ZA200104208B

ZA200104208B - Protease inhibitors.

Info

Publication number: ZA200104208B
Application number: ZA200104208A
Authority: ZA
Inventors: Marquis Robert Jr; Wells Ru Yu; Veber Daniel Frank; Commings Maxwell David; Thompson Scott Kevin; Yamashita Dennis Shinji
Original assignee: Smithkline Beecham Corp
Priority date: 1998-12-23
Filing date: 2001-05-23
Publication date: 2002-05-23

Description

. PROTEASE INHIBITORS

FIELD OF THE INVENTION

This invention relates in general to 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. etal, (1996) J. Biol. Chem. 271, 2126-2132.

Cathepsin K has been variously denoted as cathepsin O or cathepsin O2 in the literature. The designation cathepsin K is considered to be the more appropriate one.

Cathepsins function in the normal physiological process of protein de gradation 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

AN h} 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-CHN?) 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. Lemer, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated wr WO 00/38687 PCT/US99/30730 . 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, ez 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 Lerz., 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, O2 and cruzain. Other classes of compounds, such as aldehydes, nitriles, a-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 peptidy! 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 0611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L. Intemational Patent Application No.

PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- 1Bconvertase. 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 er al.,

Biochem. J., 1968, 107, 103, Garker et al., Biochem. J., 1974, 139, 555, Gray et al.,

Tetrahedron, 1971, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al., J.

Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases. In addition, J.

Med. Chem., 1992, 35, 4279, discloses certain azapeptide esters as cysteine protease inhibitors.

Antipain and leupeptin are described as reversible inhibitors of cysteine protease in

McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and

Grinde, Biochem. Biophys. 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.

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 hdve tiuw distueeied a nove: elass of 41 aming-2z2pan-2-nne compounds which are protease inhibitors, most particularly of cathepsin K.

SUMMARY OF THE INVENTION

An object of the present invention is to provide 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

N WO 00/38687 PCT/US99/30730 . 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 L

In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable camer, 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: 1 " ps R~. N _R )

RN ,

R

I wherein:

Rl! is selected from the group consisting of:

0 O o . rR RT

R’ ; R° and 1 ;

R2 is selected from the group consisting of: H, C1_galkyl, C3_scycloalkyl-Co. calkyl. Ar-Cg_galkyl, Het-Cq_galkyl, R%C(0)-, R9C(S)-, R9S0,-, R90C(0)-,

Z ry leo a LI on 5. RIRINC(0)-, RORIINC(S)-, RORI)NSO,- ~~ and

RS

Rr’ N ~~ Z ~~

R®

R3 is selected from the group consisting of: H, Cj_galkyl, C-galkenyl,

C2-6alkynyl. HetCq_galkyl and ArCq_galkyl;

R3 and R’ may be connected to form a pyrrolidine (204), piperidine or morpholine nng; : R% is selected from the group consisting of: H, C}_galkyl, C3_gcycloalkyl-Cq. galkyl, Ar-Co_galkyl, Het-Cg_galkyl, R3C(O)-, ROC(S)-, R350,-, RS0C(0)-,

RIRI3NC(0)-, and RSRI3NC(S)-;

R is selected from the group consisting of: H, Cy_galkyl, C2-galkenyl, Cp_ 6alkynyl, C3_geycloalkyl-Cq_galkyl, Ar-Cq.galkyl and Het-Cq_galkyl;

RS is selected from the group consisting of: H, Cy_galkyl, Ar-Cg.galkyl, and Het-

Co-salkyl;

R is selected from the group consisting of: H, C1-galkyl, C3 gcycloalky-Ls. galkyl, Ar-Co_galkyl, Het-Cq_galkyl, R10C(0)-, R10C(S)-, R1050,-, R100C(0)-,

RIORI4NC(0)-, and RIORI4NC(S)-;

R38 is selected from the group consisting of: H, C1.galkyl, Cp-galkenyl,

C2-62lkynyl, HetCq_galkyl and ArCq_galkyl;

RY is selected from the group consisting of: C;_galkyl, C3_gcycloalkyl-Cq_galkyl, Ar-Cp_galkyl and Het-C_galkyl;

R10 is selected from the group consisting of: Cy_galkyl, C3_gcycloalkyl-Cp_galkyl,

Ar-Cq_galkyl and Het-Cg_galkyi:

FE

N WO 00/38687 PCT/US99/30730 ] R!! is selected from the group consisting of: H, Cj _galkyl, Ar-Cg-galkyl, and Het-

Cp-galkyl;

R12 is selected from the group consisting of: H, Cj_galkyl, Ar-Cq.ealkyl, and Het-

Cp-62alkyl;

R13 is selected from the group consisting of: H, Cy_galkyl, Ar-C(_galkyl, and Het-

Co.ealkyl;

R14 is selected from the group consisting of: H, Cy_galkyl, Ar-Cg-galkyl, and Het-

Co-6alkyl;

R'is selected from the group consisting of: H, Cj_galkyl, Ar-Cp-galkyl, and Het-

Co.galkyl;

R” is selected from the group consisting of: H, Cj_galkyl, Ar-Cp-galkyl, or Het-C_ calkyl;

R™ is selected from the group consisting of: H, Cj_galkyl, C3_gcycloalkyl-Cq_ galkyl. Ar-Cq_galkyl, and Het-Cq_galkyl;

X 1s selected from the group consisting of: CH», S, and O;

Z is selected from the group consisting of: C(O) and CH»; and pharmaceutically acceptable salts, hydrates and solvates thereof. . =4 0

Rr AN

In compounds of Formula I, when R1 is R’ :

R3 is selected from the group consisting of: H, Cj-galkyl, Ca_-galkenyl,

C2-6alkynyl, Het-Cp_galkyl and Ar-Cq_galkyl;

R3 is preferably selected from the group consisting of: H, Ar-Cg_galkyl, and

Ci-6alkyl;

R3 is more preferably selected from the group consisting of:

H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl.

R3 is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.

R3 is most preferably isobutyl.

! N

R4 is selected from the group consisting of: H, Cj _galkyl, C3_gcycloalkyl-

Co-salkyl, Ar-Cg.galkyl, Het-Cq_galkyl, R3C(O)-, RSC(S)-, R580,-, RSOC(0)-,

RORI3NC(0)-, and RISRI3NC(S)-.

R# is preferably selected from the group consisting of: RSOC(O)-, R3C(0)- and

R3SO»-.

R#4 is most preferably R3C(O)-.

In some embodiments, R4 is preferably methanesulfonyi.

RS is selected from the group consisting of: C1_galkyl, Cy_galkenyl, Cp_galkynyl,

C3_geycloalkyl-Cq_galkyl, Ar-Cq._galkyl or Het-Cg_galkyl.

Preferably RS is selected from the group consisting of: Cj_galkyl, Ar-Cg_galkyl and Het-Cq_galkyl.

More preferably, and especially when R# is RIC(O)-, RJ is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially alkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methy] ; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; 1sopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially ary] substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; 2s phenyl, especially phenyl substituted with one or more halogens, more especially : 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more alkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, especially phenyl substituted with one or more sulfonyl groups, more especially 4- methanesulfonyl-phenyl; benzyl; naphthalenyl, especially naphthylen-2-yl; i benzo[1,3]dioxolyl. especially benzo[1,3)dioxol-3-yl,

furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-nitro-furan- 2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-furan-2-y}, 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; tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 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-1-yl-ethoxy)benzofuran-2-yl, 5- (2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially alkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofura-2-yl, 5,6-dimethoxy- benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro- benzofuran-2-yl(255), 5,6-difluoro-benzofuran-2-yl, especially alky! substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl; benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; especially alkoxy substituted benzo[b}thiophenyl, more especially 5.6-dimethoxy- benzo[b]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; 3 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially alkyl substituted indolyl, more especially N-methyl-indol-2-yi; pyridinyl, especially pyridin-2-yl , pyridin-3-yl, especially 1-oxy-pyridin-2-yl, : especially alkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl; thiophenyl, especially thiophen-3-yl, especially alkyl substituted thiophenyl, more especially 5-methyl-thiophen-2-yl, especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; thieno(3,2-b]thiophene, especially thieno[3,2-bjthiophene-2-yl, more especially alkyl substituted thieno[3,2-b]thiophene-2-yl, more especially 5-zerz-butyl-3-methyl- thieno[3,2-b]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially alkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl, 2- phenyl-5-trifluoromethyl-oxazol-4-yi; -

’ .

When R# is R350, RS is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.

R’is selected from the group consisting of: H, Cj-6alkyl, Ar-Co.galkyl, and Het-

Co-salkyl.

Preferably R’ selected from the group consisting of: H and naphthalen-2-yl-methyl.

Most preferably R’ is H.

R” selected from the group consisting of: H, C}_galkyl, Ar-Co-6alkyl, and Het-Cq._ calkyl.

Most preferably R” is H.

R™ is selected from the group consisting of: H, Ci.e6alkyl, C3-gcycloalkyl-

Cp-6alkyl, and Het-Cg_galkyl.

R™ is preferably selected from the group consisting of: H and 6,6-dimethyl.

Most preferably R™ is H.

In compounds of Formula I, R2 is selected from the group consisting of: H, Cj. galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Cq_galkyl, Het-Cq._galkyl, R9C(O)-, R9C(S)-, : a : Cy

R805, R%0C(0)-, R9RIINC(0)-, RORIINC(S)-, RORIINSO,-,

Ng CH, R’ ~~ ~ , and ’

Preferably R is selected from the group consisting of: Ar-Cq-galkyl, RIC( 0)-,

R®

Rr N ~ Z ~ 8

R950,, ROR INC(0)-, and R

More preferably, R2 is selected from the group consisting of: Ar-Cq-galkyl, R9C(0)-, and R9S0,.

Most preferably R2 is R9S0,.

In such embodiments:

N WO 00/38687 PCT/US99/30730 . RS is selected from the group consisting of: H, Cy_galkyl, Ar-Cq.galkyl, or Het-

Co-galkyl, preferably H.

R7 is selected from the group consisting of: H, C1_galkyl, C3_gcycloalkyl-Cq. calkyl, Ar-Cq_galkyl, Het-Cq_galkyl, R10C(0)-, R10C(S)-, R10S0,-, R100C(0)-,

RIORI4NC(O)-, RIORI4NC(S)-, R7 is preferably R100C(0).

R8 is selected from the group consisting of: H, C}.6alkyl, C2-galkenyl,

C2-6alkynyl, HetCq_galkyl and ArC(_galkyl; preferably C_galkyl, more preferably isobutyl.

RY is selected from the group consisting of: Cq_galkyl, C3_gcycloalkyl-Cy.galkyl,

Ar-Cg.galkyl, and Het-Cq_galkyl.

RY is preferably selected from the group consisting of: Cj_galkyl, Ar-Cq_galkyl, and Het-Cq_galkyl.

More preferably, RY is selected from the group consisting of: methyl; ethyl, especially Cy.galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; butyl, especially C;_gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R2 is R9OC(0); isopentyl; : phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially Cj_galkoxy phenyl, more especially 3-methoxyphenyl. 4-methoxyphenyl, 3,4- dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yl)toluyl; naphthylene, especially naphthyl-2-ene; benzoic acid, especially 2-benzoic acid; benzo[ 1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl; benzo[1,2,5}vxadiazolyl, especially benzo[1,2,5}oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; especially Cy_galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyndin-2-yl, thiophene, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl;

, 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-y1, more especially :

C.e6alky! substituted imidazolyl, even more especially 1-methyl-1H-imidazol-2-yl, 1- methyl-1H-imidazol-4-yl; 1H-[1,2,4]triazolyl, especially 1H-[1,2,4]triazol-3-yl, more especially Cj-palkyl substituted 1H-[1,2,4]triazolyl, even more especially 5-methyl-1H-[1,2,4]triazol-3-yl.

When R2 js R9S0,, R? is most preferably selected from the group consisting of: pyndin-2-yl and 1-oxy-pynidin-2-yl.

R10 is selected from the group consisting of: Cj_galkyl, C3_gcycloalkyl-Cq_galkyl,

Ar-Cq.galkyl or Het-Cq_galky!; preferably C_galkyl, Ar-Cq_galkyl and Het-Cq_galkyl.

Z is selected from the group consisting of: C(O) and CH.

RZ 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” and R™ are both H are preferred.

More preferred are compounds of Formula I wherein:

Rl is

Rr 0]

A

R’ ;

R2 is selected from the group consisting of: Ar-Cg-galkyl. ROC(O)-, R9S0,,

Re =F” N. <<” Z. <

R

ROR!INC(0)-, and R ;

R3 is selected from the group consisting of: H, C}.ealkyl. and Ar-Cq_galkyl;

R# is selected from the group consisting of: R30C(0)-, R3C(O)- and R3S0,-;

R3is selected from the group consisting of: Cy_galkyl, Ar-Cg_galkyl and Het-Cq_ ealkyl;

RO is H;

R7 is R100C(0y);

R8 is C}_galkyl:

S

. R? is selected from the group consisting of: Cj_galkyl, Ar-C(.galkyl and Het-C. ealkyl;

R10 js selected from the group consisting of: Cy_galkyl, Ar-Cq_galkyl and Het-Cg. calkyl;

R'is H;

Ris H;

R™is H; and

Z is selected from the group consisting of: C(O) and CH».

Even more preferred are such compounds of Formula I wherein R2 is selected from the group consisting of: Ar-Cg-galkyl, R°C(0)-, R9SO,.

Yet more preferred are compounds of Formula I wherein:

Ris

R Oo

A

R’ ;

R2 is selected from the group consisting of: Ar-Cg.galkyl, R9C(0)- and R9S0O, ;

R3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;

R4 is R3C(O)-;

RY is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl, especially alkoxy substituted methyl, more especially phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; 1sopentyl; cyclohexyl; : pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl;

, oo phenyl, especially phenyl substituted with one or more halogens, more especially : 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more alkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, especially phenyl substituted with one or more sulfonyl groups, more especially 4- methanesulfonyl-phenyl; benzyl; naphthylen-2-yl; benzo[1,3]dioxolyl, especially benzo[1,3)dioxol-5-y], furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-nitro-furan- 2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-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; tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 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-1-yl-ethoxy)benzofuran-2-yl, 5- (2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially alkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, S-methoxy-benzofura-2-yl, 5,6-dimethoxy- ~ benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro- benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especially alkyl substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl; benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; especially alkoxy substituted benzo[b]thiophenyl, more especially 5,6-dimethoxy- benzo[b]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and yuinolin-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 alkyl substituted indolyl, more especially N-methyl-indol-2-y1 ; pyridinyl, especially pyridin-2-yl , pyridin-5-yl, especially 1-oxy-pyridin-2-yl, especially alkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl;

] thiophenyl, especially thiophen-3-yl, especially alkyl substituted thiophenyl, more especially 5-methyl-thiophen-2-yl, especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, more especially alkyl substituted thieno[3,2-b]thiophene-2-yl, more especially 5-rert-butyl-3-methyl- thieno[3,2-b]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially alkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl , 2-phenyl-5-trifluoromethyl-oxazol-4-yl;

RY is selected from the group consisting of: methyl; ethyl, especially C;_galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; butyl, especially Cy_gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R2 is R20OC(0); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluoropheny! , 3-chlorophenyl, 4-chlorophenyl, especially Cy_galkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4- dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl ; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-ytoluyl; naphthylene, especially naphthyl-2-ene; benzoic acid, especially 2-benzoic acid; benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-y1; benzo[1,2,5]oxadiazolyl, especially benzo[1.2,5]oxadiazol-4-yl; pyndinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially 1-oxy-pyndin-2-yl, 1-oxy-pyridin-3-yl; especially Cj _galkylpyridinyl, more especially 3-methyl-pyndin-2-yl, 6-methyl-pyridin-2-yl, thiophene, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl; 1H-imidazolyl, especially 1H-imidazol-2-yl(74), 1H-imidazol-4-yl, more especially

C1-galkyl substituted imidazolyl, even more especially 1-methyl-1H-imidazol-2-yl, 1- methyl-1H-imidazol-4-yl;

R’is H;

R”is H; and

R™is H.

Most preferred are compounds of Formula I wherein;

Rls - 0 rR AN

R’ ;

R? is RISO;

R3is isobutyl;

R4 is R3C(O);

RS is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2- b]thiophen-2-yl. S-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl, preferably 3-methyl-benzofuran-2-yi;

RY is selected from the group consisting of: pyridin-2-y! and 1-oxy-pyridin-2-yl, preferably 1-oxy-pyridin-2-yl.

R’is H; and

R™ is H;

Compounds of Formula I selected from the following group are particularly prefered enfsudinenis uf the present inventisn:

Example Chemical Name

No. 1 {(S)-1-[1-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3- oxo-azepan-4-ylcarbamoyl }carbamic acid benzyl ester 2 Naphthylene-2-carboxylic acid[(S)-1-(1-benzyl-3-o0xo-azepan-4- vicarbamoyl)-3-methyl-butyl]amide

] 3 Benzo[1,3]dioxole-5-carboxylic acid [(S)-1-(1-benzyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide 4 Benzofuran-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyljamide

Benzo[b]thiophene-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide 6 Naphthylene-2-sulphonyl [(S)-1-(1-benzyl-3-o0xo0-azepan-4- ylcarbamoyl)-3-methyl-butyl}-amide 7 Quinoline-2-carboxylic acid [(S)-1-(1 -benzyl-3-oxo0-azepan-4- ylcarbamoyl)-3-methyl-butyljamide 8 3,4-dichlorobenzoic acid [(S)-1-(1-benzyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]amide 9 4-{(S)-Methyl-2-{(quinoline-2-carbonyl)-amino]pentanoylamino} - 3-0x0-1-[2-(3-pyridin-2-yl-phenyl)-acetyl]azepanium 1-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{(S)-4- methyl-2-[(2-quinoiline-2-carbonyl)-amino}-pentanoylamino)-3-

OX0-azepanium 11 1-Benzoyl-4-((S)-2-(benzo[ 1,3]dioxole-carbonylamino)-4-methyl- pentanoylamino)-3-oxo-azepanium 12 1-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl- pentanoylamino)-3-oxo-azepanium 13 3-Ox0-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-

B benzofuran-2-carbonyl]amino }-pentanoylamino)- 1-(4-methyl- ) pentanoyl)-azepanium 14 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]amide 4-((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyljamino }-pentanoylamino)-3-oxo-azepane- 1-carboxylic acid phenylamide 16 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)- 3-methyl-1-{3-oxo0-1-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4- ) ylcarbamoyl}-butyl)amide

17 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- ’ 1-( benzoyl-3-oxo-azepan-4-ylcarbamoy1)-3-methyl-butylJamide 18 5-(2-Pyrrolidin-1 -yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyllamide 19 5-(2-Piperidin- 1-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-1- (1-benzenesulfon yl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]amide 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)- 3-methyl-1-{3-oxo0- 1-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- ylcarbamoyl}-butyl)amide 21 Naphthlene-2-carboxylic acid ((S)-3-methyi-1-{3-oxo0-1-[2-(3- pyridin-2-yl-phenyljethyl}-azepan-4-ylcarbamoy! }-butyl)amide 22 1H_Indole-2-carboxylic acid ((S)-3-methyl-1-{3-oxo0-1-[2-(3- pynidin-2-yl-phenylethyl]-azepan-4-ylcarbamoyl }-butyl)amide 23 1H-Indole-2-carboxylic acid [(S)-1-(1-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide 24 Benzofuran-2-carboxylic acid [(S)- 1-(1-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl}amide

Benzofuran-2-carboxylic acid [(S)-3-methyl-1-{3-0xo0-1-[2-(3- pyridin-2-yl-phenyl)ethyl}-azepan-4-ylcarbamoy!}-butyl)amide 26 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- 3-methyi-1-(3-oxo-1-phenethyl-azepan-4-ylcarbamoyl}- butyl }amide 27 Maphthylenz-2-carhovylic acid [(R)-3-methyl-1-(3-0x0-1- phenethyl-azepan-4-ylcarbamoyl]-butyl }amide 28 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]}-butyl }-amide 29 Naphthylene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1- (pynidine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }-amide 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)- : 3-methyl-1-[3-oxo0-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl }-amide

) 31 4-{(S)-4-Methyl-2-{ [(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl}-amino }-pentanoylamino)-3-oxo-azepane- 1-carboxylic acid tert-butyl ester 32 4-((S)-4-Methyl-2-{[(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carboxylic acid [(S)-3-methyl-1-(3-ox0-azepan-4-ylcarbamoyl)- butyl }amide 33 4-Methyl-pentanoic acid {3-o0xo-1-[2-(3-pyridin-2-yl-phenyl- acetyl}-azepan-4-yl}-amide 34 ((S)-3-Methyl-1-{3-o0x0-1-[2-(3-pyridin-2-yl-phenyl)-acetyl}- azepan-4-ylcarbamoyl}-butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester (S)-4-Methyl-2-[(naphthylen-2-ylmethyl)-amino]-pentenoic acid [3-0x0-1-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-yl }-amide 36 4-[2-(2-{(S)-3-Methyl-1-[3-0x0-1 -(pyidine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butylcarbamoyl }-benzofuran-5-yloxy)-ethyl}- piperazine- 1-carboxylic acid tert-butyl ester 37 5-(2-Pipenizin-1-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3- methyl-1-[3-oxo0-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-3- : butyl }-amide 38 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3- methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}- butyl }amide : | 39 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3- methyl-1-{3-oxo-1-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- ylcarbamoyl}-butyl)amide 40 4-[2-(2-{(S)-3-Methyl-1-[3-ox0-1-(3-pyridin-2-yl-phenyl)-ethy} [azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)- ethyl]-piperazine-1-carboxylic acid rerz-butyl ester 41 5-(2-piperizin-1-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3- methyl-1-{3-oxo-1-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- ylcarbamoyl}-butyl)amide 42 (5)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-oxo- 1-(pyridine-2-sulphonyl)-azepan-4-yl}-amide

43 (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic : acid {3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-yl }- amide 44 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl-1-{3-oxo0-1-[2-(3-pyridin-2-yl- phenyDacetyl}-azepan-4-ylcarbamoyl }-butyl)amide 45 Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-1-[3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide 46 2,2,2-Trifluoro-N-((S)-3-methyl-1-{3-oxo0-1 -[2-(3-pyridin-2-yl- phenyl)-acetyl]-azepan-4-ylcarbamoyl}-butyl)-N-naphthylen-2- ylmethyl-acetamide 47 4-[(S)-(Methanesulphonyi-naphthylen-2-yimethyl-amino)-4- methyl-pentanoylamino]-3-oxo-azepane-1-carboxylic acid benzyl ester 48 Quinoline-2-carboxylic acid {(S)-3-methyl-1-[3-0xo-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide 49 Quinoline-8-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 50 Quinoline-6-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl jJamide 51 Quinoline-4-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine- - 2-sulfonyl)-azepan-4-yicarbamoylj-butyl }amide 52 Quinoline-3-carboxylic acid {(S)-3-methyl-1-{3-oxo0-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl jamide 53 Isoquinoline-3-carboxylic acid {(S)-3-methyl-1-[3-o0xo0-1- (pynidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }Jamide 54 Isoquinoline-1-carboxylic acid {(S)-3-methyl-1-[3-0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }Jamide 55 Quinoxaline-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl amide . 56 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-o0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }Jamide

N WO 00/38687 PCT/US99/30730 . 57 1,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 58 1H-Indole-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl amide 59 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methy}-1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-buty]}amide 60 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide 61 Furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide 62 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide 63 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-1-[3- oxo- 1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide 64 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3- methyl-1-[{3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl }amide 65 Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1- : (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide 66 (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo- (pyridine-2-sulfonyl)-azepan-4-yl}-amide 67 (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic . acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide 68 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-ox0o-1-(pyridine- 2-carbonyl)-azepan-4-ylcarbamoyl)-3- butyl]-amide 69 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-0xy- pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-butyl jamide 70 4-((S)-2-tert-Butyicarbonylamino-4-methyl-pentanoylamino)-3- oxo-azepane-1-carboxylic acid benzyl ester 71 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3- ox0-1-(1-methyl-1H-imidazole-4-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide

72 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[ 1-(S-methyl-1H- : [1 »2,4]triazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl)- butyl }amide 73 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(1-methyl-1H- imidazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-butyl }amide 74 Benzofuran-2-carboxylic acid { (8)-3-methyl-1-[1-(1H-imidazole- 2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-butyl }amide 75 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- I-{thiazole- 2-sulfonyl)-azepan-4-ylcarbamoyl]-buty] }amide 76 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-( I-methyl-1H- imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-buty] }amide 77 5-(4-Oxy-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S})-3-methyl-1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butyl }amide 78 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine- 3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 79 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(i-0xy- pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl}-butyl } amide 80 Quinoline-3-carboxylic acid {(S)-1-(3,4-dichloro-benzene- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl)]-3-methyl-buty| }-amide 81 5-Hydroxy-benzofuran-2-carboxylic acid { (S)-3-methyl-1-[1-(1- methyl-1H-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl }amide 82 Benzofuran-2-carboxylic acid { (S)-3-methyl-1-[3-oxo0-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl }- amide 83 2-(4-{(S)-2-{ (Benzofuran-2-carbonyl)-amino }-4-methyl- pentanoylamino }-3-oxo-azepane-1-sulfonyl)-benzoic acid 84 3-(4-{(S)-2-{ (Benzofuran-2-carbonyl)-amino}-4-methyl- pentanoylamino }-3-oxo-azepane-1-sulfonyl)-benzoic acid 85 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1- ( 1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide

< WG 00/38687 PCT/US99/30730 86 S-Bromo-furan-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1- oxy-pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }aride 87 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3- oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}- butyl }amide 88 1-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 89 (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-

I-(pyridine-2-sulfonyl)-azepan-4-yl}-amide 90 (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-o0xo-1- (pyridine-2-sulfonyl)-azepan-4-yl}-amide 91] (S)-4-Methyl-2-(3-phenyl-uriedo)-pentanoic acid [3-ox0-1- (pyndine-2-sulfonyl)-azepan-4-yl}-amide 92 Benzofuran-2-carboxylic acid {(S)-1-[6.6-dimethyl-3-oxo- 1(pynidine-sulphonyl)-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide 93 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(1-oxy-pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }Jamide ; 94 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 95 Quinoxaline-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide 96 Quinoline-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-0xy- pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 97 Thiophene-3-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1-0xy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl jJamide 98 1H-Indole-5-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(1-0xy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide 99 Benzo[1,3]dioxole-5-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoy!}-butyl }amide 100 Furan-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(1-oxy- pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide

101 (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3- . oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-yl}-amide 102 1H-Indole-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1 -0Xy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide 103 4-Fluoro-{(S)-3-methyl-1-[3-ox0-1-(1 -oxy-pyridine-2-sulphonyl)- azepan-4-carbamoyl]-butyl }-benzamide 104 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3- methyl-1-[3-oxo-(1-oxy-pyridine2-sulphonyl)-azepan-4- ylcarbamoyl]- -buty }-amide 105 Thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 106 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1- (1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide 107 6-Methyl-N-{(S)-3-methyl-1-[3-0x0-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl}-butyl}-nicotinamide 108 (S)-4-Methy!-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3- oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl}-butyl }amide 109 1H-Indole-6-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-

J 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 110 Benzo[1,3]dioxole-5-carboxylic acid {(S)-3-methyl-1-[3-0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 111 3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid {(S)-3- methyl-1-[3-0x0-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] butvllamide 112 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1- (1-oxy-pynidine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl }amide 113 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl amide 114 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 115 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid] 1-(4- methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl}-amide

< WO §0/38687 PCT/US99730730 116 3-(3-Trifluoromethyi-phenyl)-furan-2-carboxylic acid {(S)-3- methyl-1-[3-oxo0-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide 117 5-Methyl-2 —phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-1-[3- oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}- butyl}amide 118 Benzofuran-2-carboxylic acid {(S)-1-[ 1-(3,4-dimethoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-butyl }-amide 119 Benzofuran-2-carboxylic acid {(S)-1-[1-(4-bromo- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide 120 Benzofuran-2-carboxylic acid {(S)-1-[1-(benzo[1,2,5]oxadiazole- 4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide 121 Benzofuran-2-carboxylic acid {(S)-1-[1-(3,5-dimethyl-oxazole-4 - sulfonyl)-3-oxo0-azepan-4-ylcarbamoyl!]-3-methyl-butyl }-arnide 122 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide 123 Thieno([3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-

E 1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide 124 S-tert-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-ox0- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butyl }amide 125 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-1-[3- oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jarnide 126 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3- methyl-1-[3-oxo0-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl}amide 127 Quinoline-2-carboxylic acid {(S)-1-(1-methanesuifonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide 128 1-Methyl-1H-indole-2-carboxylic acid [(S)-1-(}-methanesulfonyl- 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl}-amide 129 Furan-2-carboxylic acid {[(S)-1-(1-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butylcarbamoyl}-methyl}-amide

130 5-Methoxy-benzofuran-2-carboxylic acid [(S)-1-(1- : methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide

131 Quinoxaline-2-carboxylic acid [(S)-1-(1 -methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide

132 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-1-[3- oxo-1-(pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide

133 (8)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid (1-methanesulfonyl-3-oxo-azepan-4-yl)-amide

134 Quinoline-2-carboxylic acid {[(S)-1-[1-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide

135 1-Methyl-1H-indole -2-carboxylic acid {[(S)-1-[1-(2-cyano- benzenesulfonyl)-3-oxo0-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide

136 Furan-2-carboxylic acid ({ (S)-1-[1-(2-cyano-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl}-3-methyl-butylcarbamoyl } -methyl)- amide

137 5-Methoxy-benzofuran-2-carboxylic acid {(S)-1-[1-(2-cyano-

benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide

138 Quinoxaline-2-carboxylic acid {(S)-1-[1-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyi-buiyl }- amide

139 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylj-amide

140 Quinoline-2-carboxylic acid {[(S)-1-[1-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-buty}l}- amide

141 1-Methyl-1H-indole-2-carboxylic acid {[(S)-1-[1-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide

142 Furan-2-carboxyiic acid ({(S)-1-[1-(4-methoxy-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl }-methyl)- amide 143 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-1-[1-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 144 Quinoxaline-2-carboxylic acid {[(S)-1-[1 -(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}- amide 145 (5)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide 146 1-Methyl-1H-indole-2-carboxylic acid {[(S)-1-[1-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 147 Furan-2-carboxylic acid ({(S)-1-{ 1-(4-fluoro-benzenesulfonyl)-3- 0Xo-azepan-4-ylcarbamoyl}-3-methyl-butylcarbamoyl }-methyl)- amide 148 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-1-[1-(4-fluoro- } benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide 149 Quinoxaline-2-carboxylic acid {[(S)-1-[1-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 150 (8)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl}-amide 151 Benzofuran-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide 152 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl}-3-methyl-butyl}- amide

153 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(3-chloro- . benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide

154 3,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyI)-3-oxo-azepan-4-ylcarbamoy!]-3-methyl-butyl }- amide 155 3-Methyl-benzofuran-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-buty} }- amide

156 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide

157 1-Methyl-1H-indole-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyi-butyl } - amide

158 Quinoxaline-2-carboxylic acid-{(S)-1-[1-(3-chloro- benzenesulphonyl)-3-oxo0-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide

159 Benzofuran-2-carboxylic acid- {(S)-1-[1-(2-fluoro-

benzenesulphonyl)-3-oxo0-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide

160 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyi }- amide

161 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide

162 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-yicarbamoyl}-3-methyl-butyl }- amide

163 5-Methyl-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide

} 164 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoy1}-3-methyl-buty! }- amide 165 1-Methyl- 1H-indole-2-carboxylic acid-{(S)-1-[1-(2-flucro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide 166 (S)-4-Methyl-2-(1-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide 167 Quinoxaline-2-carboxylic acid-{(S)-1-[1-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 168 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo- 1-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide 169 7-Methoxy-benzofuran-2-carboxylic acid- { (S)-3-methyl-1-[3-ox0- 1-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoy!}-butyl}-amide 170 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-3-methy!-1-[3- oxo-1-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide 171 3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo0-1- : (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-buty!}-amide 172 Benzo[b]thiophene-2-carboxylic acid-{(S)-3-methyl-1-[3-0x0-1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide 173 1-Methyl-1-H-indole-2-carboxylic acid-{(S)-3-methyl-1-[3-0xo0-1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide - 174 Quinoxaline-2-carboxylic acid-{(S)-3-methyl-1-[3-ox0-1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide 175 Benzofuran-2-carboxylic acid-{(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 176 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]}-3-methyl-butyl }- amide

177 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 178 5.6-Dimethoxy-benzofuran-2-carboxylic acid- {(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-y lcarbamoyl)-3-methyl-butyl}- amide 179 3-Methyl-benzofuran-2-carboxylic acid-{(S)- 1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 180 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 181 1-Methyl- 1H-indole-2-carboxylic acid-{(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-buty} }- amide 182 Quinoxaline-2-carboxylic acid-{(S)-1-[1-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyi]-3-methyl-butyl }- amide : 183 Benzofuran-2-carboxylic acid-{(S)-1-[1-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 184 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[ I-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyi-butyl }- amide 18% 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1 -(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl }- amide 186 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(3- methoxy-benzenesulphonyl)-3-oxo-azepan-4-yicarbamoyl]-3- methyl-butyl}-amide 187 3-Methyl-benzofuran-2-carboxylic acid-{(S)-1-{1-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide

] 188 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide 189 1-Methyl-1H-indole-2-carboxylic acid-{(S)-1-[1-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide 190 Quinoxaline-2-carboxylic acid-{(S)-1-[1-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }- amide 191 Benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-0x0-1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }-amide 192 Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[(2,2’ 4- triduetenio)-3-oxo-1-(pyndine-2-sulfonyl)-azepan-4-ylcarbarmoyl]}- butyl }amide 193 Benzofuran-2-carboxylic acid {(S)-2-methyl-1-[3-oxo0-1-(pyridine- : 2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl}-amide 194 Benzofuran-2-carboxylic acid {(S)-1-[3-oxo0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoy!}-propyl }-amide : 195 Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-ethyl }-amide 196 Benzofuran-2-carboxylic acid {(S)-1-[3-oxo-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide 197 Benzofuran-2-carboxylic acid {(S)-3-methanesulfinyl-1-{3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-propyl }-amide 198 Benzofuran-2-carboxylic acid {[3-oxo0-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoy!}-methyl }-amide 199 Benzofuran-2-carboxylic acid {(S)-1-[3-ox0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-pentyl }-amide 200 Benzofuran-2-carboxylic acid {(S)-1-[3-oxo0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide 201 Benzofuran-2-carboxylic acid {(S)-2-methyl-1-[3-oxo-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]}-propyl }-amide

202 Benzofuran-2-carboxylic acid {(S)-2-hydroxy-1-[3-oxo-1- : (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-propyl }-amide 203 Benzofuran-2-carboxylic acid {(S)-1-[3-ox0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl }-amide 204 1-(Benzofuran-2-carbonyl)-pyrrolidine-2-carboxylic acid [3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-yl}-amide 205 3,4-Dimethoxy-N-{(S)-1-{ 1-(4-methoxy-benzenesulfony!)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-benzamide 206 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[ 1-(4-imethoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide 207 Benzo[1,3]dioxole-5-carboxylic acid {(S)-1-[1-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3methyl-butyl }- amide : 208 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[1-(4- fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylJ-amide 209 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[ 1-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl }- : amide 210 Benzofuran-2-carboxylic acid {(S)-1-[1-benzoyl-3-oxo-azepan-4- ylcarbamoyl}-3-methyl-butyl }-amide 211 (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3- i oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl}-amide 212 (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3- aus 1 {pyridine-7.enlfanyi)-azepan-4-yli-amide 213 Benzofuran-2-carboxylic acid-{(S)-1-[ 1-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl}-3-methyl-butyl }- amide 214 N-{(S)-1-[1-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl}-3-methyl-butyl}-3,4-dimethoxy-benzamide 215 Cyclohexanecarboxylic acid {(S)-1-[1-(4-fluoro-benzenesulfonyl)- - 3-oxo-azepan-4-ylcarbamoyl }-3-methyl-butyl }-amide

} 216 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[1-

(methanesulfonyl)-3-oxo-azepan-4-ylj-amide

217 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-(1-methanesulfonyl- 3-0x0-azepan-4-yl carbamoyl)-3-methyl-butylj-amide

218 Benzo[1,3}dioxole-3-carboxylic acid-{(S)-1-(1-methanesulfonyl-3- oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide

219 Benzofuran-2-carboxylic acid-{(S)- 1-(1-methanesulfonyl-3-oxo- azepan-4-yl carbamoyl)-3-methyl-butyl}-amide

220 N-[(S)-1-(1-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl }-3- methyl-butyl}-3.4-dimethoxy-benzamide

221 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[1-(2- cyano-benzensulfonyl)-3-oxo-azepan-4-yl}-amide

222 N-{(S)-1-[1-(2-Cyano-benzenesuifonyl)-3-oxo-azepan-4- ylcarbamoyl}-3-methyl-butyl }-4-methanesulfonyl- 1-benzamide

223 Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]- amide

224 Benzo[1,3]dioxole-5-carboxylic acid-{(S)-1-[1-(2-cyano-

. benzenesulfonyl)-3-oxo0-azepan-4-ylcarbamoyl)-3-methyl-butyl]-

amide

225 (S)-4-Methyl-2-[4-ox0-4-((4-phenoxy-phenyl)-butyrylamino }- pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl}-amide

226 N-{(S)-1-[(1-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl}-3-methyl-buty! }-3,4-dimethoxy-benzamide

227 Cyclohexanecarboxylic acid {(S)-1-[1-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}- amide

228 4-Methansulfonyl-N-{(S)-1-[4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-carbamoyl]-3-methyl-butyl-benzamide

229 4-Methansulfonyl-N- {(S)-1-[4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-carbamoyl]-3-methyl-butyl-benzamide

230 ({(S)-3-Methyl-1-[3-oxo0-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butylcarbamoy! }-carbamic acid benzyl ester

231 (S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio}-4-methyl-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl}-amide

232 (S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio}-4- methylpentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]- amide

233 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-1-{1- (pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-butyl }amide

234 (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid {3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-ylj-amide

235 Benzofuran-2-carboxylic acid {(S)-3-methyi-1-[1-(6-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-butyl } amide

236 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1 (6- methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl}- butyl}amide

237 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(6-

: methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-yicarbamoyl}-

butyl }amide

238 7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-

g (pyridine-2-sulfonyl)-3-oxo-azepan-4-yicarbamoylj-butyl Jamide

239 5,6-Dimethoxy-benzo[blthiophene-2-carboxylic acid {(S)-3- methyl-1-[1-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl }amide

240 (R)-1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl- 1-{3-oxo-(pynidine-2-sulfonyl)-azepan-4-ylcarbamoyl}- hnryl amide

241 (S)-1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(8)-3-methyl- 1-{3-oxo-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl }amide

242 Benzofuran-2-carboxylic acid {(S)-2-cyclopropyl-1-[3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl)-amide

243 Benzofuran-2-carboxylic acid {(S)-3-methylsulfanyl-1-[3-oxo0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-propyl}-amide

Claims

We claim: )

1. A compound of Formula I:

RL. R" ~~ N YT ” X_ N R \ R I wherein: R! is selected from the group consisting of: o o o A x rR RS ~~ ZION . a Ly R® ; R and R : : R2 is selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl-Cq. galkyl, Ar-Cg_galkyl, Het-Cq_galkyl, R9C(0)-, R9C(S)-, R950,-, R90C(0)-, ZN NGA) NACH, > RIRIINC(0)-, RORVINC(S)-, RORINSOp- 7 , 7 and [= _N Zz rR’ he ~~ 8 R H R3 is selected from the group consisting of: H, Cj.galkyl, C_galkenyl, C2-6alkynyl, HetCo-galkyl and ArCq-galkyl; R3 and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring; R4 is selected from the group consisting of: H, Cj-galkyl, C3_gcycloalkyl-Co. galkyl, Ar-Cq_galkyl, Het-Cq_galkyl, R3C(0)-, R3C(S)-, R7SO5-, R30C(0)-. RSRI3NC(0)-, and RORI3NC(S)-;

: RS is selected from the group consisting of: H. Cj_galkyl, C2.6alkenyl, C2- alkynyl, C3_gcycloalkyl-Cg.galkyl, Ar-Cq_galkyl and Het-Cq_galkyl; RO is selected from the group consisting of: H, Cj_galkyl, Ar-Co-6alkyl, or Het- Co-salkyl; R7 is selected from the group consisting of: H, Cj.ealkyl, C3_geycloalkyl-Co. galkyl, Ar-Cg_galkyl, Het-Cq_galkyl, R10C(0)-, R10C(S)-, R1050,-, R100C(0)-, RIOR 14NC(0)-, and RIOR14NC(S)-; R38 is selected from the group consisting of: H, C1-galkyl. C2-6alkenyl,

C»o.ealkynyl, HetCp-ealkyl and ArCp-galkyl; RY is selected from the group consisting of: Cj_galkyl, C3.gcycloalkyl-Cg_galkyl, Ar-Cq_galkyl and Het-C_galkyl; R10 is selected from the group consisting of: C1-ealkyl. C3_gcycloalkyl-Cp_galkyl, Ar-Cq_galkyl and Het-Cq_galkyl; R11! is selected from the group consisting of: H, Cj_galkyl, Ar-Co-galkyl. and Het-

Cp.galkyl; R12 is selected from the group consisting of: H, Cj_galkyl, Ar-Cg-galkyl, and Het- Cp-6alkyl; R13 is selected from the group consisting of: H, C1-6alkyl, Ar-Cp-galkyl, and Het- - Cp-galkyl; R14 is selected from the group consisting of: H, Cy_galkyl, Ar-Cp-galkyl, and Het- Cp-ealkyl; R’ is selected from the group consisting of: H, Cy_galkyl, Ar-Cp-galkyl, and Het- i Cop-galkyl; R” is selected from the group consisting of: H, Cj_galkyl, Ar-Cp.ealkyl, or Het-Cg_ alkyl; R” is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Cq. alkyl, Ar-Cp_galkyl, and Het-Cq_galkyl; X is selected from the group consisting of: CH», S, and O: and Z is selected from the group consisting of: C(O) and CH»; and pharmaceutically acceptable salts, hydrates and solvates thereof.

0 . R AN

3

2. A compound according to Claim 1 wherein R! is R .

3. A compound according to Claim 1 wherein R3 is selected from the group consisting of: 35 H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, ]-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl.

4. A compound according to Claim 3 wherein R3 is selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.

5. A compound according to Claim 4 wherein R3 is isobutyl.

6. A compound according to Claim 1 wherein R? is selected from the group consisting of: RSOC(0)-,R5C(O)- or R3SO-.

: 7. A compound according to Claim 6 wherein R4 is R3C(0O)-.

8. A compound according to Claim 7 wherein R is selected from the group consisting of: Cj _galkyl, Ar-Cop_galkyl and Het-Cy_galkyl.

5. A compound according to Claim 8 wherein R? is selected from the group consisting of: methyl, halogenated methyl, alkoxy substituted methyl, heterocycle substituted methyl; : butyl, aryl substituted butyl; isopentyl; cyclohexyl; butenyl, aryl substituted buteny!; acetyl; :

. phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more alkoxy groups, phenyl substituted with one or more sulfonyl groups; benzyl; naphthylenyl; benzo[1,3]dioxolyl; furanyl, halogen substituted furanyl, aryl substituted furanyl; tetrahydrofuran-2-y]; benzofuranyl, alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, alkyl substituted benzofuranyl; benzo[b]thiophenyl, alkoxy substituted benzo[b]thiophenyl, quinolinyl; quinoxalinyl; 1,8 naphthynidinyl; indolyl, alkyl substituted indolyl; pyndinyl, alkyl substituted pyridinyl, 1-oxy-pyridinyl; thiophenyl, alkyl substituted thiophenyl, halogen substituted thiophenyl; thieno(3,2-b]thiophenyl; 1soxazolyl, alkyl substituted isoxazolyl; and oxazolyl.

10. A compound according to Claim 8 wherein R? is selected from the group consisting of: pentanonyl; naphthylen-2-yl; benzo[1,3]dioxol-5-yl, furan-2-yl; benzofuran-2-yl; benzo[b]thiophen-2-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalin-2-yl; 1,8 naphthynidin-2-yl; indol-3-yl, indol-5-yl; : pyridin-2-yl , pyridin-5-yl,

thiophen-3-yl; - thieno[3,2-b]thiophene-2-yl; isoxazol-4-yl; and oxazol-4-yl.

11. A compound according to Claim 8 wherein RY is selected from the group consisting of: trifluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl, 2-thiophenyl-methyl; 4-(4-methoxy)phenyl-butyl; 4-pentanonyl;

4.4-bis(4-methoxyphenyl)-but-3-enyl;

3.4-dichlorophenyl, 4-fluorophenyl, 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, 4-methanesulfonyl-phenyl; S-nitro-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-triflouromethyl-phenyl)- furan-2-yl, 5-bromo-furan-2-yl, 5-(4-chloro-phenyl)-furan-2-yl; 5-(2-piperazin-4-carboxylic acid zert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- 1 -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-yl, 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2- yl, 3-methyl-benzofuran-2-yl; 5,6-dimethoxy- benzo[b]thiophen-2-yl; N-methyl-indol-2-yl; 1-oxy-pyridin-2-yl, 2-methyl-pyridin-5-yI, 5-methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-y1; 5-tert-butyl-3-methyl thieno[3,2-b}thiophen-2-yl; 3,5-dimethyl- isoxazol-4-yl; and 5-methyl-2-pheny! oxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-4-y1.

12. A compound according to Claim 8 wherein R9 is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, 5- methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl.

) 13. A compound according to Claim § wherein R is selected from the group consisting of H and naphthalen-2-yl-methyl.

14. A compound according to Claim 13 wherein R is H. S

15. A compound according to Claim 1 wherein R” is H.

16. A compound according to Claim 1 wherein R™ is selected from the group consisting of H and 6,6-dimethyl.

17. A compound according to Claim 16 wherein R™ is H.

18. A compound according to Claim 1 wherein R" and R” are both H.

19. A compound according to Claim 1 wherein: R2 is selected from the group consisting of: H, Cj_galkyl, C3_gcycloalkyl-Cq_ galkyl, Ar-Co_galkyl. Het-Cq._galkyl, R9C(0)-, R9C(S)-, R9SO»-, R%0C(0)-, “) 0) : NGAANACO) AA RORIINC(O)-, RORIINC(S)-, ROR INSO;-, J , and R® 87 No 4 Rr : RS is selected from the group consisting of: H, Cy_galkyl, Ar-Cq.galkyl, and Het- Cop-6alkyl; R7 is selected from the group consisting of: : H, Cy_galkyl, C3_gcycloalkyl-C. galkyl, Ar-Cq_galkyl, Het-Cg_galkyl, R10C(0)-, R10C(S)-, R1050,-, R100C(O)-, RIORI4NC(O)-, and RIOR14NC(S); R8 is selected from the group consisting of: H, C1_galkyl, C2.galkenyl, C2-6alkynyl, HetCq.galkyl and ArCq.galkyi; RY is selected from the group consisting of: Cy_galkyl, C3_gcycloalkyl-Cy_galkyl. Ar-Cp_galkyl, and Het-C_galkyl;

R10 js selected from the group consisting of: Cj_galkyl, C3_gcycloalkyl-Cq_galkyl, ; Ar-Cq_galkyl or Het-Cg_galkyl; and Z 1s selected from the group consisting of: C(O) and CH».

20. A compound according to Claim 19 wherein R2 is selected from the group R R’ N ~~ Z Re consisting of: Ar-Cg.galkyl, R9C(0)-, R9S0,, ROR1INC(O)-, and

21. A compound according to Claim 20 wherein RZ is selected from the group consisting of: Ar-Co-galkyl, R9C(O)-, and R9S0,.

22. A compound according to Claim 21 wherein RZ is RISO,

23. A compound according to Claim 19 wherein RO is H.

24. A compound according to Claim 19 wherein R” is R100C(0).

25. A compound according to Claim 19 wherein R8 is Cj_galkyl.

26. A compound according to Claim 25 wherein R8is isobutyl.

27. A compound according to Claim 19 wherein RY is selected from the group consisting of: Cq_galkyl, Ar-Cq_galkyl and Het-C(_galkyl.

28. A compound according to Claim 27 wherein R? is selected from the group consisting of: methyl; ethyl, and Cy_galkyl -substituted ethyl; butyl, C;_galkyl-substituted butyl, tert-butyl; isopentyl; phenyl. halogen substituted phenyl,C{_galkoxy phenyl. cyanophenyl:

N WO 00/38687 PCT/US99/30730 . toluyl, Het-substituted toluyl; benzoic acid; naphthylenyl; benzo[1,3]dioxolyl; benzo[1,2,5]joxadiazolyl; pyridinyl, 1-oxy-pyridinyl, Cj_galkyl pyndinyl; thiophene; thiazolyl; 1H-imidazolyl, C_galkyl substituted imidazolyl; 1H-[1,2,4]triazolyl, C1_galkyl substituted 1H-[1,2,4]triazolyl; and quinolinyl.

29. A compound according to Claim 27 wherein R? is selected from the group consisting of: 2-cyclohexyl-ethyl, 3-methylbutyl; 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, Bg 2-cyanophenyl; 2-benzoic acid; naphthylen-2-yl; benzo[ 1,3]dioxol-5-yi; benzo[1,2,5]oxadiazol-4-yl; pyndin-2-yl, pyridin-3-yl , 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl, 3-methyl- pyndin-2-yl, 6-methyl-pyridin-2-yl; thiophene-2-yl; thiazol-2-yl; 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H- imidazol-4-yl; 1H-[1,2,4)tniazol-3-yl, 5-methyl-1H-[1,2 4]triazol-3-yl, and quinolin-2-yl.

30. A compound according to Claim 1 wherein:

Rr 0 AN Rl is Ro RZ is selected from the group consisting of’: R® : rR RE Ar-Co-galkyl, R9C(0)-, R9S0,, RR! INC(0)-, and R® : R3 is selected from the group H, Cj-galkyl and Ar Cg.galkyl; R% is selected from the group consisting of: RI0C(0)-, R3C(0)- or R3S0,-; R93 is selected from the group consisting of: Cj _galkyl, Ar-Cp_galkyl and Het-Cq. ealkyl, RO is H; R7 is R100C(0); R8 is C1-palkyl; Ris selected from the group consisting of: Cy_galkyl, Ar-Cq_galkyl and Het-Cp._ galkyl; R10 is selected from the group consisting of: Cy_galkyl, Ar-Cp_galkyl and Het-Cg. ealkyl; R’is H; R" is H;and R™is H.

21. A cempsund according iv Claim 30 witerein: R2 is selected from the group consisting of: Ar-Cg-galkyl, R9C(0)- and R950; R3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, l-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl; R4 is R3C(0)-; RS is selected from the group consisting of: ” methyl, halogenated methyl. alkoxy substituted methyl, heterocycle substituted methyl;

] butyl, aryi substituted butyl; 1sopentyl; cyclohexyl; butenyl, aryl substituted butenyl; acetyl; phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more alkoxy groups, phenyl substituted with one or more sulfonyl groups; benzyl, naphthylenyl; benzo[1,3]dioxolyl; furanyl, halogen substituted furanyl, aryl substituted furanyl; tetrahydrofuran-2-yl; benzofuranyl, alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, alkyl substituted benzofuranyl; benzo[b]thiophenyl, alkoxy substituted benzo[b]thiophenyl, quinolinyl; quinoxalinyl; 1,8 naphthyridinyl, : indolyl (22), alkyl substituted indolyl; pyndinyl, alkyl substituted pyridinyl, 1-oxy-pyridinyl; thiophenyl, alkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3,2-b]thiophenyl; isoxazolyl, alkyl substituted isoxazolyl; and oxazolyl; RY is selected from the group consisting of’: methyl, ethyl, Cj_galkyl -substituted ethyl; butyl, Cy_galkyl-substituted butyl; tert-butyl; isopentyl; phenyl, halogen substituted phenyl,Cj_galkoxy phenyl, cyanophenyl; toluyl, Het-substituted toluyl; benzoic acid;

naphthylenyl; : benzo[1,3]}dioxolyl; benzo[1,2,5)oxadiazolyl; pyridinyl, 1-oxy-pyridinyl, C}_galkyl pyridinyl; thiophene; thiazolyl; 1H-imidazolyl, Cj_galkyl substituted imidazolyl; 1H-[1,2,4]triazolyl, C 1-6alky! substituted 1H-[1 ,2.4)triazolyl; and quinolinyl.

32. A compound according to Claim 30 wherein: RJ is selected from the group consisting of: pentanonyl; naphthylen-2-yl; benzo[1,3)dioxol-5-yl, furan-2-yl; benzofuran-2-yl; benzo[b]thiophen-2-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalin-2-yl; 1,8 naphthyridin-2-yl; indol-3-yl, indol-5-yl; pyridin-2-yl , pyridin-5-yl, thiophen-3-yl; thieno[3,2-b]thiophene-2-yl; 1soxazol-4-yl; and oxazol-4-yl.

33. A compound according to Claim 30 wherein RY is selected from the group consisting of: trifluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl , 2-thiophenyl-methyl; 4-(4-methoxy)phenyl-butyl; 4-pentanonyl,;

’ 4,4-bis(4-methoxyphenyl)-but-3-enyl; 3,4-dichlorophenyl, 4-fluorophenyl, 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, 4-methanesulfonyl-phenyl; 5-nitro-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-triflouromethyl-phenyl)- furan-2-yl, S-bromo-furan-2-yl, 5-(4-chloro-phenyl)-furan-2-yl; 5-(2-piperazin-4-carboxylic acid rerz-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- morpholino-4-yl-ethoxy)-benzofuran-2-yl(44), 5-(2-piperazin-1-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-yl, 5-fluoro-benzofuran-2-yl, 5,6-difluoro- benzofuran-2-yl, 3-methyl-benzofuran-2-yl; 5,6-dimethoxy- benzo[b]thiophen-2-yl; N-methyl-indol-2-yl; 1-oxy-pyridin-2-y}, 2-methyl-pyridin-5-yl; 5-methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-yl; 5-tert-butyl-3-methyl thieno[3,2-b]thiophen-2-yl; 3,5-dimethyl- isoxazol-4-yl; 5-methyl-2-phenyl oxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-4-yl.

34. A compound according to Claim 30 wherein RY is selected from the group consisting of: 2-cyclohexyl-ethyl; 3-methylbutyl; 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-cyanophenyl; 2-benzoic acid; naphthylen-2-yl; benzo[1,3]dioxol-5-yl; benzo[1,2,5]oxadiazol-4-yl; pyridin-2-yl, pyridin-3-yl, 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl , 3-methyl- pyridin-2-yl, 6-methyl-pyridin-2-yl; thiophene-2-yl; thiazol-2-yl;

1H-imidazol-2-yl, 1H-imidazol-4-y], l-methyl-1H-imidazol-2-yl, 1-methyl-1H- : imidazol-4-yl,; 1H-[1,2,4]triazol-3-yl, 5-methyl-1H-[1,2,4]triazol-3-yl; and quinolin-2-yl.

35. A compound according to Claim 30 wherein: R2 is R9S05; R3 is isobutyl; R4 is R3C(O); RJ is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2- b]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, or quinolin-2-yl; and RY is selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin 2-yl.

36. A compound according to Claim 35 wherein RJ is 3-methyl-benzofuran-2-yl.

37. A compound according to Claim 35 wherein R? is I-oxy-pyndin-2-yl.

38. A compound according to Claim 1 selected from the group consisting of: {(S)-1-[1 -((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3-oxo-azepan-4- ylcarbamoyl}carbamic acid benzyl ester; } Naphthylene-2-carboxylic acid[(S)-1-(1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyljamide; Benzo[1,3]dioxole-5-carboxylic acid [(S)-1-(1-benzyl-3-0x0-azepan-4-ylcarbamoyl)-3- methyl-butyljamide; Benzofuran-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo0-azepan-4-ylcarbamoyl)-3-methyl- butyl)amide; Benzo[b]thiophene-2-carboxylic acid [(S)-1-(1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyljamide; Naphthylene-2-sulphony! [(S)-1-(1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl)- amide; Quinoline-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo0-azepan-4-ylcarbamoyl)-3-methyl- butyllamide;

3,4-dichlorebenzeic acid [(S)-1-(1-benzyl-3-oxo-azepan-4-ylcarbamoyi)-3-methyi- butyllamide; 4-{(S)-Methyl-2-[(quinoline-2-carbonyl)-amino}pentanoylamino }-3-o0xo-1 -[2-(3-pynidin-2- yl-phenyl)-acetyljazepanium; 1-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{ (S)-4-methyl-2-[(2-quinoiline-2- carbonyl)-amino]-pentanoylamino)-3-oxo-azepanium; 1 -Benzoyl-4-((S)-2-(benzo[1,3]dioxole-carbonylamino)-4-methyl-pentanoylamino)- 3-oxo- azepanium; 1-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium;

3-Ox0-4-((S)-4-methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyljamino } - pentanoylamino)-1-(4-methyl-pentanoyl)-azepanium; 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-1-(1 -benzenesulfonyl-3- 0x0-azepan-4-ylcarbamoyl)-3-methyl-butyl]lamide; 4-((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyljamino } -

pentanoylamino)-3-oxo-azepane-1-carboxylic acid phenylamide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1 -[2- (3-pyndin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl }-butyl)amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- 1-(benzoyl-3-oxo-azepan-

4-ylcarbamoyl)-3-methyl-butyljamide; 5-(2-Pyrrolidin-1-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-1-( 1-benzenesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl}amide; 5-(2-Piperidin- 1-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-1-(1-benzenesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyljamide; BN 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-0x0-1-[2-

(3-pyridin-2-yl-phenyl)ethyl}-azepan-4-ylcarbamoyl}-butyl)amide; Naphthlene-2-carboxylic acid ((S)-3-methyl-1-{3-oxo- 1-[2-(3-pyridin-2-yl-phenyl)ethyl}- azepan-4-ylcarbamoyl}-butyl)amide; 1H_Indole-2-carboxylic acid ((S)-3-methyl-1-{3-ox0-1-[2-(3-pyridin-2-yl-phenyl)ethyl}- azepan-4-ylcarbamoyl }-butyl)amide;

1H-Indole-2-carboxylic acid [(S)-1-( 1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl)amide; Benzofuran-2-carboxylic acid [(S)-1-(1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- ) methyl-butyl}lamide;

Benzofuran-2-carboxylic acid [(S)-3-methyl-1-{3-oxo-1-[2-(3-pyridin-2-yl-phenyl)ethyl]- : azepan-4-ylcarbamoyl }-butyl)amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-3-methyl-1-(3-ox0-1- phenethyl-azepan-4-ylcarbamoyl}-butyl} amide;

Naphthylene-2-carboxylic acid [(S)-3-methyl-1-(3-oxo-1-phenethyl-azepan-4- ylcarbamoyl}-butyl }amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide; Naphthylene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-

ylcarbamoyl}-butyl }-amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1- (pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl } -amide; 4-((S)-4-Methyl-2-{[(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]-amino }- pentanoylamino)-3-oxo-azepane-1-carboxylic acid tert-butyl ester;

4-((S)-4-Methyl-2-{[(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-3- methyl-1-(3-oxo-azepan-4-ylcarbamoyl]-butyl }amide; 4-Methyl-pentanoic acid {3-oxo-1-[2-(3-pyridin-2-yl-phenyl-acetyl]-azepan-4-yl}-amide; ((S)-3-Methyl-1-{3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl } - butyl)-naphthylene-2-methyi-carbamic acid tert-butyl ester;

(S)-4-Methyl-2-[(naphthylen-2-ylmethyl)-amino]-pentenoic acid [3-oxo-1-[2-(3-pyridin-2- yl-phenyl)-acetyl}-azepan-4-yl }-amide; 4-[2-(2-{(S)-3-Methyl-1-[3-oxo-1-(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butylcarbamoyl }-benzofuran-5-yloxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester; 5-(2-Piperizin-1-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-

(pyndine-2-sulfonyl)-azepan-4-yicarbamoyl]-3-butyl}-amide; 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[2-(3- pyridin-2-yl-phenyl)ethyl}-azepan-4-ylcarbamoyl}-butyl)amide;

4-[2-(2-{(S)-3-Methyl-1-[3-0x0-1-(3-pyridin-2-yl-phenyl)-ethyl [azepan-4-ylcarbamoyl]- butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester; 5-(2-piperizin-1-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo0-1-[2-(3- pyndin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide;

) (8)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-oxo-1-(pyridine- 2-sulphonyl)-azepan-4-yl}-amide; (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid {3-oxo-1-[2-(3- pyridin-2-yl-phenyl)-acetyl}-azepan-4-yl }-amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl-1-{3- oxo-1-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoy! }-butyl)amide; Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 2,2,2-Trifluoro-N-((S)-3-methyl-1-{3-oxo-1 -[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4- ylcarbamoyl }-butyl)-N-naphthylen-2-ylmethyl-acetamide; 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoylamino]-3- oxo-azepane-1-carboxylic acid benzyl ester; Quinoline-2-carboxylic acid {(S)-3-methyl-1-[3-o0xo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide; Quinoline-8-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(pynidine-2-sulfonyl)-azepan-4- ylcarbamoyi]-butyl }amide; Quinoline-6-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(pyridine-2-suifonyl)-azepan-4- ylcarbamoyl]-butyl }amide; Quinoline-4-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide; Quinoline-3-carboxylic acid {(S)-3-methyl-1-[3-oxo0- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butyl}amide; Isoquinoline-3-carboxylic acid {(S)-3-methyl-1 -[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butyl } amide; lsoquinoline-1-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide; Quinoxaline-2-carboxylic acid {(S)-3-methyl-1-[3-o0xo0-1 -(pynidine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butyi } amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1 -(pyridine-2-sulfonytl)- azepan-4-ylcarbamoyl]-butyl}amide; 1,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }amide;

1H-Indole-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- - ylcarbamoyl]-butyl } amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }amide;

5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-butyl}amide; Furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide; 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-

ylcarbamoyl}-butyl }amide; 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl jamide;

Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }amide;

: (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)- azepan-4-yl}-amide; } (S)-2-{2-(4-Fluoro-phenoxy)-acetylamino)-4-methyl-pentanoic acid [3-oxo-(pyridine-2-

sulfonyl)-azepan-4-yl}-amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-carbonyl)-azepan-4- ylcarbamoyl)-3- butyl]-amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(1-oxy-pyridine-2-carbonyl)- azepan-4-ylcarbamoyl]-butyl}amide;

4-((S)-2-tert-Butvlcarbonylamino-4-methyl-pentanoylamino)-3-oxo-azepane- 1-carboxylic acid benzyl ester;

5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-methyl-1H- imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(5-methyl-1H-[1,2,4]triazole-3-sulfonyl)-

3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(1-methyl-1H-imidazole-3-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl}amide;

. Benzoturan-2-carboxylic acid {(S)-3-methyl-1-[1-(1H-imidazole-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]}-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(1-methyl- 1H-imidazole-4-sulfonyl)-3- 0xo0-azepan-4-ylcarbamoyl]}-butyl }amide; 5-(4-Oxy-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1-[3-0xo0- 1-(pyndine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-3-sulfonyl)-azepan-4-

ylcarbamoyl]-butyl }amide;

Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(1-oxy-pyridine-3-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;

Quinoline-3-carboxylic acid {(S)-1-(3,4-dichloro-benzene-sulfonyl)-3-oxo-azepan-4- ylcarbamoyl)]-3-methyl-butyl }-amide;

5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(1-methyl-1H-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)]-3-methyl-butyl}-amide; 2-(4-{(S)-2-{(Benzofuran-2-carbonyl)-amino}-4-methyl-pentanoylamino } -3-oxo-azepane-

1-sulfonyl)-benzoic acid; 3-(4-{(S)-2-{(Benzofuran-2-carbonyl)-amino}-4-methyl-pentanoylamino }-3-oxo-aze pane- 1-sulfonyl)-benzoic acid;

Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide;

5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(1-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; 1-Oxy-pyndine-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-

4-ylcarbamoyl]-butyl }amide; (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-yl]-amide;

(S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- - yl}-amide;

(S)-4-Methyl-2-(3-phenyli-uriedo)-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- yl]-amide;

Benzofuran-2-carboxylic acid {(S)-1-[6,6-dimethyl-3-o0xo-1 (pyridine-sulphonyl)-azepan-4- ylcarbamoyl}-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyi-1-[3-0x0-1-( l-oxy-pyridine-2-

sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide;

Quinoxaline-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl}-butyl }amide;

Quinoline-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-butyl }Jamide;

Thiophene-3-carboxylic acid {(5)-3-methyl-1-[3-ox0-1-(1-0xy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl}-butyl }amide; 1H-Indole-5-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-( 1-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl}-butyl }amide;

Benzo[1,3]dioxole-3-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1 -oxy-pyridine-2-

sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; Furan-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-( 1-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide;

(S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-oxo0-1-( 1-oxy-pyridine-2- sulfonyl)-azepan-4-yl]-amide;

1H-Indole-2-carboxylic acid {(S)-3-methyl-1-[3-0xo-1-(1-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoy!]-butyl }amide; 4-Fluoro-{(S)-3-methyl- 1-[3-0xo0-1-( 1-oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]- butyl }-benzamide; 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1-[3-0x0-(1-0xy-

pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]- -buty }-amide;

Thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }amide;

. 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(1 -oxXy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide; 6-Methyl-N-{(S)-3-methyl-1-[3-ox0-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}- butyl }-nicotinamide;

(S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-oxo-1-(pyridine-2-

sulfonyl)-azepan-4-yl}-butyl}amide; 1H-Indole-6-carboxylic acid {(S)-3-methyl-1-[3-0xo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide; Benzo[1,3]dioxole-5-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(pyridine-2-sulfonyl)-

azepan-4-ylcarbamoyl}-butyl }amide; 3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(1- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl }amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;

4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-( 1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; ; 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-1-{3-oxo-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl}-butyl }amide; (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid{1-(4-methoxy-

benzenesulfonyl)-3-oxo-azepan-4-ylj-amide; . 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; 5-Methyl-2 —phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(1-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide;

Benzofuran-2-carboxylic acid {(S)-1-[ 1-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl}-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-1-[ 1-(4-bromo-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide;

Benzofuran-2-carboxylic acid {(S)-1-[1-(benzo[ 1,2,5}oxadiazole-4-sulfonyl)-3-oxo-

azepan-4-ylcarbamoyl}-3-methyl-butyl }-amide;

Benzofuran-2-carboxylic acid {(S)-1-[1-(3,5-dimethyl-oxazole-4 -sulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl }-amide;

3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-1-(pyridine-2-sulfonyl)- : azepan-4-ylcarbamoy!]-butyl }amide;

Thieno{3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-o0x0-1 -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoylj-butyl }amide;

5-tert-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-butyl }amide; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-meth yl-1-[3-oxo-1-(pyridine-

2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl amide;

Quinoline-2-carboxylic acid [(S)-1-(1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl}-amide;

1-Methyl-1H-indole-2-carboxylic acid [(S)-1-(1-methanesuifonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide;

Furan-2-carboxylic acid {{(S)-1-(1-methanesulfonyi-3-oxo-azepan-4-ylcarbamoyl)-3-

methyl-butylcarbamoyl}-methyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-1-( 1-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Quinoxaline-2-carboxylic acid [(S)-1-(1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl}-amide; 5-(4-Chloro-phenyl)-furan-2-carboxylic acid { (S)-3-methyl-1-[3-oxo0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide; Nn (8)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid ( 1-methanesulfonyl-3- oXxo-azepan-4-yl)-amide; Quinoline-2-carboxylic acid {[(S)-1-[1-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-1H-indole -2-carboxylic acid {[(S)-1-[1-(2-cyano-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoy1}-3-methyl-butyl }-amide; Furan-2-carboxylic acid ({(S)-1-[1-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyl }-methyl)-amide: 5-Methoxy-benzofuran-2-carboxylic acid {(S)- 1-[1-(2-cyano-benzenesulfonyl)-3-oxo- ) azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

: Quinoxaline-2-carboxylic acid {(S)-1-[1-(2-cyano-benzenesulfonyl)-3-oxo-azepan4- ylcarbamoyl]-3-methyl-butyl }-amide; (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-yl}-amide; Quinoline-2-carboxylic acid {[(S)-1-[1-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-1H-indole-2-carboxylic acid {{(S)-1-[1 -(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Furan-2-carboxylic acid ({(S)-1-[1-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-

ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-amide; 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-1-[1-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

Quinoxaline-2-carboxylic acid {[(S)-1-[1-(4-methoxy-benzenesulfony!)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide;

(S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; 1-Methyl-1H-indole-2-carboxylic acid {[(S)-1 -[1-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;

: Furan-2-carboxylic acid ({(S)-1-[1-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-

ylcarbamoyl]-3-methyl-butylcarbamoyl }-methyl)-amide; 5-Methoxy-benzofuran-2-carboxylic acid { [(S)-1-[1-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;

Quinoxaline-2-carboxylic acid {[(S)-1-{ 1-(4-fluoro-benzenesulfony!)-3-oxo-azepan—4- ylcarbamoyl}-3-methyl-butyl }-amide;

(S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid-{(S)-1-[1-(3-chloro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl}-3-methyi-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1 -(3-chloro-benzenesulphonyl)-3-oxo-

azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 7-Methoxy-benzofuran-2-carboxylic acid- {(S)-1-[1-(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-] 1-(3-chloro-benzenesulphonyl)-3- : oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }-amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-1-[ 1-(3-chioro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-yicarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-1H-indole-2-carboxylic acid-{(S)-1-[1 -(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoy!}-3-methyl-butyl }-amide; Quinoxaline-2-carboxylic acid-{(S)-1-[1-(3-chloro-benzenesulphonyl)-3-oxo-azepan-4-

ylcarbamoy!l]-3-methyl-butyl }-amide;

Benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide;

5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoy!]-3-methyl-butyl }-amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3- 0xo0-azepan-4-ylcarbamoyl]}-3-methyl-butyl }-amide;

: 5-Methyl-benzofuran-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3-oxo-

azepan-4-ylcarbamoyl}-3-methyl-butyl}-amide:

Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

1-Methyl-1H-indole-2-carboxylic acid-{(S)-1-[1 -(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

(S)-4-Methyl-2-(1-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-oxo0-1-(pyridine-2- sulfonyl)-azepan-4-yl}-amide;

Quinoxaline-2-carboxylic acid-{(S)-1-[1-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo-1-(thiophene-2-

sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo-1-(thiophene-2- sulfonyl)-azepan-4-ylcarbamoyl}-butyl }-amide:

] 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo-1 -(thiophene-2- . sulfonyl)-azepan-4-ylcarbamoyl}-butyl }-amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo-1 -(thiophene-2-suifonyl)- azepan-4-ylcarbamoyl]-butyl }-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-3-methyl-1-[3-o0x0-1 -(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }-amide; 1-Methyl-1-H-indole-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo-1 ~(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }-amide; Quinoxaline-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo0-1 -(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid-{(S)-1-[ 1-(4-chloro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]}-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1 -(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1 -(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-[ 1-(4-chloro-benzenesulphonyl)-3- oxo-azepan-4-ylcarbamoyl]}-3-methyl-butyl } -amide; 3-Methyl-benzofuran-2-carboxylic acid- {(S)-1-[1 -(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-1H-indole-2-carboxylic acid-{(S)-1-[1-(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Quinoxaline-2-carboxylic acid-{(S)-1-[1 -(4-chloro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoy!]-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid- {(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;

5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphony))-3- . oXxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl }-amide; Benzo[b}thiophene-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-1H-indole-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide: Quinoxaline-2-carboxylic acid-{(S)-1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo- 1-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[(2,2’ ,4-tnidueterio)-3-oxo-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide:

Benzofuran-2-carboxylic acid {(S)-2-methyl-1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide; Benzofuran-2-carboxylic acid {(S)-1-[3-oxo-1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]}-propyl}-amide;

Benzofuran-2-carboxylic acid {(8)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-ethyl }-amide;

Benzofuran-2-carboxylic acid {(S)-1-[3-oxo0-1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]j-ethyl}-amide; Benzofuran-2-carboxylic acid { (S)-3-methanesulfinyl-1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl}-propyl}-amide;

Benzofuran-2-carboxylic acid {[3-ox0-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamovil- methyl }-amide; Benzofuran-2-carboxylic acid {(S)-1-[3-oxo0-1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-pentyl }-amide; Benzofuran-2-carboxylic acid {(S)-1-[3-0x0- 1-(pyridine-2-sulfonyl)-azepan-4-

ylcarbamoyl}-butyl }-amide;

Benzofuran-2-carboxylic acid {(S)-2-methyl-1-[3-ox0-1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-propyl}-amide;

} Benzofuran-2-carboxylic acid {(S)-2-hydroxy-1-[3-oxo-1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-propy! }-amide; Benzofuran-2-carboxylic acid {(S)-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl}-amide; 1-(Benzofuran-2-carbonyl)-pyrrolidine-2-carboxylic acid [3-oxo- 1-(pyridine-2-sulfonyl)- azepan-4-yl}-amide;

3.4-Dimethoxy-N-{(S)-1-[ 1-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- 3-methyl-butyl }-benzamide; Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[ 1-(4-imethoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Benzo(1,3]dioxole-5-carboxylic acid {(S)-1-[1-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl}-3methyl-butyl }-amide; (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid{ 1-(4-fluoro-benzenesulfonyl)-3- 0xo0-azepan-4-yl]-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[ 1 -(4-fluoro-benzenesulfonyl)-3-oxo-azepan- 4-yl carbamoyl]-3-methyl-butyl }-amide; Benzofuran-2-carboxylic acid {(S)-1-[1-benzoyl-3-oxo0-azepan-4-ylcarbamoyl]-3-methyl- butyl }-amide; : (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-oxo-1-(pyridine-2- sulfonyl)-azepan-4-yl}-amide; : (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-0x0-1-(pyndine-2- sulfonyl)-azepan-4-yl}-amide; BN Benzofuran-2-carboxylic acid-{(S)-1-[ 1 -(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl }-amide; N-{(8)-1-[1-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl }-3-methyl-butyl }- 3,4-dimethoxy-benzamide; Cyclohexanecarboxylic acid {(S)-1-[1-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl }-3-methyl-butyl }-amide; (5)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[1-(methanesulfonyl)-3-oxo- azepan-4-yl}-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-1-(1-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;

Benzo[1,3]dioxole-5-carboxylic acid-{(S)-1-(1 -methanesulfonyl-3-oxo-azepan-4-yl g carbamoyl)-3-methyl-butyl]-amide;

Benzofuran-2-carboxylic acid-{(S)-1-(1-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3- methyl-butyl]-amide;

N-[(S)-1-(1-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl }-3-methyl-butyl }-3,4- dimethoxy-benzamide; (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[1-(2-cyano-benzensulfonyl)-3- oxo-azepan-4-yl}-amide; N-{(S)-1-[1-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl }-3-methyl-butyl }-4-

methanesulfonyl-1-benzamide;

Benzo[b]thiophene-2-carboxylic acid-{(S)-1-[1-(2-cyano-benzenesulfonyl)-3-oxo-azepan- 4-yl carbamoyl)-3-methyl-butyl]}-amide; Benzo[1,3]dioxole-5-carboxylic acid-{(S)-1-[1 -(2-cyano-benzenesulfonyl)-3-oxo-azepan- 4-yicarbamoyl)-3-methyl-butyl]-amide;

(S)-4-Methyl-2-[4-0x0-4-((4-phenoxy-phenyl)-butyrylamino }-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-yl}-amide; N-{(S)-1-[(1-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl } - 3,4-dimethoxy-benzamide;

) Cyclohexanecarboxylic acid {(S)-1-[1-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-

ylcarbamoyl}-3-methyl-butyl }-amide; : 4-Methansulfonyl-N-{(S)-1-[4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- ’ methyl-butyl-benzamide; 4-Methansulfonyl-N-{(S)-1-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methyl-butyl-benzamide;

({(S)-3-Methyl-1-[3-0x0-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylcarbamoyl } - carbamic acid benzyl ester; (S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl)-azepan-4-yl)-amide; (S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo-1-

(pyndine-2-sulfonyl)-azepan-4-yl}-amide; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(pyridine-2-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl }amide;

. (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-yl]-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-{1-(6-methyl-pynidine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl }amide;

5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(6-methyl-pyridine-2- sulfonyl)-3-o0xo0-azepan-4-ylcarbamoyl}-butyl}amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyi]-butyl} amide; 7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(pyridine-2-sulfonyl)-3-oxo-

azepan-4-ylcarbamoyl]-butyl }amide; 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[1-(pyridine-2- sulfonyl)-3-ox0-azepan-4-ylcarbamoyl]-butyl} amide; (R)-1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl-1-{3-oxo-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl}-butyl } amide;

(S)-1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl-1-{3-oxo-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl}-butyl } amide;

Benzofuran-2-carboxylic acid {(S)-2-cyclopropyl-1-[3-oxo-1-(pyridine-2-suifonyl)-azepan- 4-ylcarbamoyl)-ethyl]-amide; - Benzofuran-2-carboxylic acid {(S)-3-methylsulfanyl-1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-propyl]-amide; Benzofuran-2-carboxylic acid {(S)-2-naphthylen-2-yl-1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-ethyl]-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[1-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-butyl}amide;

Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[1-(3-methyl-pyridine-2- sulfonyl)-3-oxo0-azepan-4-ylcarbamoyl]-butyl} amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(3-methyl-pyridine-2-

sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo0-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide;

5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{ (S)-2-cyclohexyl-1-{3-o0xo-1- : (pynidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;

5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-{3-oxo- 1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl- 1-[6-methyl-3-o0xo-1 -(pyndine-sulphonyl)- azepan-4-ylcarbamoyl]-butyl }-amide; 5-(4-Chloro-phenyl)-furan-2-carboxylic acid{ (S)-2-cyclohexyl-1-[ 3-0xo0- 1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{ (5)-2-cyclohexyl-1-[3-ox0-1-(1-

oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide; S-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }-amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid { (5)-2-cyclohexyl-1-[3-oxo-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-ethyl }-amide:

5,5-Bis-(4-methoxy-phenyl)-pent-4-enoic acid {(S)-3-methyl-1- [3-0x0-1 ~-(pynidine-2-sulfonyl)-azepan-4-ylcarbamoy!] }-butyl }-amide; Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-1-[3-ox0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Naphthylene-1-carboxylic acid { (S)-2-naphthylen-2-yl-1-[3-oxo0-1-

(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;

Quinoline-8-carboxylic acid {(S)-1-[3-oxo-1-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl }-amide; Naphthyridine-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide;

Naphthylene-1-carboxylic acid {(S)-1-[3-0x0-1-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl }-amide: 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(cyclohexyl-proprionyl)-azepan-4-ylcarbamoyl}-butyl }-amide: 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-1-

[3-oxo-1 -(4-methyl-pentanoyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-0x0-1-(1 -0Xy-pyridine-2- carbonyl)-azepan-4-ylcarbamoyl}-butyl }-amide;

(S)-Acetylamino-4-methyl-pentanoic acid [3-0x0-1-(pyridine-2-sulfonyl)-

SE ’ wO 00/38687 PCT/US99/30730 ’ | azepan-4-yl}-amide; Quinoline-2-carboxylic acid { 1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-pentyl }-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-ox0 5-1 -(cyclohexyl-proprionyl)-azepan-4-ylcarbamoyl]-butyl }-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1- {3-0x0-1 ~(4-methyl-pentanoyl)-azepan-4-ylcarbamoyl]-butyl }-amide; Quinoline-2-carboxylic acid {(S)- 1-[3-oxo-1-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoy1]-2-phenyl-ethyl }-amide; 10 Benzofuran-2-carboxylic acid{(S)-2-benzyloxy- 1-[3-oxo-1-(pyridine-2- sulfonyl)-azepane4-ylcarbamoyl]-ethyl }-amide; Benzofuran-2-carboxylic acid{ (S)-2-hydroxy- 1-[3-ox0-1-(pyridine-2- sulfonyl)-azepane-4-ylcarbamoyl]-ethyl } -amide; “Methoxybenzofuran-2-carboxylic acid {(S)-3-methyi-1-[3-oxc- 1-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1 -(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl}-butyl }amide; 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-1 -(3-oxo-1-(thiazole-2-sulfonyl)- azepan—4-ylcarbamoyl}-butyl }amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-oxo- 1-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl}-butyl }amide; 1-Methyl-1H-indole-2-carboxylic acid {(S)-3-methy!-1-[3-oxo0-1-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoy!]-butyl }amide; Quinoxaline-2-carboxylic acid {(S)-3-methyl-1-[3-0xo-1-(thiazole-2-sulfonyl)-azepan-4- 23 ylcarbamoyl}-butyl jamide; and Quinoline-2-carboxylic acid {{( S}-1-[1-(4-fluoro-benzenesuifonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide. , 39. A pharmaceutical composition comprising a compound according to Claims 1 to 38 . 30 and a pharmaceutically acceptable carrier, diluent or excipient. -

40. A compound according to any one of Claims 1 to 38, for use in inhibiting a protease. 265 AMENDED SHEET

41. A compound according to Claim 40 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease. S

42. A compound according to Claim 41 wherein said protease is a cysteine protease.

43. A compound according to Claim 42 wherein said cysteine protease is cathepsin K.

44. A compound according to any one of Claims 1 to 38, for use in the treatment of a disease characterized by bone .

45. A compound according to Claim 44 wherein said disease is osteoporosis.

46. A compound according to Claim 44 wherein said disease is periodontitis.

47. A compound according to Claim 44 wherein said disease is gingivitis.

48. A compound according to any one of Claims 1 to 38 for use in the treatment of a disease characterized by excessive cartilage or matrix degradation.

49. A compound according to Claim 48 wherein said disease is osteoarthritis.

50. A compound according to Claim 48 wherein said disease is rheumatoid arthritis. 51 A compound of Formula II: 266 AMENDED SHEE™ i

RAF i Co ry . rr” WN, , R II wherein: R1 is selected from the group consisting of:

Ie) Oo 0 a Rt A R’ ; R’ and R® R2 is selected from the group consisting of: H, C;_galkyl, C3_gcycloalkyl-Cp. galkyl, Ar-Cg.galkyl, Het-Cq_galkyl, R9C(0)-, R9C(S)-, R9S0,-, R90C(0)-, . ZF ay @ : 10 RORIINC(O)-, RORIINC(S)-, RORIHNSO,- 7 , 7 and R® ar N Es R® : R3 is selected from the group consisting of: H, Cj_galkyl, C2-galkenyl, C2-6alkynyl, HetCq.galkyl and ArCq_galkyl; R3 and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring; R% is selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl-Cq_ ealkyl, Ar-Cq_galkyl, Het-Cg_galkyl, R°C(0)-, R5C(S)-, R580,-, RS0C(O)-, RSRI3NC(0)-, and RSRI3NC(S)-; RS is selected from the group consisting of: H, Cy_galkyl, C-galkenyl.

C3. ealkynyl, C3_gcycloalkyl-Cq_galkyl, Ar-Cq_galkyl and Het-Cq_galkyl; RO is selected from the group consisting of: H, Cj _galkyl, Ar-Cg.galkyl. or Het- Co-salkyl;

) . R7 is selected from the group consisting of: H, Cj _galkyl, C3_gcycloalkyl-Cy_ ' 6alkyl, Ar-Co.galkyl, Het-Co.galkyl, R10C(0)-, R10C(S)-, R1050,-, R100¢(0)., RIORI4NC(0)-, and RIORI4NC(S)-: R8 is selected from the group consisting of: H, Ci-galkyl, C_galkenyl, Cz-ealkynyl, HetCq.galkyl and ArCo.ealkyl; RY is selected from the group consisting of: Cj_galky!, C3_geycloalkyl-Cyp_galkyl, : Ar-Co.galkyl and Het-Cq_galkyl; R10 js selected from the group consisting of: Cj_galkyl, C3.¢cycloalkyl-Cq_galkyl, Ar-Co.ealkyl and Het-Cq_galkyt; R11 is selected from the group consisting of: H, C{_galkyl, Ar-Co.galkyl, and Het-

Co.salkyl; R12 is selected from the group consisting of: H, C1_ealkyl, Ar-Cq.galkyl, and Het- Co-salkyl; R13 is selected from the group consisting of: H, C1-6alkyl, Ar-Cq.galkyl, and Het-

Cp.galkyl; R14 is selected from the group consisting of: H, C;_galkyl, Ar-Cq.ealkyl, and Het- Cop-galkyl; R’is selected from the group consisting of: H, Cy_galkyl, Ar-Cq_ealkyl, and Het- Co-6alkyl; R” is selected from the group consisting of: H, Cy_galkyl, Ar-Cp-galkyl, or Het-Cq. 6alkyl; R™ is selected from the group consisting of: H, C 1-6alkyl, C3_gcycloalkyl-Cq. alkyl, Ar-C_galkyl, and Het-Cg_galkyl; X is selected from the group consisting of: CH», S, and O; Z is selected from the group consisting of: C(O) and CH»; and pharmaceutically acceptable salts, hydrates and solvates thereof.

52. A compound according to Claim 51 selected from the group consisting of: [(S)-1 (3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl}-carbamic acid benzyl] ester; (S)-2-Amino-4-methyl-pentanoic acid (1-benzyl-3-hydroxy-azepan-4-yl)-amide;

. (S)-2-Amino-4-methyi-pentanoic acid{3-hydroxy-1-[2-(3-pyridin-2-yl-phenyl)- acetyl]-azepan-4-yl}-amide; {(5)-1-[4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepan-1- ylmethyl]-3-methyl-butyl}-carbamic acid benzyl ester; (S)-2-Amino-4-methyl-pentanoic acid-(1-benzoyl-3-hydroxy-azepan-4-yl)-amide; (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- 1-(4-methyl-pentanoyl)-azepan- 4-yl]-amide; (S)-2-Amino-4-methyl-pentanoic acid (1-benzenesulfonyl-3-hydroxy-azepan-4-yl)- amide; thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl } amide; thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy- 1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; quinoline-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; and quinoxaline-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy-1-(1-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide.

53. A process for the synthesis of a compound according to Claim 1 comprising the step of oxidizing a corresponding compound of Claim 51 with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers.

54. The process of Claim 53 wherein the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine.

5S. The process of Claim 54 further comprising the step of separating the diasteromers by separating means.

56. The process of Claim 55 wherein said separating means is high presssure liquid ' chromatography (HPLC).

57. The process of Claim 53 further comprising the step of deuterating said diastereomers with a deuterating agent.

58. The process of Claim 57 wherein said deuterating agent is CD30D: D>O (10:1) in toethylamine.

59. Use of a compound according to any one of Claims 1 to 38 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.

60. A use according to Claim 59 wherein said protease is a cysteine protease.

61. A use according to Claim 60 wherein said cysteine protease is cathepsin K.

62. Use of a compound according to any one of Claims 1 to 38 in the manufacture of a medicament for use in treating a disease characterized by bone loss.

63. A use according to Claim 62 wherein said disease is osteoporosis.

64. A use according to Claim 62 wherein said disease is periodontitis.

65. A use according to Claim 62 wherein said disease is gingivitis.

66. Use of a compound according to any one of Claims 1 to 38 in the manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation.

67. A use according to Claim 66 wherein said disease is osteoarthritis.

68. A use according to Claim 66 wherein said disease is rheumatoid arthritis.

.

69. A compound according to Claim 1 or Claim 51, substantially as herein described and exemplified.

70. A pharmaceutical composition according to Claim 39, substantially as herein described and exemplified.

71. A compound according to any one of Claims 40, 44 or 48, substantially as : herein described and exemplified.

72. A process according to Claim 53, substantially as herein described and exemplified.

73. Use according to any one of the Claims 59, 62 or 66 substantially as herein described and exemplified. : 270A i 1 AMENDED SHEE”