PROTEASE INHIBITORS

Abstract: The present invention provides compounds of formula (I) and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, novel intermediates of such compounds, and methods of treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis, gingival disease including gingivitis and periodontitis; arthritis, more specifically osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia or malignancy and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.

Description: PROTEASE INHIBITORS FIELD OF THE INVENTION This invention relates in general to 8-14 membered ring 1 ,3-diaminoketone protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis. BACKGROUND OF THE INVENTION Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501 ,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) 7. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132. Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature. The designation cathepsin K is considered to be the more appropriate one. Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains. have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458. Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement. Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface. This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma. Several published studies have demonstrated that inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al, Biochem. J., 1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN2) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al, Biochem. Biophys. Res. Commun., 1984, 725, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium deficient diets. Lerner, et al, J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al. Bone, 1987, 8, 305, Hill, et al, J. Cell. Biochem.. 1994, 56, 1 18, and Everts, et al, J. Cell. PhysioL, 1992, 750, 221 , also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1 106, Inaoka, et al, Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al, FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells. The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, α-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, id, and references cited therein. U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, and EP 0 61 1 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L. International Patent Application No. PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-lβ convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479). Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al, Biochem. J., 1968, 707, 103, Garker et al, Biochem. J., 1974, 139, 555, Gray et al, Tetrahedron, 1977, 33, 837, Gupton et al, J. Biol. Chem., 1984, 259, 4279, Powers et al, J. Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases. In addition, J. Med. Chem., 1992, 35, 4279, discloses certain azapeptide esters as cysteine protease inhibitors. Antipain and leupeptin are described as reversible inhibitors of cysteine protease in McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and Grinde, Biochem. Biophys. Ada, , 707, 328). 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent Nos.4,749,792 and 4,638,010. Thus, a structurally diverse variety of cysteine protease inhibitors have been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance. A need therefore exists for methods of treating diseases caused by pathological levels of proteases, particularly cysteine proteases, more particularly cathepsins, most particularly cathepsin K, and for novel inhibitor compounds useful in such methods. We have now discovered a novel class of 8-14 membered ring 1 ,3-diaminoketone compounds which are protease inhibitors, most particularly of cathepsin K. SUMMARY OF THE INVENTION An object of the present invention is to provide 8-14 membered ring 1,3- diaminoketone protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to Formula I. In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula I. In still another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K. In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis. DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula I: I wherein: A is selected from the group consisting of: C(O) and CH(OH); R * is selected from the group consisting of: 0 R 2 is selected from the group consisting of: H, C j.galkyl, C3_6 ycloalkyl-Co_ galkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R ' 2 NC(0)-, R 9 R ] 2 NC(S)-, R ] 2 HNCH(R ] 2 )C(0)-, R 9 OC(0)NR ] 2 CH(R ] 2 )C(0)- ,adamantyl-C(0)-, or R° N . Z 7 ■ ■' R R B R" is selected from the group consisting of: H, Cj.^alkyl, Ar-C()-6 a lkyl, and Het- C 0 . 6 alkyl; R'" is selected from the group consisting of: H, Cj.galkyl, C3_ cycloalkyl-C )- galkyl, Ar-Co_6 a lkyl, and Het-Co-6 a lkyl; R 3 and R° are independently selected from the group consisting of: H, C2- 6alkenyl, C2-6alkynyl, Het, Ar or Cj-όalkyl optionally substituted by OR 13 , SR^ 3 , NR 13 2, R 13 NC(0)OR 5 , C0 R 13 , C0 2 NR 13 2 , N(C=NH)NH 2 , Het and Ar; R 4 is selected from the group consisting of: H, C]_5alkyl, C3_6cycloalkyl-C()- galkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 14 NC(0)-, R 5 R 14 NC(S)-, R 14 HNCH(R 14 )C(0)-, and R 5 OC(0)NR 14 CH(R 14 )C(0)-; R-\ R 9 , and R' υ are independently selected from the group consisting of: C j _ 6alkyl, C . cycloalkyl-Co-όalkyl, Ar-Co.ζalkyl and Het-Co. β alkyl; R^ is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6 a lkyl, an d Het- C 0 . 6 alkyl; R^ is selected from the group consisting of: H, C j .galkyl, C β .gcycloalkyl-Cø- 6 alkyl, Ar-C 0 _ 6 alkyl, Het-C 0 . 6 alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 15 NC(O )- 5 R10 R 15 NC(S; R15 HNCH(R 15) C( O)-, and R 10 OC(O)NR 15 CH(R 15 )C(O)-; or R° and R ' are connected to form a pyrrolidine, a piperidine, or a morpholine ring; each R' is independently selected from the group consisting of: H. C j .galkyl, Ar- Cθ-6 a 'kyl, and Uet-C Q .(,a\ky\; R 1 1 is Ar; R 12 ; R 13 t 14 anc j 1 are independently selected from the group consisting of:H, Cj.galkyl, Ar-Cθ-6 aι kyl, and Het-Co_6 a lkyl; R* is selected from the group consisting of: H, Ci .βalkyl, C3_6cycloalkyl-Co_ galkyl, Ar-Co-galkyl, and Het-Co_6alkyl; Z is selected from the group consisting of: C(O) and CH2; M is selected from the group consisting of: HC=CH; H2C-CH2; H(OR 2 )C- C(OR 2 )H; H(OR )C-CH 2 ; H(NR 2 H)C-C(NR 2 H)H; H(OR 2 )C-C(NR 2 H)H; and H(NR 2 H)C-CH 2 ; X is selected from the group consisting of: CH2, S and O n is 1-7; and pharmaceutically acceptable salts thereof. In compounds of Formula I, when R' is R 3 is selected from the group consisting of: H, C2-6 lkenyl, C2-6alkynyl, Het, Ar or Ci-6alkyl optionally substituted by OR 13 , SR 13 , NR 13 , R 13 NC(0)OR 5 , C0 2 R 13 , C0 2 NR 13 2 , N(C=NH)NH 2 , Het and Ar, preferably Cμ 6 alkyl, more preferably isobutyl; R 4 is selected from the group consisting of: H, C]_6alkyl, C3_5cycloalkyl-Co_ galkyl, Ar-C 0 _ 6 alkyl, Het-C 0 _6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 14 NC(0)-, R 5 R 14 NC(S)-, R 14 HNCH(R 14 )C(0)-, and R 5 OC(0)NR 14 CH(R 14 )C(0)-; preferably R 5 OC(0)- and R 5 C(0)-; R-> is selected from the group consisting of: C j .galkyl, C3_ cycloalkyl-C Q _ alkyl, Ar-Co-6 a lkyl and Het-Cg.galkyl; preferably Ar-Cg-galkyl and Het-C .galkyl; more preferably phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2-benzothiophenyl, and 2- quinolinyl; and R' is independently selected from the group consisting of:H, C j .galkyl, Ar-Cø- 6 a lkyl, and Het-Co_6 a lkyl; preferably H. In compounds of Formula I. when R 1 1 is R* RU is Ar, preferably 3-biphenyl; R* is selected from the group consisting of: H, C j.^alkyl, C3_6cycloalkyl-Co_ galkyl, Ar-C()-6 a lkyl, a nd Het-Co.βalkyl, preferably Cj.galkyl, most preferably isobutyl. In compounds of Formula I, R- is selected from the group consisting of: H, Cj. 6 alkyl, C 3 _6cycloalkyl-Co-6 a lkyl, Ar-C 0 _6 a lkyl, Het-C 0 _6alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R 12 NC(0)-, R 9 R 12 NC(S)-, R 12 HNCH(R 12 )C(0)-, R 9 OC(0)NR 12 CH(R 12 )C(0)-, and adamantyl-C(O)-, and R° N ,7 , R R D N . preferably R' υ Sθ2 and , wherein: R" is selected from the group consisting of: H, C j .^alkyl, Ar-Cθ-6 a lkyl, or Het- Co_6 a lkyl, preferably H; R7 is selected from the group consisting of: H, Cj.^alkyl, C3_ cycloalkyl-C(). 6 alkyl, Ar-C 0 . 6 alkyl, Het-C 0 -6 a lkyl, R 10 C(O)-, Rl°C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 15 NC( o)-, R 10 R 15 NC( s)-, R 1 HNCH(R 15 )C(0)-, and R ϊ °OC(0)NR 15 CH(R J 5 )C(0)- ; or R" and R^ are connected to form a pyrrolidine, a piperidine, or a mo holine ring; R° > is selected from the group consisting of: H, C2-6alkenyl, C2-6 a lkynyl, Het, Ar or Cι_6alkyl optionally substituted by OR 13 , SR 13 , NR 1 2 , R 13 NC(0)OR 5 , C0 2 R 13 , Cθ2NR 13 2 , N(C=NH)NH2, Het and Ar, preferably C^alkyl, more preferably isobutyl; R 9 and R^ are independently selected from the group consisting of: Cι _6alkyl, C3_6cycloalkyl-C υ -6alkyl, Ar-Co-galkyl or Het-Co_6 a lkyl; preferably Ar-Cø.galkyl and Het-Co-6 a lkyl; more preferably phenyl, benzyl, 2-naphthyl, pyridinyl, and Z is selected from the group consisting of: C(O) and CH2, preferably C(O). Compounds of Formula I wherein A is C(O) are preferred. Also preferred are compounds of Formula I wherein M is selected from the group consisting of: HC=CH and H C-CH2, R" and R'" are both H, or n is 1. More preferred are compounds of Formula I wherein: A is C(O); M is selected from the group consisting of: HC=CH and H2C-CH2; n is 1 ; and R" and R"' are both H; Yet more preferred are compounds of Formula I wherein: A is C(O); RI is selected from the group consisting of: R 3 and R 8 are C]-6alkyl; R 4 is selected from the group consisting of: R^OC(O)- and R^C(O)-; R~>, R 9 , and R^ υ are independently selected from the group consisting of: AΓ-CQ_ galkyl and Het-C()-6 a lkyl; R 6 is H; R 7 is R 10 OC(O); R' is H; R" is H; R"' is H; and Z is C(O); M is selected from the group consisting of: HC=CH and H2C-CH2; and n is 1. Especially preferred are such compounds wherein: R 3 and R 8 are independently isobutyl: or R-\ R 9 , and R ' ^ are independently selected from the group consisting of: phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2-benzo[b]thiophenyl, 2-quinolinyl, and pyridinyl. Compounds of Formula I selected from the following group are particularly preferred embodiments of the present invention: N-(N-(benzyloxycarbonyl)-L-leucinyl)-4-(R,S)-amino-l , 2,3,4,7, 8-hexahydro-3-oxo-[2-(N- (bezyloxycarbonyl)-L-lecinyl)]-azocine; N-(N-(benzyloxycarbonyl)-L-leucinyl)-4-(R,S)-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo-[2-(N- (bezyloxycarbonyl)-L-lecinyl)]-azocine; N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino-l, 2,3,4,7, 8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- l,2,3,4,5,6,7,8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino-l,2,3,4J,8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1,2, 3,4,5,6,7, 8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino-l,2,3,4,5,6,7,8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,5,6,7, 8-octahydro-3-oxo- (2-pyridinylsulfonyl)-azocine; and N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4- amino- 1, 2,3,4,7, 8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine. Specific representative compounds of the present invention are set forth in Examples 1-10. Definitions The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. The meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise. Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). "Proteases" are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis. Such proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. The compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors. The term "amino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. "Cι_6alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any C]_6alkyl group may be optionally substituted independently by one to five halogens, SR', OR', N(R')2, O)N(R')2, carbamyl or C]-4alkyl, where R' is C i-6alkyl. Cgalkyl means that no alkyl group is present in the moiety. Thus, Ar-Cøalkyl is equivalent to Ar. "C3_6cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane. cyclopentane and cyclohexane. "C2-6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6 a 'kenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included. "C2-6 a lkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. "Halogen" means F, Cl, Br, and I. "Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-6alkyl; Het-C()-6 a lkyl; Ci .βalkoxy; Ph-C()-6 a Ikoxy; Het-C()-6 a l koχ y; OH, (CH2)ι _ 6 N R 16 R 17 ; 0(CH 2 )ι_6NR 16 R 17 ; Ci-βalkyl, OR 18 , N(R 1 8 ) 2 , SR 18 , CF 3 , N0 2 , CN, C0 2 R 18 , CON(R 18 ), F, Cl, Br or I; where R 16 and R 17 are H, C^alkyl, Ph-C 0 -6 a lkyl, naphthyl-Co- ζ alkyl or Het-Co-6 a lkyl: and R^ 8 is phenyl, naphthyl, or Cj.^alkyl. As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 1 1- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from CQ. 6 AT, Cj-όalkyl, OR 1 8 , N(R 1 8 ) 2 , SR 1 8 , CF 3 , N0 2 , CN, C0 2 R 18 , CON(R 18 ), F, Cl, Br and I, where R 1 8 is phenyl, naphthyl, or Ci-6alkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl. quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazoly, as well as triazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are available by routine chemical synthesis and are stable. The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur. Here and throughout this application the term C υ denotes the absence of the substituent group immediately following; for instance, in the moiety ArCø. fj alkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCrj-galkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0. Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical. Certain reagents are abbreviated herein. CSA refers to camphorsulphonic acid, EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide, DMF refers to dimethyl formamide, DMSO refers to dimethyl sulfoxide, FMOC referes to 9- flourenylmethyloxycarbonyl, NMM refers to N-methylmorpholine, TEA refers to TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran Methods of Preparation Compounds of the general formula I are prepared in methods analogous to those in Schemes 1, 2 and 3. Boc-(D,L)-allyl glycine (1) was converted to the allyl amine 2 via formation of the diazomethyl ketone with iso-butyl chloroformate and diazomethane. The diazomethyl ketone was converted to the bromomethylketone by treatment with HBr. The bromomethylketone was reduced with sodium borohydride followed by treatment with allyl amine. Protection of the amine as an FMOC derivative, and further protection of the hydroxyl and carbamate nitrogen as an acetonide gave the precursor to ring-closing metathesis 3. Treatment with Grubb's catalyst gave the desired aza-cyclooctene skeleton 4. Deprotection of the FMOC protecting group with 20% piperidine, followed by acylation with Cbz-leucine and EDC provides the azocine 5. Deprotection of the Boc and acetonide protecting groups may be effected under acidic conditions such as TFA provides the amino alcohol 6. Compound 6 may be acylated with a carboxylic acid such as Cbz-L-leucine in the presence of a coupling agent common to the art such as EDCI to provide the alcohol 7. Alcohol 7 may be oxidised with an oxidising agent such as pyridine sulfur trioxide complex to provide the desired aza-cycloocteneone 8. Scheme 1 BocNH C0 2 H v N 1 O O O a: ClCO,iBu; NMM; CHN,; HBr, AcOH; b) NaBH 4 ; c) allyl amine; d) 2,2-dimethoxypropane, CSA; e: N-(9-fluorenylmethoxycarbonyloxy)succinimide, NaHCO,; f: bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride; g: 20% piperidine, DMF; h: Cbz- LeuOH, EDC; i: TFA, CH 2 C1 2 ; j: TFA, THF, H 2 0; k: Cbz-LeuOH, EDC; 1: DMSO, (COCl) 2 , TEA. In a similar fashion Boc-L-allyl glycine (9) may be converted to a diazomethyl ketone from the mixed anhydride and diazomethane, which may then converted to the bromide (not shown) with HBr. The ketone could be reduced with a reducing agent such as sodium borohydride to provide 10. Nucleophilic displacement of the bromide 10 with allyl amine provided the amino alcohol 11. Protection of the amine as an FMOC derivative, and further protection of the hydroxyl and carbamate nitrogen as an acetonide provides the precursor to ring-closing metathesis 12. Treatment of the diene 12 with Grubb's catalyst (cf. J Am Chem Soc, 1995, 117, 2108-2109) provides the desired aza-cyclooctene skeleton 13. Deprotection of the FMOC protecting group of 13 may be effected with 20% piperidine. The resulting amine (not shown) may be sulponylated with 2-pyridyl sulfonyl chloride to provide 14. Deprotection of the Boc and acetonide protecting groups may be effected with HC1 to provide the amino alcohol 15. Amino alcohol 15 may be acylated with an acid such as Boc-L-leucine in the presence of a coupling reagent such as EDCI to provide the alcohol 16. Deprotection of the Boc group of 16 with an acid such as HC1 followed by coupling of the resulting amine salt with an acid such as 2-benzofuran carboxylic acid in the presence of a coupling reagent such as EDCI and final oxidation with an oxidant such as Dess-Martin periodinane or pyridine sulfurtrioxide complex provide the aza-cycloocteneone 17. Scheme 2 BocNH C0 2 H 10 11 12 13 14 17 a: ClCO,iBu; NMM; CHN 2 ; HBr, AcOH; b) NaBH 4 ; c) allyl amine; d) 2,2-dimethoxypropane, CSA; e: N-(9-fluorenylmethoxycarbonyloxy)succinimide, NaHCO,; f: bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride; g: 20% piperidine, DMF; h: 2- pyridylsulfonylchloride, Hunig's base; i: 4M HCl, CH,C1,; j: 4M HCl, H,0, THF; k: Boc-LeuOH, EDC; 1: 4M HCl, CH,C1,; m: 2-benzofurancarboxylic acid, EDC; n: Dess-Martin periodinane. Reduction of the olefin of an intermediate such as 18 with hydrogen in the presence of a catalyst such as palladium provides the fully saturated azocine ring system which is oxidized with an oxidising reagent such as the Dess-Martin Reagent or pyridine sulfur trioxide complex to provide the aza-cyclooctaneone 19. l-Aza-3-hydroxy-4-amino-cyclooct-6-ene 15 (cf. Scheme 2) was acylated with 4-methyl-2-(3-biphenyl)-valeric acid (cf. J. Am. Chem. Soc. 1998, 120, 91 14-91 15) in the presence of a coupling reagent such as EDC, then was either hydrogenated with hydrogen/ Pd/ C in EtOH, and/or was directly oxidized to the desired products 20 and 21 with Dess- Martin periodinane. Scheme 3 18 19 15 20 21 22 a: 10% Pd/C, H 2 , EtOH; b: Dess-Martin periodinane; c: 4-methyl-2-(3-biphenyl)-valeric acid, EDC; Referring to the methods of preparing the compounds of Formula I set forth in Schemes 1-3 above, the skilled artisan will appreciate that the present invention includes all novel intermediates required to make the compounds of Formula I. Specifically, the present invention includes all compounds of Formula II. II wherein R is selected from the group consisting of: O N O H O O S N o More specifically, the present invention provides the following novel intermediates: 4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine N-(L-leucinyl)-4-amino- 1,2, 3,4,7, 8-hexahydro- 3-hydroxy-(2-pyridinylsulfonyl)-azocine 4-amino- 1,2, 3,4,7, 8-hexahydro-3-hydroxy-(N- (benzyloxycarbonyl)-L-luecinyl)] -azocine The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience). Coupling methods to form amide bonds herein are generally well known to the art. The methods of peptide synthesis generally set forth by Bodansky et al, THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1 , 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incorporated herein by reference. Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions. Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known. Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4 "1" are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts. This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophihzed powders for parenteral administration Powders ma\ be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use The liquid formulation may be a buffered, isotonic, aqueous solution Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation It may be desirable to add excipients such as polyvinylpyrrohdone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, man tol, sodium chloride or sodium citrate Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin Liquid earners include syrup, peanut oil, olive oil, saline and water The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms, or milling, mixing and filling for hard gelatin capsule forms When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension Such a liquid formulation may be administered directly p o or filled into a soft gelatin capsule For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository Utility of the Present Invention The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds. The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention. The present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention. The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof an inhibitor of cathepsin K, including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, , and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (1 e , allendronate), hormone replacement therapy, anti-estrogens, or calcitonin In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogemc protein, lproflavone, may be used to prevent bone loss or to increase bone mass For acute therapy, parenteral administration of a compound of Formula I is preferred An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful Typically, the parenteral dose will be about 0 01 to about 100 mg/kg, preferably between 0 1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0 4 to about 400 mg/kg/day The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0 1 to about 50 mg/kg in a manner consistent with the condition of the patient Preferably the oral dose would be about 0 5 to about 20 mg/kg No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention Biological Assays The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect Determination of cathepsin K proteolytic catalytic activity All assays for cathepsin K were carried out with human recombinant enzyme. Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product. Inhibition studies Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound. Reactions were initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progress curves were linear, apparent inhibition constants (Ki a pp) were calculated according to equation 1 (Brandt et al, Biochemitsiy , 1989, 28, 140): v = V m A /[K a (l + I/K ir app) +A] (1) where v is the velocity of the reaction with maximal velocity V m , A is the concentration of substrate with Michaelis constant of K a , and / is the concentration of inhibitor. For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give k 0 b s according to equation 2: [AMC] = v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] / k σ b s (2) where [AMC] is the concentration of product formed over time t, VQ is the initial reaction velocity and v ss is the final steady state rate. Values for k Q bs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k 0 bs / inhibitor concentration or k OD s / [I]) describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al, Adv. Enzymol. Relat. Areas Mol. Biol, 1988, 61, 201). Human Osteoclast Resorption Assay Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4°C). The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1 :3 in RPMI-1640 medium, and incubated for 30 min on ice The cell suspension was mixed frequently. The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber. Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium. The beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded. The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xlθ4/mL in EMEM medium, supplemented with 10% fetal calf serum and 1 Jg/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM 1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/ L). The tubes were incubate at 37°C for 30 min. 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water. The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope. General Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-d is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin- Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm " 1 ). Mass spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Where indicated, certain of the materials were purchased from the Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey, and Advanced Chemtech, Louisville, Kentucky. Examples In the following synthetic examples, temperature is in degrees Centigrade (°C). Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These Examples are given to illustrate the invention, not to limit its scope. Reference is made to the claims for what is reserved to the inventors hereunder. Examples 1 and 2 Preparation of N-(N-(benzyloxycarbonyl)-L-leucinyl)-4-(R,S)-amino- 1,2,3,4,7, 8- hexahydro-3-oxo-[2-(N-(bezyloxycarbonyl)-L-lecinyl)]-azocine a) 3-(R,S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl- lN-allyl-amine Isobutyl chloroformate (7.24 ml, 35.9 mmol) was added to a solution of N-Boc-D,L -allyl-glycine (9.5 g, 44.1 mmol) in N-methyl morpholine (5.82 ml, 52.9 mmol) in THF (200 mL) at -40° C. The reaction was stirred for 15 minutes whereupon it was filtered to remove the salts. The filtrate was added to a solution of diazomethane (179 mmol) in Et 2 0 (260 ml) (generated from l-methyl-3-nitro-l-nitrosoguanidine (26.3 g, 179 mmol), 40% KOH (80 ml) and Et 2 0 (260 ml)) and the reaction mixture was stored overnight in a refrigerator at 0° C. 30% HBr in AcOH (20 ml) was added dropwise at -40°C. The reaction mixture was stirred at this temperature until complete as consumption of the starting material was observed (TLC). The reaction mixture was then washed with water, aq. sat. NaHC0 3 , brine, dried (magnesium sulfate), filtered, concentrated in vacuo, and used in the next reaction without further purification. The product was then dissolved in MeOH (100 ml), then sodium borohydride was added portionwise. The reaction was stirred until the starting material was consumed as determined by TLC analysis. The reaction mixture was concentrated, diluted with ether, and extracted with water, IN HCl and brine The combined organics were dried with magnesium sulfate, filtered, concentrated m vacuo to give a white solid (5 3 g) This material material was dissolved in methanol (20 mL)and allyl amine (9.3 mL) and allowed to stir overnight at room temperature The following morning the reaction was concentrated m vacuo to give the title compound as an oil. MS ES. 271 3 (M+H). b) (3-R,S)-N-Boc-3-amιno-2-hydroxy-hex-5-enyl- lN-allyl-, lN-(9- Fluorenylmethoxycarbonyl)-amιne N-(9-Fluorenylmethoxycarbonyloxy)succιnιmιde (0.68 g, 2.03 mmol) was added to a solution of (3S)-N-Boc-3-amιno-2-hydroxy-hex-5-enyl-lN-allyl-amιne (0 5 g, 1.85 mmol) in acetone (10 ml)/ H 2 0 (5 ml), and the reaction mixture was stirred for 10 minutes. The reaction mixture was then concentrated and the residue was diluted with ethyl acetate washed with IN HCl, sat. NaHCθ3, brine and the organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0 99 g) c) l,l-dιmethylethyl-2,2-dιmethyl-4-(methyl-N-(9-fluorenylmethoxycarbonyl), N-allyl- amιno)-5-allyl-oxazolιne carboxylate (3S)-N-Boc-3-amιno-2-hydroxy-hex-5-eny 1- 1 N-allyl- 1 N-(9- Fluorenylmethoxycarbonyl)-amιne (0 91 g, 1.85 mmol) in CH2CI2 (20 mL) was added 2,2- dimethoxy-propane (2.2 ml) and camphor sulfomc acid (88 mg, 0 4 mmol). The reaction was stirred overnight at 55° C then reaction mixture was concentrated in vacuo, chromatographed (silica gel, 25% EtOAc/ hexanes) to give the title compound as a white foam (0.74 g): MS ES: 533.2 (M+H) d) 1,1-dιmethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dιmethyl-5-(9-fluorenylmethoxy- carbonyl)oxazolo[5,4-c]azocine- 1 (2/ )-carboxylate (3S)-N-Boc-3-amιno-2-hydroxy-hex-5-enyl- 1 N-allyl-, 1 N-(9-fluorenylmethoxy- carbonyl)-amιne-acetonide (0.66 g. 1.23 mmol) was dissolved in toluene (62 ml), then argon was bubbled through the solution for 5 minutes Grubb's catalyst (0.44 g, 0.53 mmol) was added and. the reaction mixtrue was stirred for 1.5 h at 80°C whereupon additional Grubb's catalyst (0.1 g) was added. The reaction was stirred at 80°C overnight whereupon it cooled to RT, concentrated in vacuo, and chromatographed (silica gel, 8: 1 hexanes:EtOAc) to give the title compound as a white foam (0.46 ): MS ES: 505.2 (M+rT). e) 1 , 1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-oxazolo[5,4-c]azocine- 1 (2H)- carboxylate 1 , 1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-(9-fluorenylmethoxy- carbonyl)oxazolo[5,4-c]azocine-l(2H)-carboxylate (0.45 g, 0.91 mmol) was dissolved in 20% piperidine/ DMF (5 ml) and was stirred at RT for 10 minutes. The reaction mixture was concentrated in vacuo. the residue was dissolved in EtOAc and washed with brine (3 x's), dried (MgS04), filtered and concentrated. The residue was chromatographed (silica gel, 19: 1 CΗ 2 Cl 2 :MeOΗ ) t0 g' ve the title compound (0.2 g): MS ES: 283.3 (M+HN f) 1 ,1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-[(N-(benzyloxycarbonyl)-L- luecinyl)]- [5,4-c]azocine-l(2//)-carboxylate To a solution of 1,1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5- oxazolo[5,4-c]azocine-l(2 )-carboxylate (0.2 g, 0.71 mmol) in CH 2 C1 2 (5 ml) was added Cbz-leucine (0.18 g, 0.71 mmol) and EDC (0.15 g, 0.8 mmol). The reaction was stirred at room temperature until complete by TLC aanalysis. The reaction was concentrated and the residue dissolved in EtOAc and washed with IN HCl, sat. NaHCθ3, brine, dried (MgSθ4), filtered and concentrated. The residue was chomatographed (2: 1 EtOAc :hexanes) to give the title compound (324 mg): MS ES: 530.4 (M+H). g) 4-amino- 1, 2,3,4,7, 8-hexahydro-3-hydroxy-(N-(benzyloxycarbonyl)-L-luecinyl)] - azocine l ,l-dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-[(N- (benzyloxycarbonyl)-L-luecinyl)]- [5,4-c]azocine-l(2H)-carboxylate (0.32 g, 0.6 mmol) was dissolved in CΗ2CI2 (5 mL) and TFA (3.0 mL) and the reaction was stirred at room temperature for 18 hours whereupon the reaction was concentrated and the residue was dissolved in EtOAc and washed with sat. K2CO3, brine, dried (K2CO3), filtered and concentrated. The residue was then dissolved in 1 :1 THF:H2θ (4 mL) and TFA was added (2 L). The reaction was stirred overnight whereupon it was concentrated then diluted with EtOAc and extracted with sat K2CO3, brine, dried (K2CO3), filtered and concentrated to give the title compound (250 mg) which was used in the next reaction without further purification: MS ES: 390.4 (M+H * ). h) N-(N-Cbz-L-leucinyl)-4-amino- 1 ,2,3,4,7,8-hexahydro-3-hydroxy-(N- (benzyloxycarbonyl)-L-luecinyl)] -azocine To a solution of 4-amino- 1,2, 3,4,7,8-hexahydro-3-hydroxy-(N- (benzyloxycarbonyl)-L-luecinyl)] -azocine (249 mg) in CH2Cl2( 5 mL) was added Cbz- leucine (187 mg) and EDC (131 mg). The reaction was stirred at room temperature for 50 minutes whereupon it was concentrated and the residue was dissolved in EtOAc and washed with IN HCl, sat. K2CO3, brine, dried (K2CO3), filtered and concentrated. Chromatography of the residue (1 : 1 hexanes:EtOAc) gave 107 mg of the faster eluting diastereomer and 1 15 mg of the slower eluting diastereomer: MS ES: 637.4 (M+H) i) N-(N-Cbz-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo-(N-(benzyloxycarbonyl)-L- luecinyl)] -azocine To a -78°C solution of oxalyl chloride (0.014 mL) was added DMSO (0.023 mL) and the reaction was stirred for 10 minutes whereupon a solution of N-(N-Cbz-L-leucinyl)- 4- amino- 1, 2,3,4,7, 8-hexahydro-3-hydroxy-(N-(benzyloxycarbonyl)-L-luecinyl)]-azocine (50 mg of the faster eluting diastereomer) in CH2CI2 (2x2 mL) was added. The reaction was stirred for 10 minutes whereupon TEA (0.076 mL) was added. The reaction was warmed to room temperature and the reaction was diluted with EtOAc, washed with sat. NaHCθ3, brine, dried (MgSθ4), filtered and concentrated. Column chromatography of the residue (2: 1 hexanes:EtOAc) gave the title compound (39 mg): MS ES 635.6 (M+H). Treatment of the slower eluting diastereomer from example 1 (I) in a similar fashion gave the second diastereomer: MS ES 635 (M+H). Example 3 Preparation of N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro- 3-oxo-(2-pyridinyIsulfonyl)-azocine a) (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl-bromide Isobutyl chloroformate (7.24 ml, 35.9 mmol) was added to a solution of N-Boc-L- allyl-glycine (10 g, 46.5 mmol) in N-methyl morpholine (6.13 ml, 55.9 mmol) in THF at - 40° C, then was stirred for 15 minutes. The reaction mixture was filtered, then a solution of diazomethane (179 mmol) in Et 2 0 (260 ml) generated from l-methyl-3-nitro-l- nitrosoguanidine (26.3 g, 179 mmol), 40% KOH (80 ml) and Et 2 0 (260 ml) was added and the reaction mixture was stored overnight in a refrigerator at 0°C. 30% HBr in AcOH (25 ml, 93 mmol) was added dropwise, then the reaction mixture was stirred an additional 7 minutes. The reaction mixture was then diluted with 15% aq. citric acid (100 ml), and the organics were repeatedly extracted (3x) with aq. sat. NaHC0 3 , then brine, then dried with magnesium sulfate, filtered, concentrated in vacuo, and used in the next reaction without further purification. The product was then dissolved in MeOH (150 ml), then sodium borohydride (3 g, 80 mmol) was added portionwise at 5° C, and the reaction was stirred an additional 15 minutes at RT. The reaction mixture was concentrated to two-thirds by rotary evaporation, then was diluted with EtOAc (100 ml), and was extracted with water, then brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo to give the title compound as a white solid (7.47 g, 63%): 1H NMR (CDC1,, 360 MHz): δ 5.85-5.70 (m, 1H), 5.14 (d, 1H), 5.12 (s, 1H), 4.60 (bs, 1H), 3.80 (bs, 1H), 3.78- 3.70 (m, 1H), 3.60-3.40 (m, 2H), 2.95 (bs, 1H), 2.45-2.25 (m, 2H), 1.42 (s, 9H). b) (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl-lN-allyl-amine Allyl amine (25 ml, 343 mmol) was added to a solution of (3S)-N-Boc-3-amino-2- hydroxy-hex-5-enyl-bromide (7.3 g, 25 mmol) in MeOH (50 ml) at RT and was stirred overnight. The reaction mixture was concentrated in vacuo, then was repeatedly (3x) concentrated from toluene (50 ml) to remove excess allyl amine to give the title compound as a yellow oil (6.6 g, 99%): MS ES: 271.2 M+H + . c) (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl-l N-allyl-, lN-(9- Fluorenylmethoxycarbonyl)-amine N-(9-Fluorenylmethoxycarbonyloxy)succinimide ( 12.7 g, 37.7 mmol) was added to a solution of (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl- lN-allyl-amine (6.6 g, 25 mmol) in acetone (40 ml)/ H,0 (40 ml), and the reaction mixture was stirred for 15 minutes. The reaction mixture was then concentrated and the residue was diluted with water (30 ml), and was repeatedly extracted (2x) with EtOAc (50 ml). The combined organics were then extracted with IN aq. HCl (20 ml), H 0 (20 ml), sat. aq. NaHCO, (20 ml), brine (20 ml), dried with magnesium sulfate, filtered, concentrated in vacuo to give the title compound as a white solid (8.2 g, 67%): MS ES: 493.2 M+H + . d) 1 , 1 -dimethylethyl-2,2-dimethy l-4-(methyl-N-(9-fluoreny lmethoxy-carbonyl), N-allyl- amino)-5-allyl-oxazoline carboxylate (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl- 1 N-allyl-, 1 N-(9- Fluorenylmethoxycarbonyl)-amine (8.1 g, 16.46 mmol) was dissolved in 2,2-Dimethoxy- propane (65 ml), then camphor sulfonic acid (88 mg, 0.4 mmol) was added ant the reaction was stirred overnight at 55° C. The reaction mixture was concentrated in vacuo, then was re-dissolved in dimethoxy-propane (65 ml), and additional camphor sulfonic acid (50 mg, 0.2 mmol) was added and the reaction was stirred at 55° C for 3 h. The reaction mixture was concentrated in vacuo, chromatographed (silica gel, 10% EtOAc/ hexanes) to give the title compound as a white foam (5.5 g, 71 %): Anal. calc. C 32 H 0 N,O 5 : Theoretical: C, 72.15; H, 7.57; N, 5.26; Found: C, 72.30; H, 7.67; N, 5.25; MS ES 533.3 (M+H + ) e) 1 , 1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethy l-5-(9-fluorenylmethoxy- carbonyl)oxazolo[5,4-c]azocine- 1 (2H)-carboxylate (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl- 1 N-allyl-, 1 N-(9-fluorenylmethoxy- carbonyl)-amine-acetonide (2.2 g, 4.14 mmol) was dissolved in toluene (120 ml), then argon was bubbled through the solution for 5 minutes. Grubb's catalyst (0.44 g, 0.53 mmol) was added and argon was bubbled through the solution for 1 minute. The reaction mixtrue was then stirred for 3 h at 85° C. Additional Grubb's catalyst (0.22 g, 0.27 mmol, cf. J Am Chem Soc, 1995, 117, 2108-2109) was added and the reaction mixture was stirred at 85° C for an additional 2 h. The reaction mixture was then cooled to RT, concentrated in vacuo, and chromatographed (silica gel. 10% EtOAc/ hexanes) to give the title compound as a white foam ( 1.35 g, 607c): MS ES: 505.4 (M+HN f) 1 , 1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-oxazolo[5,4-c]azocine- 1 (2H)~ carboxylate 1 , 1 -dimethylethyl 3a,4,5,6,9.9a-hexahydro-2,2-dimethyl-5-(9-fluorenylmethoxy- carbonyl)oxazolo[5,4-c]azocine-l (2/ )-carboxylate (2.5 g, 4.96 mmol) was dissolved in 20% piperidine/ DMF (32 ml) and was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo, chromatographed (silica gel, 5-7.5% MeOH/ CH 2 C1,) to give the title compound as a pale brown solid ( 1.2 g, 86%): MS ES: 283.2 (M+HN g) 1, 1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-(2- pyridinylsulfonyl)oxazolo[5,4-c]azocine- 1 (2H)-carboxylate 2-Pyridylsulfonyl chloride (2g, 10.64 mmol) was added to a solution of 1,1- dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimethyl-5-oxazolo[5,4-c]azocine- 1 (2H)- carboxylate (1.2 g, 4.26 mmol) in CΗ,C1, (15 ml) and Hunig's base (2 ml, 1 1.47 mmol) and was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo, redissolved in EtOAc (50 ml), extracted with H,0) (30 ml), then brine (30 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 0.7 % MeOH/ CH,C1,) to give the title compound as a white foam: Anal. calc. C 20 H 29 N 3 O,S: Theoretical: C, 56.72; H, 6.90; N, 9.92; S, 7.57; Found: C, 56.47; H, 6.80; N, 9.82; S, 7.83; MS ES 424.2 (M+H + ) h) 4-amino- 1 ,2,3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine 1,1 -dimethylethyl 3a,4,5,6,9,9a-hexahydro-2,2-dimefhyl-5-(2- pyridinylsulfonyl)oxazolo[5,4-c]azocine-l(2H)-carboxylate (1.5 g, 3.55 mmol) was dissolved in 4 M ΗC1 in dioxane (15 ml) and CΗ 2 C1, (15 ml) and was stirred for 2h at RT. The reaction mixture was concentrated in vacuo, then redissolved in 4 M HCl in dioxane (20 ml), THF (20 ml), H 2 0 (20 ml) and was stirred overnight at RT and was used in the next reaction without further purification: MS ES 284.3 (M+H + ). i) N-(N-Boc-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine HBTU ( 1.25 g, 3.3 mmol) was added to a solution 4-amino- 1 ,2, 3,4,7, 8-hexahydro- 3-hydroxy-(2-pyridinylsulfonyl)-azocine ( 1.0 g, 2.8 mmol), Boc-L-leucine (0.7 g, 2.8 mmol) in N-methyl morpholine ( 1.4 ml, 12.6 mmol) in DMF ( 12 ml) and was stirred for 3h at RT. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel, 3:2 EtOAc: hexanes) to give the title compound as a white foam (1.33 g, quan.): ES MS: 497.3 (M+H + ) j) N-(L-leucinyl)-4-amino- 1,2, 3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine N-(N-Boc-L-leucinyl)-4-amino-l, 2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine (1.3 g, 2.62 mmol) was dissolved in 4 M HCl in dioxane (10 ml) and CH,C1, (10 ml) and was stirred for 3h at RT, then was concentrated and was used in the next reaction without further purification (1.23 g, quan.): MS ES 397.3 (M+H + ). k) N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl)-azocine HBTU (250 mg, 0.66 mmol) was added to a solution of 2-benzofurancarboxylic acid (105 mg, 0.65 mmol), N-(L-leucinyl)-4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine (0.305 g, 0.65 mmol) in N-methylmorpholine (0.3 ml) and DMF (4 ml) and was stirred at RT for 4h. The reaction mixture was then diluted with EtOAc (40 ml) and was extracted with H 2 0, then brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 2 % MeOH/ CH,C1 3 ) to give the title compound as a white foam (0.27 g, 77%): MS ES: 541.4 (M+H * ). 1) N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine Dess-Martin periodinane (130 mg, 0.3 mmol) was added to a solution of N-(N-(2- benofuran-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine (110 mg, 0.20 mmol) in CH 2 C1 2 (3 ml) and was stirred for 1 h at RT. Then additional Dess-Martin periodinane (65 mg, 0.15 mmol) was added and the reaction was stirred an additional hour at RT. The reaction mixture was then diluted with CH 2 C1 (50 ml), extracted with 10% aq. NaHCO, (30 ml) 10% aq. Na 2 S 2 0„ (30 ml), dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 1.5 % MeOH/ CH,C1 2 ) to give the title compound as a white foam (83 mg, 75%): MS ES: 539.1 (M+HN 561.3 (M+NaN 584.3 (M+2Na + ); Η NMR (CDC1 3 , 400 MHz): δ 8.70 (d, 1H), 7.94-7.92 (m, 2H), 7.60 (d, 1H), 7.55-7.50 (m, 3H), 7.45-7.40 (m, 1H), 7.1 1 (t, 2H), 5.90-5.80 (m, 1H), 5.55-5.48 (m, 1H), 5.15-5.00 (m, 1H), 4.78-4.70 (m, 1 H), 4.45 (d, 2H), 3.85 (d, 1H), 3.70 (dd, 1H), 3.60-3.50 (m, 1H), 2.55-2.48 (m, 1H), 1.78-1.70 (m, 3H), 0.98 (2d, 6H). Example 4 Preparation of N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo- (2-pyridinylsulfonyl)-azocine a) N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine HBTU (0.34 g, 0.88 mmol) was added to a solution 4-amino- 1 ,2,3,4,7,8- hexahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine (0.28 g, 0.8 mmol), 4-methyl-2-(3- biphenyl-valeric acid (0.215g, 0.8 mmol), N-methyl morpholine (0.44 ml, 12.6 mmol) in DMF (12 ml) and was stirred for 3h at RT. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel, 1 :1 EtOAc: hexanes) to give the title compound as a white foam (0.33 g, 78%): ES MS: 534.1 (M+H + ). b) N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino-l,2,3,4,5,6,7,8-octahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2,3,4,7,8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine (80 mg, 0.15 mmol) was dissolved in 1 :4 EtOAc: EtOH (10 ml). Then 10% Pd/C (10 mg) was added and the reaction mixture was stirred under a balloon of hydrogen gas over 3 days at RT. Additional Pd/C (30 mg) was added and the reaction was stirred under a balloon of hydrogen gas for 2 additional hours. The reaction mixture was filtered through celite, concentrated in vacuo and was used in the next reaction without further purification (60 mg, 75%): MS ES 536.3 (M+HN c) N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2,3,4,5,6,7,8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine Dess-Martin periodinane (60 mg, 0.14 mmol) was added to a solution N-(4-methyl- 2-(3-biphenyl)valeryl)-4-amino- 1 ,2, 3,4,5, 6,7, 8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine (50 mg, 0.09 mmol) in CH,C1, (2 ml) and was stirred for 1 h at RT. Then additional Dess-Martin periodinane (30 mg, 0.07 mmol) was added and the reaction was stirred an additional h at RT. The reaction mixture was then diluted with CH 2 C1 2 (50 ml), extracted with 10% aq. NaHC0 3 (30 ml) 10% aq. Na 2 S 2 0, (30 ml), dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 1 % MeOH/ CH 2 C1 2 ) to give the title compound as a white foam (22 mg, 44%): MS ES: 534.4 (M+H + ), 579.4 (M+2Na + ); (Η NMR, CDC1 3 , 400 MHz, mixture of diasteromers): δ 8.70-8.62 (m, 1H), 8.12-7.88 (m, 2H), 7.55-7.52 9m, 2H), 7.55-7.27 (m, 8H), 6.20-6.15 (m, 1H), 5.10- 5.02 (m, 1H), 4.70-4.60 (dd, 1H), 3.80-3.70 (m, 1H), 3.12-2.92 (dd, 1H), 2.20-2.10 (m, 1H), 2.10-1.95 (m, 2H), 1.90-1.70 (m, 5H), 1.55-1.35 (m, 2H), 1.30-1.15 (m, 1H), 0.95-0.90 (m, 6H). Example 5 Preparation of N-(4-meth l-2-(3-biphenyl)valeryl)-4- amino- 1 ,2,3,4,7, 8-hexahvdro-3-oxo- (2-pyridinylsulfonyl)-azocine Dess-Martin periodinane (64 mg, 0.15 mmol) was added to a solution N-(4-methyl- 2-(3-biphenyl)vaIeryl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine (44 mg, 0.08 mmol) in CH,C1, (5 ml) and was stirred for 1 h at RT. The reaction mixture was then diluted with CH,C1 2 (50 ml), extracted with 10% aq. NaHCO, (30 ml) 10% aq. Na,S,0 3 (30 ml), dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 0.5 % MeOH CH 2 C1 2 ) to give the title compound as a white foam (30 mg, 68%): MS ES: 539.1 (M+HN 579.4 (M+2Na + ); Η NMR (CDC1 3 , 400 MHz, mixture of diasteromers): δ 8.68 (d, 1 H), 8.62 (d, 1H), 8.0-7.85 (m, 4H), 7.62 (7.30 (m, 20H), 6.75 (d, 1 H), 6.62 (d, 1H), 5.90-5.80 (m, 1H), 5.75-5.60 (m, 1H), 5.50-5.40 (m, 2H), 5.10-5.00 (m, 2H), 4.36 (d, 2H), 4.28 (d, 2H), 3.83 (d, 2H), 3.73 (d, 2H), 3.60-3.37 (m, 4H), 2.55-2.50 (m, 1H), 2.48-2.38 (m, 1H), 2.10-2.00 (m, 2H), 1.80-1.70 (m, 2H), 1.55-1.45 (m, 2H), 0.96-0.90 (m, 12H). Example 6 Preparation of N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7,8-octahvdro- 3-oxo-(2-pyridinylsulfonyl)-azocine a.) N-(N-(2-quinoline-carbonyl)-L-leu ' cinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine Following the procedure of Example 3k except substituting 2-quinoline carboxylic acid for 2-benzofuran carboxylic acid the title compound was prepared: MS ES: 552.4 (M+H + ). b.) N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7, 8-octahydro-3-hydroxy- (2-pyridinylsulfonyl)-azocine Following the procedure of Example 4b except substituting the compound of Example 6a for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1,2,3,4,7, 8-hexahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4b, the title compound was prepared: MS ES: 554.3 (M+H+). c.) N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7, 8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine To a solution of the compound of Example 6b ( 100 mg, 0.18 mmol) in DMSO was added TEA (0.3 mL) and pyridine sulfur trioxide complex (920 mg). The reaction was allowed to stir at room temperature until complete by TLC analysis whereupon it was diluted with ethyl acetate and washed with brine. The organic layer was dried, filtered and concentrated. Column chromatography (2% methanobdichloromethane) of the residue provided 50 mg of the product: MS ES 552.3 (M+H+). Example 7 Preparation of N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-octahydro-3- oxo-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 6c except substituting N-(N-(2-quinoline- carbonyl)-L-leucinyl)-4-amino- 1,2, 3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine of Example 6a for N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 , 2,3,4,5,6,7, 8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine of Example 6c, the title compound was prepared: MS ES: 550.4 (M+H + ). Example 8 Preparation of N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7,8- octahydro-3-oxo-(2-pyridinylsulfonyl)-azocine a.) N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7, 8-octahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 6b except substituting N-(N-(2-benzofuran- carbonyl)-L-leucinyl)-4-amino- 1 ,2, 3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine of Example 3k for N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,7, 8- octahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine of Example 6b, the title compound was prepared: MS ES: 543.4 (M+H+). b.) N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino-l, 2,3,4,5,6,7, 8-octahydro-3- oxo-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 4c except substituting N-(N-(2-benzofuran-carbonyl)- L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7, 8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine of Example 9b for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2,3,4,5,6,7,8-octahydro-3- oxo-(2-pyridinylsulfonyl)-azocine of Example 4c, the title compound was prepared: MS ES: 541.3 (M+H+). Example 9 Preparation of N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7,8- octahvdro-3-oxo-(2-pyridinylsulfonyl)-azocine a.) N-(N-(2-benzothiophene-carbony l)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 3k except substituting 2-benzothiophene carboxylic acid for 2-benzofuran carboxylic acid the title compound was prepared: MS ES: 557.3 (M+H + ). b.) N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7,8-octahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 4b except substituting the compound of Example 9a for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2, 3,4,7, 8-hexahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4b, the title compound was prepared: MS ES: 559 (M+H+). c.) N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,5,6,7,8-octahydro-3- oxo-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 4c except substituting the compound of Example 9b for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino-l, 2,3,4,5,6,7, 8-octahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4c, the title compound was prepared: MS ES: 557.4 (M+H+). Example 10 Preparation of N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7,8- octahvdro-3-oxo-(2-pyridinylsulfonyl)-azocine Following the procedure of Example 4c except substituting N-(N-(2- benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7,8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine of Example 9a for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- l,2,3,4,5,6,7,8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4c, the title compound was prepared: MS ES: 555.3 (M+H + ). The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims: We claim: A compound of Formula I: I wherein: A is selected from the group consisting of: C(O) and CH(OH); RI is selected from the group consisting of: R2 is selected from the group consisting of: H, Cj.^alkyl, C3_ cycloalkyl-CQ- 6 alkyl, Aτ-Co_ 6 alkyl, Het-C 0 . 6 alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R 12 NC(0)-, R 9 R 12 NC(S)-, R 12 HNCH(R 12 )C(0)-, R 9 OC(0)NR 12 CH(R 12 )C(0)- ,adamantyl-C(0)-, or R 6 N R 7 ' " ~ R a R" is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6 a lkyl, and Het- C 0 -6alkyl; R'" is selected from the group consisting of: H, Ci .galkyl, C3_6cycloalkyl-Co_ galkyl, Ar-Co_6al yl, and Het-Co-6 a lkyl; R 3 and R° are independently selected from the group consisting of: H, C2- 6alkenyl, C2-6alkynyl, Het, Ar or C i -6alkyl optionally substituted by OR * 3 , SR ' 3 , NR * 3 2, R 13 NC(0)OR 5 , C0 2 R 13 , C0 2 NR 13 2 , N(C=NH)NH 2 , Het and Ar; R 4 is selected from the group consisting of: H, Cj_6alkyl, C3_6cycloalkyl-Co- 6 alkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl. R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 14 NC(0)-, R 5 R 14 NC(S)-, R 14 HNCH(R 14 )C(0)-, and R 5 OC(0)NR 14 CH(R 14 )C(0)-; R5, R 9 , and R'^ are independently selected from the group consisting of: Cj_ βalkyl, C3_6cycloalkyl-Co-6 a l yl, Aτ-CQ. a\ky\ and Het-Crj.galkyl; R° is selected from the group consisting of: H, Cj.^alkyl, Ar-Cθ-6 a 'kyl, a °d Het- C 0 _6alkyl; R' is selected from the group consisting of: H, Cj.βalkyl, C3_6cycloalkyl-C υ _ 6 alkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 15 NC(O)-, R 10 R 15 NC(S)-, R 1 5 HNCH(R 15 )C(0)-, and R 10 OC(O)NR 1 5 CH(R 15 )C(O)-; or Ro and R ' are connected to form a pyrrolidine, a piperidine, or a moφholine ring; each R' is independently selected from the group consisting of: H, C j .galkyl, Ar- Cθ-6alkyl, and Het-Co-6 a lkyl; R ] 1 is Ar; R ! R! R14 anc j R15 are independently selected from the group consisting of:H, Cj.galkyl, Ar-Cθ-6alkyl, and Het-Co-6 a lkyl; R* is selected from the group consisting of: H, C j .galkyl, C3_6cycloalkyl-C . galkyl, Ar-Co-6 a lkyl, and Het-Co_6alkyl; Z is selected from the group consisting of: C(O) and CH2; M is selected from the group consisting of: HC=CH; H2C-CH2; H(OR 2 )C- C(OR 2 )H; H(OR 2 )C-CH 2 ; H(NR 2 H)C-C(NR 2 H)H; H(OR 2 )C-C(NR 2 H)H; and H(NR 2 H)C-CH 2 ; X is selected from the group consisting of: CH2, S and O n is 1-7; and pharmaceutically acceptable salts, hydrates and solvates thereof. 2. A compound according to Claim 1 wherein A is C(O). 3. A compound according to Claim 1 wherein R" and R'" are both H. 4. A compound according to Claim 1 wherein: A is C(O); M is selected from the group consisting of: HC=CH and H2C-CH2; n is l;and R" and R"' are both H. 5. A compound according to Claim 1 wherein: A is C(O); R' is selected from the group consisting of: R is selected from the group consisting of R 3 andR 8 areCi_6alkyl; R 4 is selected from the group consisting of: R5oC(0)- and R~*C(0)-; R-\ R 9 , and R are independently selected from the group consisting of: Ar-Cø- ^alkyl and Het-Co.βalkyl; R 6 isH; R 7 isRl°OC(0); R'isH; R" is H; R"'isH;and Z is C(O); M is selected from the group consisting of: HC=CH and H2C-CH2; and n is 1. 6. A compound according to Claim 5 wherein R 9 z is 7. A compound according to Claim 5 wherein R 3 and R° are independently isobutyl. 8. A compound according to Claim 5 wherein R-\ R 9 , and R^ υ are independently selected from the group consisting of: phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2- benzo[b]thiophenyl, 2-quinolinyl, and pyridinyl. 9. A compound of Claim 1 selected from the group consisting of: N-(N-(benzyloxycarbonyl)-L-leucinyl)-4-(R,S)-amino- 1,2,3,4,7, 8-hexahydro-3-oxo-[2-(N- (bezyloxycarbonyl)-L-lecinyl)]-azocine; N-(N-(benzyloxycarbonyl)-L-leucinyl)-4-(R,S)-amino- 1,2, 3,4,7, 8-hexahydro-3-oxo- [2-(N-(bezyloxycarbonyl)-L-lecinyl)]-azocine; N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino-l,2,3,4,5,6,7,8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino-l,2,3,4,7,8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,5,6,7, 8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4- amino- l,2,3,4,7,8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-benzofuran-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,5,6,7, 8-octahydro-3-oxo-(2- pyridinylsulfonyl)-azocine; N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4- amino- 1, 2,3,4,5,6,7, 8-octahydro-3-oxo- (2-pyridinylsulfonyl)-azocine; and N-(N-(2-benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro-3-oxo-(2- pyridinylsulfonyl)-azocine. 10. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. 11. A pharmaceutical composition comprising a compound according to Claim 9 and a pharmaceutically acceptable carrier, diluent or excipient. 12. A method of inhibiting a protease, comprising administering to a patient in need thereof an effective amount of a compound according to Claim 1. 13. A method according to Claim 12 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease. 14. A method of inhibiting a protease, comprising administering to a patient in need thereof an effective amount of a compound according to Claim 9. 15. A method according to Claim 14 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease. 16. A method according to Claim 13 wherein said protease is a cysteine protease. 17. A method according to Claim 15 wherein said protease is a cysteine protease. 18. A method according to Claim 16 wherein said cysteine protease is cathepsin K. 19. A method according to Claim 17 wherein said cysteine protease is cathepsin K. 20. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to Claim 1. 21. A method according to Claim 20 wherein said disease is osteoporosis. 22. A method according to Claim 20 wherein said disease is periodontitis. 23. A method according to Claim 20 wherein said disease is gingivitis. 24. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to Claim 1. 25. A method according to Claim 24 wherein said disease is osteoarthritis. 26. A method according to Claim 24 wherein said disease is rheumatoid arthritis. 27. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to Claim 9. 28. A method according to Claim 27 wherein said disease is osteoporosis. 29. A method according to Claim 27 wherein said disease is periodontitis. 30. A method according to Claim 27 wherein said disease is gingivitis. 31. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to Claim 9. 32. A method according to Claim 31 wherein said disease is osteoarthritis. 33. A method according to Claim 31 wherein said disease is rheumatoid arthritis. 34. A compound of Formula II: II wherein R is selected from the group consisting of: o N O O , O " S N O 35. A compound according to Claim 34 selected from the group consisting of: 4-amino- 1,2, 3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine N-(L-leucinyl)-4-amino- 1 ,2,3,4,7, 8-hexahydro- 3-hydroxy-(2-pyridinylsulfonyl)-azocine 4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy-(N- (benzyloxycarbonyl)-L-luecinyl)] -azocine

Inventors: MARQUIS ROBERT WELLS JR, VEBER DANIEL FRANK, MARQUIS, ROBERT, WELLS, JR., VEBER, DANIEL, FRANK
Applicants: MARQUIS ROBERT WELLS JR, SMITHKLINE BEECHAM CORP, VEBER DANIEL FRANK, MARQUIS, ROBERT, WELLS, JR., SMITHKLINE BEECHAM CORPORATION, VEBER, DANIEL, FRANK
Application year: 1999
Main classification: C07D401
IPC codes: A61K31, A61P19, A61P29, A61P43, C07D225, C07D401, C07D405, C07D409