PROTEASE INHIBITORS

Abstract: The present invention provides C3-C6 1-amino-1-acyl cycloalkane-substituted 4-amino-azepan-3-one protease inhibitors 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 for 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 of 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 This application claims the benefit of U.S. Provisional Application No. 60/252,508, filed November 22, 2000. FIELD OF THE INVENTION This invention relates in general to C 3 -Cg 1-amino-l-acyl cycloalkane-substituted 4-amino-azepan-3-one 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) J. 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, 125, 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, 118, and Everts, et al., J. Cell. PhysioL, 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, 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 0 611 756 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 0623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- lβconvertase. 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, 107, 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, /. 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. Acta, , 701, 328). 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent Nos.4,749,792 and 4,638,010. EP 1 008 592 A2 describes cyclic amide derivatives which inhibit cathepsin K. Thus, a structurally diverse variety of 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 C3-C6 1-amino-l-acyl cycloalkane- substituted 4-amino-azepan-3-one compounds which are protease inhibitors, most particularly of cathepsin K. SUMMARY OF THE INVENTION An object of the present invention is to provide C3-C6 1-amino-l-acyl cycloalkane- substituted 4-amino-azepan-3-one carbonyl 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 Fonnula 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: wherein: R 2 is selected from the group consisting of: H, Cι _galkyl, C3_($cycloaιkyl-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! lNC(O)-, R 9 R ! !NC(S)-, R 9 (R 1 )NS0 2 -, R is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ 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 12 NC(0)-, and R 5 R 12 NC(S)-; R^ is selected from the group consisting of: H, Ci.galkyl, C 2 -6 a lk en y > C 2 _ galkynyl, C3_gcycloalkyl-Co_6 aι ky ' C 2 -6alkanonyl, Ar-Cg-galkyl and Het-Co-βalkyl; R° is selected from the group consisting of: H, C galkyl, Ar-Cθ-6alkyl, and Het- Co-βalkyl; R is selected from the group consisting of: H, Cι _galkyl, C3_6cycloalkyl-Co_ galkyl, Ar-C 0 . 6 alkyl, Het-C 0 -6alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 13 NC(S)-; R8 is selected from the group consisting of: H, Ci-6alkyl, C 2 -6alkenyl, C 2 -6 a ky n y > HetCo_galkyl and ArCo_6alkyl; R 9 is selected from the group consisting of: Ci.galkyl, C3_6cycloalkyl-Co_6alkyl, Ar-C 0 _6alkyl, -Ar-COOH, and Het-C 0 -6alkyl; RIO is selected from the group consisting of: C^galkyl, C3_gcycloalkyl-Co-6alkyl, Ar-C()-6alkyl and Het-Co-βalkyl; RU is selected from the group consisting of: H, C^galkyl, Ar-Cθ-6 lkyl, and Het- C 0 . 6 alkyl; Rl 2 is selected from the group consisting of: H, Ci .galkyl, Ar-C()-6alkyl, and Het- C 0 _ 6 alkyl; Rl3 is selected from the group consisting of: H, C j .galkyl, Ar-Cθ-6 a lkyl, and Het- C 0 _6alkyl; R' is selected from the group consisting of: H, C galkyl, Ar-Cθ-6 lkyl, and Het- is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het- R'"is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co-6 a lkyl, and Het-Cø-galkyl; Z is selected from the group consisting of: C(O) and CH 2 ; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof. In compounds of Formula I, n is preferably 4, to provide 1-amino-l-acyl cyclohexane compounds. The cycloalkyl ring may be unsubstituted or substituted with one or more of Cι_6alkyl, C3_gcycloalkyl-Co-6alkyl, C 2 _6alkenyl, C2-6alkynyl, HetCo-galkyl, ArC Q .galkyl, or halogen. The cycloalkyl ring is more preferably unsubstituted. R4 is selected from the group consisting of: H, Cι_galkyl, C3_gcycloalkyl- C 0 _6alkyl, Ar-C 0 -6alkyl, Het-C 0 -6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 13 NC(0)-, and R 1 3 NC(S)-. R4 is preferably selected from the group consisting of: R^OC(O)-, R->C(0)- and R 5 S0 2 -. R 4 is most preferably R 5 C(0)-. In some embodiments, R 4 is preferably methanesulfonyl. R is selected from the group consisting of: H, Ci.βalkyl, C2_galkenyl, C2. galkynyl, C3_6cycloalkyl-Cø_galkyl, C2-6alkanonyl, Ar-C0_galkyl or Het-Co-6 a lkyl. Preferably R is selected from the group consisting of: Cj.galkyl, C2-6alkenyl, C2- βalkynyl, C3_6cycloal yl-Cø_6alkyl, C2-6alkanonyl, Ar-Co_galkyl and Het-Co-galkyl. More preferably, and especially when R 4 is R5C(0)-, R^ is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially Ci.galkoxy and aryloxy substituted methyl, more especially phenoxy-methyl , 4-fluoro- phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl- methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; pentanonyl, especially 4-pentanonyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or Ci.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more Cj.galkyl sulfonyl groups, more especially 4-methanesulfonyl-phenyl; benzyl; naphthalenyl, especially naphthylen-2-yl; benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; furanyl, especially furan-2-yl, especially nitro substituted furanyl, more especially 5-nitro-furan-2-yl, more especially halogen substituted furanyl, even more especially 5- bromo-furan-2-yl, more especially aryl substituted furanyl, even more especially 5-(4- chloro-phenyl)-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)- furan-2-yl, more especially Cj.galkyl substituted furanyl, even more especially 3-methyl- furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; tetrahydrofuranyl, especially tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, especially Cι_galkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-l-yl- ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl, 5-methoxy-3-methyl- benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl- benzofuran-2-yl; especially halogen substituted benzofuranyl, more especially 5-fluoro- benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, 5-fluoro-3-methyl-benzofuran-2-yl, 6- fluoro-3-methyl-benzofuran-2-yl; especially C j .galkyl substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl- benzofuran-2-yl; naphtho[2,l-b]-furanyl, especially naphtho[2,l-b]-furan-2-yl, alkyl substituted naphtho [2, 1-b] -furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[έ]thiophenyl, especially benzo[Z?]thiophen-2-yl; especially C j .galkoxy substituted benzo[6]thiophenyl, more especially 5,6-dimethoxy- benzo[έ]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalinyl, especially quinoxalin-2-yl; 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, indol-6-yl, indol-5-yl, especially C j .galkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C j .galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C j .galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiopheneyl, especially thiophene-3-yl, also thiophene-2-yl, especially C j .galkyl substituted thiopheneyl, more especially 5-methyl-thiophene-2-yland 5-methyl-thiophene- 3-yl, especially halogen substituted thiopheneyl, more especially 4,5-dibromo-thiophene-2- yi; thieno[3,2-Z?]thiophene, especially thieno[3,2-έ>]thiophene-2-yl, more especially Cj.galkyl substituted thieno[3,2-έ]thiophene-2-yl, more especially 5-tert-butyl-3-methyl- thieno[3,2-έ]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially C j .galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, especially aryl substituted oxazolyl, more especially 5-methyl-2-phenyl oxazol-4-yl, especially C j .galkyl substituted oxazolyl, more especially 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl. When R 4 is R^S0 2 , R-* is preferably pyridin-2-yl or l-oxo-pyridin-2-yl. R' is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het- Cθ-6 alk y Preferably R' is selected from the group consisting of: H and naphthalen-2-yl- methyl. Most preferably R' is H. R" is selected from the group consisting of: H, C j .galkyl, Ar-Co-6alkyl, and Het- C 0 .galkyl. Most preferably R" is H. R'" is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl- Co-6alky , and Het-Co-galkyl. R'" is preferably selected from the group consisting of: H and C j .galkyl. R'" is more preferably selected from the group consisting of: H and methyl. Most preferably R'" is methyl. In compounds of Formula I, R 2 is selected from the group consisting of: H, Cj.galkyl, C 3 .gcycloalkyl-C 0 .galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R n NC(0)-, R 9 R n NC(S)-, R 9 RHNS0 2 -, More preferably R 2 is selected from the group consisting of: Ar-Cθ-6 a lkyl, R D R 7 ^ R 9 C(0)-, R 9 S0 2 , R 9 R n NC(0)-, and R Even more preferably, R 2 is selected from the group consisting of: Ar-Cθ-6 a lkyl, R 9 C(0)-, and R S0 2 . Most preferably R 2 is R 9 S0 2 . In such embodiments: R6 is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, or Het- Cø-galkyl, preferably H. R^ is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 14 NC(O)-, and R 10 R 14 NC(S)-. R 7 is preferably R 10 OC(O). R^ is selected from the group consisting of: H, Cj.galkyl, C2-6 a lkenyl, C2-6 a kynyl, HetC Q .galkyl and ArCo_galkyl; preferably Cj.galkyl, more preferably isobutyl. R 9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Co-galkyl, -Ar-COOH, and Het-CQ-galkyl. R 9 is preferably selected from the group consisting of: Cj.galkyl, Ar-Cø-galkyl, - Ar-COOH, and Het-C 0 .galkyl. More preferably, R 9 is selected from the group consisting of: methyl; ethyl, especially C3_gcycloalkyl-Co_galkyl-substituted ethyl, more especially 2- cyclohexyl-ethy 1 ; propyl; butyl, especially Cj.galkylbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(0); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, especially C j .galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyρhenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C j .galkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cj.galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yl)toluyl; naphthylene, especially naphthyl-2-ene; benzoic acid, especially 2-benzoic acid; benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; benzo[l,2,5]oxadiazolyl, especially benzo[l,2,5]oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1 -oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially C .galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; thiopheneyl, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl; lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, more especially C j .galkyl substituted imidazolyl, even more especially l-methyl-lH-imidazol-2-yl, 1- methyl- lH-imidazol-4-yl, and l,2-dimethyl-lH-imidazol-4-yl; triazolyl, especially lH-[l,2,4]triazolyl, more especially lH-[l,2,4]triazol-3-yl, especially Cj.galkyl substituted lH-[l,2,4]triazolyl, more especially 5-methyl-lH- [l,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl. When R 2 is R Sθ2, R 9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl. When R 2 is R 9 S0 2 R! 1 NC(0)-, R 9 is preferably Ar-C 0 .galkyl, more preferably Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl. RU is selected from the group consisting of: H, C j .galkyl, Ar-Co-6alkyl, and Het-C 0 .galkyl. When R 2 is R 9 S0 2 R π NC(0)-, R 11 is preferably H. When R 2 is R 9 C(0)-, R 9 is preferably selected from the group consisting of C j . galkyl, C3_gcycloalkyl-Co_galkyl, and Het-Co-galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl. When R 2 is Ar-Co_galkyl, R 2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl. When R 2 is C j .galkyl, R 2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl. When R 2 is Het-Co_galkyl, Het-Cø.galkyl is preferably Het-methyl, and Het in Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially C j .galkylpyridinyl, more especially 6- methyl-pyridin-2-yl; thiopheneyl, especially thiophene-2-yl, more especially thiophene-2-yl or benzo[b]thiophene-2-yl; thiazolyl, especially thiazol-4-yl such as l-(2-morpholin-4-yl-thiazol-4-yι), and 1- (isothiazol-3-yl); lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especially Cj_ galkyl substituted imidazolyl, more especially l-methyl-lH-imidazol-2yl; triazolyl, especially 3H-[l,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl, especially C j .galkyl substituted 3H-[l,2,3]triazolyl, more especially 3-phenyl-3H- [l,2,3]triazolyl -4-yl; quinolinyl, especially quinolin-2-yl, quinolin-2-yl; furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-ethyl-furan- 2-yl; and thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, especially Cj_ galkyl substituted thieno[3,2-b]thiopheneyl, especially 3,4-dimethyl-thieno[3,2- b]thiophene-2-yl. R 2 is also preferably: H; toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl. Compounds of Formula I where R" is H and R'" is methyl are preferred. More preferred are compounds of Formula I wherein: R 2 is selected from the group consisting of: Ar-Cθ-6alkyl, R 9 C(0)-, R 9 S0 2 , R 6 R- Z - R 9 R π NC(0)-, and R ; R 4 is selected from the group consisting of: R 5 OC(0)-, R 5 C(0)- and R 5 S0 2 -; R^is selected from the group consisting of: Cj.galkyl, C 2 _galkenyl, C 2 .galkynyl, C3.gcycloalkyl-Co_galkyl, C 2 _galkanonyl, Ar-Cø_galkyl and Het-Cg-galkyl; R 6 is H; R 7 is R 10 OC(O); R 8 is Cj.galkyl; R 9 is selected from the group consisting of: Cj.galkyl, Ar-Cg-galkyl, -Ar-COOH, and Het-Co_galkyl; RIO i s selected from the group consisting of: Cj.galkyl, Ar-Co-galkyl and Het-Cg. galkyl; R'is H; R" is H; R'" is methyl; and Z is selected from the group consisting of: C(O) and CH . Even more preferred are such compounds of Formula I wherein R 2 is selected from the group consisting of: Ar-Cθ-6 a lkyl, R 9 C(0)-, R 9 S0 2 . Yet more preferred are compounds of Formula I wherein: R 2 is selected from the group consisting of: Ar-C()-6alkyl, R C(0)- and R 9 S02ϊ R 4 is R 5 C(0)-; R5 is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially C j .galkoxy and aryloxy substituted methyl, more especially phenoxy-methyl , 4-fluoro- phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl- methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; pentanonyl, especially 4-pentanonyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or Cj.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more C j .galkyl sulfonyl groups, more especially 4-methanesulfonyl-phenyl; benzyl; naphthalenyl, especially naphthylen-2-yl; benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; furanyl, especially furan-2-yl, especially nitro substituted furanyl, more especially 5-nitro-furan-2-yl, more especially halogen substituted furanyl, even more especially 5- bromo-furan-2-yl, more especially aryl substituted furanyl, even more especially 5-(4- chloro-phenyl)-furan-2-yl, 5-(4-nitroρhenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)- furan-2-yl, more especially Cj.galkyl substituted furanyl, even more especially 3-methyl- furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; tetrahydrofuranyl, especially tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, especially Cj.galkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-l-yl- ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl 5-methoxy-3-methyl- benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl- benzofuran-2-yl; especially halogen substituted benzofuranyl, more especially 5-fluoro- benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, 5-fluoro-3-methyl-benzofuran-2-yl, 6- fluoro-3-methyl-benzofuran-2-yl; especially C j .galkyl substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl- benzofuran-2-yl ; naphtho[2,l-b]-furanyl, especially naphtho[2,l-b]-furan-2-yl, alkyl substituted naphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[έ]thiophenyl, especially benzo[£]thiophen-2-yl; especially Cj.galkoxy substituted benzo[έ>]thiophenyl, more especially 5,6-dimethoxy- benzo[έ]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalinyl, especially quinoxalin-2-yl; 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially C j . g a lkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C j .galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C j .galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiopheneyl, especially thiophen-3-yl, also thiophen-2-yl, especially Cj.galkyl substituted thiopheneyl, more especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3- yl, especially halogen substituted thiopheneyl, more especially 4,5-dibromo-thiophen-2-yl; thieno[3,2-£]thiophene, especially thieno[3,2-έ]thiophene-2-yl, more especially Cj.galkyl substituted thieno[3,2-Z?]thiophene-2-yl, more especially 5-tert-butyl-3-methyl- thieno[3,2-£]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially C j .galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, especially aryl substituted oxazolyl, more especially 5-methyl-2-phenyl oxazol-4-yl, especially C j .galkyl substituted oxazolyl, more especially 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl. R 9 is selected from the group consisting of: methyl; ethyl, especially C3_gcycloalkyl-Co_galkyl-substituted ethyl, more especially 2- cy clohexy 1-ethy 1 ; propyl; butyl, especially C j .gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(0); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 3-fluoroρhenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, especially C j .galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C j .galkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially C j .galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yl)toluyl; naphthylene, especially naphthyl-2-ene; benzoic acid, especially 2-benzoic acid; benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; benzo[l,2,5]oxadiazolyl, especially benzo[l,2,5]oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1 -oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially Cj.galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; thiopheneyl, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl; lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, more especially C j .galkyl substituted imidazolyl, even more especially 1 -methyl- lH-imidazol-2-yl, 1- methyl-lH-imidazol-4-yl, and l,2-dimethyl-lH-imidazol-4-yl; triazolyl, especially lH-[l,2,4]triazolyl, more especially lH-[l,2,4]triazol-3-yl, especially Cj.galkyl substituted lH-[l,2,4]triazolyl, more especially 5-methyl-lH- [l,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl. R' is H; R" is H; and R'" is methyl. Most preferred are compounds of Formula I wherein: R 2 is R 9 S0 2 ; R 4 is R 5 C(0); R-> is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran- 2-yl, 5-methoxybenzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, quinoxalin-2-yl, and quinolin- 2-yl, preferably selected from the group consisting of: benzofuran-2-yl and thieno[3,2- b]thiophen-2-yl, most preferably benzofuran-2-yl; R 9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl, preferably pyridin-2-yl. R' is H; and R'" is methyl. The following compounds of Formula I are particularly preferred embodiments of the present invention: benzofuran-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; benzofuran-2-carboxylic acid ( l-[(R)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -cyclohexyl } -amide ; thieno[3,2-b]thiophene-2-carboxylic acid { l-[(+/-)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl }-amide; benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; 2,2,4-trideutero-benzofuran-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl } -amide 2,2,4-trideutero- benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; 2,2,4-trideutero-thieno[3,2-b]thiophene-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; and 2,2,4-trideutero-thieno[3,2-b]thiophene-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl } -amide. The following compound of Formula I is the most preferred embodiment of the present invention: benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-cyclohexyl}-amide; Specific representative compounds of the present invention are set forth in Example 1-8. Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds of the present invention are configurationally more stable at the carbon center alpha to the ketone. The present invention includes deuterated analogs of the inventive compounds. A representative synthesis of deuterated analogs is shown in Scheme 8. The deuterated compounds of the present invention should exhibit superior chiral stability compared to the protonated isomer. Where possible the present invention includes quaternary salts of the inventive compounds. 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. A representation of an element is understood to include all isotopes of that element. Thus, for example, the term "H" includes all isotopes of hydrogen, including deuterium. "Cj-galkyl" 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. Cj.galkyl may be optionally substituted by a moiety selected from the group consisting of: OR* 4 , C(0)R1 4 , SR 14 , S(0)R 14 , NR 14 2 , R 14 NC(0)OR 5 , C0 2 R 14 , C0 2 NR 14 2 , N(C=NH)NH 2 , Het, C 3 _ gcycloalkyl, and Ar; where R^ is selected from the group consisting of: H, Cj.galkyl, C2- galkenyl, C 2 -6 a lkynyl, C3.gcycloalkyl-Co_galkyl, Ar-Cg-galkyl and Het-Co_galkyl; and R^ 4 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het-Cø- galkyl; "C3_gcycloalkyl" 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 lkenyl 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. "C2-6 a lkanonyl" means an acyl group of 2 to 6 carbons wherein one non-terminal carbon is substituted by the =0 group. C 2 _galkanonyl includes, for example, acetyl, 1- and 2-propanonyl, 1-, 2-, and 3-butanonyl, 1-, 2-, 3- and 4-pentanonyl and 1-, 2-, 3-, 4- and 5- hexanonyl. "Halogen" means F, CI, Br, and I. "Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-C Q -galkyl; C j .galkoxy; Ph-C Q .galkoxy; Het-Co-galkoxy; OH, (CH 2 ) j . gNR 15 R 16 ; 0(CH 2 ) j _gNR 15 R 16 ; Cj.galkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF3, N0 2 , CN, C0 2 R 17 CON(R 17 ) 2 , F, CI, Br or I; where R 15 and R 16 are H, Cj.galkyl, Ph-C 0 .galkyl, naphthyl-C()_galkyl or Het-CQ-galkyl; and R 7 is phenyl, naphthyl, or Cj.galkyl. As used herein "Het" or "heterocychc" represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocychc 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 heterocychc rings is fused to a benzene ring. The heterocychc 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 C 0 .gAr, Cj.galkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF 3 , N0 2 , CN, C0 2 R 17 , C0N(R 17 ), F, CI, Br and I, where R 17 is phenyl, naphthyl, or C j.galkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo[b]thiophenyl, thieno[3,2- bjthiophenyl, benzo[l,3]dioxolyl, 1,8 naphthyridinyl, pyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl, thiadiazolyl, oxadiazolyl, 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 CQ denotes the absence of the substituent group immediately following; for instance, in the moiety ArCo-galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo-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. m-CPBA refers to 3-chloroperoxybenzoic acid, EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide, DMF refers to dimethyl formamide, DMSO refers to dimethyl sulfoxide, HBTU refers to O-Benzotriazol- l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, TEA refers to triethylamine, NMM refers to N-methylmorpholine, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran. Methods of Preparation Compounds of the general formula I may be prepared in a fashion analogous to that outlined in Schemes 1-11. Alkylation of tert-butyl N-allylcarbamate (1) with a base such as sodium hydride and 5- bromo-1-pentene provides the diene 2. Treatment of 2 with either 2,6- diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IN) dichloride olefin metathesis catalysts developed by Grubbs provides the azepine 3. Epoxidation of 3 with standard oxidizing agents common to the art such as w-CPBA provide the epoxide 4. Νucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon. Acylation of 5 with an acid such as Cbz-amino-cyclohexanecarboxylic acid in the presence of a coupling agent such as EDC followed by removal of the BOC protecting group under acidic conditions provides the amine salt 6. Coupling of 6 with Cbz-amino- cyclohexanecarboxylic acid may be effected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7. Scheme 1 4 7 Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 2,6-diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, toluene c.) /H-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H 2 0, NH 4 C1; e.) 10% Pd/C, H 2 , f.) Cbz-amino-cyclohexanecarboxylic acid, EDC, CH 2 C1 2 ; g.) HCl, EtOAc; h.) Cbz- amino-cyclohexanecarboxylic acid, EDC, CH 2 C1 2 ; i.) pyridine sulfur trioxide complex, DMSO, TEA. Compounds of the general formula I wherein R 1 and R 2 are amides may be prepared in the general fashion outlined in Scheme 2. Alkylation of N-Cbz allyl amine (8) with a base such as sodium hydride and 5-bromo-l-pentene provides the diene 9. Treatment of 9 with bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride olefin metathesis catalyst developed by Grubbs provides the azepine 10. Epoxidation of 10 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 11. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine. Acylation of 12 with N-Boc- amino-cyclohexanecarboxylic acid and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13. Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HCl or TFA provides intermediate 14. Acylation of 14 may be effected with a carboxylic acid in the presence of a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15. Scheme 2 10 11 12 13 14 15 Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CH j Cl.,; c.) m-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H 2 0, NH 4 C1; e.) propanedithiol, CH 3 OH, TEA; f.) Boc-amino- cyclohexanecarboxylic acid, EDC, CH.C1-; g.) 10% Pd/C, H 2 ; h.) R^O-H, EDC, CH.C1. or R,COCl, CH 2 C1 2 ; i.) HCl/ EtOAc; j.) R j CO.H, EDC, CIi,Cl 2 ; k.) pyridine sulfur trioxide complex, DMSO, TEA. Compounds of the general formula I wherein R 2 is an alkyl, urea or sulphonamide group and R 1 is an amide may be prepared in the general fashion outlined in Scheme 3. Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N- Boc group under acidic conditions provides the amine salt 16. Coupling of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Alternatively, treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18. Acylation and oxidation provides the ketone 19. Further derivatization of amine 13 may be effected by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20. Acylation and oxidation provides the ketone 21. Scheme 3 Reagents and conditions: a.) R,CHO, NaBH(OAc) 3 ; b.) HCl; c.) R,C0 2 H, EDC, CH,C1 2 ; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R 1 S0 2 C1, TEA, CH 2 C1 2 . The individual diastereomers of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(2,2',4- trideuterio)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide 31 and 32 may be prepared as outlined in Scheme 4. Alkylation of allyl-carbamic acid benzyl ester 22 with 5-bromo-l-pentene in the presence of a base such as sodium hydride provides the diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride developed by Grubbs provides the 2,3,4,7-tetrahydro-azepine-l-carboxylic acid benzyl ester 24. Epoxidation of azepine 24 may be effected with standard oxidizing agents common to the art such as m-CPBA to provide epoxide 25. Nucleophilic epoxide ring opening of 25 may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown). The intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water. Acylation of 26 may be effected with an acid such as N-Boc-amino-cyclohexanecarboxylic acid in the presence of a coupling agent such as EDC. Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 27. Treatment of the amine 27 with 2-pyridinesulphonyl chloride in the presence of triethylamine or saturated sodium bicarbonate and CH 2 C1 2 followed by removal of the tert-butoxycarbonyl protecting group under acidic conditions provides 28. Coupling of 28 with benzofuran-2-carboxylic acid may be effected with a coupling agent such as EDC to provide intermediate alcohol 29. Alcohol 29 may be oxidized with an oxidant such as sulfur trioxide pyridine complex in DMSO and triethylamine to provide the ketone 30 as a mixture of diastereomers. Scheme 4 22 23 24 25 26 27 28 29 30 Reagents and Conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH 2 C1 2 ; c.) /7J-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H,0, NH 4 C1; e.) 1,3-propanedithiol, TEA, methanol; f.) N-Boc-amino- cyclohexanecarboxylic acid, EDC, CH 2 C1 2 ; g.) 10% Pd/C, H 2 ; h.) 2-pyridinesulphonyl chloride, TEA, CH 2 C1 2 ; i.) 4 N HCl dioxane, methanol; j.) benzofuran-2-carboxylic acid, EDC, CH 2 C1 2 ; k.) pyridine sulfur trioxide complex, DMSO, TEA The quatemized, 4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 5. The skilled artisan will understand from Scheme 5 how to make any of the quatemized, 4-amino-azepan-3-one compounds of the present invention. Reductive animation of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N-Boc group under acidic conditions provides the amine salt 16. Treatment of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Quatemization of the amine of 17 may be effected by treatment with an alkylating agent such as iodomethane to provide the quaternary amine salt 41. Scheme 5 Reagents and conditions: a.) R^HO, NaBH(OAc) 3 ; b.) HCl; c.) R 2 C0 2 H, EDC, CH 2 C1 2 ; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) iodomethane The 6-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 6. 2-Methyl-pent-4-enoic acid ethyl ester is converted to a N-2-pyridinesulfonyl-azapine by reduction to the aldehyde, reductive amination with allylamine, sulfonylation with 2-pyridyl sulfonyl chloride, and olefin metathesis with Grubbs' catalyst. Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography. The syn epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine. Acylation of the free amine with Boc-amino-cyclohexanecarboxylic acid and a coupling reagent such as HBTU or EDC, followed by deprotection of the Boc group with HCl, and acylation with a variety of aromatic carboxylic acids and coupling reagents such as HBTU or EDC gives the intermediate alcohols. Final oxidation with Dess-Martin periodinane and HPLC affords the desired ketones. Scheme b 1) DIBAI 2) 3) su 4) pβnodinane The 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 7. Carbobenyzloxy-D-alaninol (Cbz-D- alaninol)is first converted to an iodide, then is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl organometallic reagent. The amine is then alkylated with allyl iodide. Grubbs' catalyst is then used to form the azapine ring by ring closing metathesis. Epoxidation of the alkene followed by separation of the diastereomers followed by opening of the epoxide of the minor component with sodium azide provides the intermediate azido alcohol. Reduction of the azide followed by acylation of the amine with a lN-protected cycloalkane-carboxylic acid such as N-Boc-1-amino-cyclohexane-l-carboxylic acid and a peptide coupling reagent such as HBTU or EDC, followed by deprotection of the Cbz gives the intermediate secondary amine, which is then sulfonylated with an sulfonyl chloride. Deprotection of the Boc group followed by acylation with a carboxylic acid and a peptide coupling reagent such as HBTU or EDC, and final oxidation of the secondary alcohol to the ketone with an oxidant such as Dess-Martin periodinane or sulfurtrioxide pyridine complex with triethylamine provides the desired product. Scheme 7 Grubbs CbzNH 4) 2-pyridyl sulfonyl chloride The 2,2-4-trideutero-4-amino-azeρan-3-one compounds of the present invention may be conveniently prepared according to Scheme 8. Deuterated inhibitors can be prepared from the parent inhibitors such as benzofuran-2-carboxylic acid {(S)-3-methyl-l- [(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide by treating with a base such as triethyl amine and stirring for several days in a deteurated protic solvent such as CD 3 OD: D 2 0. Scheme 8 The 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 9. Intermediate (S)-3-Cyclohexyl-N- ((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-2-methyl-propionamide, as described in Scheme 3, is reductively aminated with an aldehyde or a ketone such as propionaldehyde, then treated with a reducing agent such as sodium borohydride. Deprotection of the Boc group followed by acylation with an acylating agent such as 2-furan carboxylic acid, HBTU, NMM, and final oxidation of the secondary alcohol to the ketone with an oxidant such as sulfur trioxide-pyridine provides the desired products. Scheme 9 The 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 10. Intermediate 1-Methyl- cyclohexanecarboxylic acid ((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-arnide, as described in Scheme 3, is acylated with an isocyanate such as (S)-(-)-2-isocyanato-4- methyl valeric acid methyl ester. Deprotection of the Boc group followed by acylation with an acylating agent such as benzofuran-2-carboxylic acid, HBTU, NMM, and final oxidation of the secondary alcohol to the ketone with an oxidant such as Dess-Martin periodinane or sulfur trioxide-pyridine provides the desired products. Scheme 10 3) Dess-Martin periodinane The 5-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 11. The synthesis of the C-5 methyl azepinone, 4,5 (R,S)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[5-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide, (Example 61) is outlined below in Scheme 7. Michael addition of nitromethane to ethyl crotonate 7-1 followed by reduction of the intermediate ester with a reducing agent such as diisobutyl aluminum hydride (Dibal-H) provides the aldehyde 7-2. Reductive amination of 7-2 with N-benzyl ethanolamine in the presence of a reducing agent such as sodium triacetoxyborohydride provides the nitro-alcohol 7-3. Oxidation of 7-3 using an oxidant common to the art such as DMSO and oxalyl chloride followed by treatment of the cmde intermediate aldehyde with a base such as triethylamine effects the nitro-aldol reaction to give the azepanol 7-4. Reduction of the nitro group with zinc in the presence of hydrochloric acid followed by coupling of the resulting amine with N-Boc-amino-cyclohexanecarboxylic acid in the presence of a coupling agent common to the art such as EDC provides intermediate 7-5. Reductive removal of the N-benzyl moiety with hydrogen gas in the presence of a catalyst such as 10% Pd on carbon followed by sulfonylation with a sulfonyl chloride in the presence of a base such as N-methylmorpholine or triethyl amine provides the sulfonamide intermediate 7-6. Removal of the N-Boc protecting group under acidic conditions followed by coupling of the resulting amine salt with benzofuran-2-carboxylic acid and oxidation of the alcohol with an oxidant common to the art such as pyridine sulfur trioxide complex or Dess-Martin periodinane provides the ketone 7. The individual diastereomers of 7-7 may be separated by HPLC methods to provide diastereomers 7-8, 7-9, 7-10 and 7- 11. Scheme 11 Na(OAo) 3 BH HPLC Separation 2 2-benzofuran carboxylic acid, EDC 3 Pyr-S0 3 oxidation 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- Veriag, 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+ 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. Quaternary ammonium salts are prepared by treating a parent amine compound with an excess of alkyl halide, such as methyl iodide. 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 lyophilized powders for parenteral administration. Powders may 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 polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, 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 carriers 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. Novel Intermediates Referring to the methods of preparing the compounds of Formula I set forth in Schemes 1-11 above, the skilled artisan will appreciate that the present invention includes all novel intermediates required to make the compounds of Formula I. In particular, the present invention provides the compounds of Formula II: wherein: R 2 is selected from the group consisting of: H, Ci .galkyl, C3_gcycloalkyl-Co_galkyl, Ar- C 0 .galkyl, Het-C 0 .galkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R! iNC(O)-, R 9 R! !NC(S)-, R 9 (R !)NS0 2 - , R 6 R ; and R 9 S0 2 R H NC(0)- ; R4 is selected from the group consisting of: H, Ci .galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R 12 NC(S)-; R^ is selected from the group consisting of: H, Ci .galkyl, C 2 .galkenyl, C 2 . galkynyl, C3_gcycloalkyl-Co_galkyl, C 2 _galkanonyl, Ar-CQ.galkyl and Het-Co_galkyl; R6 is selected from the group consisting of: H, Ci .galkyl, Ar-Cθ-6 a lkyl, or Het- C 0 .galkyl; R^ is selected from the group consisting of: H, Ci .galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 13 NC(S)-; R8 is selected from the group consisting of: H, Ci .galkyl, C 2 .galkenyl, C 2 .galkynyl, HetCrj-όalkyl and ArCo_6alkyl; R 9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-C()-galkyl, Ar-C 0 .galkyl, Ar-COOH, and Het-C 0 _galkyl; RIO is independently selected from the group consisting of: Ci .galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Cr j -galkyl and Het-Co-galkyl; RU is selected from the group consisting of: H, Ci .galkyl, Ar-C υ -6 a lkyl > and Het- C 0 .galkyl; R* 2 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het- Co-galkyl; R 3 is selected from the group consisting of: H, C j .galkyl, Ar-Cθ-6alkyl, and Het- Co-galkyl; R' is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het- R" is selected from the group consisting of: H, C j .galkyl, Ar-Cθ-6 a lkyl, or Het-Cø. galkyl; R'" is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co_galkyl, and Het-Cø_galkyl; Z is selected from the group consisting of: C(O) and CH 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof. The following compounds are preferred novel intermediates: benzofuran-2-carboxylic acid { l-[(+/-)-3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl }-amide; thieno[3,2-b]thiophene-2-carboxylic acid { l-[(+/-)-3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -cyclohexyl } -amide ; benzofuran-2-carboxylic acid { l-[(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl}-amide; and thieno[3,2-b]thiophene-2-carboxylic acid { l-[(3S,4S,7R)-3-hydroxy-7-methyl~l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide. Process for Synthesis of Inventive Compounds Referring to Schemes 1-11 herein above, the present invention provides a process for the synthesis of compounds of Formula (I) comprising the step of oxidizing the appropriate compound of Formula (II) with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers. Preferably the oxidant is Dess-Martin periodinane or pyridine sulfur trioxide complex in DMSO and triethylamine. Referring to Scheme 8, the present invention also provides a process for the synthesis of deuterated compounds of Formula (I). Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound of Formula (I) as a mixture of diastereomers is added to the synthesis. Preferably, the deuterating agent is CD 3 OD:D 2 0 (10:1) in triethylamine. The process further comprises the step of separating the diasteromers of Formula (I) by separating means, preferably by high presssure liquid chromatography (HPLC). 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, especially the preferred 1-amino-l-acyl cyclohexane compounds exhibit superior selectivity for cathepsin K versus cathepsins L,S, and B when compared to structurally similar compounds containing a leucine instead of 1-amino-l-acyl cyclohexane. The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cmzi, 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 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 (i.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 morphogenic protein, iproflavone, 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,app) were calculated according to equation 1 (Brandt etal., Biochemitsry, 1989, 28, 140): v = V m A /[K a (l + I7Ki, ap p) +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 jj S according to equation 2: [AMC] = v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] / k σ bs (2) where [AMC] is the concentration of product formed over time t, vo is the initial reaction velocity and v^ is the final steady state rate. Values for k 0 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 0 bs / [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). This assay measures the affinity of inhibitors to cysteine proteases, in this case, especially cathepsin K, as well as cathepsins L,S, and B. The skilled artisan would consider any compound exhibiting a Kj value of less than 1 micromolar to be a potential lead compound for further research, and an inhibitor exhibiting a Kj of less than 100 nM to be a dmg development dmg candidate assuming an acceptable pathology/toxicology profile and in vivo activity. Table I, below, provides inhibition assay data for selected compounds of the present invention. These data demonstrate that the inventive compounds efficiently inhibit cathepsin K. These data also show that the present compounds are highly selective for binding with cathepsin K, compared to binding with cathepsins L, S, or B. 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 x 10. 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 semm and 1.7g/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 (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). 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. Table 1 Assay Data 1) Benzofuran-2-carboxylic acid {l-[(S)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl} -amide (Example 1): Ki = 1.4 nM (human Cathepsin K) Ki = 239 nM (human Cathepsin L) Ki = 390 nM (human Cathepsin S) Ki = 926 nM (human Cathepsin B) 2) Benzofuran-2-carboxylic acid {l-[(R)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide (See Example 1): Ki = >26 nM (human Cathepsin K), sample may not have been completely free of S isomer. 3) Thieno[3,2-b]thiophene-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-cyclohexyl}-amide (Example 2): Ki = 0.58 nM (human Cathepsin K) Ki = 270 nM (human Cathepsin L) Ki = 632 nM (human Cathepsin S) Ki = 434 nM (human Cathepsin B) 4) Furo[3,2-b]pyridine-2-carboxylic acid {(S)-3-methyl-l-[(4S,7R)-7-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide (Example 3) : Ki = 1.8 nM (human Cathepsin K) Ki = 124 nM (human Cathepsin L) Ki = 317 nM (human Cathepsin S) Ki = 198 nM (human Cathepsin B) 5) Thieno[3,2-b]thiophene-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl] -cyclohexyl} -amide (Example 5): Ki = 0.3 nM (human Cathepsin K) Ki = 69 nM (human Cathepsin L) Ki = 175 nM (human Cathepsin S) Ki = 173 nM (human Cathepsin B) General Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Braker AM 250 or Broker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-dg 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 (cπf 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. Example 1 Preparation of Benzofuran-2-carboxylic acid { l-r(S)-3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyll-cyclohexyl i-amide a.) Allyl-pent-4-enyl-carbamic acid benzyl ester To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added benzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon 5- bromo-1-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40°C for approximately 4 hours whereupon the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2x's), brine, dried (MgS04), filtered and concentrated. Column chromatography of the residue (10% ethyl acetate :hexanes) provided 10.3 grams of the title compound as an oil: MS(EI) 260 (M+H+). b.) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid benzyl ester To a solution of allyl-pent-4-enyl-carbamic acid benzyl ester (50 g) in dichloromethane was added bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (5.0 g). The reaction was heated to reflux until complete as determined by TLC analysis. The reaction was concentrated in vacuo. Column chromatography of the residue (50% dichloromefhane:hexanes) gave 35 g of the title compound: MS(EI) 232 (M+H+). c.) 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester To the solution of 2,3, 4,7-Tetrahydro-azepine-l -carboxy lie acid benzyl ester (13 g, 56.3 mmol) in CH 2 C1 2 (500 ml) was added NaHC0 3 (14.2g, 169 mmol) and then mCPBA (29g, 169mmol) in portions. Stirred at RT for 4h before worked up by washing with 15% NaOH, saturated K,C0 3 and brine. Dried over Na 2 S0 4 . The reaction mixture was concentrated by rotary evaporation, the title compound was prepared: MS(EI) 248 (M+H+), 270(M+Na+). d.) 4-Azido-3-hydroxy-azepane-l -carboxylic acid benzyl ester To a solution of 8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (2.0 g, 8.1 mmol) in methanokwater (8:1 solution) was added NH 4 C1 (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). The reaction was heated to 40°C until complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic layer was washed with sat. NaHC0 3 , water, brine dried (MgS0 4 ), filtered and concentrated. Column chromatography (20% ethyl acetate:hexanes) of the residue provided 1.3 g of the title compound: MS(EI) 291 (M+H + ) plus 0.14 g of trans-4-hydroxy-3-azido-hexahydro-lH-azepine e.) 4-amino-3-hydroxy-azepane-l-carboxylic acid benzyl ester To a solution of 4-azido-3-hydroxy-azepane-l -carboxylic acid benzyl ester (1.1 g, 3.79 mmol) in methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1,3- propanedithiol (1.1 mL, 11.37 mL). The reaction was stirred until complete consumption of the starting material was observed by TLC analysis whereupon the reaction was concentrated in vacuo. Column chromatography of the residue (20% methano dichloromethane) provided 0.72 g of the title compound: MS(EI) 265 (M+H+). f.) 4~{[l-(l-tert-Butoxycarbonylamino-cyclohexyl)-methanoyl]-amino}-3-hydroxy- azepane-1 -carboxylic acid benzyl ester To a solution of the amino alcohol of 4-amino-3-hydroxy-azepane-l-carboxylic acid benzyl ester (1.17g, 3.89 mmol) in 10ml DMF was added HBTU (1.47g, 3.89mmol), NMM(1.57g, 15.6mmol) and B oc-1 -amino- 1 -cyclohexane carboxylic acid(0.95g, 3.89mmol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was diluted with ethyl acetate and washed with sat. NaHCθ3, water, brine, dried (MgS04), filtered and concentrated to give 2.0 g of the title compound: MS(EI) 490.4 (M+H+). g.) [l-(3-Hydroxy-azepan-4-ylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester To a solution of 4-{ [l-(l-tert-butoxycarbonylamino-cyclohexyl)-methanoyl]- amino}-3-hydroxy-azepane-l-carboxylic acid benzyl ester (1.6g, 3.27mmol) and 10% Pd/C (0.4g, catalytic) in ethanol was affixed a balloon of hydrogen. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo to provide 1.0 g of the title compound: MS(EI) 356.4 (M+H+). h.) { l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester To a solution of the compound of [l-(3-hydroxy-azepan-4-ylcarbamoyl)- cyclohexyl] -carbamic acid tert-butyl ester (0.45 g, 1.27 mmol) in CH 2 C1 2 was added pyridosulphonylchloride (0.23g, 1.27 mmol) followed by NMM (0.26g, 2.54 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with CH 2 C1 2 washed with sat. NaHCθ3, water, brine, dried (Na 2 Sθ4), filtered and concentrated. Column chromatography of the residue (2% methanohdichloromethane) gave 0.44g of the title compound: MS(EI) 497.4 (M+H+). i.) 1-Amino-cyclohexanecarboxylic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan- 4-yl]-amide To a solution of the compound of { l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -cyclohexyl} -carbamic acid tert-butyl ester (0.44g, 0.89mmol) in 1.4-dioxan (3 mL) was added 4M HCl in dioxane (4.4 mL). The reaction was stirred at room temperature for 2hr whereupon it was concentrated in vacuo to give 420 mg of the title compound: MS(ES) 397.2(M+H+). j.) Benzofuran-2-carboxylic acid { l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoylj-cyclohexyl }-amide To a solution of the amine salt of 1-amino-cyclohexanecarboxylic acid [3-hydroxy- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide (420 mg, 0.89 mmol) in DMF was added NMM (0.36g, 3.56 mmol), HBTU (405 mg, 1.07 mmol) and 2-benzofuran carboxylic acid (173mg, 1.07 mmol). The reaction was stirred until complete by TLC analysis whereupon solvent was removed in vacuo and the residue was dissolved with ethyl acetate and washed with sat. NaHCθ3, water, brine, dried (Na Sθ4), filtered and concentrated. Column chromatography of the residue (3% methanohdichloromethane) gave 400mg of the title compound: MS(EI) 541.2 (M+H+). k.) Benzofuran-2-carboxylic acid { l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoylj-cyclohexyl } -amide To a solution of benzofuran-2-carboxylic acid {l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide (200 mg, 0.37 mmol) in 5 ml CH 2 C1 2 , was added Dess-Martin reagent (240 mg, 0.56 mmol) at RT. The solution was stirred for 2 h when 50 ml CH 2 C1 2 was added and then washed with 1:1 mixture of 10% NaHC0 3 and 10% Na S 2 θ3 and brine. Purification by column chromatograghy (2% methanohdichloromethane) gave the title compound (120 mg, 60 % yield): Η NMR (CDC1 3 ): 5. = 8.70-8.69 (d, IH), 7.98-7.91(m, 2H), 7.71-7.69(d, IH), 7.58-7.28(m, 6H), 6.74(s, IH), 5.15-5.10(m, IH), 4.78-4.73(d, IH), 4.13-4.09(d, IH), 3.84-3.79(d, IH), 2.74- 2.68(t, IH), 2.37-1.37(m,14H); MS(EI) 539.2 (M+H+) Separation of the enantiomers by HPLC provided enantiomer 1: MS (El) 593.2(M+H + ), and enantiomer 2: MS (El) 593.2 (M+H+). Example 2 Preparation of Thieno[3,2-blthiophene-2-carboxylic acid {l-r(+/-)-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamovn-cyclohexyl)-amide Following the procedure of Example 1, except substituting "thieno[3,2- b]- thiophene-2-carboxylic acid (as described in Kukolja, Stjepan; et al. J.Med.Chem.1985, 28, 1896-1903)" for "benzofuran-2-carboxylic acid" gives the title compound: IH NMR: (DMSO): δ. = 8.76-8.74 (d, IH), 8.30(s, IH), 8.13-8.1 l(d, 2H), 8.00-7.98(d, IH), 7.87- 7.86(d, IH), 7.72(m, IH), 7.60-7.58(d, IH), 7.51-7.50(d, IH), 4.78(m, IH), 4.45-4.40(d, IH), 3.91-3.86(d, 2H), 2.87(m, IH), 2.20(m, 2H), 1.84-1.77(m,5H), 1.56(m, 6H), 1.27(m, IH); ESMS: (M+H+)= 561.2 Example 3 Preparation of Benzofuran-2-carboxylic acid l l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-cyclohexyl}-amide a. ((R)-2-Iodo-l-methyl-ethyl)-carbamic acid benzyl ester Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH 2 C1 2 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes ((R)-2-hydroxy-l-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT then stirred for 3 h. Then, H 2 0 (7 ml) was added and the reaction mixture was partitioned between CH 2 C1 2 (300 ml) and H 2 0 (600 ml). The aqueous layer was extracted again with CH 2 C1 2 (200 ml). The combined organic layer was then washed with a solution of 1:9 aq. saturated Na 2 S 2 0 3 : H 2 0 (140 ml), then brine (400 ml). The combined organics were dried with MgS0 , filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 15% EtOAc/ hexanes (1.5 liter). The solution was concentrated in vacuo, then the solid was washed with hexane and the resultant white solid was used in the next reaction without further purification (llg, 75%). b. ((R)-l-Methyl-pent-4-enyl)-carbamic acid benzyl ester Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml), then was cooled to -78 degrees C. A solution of allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added dropwise, then the solution was stirred for 30 minutes. ((R)-2-Iodo-l-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled THF (3 ml) was added dropwise, then the reaction was warmed to -40 degrees C and was stirred for 2.5 h. The reaction mixture was quenched with aq. sat. NH C1 (4 ml) at -40 degrees C, warmed to RT and the gray reaction mixture turned sky blue. THF was removed in vacuo. Then, Et 2 0 was added and the reaction mixture was filtered to remove precipitated solids. The solids were washed with additional Et 2 0. The combined organics were extracted with 10% NH OH (3x), then brine. The combined organics were dried with MgS0 4 , filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 20% EtOAc/ hexanes (100 ml). The solution was concentrated in vacuo, then the resultant colorless oil was used in the next reaction without further purification (0.8 g, 73%). c. Allyl-((R)-l-methyl-pent-4-enyl)-carbamic acid benzyl ester ((R)-l-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction was stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol) was added and the reaction mixture was stirred for 3 h at 0 degrees C. H 2 0 (10 ml) was added, then 2N HCl was added dropwise adjusting the pH to 1. The reaction mixture was extracted with Et 2 0 (2 x 50 ml). The combined organics were washed with aq. 2N HCl, then aq. NaHC0 3 , then brine. The combined organics were dried with MgS0 4 , filtered, concentrated in vacuo, then chromatographed on silica gel (5% EtOAc/ hexanes) to yield the title compound as a colorless oil (883 mg, 95%). d. 2-Methyl-2,3,4,7-tetrahydro-azepine-l-carboxylic acid benzyl ester Allyl-(l-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19 mmol) was dissolved in CH 2 C1 2 (10 ml) and a stream of argon gas was bubbled into the reaction mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine mthenium(IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and the reaction mixture was refluxed for 2 h. Additional bis(tricyclohexylphosphine)benzylidine mthenium(IV) dichloride ( mg, 0.0108 mmol) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to RT under argon overnight, then was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 5% EtOAc/ hexanes) to give the title compound (0.72 g, 92%): IH NMR: 7.35-7.20 (m, 5H), 5.65 (IH, m), 5.13 (2H, AB), 4.45-4.05 (m, 2H), 3.56 (IH, d), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H + = 246.2. e. (lS,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester m-Chloro-perbenzoic acid (1.10 g, 57-86% pure) was added to a solution of 2- methyl-2,3,4,7-tetrahydro-azepine-l-carboxylic acid benzyl ester (0.72 g, 2.94 mmol) in CH 2 C1 2 at 0 degrees C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloro-perbenzoic acid (0.660 g, 57-86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc :hexanes) to give (lS,4R,7S)-4-methyl-8-oxa-3- aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield): IH NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (IH, d), 3.12-2.95 (IH, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H + = 262.0. f. (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester Sodium azide (0.139 g, 2.14 mmol) was added to a solution of (lS,4R,7R)-4- methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) in MeOH (1.5 ml) and H 2 0 (0.15 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgS0 4 , filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.192 g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m, 2H), 3.10 (IH, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H + = 305.2. g. (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-5- azido-6-hydroxy-2-methyl-azepane-l -carboxylic acid benzyl ester (0.193 g, 0.635 mmol) in THF (10 ml) and H 2 0 (0.04 ml), then was heated to 45 degrees C overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et 2 0 and the resulting salt was collected following filtration and was used in the next reaction without further purification (0.27 g, 90%). h. (2R,5S,6S)-5-{[l-(l- tert -Butoxycarbonylamino-cyclohexyl)-methanoyl]-amino}-6- hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester 4-methylmorpholine (388mg, 0.42 ml, 3.84 mmol) was added to a solution of Boc- 1-amino-cyclohexanecarboxylic acid (255 mg, 1.05 mmol), HBTU(398 mg, 1.05 mmol), and (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester (300 mg, 0.96 mmol) in DMF (5.0 ml). The reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml) after the removal of DMF, washed with NaHCO3(50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexanes) to yield the title compound (320 mg, 66 %): Electrospray mass spec: M+H + = 504.2 i. [l-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-cyclohexyl]-carbamic acid - tert-butyl ester (2R,5S,6S)-5-{ [1-(1- tert -Butoxycarbonylamino-cyclohexyl)-methanoyl]-amino}- 6-hydroxy-2-methyl-azepane-l -carboxylic acid benzyl ester (320 mg, 0.636 mmol) was dissovled in EtOH (10 ml). Then 10% Pd/C (0.1 g ) was added and the reaction was stirred for 5h under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.24 g): Electrospray mass spec: M+H + = 370.2 j. {l-[(3S,4S,7R)-3-Hydroxy-7-methyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- cyclohexyl} -carbamic acid-tert-butyl ester 2-Pyridine sulfonyl chloride (114 mg, 0.64 mmol) was added to a solution [1- ((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-cyclohexyl]-carbamic acid -tert- butyl ester (240 mg, 0.64 mmol), Triethylamine (194 mg, 1.92 mmol) in CH 2 C1 2 (5 ml) and was stirred at RT over night. The reaction mixture was diluted with CH 2 C1 2 (100 ml), washed with NaHC03, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% to 75% EtOAc/hexanes) to yield the title compound (0.2 g, 61%): Electrospray mass spec: M+H 1" = 511.2 k. 1-Amino-cyclohexanecarboxylic acid [(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2- sulfonyι)-azepan-4-yl]-amide HCl in dioxane (4.0 M, 5.0 ml) was added to a stirred solution { l-[(3S,4S,7R)-3- Hydroxy-7-methyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-carbamic acid-tert-butyl ester (200 mg, 0.39 mmol) in MeOH (1.0 ml). The reaction mixture was stirred for 2h at RT, then was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (190 mg). M+H + = 411.4 1. Benzofuran-2-carboxylic acid {l-[(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl }-amide 4-methylmorpholine (81 mg, 0.8 mmol) was added to a solution of benzofuran-2- carboxylic acid (38.4mg, 0.24 mmol), HBTU(91 mg, 0.24 mmol), and 1-Amino- cyclohexanecarboxylic acid [(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2-sulfonyl)- azepan-4-yl]-amide (95 mg, 0.2 mmol) in DMF (5.0 ml). The reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml) after the removal of DMF, washed with NaHCθ3(50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2.0% MeOH/ CH 2 C1 2 ) to yield the title compound (90 g, 81%): Electrospray mass spec: M+H + = 555.4 m. Benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl}-amide Dess-Martin periodinane (137 mg, 0.324mmol) was added to a solution of . Benzofuran-2-carboxylic acid { l-[(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl} -amide (90 mg, 0.162 mmol) in CH 2 C1 2 (5 ml) and was stirred at RT for 2 h. The solution was washed with 10% aq. Na 2 S 2 0 3 , then aq. sat. NaHC0 3 , then brine. Purification by column chromatography (silica gel, 2.0% MeOH/ CH 2 C1 2 ) gave the title compound (58mg, 64%): IH NMR: (CDC1 3 ): δ. = 8.74-8.73 (d, IH), 8.02-7.91(m, 2H), 7.71-7.69(d, IH), 7.58-7.28(m, 6H), 6.73(s, IH), 5.10-5.08(m, IH), 4.78-4.73(d, IH), 4.44(m, IH), 3.86-3.81(d, IH), 2.33-2.01(m, 6H), 1.98-1.40(m,8H), 0.99-0.97(d, 3H); MS(EI): (M+H+)= 553.4 Example 4 Preparation of 2,2,4-Trideutero- Benzofuran-2-carboxylic acid I l-r(4S.7R)-7-methyl-3-oxo- 1 -(pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl1 -cyclohexyl ) -amide Benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -cyclohexyl} -amide is dissolved in d4-methanol (CD 3 OD) and D 2 0 (10:1), then triethyl amine is added and the reaction mixture is stirred for 3 days. Azeotroping with toluene by concentrating in vacuo provides the title compound. Example 5 Preparation of Thienor3,2-b1thiophene-2-carboxylic acid ( l-r(4S,7R)-7-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-cyclohexyl)-amide Following the procedure of Example 3, except substituting "thieno[3,2- b]- thiophene-2-carboxylic acid (as described in Kukolja, Stjepan; et al. J.Med.Chem.1985, 28, 1896-1903)" for "benzofuran-2-carboxylic acid" gives the title compound: IH NMR: (CDC13) δ. = 8.65-8.64 (d, IH), 7.92-7.85(m, 2H), 7.76(s, IH), 7.47-7.41 (m, 3H), 7.21- 7.20(d, IH), 6.08(s, IH), 5.01-4.96(m, IH), 4.69-4.64(d, IH), 4.35-4.33(m, IH), 3.77- 3.72(d, IH), 2.25-1.26(m, 14H), 0.90(m, 3H); ESMS: (M+H+)= 575.2 Example 6 Preparation of 2.2,4-Trideutero-Benzofuran-2-carboxylic acid { l-r(+/-)-3-oxo-l-(pyridine- 2-sulf onyl)-azepan-4-ylcarbamoyl1-cyclohexyl ) -amide Following the procedure of Example 4, except "benzofuran-2-carboxylic acid { l-[(+/-)-3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide" for " Benzofuran- 2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide " gives the title compound. Example 7 Preparation of 2,2,4-Trideutero-Thienor3,2-blthiophene-2-carboxylic acid j l-[(S)-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-cyclohexyl}-amide Following the procedure of Example 4, except "thieno[3,2-b]thiophene-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide " for " Benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-cyclohexyl}-amide " gives the title compound. Example 8 Preparation of 2,2.4-Trideutero-thienor3.2-blthiophene-2-carboxylic acid (l-r(4S,7R)-7- methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-cyclohexyl}-amide Following the procedure of Example 4, except "thieno[3,2-b]thiophene-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(ρyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}- amide " for " Benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide " gives the title compound. 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: wherein: R 2 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R π NC(0)-, R 9 R π NC(S)-, R 9 (R π )NS0 2 -, R D R ,7 - R° , and R9sθ 2 R 1 1 NC(O)-; R4 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R 12 NC(S)-; R^ is selected from the group consisting of: H, C j .galkyl, C2-6 h enyl, C 2 . galkynyl, C3_gcycloalkyl-Co_galkyl, C 2 -6alkanonyl, Ar-Co_galkyl and Het-Co_galkyl; R6 is selected from the group consisting of: H, C j .galkyl, Ar-Cθ-6 a lkyl, and Het- C 0 .galkyl; R is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC( o)-, and R 10 R 1 NC(S)-; R8 is selected from the group consisting of: H, Cj.galkyl, C 2 -6alkenyl, C 2 _galkynyl, HetC Q _galkyl and ArCr j -galkyl; R 9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Co-galkyl, Ar-COOH, and Het-C 0 .galkyl; RlO is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-C()-galkyl, Ar-Co-galkyl and Het-C Q .galkyl; Rl 1 is selected from the group consisting of: H, C .galkyl, Ar-C()-6 a lkyl > and Het- C 0 _galkyl; Rl is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6 a lkyl, and Het- Co_galkyl; Rl 3 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6 a lkyl, and Het- Co-galkyl; R' is selected from the group consisting of: H, C .galkyl, Ar-Cθ-6 a lkyl, and Het- C 0 .galkyl; R" is selected from the group consisting of: H, C .galkyl, Ar-Cθ-6 a lkyl, and Het- Cø.galkyl; R'" is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co_galkyl, and Het-Cr j -galkyl; Z is selected from the group consisting of: C(O) and CH 2 ; and n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof. 2. A compound according to Claim 1 wherein n is 4. 3. A compound according to either Claim 1 or 2 wherein R^ is selected from the group consisting of: R 5 OC(0)-,R 5 C(0)- or R 5 S0 2 -. 4. A compound according to Claim 3 wherein R^ is R^C(O)-. 5. A compound according to Claim 4 wherein R^ is selected from the group consisting of: C j .galkyl, C 2 .galkenyl, C3_gcycloalkyl-Crj_galkyl, C 2 _galkanonyl, AΓ-CQ. galkyl and Het-C Q .galkyl. 6. A compound according to Claim 5 wherein: C j .galkyl is selected from the group consisting of: methyl, halogenated methyl, Cj.galkoxy and aryloxy substituted methyl, heterocycle substituted methyl; ethyl, heterocycle substituted ethyl; butyl, aryl substituted butyl; and isopentyl; C3_gcycloalkyl-Co_galkyl is cyclohexyl; C 2 -6alkenyl is selected from the group consisting of: butenyl, and aryl substituted butenyl; C 2 _galkanonyl is selected from the group consisting of: acetyl; and pentanonyl; Ar-Co-galkyl is selected from the group consisting of: phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more aryloxy or C j .galkoxy groups, phenyl substituted with one or more Cj.galkyl sulfonyl groups; benzyl; and naphthylenyl; and Het-Co-galkyl is selected from the group consisting of: benzo[l,3]dioxolyl; furanyl, nitro substituted furanyl, halogen substituted furanyl, aryl substituted furanyl, Cj.galkyl substituted furanyl; tetrahydrofuranyl; benzofuranyl, C j .galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C j .galkyl substituted benzofuranyl; napththo [2, 1-b] -furanyl, C .galkyl substituted napththo [2, 1-b] -furanyl; benzo[έ]thiophenyl, C j .galkoxy substituted benzo[&]fhiophenyl; quinolinyl; quinoxalinyl; 1,8 naphthyridinyl; indolyl, C j .galkyl substituted indolyl; pyridinyl, C j .galkyl substituted pyridinyl, 1-oxy-pyridinyl; furo[3,2-b]-pyridinyl, C j .galkyl substituted furo[3,2-b]-pyridinyl; thiophenyl, C j .galkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3,2-&]thiophenyl C j .galkyl substituted thieno[3,2-£]thiophen-2-yl; isoxazolyl, C j .galkyl substituted isoxazolyl; oxazolyl, aryl substituted oxazolyl, C j .galkyl substituted oxazolyl; and lH-benzoimidazolyl. 7. A compound according to Claim 6 wherein: halogenated methyl is trifluoromethyl; C .galkoxy substituted methyl is selected from the group consisting of: phenoxy- methyl and 4-fluoro-phenoxy-methyl; heterocycle substituted methyl is 2-thiophenyl-methyl; heterocycle substituted ethyl is piperidin-1-yl-ethyl; aryl substituted butyl is 4-(4-methoxy)phenyl-butyl; pentanonyl is 4-pentanonyl; aryl substituted butenyl is 4,4-bis(4-methoxyphenyl)-but-3-enyl; phenyl substituted with one or more halogens is selected from the group consisting of: 3,4-dichlorophenyl and 4-fluorophenyl; phenyl substituted with one or more aryloxy or C j .galkoxy groups is selected from the group consisting of: 3,4-dimethoxy-phenyl and 3-benzyloxy-4-methoxy-phenyl; phenyl substituted with one or more C j .galkyl sulfonyl groups is 4- methanesulf onyl-phenyl ; naphthylenyl is naphthylen-2-yl; benzo[l,3]dioxolyl is benzo[l,3]dioxol-5-yl, furanyl is furan-2-yl; nitro substituted furanyl is 5-nitro-furan-2-yl; aryl substituted furanyl is selected from the group consisting of: 5-(4-nitrophenyl)- furan-2-yl, 5-(3-triflouromethyl-phenyl)-furan-2-yl, and 5-(4-chloro-phenyl)-furan-2-yl); halogen substituted furanyl is 5-bromo-furan-2-yl; C j .galkyl substituted furanyl is selected from the group consisting of: 3-methyl- furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-2-yl; tetrahydrofuranyl is tetrahydrofuran-2-yl; benzofuranyl is benzofuran-2-yl; C j .galkoxy substituted benzofuranyl is selected from the group consisting of: 5-(2- piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4- yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- l-yl-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl- ethoxy)-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofura-2-yl, 5,6- dimethoxy-benzofuran-2-yl5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl- benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; halogen substituted benzofuranyl is selected from the group consisting of: 5-fluoro- benzofuran-2-yl 5,6-difluoro-benzofuran-2-yl5-fluoro-3-methyl-benzofuran-2-yl, and 6- fluoro-3-methyl-benzofuran-2-yl; C j .galkyl substituted benzofuranyl is selected from the group consisting of: 3- methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; napththo[2,l-b]-furanyl is napththo[2,l-b]-furan-2-yl; C j .galkyl substituted napththo[2,l-b]-furanyl is l-methyl-naphtho[2,l-b]-furan-2- yi; benzo[&]thiophenyl is benzo[έ]thiophen-2-yl; C j .galkoxy substituted benzo[έ]thiophenyl is 5,6-dimethoxy- benzo[Z?]thiophen-2- yl; quinolinyl is selected from the group consisting of: quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalinyl is quinoxalin-2-yl; 1,8 naphthyridinyl is 1,8 naphthyridin-2-yl; indolyl is selected from the group consisting of: indol-3-yl and indol-5-yl; Cj.galkyl substituted indolyl is N-methyl-indol-2-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl, and pyridin-5-yl; 1-oxy-pyridinyl is selected from the group consisting of: l-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl; Cj.galkyl substituted pyridinyl is 2-methyl-pyridin-5-yl; furo[3,2-b]-pyridinyl is furo[3,2-b]-pyridin-2-yl; C j .galkyl substituted furo[3,2-b]-pyridinyl is 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl is thiophen-3-yl; halogen substituted thiophenyl is 4,5-dibromo-thiophen-2-yl; Cj.galkyl substituted thiophenyl is 5-methyl-thiophen-2-yl; thieno[3,2-Z>]thiophenyl is thieno[3,2-£]thiophene-2-yl; C j .galkyl substituted thieno[3,2-£>]thiophen-2-yl is 5-tert-butyl-3-methyl thieno[3,2-Z?]thiophen-2-yl; isoxazolyl is isoxazol-4-yl; Cj.galkyl substituted isoxazolyl is 3,5-dimethyl- isoxazol-4-yl; oxazolyl is oxazol-4-yl; aryl substituted oxazolyl is 5-methyl-2-phenyl oxazol-4-yl; C j .galkyl substituted oxazolyl is 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl is lH-benzoimidazol-5-yl. 8. A compound according to Claim 7 wherein R^ is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 5-methoxybenzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, quinoxalin-2-yl, and quinolin-2-yl. 9. A compound according to Claim 8 wherein R^ is selected from the group consisting of: benzofuran-2-yl and thieno[3,2-b]thiophene-2-yl. 10. A compound according to Claim 9 wherein Rp is benzofuran-2-yl. 11. A compound according to either Claim 1 or 2 wherein R is selected from the group consisting of H and naphthalen-2-yl-methyl. 12. A compound according to Claim 11 wherein R is H. 13. A compound according to either Claim 1 or 2 wherein R" is H. 14. A compound according to either Claim 1 or 2 wherein R'" is selected from the group consisting of H and methyl. 15. A compound according to Claim 14 wherein R'" is methyl. 16. A compound according to either Claim 1 or 2 wherein R" is H and R'" is methyl. 17. A compound according to either Claim 1 or 2 wherein R 2 is selected from the group consisting of: Ar-Cθ-6alkyl, R 9 C(0)-, R 9 S0 2 , R 9 R n NC(0)-, 18. A compound according to Claim 17 wherein R 2 is selected from the group consisting of: Ar-Cfj-6alkyl, R 9 C(0)-, and R 9 S0 2 . 19. A compound according to Claim 18 wherein R 2 is R 9 S0 2 20. A compound according to Claim 17 wherein R" is H. 21. A compound according to Claim 17 wherein R' is Rl"OC(0). 22. A compound according to Claim 17 wherein R° is Cj.galkyl. 23. A compound according to Claim 22 wherein R^ is isobutyl. 24. A compound according to Claim 17 wherein R 9 is selected from the group consisting of: Cj.galkyl, Ar-Co-galkyl, -Ar-COOH and Het-Cg-galkyl. 25. A compound according to Claim 24 wherein: C j .galkyl is selected from the group consisting of: methyl; ethyl, C3_gcycloalkyl-Co_galkyl-substituted ethyl; propyl; butyl, Cj.galkyl-substituted butyl; tert-butyl; and isopentyl; Ar-Co_galkyl is selected from the group consisting of: phenyl, halogen substituted phenyl,Cj.galkoxy phenyl, C j .galkyl substituted phenyl, cyanophenyl, C j .galkyl sulfonyl substituted phenyl; toluyl, Het-substituted toluyl; and naphthylenyl; -Ar-COOH is benzoic acid; Het-Co-galkyl is selected from the group consisting of: benzo[l,3]dioxolyl; benzo[l,2,5]oxadiazolyl; pyridinyl, 1 -oxy-pyridinyl, C j .galkyl pyridinyl; thiophene; thiazolyl; lH-imidazolyl, C j .galkyl substituted imidazolyl; lH-[l,2,4]triazolyl, C j .galkyl substituted lH-[l,2,4]triazolyl; isoxazolyl, and Cj.galkyl substituted isoxazolyl. 26. A compound according to Claim 25 wherein: ethyl is 2-cyclohexyl-ethyl; butyl is 3-methylbutyl; phenyl is selected from the group consisting of: 3,4-dichlorophenyl, 4- bromophenyl, 2-fluorophenyl, 3-fluorophenyl 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-cyanophenyl; 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; and naphthylen-2-yl; benzoic acid is 2-benzoic acid; benzo[l,3]dioxolyl is benzo[l,3]dioxol-5-yl; benzo[l,2,5]oxadiazolyl is benzo[l,2,5]oxadiazol-4-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl , 3- methyl-pyridin-2-yl, and 6-methyl-pyridin-2-yl; 1-oxy-pyridinyl is selected from the group consisting of: l-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl; thiopheneyl is thiophene-2-yl; thiazolyl is thiazol-2-yl; lH-imidazolyl is selected from the group consisting of: lH-imidazol-2-yl, 1H- imidazol-4-yl, l-methyl-lH-imidazol-2-yl, 1 -methyl- lH-imidazol-4-yl, , and 1,2-dimethyl- lH-imidazol-4-yl; lH-[l,2,4]triazolyl is selected from the group consisting of: lH-[l,2,4]triazol-3-yl and 5-methyl-lH-[l,2,4]triazol-3-yl; and 3,5-dimethyl-isoxazolyl is 3,5-dimethyl-isoxazol-4-yl. 27. A compound according to either Claim 1 or 2 wherein: R 2 is selected from the group consisting of: R b N . ,7/ " ' \ Ar-Co-6alkyl, R 9 C(0)-, R 9 S0 2 , R 9 R ! !NC(0)-, and R° R 4 is selected from the group consisting of: R 5 OC(0)-, R 5 C(0)- or R 5 S0 2 -; R-> is selected from the group consisting of: C j .galkyl, C 2 -6alkenyl, C _ gcycloalkyl-Co-galkyl, C 2 _galkanonyl, Ar-CQ-galkyl and Het-CQ.galkyl; R 6 is H; R 7 is R 10 OC(O); R 8 is Cj-galkyl; R 9 is selected from the group consisting of: Cj.galkyl, Ar-Cr j -galkyl, -Ar-COOH and Het-Co-galkyl; RIO is selected from the group consisting of: C j .galkyl, Ar-Cø-galkyl and Het-CQ. galkyl; R' is H; R" is H; and R'" is methyl. 28. A compound according to Claim 27 wherein: R 2 is selected from the group consisting of: Ar-Cθ-6 a lkyl, R C(0)- and R 9 S0 2 ; R 4 is R 5 C(0)-; and in R 5 : Cj.galkyl is selected from the group consisting of: methyl, halogenated methyl, C j .galkoxy substituted methyl, heterocycle substituted methyl; ethyl, heterocycle substituted ethyl; butyl, aryl substituted butyl; and isopentyl; C3_gcycloalkyl-Co_galkyl is cyclohexyl; C 2 _galkenyl is selected from the group consisting of: butenyl, and aryl substituted butenyl; C 2 -6alkanonyl is selected from the group consisting of: acetyl; and pentanonyl; Ar-Co_galkyl is selected from the group consisting of: phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more aryloxy or Cj.galkoxy groups, phenyl substituted with one or more Cj.galkyl sulfonyl groups; benzyl; and naphthylenyl; and Het-C .galkyl is selected from the group consisting of: benzo[l,3]dioxolyl; furanyl, nitro substituted furanyl, halogen substituted furanyl, aryl substituted furanyl, C j .galkyl substituted furanyl; tetrahydrofuranyl; benzofuranyl, Cj.galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, Cj.galkyl substituted benzofuranyl; napththo[2,l-b]-furanyl, Cj.galkyl substituted napththo [2, 1-b] -furanyl; benzo[έ]thiophenyl, C j .galkoxy substituted benzo[έ]thiophenyl; quinolinyl; quinoxalinyl; 1,8 naphthyridinyl; indolyl, Cj.galkyl substituted indolyl; pyridinyl, Cj.galkyl substituted pyridinyl, 1-oxy-pyridinyl; furo[3,2-b]-pyridinyl, C j .galkyl substituted furo[3,2-b]-pyridinyl; thiophenyl, C j .galkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3,2- ?]thiophenyl Cj.galkyl substituted thieno[3,2-&]thiophen-2-yl; isoxazolyl, C j .galkyl substituted isoxazolyl; oxazolyl, aryl substituted oxazolyl, C j .galkyl substituted oxazolyl; and lH-benzoimidazolyl. 29. A compound according to Claim 28 wherein: halogenated methyl is trifluoromethyl; C j .galkoxy substituted methyl is selected from the group consisting of: phenoxy- methyl and 4-fluoro-phenoxy-methyl; heterocycle substituted methyl is 2-thiophenyl-methyl; heterocycle substituted ethyl is piperidin-1-yl-ethyl; aryl substituted butyl is 4-(4-methoxy)phenyl-butyl; pentanonyl is 4-pentanonyl; aryl substituted butenyl is 4,4-bis(4-methoxyphenyl)-but-3-enyl; phenyl substituted with one or more halogens is selected from the group consisting of: 3,4-dichlorophenyl and 4-fluorophenyl; phenyl substituted with one or more aryloxy or Cj.galkoxy groups is selected from the group consisting of: 3,4-dimethoxy-phenyl and 3-benzyloxy-4-methoxy-phenyl; phenyl substituted with one or more C j .galkyl sulfonyl groups is 4- methanesulfonyl-phenyl; naphthylenyl is naphthylen-2-yl; benzo[l,3]dioxolyl is benzo[l,3]dioxol-5-yl, furanyl is furan-2-yl; nitro substituted furanyl is 5-nitro-furan-2-yl; aryl substituted furanyl is selected from the group consisting of: 5-(4-nitrophenyl)- furan-2-yl, 5-(3-triflouromethyl-phenyl)-furan-2-yl, and 5-(4-chloro-phenyl)-furan-2-yl); halogen substituted furanyl is 5-bromo-furan-2-yl; C j .galkyl substituted furanyl is selected from the group consisting of: 3-methyl- furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-2-yl; tetrahydrofuranyl is tetrahydrofuran-2-yl; benzofuranyl is benzofuran-2-yl; C j .galkoxy substituted benzofuranyl is selected from the group consisting of: 5-(2- piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4- yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- l-yl-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl- ethoxy)-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofura-2-yl, 5,6- dimethoxy-benzofuran-2-yl5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl- benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; halogen substituted benzofuranyl is selected from the group consisting of: 5-fluoro- benzofuran-2-yl 5,6-difluoro-benzofuran-2-yl5-fluoro-3-methyl-benzofuran-2-yl, and 6- fluoro-3-methyl-benzofuran-2-yl; C j .galkyl substituted benzofuranyl is selected from the group consisting of: 3- methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; napththo [2, 1-b] -furanyl is napththo[2,l-b]-furan-2-yl; Cj.galkyl substituted napththo[2,l-b]-furanyl is l-methyl-naphtho[2,l-b]-furan-2- yi; benzo[έ>] thiophenyl is benzo[έ]thiophen-2-yl; Cj.galkoxy substituted benzo[έ]thiophenyl is 5,6-dimethoxy- benzo[ >]thiophen-2- yi; quinolinyl is selected from the group consisting of: quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalinyl is quinoxalin-2-yl; 1,8 naphthyridinyl is 1,8 naphthyridin-2-yl; indolyl is selected from the group consisting of: indol-3-yl and indol-5-yl; C .galkyl substituted indolyl is N-methyl-indol-2-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl, and pyridin-5-yl; 1-oxy-pyridinyl is selected from the group consisting of: l-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl; C j .galkyl substituted pyridinyl is 2-methyl-pyridin-5-yl; furo [3, 2-b] -pyridinyl is furo[3,2-b]-pyridin-2-yl; C j .galkyl substituted furo[3,2-b]-pyridinyl is 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl is thiophen-3-yl; halogen substituted thiophenyl is 4,5-dibromo-thiophen-2-yl; C j .galkyl substituted thiophenyl is 5-methyl-thiophen-2-yl; thieno[3,2-&]thiophenyl is thieno[3,2-έ]thiophene-2-yl; C j .galkyl substituted thieno[3,2-Z?]thiophen-2-yl is 5-tert-butyl-3-methyl thieno[3,2--.]thiophen-2-yl; isoxazolyl is isoxazol-4-yl; Cj.galkyl substituted isoxazolyl is 3,5-dimethyl- isoxazol-4-yl; oxazolyl is oxazol-4-yl; aryl substituted oxazolyl is 5-methyl-2-phenyl oxazol-4-yl; C j .galkyl substituted oxazolyl is 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl is lH-benzoimidazol-5-yl. 30. A compound according to either Claim 28 or 29 wherein in R 9 : Cj.galkyl is selected from the group consisting of: methyl; ethyl, C3_gcycloalkyl-C()-galkyl -substituted ethyl; propyl; butyl, C .galkyl-substituted butyl; tert-butyl; and isopentyl; Ar-Co-galkyl is selected from the group consisting of: phenyl, halogen substituted phenyl,C j .galkoxy phenyl, C j .galkyl substituted phenyl, cyanophenyl, Cj.galkyl sulfonyl substituted phenyl; toluyl, Het-substituted toluyl; and naphthylenyl; -Ar-COOH is benzoic acid; Het-Co-galkyl is selected from the group consisting of: benzo[l,3]dioxolyl; benzo[l,2,5]oxadiazolyl; pyridinyl, 1 -oxy-pyridinyl, C j .galkyl pyridinyl; thiopheneyl; thiazolyl; lH-imidazolyl, Cj.galkyl substituted imidazolyl; lH-[l,2,4]triazolyl, Cj.galkyl substituted lH-[l,2,4]triazolyl; isoxazolyl, and Cj.galkyl substituted isoxazolyl. 31. A compound according to Claim 30 wherein: ethyl is 2-cyclohexyl-ethyl; butyl is 3-methylbutyl; phenyl is selected from the group consisting of: 3,4-dichlorophenyl, 4- bromophenyl, 2-fluorophenyl, 3-fluorophenyl 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-cyanophenyl; 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; and naphthylen-2-yl; benzoic acid is 2-benzoic acid; benzo[l,3]dioxolyl is benzo[l,3]dioxol-5-yl; benzo[l,2,5]oxadiazolyl is benzo[l,2,5]oxadiazol-4-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl , 3- methyl-pyridin-2-yl, and 6-methyl-pyridin-2-yl; 1-oxy-pyridinyl is selected from the group consisting of: l-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl; thiopheneyl is thiophene-2-yl; thiazolyl is thiazol-2-yl; lH-imidazolyl is selected from the group consisting of: lH-imidazol-2-yl, 1H- imidazol-4-yl, l-methyl-lH-imidazol-2-yl, 1 -methyl- lH-imidazol-4-yl, , and 1,2-dimethyl- lH-imidazol-4-yl; lH-[l,2,4]triazolyl is selected from the group consisting of: lH-[l,2,4]triazol-3-yl and 5-methyl-lH-[l,2,4]triazol-3-yl; and 3,5-dimethyl-isoxazolyl is 3,5-dimethyl-isoxazol-4-yl. 32. A compound according to Claim 27 wherein: R 2 is R 9 S0 2 ; R 4 is R 5 C(0); R^ is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran- 2-yl, 5-methoxybenzofuran-2-yl, thieno[3,2-b]thiophene-2-yl, quinoxalin-2-yl, and quinolin-2-yl, and R 9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl. 33. A compound according to Claim 32 wherein R^ is selected from the group consisting of: benzofuran-2-yl and thieno[3,2-b]thiophene-2-yl. 34. A compound according to Claim 33 wherein R^ is benzofuran-2-yl. 35. A compound according to Claim 32 wherein R 9 is pyridin-2-yl. 36. A compound according to either Claim 1 or 2 -selected from the group consisting of: benzofuran-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoylj-cyclohexyl }-amide; benzofuran-2-carboxylic acid { 1 - [(R)-3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoylj-cyclohexyl }-amide; thieno[3,2-b]thiophene-2-carboxylic acid { l-[(+/-)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl }-amide; benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; 2,2,4-trideutero-benzofuran-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl}-amide; 2,2,4-trideutero- benzofuran-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; 2,2,4-trideutero-thieno[3,2-b]thiophene-2-carboxylic acid { l-[(S)-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; and 2,2,4-trideutero-thieno[3,2-b]thiophene-2-carboxylic acid { l-[(4S,7R)-7-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide. 37. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 36 and a pharmaceutically acceptable carrier, diluent or excipient. 38. A method of inhibiting a protease, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Claims 1 to 36. 39. A method according to Claim 38 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease. 40. A method according to Claim 39 wherein said protease is a cysteine protease. 41. A method according to Claim 40 wherein said cysteine protease is cathepsin K. 42. 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 any one of Claims 1 to 36. 43. A method according to Claim 42 wherein said disease is osteoporosis. 44. A method according to Claim 42 wherein said disease is periodontitis. 45. A method according to Claim 42 wherein said disease is gingivitis. 46. 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 Claims 1 to 36. 47. A method according to Claim 46 wherein said disease is osteoarthritis. 48. A method according to Claim 46 wherein said disease is rheumatoid arthritis. 49. A compound of Formula II: II wherein: R 2 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 .galkyl, Het-C 0 _galkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R! lNC(0)-, R 9 R! R 6 R 7 ' R ° ; and R9sθ 2 R 11 NC(0)- ; R 4 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R 12 NC(S)-; R5 is selected from the group consisting of: H, Cj.galkyl, C 2 _galkenyl, C 2 . galkynyl, C3_gcycloalkyl-Co.galkyl, C _galkanonyl, Ar-Co_galkyl and Het-Cø.galkyl; R6 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6 a lkyl, or Het- Co-galkyl; R 7 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 1 NC(S)-; R 8 is selected from the group consisting of: H, Cj.galkyl, C 2 _galkenyl, C 2 .galkynyl, HetCo-6alkyl and ArCθ-6 a lkyl; R 9 is selected from the group consisting of: C j .galkyl, C3_gcycloalkyl-C ( )-galkyl, Ar-C 0 _galkyl, -ArCOOH, and Het-C 0 .galkyl; RIO is independently selected from the group consisting of: C .galkyl, C3_gcycloalkyl-C () -galkyl, Ar-Co-galkyl and Het-Cr j .galkyl; RU is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het- Co-6 ikyi; Rl 2 is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6 a lkyl, and Het- Co-galkyl; Rl 3 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het- Co-galkyl; R' is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6 a lkyl, and Het- Co-galkyl; R" is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6 a lkyl, or Het-Cø. galkyl; R'" is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co_galkyl, and Het-Co_galkyl; Z is selected from the group consisting of: C(O) and CH 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof. 50. A compound according to Claim 49 selected from the group consisting of: benzofuran-2-carboxylic acid { l-[(+/-)-3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid { l-[(+/-)-3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl}-amide; benzofuran-2-carboxylic acid { l-[(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl }-amide; and thieno[3,2-b]thiophene-2-carboxylic acid { l-[(3S,4S,7R)-3-hydroxy-7-methyl~l-(pyridine- 2-sulfonyl)-azeρan-4-ylcarbamoyl]-cyclohexyl}-amide. 51. A process for the synthesis of a compound according to Claim 1 comprising the step of oxidizing a corresponding compound of Claim 49 with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers. 52. The process of Claim 51 wherein the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine. 53. The process of Claim 51 further comprising the step of separating the diasteromers by separating means. 54. The process of Claim 53 wherein said separating means is high presssure liquid chromatography (HPLC). 55. The process of Claim 51 further comprising the step of deuterating said diastereomers with a deuterating agent. 56. The process of Claim 55 wherein said deuterating agent is CD3OD: D 2 0 (10:1) in triethylamine. 57. Use of a compound according to any one of Claims 1 to 36 in the manufacture of a medicament for use in inhibiting a protease selected from the group consisting of a cysteine protease and a serine protease. 58. A use according to Claim 57 wherein said protease is a cysteine protease. 59. A use according to Claim 58 wherein said cysteine protease is cathepsin K. 60. Use of a compound according to any one of Claims 1 to 36 in the manufacture of a medicament for use in treating a disease characterized by bone loss. 61. A use according to Claim 60 wherein said disease is osteoporosis. 62. A use according to Claim 60 wherein said disease is periodontitis. 63. A use according to Claim 60 wherein said disease is gingivitis. 64. Use of a compound according to any one of Claims 1 to 36 in the manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation. 65. A use according to Claim 64 wherein said disease is osteoarthritis. 66. A use according to Claim 64 wherein said disease is rheumatoid arthritis.

Inventors: MARQUIS ROBERT W JR, VEBER DANIEL F, YAMASHITA DENNIS S, MARQUIS, ROBERT, W., JR., VEBER, DANIEL, F., YAMASHITA, DENNIS, S.
Applicants: MARQUIS ROBERT W JR, SMITHKLINE BEECHAM CORP, VEBER DANIEL F, YAMASHITA DENNIS S, MARQUIS, ROBERT, W., JR., SMITHKLINE BEECHAM CORPORATION, VEBER, DANIEL, F., YAMASHITA, DENNIS, S.
Application year: 2001
Main classification: A61K
IPC codes: A61K31, A61P1, A61P19, A61P29, A61P43, C07D405, C07D409, C07D495