3-SUBSTITUTED PYRROLIDINES USEFUL AS INHIBITORS OF MATRIX METALLO-PROTEINASES

Abstract: The present invention provides novel 3-substituted pyrrolidines of formula (1) useful as inhibitors of matrix metallo-proteinases (MMPs). Pharmaceutical compositions containing said compounds as well as methods of treating disease states responding to inhibition of matrix metallo-proteinase are also claimed herein.

Description: 3-SUBSTITUTED PYRROLIDINES USEFUL AS INHIBITORS OF MATRIX METALLO-PROTEINASES BACKGROUND OF THE INVENTION The matrix metalloproteinases (MMPs) are a family of zinc containing endopeptidases which are capable of cleaving large biomolecules such as the collagens, proteoglycans and gelatins. Expression is upregulated by pro-inflammatory cytokines and/or growth factors. The MMP's are secreted as inactive zymogens which, upon activation, are subject to control by endogenous inhibitors, for example, tissue inhibitor of metalloproteinases (TEVIP) and α - macroglobulin. Chapman, K.T. et al., J. Med. Chem. 36, 4293-4301 (1993); Beckett, R.P. et al., DDT 1, 16-26 (1996). The characterizing feature of diseases involving the enzymes appears to be a stoichiometric imbalance between active enzymes and endogenous inhibitors, leading to excessive tissue disruption, and often degradation. McCachren, S.S., Arthritis Rheum. 34, 1085-1093 (1991). The discovery of different families of matrix metalloproteinase, their relationships, and their individual characteristics have been categorized in several reports. Emonard, H. et al., Cell Molec. Biol. 36, 131-153 (1990); Birkedal-Hansen, H., J. Oral Pathol. 17, 445-451 (1988); Matrisian, L.M., Trends Genet. 6, 121-125 (1990); Murphy, G.J.P. et al., FEBS Lett. 289, 4-7 (1991); Matrisian, L.M., Bioessavs 14, 455-463 (1992). Three groups of MMPs have been delineated: the collagenases which have triple helical interstitial collagen as a substrate, the gelatinases which are proteinases of denatured collagen and Type IV collagen, and the stromelysins which were originally characterized as proteoglycanases but have now been identified to have a broader proteolytic spectrum. Examples of specific collagenases include fibroblast collagenase (MMP-1 ), neutrophil collagenase (MMP-8), and collagenase 3 (MMP- identified to have a broader proteolytic spectrum. Examples of specific collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP- 13). Examples of gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP-9). Examples of stromelysins include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). Other MMPs which do not fit neatly into the above groups include metalloelastase (MMP-12), membrane-type MMP (MT-MMP or MMP-14) and stromelysin 3 (MMP-11). Beckett, R.P. et al., supra. Over-expression and activation of MMPs have been linked with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as emphysema and smoking-induced emphysema; cardiovascular disorders, such as atherosclerosis; coraeal ulceration; dental diseases such as gingivitis and periodontal disease; and neurological disorders, such as multiple sclerosis. For example, in adenocarcinoma, invasive proximal gastric cells express the 72 kDa form of collagenase Type IV, whereas the noninvasive cells do not. Schwartz, G.K. et al., Cancer 73, 22-27 (1994). Rat embryo cells transformed by the Ha-ras and v-myc oncogenes or by Ha-ras alone are metastatic in nude mice and release the 92 kDa gelatinase/collagenase (MMP-9). Bernhard, E.J. et al., Proc. Natl. Acad. Sci. 91, 4293-4597 (1994). The plasma concentration of MMP-9 was significantly increased (P < 0.01) in 122 patients with gastrointestinal tract cancer and breast cancer. Zucker, S. et al, Cancer Res. 53, 140-146 (1993). Moreover, intraperitoneal administration of batimastat, a synthetic MMP inhibitor, gave significant inhibition in the growth and metastatic spread and number of lung colonies which were produced by intravenous injection of the B16-BL6 murine melanoma in C57BL/6N mice. Chirivi, R.G.S. et al., Int. J. Cancer 58, 460-464 (1994). Over-expression of TIMP-2, the endogenous tissue inhibitor of MMP-2, markedly reduced melanoma growth in the skin of immunodeficient mice. Montgomery, A.M.P. et al, Cancer Res. 54, 5467-5473 (1994). Accelerated breakdown of the extracellular matrix of articular cartilage is a key feature in the pathology of both rheumatoid arthritis and osteoarthritis. Current evidence suggests that the inappropriate synthesis of MMPs is the key event. Beeley, N.R.A. et al., Curr. Opin. Ther. Patents, 4(1), 7-16 (1994). The advent of reliable diagnostic tools have allowed a number of research groups to recognize that stromelysin is a key enzyme in both arthritis and joint trauma. Beeley, N.R.A. et al., Id.; Hasty, K.A. et al, Arthr. Rheum. 33, 388-397 (1990). It has also been shown that stromelysin is important for the conversion of procollagenase to active collagenase. Murphy, G. et al., Biochem. J. 248, 265-268 (1987). Furthermore, a range of MMPs can hydrolyse the membrane-bound precursor of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). Gearing, A.J.H. et al, Nature 370, 555-557 (1994). This cleavage yields mature soluble TNF-α and the inhibitors of MMPs can block production of TNF-α both in vitro and in vivo. Gearing, A.J.H. et al., Id.; Mohler, K.M. et al., Nature 370, 218-220 (1994); McGeehan, G.M. et al, Nature 370, 558-561 (1994). This pharmacological action is a probable contributor to the antiarthritic action of this class of compounds seen in animal models. Beckett, R.P. et al., supra. Stromelysin has been observed to degrade the αi-proteinase inhibitor which regulates the activity of enzymes such as elastase, excesses of which have been linked to chronic inflammatory disorders such as emphysema and chronic bronchitis. Beeley, N.R.A. et al., supra.; Wahl, R.C. et al.. Annual Reports in Medicinal Chemistry 25. 177-184 (1990). In addition, a recent study indicates that MMP- 12 is required for the development of smoking- induced emphysema in mice. Science, 277, 2002 (1997). Inhibition of the appropriate MMP may thus potentiate the inhibitory activity of endogenous inhibitors of this type. High levels of mRNA corresponding to stromelysin have been observed in atherosclerotic plaques removed from heart transplant patients. Henney, A.M., et al., Proc. Natl. Acad. Sci. 88, 8154-8158 (1991). It is submitted that the role of stromelysin in such plaques is to encourage rupture of the connective tissue matrix which encloses the plaque. This rupture is in turn thought to be a key event in the cascade which leads to clot formation of the type seen in coronary thrombosis. MMP inhibition is thus a preventive measure for such thromboses. Collagenase, stromelysin and gelatinase have been implicated in the destruction of the extracellular matrix of the cornea. This is thought to be an important mechanism of morbidity and visual loss in a number of ulcerative ocular diseases, particularly those following infection or chemical damage. Burns, F.R. et al, Invest. Opthalmol. and Visual Sci. 32, 1569-1575 (1989). The MMPs present in the eye during ulceration are derived either endogenously from infiltrating leucocytes or fibroblasts, or exogenously from microbes. Collagenase and stromelysin activities have been identified in fibroblasts isolated from inflamed gingiva and the levels of enzyme have been correlated with the severity of the gingivitis observed. Beeley, N.R.A. et al., supra.; Overall, CM. et al., J. Periodontal Res. 22, 81-88 (1987). Excessive levels of gelatinase-B in cerebrospinal fluid has been linked with incidence of multiple sclerosis and other neurological disorders. Beeley, N.R.A. et al., supra.; Miyazaki, K. et al., Nature 362, 839-841 (1993). The enzyme may play a key role in the demyelination of neurones and the breakdown of the blood brain barrier which occurs in such disorders. SUMMARY OF THE INVENTION The present invention provides novel 3-substitutedpyrrolidines of formula (1 ): R, formula ( 1 ) wherein e is an interger from 0 to 2; A is selected from the group consisting of -OH and -NRR'; wherein R and R' are independently selected from the group consisting of hydrogen and Cι-C 6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ri is selected from the group consisting of hydrogen, Cι-C 6 alkyl, -(CH 2 ) a -CO2R 5 , -(CH 2 ) a -C(O)NH 2 , -(CH 2 ) 4 NH 2 , -(CH 2 ) 3 -NH-C(NH)NH 2 , -(CH 2 ) 2 -S(O) b -CH 3 , -CH 2 -OH, -CH(OH)CH 3 , -CH 2 -SH, -(CH 2 ) d -Ar,, and -CH 2 -Ar 2 ; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4; R 5 is selected from the group consisting of hydrogen, Cι_C 4 alkyl, and benzyl; Aj] is a radical selected from the group consisting of wherein R 6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι.C alkyl, hydroxy, and C 1 -C4 alkoxy; R 7 is selected from the group consisting of hydrogen, halogen, C|.C 4 alkyl, and Cι-C 4 alkoxy; Ar 2 is a radical selected from the group consisting of R 2 is a radical selected from the group consisting of wherein wherein R 2 - is from 1 to 2 substituents selected from the group consisting of hydrogen, halogen, Cι-C 4 alkyl, and Cι-C 4 alkoxy; R 3 is selected from the group consisting of Cι-C 6 alkyl, -(CH 2 ) m -W, -(CH2) P -Ar 3 , -(CH 2 ) k -CO 2 R 9 , -(CH 2 ) m -NR 8 SO 2 -Y,, and -(CH 2 ) m -Z-Q wherein m is an integer from 2 to 8; p is an integer from 0-10; k is an integer from 1 to 9; W is phthalimido; Ar 3 is selected from the group consisting of wherein R 23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C|-C 4 alkyl, and Cι-C 4 alkoxy; R 8 - is hydrogen or C]-C 6 alkyl; R is hydrogen or Cι-C 6 alkyl; Yι is selected from the group consisting of hydrogen, -(CH 2 ) j -Ar 4 , and -N(R 24 ) 2 wherein j is 0 or 1 ; R 24 each time selected is independently hydrogen or Cι-C 6 alkyl or are taken together with the nitrogen to which they are attached to form N-morpholino, N- piperidino, N-pyrrolidino, or N-isoindolyl; Ar 4 is wherein R 25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C 4 alkyl, and C C 4 alkoxy; Z is selected from the group consisting of -O-, -NR -, -C(O)NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NH-, -NR 8 C(O)O -, and -OC(O)NH-; wherein R 8 is hydrogen or Cι-C 6 alkyl; Q is selected from the group consisting of hydrogen, -(CH 2 ) n -Y 2 , and -(CH 2 ) -Y 3 ; wherein n is an integer from 0 to 4; x is an integer from 2 to 4; Y is selected from the group consisting of hydrogen, -(CH 2 ) n -Ar5 and -(CH 2 ),-C(O)OR 2 7 wherein Ar, is selected from the group consisting of wherein R 26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C 4 alkyl, and Cι-C 4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R 27 is hydrogen or Cι-C 6 alkyl; Y 3 is selected from the group consisting of -N(R 28 ) 2 , N-morpholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein R 2 g each time taken is independently selected from the group consisting of hydrogen and Cj-C 6 alkyl; R4 is selected from the group consisting of hydrogen, -C(O)Rιo, -C(O)-(CH 2 ) q -K and -S-G wherein Rio is selected from the group consisting of hydrogen, Cι_C 4 alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from the group consisting of N— R, R ιι ' wherein V is selected from the group consisting of a bond, -CH 2 -, -O-, -S(O),-, -NR 21 -, and -NC(O)R 22 -; wherein r is 0, 1 , or 2; R 21 is selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl; R 22 is selected from the group consisting of hydrogen, -CF 3 , C 1 -C 10 alkyl, phenyl , and benzyl; Rπ is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl; Ri 1 - is selected from the group consisting of hydrogen, Cι_C 4 alkyl, and benzyl; G is selected from the group consisting of wherein w is an integer from 1 to 3; Ri 2 is selected from the group consisting of hydrogen, Cι-C 6 alkyl, -CH 2 CH2S(O)fCH 3 , and benzyl; wherein f is 0,1, or 2; R 13 is selected from the group consisting of hydrogen, hydroxy, amino, Cι-C 6 alkyl, N-methylamino, N,N-dimethylamino, -CO 2 R 1 7, and -OC(O)R] 8 ; wherein Rπ is hydrogen, -CH 2 O-C(O)C(CH 3 ) 3 , C,.C 4 alkyl, benzyl, or diphenylm ethyl; Ri 8 is hydrogen, C|-C 6 alkyl or phenyl; Rι 4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι-C 4 alkyl, Cι_C alkoxy, or halogen; V] is selected from the group consisting of -O-, -S-. and -NH-; V 2 is selected from the group consisting of -N- and -CH-; V 3 is selected from the group consisting of a bond and -C(O)-; V 4 is selected from the group consisting of -O-, -S-, -NR ! 9 -, and -NC(O)R 2 o-; wherein R 1 9 is hydrogen, Cι_C alkyl, or benzyl; R 2 o is hydrogen, -CF 3 , Cj-Cio alkyl, or benzyl; R 15 is selected from the group consisting of hydrogen, Cι-C 6 alkyl and benzyl; R I O is selected from the group consisting of hydrogen and Cι-C 4 alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof. The present invention further provides a method of inhibiting matrix metalloproteinases (MMPs) in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of formula (1). As such the present invention provides a method of treating a neoplastic disease state or cancer; rheumatoid arthritis; osteoarthritis; osteoporosis; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases, such as gingivitis or periodontal disease; and neurological disorders, such as multiple sclerosis; chronic inflammatory disorders, such as emphysema and especially smoking-induced emphysema. In addition, the present invention provides a composition comprising an assayable amount of a compound of formula (1) in admixture or otherwise in association with an inert carrier. The present invention also provides a pharmaceutical composition comprising an effective MMP inhibitory amount of a compound of formula (1 ) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. As is appreciated by one of ordinary skill in the art the compounds of formula (1) exist as stereoisomers. Specifically, it is recognized that they exist as stereoisomers at the point of attachment of the substituents R,, -(CH 2 ) e -R 2 , R3, and -SR 4 , -C(O)NH-CHR,-C(O)A, R, 2 , and -NHR 1 5. Where indicated the compounds follow either the (+)- and (-)- designation for optical rotation, the (D)- and (L)- designation of relative stereochemistry, or the Cahn-Ingold- Prelog designation of (R)-and (S)- for the stereochemistry of at specific postions in the compounds represented by formula (1 ) and intermediates thereof. Any reference in this application to one of the compounds of the formula (1) is meant to encompass either specific stereoisomers or a mixture of stereoisomers. The specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials which are well known in the art. The specific stereoisomers of amino acid starting materials are commercially available or can be prepared by stereospecific synthesis as is well known in the art or analogously known in the art, such as D. A. Evans, et al. J. Am. Chem. Soc, 112, 401 1-4030 (1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W.Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989); Synthesis of Optically Active α-Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis, Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schδllkopf, Pure Appl. Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem., 44, 3748-3752 (1979); M. J. O'Donnell et al. Tet Lets.. 2641 -2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al. J. Am. Chem. Soc. 110, 8520-8525 (1988). The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and are described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994) and Enantiomers. Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981). As used in this application: a) the term "halogen" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom; b) the term "Cι-C 6 alkyl" refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, etc.; c) the term "C1-C4 alkyl" refers to a saturated straight or branched chain alkyl group containing from 1 -4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, s- butyl, isobutyl, and t-butyl; d) the term "C1-C4 alkoxy" refers to a straight or branched alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy. isobutoxy, t- butoxy, etc.; e) the designation " Λ ' * refers to a bond for which the stereochemistry is not designated; f) the designation " ~~ ~~ " refers to a bond that protrudes forward out of the plane of the page. g) the designation " " refers to a bond that protrudes backward out of the plane of the page. h) as used in the examples and preparations, the following terms have the meanings indicated: "g" refers to grams, "mg" refers to milligrams, "μg" refers to micrograms, "mol" refers to moles, "mmol" refers to millimoles, "nmole" refers to nanomoles, "L" refers to liters, "mL" or "ml" refers to milliliters, "μL" refers to microliters, "°C" refers to degrees Celsius, "R t " refers to retention factor, "mp" refers to melting point, "dec" refers to decomposition, "bp" refers to boiling point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to nanometers, "brine" refers to a saturated aqueous sodium chloride solution, "M" refers to molar, "mM" refers to millimolar, "μM" refers to micromolar, "nM" refers to nanomolar, "HPLC" refers to high performance liquid chromatography, "HRMS" refers to high resolution mass spectrum, "DMF" refers to dimethylformamide, "μCi" refers to microcuries, "i.p." refers to intraperitoneally, "i.v." refers to intravenously, and "DPM" refers to disintegrations per minute; i) for substituent Z, the designations -C(O)NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NH-. -NR 8 C(O)O-, and -OC(O)NH- refer to the functionalities represented, respectively, by the following formulae showing the attachment of the group (Q): these designations are referred to hereinafter as amido, amide, urea, N-carbamoyl, and O-carbamoyl, respectively; j) the term "pharmaceutically acceptable salts" thereof refers to either an acid addition salt or a basic addition salt. The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (1) or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points. The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by formula (1) or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. As with any group of structurally related compounds which possess a particular utility, certain groups and configurations of substituents are preferred for the compounds of formula (1). Preferred embodiments are given below: The compounds in which Ri is selected from the group consisting of C-C 6 alkyl and -(CH 2 ) d -Ari are preferred; The compounds in which Ri is -(CH ) d -Arι are more preferred; The compounds in which R| is -(CH 2 ) d -Arι in which d is 1 or 2 and An is phenyl are most preferred; Compounds in which R is selected from the group consisting of hydrogen, -C(O)Rιo and -SG are preferred; Compounds in which R 4 is selected from the group consisting of -C(O)Rιo and R J O is Cι_C 4 alkyl more preferred; Compounds in which A is -OH are preferred; and Compounds in which A is -NRR' wherein R is hydrogen and R " is methyl are preferred. Examples of compounds encompassed by the present invention include the following. It is understood that the examples encompass all of the isomers of the compound and mixtures thereof. This list is meant to be representative only and is not intended to limit the scope of the invention in any way: The compounds of formula (1) can be prepared by a variety of procedures readily known to those skilled in the art. Such procedures include, peptide coupling, such as solid phase sequential procedures and solution phase sequential procedures using suitable amino acids and substituted acids and displacement, modification, and functionalization procedures, as required, utilizing suitable protecting groups and deprotection procedures. As used herein the term "amino acid" refers to naturally occurring amino acids as well as non-naturally occurring amino acids having substituents encompassed by R] and R 2 as described above. The naturally occurring amino acids included are glycine, alanine, valine, leucine, isoleucine. serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, histidine. aspartic acid, asparagine, glutamic acid, glutamine, arginine, ornithine, and lysine. Non-naturally occurring amino acids within the term "amino acid," include without limitation, the D-isomers of the naturally occurring amino acids, norleucine, norvaline, alloisoleucine, t-butylglycine, methionine sulfoxide, and methionine sulfone. Other non- naturally occurring amino acids within the term "amino acid," include without limitation phenylalanines, phenylglycines, homophenylalanines, 3-phenylpropylglycines, 4- phenylbutylglycines; each including those substituted by R 6 and R 6 as described above; and 1-naphthylalanines and 2-naphthylalanines; including those substituted by R 7 and R 7 - as described above. The compounds of formula (1) can be prepared by utilizing techniques and procedures well known and appreciated by one of ordinary skill in the art. To illustrate, general synthetic schemes for preparing intermediates and the compounds of formula (1) are set forth below. In the reaction schemes below, the reagents and starting materials are readily available to one of ordinary skill in the art and all substituents are as previously defined unless otherwise indicated. Reaction Scheme A R-, In Scheme A, step 1, an appropriate protected compound of the formula (2a) is coupled with an appropriate compound of formula (3a) to give a compound of formula (2b). An appropriate protected compound of the formula (2a) is one in which R2 is as desired in the final compound of formula (1) or gives rise after deprotection to R 2 as desired in the final compound of formula (1), e is as desired in the final product of formula (1), and Pgi is an amine protecting group. In addition, an appropriate compound of formula (2a) may also be one in which the stereochemistry at the carboxy and -(CH 2 ) e -R2 bearing carbons is as desired in the final product of formula (1 ). In Reaction Scheme A the protecting group, Pgi, is one in which the can be removed in the presence of the amide formed in this step. The use and removal of amine protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991). In Reaction Scheme A, the use of t-Boc and F-moc for Pgi is preferred. An appropriate compound of the formula (3a) is one in which Ri is as desired in the final compound of formula (1) or gives rise after deprotection to R| as desired in the final compound of formula ( 1 ) and A ' is -NRR' as desired in the final product of formula (1 ) or a protected carboxy group which gives rise to -OH as desired in the final product of formula (1). A * may also be an attachment to a suitable resin. Such a protected carboxy or resin is chosen so that it does not interfere with subsequent deprotection, displacement, derivitivization, functionalization, or modification reactions, as are required. The use and removal of carboxy protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley- Interscience, 2nd Edition, 1991 ). In addition, an appropriate compound of formula (3a) may also be one in which the stereochemistry at the Ri bearing carbon is as desired in the final product of formula (1). Such coupling reactions are carried out by a variety of procedures readily known to those skilled in the art. Such procedures include, peptide coupling, such as solid phase sequential procedures and solution phase sequential procedures using suitable amino acids and substituted acids followed by displacement, modification, and functionalization procedures, as required, utilizing suitable protecting groups and deprotection procedures. As used herein the term "amino acid" refers to naturally occurring amino acids as well as non-naturally occurring amino acids having substituents encompassed by Ri and -(CH 2 ) e -R 2 as described above. The naturally occurring amino acids included are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, ornithine, and lysine. Non-naturally occurring amino acids within the term "amino acid," include without limitation, the D-isomers of the naturally occurring amino acids, norleucine, norvaline, alloisoleucine, t-butylglycine, methionine sulfoxide, and methionine sulfone. Other non-naturally occurring amino acids within the term "amino acid," include without limitation phenylalanines substituted by R 6 as described above; phenylglycines, homophenylalanines, 3- phenylpropylglycines, 4-phenylbutylglycines; including those substituted by R 6 as described above; and 2-naphthylalanines, including those substituted by R 7 as described above. The preparation of amino acids bearing -(CH 2 ) e -R2 are knkown in the art and described herein. Solid phase sequential procedures can be performed using established methods, including automated methods such as by use of an automated peptide synthesizer. Steward and Young, Solid Phase Peptide Synthesis (Freeman 1969) and B. Merrifield, Peptides: Synthesis, Structures, and Applications (B. Gutte, Ed., Acedemic Press 1995). In this procedure a protected amino acid bearing Ri or protected Ri is bound to a resin support. The resin support employed can be any suitable resin conventionally employed in the art for the solid phase preparation of poly-peptides, preferably polystyrene which has been crossed away with about 0.5 to about 3 percent divinyl benzene, which has been either in chloromethylated or hydroxymethylated to provide sites for ester formation with the initially introduced protected amino acid. Suitable resins are well known and appreciated in the art, including those described in Rink, Tet. Let., 28, 3787 (1987) and Sieber, Tet. Let., 28, 2107 (1987). Included within the solid phase methods are combinatorial methods which are known in the art. K. S. Lam, Chem. Rev., 97, 41 1-448 (1997). In a subsequent step the resin-bound protected amino acid bearing Ri is sequentially amino deprotected and coupled with a protected amino acids bearing -(CH 2 ) e -R 2 to give a resin-bound protected dipeptide. This resin bound protected dipeptide is sequentially amino deprotected and coupled with a protected amino acid bearing R 3 or protected R 3 to give a protected tripeptide. Alternately, an appropriate protected dipeptide may be coupled by the solution method prior to coupling with the resin-bound amino acid. Each protected amino acids or amino acid sequence is introduced into the solid phase reactor and about a two-fold to four-fold excess. The coupling is carried out in a suitable medium, for example dimethylformamide, dichloromethane, or mixtures of dimethyl formamide and dichloromethane. As is well known and appreciated in the art, wherein complete coupling occurs, the coupling in procedure is repeated before removal of the protecting group, prior to the coupling of the next amino acids in the solid phase reactor. After the compound of formula (1 ) or protected compound of formula (1 ) has been obtained it is removed from the resin under conditions well known in the art which are appropriate for the resin selected. Compounds of formula (1) obtained by solid phase sequential procedures can be purified by procedures well known and appreciated in the art, such as chromatography, lyophilzation, trituration, salt formation, and crystallization. The compounds of formula (1) can also be prepared by solution phase sequential procedures well known and appreciated in the art. Accordingly, suitably protected amino acids, substituted acids or dipeptides are coupled by procedures requiring activation of the carbonyl group and coupling reaction with amine function of an appropriate protected amino acid or dipeptide. These procedures are well known appreciated in the art. The selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable coupling reagents include N-((dimethylamino)-lH-l ,2,3-triazolo[4,5- b]pyridin-l-ylmethylene)-N-methylmethanaminium hexafluororphosphate N-oxide (HATU), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-benzotriazole or N,N'-diisopropylcarbodiimide and 1-hydroxy-benzotriazole. Other coupling agents are pyridine benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate complex , carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide); cyanamides (e.g., N,N- dibenzylcyanamide); (3b) ketenimines; isoxazolium salts (e.g., N-ethyl-5-phenyl-isoxazolium- 3'-sulfonate; monocyclic nitrogen containing heterocyclic amides of aromatic character containing one through four nitrogens in the ring such as imidazolides, pyrazolides, and 1 ,2,4- triazolides. Specific heterocyclic amides that are useful include N,N' -carbonyl diimidazole and N,N-carbonyl- di-l,2,4-triazole; alkoxylated acetylene (e.g., ethoxyacetylene); reagents which form a mixed anhydride with the carboxyl moiety of the amino acid (e.g., ethylchloroformate and isobutylchloro formate). Other activating reagents and their use in peptide coupling are described by Kapoor, J. Pharm. Sci., 59, 1-27 (1970). Such coupling reactions to form amides are carried out in suitable solvents, such as dichloromethane, tetrahydrofuran, diethyl ether, chloroform, and the like, and using suitable bases, such as triethylamine, N-methylmorpholine, N,N-disopropylethylamine, pyridine, and the like, and coupling reagents, as required, and are well known and appreciated in the art. The reactions are generally carried out at -10°C to the refluxing temperature of the solvent and generally require form 1 hour to 2 days. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophilization, chromatography, and recrystallization. In Reaction Scheme A, step 2, the amine protecting group, Pgi, of the compound of formula (2b) is selectively removed to give the compound of formula (2c). Such selective amine deprotection reactions are well known and appreciated in the art. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, salt formation, trituration, lyophilization. chromatogranhv. and recrvstallization. In Reaction Scheme A, step 3, a compound of formula (2c) coupled with an appropriate acid derivative bearing R 3 ' and Y (compound of formula (3b)) to give a compound of formula (4). Such coupling reactions are well known and appreciated in the art and discussed above. The product can be isolated and purified by techniques well known in the art such as extraction, evaporation, salt formation, trituration, lyophilization, chromatography, and recrystallization. An appropriate compound of formula (3b) is one in which R 3 - is R 3 as desired in the final product of formula (1) or gives rise after deprotection to R 3 as desired in the final product of formula (1 ) and Y is a protected thio substituent or Y may be a protected hydroxy substituent or bromo which gives rise upon selective deprotection and displacement or displacement and further deprotection and/or elaboration, if required, to -SR 4 as desired in the final product of formula (1). Alternately, an appropriate compound of formula (3b) may also be one in which R 3 - gives rise to R 3 - which, upon derivatization, gives rise R 3 as desired in the final product of formula (1) and Y is a protected thio substituent. In addition, an appropriate compound of formula (3b) may also be one in which the stereochemistry at the R 3 - and Y bearing carbon is as desired in the final product of formula (1 ) or gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1). The activating group (A) is one which undergoes an amidation reaction. As is well known in the art an amidation reaction may proceed through an acid, X is -OH; or an acid may be first converted to an acid chloride, X is -Cl; or an activated intermediate; such as an anhydride; a mixed anhydride of aliphatic carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroacetic acid, trifluoroacetic acid, and the like; of aromatic carboxylic acids, such as benzoic acid and the like; of an activated ester, such as phenol ester, p-nitrophenol ester, 2,4-dinitrophenol ester, pentafluorophenol ester, pentachlorophenol ester, N-hydroxysuccinimide ester, N- hydroxyphthalimide ester, 1 -hydroxy- lH-benztriazole ester, and the like; activated amide, such as imidazole, dimethylpyrazole, triazole, or tetrazole; or an intermediate formed in the presence of coupling agents, such as dicyclohexylcarbodiimide or l-(3-dimethyaminopropyl)- 3- ethylcarbodiimide. Acid chlorides and activated intermediates may be prepared but are not necessarily isolated before the addition of a compound of formula (3b). The use and selection of appropriate protecting groups is within the ability of those skilled in the art and will depend upon compound of formula (3b) to be protected, the presence of other protected amino acid residues, other protecting groups, and the nature of the particular R 3 and/or R 4 group(s) ultimately being introduced. Compounds of formula (3b) in which Y is bromo and protected thio are commercially available or can be prepared utilizing materials, techniques, and procedures well known and appreciated by one of ordinary skill in the art or described herein. See PCT Application WO 96/11209, published 18 April 1996. Examples commercially available compounds of formula (3b) in which Y is bromo include 2- bromopropionic acid, 2-bromobutyric acid, 2-bromovaleric acid, 2-bromohexanoic acid, 6- (benzoylamino)-2-bromohexanoic acid, 2-bromoheptanoic acid, 2-bromooctanoic acid, 2- bromo-3-methylbutyric acid, 2-bromoisocaproic acid, 2-bromo-3-(5-imidazoyl)proionic acid, (R)-(+)-2-bromopropionic acid, (S)-(-)-2-bromopropionic acid. In Reaction Scheme B a final product of formula (1) is prepared from a compound of formula (4) (prepared as described in Reaction Scheme A) in which R 3 - is R 3 as desired in the final product of formula (1) or gives rise after deprotection to R 3 as desired in the final product of formula (1) and Y is a protected thio substituent or hydroxy or bromo. Reaction Scheme B R, (formula (1) or protected formula (1)) In Reaction Scheme B, step 1, a compound of formula (4) in which Y is protected thio gives rise upon selective deprotection to give a compound of formula (5). For example, compounds of formula (4) in which Y is a protected thio substituents are selectively deprotected to give a thiol of formula (5). Protected thio substituents include thioesters, such as thioacetyl or thiobenzoyl, thioethers, such as thiobenzyl, thio-4- methoxybenzyl, thiotriphenylmethyl, or thio-t-butyl, or unsymmetrical sulfides, such as dithioethyl or dithio-t-butyl. The use and selective removal of such thio protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991). In Reaction Scheme B, step 2, a compound of formula (5) undergoes modification reaction to give a compound of formula (6). Such modification reactions include, thiol esterification and disulfide formation. Compounds of formula (6) in which R-j is -C(O)Rιo or -C(O)-(CH2) q -X group can be synthesized by thiol esterifications according to techniques well known and appreciated by one of ordinary skill in the art, such as those disclosed in U.S. Pat. Nos. 5,424,425, issued Jun. 13, 1995. For example, in a thiol esterification a compound of formula (5) is contacted with about an equimolar amount of an appropriate acid, such as HO-C(O)Rιo or HO-C(O)-(CH 2 ) q -K in the presence of a suitable coupling agent to give a compound of formula (6) in which R 4 is -C(O)Rjo or -C(O)-(CH ) q -K. The reaction is carried out in the presence of a coupling agent such as 2-fluoro-l-methylpyridinium p-toluenesulfate, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, 1- ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline. or diethylcyanophosphonate in a suitable aprotic solvent such as methylene chloride. The reaction is generally carried out at temperature of between -20°C and the boiling point of the solvent. Generally, the reaction requires 1 to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophilization, chromatography, and recrystallization. Compounds of formula (6) in which R4 is -S-G group can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art, as disclosed in PCT Application No. WO 95/21839, published 17 August 1995 and U.S. Patent Nos. 5,491,143, issued February 13, 1996, and 5,731,306, issued March 24, 1998, and Roques, B.P. et al., J, Med. Chem. 33, 2473-2481 (1992). For example, in a disulfide formation a compound of formula (5) is contacted with an appropriate compound of formula (7). (7) An appropriate compound of formula (7) is one which gives G as desired in the final product of formula (1) or gives rise upon deprotection to G as is desired in the final product of formula (1). In addition, the compound of formula (7) may have stereochemistry as desired in the final product of formula (1). The reaction is carried out in a suitable solvent, such as ethanol, methanol, dichloromethane, or mixtures of ethanol or methanol and dichloromethane. The solvent is degassed by passing a stream of nitrogen gas through it for 15 minutes before the reaction is carried out. The reaction is carried out using from 1.0 to 4.0 molar equivalents of an appropriate compound of formula (7). The reaction is carried out at temperatures of from 0°C to the refluxing temperature of the solvent, with a temperature of 10°C to 30°C being preferred. The reaction generally requires from 1 to 48 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. In Reaction Scheme B, step 3, a compound of formula (4) in which Y is hydroxy or bromo can be displaced by an appropriate thiol, HSR 4 , to give a compound of formula (1) or a protected compound of formula (1). In Reaction Scheme B, step 3, an appropriate thiol HSR 4 is one which gives R as desired in the final product of formula (1 ) or gives rise to R4 as desired in the final product of formula (1 ). In Reaction Scheme B, step 3, a compound of formula (4) in which Y is hydroxy (obtained from protected hydroxy compounds of formula (4)) undergoes a displacement reaction with an appropriate thio introducing reagent by the method of Mitsunobu to give a compound of formula (4) in which Y is a protected thio substituent or -SR 4 as desired in the final compound of formula ( 1 ) For example, a compound of formula (4) in which Y is hydroxy reacts with thioacetic acid or thiobenzoic acid, tπphenylphosphine, and diethylazodicarboxylate in a suitable aprotic solvent, such as tetrahydrofuran to give a compound of formula (4) in which Y is thioacetyl or thiobenzoyl Selective removal of the thioacetic acid or thiobenzoic acid moiety gives the desired compound of formula (5) The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, tπturation, lyophilization, chromatography, and recrystal zation Also, in Reaction Scheme B, step 3, a compound of formula (4) in which Y is bromo undergo a displacement reaction with an appropriate thio introducing reagent to give a compound of formula (4) in which Y is protected thio substituent which gives πse upon deprotection and subsequent elaboration, if desired, the -SR4 as desired in the final compound of formula (1) An appropπate thio introducing reagent is also one which introduces a group -SR as desired in the final compound of formula (1) For example, a solution of p-methoxybenzylmercaptan a suitable organic solvent such as dimethyl formarmde is degassed and treated with a suitable base such as sodium hydπde, sodium hydroxide, or cesium carbonate After about 1 to 2 hours, a solution of a compound of formula (4) in which Y is bromo is added The reaction may benefit from the addition of a suitable catalyst, such as tetra-n-butylammomum iodide The reaction mixture is carried out for 1 to 25 hours at temperatures ranging form 0°C to about 100°C Selective removal of the 4-methoxybenzyl moiety gives the desired compound of formula (1 ) The product can be isolated and puπfied by techniques well known in the art, such as extraction, evaporation, tπturation, lyophilization, chromatography, and recrystalhzation In addition, in Reaction Scheme B, step 3, a compound of formula (4) m which Y is bromo can be displaced by an appropπate thio ester, Ph 3 S-C(O)-(CH2) q -X by techniques well known and appreciated in the art. as disclosed in U S Pat No 5,424,425, issued Jun 13, 1995 In Reaction Scheme B, in an optional step, a protected compound of formula (1) is deprotected to give a compound of formula (1 ). Such deprotection reactions are well known appreciated in the art and may include selective deprotections. In Reaction Scheme C a final product of formula (1 ) is prepared from a compound of formula (4) (prepared as described in Reaction Scheme A) in which R 3 - gives rise to R 3 - and Y is -SR as is desired in the final product of formula (1) or a protected thio substituent gives a compound of formula (1). (formula (1) or protected formula (1 )) In Reaction Scheme C, step 1 , an appropriate compound of formula (4) is deprotected, hydrolyzed, or reduced to give a compound of formula (4a). In Reaction Scheme C, step 1, an appropπate compound of formula (4) is one in which R 3 gives rise to a compound of formula (4a) in which R 3 undergoes further deπvitization (step 2) to give a compound of formula (4) in which R-, is -(CH 2 ) n. -NR 8 -SO 2 -Yι or -(CH 2 ) m -Z-Q as desired m the final product of formula ( 1 ) In Reaction Scheme C, step 1. an appropπate compound of formula (4) is one in which Y is -SR as desired in the final compound of formula (1) or Y is protected thio which gives πse upon deprotection or deprotection and further functionalization to give -SR , as desired, in the final product of formula (1) as descπbed in Reaction Scheme B, step 2, above For example, in a deprotection a compound of formula (4) in which R 3 is -(CH 2 ) m -W (W is a phthahmido group) is contacted with a molar excess of hydrazme monohydrate to give a compound of formula (4a) in which R 3 is -(CH 2 ) m -NHR 8 in which R 8 is hydrogen The reaction is typically earned out in a protic organic solvent, such as methanol or ethanol. The reaction is generally carried out at room temperature for a peπod of time ranging from 5-24 hours The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be puπfied by chromatography and recrystalhzation. Alternately, for example, in a deprotection a compound of formula (4) in which R is -(CH ) m -NR 8 -t-Boc is contacted with a molar excess of a suitable acid to give a compound of formula (4a) in which R 3 is -(CH ) m -NHR The reaction is typically carried out in a organic solvent, such as methanol, ethanol, ethyl acetate, diethyl ether, or dioxane Suitable acids for this reaction are well known in the art, including hydrochloric acid, hydrobromic acid, tnfluoroacetic acid, and methanesulfomc acid The reaction is generally carried out at room temperature for a peπod of time ranging from 1-10 hours The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be puπfied by chromatography and recrystalhzation For example, in a hydrolysis a compound of formula (4) in v\ hich R 3 is -(CH 2 )m-C(O)OPg- and Pgi is methyl or ethyl is contacted with about 1 to 2 molar equivalents of lithium hydroxide, sodium hydroxide, or potassium hydroxide to give a compound of formula (4a) in which R 3 is -(CH 2 )m-CO 2 H The reaction is earned out in a suitable solvent, such as methanol. ethanol methanol/water mixtures, ethanol/water mixtures, or tetrahydrofuran water mixtures and generally requires 1 to 24 hours The reaction is carried out at temperatures of from about 0°C to the refluxing temperature of the solvent. The resulting acid is isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, and precipitation and can be purified by trituration, precipitation, chromatography, and recrystalhzation. For example, in a reduction a compound of formula (4a) in which R 3 is -(CH2)m-i-CO 2 Pg 3 in which Pg 3 is methyl or ethyl is contacted with a suitable reducing agent, such as lithium borohydride, diisobutylaluminum hydride, 9-borabicyclo[3.3.1]nonane, preferably lithium borohydride to provide a compound of formula (4a) in which Ry is - (CH 2 ) π ι-CH 2 OH. The reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, or toluene, with tetrahydrofuran being preferred. The reaction is carried out at a temperature of from about -30°C to about 50°C and generally requires from 2 to 12 hours. The product can be isolated by quenching, extraction, evaporation, and precipitation and can be purified by trituration, chromatography, and recrystalhzation. In Reaction Scheme C, step 2, a compound of formula (4a) undergoes a derivitization reaction to give a compound of formula (5) in which R 3 is as desired in the final product of formula (1). Such derivitization reactions include hydrolysis of esters and ester formations as are well known in the art, ether formation, amine alkylation, formation of amides, urea formation, carbamate formation, and formation of sulfonamide. In Reaction Scheme C, step 2, the compound of formula (4a) is one in which Y is a protected thio group, such as thioacetyl, thiobenzoyl, 4-methoxybenzyl thiol or t-butylthiol. For example, in an ether formation a compound of formula (4a) in which R 3 - is -(CH 2 ) m .|-CH 2 OH is contacted with 1 to 10 molar equivalents of a suitable alkylating agent to give a compound of formula (5) in which R 3 is -(CH 2 ) m -Z-Q in which Z is -O-. A suitable alkylating agent is one which transfers Q or protected Q as desired in the final product of formula (1), such as benzyl bromide, benzyl chloride, substituted benzyl bromide, substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoaceate, ethyl 3-chloropropionate, ethyl 3- bromopropionate, ethyl 5-bromovalerate, ethyl 4-bromobutyrate, 3-chloropropionamide, 2- bromoethylbenzene, substituted 2-bromoethylbenzene, l-chloro-3-phenylpropane, l-bromo-4- phenylbutane, and the like, or nitrogen mustards, including 2-dimefhylaminoethyl chloride, 2- diethylaminoethyl chloride, and 3-dimethylaminopropyl chloride. The reaction is carried out in a suitable solvent, such as diethyl ether, tetrahydrofuran. dimethylformamide, dimethyl sulfoxide, or acetonitrile and using a suitable base, such as sodium hydride, potassium hydride, potassium t-butoxide, and lithium diisopropylamide. The reaction is generally carried out at temperatures of -70°C and room temperature and require from about 1-24 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystalhzation. Alternately, as appreciated by those skilled in the art, an ether formation can also be carried out by a procedure similar to the one above using a compound of formula (4a) in which R 3 - is -(CH 2 ) m -ι-CH 2 OH in which the hydroxy group is first converted to a leaving group, such as chloro, bromo, or mesylate and a suitable alcohol which transfers Q or protected Q as desired in the final product of formula (1 ), such as benzyl alcohol, substituted benzyl alcohol, phenol, substituted phenol, and the like. The conversion of hydroxy to leaving groups, such as chloro, bromo, and mesylate are well known and appreciated in the art. For example, in an amine alkylation a compound of formula (4a) in which R 3 • is -(CH 2 ) m -NHR 8 is contacted with 1 to 10 molar equivalents of a suitable alkylating agent to give a compound of formula (5) in which R 3 is -(CH 2 ) m -Z-Q in which Z is -NR 8 -. The reaction may be carried out after protection of the amine function of R 3 - in which R 8 is hydrogen by a suitable protecting group, such as benzyl or t-Boc. For an amine alkylation a suitable alkylating agent is one as described above for the ether formation and also includes alkylhalides, such as methyl iodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride, butyl bromide, butyl chloride, and the like. The reaction is carried out in a suitable solvent, such as methanol, ethanol, dimethylformamide, or pyridine and using a suitable base, such as sodium carbonate, triethylamine, N,N-diisopropylethylamine or pyridine. The reaction is generally carried out at temperatures of room temperature to the refluxing temperature of the solvent and require from about 1-24 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystalhzation. Alternately, for example, in an amine alkylation a compound of formula (4a) in which R 3 - is -(CH 2 ) m -NHR 8 is contacted in a reductive alkylation with a suitable aldehyde to give a compound of formula (5) in which R 3 is -(CH 2 ) m -Z-Q in which Z is -NRg-. A suitable aldehyde is one which transfers Q or protected Q as desired in the final product of formula (1), such as benzaldehyde and substituted benzaldehydes. The reaction is carried out in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran. The reaction may be carried out in the presence of a drying agent, such as sodium sulfate or molecular sieves. The reaction is carried out in the presence of from 1.0 to 6.0 molar equivalents of a suitable reducing agent, such as, sodium borohydride or sodium cyanoborohydride with sodium cyanoborohydride being preferred. It may be advantageous to maintain the pH in the range of about 4 to 6. The reaction is generally carried out at temperatures of from 0°C to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystalhzation. For example, in an amido formation a compound of formula (4a) in which R 3 >- is is -(CH 2 ) m -C0 2 H is contacted with a suitable amine in an amide formation to give a compound of formula (5) in which R is -(CH 2 ) m -Z-Q in which Z is amido. Such amide formation reactions using carboxy activation or suitable coupling agents are well known in the art and described above. A suitable amine, HNR 8 Q, gives rise to R 8 and Q as desired in the final product of formula (1), such as methylamine, ethylamine, propylamine, butylamine, N- methyl benzylamine, benzyl β-alanine, 4-(3-aminopropyl)morpholine, and the like. For example, in an amide formation a compound of formula (4a) in which R 3 - is is -(CH 2 ) m -NHR 8 is contacted with a suitable carboxylic acid in an amide formation to give a compound of formula (5) in which R 3 is -(CH 2 ) m -Z-Q in which Z is amide. Such amide formation reactions using carboxy activation or suitable coupling agents are well known in the art and described above. Suitable carboxylic acids, QC(O)-OH, are ones give rise to Q as desired in the final product of formula (1), such as benzoic acid, substituted benzoic acids, phenyl acetic acids, substituted phenylacetic acids, mono-t-butyl malonate, and the like. For example, in a urea formation a compound of formula (4a) in which R 3 is is -(CH2) m -NHR8 is contacted with an appropriate isocyanate, O=C=N-Q, to give a compound of formula (5) in which R 3 is -(CTLVrZ-Q in which Z is urea. An appropriate isocyanate is one which gives rise to Q as desired in the final product, such as phenyl isocyanate, substituted phenyl isocyanate. napthyl isocyanate, ethyl isocyanatoacetate, and the like. The reaction is carried out by adding an equivalent of, or a slight molar excess of, an appropriate isocyanate is added to a solution of a compound of formula (4a) in which R 3 - is -(CH ) m - NHR 8 in a suitable solvent, such as diethyl ether, benzene, or toluene. The reaction is carried out at temperature of from about 0°C to the refluxing temperature of the solvent and require about 1-24 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystalhzation. For example, in an N-carbamoyl formation a compound of formula (4a) in which R 3 - is -(CH 2 ) m -NHR 8 is contacted with an appropriate chloroformate to give a compound of formula (5) in which R 3 is -(CH ) m -Z-Q in which Z is N-carbamoyl. An appropriate chloroformate is one which gives rise to Q as desired in the final product of formula (1). Examples of chloro formates include benzyl chloroformate, naphthyl chloroformate, phenyl chloroformate, and substituted phenyl chloro formates, such as 4-chlorophenyl chloroformate, 4-methylphenyl chloroformate, 4-bromophenyl chloroformate, 4-fluorophenyl chloroformate, 4-methoxyphenyl chloroformate and the like. The reaction is carried out by adding an equivalent of, or a slight molar excess of, an appropriate chloro formate to a solution of a compound of formula (4a) in which R 3 is -(CH 2 ) m -NHR 8 in a suitable solvent, such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform. The reaction is carried out in the presence of an excess of a suitable base, such as triethylamine, sodium carbonate, potassium bicarbonate, pyridine or N,N-diisopropylethylamine. The reaction is carried out at a temperature of from -70°C to the refluxing temperature of the solvent and generally requires from 30 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystalhzation. For example, in an O-carbamoyl formation a compound of formula (4a) in which R 3 '- is -(CH 2 )m- ! -CH 2 OH is contacted with an appropriate isocyanate, as defined above for urea formation, to give a compound of formula (5) in which R 3 is -(CH 2 ) m -Z-Q in which Z is O- carbamoyl. The reaction is carried out in a suitable solvent, such as diethyl ether, tetrahydrofuran, dimethylformamide, or acetonitrile. The reaction may be facilitated by the use of catalytic amount of a suitable base, such as sodium hydride, potassium hydride, or potassium t-butoxide. The reaction is generally carried out at temperatures of from -20°C to room temperature and require from about 1-24 hours. The product can be isolated by techniques well known in the art. such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystalhzation. For example, in a sulfonamide formation to prepare a compound in which R 3 is -(CH ) m -SO 2 NR 8 -Y], a compound of formula (4a) in which R 3 - is -(CH2) m -NHR 8 is contacted with an appropriate sulfonamide forming reagent. An appropriate sulfonamide forming reagent, such as a sulfonyl chloride, YιS(O) 2 Cl, or sulfonyl anhydride, Yι(O) 2 S-O-S(O) 2 Yi, is one which gives rise to Yi as desired in the final product. Examples of appropriate sulfonamide forming reagents are, benzenesulfonyl chloride, 1-napthalenesulfonyl chloride, 2- napthalenesulfonyl chloride, dansyl chloride, N-morpholinylsulfonyl chloride, N- piperidinylsulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, 2,5- dichlorobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2- mesitylenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-t- butylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3,4-trichlorobenzenesulfonyl chloride, 2.5-dimethoxybenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 3,4- dimethoxybenzenesulfonyl chloride, 2,6-dichlorobenzenesulfonyl chloride, 3- bromobenzenesulfonyl chloride, 4-n-butylbenzenesulfonyl chloride, benzenesulfonic anhydride, 4-toluenesulfonic anhydride, and 2-mesitylenesulfonic anhydride. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dichloromethane, pyridine, or chloroform and in the presence of an excess of a suitable base, such as triethylamine, sodium carbonate, pyridine, or N,N-diisopropylethylamine. The reaction is carried out at a temperature of from -50°C to the refluxing temperature of the solvent. The reaction generally requires from 30 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystalhzation. In Reaction Scheme C, step 3, a compound of formula (5) in which R 3 is as desired in the final product of formula (1) undergoes a selective thiol deprotection to give a compound of formula (5). Such selective thiol deprotections using suitable protecting groups are well known and appreciated in the art as discussed in Reaction Scheme B. step 1, above. In Reaction Scheme C, step 4, a compound of formula (5) undergoes a modification reaction to give a compound of formula (1) or protected compound of formula (1) as described in Reaction Scheme B, step 2, above. In Reaction Scheme C, step 5, a compound of formula (4) in which Y is protected thio is deprotected to give a compound of formula (1) or to a protected compound of formula (1 ). In Reaction Scheme C, in an optional step, a protected compound of formula (1) is deprotected to give a compound of formula (1). Such deprotection reactions are well known appreciated in the art and may include selective deprotections. Alternate routes for preparing the compounds of formula (3b) in which Y is bromo are presented in Reaction Schemes F.l and F.2. Reaction Scheme F.1 ( 8 ) ((3) in which Y { is bromo and X is -OH) In Reaction Scheme F.l, an appropriate α-amino carboxylic acid of formula (8) is deaminobrominated to give a compound of formula (3b) in which Y is bromo and X is -OH. An appropriate α-amino carboxylic acid of formula (8), and protected forms thereof, is one which is one in which R 3 - is R 3 as desired in the final product of formula (1) or gives rise after deprotection to R 3 as desired in the final product of formula (1) In addition, α-amino carboxylic acid of formula (8) may also be one in which the stereochemistry at the R 3 bearing carbon gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1). Such appropriate α-amino carboxylic acid of formula (8), are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, L-alanine, D-alanine, L- valine, D-valine, D-norvaline, L-leucine, D-leucine, D-isoleucine, D-tert-leucine, glycine, L- glutamic acid, D-glutamic acid, L-glutamine, D-glutamine, L-lysine. D-lysine, L-ornithine, D- ornithine, (D)-(-)-2-aminobutyric acid, D-threonine, D-homoserine, D-allothreonine, D-serine, D-2-aminoadipic acid, D-aspartic acid, D-glutamic acid, D-lysine hydrate, 2,3- diaminopropionic acid monohydrobromide, D-ornithine hydrochloπde, D,L-2,4- diaminobutyric acid dihydrochloride, L-meta-tyrosine, D-4-hydroxyphenylglycine, D- tyrosine, L-phenylalanine, D-phenylalanine, D,L-2-fluorophenylalanine, beta-methyl-D,L- phenylalanine hydrochloride, D,L-3-fluorophenylalanine, 4-bromo-D, L-phenylalanine, L- phenylalanine, L-phenylglycine, D-phenylglycine, D,L-4-fluorophenylalanine, 4-iodo-D- phenylalanine, D-homophenylalanine, D,L-2-fluorophenylglycine, D,L-4- chlorophenylalanine, and the like, are all commercially available and the methods in D. A. Evans, et al. J. Am. Chem. Soc, 1 12, 401 1-4030 (1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W. Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989); Synthesis of Optically Active α-Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis, Tetrahedron Symposia in print, No. 33. Tetrahedron 44. No. 17 (1988); U. Schollkopf. PureAppl. Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem., 44. 3748-3752 (1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al. J. Am. Chem. Soc, 1 10, 8520- 8525 (1988). The deaminobromination described in Reaction Scheme F.l can be performed utilizing conditions described in Compagnone, R.S. and Rapoport, H., J. Org. Chem., 51, 1713-1719 (1986); U.S. Pat. No. 5,322,942, issued June 21, 1994; Overberger, C.G. and Cho, I., J. Org. Chem., 33, 3321-3322 (1968); or Pfister, K. et al., J. Am. Chem. Soc, 71, 1096-1 100 (1949). For example, an α-amino carboxylic acid of formula (8) and a suitable bromide, such as hydrogen bromide or potassium bromide in acidic solution, such as sulfuric acid, is treated with sodium nitrite. The reaction temperature is carried out at temperatures of from about - 25°C to about ambient temperature and require about 1 to 5 hours. The product can be isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, chromatography, and recrystalhzation to give the compound of formula (3b) in which Y is bromo and X is -OH. The product can be isolated and purified by techniques well known and appreciated in the art, such as acidification, basification, filtration, extraction, evaporation, trituration, chromatography, and recrystalhzation. Reaction Scheme F.2 (9) Br ((3) in which Y { is bromo and X is -OH) In Reaction Scheme F.2, an appropriate carboxylic acid of formula (9) is brominated to give compound of formula (3b) in which Y is bromo and X is -OH. An appropriate carboxylic acid of formula (9), and protected forms thereof, is one which is one in which R 3 is R 3 as desired in the final product of formula (1) or gives rise after deprotection to R 3 as desired in the final product of formula (1). For example, a mixture of a carboxylic acid of formula (9) and dry red phosphorous are treated dropwise with bromine at temperature ranging from about -20° to about 10°C. The reaction mixture is then warmed to room temperature and then heated to about 80°C for about 2-5 hours. The reaction mixture is then cooled to room temperature, poured into water containing sodium bisulfite, and neutralized using solid sodium carbonate. The aqueous layer is extracted and acidified with a suitable acid, such as concentrated hydrochloric acid. The precipitate is collected by filtration and dried to give the compound of formula (3b) or formula (3b2)in which Y is bromo and X is -OH. The product can be isolated and purified by techniques well known and appreciated in the art, such as acidification, basification, filtration, extraction, evaporation, trituration, chromatography, and recrystalhzation. Compounds of formula (8) and (9) in which R 3 - is a -(CH 2 ) m -W for use in Reaction Schemes F.l and F.2 are prepared according to Reaction Scheme G.l and G.2. Reaction Scheme G.1 o iψ (αyr N - (CH.) OH OH ^ o (11) (9) in which R 3 . is W-(CH 2 ) m - In Reaction Scheme G.l an appropriate ω-amino carboxylic acid of formula (11) is converted to an compound of formula (9) in which R 3 - is W-(CH 2 ) m -- An appropriate ω- amino carboxylic acid of formula (11) is one in which m is as desired in the final product of formula (1) and are readily available in the art. For example, the reaction is carried out in a suitable polar solvent, such as water, ethanol, diethyl ether, tetrahydrofuran, or a water/ethanol solvent mixture using a suitable base, such as sodium carbonate and N- carbethoxyphthalimide. The reaction mixture is typically stirred at about ambient temperature for 1-5 hours. The product can be isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, chromatography, and recrystalhzation to give the desired compound of formula (9) in which R 3 > is W-(CH 2 ) m -. Reaction Scheme G.2 (8) in which R-,. is W-(CH 2 ) m - Reaction Scheme G.2, step 1, an appropriate α,ω-di amino acid of formula (12) undergoes a selective N-α-protection to give an N-α-protected-ω-diamino acid of formula (13). An appropriate α,ω-diamino acid of formula (12) is one in which m is as desired in the final product of formula (1). For example, a selective N-α-protection of a suitable α,cD-diamino acid, such as L- lysine (formula 12 in which m is 4), is accomplished by masking the ω-amino group by formation of a benzylidene imine. The benzylidene imine is formed by dissolving L-lysine monohydrochloride in lithium hydroxide and cooling the solution to a temperature ranging from about 0° to 10°C Freshly distilled benzaldehyde is then added and the solution is shaken. N-ω-benzylidene-L-lysine is recovered by filtration and evaporation. The α-amino group of the N-ω-benzylidene-L-lvsine then undergoes protection, such as the introduction of a Cbz or t-Boc group, followed by hydrolytic cleavage of the imine in situ to give N-α- benzyloxy-carbonyl-L-lysine. Accordingly, N-c -benzylidene-L-lysine is added to a mixture of sodium hydroxide and ethanol, cooled to a temperature of from about -5°C to about -25°C Then, precooled solutions of benzyloxycarbonyl chloride in a solvent, such as ethanol, is added to the reaction mixture. The temperature is maintained in a range of from about -10°C to about -25°C during the course of addition, and may allowed to rise afterwards. The reaction mixture is then acidified using a suitable acid, such as precooled hydrochloric acid, and N-α-benzyloxycarbonyl-L-lysine, which corresponds to formula (13) where m is 4, is recovered by filtration evaporate and recrystalhzation. In Reaction Scheme G.2, step 2, N-α-benzyloxycarbonyl-L-lysine or other compounds of formula (13) is converted to ω-phthalimido-α-benzyloxycarbonyl-L-lysine or other ω- phthalimido-α-aminoprotected carboxylic acid of formula (14) by the method described in Reaction Scheme G.l, above. In Reaction Scheme G.2, step 3, the ω-phthalimido-α-aminoprotected carboxylic acid of formula (14) is deprotected to give compound of formula (8) in which R 3 is W-(CH 2 ) m -. For example, ω-phthalimido-α-benzyloxycarbonyl-L-lysine is contacted with hydrogen in the presence of a hydrogenation catalyst, such as 10% palladium/carbon. The reactants are typically contacted in a suitable solvent mixture such as ethanol, methanol, water, ethanol/water mixtures, or methanol/water mixtures. The reactants are typically shaken under a hydrogen atmosphere of 35-45 psi at room temperature for a period of time ranging from 5-24 hours. The product is typically recovered by filtration and evaporation of the solvent. A route for preparing the compounds of formula (3b) and formula (3b2) in which Yi is protected thio is presented in Reaction Scheme H. The reagents and starting materials are readily available to one of ordinary skill in the art. In Reaction Scheme H all substituents, unless otherwise indicated, are as previously defined. Reaction Scheme H Br - Y 0 — Pg 5 step 1 O— Pg 5 (15) (17) In Reaction Scheme H, step 1, a bromoacetate of formula (15) is contacted with an appropriate thiol to give a protected acetic acid ester of formula (17). In a bromoacetate of formula (15) Pg 5 is a protecting group, such as methyl, ethyl, t-butyl, and benzyl. An appropriate thiol is one which gives rise to a protected thio group, Y, in the product of formula (3b). In Reaction Scheme H, step 1, the use of 4-methoxybenzylmercaptan is preferred. For example, a bromoacetate of formula (15) is contacted with an appropriate thiol in a suitable organic solvent, such as dimethylformamide. Advantageously, the solvent is degassed. The reaction is carried out using a suitable base, such as sodium hydroxide, triethylamine, or N,N-diisopropylethylamine. The reaction is carried out at temperatures of from about -50°C to about ambient temperature and requires about 1 to 72 hours. The protected acetic acid ester of formula (17) can be isolated and purified by methods well known and appreciated in the art, such as extraction, evaporation, chromatography, and distillation, and recrystalhzation. In Reaction Scheme H, step 2, the protected acetic acid ester of formula ( 17) is alkylated with an appropriate akylating agent to give a compound of formula (18). In Reaction Scheme H, step 2, an appropriate alkylating agent is one which transfers Ry which is R 3 as desired in the final product of formula (1 ) or gives rise after deprotection to R 3 as desired in the final product of formula (1) or gives rise to R 3 as defined in Reaction Scheme C, step 1. Appropriate alkylating agents include alkylhalides, such as methyl iodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride, butyl bromide, butyl chloride, and the like; benzyl bromide, benzyl chloride, substituted benzyl bromide, substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoaceate, ethyl 3-chloropropionate, ethyl 3- bromopropionate, ethyl 5-bromovalerate, ethyl 4-bromobutyrate, 3-chloropropionamide, 2- bromoethylbenzene, substituted 2-bromoethylbenzene, l -chloro-3-phenylpropane, l-bromo-4- phenylbutane, and the like, N-(2-bromoethyl)phthalimide, , N-(3-bromopropyl)phthalimide, N-(4-bromobutyl)phthalimide, and the like; 1 -bromo-2-phenylethane, l-bromo-3- phenylpropane, 1 -bromo-4-phenylbutane, and the like. For example, a protected acetic acid ester of formula (17) is alkylated with an appropriate alkylating agent. The reaction is carried out in a suitable solvent, such as diethyl ether, tetrahydrofuran, dimethylformamide, and toluene using a suitable base, such as sodium hydride, potassium hydride, potassium t-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or lithium diisopropylamide. The reaction is generally carried out at temperatures of about -70°C to about room temperature and require from about 1-24 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystalhzation. In Reaction Scheme H, step 3, the compound of formula (18) the carboxy protecting group Pg 5 is selectively removed to give a compound of formula (3b) in which Y is protected thio. Such deprotection of esters to acids in the presence of suitable thio protecting groups are well known and appreciated in the art. Reaction Scheme I describes the preparation of a specific diastereomer of the compounds of formula (2a). (25a) (2a as a specific diastereomer) In Reaction Scheme I, step 1 , an appropriate aldehyde of formula (20) is converted to a compound of formula (21 ) in which Pg is a protecting group. Such conversions can be accoplished by Aldol-type condensation reactions or Wittig-type olefination reactions, each of which are well known in the art. An appropriate aldehyde of formula (20) is one in which e and R 2 are as desired in the final product of formula (1). Appropriate aldehydes of formula (20) include, benzaldehyde, substituted benzaldehydes, 1-naphthaldehyde, substitued 1- naphthaldehydes, 2-naphthaldehyde, substitued 2-naphthaldehydes, phenylacetaldehyde, substituted phenylacetaldehydes, hydrocinnamaldehyde, and substituted hydrocinnamaldehyde. Suitable Aldol-type condensations include the Claisen-Schmidt and Knoevenaglel reactions. Modern Synthetic Reactions, H.O. House (2 nd Ed. The Benjamin/Cummings Publishing Co. 1972). As is appreciated by one of skill in the art the Claisen-Schmidt reaction using malonic acid, or esters thereof, give compounds of formula (22) upon decarboxylation or hydrolysis and decarboxylation. Sutiable Wittig-type reacations include the Wittig and Wadswoth-Edmonds reactions. For example, an appropriate aldehyde of formula (20) is reacted with an appropriate reagent, such as (carbethoxymethylene)triphenylphosphorane or dimethyl trimethylsilyloxycarbonylmethyl phosphonate. The reaction is carried out in solvent, such as ethanol, benzene, toluene, or tetrahydrofuran. Typically the reaction is carried out at temperature of from about -20° to reflux and require about 4 to 48 hours. The product can be isolated and purified by techniques well known and appreciated in the art, such as quenching, acidification, filtration, extraction, evaporation, trituration, chromatography, and recrystalhzation. Alternately, for example, an appropriate aldehyde of formula (20) is reacted with an appropriate reagent, such as dimethyl trimethylsilyloxycarbonylmethyl phosphonate. The reaction is carried out in solvent, such as benzene, toluene, diethyl ether, or tetrahydrofuran. The reaction is carried out using a suitable base, such as potassium t-butoxide, sodium hydride, lithium diisopropylamide, or sodium or potassium bis(trimethylsilyl)amide. Typically the reaction is carried out at temperature of from about -70° to ambient temperature and require about 1 to 48 hours. The product can be isolated and purified by techniques well known and appreciated in the art, such as quenching, acidification, filtration, extraction, evaporation, trituration, chromatography, and recrystalhzation. In Reaction Scheme I, step 2, a compound of formula (21) is hydrolysed to give a compound of formula (22). Such hydrolysis of esters under acidic or basic conditions is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991). For example, a compound of formula (21) is reacted with a suitable hydrolyzing agent, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or sodium carbonate to give an acid. The hydrolysis reaction is carried out in a suitable solvent, such as water, ethanol, methanol, or water/methanol mixtures, water/ethanol mixtures, water/tetrahydrofuran mixtures. The reactions are carried out at temperatures of from 0°C to the refluxing temperature of the solvent and generally require from 30 minutes to 48 hours. The acid produced in the hydrolysis reaction can be isolated using techniques well known in the art, such as acidification, extraction, and evaporation. The acid may be used after isolation without further purification or may be purified by chromatography, tritruration, and recrystalhzation as is known in the art. As is appreciated by the skilled person, some of the compounds of formual (22) are readily available and may be available in activated form, such trans-cinnamic acid, substituted trans-cinnamic acids, cinnamoyl chloride, and substituted cinnamoyl chlorides. In Reaction Scheme I, step 3, a compound of formula (22) is activated and reacted with a lithiated 4-substituted-oxazolidin-5-one to give a compound of formula (23). Suitable 4-substituted-oxazolidin-5-ones include 4-phenyl-2-oxazolidinone, (R)-4-phenyl-2- oxazolidinone, (S)-4-phenyl-2-oxazolidinone, 3,3-dimethyl-4-phenyl-2-oxazolidinone, (R)- 3,3-dimethyl-4-phenyl-2-oxazolidinone, and (S)-3,3-dimethyl-4-phenyl-2-oxazolidinone. The use of (R)-4-phenyl-2-oxazolidinone is depicted in Reaction Scheme I. For example, the compound of formula (22) in a suitable organic solvent, such as tetrahydrofuran diethyl ether, is treated with a suitable tertiary organic amine such as triethylamine or N-methylmorpholine and cooled to -78°C. A suitable acid halide such as trimethylacetyl chloride is added and the mixture is transferred to an ice bath for 0.5 to 1.0 hours, then recooled to -78°C The resulting slurry is treated with lithiated (R)-4-phenyl-5- oxazolidinone, prepared by adding n-butyllithium to (S)-4-phenyl-2-oxazolidinone in tetrahydrofuran, and allowed to warm gradually to ambient temperature over a period of time ranging from about 10 to 20 hours. The product can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography. In Scheme I, step 4, a compound of formula (23) undergoes a 1,4-addition of a vinyl group to give a compound of formula (23a). For example, a compound of formula (23) and trimethylsilyl chloride in a suitable solvent, such as tetrahydrofuran is added to a prepared solution of copper (I) iodide and N,N.N', N'-tetramethylethylenediamine and vinylmagnesium bromide in tetrhydrofuran. The reaction is carried out at temperatures of form about -78°C to about 0°C and requires form about 1 to 12 hours. The product can be isolated and purified by techniques well known and appreciated in the art, such as quenching, acidification, filtration, extraction, evaporation, trituration, chromatography, and recrystalhzation. In Scheme I, step 5, a compound of formula (23a) undergoes an azide introduction reaction with a suitable azide transfer agent to give a compound of formula (23b). Such azide introductions are described in the art in J. Am. Chem. Soc, 112, 401 1-4030 (1990). For example, a solution of a suitable amide such as potassium bis(trimethylsilyl)amide in a suitable organic solvent, such as tetrahydrofuran, is cooled to -78°C and treated with a solution of a compound of formula (32a) in tetrahydrofuran, precooled to -78°C. A solution of a suitable azide transfer agent, such as trisyl azide, prepared by the method described in J. Org. Chem., 38, 1 1-16 (1973), in a suitable organic solvent, such as tetrahydrofuran, precooled to -78°C is then added. The solution is stirred, quenched with acetic acid. After a period of time ranging from about 12 to 48 hours, the product is isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known in the art, such as flash chromatography. In Reaction Scheme I, step 6, a compound of formla (23b) is hydrolyzed and esterified to give a compound of formula (24). For example, a compound of formula (23b) is reacted with a suitable hydrolyzing agent, such as lithium hydroxide and hydrogen peroxide. The hydrolysis reaction is carried out in a suitable solvent, such as water/tetrahydrofuran mixtures. The reactions are carried out at temperatures of from 0°C to the refluxing temperature of the solvent and generally require from 30 minutes to 48 hours. The acid produced in the hydrolysis reaction can be isolated using techniques well known in the art, such as quenching of peroxides, acidification, extraction, and evaporation. The acid may be used after isolation without further purification or may be purified by chromatography, tritruration, and recrystalhzation as is known in the art. The acid is then esteπfied to give a compound of formula (24). For example, to give the methyl ester depicted in Reaction Scheme I, the acid is contacted with a ester forming reagent, such as (trimethylsilyl)diazomethane. This reaction is carried out in a suitable solvent, such as methanol or methanol/tetrahydrofuran mixtures. The reactions are carried out at temperatures of from 0°C to the refluxing temperature of the solvent and generally require from 12 to 48 hours. The product can be isolated and purified techniques well known in the art, such as acidification, extraction, evaporation, chromatography, tritruration, and recrystalhzation. Alternately, for example, to give the methyl ester depicted in Reaction Scheme I, the acid is contacted with methanol under acidic conditions. The reactions are carried out at temperatures of from 0°C to the refluxing temperature of methanol and generally require from 1 to 48 hours. The product can be isolated and purified techniques well known in the art, such as acidification, extraction, evaporation, chromatography, tritruration, and recrystalhzation. In Reaction Scheme I, step 7, a compound of formula (24) is reduced and cyclized to give a compound of formula (25). For example, a compound of formula (24) is contacted with a suitable recucing agent, such as dicyclohexylborane. The reaction is carried out in a suitable solvent, such tetrahydrofuran. The reactions are carried out at temperatures of from -20°C to ambient temperature and generally require from 1 to 48 hours. The product can be isolated and purified techniques well known in the art, such as quenching, extraction, evaporation, chromatography, tπtruration, and recrystalhzation. In Reaction Scheme I, step 8, a compound of formula (25) is protected to give a compound of formula (2a). The use of amine protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis. Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991). The following examples present typical syntheses as described in the Reaction Schemes above. These examples and preparations are understood to be illustrative only and are not intended to limit the scope of the invention in any way. PREPARATION 1 Synthesis of 2-bromo-6-phthalimidohexanoic acid Combine 6-aminohexanoic acid (6-aminocaproic acid) (8.0 g, 60 mmol) and water (100 mL). Add sodium carbonate (6.84 g, 64 mmol) and N-carbethoxyphthalimide (14.0 g, 64 mmol). After 1.5 hours, extract the reaction mixture with ethyl acetate (100 mL). Cool the aqueous layer in an ice bath and acidify using concentrated hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give 6-phthalimidohexanoic acid (12.7 g, 80% yield). Combine 6-phthalimidohexanoic acid (12.7 g, 48 mmol) and dry red phosphorous (1.95 g, 63 mmol). Cool in an ice bath and add dropwise bromine (12.7 mL, 246 mmol). Warm to room temperature and then heat to 80°C. After 3 hours, cool the reaction mixture to ambient temperature, pour into water (300 mL) containing sodium bisulfite, and neutralize using solid sodium bicarbonate and extract with diethyl ether (about 150 mL). Acidify the aqueous layer with concentrated hydrochloric acid give a solid. Collect the solid by filtration and dry to give the title compound (15 g, 91.5% yield, 73.2% for both steps). PREPARATION 2 Synthesis of (R)-2-bromo-6-phthalimidohexanoic acid Combine (R)-2-N-carbobenzyloxy-6-aminohexanoic acid ((R)-Nα-Cbz-lysine) (14.0 g, 50 mmol) and water (500 mL). Add sodium carbonate (5.65 g, 53 mmol) and N- carbethoxyphthalimide (13.15 g, 60 mmol). After 1.5 hours, acidify using concentrated hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give (R)-2-N-carbobenzyloxy-6-phthalamidohexanoic acid. Combine (R)-2-N-carbobenzyloxy-6-phthalamidohexanoic acid obtained above, methanol (200 mL), 10% palladium-on-carbon (I e and treat with hvdroeen at atmosnheric pressure. After 18 hours, filter, add to the filtrate a solution of hydrochloric acid in methanol (50 mL, 1 M, 50 mmol), and evaporate in vacuo to give (R)-2-amino-6-phthalamidohexanoic acid hydrochloric acid salt. Combine (R)-2-amino-6-phthalamidohexanoic acid hydrochloric acid salt (12.5 g, 40 mmol) and a 2.5 M aqueous sulfuric acid solution (40 mL). Cool in a salt-ice bath. Add 49% aqueous hydrobromic acid solution (13.2 g). Add dropwise over about 20 minutes, an aqueous solution of sodium nitrite (2.8g, 40 mmol, in 20 mL of water). After 3 hours, warm to ambient temperature. After 18 hours, collect the resultant solid by filtration, rinse with water and dry in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/dichloromethane containing 5% acetic acid to give the title compound. PREPARATION 3 Synthesis of 1 -Fmoc-trans-3-((R)-(naphth-2-yl)-2(S)-carboxypyrrolidine Combine 2-naphthaldehyde (7.8 g, 50 mmol) and (carbethoxymethylene)triphenylphosphorane (18.3 g, 52.5 mmol) in 50 mL ethanol (50 mL). After 18 hours, the reaction mixture was diluted with diethyl ether (500 mL) and washed with aqueous 1 M phosphoric acid solution (2 x 100 mL), saturated sodium bicarbonate 100 mL), water (100 mL), and then brine (100 mL). Dry the organic layer over MgS04, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 9:1 hexane:ethyl acetate to give ethyl trans-3-(naphth-2-yl)-propenoate as an 85:15 mixture of geometric isomers (favoring trans by nmr). Recrystallize from hexane/ethyl acetate to give ethyl trans-3-(naphth-2-yl)-propenoate as a 97:3 mixture of isomers (favoring trans by nmr). Concentrate the mother liquor and recrystallize to recover an additional 2.9 g. (total yield 65%). NMR (CDC1 3 ) δ 7.93 (s, 1 H); 7.88-7.83 (c, 4 H); 7.67 (dd, 1 H, J = 1.6, 8.6 Hz); 7.53- 7.50 (c, 2 H); 6.55 (d, 1 H, J = 16.0 Hz); 4.30 (q, 2 H, J = 7.1 Hz); 1.42 (t, 3 H, J = 7.1 Hz). Combine ethyl trans-3-(naphth-2-yl)-propenoate (4.24 g, 18.8 mmol) and tetrahydrofuran (75 mL). Add litium hydroxide hydrate (2.36 g, 56.3 mmol) in water (19 mL). After 18 hours, acidified to a pHof about 2 with aqueous 12 M hydrochloric acid solution to give a precipitate. Extract with ethyl acetate (3 x 150 mL). Dry the combined extracts over Mg so 4. filter, and concentrated in vacuo to give trans-3-(naphth-2-yl)-propenoic acid as a white solid (3.66 g, 98% yield). NMR (CDC1 3 ) δ 7.97 (d, 1 H, J = 15.7 Hz); 7.90 (d, 1 H, J = 15.3 Hz); 7.90-7.83 (c, 3 H); 7.70 (dd, 1 H, J = 1.6, 8.6 Hz); 7.57-7.50 (c, 2 H); 6.58 (d, 1 H, J = 16.0 Hz). Combine trans-3-(naphth-2-yl)-propenoic acid (3.66 g, 18.5 mmol) and triethylamine (1.87 g, 2.56 mL, 18.5 mmol) in tetrahydrofuran (74 mL). Cool to -78°C Add pivaloyl chloride (2.35 g, 2.40 mL, 19.4 mmol). After 10 minutes, warm in an ice-bath. After 10 minutes, cool to -78°C Prepare l-lithio-4-phenyl-2-oxazolidinone in a separate flask by the addition of n-butyl lithium (1.6 M in hexane, 1 1.6 mL, 18.5 mmol) to 4-phenyl-2- oxazolidinone (3.31 g, 20.3 mmol) in anhydrous tetrahydrofuran (74 mL) at -78°C After 1.5 hours, add the mixed anhydride prepared abpve via cannula and place the reaction mixture in an ice-bath. After 1 hour, warm to ambient temperature. After 18 hours, quench with a saturated aqueous ammonium chloride soluiton (50 mL) and evaprorate to remove most of the tetetrahydrofuran. Extract with dichloromethane (3 x 75 mL), combine the organic layers, extract an aqueous 1 M sodium hydroxide solution (2 x 50 mL), dried dry over Mg so 4 , filter, and concentrate in vacuo to give a residue. Recrystallize the residue from ethyl acetate/hexane to give trans-3-(naphth-2-yl)-propenoic acid * as a white solid (61 %). NMR (CDC1 3 ) δ 8.05 (d, 1 H, J = 15.7 Hz); 7.94 (d, 1 H, J = 15.4 Hz); 7.87-7.81 (c, 3 H); 7.76 (dd, 1 H, J = 1.5, 8.6 Hz); 7.53-7.47 (c, 2 H); 7.41-7.34 (c, 5 H); 5.58 (dd, 1 H, J = 8.7, 3.9 Hz); 4.76 (t, 1 H, J = 8.7 Hz); 4.33 (dd, 1 H, J = 8.8, 3.9 Hz). (3'R4S)-3-(3'-(2''-NaphthylV4'-pentenoyl)-4-phenyl-2-oxazolidinone (4) To a solution of Cul (3.96 g, 20.9 mmol) and N.N.N " , N'-tetramethylethylenediamine (2.66 g, 3.46 mL, 22.9 mmol) in anhydrous tetrahydrofuran (92 mL) at -78°C was added vinylmagnesium bromide (1.0 M in tetrahydrofuran, 20.9 mL, 20.9 mmol). The mixture was stirred for 15 minutes. In a separate flask trimethylsilyl chloride (5.69 g, 6.64 mL, 52.2 mmol) was added to a solution of unsaturated imide 3 (3.87 g, 11.3 mmol) in anhydrous tetrahydrofuran (42 mL). Owing to insolubility of the imide, the septum of the flask containing the cuprate reagent was removed and the slurried imide added in one portion rinsing quickly with a small amount of tetrahydrofuran. The bath temperature was raised to - 30°C and stirring continued for 1 h. The reaction mixture was poured into 250 mL of a 3:2 mixture of saturated Ammonium chlroide: concentrated NH4OH. The layers were separated and the aqueous layer extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed sequentially with saturated Ammonium chlroide (1 x 100 mL) and water (1 x 100 mL). The organic layer was dried dry over Mg so 4. and concentrated under reduced pressure. The residue was purified by passage through a plug of SiO2 eluting with 4:1 hexane:ethyl acetate. The eluant was concentrated in vacuo to recover a white solid (3.64 g, 9.81 mmol, 87% yield). NMR (CDC1 3 ) δ 7.87-7.82 (c, 3 H); 7.72 (s, 1 H); 7.54-7.27 (c, 8 H); 6.1 1 (ddd, 1 H, J = 6.7, 10.4, 17.0 Hz); 5.34 (dd, 1 H, J = 8.6, 3.5 Hz); 5.10 (d, 1 H, J = 8.2 Hz); 5.08 (d, 1 H, J = 17.2 Hz); 4.56 (t, 1 H, J = 8.8 Hz); 4.26 (dd, 1 H, J = 8.8, 3.5 Hz); 4.16 (ddd, 1 H, J - 8.1, 7.0, 6.9 Hz); 3.68 (dd, 1 H, J = 8.4, 16.5 Hz); 3.50 (dd, 1 H, J = 6.5, 16.5 Hz). (2 , S3 , R4S)-3-(2 , -Azido-3 , -(2"-naphthyl)-4'-pentenoyl)-4-phenyl-2-oxazolidinone (5) Potassium hexamethyldisilazide (0.5 M in toluene, 25.5 mL, 12.8 mmol) was added in one portion to anhydrous tetrahydrofuran (34 mL) at -78°C. Imide 4 (3.64 g, 9.81 mmol) was slurried in tetrahydrofuran (34 mL) and added via cannula, rinsing with tetrahydrofuran (2 x 11 mL) to complete the transfer. After 30 min, trisylazide (4.40 g, 14.2 mmol) was dissolved in tetrahydrofuran (34 mL), cooled to -78°C, and added via cannula. Thirty minutes later, AcOH (1.41 g, 1.34 mL, 23.4 mmol) was added to quench the reaction. The mixture was stirred at room temperature overnight. The mixture was partitioned between dichloromethane (300 mL) and dilute brine (150 mL). The layers were separated and the aqueous phase extracted with dichloromethane (3 x 150 mL). The combined organic layers were dried dry over M g so4. and concentrated under reduced pressure. The residue was purified by flash chromatography to recover the product (3.41 g, 8.28 mmol, 84 % yield). Proton nmr indicated that a byproduct derived from trisyl azide was also present. NMR (CDC1 3 ) δ 7.85-7.82 (c, 3 H); 7.72 (s, 1 H); 7.53-7.47 (c, 2 H); 7.42 (dd, 1 H, J = 1.7, 8.5 Hz); 7.37-7.31 (c, 3 H); 7.18- 7.15 (c, 2 H); 6.28 (ddd, 1 H, J = 8.2, 10.2, 17.1 Hz); 5.63 (d, 1 H, J = 10.2 Hz); 5.37 (d, 1 H, J = 17.0 Hz); 5.34 (d, 1 H, J = 10.2 Hz); 4.83 (dd, 1 H, J = 3.0, 8.3 Hz); 4.14 (t, 1 H, J = 7.2 Hz); 4.07 (dd, 1 H, J = 9.3, 17.9 Hz); 3.94 (dd, 1 H, J = 3.0, 5.8 Hz); 3.68 (t, 1 H, J = 8.6 Hz). Notes: Trisylazide is not commercially available. Sulfonyl azides can be prepared according to J. Org. Chem. 1973, 38, 11-16. The azide transfer can be difficult. See J. Am. Chem. Soc. 1990, 1 12, 401 1-4030 for a full discussion. After the addition of the trisylazide, an intermediate that is more polar than starting material is rapidly formed. After addition of AcOH, the polar intermediate slowly disappears and the product azidoimide spot begins to form. It is only slightly less polar than the starting imide. A decomposition product of trisylazide nearly coelutes with the product. Timing of this reaction is critical as the yield erodes with increasing time between addition of the trisyl azide and the acetic acid. Methyl (2S3R)-2-Azido-3-(naphth-2-yl)-4-pentenoate (6) To a solution of imide 5 (3.41 g, 8.28 mmol) in tetrahydrofuran (62 mL) was added water (21 mL), 35% H2O2 (2.7 mL), and LiOH-H2O (695 mg, 16.6 mmol). After 2 hours sodium sulfite (4.17 g, 33.1 mmol) was added as a solution in water (41 mL). The mixture was stirred for 15 minutes and tetrahydrofuran removed under reduced pressure. The aqueous solution was acidified with hydrochloric acid and extracted with ethyl acetate (2 x 150 mL). The combined extracts were dried dry over MgS04. and concentrated under reduced pressure. The residue was passed through a SiO2 plug column eluting with 1 : 1 hexane:ethyl acetate to recover, after concentration, a white solid that was presumably a mixture of the carboxylic acid and chiral auxiliary. Recrystalhzation from hexane/ethyl acetate yielded the chiral auxiliary as needles. The mother liquor was concentrated and carried on to the esterification step. The residue containing the crude carboxylic acid was dissolved in anhydrous MeOH (46 mL) and cooled to 0°C. Thionyl chloride (1.18 g, 0.725 mL, 9.94 mmol) was added and, after 10 minutes, the mixture heated at reflux for 2 hours. Water (1.0 mL) was added to the mixture, stirred for 10 minutes, and the contents of the flask concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 mL) and brine (100 mL). The layers were separated and the organic layer was dried dry over M g so 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (19:1 hexane:ethyl acetate) to recover the methyl ester (1.54 g, 5.48 mmol, 66% yield). NMR (CDC1 3 ) δ 7.84- 7.80 (c, 3 H); 7.71 (s, 1 H); 7.50-7.46 (c, 2 H); 7.39 (dd, 1 H, J = 1.8, 8.5 Hz); 6.23 (ddd, 1 H, J = 8.3, 10.9, 17.6 Hz); 5.30 (d, 1 H, J = 9.9 Hz); 5.28 (d, 1 H, J = 17.7 Hz); 4.22 (d, 1 H, J = 7.5 Hz); 4.06 (t, 1 H, J = 7.9 Hz). Notes: The intermediate carboxylic acid and chiral auxiliary tend to coelute by flash chromatography and the indicated recrystalhzation only removed a layer of the auxiliary. The auxiliary was thus present for the esterification step without complication. However under these conditions it has been observed that the auxiliary can ring open and subsequently decarboxylate leaving a primary amine which can attack the ester. If the esterification is run with the auxiliary present, the reaction should be monitored carefully. Trans-3-(naphth-2-yl)-L-proline methyl ester (7) Borane-methyl sulfide complex (2.0 M in tetrahydrofuran, 6.57 mL, 13.1 mmol) was diluted with anhydrous tetrahydrofuran (26 mL) and cooled to 0°C Cyclohexene (2.16 g, 2.66 mL, 26.3 mmol) was added cautiously via syringe. After 30 minutes a white precipitate had formed. Stirring was continued for three hours. The contents of the flask were concentrated in vacuo. Note: Care should be taken to minimize air exposure as dicyclohexyl borane is extremely moisture sensitive. The reagent was slurried in dichloromethane (36 mL) and cooled to 0°C. Vinyl azide 6 (1.23 g, 4.38 mmol) was dissolved in dichloromethane (9 mL) and added via cannula. The reaction mixture became pale yellow and gas evolution was evident. The mixture was warmed to room temperature overnight. Added MeOH (26 mL) and stirred for an additional 15 minutes. The mixture was concentrated under reduced pressure. The residue was taken up in diethyl ether (25 mL) and extracted with 0.1 M hydrochloric acid (5 x 25 mL). The aqueous extracts were basicified with saturated sodium bicarbonate and extracted with dichloromethane (3 x 100 mL). The organic extracts were dried dry over g so 4. and concentrated in vacuo to recover the cyclized product along with some dicyclohexyl borane derived contaminants (974 mg, 3.82 mmol, 87% yield of crude material). NMR (CDC1 3 ) I 7.84-7.78 (c, 3 H); 7.71 (s, 1 H); 7.49-7.41 (c, 3 H); 3.91 (d, 1 H, J = 6.9 Hz); 3.69 (s, 3 H); 3.63 (m, 1 H), 3.48 (dd, 1 H, J = 8.2, 15.4 Hz); 3.27 (d, 1 H, J = 7.8 Hz); 3.25 (d, 1 H, J = 7.8 Hz); 2.33 (m, 1 H), 2.09 (m, 1 H). Note: The cyclization can be capricious. The best results were obtained when fresh bottles of borane were employed. A suggestion is to make the dicylcohexylborane reagent in dry diethyl ether using neat borane-methyl sulfide complex (approximately 10 M). N-Fmoc-trans-3-(naphth-2-yl)-L-proline (8) A solution of amino ester 7 (4.31 mmol) in 5 M hydrochloric acid (20 mL) was heated at 100°C overnight. The reaction mixture was concentrated in vacuo to recover the amino acid. To a solution of the crude amino acid in acetone (22 mL) was added 20% aqueous Na2CO3 until the pH of the mixture was 9 - 10 (pH paper). Fmoc-O-succinimide (1.60 g, 4.74 mmol) was added, the pH readjusted, and the reaction mixture stirred overnight. The mixture was carefully acidified with concentrated hydrochloric acid to about pH = 2 and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried dry over Mg so 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (97:3 dichloromethane:MeOH). By tic some impurities remained. These could be removed by boiling the residue in a small amount of dichloromethane, filtering, and washing the tan solid with hexane to deliver clean product (930 mg, 2.00 mmol, 46% yield) as judged by tic, HPLC, and nmr. NMR (d 6 -DMSO) δ 7.95-7.80 (c, 6 H); 7.68 (d, 1 H, J = 7.3 Hz); 7.60 (d, 1 H, J = 7.4 Hz); 7.50-7.34 (c, 6 H); 7.25 (m, 1 H). 4.39-4.15 (c, 4 H); 3.70-3.48 (c, 3 H); 2.29 (m, 1 H); 2.14 (m, 1 H). Note: The final target can also be recrystallized from hexane/ethyl acetate. The present invention provides a method of inhibiting matrix metalloproteinase (MMP) to a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of formula (1). As used herein, the term "patient " refers to warm-blooded animals or mammals, including guinea pigs, dogs, cats, rats, mice, hamsters, rabbits and primates, including humans. A patient is in need of treatment to inhibit MMP when it would be beneficial to the patient to reduce the physiological effect of active MMP. For example, a patient is in need of treatment to inhibit MMP when a patient is suffering from a disease state characterized by excessive tissue disruption or tissue degradation, such as, but not limited to, a neoplastic disease state or cancer; rheumatoid arthritis; osteoarthritis; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases, such as gingivitis or periodontal disease; and neurological disorders, such as multiple sclerosis; chronic inflammatory disorders, such as emphysema and especially smoking-induced emphysema. The identification of those patients who are in need of treatment to inhibit MMP is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination and medical/family history, those patients who are suffering from disease states characterized by excessive tissue disruption or tissue degradation. An "effective matrix metalloproteinase inhibiting amount" of a compound of formula (1) is an amount which is effective, upon single or multiple dose administration to the patient, in providing relief of symptoms associated with MMP and is thus effective in inhibiting MMP-induced tissue disruption and/or MMP-induced tissue degradation. As used herein, "relief of symptoms" of MMP-mediated conditions refers to decrease in severity over that expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the disease. Relief of symptoms is also intended to include prophylaxis. An effective matrix metalloproteinase inhibiting dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of the patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication. An effective matrix metalloproteinase inhibiting amount of a compound of formula (1) will generally vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 300 milligrams per kilogram of body weight per day (mg/kg/day). A daily dose of from about 1 mg/kg to about 100 mg/kg is preferred. A neoplastic disease state refers to an abnormal state or condition characterized by rapidly proliferating cell growth or neoplasm. Neoplastic disease states for which treatment with a compound of formula (1) will be particularly useful include: Leukemias, such as, but not limited to, acute lymphoblastic, chronic lymphocytic, acute myeloblastic and chronic myelocytic; Carcinomas and adenocarcinomas, such as, but not limited to, those of the cervix, oesophagus, stomach, small intestines, colon, lungs (both small and large cell), breast and prostate; Sarcomas, such as, but not limited to, oesteroma, osteosarcoma, lipoma, hposarcoma, hemangioma and hemangiosarcoma; Melanomas, including amelanotic and melanotic; and mixed types of neoplasias such as, but not limited to carcinosarcoma, lymphoid tissue type, follicullar reticulum. cell sarcoma and Hodgkin's Disease. Neoplastic disease states for which treatment with a compound of formula ( 1 ) will be particularly preferred include carcinomas and adenocarcinomas, particularly of the breast, prostate and lung. Atherosclerosis is a disease state characterized by the development and growth of atherosclerotic lesions or plaque. The identification of those patients who are in need of treatment for atherosclerosis is well within the ability and knowledge of one of ordinary skill in the art. For example, individuals who are either suffering from clinically significant atherosclerosis or who are at risk of developing clinically significant atherosclerosis are patients in need of treatment for atherosclerosis. A clinician of ordinary skill in the art can readily determine, by the use of clinical tests, physical examination and medical/family history, if an individual is a patient in need of treatment for atherosclerosis. The term "chronic inflammatory disease" refers to diseases or conditions characterized by persistent inflammation in the absence of an identifiable irritant or microbial pathogen. Inflammatory diseases for which treatment with a compound of formula (1) will be particularly useful include: emphysema, chronic bronchitis, asthma, and chronic inflammation, and especially smoking-induced emphysema. In effecting treatment of a patient, a compound of formula (1) can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, topically, intranasally, rectally, inhalation, and the like. Oral and inhalation administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the disease state to be treated, the stage of the disease, and other relevant circumstances. Remington ' s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990). A compound of formula (1) can be administered in the form of pharmaceutical compositions or medicaments which are made by combining a compound of formula (1) with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration, and standard pharmaceutical practice. The pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, gels, ointments, aerosol or the like. The pharmaceutical compositions may be administered orally, for example, with an inert diluent or with an edible caπier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, a compound of formula (1 ) may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of a compound of formula (1), the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70%) of the weight of the unit. The amount of the active ingredient present in compositions is such that a unit dosage form suitable for administration will be obtained. The tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1 % of a compound of the invention, but may be varied to be between 0.1 % and about 50% of the weight thereof. The amount of the active ingredient present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations are able to be determined by one skilled in the art. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for iniection, saline solution, fixed oils, oolvethvlene glvcols. glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic The compounds of the present invention may also be administered by inhalation, such as by aerosol or dry powder. Delivery may be by a liquefied or compressed gas or a suitable pump system which dispenses the compounds of the present invention or a formulation thereof. Formulations for administration by inhalation of compounds of formula (1 ) may be delivered in single phase, bi-phasic, or tri-phasic systems. A variety of systems are available for the administration by aerosol of the compounds of formula ( 1 ). Dry powder formulations are prepared by either pelletizing or milling the compound of formula (1) to a suitable particle size or by admixing the pelletized or milled compound of formula (1 ) with a suitable carrier material, such as lactose and the like. Delivery by inhalation includes the necessary container, activators, valves, subcontainers, and the like. Preferred aerosol and dry powder formulations for administration by inhalation can be determined by one skilled in the art. The MMP inhibitors of the present invention can be evaluated by the procedures that follow. EXAMPLE A Source and Activation of proMMP-12 ProMMP-1 (EC 3.4.24.7; interstitial collagenase) was purified from culture medium of human rheumatoid synovial fibroblasts stimulated with macrophage-conditioned medium according to Okada, Y. et al., J. Biol. Chem. 261, 14245-14255 (1986). The active MMP-1 was obtained by treatment of proMMP-1 with trypsin (5 μg/mL) at 37°C for 30 minutes, followed by addition of soybean trypsin inhibitor (50 μg/mL). Determination of Inhibition Constant (K,) for MMP-1 The activated MMP-1 is assayed using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu- Dpa-Ala-Arg-NH 2 , Knight, C.G. et al., FEBS Lett. 296, 263-266 (1992), at 37°C in 2.0 mL of assay buffer containing 50 itiM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02%) Brij-35. The increase in fluorescence due to cleavage of Gly-Leu peptide bond by MMP-3 was monitored with Perkin-Elmer LS50B Fluorimeter (λ e 328 nm, λ em 393 run, excitation slit 2.5, emission slit 10). Substrate and inhibitor stock solutions were made in DMF. For determination of K, values for MMP-1 inhibitors, a series of intermediate inhibitor solutions were prepared in DMF and 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2 mM substrate solution in DMF in a quartz cuvette containing 2 mL of assay buffer. The enzyme (10 μL of 0.2 μM MMP-3 dilution in assay buffer) was added at the last to start the reaction. For routine measurement of a K, value for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations (two concentrations above K, and two concentrations below K,) were measured using [S] = 1 μM (« Km) and [MMP-1] = 0.8 nM. Under these conditions, the measured K, ) app is close to true K,. Calculation of K, Values The K, for a competitive inhibitor is calculated using: v 0 /v, = (1 + [I]/K, > a pp) and K, = K, ) apP /(l + [S]/K m ), where v 0 is the initial rate in the absence of inhibitor, v, is the initial rate in the presence of inhibitor at the concentration of [I], [S] is the substrate concentration, and K m is the Michaelis constant. If slow binding is observed (i.e. if the approach to the binding equilibrium is slow), the final steady-state rate rather than the initial rate is taken as v,. EXAMPLE B Source and Activation of proMMP-2 Recombinant MMP-2 was purified from the fermentation broth of yeast Pichia pastoris that carries the integrated MMP-2 gene into its chromosome. In brief, the full-length cDNA for MMP-2 was obtained by reverse transcription of RNA from human melanoma A375M cell line by the reverse transcriptase polymerase chain reaction (RT-PCR) using sequence specific oligonucleotides. The nucleotide sequence was confirmed by Taq cycle sequencing. The cDNA was ligated into the Pichia pastoris expression vector pHIL-D2 in such a way that the expression of pro-MMP-2 is under the control of the methanol inducible alcohol oxidase promoter. The expression construct was digested with either Sail or Nsil and used to transform the Pichia pastoris strains KM71 and SMD1 168. A large-scale culture of a selected clone designated 24S was performed in a high cell density fermentor and the recombinant MMP-2 was purified from the culture supernatant by gelatin-sepharose 4B (Pharmacia). The enzyme is sufficiently pure at this stage for routine measurement of inhibition. If desired, however, the enzyme may be further purified by Ac A 44 gel filtration (Spectra). Determination of Inhibition Constant (K,) for MMP-2 The active MMP-2 was obtained by activation of proMMP-2 at 37°C for 1 h with 4- aminophenylmercuric acetate which was then removed by a Sephadex G-50 spin column. The enzyme is assayed using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2 , at 37°C in 2.0 mL of assay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, 0.02% Brij-35, and 50 μM β-mercaptoethanol. The increase in fluorescence is monitored (λ ex 328 nm, λ em 393 nm). Substrate and inhibitor stock solutions are made in DMF. The enzyme is added at the last to start the reaction. For routine measurement of a K, value for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations (two inhibitor concentrations above K, and two below K,) are measured using [S] = 1 μM («K m ) and [MMP-2] = 0.4 nM. Under these conditions, the measured K lι app is close to true K,. EXAMPLE C Source and Activation of proMMP-3 ProMMP-3 (EC 3.4.24.17; Stromelysin- 1 ) was purified from culture medium of human rheumatoid synovial fibroblasts stimulated with macrophage-conditioned medium according to Okada, Y. et al., J. Biol. Chem. 261, 14245-14255 (1986). The active MMP-3 was obtained by treatment of proMMP-3 with trypsin (5 μg/mL) at 37°C for 30 minutes, followed by addition of soybean trypsin inhibitor (50 μg/mL). Aliquots of the activated MMP-3 were stored at -20°C. Determination of Inhibition Constant (K,) for MMP-3 The activated MMP-3 is assayed using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu- Dpa-Ala-Arg-NH 2 , Knight, C.G. et al, FEBS Lett. 296, 263-266 (1992), at 37°C in an assay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02%) Brij-35. The increase in fluorescence due to cleavage of Gly-Leu peptide bond by MMP-3 was monitored with Perkin-Elmer LS50B Fluorimeter (λ e 328 nm, λ eπ . 393 nm, excitation slit 2.5, emission slit 10). Substrate and inhibitor stock solutions were made in DMF and 0.1%) HCl-DMF, respectively. For determination of K, values for MMP-3 inhibitors, a series of intermediate inhibitor solutions were prepared in 0.1% HCl-DMF and 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2 mM substrate solution in DMF in a quartz cuvette containing 2 mL of assay buffer. The enzyme (10 μL of 0.2 μM MMP-3 dilution in assay buffer) was added at the last to start the reaction. For routine measurement of a K, value for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations (two concentrations above K, and two concentrations below K,) were measured using [S] = 1 μM (« K m ) and [MMP-3] = 1 nM. Under these conditions, the measured K,, ap is close to true K,. Calculation of K, Values The K, for a competitive inhibitor is calculated using: V 0 /v, = (1 + [I]/K,, app ) and K, = ,, apP /(l + [S]/K m ), where v 0 is the initial rate in the absence of inhibitor, v, is the initial rate in the presence of inhibitor at the concentration of [I], [S] is the substrate concentration, and K m is the Michaelis constant. If slow binding is observed (i.e. if the approach to the binding equilibrium is slow), the final steady-state rate rather than the initial rate is taken as v,. EXAMPLE D Source of MMP- 12 (macrophage metalloelastase) MMP- 12 (EC 3.4.24.65) was cloned, expressed and purified according to Shapiro, S.D. et al., J Biol. Chem. 268, 23824-23829 (1993). Autoactivation resulted in the fully processed active form of the enzyme. Aliquots of MMP- 12 were stored at -70C. Determination of the inhibition constant (K,) for MMP- 12. The potency of inhibitors of MMP- 12 was measured using either quartz cuvettes or microtiter plates. The activity of MMP- 12 was measured using a fluorogenic substrate, Mca- Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2 , Knight, C.G. et al., FEBS Lett. 296, 263-266 (1992), at 25°C in an assay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02%o Brij-35. The increase in fluorescence due to cleavage of Gly- Leu peptide bond by MMP-12 was monitored with a Perkin-Elmer LS50B Fluorimeter (lex 328 nm, lem 393 nm, excitation slit 2.5, emission slit 10) for the cuvette assay and with a Molecular Devices Fmax fluorescence plate reader (λ e 320 nm, λ em 405 nm) for the microtiter plate assay. Substrate and inhibitor stock solutions were made in N,N- dimethylformamide (DMF) and 0.1% HCl-DMF, respectively. K, values were determined using the cuvette method by preparing a series of intermediate inhibitors solutions in 0.1% HCl-DMF and mixing the inhibitor with substrate (final concentration 2 mM) in a quartz cuvette containing 2 ml of assay buffer. MMP- 12 was added to start the reaction at a concentration of 2 nM and progress curves were generated. For routine measurement of a K, value for a reversible competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations ( two concentrations above and two concentrations below the K,) were measured [S] = 2 mM («K m ) and [MMP- 12] = 2 nM. Under these conditions, the measured K,, app is close to the true K,. K, values were determined using the microtiter plate method in a manner similar to that described for the cuvette method with some modifications. Four different inhibitor concentrations (50 ml in assay buffer)of each compound were added to separate wells of a microtiter plate and substrate was added (100 ml) to get a final concentration of 4 mM. MMP-1 2 was added to a final concentration of 2 nM (50 ml) to start the reaction. Cleavage of substrate was recorded every 30 seconds for 30 minutes and progress curves were generated. Calculation of K^values The K, for a competitive inhibitor is calculated using: V 0 /v, = (1 + [I]/K . , apP ) and K, = K,, a p P /(l + [S]/K m ), where v 0 is the initial rate in the absence of inhibitor, v, is the initial rate in the presence of inhibitor at the concentration of [I], [S] is the substrate concentration, and K m is the Michaelis constant. If slow binding is observed (i.e. if the approach to the binding equilibrium is slow), the final steady-state rate rather than the initial rate is taken as v,.

Claims: WHAT IS CLAIMED IS: 1. A compound of the formula wherein e is an interger from 0 to 2; A is selected from the group consisting of -OH and -NRR'; wherein R and R' are independently selected from the group consisting of hydrogen and Cι-C 6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ri is selected from the group consisting of hydrogen, Cι-C 6 alkyl, -(CH 2 ) a -CO 2 R 5 , -(CH 2 ) a -C(O)NH 2 , -(CH 2 ) 4 NH 2 , -(CH 2 ) 3 -NH-C(NH)NH 2 , -(CH 2 ) 2 -S(O) b -CH 3 , -CH 2 -OH, -CH(OH)CH 3 , -CH 2 -SH, -(CH 2 ) d -Ar,, and -CH 2 -Ar 2 ; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4; R 5 is selected from the group consisting of hydrogen, Cι_C 4 alkyl, and benzyl; Ari is a radical selected from the group consisting of wherein R 6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C 4 alkyl, hydroxy, and Cι-C alkoxy; R is selected from the group consisting of hydrogen, halogen, Cι_C 4 alkyl, and Cι-C 4 alkoxy; Ar 2 is a radical selected from the group consisting of R 2 is a radical selected from the group consisting of wherein wherein R 2 - is from 1 to 2 substituents selected from the group consisting of hydrogen, halogen, C)-C 4 alkyl, and Cι-C 4 alkoxy; R 3 is selected from the group consisting of Cι-C 6 alkyl, -(CH 2 ) m -W, -(CH 2 ) P -Ar 3 , -(CH 2 ) k -CO 2 R 9 , -(CH 2 ) m -NR 8 -SO 2 -Y,, and -(CH 2 ) m -Z-Q wherein m is an integer from 2 to 8; p is an integer from 0-10; k is an integer from 1 to 9; W is phthahmido; Aτ 3 is selected from the group consisting of wherein R 23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C]-C 4 alkyl, and C| -C 4 alkoxy; R 8 - is hydrogen or C|-C 6 alkyl; Ro is hydrogen or Ci-C 6 alkyl; Yi is selected from the group consisting of hydrogen, -(CH 2 ) j -Ar 4 , and -N(R 2 ) 2 wherein j is 0 or 1 ; R each time selected is independently hydrogen or Cι-C 6 alkyl or are taken together with the nitrogen to which they are attached to form N-morpholino, N- piperidino, N-pyrrolidino, or N-isoindolyl; Ar is wherein R 5 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C]-C 4 alkyl, and C-C 4 alkoxy; Z is selected from the group consisting of -O-, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NH-, -NR 8 C(O)O -, and -OC(O)NH-; wherein R 8 is hydrogen or Cι-C 6 alkyl; Q is selected from the group consisting of hydrogen, -(CH 2 ) n -Y 2 , and -(CH 2 ) X -Y 3 ; wherein n is an integer from 0 to 4; Y 2 is selected from the group consisting of hydrogen, -(CH 2 ) h -Ar 5 and -(CH 2 ) t -C(O)OR 27 wherein Ar 5 is selected from the group consisting of wherein R 26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C 4 alkyl, and Cι-C alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R 27 is hydrogen or Cι-C 6 alkyl; x is an integer from 2 to 4; Y 3 is selected from the group consisting of -N(R 28 ) 2 , N-morpholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein R 28 each time taken is independently selected from the group consisting of hydrogen and Cι-C 6 alkyl; R 4 is selected from the group consisting of hydrogen, -C(O)Rιo, -C(O)-(CH 2 ) q -K and -S-G wherein Rio is selected from the group consisting of hydrogen, Cι-C 4 alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from the group consisting of N— R, R n ' wherein V is selected from the group consisting of a bond, -CH 2 -, -O-, -S(O) , -NR21-, and -NC(O)R 22 -; wherein r is 0, 1, or 2; R 21 is selected from the group consisting of hydrogen, Cι_C 4 alkyl, and benzyl; R 22 is selected from the group consisting of hydrogen, -CF 3 , Ci-Cio alkyl, phenyl , and benzyl; Rπ is selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl; Ri r is selected from the group consisting of hydrogen, Cι_C 4 alkyl, and benzyl; G is selected from the group consisting of 0 2 R 16 wherein w is an integer from 1 to 3; Ri 2 is selected from the group consisting of hydrogen, Cι-C 6 alkyl, -CH 2 CH 2 S(O)fCH 3 , and benzyl; wherein f is 0,1, or 2; Rπ is selected from the group consisting of hydrogen, hydroxy, amino, Cι-C 6 alkyl, N-methyl amino, N,N-dimethylamino, -CO 2 Rι 7 , and -OC(O)Rι 8 ; wherein R, 7 is hydrogen, -CH 2 O-C(O)C(CH 3 ) 3 , C,.C 4 alkyl, benzyl, or diphenylmethyl; Rι 8 is hydrogen, Cι-C 6 alkyl or phenyl; Rι 4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι_C 4 alkyl, Cι_C 4 alkoxy, or halogen; Vi is selected from the group consisting of -O-, -S-, and -NH-; V 2 is selected from the group consisting of -N- and -CH-; V 3 is selected from the group consisting of a bond and -C(O)-; V is selected from the group consisting of -O-, -S-, -NRIQ-, and -NC(O)R 2 oS wherein R] 9 is hydrogen, C|.C 4 alkyl, or benzyl; R2 0 is hydrogen, -CF 3 , C1-C1 0 alkyl, or benzyl; R1 5 is selected from the group consisting of hydrogen, Cι-C 6 alkyl and benzyl; Ri 6 is selected from the group consisting of hydrogen and Cι_C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof. 2. A compound of claim 1 wherein R \ is a -(CH 2 )d-Arι group; 3. A compound of claim 2 wherein d is 1 or 2 and Ari is phenul or substituted phenyl; 4. A compound of claim 1 wherein R4 is -C(O)Rιo; 5. A compound of claim 4 wherein Rio is C].C 4 alkyl; 6. A compound of claim 1 wherein A is -OH; 7. A compound of claim 1 wherein A is -NRR'; 8. A compound of claim 7 wherein R is hydrogen and R'; 9. A compound of claim 1 wherein R 4 is -SG; 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 11. A method of inhibiting matrix metalloproteinase in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1. 12. A method of inhibing MMP-induced tissue disruption and/or MMp-induced tissue degradation in a patient in need thereof which comprises administering to the patient and effective matrix metalloproteinase inhibiting amount of a compound of claim 1. 13. A method of treating a neoplastic disease state in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compund of claim 1. 14. A method of treating a smoking-induced empphysema in a patient thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1.

Inventors: FLYNN GARY A, FLYNN, GARY, A.
Applicants: AVENTIS PHARMA INC, AVENTIS PHARMACEUTICALS INC.
Application year: 1999
Main classification: C07D207
IPC codes: A61P43, C07D207