) O-heteroaryl, -N (H) C (0) 0- P1123 alkyl-heteroaryl, -N (H) C (O) O-cycloalkyl, N (H) C (0) N (H) alkyl, -N (H) C (O) N (alkyl) 2, -N ( H) C (O) N (H) aryl, -N (H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) -heteroaryl, N (H) C (O ) N (H) -alkyl-heteroaryl, -N (H) C (O) N (H) -cycloalkyl, -S-alkyl, -S-aryl, -S-alkylaryl, -S (O) 2 alkyl, S ( O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or CH2N (alkyl) 2, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, -alkyl-cycloalkyl, -alkylaryl, alkylheteroaryl or alkylheterocyclyl, wherein a hydrogen atom attached to any carbon atom of -aryl or -heteroaryl is optionally replaced with R11, and a hydrogen atom attached to any nitrogen atom is optionally replaced with R1, and each R11 is independently -OH, -SH, -F, -Cl, -Br ", -I, -N02, -CN, -NH2, -C02H, -C (0) NH2, -N ( H) C (0) H, - N (H) C (0) NH 2, -alkyl, -cycloalkyl, -perfluoro-alkyl, -O-alkyl, -O-aryl, -O-alkylaryl, -N (H) alkyl, -N (H) aryl, N (H) alkylaryl, -N (alkyl) 2, -C (O) N (H) alkyl, C (O) N (alkyl) 2, -N (H) C ( O) alkyl, -N (H) C (O) N (H) alkyl, N (H) C (O) N (alkyl) 2, -S-alkyl, -S-aryl, -S-alkylaryl, S (0) 2alkyl, -S (O) alkyl, -C (O) alkyl, -CH2NH2, CH2N (H) alkyl or -CH2N (alkyl) 2; and R 12 is -C (O) alkyl, -C (O) cycloalkyl, C (O) alkenyl, -C (O) alkylaryl, -C (O) alkylheteroaryl, C (O) heterocyclyl, or -C (O) alkylheterocyclyl . P1123
5. The compound according to claim 2 or 4, wherein Y is: and V is: CH30, P1123
6. The compound according to any of claims 1-5, wherein R 4 and R 5 together with the atoms to which they are attached form a ring system selected from: wherein a hydrogen atom attached to any carbon atom of -alkyl or -cycloalkyl is optionally replaced with R10; or R4 and an R5 together with the atoms to which they are attached, form a ring system: P1123
7. The compound according to claim 6, wherein one R3 is -H and the other R3 is methyl, isopropyl or tert-butyl, -CH2SR8, CH2S02R8, -CH2CH2SR8 or -CH2CH2S02R8.
8. The compound according to claim 7, wherein one R3 is -H and the other R3 is methyl.
9. The compound according to claim 8, wherein R1 is -C (0) R8 or -C (0) C (0) R8.
10. The compound according to claim 6, wherein R4 and an R5 together with the atoms to which they are attached form a ring system selected from: P1123 and the other R5 is H, wherein a hydrogen atom attached to any carbon atom -alkyl or -cycloalkyl is optionally replaced by R10.
11. The compound according to claim 10, wherein one R3 is -H and the other R3 is methyl, isopropyl, tert-butyl, -CH2SR8, -CH2S02R8, -CH2CH2SR8 or -CH2CH2S02R8.
12. The compound according to claim 11, wherein one R3 is -H and the other R3 is methyl.
The compound according to claim 12, wherein R 1 is -C (0) R 8 or -C (0) C (0) R 8.
The compound according to claim 6, wherein one R4 and one R5 together with the atoms to which they are attached form a ring system: and the other R5 is H.
The compound according to claim 14, wherein one R3 is -H and the other R3 is methyl, isopropyl, tert-butyl, -CH2SR8, -CH2S02R8, -CH2CH2SR8 or -CH2CH2S02R8.
16. The compound according to claim 15, wherein one R3 is -H and the other R3 is methyl.
17. The compound according to claim 16, wherein R1 is -C (0) R8 or -C (0) C (0) R8. P1123
18. The compound according to claim 1 or 3, selected from the group consisting of: 5a-5bd, 7a-7at, 20a-20t, 23a-23i, 24a-24e, 26d, 26e, 29a-29s, 32a-s , 34, 42, 46, 52, 57, 61, 65, 69, 73, 121 and 122a-v.
19. The compound according to claim 4, selected from the group consisting of: 41, 45, 51, 56, 60, 64, 68, 72, 76-93, 98a-z, 98aa-az, 98ba and 98bb, 101 , 102a, 102b, 108a-108d, 110, 111, 116a-116h and 120a and 120b.
20. A compound selected from the group consisting of: 37, 38, 39, 43, 44, 49, 50, 54, 55, 58, 59, 67, 71, 75, 96a-96c, 97a-97c, 100, 106 , 107, 109, 115a-115c, 120a, 120b, P1123
21. A pharmaceutical composition comprising: a) a compound according to any of claims 1-19; and b) a pharmaceutically acceptable adjuvant carrier or vehicle.
22. A method for the treatment or prevention of a disease selected from a disease mediated by IL-1, apoptosis, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a Necrotic disease, an excess alcoholic disease, a virus-mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, adult respiratory pain syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, reaction disease from host to graft, osteoporos is, disorders related to leukemia, myelodysplastic syndrome, bone disorder related to multiple myeloma, acute myelogenous leukemia, myelogenous leukemia Chronic P1123, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic attack, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, miscardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, encephalitis related to HIV, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, rejection of organ transplantation, hepatitis B, hepatitis C, hepatitis G, yellow fever, dengue fever or Japanese encephalitis, in one patient , the method comprises the step of administering to the patient a compound according to any of claims 1-19 or a pharmaceutical composition according to claim 21.
23. The method according to claim 22, wherein the disease is rheumatoid arthritis, Inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis, attack I know optic, pancreatitis, traumatic brain injury, rejection of organ transplantation, osteoarthritis, asthma, psoriasis, Alzheimer's disease, atopic dermatitis, leukemia and related disorders, myelodysplastic syndrome or multiple myeloma.
24. A method for inhibiting a function mediated by ECI in a patient, comprising the step of administering to the patient a compound in accordance with a P1123 of claims 1-19 or a pharmaceutical composition of claim 21.
25. A method for decreasing the production of FIIG or INF-? in a patient, comprising the step of administering to the patient a compound according to one of claims 1-19 or a pharmaceutical composition of claim 21.
26. The use of a compound according to any one of claims 1 -19, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for the treatment or prevention of a disease selected from a disease mediated by IL-1, a disease mediated by apoptosis, an inflammatory disease, a disease autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a necrotic disease, a disease by excessive alcohol intake, a virus-mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, respiratory distress syndrome adult, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, escl eroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, hepatitis Chronic active p1123, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, host-to-graft reaction disease, osteoporosis, leukemia and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic attack, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, encephalitis related with HIV, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, rejection of organ transplantation, hepatitis B, hepatitis C, hepatitis G, yellow fever, dengue fever or Japanese encephalitis, in a patient, the method comprises the step of administering the patient.
27. The use according to claim 26, wherein the disease is rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis, septic attack, pancreatitis, traumatic brain injury, organ transplant rejection, osteoarthritis. , asthma, psoriasis, Alzheimer's disease, atopic dermatitis, leukemia and P1123 related disorders, myelodysplastic syndrome or multiple myeloma.
The use of a compound according to any one of claims 1-19 or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for inhibiting a function mediated by ECI in a patient.
29. The use of a compound according to any one of claims 1-19 or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for decreasing the production of FIIG or INF-? in a patient. P1123