AU2003261482B2

AU2003261482B2 - Protease inhibitors

Info

Publication number: AU2003261482B2
Application number: AU2003261482A
Authority: AU
Inventors: Maxwell David Cummings; Robert Wells Marquis Jr; Yu Ru; Scott Kevin Thompson; Daniel Frank Veber; Dennis Yamashita
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1998-12-23
Filing date: 2003-11-06
Publication date: 2007-01-25
Anticipated expiration: 2019-12-21
Also published as: AU2003261482A1

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: SmithKline Beecham Corporation ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Protease inhibitors" The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPERKBM\2003\NVI236349O 310.DOC 6/11/03 P:OPERl\h,\I2363490 div.caimdow.611/03 -1- PROTEASE INHIBITORS This is a divisional of Patent Application No. 19411/00, the entire contents of which is incorporated herein by reference.

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, osteoporosis, peridontitis, 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. et al., (1996) J. Biol.

Chem. 271, 12517-12524; Drake, et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, et al., (1996) J Biol. Chem. 271, 2126-2132.

Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature. The designation cathepsin K is considered to be the more appropriate one.

Cathepsins function in the normal physiological process of protein degradation in animals, including humans, in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, 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 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 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 leupeptin, Z-Phe-Ala-CHN 2 prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al., Biochem. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium deficient diets. Lerner, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al., Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Evens, et al., J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, et al., Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.

The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.

Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis., Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.

Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, 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 peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L. International Patent Application No.

PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- Ip3convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No.

PCT/GB9 1/01479), 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. 1968, 107, 103, Garker er al., Biochem. 1974, 139, 555, Gray et al., Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al., J.

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

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

Antipain and leupeptin are described as reversible inhibitors of cysteine protease in McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. 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 have now discovered a novel class of 4 -amino-azepan-3-one compounds which are protease inhibitors, most particularly of cathepsin K.

SUMMARY OF THE INVENTION Advantageously at least one embodiment of the present invention may provide 4amino-azepan.3-one carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.

Accordingly, in the first aspect, this invention provides a compound according to Formula I.

In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.

In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula I.

In still another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.

In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival.diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula I: R N/ R"

R"^N

R

2

I

wherein:

R

1 is selected from the group consisting of: R, 0 0 0 R i

R

5

R

3 and R

R

2 is selected from the group consistin' of: H, C I 6 alkyl, C 3 .6cYcloalkyl-CQ.

6 alkyl. Ar-CO.

6 alkyl, Het-CO.

6 alkyl, R 9

R

9

R

9

R

9 OC

R

9 RI 1

R

9

R

1 1

R

9

(R

1 1

)NSO

2 and R 6 7 'N

Z

R

3 is selected from-the- croup consisting-of: H, Ci-6alkyl, C2.6alkenyl, C2-6alkynyl, HeEC 0 6 alkyl and ArC 0 6 alkyl;

R

3 and R' may be connected to form a pyrrolidine (204), piperidine or morpholine fn-:~

R

4 'is 's *ele cted from the group consisting of: H, C 1 6 alkyl, C 3 .6cYcloalky].C 0 6 alkyl, Ar-C 0 6 alkyl, Het-C 0 6 alkyI, R 5

R

5

R

5 S0 2

R

5 OC

R

5 Rl 3 and R 5

R

1 3

NC(S)-;

R

5 is selected from the group consisting of: H, CI.

6 alkyl, C2.6alkenyl, C1.

6 alkynyl, C 3 6 CYCloalkyl-CO.

6 alkyl, Ar-CO.

6 alkyl, Het-CO 0 6 alkyl, halogenated methyl and acetyl;

R

6 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO.6alkyl, and Het- CO 6alkyl;

R

7 is selected from the group consisting of: H, CI- 6 alkyl, C3.6cycloalkyl.Co.

6 alkyl, Ar-CO- 6 alkyl, Het-CO.

6 alkyl, RIOC(0)., RIOC(S)-, RI 0 SOI,., RIO0C(0)-., R I R 14 and R I R I 4

NC(S)-;

R

8 is selected from the group consisting of: H, C I 6alkyl, C2.6alkenyl, C2.6alkynyl, HetC 0 6 alkyl and ArC 0 6 alkyl;

R

9 is selected from the group consisting of: CI- 6 alkyl, C3-6cYcloalkyl.CO.

6 a~kyl, Af-CO 0 6 alkyl and Het-CO 0 6 alkyl; R 10 is selected from the group consistinga of: C 6 lyC.ccoly.Qakl Ar-CO 0 6 alkyl and I-et-CO.

6 alkvI: P:%0PERXb~nZ4J2319 ip"dAm. 12A)3/03 R" is selected from the group consisting of: H, C,.

6 alkyl, Ar-CO.

6 alkyl, and Het- C0.

6 alkyl; R'1 2 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO.

6 alkyl, and Het-

CO.

6 alkyl; R 1 3 is selected from thle group consisting of: H, C 1 6 alkyl, Ar-CO.

6 alkyl, and Het-

CO.

6 alkyl; R 1 4 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO.

6 alkyl, and Het- C0.

6 alkyl; R' is selected from the group consisting of:- H, C,.

6 alkyl, Ar-CO.

6 alkyl, and Het-

CO.

6 alkyl; R" is selected from thle group consisting of: H, C,.

6 alkyl, Ar-CO.

6 alkyl, or Hetis selected from the group consisting of: H, C1.

6 alkyl, C3.

6 cycloalkyl-CO.

6 alkyl, Ar-CO- 6 alkyl, and.Het-CO.

6 alkyl;.

1 5 X is selected from the group consisting of: CH 2 S, and 0; Z is selected from the group consisting of: C(O) and CH 2 wherein each G 1 6 alkyl may be optionally substituted by a moiety selected from the group consisting of OR' 2

C(O)R'

2

SR'

2

S(O)R'

2

N(R

2 2

R'

2 NC(O)0R', CO 2

N(R

2 2

N(C=NH)NH

2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more Ph-C0.

6 alkyl, Het-CO.

6 alkyl, C 6 alkoxy, Ph-CO.

6 alkoxy, Het-CO.

6 alkoxy, OH, (CH 2 6 NR' R' 6

O(CH

2 )1.

6

NR'

5 R, C I .alkyl, N(R 7 2

SR'

7

CE

3

NO

2 CN, CO 2

R'

7

CON(R'

7 F, Cl, Br or 1; where R" 5 and R'1 6 are H, C1.

6 alkyl, Ph-CO.

6 alkyl, naphthyl-C 0 6 alkyl or Het-CO.

6 alkyl; and

R"

7 is phenyl, naphthyl, or C,.

6 alkyl; and wherein each Het is optionally substituted with one or two moieties selected from Ar-CO.

6 alkyl, C,-6alkyl,

N(R'

7 2

SR'

7

CF

3

NO

2 CN, CO 2

R'

7 CON(R 7 F, Cl, Br and 1, where R 1 7 is phenyl, naphthyl, or C1.

6 alkyl; and pharmaceutically acceptable salts, hydrates and solvates thereof.

0 In compounds of Formula I, when R' is

W

3 is selected from the group consisting of: H, C, 4 6alkyl, C 2 6 alkenyl, C 2 6 alkynyl, Het-Co.

6 alkyl and Ar-CO.

6 alkyl; R 3 is preferably selected from the group consisting of: H, Ar-CO-6alkyl, and CI.

6 alkyI; POPERMWIU,~412389 spmcdoc. 12A)3A)3 R 3 is more preferably selected froin thle group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyc lohexylm-ethyl, 2-methanesu lfinyl-ethyl, 1 -hydroxyethyl, toluyl, naphthalen-2.ylmethyl, benzyloxymethyl, and hydroxymethyl.

R 3 is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.

R 3 is most preferably isobutyl.

R' is selected from thle group consisting of: H, C1.

6 alkyl, C 3 6 cycloalkyl-CO.

6 alkyl, Ar-CO.

6 alkyl, H-et-Co.

6 alkyl, R 5

R

5 R'S0 2 RsOC(O)-, RIR 1 3 and

R

5

R'

3

NC(S)-.

R 4 is preferably selected from the group consisting of: R 5

R

5 and R'S0 2 R 4 is most preferably R 5 In some embodiments, R 4 is preferably. methanesulfonyl.

1 5 R' is selected from the group consisting of: C,.

6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl,

C

36 cycloalkyl-CO.

6 alkyl, Ar-CO.

6 alkyl or Het-C 0 6 alkyl.

Preferably R 5 is selected from the group consisting of: C,.

6 alkyl, halogenated methyl, acetyl, Ar-CO.

6 alkyl and Het-CO-6alkyl; wherein each C,.

6 alkyl may be optionally substituted by a moiety selected from the group consisting of OR" 2

SR"

2

S(O)R'

2

N(R'

2 2

R'

2 NC(O)0R 5 CO0 2

N(R'

2 2

N(C=NH)NH

2 Het, C 36 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more -Ph-CO.

6 alkyl, Het-CO.

6 alkyl, C 1 6 alkoxy, Phl-CO.

6 alkoxy, Het-CO.

6 alkoxy, OH, (CH 2 1 6 NR' SRI

O(CH

2 1 .6NR 1 5

R'

6

C

1 .6alkyl, OR" 7

N(R'

7 2

SR'

7

CE

3

NO

2 CN, CO 2

R'

7 CON(R"), F, Cl, Br or I; where R' 5 and R 1 6 are H, C 16 alkyl, Ph-Co-6alkyl, naphthyl-Co-6alkyl or Het-CO-6alkyl; and R'1 7 is phenyl, naphthyl, or C 1 _6alkyl; and wherein each Het is optionally substituted with one or two moieties selected -from.

Ar-CO.

6 alkyl, C 16 alkyl, OR'1 7 N(R1 7 2

SR"

1

CF

3

NO

2 CN, CO 2

CON(R'

7 F, Cl, Br and 1, where R" 7 is phenyl, naphthyl, or CI.

6 alkyl.

More preferably, and especially when R 4 is R 5

R

5 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; P.%OPERKbinU2139 sp=.CdO1 2A).1A)3 butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4methoxyphenyl)-but-3 -enyl; acetyl; 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-4methoxy-phenyl, especially phenyl substituted with one or more sulfonyl groups, more especially 4-niethanesulfonyl-phenyl;benzyl; naphthalenyl, especially naphthylen-2-yl; benzo[ 1,3]dioxolyl, especially benzo [1,3]dioxol-5-yl, furanyl, especially furan-2-yl, especially substituted furanyl, such as 2-yl. 5-(4-nitrophenyl)-fuan-2-yl 5-(3-trifluorornethyl-phenyi)-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-(2morpholino-4-yl-ethoxy)-benzofuran-2.yl, 5-(2-piperazin-1 -yl-ethoxy)benzofuran-2-yI, 2 -cyclohexyl-ethoxy)..benzofuran2yl; especially alkoxy substituted benzofuranyl, more especially 7 -methoxy-benzofuran-2..yl, 5-methoxy-benzofura-2-yl, 5,6-dimethoxybenzofuran-2-yi, especially halogen substituted benzofuranyl, more especially benzofuran-2-yl(255), 5,6-diflu'oro-benzofuran-2-yi, especially alkyl substituted benzofuranyl, most especially 3 -methyl-benzofuran-2.yl: benzofbljthiophenyl, especially benzo[blthiophen-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; 1,8 naphthyridinyl, especially 1,8 naphtbyridin-2-yl; indolyl, especially indol-2-yl. especially indol-6-yl, indol-5-yl, especially alkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl pyridin-5-yl, especially l-oxy-pyridin-2-yI, especially alkyl substituted pyridinyl. more especially 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-blthiophene-2-yl, more especially alkyl substituted thieno[3,2-b]thiophene-2-yl, more especially 5-terr-butyl-3-methylthieno[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, 2phenyl.5-trifluoromethyl.oxazol.4.yl; When R 4 is R 5 S0 9

R

5 is preferably pyridin-2-yl or 1 -oxo-pyridin-2-yl.

R' is selected from the group consisting of: H, C I 6 alkyl, Ar-Cc-6alkyl, and Het-

CO-

6 alkyl.

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, CJ- 6 alkyl, Ar-CO-6alkyl, and Het-C 0 6 alkyl.

Most preferably R" is H.

R-'is selected from the group consisting of: H, CI- 6 alkyl, C3-6cycloalkyl- CO-6alkyl, and Het-CO 0 6 alkyl.

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

Most preferably R' is H.

In compounds of Formula I, R 2 is selected from the group consisting of: H, C 1 6 alkyl, C3..6cycloalkyl-C 0 6 alkyl, Ar-CO- 6 alkyl, Het-CO- 6 alkyl, R 9

R

9 'N C(O)

R

9 S0 2

R

9

R

9 R I INC(O)-, R 9 R I INC(S)-, R 9 R I INSO,-, P.6

R

and R Preferably R 2 is selected from the group consisting of: -Ar-CO-alkyl, R 9 R 6 7 'N

Z

R

9 S0 2

R

9 R1 1 and AS More preferably, R 2 is selected from the group consisting of: Ar-CO-6alkyI,

R

9 and R 9 S0 9 Most preferably R 2 is R 9

SO,.

In such embodiments: PAO0PET4.U,.4223B9 %=e.docIZM1f3h R 6 is selected from the group consisting of: H, C 1 6 alkyl, Ar-C 0 6 alkyl, or Het-Ca.

6 alkyl, preferably H.

R' is selected from the group consisting of: H, C 1 6 alkyl, C 3 6 cycloalk-CO.

6 alkyl, Ar-CO.

6 alkyl, Het-CO.

6 alkyl, R' 0

R'

0

R'

0 S0 2

R'

0

R'

0

RIINC(O)-,

R'

0

R'

4 R' is preferably R' 0 0C(O).

R 8 is selected from the group consisting of: H, C,.

6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, HetC 0 6 alkyl and ArC 0 6 alkyl; preferably C,.

6 alkyl, more preferably isobutyl.

R

9 is selected from the group consisting of: CI.

6 alkyl, C 3 6 cycloalkyl-CO.

6 alkyl, Ar-CO.

6 alkyl, and Het-CO.

6 alkyl.

1 0 R 9 is preferably selected from the group consisting of: C,.

6 alkyl, Ar-CO.

6 alkyl, and Het-CO.

6 alkyl, wherein each C,.

6 alkyl may be optionally substituted by a moiety selected from the group consisting of C(O)R' 2

SR"

2 S(O)R N(R' 2 2

R'

2 NC(O)0R CO 2 N(R')2,

N(C=NH)NH

2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substitutad by one or more Ph-CO.

6 alkyl, Het-CO.

6 alkyl, C,.6alkoxy, Ph-CO.

6 alkoxy, Het-CO.

6 alkoxy, OH, (CH 2 6 NR's R',

O(CH

2 16

NR'

5 R 6 C1, 6 alkyl, OR" 7

N(R'

7 2

SR'

7

CE

3

NO

2 CN, CO 2 RII, CON(R' 7 F, Cl, Br or 1; where R1 5 and R 1 6 are H, C,.

6 alkyl, Ph-Co.

6 alkyl, naphithyl-CO.

6 alkyl or Het-CO.

6 alkyl; and R 1 7 is phenyl, naphthyl, or C,-6alkyl; and wherein each Het is optionally substituted with one or two moieties selected from Ar-C 0 6 alkyl, C1.6alkyl, OR", N(R 1 7 2 SR", CF 3

NO

2 CN, CO 2 R"7, CON(R"7), Br-and 1, where R" is phenyl, naphthyl, or C,- 6 alkyl.

More preferably, is selected from the group consisting of: methyl; ethyl, especially C 1 6 alkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; butyl, especially C,.

6 butyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is ROC(O); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3 ,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C, 6 alkoxy phienyl, more especially 3 -methoxyphenyl, 4-methoxyphenyl, 3,4dimethoxyphenyl, 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; PAOPERXKb.,%2A2I3Z9 4-4o-12I2AU benzo[1I,3]dioxolyl, especially benzo[1I,3]dioxol-5-yl; benzo[1I,2,5]oxadiazolyl, especially benzo[l1,2,5]oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially I -oxy-pyridin-2-yl, 1 -oxy-pyridin-3-yl; especially Cl.

6 alkylpyridinyl, more especially 3 -methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl, thiophene, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl; 1 H-imidazolyl, especially I H-imidazol-2-yl, 1 H-imidazol-4-yl, more especially

C

1 6 alkyl substituted imidazolyl, even more especially 1-methyl-1H-imidazol-2-yl, 1-methyl- 1 H-iimidazol-4-yl; I I ,2,4]triazolyl, especially 1 H-f 1 ,2,4]triazol-3 -yl, more especially C 16 alkyl Substituted I H-fl ,2,4]triazolyl, even more especially 5-methlyl-I H-fl ,2,4]triazol-3 -yl.

When R 2 is R1 9 S0 2 -1 9 i§ most-preferWby Selected -from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.

W'

0 is selected from the group consisting of: C 1 6 alkyl, C 3 6 cycloalkyl-C 0 6 alkyl, Ar-CO.

6 alkyl or Het-CO.

6 alkyl; preferably C 1 6 alkyl, Ar-CO.

6 alkyl and Het-CO.

6 alkyl.

Z is selected from the group consisting of: C(O) and CH 2 R 2 is also preferably:

H;

toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yI)phenyl] ethyl.

Compounds of Formula I where R" and are both H are preferred.

More preferred are compounds of Formula I wherein: R' is 0 3

R

P:\OPERKbnUJ223S') spec dec- I VOIA)3 R 2 is selected from the group consisting of: Ar-CO.

6 alkyl, R 9 R'S0 2 R 6

R

9 and

R

8 R 3 is selected from the group consisting of. H, C 16 alkyl, and Ar-C 0 6 alkyl; R(4 is selected from the group consisting of: R 5

R

5 and R 5 S0 2 R 5 is selected from the group consisting of: C1.

6 alkyI, halogenated methyl, Ar-CO 0 6 alkyl and Het-CO.

6 alkyl; R6 is H; R' is R' 0 00(O); R(8 is C,.

6 alkyl; R(9 is selected from the group consisting of: C,.

6 alkyl, Ar-CO.

6 alkyl and Het-CO.

6 alkyl; W(1 is selected from the group consisting of:. C,.

6 alkyl, Ar-CO.

6 alkyl and Het-CO.

6 alkyl; R' is H; R" is H; is H; and 1 5 Z is selected from the group consisting of: C(O) and CH 2 wherein each C,.

6 alkyl may be optionally substituted by a moiety selected from the group consisting of OR"1, C(O)R 1 2

SR"

2 S(O)R1 2 N(R1 2 2 R1 2 NC(O)0RI, CO 2 N(R 1 2 2

N(C=NH)NH

2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more Ph-CO.

6 alkyl, Het-Co- 6 alkyl, C 1 6 alkoxy, Ph-CO.6alkoxy, Het-CO- 6 alkoxy, OH, (CFI 2 )1.

6

NR'

5

R'

O(CH

2 )1.

6

NR'

5 R 6

CI-

6 alkyl, OR"1, N(R' 7

SR"

7 CF,, NO,, CN, CO 2 RII, CON(RI), F, Cl, Br or 1; where R(1s and R 1 6 are H, C1.6alkyl, Ph-CO.

6 alkyl, naphthyl-CO.

6 alkyl or Het-C0.

6 alkyl; and 17 is phenyl, naphthyl, or C,.

6 alkyl, C1.

6 alkyl, OR 17, N(R 1 7 2 SR 1 7

CE

3 NO,, CN, C0 2 R"7, CON(R' 1 F, Cl, Br and 1, where R 1 7 is phenyl, naphthyl, or C1.

6 alkyl.

P:OPER\Kb..\Z42Z3S9 p..do.-IAM.AII Even more preferred are such compounds of Formula I wherein R 2 is selected from the group consisting of Ar-CO.

6 alkyl, R 9

R

9 S0 2 Yet more preferred are compounds of Formula I wherein: Ris 0 R3 R2 is selected frmtegroup consisting o:Ar-CO.

6 alkyl, R 9 adR 9 S0 2 R 3 is selected fromthe group consisting~of:. H,-methylI, 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; R' is R 5

R

5 is selected from the group consisting of: methyl, especially halogenated methyl, 1 5 more especially trifluoromethyl, especially alkoxy substituted methyl, more especially phienoxy-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; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl. substituted butenyl, more especially 4,4-bis(4methoxyphenyl)-but-3 -enyl; acetyl; 13A phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichiorophenyl 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 suifonyl groups, more especially 4methanesulfonyl-phenyl; benzyl; naph thy len-2-yl; benzo[ I,3]dioxolyl, especially benzo[1I,3]dioxol-5-yl, furanyl, especially furan-2-yl, especially substituted furanyl, such as 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-chloromphenyl)-furan-2-yl; tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 5-( 2 -piperazin-4-carboxylic acid rert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2morpholino-4yl-ethoxy)-benzofuran :2yll, 5-(2-piperazi.n- I 2 -cyclohexyl-ethoxy)-benzofuran-2-yl; especially alkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxv-benzofura-2-yl, 5,6-dimethoxybenzofuran-2-yl, especiay halogen substituted benzofuranyl, more especially 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[blthiophenyl, 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; 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-yl pyridinyl, especially pyridin-2-yl pyridin-5-yl, especially I-oxy-pyridin-2-yl, especially alkyl substituted pyridinyl, more especially 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-tert-butyl-3-rnethylthieno[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-pheniyl-5-trifluoromethyl-oxazol.4-yl;

R

9 is selected from the group consisting of: methyl; ethyl, especially CI-6alkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl: butyl, especially CjI 6 butyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9

OC(O);

isopentyl; phenyl, e specially halogen substituted phenyl, more especially 3,4-dichlorophenyl 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl 3-chlorophenyl, 4-chiorophenyl, especially C I -alkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4dimethoxyphenyl, 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[1I,2,5]oxadiazolyl, especially benzo[1I.2,5]oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially I1-oxy-pyridinyl, more especially I-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially C 1 6 alkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl, thiophene, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl; 1H-imidazolyl, especially IH-imidazol-2-yl(74), IH-imidazol-4-yl, more especially C I 6 alkyl substituted imidazolyl, even more especially 1 -methyl- I H-imidazol-2-yl, 1 methyl- I H--imidazol-4-yl; I H-[l ,2,4]triazolyl, especially 1 I ,2.4ltriazol-3-yl, more especially C I -alkyl substituted I I,2,4]triazolyl, even more especially 5-methyl-I H-[1I,2,4]triazol-3-yl; R'is H; R"is H; and R'is H.

Most preferred are compounds of Formula I wherein:

R

1 is 0.

R'

R

2 is R 9 S0 2

R

3 is isobutyl;

R

4 is R 5

C(O);

R

5 is selected from the group consisting of:- 3-methyl-benzofurah-2.yl; thieno[3,2b] thiophen-2-yl. 5-rnethoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl, preferably 3-methyl-benzofuran-2-yl;

R

9 is selected from the group consisting of: pyridin-2-yl and I-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 preferred embodiments of the present invention: Example Chemical Name No.

I -((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3oxo-azepan-4-ylcarbanioyl~carbamic acid benzyl ester 2 Naphthylene-2-carboxylic acid[(S)- 1 -benzyl-3-oxo-azepan-4y lcarbamoyl)-3-rnethyl-butyl]amide 3 Benzo[ I,3ljdioxole-5-carboxylic acid 1-(1 -benzyl-3-oxoazepan-4-ylcarbanioyl)-3-methyl-butyl]amide 4 Berizofuran-2-carboxylic acid I -benzyl-3-oxo-azepan-4ylcarbamoyl)-3-rnethyl-butyljamide Benzo~b~thiophene-2-carboxylic acid 1 -benzyl-3-oxoazepan-4-ylcarbamoyl)-3-methyi-buryljamide 6 Naphthylene-2-sulphonyl f(S)-I -benzyl-3-'oxo-azepan-4ylcarbainoyl)-3-methyl-butyl)-amide 7 Quinoline-2-carboxylic acid 1-(1 -benzyl-3-oxo-azepan-4ylcarbamoyl)-3-niethyl-butyljanide 8 3,4-dichlorobenzoic acid -benzyl-3-oxo-azepan-4ylcarbamoyl)-3-methyl-butyllamide 9 (S)-Methyl- 2 -[(quinoline-2-carbony)-aminojpentanoylamino 1- 3-oxo- I 2 -(3-pyridin-2-yI-phenyl)-acetyl]azepanium 1 2 -Benzyloxycarbonylamino-4-methyl-pentyl).4. methylI-[~(2-quinoiline-2-carbonyl)-amino]-pentanoylamino)-3.

oxo-azepanium I1 1 -Benzoyl-4-((S)-2-(benzo[ I ,3jdioxole-carbonylaxnino)-4-methylpentanoylamino)-3-oxo-azepanium 12 1 -Benzoyl-4-((S)-2-(4-fluoro.benzoylamino)-4methyl.

pentanoylamino)-3-oxo-azepanium 13 3-Oxo-4-((S)-4-methyi-2- {[5-(2-morpholino-4-yI-ethoxy)benzofuran-2-carbonyl~amino 1-pentanoylamino)- I -(4-methylpentanoyl)-azepanium 14 5-( 2 -Morpholin-4-yI-ethoxy)-benzofuran-2-carboxylic acid I- (1 -benzenesulfonyl-3-oxoazepan4ylcarbamoyl).3-methyl.

butyllarnide 4-((S)-4-Methyl-2- {[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2carbonyllanino )-pentanoylamino)-3-oxo-azepane- I -carboxylic acid phenylamide 16 5-( 2 -Morpholino-4-yI-ethoxy)-benzofuran-2carboxylic acid 3-methyl-I -I 3-oxo- l-[ 2 3 -pyridin-2-yI-phenyl)acetyl-azepan.4.

ylcarbamoyl }-butyl)arnide 17

S-(

2 -Morpholino-4-y1-ethoxy)-benzofuran-2.carboxylic acid I -(benzoyl- 3 -oxo azepan-4-ycarbamoy)3methy-butyI)mide 18 5-(2-Pyrrolidin- I -yl-ethoxy)-benzofuran-2-carboxylic acid I (I -benzenesulfonyl-3-oxo-azepan-4.ylcarbamoyl)-3methyIbutyljlaxnide 19 5-(2-Piperidin- I -yl-ethoxy)-benzofuran-2-carboxylic acid 1 (I -benzenesulfony-3-oxo..azepan4ylcabamoyl)-3methy..

butyl~amide 5-( 2 -Morpholino-4-yI-ethoxy)-benzofuran-2.carboxylic acid 3-methyl- I-fI 3-oxo- 1 2 3 -pyridin-2-yl-phenyl)ethyl]-azepan-4.

ylcarbarnoyl) -butyi)amide 21 Naphthlene-2-carboxylic acid ((S)-3-methyl- I-fI 3-oxo- 1 pyridin-2-yI-phenyl)ethyl 3-azepan-4-ylcarbamoyI 1-buryl)amide 22 1 IHIndole-2-carboxyiic acid ((S)-3-methyl- 1-f3-oxo-l1-[2-(3pyridin- 2 -yi-phenyl)ethyl]-azepa-4-ylcarbamoyl }-butyl)amide 23 1 H-Indole-2-carboxylic -acid- -benzenesulfonyl*-3-oxoazepan-4-ylcarbamoyl)-3-methyl.butylIamide 24 Benzofuran-2-carboxylic acid 1-(1 -benzenesulfonyl-3-oxoazepan- 4 -ylcarbamoyly.3-methyl-butyl]amide Benzofuran-2-carboxylic acid- [(S)-3-methy]l--f 3-oxo- pyridin- 2 -yl-phenyl)ethyll-azepan-4ylcarbamoyl }-butyl)amide 26 5-( 2 -Morpholino-4-yI-ethoxy)-benzofuran-2-carboxylic acid 3-methy.l-I-(3-oxo- I-phenethyl-azepan-4-ylcarbamoyl]butyl laride 27 Naphthylene-2-carboxylic acid [(S)-3-methyl- I -(3-oxo- I pbenethyl-azepan..4.ylcarbamoyl]pbutyl )amide 28 Benzofuran-2-carboxylic acid I (S)-3-methyl- I -[3-oxo- I -(pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyl]..butyl }-amide 29 Naphthylene-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I1- (pyridine-2-sulfony)-azepan-4-ylcarbamoy1]-butyI I-amide 5-( 2 -Morpholino-4-yl-ethoxy)-benzofuran.2-carboxylic acid f(S)- 3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan.4ylcarbamoyl..

butyl }-arnide J I 4-((S)-4-Methyl-2-f IX-(2-morphoinoyl-ethoxy)benzofua-2carbony!]-amino)-pentaioylamino).3-oxo.azepane. 1-carboxylic acid tert-butyl ester 32 4-((S)-4-Methyl-2- 2 -morpholino-4-yl-ethoxy)-benzofurn.2 carboxylic acid [(S)-3-methyl- I 3 -oxo-azepan-4-ylcarbamoyl].

butyl Jamide 33 4-Methyl-pentanoic acid 13-oxo- I 2 -(3-pyridin-2-yi-phenylacetyl]-azepan-4-yI}-amicie 34 ((S)-3-Methyl- I f 3-oxo- I 2 3 -pyridin-2-yJ-phenyl)-acetyl..

azepan-4-yicarbamoyl }-butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester (S--ehl2[nptye-2ymty)aio-etni acid [3-oxo- l-[ 2 3 -pyridin-2-yl-phenyi)-acetylj..azepan.

4 -y 1 }-amide 36 (S)-3-Methyl- I -[3-oxo- 1 -(pyidine-2-sulfonyl)-zepan.4ylcarbamoyl]-butylcarbamoyl I -benzofuran-S-y loxy)-ethyllpiperazine- I -carboxylic acid tert-butyl ester 37 5-(2-Piperizin-1I-yl-ethoxy)-benzofuran-2-carboxylic acid methyl-I- [3-oxo- 1-(pyridine-2-sufony)-azepan4ycabamoy1J-3.

buty! 1-aride 38 5-( 2 -Cyclohexy-ethoxy)-benzofurn2-carboxylic acid methyl-lI-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4..ycaramoy]..

butyl )amide 39 5-( 2 -Cycohexy-ehoxy)benzofrn2-.caroxylic acid methyl-I- {3-oxo- I-[ 2 3 -pyridin-2-yI-phenyl)ehyl-azepan.4 ylcarbarnoyl }-butyl)amide (S)-3-Metbyl- 1 -[3-oxo- I 3 -pyridin-2-yi-phenyl)-ethyl (azepan- 4 -ylcarbamoyl]-butylcarbamoyl ethyll-piperazine- 1-carboxylic acid tert-buryl ester 41 5-(2-piperizin- 1 -yI-ethoxy)-benzofuran-2-carboxylic acid methyl- I -f{3-oxo- 1- 2 3 -pyridin-2-y-phenyl)ethy)-azepan.4 ylcarbaxnoyl }-butyl)amide 42 (S--ehl2(ehlnptaln2ymty-mn~etni acid [3-oxo- I-(pyridine-2-sulphonyl)-azepan..4.yi]-amide 43 (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid 3-oxo- l-[ 2 -(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4yI}amride 44 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-rnethyl- 1 -1 3-oxo- I -[2-(3-pyridin-2-yIphenyl)acetyl)-azepan-4-ylcarbamoyl 1-butyl)amide Benzofuran-2-carboxylic acid methyl (S)-3-rnethyl- I -[3-oxo- I (pylidine-2-sulfonyl)-azepan-4-ylcarbarnoyl)-3-methyl-butyllarnide 46 2,2,2-Trifluoro-N-((S)-3-methyl- I f 3-oxo- I -[2-(3-pyridin-2-ylphenyl)-acetyl]-azepan-4vlcarbamoyl J -butyl)-N-naphthylen-2yimethyl-acetamide 47 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino).4methyl-pentanoylamino] -3-oxo-azepane-lI-carboxylic acid benzyl ester 48 Quinoline-2-carboxylic' acid (S)-3-methyl- I -[3-oxo-l -(pyridibe- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide 49 Quinoline-8-carboxylic acid f (S)-3-methyl-1 -[3-oxo-lI-(pyi-idine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide Quinoline-6-carboxylic acid ((S)-3-methyl- I-[3-oxo- I-(pyridinie- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide 51 Quinoline-4-carboxylic acid (S)-3-rnethyl- 1 -[3-oxo- 1 -(pyi-idine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 52 Quinoline-3-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide 53 Isoquinoline-3-carboxylic acid I (S)-3-methyl- I -[3-oxo- 1 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ~amide 54 Isoquinoline- I -carboxylic acid J (S)-3-methyl- 1 -[3-oxo- 1 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide Quinoxaline-2-carboxylic acid (S)-3-methyl- I -[3-oxo- 1 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl amide 56 Benzo[b]thiophene-2-carboxylic acid (S)-3-methyl-lI-[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-buty amide 57 1 ,8-Naphthyridine-2-carboxylic acid (S)-3-methyl- 1-[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbahoyl-butyI Janiide 58 1 H-Indole-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -(pyridine- 2-sulfonyl)-azepan-4-ylcarbanioyl]-butyl amide 59 5-Methoxy-benzofuran-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl 1-butyl I amide 5-Bromo-furan-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl-buty Jamide 61 Furan-2-carboxylic acid (S)-3-methyl-l1-[3-oxo-lI-(pyridine-2sulfonyl)-azepan-4-ylcarbanioyl]-butyl }amide 62 5-Nitro-furan-2-carboxylic acid I (S)-3-methyl- 1 -[3-oxo- 1 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide 63 5-(4-Nitro-phenyl)-furan-2-carboxylic acid (S)-3-methyl-l1-[3oxo- I -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide 64 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid methyl- 1-[3-oxo- l(pyridine-2-sulfonyl)-azepan'4-ylcarbamoyl]butyl }amide Tetrahydro-furan-2-carboxylic acid (S)-3-methyl-l1-[3-oxo- 1- (pyridine-2-suifonyl)-azepan-4-ylcarbamoyl-buty )anide 66 (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanic acid [3-.oxo- (pyridine-2-sulfonyl)-azepan-4-yIII-amide 67 (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yI]-amide 68 Benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-lI-(pyridine- 2-carbonyl)-azepan-4-ylcarbamoyl)-3- butyl]-axnide 69 Benzofuran-2-carboxylic -acid (S)-3-methyl- 1-[3-oxo-l1-(1 -oxypyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-butyl }amide 4-((S)-2-tert-Butylcarbonylamino-4-methyl-pentanoylamino)-3oxo-azepane- 1-carboxylic acid benzyl ester 71 5,6-Dimethoxy-benzofuran-2-carboxylic acid I (S)-3-methyl-l1-[3oxo- I -methyl- I H-imidazole-4-sulfonyl)-azepan-4ylcarbaxnoyl]-butyl amide 72 Benzofuran-2-carboxylic acid (S)-3-methyl- 1-(5-methyl- IH- [1 2 4 tiazole- 3 -sulfony1)-3-oxo-azepan-4-ylcarbamoyl].

butyl Jamide 73 Benzofuran-2-carboxylic acid (S)-3-methyl-l1-[1 -(1-methyl-I Himidazole-3-sulfony)-3-oxo-azepan..4-ylcarbamoyl)-buty )amide 74 Benzofuran-2-carboxylic acid f (S)-3-methyl- 14 I-I -imidazole- 2-sulfony1)-3-oxo-azepan-4-ylcarbamoyl-buy }amide Benzofuran-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -(thiazole- 2 -sulfonyl)-azepan-4-ylcarbamoyl)-butyzlamide 76 Benzofuran-2-carboxylic acid f (S)-3-methyl- I -[1I -(I1-methyl- I Himidazole-4-sulfonyI)-3-oxo-azepan-4ylcabamoyl]-buty }aride 77 5-( 4 -Oxy-morpholino-4-yl-ethoxy)-benzof1Jan-2-caboxylic acid f (S)-3-methyl- I -[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-.4ylcarbamoyl]-butyl J amide 78 Benzofuran-2-carboxyuic acid (S)-3-methyl- I -[3-oxo- 1 -(pyridine- 3 -sulfonyl)-azepan-4-ylcarbamoylp butyI I amide 79 Benzofuran-2-carboxylic acid (S)-3-methyl- 1-[3-oxo-l1-( I-oxypyridine- 3 -sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide Quinoline-3-carboxylic acid J -(3,4-dichloro-benzenesulfonyl)- 3 -oxo-azepan4ylcarbamoyl)..3methyl.butyl }-amide 81 5-Hydroxy-benzofuran-2-carboxylic acid (S)-3-methyl- 141 methyl-i H-imidazole-4-sulfonyl)-3oxo-azepan-4.ylcaramoyl..

butyl }amide 82 Benzofuran-2-carboxylic acid (S)-3-methyl- I-[3-oxo- I-(I -oxypyridine- 2 -sulfony1)-azepan4ylcarbamoyI)]3methyl-butyl)Iarnide 83 {(Benzofuran-2-carbonyl)-amino)}-4-methylpentanoylamino)}-3-oxo-azepane-1I-sulfonyl)-benzoic acid 84 f (Benzofuran-2-carbonyl)-amino]-4methiy.

pentanoylaniino)I-3-oxo-azepane-1I-sulfonyl)-benzoic acid Benzo[blthiophene-2-carboxylic acid ((S)-3-methyl-1- [3-oxo- 1- (I -oxy-pyridine- 2 -sulfony1)-azepan-4ylcarb~amoyl].buty amide 86 5-Brorno-furan-2-carboxylic acid f (SY-3-inethyl- I -[3-oxo- I oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbanioyl-buty laniide 87 5,6-Dimethoxy-benzofuran-2-carboxylic acid (S)-3-methyl- 1 oxo- I -oxy-pyridine-2-sulfonyl)-azepan-4-ycarbamoyl]butyl )aniide 88 1 -Oxy-pyridine-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I (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-ylI-amide (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-yl]-aniide 91 (S)-4-Methyl-2-(3-phenyl-uriedo)-pentanoic acid [3-oxo- 1-.

(pyridine-2-sulfonyl)-azepan-4-ylI-anide 92 Benzofuran-2-carboxylic acid I (S)-]I-[6,6-dimethy!-3-oxo- I (pyridine-sulphonyl)-azepan-4-ylcarbamoyll-3-methyl-butyl amnide 93 5-Methoxy-benzofuran-2-carboxylic acid I (S)-3-methyl- I [3-oxo- 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl) amnide 94 Thieno[3,2-blthiophene-2-carboxylic acid I (S)-3-methyl-l1-[3-oxo- I-(I -oxy-pyridine-2-sulfonyl)-azep an-4-ylcarbamoyl]-butyl I amide Quinoxaline-2-carboxylic acid ((S)-3-methyl-l1-[3-oxo-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide 96 Quirioline-2-carboxylic acid (S)-3-inethyl- I -[3-oxo- I -oxypyridine-2-sulfonyl)-azepan-4-ylcarbanioyl]-butyl )aniide 97 Thiophene-3-carboxylic acid I (S)-3-methyl- I -[3-oxo- 1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbaxnoyl]-butyl )amide 98 1 H-Indole-5-carboxylic acid (S)-3-rnethyl-l1-[3-oxo-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbanioyl)-butyl amnide 99 Benzo[1I,3)dioxole-5-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl aide 100 Furan-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl I amide 101 (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-peltanoic acid [3oxo-l1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4-yII-anide 102 1 H-Indole-2-carboxylic acid (S)-3-methyl-lI-[3-oxo- 17( 1-oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }axide 103 4-Fluoro- (S)-3-methyl- 1 -[3-oxo- I -oxy-pyridine-2-sulphonyl)azepan-4-carbamoyl]-butyl)}-benzamide 104 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxyiic acid methyl- 1-[3-oxo-(1-oxy-pyridine2-sulphonyl)-azepan-4ylcarbamoyl]- -bury }-amide 105 Thiophene-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 106 3-Methyl-benzofuran-2-carboxylic acid (S)-3-methyl-1- [3-oxo- 1- (I -oxy-pyridine-2-sulfonyl)-azepan-4-ytcarbamoyll-butyl amide 107 6-Methyl-N- (S)-3-methyl- I [3-oxo- 1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-butyl)}-nicotinamide 108 (S.)-4-Methyl-2-(2-thiophen-yl-aceylaxnino)-pentanoic-acid-[3oxo- I -(pyridine-2-sulfonyl)-azepan-4-yli-butyl }amide 109 1 H-Indole-6-carboxylic acid (S)-3-methyl- 1 [3-oxo- 1 -(pyridine- 2--sulfonyl)-azepan-4-ylcarbamoyl]-butyl laride 110 Benzo[ I,3]dioxole-5-carbox~ylic acid (S)-3-methyl- I-[3-oxo- I- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide 111 3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid J(S)-3methyl- I -[3-oxo- 1 -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl] butyl }amide 112 5-Methyl-thiophene-2-carboxylic acid ((S)-3-methyl-I1-[3-oxo- I- (I -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide 113 4,5-Dibrorno-thiophene-2-carboxylic acid I (S)-3-niethvl-lI-[3-oxo- 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )axmde 114 3,5-Dimethyl-isoxazole-4-carboxylic acid I (S)-3-rnethyl- 1-[3-oxo- 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbarnoyl]-butyl amide 115 (S)-2-(2-Benzyloxy-acerylainino)-4-methyl-pentanoic acid[]1-(4methoxy-benzenesulfonyl)-3-oxo-azepan-4-yi]-amide 116 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid methyl-I -[3-oxo- I -oxy-pyridine-2-sulfonyl)-azepan4ylcarbamoyl]-btyl Jamide 117 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid I (S)-3-methyl- 1 oxo- 1 -(1I -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyljbutyl Jaride 118 Benzofuran-2-carboxylic acid 1-(3,4-dmethoxybenzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl }-amide 119 Benzofuran-2-carboxylic acid [I-(4-bromobenzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl 1amide 120 Benzofuran-2-carbox-ylic acid I -[41 -(benzof I 4 -sulfonyl)-3-oxo-azepan-4-ylcarbarroyl]-3-methyl-buty I -amide 121 Benzofui-an-2-carboxylic acid {(S)-1-[1-(3,5-dimethyl-oxazole-4 sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl }-aride 122 3-Methyl-benzofuran-2-carboxylic -acid {(S)-3-methyl-1- [3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl }anide 123 Thieno[3,2-bthiophene-2-carboxylic acid (S)-3-methyl- 1- [3-oxo- 1 -(pyridine-2-sulfonyl)-azepan4ylcarbanioyl]-butyl Ianxide 124 5-tert-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid.

(S)-3-metbyl-1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyll-butyl )amide 125 5-Methyl-2-phenyl-oxazole-4-carboxylic acid (S)-3-methyl-l143oxo-l1-(pyridine-2-sulfonyl)-azepan-4.ylcarbarnoyl]-buryl }amide 126 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid methyl-i -[3-oxo- I-(pyridine-2-sulforiyl)-azepan-4-ylcarbamoyllbutyl )amide 127 Quinoline-2-carboxylic acid f(S)-I -methanesulfonyl-3-oxoazepan-4-ylcarbamoyl)-3-methyl-butyl]-amide 128 1-Methyl- 1H-indole-2-carboxylic acid f(S)-I 1-methanesulfonyl- 3-oxo-azepan-4-ylcarbanioyl)-3-methyl-butyl]-amide 129 Furan-2-carboxylic acid -methanesulfonyl-3-oxoazepan-4-ylcarbamoyl)-3-methyl-butylcarbarnoyl]-methyl) -amnide 130 5-Methoxy-benzofuran-2-carboxylic acid 1-(1methanesulfonyl-3-oxo-azepan-4-ylcarbanioyl)-3-methyl-butyl]axnide 131 Quinoxaline-2-carboxylic acid I -methanesulfonyl-3-oxoazepan-4-ylcarbamoyl)-3-methyl-butyl]-arnide 132 5-(4-Chloro-phenyl)-furari-2-carboxylic acid (S)-3-methyl-l1-[3oxo-]I-(pyridine-2-sulfonyl)-azepan-4-ylcarbarnoylj-butyl }amide 133 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-penanoic acid (1 -methanesulfonyl-3-oxo-azepan-4-yl)-amide 134 Quinoline-2-carboxylic acid 1I-[ I -(2-cyanobenzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl 1amide 135 1-Methyl-i H-indole -2-carboxylic acid I-(2-cyanobenzenesulfonyl)-3-oxo-azepan-4-vlcarbamoyl]-3-methy]-butyI amide 136 Furan-2-carboxylic acid (I (S)-I-[I-(2-cyano-benzenesulfonyl)-3oxo-azepan-4-ylcarbamoyl 1-3-methyl-butylcarbamoyl }-methyl)amide 137 5-Methoxy-benzofuran-2-carboxylic acid I 1- -1 -(2-cyanobenzenesulfonyl)-3-oxo-azepan-4-ylcarbarnoyl]-3-rnethyl-butyl Iamide 138 Quinoxaline-2-carboxylic acid 1I-[ 1-(2-cyanobenzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl amnide 139 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-rnethyl-pentanoic acid (1 -(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-yl]-anide 140 Quinoline-2-carboxylic acid 1-[1 -(4-methoxybenzenesulfonyl)-3-oxo-azepan-4-ylcarbaxnoyl]-3-methyl-buty amnide 141 1 -Methyl- I H-indole-2-carboxylic acid I I-r[I -(4-methoxybenzenesulfonyl)-3-oxo-azepan-4-ylcarbarnoyl]-3-methyl-butyl amide 142 Furan-2-carboxylic acid U((S)-I-ti -(4-methoxy-benzenesulfonyl)- 3 -oxo-azepan-4-ylcarbamoyll-3-methyl-butylcarbamoyI 1-methyl)arnide 143 5-Methoxy-benzofuran-2-carboxylic acid I -(4.-rethoxybenzenesulfony1)-3-oxo-azepan-4-ylcarbamoylI-3-methyl-buyl arnide 144 Quinoxaline-2-carboxylic acid I 1 1-(4-methoxybenzenesulfonyl)-3-oxo-azepan-4-ylcabamoyI-3.met1hylbutI

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amide 145 2 -t 2 4 -Methoxy-phenyl)-acetylaniino)..4-rnethyl-pentanoic acid [1 4 -methoxy-benzenesulfonyl)-3-oxo..azepan-4.ylp-amide 146 1I-Methyl-i I-i-indole-2-carboxylic acid{ 141 ]-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4.ylcarbamoyll.3-methyl.butyIamide 147 Furan-2-carboxylic acid (f I -(4-fluoro-benzenesulfonyl)-3oxo.-azepan- 4 -ylcarbamoyi)-3-methyl-butycarbamoyl I-methyl)amide 148 5-Methoxy-benzofuran-2-carboxylic acid I 1 1 -(4-fluorobenzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyly3-methyl-butyI I amnide 149 Quinoxaline-2-carboxylic acid 1-[1 -(4-fluorobenzenesulfonyl)-3-oxo-azepan4-ylcarbamoyll3methyl-butyI I arnide 150 2 2 4 -Methoxy-phenyl)-acetylamino)-4-methyl-penanoic acid [1 4 -fluoro-benzenesulfonyl)-3-oxo-azepan4yl)-amide 151 Benzofuran-2-carboxylic acid- 1-(3-chlorobenzenesulphonyl)-3-oxo-azepan-4.ylcarbamoyly-3.methyl-butyl

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amide 152 5-Methoxy-benzofuran-2-carboxylic acid- I- [1I-(3-chlorobenzenesulpbonyl)-3-oxo-azepan-4-ylcarbamoyll-.3methyl-butyl)Iamide IZO 7 -Methoxy-benzofuran-2-carboxyiic acid-fI(S)- 1 -I -(3-chlorobenzenesuphony)3oxoaepan-4ycabamoy1-3-methylbut, amide 154 5, 6 -Dimethoxy-benzofuran-2-carboxyliic acid-f((S)- 1-[ri -(3-chiorobenzenesulphony)3oxo-azepan-4-yicarbamoylj-3methyl-butyI

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amide 155 3 -MethyI-benzofuran-2carboxylic acid-f 1-[l -(3-chiorobenzenesulphonyl)3oxoazepan4ylcarbamoy].3-methlbuty amide 156 Benzo[bthiophene2caroxylic acid- J 1-ri -(3-chiorobenzenesuphony)3oxo-aepa4-yicarbaoy]-3methybutyI I amide 157 i-Methyl-i H-indole-2-carboxylic acid-({ 1-[l1-(3-chiorobenzenesulphony)3oxo-azepan4ylcarbamoyI-3-methyl-buty 1arnide 158 Quinoxaline-2-carboxylic 1 -(3-chlorobenzenesuphony)3oxoazepan4vlcarbamoyl]-3methyl-bty arnide 159 Benzofuran-2-carboxylic acid-f((S)- I-[i -(2-fluorobenzenesuphony)3oxoazepan4ylcarbaoyI3-methyl-buty arnide 160 5-Methoxy-benzofuran2carboxylic acid- I(S)-1-ri 1-(2-fluorobenzenesulphony)-3oxozepan..4vlcabamoyi-3-methyl-butyI I amide 161 7 -Methoxy-benzofuran-2-caboxylic acid-Ij(S)-I 1 fluorobenzenesulphony)3oxo-azepan4-ycramoylI3-methyl-butyI

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amide 162 5, 6 -Dirnethoxy-benzofuran-2.carboxylic acid-fI 1-ri -(2-fluorobenzenesuphony)3oxo-azepan4-yicabamoy]3-methylbutyI

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arnide 163 5-Methyl-benzofuran 2-carboxylic acid- I -(2-fluorobenzenesuiphony)3oxoaepan-4ycarbamoylI3-methyl-butyI

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arnide 164 Benzo[b]thiophene-2-carboxylic acid-fI(S)- I -(2-fluorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbarnoyl]-3-methyl-butyl amide 165 1-Methyl-I H-indole-2-carboxylic acid-({ 1I-[1I -(2-fluorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoylj-3-methyl-buty amide 166 (S)-4-Methyl-2-( 1-oxy-pyridine-2-sulfonylarnino)-pentanoic acid [3-oxo-l1-(pyridine-2-sulfonyl)-azepan-4-ylJ-amide 167 Quinoxaline-2-carboxylic acid-f 14[1 -(2-fluorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoylj-3-methyl-butyl 1amide 168 5-Methoxy-benzofuran-2-carboxylic -acid- ((S)-3-methyl- I -[3-oxo- I -(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl I -amide 169 7-Methoxy-benzofuran-2-carboxylic acid-fI (S)-3-rnethyl- 1 [3-oxo- 1 -(thlophene-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl) -amnide 170 5 ,6-Dimethoxy-benzofuran-2-carboxylic acid-f (S)-3-methyl- 1 oxo- I -(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-arnide 171 3-Methyl-benzofuran-2-carboxylic acid-fI (S)-3-methyl-lI-[3-oxo- I (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl I -aride 172 Benzo[blthiophene-2-carboxylic acid-f (S)-3-rnethyl- 1 -[3-oxo- 1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )-amide 173 1-Methyl-I -H-indole-2-carboxylic acid-f (S)-3-methyl- 1 -[3-oxo- 1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI }-amide 174 Quinoxaline-2-carboxylic acid- I (S)-3-methyl- 1- [3-oxo- 1 (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl I-amide 175 Benzofuran-2-carboxylic acid- I 1 1 -(4-chiorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl)Iamide 176 5-Methoxy-benzofuran-2-carboxylic acid- I 1-[I1 -(4-chlorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl)}amide I II7-Methoxy-benzofuran-2-carboxylic acid-fJ 14[1 -(4-chiorobenzenesulphonyl)-3-oxo-azepan4.yIcarbamoylp3-methyl-buty 1amide 178

S,

6 -Dimethoxy-benzofuran-2-carboxylic acid- I-[I -(4-chiorobenzenesulphonyl)-3-oxo-azepan4ylcarbamoyl-3-mety.buty amide 179 3-Methyl-benzofturan-2-carboxylic acid-[ -[Il-(4-chiorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoy1I3methyl-buty amide 180 Benzofbjthiophene-2-carboxylic acid- 1I-[1I -(4-chlorobenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl I-3-rnethyl-butyl)Iamide 181 1 -Methyl- II--indole-2-carboxylic acid-f((S)- I -I -(4-chiorobenzenesulphonyl)-3-oxo-azepa4-ylcarbamoyly3-methyl.buty

I

amide 182 Quinoxaline-2-carboxylic, acid- I I 1-(4-chlorobenzenesulphonvl)-3-oxo-azepan.4-.ycarbamoyl]3methyl-butyI amide 183 Benzofuran-2-carboxylic acid-f((S)- I- 1-(3-rnethoxybenzenesulphony)-3-oxoazepan4.ylcarbarnoyI3methyl-buty amide 184 5 -Methoxy-benzofuran-2-carboxylic acid-( 1-(3-methoxybenzenesulphony)3-oxozepan4.ylcabamoyI>3-methyl-butyl amide 185 7 -Methoxy-benzofurai-2-carboxylic acid-fI(S)- I- 41-(3-metboxybenzenesulphony)-3-oxo-zepan4ycarbamoyl]y3methyl-butJ amide 186 5, 6 -Dimethoxy-benzofuran-2-carboxylic acid- f I 1-(3methoxy-benzenesuphony)3-oxo-azepn-4.ycaramoyl].3methyl-butyl }-amide 187 3-Methyl-benzofuran-2-carboxylic acid-f((S)- I- 1-(3-methoxybenzenesulphony)3oxoazepan4vcamoylI3 -methyl-butyl)Iarnide 188 Benzofb]thiophene-2-carboxylic acid-( 141 -(3-methoxybenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-niethyl-buty amide 189 1-Methyl-I H-indole-2-carboxylic acid-({ 141 1-(3-methoxybenzenesulphonyl)-3-oxo-azepan-4-ylcarbamoylj-3-methyl-butyl 1amide 190 Quinoxaline-2-carboxylic acid- f I 1-(3-methoxybenzenesulphonyl)-3-oxo-azepan-4-ylcarbanoyl-3-methyl-butyl 1amide 191 Benzofuran-2-carboxylic acid- I (S)-3-methyl- I -[3-oxo- I1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoy )-butyl I -amnide 192 Benzofuran-2-carboxylic acid f 3-methyl-I ,4tridueterio)-3-oxo- I -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoylIbutyl }aride 193 Benzofuran-2-carboxylic acid I (S)-2-methyl- I -[3-oxo- I -(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI }-amide 194 Benzofuran-2-carboxylic acid [3-oxo-lI-(pyridine-2sulfonyl)-azepan-4-ylcarbaxnoyl]-propyl )-amide 195 Benzofuran-2-carboxylic acid I (S)-2-cyclohexyl- I -[3-oxo- I1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethy I-amide 196 Benzofuran-2-carboxylic acid [3-oxo- I-(pyridine-2sulfonyl)-azepan-4-ylcarbarnoylj]-ethyl I-amide 197 Benzofuran-2-carboxylic acid f (S )-3-rnethanesulfinyl- I -[3-oxo- 1 (pyridine-2-sulfonyl)-azepan-4-ylcarbanioyl]-propyI }-amide 198 Benzofuran-2-carboxylic acid 4 [3-oxo-1I-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl I-methyl }-amide 199 Benzofuran-2-carboxylic acid f(S)-i -[3-oxo-lI-(pyridine-2sulfonyl)-azepan-4-ylcarbarnoyl]-pentyl I-arnide 200 Benzofuran-2-carboxylic acid 1-[3-oxo- 1-(pyridine-2sulfonyl)-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 f (S)-2-hydroxy- 1-f 3-oxo- I1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyI I -amide 203 Benzofuran-2-carboxylic acid f(S)-I -[3-oxo- I-(pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-eihyI I -amide 204 1 -(Benzofuran-2-carbonyl)-pyrrolidine-2-carboxylic acid [3-oxo- I- (pyridine-2-sulfonyl)-azepan-4-yI]-amide 205 3,4-Dimethoxy-N- 1 I-(4-methoxy-benzenesulfonyl)-3-oxoazepan-4-ylcarbamoylj-3-methyl-butyl 1-benzamide 206 Benzo[b]thiophene-2-carboxylic acid-f 141 -(4-imethoxybenzenesulfonyI)-3-oxo-azepan-4-IcarbamoyI-3-methy-butyI amide 207 Benzo[ I ,3]dioxole-5-carboxylic- acid 1-[1 -(4-fluorobenzenesulfonyl)-3-oxo-azepan.4-ylcarbamoyl].3methyl-butyl amide 208 2 -(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[ 1 fluoro-benzenesulfonyi)-3-oxo-azepan-4-yl-anide 209 Benzo[b~thiophene-2-carboxylic acid-f (S)-1-fl ]-(4-fluorobenzenesulfonyl)-3-oxo-azepan-4-yI carbamoyl 1-3-methyl-butyl amide 210 Benzofuran-2-carboxylic acid I -benzoyl-3-oxo-azepan-4ylcarbaxnoyl]-3-methyl-butyl I-amide 211 4 -Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3oxo- I -(pyridine-2-sulfonyl)-azepan-4-ylI-amide 212 4 -Methyl-2-(napbthylene-2-sulfonylamino)-pentanoic acid [3oxo- I -(pyridine-2-sulfonyl)-azepan.4-yII-amide 213 Benzofuran-2-carboxylic acid-{(S)-i 1 .(4-fluorobenzenesulfonyl)-3-oxo-azepan-4-yI carbamoyl]-3-methyl-butyl Iamide 214 14[1 -(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4.

ylcarbamovl }-3-methyl-butyl }-3,4-dimethoxy-benzanxide 215 Cyclohexanecarboxylic acid I-[l -(4-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl)}-3-rnethyl-butyl -ainide 216 2 -Benzyloxy-acetylarnino)4-methyl-penanoic acid[ 1- (methanesulfonyl)-3-oxo-azepan-4-yI]-amide 217 Benzofb]thiophene-2-carboxylic acid-({ I -methanesulfonyl- 3-oxo-azepan-4-yl carbarnoyl)-3-methyl-butylj-amide 218 Benzo[ I ,3ldioxoie-5-carboxylic acid- I -methanesulfonyl-3oxo-azepan-4-yl carbamoyl)-3-methyl-butyl-axnide 219 Benzofuran-2-carboxyiic acid- f I -methanesulfonyl-3-oxoazepan-4-y] carbamoyl)-3-methyl-butyl]-anide 220 I -Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyI methyl-butyl) -3,4-dimethoxy-benzamide 221 2 2 -Benzyioxy-acetylamino)4-methyl-penanoic acid[l1-(2cyano-benzensulfonyl)-3-oxo-azepan-4-yI]-amide 222 N-f(S)-i -[1-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4ylcarbamoyl I -3-methyl-butvi -4-methanesulfonyl- I -benzainide 223 Benzo[blrhiophene-2-carboxylic acid- I-[1I -(2-cyanobenzenesulfonyi)-3-oxo-azepan-4-yI carbarnoyl)-3-methyl-butyl]amide 224 Benzo[ I ,3]dioxole-5-carboxylic acid-f i-ri1 -(2-cyanobenzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butylamide 225 (S)-4-Methyl-2-[4-oxo-4-((4-phenoxy-phenyl)-butyryiamino

I-

pentanoic acid [3-oxo- I -(pyridine-2-sulfonyl)-azepan-4-yI]-amide 226 N-f I -(2-cyano-benzenesulfonvl)-3-oxo-azepan-4ylcarbamoyl I-3:-methyl-butyl 1-3,4-dimethoxy-benzamide 227 Cyciohexanecarboxylic acid If(S)-i -(4-methoxybenzenesuifonyl)-3-oxo-azepan-4-ylcarbamoyl I -3-methyl-butyl amide 228 4-Methansulfonyl-N-{I (S)-i]-f4-methoxy-benzenesulfonyl)-3-oxoazepan-4-carbamoyi]-3-methyl-buty-benzamide 229 4-Methansulfonyl-N- I (S)-i1-[4-fluoro-benzenesulfonyl)-3-oxoazepan-4-carbamoyl]-3-methyl-butyl-benzamide 230 (f (S)-3-Methyl-l1-[3-oxo- I-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyi]-butyicarbamoyl }-carbamic acid benzyl ester 231 (S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo- I-(pyridine-2-suifonyl)-azepan-4-yIJ-amide 232 (S)-2-f2-(3-Benzyloxy-4-methoxy-phenyl)-acetylarnnio]-4methylpentanoic acid [3-axe-I -(pyridine-2-sulfonyl)-azepan-4-yI]amide 233 5,6-Difluoro-benzofuran-2-carboxylic acid (S)-3-methyl- 1 -flI (pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbarnoyl)-butyl lamide 234 (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid [3-oxo- I- (pyridine-2-sulfonyl)-azepan-4-yI]-ainide 235 Benzofuran-2-carboxylic acid (S)-3-methyl- 1 1-(6-methylpyxidine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-butyl amide 236 5-Methoxy-benzofuran-2-carboxylic acid J(S)-3-methyl--f 1 methyl-pyridine-2-sulfonyl )-3-oxo-azepan-4-ylcarbamoyl]butvl ~amide 237 3-MethyI-benzofuran-2-carboxylic acid j (S)-3-methyl- 1 1-(6methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbanoyl]butyl lamide 238 7-Methoxy-benzofuran-2-carboxylic acid -methyl- 1-[fl (pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl )amide 239 5 .6-Dimethoxy-benzo~b]thiophene-2-carboxylic acid methyl- I -[1I -(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbanmoyl]buty I Iamide 240 (R)-lI-Benzyl-5-oxo-pyi-rolidine-2-carboxvlic acid (S)-3-methyl- I- I 3-oxo-(pyridine-2-sulfonyl)-azepan-4-ylcarbarnoyl]butyl lamide 241 I -Benzyl-5-oxo-pyrrolidine-2-carboxyiic acid I (S)-3-methyl- I- 3-oxo-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl }axide 242 Benzofuran-2-carboxylic acid (S)-2-cyclopropyl- I -[3-oxe- I- (pyridine-2-sulfonyl)-azepan-4-ylcarbanioyl)-ethyl]-amide 243 Benzofuran-2-carboxylic acid 4 (S)-3-methylsulfanyl-lI-[3-axe-i- (pyridine-2-sulfonyl)-azepan-4-ylcarbaxnoyl)-propyl]-anide 244 Benzofuran-2-carboxylic acid (S)-2-naphthylen-2-y.. I -[3-oxo- I- (pyridine-2-sulfony)azepan4-ycrbamoy)ethyI]-amide 245 Thieno[3,2-b]thiopene2carboxylic acid (S)-3-methyl.. methy-pyridine2sufony)3oxoaepan-4-ylcabamoyiIbutyl jaride 246 Thieno[3,2-b~thiophene-2-carboxylic acid I (S)-3-methyl- I -[I1 methyJ-pyridine2sufony)3oxozep~an-ylcarbamoyl]butyl }amide 247 3 -Methyl-benzofuran2carboxylic acid f (S)-3-methyl- 1 methyl-pyidine2sufony)3ox-azepa-4-ylcarbamoyl] butyl )amide 248 5-Methoxy-benzofuran.2-carboxylic acid f (S)-3-methyl- I butyl Jaride 249 5,6-Difluoro-benzofuran..2.carboxylic acid f (S)-3-methyl- 1 oxo- 1 -oxy-pyridine-2-sufonyl)azepan-4.ylcabamoyl]butyl }amide 250 5-( 3 -TrifluoromethyI-pheny)fran-2.caboxylic acidi{(S)-2cyclohexyl- I- {3-oxo- I-(pyridine-2-sulfonyl)-azepan4 ylcarbarnoyl ]-ethyl) -amide 251 5-( 4 -Chloro-phenyl)-furan-2-carboxylic acid I (S)-2-cyclohexyl- I f3-oxo- I }-yiie2sloy)aepn4ycraol-ty amide 252 Benzofuran-carboxylic acid- I (S)-3-methyl- I -[6-rnethyl-3-oxo- I (pyridine-sulphonyl)azepan-4.ylcarbamoyI)-butyI }-amide 253 5-( 4 -Chloro-phenyI)-furan-2car.boxylic acid( (S)-2-cyciohexyl- I [3-oxo- I -oxy-pyridine- 2 -sufony).azepan.4ycamoyI]ethyl }-aniide 254 5-( 3 -Trifluoromethy-pheny)furn2-carboxylic acid( cyclohexyl- I-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)yazepan.4ylcarbamoyl]-ethyl }-amide 255 5-Fluoro-benzofizran-2-carboxylic acid (S)-3-rnethyIl--[3-oxo- 1- (pyridine- 2 -sufonvyD-azepan4ylcarbamoyl]-butyI }-amide 256 5, 6 -Dirnethoxy-benzofuran2carboxylic acid({ (S)-2-cyclohexyl- 1 (3-oxo- -oxy-pyridine- 2 -suffony1)-azepan.4-ylcarbamoy)..

ethyl)}-arnide 257 5,5-Bis-(4-methoxy-pheny)-pent-4-enoic acid (S)-3-methyl- I- [3-oxo-lI-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl])I-buryl 1amide 258 Quinoiine-8-carboxylic acid (S)-2-naphthylen-2-yI- I- [3-oxo- 1- (pyridine- 2 -sulfonyl)-azepan4ylcarbamoyl)-ety]amide 259 Naphthylene- I -carboxylic acid f (S)-2-naphthylen-2-yl- I -[3-oxo- I1- (pyridine- 2 -sulfonyl)-azepan4-ylcarbamoyl)-ethyl..amide 260 Quinoline-8-carboxylic acid I I -[3-oxo- I -(pyridine-2 -sulfonyl).azepan-4-ylcabamoyI]-2-phenyl-ethyl)I-amide 261 Naphthyridine-2-carboxylic acid {(S)-3-methyl- 1 [3-oxo- I (pyridine-2sulfonyl)-azepan-4-ylcarbamoyl].butyI I-amide 262 Naphthylene-1-carboxylic acid, [3-oxo-I.1-(pyridine-2 -sulfonyI)-azepan-4..ylcarbamoyI]-2-phenyi-ethyl)I-amide 263 3-Methylbenzofuran-2-carboxylic acid (S)-3-methyl- I-[3-oxo- I -(cyclohexyl-proprionyl)-azepan4ylcarbamoyIl-butyl }-amide 264 3-Methylbenzofuran-2-carboxylic acid (S)-3-methyl- 1 [3-oxo- 1 4 -methyl-pentanoyl)-azepan.4ylcarbamoyl].butyl amide 265 3 -Methylbenzofuran-2-carboxylic acid (S)-3-methyl-I- [3-oxo- I- (1 -oxy-pyridine-2-carbonyl)-azepan-4ylcarbamoyl..butyl)I-amide 266 (S)-Acetylamino-4-methyl-pentanoic acid [3-oxo-lI-(pyridine-2sulfonyl)azepan-4-yl]-aniide 267 Quinoline-2-carboxylic acid (1 -[3-oxo-lI-(pyridine-2-sulfonyl)azepan- 4-ylcarbamoylj-pentyl }-aniide 268 Benzofuran-2-carboxylic acid (S)-3-methyl- I-[3-oxo -1 -(cyclohexyl-proprionyl)-azepa-4-ylcarbamoyl]-butyl)I-amide P:\OPERXKbm/IZ363490.div cIainmi o-06 11/03 37 269 Benzofuran-2-carboxylic acid -methyl- I -[3-oxo- 1 -(4-methylpentanoyl)-azepan-4-ylcarbamoyl]-butyl) -amide 270 Quinoline-2-carboxylic acid 1-[3-oxo-l1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl] -2-phenyl-ethyl)}-amnide 271 Benzofuiran-2-carboxylic acid {(S)-2-benzyloxy-l1-[3-oxo-l1-(pyridine-2sulfonyl)-azepane-4-ylcarbamoyl] -ethyl) -amide 272 Benzofuran-2-carboxylic acid {(S)-2-hydroxy- 1 -[3-oxo- 1 -pyridine-2sulfonyl)-azepane-4-ylcarbamoyl] -ethyl I -amide- 273 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl- 1 -oxo- I1- (thiazole-2-sulfonyl)-)-azepan-4-ylcarbamoyl] -butyl -amide 274 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl- 1 -[3-oxo- I1- (thiazole-2-sulfonyl)-)-azepan-;4-ylcarbamoyl] -butyl -amide 275 3-Methoxybenzofuran-2-carboxylic acid -methyl- I -oxo- 1 (thiazole-2-sulfonyl)-)-azepan-4-ylcarbamoyl] -butyl -amide- 276 Benzo[b]thiophene-2-carboxylic acid -methyl-i -[3-oxo-lI-(thiazole-2sulfonyl)-)-azepan-4-ylcarbarnoyl]-butyl} -amide 277 1-Methyl-i H-indole-2-carboxylic acid -methyl-i -oxo-l1-(thiazole- 2-sulfonyl)-)-azepan-4-ylcarbamoyl] -butyll}-amide 278 Quinoxaline-2-carboxylic acid {(S)-3-methyl-lI-[3-oxo-lI-(thiazole-2sulfonyl)-)-azepan-4-ylcarbamoyl]-butyl} -amiide 279 Quinoline-2-carboxylic acid 1-ri-(4-fluoro-benzenesulfonyl)-3-oxoazepan-4-ylcarbamoyl]-3-methyl-butyl} -amide In one aspect of the present invention, there is provided a method of inhibiting a protease comprising administering a patient in need thereof an effective amount of a compound of Formula I as defined above.

In another aspect of the present invention, there is provided a method of treating a disease characterised by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound of formula I as defined above.

P:\OPER\Kb\12363490.dcl.limsdoc-6/ 1/03 -37A- In another aspect of the present invention, there is provided a method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound of Formula I as defined above According to a further aspect of the invention there is provided a use of a compound of Formula I as defined above in the manufacture for use in inhibiting a protease selected from the group consisting of a cysteine protease and a serine-protease.

According to another aspect of the invention there is provided a use of a compound as defined above in the manufacture a medicament for use in treating a disease characterized by bone loss.

According to another aspect of the invention there is provided a use of a compound of Formula I as defined above in the manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation.

Specific representative compounds of the present invention as set forth in Examples 1-279.

Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compound of the present invention are configurationally more stable at the carbon center alpha to the ketone.

The present invention includes deuterated analogs of the inventive compounds. A representative example of such a deuterated compound is set forth in Example 192. A P:OPER\Kbn\2422B9 spcc.doc-. lI 03 representative synthetic route for the deuterated compounds of the present invention is set forth in Scheme 4, below. The deuterated compounds of the present invention exhibit superior chiral stability compared to the protonated isomer.

Definitions Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge, in Australia.

The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.

Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis and trans isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

The meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.

Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).

P:OPER\Kbm\24223R9) pcc.doc.l2/ll 13 "Proteases" are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis. Such proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. The compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognising and hydrolyzing natural substrates and thereby act as inhibitors.

38A The term "amino acid" as used herein refers to the or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, gluaie glutarnic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylaanine, proline, serine, threonine, tryptophan, tyrosine and valine.

T C 6alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, npentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. C I.6alkyl may be optionally substituted by a moiety selected from the group consisting of: OR 12 C(O)R 12 SR 12 S (O)R 12 NR1 2 2 R I 2 NC(O)OR5, C0 2 R 12 CO2)NR 12 2, N(C=NH)NH, Het, C3-6cycloalkyl, and Ar; where R 5 is selected from the group consisting of: H, C 1 6alkyl, C2..6alkenyl, C-'76a~kynyl, C3-6ccvcloalkyl.CO- 6 alkyl, Ar-CO- 6 alkyI and Het-Co- 6alkyl; and R 12 is selected from the gru cnIn of -,C..akl rC kl n Het-CO 0 6 alkyl; "C3-6cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.

T2-6 alkenyl" as applied herein meansan alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2..6alkenyl includes ethylene, 1 -propene, 2-propene, I1-butene. 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.

"C26alkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon.

single bond is replaced by a carbon-carbon triple bond. C-6 alkynyl includes acetylene, Ipropyne. 2 -propyne, I -butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

"Halog~en" means F, Cl, Br, and I.

"Ar or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-CO- 6 alkyl; Het-CO.

6 alkyl; C 1 6 alkoxy; Ph-COj.

6 alkoxy; Het-CO4 6 alkoxy-, OH, (CHI) 1

I

6

NR

15

R

16

O(CH

2 I 6 NR 15 R 1 6 C 1-6alkyl, OR 7 NCR 7 2 SRI 7

CF

3 NO,, CN, C0)R 1 7 CON(R 17 F, Cl, Br or 1; where R 15 and R 16 are H, C I 6 alkyl, Ph-CO 0 6 alkyl, naphthyl-C 0 6 alkyl or Het-CO- 6 alkyl; and R 17 is phenyl, naphthyl, or C 1 6 alkyl.

As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic, a stable 7- to IlO-membered bicyclic. or a stable I11- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S.

and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heceroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected firom ArCo.

6 alkyl, Cl.salkyl, OR' 7

N(R'

7 2

SR"

7 CF3, NO 2 CN, CO 2

R",

CON(R

17 F, Cl, Br and I, where R 1 7 is phenyl, naphthyl, or CI-6alkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2 -oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, l-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl. morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyraryl, benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo[b)thiophenyl, thieno[3,2b]thiophenyl, benzol,3)dioxolyl, 1,8 naphthyridinyl, pyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzoxazoly]; thiamorpholinyl sulfoxide, thiamorpholinyl sulfone. and oxadiazolyl, as well as triazolyl, thiadiazolyl, oxadiazolyl, isothiazoly], imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are available by routine chemical synthesis and are stable. The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur.

Here and throughout this application the term CO denotes the absence of the substituent group immediately following; for instance, in the moiety ArC 0 6 alkyl, when C is 0. the substituent is Ar, phenyl. Conversely, when the moiety ArCO-6alkyl is identified as a specific aromatic group, phenyl, it is understood that the value of C is 0.

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical.

Certain reagents are abbreviated herein. m-CPBA refers to 3 -chloroperoxybenzoic acid, EDC refers to N-ethyl-Ndimethylaminopropyl)-carbodiimide, DMF refers to dimethyl formamrnide, DMSO refers to dimethyl sulfoxide, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran.

Methods of Preparation Compounds of the general formula I may be prepared in a fashion analogous to that outlined in Schemes 1, 2 and 3. Alkylation of tert-butyl N-allylcarbamate with a base such as sodium hydride and 5-bromo-1-pentene provides the diene 2. Treatment of 2 with either 2 6 -diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride olefin metathesis catalysts developed by Grubbs provides the azepine 3. Epoxidation of 3 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 4. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon. Acylation of with an acid such as Cbz-leucine in the presence of a coupling agent such as EDC followed by removal of the BOC protecting group under acidic conditions provides the amine salt 6.

Coupling of 6-withCbz-leii iie mnaybeeffected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.

Scheme I a 0 00 oo !1W/ 1 2 3

HO

0 0 2 3 0 O 0 OH H h-iHN0 2 N 0 N O N_/-Nj<

HH

H K. 0 6 7 Reagents and conditions: NaH-, 5-bromo-l-pentene. DMF; 2,6-diisopropylphenylimido neophylidene molybenum- bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst. toluene m-CPBA, CHCI.: NaN,, CH OH. H.0, NHCl; Pd/C, Cbz-leucine, EDC, CI-LCI,; g)HCI. EtOAc; Cbz-leucine, EDC, CIC1 i.) pyridine sulfur trioxide complex. DMSO, TEA.

Compounds of the general formula I wherein R' and R2 are amnides may be prepared in the general fashion outlined in Scheme 2. Alkylation of N-Cbz allyl amnine with a base such as sodium hydride and 5-bromno- I -pentene provides the diene 9. Treatment of 9 with bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride olefin metathesis catalyst developed by Grubbs provides the azepine 10. Epoxidation of 10 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 11. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine. Acylation of 12 with N-Bocleucine and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13. Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HCI or TFA provides intermediate 14.

Acylation of 14 may be effected with a carboxylic acid in the presence of a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone Scheme2 0 0 a 0 'N 0'N

H

b qO, 1N- 0 C 0 0

OH

d. e r>NH2

K

0 f, g OH OH 0 r H 11 H h, i NC k NN H R H' 6 13 14 1 Reagents and conditions: NaH-. 5-bromo- 1-pentene, DMF; b.) bis(Ericyclohexylphosphine)tbenzylidine ruthenium (IV) dichloride catalyst, CHCl,; m-CPBA, CHCI,; NaN 3

CH

3 OH. HO, NH 4 CI; propanedithiol, CH 3 OH. TEA; Boc-leucine, EDC, CILCI.; g)10% Pd/C, H 2 RCOH, EDC. CH.Cl, or R,CQCI, CH C1,; 0. HCII EtOAc; j.) R.CO,H, EDC. CHCI,; pyridine sulfur trioxide complex, DMSO, TEA.

Compounds of the general formula I wherein R 2 is an alkyl, urea or sulphonamide group and R' is an amide may be prepared in the general fashion outlined in Scheme 3.

Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N- Boc group under acidic conditions provides the amine salt 16. Coupling of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Alternatively, treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18. Acylation and oxidation provides the ketone 19. Further derivatization of amine 13 may be effected by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20. Acylation and oxidation provides the ketone 21.

Scheme 3 OH

H

N N O a.b N NH.Cl- S O H R vN 0 H N 13 16 e\ OH S e. b H c. d N NH +CI- R1 N, 0 18 1

TO

0 N R2

_,NN

17 H HI: Hl- N 0

R

FW N 0 19 OH H

H

o r

N

YNH,.+C-

?N 0 o i H l N o N 0R j 0 H o c.d Reagents and conditions: R,CHO, NaBH(OAc),; HC1; LRCO.H, EDC. CCI.,; d.) pyridine sulfur trioxide complex, DMSO, TEA; R,NCO, base; R,SO2CI, TEA. CH,CI,.

The deuterated compound of the Example 192 may be conveniently prepared according to Scheme 4. The skilled artisan will understand from Example 192 and Scheme 4 how to make any of the the deuterated compounds of the present invention.

The individual diastereomers of benzofuran-2-carboxylic acid {(S)-3-methyl-1- [(2,2',4-trideuterio)-3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide 31 and 32 may be prepared as outlined in Scheme 4. Alkylation of allyl-carbamic acid benzyl ester 22 with 5-bromo- -pentene in the presence of a base such as sodium hydride provides the diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride developed by Grubbs provides the 2,3,4,7-tetrahydro-azepine-1carboxylic acid benzyl ester 24. Epoxidation of azepine 24 may be effected with standard oxidizing agents common to the art such as m-CPBA to provide epoxide 25. Nucleophilic epoxide ring opening of 25 may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown).

Scheme 4 Ha 0 0N~ b 0 N, 6 0 CX t d, de 0

OH

0 f. g

OH

N

H

H'H

h.

OH

IH

'.0 N.0 28

OH

0H

NN

k 0

H

0 0 H 0-K"

,N

D H rn ~I D DNH i,0 N< H N 0ON 4 0

KN

31 D 0 o 0

N

32 Reagents and Conditions: NaH, .5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH,C1.,; c. m-CPBA, CI{C1,; d-) NaN 3 CH,OH. ILO0, NHCI; 1,3-propanedithiol. TEA, methanol; N-Boc-leucine, EDC, CFLCI,; g)10% Pd/C, 2-pyridinesuiphonvi chloride. TEA, CH.CL; 4 NHCIldioxane, methanol; benzofuran-2-carboxylic acid, EDC CH,CI.; pyridine sulfur trioxide complex, DMSO. TEA: CD 1 OD;D.O TEA, in.) HPLC separation.

The intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water. Acylation of 26 may be effected with an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC. Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 27. Treatment of the amine 27 with 2-pyridinesulphonyl chloride in the presence of triethylamine or saturated sodium bicarbonate and CH,Cl, followed by removal of the tert-butoxycarbonyl protecting group under acidic conditions provides 28. Coupling of 28 with benzofuran-2-carboxylic acid may be effected with a coupling agent such as EDC to provide intermediate alcohol 29. Alcohol 29 may be oxidized with an oxidant such as sulfur trioxide pyridine complex in DMSO and triethylamine to provide the ketone 30 as a mixture of diastereomers. Treatment of ketone 30 with triethylamine in CDOD:D,O at reflux provides the deuterated analog as a mixture of diastereomers which are separated by HPLC to provide the deuterated compounds 31 and 32.

Compounds of the- general formula I may also be prepared as outlined in Scheme The amine of compound 12 may be protected with with di-tert-butyldicarbonate to provide the N-Boc derivative 33 (Scheme Removal of the benzyloxycarbonyl protecting group may be effected by treatment of 33 with hydrogen gas in the presence of a catalyst such as .10% Pd/C to provide the amine 34. Treatment of amine 34 with a sulfonyl chloride such as 2-pyridinesulfonyl chloride in the presence of a base such as N-methylmorpholine or triethylamine provides the sulfonamide derivative 35. Removal of the terr-butoxycarbonyl protecting group may be effected with an acid such as hydrochloric acid to provide intermediate 36. Coupling of 36 with an acid such as N-Boc-cyclohexylalanine in the presence of a coupling agent common to the art such as HBTU or polymer supported EDC provides the alcohol intermediate 37. Removal of the terr-butoxycarbonyl protecting group under acidic conditions provides amine 38. Coupling of 38 with an acid such as benzofuran-2-carboxylic acid in the presence of a coupling agent such as HBTU or polymer supported EDC provides alcohol 39. Alcohol 39 may be oxidized with an oxidant common to the art such as pyridine sulfur trioxide complex in DMSO and triethylamine or the Dess- Martin periodinane to provide the ketone Scheme OH H OH H PH MN a' 0b 0 N N 0 12 33 34 OH PH C BOCNH d HN e 'N A

N

00" 0 0 36 H OH H OH N N

N

0 0 0 0 37 38 0 O~H 0 HO 0 N J-N~ N NQ H j- H 0 N I 0 0 0 0 39 Reagents and Conditions: Di-tert-butyldicarbonate. THF: 10% Pd/C. EtOAc; 2pyridylsulfonyl chloride, TEA HCI, EtOAc; N-Boc-cylohexylalanine, P-EDC. CH.Cl,; (f) HCI. CH,L; ()benzofuran-2-carboxylic acid. P-EDC, CELCI,; Dess-Martin periodinane.

methylene chloride.

The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. 1-VI (published by Wiley-Interscience).

Coupling methods to form amide bonds herein are generally well known to the art.

The methods of peptide synthesis- generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlagy, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. are generally illustrative of the technique and are incorporated herein by reference.

Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions.

Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS.IN ORGANIC SYNTHESIS, John Wiley Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.

Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic. succinic or methanesulfonic. Certain of the compounds form inner salts or zwittenons which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li+, Na+, Ca Mg" and NH 4 are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.

This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament; Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by-addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.

Novel Intermediates Referring to the methods of preparing the compounds of Formula I set forth in Schemes 1-4 above, the skilled artisan will appreciate that the present invention includes all novel intermediates required to make the compounds of Formula I. In particular, the present invention provides the compounds of Formula II: R, N R"

N

R"OH

N

R

2

II

wherein: R' is selected from the group consisting of: 0 0 0 j 3 R 3 and R 3

R

2 is selected from the group consisting of: H, C I 6 alkyl, Ct1 6 cYcloalkyl-CO.

6 alkyl, Ar-CO- 6 alkyl, Het-CO 0 6 alkyl, R 9

R

9

R

9 S0 2

R

9 0C(O)-, N N~kCH, N Z and

R

3 is selected from the group consistingo:HClakIC2aknl C2-6alkynyl, HetCO-alky1 and ArCO-6alkyl;

R

3 and R' may be connected to form a pyrrolidine, piperidine or morpholine. ring;

R

4 is selected from the group consisting of: H, CI- 6 alkyl, C 3 6 cycloalkyl-C 0 6akl Ar-CO- 6 alkyI, Het-CO 0 6 alkyl, R 5

R

5

R

5 S0 9

R

5 OC(0)-, 3 and R 5

R

1 3

NC(S)-;

R

5 is selected from the group consisting of: H, Cj- 6 alkyl, C2)-alkenyl, C 2 6alkynYl, C 3 6 cYcloalkyl-CO- 6 alkyl, Ar-CO.

6 alkyI and Het-CO- 6 alkyl;

R

6 is selected from the group consisting of: H, C0I 1 6 alkyl, Ar-CO-6alkyl, or Het-

CO

0 6 alkyl;

R

7 is selected from the group consisting of: H, CI- 6 alkyl, C 3 6 cYcloalkyl-CO- 6 alkyl, Ar-CO- 6 alkyl, Het-CO- 6 alkyl, R 1 I R IOC(S)-, R I OS0 9

R

1 I 0C(0)-,

RI

0

R

14 and RI 0

R

14

NC(S)-;

R

8 is selected from the group consisting f ,C~lyC.aknl C?26alkynyl, HetCO-6alkyl and ArCO-6alkyl;

R

9 is selected from the group consisting of: C I 6 alkyl, C 3 6 cYcloalky1-CO- 6 alkyl, Ar-C 0 6 alkyl and Het-C 0 6 alkyl: R 1 0 is independently selected from the group consisting of: C 1 6 alkyl, C3-6cYcloalkyl-CO- 6 alkyl, Ar-C 0 6 alkyl and Het-CO- 6 alkyl;

R

1 is selected from the group consisting of: H, C I 6 alkyl, Ar-CG-6alkyl, and Het-

CO-

6 alkyl;

R

12 is selected from the group consisting of: H. C I 6 alkyI, Ar-CO-6alkyl, and Het-

CO

0 6 alkyl; R 13 is selected from the group consisting of: H. C j 6 alkyl, Ar-CO-6alkyl, and Het-

CO

0 6 alkyl; R 1 4 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO-6alkyl, and Het-

CO-

6 alky1; R' is selected from the group consisting of: H, C I 6 alkyl. Ar-CO-6alkyl, and Het-

CO

0 6 alkyl; R" is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO-6alkyl, or Het-C 0 6 alkyl; R' is selected from the group consisting of: H, C 1 6 alkyl, C3-6cycloalkyl-C 0 6 alkyl, Ar-C 0 6 alkyl, and Het-COy.

6 alkyl; X is selected from the group consisting of: S, and 0; Z is selected from the group consisting of: C(O) and CH,); and pharmaceutically acceptable salts, hydrates and solvates thereof.

The following compounds are preferred novel intermediates: Il( 3 -Hydroxy-azepan-4-ylcarbamoyI>-3.methyl-buty1I..carbamic acid benzyl ester; 2 -Amino-4-methyl- pentanoic acid (1 -benzyl-3-hydroxy-azepan-4.yl)-amide; 2 -Amino-4-methyl-pentanoic acid 3-hydroxy- I-[2-(3-pyridin-2-yI-phenyl)acetyl]-azepan-4-y1 I amnide; I 4 -((S)-2-An-no-4-methyl-.pentanoylamino)-3.hydroxy..azepan- I ylmethyl]-3-methyl-butyl}-carbamic acid benzyl ester; 2 -Axnino-4-methyl-pentanoic acid-( 1-benzoyI-3-hydroxy-azepan4y)-anmjde; 2 -Amino-4-methyl-pentanoic acid [3-hydroxy- 1-(4-methyl-pentanoyl)-azepan- 4-yl]-amide; 2 -Amino-4-methyl-pentanoic acid (1 -benzenesulfonyl-3-hydroxv-azepan.4.yl)amide; thieno 3 ,2-b~thiophene-2-carboxylic acid ((S)-3-rnethyl- I-[3-hydroxy- I-oxypyridine-2-sulfonyl)-azepan-4ylcarbamoyl..butyl amide; 5-methoxybenzofuran-2-carboxylic acid f (S)-3-methyl- I -[3-hydroxy- I -oxypyridine- 2 -sulfonyl)-azepan-4.ylcarbamoyl]-butyI amide; thieno[3,2-b]thiophene-2-carboxylic acid f (S)-3-methvl- I -[3-hydroxy- 1 -(pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyl)-butyl }amide; 3 -methylbenzofuran-2-carboxylic acid I (S)-3-rnethyl- I -[3-hydroxy- I -oxypyridine- 2 -sulfonyl)-azepan-4.ylcarbamoyl]jbutyj Jamide; quinoline-2-carboxylic acid (S)-3-methyl- I-[3-hydroxy- I-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-butyl }axnide; and quinoxaline-2-carboxylic acid {(S)-3-methyl- I-j13-hydroxy- I-oxy-pyridine-2sulfonyl)-azepan-4-ylcarbaxnoyl]pbutylI amide.

Process for Synthesis of Inventive Compounds Referring to Schemes 1-5 herein above, the present invention provides a process for the synthesis of compounds of Formula comprising the step of oxidizing the appropriate compound of Formula (II) with an oxidant to provide the compound of Formula as a mixture of diastereomers. Preferably the oxidant is sulfur trioxide pyridine complex in DMS0 and triethylarnine.

Referring to Scheme 4, the present invention also provides a process for the synthesis of deuterated compounds of Formula Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating a gent to provide the deuterated compound of Formula as a mixture of diastereomers-is added to-the synthesis. Preferably, the deuterating agent is CD 3 OD: D,O (10: 1) In triethylamnine.

The process further comprises the step of separating the diasteromers of Formula* by separating means, preferably by high presssure liquid chromatography

(HPLC).

Utility of the Present Invention The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.

The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.

Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.

The present invention also provides methods of treatment of diseases caused.by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention. The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof an inhibitor of cathepsin K, including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.

This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.

For acute therapy, parenteral administration of a compound of Formula I is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K. The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.

No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.

Biological Assays The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.

Determination of cathepsin K proteolytic catalytic activity All assays for cathepsin K were carried out with human recombinant enzyme.

Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM: emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes.

following formation of AMC product.

Inhibition studies Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound. Reactions were initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progress curves were linear, apparent inhibition constants (Ki,app) were calculated according to equation 1 (Brandt et al., Biochemitsry; 1989, 28, 140): v VmA /[Ka(l I/Ki, app) (1) where v is the velocity of the reaction with maximal velocity Vm, A is the concentration of substrate with Michaelis constant of Ka, and I is the concentration of inhibitor.

For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give kobs according to equation 2: [AMC] Vss t (vo vss) [1 exp (-kobst)]/ kobs (2) where [AMC] is the concentration of product formed over time t, v 0 is the initial reaction velocity and vss is the final steady state rate. Values for kobs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (kobs inhibitor concentration or kobs describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol.. 1988, 61, 201).

Human Osteoclast Resorption Assay Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for min on ice The cell suspension was mixed frequently.

The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, min at 4 0 C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.

Sufficient magnetic beads (5 mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium: The beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded.

The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5x 10 4 /mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEMI diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37°C for 30 min.

0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37 0 C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37 0 C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37 0 C. The slices were then washed in cold water and incubatedin coldacetate buffer fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.

The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.

General Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDC13 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD30D is tetradeuteriomethanol. Chemical shifts are reported in parts per million downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s singlet, d doublet, t triplet, q quartet, m multiplet, dd doublet of doublets, dt doublet of triplets, app apparent, br broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin- Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers Mass spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.

Where indicated, certain of the materials were purchased from the Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey, and Advanced Chemtech, Louisville, Kentucky.

Examples In the following synthetic examples, temperature is in degrees Centigrade Unless otherwise indicated, all of the starting materials were obtained from commercialsources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These Examples are given to illustrate the invention, not to limit its scope. Reference is made to the claims for what is reserved to the inventors hereunder.

Example 1 Preparation of -((S)-2-Benzvloxvcarbonvlamino-4-methvl-pentanoyl)-3-oxoazepan-4-vlcarbamoyl }carbamic acid benzvl ester Allyl-pent-4-enyl-carbamic acid terr-butyl ester To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed with hexanes) in DMF (30 mL) was added terr-butyl N-allylcarbamate (6.0 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately minutes whereupon 5-bromo-l-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40"C for approximately 2 hours whereupon the reaction was partitioned between ethyl acetate and water; The organic layer was washed with water (2 brine, dried (MgSO,), filtered and concentrated to give 10 grams of the title compound as an oil: MS(EI) 226 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid terr-butyl ester To a solution of compound of Example la (4.5 g) in benzene was added the 2,6diisopropylphenylimidoneophylidene molybdenum bis(t-butoxide) (600 mg). The reaction was heated to reflux for 1.5 hours whereupon the reaction was concentrated in vacuo.

Chromatography (50% CHCl:hexanes) of the residue gave 3.92 g of the product: 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid tert-butyl ester To a solution of the compound of Example Ib (3.0 g, 15.2 mmol) in CH2Cl 2 was added m-CPBA (7.8 g, 45.6 mmol). The mixture was stirred overnight at room temperature whereupon it was partitioned between CH:C1 and staurated KCO,. The organic layer was washed with sat. NaHCO,, water, brine, dried (MgSO), filtered and concentrated to give 3.11 g of the title compound as an oil: MS(EI) 214 4-Azido-3-hydroxy-azepane- -carboxylic acid terr-butyl ester To a solution of the epoxide from Example Ic 3.92 g, 20 mmol) in methanol:water (180 mL of an 8:1 solution) was added NH 4 CI (3.18 g, 60 mmol) and sodium azide (3.9 g, 60 mmol). The reaction was heated to 40"C until complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was diluted with ethyl acetate and washed with water, brine dried (Na2S0 4 filtered and concentrated. Column chromatography (40% ethyl acetate:hexanes) of the residue provided 3.43 g of the title compound.

4 -Amino-3-hydroxy-azepane- I-carboxylic acid tert-butyl ester To a solution of the azido alcohol of Example Id (3.4 g) and 10% Pd/C (catalytic) in ethyl acetate:methanol (2:1 solution) was affixed a balloon of hydrogen. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo. Column chromatography of the residue (25% methanol:dichloromethane) provided 2.57 g of the title compound: MS(EI) 231 4 2 -benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid ten butyl ester To a solution of the amino alcohol of Example le (160 mg, 0.70 mmol) in CH 2

CI

2 was added EDC (134 mg), HOBt (94 mg) and Cbz-leucine (185 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with IN HCI, sat. K 2 C0 3 water, brine, dried (MgSO 4 filtered and concentrated. Column chromatography of the residue methanol:dichloromethane) gave 200 mg of the title compound: MS(EI) 478 500 3 -hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester A solution of the compound of Example If (200 mg, 0.42 mmol) in methanol mL) was added 4M HCI in dioxane (5 mL). The reaction was stirred at room temperature for approximately 2 hours whereupon the solvent was removed in vacuo to provide 168 mg of the title compound: MS(EI) 378 l-[ 4 2 -Benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxyazepane-1-carbonyl]-3-methyl-butyl carbamic acid benzyl ester To a solution of the amine salt of Example I g (168 mg, 0.42 mmol) in CH,)C1 9 was added EDC (81 ing), HOBt (57 mg), triethylamine (0.09 mnL) and Cbz-leucine (Ill ma) The reaction was stirred until complete by TLC analaysis. Workup followed by column chromatography

CH

3 0H:CH 9

)C]

2 provided 159 mg of the title compound: MS(EI) 625 i0 1 Il-[ 4 2 -Benzyloxycarbonylamino.4-methyk-pentanoylamino)..3 oxo.

azepane-] -carbonyll-3-methyl-butyl }carbamic acid benzyl ester To a solution of the alcohol of Example Ilh (130 mg, 0.21 mnmol) in DMSO was added TEA 17 m-L) and pyridine sulfur t~rioxide complex (97 mg, 0.62 mmol). The reaction was stirred at room temperature for approximately 2 hours whereupon it was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated. Column chromatography of the residue

CH

3 OH :CH-,C1 2 provided 100 mg, of the title compound as a mixture of diastereomers: 'H NMR (CDCI 3 8 1.0 M, 12H), 1.5-2.1 (in, 8H), 2.2 (in, 4H). 3.0 (in, lH), 3.5 lH). 3.6 4.01 (in. IH), 4.5 (in, 2H1), 4.7 (in, lH), 5.0 m, 5H), 7.3 (in, lOH): MS (El) 623(M+H+), 645 Separation of the diastereomers by HPLC provided diastereomer L MS (El) 623 645 and diastereoiner 2: MS (ES) 623 645 Example 2 Preparation of Naphthvlene-2-carboxylic acidr(S)- -benzyl-3-oxo-azepan-4vlcarbamovl)-3-methvl-butvllamide Allyl-pent-4-enyl-carbamic acid benzyl ester To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added benzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon bromo- -pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40°C for approximately 4 hours whereupon the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2x's), brine, dried (MgSO 4 filtered and concentrated. Column chromatography of the residue ethyl acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(EI) 260 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester To a solution of compound of Example 2a (50 g) in dichloromethane was added bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (5.0 The reaction was heated to reflux until complete as determined by TLC analysis. The reaction was concentrated in vacuo. Column chromatography of the residue dichloromethane:hexanes) gave 35 g of the title compound: MS(EI) 232 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester Following the general procedure of Example Ic except substituting the compound of Example 2b the title compound was prepared: MS(EI) 248 270 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester To a solution of the epoxide from Example 2c (2.0 g, 8.1 mmol) in methanol:water (8:1 solution) was added NHC1 (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). The reaction was heated to 40 0 C until complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic layer was washed with sat. NaHCO,, water, brine dried (MgSO,), filtered and concentrated. Column chromatography (20% ethyl acetate:hexanes) of the residue provided 1.3 g of the title compound: MS(EI) 291 (M+H plus 0.14 g of trans-4hydroxy-3-azido-hexahydro- IH-azepine 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester To a solution of the azido alcohol of Example 2d (1.1 g, 3.79 mmol) in methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol mL, 11.37 mL).

The reaction was stirred until complete consumption of the starting material was observed by TLC analysis whereupon the reaction was concentrated in vacuo. Column chromatography of the residue (20% methanol:dichloromethane) provided 0.72 g of the title compound: MS(EI) 265 4-((S)-2-rert-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan- 1-carboxylic acid benzyl ester To a solution of the amino alcohol of Example 2e (720 mg, 2.72 mmol),in CH 2 Cl2 was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with IN HCI, sat. K2C0 3 water, brine, dried (MgSO 4 filtered and concentrated. Column chromatography of the residue methanol:dichloromethane) gave 1.0 g of the title compound: MS(EI) 478 [(S)-1-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester To a solution of the compound of-Example 2f (1.0 g) and 10% Pd/C (catalytic) in ethyl acetate:methanol (2:1 solution) was affixed a balloon of hydrogen. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis.

The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo to provide 0.82 g of the title compound: MS(EI) 344 -Benzyl-3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester To a solution of the compound of Example 2g (0.69 g, 2.01 mmol) in CH 2 C1 2 was added benzaldehyde (0.32 mL, 3.01 mmol) followed by sodium triacetoxyborohydride (0.85 g, 4.02 mmol). The reaction was stirred until complete as determined by TLC analysis whereupon several drops of water were added to the reaction to destroy the excess sodium triacetoxyborohydride. The mixture was diluted with ethyl acetate washed with sat.

NaHCO 3 water, brine, dried (Na 2

SO

4 filtered and concentrated. Column chromatography of the residue methanol:dichloromethane) gave 800 mg of the title compound: MS(ES) 434 2 -Amino-4-methyl-pentanoic acid (l-benzyl-3-hydroxy-azepan-4-yl)-amide To a solution of the compound of Example 2h (800 mg) in methanol (15 mL) was added 4M HCI in dioxane (15 mL). The reaction was stirred at room temperature overnight whereupon it was concentrated in vacuo to give 800 mg of the title compound: MS(ES) 334 Naphthylene-2-carboxylic acid -benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3methyl-butyl]-amide To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH2CI 2 .was added triethylamine (0.17 mL, 1.22 mmol), EDC (103.5 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and 2-naphthoic acid (93 mg, 0.54 mmol). The reaction was stirred until complete by TLC analysis. The reaction was diluted with ethyl acetate and washed with sat. NaHC0 3 water, brine, dried (Na2SO 4 filtered and concentrated. Column chromatography of the residue methanol:dichloromethane) gave 0.14 g of the title compound: MS(EI) 488 Naphthylene-2-carboxylic acid[(S)- 1-(1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3methyl-butyl]-amide Following the general procedure of Example li except substituting the compound of Example 2j for the compound of Example li the title compound was prepared: 'H NMR (CDCl 3 8 1.0 m, 6H), 1.5-2.1 m, 5H), 2.2 m, 2H), 2.9 1H), 3.2 (dd, 1H). 3.4 (m, 1H), 3.7 2H), 4.7 m, 1H), 5.2 m, 1H), 7.2-8.4 12H): MS(EI): 486 (M+WT, 100%). Separation of the diastereomers by HPLC provided diastereomer 1: MS (El) 486.3 and diastereomer 2: MS (ES) 486.3 Example 3 Preparation of Benzor I .31dioxgle-5-carboxylic acid I -benzvl-3-oxo-azeinan-4ylcarbamovl)-3-rnethyl-butyllamide Benzo[ I,3]dioxole-5-carboxylic acid -(1-benzyl-3-hydroxy-azepan-4ylcarbamoyl)-3-methyl-butyljamide Following the generai .procedure of Example 2j except substituting piperonylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 482 Benzo[ I ,3]dioxole-5-carboxylic acid -benzyl-3-oxo-azepan-4ylcarbamoyl)-3-methyl-butyl]amide Following the general procedure of Example 11 except substituting the. compound of Example 3a the title compound was prepared: 'H NMR (CDCI,): 5 1.0 6H), 1.5-2.1( m, 5H), 2.2 2H), 2.9 (in, lH), 3.0 11H). 3.2 1H), 3.5 IH), 3.7 (mn, 2H), 4.7( mn, IlH), 5.2 I 6.0 2H), 6.8 (mn, 2H).7.2 (in, 6H); MS(EI): 480 The diastereoiners were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereoiner 1: MS (El) 480.3 959.6 2M+H+) and diastereoiner 2: MS (ED) 480.3 959.6 2M+H+).

Example 4 Preparation of Benzofuran-2-carboxylic acid -I-l-benzvl-3-oxo-azepan-4vlcarbamovl)-3-methv..butyl lamide Benzofuiran-2-carboxylic acid 1I-(1 -benzyl-3-hydroxy-azepan-4-ylcarbamoyl 3-methyl-butyl]amide Following, the general procedure of Example 2j except substituting benzofuran-2carboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 478 Ben zofuran-2-carboxy lie acid -benzy l-3-oxo-azepan-4-ylcarbamoyl)-3methyl-butyl~amide Following the general procedure of Example I i except substituting the compound of Example 4a the title compound was prepared: 476 MS(EI): 492 (M+lE, 100%). The diastereomers were separated by preparative scale HPLC. L-yophilisation of the eluents provided diastereomer 1: MS (El) 476.4 951.6 and diastereomer 2: MIS (El) 476.4 951.6 2M+H+).

Example Preparation of Benzofbthiohene-2-carboxvlic acid -benzvl-3-oxo-azepan-4vlcarbamovl)-3-methvl-butvilamide Benzo[blthiophene-2.carboxylic acid 1-(1 -benzyl-3-hydroxy-azepan-4ylcarbamoyl)-3-methyl-butyljamide Following, the general procedure of Example 2j except substituting benzothiophene-2-carboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 494 Benzofb)thiophene-2-carboxylic acid -benzyl- 3 -oxo-azepan-4..ylcarbamoyl)-3methyl-butyllamide Following the general procedure of Example I i except substituting the compound of Example 5a the title compound was prepared: 'H NMR (CDCI,): 5 1.0 in, 6H), 1.5-2.1( mn, 5H), 2.2 (in, 2H), 2.9 (mn, INH), 3.2 (dd, INH). 3.4 (in, I 3.7 (in, 4.7 (mn, INH), 5.2 m, 7.2-8.4 (in, ION): MS(EI): 492 (M+H',lOO%) The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer I: MS (El) 492.4 983.7 2M.1-I) and diastereomer 2: MS (El) 492.4 983.7.2M+H+).

Example6 Preparation of Naphthvlene-2-sulphonvl -benzvl-3-oxo-azepan-4-v lcarb~rioyl)-3methvi-butvill-amide Naphthylene-2-sulphonyl I-benzyl-3-hydroxy-azepan4ylcarbamoyl)-3 methyl-buty 1)-ainide To a solution of the amine salt of Example 2i (200 mg, 0.49 iniol) in CH-)C1 2 was added triethylamine (0.24 mL, 1.72 mmol) and 2-naphthalenesulphonyl chloride (122 mg, 0.54 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. The reaction was worked-up, dried (Na,)SO 4 filtered and concentrated.

Column chromatography of the residue (10% inethanol:dichloromethane) provided 52 mng of the title compound: MS(EI) 524 Naphthylene-2-sulphonyl -benzyl- 3 -oxoazepan4ylcarbaioyl)3-ethyl.

butyl]-ainide Following, the general procedure of Example I i except substituting the compound of Example 6a the title compound was prepared: 'H NMR (CDClj: S 1.0 n,6H), 1.5-2.1 in, 5H), 2.2 in, 2H), 2.7 (in, I 3.0 (dd, I 3.3 (in, INH), 3.6 (in, 2H). 3.7 m, IlH), 4.7 (mn, IN), 5.3 m, lH), 7.2-8.4 (mn, 12H): MS(EI): 522 (M+W,100%) Example7 Preparation of Ouinoline-2-carboxvlic acid 1 -benzvi-3-oxo-azepan-4-ylcarbamovl)- 3-methyl-butyllamide Quinoline-2-carboxylic acid -benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3methyl-butyl]amide Following the general procedure of Example 2j except substituting 2quinolinecarboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 489 Quinoline-2-carboxylic acid 1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl.

butyl]amide Following the general procedure of Example 11 except substituting the compound of Example 7a the title compound was prepared: 'H NMR (CDCL,): 6 1 .0 m, 6H), 1.5-2.1( mn. 5H), 2.2 m, 2H), 2.9 1 3.2 (dd, IlH). 3.4 (in. I 3.7 (mn, 2H), 4.7 m, I H), 5.2 mn, I1H), 7.2-8.4 (in, I I MS(EI): 487 The diastereorners were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MIS (El) 492.4 983.7 2M+H+) and diastereoiner 2: MS (El) 492.4 983.7 2M+H+).

Example 8 Preparation of 3,4-dichlorobenzoic acid r(S)-I -benzvl-3-oxo-azep~an-4-vlcarbamoyl)y3 methyl-butyllanide 3,4-dichlorobenzoic acid 1-(1 -benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3methyl-butyl~amide Following the general procedure of Example 2j except substituting 3,4dichlorbenzoic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 506 3,4-dichlorobenzoic acid 1-(1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methylbutyl]amide Following the general procedure of Example li except substituting, the compound of Example 8a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 m, 6H), 1.5-2.1( m. 5H), 2.2 m, 2H), 2.9 (in, IN), 3.2 (dd, IH). 3.4 (in, 3.7 (in, 2H), 4.7 mn, 2H), 5.2 7.2-8.4 (in, 8H); MS(EI): 504 Example9 Preparation of 4- (S)-Methyl-2-[(puinoline-2-carbonvl)-aininollpentanovlamino 1-3-oxo- 1I r2-(3-Pvridin.2 henvl )-acetyl lazepanium 4 2 -ter-Butoxycarbonylamino.4-methypentanoylaino)3hydroxyl[2-(3pyridin-2-yi-phenyl)-acetyl]-azepaniuin To a solution of the compound of Example 2g, (0.5g, 1.46 inmol) in CH2)CI 2 was added EDC.(307 mng, 1-.60.mmol), HOBt (216.mg, 1.60 minol) and -3-(2-pyridyl)ohenyl acetic acid (341 mng, 1.60 minol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (2% methanol :dichloromethane) provided the title compound: MS(ES) 539 )-Ainino-4-methyl-pentanoylamino)-3-hydroxy- I -[2-(3-pyridin-2-yl-phenyl)acetyl ]-azepanium To a solution of the compound of Example 9a (1.3 g)dissolved in methanol (20 mL.

was added 4M HCI in dixoane (20 The reaction was stirred until complete by TLC analysis whereupon it was concentrated in vacuo to give 1. 1 a, of the title compound: MS(EI) 439 (M+H 4 4- (S)-Methyl-2-[(quinoline-2-carbonyl)-amino~pentanoylamino I -3-hydroxy- 1 -f2- 3 -pyridin-2-yl-phenyl)-acetyl~azepanium Following the procedure of Example 7a except substituting the compound of Example 9b the title compound was prepared: MS(EI) 594 4- 1 (S)-Methyl.2-[(quinoline-2-carbonyl)-amino~pentanoylamino }-3-oxo- I pyridin- 2 -yl-phenyl)-acetyljazepanium Following the procedure of Example I i except substituting the compound of Example 9c the title compound was prepared: 'H NMR (CDCI,): 5 1.0 m, 6H), 1.5-2.1( 5H), 2.2 (in, 2.9 (in, I 3.4 (dd. I1-H). 3.8 (in. 3H), 4.1 (mn, 4.7 m, 3H), 5.4 mn, I1-H), 7.2-8.4 (in, 14H); MS(EI): 592 (M+H,I100%) Example Preparation of I 2 -Benzyloxvcarbonvlarino4methyl-pentvl f (S)-4-methvl-2-F (2guniie2croy)aio-etnvaio--x-z~nu I 2 -Benzyloxycarbonylamino-4-methyl-pentyl)..4.((S )-2-terrbutoxycarbonylariinomethylpenoyaino)3hydroxyaepaium Following the procedure of Example 2h except substituting Cbz-leucinal for benzaldehyde the title compound was prepared: MS(EI) 577 2 -Amino- 4 -methy-pentanoylainino)- I -((S)-2-terr-benzylxycarbonylanino.4methyl-pentyl)-3-hydroxy-azepaniuin Following the procedure of Example 2i except substituting the compound of Example 10a the title compound was prepared: MS(EI) 477 I 2 -Benzyloxycarbonylarnino-4-methyl-pentyl).zb {(S)-4-inethyl-2-[(2- Following the procedure of Example 7a except substituting the compound of Example l~b the title compound was prepared: MS(EI) 632 1 2 -Benzyloxycarbonylanino-4-methyl..pentyl)..4- (S)-4-methyl-2-[(2quniie2croy)arn)petnyaio--x-zpnu Following the procedure of Example I i except substituting the compound of Example 10c the title compound was prepared: 'H NMR (CDCI,): 8 1.0 m, 12H), 1.5-2.1( m, I OH), 71 2.2 m, 4H), 2.9 (in, I 3.4 M, 2H). 3.7 (in, I1H), 4.7 m, 2H1), 5.2 (in, 3H), 7.2 (in, 4H), 7.5 (mn, 1H), 7.6 (mn, IH), 7.7 (in, 1H), 8.1 (in, lH), 8.2 (mn, 8.5 (in, 18); MS(EI): 630 100%) Example I I Preparation of I -Benzovl-4-((S)-2-(benzor I 3 1dioxole-carbonylaino-4-methv..

pentanoviainino)-3-oxo-azepanium I Bnol4(S--etbtxcroyann--ehlpnaolmn)3 hydroxy-azepanium Following the procedure of Example 9a except substituting benzoic acid for 3-(2pyridyl)phenyl acetic acid the title compound was prepared: MS(EI) 448(M+H+).

4 2 -Arrino-4-methyl-pentanoylaruno)- I -benzoyl-3-hydroxy-azepanium Following the procedure of Example I except substituting the compound of Example I I a the title compound was prepared: MS(EI) 348 I -Benzoyl-4-((S)-2-(benzo[ I 3 ]dioxole-carbonylaino)-4-inethyl-pentanoylamino)- 3 -hydroxy-azepanium Following the procedure of Example 2j except substituting the compound of Example I1I b for the compound of Example 2j and piperonylic acid for 2-naphthoic acid the title compound was prepared: MS(EI) 496 1.-Benzoyl-4-((S)-2-(benzo[ I 3 ]dioxole-carbonylanino)-4iethylpenanoylmno)-3 oxo-azepanium Following the procedure of Example li except substituting the compound of Example I I c the title compound was prepared: 'H NMvR (CDC 3 8 1.0 mn, 68), 1.5-2.1( in, 5H), 2.2 (in, 2H), 2.9 (mn. 18H), 3.2 (dd, 18H). 3.4 (in, 18H), 3.7 (mn, 2H), 4.7 (im, 18H), 5.2 m, I 6.0 2H), 7.2-8.4 (mn, 8H); MS(EI): 494 Example I2 Preparation of I -BenzoyI-4-((S)-2-(4-fluoro-benzovian.,no)4methyl-Rentanovlarmjno)-3 oxo-azepaniurn I -Benzoyl-4-((S)-2-(4-fluoro-benzoyarno)4-methyl-pentanoylarmino-3-hydroxyazepanium Following the procedure of Example 1 Ic except substituting 4-fluorobenzoic acid for piperonylic acid the title compound was prepared: MS(El) 470 I -Benzoyl-4-((S)-2-(4fluoro-benzoylan-jno)4methyl-pentanoylamino-3-oxoazepanium Following the procedure of Example 11 except substituting the compound of Example 12a the title compound was prepared: 'H NMR (CDCl):S10(m 6) m, 5H), 2.2 (in, 2H), 2.7 (in, IN), 3.0 (dd, 1iH). 3.6 (mn, 1H), 4.0 2H), 4.7 (in. lH), 5.2 7.2-8.4 (in, 9H); MS(EI): 468 (M+WF, 1 Example 13 Preparation of 3-Oxo-4-((S)-4-nethl-2- ([5-(2-moERpolino-4-yl-ethoxy)-benzofuran-2carbonyl Iamino I -pentanoviainino)- I -(4-inethvl-pentanoyl)-azepaniuin 4 2 -rn-butoxycarbo~nylarrino-4-methylpentnoylamino-3-hydroxy- 1 methyl-pentanoyl)-azepanium Following the procedure of Example 9a except substituting iso-caproic acid for 3- (2-pyridyl)phenyl acetic acid the title compound was- prepared: MS(EI) 442 4 2 -Ainino-4-methyl-pentanoylamino)-3-hydroxy- 1 -(4-methyl-pentanoyl)azepanium Following the procedure of Example 2i except substituting the compound of Example 13a. the title compound was prepared: MS(EI) 342 3-Hydroxy-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2carbonyllamino }-pentanoylamino)- I -(4-methyl-pentanoyl)-azepanium To a solution of the compound of Example I 3b (200 mg, 0.53 mmol) in dichioromethane was added EDC (Ill 0.58 mmol), HQBt (78 mg, 0.58 mrnol), TEA 11 m.L, 0.79 mmol) and 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid.

The reaction was stirred at room temperature until complete as indicated by TLC analysis.

Workup and column chromatography methanol:dichloromethane) provided 160 mg of the title compound: MS(EI) 615 3-Oxo-4-((S)-4-methyl-2- [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2carbonylijamino }-pentanoylamino)-lI-(4-methyl-pentanoyl)-azepanium Following the procedure of Example I i except substituting the compound of Example 13d the title compound was prepared: 'H NMR (CDC 3 5 1.0 ,12H), 1.5-2.1( m, 8H), 2.2 (in, 2H). 2.3 (in, 2.4-2.5 (in, 2H), 2.6 (mn 5H), 2.7 (in, 2H), 2.9 (in. 1H), 3.4 (in. 1H), 3.7 (mn, 4H), 4.1 (mn, 2H), 4.5-4.6 (mn, 2H), 5.2 m, 111), 7.2-8.4 (in, 4H): MS(EI): 613 (M+HW,l00%). The diastereoiners were separated-by preparative scale HPLC.

Lyophilisation of the eluents provided diastereomer I and diastereorner 2.

Example 14 Preparation of 3-Oxo-4-((S)-4-iethvl-2- f 5-(2-momRholino-4-vl-ethoxy)-benzofuran-2carbon vl Iamino I -pentanovi amino)- I -ben zenesulphonvl -azevanium 1 -Benzenesulphonyl-4-((S)-2-terr-butoxycarbonylamino-methyl-pentanoylainino)- 3-hydroxy-azepanium To a solution of the amine of Example 2cg (0.5 g,1.46 minol) in dichioromethane was added triethylamine (0.4 iL, 2.92 minol) followed by benzenesulphonyl chloride (0.28 inL. 2.18 rnunol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography methanol :dichloroinethane) provided 450 mg,. of the title compound: MS(EI) 484 4-((S)-2-Amino-methyl-pentanoylamino) I -benzenesulphonyl-3-hydroxyazepanium Following the procedure of Example 2i except substituting the compound of Example 14a the title compound was prepared: MS(EI) 384 3-Hydroxv-4-((S)-4-methyl-2- [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2carbonyllamino) -pentanoylamino)- I benzenesulphonyl-azepanium Following the procedure of Example 1 3c except substituting the compound of Example 14b the title compound was prepared: MS(EI) 657 3-Oxo-4-((S)-4-methyl-2- ((5-(2-morpholino-4-yl-ethoxy)-benzofurancarbonyl~amino -pentanoylamino)- I -benzenesulphonyl-azepanium Following, the procedure of Example I i except substituting the compound of Example 14c the title compound was prepared: 'H NMR (CDCI.): 8 1.0 m, 6H). 1.5-2.1 m, 5SH), 2.2 (in, 2H), 2.4 (in, I 2.7 (in, 4H), 2.8 (mn, 2H), 3.5 (mn, I 3.8 (mn. 4H), (mn, IH). 4.1 (in, 2H), 4.4 (in, 11-1), 4.5 (mn. IH),.4.7 (in, 11H), 5.1 (im, 7.0 (mn, 3H), 7.3 2H), 7.5 (in,3H), 7.7 (in.2H): MS(EI): 655 100%).

Analysis of the diastereorneric mixture by analytical HPLC (40:60 to 45:55

CH

3 CN:20 mm KHP0 4 (pH 7 buffer) 60 min. gradient 1 inL/iin.; inertsil ODS-3 column 4.6 x 250 mm; LUV detection at 215 nM) showed two peaks (Rt 44.6 mins. and 45.9 mins). The diastereomers were separated by preparative scale I-PLC (40:60 to 50:50

CH

3 CN: mm KHP0 4 (pH 7 buffer) gradient, 12 inlmin.. 60 mins: inertsil ODS-3 column 250 x 20 mm; LTV detection at 215- nM). Lyophilisation of the eluents provided diastereoiner I (anal. Rt 44.6 mins.) and diastereomer 2 (anal. Rt 45.9 mins).

Examvle Preparation of 4-((S)-4-Methvl-2-1 r5-(2-molRholino-4-vl-ethoxv)-benzofuran-2carbonyllami nolI-Rentanoylamino)-3-oxo-azepane- I-carboxyl ic acid phenylamide I -(3-Hydroxy- I -phenylcarbamoyl-azepan,-4-ylcarbamoyl)-3-methyl-butyl]carbamic acid tert-butyl ester To a solution of the amine of Example 2a (0.5 g,1.46 mmol) in dichloromethane mL) was added phenyl isocyanate (0.24 mL, 2.18 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography methanol:dichloromethane) provided 578 mg of the title compound: MS(EI) 463 (M+H 4 4-((S)-2-Amino-methyl-pentanoylamino)-3-hydroxy-azepane- I -carboxylic acid phenyl amide Following the procedure. of Example 2i except substituting the compound of Example 15a the title compound was prepared: MS(EI) 363 3-Hydroxy-4-((S)-4-Methyl-2- [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2carbonylI]amino) -pentanoylamino)-azepane- 1 -carboxylic acid phenylamide Following the procedure of Example 1 3c except substituting the compound of Example 15b the title compound was prepared: MS(EI) 636 4-((S)-4-Methyl-2- [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino pentanoylamino)-3-oxo-azepane-1I-carboxylic acid phenylamide Following the procedure of Example -li except substituting the compound of Example 15c the title compound was prepared: 'H NMR (CDCI): 8 1.0 m, 6H), 1.5-2.1 (in. 5H), 2.2 (in, 2H1), 2.7 (in, 4H), 3.0 (mn, 2H), 3.1 114), 3.8 (mn, 1H), 3.9 (mn, 4H), 4.2 (in, 1H), 4.3 (in, 2H), 4.9 (mn, 2H), 5.2 m, 11H), 7.2-8.4 (mn, 9H1): MS(EI): 634 (M+H',l0O%) Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH 3 CN:20 M KHP0 4 (pH 7 buffer) isocratic, I mL/iin.; inertsil ODS-3 column 4.6 x 250 mm: UV detection at 215 nM) showed two peaks (Rt 27.3 mins. and 30.1 mnins). The diastereomers were separated by preparative scale HPLC (40:60 to 50:50 CH- 3 CN: 20 M KHP0 4 (pH 7 buffer) gradient, 12 mJ.Umin., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaJ-C0 3 :ethyl acetate extraction provided diastereomer I (anal. Rt 27.3 mins.) and diastereomer 2 (anal. Rt 30.1 mins).

Example 16 Preparation of 5-( 2 -Morpholino.4-v-ethoxy)..benzofuran2.carboxlic acid -3-methyl- 1- 13-oxo- I-r 2 -(3-pvridin-2-vl-phenvl )acetvl 1-azepan-4-ylcarbamovl -butvl)amnide 5-( 2 -Morpholino-4-yl-ethoxy)-benzofura-2caboxylic acid ((S)-3-methyl-lI- {3hvdroxy- I 3 -pyridin-2.yl-phenyl)acetyuI-azepan4lcaramoyl)-butyl)amide Following the procedure of Example 13c except substituting the compound of Example. 9b the title compound was prepared: MS(EI) 712 5-( 2 -Morpholino-4-yl-ethoxy-benzofuran2carboxylic acid ((S)-3-methyl- I 3oxo- l-[ 2 3 -pyridin-2-yl-phenyl)acety1I-azepan-4.ylcarbmoyl)I-butyl)amide Following, the procedure of Example I i except substituting the compound of Example 16c the title compound was prepared: 'H NMR (CDCl): 1.0 m, 6H), 1.5-2.1 (in, 5H), 2.2 mn, 2H), 2.7 (in, 4H), 2.8 (in, 2H), 2.9 (in, lH), 3.5 (in, 1H), 3.7 (in, 4H), 3.9 (in, 3H), 4.3 (in, 2H), 4.7 (mn. 2H), 5.4 mn, IH), 7.2-8.0 (in, 13H), 8.5 (in, IH); MS(EI): 710 (M-iW,l100%)

MS(EI).

Analysis of the diastereomneric mixture by analytical I-PLC (40:60 CH 3 CN:20 M KHP0 4 (pH 7 buffer) isocratic, 1 mnLmin.; inertsil ODS-3 column 4.6 x 250 mm; IJV detection at 215 nM) showed two peaks (Rt 33.9 mins. and 37.9 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 45:55 CH 3 CN: 20 M K.HP0 4 (pH 7 buffer) gradient, 12 mL/mrin., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHCO 3 :ethyl acetate extraction provided diastereoiner 1: MS(EI) 710.3 (anal. Rt 33.9 mins.) and diastereoiner 2: MS(EI) 710.3 (M-i-H1) (anal. Rt 37.9 mins).

Example 17 Preparation of 5-(2-Morpholino-4-vl-ethoxy)-benzofuran-2-carboxvlic acid f(S)-I -(benzovl- 3-oxo-azepan-4-vicarbamoyl)-3-methvi-butyllarmide 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid 1 -(benzoyl-3hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyllarnide Following the procedure of Example I 3c except substituting the compound of Example I l b the title compound was prepared: MS(EI) 621 (M+H 4 5-(2-Morphol ino-4-yl-ethoxy)-benzofuran-2-carboxylic acid 1-(benzoyl-3oxo-azepan-4-ylcarbamoyl )-3-methyl-butyljamide Following the procedure of Example li except substituting the compound of Example 17a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 m, 6H), 1.5-2.1( m, 2;2 (mn, 2H), 2.7 (in, 4H), 2.9 (mn, 2H), 3.0 I 3.7' (mn, 5H), 4.0 (in, I 4. 1 (in, 2H), 4.7 (in, 2H). 5.4 m, IH), 7.2-8.4 (in, I lH): MS(ED): 619 (M+H'.100%) Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 55:45

CH

3 CN:20 mM KHP0 4 (pH 7 buffer).30 mn. gradient, I in~min.; inertsil ODS-3 column 4.6 x 250 mm; LTV detection at 215 nM) showed two peaks (Rt mins. 13.5 and 17.6 inins). The diastereomers were separated by preparative scale HPLC (40:60 to 45:55

CH-

3 CN: mM KHP0 4 (pH17 buffer) 60 min. gradient, 15 inLimin.. 60 mins, inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHCO 3 :ethyl acetate extraction provided diastereomer I (anal. Rt 13.5 inins.) and diastereoiner 2 (anal. Rt 17.6 mins).

Example 18 Preparation of 5-(2-Pvrrolidin- I -vl-ethoxy)-benzofuran-2-carboxylic acid I benzenesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-methyl-butyllamide 5-(2-Pyrrolidin-1I-yi-ethoxy)-benzofuran-2-carboxylic acid Il(S)-I -benzenesuffonyl- 3 -hydroxy-azepan-4-ylcarbarnoyl)-3-methyl-butyl]amide Following the procedure of Example 14c except substituting 5-(2-pyrrolidin- Il-ylethy loxy)-benzofuran-2-carboxylic acid for 5-(2-morphoiLin-4-yl-ethyloxy)benzofuiran-2carboxylic acid the title compound was prepared: MS(EI) 641 5-( 2 -Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid 1 -(benzoyl-3oxo-azepan-4-ylcarbamoyl)-3-methyl-butyllamide Following the procedure of Example I i except substituting the compound of Example 18a the title compound was prepared: 'H NMR (CDCl): 8 1.0 m, 6H), 1.5-2.1( m, 9H), 2.2 m, 2H), 2.5 IH), 2.7 (mn, 4H), 3.0 (in, 2H), 3.4 (in, I 4.0 IlH), 4.1 (in. 2H), 4.5 (in, 1H), 4.6 1H), 5.0 mn, lH), 7.2-8.4 (mn, I I MS(EI): 639 (M+H,I100%) Example 19 Preparation of 5-(2-Piperidin- I -vl-ethoxv)-benzofuran-2-carboxylic acid 141I benzenesulfonvl-3-oxo-azepan-4-vlcarbamoyl)-3-methyl-butvl lamide 5-(2-Piperidin- 1-yl-ethoxy)-benzofuran-2-carboxylic acid -benzenesulfonyl-3oxo-azepan-4-ylcarbanoyl)-3-nethyl-butyllanide Following the procedure of Example 14c except substituting 5-(2-piperidin- I-ylethyloxy)-benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2carboxylic acid the title compound was prepared: MS(EI) 655 5-(2-Piperidin-1I-yl-ethoxy)-benzofuran-2-carboxylic acid 1-(1 -benzenesulfonyl-3hydroxy-azepan4-ylcarbaroy)3methyl..butyljamide Following the procedure of Example I i except substituting the compound of Example 18a the title compound was prepared: 'H NMR (CDCI 3 8 1.0 (in, 6H), 1.5-2.1( m, IllIH), 2.2 (in, 2H), 2.5 (mn, 5H), 2.7 (in, 2H), 3.5 (in, INH), 4.0 (in, I 4.1 (in, 2H), (in, INH), 4.6 (in, IlH), 5.0 (mn, I 7.2-8.4 (in, I I MS(EI): 653 (M+H,l100%) Example Preparation of 5-(2-Morpholino-4-y-ethoxv).benzofuran..xcarboxvlic acid ((S)-3-nethvl- 1-1 3-oxo- l-r 2 3 -Dvridin-2-vl-phenvl)ethyl -azepan-4-vcarbamovl 1-butvl)amide 5-( 2 -morpholin-4-yl-ethyloxy)benzofuran.2-carboxylic acid methoxy methyl amide To a solution of 3-(2-pyridyl)phenyl acetic acid (lg) in dichioroinethane was added N, O-diinethylhydroxylamine hydrochloride (0.92 triethylainine (1.3 HOBt (0.96 g) and EDC (1.1I The reaction wasstirred until.complete.- Workupand -column chromatography (40% ethyl acetate:hexanes provided 1. 1 gof the title compound: MS(EI) 257 5-( 2 -inorpholin-4-yl-ethyloxy)benzofura72carbaldehyde To a solution of 5-( 2 -morpholin..4-yl-ethyloxy)benzofuran2carboxylic acid methoxy methyl amide (0.2 g)of Example 20a in THIF was added LAN (2.0 ml, of a 1 M solution in THF). The reaction was stirred until complete consumption of the starting material. Workup gave 160 mg of the title compound.

{3-hydroxy- I-[ 2 3 -pyridin-2-yl-phenyl)-ethyl-azepan.4ylcarbamoyl }-3-inethylbutyl)-carban-ic acid tenr butyl ester Following the general procedure of Example 2g except substituting 5-(2morpbolin- 4 -y-ethyloxy)benzofran2caraldehyde for benzaldehyde the title compound was prepared: MS(EI) 525 (S)-2-Amino-4-methyl-pentanoic acid- I 3-hydroxy- I -[2-(3-pyridin-2-yl-phenyl)-ethyljazepan-4-yl 1-amide Following the procedure of Example 21 except substituting the compound of Example 20c the title compound was prepared.

5-( 2 -Morpholino-4-y-ethoxy)-benzofuran.2carboxylic acid ((S)-3-methyl- 1 f3hydroxy-- I-[ 2 3 -pyridin-2-yl-phenyl)ethyl I-azepan-4-ylcarbamoyI -butyl)axnide Following the procedure of Example 13c except substituting the compound of Example 20d the title compound was prepared.

5-( 2 -Morpholino-4-yl-ethoxy)-benzofuran-2carboxylic acid ((S)-3-methvl-1I-1{3-oxyl-[ 2 3 -pyridin- 2 -yl-phenyl)ethyl)-azepan.4.ylcarbamoyl }-butyl)amide Following the procedure of Example I i except substituting the compound of Example 20e the title compound was prepared: 'H NMR (CDCI,): 6 1.0 mn, 6H), 1.5-2.1( in, 5H), 2.2 (in, 2H), 2.7 (in, 4H), 2.8 (mn. 6H), 3.1 (in, I 3.3 (mn, I 3.5 (in, iIH), 3.7 (in, 4H), 4.2 (mn, 3H), 4.6 (in, 1H), 5.2 in, 1H), 7.2-8.4 (in, 13H), 8.6 (in, I MS(EI): 696 The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoeiner; MS(EI): 696 100%), and the slower eluting diastereomer; MS(EI): 696 100%).

Example 21 Preparation of .Naphthlene-2-carboxylic acid ((S)-3-methyl- I-f 3-oxo-lI- T2-(3-pyridin-2-vl- Rhenvl)ethyll-azepan-4..vlcajibaiovl)I-butvl)ainide Naphthlene-2-carboxylic acid ((S)-3-methyl- I- {3-hydroxy- I- [2-(3-pyridin-2-ylphenyl)ethyl)-azepan..4-ylcarbamoyI }-butyl)axnide Following the procedure of Example 20f except substituting 2-naphthoic acid for 2 -morpholin-4-yl-ethyloxy)benzofuran-2carboxylic acid the title compound was prepared: MS(EI) 579 Naphthlene-2-carboxylic acid ((S)-3-methyl- I 3-oxo- 1 -[2-(3-pyridin-2-yIphenyl)ethyll-azepan-4-ylcarbamoyl }-butyl)ainide Following the procedure of Example I i except substituting the compound of Example 2 1b the title compound was prepared: 'H NMR (CDCI 3 8 1.0 (im, 6H), 1.5-2.1( mn, 614), 2.2 (mn, 2H), 2.9 (in, 4H), 3.0 (mn, I 3.4 I 3.5 (mn, I 4.7 m, I1H), (in. I 6.8-7.2 (in, 6H4), 7.3 (in, I 7.5 (in, 2H), 7.9 (in. 614), 8.2 IJH), 8.7 (in, lH): MS(EI):577 Examnle 22 Preparation of I H-Indole-2-carboxylic acid (MS-3-methyl- I -f 3-oxo- I -r2-(3-nvridin-2-ylv~henvl )ethyl 1-azepan-4-vlcarbainovli -butyllainide )-3-methyl- I j 3-hydroxy- I 2 -(3-pyridin-2-yl-phenyl)ethyl]-azepan.4ylcarbamoyl )-butyl)amide Following the procedure of Example 20f except substituting I H-indole-2carboxylic acid for 5-(2-inorpholin-4-yl-ethyloxy)benzofuran~-2-carboxyljc acid the title compound was prepared: MS(EI) 568 ((S)-3-methyl- I I 3-oxo- I -[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan4ylcarbamnoyl }-butyl)ainide Following the procedure of Example I I except substituting the compound of Example 22b the title compound was prepared: 'H NMR (CDCI,): 8 1.0 2.1 m, 5H), 2.2 (mn, 2H), 2.9 (in, 4H), 3.0 (mn, 1H), 3.4 1H). 3.5 (mn, IH), 4.7 (im, 1H), 5.0 mn, 1H), 6.8-7.2 (in, 6H), 7.0-7.9 (mn, 12H), 8.7 (mn, 1H), 9.5 (mn, IH): MS(EI): 566 (M+H',100%) Example 23 Preparation of I H-lndole-2-carboxvlic acid f 1 -benzenesulfonvl-3-oxo-azepan-4vlcarbamovl)-3-methvl-butyllamide 1 H-Indole-2-carboxylic acid 1-(1 -benzenesulfonyl-3-hydroxy-azepan-4vi carbarnoyl )-3-methyl-butyljaxnide Following the procedure of Example 2j except substituting the compound of Example 14b and substituting I1N-indole-2-carboxylic acid for naphthoic acid the title compound was prepared: MS(EI) 527 I H-Indole-2-carboxylic acid I-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3methyl-butyllamide Following the procedure of Example 1i except substituting the compound of Example 23b the title compound was prepared: 'H NMR (CDCI,): 8 1.0 m, 6H), 1.5-2.1( 2.2 (in, 2H), 2.5 (mn, 1LH), 3.5 (dd, IlH). 3.9 (in, INH). 4.5 (dd. 2H), 4.7 (mn, I H), m, IlH), 7.2 -7.6 (in, I OH). 9.5 I MS(EI): 525 Example 24 Preparation of Benzofuran-2-carboxvlic acid f(S)-I -benzenesulfonvl-3-oxo-azepan-4vlcarbamovl )-3-inethvl-butvllarn de Benzofuran-2-carboxylic acid 1--benzenesulfonyl-3-hydroxy-azepan-4ylcarbamoyl)-3-methyl-butyl~amride Following the procedure of Example 23a except substituting benzofuran-2carboxylic acid for iN-indole 2-carboxylic acid the title compound was prepared: MS(EI) 528 Benzofuran-2-carboxylic acid -benzenesulfonyl-3-oxo-azepan-4ylcarbainoyl)-3-inethyl-butyl]amide Following the procedure of Example. Ii except substituting the compound of Example 24b the title compound was prepared: 'N NMR (CDCI,): 8 1.0 mn, 6H), 1.5-2.1( m, 5H), 2.2 (in. 2H), 2.6 I1H), 3.5 I1H). 4.1 (mn, I 4.7 5.0 1 in 7.2- 7.2 (in, I OH).

Example Preparation of Benzofuiran-2-carboxvlic acid f(S)-3-methvl- 1-C3-oxo-] 2-(3-pyridin-2-vlphenvl)ethvl1-azepan..4-vlcarbainoyI 1-burvl~ainide Benzofuran-2-carboxylic acid [(S)-3-methyl.-{ 3-hydroxy-l1-[? 2 -(3-pyi-idin-2-ylphenyl)ethyl]-azepan.4-ylcarbainoyl -butyl)amnide Following the procedure of Example 20e except substituting, benzofuran-2carboxylic acid for 5-( 2 -inorpholin-4-y-ethyloxy)benzofura2croxylic the-title compound was prepared: MS(EI) 569 Benzofuran-2-carboxylic acid [(S)-3-inethyl-1-{ 3 -oxo-1-[2-(3-pyridin-2-yl.

phenyl )ethylj-azepan-4-yicarbainoyl)}-butyl)aniide Following the procedure of Example I i except substituting the compound of Example 25b the title compound was prepared: NMvR (CDCI.): 8 1.0 (in, 6H), 1.5-2. 1 (in. 5H), 2.2 (in, 2H), 2.7 (mn, 5H), 3.0 (mn, IH). 3.3 (in, 11H), 3.5 (in, 1H), 4.7 IH). 5.2 (in. 114), 7.2-7.7 (in, 14H), 8.7 (in. IH): MS(EI): 567 (M+W',I00%) The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 656 100%), and the slower eluting diastereoiner;

MS(EI):

656 Example 26 Preparation of 5-(2-MolRholino-4-yl-ethoxy) enzofuran.2-carboxylic acid f(S)-3-nethvl-]I- (3-oxo- 1-nhenethvl-azepan-4-vlcarbamoyv11butvI lamide, Following the procedures of Examples 20c-f except substituting phenylacetaldehyde for 5-2mrhln4y-tyoy~ezfrn2cradhd of Example 20c the title compound was prepared: 'H NMR (CDC1,): 8 1.0 mn, 6H), 1.5-2.1 m, 5H). 2.2 mn, 2H), 2.4 (in, 1H), 2.6 2.7 (in. 6H), 3.0 (in, 111), 3.3 (dd, IH), I 3.7 m, 4H). 4.2 (in, 2H), 4.7 (m,1IH), 5.0 mIH), 7.2-7.2 (mn, I I1H); MS(EI): 619 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer:, MS(EI): 619 and the slower eluting diasrereomer; MS(EI): 619 Example 27 Preparation of Naphthylene-2-carboxylic acid f(S)-3-inethvl- 1-(3-oxo- I-phenethyl-azepan- 4-vlcarbamovil-butvl lamide Following the procedures of Examples 2h-k except substituting phenylacetaldehyde for benzaldehyde of Example 2h the title compound was prepared: 'H NMR (CDCI,): 8 6H), 1.5-2.1 5H), 2.2 2H), 2.4 (in, IH), 2.7 (mn, 4H), 3.0 (mn, IH), 3.7 1I), 3.5 11H), 4.7 IH), 5.1 1H), 6.9 -7.2 (in, 7.5 (in. 2H), 7.9 (in, 4H) 8.4 (mn. IH); MS(EI): 500 (M+HW,100%) Example 28 Preparation of Benzofuran-2-carboxvlic acid f(S)-3-methyl- 1-f3-oxo- 1-(Rvridine-2sulfonvl )-azep~an-4-ylcarbamovll-butyIl amide (S)-2-Ainino-4-methyl-pentanoic acid [3-hydroxy-l1-(pyridine-2-sulfonyl)-azepan-4-yI]amide Following the procedure of Examples 14a-b except substituting 2-pyridinesulfonyl chloride for benzenesulfonyl chloride of Example 14a the title compound was prepared: MS(EI) 385 Benzofuran-2-carboxylic acid (S)-3-inethyl-l1-[3-hydroxy- 1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl) }amide To a solution of (S)-2-ainino-4-methyl-pentanoic acid [3-hydroxy- 1 -(pyridine-2sulfonyl)-azepan-4-yi]-ainide of Example 28a (0.15 g) in dichioromethane was added TEA (0.11 mL), HOBt (49 mg), EDC (69 mng) and benzofuran-2-carboxylic acid (58 mng). The reaction was stirred until complete. Workup and 'column chromatography methanol:ethyl acetate) provided the title compound: MS(EI) 529 Benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-lI-(pyridine-2-sulfonyl)-azepan-4yicarbamoyll-butyl }amide Following the procedure of Example I i except substituting the compound of Example 28b the title compound was prepared: 'H NMR (CDC 1 8 L'O m, 6H), 1.5-2.1( m, 5H), 2.2 (in, 2H), 2.7 (in, 11.1), 3.7 (dd, I 4.0 (mn, I 4.7 (mn, 2H), 5.0 (in, INH), 7.2- 7.3 (in, 3H), 7.4 (mn, 4H), 7.6 (in, 8.0 (in, 2H), 8.7 (mn, 1H); MS(EI): 527 (M+H, The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoeiner; 'HNMR: 8 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.7 IlH), 3.7 (d, I H) 4.0 I 4.7 (mn, 2H), 5.0 (in, I 7.2-7.3 (in, 3H), 7.4 (in, 7.6 (mn, IlH), (in. 2H), 8.7 (mn, INH): MS(EI): 527 100%). and the slower eluting diastereomer; 'HNMR: 5 1.0 (in, 6H), 1.5-2.1 (mn, 5N), 2.2 (in, 2H), 2.7 1H), 3.7 IN); 4.0 IH), 4.7 (in, 2H), 5.0 (in, IH), 7.2-7.3 (mn, 3H4), 7.4 (in, 4H), 7.6 (in, 8.0. (in, 2H), 8.7. (in, INH); MS(EI): 527 100%).

Example 29 Preparation of Naphthvlene-2-carboxylic acid f(S)-3-inethvl- I -43-oxo- I -(pvridine-2sulfonvl )-azeyan-4-vlcarbainovll-butvI lainide Naphthylene-2-carboxylic- acid, f (S)-3-inethyl- I [3-hydroxy-l1-(pyridine-2-sulfonyl)azepan-4-ylcarbainoyl]-butyl lam.-ide Fol lowing the procedure of Example 28b except substituting 2-naphthoic acid -for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 539 Naphthylene-2-carboxylic acid (S)-3-rnethyl-l1-[3-oxo-l1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl )amide Following the procedure of Example Ii except substituting the compound of Example 29a the title compound was prepared: 'H NMR (CDClj:- 8 1.0 in, 6H), 1.5-2.1( in, 5N). 2.2 m, 2H1). 2.7 (mn, INH), 3.7 (dd, INH). 4.0 (in, INH), 4.7 mn, 2H), 5.0 in, IlH), 7.2-7.3 (in. 2H), 7.5 (mn, 3H), 7.9 (mn, 68), 8.3 (in, 1H), 8.4 (mn, I MS(EI): 537 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 537 100%), and the slower eluting diastereomer; MS(EI): 537 100%).

Example Preparation of 5-(2-Morpholino-4-vl-ethoxv)-benzofuran-2-carboxvlic acid- (S)-3-inethYl- 1 -[3-oxo- I -(pvridine-2-sulfonvl)-azepan-4-vlcarbamovl 1-butvlI amide 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid (S)-3-methyl-l1-[3hydroxy-lI-(pyridine-2-sulfonyl)-azepan-4-ylcarbanioyl 1-butyl amide Following the procedure of Example 1 3c except substituting the compound of Example 28a the title compound was prepared: MS(EI) 658 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-oxo- I- (pyridine-2-sulfonyl)-azepan-4-ylcarbanoyl]-butyl }arnide Following the procedure of Example I i except substituting the compound of Example 29a the title compound was prepared: 'H NMR (CDCI 3 5 1.0 (mn, 6H), 1.5-2.1 mn, 2.2 (in, 28), 2.7 (mn, 18H), 3.5 mn, 4H). 3.7 (mn. 6H), 4.1 (mn, IlH), 4.5 (in. 2H), 4.7 (in, 2H), 5.0 (in, IH), 7.2-7.3 (mn, 48), 7.4 (in. 2H), 8.0 (mn, 2H), 8.7 (in, IH), 8.7 (in, 18H); MS(EI): 656 (M+HW,100%).

The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoeiner; MS(EI): 656 100%), and the slower eluting diastereorner; MS(EI): 656 100%).

Example 31 Preparation of 4-((S)-4-Methvl-2-fr(5-(2-morpholino-4vl-ethoxv)-benzofuran2caonv1.

amino) -ventanovamino)-3-oxo.azeyane-1I-carboxylic acid tert-butyl ester 4 2 -Arrino4-methyl-pentanoyarno)3hydroxy-azepane- I -carboxylic acid tert-butyl ester To a solution of the compound of Example If (0.89 g) in ethyl acetate:methanol mL of a 2:1 mixture was added 10 Pd/C and a balloon of hydrogen gas was attached.

The reaction was stirred until complete by TLC analysis whereupon it was filtered and concentrated to provide the title compound (0.57 a).

4-((S)-4-Methyl-2-f 2 -morpholino-4-vl-ethoxy)-benzofuran-2.carbonyl]-.

amnino }-pentanoylanmino)-3-hydroxy-azepane 1 -carboxylic acid tert-butyl ester Following the procedure of Example 1 3c except substituting the compound of Example 3] a the title compound was prepared.

4-((S)-4-Methyl-2- 2 -morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl 1amino I -pentanoylamino)-3-oxo-azepane- 1 -carboxylic acid tert-butyl ester Following the procedure of Example I i except substituting the compound of Example 3 1b, the title compound was prepared: NMR (CDC1 3 8 1.0 (in, 6H), 1.5 (in, 9H), 1.7 (in, 5H), 2.2 (in, 2H), 2.5 (mn, 5H), 2.7 (mn, 2H), 3.5 (in, 1H). 3.8 (in, 4H), 4.1 (in, 3H). 4.2 (in. IH), 4.7 (in, 2H), 5.0 (in, IH), 7.2-7.3 (in, MS(EI): 615 Exaznple 32 Preparation of 4-((S)-4-Methvl-2-i 2 -inorr~holino-4-yl-ethoxv)-benzofuran-2.carboxvlic acid (S)-3-nethvl-]I-( 3 -oxo-azepan-4-vlcarbamovll-butyl Iainide To a solution of the compound of Example 31c in THF (5 mL) was added IM HCI in ether (5 mL). Th reaction was stirred overnight whereupon it was concentrated to provide the title compound: 'H NMR (CDC1.): 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.7 (in, 4H), 3.2 (dd, 3H). 3.7 (in, 6H), 4.0 (in, 4.5 (in, 2H), 5.0 (mn, 7.2-7.3 (mn, 6H); MS(EI): 515 Example 33 Preparation of 4-Methvl-ventanoic acid 13-oxo- I -f2-(3-p~vridin-2-vi-phenvl-acetvI I-azepan- 4-vI 1-arnide 3 -Hydroxy-4-(4-methyl-pentanoylamino)-azepane- I -carboxylic acid tert-buryl ester Following, the procedure of Example If except substituting 4-methylpentanoic acid for Cbz-leucine the title compound was prepared: MS(EI) 329 4-Methyl pentanoic acid (3-hydroxy-azepan-4-vl )-amyide To a solution of the compound of Example 33a (200 ing) in methanol (5 inL) was added 4M HCI dioxane (5 The reaction was stirred until complete whereupon it was concentrated to provide the title compoun&(132 mng): MS(EI) 229 4-Methyl-pentanoic acid f 3-hydroxy- 1 2 3 -pyridin-2-yl-phenyl-acetyl]-azepan-4-yl

I

arnidle Following the procedure of Example 9a except substituting the compound of Example 33b the title compound was prepared: MS(EI) 424 4-Methyl-pentanoic acid 3-oxo-lI-[ 2 3 -pyridin-2-y-phenyl-acetyl-azepan4-yl amnide Following, the procedure of Example 11 except substituting the compound of Example 33c the title compound was prepared: 1 H NR (CDCI, 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.7 (in, IH), 2.9 (mn, IH), 3.5 (in, 1H), 3.7 (in, 2H), 4.1 (in, 3H), 4.6 (mn, 1H), 5.3 (mn, IH), 7.2-8.0 (mn, 7H), 8.7 (mn. IH); MS(EI): 422 (M+HW,100%).- Example 34 Preparation of ((S)-3-Methyl- 1-f~3-oxo- I-[2-(3-pvridin-2-vl-phenvl)-acetyl 1-azepan-4vlcarbamovi -butvl )-naphthvlene-2-methyl-carbanmic acid tert-butyl ester 4 -Methyl-2-naphthaene-2-ylmethy)ino-pentanoic acid methyl ester To a solution of leucine methyl ester hydrochloride (0.5 g)in dichlormethane was added triethylarnine (0.9 ruL), 2-naphthaldehyde (0.43 g)and sodium triacetoxyborohydride (0.87 g.The mixture was stirred until complete. Workup and column chromatography ethyl acetate:dichloromethane) provided 0.4 gof the title compound: MS(EI) 286 2 -(terr-Butoxycarbonyl-naphthlen-2ymethyl.rino)..-metyhyI pentanoic acid methyl ester To a solution of the compound of Example 34a (0.35 g)in dichloromethane was added di-tert-butyldicarbonate (0.29 g;After 2 hours. at room temperature triethylam-ine was added and the reaction heated to reflux. Upon completion, the reaction was concentrated and the residue was purified by column chromatography hexane:dichloromethane) to provide 0. 17 gof the title compound: MS(EI) 386 2 -(ter-Butoxycarbonylnaphthen2ylmethyl-amino)-4methyI pentanoic acid To a solution of the compound of Example 34b 17 g) in THF:methanol (15 mL of a 2:1 solution) was added LiOH (0.0 19 The reaction was stirred overnight whereupon it was concentrated to provide the title compound 4 -[(S)-terrbutoxycarbony-naphthyen2ylmethyl-amino)-4-methylpentanoylarmino]-3-hydroxy-azepane I -carboxylic acid benzyl ester To a sloution of the compound of Example 2e 11 g)in dichloromethane was added EDC (0.08 HOBt (0.06 g) and the acid of Example 34C. Upon completion the reaction was worked up and chromatographed methanol:dichloromethane) to provide the title compound 18 MS (EI) 618 I -Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-naphthylen-2-ylmethy carbamic acid teri-butyl ester To a solution of the compound of Example 34d 17 a) in ethyl acerate:methanol 10 mL) was added 10% Pd/C. A balloon of hydrogen was attached and the reaction was stirred until complete consumption of the starting material. The reaction was filtered and concentrated to provide the title compound 1lOg): MS(ED) 484 )-3-Methyl- 1-f 3-hydroxy-l1-[2-(3-pyridin-2-yl-phenyl)-acetyl ]-azepan-4ylcarbamoyl -butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester Following the procedure of Example 9a except substituting the compound of Example 34e the title compound was prepared: MS(EI) 679 )-3-Methyl- I1- 3-oxo- 1 -[2-(3-pyridin-2-yl-phenyl)-acetyfl-azepan-4ylcarbamnoyl -butyl)-naphthvlene-2-methyl-carbaniic acid terr-buty I ester Following the procedure of Example I i except substituting the compound of Example 34f the title compound was prepared: 'H NMR (CDCL.): 5 1.0 (in, 1.5-2.2 (in. 16H-), 2.7 (in, lH), 3.2 (in, 1H). 3.7 (in, 3H). 4.0 (in, lH), 4.7 (in, 2H), 5.2 (mn, III), 7.2-7.3 (in. 16H), 8.6 (in, III); MS(EI): 677 Example Preparation of (S)-4-Methvl-2-[(naphthven-2-vinethvl )-aininol-pentenoic acid r3-oxo- 14-2- (3-pvridin-2-vI-Rhenvl)-acetvll-azepan.4-vI I-amide To a solution of the compound of Example 34g (20 mg) in THF was added 1 M HCI in ether. The reaction was stirred until complete consumption of the starting material whereupon it was concentrated to provide the title compound: 'H NMR (CDCl 3 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.5 (in, IH), 3.5 (in, 5H). 4.0 (mn, 1H), 4.7 (mn, 2H), 4.4 (mn, I 7.2-8.0 (in, 16H), 8.7 (in, INH); MS(EI): 577 100%) Exam~le 36 Preparation of 4-f 2-(2-f (S)-3-Methyl- 1-f 3-oxo- I-(Rvidine-2-sulfonvl )-azepan-4ylcarbamovll-butvlcarbamovl I-benzofuran-5-vloxv)-ethvl 1-Piperazine-1l-carboxylic acid terr-butvl ester {(S)-3-Methyl- 1 -[3-hydroxy- 1 -(pyidine-2-sulfonyl)-azepan-4-ylcarbamovlbutylcarbamoyl }-benzofuran-5-yloxy)-ethyll-piperazine- I -carboxylic acid tert-butyl ester To a solution of the compound of Example 28a 15 g)in dichloromethane was added EDC (0.07 HO~t (0.05 triethylamine (0.1 11 mL) and 4-[2-(2-carboxyacid terr-butyl ester. The reaction was stirred until complete. Work up and column chromatography (10 methanol:*ethyl acetate) provided the title compound 10 MS(EI) 757 (S)-3-Methyl- I -[3-oxo- 1 -(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]- I-carboxylic acid tert-butyl ester Following the procedure of Example I i except substituting the compound of Example 36a, the title compound was prepared: 'H NMR 8 1.0 (in, 6H), 1.5-2.1 (in, 14H), 2.2 (mn, 2H), 2.7 (in, 1H), 3.0 (mn, 2H), 3.5 (in, 4H). 3.7 (in, 6H), 4.1 (in, 1H), (mn, 2H), 4.7 (in, 2H), 5.0 1H), 7.0-7.6 (in, 6H), 8.0 (in, 2H), 8.7 (in, MS(EI): 755 (M+WT,100%) Example 37 Preparation of 5-(2-Piperizin-lI-vI-ethoxv)-benzofuran-2-carboxvlic acid I (S)-3-methvl- I- [3-oxo-lI-(pyridine-2-sulfonv')-azepan-4-vcarbanovl)-3-butll..aride The compound of Example 36b (0.02 a) was dissolved in 4M HCI in dioxane. The reaction was stirred until complete whereupon it was concentrated to provide the title compound: 'H NMR (CDCI 3 8 1. 0 (in. 6H), 1.5- 1.7 (in, 7H), 2.7 (mn, 211), 3.3 2H1), (in, I 3.8 (in, 5H1), 4.1 (mn, 3H), 4.7 (in, 4H), 5.0 (in, I1H), 7.0-7.3 (in, 2H1), 7.4 (in, 6H), 8.0 (in, 2H), 8.7 lH): MS(EI): 655 100%) Eample 38 Preparation of 5-( 2 -Cvclohexvl-ethoxy)-benzofuiran-2-arboxylic acid f (S)-3-methvl- 143oxo- I -(pvridine-2-sulfonvl )-azepan-4-vlcarbamovll-butvIl amide 5-( 2 -Cyclohexyl-ethoxy)-benzofuran-2.carboxylic acid (S)-3-methyl- 1 hydroxv- I -(pyridine- 2 -sulfonyl)-azepan-4ylcarbamoyl 1-butyl }amide' to a solution of the compound of Example 28a (0.15 a) in dichioromethane was added EDC (0.07 1-OBt (0.05 triethylamrine 11 mL) and 5-(2-cyclohexyl-ethoxy)benzofuran carboxylic acid (0.01 The reaction was stirred until complete by TLC analysis. Workup and column chromatography (100% ethyl acetate) provided the title compound 15 MS(EI) 655 5-( 2 -Cvclohexyl-ethoxy)-benzofuran-2ca5 0 xyijc acid I (S)-3-methvl- 1-f 3-oxo- 1 (pyridine- 2 -sulfonyl)-azepan4ylcarbamoyl]-butyl amide Following the procedure of Example I i except substituting the compound of Example 38a the title compound was prepared: MS(EI) 653 Example 39 Preparation of 2 -Cvclohexyl-ethoxv)-benzofuran-2-carboxylic acid ((S)-3-methvl- I -f 3: oxo-I I-F 2 3 -Dvridin-2-vl-Dhenvl)ethvll-azepan-4..vlcaamovJ )-butyl)amide 5-( 2 -Cyclohexyl-ethoxy)-benzofuran-2carboxylic acid ((S)-3-methyl- I1- {3 3hydroxy-1- 2 3 -pyridin-2-yl-phenyl)ethyl]-azepan4-ylcarbamoyl )-butyl)amide To a solution of the compound of Example 20d 15 g) in dichioromethane was added EDC (0.06 ),HOBt (0.04 triethylamine (0.14 mL) and 5-(2-cyclohexyl-ethoxy)benzofuran carboxylic acid (0.09 The reaction was stirred until complete by TLC analysis. Workup and column chromatography (100% ethyl acetate) provided the title compound 10 MS(EI) 695 5-( 2 -Cyclohexyl-ethoxy)-benzofuran-2.carboxylic acid ((S)-3-methyl-l1-{ 3-oxo- 1- 2 3 -pyridin-2-yl-phenyl)ethyl]..azepan.4ylcarbamoyl }-bucyl)axnide Following the procedure of Example I i except substituting the compound of Example 39a the title compound was prepared: 'H NMR (CDCIj: 5 1.0 (in. 6H), 1.5-2.1 (mn, 18H), 2.2 (mn. 2H), 2.7 (mn, 3H), 3.2 (in, I 3.5 (mn, INH). 3.9 (mn, 4.7 (mn, 2H), (in, I 7.2-7.3 (in, 13H), 8.7 (mn, I MS(EJ): 693 100%) Example Preparation of 4-r2-(2- I (S)-3-Methvl- I-[3-oxo- I-(3-pvridin-2-vl-phenyl )-ethyI fazepan-4vlcarbamoyl -butvlcarbamoyl)I-benzofuran-5-vloxv).ethvl 1-inerazine- I-carboxylic acid tert-butvI ester {(S)-3-Methyl- I-[3-hydroxy- I-(3i-pyridin-2-yl-phenyl)-ethyl [azepan-4ylcarbainoylj-butylcarbamoyl }-benzofuran-5-yloxy)-ethyl 1-piperazine- I-carboxylic acid tert-butyl ester To a solution of the compound of Example 20d 15 g)in dichioromethane was added EDC (0.06 HOBt (0.04 ).triethylainine 14 m.L) and 4-[2-(2-carboxy- 1 -carboxylic acid tert-butyl ester 12 The reaction was stirred until complete by TLC analysis. Workup and column chromatography methanol:ethyl acetate) provided the title compound (0.09 MS(EI) 797 {(S)-3-Methyl-1- [3-oxo- I-( 3 -pyridin-2-yl-phenyl).cthyI [azepan-4ylcarbamoyl]- butylcarbainoyl)}-benzofuran-5-yloxy)-ethyll-piperazine-i -carboxylic acid rerr-butyl ester Following the procedure of Example I i except substituting the compound of Example 40a the title compound was prepared: MS(EI) 795.9 Example 41 Preparation of 5-(2-piperizin- I -vl-ethoxv)-benzofuran-2-carboxylic acid )-3-inethyl- I- 1 3-oxo- I -r2-(3-pvridin-2-vl-phenvl )ethyl ]-azepan-4-vlcarbamoyI I-butyl )amide Following the procedure of Example 37 except substituting the compound of Example 40b the title compound was prepared: 'H NMR (CDCI 1 6 1 '0 (in, 1.5-2.1 (mn, 5H1), 2.2 2H), 3.4-3.6 (in, 19H), 4.5 (in, IH), 4.7 (mn, 2H), 5.0 (mn, 1H), 7.2 (in, I H).9 7.4 (in, I 7.5 (mn, 2H), 7.7 (in, 2H), 7.8 (in. IH), 8.J (mn. 2H), 8.4 (in, I 8.7 (in, 111); MS(EI): 695 Example 42 Preparation of 4 -Methvl-2--(methvl-naphthalen-2-vlmethvl-amjnO)2entanoic acid [3 oxo- I-(pvridine-2-sulphonvl )-azep~an-4-vl 1-affnide 4 2 -(rerr-Butoxycarbonyl-inethyl-aniino)-4-inethyl-pentanoy lamino]-3hydroxy-azepane-] -carboxylic acid benzyl ester To a solution of the compound of Example 2e (0.35 g)in dichloroinethane was added N-methyl-N-Boc-leucine (0.36 g.HOBt (0.2 g) and EDC.(0.28 g.The reaction-was stirred until complete. Workup and column chromatography methanol:dichloromethane) provided 0.6 gof the title compound: MS(EI) 492 3 -Hydroxy-azepan.4-ylcarbamoyl)-3-inethyl-butyly-methyl.carbamic acid ie'rr-butyl ester To a solution of the compound of Example 42a (0.6 in methanol:ethyl acetate (10:20 inL) was added 10% Pd/C and a balloon of hydrogen was attached. The reaction was stirred overnight whereupon it was filtered and concentrated to provide 0.50 g of the title: MS(EI) 358 (M+H 4 1-[3-Hydroxy-l1-(pynidine-2-sulfonyl)-azepan-4-ylcarbainoyl]-3-methyl-butyl

I-

inethyl-carbainic acid tert-butyl ester To a solution of the compound of Example 42b (0.2 g)in dichioroinethane was added triethylam-ine (0.16 nil-) and 2-pyridinesulfonyl chloride (0.15 The reaction was stirred until complete. Workup and columrn chromatography methanol:ethyl acetate) provided the title compound (0.23 MS(EI) 499 (S)-4-Methyl-2-methylamino-pentanoic acid [3-hydroxy-1I-(2-pyridine-2-sulfonyl)azepan-4-yl]-amide To a solution of the compound of Example 42c (0.23 g) in methanol (3.0 mL) was added 4M HCl in dioxane (3.0 mL). The reaction was stirred until complete.

Concentration provided the title compound: MS(E 399 (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-hydroxy-1I- (pyridine-2-sulphonyl)-azepan-4-yi)-amide To a solution of the compound of Example 42d (0.05 g)in dichloromethane was added triethylamine (0.07 mL), 2-naphthaldehyde (0.05 g)and sodium triacetoxyborohydride 11 The reaction was stirred until complete. Workcup and column chromatography methanol ethyl acetate) provided the title compound (0.03 g): MS(EI) 539 (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-oxo- 1- (pyridine-2-sulphonyl)-azepan-4-yl]-arride Following the procedure of Example I I except substituting the compound of.

Example 42e the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in, 6H1), 1.5-2.1 (mn, 511), 2.2 (in, 5H), 2.6 (in, I1H), 3.3 (mn. I 3.7 (in, 2H), 4.1 (in, IlH), 4.7 (in, I1H), 5.2 (in. 111), 7.2-8.0 (in, 1011), 8.7 (in, MS(EI): 537 Example 43 Preparation of (S)-4-Methyl-2-(inethyl-naphthalen-2-vlmethvl-anino~pentanoic acid 13oxo-1I-F2-(3-pvridin-2-vl-phenvl)-acetyll-azepan-4-vI I -aride I1- 3-Hydroxy- I -[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl inethyl-butyl)-methyl-carbainic acid tert-butyl ester To a solution of the compound of Example 42b (0.25 g)was added 3-(2pyridyl)phenyl acetic acid 16 ),HOBt 12 g0 and EDC 15 The reaction was stirred until complete. Workup and column chromatography methanoLethyl acetate) provided the title compound (0.24 MS(EI) 553 4 -Methyl-2-methylamino-pentanoic acid 3-hydroxy- I -f2-(3-pyridin-2-ylphenyl )-acetyl ]-azepan-4-yl )-amide Following the procedure of Example 42d except substituting the compound of Example 43a the title compound was produced: MS(EI) 453 4 -Methyl-2-(methyl-naphthalen-2ylmethyl-arnino)pentanoic acid 3-oxo- i 3 '-pyridin-2-vl-phenyl)-acetyll-azepan-4-yl }-amide Following the procedures of Examples 42e-f except substituting the compound of Example 43b the title compound was produced: 'H NMR (CDCI.): 5 1.0 (in. 6H), 1.5-2.1 (in. 5H). 2.2 (mn, 5H), 3.0 (in, I 3.5 (in, I 3.7 (in. 4H), 4.1 (in. I 4.7 (mn. 2H). 5.2 (mn. IH). 7.2-8.0 (in, 15H), 8.7 (in, IH): MS(EI): 591 Example Preparation-of 5-( 2 -MorRpholino-4-vi-ethoxv)-benzofuran2carboxvlic acid methyl met hy I- 1- 13-oxo- I r 2 3 -pvridin 2 -vl-phenvI)acetvl Iazepan..4-ycarbamovi -butv Daide 5-( 2 -Morpholino-4-yl-ethoxy)-benzofuran.2-carboxylic acid methyl ((S)-3-methyl- 1- (3-h ydroxy- l-[ 2 3 -pyridin- 2 -yJ-phenyl)acetyl]-azepan-4ylcarbamoyl)}-butyl)ainide To a solution of the compound of Example 43b 1 g) in dichloroinethane was added 5-( 2 -morpholin4 v-ethyloxy)benzofuran-2carboxylic acid (0.06 HOBt (0.026 TEA (0.07 inL) and EDC (0.04 The reaction was stirred until complete. Workup and chromatography (20% methanol :ethyl acetate) provided the title compound (0.07 g): MS(EI) 726 5-( 2 -Morpholino-4-yl-ethoxy)-benzofuran-2carboxylic acid methyl ((S)-3-methyl- 1-f 3-oxo- l-[ 2 3 -pyridin-2-yl-phenyl)acetyl-azepan.4i.ylcarbanoyl)}-butyl)arnide Following the procedure of Example li except substituting the compound- of Example 44a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in. 6H), 1.5-2.1 (mn. 5H), 2.2 (in, 5H), 2.7 (in, 4H), 2.8 (in, 2H), 2.9 (mn, IH), 3.5 (in, 3.7 4H), 3.9 (in, 3H), 4.3 (in, 2H), 4.7 (in, 2H), 5.4 (in, lH). 7.2-8.0 (mn, 12H), 8.5 (in, I1H); MS(EI): 724 Example Preparation of Benzofuran-2-carboxylic acid methyl f(S)-3-methvl I -r3-oxo- I -(1nvridine-2sulIfonv i)-azepan-4-vlcarbamovl )-3-methvl-butvl -arnide Benzofuran-2-carboxylic acid methyl f (S)-3-inethyl- I-[3-hydroxy- I-(pyridine-2su Ifonyl )-azepan-4-ylcarbamoyl)-3-methyl-butyl]-arnide To a solution of the compound of Example 42d 1 g) in dichioromethane was added benzofuran-2-carboxylic acid (0.04 Z-0; TEA (excess), HOBt (0.03 and EDC (0.04 The reaction was stirred until complete. Workup and column chromatography methanol: dichloromethane) provided the title compound (0.04 MS(EI) 542.9 Benzofuran-2-carboxyl ic acid methyl- ((S)-3-inethyl-lI-1j3-oxo- I-(pyridine-2sul fonvl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide Following the procedure of Example 11i except substituting the compound of.

Example 45a the title compound was prepared: 'H NMvR (CDCL): 5 1.0 (in, 6H), 1.5-2.1 (in. 8H), 2.2 (in, 2H), 2.7 (mn. 1H), 3.0 (mn, IH), 3.7 (in, 2H), 4.1 (in, IH), 4.7 (in, IH), 5.2 (mn. I 7.2-8.0 (in, 8H), 8.7 (in, I MS(EI): 541 Example 46 Pieparation of 2.2.2-Trifluoro-N-((S)-3-inethvl- I- 3-oxo-lI-r2-(3-p)yridin-2-yl-p~henvl)acetvi l-azepan-4-vicarbainovl I -butvl)-N-naphthvlen-2-vlinethvl-acetainide (S)-4-Methyl-2-[naphthylen-2-ylinethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoic acid methyl ester To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added potassium carbonate (catalytic amount), and trifluoroacetic acid (0.44 ).The reaction was stirred at room temperature for 1 hour whereupon it was concentrated and chromatographed (20% ethyl acetate:hexane.) to provide the title compound.

(S--ehl2[ahhln2ymty-2,,-rfur-ctl-nio-etni acid lithium salt To a solution of the compound of Example 46a (0.49 g)in THF:water (3 mL of a 2:1 solution) was added lithium hydroxide monohydrate (0.06 ).The reaction was stirred overnight whereupon it was concentrated to provide the title compound (0.46 MS(EJ) 366 (M+HW).

3-I-ydroxy-4. 4 -methyl-2-[naphthylen-2-ylmethyl-(2.2,2-trifluoro.acetyl)aminol-pentanoylamino)}-azepane- I-carboxylic acid benzyl ester To a solution of the compound of Example 2e (0.29 in dichioromethane was added EDC (0.24 HOBt 16 a) and the compound of Example 46b (0.46 The reaction was stirred until complete. Workup and column chromatography. methanol:ethyI acetate) provided the title compound (0.25 MS(EI) 614 2,2,2-Trifluoro-N-[(S)- 1 -(3-hydroxy-azepan-ylcarbarnoyl)-3-methvl-butyl].Nnaphthlen-2-ylmethyl-acetamide Following the procedure of Example 42b except substituting the compound of Example 46c the title compound was produced: MS(EI) 480 2,2-,2--Trifluoro-N-((S)-3-methyl-lI- {3-hydroxy- I-[2-(3-pyridin-2-y-l-phenyl)-acetyl]azepan-4-ylcarbamoyl }-butyl)-N-naphthylen-2-ylmethyl-acetamjde Following the procedure of Example 43a except substituting the compound of Example 46d the title compound was produced: MS(EI) 675 2,2,2-Trifluoro-N-((S)-3-rnethvl- 1- {3-oxo- I-[2-(3-pyridin-2-yl-phenyl)-acetyl]azepan-4-ylcarbamoyl )-butyl)-N-naphthylen-2-ylmethyl-acetan-ide Following the procedure of Example I i except substituting the compound of Example 46e the title compound was prepared: 'H NMR (CDCI 3 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.7 (in, 1H), 3.2 (in, IH), 3.7 (in, 3H), 4.1 (mn, IH), 4.5 (in, 4.7 (mn, 5.2 (in, I 7.2-8.0 (in, 14H), 8.7 (in, I MS(El): 673 100%) 99..

ExAmple 47 Preparation of 4 -f(S)-(Methanesulphonyl-naphthylen-2-Xlmethyl-apano)-methyl.

p-entanovlaminol-3-oxo-azepane- 1-carboxylic acid benzyl ester 2 -(Methanesulfonyl-naphthylen-2ylmethylarino)4methyl-pentanoic acid methyl ester To a solution of the compound of Example 34a (0.5 gY) in dichioromethane was added triethylarnine (0.36 mL) and methansulfonyl chloride 16 The reaction was stirred at room temperature until complete. Workup, and chromatography (20% ethyl acetate:hexanes) provided the title compound (0.24 g).

2 -(Methanesulfonyl-naphthylen-2-ylmethyl-amino)-4-~methyl-pentanoic acid lithium salt Following the procedure of Example 46b except substituting the compound of Example 47a the, -title Pompound was. prepared. MS(EI) .348 4- [(S)-(Methanesulphonyl-naphthylen-2-ylmethyl..an-no)-4-methylpentanoylamnino]-3-hydroxy-azepane-lI-carboxylic acid benzyl ester Following the procedure of Ex ample 46c except substituting the compound of Example 47b the title compound was prepared: MS(EI) 596 4 -[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-anmno)-...methylpentanoylarnino]-3-.oxo-azepane- 1 -carboxylic acid benzyl ester Following the procedure of Example Ii except substituting the compound of Example 47c the title compound was prepared:.H HNMR (CDCI): 1.0 (mn, 6H), 1.5-2.1 (in. 5H1), 2.2 (in, 5H1), 3.0 (mn, I1H), 3.5 (in. IH), 4.1 (in, 11H), 4.5 (mn, 4.7 (in, I 5.2 (mn, 3H), 7.2-8.0 (mn, 13H); MS(EI): 596 100%) Example 48 Preparation of Ouinoline-2-carboxvlic acid I(S )-3-rethvi- I -f3-oxo- I -(pyridine-2-sulfonyh)agepan-4-vicarbamnovll-butvl )amide Quinoline-2-carboxylic acid J (S)-3-methyl- l-[3-hydroxy- I -(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl )amide Following the procedure of Example 28b except substituting quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 Quinoline-2-carboxyli c acid (S)-3-methyl-lI-[3-oxo- I-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyfl-butyl }amide Following the procedure of Example 1i except substituting the compound of Example 48a the title compound was prepared: 'H NMR (CDCIJ: 5 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.7 (in, I 3.7 I 4.1 (in, I 4.7 (mn, 2H), 5.0 (in, I1H), 7.0-7.2 (mn, I1H), 7.3 (in, IlH), 7.5 (in, I 7.7 (in, I 7.8 (in, 3H), 8.1 (in. IH), 8.3 (in, 2H), 8.7 (in. 2H): MS(EI): 538 100%) The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoeiner; MS(EI): 538 100%). and the slower eluting diastereomer: MS(EI): 538 (M+H.I100%).

Example 49 Preparation of uinoline-8-carboxvl'c acid I (S Y3-methvl- I -f3-oxo- I -(pyridine-2-sulfonvl)agepan-4-vlcarbainovil-butyl I amnide Quinoline-8-carboxylic acid (S)-3-rnethyl-l1-[3-hydroxy-l1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl }amide Following the procedure of Example 28b except substitutingc quinoline-8-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540

(M+H

4 W. Quirioline-8-carboxylic acid (S)-3-methyl-l1 .3-oxo- I-(pyridine-2-sulfonyl)azepan-4-ylcarbarnoyll-butyl Jamide Following the procedure of Example I i except substituting the compound of Example 49a the title compound was prepared: 'H NMR 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.7 (in. I 3.7 I 4.0 (in, I 4.7 (mn, 2H), 5 .0 (in, I1H), (in, 4H), 7.6 (in, I1H, 7.7 (mn, 3H), 8.2 (in, I 8.6 (in, I 8.7 (in, I1H), 8.9 (in, 1I-H) MS(EI): 538 Example Preparation of Ouinoline-6-carboxvlic acid f (S)-3-inethvl- I -F3-oxo- I -(pvridine-2-sulfonyl)azepan-4-vlcarbamovi I-butvl ~arnide Quinoline-6-carboxyhlc acid f (S)-3-methyl- I -[3-hydroxy- I -(pyidine-2-sulfonyI)azepan-4-ylcarbamoyly-butyl Jainide Following the procedure of Example '28b~except-substituting quinoline-6-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 Quinoline-6-carboxylic acid (S)-3-methyl- l-[3-oxo-lI-(pyridine-2-sulfonyl)azepan-4-ylcarbainoyl]-butyl )amide Following the procedure of Example li except substituting the compound of Example 50a the title compound was prepared: 'H NMR (CDCL): 861.0 (in, 6H), 1.5-2.1 (mn. 5H), 2.2 (in, 2H) 2.7 (in, I1H), 3.7 I 4.0 (mn, I1H), 4.7 (in. 2H), 5.0 (in, INH), 2H), 7.5 (in, 2H), 7.9 (mn, 2H), 8.0 (mn, 3H), 8.2 (in, lH). 8.7 1W., 8.9 (mn, 1H); MS(EI): 538 The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 100%), and the slower eluting diastereomer; MS(EI): 538 (M+1-rl00%).

Example 51 Preparation of Ouinoline-4-carboxvlic acid I (S)-3-methvl- 3-oxo- I-(pvridine-2-sulfonvl)azepan-4-ylcarbamovll-butvl Jamide Quinoline-4-carboxylic acid (S)-3-methyl- I-[3-hydroxy-] -(pyridine-2-sulfonyl)azepan-4-ylcarbamoyly-butyl I amide Following the procedure of Example 28b except substituting quinoline-4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 Quinoline-4-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine- 2-sulfonyl)azepan-4-ylcarbamoyI]-butyl) amide Following the procedure of Example I i except substituting the compound of Example 5 1a the title compound was prepared: 'H NMR (CDCI,): 5 1.0 (in, 6H), 1.5-2.1 5H), 2.2 (in. 2H), 2.7 (mn, I1H), 3.7 I 4.0 (in, I1H-), 4.7 (in, 2H), 5.0 (in, IRH). 7.2 (in. 7.4 (in. 2H), 7.5 (mn, I1H), 7.7 (mn, IlH), 7.9 (mn, 2H), 8.0 (in. I 8.2 (mn, I1H), 8.7 (in, I 8. 9 (mn, I MS(EI): 538 (M+H',100%) The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 100%), and the slower eluting diastereomer;

MS(EI):

538 100%).

Example 52 Preparation of Ouinoline-3-carboxvlic aid I(S)-3-methvl-r-3-oxo- I-(p~yridine-2-sulfonyl)- Azean-4-vlcarbamovlI-butvl I amide Quinoline-3-carboxylic acid (S)-3-methyl- 1-13-hydroxy-lI-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyll-butyl )arnide Following the procedure of Example 28b except substituting quinoline-3-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 Quinoline-3-carboxylic acid (S)-3-methyil1-[3-oxo- I-(pyridine-2-sulfonyl)azepan-4-ylcarbamoylj-butyl Jamide Following the procedure of Example I i except substituting the compound of Example 52a the title compound was prepared: 'H NMR (CDCI,): 5 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in. 2H), 2.7 (in, I 3.7 I 4.0 (in, I 4.7 (in, 2W). 5.0 (mn, I 7.2 (m 2H), 7.5 (mn, 18H), 7.6 (mn, I 7.7-7.9 (in, 4H), 8.1 (in, I 8.5 (in, I 8.6 (in, 111). 9.3 (in, 111); MS(EI): 538 The diastereomeric mixture was separated by HPLC to provide the fast-er eltitingdiastereoeiner; MS(EI): 538 100%), and the slower eluting diastereomer; MS(EI): 538 Example 53 Preparation of Isoguinoline-3-carboxvlic acid f (S)-3-methvl- I -r3-oxo- I -(pvridine-)sul fonvi )-azepan-4-vlcarbamovl 1-butvl I amide Isoquinoline-3-carboxylic acid (S)-3-inethyl-lI-[3-hydroxy-lI-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl )amide Following the procedure of Example 28b except substituting isoquinoline-3carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 Isoquinoline-3-carboxylic acid (S)-3-inethyi-lI-[3-oxo-l1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl }amide Following the procedure. of Example I i except substituting the compound of Example 53a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 211), 2.7 (in, I 3.7 I 4.0 (mn, 1 4.7 (in, 2H), 5.0 (in, I (in, IH). 7.5 (in, 18), 7.7 (in, 2H), 7.9 (mn, 411), 8.7 (in, 3H1), 9.2 (mn, 1W); MS(EI): 538 100%) Example 54 Preparation of Isoguinoline- I -carboxylic acid f(S)-3-methvl- I -[3-oxo- I -(Rvridine-2sul fonvl )-azernan-4-vlcarbamovl 1-butvl) amnide Isoquinoline- I-carboxylic acid (S)-3-methyl-lI-[3-hydroxy-l1-(pyridine-2-sulfonyl)azepan-4-ylcarbarnoylj-buty amide Following the procedure of Example 28b except substituting isoquinoline-lIcarboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 Isoquinoline- I-carboxylic acid (S)-3-methyl- I-[3-oxo-lI-(pyridine-2-sulfonyl)azepan-4-vlcarbarnoyl]-buty amide Following the procedure of Example I i except substituting the compound of Example 54a the title compound was prepared: 'H NMR (CDCL): 5 1.0 (in. 6H), 1.5-2.1 (mn. 5 2.2 (in. 2H), 2.7 (in, I 3.7 I 4.0 (mn; I 4.7 (in, 2H), 5.0 (in, I 7. 3 (in. 7.5 (mn. 11H), 7.7-8.0 (in, 6H), 8.7 (mn, 3H). 9.5 lH); MS(EI): 538 The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 537 and the slower eluting diastereorner; MS(EI): 537 100%).

Example Prep~aration of Quinoxaline-2-carboxylic acid I (S)-3-methvi- I -[3-oxo- I -(pyridine-2sulfonvl)-azep~an-4-vlcarbamoyfl-butyI I amnide Quinoxaline-2-carboxylic acid (S)-3-inethyl- I-[3-hydroxy-l1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyllainide Following the procedure of Example 28b except substituting quinoxaline-2carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 541 Quinoxaline-2-carboxylic acid (S)-3-methyl-1 -[3-oxo- I -(pyridine-2-sulfonyl)azepan-4-ylcarbainoyl]-butyl amide Following the procedure of Example I I except, substituting the compound of Example 55a the title compound was prepared: 'H NMR (CDCI,): 8 1'.0 (in, 6H), 1.5-2.1 (mn. 5N), 2.2 (in, 2H), 2.7 (mn, INH), 3.7 I 4.0 (in, INH), 4.7 (in, 2H), 5.0 (mn, I 7.2 (in, 2H), 7.5 (in, 1H), 7.7 (mn, 3H), 8.2 (in. 2H), 8.3 (in, 111), 8.7 (in, IN), 9.5 (mn, I MS(EI): 539 Example 56 Preparation of Benzofblthiophene-2-carboxylic acid f (S )-3-methyl- I -[3-oxo- I -(pyridine-2sulfonvl)-azepan-4-vlcarbamovll-butvl amide Benzo[b]thiophene-2-carboxylic acid I (S)-3-rnethyl- I -[3-hydroxy- I -(pyridirie-2sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide Following the procedure of Example 28b-except substituting benzo[b~thiophene-;2-; carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 545 Benzo[b]thiophene-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine-2sulfonyl)-azepan-4-ylcarbainoyl]-butyl }amide Following the procedure of Example 1i except substituting the compound of Example 56a the title compound was prepared: 'H NMR (CDCI 3 8 1.0 (mn, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.7 (mn, INH), 3.7 IlH). 4.0 (in. INH), 4.7 (in, 2H1), 5.0 (in, I1H), 6.8- 7.2 (in, IN), 7.5 (in, 3H1), 8.0 (mn, 6H), 8.7 1H); MS(EI): 543 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoerner;'HNMR (CDC1 3 8 1.0 (in, 6H), 1.5-2.2 (in, 6H), 2.7 (in, 1H), 3.8 (in,Mi).

4.1 (in, 1H), 4.7 (mn, 2H), 5.1 (in, lH), 7.4-8.0 (in, 8H), 8.7 (in, 111); MS(EI): 543 100%), and the slower eluting diastereomer; 1.0 (in, 6H), 1.5-2.2 (mn, 6H), 2.7 (mn, IN), 3.8 4.1 (in, 1H), 4.7 (in, 2H), 5.1 (in. iN), 7.4-8.0 (in, 8H), 8.7 (in, IH); MS(EI): 543 (M+HW,100%)..

Example 57 Preparation of I .8-Naphthvridine-2-carboxylic acid f(S)-3-methvi- I -[3-oxo- 1 -(pvridine-2su Ifonvl )-azepan-4-ylcarbamovl -butyl Iamide I ,-Naphthyridine-2-carboxylic acid (S)-3-methyl- I -[3-hydroxy- 1 -(pyridine-2sulfonyl)-azepan-4-ylcarbamoylj-butyl) ami de Following the procedure of Example 28b except substituting I ,8-naphthyridine-2carboxylic acid for benzofuran-2-ca-boxylic acid the title compound was prepared: MS(ED) 541 I .8-Naphthyi-idine-2-carboxylic acid (S)-3-methyl-] -[3-oxo- I-(pyridine-2sulfonyl)-azepan-4-ylcarbamoylj-butyl }arnide Following the procedure of Example 11 except substituting the compound of Example 57a the title compound was prepared: 'H NMR (CDCL): 5. 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.7 (mn, I 3.7 11H). 4.0 (mn, 4.7(m, 2H), -5.0 (in, 1 7.2 (in. IH), 7.6 (in. 2H), 7.9 (in, 2H), 8.3 (in, lH), 8.4 (in, 2H), 8.5 (in, 2H). 9.2 I H); MS(EI): 539 100%) Example 58 Preparation of 1 H-lndole-2-carboxylic acid I (S)-3-inethvl-] -[3-oxo- I-(Rvfidine-2-sulfonvl)azepan-4-vlcarbamovll-butvl }amide 1 H-lndole-2-carboxylic acid I(S )73-iethyl-lI-[3-hydroxy-lI-(pyridine-2-sulfonyl)azepan-4-ylcarbarnoyl]-butvl )ami~de Following the procedure of Example 28b except substituting IH-indole-2carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 528 1 H-Indole-2-carboxylic acid (S)-3-methvl- l-113-oxo-1 -(pyridine-2-sulfonyl)azepan-4-ylcarbainoyl]-butyl Iami~de Following the procedure of Example I i except substitutingc- the compound of Example 58a the title compound was prepared: H NMR (CDCL 4 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H). 2.2 (mn, 2.7 (mn, I1H), 3.7 I1H). 4.0 I 4.7 (mn, 2H), 5.0 (mn, I 6.8 (mn, I 7.1 (in, I1H), 7.3 (mn, 3H), 7.4 (in, I 7.5 (mn, I 7.6 (in, I1H), 8.0 (mn, 2H-), 8.7 (mn, I 9.4 11H); MS(EI): 526 Example 59 Preparation of 5-Methoxybenzofuran-2-carboxvlic acid I(S)-3-methvl- I -[3-oxo- I -(pyridine- 2-sulfonvl)-azepan-4-vlcarbamovl 1-butyl I amide 5-Methoxybenzofuran-2-carboxylic acid (S)-3-methyl- I -[3-hydroxy- I -(pyridine-2sulfonyl)-azepan-4-ylcarbamoylj-butyl Jan-de Following the procedure of Example 28b except substituting 2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 559 5-Methoxybenzofuran-2-carboxylic acid I (S)-3-methyl- I -[3-oxo I -(pyridine-2sulfonyl)-azepan-4-ylcarbainoyl]-butyl amide Following the procedure of Example 1i except substituting the compound of Example 59a the title compound was prepared: 'H NMR (CDCl): 8 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (mn, 2H), 2.7 (in, 1H), 3.7 4H). 4.0 (mn, 1H), 4.7 (in, 5.0 (in. IH), (mn, 4H), 7.6 (mn, 3H), 8.0 (mn, 2H), 8.7 (mn, MS(EI): 557 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoeiner; 'HNMR (CDClj: 8 1.0 (mn. 6H), 1.5-2.1 5H), 2.2 (in, 2H), 2.7 I1H), 3.7 4H). 4.0 1H), 4.7 (mn, 2H), 5.0 IH), 7.0 4H), 7.6 (mn, 3H), 8.0 (mn, 2H), 8.7 I1H); MS(EI): 557 (MAT,I100%), and the slower eluting, diastereomer; MS(EI): 557 100%).

Example Preparation of 5-Bromo-furan-2-carboxylic acid f(S)-3-methvl- I -13-oxo- I -(tpvn'dine-2sulfonvl)-azepan-4-vlcarbamovll-butvilamide 5-Bromo-furan-2-carboxylic acid (S)-3-methyl- I -[3-hydroxy- I -(pyridine-2sulfonyl)-azepan-4-ylcarbamoylj-butyl }amide Following the procedure of Example 28b except substituting 5-bromo-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 558 5-Bromo-furan-2-carboxylic acid (S)-3-methyl. I-[3-oxo-l1-(pyridine-2-sulfonyl azepan-4-ylcarbamoyl]-butyl amride Following the procedure of Example I i except substituting the compound of Example 60a the title compound was prepared: 'H NMR (CDCL): 6 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (mn, 2H), 2.7 (in, IH), 3.7 lIi). 4.0 (mn, 4.7 (in, 2H), 5.0 (in, lH). (in, I 6.7 (mn, I1-H), 7.1 (in, 2H), 7.5 (in, I1H), 8.0 (mn, 2H), 8.7 (in, I MS(EI): 555- The diastereoinic mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 555 100%), and the slower eluting diastereomer; MS(EI): 555 100%).

Example 61 Preparation of Furan-2-carboxvljc ~acid I(S )-3-inethvl- -3:oxo- 1-(pvridine-2-sulfonyl)azevan-4-vlcarbamovil-butvi lainde Furan-2-carboxylic acid f (S)-3-methyl- I -[3-hydroxy- I -(pyridine-2-sulfonyl)azepan-4-ylcarbanoyl]-butyl jamnide Following the procedure of Example 28b except substituting 2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 479 Furan-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan4.

ylcarbamoyl]-butyl }amride Following the procedure of Example I i except substituting the compound of Example 61 a the title compound was prepared: '14 NMR (CDC]I 3 'S 1.0 (in, 6H), 1.5-2.1 (in, 5H4), 2.2 (in. 2H), 2.7 (in, I 3.7 I 4.0 (in, I1-H), 4.7 (mn, 2H), 5.0 (in, I (in, lH), 7.2 (in, 7.5 (mn, 2H4), 8.0 (in, 2H), 8.7 (in. I MS(EI): 477 Example 62 Preparation of 5-Nitro-furan-2-carboxvlic acid f(S )-3-ethvi- I 43-oxo- I -(vvridine-2su Ifonvl )-azepan-4-vlcarbamovl1-buty! anide 5-Nitro-furan-2-carboxyuic acid f (S)-3-methyl- I -[3-hydroxy- I -(pyridine-2sulfonyI)-azepan-4-ylcarbainoyly-butyl amnide Following the procedure of Example 28b except substituting 5-nitro-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI.) 524 5-Nitro-furan-2-carboxylic acid I(S)-3-inethyl- 1 -[3-oxo- I -(pyridine-2-sulfonyl)azepan-4-ylcarbainoyl]-butyl jainide Following the procedure of Example I i except substituting the compound of Example 62a the title compound was prepared: 'H NMR (CDCL): 8 1.0 (in, 614), 1.5-2.1 (in, 5H4), 2.2 (mn. 2.7 (in, 114), 3.7 11H). 4.0 (in, 1H), 4.7 (in, 214), 5.0 (in, 114), 7.2 (mn, 1H), 7.3 (mn, IH). 7.5 (mn, 1H), 7.9 (in, 2H4), 8.7 (mn, 114): MS(EI): 522 Example 63 Preparation of 5-( 4 -Nitro-phenyl)-furan-2-carboxvljc acid I (S)-3-methvi- I -f3-oxo- I (Dvridine-2-sulfonvl )-azepan-4-vicarbamoyll-butvI Jamide 5-(4-Nitro-phenyl)-furan-2..carboxylic acid (S)-3-inethyl-lI-[3-hydroxy-

I-

(pynidine- 2 -sulfonyl)-azepan-4ylcarbamoyll-butyl amide Following the procedure of Example 28b except substituting 5-(4-nitrophenyl)-2furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 600 5-( 4 -Nitro-phenyl)-furan-2-carboxylic acid (S)-3-inethvl- I -[3-oxo- I -(pyridine-2sulfonyl)-azepan-4-ylcarbamoyly-butyl) amnide Following the procedure of Example I i except substitutingL the compound of Example 63a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 6H), 1.5-2.] 5H). 2.2 (in, 2H), 2.7 (in, I1H), 3.7 I 4.0 IH), 4.7- (in. 2H),'5.0 (in, I1H), 6:.9 I 7.2 (in, I 7.5 (mn, 2H), 7.9-8.0 (mn, 4H), 8.5 I 8.6 (mn. 1IH): MS(EI): 598 Example 6 Preparation of 5-(3-Trifluoronethvl-phenvl '-furan-2-carboxvlic acid f (S}-3-methvl- I 4f3o, o-l-(pvridine-2-sulfonvfl.-azepan-4-vcarbamo)vlb-butvllainide I 3 -Trifluoromethyl-phenyl)-furan-2carboxylic acid f (S)-3-methyl. 1 -[3-hydroxy- I -(pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyly-butyl Jarrde Following the procedure of Example 28b except substituting 5-[3- (trifluoromethyl)phenyl]-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 623 5-( 3 -Trifluoromethyl-phenyl)-furan-2-carboxyic acid (S)-3-inethyl- I-[3-oxo- I- (pyridine- 2 -sulfonyl)-azepan4ylcarbamoyll-butvl )amide Following the procedure of Example I i except substituting the compound of Example 64a the title compound was prepared: ~H NMR (CDCI,): 5 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (mn, 2H), 2.7 (in. IH), 3.7 INH). 4.0 (nm. I 4.7 (mn, 2H), 5.0 (mn, I 7.1 (in, IN), 7.5 3H), 8.0 (mn, 4H) 8.7 (in, I MS(EI): 621 The diastereomeric mixture was separated by 1-PLC to provide the faster eluting diastereoemer; MS(EI): 621 (M+HW, 100%), and the slower elutingc diastereomer;

MS(EI):

621 Example Preparation of Tetrahvdro-furan.2.carboxvlic acid I(S )-3-methvyl--r3-oxo- 1-(p~vridine-2sul fonvi )-azepan-4-vcarbamovl -butvl Iamide Tetrahydro-furan-2carboxylic acid (S)-3-methyl-l1-[3-hydroxy-]I-(pyridine-2sulfonyl)-azepan..4.ylcarbamoyly-butyl ~aride Following the procedure of Example 28b except substituting tetrahydrofuran-2carboxylic acid for benzofuran-2-carboxylhc acid the title compound was prepared: MS(EI) 483 Tetrahydro-furan-2-carboxylic acid (S)-3-methyl- 1 -[3-oxo- I -(pyridine-2-sulfonyl)-' azepan.4-ylcarbamoyl)-butyl ainide Following the procedure of Example ij except, substituting the compound of Example 65a the title compound was prepared: 'H NMR (CDCI,): 6 1.0 (in, 6H), 1.5-2.2 (mn. 12H). 2.7 I 3.8 (mn, 3H). 4.0 (mn. I 4.5 (mn. 2H), 4.8 (in, I1H), 5.0 INH), (in. I 7.5 (in, I 7.9 (in, 2H), 8.7 (in, lH). MS(EI): 481 Example 66 Preparation of (S )-Methvl- 2 -(2-phenoxv-acetvlamino)-pentanoic acid 3 -oxo-(vridine-2sulfonyl )-azepan-4-vl -ainide 4 -Methyl-2-(2-phenoxy-acetyla nno)-pentanoic acid [3-hydroxy-(pyridine-2sulfonyl )-azepan-4-yl]-arnide Following the procedure of Example 28b except substituting phenoxvacetic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 519 4 -Methyl- 2 -(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2sulfonyl)-azepan-4-yl]-amide Following the procedure of Example I i except substituting the compound of Example 66a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in. 1.5-2.1 (inHS), 2.2 (in, 2H), 2.7 (in, I 3.7 IlH). 4.0 (in, I 4.5 (in, 3H), 4.7 (in, I 5.1 In 7.0 (in, 3H), 7.3 (in, 2H), 7.5 (mn, IlH), 7.9 (in, 2H), 8.6 (in, I MS 517 Example 67 Preparation of (S--2(-loOReov-ctimnl4mty-etni acid r3-oxo- (pvridine-2-sulfonvl)-azepan.4vl-arde 2 4 2 -(4-Fluoro-phenox y)acetylanmino 1-4meth yl-pen tanoic acid [3-hydroxy- (pyridine-2-sulfonyl)-azepan.4-yli]am.ide Following the procedure of Example 28b except substituting 4-fluorophenoxyacet'ic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ED) 537 2 2 4 -Fluoro-phenoxy)-acetylainlno]-4inethyl.pentanoic acid [3-oxo- (pyridine-2-sulfonyl)-azepan.4-yl]-amide Following the procedure of Example I i except substituting the compound of Example 67a the title compound was prepared: 'H NMR (CDC 1 8 1.0 (m.n 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.7 (in, I 3.6 18H). 4.0 (mn, I1H), 4.5 4.8 (mn, I1H), 5.1 (in, 181), 7.0 (in, 48), 7.5 (mn, 18), 7.9 (in, 2H), 8.6 (in. MS(EI): 535 Examtnie 68 Preparation of Benzofuran-2-carboxylic acid I(S)-3-methvi- I -r3-oxo- I -(Dyridine-1carbonvi )-azepan-4-vlcarbamoyl)-3- butyll-amide f(S)-I -[3-Hydroxy-lI-(pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-3-methyl-buyl carbamic acid terr-butyl ester To a solution of the compound of Example 2g (0.25 g) in dichioromethane was added picolinic acid (0.09g), EDC (0.14 g)and HOBt (0.10 The reaction was stirred until complete. Workup and column chromatography methanol:ethyl acetate) p rovided the title compound (0.35 g).

(S)-2-Am-ino-4-methylpentanoic acid [3-hydroxy-l1-(pyridine-2-carbonyl)-azepan-4yl 1-amide To a solution of the compound of Example 68a (0.34 g) in methanol (6 mL) was added 4M HCI in dioxane (6 Thereaction was.stirred -until-complete whereupon-it- was concentrated to provide the title compound (0.34 MS(EI) 349 Benzofuran-2-carboxylic acid )-3-methyl- 3-hydroxy- I-(pyridine-2-carbonyl)azepan-4-ylcarbamoyl)-3- butyll-amide Following, the procedure of Example 28b except substituting the compound of Example 68b the title compound was prepared: MS(EI) 493 Benzofuran-2-carboxylic acid (S)-3-methyl. 1 -3-oxo-l1-(pyridine-2-carbonyl)azepan-4-ylcarbamoyl)-3- butyll-amide Following the procedure of Example l1i- except substituting the compound of Example 68c the title compound was prepared: 'H NMR (CDCL): 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.5 (in, 1H), 3.7 (in, 111), 4.7 (mn, 4H), 5.0 (mn, 1H), 7.0-7.5 (mn, 8H), 8.2 (in, I1H); NIS(EI): 491 (M*X 100%).

Example 69 Preparation of Benzofuran-2-carboxyljc acid I(S'i-3-methvl- I- 43-oxo- 141( -oxy-2yridine-2carbon yl)-azenan-4-vlcarbamoyl butvl lanmide Following the procedures of Examples 68a-d except substituting, picolinic acid Noxide for picolinic acid of Example 68c the title compound was prepared: 'H NMR 8 1 .0 (mn, 6H), 1.5-2.1 (in, 5H), 2.2 (in. 2H), 2.5 (in, I 3.5 I 4.0 (in, I H), 4.7 (in, 3H), 5.5 (in, I 7.0 (in, 2H), 7.2-7.5 (mn, 7H), 8.1 (mn. 2H); MS(EI): 507 Example Preparation of 4 2 -rr-Butvlcarbonvlamino-.4-methvlpentanovlamino)-3oxoazeanel-carboxvlc acid benzvl ester Following the procedure of Example 92j. except substituting 4-((S)-2-rert- Butoxycarbonylamino-4-nethyl-pentanoylamino).3-hydroxyazepae I -carboxylic acid benzy I ester for benzofuran-2-carboxylic acid f(S)-I -[3-hydroxy-6,6-dirnethyl-lI-(pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyl 1-3-inethyl-butyl )-aLmide, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 476.2; 1 H-NMR (400 MHz, CDCI 3 -7.40-6.95(m, 7H), 5.25-4.60(mn, 4H), 4.40-4.06(mn, 2H). 3.70-3.58(t, 1H), 2.70-2.50(m, IH), 2.25-1.30(m. I 6H); and the second eluting diastereomer:, LOO0-0.85(d, 6H); and the second eluting diastereomer: MIS 476.

Example 71 Preparation of 5.6-Dimethoxvbenzofuran-2-carboxylic acid (S)-3-methvl- 1-f3-oxo-I1-(1 methyl-i H-imidazole-4-sulfonyl)-azepan4..vlcarbainovll-butvl Iainide -[3-H-ydroxy-lI-(1-methyl-i H-imidazole-2-sulfonyl)-azepan-4-ylcarbamoyl)I- 3-methyl-butyl 1-carbamic acid trn-butyl ester To a solution of the amnine of Example 2g in methylene chloride (SinI) was added pyridine (92gi1. l.l4minol) followed by 1-methylimidazole-4-sulfonvlchloride (0.1 12g, 0.623mmo1). The reaction was allowed to stir for 16h at room temperature. The solution was then washed with saturated aqueous NaHCO 3 water and brine. The product was purified by column chromatography (silica gel: mnethanol/ rnethylenechloride) to yield the title compound as a white solid 172g, 'HNMR (400MHz, CDCI,) 8 7.6 I H), 7.5 IH), 6.6 IH), 3.8 3H), 1.5 9H), I 6H); MS(ESI): 488.2 (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-lI-(1-methyl-I H-imidazolesulfonyl)-azepan-4-yl]-amide To a solution of the compound of Example 71 a (0.1 72-, 0.353mmo1) in minimal MeOH was added 4M HCI in dioxane (IlOmL) and stirred for 4h at room temperature. The reaction mixture was concentrated and azeotroped with toulene (2x's) to yield the title compound as an off white solid: MS(ESI): 388.2 5,6-Dirnethoxybenzofuran-2-carboxyli'c acid (S)-3-methyl-l1-[3-hydroxy- Imethyl-I H-inmidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Iami~de To a stirring solution of the compound of Example 7 1b 137-, 0.353 mmol), 5,6dimethoxybenzofuran-2-carboxylic acid (0.86g, 0. 388mmol), triethylamine (246 mL, 1.77 mmol) and Il-hydroxybenzotniazole (0.0 1. 0.O7Ommol) in DMF (5mL) was added l-(3dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.074-, 0.388mmo1). After stirring at room temperature for 1 6h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and saturated brine.

The organic layer was dried over NaS,S0, filtered and concentrated. The product was purified by column chromatography silica gel-, methanolldichloromethane) to yield the title compound as a white solid (0.088g-,42%): MS(ESI): 592.1 5,6-Dimethoxybenzofuran-2-carboxylic zcid (S)-3-methyl- I -[3-oxo- 1 -methyl- I H-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide Oxalyl chloride (52p.L, 0.596rmnol) chloride was cooled to To this was added dimethyl sulfoxide (I1064., 1 .49mmoI) in methylene chloride dropwise. After stirring for I 5min at the alcohol in methylene chloride was added slowly and allowed to stir for 1 h when EtN (41 6pL,2.98mmol) was added. The solution was then brought to room temperature and quenched with water and extracted into methylene chloride. The organic layer was separated and washed with brine, dried over MgSO 4 filtered and concentrated.

The product was purified by column chromatography (silica gel: methanoL/methylene chloride) to yield the title compound as white solid (0.068g, 'H NMR (400MHz, CDCl 2 56.8-7.6 (in, 14H), 4 12H), I 12H); MS(ESI): 590.1 Example 72 Preparation of Benzofuran-2-carboxylic acid I(S)-3-methyl- I-fl ]-(5-methyl- I H- 1,2.4lcriazole-3-sulfonyl )-3-oxo-azepan-4-ylcarbamovI 1-butyl I amide 4 2 -Arrino-4-methy-pentanoylarno)3hydroxyzepane- I -carboxylic acid benzyl ester To a stirring solution of the compound of Example 2f (3.5 g, 7.33 minol) in EtOAc mL) was added 4M HCI in dioxane (12.8 mL). The mixture was stirred for Ilh at room temperature. The reaction mixture was then concentrated and azeotroped with toluene (2x20 m.L) to yield the title compound as a pale yellow oil 3 .13g, 100%): MS(ESI) 378.4 (M+H)y 4- 2 -f (Benzofuran-2-carbonyl)-amino]-4-methyl-pentanovlaino }-3-hydroxyazepane-lI-carboxylic acid benzyl ester To a stirring, solution of the compound of Example 72a (3.1 3g, 7.57mmol), benzofuran-2-carboxylic acid (1.35g, 8.32minol), triethylamine 17m1, 8.25mmol) and 1 hydroxybenzotriazole (0.2g, 1 .48mmol) in DMF (3QinL) was added 1-(3dimethylaminopropyl)3-ethylcarbodimide hydrochloride (1.6g. 8.33mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over NaS,S. filtered and concentrated. The product was purified by column chromatography (silica gel; ethylacetate/dichloromethane) to yield the title-compound (3.72g, 'HNMR (400MHz, CDCI 3 6 6.8-7.7 (in, 12H), 5.35 2H), 1.0 6H): MS(ESI): 522 c. Benzofuran-2-carboxylic acid 3 -hydroxy-azepan.4-ylcarbaroyl)3methyl butyl-amnide To a solution the compound of Example 72b (2.6 g, 4.9 inmol) in EtOAc (150 m.L) was added 10% palladium on carbon (1.3 g) and stirred at room temperature for 64 h under hydrogen atmosphere. The mixture was then filtered through celite and the filtrate concentrated to yield the title compound as a white solid (1.92 g,100%): NMR (400MHz, CDC 3 8 6.8-7.7(m, 7H), 1.02 6H); MS(ESI) 388 Benzofuran-2-carboxylic acid (S)-3-methvl- 1-[1 -(5-methyl- 1H-[1I,2,4jtriazole-3sulfonyl)-3-hydroxy-azepan-4-ylcarbarnoyl]-butyl )amnide To a stirring solution of the compound of Example 72c 1 06g, .Sml n triethylamine (354±, 0.25mmol) in methylene chloride (2rnL) was added 5-methyl- 114f- 1,2,4-triazolesulfonylchioride (0.043g, 0.25mmol). The reaction was allowed to stir for min and washed with saturated aqueous NaHCO 3 water and saturated brine. The orgyanic layer was dried over NaS,S0, filtered and concentrated. The compound was purified by column chromatography'(silica gel; ethylacetate/ hexane) to yield the title compound as a pale yellow oil 111. MS(ESI) 532.73 Benzofuran-2-carboxylic acid (S)-3-methyl-l1-[1 -(5-methyl-I 1,2,4]triazole-3sulfonyl )-3-oxo-azepan-4-ylcarbamoyl 1-butyl )ami To a stirring solution of the compound of Example 72d 1 Ogg, 0.2O6mmol) in dimethylsulfoxide (2mL) was added triethylamine (172j±L 1.23mmol) followed by sulfur trioxide pyridine (0.1 116g, 0.718mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water The organic layer was dried over NaSO,, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.084, 8 'HNMR (400MHz, CDCI) 5 7.1-7.7 (in, 7H), 2.65 3H), 1.0 (d, MS(ESI): 552.71 (M+Na)* Example 73 Preparation of Benzofuran-2-carboxylic acid f(S )-3-methyl- 1-11 41 -methyl- I H-iridazole-3su Ifon vi )-3-oxo-azepanA-vlcarbamovl -butvl Iamide Benzofuran-2-carboxylic acid (S)-3)-methyl- 1 -tI -methyl-I IH-Imidazole-3sulfonyl)-3 -hydroxy-azepan.4-ylcarbamoyl]-butyl I amnide To a stirring solution of the compound of Example 72c 100,-, 0.25mmol) and triethylamine (35g.L, 0.2Smmol) was added 1-methylimidazole sulfonyl chloride (0.046-, 0.255mmol). The reaction was allowed to stir for 10min and washed with saturated aqueous NaHCO... water and saturated brine. The organic layer was dried over NaSO., filtered and concentrated. The compound was purified by column chromatography (silica gel ethylacetate /hexane) to yield the title compound as a pale yellow oil 113g, 82%): 'HNMR (400 MHz, CDCl,) 86.9-7.7 (in, 9H), 3.9 (2s, 3H). 1.0 6H); MS(ESI): 531.8 Benzofuran-2-carboxylic acid (S)-3-methyl- I I -methyl- I H-imidazole-3sulfonl 3 -oxo-azepan-4-ylcarbamoyl 1-butyl I amide To a stirring solution of the compound of Example 73a (0.085g, 0.lS59mmol) in dimethylsulfoxide was added triethylamine (I]33gL, 0.95mmol) followed by sulfurtrioxide pyiie O0g 0.5mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water The organic layer was dried over Na.S0 4 filtered and conentrated. The crude product was purified by column chromatography (silica gel;- methanol/methylenechionide) to yield the title compound as a white solid (0.072-, MS(ESI): 529.76 Example 74 Preparation of Benzofuran-2-carboxylic acid f (S)-3-nmethyl- I -Fl 141 H-imidazole-2-sulfonyl 3-oxo-azepan-4-vlcarbamovlI-butyI laride Benzofuran-2-carboxylic acid f (S)-3-methyl- I -[1I H-imidazole-2-sulfonyl)-3-oxoazepan-4-ylcarbamoyl]-butyllanide To a stirring solution of the compound of Example 72c 1 00g, 0.25 mmol) and triethylamine (35p.L, 0.25mmol) was added 2-imidazolesulfonyl chloride (0.046g,, 0.255mmo1). The reaction was allowed to stir for 10min and washed with saturated aqueous Na.HCO 3 water and saturated brine. The organic layer was dried over NaSO filtered and concentrated. The compound was purified by column chromatography (silica gel; ethylacetate/hexane) to yield the title compound as a pale yellow oil 113g, 82%): 'HNMR (400MHz, CDCL) 8 7.1-7.7 (in, 9H), 4.8 I1H), d. MS(ESI): 517.76 Benzofuran-2-carboxylic acid f (S)-3-methyl- 1 -[1I I H-imnidazole-2-sulfonyl)-3-oxoazepan-4-ylcarbamoyl ]-butyl) }amide To a stirring solution of the compound of Example 74a (0.107g, 0 .2O6mrnol) in dimethylsulfoxide (2mL) was added triethylamine (1 72p-L, 1 .23mmol) followed by sulfurtrioxide pyridine (0.11l5g, 0.7 l8minol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water The organic layer was dried over NaSS0 4 filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanollmethylenechloride) to yield the title compound as a white sol id (0.09g, MS(ESI): 515.84 (M+HY* Example Preparation of Benzofuran-2-carboxylic acid f (S)-3-methyl- I -l[3-oxo- I-(thiazole-2su Ifonvi )-azep~an-4-vlcarbamovl -butvIl amide I-[3-Hydroxy- I-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl 1-3-methylbutyl }-carbamic acid tert-butyl ester To a solution of the compound of Example 2a 7.29mmol) in DCE (100 mL) was added P-NMM (4.0 g)and thioazole-2-sulphonyl chloride (1.6 g, 8.75 mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (2.50g. 5.10 mmol, MS: 490.91 b. 1 Benzofuran-2-carboxylic acid (S)-3-methyl- I -[3-hyroxy- I -(thiazole-2-sulfonyl)azepan-4-ylcarbamoyi]-butyl I-amide To a solution of the compound of Example 75b'(0. 15 g.0.45 mmol) in CH,CI, mL) was added benzofuran-2-carboxylic acid (0.109 a, 0.172 mnmol), Ihvdroxvbenzotriazole (0.106 a, 0.762mmo1), and P-EDC (0.85a, Ilmmollg) in CH,CI, nl). After shaking at room temperature overnight, the solution was treated with tisamine (0.589-. 3.75mmolUg). After shaking for another 2hr, the solution was filtered and concentrated to yield the title compound as a white solid (166.7 mg, MS (ESI): 535.3 Benzofuran-2-carboxylic acid I S 1-3-methyl- I -[3-oxo- I -(thiazole-2-sulfonyl)azepan-4-ylcarbamoyl)-butyl)}-arnide To a stirrng solution of the compound of Example 75c (166.7 tug, 0.313 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (265.5 mug. 0.626 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 tuL of 10% in water) and saturated aqueous sodium bicarbonate (2 tuL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane The organic phases were combined, washed with saturated brine. dried (MgSO.), filtered and concentrated. The residue was purified by HPLC (50:50 ethanol: hexane, 2OmL-Jmin. 25min. WhelkO- I(R,R) 2 1x250mm column, UV detection at 280 nm and 305 nm) to yield the first elution as a white solid (84.8mg, 50.8 MS (ESI): 533.2 and the second elution as a white solid (50.1mg, 30.0%) MS: 533.2 (M+HD).

Example 76 Preparation of Benzofuran-2-carboxyiic acid f (S)-3-methvi. 14-[1 -0 -methyl- I H-imidazole-4sulfonyl)-3-oxo-azepan-4-vlcarbamoyll-butvl lamide I -[3-Hydroxy- 1-methyl- I H-imidazole-2-sulfonyl)-azepan-4-ylcarbamoyl)I- 3-methyl-butyl}1-carbamic acid terr-butyl ester To a solution of the amine of Example 2g in methylenechioride (5m.I) was added pyridine (92;iL, 1. 14mmol) followed by I1-methylimidazole-4-sulfonylchloride 1 l2g, 0.623mmo1). The reaction was allowed to stir for 16h at room temperature. The solution was then washed with saturated aqueous NaHCO,. water and brine. The product was purified by column chromatography (silica gel:, methanol! methylenechioride) to yield the title compound as a white solid 172-, 'HNMRk (400MHz, CDC 3 8 7.6 lH), IH), 6.6 3.8 3H), 1.5 9H), I 6H); MS(ESI): 488.2 (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l1-(1-methyl- 1H-imidazole-2sulfonyl)-azepan-4-yl]-amide To a solution of the compound of Example 76a 172g, 0.353 mmol) in minimal MeOH was added 4M HCI in dioxane (I Oml-) and stirred for 4h at room temperature. The reaction mixture was concentrated and azeotroped with toulene (2x's) to yield the title compound as an off white solid. MS(ESI):- 388.2 Benzofuran-2-carboxylic acid (S)-3-methyl- 1 I -(I1-methyl- 1 H-imidazole-4sulfonyl)-3-hydroxy-azepan-4-ylcarbarnoyl)-butyl )amide To a stirring solution of the compound of Example 72c (0.2g, 0.471mrmol), benzofuran-2-carboxylic acid (0.084 g,0.388 mmol), triethylamine (72p.L, 0.5 l7mmol) and 1-hydroxybenzotriazole (0.012 g, 0.088 mmol) in DMF (5 ML) was added 1-(3dimethylarninopropyl)3-ethylcarbodimide hydrochloride (0.099g, 0.5 l5mmol). After stirring at room temperature for 1 6h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and saturated brine.

The organic layer was dried over NaS0, filtered and concentrated. The product was purified by column chromatography (silica gel; methanolldichloromethane) to yield the title compound as a white solid (0.226g, 'HNMR (400MHz, CDC 3 8 6.9-8.1 (in, 18H), 3.75 (2s, 6H), I 12H); MS(ESI): 531.80(M+Hy* Benzofuran-2-carboxylhc acid I(S)-3-methyl- I-(1-methyl-I H-imidazole-4sulfonyl)- 3 -oxo.azepan..4-ylcarbamoyl..butyl }ami~de To a stirring solution of the compound of Example 76a (0.226 a, O.426minol) in dimethylsulfoxide (2m.L) was added triethylamine (355piL, 2.55mmol) followed by sulfur trioxide pyridine (0.238g, I .48mmoJ) and stirred for I 6h at room temperature. The reaction mixture was diluted with EtOAc and washed with water The organic layer was dried over NaS,S0, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanob/methylenechloride) to yield the title compound as a white solid (0.168g, 'HNMR (400MHz. CDCI) 567.1-7.7 9m. 1814), 3.7 (2s, 6H), 0.9 12H): MS(ESI): 529.80 Example 77 Preparation of 5-4Oym[hln--lehov-ezfrn2crovi acid f methyl-I -f3-oxo- I (vidine-2-sulfonyvi)-aea--labiol-uy md To a solution of the compound of Example 30b (0.01 g)in dichioromethane (2 mL) was added in-CPBA (0.008 The reaction was stirred overnight. Workup and column chromatography (30% methanol :dichloromethane) provided the title compound: 'H NMR (CDCI,): 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in. 2H), 2.5 (mn, 4H), 2.7 (mn, I 2.8 (m 2H), 3.7 (in, 4H), 3.8 11H). 4.0 (in, 4.7 (mn. IN). 4.8 (in, 5.0 (in, 1H), 7.0 (in, 3H), 7.4 (in, 2H), 7.5 (mn, I1-H), 7.9 (in, 2H), 8.6 I MS(EI): 671 100%) Examprle 78 Preparation of Benzofuran-2-carboxvlic acid I (S )-3-methyl- 1 -r3-oxo- 1 -(pvridine-3sulfonyl)-azepan-4-vlcarbamovll-butyjI arnide, 4 2 -Armino-4-methyl-pentanoylanrino)-3.4iydroxy-azepane- I -carboxylic acid benzyl ester To a solution of 4 2 -tert-butoxycarbonylarnino-4-methyl-pentanoylamijno)-3 hydroxy-azepan- I1-carboxylic acid benzyl ester of Example 2f (4.0 g) in methanol (20 ml-) was added 4M HCI in dioxane (20 The reaction was stirred at room temperature for 2 hours whereupon it was concentrated to provide the title compound (3.8 MS(EI) 378 4-f 2 -[(Benzofran.2-carbonyl)-amrino-4-methyl-pentanoylamino }-3-hydroxyazepane-l-carboxylic acid benzyl ester To a solution of 4 2 -amino 4-methyl~pentanoylamino)4.hydroxy-azepane- I carboxylic acid benzyl ester of Example 78a (3.2 g) in dichloromethane (200 ml-) was added EDC (1.48 ),HOBt (1.05 ),TEA (1.29 ml) and benzofuran-2-carboxylic acid.

The reaction was stirred until complete. Workup and column chromatography (2% methanol:dichloromethane) provided the title compound (3.78 MS(EI) 521 Benzofuran-2-carboxylic acid -(3-hydroxy-azepan-4-ylcarbamoyl)-3-methylbutylil-amide To a solution of 4- 2 -Ii(benzofuran-2-carbonyl)-amino]-4-methylp'entanoylamino -3-hydroxy-azepane- I -carboxylic acid benzyl ester of Example 78b (1.6 g in methanol:ethyl acetate-(50 mL.:100 ml.) was added 10% Pd/C. The reaction was stirred under a balloon of hydrogen for 2 hours whereupon it was filtered and concentrated to prvde the title compound (1.16 MS(EI) 387 Benzofuran-2-carboxylic acid (S)-3-methyl- 1-[3-hydroxy-lI-(pyridine-3-sulfonyl)azepan-4-ylcarbamoyll-butyl I amnide To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan.4ylcarbamoyl)-3-methyl-butylj-amide of Example 78c (0.3 o) in dichioromethane was added triethylamnine (0.17 ml) followed by 3-pyridinesulfonyl chloride (0.25 The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography methanol :ethyl acetate) provided 0.32 g of the title compound: MS(EI) 528 Benzofuran-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- 1 -(pyridine-3-sulfonyl)azepan-4-ylcarbamoyl]-butyl I}amide Following the procedure of Example I i except substituting benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-hydroxy-lI-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyljbutyl~amnide of Example 78d the title compound was prepared: 'H NMR (CDCI 3 6 1.0 (in.

6H), 1.5-2.1 (mn, 5N), 2.2 (in, 2.5 (in, IN), 3.5 1H). 4.0 (in, 1H), 4.7 (in, IH), 4.8 (in, I 5 .0 (in, I1H), 7.0 (in, 2H), 7.2-7.5 (in, 6H), 8.1 (mn, INH). 8.9-9.0 (mn, 2H); MS(EI): 526 Example 79 Preparation of Benzofuran-2-carboxvlic -acid f(S)-3-methyi- I-f3-oxo-1i-( 1-oxv-pvridine-3sul fon vi)-azepan -4-vlcarbamovi 1-butvlI )amide Benzofuran-2-carboxylic acid )-3-methyl-l1-[3-hydroxy-] -(1-oxy-pyridine-3sulfonyl)-azepan-4-ylcarbainoyl]-butyl Iainide To a solution of benzofuran-2-carboxylic acid (S)-3-inethyl- I -[3-hydroxy-1I (pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl] -butyllainide of Example 78d (0.05g) in dichloroinethane was added in-CPBA (0.05 The reacrton was stirred overnight.

Workup and column chromatography (10% methanol:dichloromethane) provided the title compound (0.03 MS(EI) 544 Benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1 -oxy-pyridine-3sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide Following the procedure of Example li except substituting benzofuran-2-carboxylic acid ((S)-3-methyl-lI-13-hydroxy-l1-(1 -oxy-pyridine-3-sulfonyl)-azepan-4-vlcarbanoyl]butyl I amide of Example 79a the title compound was prepared: 'H NMR (CDC1 3 8 1.-0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (mn, 2H), 2.5 (mn, IN), 3.5 IN). 4.0 (mn, 1H), 4.5 (in, IN), 4.7 (in, iN). 5.0 (in, IH), 7.2-7.5 (in, 7H), 8.1-8.2 (in, 2H). MS(EI): 542 Example Preparation of Quinoline-3-carboxylic acid f I -(3.4-dichloro-benzene-sulfonvl)-3-oxoazepan-4-vlcarbamovl)1-3-methv.iutvl D-aniide Following the procedures of Example 75a-d except substituting 3,4dichlorosulfonyl chloride for thioazole-2-sulphonyl chloride of Example 75a and quinoline- 3-carboxylic acid for benzofura-2-carboxylic acid the title compound was prepared: 'H NMR(CDCI, 3400 MHz) 8 9.34 1H). 8.61 IH), 8.14 (mn, 7.81 (in, 3H), 7.60 (in, 3H), 7 .19 m, 2H), 5.09(mn, 1H), 4.88 IH), 4.50 IH), 3.92 1H), 3.51 (mn, IH), 7 (in, I 2.2 3 (mn, 2H), 1.60 1.0 1 6H).

Example 81 Prepeparation of -Hvdroxv-benzofuran-2-carboxvhic acid f (S)-3-inethyl- 14 1 -01-methyl- I H-mdzl-4slov -3-xI e~n4ycra~vlb larnide 5-Hydroxy-benzofuran-2-carboxylic acid (S)-3-methyl-l1-[1 -(I-methyl-I Hinldazole- 4 -sulfonyl)-3-hydroxyazepan4.ylcartamoyl]-buty amide To a stirring solution of the compound of Example 76b 1 g, 0.235 mmol), hydroxybenzofuran-2.carboxyuic acid(0.046g, 0.256mino1), triethylamine (36 IiL, 0.258 minol) and I -hydroxybenzotriazole (0.006g, 0.O44mmoI) in DMF (5inL) was added i-(3dimethylaminopropyl)3.ethyicarbodimide hydrochloride (0.05g. 0.26mmol). After stirring at room temperature for 16h. the solution was diluted with EtOAc and washed successively wi th saturated aqueous sodium bicarbonate, water and saturated brine. The organic layer was dried over NaS,S0, filtered and concentrated. The product was purified by column chromatography silica gel: methanolldichloromethane) to yield the title compound as a white solid (0.129g, 100%). 'HNMR (400MHz, CDC 3 8 6.8-8 (mn, 16H), 3.6 (2s, 0.85 12H).

MS(ESI): 547.88(M-tH)* 126 5-Hydroxy-benzofuran-2-carboxylic acid (S)-3-methyl-I -(I-methyl-I Himi~dazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl }arnide Oxalyl chloride (13 jil-, 0.149 mmol) chloride was taken to To this was added dimethyl sulfoxide (28 pL, 0.394mmo1) in methylene chloride dropwise. After stirring for 1 5mm at -78 0, the alcohol of Example 8 ]a in methylene chloride was added slowly and allowed to stir for I h when Et,N (7 p.L, 0.05 mmol) was added. The solution was then brought to room temperature and quenched with water and extracted into methylene chloride. The organic layer was separated and washed with brine, dried over MgSO 1 filtered and concentrated. The product was purified by column chromatography (silica gel: methanollmethylene chloride) to yield the title compound as white solid (0.021-g, 78%): MS(ESI) 545.9(M+H)+ Example 82 Preparation of Benzofuran-2-carboxvlc acid f (S )-3-methvl- I -f 3-oxo- 14-1 -oxy-pvridine-2sulfonvi )-azepan-4-vlcarbamoyl)1-3-methvl-butvI I -amide Benzofuran-2-carboxyl ic acid I(S)-3-methyl-l1-[3-hydroxy-l1-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl)J-3-methyl-butyI }-amide To a solution of benzofuran-2-carboxylic acid I -(3-hydroxy-azepan-4ylcarbamoyl)-3-methyl-butyl]-amidde of Example 78c (0.10 g) in dichloromethane was added triethylamnine (0.07 mL) followed by 2-pyidinesulphonylchloride N-oxide. The reaction was stirred at room temperature overnight. Workup and chromatography methanol:dichloromethane) provided the title compound (0.01 MS(EI) 544 (S)-3-methyl- I -[3-oxo- I -oxy-pyridine-2-sulfonyl)-azepan4-ylcarbamoy))-3methyl-butyll}-amide Following the procedure of Example 1i except substituting benzofuran-2carboxylic acid (S)-3-methyl- 1 -[3-hydroxy- I -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbarnoyl)]-3-methyl-butyl )-axnide of Example 82a the title compound was prepared: H NMR (CDOJ: 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (mn, 2H), 2.7 (in, I1-1), 3.8 INH). (in, 18H). 4.7 (in, I 4.8 (mn, I 5.0 (in, I1-H), 7.0 -7.5 (in, 9H), 8.1-8.2 (in, 2H). MS(ED): 542 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR 8 1.0 (in, 6H), 1.5-2.1 (mn. 5H), 2.2 (in, 2.7 1H-), 3.8 I 4.0 I 4.7 (mn, I 4.8 INH). 5.0 (in, 18H), 7.0 -7.5 (mn, 9H), 8.1-8.2 (in, 28); MS(EI): 542 and the slower eluting- diastereoiner; MS(EI): 542 100%).

Example 83 Preparation of (Benzofuran-2-carbonyl i-aminolI-4-inethvl-p~entanovlainino 1-3oxo-azepane- I -sulfonvi)-benzoic acid (S)-2-[(Benzofuran-2-carbonyl)-amino]..4-inethyl-pentanoylamino 1-3hydroxy-azepane- I -sulfonyl)-benzoic acid methyl ester Following, the procedure of Example 75a-c, except substituting '2carboxyinethylsulphonyl chloride for 2-thiazolesulfonyl chloride, the title compound was prepared: MS 585.56, M+Na* 607.76, 2M+-V 1170.48.

[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylaniino hydroxy-azepane-lI-sulfonyl)-benzoic acid 2 -[(benzofuran-2-carbonyl)-amino]..4-inethyl-pentanoylamino 1-3hydroxy-azepane-lI-sulfonyl)-benzoic acid methyl ester (compound 83a, 180 mng, 0.309 mmiol) was dissolved in 5:1 MeOHlwater (6 ml) LiOH (14 mng, 0.34 mmol) was added and the reaction mixture was stirred and refluxed for 6 h. The reaction mixture was then quenched with water and 6 N HCI (adjusted to pH=2), extracted with EtOAc (3 x 10 ml), dried with MgSO,, filtered, concentrated, and chrornatographed (silica gel, 1% acetic acid/ 4% MeOH/!CH,Cl,) to yield the title compound as a white solid (48 mg. M+W 572.2 f 2 [(Benzofuran-2-carbonyl)-amino]-4-methyl-pentan oy amino 1-3-oxoazepane- I -sulfonyl)-benzoic acid Following the procedure of Example 75d, except substituting [(benzofuran-2-carbonyl)-amino]..4-methyl-pentanoylamino }-3-hydroxv-azepane- I sulfonyl)-benzoic acid for benzofuran-2-carboxylic acid (S)-3-methyl- 1 -[3-hydroxy- I (thiazole- 2 -sulfonyl)-azepan..4-ylcarbamoyl]ybutyl }amide, the title compound was prepared: MS 570.2 IH NMR(40OHz,CDCl 3

-CD

3 OD): 8 8.05-7.95 (in, lH). 7.70- 7.15 (in, 8H), 5.15-5.00 IH), 4.95-4.75 (in, 2H), 4.15-4.00 (in, I 3.65 I 2.85- 2.70 lH), 2.25-2.05 (in, 28), 1.90-1.70 (in, 4H), 1.60-1.45 (in, 18). 0.95 6H).

Example 84 Preparation of (S )-2-f(Benzofuran-2-carbonvl)-arni no.-4-methyl-pentanovlamino 1-3oxo-azepane- I -suffonvl)-benzoic acid Following the procedure of Example 83, except substituting 3carboxymethylbenzenesuiphonyl chloride for 2-carboxymethylbenzenesulfonyl chloride," the title compound was prepared: MS 570.2 IH NMR (4008z,CDCI 3

CD

3 OD): 8 8.46 IH), 8.31-8.25 (mn,1IH), 8.00-7.97 IH), 7.70-7.62 (in, 2H), 7.55-7.46 (in, 18), 7.45-7.35 (in,IH), 7.30-7.25 (mn. IH), 5.10-5.05 4.95-4.78 (rn,IH), 4.75- 4.55 IH), 4.00 IH), 3.5 I1H), 2.60-2.40 (mn, 2H), 2.25-2.15 (mn,1IH), 1.95-1.70 (in, 41H), 1.55-1.40 (mn, IH), 0.98 6H).

Example Preparation of Benzofblthiophene-2-carboxylic acid- I (S-3-methvl- I -I'3-oxo- I -oxypvridine-2-sulfony)-azepan-4-vlcarbamoyfl.butvl )amride f(S)-i -[3-Hydroxy- 1-(1 -oxy-pyridine-sulfonyl)-azepan-4-ylcarbamoylj-3-methylbucyl-carbami~c acid teri-butyl ester To a solution of [(S)-1I-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyljcarbamic acid tern butyl ester of Example 2- (2.5 g) in dichloromethane (100 m.L) and saturated sodium bicarbonate was added freshly prepared 2-pyidinesuiphonyl chloride Noxide (prepared by bubbling chlorine gas through a solution of 2-mercaptopyridine-Noxidein 9M HCI for approximately 90 minutes. Removal of excess chlorine under vacuum provided the 2-pyridinesulfonyl chloride-N-oxide). The reaction was stirred at room temperature for I hour. Workup and column chromatography methanol:dichloromethane) provided the title compound (2.0 ):MS(EI) 500 (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- I I -oxy-pyyridine-sulfonyl)azepan-4-yl 1-amide To a solution of -[3-hydroxy- 1-(1 -oxy-pyridine-sulfonyl)-azepan-4vlcarbamoylj-3-methyl-butyl-carbarric acid tert-butyl ester of Example 85a (2.0 g) in methanol (20 m.l) was added 4M HCI in dioxane (20 mL). The reaction was stirred at room temperature for 1.5 hours whereupon it was concentrated to provide the title compound (1.8 MS(EI) 400 Benzo[b]thiophene-2-carboxylic acid f (S)-3-methyl-lI-[3-hydroxy- 1-oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl )amide To a solution of (S)-2-arnino-4.-methyl-pentanoic acid [3-hydroxy-1 -(Il-oxypyyridine-sulfonyl)-azepan-4-yl]-arijde of Example 85b (0.25 g) in dichloromethane (12 ml) was added triethylarnine 12 mL), EDC 11 HOBt (0.077 and benzo~b]thiophene-2-carboxylic acid. The reaction was stirred until complete. Workup and column chromatography (10% methanol: dichloromethane) provided the title compound (0.26 g:MS(EI) 560 Benzo~b]thiophene-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- 1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-butyli amide Following the procedure of Example li except substituting benzofbjthiophene-2carboxylic acid J (S)-3-methyl- 1 -[3-hydroxy- I -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl }amide of Example 85c the title compound was prepared: 'H NMR (CDCI,): 5 1.0 (in, 1.5-2.1 (in, 5H), 2.2 (in, 2.7 (in, IH), 3.8 IH). 4.0 (in, IH), 4.7 (in, IH), 4.8 (in, IH), 5.0 (in, IN). 7.5 (in, 7.8 (mn, 3H), 8.1-8.2 (in. 2H). MS(EI): 558 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 558 100%), and the slower eluting diastereomer; MS(EI): 558 100%).

Example 86 Preparation of -5-Brono-furan-2-carboxvlic acid f (S)-3-methvl- I -13-oxo- 14-1 -oxy-Rvridine- 2-sul fonyl)-azepan-4-vlcarbainoyll-butv] I amide a. 5-Bromo-furan-2-carboxyiic acid I (S )-3-inethyl- I -[3-hydroxy- I -oxy-pyridine-2sulfonyl)-azepan.4-ylcarbainoyl]-butyl ainide Following the procedure of Example 85c except substituting 5-broino-2-furoic acid.

for benzo[blthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 574 5-Bromo-furan-2-carboxylic acid (S)-3-inethyl-lI-[3-oxo- 1-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl ]-butyl I amnide Following the procedure -of Example I I except substituting 5-bromo-furan-2carboxylic acid 4 (S)-3-methyl- 1 -[3-hydroxy- 1 -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbainoyl]-buryl }amide of Example 86a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (mn, 2H), 2.7 (mn, IH), 3.8 IN). 4.0 (mn, 1H), 4.7 (in, IH), 4.8 (mn, 1H), 5.0 (mn, IH), 7.0 (in, 2H), 7.4 (in, 2H), 8.1-8.2 (in, 2H); MS(EI): 570 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 572 and the slower eluting diastereomer; MS(EI): 572 Examnle 87 Prep~aration of 5.6-Dimethoxybenzofuran-2-carboxylic acid I(S)-3-methvl- I -13-oxo- I oxy-pvridine-2-sulfonyl )-azepan-4-vlcarbarnoyI 1-butvl) IAmide 5.6-Dimethoxybenzofuran-2-carboxylic acid (S)-3-merhyl-l1-[3-hydroxy-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide Following the procedure of Example 85c except substituting 5,6dimethoxybenzofuran-2-carboxylic acid for benzo[bjthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 604 5 ,6-Diinethoxybenzofuran-2-carboxylic -acid, 3-inethyl- 1 -[3-oxo-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl )ainide Following the procedure of Example I I except substituting 5,6dimethoxybenzofuran-2-carboxylic acid (S)-3-inethyl-1- [3-hydroxy-l1-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbanoyl]-butyl }.mide of Example 87a the title compound was prepared: 'H NMR (CDC1 3 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.7 (mn, 1H), 3.8 (mn, 7H). 4.0 (mn, IH), 4.7 (in, iF!), 4.8 (mn, I 5.0 (in, I1H), 7.0-7.5 (in, 511), 8.1-8.2 (mn. 2H); MS(EI): 602 The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 602 and the slower eluting diastereomer; MS(EI): 602 (Mr, 100%)'.

Example 88 Preparation of 1 -Oxy-pvridine-2-carboxvlic acid f (S)-3-methvl- I -13-oxo- I -(Rvridine-2sul fonvi '-azepan-4-vlcarbamovl 1-butvl I amide I -Oxy-pyridine-2-carboxylic acid (S)-3-methyl- I- [3-hydroxy-l1-(pyridinesulIfonyl )-azepan-4-ylcarbamoyl]-butyl arnide Following the procedure of Example 28b except substituting picolinic acid N-oxide for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 505 I -Oxy-pyridine-2-carboxylic acid f (S)-3-methyl- I -[3I-oxo- I -(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl }amride Following the procedure of Example I i except substituting I -oxy-pyridine-2carboxylic acid )-3-methyl- I -[3-hydroxy- I -(pynidine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl~amide of Example 88a the title compound was prepared: 'H NMR (CDC[3: 8 1.0 (in. 1.5-2. 1 (in, 5H), 2.2 (in, 2H), 2.7 (in, I 3.8 I 4.1 (in, INH), 4.7 (in. 5.0 (mn, 7.5 (mn, 3H), 7.9 (m 2H), 8.3-8.4 (in, 2H), 8.6 (in. IH); MS(EI): 503 100%) Example 89 Preparation of (S--ehi2(yiie2slovario-etni acid r3-oxo- 1- (pvridine-2-sulfonvl')-azep~an-4-yll-aide (S 4 -Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy- I-(pyridine- 2 -sulfonyl)-azepan-4-yl]-arrude To a solution of (S)-2-ainino-4-inethyl-pentanoic acid [3-hydroxy-l-(pyridine-2sulfonyl)-azepan-4-yl]-arnide of Example 28a (0.25 g)in dichioromethane was added triethylamine (0.27 inL) and 2-pyfidinesulfonyl chloride 15 The reaction was stirred until complete. Workup and colun chromatography methanol:dichloromethane) provided the title compound (0.09 MS(EI) 525 4 -Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy- I -(pyridine- 2 -sulfonyl)-azepan-4-yl]-aniide Following the procedure of Example 11 except substituting (S)-4-methyl-2- (pyridine-2-sulfonylamino).pentanoic acid [3-hydroxy- I-(pyridine-2-sulfonyl)-azepan-4yl)-amide of Example 89a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (mn, 2H), 2.7 (mn, IN), 3.8 4.0 (in, IH), 4.7 (mn, IN), (in, 1H), 5.5 (mn, IN), 7.0 (m IN), 7.5 (in, 2H), 7.9 (mn 3H), 8.6 (in, 2H). MS(EI): 523 100%) Example Preparation of 2 3 -Benzvl-ureido)-4-methvl-pentanoic acid r3-oxo-]I-(pvridine-2sulfonvi )-azep~an-4-vl -ai-Ie 2 3 -Benzyl-ureido)..4-inethvl-pentanoic acid [3-hydroxy-lI-(pyridine-2sulfonyl)-azepan-4-ylj-aide To a solution of (S)-2-amnino-4-merhyl-pentanoic acid [3-hydroxy-]I-(pyyridinesulfonyl)-azepan-4-yl]-amide of Example 28a (0.25 g)in dichioroinethane was added triethylainine 17 inL and benzyl isocyanate (0.088g). The reaction was stirred until complete. Work-up and column 'chromatography methanol: dich loronethane) provided the title compound 12 a).

2 3 -Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo- I -(pyridine-2-sulfonyl azepan-4-yl ]-ainide Following the procedure of Example 1 i except substituting (S)-2-(3-benzyl-ureido)- 4-methyl-pentanoic acid [3-hydroxy- I -(pyridine-2-sulfonyl)-azepan-4-y)-anide of Example 89a the title compound was prepared: 'H NMR 5 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (mn, 2H), 2.7 (mn, I 3.8 INH). 4.0 (in, 3H), 4,5 I 4.7 (in. INH), 5.0 (mn, IN), 7.2 7.5 (in,iN), 7.9 2N), 8.6 1H); MS(EI): 515 (lE, The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 516 and the slower eluting diastereomer; MS(EI): 516 100%).

Examnle 91 Preparation of (S)-2-(3-Phenvl-uriedo)-4-methyl pentanoic acid [3-oxo-]I-(Ipvridine-2sulfonvl )-azep~an-4-vil-amide (S)-2-(3-Phenyl-ureido)..4-methyl-pentanoic acid [3-hydroxy-]I-(pyridine-2sulfonyl )-azepan-4-yl]-amnide Following the procedure of Example 90a except substituting phenyl isocyante for benzyl i socyanate the title compound was prepared:: MS(EI) 503 2 -(3-Phenyl-ureido)..4-methyl-pentanoic acid [3 -oxo- I -(pyridine-2-sulfonyl)azepan-4-yl3-amide Following the procedure of Example I i except substituting (S)-2-(3-phenylureido)-4-methyl-pentanoic acid [3-hydroxy- 1 -(pyridine-2-sulfonyl )-azepan-4-yl]-amide of Example 9 1a the title compound was prepared: 'H NMR (CDCI.): 8 1.0 (in, 1.5-2.1 (in. 5H), 2.2 (mn, 2H), 2.7 (in, 1H), 3.8 lH). 4.0 (in. lH), 4.7 (mn, IlH), 5.0 (mn, I 7.0-7.9 (in. 8H), 8.6 (mn, I1H). MS(EI): 501 Example 92 Preparation of Benzofuran--2-carboxvlic acid I-[6.6-dimethyl-3-oxo- I(Rvridinesulphonvl )-azepan-4-vlcarbamoyll-3-methvl-butvli)-amnide Ally]l-(2,2-dimethyl-pent..4-eny lidene)-amine 2.2-Dimethyl-4-pentenal (2.8 g, 25 mmol) was dissolved in 15 mL benzene. To this solution allylamine (2.85 g, 50 mmol) was added. A few molecular sieves were used to absorb water generated during the reaction. The mixture was stirred at room temperature overnight. Removal of the solvent and excess amount of allylainine on rotavapor provided 3.76 gof the title compound as clear liquid (yield 100%). 1 H-NMR (400 MHz, CDCI 3 7.52(s, 1H), 5.

9 9-5.90(m, IH), 5.80-5.70(m, IH), 5.15-4.99(m, 4H), 4.01-3.99(m, 2H), 2.17(d. 2H), 1.06(s, 6H).

Allyl-(2,2-dimethyl-pent-4-enyl)-amine Allyl-(2,2-dirnethyl-pent-4-enylidene)-anine of Example 92a (3.

7 6er, 2SinmoI) was diluted in 5mi MeOH. To the solution NaBH 4 (0.95g, 25mmoI) was added at 0 0 C. After addition the mixture was stirred at r.t. for 5h. Methanol was removed on rotavapor and the residue was partitioned between EtOAc! 20% NaOH. The organic layer was dried over Na SO, fitered and evaperated to give 2.26 g of the title compound: MS 154.0; H-NMR (400 MHz, CDCI 3 5.93-5.76(m, 5.29-4.99(m, 4H), 3.22(d, 2H), 2.34(s, 2H), 2.0 1 2H), 0.94(s, 6H).

Pyridine-2-sulfonic acid allyl-(2,2-dimethyl-pent-4-enyl)-axnide Allyl-(2,2-dimethyl-pen(-4-enyl)-amine (0.43 g. 2.8 mmol) and NMM (0.57ga 5.6mmol) were mixed in 30 mL CHiC12. 2-pryridinesuiphonyl chloride was added slowly to the solution while it was cooled in an ice-water bath. After addition, the reaction mixture was stirred at r.t. overnigaht. Washed by 10% NaHCO 3 and the brine. Purified by column chromatography gave 0.6 gcolorless oil in 73% yield. MIS 295.2; 1 H-NMR (400 MHz, CDCI 3 8.71l-8.70(d, I 7.98 -7.86(m, 2H), 7.48-7.46(m, tH),'5.88-5.77(m, I1H), 5.55-5.45(m, lH), 5.13-5.00(m, 4H), 4.05-4.04(d, 2H), 3.24(s, 2H), 2.07-2.05(d, 2H), 0.96(s, 6H) .3,3-Dimethyl- I -(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro- 1 H-azepine Pyridine-2-sulfonic acid allyl-(2.2-dimethyl-pent-4-enyl)-amide (0.6g, 2mmol) was diluted in CH,)C12 (50mI). After carefully degass by Ar, Grubbs catalyst (0.1%g 0.2mmol) was added under Ar protection. The mixture was then refluxed for 2h before the solvent was removed on rotavapor. The crude product was purified by column chromatography E/H) to give 0.47a of the title compound in 87% yield. MS 267.0; 1

H-

NMR (400 MHz, CDCI 3 8.70-8.69(d, I 7.96-7.88(m, 2H), 7.49-7.46(m, 1iH), 5.8 1 5.70(m, 2H), 3.93-3.92(d, 2H), 3.26(s, 2H), 2.13-2.12(d, 2H), 1.00(s, 6H) 5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5. To the solution of the compound of Example 92d (1.2 g, 4.5 mmol) in 50 m.L

CH

2 was added NaHCO 3 (2.4 g, 13.5 rnmol) and then MCPBA (1.20, 13.5 mimol) in portions. The reaction was stirred at r.t. for 4h before it was worked up by washing with NaOH, saturated K2)C0 3 brine and dried (Na,5S0 4 to give. 1.0- crude product in 79 yield good enough for next reaction without further purification.) MS 283.0; IH-NMR (400 MHz, CDCI 3 8.68-8.67(d, 1H), 8.03-7.87(m, 2H), 7.49-7.40(m, 1 H), 4 4 4-3.89(q, IH), 3.62-3.59(d, lH), 3.50(m, IH), 3.00(m, IH), 2.

7 8-2.62(rm. 2H), 2.12- 2.06(m, I 1.

52 -1.4 6 I 1.20(s, 0.89(s, 3H).

4-Azido-6.6-dimethyl- I -(pyridine-2-sulfonyl)-azepan-3-o ,-Dimethy-3-(pyridine-2-sufonyl)-8-oxa-3-azabicyclo[5. i.Ojoctane from Example 92e (1.2 g, 4.3 mmol) was dissolved in the mixture of 7 ml MeOH and I ml NaN 3 (0.83 g, 13 mmol) and NI- 4 C1 (0.7 gy, 13 mmol) were added to the solution. The resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO 3 and brine. Purified on column chromatography gave 0.4o 4-azido-6,6-dimethyl- 1 -(pyridine-2-sulfonyl)-azepan-3-oI (yield MS 326.2; 1 H-NMR (400 MHz. CDCl-): -8.68-8.67(m. IH), 8.05-7.90(m, 2H), 7 5 3-7.50(m. INH), 3.

7 5-3.60(m, 3H), 3.49-3.30(m, 311). 1.

7 3-1.66(m, IlH), 1.56- 1.52(d, 1H), 1.07(s, 3H), 0.99(s, 311) 4. 4-Amino-6,6-dimethvl- I -(pyridine-2-su lfonyl)-azepan-3-ol 4-Azido-6,6-dimethyl- I -(pyridine-2-sulfonyl)-azepan-3-o from Example 92f (0.4 g1.23 mmol) was dissolved in THE (50 ml) and HiO (0.2 ml). PPh 3 (0.48 g.,1.85 mmol) was added to this solution. The reaction mixture was stirred at 45*C over nigrht. TLC showed no starting material left. THF was evaporated, azeotroped with toluene The resulting thick oil was dissolved in MeOH. treated with HCI in ether to adjust pH to acidic.

More ether was added and the solution turned cloudy. 0.22 gwhite precipitate of the title compound was collected. (45 yield); I H-NMR (400 MHz, CD 3 OD): -8.68(m, 11H), 8. 1.93(m, 2H1), 7.62(m, 111), 3.90(m, lH), 3.68(m,lH), 3.40-2.90(m, 4H1), 1.82(m, LH), 1.53(d, 1H1), 1.05(s, 6H) 1 -[3-Hydroxy-6,6-dimethyl- 1 -(pyridine-2-sufonyl)-azepan.4-ylcarbamoyl]-3methyl-butyl )-carbamnic acid tert-butyl ester 4-Arnino-6,6-dimethyl- I -(pyridine-2-sulfonyl)-azepan-3-ol HCl salt from Example 92g, (0.22 g, 0.6 mmol) was dissolved in 5ml DMF. To this solution, was added Boc-Leu- OH (0.22 g, 0.9 mmol)and HBTU (0.34 g. 0.9 mmol) and then NMM (0.24 g.2.4 mmol).

The mixture was stirred at r. t. overnight. DMF was removed under higyh vacuum. The residue was diluted with EtOAc and washed with H 2 0O, 10% NaHCO 3 and brine.

Purification by column chromatography gave 0 .22 gof the title compound (72% yield); MS 512.9; IH-NMR (400 MHz, CDCI 3 8.68-8.67(d, IH), 7 .97-7.88(m, 2H), 7.69-7.64(m, I 6 62 -6.53(m, I 5.06-5.00(m, l 4.03-3.18(m, 1.80-1.42(m, 15H), 1.04-0.92(m. 12H).

Benzofuran-2-carboxylic acid I -[3-hydroxy-6,6-dimethyl- I -(pyridine-2sulfonyl)-azepan4-ylcarbamoyl]-3.methyl.buty I -amide To -[3-Hydroxy-6,6-dimethyl-l1-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-3-methyl-butyl)-carbamic acid trn-butyl ester of Example 92h (0.22g," 0.43mmol) was added HCI/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t.

for 2h before solvents and excess amount of HCI was removed on rotavapor. The resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic id (84 mg, 0.52 mmol), HBTU (0.2 0.52 mmol) and NMM (0.2 -,2rnmol). The mixture was stirred at r.t. overnighit. DMF was then removed and the residue was redissolved in EtOAc (50 ml), washed-with .10% NaHCO'-(50 ml x 2) and brine (50 ml).

Evaporation of the solvent gave crude product 0.26 a. Purification by column chromatograghy gave the title compound 0.15 g in 63% total yield; MS 556.8; IH..NMR (400 MHz, CDCI 3 -8.66-8.63(m, IH), 7.94-7.1 l(m, lOH), 4.72(m, 1H), 4.01- 2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H).

Benzofuran-2-carboxylic acid [3-oxo-6,6-dimethyl-lI-(pyridine-2-sulfonyl)azepan-4--ylcarbamoyl]-3-rnethyl.butyI )-aniide To a solution of benzofuran-2-carboxylic acid -[3-hydroxy-6,6-dimethyl- I (pyridine- 2 -sulfonyl)-azepan.4.ylcarbamoyl]3methyl-butyl }-amide from Example 92i (100 mg, 0.1 Smmol)-in 2. ml CH-Cl,,was added Dess-Martin reagent (76 mg, 0.18 mrnol) at The solution was stirred for 2h when 20 ml CH,CI, was added and then washed with NaHCO 3 and brine. Purification by column chromatograghy (50% ethyl acetate in hexane) gave 70 mg of the title compound in 70% yield. MS 555.4; IH-NMR (400 MHz, CDCI 3 -8.68-8.67(d, 1H), 7 .97-7.93(m, 2H), 7.69-7.28(m, 6H), 7.32-6.92(m, 2H), 5.24(m, I 4 7 9 -4.69(m, 2H), 3 .80-3.7 1(m, 2H), 2.54-2.50(d, I1H), 1.92-1.76(m, 4H), 1.45- 1.40(m, 4H), 1.0 1-0.91 9H).

The diastereomeric mixture was separated by HPLC to provide the faster elutingy diastereoemer, MS 555.2, and the slower eluting diastereomer; MS 555.2.

Example 93 Preparation of 5-Methoxvbenzofuran-2-carboxyic acid I(S)-3-methvl -f [3-oxo- I-oxypvridine-2-sulfonv)-azepan.4-vicarbamoyl l-butvI Jamide 5-Methoxybenzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-hydroxy- 1-(1 -oxypyridine- 2 -sulfonyl)-azepan.4-vlcarbamoyll-butyl }amide Following the procedure of Example 85c except substituting 2-carboxylic acid for benzofb]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 57.4 5-Methoxybenzofuran-2-carboxylic acid, (S)-3-methyl- I -[3-oxo- I 1-oxy-pyridine- 2 -sulfonyl)-azepan..4-ylcarbamoyfl-butyl }amide Following the procedure of Example I i except substuting 5-methoxybenzofuran-2carboxylIic acid (S)-3-methyl- I- [3-hydroxy- 1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl~axnide of Example 93a the title compound was prepared: 'H NMR (CDCI,): 5 1.0 (in, 6H), 1.5-2.1 (mn, 2.2 (in, 2H), 2.7 (in, I 3.8 m, 4H). 4.0 (in, INH), 4,5 I1H), 4.7 (mn, I1H), 5.0 (in, I 7.4-8.6 (in, 8H) 8.0-8.2 (mn, MS(EI): 572 The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoeiner; 'HNMR (CDC 3 8 1.0 (mn, 611), 1.5-2.1 (in, 5H), 2.2 (mn, 2H1), 2.7 I H), 3.7 311), 3.8 11H). 4.0 I 4,7 (mn, I 4.8 I 5.0 (in, I1H), 7.4-8.6 (mn, 811) 8.0-8.2 (mn. 2H); MS(EI): 573 (M+W,100%) and the slower eluting" diastereoiner; MS(EI): 573 100%).

ExaMple 94 Preparation of Thienof3.2-blthiophene-2-carboxvlic acid f(S )-3-methyl- I -r 3-oxo- 1 -01 -oxv- Rvridine-2-su Ifonvl)-azepan-4-vlcarbamoyjj-butyl) amnide Thieno[3 ,2-bjthiophene-2-carboxylic acid f (S)-3-methyl- I -f3-hydroxy- I -oxypyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide Following the procedure of Example 85c except substituting thienoil3,2b]thiophene-2-carboxylic acid for benzofbjthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 566 Thieno[3,2-b]thiophene-2-carboxylic acid (S)-3-methyl- 1-13-oxo- 1-(1 -oxypyridine- 2 -sulfonyl)-azepan.4-ylcarbamoyly-butyl armde Following the procedure of Example I i except substuming thieno[3,2-bjthiophene-2carboxy lic acid f (S)-3-methyl-1- [3-hydroxy-l1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl }amide of Example 94a the title compound was prepared:. 'H NMR (CDCI,): 5 1.0 1.5-2.1 (in, 5H), 2.2 (in, 2.7 (mn, IH), 3.8 IH). 4.0 (in, I H), INH), 4.7 (in, I1H), 5.0 (in, INH), 7.4-7.5 (in, 6H), 7.7 I 8.0-8.2 (in, 2H). MS(EI)- 564 (M-100%).

The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoeiner; 'HNMR (CDCI,): 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.7 IH), 3.8 I 4.0 I 4,5 (in, I1H), 4.7 I1H). 5.0 (in, INH), 7.4-7.5 (mn, 6H), 7.7 IlH), 8.0-8.2 (in,2H); MS(EI): 565 and the slower eluting diastereoiner; MS(EI): 565 Example Preparation of Quinoxaline-2-carboxylic acid f(S)-3-methvi- I -f3-oxo- 14-( -oxv-pvridine-2sulfonvl)-azepan-4-ylcarbamovll-butyl lamide Quinoxaline-2-carboxylic acid f (S)-3-methyl- 1 -[3-hydroxy- I -oxy-pyridine-2sulfonyl)-azepan-4-yicarbamoy)-butyl )amnide Following the procedure of Example 85c except substituting quinoxaline-2carboxylic acid for benzo[bjthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 556 Quinoxaline-2-carboxylic acid (S)-3-methyl-lI- [3-oxo-l1-(1 -oxy-pyridine-2sulfonyl )-azepan-4-ylcarbamoyl]-butyl amide Following the procedure of Example I i except substuting quinoxaline-2-carboxylic acid I(S)-3-methyl-lI-[3-hydroxy- I-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyfl] butyl }amide of Example 95a the title compound was prepared: 'H NMR 8 1.0 (in, 6H), 1.5-2.1 (in. 5H), 2.2 (in. 2H), 2.7 (in, I1H), 3.8 I 4.0 (mn, I 4,5 I1H), 4.7 (mn, I1H), 5.0 (in.

111!), 7.4-7.5 (in, 2H), 7.9 (in, 1H), 8.0-8.4 4H, 9.6 1H); MS(EI): 554 The diastereoineric mixture was separated by I-PLC to provide the faster eluting diastereoemer; MS(EI): 555 (M+W,I100%) and the slower eluting diastereomer; MS(EI): 555 Example 96 Preparation of uinoline-2-carboxylic acid f (S)-3-methvi- I 43-oxo-l 4-1 -Oxv-Rvridine-2sulfonvl)-azepan-4-vlcarbarnovll-butvI I amnide Quinoline-2-carboxylic acid (S)-3-methyl- l-[3-hydroxy-l1-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbaxnoyl]-butyl I amide Following the procedure of Example 85c except substituting quinoline-2-carboxylic acid for benzo[blthlophene-2-carboxylic acid the title compound was prepared: MS(EI) 555 Quinoline-2-carboxylic acid ((S)-3-methyl-lI-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl I amnide Following the procedure of Example I i except substuting quinoline-2-carboxylic acid (S)-3-methyl- I-[3-hydroxy-lI-( I-oxy-pyridine-2-sulfonyl)-azepan4.ylcarbamoyJ..

butyl jamide of Example 96a the title compound was prepared: 'H NMR (CDCI 3 8 (in. 6H), 1.5-2.1 (mn, 5N), 2.2 (mn, 2.7 (in, INH), 3.8 I 4.0 (mn, I 4,5 I1-H), 4.7 (mn, INH), 5.0 (in, I 7.4-8.6 (in, I OH); MS(ED): 553 (M,100%) The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 554 100%) and the slower eluting diastereomer; MS(EI): 554 (M+H,l100%).

Example 97 Prep~aration of Thiophene-3-carboxvlic acid f (S)-3-methvl. -f 3-oxo- I I -OXV-Dvridine-2sulfonvl)-azepan-4-vlcarbamovll.butvIl anide Thiophene-3-carboxylic acid (S)-3-methyl-l1-[3-hydroxy- 1-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl].butyl }ainide Following the procedure of Example 85c except substituting thiophene-3carboxylic acid for benzollblthiophene-2-carboxylic acid the title compound was prepared: Thiophene-3-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-( I-oxy-pyridine-2-sulfonyl)azepan-4-ylcarbainoyl]-butyl }aiide Following, the procedure of Example I i except substuting thiophene-3-carboxylic acid (S)-3-inethyl- I-[3-hydroxy-l1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4.ylcarbamoyl..

butyllainide of Example 97a the title compound was prepared: 'H NMR (CDCI 3 8 1.-0 (I, 6H), 1.5-2.1 (mn, 5H), 2.2 (mn, 2H), 2.7 (in, 1H), 3.8 4.0 (mn, 1H), 4,5 1H), 4.7 (mn, 1H), 5.0 (mn, 1H), 7.4-8.0 (mn, 4H), 7.8 (in, 1H), 8.1-8.2 (mn, 2H); MS(EI): 508 Example 98 Preparation of I H-Indole-5-carboxylic acid f(S)-3-methvi- I -[3-oxo- 14-1 -oxy-pvridine-2sulfonvi )-azepan-4-vlcarbamovl -butvlI arnide I H-Indole-5-carboxylic acid f (S)-3-methyl- I -[3-hydroxy- I -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-butyl) Jamide Following the procedure of Example 85c except substituting carboxylic acid for benz6[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 543 I H-Indole-5-carboxylic acid J (S)-3-methyl- 1 -[3-oxo- I I -oxy-pyridine-2-sulfonyl)azepan-4--ylcarbanioyl]-butyl amnide Following the procedure of Example I i except substuting of carboxylic acid (S )-3'-methyl-l1-[3-hydroxy-l1-( I-oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl }amide of Example 98a the title compound. was. prepared:. 1H NMR

(CDCI

3 8 1 .0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H) ,2.7 (mn, IH), 3.8 IH); 4.0 (mn, 1H), IN), 4.7 (mn, lH), 5.0 (in, IN), 7.4-8.0 (in. 7H), 8.1-8.2 (in, 2H), 8.6 1H); MS(EI): 541 The diastereoineric mixture was separated by 1-PLC to provide the faster elutin~g diastereoeiner; MS(EI): 542 and the slower eluting diastereomer; MS(EI): 542 ExaMRle 99 Preparation of Benzo[ 1.31dioxole-5-carboxvlic acid A (S)-3-methvl-l I-oxvpvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butyI arride Benzo[ 1,3]dioxole-5-carboxylic acid (S)-3-inethyl- I-[3-hydroxy-l1-( 1-oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }arride Following the procedure of Example 85c except substituting Benzo[ 1,3]dioxole-5carboxylic acid for benzo[b~thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 548 Benzo[1I,3ldioxole-5-carboxylic acid ((S)-3-methyl-lI-[3-oxo- 1-(1 -oxy-pyridine-2sulfonyl)-azepan-4ylcarbamoylj-butyl }amxide Following the procedure of Example I i except substuting benzof carboxylic acid (S)-3-methyl- I-[3-hydroxy- 1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl Jamide of Example 99a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in. 2H), 2.7 (mn, lH), 3.8 IH); 4.0 (mn, 1H), IH), 4.7 (in, IH), 5.0 (in, IH), 6.0 2H), 7.4-8.0 (in, 5H), 8.1-8.2 (in, 2H); MS 546 (M,l100%) The diastereorneric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 547 100%) and the slower eluting diastereomer; MS(EI): 547 Example 100 Preparation of Furan-2-carboxylic acid I(S)-3-nethvl I -r3-oxo- 14-1 -oxv-pvridine-2sulfonvl)-azevan4-vlcarbainovl 1-but-vil amide Furan-2-carboxylic acid ((S)-3-methyl-l1-[3-hydroxy-l1-(1 -oxy-pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl Iamide Following the procedure of Example 85c except substituting furoic acid for benzolbthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 494 Furan-2-carboxylic acid I(S)-3-inethyl- 1-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl laTTide Following the procedure of Example I i except substuting furan-2-carboxylic acid ((S)-3-methyl-lI-[3-hydroxy- I I-oxy-pyridine-2-sulfonyl)-azepan..4-ylcarbamoylybutyl) amide of Example Il00a the title compound was prepared: 1 H NMR (CDC1 3 8 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (mn, 2H), 2.7 (in, 111), 3.8 111); 4.0 (mn, 11H), 4,5 1H), 4.7 (mn, I1H), 5.0 (in,4 IH), 7.4-8.0 (mn, 5H), 8.1-8.2 (mn, 2H1); MS(EI): 492 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer MS(EI): 493 (M+Wf j00%) and the slower eluting diastereoiner; MS(EI): 493 100%).

Example 101 Preparation of (S )-4-Methvl-2-(2-thiophen-2-vJ-acetylamino)-pentanoic acid r3-oxo- 1 -01 ox v-pyridine-2-sulfon v D-azepan-4-v I I-aride 4 -Methyl-2-(2-thiophen-2-y-acetyanino)-pentanoic acid [3-hydroxy- I I -oxypyridine-2-sulfonvl)-azepan-4-ylj-amide Following the procedure of Example 85c except substituting thiophene-2-acetic acid for benzo[bjthlophene-2-carboxylic acid the title compound was prepared.

4 -Methyl-2-(2-thiophen-2-yl-acetylanino)-pentanoic acid [3-oxo-]1-(1 -oxypyridine-2-sulfonyl)-azepan-4-y -ami~de Following the procedure of Example 11 except substuting (S)-4--methyl-2-(2thiophen-2-vl-acetylamrino)-pentanoic acid [3-hydroxy- I-oxy-pyridine-2-sulfonyl)azepan-4-yl]-amide of Example 101la the title compound-was prepared: 'H NMR (CDCI,): 5 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 2H), 2.7 (in, IH), 3.8 (in, 3H); 4.0 (in, lH), 4,5 1H), 4.7 (mn, IH), (in. IH), 7.4-8.0 (in, 5H), 8.1-8.2 (in, MS(EI): 522 Example 102 Preparation of 11 H-Indole-2-carboxvlic acid 1 (S)-3-methvl-lI- r3-oxo-l1-(1 -oxv-pyridine-2sulfonyl )-azepan-4-vlcarbamoyl'i'butyI I arnide I H-Indole-2-carboxylic acid (S)-3-methyl-l1-[3-hydroxy-lI-(1 -oxy-pyridine-2sulfonyl)-azepan-4-ylcarbwmoyl]-butyl Jamide.

Following the procedure of Example 85c except substituting lH-indole-2carboxylic acid for benzo[blthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 543 I H-Indole-2-carboxylic acid- (S)-3-inethyl- I -[3-oxo- I I -oxy-pyi-idine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl }am-ide Following the procedure of Example li except substuting IH-indole-2-carboxylic acid (S)-3-methyl-l1-[3-hydroxy-lI-(1 -oxv-pyridine-2-sulfonyl)-azepan-4-ylcarbanoyl]butyl )amide of Example 102a the title compound was prepared: 'H NMR (CDCI,): 8 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.7 (in, 1WH), 3.8 I 4.0 (mn, I1H), 4,5 I 4.7 (in, 1H), 5.0 (in, I1H),7.4-8.0 (in, 7H), 8.1-8.2 (mn, 2H), 9.4 IlH); MS(EI): 541 100%) The diastereomeric mixture was separated by H-PLC to provide the faster eluting diastereomer: MS(EI): 542 and the slower eluting diastereomer; MS(EI): 542 Example 103 Preparation of 4-Fluoro-f (S)-3-methvi- I -r3-oxo- I I-oxv-pvridine-2-sulphonvl )-azepan-4carbainoyll-butyl I-benzarnide 4-Fluoro- {(S)-3-methyl-lI-[3-hydroxv- 1 -ox y-pyridine-2 -su IphonylI)-azepan-4carbainoyl-butyl )-benzainide Following the procedure of Example- 85c except-substituting -4-fluorobenzoic acid for benzo[blthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 522 4-Fluoro- (S)-3-rnethyl- 1 -[3-oxo- 1 -oxy-pyridine-2-sulphonyl)-azepan-4carbainoyl]-butyl -benzamnide Following the procedure of Example 1i except substuting 4-fluoro-{(S)-3-inetbyl-l- [3-hydroxy-l1-(1 -oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]-butyl )-benzainide of Example 103a the title compound was prepared: 'H NMR 5 1.0 (mn. 6H), 1.5-2.1 (in, 5H), 2.2 2H), 2.7 (in, IH), 3.8 IH); 4.0 (mn, lH), 4,5 11H), 4.7 (mn, 11H), 5.0 (mn, IH),7.4-8.0 (mn, 6H), 8.1-8.2 (mn, MS(ED): 520 100%) The diastereoineric mixture was separated by HPLC to provide the faster elutinig diastereoiner: MS(EI): 521 (M+W,100%) and the slower eluting diastereomer MS(EI): 521 (M+Wr,100%).

Example Preparation of 5-(2-Morpholin-4-v!-ethoxy)-benzofuran-2-carboxvlic acid (S)-3-methyl- I- I -oxy-pvridine2-sulphonvJ )-azepan-4-vlcarbamovl 1-but", I -amide 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid f (S)-3-methyl- 1 hydroxy-( I -oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl].buty I -arnde Following the procedure of Example 85c'except substituting 5-(2-morpholin-4-ylethyloxv)benzofuran-2-carboxylic acid for benzo[b~thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 673 5-(2-Morpholin-4-yI-ethoxy)-benzofuran-2-carboxylic acid (S)-3-methyl- I -3-oxo- (I -oxy-pyridine2-sulphonyl )-azepan-4-yicarbamoyl3-buty -amide Following the procedure of Example 1i except substutingc 5-(2-morpholin-4-ylethoxy)-benzofuran-2-carboxylic acid (S)-3-methyl-1 -13-hydroxy-( 1-oxy-pyridine2sulphonyl)-azepan-4-ylcarbamoyl]-buty)-arnide of Example 104a the title compound was prepared: 'H NMR (CDCI 3 8 1.0 (in, 6H), 1.5-2.1 (in. 5H), 2.2 (mn. 2H), 2.5 (mn, 2.7 (in. 3H). 3.7 (mn. 4H); 3.9 (mn, IlH), 4,5 (in, 3H). 4.7 (mn, I 5.0 (in, IlH). 7.4-8.0 (in, 6H), 8.1- 8.2 (in, 2H); MS 671 100%) The diastereomneric mixture was separated by HPLC to provide the faster eluting dia stereomer: MS(EI): 672 (M+HW.100%) and the slower eluting diastereomer MS(EI): 672 100%).

Example 105 Preparation of Thiophene-2-carboxylic acid I(S)-3-methvl- I -43-oxo- 1 -oxy-pvridine-2sulfonvl)-azepan-4-vlcarbamoyll-butvl I amide Thiophene-2-carboxylic acid (S)-3-methyl-l1-[3-hydroxy-lI-( I-oxy-pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide Following the procedure of Example 85c except substituting thiophene-2carboxylic acid for benzo[blthiophene-2-carboxylic acid the title compound was prepared; Thiophene-2-carboxylic acid (S)-3-methyl. I -13-oxo- I -oxy-pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl Iaride Following the procedure of Example I i except substuting thiophene-2-carboxylic acid (S)-3-methvl-l1-[3-hydroxy-lI-( I-oxy-pyridine-2-sulfonyl)-azepan-4ycarbamoyl..

butyl I}amide of Example 105a the title compound was prepared: 'H NMR (CDCI,): 5 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (mn, 2H), 2.7 (in, IH), 3.8 1H); 4.0 (in, IH), 4,5 IH), 4.7 (mn, I1H), 5.0 (in, I 7.4-8.0 (in, 5H), 8.1-8.2 (in, 2H); MS(EI): 508 The diastereoineic mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 509 (M+W,100%) and the slower eluting, diastereomer MS(EI): 509 Example 106 Pqrearation of 3-Methvibenzofuran-2-carboxylic acid I (S)-3-methyl- I -r3-oxo- 1 -oxvpvridine-2-sulfonyl )-aZepan-4-vlcarbamovll-butvlI amide 3 -Methylbenzofuran-2-carboxylic acid f (S )-3-inethvl- 1 -[3-hydroxy- 1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbainoyl]jbutyl I amride Following the procedure of Example 85c except substituting 3-methylbenzofuran-2carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 558 3-Methylbenzofuran-2-carboxylic acid ((S)-3-inethyl- I-f3-oxo-l1-( 1-oxy-pyridine-2sulfonyl)-azepan-4-ylcarbanoyl).butyl }aiide Following the procedure of Example I i except substuting, 3-inethylbenzofuran-2carboxylic acid I(S)-3-methyl-lI-[3-hydroxy- 1-(1 -oxy-pyridine-2-sulfonyl)-azepan.4 ylcarbamoyl]-butyl I amide of Example 106a the title compound was prepared: 'H NMR (CDCI,): 5 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (in. 2H), 2.5 3H), 2.7 (mn, IH), 3.8 IH); (mn, I 4.5 I1H), 4.7 (mn, INH), 5.0 (mn, I 7.4-8.0 (in, 6H), 8.1-8.2 (mn, 2H); MS(EI): 556 The diastereomeenc mixture was separated by HPLC to provide the faster eluting diastereoemer: 'N NMR (CDCI 3 5 1.0 (mn, 6H), 1.5-2.1 (in, 5N), 2.2 (in. 2H), 2.6 3H), 2.7 INH). 3.8 I1H); 4.1 IlH), 4,7 (mn, I1H), 4.7 I 5.0 (mn, I 7.0 (mn, 2H), 7.3 (mn, 2H), 7.4 (in, 4H), 8.1 I1-H), 8.2 (d7 I1H); MS(EI): 557 100%) and the slower eluting diastereomer MS(EI): 557 100%).

Example 107 Preparation of 6-Methyl-N- f(S)-3-methvl- I -f 3-oxo- I -(1I -oxv-p~vridine-2-sulfonvl )-azepan-4vicarbamovil-butvl 1-nicotinainide 6-Methyl-N- (S)-3-methyl- I -f3-hydroxy- I -oxy-pyridine-2-sulfonyl )-azepan-4ylcarbamoyl)-butyl -nicotinarnide Following the procedure of Example 85c except substituting 6-methylnicotinic acid for benzollblthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 519 6-Methyl-N- {(S)-3-methyl- I-[3-oxo-lI-(1 -oxy-pyridine-2-sulfonyl)-azepan-4vlcarbamoyl]-butyl )-nicotinainide Following the procedure of Example 11 except substutingy of 6-methyl-N-({(S)-3methyl-l1-[3-hydroxy-l1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl nicotinainide Example 107a the title compound was prepared: 'H NMR (CDCI 3 8 1 .0 (mn, 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.6 3H), 2.7 (in. I 3.8 I1H); 4.0 (mn, I I 4.7 (in, I 5.0 (in, I 7.4- 8.0 (in, 3H), 8.1- 8.2 (mn, 3 9.0 (in, I1H); MS (EI): 517 The diastereomeric mixture was separated by H-PLC to provide the faster eluting diastereoemer: MS(EI): 518 and the slower eluting diastereomer MS(EI): 518(M+HW,100%).

Example 108 Preparation of (S--ehi2(-hoRe-v-ctimn)ietni acid-t3-oxo- I (pvridine-2-sulfonyl )-azepan-4-vll-butyl Iaride (S--ehl2(-hohn-laeyaio-etni acid-[3-hydroxy- I -(pyridine- 2 -sulfonyl)-azepan-4-yly-butyl arnide Following the procedure of Example 28b except substituting thiophene-2-acetic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ESI) 508.8 4 -Methy]-2(2thiophenyacetyano)penanoc acid-[3-oxo-1I-(pyridine-2sulfonyl)-azepan.4-y1I-butyl )amide Following the procedure of Example I i except substuting (S)-4-rnethyl-2-(2thiophen-y-acetylamino)pentanoic acid- [3-hydroxy- I -(pyridine-2-sulfonyl)-azepan.4-y].

butyl)amide of Example .108a the title compound was prepared: MS(ESI) 506.8 Example 109 Prearation of I H-Indole-6-carboxylic acid (S)-3-m-ethyl- I 3-oxo- I-(Rvridine-2-sulfonvl)azepan-4-vlcarbamovl -butyl lanmde 1 H-Indole-6-carboxylic acid I (S)-3-methyl- I -[3-hydroxy- I -(pyridine-2-sulfonyl)azepan-4-ylcarbamoyly-butyl lamide Following the procedure of Example 28b except substituting IH-indole-6.

carboxylic acid for benzofuiran-2-carboxylhc acid the title compound was prepared: MS(EI) 527 1 H-Indole-6-carboxylic acid (S)-3-methyl- I-[3-oxo-] -(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl)-butyl Jamide Following the procedure of Example 1 i except substuuing 1 H-indole-&-carboxylic acid ((S)-3-methyl- I-[3-hydroxy-lI-(pyridine-2-sulfonyl)-azepan-4ylcarbamoy]..

butyl )amide of Example 1 09a the title compound was prepared: MS(EI) 525 Example 110 Preparation of Benzof I .31dioxole-5-carboxylic acid f(S)-3-methvi- I -I 3-oxo- I -(pRyddine-2sulfonvl)-azepan-4-vlcarbamovl l-butv) aide Benzo[ I .3loxole-5-carboxylic acid ((S)-3-methyl- I -[3-hydroxy- I -(pyridine-2sulfonyl)-azepan-4-ylcarbamoylj-butyl amnide Following the procedure of Example 28b except substituting, piperonylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 532.7 Benzo[ 1 .3]dioxole-5-carboxylic acid I (S)-3-methyl- I -f3-oxo- I -(pyridine-2sulfonyl )-azepan-4-ylcarbamoyl 1-butyl amnide Following the procedure of Example I I except substuting benzo[ 1,3]dioxole-5carboxylic acid (S)-3-methyl- I -[3-hydroxv- I -(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl)-butyl) amide of Example I I Oa the title compound was prepared: MS(EI) 530.8 Example Ill Preparation of 3.4-Dihvdro-2)H-benzorblI' I.41dioxepine-7-carboxvlic acid l(S)-3-methvl-lr3-oxo- I-oxv-2vridine-2-sulfonvl )-azepan-4-vlcarbamovll-butvl Iamide 3 ,4-Dihvdro-2H-benzo[b) [1 ,4)dioxepine-7-carboxylic acid (S)-3-mnethyl-1-1:3hydroxy- I-oxy-pyridine-2-sulfonyl)-azepan-4-vlcarbamoyl]-butyl )amide Following the procedure of Example 85c except substituting 3,4-dihydro-2H-1,5benzodioxepine-7-carboxylic acid for benzo[b~thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 576 3,4-Dihydro-2H--benzo[b] [1 .4]dioxepine-7-carboxylic acid (S)-3-rnethyl-l1-[3-oxo- 1 I-oxy-pyridine-2-sulfonyl)-azepan-4ylcarbamoyl-butyl amide Following the procedure of Example I I except substuting 3,4-dihydro-2Hbenzo~b][ I,4]dioxepine-7-carboxylic acid (S)-3-methyl- I-[3-hydroxy-lI-( I-oxy-pyridine-2sulfonyl)-azepan-4-ylcarbarnoyl]-butyl Iamide of Example IlIIa the title compound was prepared: 'H NMR (CDClO-,: 8 1.0 (in, 1.5-2.1 (in. 5H), 2.2 (in, 4H), 2.5 3H). 2.7 (in, I 3.8 I 4.0 (mn, INH), 4.2 (in, 4H), 4,5 I 4.7 (in, INH), 5.0 (mn, I1H), 7.4-8.0 (mn, 5H), 8.1-8.2 (in, 2H); WSEI): 575 (M+W,l0O%).

The diastereoineric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 575 100%) and the slower eluting- diastereoiner MS(EI): 575 100%).

Example 112 Preparation of 5-Methvl-thiovhene-2-carboxylic acid f (S)-3-methvl I-f3-oxo- 1-(1 -oxvpvridine-2-sulfonvl )-azepan-4-ylcarbainoyll.butvlI lamide 5-Methyl-thiophene-2-carboxylic acid (S)-3-methyl-lI-[3-hydroxy-l1-(1 -oxypyridine- 2 -sulfonyl)-azepan4ylcarbmoyl]-butyi )ainide Following the procedure of Example 85c except substituting 5-methyl thiophene-2carboxylic acid for benzo~bjthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 524 5-Methyl-thiophene-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1 -oxy-pyridine-2sulfonyl)-azepan-4ylcarbainoyl].butyl 1arnide Following the procedure of Example li except. substuting 5-inethyl-thiophene-2carboxylic acid f (S)-3-methyl- I- [3-hydroxy- 1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4ylcarbainoyl]-butyl )amide of Example 11 2a the title compound was prepared: 'H NMR (CDCl 3 8 1.0 6H), 1.5-2.1 (in, 5H), 2.2 2H), 2.5 3H), 2.7 (in, IN), 3.8 IH); (mn, I1-H), 4,5 INH), 4.7 (in. IH), 5.0 (in, I 7.4-8.0 (in, 41H), 8.1-8.2 (in, 2H); MS(EI): 523 The diastereoineric mixture was -separated by HPLC to provide the faster eluting diastereoerner: MS(EI): 523 100%) and the slower eluting diastereoiner MS(EI): 523 (M+W,l00%).

Example 113 Preparation of 4.5-Dibromo-thiophene-2-carboxylic acid f (S)-3-methyl- 1 -f3-oxo- 1 -0I -oxvpvridine-2-sulfonvl )-azepan-4-vlcarbamoyll-butvlI lamide 4.5-Dibromo-thiophene-2-carboxylic acid f(S)-3-methyl- I-[3-hydroxv-l1-(1 -oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoylI-butyll}ami-de Following the procedure of Example 85c except substituting thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 668 4.5-Dibromo-thiophene-2-carboxylic acid (S)-3-methyl- I-[3-oxo- 1-(1 -oxypyridine-2-sulfonyl )-azepan-4-ylcarbamoyl]-butyl I amide Fllwn the procedure of Example I I except substuting thiophene-2-carboxylic acid (S)-3-methyl-lI-[3-hydroxy-l1-(1 -oxy-pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl )amide of Example 1 13a the title compound was prepared: 'HI NMR (CDCI.): 5 1.0 (in. 6H), 1.5-2.1 (in. 5H), 2.2 (in. 2H), 2.7 (in, 1H). 3.8 IH): I 4.5 I1-1). 4.7 (mn, I 5.0 (in, IlH), 7.4-8.0 (in, 3H), 8.1-8.2 2H); MS(EI): 665 100%).

Example 114 Preparation of 3.5-Dimethv-isoxazole-4-carboxvlic acid f (S)-3-methvi-1 I-oxvpvridine-2-sulfonvl)-azepan-4-ylcarbamovll-butyl lamide 3,5-Diinethyl-isoxazole-4-carboxylic acid I (S)-3-inethyl-l1-[3-hydroxy- I-oxypyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl I amide Following the procedure of Example 85c except substituting isoxazole-4-carboxylic acid for benzo[bllthiophene-2-carboxylic acid the title compound was prepared: MS(EI) 524 3 ,S-Dimethyl-isoxazole4-carboxylic acid f(S)-3-methyl- I-[3-oxo- 1-(1 -oxypyridine- 2 -sulfonyl)-azepan4-ylcaramoyll-but,1)amide Following the procedure of Example I i except substuting 3 4-carboxylic acid (S)-3-methyl- I-[3-hydroxy-lI-( I-oxy-pyridine-2-sulfonyl).azepan4 ylcarbamoyl]-butyl )amide of Example 1 14a the title compound was prepared: 'H NMR (CDCIj: 8 1.0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.4 (mn, 3H), 2.6 (mn, 3H), 2.7 (in. I H), 3.8 I1-H); 4.0 (in, I1H), 4,5 I 4.7 (in, I 5.0 (mn, INH), 7.4-8.0 (mn, 5H), 8.1-8.2 (mn, MS(EI): 521 Example 115 Preparation of (S--2Bnzlx-ctva n)4methyl pntanoic acid r I -(4-methoxy.

benzenesulfonvi)3oxoaepan..4yl-amde f (S)-I1 -Hydroxy- Il-( 4 -methoxy-benzenesufonyl)epa-4-ylcarbamoyl- 3 methyl-butyl 1-carbamic acid-tert-butyl -ester.

Il-( 3 -Hydroxy-azepan4.ylcarbainoyl)-3inethyl butyl ]-carbamic acid-tertbutyl ester (compound 2g, 0.8 g. 2.33 inmol) was dissolved in I, 2 -dichloroethane (DCE, ml). Then, inorpholineinethyl polystyrene resin beads (1.26 a, 3.7 inmol/, Nova) were added and the solution was shaken for 5 minutes. T'hen, p-methoxybenzenesulfonyl chloride (0.48 g, 2.33 minol) was dissolved in DCE (10 ml), and this solution was added to the reaction mixture. The reaction was shaken overnight, filtered, washed with DCE (2 x ml). then (10 ml). The combined organics were concentrated in vacuo, and used in the -next reaction without further purification: M+H- 5 14.2.

2 -Amino.4-methyl.pentanoic acid [3-hydroxy-1I-( 4 -inethoxy-benzenesulfonyl)azepan-4-yl]-ainide.HCI salt f(S)-I -[3-Hydroxy-

I-(

4 -methoxy-benzenesufonyl)azepan.4ylcarbmoyI]- 3 methyl-butyl }-carbamic acid-tert-butyl ester (compound 207a, 0.59 1. 15 minol) was dissolved in CH,Cl, (8 ml), then a solution of 4 M HCI in dioxane (8 ml) was added and the reaction was stirred at RT for 4h. The reaction mixture was concentrated in vacuo, azeotroped from toluene twice (10 ml) in vacuo, and was used in the next reaction without further purification: M+W' 413.8.

2 2 -Benzyloxy-acetylamino).4-methyl-pentanoic acid [3-hydroxy-l1-(4methoxy-benzenesulfonyl)-azepan-4-yJ-anide (S)-2-Amino-4-methyl-pentanoic acid [3-hvdroxy-1I-(4-methoxy-benzenesulfonyl)azepan-4-yi]-amide-HCI salt (crude product from reaction mixture of I 15b) was dissolved in MeOH (10 ml) and was treated with carbonate-polystyrene resin beads (1.75 2.63 mmoi/g, 4.6 mmol) and was shaken for 2h, filtered, washed with MeOH (10 ml) and the combined organics were concentrated in vacuo. The product was then dissolved in DCE (2 ml) and morpholinemethyl polystyrene resin beads (0.25 g, 3.77 mmollgC,, 0.91 mmol, Nova) were added and the reaction was shaken for 5 minutes. Then, benzylacetyl chloride (0.081 g, 0.44 mmol) was added and the reaction mixture was shaken overnight. Then, trisamine polystyrene beads 1g, 3.66 mmollg. 0.366 mmol) was added and the reaction mixture was shaken for 1.5 h. The reaction mixture was then filtered, washed with DCE (2x 10 ml) and CHCI, (10 mli), and the combined organics were concentrated in vacuc. The crude product was used in the next reaction without further purification: M+W* 562.2.

(S)-2-(2-Benzvloxy-acetylamino)-4-methyl-pentanoic acid [1 -(4-methoxybenzenesulfonyl)-3-oxo-azepan- 4-yl]-amide (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy- 1-(4methoxy-benzenesulfonyl)-azepan-4-yl]-amide (compound 207c. 0.24 a, 0.44 mmol) was dissolved in CH,CL, (5 ml), then Dess-Martin periodinane (0.3 a, 0.7 mmol) was added and the reaction was stirred for 30 min. The reaction was diluted with CHCI, (20 ml), then was extracted with aqueous 10% NaS,0 5 (10 ml), then aqueous 10% NaHCO, (10 ml), water ml), brine (10 ml). The combined organics were concentrated in vacuo. The residue was purified by HPLC (50:50 Ethanol: hexanes, 2OmUmin, 25min, WhelkO-1I(R,R) 21x250mm column, UV detection at 280nm and 305nm) to yield the first elution as a white solid (47 mg, 43 MS 560.4 IH NMR (400Hz,CDC1 3 5 7.73 2H), 7.40- 7.30 (in, 5H), 7.05 3.99 2H1), 3.88 3H), 2.28-2.10 (mn, 211), 0.95 6H-) and second eluting, diastereomer: MS 560.2 Example 116 Preparation of 5-(3-Trifluorornethyl-phenyl)-furan-2-carboxylic acid f (S )-3-methyl- 14f3oxo- 1 -oxv-pvyridine-2-sulfonyl )-azepan-4-yicarbamoyl1-butyI I amide 5-(3-Trifluoromethyl-phenyl)-fuiran-2-carboxylic acid f (S)-3-methyl- I -[3-hydroxy- I -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide Following the procedure of Example 85c except substituting 5-(3-trifluoromethylphenyl)-furan-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 638 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxyl ic acid (S)-3-methyl-lI-[3-oxo- I-(1oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl }amide Following the procedure of Example 1i except substuting 5-(3-trifluoromethylphenyl)-furan-2-carboxylic acid I(S)-3-methyl- I -13-hydroxy- I -oxy-pyridine-2sulfonylI)-azepan-4-ylcarbamoyl)-butyl I amide of Example- 1'1 6a- the- title compound was prepared: 'H NMR (CDC1 3 8 1.0 (in, 6H), 1.5-2.1 (mn, 5H), 2.2 (in, 2H), 2.6 3H), 2.7 (in. 3 .8 I 4.1 (in, I1H), 4,7 I1H), 4.8 (mn, I 5.0 (in, IlH), 7.4-8.0 (in, 9H), 8.1-8.2 2H); MS(EI): 637 100%) The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 637 100%) and the slower eluting diastereomer MS(EI): 637 100%).

Example 117 Preparation of 5-Methyl-2 -ihenvl-oxazole4-carboxylic acid I(S)-3-inethv1-l1-f 3-oxo- 1-(1oxv-ovridine-2-sulfonyl)-azepan-4-ylcarbanioyll-butyI I amnide 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid (S)-3-methyl- I -[3-hydroxy- 1 oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbaxnoyll-butyl }amide Following the procedure of Example 85c except substituting 5-methyl-2-phenyloxazole-4-carboxylic acid for benzo[b~thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 585 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid I (S)-3-methyl- I-[3-oxo- 1-(1 -oxypyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyzj-butyl lamide Following the procedure of Example I i except substuting 5-methyl-2 -phenyloxazole-4-carboxylic acid (S)-3-methyl-l1-13-hydroxy- I-oxy-pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl I amride of Example I1I 7a the title compound was prepared: 'H- NMR (CDCI 3 8 1 .0 (in, 6H), 1.5-2.1 (in, 5H), 2.2 (in, 2H), 2.6 3H), 2.7 (mn. I 3.8 (q.

I 4.0 (in, I 4,5 i 4.7 (in, I 5.0 (in, I1H), 7.4-8.0 (in. 7H), 8.1-8.2 (in, 2H); MS(ED: 584 (M+Wr, 100%).

The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoeiner: MS(EI): 584 100%) and the slower eluting diastereomer MS(EI): 584 (M+WF, 100%).

Example 118 Preparation of Benzofuran-2-carboxvlic acid I(S)-I 1 -(3.4-dimethoxv-benzenesulfonvl)-3oxo-azepan-4-vlcarbamoyll-butvl -anide Benzofuran-2-carboxylic acid 14[ 1-(3,4-diinethoxy-benzenesulfonyl)-3hydroxy-azepan-4-ylcarbamoyl)-butyl }-arnide To a solution of benzofuran-2-carboxylic acid I-(3,4-dimethoxybenzenesulfonyl)-3-oxo-azepan.4-ylcarbamoyl]-buty J-ainide of Example 78c 175 g)in dichloromethane was added triethylainine 1 inL) and 3>,4-dimethoxybenzenesulfonyl chloride 12 The reaction was stirred until complete. Workup and column chromatography methanol:dicloromethane) provided the title compound (0.21 g): MS(ED) 587 Benzofuran-2-carboxylic acid 1-(3,4-diinethoxv-benzenesulfonyl)-3-oxoazepan-4-ylcarbamoylj-butyl }-amiide Following the procedure of Example I i except substuting benzofuran-2-carboxylic acid 1-ri 3 4 -dimethoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbanoyl-butyl)Iamnide of Example I I18a the title compound was prepared: 'H NMR (CDC1 3 5 1.-0 (171, 6H), 1.5-2.1 (in, 6H), 2.6 1H), 3.5 I 3.7 6H), 4.0 (mn, I 4,5 I1H), 4.7 (mn, 5.0 1H), 7.4-8.0 (in, 8H); MS(EI): 586 100%).

Example 119 Preparation of Benzofuran-2-carboxvlic acid 14 1 -(4-bromo-benzenesulfonyl )-3-oxoazepan-4-vlcarbamovl-3methl..butvI I-anide Benzofuiran-2-carboxylic acid 141 4 -bromo-benzenesulfonyl)-3-hydroxyazepan-4-ylcarbamoyl]-3-methyl-butyl }-amide Following the procedure of Example I1I 8a except substituting 4bromobenzenesulfonyl chloride for 3 A4-dimethoxybenzenesulfonyl chloride the title compound was prepared: MS(EI) 606 Benzofuran-2-carboxylic acid I 1 -[1I 4 -bromo-benzenesulfonyl)-3-oxo-azepan- 4 -ylcarbamoyl]-3-methyl-butyl I -ami~de Following the procedure of Example I i except substituting benzofuran-2-carboxylic acid f(S)-I 4boobneneufnl--yroyaea--laraol--ehl butyl}-am-ide of Example 1 19a -the title compound was prepared: 'H NMR(CDC1 3 5 (in, 6H), 1.5-2.1 (in, 2.6 (mn, I 3.5 I 4.0 (mn, I 4.5 I 4.7 (in, I (mn, I 7.4-8.0 (mn. 9H): MS(ED: 604 100%).

Exam le 120 Preparation of Benzofuran-2-carboxylic acid i 41r -(benzof 1 .2.51oxadiazole-4-sulfonyl 3 -oxo-azepan-4-vlcarbanovll-3-methvl..butvl I-arnide Benzofuran-2-carboxylic acid -(benzo [1 ,2,5]oxadiazole-4-sulfonyl)-3hydroxy-azepan-4.ylcarbanoyl.3-methyl..butyl 1-amnide Following the procedure of Example I I a except substituting benzofurazan-4sulfonyl chloride for 3,4-dimethoxybenzenesuffonyl chloride the title compound was prepared: MS(EI) 569 Benzofuran-2-carboxylic acid I -(benzo[ I .2,5)oxadiazole-4-#sulfonyl)-3-6xoazepan-4-ylcarbainoyl]-3-methyl-butyI I}-amide Following the procedure of Example I i except substituting Benzofurancarboxylic acid If(S)- I 41 -(benzo[ 1 2 .5]oxadiazole-4-sulfonyl)-3-hydroxy-azepan-4 ylcarbamoylj-3-methyl-butyll..amide of Example 120a the title compound was prepared: 'H NMR (CDCl,): 8 1.0 (in, 6H), 1.5-2.1 (mi, 2.6 (in, 1H), 3.7 (mn, 1H); 4.1 (mn, IH), 4.7 (in, 2H), 5.2 (in, I 7.4-8.0 (mn, 8H); MS(EI): 568 100%).

Example, 121 Preparation of Benzofuran-2-carboxvl ic acid f -(3.5-dimethvl-oxazole-4 -sulfonyl 3 -oxo-azepan-4-ylcarbamovl-3-methv...butyl l-amide Benzofuran-2-carboxylic acid I 1.4 1 -(3,5-dimethyl-oxazole-4 -sulfonyl)-3hydroxy-azepan-4-ylcaI-bamoyl]y3inethy1..butyI I -amnide Following the procedure of Example 1 18a except substituting 4-suiphonyl chloride for 3 4 -dimethoxybenzenesulfonyi chloride the title compound was prepared: MS(EI) 546 Benzofuran-2-carboxylic acid 1-[1 ,5-dimethyl-oxazole-4. -sulfonyl)-3-oxoazepan-4-ylcarbamoyll-3-methyl.butyl )-amide Following the procedure of Example 11 except substituting benzofuran-2carboxylic acid f I 3 ,5-dimethyl-oxazole-4-sulfonyl)-3-hydroxyazepa.4ylcarbamoyll-3-inethyl-butyl)-amide of Example 121a the title compound was prepared: 'H NMR (CDCI 1 6 1.0 (in, 6H), 1.5-2.2 (in, 2.2 (in, 2H), 2.4 3H), 2.7 3H), 3.6 IHI), 4.1 (in. I 4.4 IlH), 4.7 (mn, I1H), 5.2 (Mn, I 7.4-8.0 (in, MS(EI): 544 100%).

Example 122 Preparation of 3-Methvlbenzofuran-2-carboxyuic acid I(S)-3-nethvi- 14 3-oxo- I -(pyridine- 2 )-sulfonyl)-azepan-4-vlcarbainoyll-butyl I amnide 3-Methylbenzofuran-2-carboxylic acid (S)-3-inethyl- I-[3-hydroxy-l1-(pyridine-2sulfonyl)-azepan-4ylcarbamoyl]-buty ainide Following the procedure of Example 28b except substituting 3-methylbenzofuran- 2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 542 3 -Methylbenzofuran-2.carboxyiic acid f (S)-3-rnethyl- 1 -[3-oxo- I -(pyridine-2sulfonyl)-azepan-4-ylcarbamoyI]-butyl )ainide Following the procedure of Example li except substituting 3-methylbenzofuran-2carboxylic acid (S)-3-methyl- I-[3-hydroxy- I-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl~amide of Example 122a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (mn, 6H), 1.5-2.2 (in, 6H), 2.2 (mn, 2H), 2.6 3H), 2.7 (mn, IH), 3.8 (mn, 4.1 (in, 1H), 4.7 (in, 2H), 5.2 (mn, IH), 7.4-8.0 (mn, 7H): 8.7 (mn, IH); MS(EI): 540 100%).

The diastereoneic mixture was separated by HPLC to provide the faster eluting diastereoemer: 'H NMR 8 1.0 (mn, 6H), 1.5-2.2 (mn, 6H), 2.2 (mn, 2H), 2.6 3H), 2.7 I 3.8 IlH); 4.1 IlH), 4.7 (in, 2H), 5.2 (mn, I 7.4- 8.0 (mn, 7H); 8.7 (in, lH); MS(EI): 541 (M+W,100%) and the slower eluting diastereomer MS(EI): 541 100%).

ExaMple 123 Preparation of Thienof3.2-blthiophene-2-carboxvlic acid f(S)-3-nethvl- I-[3-oxo- 1- (pyridine- 2 -sulfonyl)-azepan-.4.vlcarbainoyll-butvl Iamide Thieno[3,2-b]thiophene-2-carboxylic acid 4 (S)-3-inethyl-lI-[3-hydroxy-lI-(pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyl]-butyl}anide Following the procedure of Example 28b except substituting thieno[3,2blrhiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 550 ThienoII3,2-blthiophene-2..carboxylic acid I (S)-3-methyl- I -[3-oxo- 1 -(pyridine-2sulfonyl)-azepan-4-ylcarbaxnoyl]-butyl) )amide Following the procedure of Example I i except substituting thieno[3,2-b]thiophene- 2-carboxylic acid 4 (S)-3-methyl-1I-[3-hydroxy-lI-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-butyl )ainide of Example 123a the title compound was prepared: 'H NMR (CDCL.): 5 1.0 (mn, 6H), 1.5-2.2 (mn, 6H), 2.2 (mn, 2H), 2.7 (mn, 1H), 3.8 (mn, IH); 4.1 (mn, I1-H), 4.7 (mn. 2H), 5.2 (mn, 1H), 7.4-8.0 (in, 8H): 8.7 (mn, I MS(EI): 548 100%).

The diastereomenic mixture was separated by HPLC to provide the faster eluting diastereoemer: 'HNMR 8 1.0 (in, 6141), 1.5-2.2 (mn, 6H), 2.2 (mn, 214) 2.7 t, I 3.8 IH4); 4.1 114), 4.7 (in, 28), 5.2 (mn, IH), 7.4-8.0 (in, 8H): 8.7 IH); MS(EI): 549 100%) and the slower eluting diastereomer MS(EI): 549 100%).

Example 124 Preparation of 5-rn-Buryl-3-methvl-thienof3.2-blthiophene-2carboxyl ic acid I (S methyl- I-[3-oxo- I-(pvridine-2-sulfonyl)-azepan-4-vlcarbamovil-butvl Iamide 5-rerr-Butyl-3-methyl-thieno[3,2-b~thiophene-2-carboxylic acid (S)-3-mnethyl-l1-[3hydroxy- I-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)ybutyl arnide Fol lowing the procedure of Example 28b except substituting 5-rerr-butyl-3 -methylthieno(3.2-b~thiophene-2-carboxylic acid for benzofuiran-2-carboxylic acid the title compound was prepared: MS(EI) 620 (MI).

5-zerr-Butyl-3-methyl-thieno[3,2.blthiophene-2carboxyic acid I (S)-3-methyl- 1 oxo- I-(pyridine-2-sulfonyl)-azepan4.ylcarbamoyly-butyl }ainide Following the procedure of Example I i except substituting 5-tert-butyl-3-inethylthieno[3.2-b]thiophene-2-carboxylic acid ((S)-3-methyl-lI-[3-hydroxy: 1 -(pyridine-2sulfonyl)-azepan-4-ylcarbamoyl]-butyI Jarnide of Example 124a the title compound was prepared: 'H NMR (CDCIlj: 8 1.0 (in, 6H), 1.45 9H), 1.5-2.2 (in, 68). 2.2 (in, 2H) 2-4 3H). 2.7 (mn, 18), 3.8 (in, IH), 4.1 (in, 18), 4.7 (in. 2H), 5.2 (in, 1H), 7.4-8.0 (in, 4H); 8.7 (mn. I MS(EI): 618 100%).

Example 125 Preparation of 5-Methyl-2-phenyl-oxazole-4-carboxylic acid f (S }-3-methvl- I 43-oxo- 1- (pvridine-2-sulfonvl)-azepan-4-vlcarbamovll -butyl ami~de 5-Methyl-2-phenyl-oxazole-4-carboxylic acid (S)-3-methyl- I-[3-hydroxy- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoylJ-butyI amnide Following the procedure of Example 28b except substituting 5-methyl-2-phenyloxazole-4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 569 5-Methyl-2-phenyl-oxazole-4-carboxylic acid f (S)-3-inethyl- 1 -13-oxo- I -(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide Following the procedure of Example I i except substituting 5-inethyl-2-phenyloxazole-4-carboxylic acid I (S)-3-methyl- 1 -[3-hydroxy- I -(pyridine-2-sulfonyl)-azepan-4ylcarbamoyll-butyl)amide of Example 125a the title compound was- prepared: 'H NMR (CDCI,): 8 1.0 (mn, 6H), 1.5-2.2 (in, 6H), 2.2 (mn, 2H), 2.7 (in, 1H), 2.6 (in. 3H), 3.8 (mn, I1H); 4.1 (mn, 4.7 (in, 2H), 5.2 (mn, 1H), 7.4-8.0 (mn, 8H); 8.7 (in, I1H); MS(EI): 567 100%).

The diastereomeric mixture was separated by HPLC to provide the faster eluting diasterecemer: MS(EI): 568 and the slower eluting diastereomer MS(EI): 568 (M+W,100%) Example 126 Preparation of 2-Phenvl-5-trifluoromethvl-oxazole-4-carboxylic acid I (S)-3-mnethyl- 1-13oxo- I-(2yridine-2-sulfonyfl-azepan-4-ylcarbamoyll-butvl Iamide 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid I (S)-3-methyl-1 -[3-hydrox- I (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl amide Following the procedure of Example 28b except substituting trifluoromethyl-oxazole-4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 623 2 -Phenyl-5trfluoromethyl.oxaole-4..caoxylic acid (S)-3-methyl-lI-[3-oxo-

I-

(pyridine- 2 sulfony)azepa-4ylcarbamoyl]-buty Jami~de Following the procedure of Example I i except substituting trifluoromethyl-oxazole-4carboxylic acid (S)-3-methyl-lI-[3-hydrox- I-(pyridine-2sulfonyl)-azepan-4-yicarbamoyl]-butyl~amide of Example 126a the title compound was prepared: 'H NMR (CDCI 3 8 1.0 (in. 6H), 1.5-2.2 (in, 6H), 2.2 (in, 2H), 2.7 (in. IH), 3.8 (in, I 4.1 (in, I 4.7 (mn, 2H), 5.2 (in, I 7.4-8.0 (in, 8.7 (in, I MS(EI): 621 100%).

The diastereomeric mixture was separated by HPLC to provide the faster eluting, diastereoemer: MS(EI): 622 and the slower eluting diastereomer:

MS(EI):

622 (M 100%).

Example 127 Preparation of Ouinoline-2-carboxvlic acid f(S)-I I -ethanesulfonvl-3-oxo-azrpan-4 vlcarbaiov)3methvlbutvl-atd Following the procedure of Example 75, except substituting mnethanesulfonyl chloride for thiazole-2-sulfonyl chloride and 2 -quinoline carboxylic acid for benzofuran-2carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting- diastereomer; MS 475.2; IH-NMR (400 MHz, CDCI 3 8.65(d, IH), 8.

35 -8.28(q, 8.20-8.18(d. lH), 7.9 I-7.89(d, lH), 7.80-7.78(t, lH), 7.67-7.65(t, 1H), 7.I10(d, I 5.08(m, I 4.73 (mn, I 4.56-4.5 1(d, I 4 .00(m, I 3.67-3.62(d, I H), 1.91 3H), 2.70(m, 1H), 2 3 2-2. 10(m, 1.

9 5 -1.40(m, 5H), 1.0 2 -l1.00(m, 6H); and the second eluting diastereomer: MS 475.2 Example 128 Preparation of I -Methyl- I H-indole-2-carboxvlic acid (S 1 -iethanesulfonv-3.oxoazepan-4-vlcarbamoyl 3 -methvl-butvll-aride Following the procedure of Example 75. except substituting inethanesulfonyl chloride for thiazole-2-sulfonyl chloride and N-methylindole.2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by 1{PLC. First eluting diastereomer; MS 477.2; 1 H-NMR (400 MHz, CDCI 3 7.65-7.63(d, 1H), 7.39-7.33(m, 2H), 7.17-7.14(t, 6.98-6.95(m, 2H1), 6.65(d, 114), 5.08(m, I 4.68 (in, I1H) 4.56-4.52(d, I 4.03(rm, 4H), 3.67-3.63(d, I 2.92(s, 3H), 2.7 1 I 2.32-2.l1O(m, 2H), 1.95-1.40(m, 5H), ].02-l1.00(d, 6H1); and the second eluting diastereomer: MS 477.2 Example 129 Preparation of Furan-2-carboxylic acid 1 -methanesulfonvl-3-oxo-azepa-4vlcarbamovl)-3-methvl-butylcarbamovl-methyl)-amide Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine for benzofuran- 2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC.

First elutingy diastereomer; MIS 471L2; 1 H-NMR (400 MHz-CDC1 3 -7.50(m, 1H), 7.15(m. 1H), 7.05(m, IH), 6.90(d, 1H), 6.55(m,. 2H), 5.08(mn. I 4.55 (mn, 2H), 4.12(m, 2H), 4.05(m, I 3.70(d, I 2.92(s, 3H), 2.75(m, I1H), 2.20-1.40(m, 7H), 0.95 (in, 6H); and the second eluting diastereomer: MIS 471.4.

Example 130 Preparation of 5-Methoxvbenzofulran-2-carboxylic acid F(S)-I -methanesulfonvl-3-oxoazep~an-4-vlcarbamovl )-3-methvl-butyll-arnide Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer, MIS 494.2; 1 H-NMR (400 MHz, CDC1 3 7.42-7.40(d, 2H), 7.08-6.94(mn, 4H), 5.10(m, 4.71l(m, IH), 4.56-4.52(d, IH), 4.02(m, III), 3.86(s, 3H), 3.68-3.63(d, 1H), 2.92(s, 3H), 2.72(m, 1H), 2.30-1.15(m, 2H), 1.95- 1 .40(m, 5H), 0.99 6H); and the second eluting diastereomer: MIS 494.2.

Example 131 Preparation of Quinoxal ine-2-carboxvlic acid 1-(0 -methanesulfonvl-3-oxo-azepan.4vicarbamovl )-3-methvl-butvl Varnide Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran- 2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC.

First eluting diastereomer; MS 476.2; 1 H-NMR (400 MHz, CDC1 3 9.66(s, 1 8.38(d, I 8.20-8.18(m, 2H), 7.88(m, 2H), 7.01 I 5. 1O(m, IlH), 4.77(m, I H), 4.57-4.52(d, IH), 4.08-4.00(m, IH), 3.69-3.64(d, 1H), 2.92(s, 3H), 2.71(m, 2.42- 2.15(m, 2H), 1.95-1.42(m, 5H), 1.02-1.01(d, and the second eluting diastereomer: MIS 476.2.

Example 132 Preparation of 5-(4-Chloro-phenv)-furan-2-carboxvhtic acid f (S)-3-methvI- 1 43-oxo- 1- (Pvridine-2-sulfonvl )-azepan-4-vlcarbamovll-butvl Iamide 5-(4-Chloro-phenyl)-furan-2-carboxylic acid (S)-3-methyl-lI-[3-hydroxy- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamov]-butyl )arnide Following4 the procedure of Example 28b except substituting 5-(4-chlorophenyl)-2furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 590 5-(4-Chloro-phenyl)-furan-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine-2sulfonyl)-azepan-4-ylcarbamoyl)-butyl )axnide Following the procedure of Example I i except substituting 5-(4-chloro-phenyl)furan-2-carboxylic acid (S)-3-methyl-lI-[3-bydroxy-l1-(pyridine-2-sulfonyl)-azepan-4ylcarbaxnoyl]-butyl) )anide of Example 132a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (mn, 6H), 1.5-2.1 (mn, 5H), 2.2 (mn, 2H), 2.7 lH), 3.7 1W), 4.0 (mi, 1H), 4.7 (mn, 2H), 5.0 (mn, I 6.7 (in, I 7.2 (in, I 7.3 (in, 2H), 7.5 (mn, I 7.7 (mn, 2H), (mn, 2H), 8.7 (in, 1H): MS(EI): 587 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 587 100%) and the slower eluting, diastereomer: MS(EI): 587 100%).

Example 133 Preparation of (S)-2-r2-(4-Methoxy-phenyl )-acetvlami~no)-4-methvl-pentanoic acid (1Imethanesulfonvl-3-oxo-azepan-4-vl)-amide Following the procedure of Example 75, except substituting 4- methanesulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 468.2; 1 H-NMR (400 MHz, CDCI 3 7.19-7.17(d, 2H), 6.90-6.88(d, 3H), 5.83-5.8 1(d, I 5.00(m, I1H), 4.53-4.40(m, 2H), 4.03- 3.99(m, IH), 3.81(s, 3H), 3.66-3.61(d, IH), 3.53(s, 2H), 2.91(s, 3H). 2.73(t, LH), 2.22- 2. 10(m, 2H), 1.99( m, I 1.62-1.35(m, 4H), 0.90-0.88(d, 6H); and the second eluting diastereomer: MS (M+H 4 468.2.

Example 134 Preparation of Ouinoline-2-carboxylic acid I-fl -(2-cvano-benzenesulfonvl)-3-oxoazepan-4-ylcarbamovll-3-methvl-butyI I -amide Following the procedure of Example 75, except substituting 2 cyanobenzenesulfonyl chloride for thiazole-2-sulfonyl chloride and quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 562.2; 1 H-NMR (400 MHz,

CDCI

3 8.65(d, I 8.48-8.40(q. 2H), 8.

2 5-8.l10(q, 2H), 7.91-7.65(m, 6H); and the second eluting diastereomer:, 7.12(d, I1H), 5.I0 I 4.73 (mn, I H) 4,61-4.56(d, IH),4.20(m, IH),3.73-3.68(d, IH), 2.80(m, IH), 2.27(m, 2H1), 1.91-1.40(m, 5H), 1.03- 1(m, 6H); and the second eluting diastereomer: MS 562.2.

Example 135 Preparation of I -Methyl-I H--indole -2-carboxylic acid I I -rI -(2-cvanobenzenesulfonvl )-3-oxo-azepan-4-ylcarbarnovl i-3-methvl-butvl -amidde Following the procedure of Example 75, except substituting 2cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methylindole-2carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The resdue was purified by HPLC. First eluting diastereorner; MS 564.2; 1

H-NMR

(400 MHz, CDCI 3 8.13(d, I 7.89(d, IH), 7.77-7.67(m, 3H), 7.38-7.16(m, 4H), 6.97(s, I 6.70(d, IlH), 5.05(m, I 4.70-4.60 (in, I 4.55-4.50(d, I 4.07(m, I1-H), 4.05(s, 33H), 3.76-3.7 1(d, I 2.75(m, I 2.30(m, 2H), 2.00-1.45(m, 5H), 1.00(d, 6H); and the second eluting diastereomer: MS 564.2.

Example 136 Preparation of Furan-2-carboxvlic acid U I -(2-cvano-benzenesulfonyl)-3-oxo-azepan- 4-vlcarbamovl 1-3-methvl-butvlcarbamovl) -methyl )-amide Following the procedure of Example 75, except substituting 2cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)glycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 558.2; 1 H-NMR (400 MHz, CDCIM: 8.14-8.12(d, IH), 7.91-7.90(d. 1H), 7.80-7.72(m. 2H), 7.48(s, 1H), 7.14(d, 2H), 6.98(d, IH), 6.80(d, 1H), 6.52-6.51I(t, IH), 5.03(m, lH), 4.60-4.53 2H), 4.17- 4.14(m,. 3H), 3.74-3.69(d, I 2.80(m, I 2.25(m, 2H), 2.00-1.40(m, 5H), 1.03-l1.0 1(m.

6H); and the second elutinig diastereomer: MS 558.2.

Examle 137 Preparation of 5-Methoxvbenzofuran2carboxylic acid f I- J 142-cvanobenzenesulfgnl)3oxoaze~yan-vcraovl3methybuty I-amide Following the procedure of Example 75, except substituting 2cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2carboxylic acid for benzofuran-2-carboxylic acid, the title compounid was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 581.4; 1

H-NMR

(400 MHz, CDCI 3 8. 15-8.13(d, 111), 7.92-7.90(d. 111), 7 .81-7.74(m, 7 4 2-7.40(m, 2H). 7 .08-7.03(m, 6.96(d, I 5.10(m, 1H1), 4.72-4.60 (in, 2H), 4.17 IH), 3.85(s, 3H), 3.75-3.70(d, IH), 2 .83-2.76(t, 1H), 2.27(m. 2H), 1.

9 2-1.51(mn, 5H), 1.

02 -1.01(m, 6H); and the second eluting diastereomer: MS 581.2.

Example 138 Preparation of uinoxaline-2-carboxylic acid f(s)-l -r I 2 -cvano-benzenesulfonv)3oxoazepan-4-vlcarhamnvll'Imethvl-butvl- amide Following the procedure of Example 75, except substituting 2cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was-prepared. Thie residue was purified by I-PLC. First eluting, diastereomer: MS 563.2; IH-NMR (400 MHz, CDC1 3 9.65(s, IH), 8.40(m, 111), 8.

2 2 -8.10(m, 3H), 7 9 0- 7 .22(mn, 5H), 7.00(d, IH), 5.10(m. IH), 4.75(m, 4.65-4.60(d, IH), 4 2 0-4.10(m, IH), 3.72-3.70(d, lH), 2.70(mn, IH), 2.38(m, 2H), 1.

9 5 -1.40(m, 5H), 1 .02(d, 6H); and the second eluting diastereomer: MS 563.2.

Example 139 Preparation of 2 -r 2 4 -Methoxy-Rhenvl)-acetvarino)-.4-methvl-Rentanoic acid 14-2cvano-benzenesulfonvl )-3-oxo-azepan-4-vl 1-amide Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 555.2; IH-NMR (400 MHz, CDCI 3 8.14-8.12(d, lH), 7.91-7.89(d, IH), 7 .79-7.73(m, 2H), 7.19-7.17(d. 2H), 6.90-6.88(d, 3H-), 5.80(d, I 5.02(m, I1H), 4.59-4.55(d, I1-H), 4 .45-4.42(m. I 4.18-4.15(m, I 3.82(s.

3H), 3.72-3.67(d, 3.53(s, 2H), 2.82-2.79(t, IH), 2.22(m, 2H), 1.92( m, 1H), 1.60- 1.30(mn, 4H), 0.9 1-0.89(d, 6H); and the second elutin'a diastereomer: MS (M 555.2.

Example 140 Preparation of Quin ol ine-2-carbox ylic acid f 1-rfI -(4-methoxv-benzenesulfonvl)-3-oxoazepan-4-vlcarbarnovll-3-methv-butvl) -amide Following the procedure of Example 75, except substituting 4methoxybenzenesulfonyl chloride for thiazole-2-sulfonyl chloride and 2-quinoline carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 567.2: 1

H-NMR

(400 MHz, CDCI 3 8.72-8.61(d, 1H), 8.

3 5-8.28(q, 2H) 8.21-8.18(d, I1H), 7.91-7.60(m, 5H), 7.10-6.99(m, 5.05(m, I 4.73 (in, I H) 4,59-4.52(d, I H),4.00(m. I 3.88(s, 3H), 3.45-3.38(d, 1H), 2.42(m, IN), 2.30-1.35*(Mn, 7H), 1.03-1.01(m, 6H), and the second eluting diastereomer: MS (M+H 4 567.2.

Example 141 Preparation of I1-Methyl- I 11-indole-2-carboxylic acid f r(S)-I14fl -(4-rnethoxybenzenesulfonyl )-3-oxo-azepan-4-vlcarbamoyl 1-3-methvl-butyI I -amide Following the procedure of Example 75, except substituting 4methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methyl-indole-2carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MIS 569.2; IH-NMR (400 MHz, CDCI 3 7.78-7.72(d, 2H), 7.70-7.65(d, I 7.42-7.30(m, 7.17-7.14(t, IH), 7 .05-6.95(m, 4H), 6.65(d, lH), 5.05(m, IH). 4.70-4.50 (in, 2H), 4.03(s, 3H), 3.88(s, 3H), 3.45-3.40(d, I1H), 2.45(m, I1-H), 2.30-2. 10(m, 1.90-1.35(m, 6H); and the second eluting diastereomer:, 1 .00(d, 6H), and the second eluting diastereomer: MS 569.2.

Example 142 Preparation of Furan-2-carboxvlic acid I -[1I -(4-methoxv-benzenesulfonvl)-3-oxoazepan-4yicarbamoyl1-3-methyl-butvlcarbamovI 1-methyl )-arnide Following the procedure of Example 75. except substituting 4inethoxyphenylsulfonyl chloride for thiazole-2-sulfonvl chloride and N-(2-furan-carbonyl)gl,-ycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 563.2; 1 H-NMR (400 MHz, CDCI 3 7.74-7.72(d, 2H), 7.47 I 7.15-6.99(m, 4H), 6.9 1(d, IlH), 6.70(d, I H), 6 .5 2 -6.5 1(m, 1LH), 5.01(mn, I 4.53-4.49 2H), 4.17-4.14(m, 2H), 4 .OO-3.90(m, I H), 3.88(s, 3H), 3.45-3.41(d, IH), 2.47(m, I 2.17(m, 1.85-1.40(m, 5H), 0.95(m, 6H); and the second eluting diastereomer: MS 563.2.

Example 143 Preparation of 5-Methoxvbenzofuran-2-carboxylic acid f I-fi I-(4-methoxybenzenesulfonyl)-3-oxo-azepan-4-vlcarbamo-Yll-3-methvl-butvI I-arnide Followinga the procedure of Example 715, except substituting 4methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 586.2; IH-NMR (400 MHz, CDC1 3 7.75-7.73(d, 2H), 7.42-7.40(m, 2H), 7.08- 6.99(m, 5H), 6.91(d, IH), 5.05(m, IH), 4.70-4.55(mn, 2H), 4.05-4.00(m, 1H), 3.89(s, 3H-), 3.86(s, 3I), 3.45-3.40(d, I 2.50-2.40(m, I1H), 2.30-2. 10(m, 2H), 1.90-1.35(m, 1.0O1(m, 6H), and the second eluting diastereomer: MS 586.2.

Example 144 Preparation of Quinoxaline-2-carboxvlic acid (S I -1 -(4-methoxv-benzenesulfonvl)-3oxo-azepan-4-vicarbamovl-3-methvl-butvl -amide Following the procedure of Example 75, except substituting- 4methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The ridue was purified by HPLC. First eluting diastereomer; MS (M+H 4 568.2; 1 H-NMR (400 MHz, CDC1 3 9.66(s, 1H), 8.40-8.35(m, I 8.19(m, 2H), 7.88(m, 2H), 7.75- 7.73(d, 7.02-6.90(m, 5.10-5.05(m, 1H), 4.75(m, IH), 4.60-4.55(d, 1H), 4.05- 3.95(m, I1H), 3.89(s, 3H), 3.45-3.4 1(d, I1-H), 2.45(m-, I 2.30-2. 10(m, 2H), 1.95-1.40(m, 1.04-1 .02(d, 6H); and the second eluting, diastereomer: MS 568.2.

Example 145 Preparation of (S )-2-r2-(4-MethoxY--phenyl)-acetylarmino)-4-methyl-pentnoic acid r 1 methoxv-benzenesulfonvl )-3-oxo-azepan-4-vll-amide Following the procedure of Example 75, except substituting 4methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MIS 560.4; 1

H-NMR

(400 MHz, CDCI 3 7.74-7.7 1(d, 2H), 7.19-7.17(d, 2H), 7.01-6.99(d, 2H), 6.90-6.88(d, 2H). 6.85(d, IH), 5.8 1(d, IH), 4.99(m, IH), 4.55-4.44(m, 2H), 3.97(m, lH), 3.88(s, 3H), 3.8 1 3H), 3.53(s, 2H), 3.43-3.38(d, I 2.43(t, I 2.14(m, 2H), 1.85-1.35(m, 0.90-0.89(d, 6H); and the second eluting diastereomer: MS 560.2.

Example 146 Preparation of I1-Methyl- I H-indole-2-carboxylic acid I 14 14-4-fluorobenzenesulfonyl)-3-oxo-azepan-4-vlcarbanoyll-3-methvl-butvl I -amide Following the procedure of Example .75, except substituting 4fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-rnethyl-indole-2carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diast ereomer; MS 557.2; IH-NMR (400 MHz, CDC1 3 -7.84-7.80(m, 2H1), 7.66-7.65(d, 111), 7.40-7.14(m, 6.95(m, 2H), 6.65-6.63(d, I1H), 5.07(m, IlH), 4.68-4.55 (in, 2H), 4.04(s, 3H), 3.48-3.43(d, I 2.49(m, IH), 2.25(mn, 2H), 1.89-1.38(m, 6H); and the second eluting diastereomer:, 1.01(d, 6H1); and the second eluting diastereomer: MS (M+H 4 557.4.

Example 147 Preparation of Furan-2-carboxylic acid I-r I -(4-fluoro-benzenesulfonyl)-3-oxoazepan-4-ylcarbamoyl 1-3-rnethvJ-burylcarbamoyl)I-methyl)-amide Following the procedure of Example 75, except substituting 4fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)glycine for benzofuran-2-carboxyiic acid. the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 551.4; 1 H-NMR (400 MHz, CDCI 3 7.8 1I(m, 7.48(s, I 7 27 -7.16(m, 3H), 7.05(m, I 6.90(d, I H), 6.52(m, 2H), 5.00(m, I 4.60-4.48 (mn, 2H), 4.14(m, 2H), 4.00-3.90(d, I1H), 3.48-3.44(d, 1W), 2.50(m, 1H), 2.20(m, 2H), 1.90-1.40(m. 5H), 0.95(m, 6H); and the second eluting diastereomer: MS 551.2.

Exampile 148 Preparation of 5-Methoxvbenzofuran-2-carboxylic acid f 1-(4-fluorobenzenesulfonvl 3 -oxo-aZepan-4vlcarbamoyll-3-methvl-butyl I-amide Following the procedure of Example.75, except substituting 4fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2carboxylic acid for benzofuran-2-carboxyiic acid, the title compound was prepared. The residue was purified by H-PLC. First eluting diastereomer; MS 574.2; 1

H-NMR

(400 MHz, CDC1 3 7 8 4-7.81(m, 2H), 7 .42-7.40(mn, 2H), 7.27-7.22(m, 2H), 7.08-7.04(m, 3H),P 6.93(d, I 5.10-5.02(m, I 4 .6 9 -4.55(m, 2H), 4 .05-4.00(m, I1H), 3.86(s, 3H), 3.47- 3.43(d, 1WH). 2.49(m, I1H), 2.24(mn, 2H), 1.

9 0-1.40(m, 5H), 1.0i1(m, and the second eluting diastereoiner: MS 574.2 Example 149 Preparation of Ouinoxaline-2-carboxylic acid 14-[1 -(4-fluoro-benzenesulfonyl)-3-oxazepan-4-vlcarbamovll-3-methyl-butyI I-amide Following the procedure of Example 75, except substituting 4fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and qui noxaline-2carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MIS 556.2; 1

H-NMR

(400 MHz, CDCI 3 9.66(s, ILH), 8.40-8.35(d, I 8.21-8.18(m, 2H), 7.90-7.8 1(m, 4H), 7.27-7.22(m, 2H), 6.97(d, I 5.10-5.02(mn, I 4.75(m, I1H), 4.59-4.55(d, I 4.05- 4.39(m, IH), 3.48-3.44(d, IH), 2.49(m, IN), 2.32-2.10(m, 2H), 1.90-1.40(m, 5H), 1.03- 1 .02(d, 6H); and the second eluting diastereomer: MS 556.2.

Examn~Ie 150 Preparation of (S)-2-[2-(4-Methoxv-phenyl)-acetvlamnino)-4-methvl-pentanoic acid 1-44 fluoro-benzenesulfonvl)-3-oxo-azepan-4-vll-amide Following the procedure of Example 75, except substituting 4fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 548.2; 1

H-NMR

(400 MHz, CDCI 3 7.83-7.80(m, 2H), 7.27-7.17(m, 4H), 6.90-6.88(d, 3H), 5.85(d, 1H), 4. 98(m, INH), 4.55-4.43(m. 2H), 4.00-3.97(m, IH), 3.8 1(s, 3H), 3.53(s, 2H), 3.45-3.41(d, I1H), 2.48(t, I 2.17-2.14(m, 1.90-1.30(m, 5H), 0.90-0.88(d, 6H), and the second eluting diastereomer: MS 548.4.

174 Example 151 Preparation of Benzofuran-2-carboxyljc acid- f (S I-[1 -(3-chloro-benzenesulphonyl )-3-oxoazepan-4-vlcarbamoyll-3-methyl-butyI I-amide I 1-(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan..4-ylcarbamoyl]-3-methylbutyl }-carbaxniic acid tert-butyl ester To a solution of the compound of Example 2g (2.50g, 7.29mmol) in DCE (100m]) was added P-NMM (4.0g) and 3-chlorobenzenesulphonyl chloride (1.85g, 8 After shakingy at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (3.13g, MS: 539.78 (S)-2-Arniino-4-methyl-pentanoic acid [I -(3-chloro-benzenesulfonyl)-3-hydroxyazepan-4-yl]-amride To a stirring solution of the compound of Example 151 a (1.0g, 1 .93mmol) in rnethnol (10 ml) was added HCI (4M in Dioxane) (10 ml). After stirring at room temperature for 3 hr the solution was concentrated to provide a white solid. To a solution of the white solid (0.68 g, 1.50 mmol, 78%) in methnol (37 ml) was added P-CO 3 (2.85c, 2.63mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.59g., 1.42 mmol, MS: 417.86 Benzofuran-2-carboxylic acid- -(3-chloro-benzenesulphonyl)-3-hydroxyazepan-4-ylcarbaxnoyl]-3-methyl-butyI -amide To a solution of the compound of Example 151b (0.14ga, 0.33 mmol) in CH,Cl, mL) was added benzofuran-2-carboxylic acid (0.81, 0.50 mmol), I1-hydroxybenzotriazole (0.77 0.57 mmol). and P-EDC (0.67g, 1 mmollg) in CI-,C1, (10 mL). After shaking at room temperature overnight, the solution was treated with tisamine (0.45 g, 3.75 mmollg).

After shaking, for another 2 hr. the solution was filtered and concentrated to yield the title compound as a white solid (122 mg, MS (ESI): 562.2 Benzofuran-2-carboxylic acid- I -(3-chloro-benzenesulphonyl)-3-oxoazepan-4-ylcarbamoyl]-3-methyl-butyl }-amide To a stirring solution of the compound of Example 15 1c (122 mg, 0.22 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (185 mg, 0.44 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mIL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous layer was extracted with dichlorornethane The organic phases were combined, washed with saturated brine. dried (1460,), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (62.7 mg, 51.6 MS (ESI): 560.2 and the second eluting diastereomer as a white solid (40.2 mg, 33.1 MS (ESI): 560.2 Example 152 Preparation of 5-Methoxybenzofuran-2-carboxvlic acid-( -r1 -(3-chlorobenzenesulphonvl)-3-oxo-azepan-4-v.lcarbamovll-;3-methvl-butvI I -amide Following the procedure of Example 151c-d, except substituting methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 15 1 c provided the title compound which was separated by HPLC-to give the first eluting diastereomer as a white solid (64.4 mg, MIS (ESI): 590.2 and the second eluting distereomner as a white solid (44.4 mg, MS (ESI): 590.2 Example 153 Preparation of 7-Methoxybenzofuran-2-carboxvlic acid-( -r l-(3-chlorobenzenesulphonvl')-3-oxo-azepan-4-ylcarbamovll-3-methvl-butvl I-amnide Following the procedure of Example 15 1 c-d except substituting 7methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 15 1c provided the title compound which was separated by HPLC to give first eluting diastereomer as a white solid (51.1mg, MS (ESI): 590.2 and the second eluting diastereomer as a white solid (36.7 mg, MS (ESI): 590.2 ErnpIe 14 Preparation of 5.

6 -Dimethoxybenzofuran-2car.boxyI ic acid- I I -f -(3-chlorobenzenesulphonvl)3oxo.azean4vicarbamoli-3methvl-butvI I -amfide Following the procedure of Example 151Ic-d except substituting 5,6dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 15 1 c provided the title compound which was separated by HPLC to grive first eluting diastereomer as a white solid (5 1. 1mg, MIS (ESI): 622.2 and the second eluting diastereomer as a white solid (36.7 mg, MIS (ESI): 622.2 Example 155 Preparation of 3 -Methvbenzofuran-2-carboxvlic acid-I I1-fl -(3-chioroben zenesu lphonv)3oxoaean.4-vlcairbamovI 1-3methvl-butv I-amide Following the procedure of Example 15 1 c-d except substituting 3methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 15 1c poided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid 7 8.6mg, 63. MIS (ESI): 574.2 and the second eluting diastereomer as a white solid (40.7mg, MS (ESI): 574.2 Example 156 Preparation of Benzofbthiohene-2.carboxvlic acidi 1-Fl 3-chiorobenzenesulphonvl 3 -oxo-azepan-4-vlcarbamoyv13-methl.but1 I -amide Following the procedure of Example 15 lc-d except substituting benzo~b]thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid in step 15 1 c provided the title compound which was separated by 1-PLC to give the first eluting diastereomer as a white solid (41.0 mei, MS (ESI): 576.2 and the second eluting diastereomer as a white solid (31.0 mg, MIS (ESI): 576.4 Example 157 Preparation of I -Methvl- I H-indole-2-carboxvlic- acid- (f(S -1i-fi -(3-chiorobenzenesulphonvl)-3oxo-aean-.vcarbamovl 1-3-methyl-butvI I-amide Following the procedure of Example 151c-d except substituting 1-methylindole-2carboxylic acid for benzofuran-2..carboxylic acid in step 151c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (28.5 Ma, MS (ESI): 573.2 and the second eluting, diastereomer as a white solid 2 8 .5mg, MS (ESI): 573.2 Example 158 Preparation of uinoxaine-2-carboxvlic acid-(f CS)- I-[1 3 -chloro-benzenesulphonvl)-3 oxo-aze an-4-vcarbamovl -3-meth 1-butvi -amid-e Following the procedure of Example 15 1c-d except substituting quinoxaline-2carboxylic acid for benzofuran-2-carboxylic acid in step 15 1ic provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (63.1 mg. MIS (ESI): 572.2 and the second-eluting distereomer as a white solid (43.2 mg, MS (ESI): 572.2 Example 159 Preparation of Benzofuran-2..carboxylic acid- I-r I 2 -fluoro-benzenesulphonyl)3oxoazepan- 4 -yicarbamoyI1.3-me hyl-butyl -aride I 1-( 2 Fluorobenzenesunlf3hon)3yarox-4ylcamycl] 3 ehyl butyl)}-carbarnic acid tert-butyl ester To a solution of the compound of Example 2g (1.03 a. 3.00 mmol) in DCE (20 ml) was added P-NMM (1.65 g. 3.64 mmol',g) and 2 -fluorobenzenesulphony Ichloride (0.70 ga 3.60 mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (1.13 g, MS: 523.88 2 -Amino4-methyl-pentanoic acid [l-(2-fluoro-benzenesulfonyl)-3-hydroxyazepan-4-yl]-amide To a stirring solution of the compound of Example 159a (1.13 g, 2.25 mmol) in methnol (15 ml) was added HCI (4M in dioxane) (15 ml). After stirring at room temperature for 3 hr, the solution was concentrated to get white solid. To a solution of the white solid (1.11 g, 2.60 mmol, 75%) in methnol (50 ml) was added P-CO, (5.70 g, 2.63 mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.868g, 2.16mmol, MS: 401.96 Benzofuran-2-carboxylic acid- 1 -(2-fluoro-benzenesulphonyl)-3-hydroxyazepan-4-ylcarbamoyl]-3-methyl-butyl} -amide To a solution of the compound of Example 159b (0.11 g, 0.26 mmol) in CH,C1, mL) was added benzofuran-2-carboxylic acid (64.7 mg, 0.39 mmol), 1hydroxybenzotriazole (61.1g, 0.45 mmol), and P-EDC (0.53 g, I mmol/g) in CHLC1, mL). After shaking at room temperature overnight, the solution was treated with tisamine (0.35 g, 3.75 mmol/g). After shaking for another 2 hr, the solution was filtered and concentrated to yield the title compound as a white solid (103.5 mg, MS (ESI) 546.2 Benzofuran-2-carboxylic acid- 1-(2-fluoro-benzenesulphonyl)-3-oxoazepan-4-ylcarbamoyl]-3-methyl-butyl }-amide To a stirring solution of the compound of Example 159c (103.5 mg, 0.19 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (164.7 mg, 0.39 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane The organic phases were combined, washed with saturated brine, dried (MgSO 4 filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (76.2 mg, 73.6 MS (ESI) 544.2 (M+H) and the second eluting diastereomer as a white solid (20.7mg, 20.0%) MS (ESI) 544.4 (M+H) Example 160 Prenaration of S-Methoxvbenzofuran-2-cariboxvlic acid- I- IF -(2-fluorobenzenesulphonyl)-3-oxoazepan.4..lcarbamovl-3methvl-butvI I-amide Following the procedure of Example 159c-d, except substituting methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 1 59c provided the title compound which was separated by HPLC to give the first eluting diastereorner as a white solid (48.3 mg, 59.2%) MS (ESI): 574.2 and the second eluting diastereomner as a white solid (24.2mg, 29.6%) MS (ESI): 574.2 Example 161 Preparation of 7 -Methoxvbenzofuran-2-carboxvic acid- f 14 1 -(2-fluorobenzenesulphonvl 3 -oxo-azepan-4ylcarbamovl 1-3-methyl-butyl -amide Following the procedure of Example 159c-d except substituting 7methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (47.7 mg, MS (ESI) 574.2 and the second elutin2 diastereomer as a white solid (27.7 mg, 33.9%).

Exmple 162 Pr eparation of 5 6 -Dimethoxvbenzofuran-2-carboxvlic acid- 14 -(2-fluorobenzenesulphonyl).3-oxo-azepan.4-vlcarbamovl1.3-methyl-butyl -arrde Following the procedure of Example 1 59c-d except substituting 5,6dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 1 59c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MS (ESI) 606.4 and the second eluting, diastereomer as a white solid MS(ESI) 606.4 180 Example 163 Preparation of 3-Methvlbenzofuran-2-carboxylic acid-I 1-4 -(2-fluorobenzenesulphonvl )-3-oxo--azepan-4-vlcarbarrovI 1-3-methvl-butv] -amide Following the procedure of Example 159c-d except substituting 3methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 160c prvded the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (50.5 mg, MS (ESI) 558.2 and the second elutinfg, diastereoemer as a white solid (20.6 mg); MS 558.2 Example 16 Preparation of Benzorblthiophene-2-carboxvlic acid- f(S I -r I -(2-fluorobenzenesulphonyl 3 -oxo-azepan-4-vicarbamovil-3-methvi-butvI I -amide Following the procedure of Example I 59c-d except substituting benzo[bjthiophene- 2-carboxylic acid for benzofuiran-2-carboxylic acid in step 159c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (52.5 mg, MS (ESI) 560.2 and the second eluting diastereomer as a white solid (20.7mg, MS(ESI) 560.2 Example 165 Preparation of -Methyl- I H-indole-2-carboxvlic acid-f (S I -fl (2-fluorobenzenesulphonv)-3-oxo-aze~an4.ylcarbamovll3methvl-butyI I-amide Following the procedure of Example 159c-d except substituting 1-methylindole-2carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (51.4 mg, MS (ESI) 557.2 and the seond eluting diastereoemer as a white solid (21 .0 ma, 26.5 MS 557.2 carboxylic acid for benzofuran-2.croxylic acid in step 75c provided the title compound which was purified by HPLC to give the first eluting diastereomer as a while solid (71 mg.

MS (ESI) 562.2 and the second eluting diastereomer as a white solid (21.6 mg, 20.0%) MIS (ES 562.2 Example 169 Preparation of 7 -Methoxvbenzofuran-2-carboxvlic acid- f(S)-3-methvl- I -r3-ozo- I- (thiophene-2-sulfonyl )-azepan--vlcarbamovI 1-butvI I -amide Following the procedure of Example 168 except substituting 7methoxybenzoftiran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxy lic acid provided the title compound which ws purified by H-ILC to give the first eluting diastereomner as a white solid (88 mg, MIS (ESI) 562.2 and the second eluting diastereomer as a white solid (18 mg, 16%) NIS (ESI): 562.2 Example 170 Preparation of 6 -Dimethoxybenzoftiran-2carboxvlic aid-f (S )-3-methvl- I-f 3-oxo- I- (thiophene- 2 -sulfonvl)-azepan-4-vcarbamovl 1-butvI -amide Following the procedure of Example 168 except substituting 5.6dimethoxybenzofuran-2carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was purified by HPLC to giethe first eluting, diastereomer MIS (ESI) 594.2 and the second eluting diastereomer.

Example 171 Preparation of 3 -Methvibenzofuran-2-carboxylic acid- I (SI-3-methvl- I -r3-oxo- I -(thiophene- 2 sulfonvl)-azepan-4-vlcarbamovll-butyI I -aride Following the procedure of Example 168 except substituting 3-methybenzofuran-2carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was purified by HPLC to give the first eluting diastereomer as a white solid (88 mg, MIS (ESI) 546.2 and the second eluting diastereomer as a white solid (16 mg, MIS(ESI) 546.2 Example 172 Preparation of Benzofblthiophene-2-carboxylic acid- f (S)-3-methvl- 14-3-oxo- I -(thiovhene- 2-sulfonvl)-azepan-4-ylcarbamovl 1-butvl) -amide Following the procedure of Example 168 except substituting benzo[b)thiophene-2carboxylic acid 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was purified by HPLC to give the first eluting diastereomer as a white solid (43.4 mg, 4] MS (ESI) 548.4 and the second eluting diastereomer as a white solid (33.4 mg. 3 MS (ESI) 548.2 Example 173 Preparation of I -Methyl-]I H-indole-2-carboxylic acid- f(S)-3-ffethvi- I -f3-oxo- I -(thiophene- 2-su lfonvl)-azepan-4-vlcarbamoyll-butvI I -amide Following the procedure of Example 168 except substituting l-methylindole-2carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (35.8 MS (ESI) 545.2 and the second eluting diastereorner as a white solid (45.8 mg, MS (ESI) 545.2 Example 174 Preparation of Quinoxal ine-2-carboxyliq acid- I (S)-3-methvl- I -r3-oxo- I -(thiophene-2sulfonvl)-azepan-4-vlcarbamoyll-butyl)I-amide Following the procedure of Example 168 except substituting quinoxaline-2carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was separated by H-PLC to give the first eluting diastereomer as a white solid mg. MS (ESI) 544.4 and the second eluting diastereomer as a white solid (38.7 mg, MS (ESI) 544.4 Example 175 Preparation of Benzofuran-2-carboxylic acid- 14f 1-(4-chloro-benzenesulphonvl )-3-oxoazepan-4-ylcarbamovl1-3-methyl-butyI 1-arnide 3 -Chloro-benzenesulfonyl)-3-hydroxy-azepan-4ylcarbamoylj-3methyl.

butyl 1-carbamic acid terr-butyi ester To a solution of the compound of Example 2g 2 .50ga, 7 .29mmol) in DCE (100 ml) was added P-NMM (4.0g) and 4-chlorobenzenesulphonyl chloride (1.85g. 8.75mmol).

After shaking at room temperature for over night, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid 3 .13g, MS: 539.78 2 -Ami*no-4-methylI-pen tanoic acid [1 -(3-chloro-benzenesulfonyl)-3-hydroxyazepan-4-yI]-amide To a stirring solution of the compound of example 175a (LO L93mmol) in methnol (10 ml) was added HCI (4M in dioxane) (10 ml). After stirring at room temperature for 3 hr, the solution was concentrated to provide a white solid. To a solution of the white solid (0.68 g,1.50 rnmol, 78%) in methnol (37 ml) was added P-CO. (2.85 g 2.63 mmollgo,). After shaking for 2hr, the solution was. filtered and concentrated to yield the title compound as white solid (0.

5 1.42 mmol. MS: 417.86 Benzofuran-2-carboxylic acid-fI 1 1 4 -chloro-benzenesulphonyl)-3-hydroxy.

azepan-4-ylcarbamoyl)-3-methyl-butyl)}-arnide To a solution of the compound of Example 175b 14 g, 0.335 mmol) in CHCI, mL) was added benzofuran-2-carboxylic acid- (0.81, 0.50 mmol), I1hydroxybenzotriazole (0.77g. 0.S69mmol), and P-EDC (0.67g, lmmoblg) in CH,CI, mL) After shaking at room temperature overnight, the solution was treated with tisamine (0.446 0% 3.75 mmollg). After shaking for another 2 hr, the solution was filtered and concentrated to yield the title compound as a white solid (122.2 mug, MS (ESI): 562.2 Benzofuran-2-carboxylic acid-({ I -(4-chloro-benzenesulphonyl)-3-oxoazepan-4-ylcarbamoyll-3-methyl-butyI I}-amide To a stirring solution of the compound of Example 175c (122.2mg, 0. 2l7mmol) in dichloromethane (4 mL) was added Dess-Martin reagent 0184.8mg, 0.436mmo1). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 ml) were added simultaneously to the solution. The aqueous was extracted with dichloromethane The organic phases were combined, washed with saturated brine, dried (MgSO,), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid 6 2.7mg, 51.6 MS (ESI) 560.2 and the second elution as a white solid (32.7mg, 26.9 MS (ESI) 560.2 Example 176 Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid- ISM-l 1 4-chlorobenzenesulphonvl 3 -oxo-azepan-4-ylcarbanov'J -3-methyl-butyI I -amide Following the procedure of Example I 75c-d except substituting methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (64.4 mg, MS (ESI) 590.2 and the second eluting, diastereoemer as a white solid (32.2 mg. MIS (ESI) 590.0 Example 177 Preparation of 7-Methoxvbenzofuran-2-carboxvlic acid- I(S)-I 14 144-chlorobenzenesulphonyl)-3-oxo-azean4ylcarbamovll13-methvi-butyI I -amide Following the procedure of Example 175c-d except substituting 7methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 1 provided the title compound which was separated by HPLC to give the first eluting diseroe a hiesoi 511m, 0):M ES)50 rMH>an h scn eugdiastereoemer as a white solid 4 1 mg, MS (ESI) 590.2 n hescn Example 178 Preparation of 5 .6-Dimethoxvbenzofuran-2-carboxvlic acid-f (S 141 -(4-chlorobenzenesulphonvl )-3-oxo-azepan-4-vlcarbamoyl 1-3-methvl-butvI I -amide Following the procedure of Example 175c-d except substituting 5,6dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MIS (ESI) 622.2 and the second eluting diastereoemer: MS (ESI) 622.2 Example 179 Preparation of 3-Methvlbenzofuran-2-carboxvlic acid- f 1-[i -(4-chlorobenzenesulphonvl)-3-oxo-azepan-4-vcarbamoil-3methl-butvl I amide Following the procedure of Example I 75c-d except substituting 3methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to-give the first eluting diastereomer as a white solid (78.6 mg, MIS (ESI) 574.2 and the second eluting diastereoemer as a white solid (27.6 mg, MS (ESI) 574.2 Example 1SO Preparation of Benzofblthiophene-2-carboxylic acid-f (S)-I-ri -(4-chlorobenzenesulphonvl)-3-oxo-azean-4-lcarbamovl-3-methl-butyI I-amide Following the procedure of Example 1 75c-d except substituting benzolb)thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by H-PLC to give the first eluting diastereomner as a white solid (41 mg, MIS (ESI) 576.2 and the second eluting diastereoemer as a white solid (32.6 mg. MS (ESI) 576.2 (M4-1)+ Example 181 Preparation of 1-Methyl-I H-indole-2-carboxylic acid- I I -fi -4-chlorobenzenesulphonvl )-3-oxo-azepan-4-ylcarbamoyl 1-3-methvl-butvli)-amide Following the procedure of Example 175c-d except substituting I-methylindole-2carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (28.5 MS (ESI) 573.2 and the second eluting diastereoemer as a white solid (38.5 mg. 31 MIS (ESI) 573.2 Example 182 Preparation of Ouinoxaline-2-carboxylic acid- I (S 14r 1 44-chloro-benzenesulphonyl)-3oxo-azepan-4-ylcarbamovi 1-3-methvl-butv) 1-amide- Following the procedure of Example I 75c-d except substituting quinoxaline-2carboxylic acid for benzofuran-2-carboxylic acid in step 1 75c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (63 51 MS (ESI) 572.2 and the second eluringo diastereoemer as a white solid (44.5 mg, MS (ESI) 572.2 Example 183 Preparation of Benzofuran-2-carboxylic acid-fI I -rl -(3-mrethoxv-benzenesulphonyl)-3oxo-azepan-4-ylcarbamol-3-methvl.bu~yI I -amide 1-( 3 -Methoxy-benzenesulfonyl)-3-hydroxy-azepan..4.ylcarbamoyl]-3 methyl-butyl I}-carbamnic acid tert-butyl ester To a solution of the compound of Example 2- (1.60g, 4 .66mmol) in DCE (50m1) was added P-NMM (2.56g, 3.64mmoL/g and 3-methoxy-benzenesulphonyl chloride 15g% 5.S9mmol). After shaking at room temperature for over night, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (1.70g, MS 535.8 2 -Amino-4-methyl-pentanoic acid [1-(3-methoxy-benzenesulfonyl)-3-hydroxyazepan-4-yl]-amide To a stirring solution of the compound of example 183a (1.70 g, 3.31mmol) in methnol (22 ml) was added HCI (4M in dioxane) (22 ml). After stirring at room temperature for 3 hr, the solution was concentrated to get white solid. To a solution of the white solid (1.19 g, 2.64 mmol, 80%) in methnol (50 ml) was added P-CO, (5.02 g, 2.63 mmol/g). After shaking for 2 hr the solution was filtered and concentrated to yield the title compound as white solid (1.03 g, 2.49 mmol, MS 413.90 Benzofuran-2-carboxylic acid- 1-(3-methoxy-benzenesulphonyl)-3hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide To a solution of the compound of Example 183b (0.11 g, 0.26 mmol) in CH,C1, mL) was added benzofuran-2-carboxylic acid (64.69mg, 0.399 mmol), 1hydroxybenzotriazole (61.1g, 0.452mmol), and P-EDC (0.532g, Immol/g) in CH,CI, mL). After shaking at room temperature for over night, the solution was treated with tisamine (0.355g, 3.75mmol/g). After shaking for another 2hr, the solution was filtered and concentrated to yield the.title compound as a white solid (103.5 mg, MS (ESI) 558.2

(M+H)

Benzofuran-2-carboxylic acid- 1-(3-methoxy-benzenesulphonyl)-3-oxoazepan-4-ylcarbamoyl]-3-methyl-butyl )-amide To a stirring solution of the compound of Example 183c (103 mg, 0.19 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (157 mg, 0.37 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane The organic phases were combined, washed with saturated brine, dried (MgSO), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (76.2 mg, 73.6 MS (ESI: 556.2 (M+H) and the second eluting diastereomer as a white solid (24.1 mg, 23.3 MS (ESI) 556.2 (M+H) Example 184 Prep~aration of 5-Methoxvbenzofuran-2-carboxylic acid- I-fl -(3-methoxybenzenesulphonvl )-3-oxo-azepan-4-ylcarbamoyI 1-3-methvi-butyl -amide Following the procedure of Example I 83c-d except substituting methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step I183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (33 mg, 31 MS (ESI) 586.2 and the second eluting diastereoemer as a white solid (35.2 mg, MS (ESI) 586.2 Example 185 Preparation of 7-Methoxybenzofuran-2-carboxvlic acid-( (S)-i-41 -(3-methoxybenzenesulphonyl )-3-oxo-azepan-4-vlcarbamoyll-3-metlvl-butvI I-amide Following the procedure of Example 1 83c-d except substituting 7methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 1 83c provided the title compound which was separated by H-PLC to give the first eluting diastereomer as a white solid (41 mg, MS (ESI) 586.4 and the second elutingy diastereoemer as a white solid (39.5 mg, MIS (ESI) 586.2 Example 186 Preparation of 4.5-Dimethoxvbenzofuran-2-carboxylic acid-( 1-i-(3-rnethoxybenzenesulp~honvp)-3-oxo-azepan-4-ylcarbamoyil-3-methyl-butvl I-amide Following the procedure of Example I 83c-d except substituting 5,6dirnethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 1 83c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MIS (ESI) 618.4 and the second eluting diastereoemer.

190 Example 187 Preparation of 3 -Methvibenzofuran-2-carboxylic acid- f I -r I-(3-methoxqbenzenesulp1honvl 3 -oxo-azepan-4-ylcarbamoyl1-3-methy1-butyl) -amide Following the procedure of Example 1 83c-d except substituting 3methylbenzofuran-2-carboxyuic acid for benzofuran-2-carboxylic acid in step 1 83c provided the title compound which was separated by I-PLC to give the first eluting diastereomer as a white solid (76 mg, MS (ESI) 570.2 and the second eluting diastereoemer as a white solid (23.2 mg-, MS (ESI) 570.2 Example 188 Preparation of Benzo b thionhe-ne--carbox--- c d-f (S I -(mehoxvbenzenesulphonyvL 3 -oxo-azepan-4-vicarbamovl 1-3-methvl-butvI I -amide Following the procedure of Example I 83c-d except substituting benzo[b]thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid in step 1 83c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (37 mg, MS (ESI) 572.2 and the second eluting diastereoemer as a white solid (31 mg, MS (ESI) 572.2 Example 189 Preparation of I -Methyl- I H-indole-2-carboxylic acid- f 14 1-(3-methoxybenzenesulphonyl)-3oxo-azean4vlcarbamoll-3-methvl-butvI I -amide Following the procedure of Example 1 83c-d except substituting -I -methylindole-2carboxylic acid for benzofura-2-carboxylic acid in step 1 83c: provided the title compound which was separated by HPLC to give the first eluting diastereorner as a white solid (34 mg, MS (ESI) 569.2 and the second eluting diastereoemer as a white solid (38 mg, MS (ESI) 569.4 Example 190 Preparation of Ouinoxaline- I(S)-I 43-methoxv-benzenesulphonvl)-3-oxo-azepan4 vlcarbamovfl-3-methvl-butyl 1-armde Following the procedure of Example I 83c-d except substituting quinoxaline-2carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (71 mg, MS (ESI) 568.2 and the second eluting diastereoemer as a white solid (27 mug. MS (ESI) 568.2 Example 191 Preparation of Benzofuran-2-carboxvlic acid-f (S)-3-methvl- I-r3-oxo- 1-(thiophene-2su lfonvlI)-azepan-4-vlcarbamovll-butvI I -amide Following the procedure of Example- 168 except substituting benzofuran-2carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which ws purified by HPLC to give the first elutin- diastereomer as a white solid (76 ng, MS (ESI) 532.2 and the second eluting diastereomer as a white solid mg, 23%) MS (ESI): 532.2 Example 192 Preparation of Benzofuran-2-carboxylic acid f()3meh l-(.'.4-trideuterio)-3-oxo-l- (pRigdine-2-sulfonyl)-azepan-4-vlcarbamoyll-butyI I amide To a solution of benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide of Example 28c (0.03 g) in D,O:CD.OD mL) was added triethylamine (0.04 mL). The reaction was heated to reflux for 2 hours whereupon it was concentrated and dried under vacuum. The residue was the redissolved in the same mixture and heated to reflux overnight. The reaction was concentrated and the residue purified by column chromatography rnethanol:dichloromethane) to provide the title compound (0.02 'HNMR: 5 1.0 (in. 6H), 1.5-2.2 (in. 6H), 2.7 (in, IH), 4.1 (in, IH), 4.7 (mn, 2H), 7.4-8.0 (in, 8H), 8.7 (in, IH); MS(EI): 529 The diastereomeric mixture was separated by NPLC to provide the faster eluting diascereoemer: MS(EI): 530 (M+H,I100%) and the slower eluting diastereomer:

MS(EI):

530 (M 100%).

Example 193 Preparation of Benzofuran-2-crxlc acdI( ehL -oxo- I -(pvridine-2sulfonvl )-azepa-vcralb~ -ainide 4 -tert-Butoxycarbonylamino.3-hydroxy.azepane- I -carboxylicacid benzyl ester To a stirring solution of compound of Example 2e (1.04 g, 3.92mmol) in THF was added di-tert-butyldjcarbonate (0.864 ).After stirring at room temperature for 30 minutes, the reaction mixture was diluted with diethylether and extracted with saturated NaH-C0 3 The organic layer was dried -over anhydrous NaSO 1 filtered, concentrated, and purified by silica gel column to give the title compound as a yellow oil (0.963 g. 2.64 mmol,

MS

(ESI): 365.03 (M+1-1Y.

3 -Hydroxyazepan4yl)carbmic acid tert-butyl ester To a solution of compound of Example 1 93a (0.

9 63g, 2.64mmol) in ethyl acetate (16 ml) was added 10% palladium on carbon (500 mng). After stirring the solution at room temperature for 48 hours, the mixture was filtered through celite. The filterate was concentrated to yield the title compound 0.529 g, 2 29 mmol, MS(ESI): 231.92 [3 -Hydroxy- Il-(pyridine-2-sulfonyl)-azepan.4-yi)carbamic acid tert-butyl ester To a solution of the compound of Example 1 93b (0.53, 2.29 inmol) in dichloromethane (20 ml) was added triethylamine (232 mg) and pyridine-2-sulfonyl chloride (4 10 ma, 2.32 mmol). After stirring at room temperature for 30 minutes, the mixture was washed with saturated NaHCO. The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound as a solid (0.58 g1.57 rniol. MS(ESI): 372.95 4-Amino-1 -(pryidine-2-sulfonyl)-azepan-3-ol To a stirring solution of the compound of Example 193c (0.583 g, 1.57mmol) in ethyl acetate (0.5 ml) was added HCI (4M in dioxane, 3.9 ml). After stirring the reaction mixture for 30 minutes at room temperature, the mixture was concentrated to yield a white solid. The solid was treated with NaOH and then extracted with ethylacetate. The organic layer was dried, filtered, and concentrated to yield a yellow solid (0.35 g, 1.28 mmol, 81%): MS (ESI) 272.93 -[3-Hydroxy-1 -(pryidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-meth-butyl carbamic acid terr-butyl ester To a solution of the compound of example 193d (19 mg, 0.070 mmol) in CH,CI, was added N-Boc-isoleucine (24.5 mg, 0.10 mmol), l-hydroxybenzotriazole (16.1 mg, 0.12 mmol). and P-EDC (140 mg, 0.14 mmol in CH,C1 After shaking at room temperature overnight, the mixture was treated with PS-Trisamine. After shaking for another 2 hours, the mixture was filtered and concentrated to yield the title compound as a solid. MS (ESI) 484.97 (S)-2-Amino-3-methyl-penatanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan- 4-yl]-amide To a stirring solution of the compound of example 193e (34 mg, 0.07 mmol) in CH,CI, (0.50 ml) was added HCI (4M in dioxane) (0.165 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated, giving a white solid. The white solid was azeotroped with toluene then treated with MP-carbonate (0.35 mmol) in methanol. After four hours of shaking, the mixture was filtered and concentrated to give the title compound as a solid.: MS(ESI) 384.9 Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl }-amide To a solution of the compound of example 193f (27 mg, 0.070 mmol) in CHIC1I was added 2-benzofurancarboxylic acid (17.0 mg, 0.106mmol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol in CH,C1, After shaking at room temperature overnight, the mixture was treated with PS-Trisamine. After shaking for another 2 hours, the mixture was filtered and concentrated to yield the title compound as a solid: MS (ESI) 528.9 Benzofuran-2-carboxylic acid (S)-2-methyl- I-[3-oxo -1I-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoylj-butyl 1-amnide To a stirring solution of the compound of example 1 93- (37 mg, 0.07 mmol) in CH..CI. (0.5 ml]) was added Dess-Martin reagent (45 mg, 0. 105 mmol). After stirring for minutes, solutions of sodium thiosulfate (10% in water, 0.50 ml) and saturated aqueous sodium bicarbonate (0.50 ml) were added simultaneously to the reaction. The mixture was then extracted with dichloromethane (2 times). The organic layer was dried, filtered, and concentrated. The residue was purified by HPLC to yield the two diastereomers of the title compound as solids (first eluting: 7mg, second eluting: 5.5 mg): MIS (ESI) 526.91 Example 194 Preparation of Benzofuran-2-carboxvlic acid I- 43-oxo- I -(Rvridine-2-sulfonyl)-azepan- 4 -vicarbamovilkpro yl I-amide Following the procedure of Example 193e-h, except substituting N-Boc-alphaaminobutyric acid in step 1 93e the title compound was purified to yield two diastereomers as solids (first eluting: 5 mng, second eluting: 5 mg) MS(ESI) 543.8 Example 195 Preparation of Benzofuran-2-carboxylic acid (S)-2-cvclohexyl- 1-f 3-oxo- I-(pyridine-"sulfonyl)-azepan-4-vlcarbamovll-ethvI I-amide Following the procedure of Example 193e-h, except substituting N-Boccyclohexylalanine in step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4.5 mg second eluting: 4 .5 mg): MS(ESIy* 566.87 Example 19 Preparation of Benzofuran-2-carboxylic acid I -rf3-oxo- I -(pyridine-2-sulfonyl)-agepan- 4-vlrbamovlk-thyl I-anide Following the procedure of Example 193e-hi, except substituting N-Boc-alanine for step 1 93e, the title compound was purified to yield two diastereomers as solids (first eluting: 5.5 mg, second eluting: 5 mg).

Example 197 Preparation of Benzofuran-2-carboxvlic acid f(S)-3-methanesulfinvl- i-r3-oxo- I-(pyridine- 2'-suI fon vI)-azepan-4-vlcarbarnoyl 1-prop~vl -amide Following the procedure of Example 193e-h, except substituting N-Boc-Lmethionine for step the title compound-was purified-to yield two diastereomers as solids (first eluting: 3 mg, second eluting: 3 mg). MS(ESI): 560.7 Example 198 Preparation of Benzofuran-2-carboxylic acid f 3-oxo- I -(p~vridine-2-sulfonvl)-azepan.4vlcarbamovl-methvl 1-an-ide Following the procedure of Example 193e-h. except substituting N-Boc-glycine for step 1 93e, the title compound was purified to yield two diastereomers as solids (first eluting: 3mg ,second eluting: 3 mg). MS(ESI): 470.81 Example 199 Preparation of Ben zofuran-2-carboxvl ic acid I'(S I-f3-oxo I-(pyridine-2-sulfonvl)-azepan- 4 -vlcarbamovll-ventvl I-amide Following the procedure of Example I 93e-h, except substitutinga N-Boc-norleucine for step 193e, the title compound was purified to yield two diastereorners as solids (first eluting: 4 mg, second eluting: 5 mg). MS(ESI): 526.85 Example 200 Prevaration of Benzofuran-2-carboxvljc acid I(S)-lI-f3-oxo- I-(p~vridine-2-sulfonyl)-azepan- 4-ylcarbamovll-butvl 1-amide Following, the procedure of Example I 93e-h, except substituting N-Boc-norvaline for step 1 93e, the title compound was purified to yield two diastereomers. as solids (first eluting: 7.5 second eluting: 3.5 mg). MS(ESI): 512.8 (M+H)Y.

Example Preparation of Benzofuran-2-carboxylic acid f (S)-2-methvl- I -r3-oxo- I -(pvridine-2sulfonvl )-azepan-4-vlcarbamovl 1-propvI -amide Following the procedure of Example- 193e-h, except substituting N-Boc-valine for step: 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 6 second eluting: 4.5 mg). MS(ESI): 512.8 Example 202 Preparation of Benzofuran-2-carboxvlic -acid I(S)-2-hvdroxv- 1-[3-oxo-lI-(pvridine-2sulfonvi )-azenan-4-vlcarbamovllipropvI J-arijde Following the procedure of Example I 93e-h. except substitutingc N-Boc-Lthreonine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 3 mg-, second eluting: 3 mg).

Exampe 203 Preparation ofBenzofuran-2car~boxvlic acid I -[3-oxo- I -_.(pyridine-2-sulfonyl)-azepah 4 -vic rbamoyl1-2Phenvl-ethyl 1-amnide Following the procedure of Example 193e-h, except substituting N-Bocphenylalanine for step 1 93e, the title compound was purified to yield two diastereomers; as solds fir eutig:Sgsecond eluting: 5mng). MS(ESI): 560.8 Example 204 Preparation of Benzofuran2-carbonvl)pv- ldn~c.o i aId 3-oxo- 1-(pvridine- 2)-sulfonvl )-azenan-4-vll-armide Following the procedure of Examplel 193e-h 'except substituting N-Boc-L-proline forstep 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4 mg, second eluting: 5mg). MS(ESI): Example 205 PreRation of 3,4-Dimethoxy-N- 4 4 -imethoxv-benzenesulfonl)3xo-zepa-4.

vlcarbamovll-3-methvl-buty!l)-benzamide Following the procedure of Example 115. except substituting 3,4dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared.

The residue was purified by HPLC. First eluting diastereomer: MS 576.4(M+H+). I H NMR (500 MHz,CDC] 3 8 7.68 2H),7.00 IH), 6.89 2H),3.84 3H),3.77 6H), 2.38 IH), 0.94 6H): MS 576.4 Example 206 Preparation of Benzorblthiophene-2carboxxylic acid-I(S)- I -r I -(4-imethoxvbenzenesulfonv1)-3-oxo-azepan.4-vlcarbamoylV3-methyl-butyl)-amide Following the procedure of Example 115, except substituting 2-thiophene-carbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 572.2 I H NMR (500 MHz,CDCI 3 6 7.80-7.68 (in. 5H), 7.38-7.34 (in, 2H). 7.0 1-6.93 (mn, 4H), 3.83 3H), 2.38 I 0.97 6H). Second eluting diastereomner: MS 572.2 .7 Example 207 Preparation of Benzor 1,31dioxole-5-carboxvlic acid 1-fl-(4-fluoro-benzenesulfonyl)-3oxo-azepan-4-vlcarbamovll-3inethvl-butyl I -amide Following the procedure of Example 115, except substituting, 4fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4inethylenedioxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 548.2 I H NMR (400Hz.CDCI 3 6 7.85-7.7 8 (mn, 2H), 7.3 8-7.20 (in, 4H). 7.05 I H), 2.52-2.40 IH), 1.0 6H). Second eluting diastereomer: MS 548.2 Example 208 Preparation of 2 -(2-Benzvloxv-acetvlamnino)-4iethyl-rpentanoic acid[ I -4-fluorobenzenesulfonvl)-3-oxo-azepan-4-vl 1-amide Followingy the procedure of Example 115, except substituting 4fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by H-PLC. First eluting diastereomer: MS 548.2 1I HNMR (400Hz,CDCI 3

-CD

3 OD) 8 7.88-7.80 (in, 2H), 7.45-7.30 (in, 5H), 7.30-7.20 (in, 2H), 4.00 2H), 2.60-2.48 (m,lIH), 0.96 6H): MIS 548.2 Example 209 Preparation of Benzorblthiophene-2-carboxylic acid-f 1--rI -(4-fluoro-benzenesulfonvl 3-oxo-azepan-4-vl carbamoyl 1-3-methvl-butyl)-aide Following the procedure of Example 115, except substituting 4fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzo[b~thiophenecarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by WPLC. First eluting diastereorner: MS 560.2 IH NMR (500 MHz,CDC1 3 8 7.80-7.72 (mn, 5H).7.37-7.34 (mn, 2H), 7.33-7.15 (mn, 4H), 2.43 IH). 0.96 6H). Second eluting diastereomer: MIS 560.2 Example 210 Preparation of Benzofuran-2-carboxvlic acid 141 -benzovl-3-oxo-azepan-4ylcarbamoyll-3-inethvl-butyl 1-amide Benzofuran-2-carboxylic acid f (S)-1I -[1I -benzoyl-3-hydroxy-azepan-4-ylcarbamoyl]- 3-methyl-butyl )-ainide To a solution of benzofuran-2-carboxylic acid [(S)-1-(3-hydroxy-azepan-4ylcarbainoyl)-3-inethyl-butyl]-anmide of Example 78c (0.2 g)in dichioroinethane was added benzoic acid (0.12 HOBt (0.07 g)and EDC (0.99 The reaction was stirred until 200 complete. Workup and column chromatography (5%c methanol:dichloromethane) provided the title compound (0.2 'H NMR (CDCL): 8 1.0 (in, 6H4), 1.5-2.2 (in, 2.7 (mn, 1H), 3.8 (mn, IH), 4.1 (in, I1H), 4.7 (in, 2H), 5.1 (in, I 7.0-7.7 (in, IGOH), 8.7 (mn, I MS(EI): 492 100%).

Benzofuran-2-carboxylic acid f(S)-I -benzoyl-3-oxo-azepan-4-ylcarbamoyl]-3methyl-butyl }-ainide Fol lowing the procedure of Example I i except substituting benzofuran-2carboxylic acid [1-benzoyl-3-hydroxy-azepan-4.ylcarbamoyl]-3-methyl-buty 1amnide of Example 210Oa the title compound was prepared: 'H NMR (CDCl 3 5 1.0 (in, 6H), 1.5-2.2 (in, 6H), 2.7 (in, I 3.7 (m,lIH), 4.0 (in, I 4.7 (mn, 2H), 5.1 (mn, I1H), 7.4-8.0 (in, 8H); MS(EI): 490 100%).

Example 211 Preparation of (S-4-Methyl-2(guinoline-8-sulfonvian-ino)-pentanoic acid [3-oxo- 1- (pvridine-2-sulfonvl)-azepan-4-vi 1-amide 4 -Methyl-2-(quinoline-8-sulfonylanino)-pentanoic acid [3-hydroxy- 1- (pyridine-2-sulfonyl)-azepan-4-yll-an-Lide Following the procedure of Example 89a except substituting 8-quinolinesulfonyl chloride for 2-pyridinesulfonyl chloride the title compound was prepared: MS(EI) 576 4 -Methyl-2-(quinoline-8-sulfonlamino)-pentanoic acid [3-oxo-l1-(pyridine-2sulfonyl)-azepan-4-yl]-amide Following the procedure of Example I i except substituting (S)-4-inethyl-2- (quinoline-8-sulfonylamino)-pentanoic acid [3-hydroxy-lI-(pyridine-2-sulfonyl)-azepan-4yl]-ainide of Example 211 a the title compound was prepared: 'H NMR (CDC 3 850.5-0.8 (in, 6H), 1.4-1.8 (mn, 7H), 2.5 (in, IN), 3.5-3.9 (mn, 3H), 4.4 (mn, 1H), 4.6 (mn, IH), 5.5 (in, 1H), 6.7 -7.0 (mn, 2H), 7.5 (mn, 3H), 8.0 (in, 2H). 8.3'(mn, 2H), 8.6 (mn, IH), 9.0 (in, 1H); MS(EI): 674 100%).

ExaMple 212 Preparation of (S 4 -Methvl-2-(nanhthvlene-2sulfon-ylainof) ,entanoic acid F3-oxo- 1- (Ryridine-2-sulfonvl )-azepan-4-vil -amride 4 -Methy1-2(naphthyene2sulfonylan-jno)-pentaoic acid [3-hydroxy- 1- (pyridine-2-sulfonyl)aepan.4ylp-arrde Following the procedure of Example 89a except substituting 2-naphthylenesulfonyl chloride for 2-pyridinesulfonyl chloride the title compound was prepared: MS(EI) 575 (S)-4-Methyl-2-(naphthylene2sulfonyai-no)pentanoic acid [3-oxo-]I-(pyridine- 2-sulfonyl )-azepan-4-yl]-amide Following the procedure of Example 1i except substituting (S)-4-methyl-2- (naphthylene- 2 -sulfonyaino)penaoic acid [3-hydroxy- 1-(pyridine-2-sulfonyl)-azepan- 4-yl]-amide of Example 212a the titlecompound was prepared, 'H NMR (CDCI'): 5 0.8 (in. 6H), 1.4-1.8 (mn, 7H), 2.5 (mn, IH), 3.5-3.9 (in, 3H), 4.5 (mn, IH), 4.6 (in, IH), 6.7 (in, 1H), 7.5-8.0 (mn, 8.5-8.6 (in, 2H); MS(EI): 673 100%).

Example 213 Preparation of Benzofuran-2-carboxylic acid-i5-u -rI-(4-fluoro-benzenesulfonvl)-3-oxoaggpan-4-vl carbamoyll-3-nethyl-butyl I-amide Following the procedure of Example 115, except substituting 4fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 2benzofurancarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereoiner:

MS

IH NMR (500 M~iz,CDC1 3 8 7.79-7.77 (in, 2H), 7.61 I 7.46-7.38 (mn. 3H), 7.25-7.06 (mn, 5H), 2.43 1H), 0.95 6H). Second eluting diastereoiner: MS 544.4 202 Example 214 Preparation of N- (S 141-(4--Fluoro-benzenesulfonvl )-3-oxo-azepan-4-vlcarbamoyl 1-3methyl -butvi I- 3 4 -dimethoxv-benzamride Following the procedure of Example 115, except substituting 4fluorobenzenesulphonyl chloride for 4 -methoxybenzenesulfonyl chloride and 3,4dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared.

The residue was purified by HPLC. First eluting diastereomer: MS I H NMR (500 MHz,CDCI 3 8 7.80-7.76 2H),7.19 2H),7.05 I1-H), 6.88 2H), 6.78 IJH), 6.53 I 3.77 6H), 2.43 I1-H), 0.94 Second eluting diastereomer: MS 546.2 (M+H 4 Example 215 Prep~aration of Cvclohexanecarboxvlic acid I(S)-l-rl -(4-fluoro-benzenesulfonyl)-3-oxoazepan-4-vicarbamoyl I -3-methyl-butyl I-amide Following the procedure of Example 115, except substituting 4fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and cyclohexylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 51 I H NMR (400Hz,CDCI 3 8 7.83-7.80 (in, 2H), 7.27-7.20 (in. 2H), 6.92 (d.

IlH), 6.95 IlH). 2.50 1H), 1.90-1.20 (mn, 15H), 0.94 6H1). Second eluting diastereomer: MS 510.2 Example 216 PrepRmation of 2 2 -Benzvox-acetyaino)-4-met Vl-Rentanoic acid[ 1- (methanesulfonvl)-3-oxo-azepan.4.vl-aniide Following the procedure of Example 115, except substituting inethanesuiphonyl chloride for 4 -methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 NMR (500 MHz,CDCI 3 6 7.37-7.24 (in, 4H), 6.93-6.9 1 (mn, 2H), 5.02-5.00 (mn, IH), 2.88 (s, 2.70 IH), 0.92 6H). Second eluting diastereomer: MS 468.2 Example 217 Prep~aration of Benzo~bthiophene-2-carboxylic acid- f(S)-I 141 -methanesulfonvl-3-oxoazelpan-4-yI carbamoyl)-3-methyl-butyll-amide Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesuffonyl chloride and benzo~b]thiophenecarbonyl chloride for benzyloxyacetyl chloride, the-title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 480.2 1 H NMR (500 MHz,CDCl 3 7.83-7.78 (in, 3H),7.42-7.37 (mn, 2H),6.94 IH), 6.75 11H), 2.89 3H), 2.68 11-).

0.97 6H). Second eluting diastereomer: MS 480.2 Example 218 Preparation of Benzor I .31dioxole-5-carboxylic acid-( I-(0 -methanesulfonyl-3-oxoazepan-4-vl carbamovl)-3-methyl-butvll-amide Following the procedure of Example 115. except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and piperonylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 IH NMR (500 MHz,CDCl 3 8 7.31-7.24 (mn, 2H), 6.91 1H), 6.00 2.89-(s, 3H), 2.67 IH), 0.95 6H).

Second eluting diastereomer: MS 468.2 204 Example 219 Preparation of Benzofuran-2-carboxylic acid- I-(1 -methanesulfonvl-3-oxo-azepan-4-yI carbamovl)-3-methvl-butyl -armide Following the procedure of Example 115, except substituting inethanesuiphonyl chloride for 4 -methoxybenzenesulfonyl chloride and 2-benzofurancarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MIS 464.2 IH NMR (500 MHz,CDCI 3 6 7.64 IH), 7.51-7.37 (in, 3H), 7.29-7.28 (in, IN), 2.89 3H), 2.67 1H), 0.97 6H).

Second eluting diastereoiner: MS 464.2 Example 220 Preparation of 1 -Q1 -Methanesulfonvl-3-oxo-azepan4.ylcaramov 1-3-methylbutvl 1-3.4-dimethoxv-benzainide Followingy the procedure of Example 115. except substituting methanesuiphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4-dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 484.2 IH NMR (500 MHz,CDCI 3 6.94-6.88 (mn, 3H), 6.58-6.55 (mn, 2H), 3.80 6H), 2.89 3H), 0.95 6H). Second elutin- diastereomer: MS 484.2 Example 221 Preparation of 2 2 -Benzvloxy-acetvlaniino).4.methyl..pentanic acid[ I -(2-cyanobenzensulfonyl)-3-oxo-azepan-4..ylb-anmde Following the procedure of Example 115. except substituting 2cyanophenylsulphonyl chloride for 4-inethoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 IH NMR (500 MHz,CDCI 3 5 8. 10 I 7.86 IH), 7.76-7.70 (in, 2H), 205 7.35-7.3 1 (mn, 5H1), 6.93 2H), 4.61-4.47 (in, 4H), 2.77 1H), 0.92 6H). Second eluting diastereomer: MS 555.2 Example 222 Preparation of N- f 1-r l -(2-Cvano-benzenesulfonvi 3 -oxo-aze an-4-vlcarbamoyl 1-3methyl-butyl I -4-methanesulfonyl- I-benzarnide Following the procedure of Example 115, except substituting 2cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 4methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was-purifi ed by HPLC. First eluting diastereomer: MS 589.2 IH NMR (500 MHz,C DCI 3 8 8. 10 IH), 7.96 4H), 7.88 7.78-7.71 (mn. 2H), 3.05 3H), 2.79 0.97 6H4). Second eluting diastereomner: MS 589.2 Example 223 Preparation of Benzorblthiophene-2-carboxylic acid-I I1-fl -(2-cyano-benzenesulfonyl 3-oxo-azepan-4-vi carbanol)-3-nethyl-butvll-amjde Following the procedure of Example 115, except substituting 2cyanophenylsuiphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzollb]thiophene-2-carbonyl chloride for benzyloxyacetyl chloride, the title compound was .prepared. The residue was purified by HPLC. First eluting diastereomer: MS 567.2 IH NMR (500 MHz.CDC1 3 8 8. 10 IlH), 7.86-7.70 (in, 6H), 7.37-7.30 (in, 2H), 2.76 1H), 0.98 6H). Second eluting diastereomer: MS 567.2 Example 224 Preparation of Benzor I .3]dioxole-3-carboxylic acid- I1-f -(2-cvano-benzenesulfonvl oxo-azepan-4-vlcarbamovl)-3-methyl-butl 1-amide Following the procedure of Example 115, except substituting 2cyanophenylsuiphonyl chloride for 4-methoxybenzenesulfonyl chloride and piperonyloyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 I H NMR (500 MHz,CDCI 3 5 8.11 lH), 7.87 1H), 7.76-7.71 (in, 7.3 1-7.24 (in, 2H), 6.00 (s, 2H), 2.77 IH), 0.97 6H). Second eluting diastereomer: MS 555.4 Example 225 Preparation of (S )-4-Methvl-2-[4-oxo-4-.((4-Rhenoxv-phenvl)-butvrvlamino I -pentanoic acid r3-oxo-lI-(pvridine-2-sulfonvl)-azepan-4-yl 1-amide Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for thiaxole-2-sulfonyl chloride and 4-phenoxyphenyl-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MIS 635.4; 1 H-NMR (400 MHz, CDCI 3 8.69(d, IH), 7.99-7.94(mn, 4H), 7.5 3-7.39(m, 3H), 7.23-6.95(m, 7H), 6.20(d, IH), 5.07(m, IH), 4.77-4.72(d. IH), 4.46(m, IH), 4.13-4.09(m, 1H), 3.85-3.80(d. 1H), 3.33(m, 2H), 2.70- 2.64(m, 3H), 2.20-1 .40(m, 6H); and the second eluting, d~astereomer:. 0.96-0.92(m, 6H); and the second eluting diastereomer: MS 635.4.

Example 226 Preparation of N- I I -(2-cvano-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamoyI 1-3methyl-burv) 1-3.4-dimethoxv-benzamide Following the procedure of Example 115, except substituting 2cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3.4- 207 dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared.

The residue was purified by HPLC. First eluting diastereozner: MS 571.4 1

IH

NMR (500 MHz,CDC1 3 8 8. 10 IH), 7.87 IH), 7.76-7.70 (in, 2H), 6.98 2H), 6.89 214), 3.79 6H), 2.76 0.96 6H). Second eluting-diastereomer: MIS 571.4 Example 227 Preparation of Cyclohexanecarboxylic acid 1-F]4- 4 -methoxv-benzenesulfonvl)-3-oxoazepan-4-ylcarbamovl 1-3-methyl-butvI I -amide Following the procedure of Example 11 5, except substituting cyclohexylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MIS 522.4 IH NMR (500 MHz,CDC1 3 8 7.70 2H), 6.97 2H), 2.40 I 1.90-1.20 (in, 16H), 0.92 6H).

Second eluting, diastereomer: MS 522.4 Example 228 Prep~aration of 4-Methansulfonvl-N- -f4-methoxy-benzenesulfony)3ox-azepan.4.

carbamoyl 1- 3 -methyl-butvl-benzamide Following the procedure of Example 115. except substituting 4methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 594.2 IH NMR (500 MHz,CDC1 3 8 7.96 4H), 7.69 2H), 7.25 (d,1IH), 6.98 3.85 3H), 3.04 3H), 2.42 1H), 0.95 6H). Second eluting diastereomer: MS 594.2 208 Example 229 Preparation of 4-Methansulfonyl-N- (S I-r4-fluoro-benzenesulfonvl )-3-oxo-azepan-4carbamovi 1-3-methvl-butvl-benzamide Following the procedure of Example 115, except substituting- 4fluorophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and substituting 4methanesulfonylbenzoyl chloride for benzyloxvacetyl chloride, the title compound was prepared. The residue was purified by H-PLC. First eluting diastereomer: MS 582.2 IH NMR (500 MHz,CDCI 3 5 7.94 4H), 7.80-7.77 (in, 2H), 7.25-7.19 (mn, 3H), 7.00 IH), 3.04 3H), 0.96 6H). Second eluting diastereomer: MS 582.2 ExamRle 230 *Preparation of (f (S)-3-Methyl 1-43 oxo- I -pvridine-2-sulfonyl )-azepan4-vlcarbamovll-"* butvlcarbamoyl 1-carbamic acid benzvl ester Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and N-carbobenzyloxycarbonyl-glycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS 574.2; IH-NMR (400 MHz, CDC1 3 8.60(d, 1H), 7 .9 7 7 .90(mn, 2H), 7.50(m, iIH). 7.42-7.25(m, 5H). 6.90(m, IH), 6.42(m, IH), 5.38(m, INH), 5.18-5. 10(rn, 4H), 4.78-4.72(d. I 4.50(m, IlH), 4.12-4.05(m, I1H), 3.95- 1:85(m, 2H), 2.72(m, I 2.25-2. 10(m, 2H), 1.90-1.40(m, 5H), 0.92(m, 6H); and the second eluting diastereonier: MS 574.2.

Example 231 Preparation of (S)-2-r5-(4-Methoxv-Rhenvl-)-pentanovlamnio1-4-methyl-Rentanoic acid f3oxo- I -(vvridine-2-sulfonvl)-azepan-4-yl 1-amide Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and 5-(4-methoxyphenyl)-pentanoic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomner; MS 573.4; 1 H-NMR (400 MHz. CDCI 3 8.59(d, INH), 7 .97-7.94(m, 2H), 7.53(m, I 7.09-7.07(d, 2H), 6.89-6.8 1(m, 3H), 5.90(m, I 5.12(m, IlH), 4.79-4.74(d, I 4.48(m, 4. 12(m, I 3.86-3.81 IlH), 3.79(s, 314). 2 .69(m, INH), 2 .59-2.57(m, 2H), 2.23-2. 1 3H), 1.75-1.45(m, I ON), 0.96-0.95(m, and the second eluting diastereomer: MIS 573.4.

Example 232 Preparation of (S)-2-r2-(3-Benzvloxy-4-methoxv-phenyl )-acetvlamniol-4-methvlpentanoic acid r3-oxo- I-(Pvridine-2-sulfonyl)-azepan-4-vll-amide Following the procedure of Example 75, except substituting 2-pyridylsuifonyl chloride for benzenesulfonyl chloride and (3-benzyloxy-4-methoxy-phenyl)-acetic acid. for.

benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomner; MS 637.4; 1 H-NMR (400 MHz, CDCl 3 8.69(d, I 7 .98-7.9 1(m, 2H), 7.53-7.30(m, 6H); and the second eluting- diastereomer:, 6.89-6.82(m, 4H), 5.82(m, INH), 5.1 4-5 .07(mn, 3H), 4.78-4.73(d, IlH), 4.43(m, I 4.09(m, I 3.89(s, 3H), 3.82(d, IlH), 3.49(s, 2H), 2.69(m,- 1H), 2.14(m, 2H), 1.82-1.40(m, SN), 0.89(d, 6H); and the second eluting diastereomner: MS 637.4.

210 ExaMple 233 Preparation of 5.

6 -Difluoro-benzofuran-2-carboxviic acid (S )-3-methyl- I1-[1 -(pyridine-2sulfonvJV.

3 -nx -azepan-4.ylcarbamov11.buty ami de 5.

6 -Difluoro-benzofuran-2..carboxylic acid (S)-3-methyl- I -(pyridine-2sulfonyl)- 3 -hydroxyazepan4ylcarbamoyl].butyl }aniide Following the procedure of Example 28b except substituting 5,6difluorobenzofuran-2-carboxylic acid for bernzofuran-2-carboxylic acid provided the title compound: MS 564 5, 6 -Difluoro-benzofuran-2carboxylic acid f (S)-3-methyl- I -[lI -(pyzidine-2sulfonvl)-3-oxo-azepan4ylcarbamoyl..butyl I amnide Following the procedure of Example I i except substituting the compound of Example 233a provided the title compound. The residue was purified by HPLC. First eluting diastereomer; MS 562; and the second-eluting diastereomer: MS 562.

Example 234 Preparation- of (S 4 -Methyl- 2 -(5-oxohexanovlamino)-pentanoic acid r3-oxo- I -(Pvridine-2sulfonyl }-azep an-4-yll-amide Following the procedure of Example 115, except substituting 2-pyridinesulphonyl chloride for 4 -methoxybenzenesulfonyl chloride and substituting 5-oxo-hexanoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereorner: MS 495.4 Second eluting diastereomer: MS 495.4 Exam2le 235 Preparation of Benzofuran-2-carboxylic acid I (SO--methyl- 14F 1 (6-methvl-pyridine-2sulfonvi )-3-oxo-azepan-4-vlcarbamoyl ]-bury]l amide 6-methyl-pyridine-2-sulphonyl chloride The title compound was prepared in a similar fashion as that described in Example for the preparation of 2-pyridinesulfonyl chloride-N-oxide.

-[3-Hydroxy- I -(6-methyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3methyl-butyl)}-carbarnic acid zeri-butylester To a solution of 1(S)-I -(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]carbamic acid tert-butyl ester of Example 2g (1.0 g)in dichloromethane (20 mL) was added saturated sodium bicarbonate (50 mL). To this solution was added 6-methyl-pyridine-2sulphonyl chloride (6.44 mL of a 0. 13 g/m.L solution in 9M HCI). The reaction was stirred until complete. -Workup-and -column. chromatography (5 methanol~dichloromethane)* provided the title compound (1.2 g).

(S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- I -(6-methyl-pyridine-2sulfonyl)-azepan-4-yl]-amide To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(6-methylpyridine-2-sulfonyl)-azepan-4-y]-axnide of Example 235a (1.2 g) in methanol (20 mL) was added 4M HCI in diopxane (20 mL). The reaction was stirred until complete whereupon it was concentrated to provide the title compound (1 Benzofuran-2-carboxylic acid (S)-3-methyl-l1-[1 -(6-methyl-pyridine-2-sulfonyl)-3hydroxy-azepan-4-ylcarbamoyl]-butyl )ami~de Following the procedure of Example 28b except substituting (S)-2-amino-4methyl-pentanoic acid [3-hydroxy- 1 -(6-methyl-pyridine-2-sulfonyl)-azepan.4-yl]-arnide of Example 235c the title compound was prepared: MS(EI) 542 212 Benzofuran-2-carboxylic acid (S)-3-methyl- I1-[1 -(6-miethyl-pyi-idine-2-sulfonyl)-3 oxo-azepan-4-ylcarbamoyli..butyl I amide Following the procedure of Example I i except substituting benzofuran-2carboxylic acid (S)-3-methyl- l-[I 6 -methyI-pyridine-2-sufonyl)-3-hydroxyazepn4.

ylcarbamoyll-butyl }amide of Example 235d the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (in, 6H), 1.5-2.2 (in, 2.6 (in, 3H), 2.7 (in, lH), 4.1 (in, IH), 4.7 (mn, 2H-), 5.3 (in, IN), 7.4-8.0 (in, MS(EI); 540 100%l).

Example 236 Preparation of 5-Methoxvbenzofuran-2-carboxylic acidI (S)-3-methvi- I -f -(6-methyl- Rvridine-2-sulfonvl b 3 -oxo-azp-4- vlcArb- ol1-uvIamd 5-Methoxybenzofuran-2-carboxylxc acid (S)-3-methyl- I -[1I -(6-methyl-pyridine-2sulfonyl)- 3 -hydroxy-azepan..4-ylcarbamoyl]-buty amide Following the procedure of Example 28b except substituting 2-carboxylic acid for benzofuran-2-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy- I 6 -inethyl-pyridine-2-sulfonyl)-azepan4yl)-amide of Example 235c for 2 -ainino-4-inethyl-pentanoic acid [3-hydroxy- 1-(pyridine-2-sulfonyl)-azepan-4-yljamnide of Example 28b the title compound was prepared: MS(EI) 572 5-Methoxybenzofuran-2-carboxylic acid (S)-3-inethyl- I-[1 -(6-methyl-pyridine-2sulfonyl)-3-oxo-azepan-4.ylcarbamoyll.butyl )arnide Following the procedure of Example I i except substituting 2-carboxylic acid f (S)-3-inethyl- 141 6 -methyl-pyridine-2-sulfonyl)-3-hydroxyazepan-4 ylcarbamoyl]-butyl )ainide of Example 236a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 (mn, 6H), 1.5-2.2 (in, 6H), 2.6 (mn, 3H), 2.7 (in, IH), 3.8 3H); 4.1 (mn, 1H), 4.7 (in, 2H), 5.3 (mn, IH), 7.4-8.0, (in, 7H); MS(EI): 570 100%).

213 Example 237 Preparation of 3 Methvylbenzofuran-2-carboxylic acid f (S )-3-rnethyl- I -f I -6-methyl- Pvrldine- 2 -sulfonvl)-3-oxo-azepan-4..vlcarbamoyl bbutvl Iamide 3 -Methylbenzofurani.2carboxylic acid f (S)-3-methyl- I I -(6-methyl-pyridine-2sulfonyl)-3-hydroxy-azepan-4ylcabamoyJ..butyl) amide Following the procedure of Example 236a except substituting 3-methy)benzofuran- 2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 556 3 -Methylbenzofuran-2-carboxylic acid (S)-3-methyl- I -[1I -(6-methyl-pyridine-2sulfonyl 3 -oxo-azepan..4-ylcarbamoyl I-butyl }amide Followingc the procedure of Example I i except substituting 3-methylbenzofuran-2carboxylic acid f (S)-3-methyl- I 6 -methyl-pyridine-2-sulfonyl)-3hydroxy.azepa.-4ylcarbamoyl]-butyl }amide of Example 237a. the title compound was prepared: 'H N-MR (CDCI,): 8 1.0 (in, 6H), 1.5-2.2 (mn, 6H), 2.6 (in, 3H), 2.7 (in, IH), 3.8 111); 4.1 (mn, IH), 4.7 (mn, 2H), 5.3 (in, 7.4-8.0 (in, 6H); MS(EI): 564 100%).

Example 238 Preparation of 7 -Methoxvbenzofuran-2-carboxvlic acid f(S )-3-methvl- 141 -(v~vridine-2sulfonyl 3 -oxo-azepan-4-vlcarbamovll.burvlI lamide 7 -Methoxybenzofuran-2..carboxylic acid (S)-3-methyl- I 1-(6-inethyl-pyridine-2sulfonyl)- 3 -hydroxy-azepan4ylcarbamoy]-buty }amride Following the procedure of Example 28b except substituting, 7methoxybenzofuran-2.carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 559 7 -Methoxybenzofuran-2-carboxylic acid (S)-3-methyl- I I-(6-methyl-pyridine-2sulfonyl)- 3 -oxo-azepan-4-ylcarbamoyl].butyl )amide Following the procedure of Example I i except substituting 7-inethoxybenzofuran- 2-carboxylic acid (S)-3-inethvl- 14 l-( 6 -methyl-pyrdine-2sulfonyl)3hydroxy-aepan-4- 214 ylcarbamoyl]-butyl )amide of Example 238a the title compound was prepared: MS(EI) 557 Example 239 Preparation of 5.

6 -Dimethoxv-benzofblthiophene2carboxylic acid I(S)-3-methyl- I1-flI (pvridine-2-sul-fonvl 3 -oxo-azeyan-4-ylcarbarnoyll-butyl I amide 5, 6 -Dimethoxy-benzobthiophene2carboxylic acid I (S)-3-rnethyl- 1-[ri -(6-methylpyiie2sloy) -yrx-zpn4Ilabmy]btl amnide Following the procedure of Example 28b except substituting 5,6-dimethoxybenzofbjthiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 604 5 6 -Dimethoxy-benzo[b~thlophene-2-carboxylic acid (S)-3-methyl- 1 -[1I -(6-methylpyridine- 2 -sulfony)-3oxoazepan-4ylcarbamoyI 1-butyl amnide Following the procedure of Example I i except substituting 5,6-dimethoxybenzo[bljthiophene-2-carboxylic acid (S)-3-methyl- 1-i -(6-methyl-pyridine-2-sulfonyl).3 hydroxy-azepan-4-ylcarbamoyl]-butyl Jamide of Example 239a the title compound was prepared: MS(EI) 602.9 Example 240 Preparation of I -Benzvl-5-oxo-vrroidine-2.ca-ioxvlic acid I (S)-3-methvi- 1 f3-oxo- (Rrdn--slov)ae I4ycramvlbtl amide Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for thiazole-2-sulfonyl chloride and (R)-lI-benzyl-5-oxo-pyrrolidine.2-carboxylic acid for benzofiiran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 5 84.4; 1 H-NMR (400 MHz, CDC1 3 -8.69(d, I 7 9 9 7 .92(m, 2H), 7.52(m, I 7 .32-7.22(m, 5H), 6.92(d, ILH), 6.38(d, IH), 5.15-5.08(m. 4.80-4.75(d, IH), 4 4 7 4 .44(m. 1H), 4 .1 4 -4.10(mn, IH), 3 89 -3.80(mn, 3H), 2.

7 5-2.63(m, 2.

4 6 -1.44(m, lOH), 0.95(d, 6H), and the second eluting diastereomer: MIS 584.4.

Example 241 Preparation of (S I -Benzvl-5-oxo-pvrrolidine-2-carboxylic acid ffS)-3-methvl- 1- 3-ox- (pvridine-2-sulfonvl)-azepan-4-ylcarbamoyllVbutvl lamide Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and (S)-lI-benzyl-5-oxo-pyrrolidine-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. T1he residue was purified by HPLC. First eluting diastereomer; MIS 584.4; 1 H-NMR (400 MHz, CDC1 3 -8.69(d, IH), 7.98-7.92(m, 2H), 7.52(m, IH), 7.32-7.22(m, 5H). 6.92(d, LH), 6.38(d, IH), 5.22-5.18(d, lH), 5.10(mn, lH), 4.80-4.75(d, 1H), 4.5 1(m, IH), 4.12-4.08 (in, I 3.91-3.79(m, 3H), 2.71-1.38(m. 12H), 0.97(d, and the second eluting diastereorner: MS 584.4.

ExamRle 242 Preparation of Benzofuran-2-carboxylic acid f(S )-2-cvclopropvl- I -13-oxo- I -(pvridine-2sulfonvi )-azepan-4-vlcarbamovl)-ethvll-anmide Following the procedure of Example 193e-h except substituting N-Boccyclopropylalanine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 8 mg, second eluting: 8 mng): MS(ESI): 525 ExampIle 243 Preparation of Benzofuran-2-carboxylic acid I(S)-3-methylsulfanvl- I 43-oxo-lI-(pvridine-2)sulfonyl')-azepan-4vlcarbamov)-ropvl-anide Following the procedures of Examples 193e-g except substituted N-Boc-Lmethionine in step 193e. The oxidation of Example 193a was performed by adding sulfur trioxide-pyridine complex (34mgr, 0.211 minol and triethylamine (0.077 ml) to the alcohol intermediate in DMS0 solvent (0.200 After stirring at room temperature for two hours, the mixture was diluted with water and extracted with ethyl acetate. The organic 216 layer was dried, filtered, concentrated, and purified by HPLC to yield two diastereoniers of the title compound as solids (first eluting: 8mg, second eluting: 5 mg). MS(ESI): 545 Example 24 Preparation of Benzofuran-2-carboxvlic acid fS)-2-naphthylen-2-yi-l -f 3-oxo- I -(pvridine- 2-su fonvl)-azepan-4-ylcarbamoyl)-ethyll-amide Following the procedure of Example 1 93e-h except substituting except substituting N-(t-butoxycarbonyl)-3-(2-naphthyl)-L-alanineI the title compound was purified to yield two diastereomers as solids (first eluting: 5.3 mg, second eluting: 3.3 mig): MS(ESI): 610.8 Example 245 Preparation of Thieno[3.2-blthiophene-2-carboxvlic acid f (S)-3-methvl- 141r -(6-methylpvridine-2-sulfonyl)-3-oxo-azepan-4-vlcarbamoyl 1-butvl Iamide Tieno[3.2-b~thiophene-2-carboxylic acid ((S)-3-methyl-lI-[ I-(6-methyl-pyfidine-2sulfonyl)-3-hydroxv-azepan.4-ylcarbamoyl)-butyl )amide Following the procedure of Example 236a except substituting thieno[3,2b]thiophene-2-carboxylic acid for S-methoxybenzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 564 Thieno[3 .2-b]thiophene-2-carboxylic acid (S)-3-methyl-lI-[1 -(6-methyl-pyridine-2sulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-butyl jamide Following the procedure of Example I i except substituting thieno[3,2-b]thiophene- 2-carboxylic acid I (S)-3-methyl- I 1-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4ylcarbamoylj-butyl amide of Example 245a. the title compound was prepared: 'H NMR (CDCl 3 6 1.0 (in, 6H), 1.5-2.2 (in, 6H), 2.6 (in, 3H) 2.7 (mn, IH), 3.8 1H); 4.1 (in, 1H), 4.7 (mn, 2H), 5.3 (in, 1H), 7.4-8.0 (mn, 6H); MS(EI): 562 100%).

217 ExamRie 246 Preparation of Thienof3.2-blthiophene-2-carboxylic acid (S)-3-methyl- 14I ]-(3-methylpyridine-2-sulfonvl )-3-oxo-azepan-4-vlcarbamovl 1-butyl) amnide (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-1I-(3-methyl-pyridine-2sulfonyl)-azepan-4-yl]-amide Following the procedure of Examples 235b-c except substituting 3-methylpyridine-2-sulfonyl chloride for 6-methyl-pyridine-2-sulfonyl chloride the title compound was prepared: MS(E1) 399 Thieno[3 ,2-b]thiophene-2-carboxylic acid ((S)-3-methyil- 41-(3-methyl-pyridine-2sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl 3-butyl )arnide To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(3-methylpyridine-2-sulfonyl)-azepan-4-ylJ-amide of Example 246a (0.25 g)in dichloromethane was added thieno[3 ,2-bjthiophene 10 ),triethylamine 12 mL), HOBt (0.085 g)and EDC 12 ).The reaction was stirred until complete. Workup and column chromatography methanol: dichloromethane) provided the title compound (0.18 MS(EI) 564 Thieno[3 ,2-blthiophene-2-carboxylic acid (S)-3-rnethyl-l1-[1 -(3-methyl-pyridine-2sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}arnide Following the procedure of Example 1i except substituting thieno[3,2-blthiophene- 2-carboxylic acid (S)-3-methyl- 1-[l -(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4ylcarbamoyl]-butyl amide of Example 245a the title compound was prepared: 'H NMR (CtDCI.): 6 1.0 (in. 6H), 1.5-2.2 (in, 6H), 2.6 (in, 3H) 3.0 (mn, IH), 3.8 3H); 4.1 (in, 2H), 4.7 (in, 2H), 5.3 (in, I 7.4-8.0 (in, 5H), 8.4 IH); MS(EI): 562 (M*X 100%).

Example 247 Preparation of 3-Methylbenzofuran-2-carboxylic acid I(S )-3-methvl- I1-fl -(3-methylpyridine-2-su lfonvl)-3-oxo-azepan-4-vlcarbanovz 1-butvl Iamide 3-Methylbenzofuran-2-carboxylic acid f (S)-3-inethyl- I I -(3-methyl-pyridine-2sulfonyl)-3-hydroxy-azepan.4ylcarbamoyl]-buty Jamide Following the procedure of Example 246c except substituting 3-methylbenzofuran- 2-carboxylic acid for thieno[3,2-bjthiophene the title compound was prepared: MS(ED) 556 3 -Methylbenzofuran-2-carboxylic acid I (S)-3-methvl- 1-[fl -(3-methyl-pyridine-2sul fonyl 3 -oxo-azepan-4-ylcarbamoyl 1-butyl }amide Following the procedure of Example 11 except substituting 3-rnethylbenzofuran-2carboxylic acid (S)-3-methyl- 1-[1 -(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4 ylcarbamoyl]-butyl )amide of Example 247a the title compound was prepared: 'H NMR (CDCI,): 8 1.0 6H), 1.5-2.2 (in, 6H), 2.6 38), 2.6 (in, 3H), 3.0 (in, lH), 4.1 (in, 2H), 4.7 (in, 2H), 5.3 (in, 114), 7.4-8.0 (mn, 6H), 8.4 (in, I MS(EI): 554 100%).

Example 248 Preparation of 5-Methoxvbenzofuran-2.carjoxylic acid f MS-3-methyl-4 i-f -3-methv Ipyvidine-2-sulfonv)-3-oxo-aze~an-4..vcarbamovll-butvl Iamide 5-Methoxybenzofuran-2-carboxylic acid (S)-3-methyl- 1 -[1I -(3-methyl-pyridine-2sulfonyl)-3-hydroxy-azepan-4-ylcarbamoylI-butyl )amide Following the procedure of Example 246c except substituting inethoxybenzofuran-2-carboxylic acid for thieno[3,2-b]thiophene the title compound was prepared: MS(EI) 572 5-Methoxybenzofuran-2-carboxylic acid (S)-3-methyl- 1 1 -(3-methyl-pyridine-2sulfonyl)-3-oxo-azepan-4-ylcarbamoyl])-butyl)I amide Following the procedure of Example I i except substituting 2-carboxylic acid I(S)-3-methyl-1- [1 -(3-methyl-pyridine-2-sulfonyl)-3-hvdroxy-azepan-4- 219 yicarbanloyll-butyllamjde of Example 247a the title compound was prepared: 'H NMR (CDCI 3 6 1 .0 (in, 6H), 1.5-2.2 (in, 6H1), 2.6 3H1), 3.0 (mn, I 3.8 3H); 4.1 (in, 211), 4.7 (mn, 211), 5.3 (in, I 7.4- 8.0 (in, 6H1), 8.4 (mn, I1H); MS(EI): 570 100%).

Example 249 Preparation of 5.

6 -Difluoro-benzofuran-2carboxvlic acid f (S )-3-meth v- I -F3-oxo-]1-(1 -oxypyridine-2-sulfony I)-azepan-4-vicarbamovl-butyl lamide 5, 6 -Difluoro-benzofuran2carboxylic acid (S)-3-inethyl- I-[3-hydroxy- 1-(1 -oxypyrdine- 2 -sulfonyl)-azepa...4.ylcarbamoy1J-butyl amnide Following the procedure of Examnple.85c exept substituting 5, 6 -difluorobenzofuran- 2-carboxylic acid for benzofb]thiophene-2-carboxylic acid the title compound was prepared: MS(ESD) 580.9 5.

6 -Difluoro-benzofura-2-caboxylic acid f (S)-3-methyl- I -[3-oxo- 1 -oxyT pyridine- 2 -sufonyl)aep~an-4ylcarbainoyl]-butyl }amide Following the procedure of Example li exept substituting the compound of Example 249a the title compound was prepared: MS(ESI) 578.87 (M+HW).

Example 250 Preparation of 54( 3 Tffluoromethyl-phen"] -fran..2.arboxylic acid i (S')-2-cvclohexvi-. 1f3-oxo-l1-(Pryidine-2-sulfonyl )-azepan-4-ylcarbainoyl -ethvl-amide 4-()2tr-uoyabnlmn--ycoey-rpinlmn)3hdoy azepane-l1-carboxylic acid benzyl ester To a solution of the compound of Example 2e (3.2 g,12.2 inmol) in DMF (35 mL) was added N-Boc-cyclohexylalanine (3.3 HQBt (1.8 g) and EDC (2.56 The reaction was stirred until complete. Workup and column chromatography of the residue hexanes:ethyl acetate) provided 5.5 g of the title compound.

2720 [(S)-Cyclohexyl--(3-hydroxy-azepan-4-ylcarbamoyl)-ethyl-carbamic acid tertnbutyl ester To a solution of the compound of Example 250a (5.5 g) in etyhl acetate:methanol (185 mL:40 mL) was added 10% Pd/C. This mixture was stirred under an atmosphere of hydrogen until complete consumption of the starting material was observed. The reaction was filtered and concentrated to provide 3.75 g of the title compound.

{(S)-2-Cyclohexyl-I-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoylethyl }-carbamic acid tert-butyl ester To a solution of the compound of Example 250 b (1.0 g, 1.91 mmol) in dichloromethane (5 mL) was added water (10 mL) and sodium bicarbonate To this mixture was added 2 -pryidinesulfonyl chloride (0.55 g in 5 mL dichloromethane) dropwise.

The mixture was stirred for 20 minutes whereupon the organic layer was separated and washed with water, brine, dried filtered and concentrated. Column chromatography (2% methanol:dichloromethane) of the residue provided 1.0 g of the title compound: MS (ESI) 525 2 -Amino-3-cyclohexyl-N-[3-hydroxy-(pyridine-2-sul fonyl)-azepan-4-yl]proprionamide To a solution of the compound of Example 250c (1.0 g) in methanol (10 mL) was added HCI (10 mL of 4M HCI in dioxane). The reaction was stirred until complete consumption of the starting material whereupon it was concentrated. The residue was azeotroped with toluene then washed with ether to provide 0.95 g of the title compound.

5-( 3 -Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-2-cyclohexyl- 1-13hydroxy- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide To a solution of the compound of Example 250d (0.20 g, 0.4 mmol) in DMF mL) was added diisopropylethylarmine (0.16 mL), HOBt (0.06 EDC (0.084 g) and 5-[3- (trifluoromethyl)phenyl]-2-furoic acid (0.11 The reaction was stirred until complete consumption of the starting material. Workup and column chromatography 4% methanol:dichloromethane) provided 0.23 g of the title compound.

5-( 3 -Trifluoromethyl-phenyl).furan-2-carboxylic acid (S)-2-cyclohexyl- I f 3-oxo- Il-(py idine- 2 -sulfonyl)-azepan4ylcarbamoy]..ethy J-amide Following the procedure of Example 75d except substituting the compound of Example 250e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting disatereonier (52 mig): MS (ESI) 661.4 and the second eluting diastereomer (45.8 mg): MS (ESI) 661.6.

Example 251 Preparation of 5-( 4 -Chloro-phenvi)-furan-2-carboxvlic acid S)-2-cyclohexyl- I1- f3-oxo- 1I (pvridine-2-sulfonvl )-azep~an-4-ylcarbamoyl 1-ethyl I -amide Following the procedures of Example 250e-f except substituting 54(4chlorophenyl)-2-furoic acid for 5-13-(trifluoromethyl)phenvl -2-furoic acid of Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer (57 mg): MS (ESI) 627.4 and the-second eluting diastereomer (53 mg): MS (ESI) 627.4.

Examole 252 Preparation of Benzofuran-2-carboxylic acid f(S)-3-methvl- I 46-methyl-3-oxo- I -(Pyridinesulphonyl)-azerpan-4-vlcarbamovil-butyl I -amnide Following the procedure of Example 92 "except substituting, 2-methyl-4-pentenal for 2,2-dimethyl-4-pentenal the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 541.2; 1 H-NMR (400 MHz, CDC1 3 8.71-8.66(m, IH), 7 9 8 -7.93(m, 2H), 7.91(d, IH), 7 6 7 -7.29(m, 5H), 7.15-6.92(m, 2H1), 5.28-5.20(m, III), 4 .8 2 -4.47(m, 2H), 3 .9 7 -3.78(m, 1H), 3.65-2.98(m, IH), 2.37-2.34(m, 1H), 2 2 0-1.55(m, 3H), 1.

2 2 -1.19(m, 3H), 1.00-0.86(m, 9H).

Example 253 Preparation of 5-( 4 -Chloro-phenyl)-furan-2-carboxylic acid I (S)-2-cvclohexvl- i -r3-oxo- 1 (1-oxv-o~vndine-2-sulfonvl )-azepan-4-vlcarbamovl 1-ethyl I-amide Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c and substituting 5-(4chlorophenyl)-2-furoic acid for 5-[ 3 -(trifluorornethyl)phenylj-2-furoic acid of Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2.

Example 254 Preparation of--( 3 -Trifluoromethvl-henv)furan-2carboxviic acid f(S)-2-cvclohexyl- 1413oxo- I I -oxv-pvridine-2-sulfonyfl)azep~an-4-vlcarbamovl 1-ethyli)-arnide Following the procedures of Example 250c-f except substituting 2-pyidinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer: MS (ESI) 677.2 and the second eluting diastereomer: MS (ESI) 677.4.

Example 255 Preparation of 5-Fluoro-benzofuran-2-carboxvlic acid (S)-3-methvl- I 4[3-oxo- I -(p~vridine- 2 )-sulfonvl)-azepan-4-vlcarbamoyll-butyI I-amide 5-Fluoro-benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-hydroxy-lI-(pyridine-2sulfonyl)-azepan-4-ylcarbamoyl].butyl }-amide Following the procedure of Example 28b except substituting 5-fluorobenzofuran-2carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: -MS (ESI) 547 (M+W}r) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl- I -[3-oxo- 1 (pyridine-2sulfonyl)-azepan-4-ylcarbaxnoyl]-butyl }-arnide Following the procedure of Example I i except substituting the compound of Example 255a the title compound was prepared: MS(ESI) 544.9 51 ExaMple 256 Preparation of 5,6-Dimethoxvbenzofuran-2-carboxvlc a cid f (S)-2-cvclohexyl-I -[3-oxo- I- NI -OxY-Rvridine-2-sulfonvl)-azepan-4-vlcarbamoyl1-ethyl I -amide Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c and substituting 5.6dimethoxybenzofuran-2-carboxylic acid for 5-[3-(trifluoromethyl)phenyl]-2-furoic acid of Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2.

Example 257 Preparation of 5.5-Bis-44-methoxy-Rhenvl )-pent-4-enoic acid (S)-3-methyl-lI-13-oxo- 1- (Pvridine-2-sulfonvl)-azepan-4-vlcarbamoyll 1-butyI I -amide Following, the procedure of Example 75 except substituting 2-pyridylsulfonyl chloride for thiazole-2-sulfonyl- chloride and 5,5-bis-(4-methoxy-phenyl)-pent-4-enoic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 677.4; 1H-NMR (400 MHz, CDC1 3 -8.69(d, I 7.98-7.92(m, 2H), 7.53-7.50(m, I 7.27-6.77(m, 10H), 6.00- 5.87(m, 2H), 5.08(mn, IH), 4.76-4.72(d, 1H), 4.48(m, 1H), 4.08(m, lH), 3.83(s, 3H), 3.78(s, 3H), 2.70-1.35(m, 12H), 0.9 1(d, 6H); and the second eluting diastereomer: MS 677.4.

224 Example 258 Preparation of Ouinoline-8-carboxvlic acid f(S)-2-naphthylen-2-vl- 1 43-oxo- 1-(p~vrdine-2sulfonvl)-aze]2an-4-ylcarbamovl )-ethyll-amide 4-Amino- I -(pyridine-2-sulfonyl)-azepan-3-ol To a solution of the compound of Example 1 93c (1.5 a) in methanol (10 mL) was added HCI (10 mL of 4M HCI in dioxane). The reaction was stirred until complete by TL.C analysis whereupon it was concentrated to provide 1.2 gof the title compound as a white solid.

I -13-hydroxy-] -(pyridine- 2 -sulfonyl)-azepan4ylcarbamoyl-2-napthylene-2yl-ethyl)I-carbamic acid tert-butyl ester To a solution of the compound of Example 258a (225 mg) in dichloromethane was added TEA 15 mL), HOBt (99 mg), EDC (140 mg) and N-Boc-L-2-naphthylaanine (230 mg). The reaction was stirred until complete. Workup and column chromatography of the residue methanol: dichloromethane) provided 0.35gy of the title compound: MS(ESI) 569 (S)-2-Arrino-N-[3-hydroxy-lI-(pyridine- 2 -sulfonyl)-azepan4-yl]-3naphthylen-2yl.

proprionarnide To a solution of the compound of Example 258b (0.35 g) in methanol (5 mL) was added HCI (5 mL of 4M HCI in dioxane). The reaction was stirred until complete by TLC analysis whereupon it was concentrated to provide 0.31 gof the title compound as a white solid.

Quinoline-8-carboxylic acid (S)-2-naphthylen-2-yi- 1 -13-hydroxy- I -(pyridine-2sulfonyl)-azepan.4.ylcarbanoyl)-ethylJ..amide To a solution of the compound of Example 258c (131 mg) in dichioromethane was added TEA, HQBt (39 mg), EDC (55 mg) and quinoline-8-carboxylic acid (51 mg). The reaction was stirred until complete. Workup and column chromatography of the residue methanol:dichloromethane) provided 0.35- of the title compound: MS(ESI) 574

(M+HW).

225 Quinoline-8-carboxylic acid I (S)-2-naphthylen-2-yl- I -[3-oxo- 1 -(pyridine-2sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide Following the procedure of Example li except substituting the compound of Example 258d the title compound was prepared.

Example 259 Preparation of Naphthvlene- I -carboxylic acid f (S )-2-naphthvlen-2-vl- I -r3-oxo- I -(pyridine, 2-sulfonvl)-azepan-4-ylcarbamoyl )-ethvll-amide Following the procedures of Examples 258d-e except substituting I -naphthoic acid for quinoline-8-carboxylic acid the title compound was prepared.

Example 260 -Prevaration of Ouinoline-8-carboxylic acid I -[3-oxo- I -(pvridine-2-sulfonyl)-azepan-4vicarbamovll-2-phenyi-ethyl I -amide Following the procedures of Examples 258a-e except substituting N-Bocphenylalanine for N-Boc-L-2-naphthylaianine the title compound was prepared.

Example 261 Preparation of Naphthyridine-2-carboxylic acid f (S)-3-methyl- I -f 3-oxo- I -(pvridine-2sulfonyl)-azepan-4-vlcarbamoyll-butyl I -amide Following the procedure of Example 28b-c exept subsituting I ,6-naphthyridine-2carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared.

Example 262 Preparation of Naphthylene- I-carboxylic acid -I'3-oxo- I-(pyridine-2-sulfonvi azenan-4-ylcarbamo 1 -2-hnltv -md Following the procedure of Example 260 except substituting I -naphthoic acid for quinoline-8-carboxylic acid the title compound was prepared.

Example 263 Preparation of 3 -Methylbenzofuran-2-carboxvl ic acid-f (S)-3-methvl- -f3-oxo- 1- (cvclohexyl-propRionyl)azepan-4-ylcarbamoyl 1-butvI I -amide 4-f{ 2 3 -Methylbenzofuran2carbonyl)amnoIA -methyl-pentanoylamino J-3hydroxv-azepane- I -carboxylic acid benzyl ester To a solution of the compound of Example 72a (1.2 2.67 mmol) was added EDC (0.56 HOBt (0.36 TEA (0.67 g) and 3 -methylbenzofuran-2-carboxylic acid (0.47 The reaction was stirred until complete consumption of the starting material was observed.

Work-up and colum chromatography (4:1 hexanes:ethyl acetate) provided 1.05 gof the title compound: MS (ESI) 536 (M+Ir).

3 -Methylbenzofuran-2-carboxylic acid 3 -hydroxy-azepan-4-ylcarbamoyl methyl-butyl]-arnide Following the procedure of Example 2g except substituting the compound of Example 263a the title compound was prepared: MS (ESI) 402 3 -Methylbenzofuran-2..carboxylic acid (S)-3-methyl. 1 -13-hydroxy- I -(cyclohexylproprionyl)-azepan-4-ylcarbarnoyl]-butyl }-amide Following the procedure of Example 263a except substituting the compound of 'Example 263b and 3-cyclohexyipropionic acid for 3 -methylbenzofuran-2-carboxylic acid the title compound was prepared: MIS (ESI) 540 227 3-Methylbenzofuran-2-carboxylic acid (S)-3-methyl- I -[3-oxo- 1 -(cyclohexylproprionyl)-azepan-4.ylcarlbamoyl]-butyl }-anude Following the procedure of Example li except substituting the compound of Example 263c the title compound was prepared: MS (ESI) 538 (M#Wr).

Example 26 Preparation of 3-Methylbenzofuran-2-carboxylic acid f (S)-3-methvl- I -[3-oxo- I -(4-methvlp~entanoyl)-azepan-4-vlcarbamovyl-butyl 1-amide Following the procedures of Example 263c-d except substituting 4-methylpentanoic acid for 3 -cyclohexylpropionic acid the title compound was prepared: MS (ESI) 498

(M+H

4 Example 265 Preparation of 3 -Methylbenzofuiran-2-carboxyl ic acid I (S)-3-methv]l-f 3-oxo- 1-(1 -oxv- Pvrldine- 2 -carbonvl)-azepan-4-vlcarbamovll-butyl-ami de Following the procedures of Example 263c-d except substituting picolinic acid Noxide for 3 -cyclohexylpropionic acid the title compound was prepared: MS (ESI) 498 Example 266 Preparation of (S )-Acetvlaino4-methyl-entanoic acid 3-oxo-l1-(o2vridine-2-sulfonvl)azepan4-yll-amide Following the procedure of Example 75c-d except substituting acetic acid for benzofuran-2-carboxyiic acid in step 75c provided the title compound which was separated by HPLC to give the first eluting, diastereoemer: MS 425.2; 1 H-NMR (400Hz, CDCl 3 8.69(d, I1H), 7 .96-7.94(m, 2H), 7 5 3 7 .52(m, 1IH), 7.05(m, 1I-H), 5.92(m, I H), 5.08(m, IH), 4 .69-4.53(m, 2H), 4 .05-3.90(m, 2H), 2.80(m, 114), 2 2 5-2.12(m, 2H), 1.64(s, 228 1.90-I1.40(m, 5H), 0.95(mn, 6H); and the second eluting distereomer: MIS 425.2 Example 267 Preparation of Ouinoline-2-carboxylic acid f I-r3-oxo- I -(pvridine-2-sulfonvl)-azepan-4vlcarbarnovi I-pentyl I-amide 4 2 -trt-Butoxycarbonylarmino-hexanoylanno)3hydroxy-azepane- I carbox'ylic acid benzyl ester To a stirring solution of compound of the amino alcohol of Example 2e (200 mg, O.74mmol) in DMF (4 ml) was added N-Boc-norleucine (175 mg, 0.76mniol), EDC-HCI (145 mg, 0. 76mmol), and Il-hydroxybenzotriazole (21 mg, 0.1 l6rmol). Reaction allowed to proceed overnight at room temperature. The following morning the mixture was diluted with ethyl acetate, washed with sat. NaHCO, HO, and brine. Dried on MgSO 4 filtered and purified by column chromatography to give 300 mg- of the title compound: MS(ESI) 478.11 I 3 -Hydroxy-azepan-4-ylcarbamoyl)7pentyl]-carbamic acid tert-butyl ester To a solution of compound of Example 267a (300 mg, 0.6 3mmol) in ethyl acetate ml) was added 10% palladium on carbon (160 mg) and H, from a filled balloon. After stirring, the solution at room temperature for 48 hours, the mixture was filtered through celite. The filterate was concentrated to yield the title compound (crude, 161mg, 0.47mmol): MS(ESI): 344.19 1 -[3-Hydroxy-lI-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl}carbaxnic acid rerr-butyl ester To a solution of the compound of Example 267b (161 mg,0.47 mmol) in dichloromethane (6 ml) was added triethylamine (0.065 ml, 0.47mmol) and pyridine-2sulfonyl chloride (83mg, 0.47 mmol). After stirring at room temperature for I hr the mixture was washed with saturated NaHCO 3 The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound (142mg, 0.29mmol): MS(ESI): 485.10 2 -Amino-hexanoic acid {3-hydroxy- -(pyridine-2-sulfonyl)-azepan-4-yl]amide To a stirring solution of the compound of Example 267c (142mg, 0.29mmol) in ethyl acetate was added HCI (4M in dioxane) (0.760 ml, 3.0 mmol). After stirring the reaction mixture for 1 hr at room temperature, the mixture was concentrated to yield a white solid. The solid was azeotroped with toluene twice on rotavap and then treated with a resin bound carbonate (1.47 mmol) in methanol and placed on a shaker. After 4 hr the suspension was filtered and concentrated to yield 104 mg crude product: MS (ESI) 385.08 Quinoline-2-carboxylic acid {(S)-1-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-pentyl }-amide To a solution of the compound of Example 267d (104 mg, 0.

2 7mmol) in CH,C1, was added quinaldic acid (47mg, 0.27 mmol), 1-hydroxybenzotriazole .055 mmol), EDC-HCL (52 mg, 0.27 mmol) in DMF.(2 ml). After stirring at room-temperature overnight, the mixture was diluted with ethylacetate, washed with sat. NaHCO,, HO, dried on MgSO, and filtered to obtain 172mg crude product: MS(ESI) 539.90 Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-pentyl }-amide To a stirring solution of the compound of Example 267e (172mg crude. 0.32mmol) in 1 ml DMSO was added sulfur trioxide-pyridine complex 260mg, 1.6 mmol) and triethylamine (0.88 ml, 3.2mmol). After stirring at room temperature for two hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, concentrated, and purified by HPLC to yield two diastereomers of the title compound as solids (first: 40 mg: second:43mg): MS(ESI) 537.86 230 Example 268 Preparation of Benzofuran-2-carboxvlic acid ((S)-3-methvJ- I-f3-oxo- I-(cvclohexylproprionvi )-azepan 4-vicarbamovl 1-buty! I-amide Following the procedures of Example 263a-d except substituting benzofuran-2carboxylic acid for 3 -mechylbenzofuran-2-carboxylic acid of Example 263a the title compound was prepared: MS(ESI) 524 Example 269 Preparation of Benzofuran-2-carboxylic acid I (S)-3-methvl- I-f3-oxo-lI-(4-methylpentanovl _)-azepan-4-vlcarbamovl 1-butvI -amide Following the procedures of Example 263a-d except substituting benzofuran-2carboxylic acid for 3 -methylbenzofuran-2-carboxylic acid of Example 263a and pentanoic aicd for cyclohexyl propionic acid the title compound was prepared: MS(ESI) 484 Example 270 Preparation of Quinoline-2-carboxylic acid I -f 3-oxo- I -(pvridine-2-sulfonyl)-azepan-4 vlcarbamovll-2-phenyl-ethyl I -amide Following the procedure of Example 267a-f except substituting N-Bocphenylalanine for N-Boc-norleucine in step 267a the title compound was prepared.

Separation of the mixture by HPLC provided two diastereomers as solids (first eluting: 20.5 mg; second eluting: 27 mg MS(ESI) 571.95 Example 271 Preparation of Benzofuran-2-carboxylic acid f(S)-2-benzvloxv- I -f 3-oxo- I -(Vvridine-2sulfon vl)-azepane-4-ylcarbamoyl 1-ethyl )-amide Following the procedure of Example 193e-h, except substituting N-Boc-O-benzy]- L-serine in step 1 93e the title compound was prepared as a mixture of distereoemers. To a solution of benzofuran-2-carboxylic acid (S)-2-benzyloxy-l -[3-oxo-l1-(pyridine-2sulfonyl)-azepane-4-ylcarbamoyl]-ethyl }-amide (90 mg) in ethyl acetate (2 tuL) was added 10% Pd/C (50 Upon hydrogenolysis of approximately 50% of the starting benzyl ether the reaction was filtered and concentrated. Purification of this 4 component mixture by HPLC provided the first eluting diastereomer of the title compound (1 mg-) and the second eluting diastereomer of the title compound (0.3 mg): MS(ESI): 590.94(M+H)'.

Additionally the two individual diastereoemers of benzofuran-2-carboxylic acid{(S)-2hydroxy- 1 [3-oxo- I -(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyI )-ethyl)} -arnide, were also isolated as described below in Example 272.

Example 272 Preparation of Benzofuran-2-carboxylic acid I S)-2-hvdroxv- I-[3-oxo- I-(pvridine-2sulfonvi)-azepane-4-vicarbamovl 1-ethyl I -amide The title compound was obtained as discussed above in Example 27 1.

Purification of the mixture by HPLC provided the two diastereorners in solid form (first eluting: 1.6 mg; second eluting 2.1 mg): MS(ESI): 500.9 Examnle 273 Preparation of 5-Methoxybenzofuran-2-carboxvlic acid f (S)-3-methvl-I 43-oxo- I -(thiazole- 2-sulfonyl)-azepan-4-vlcarbamoyll-butvl lamide Following the procedure of Example 75c-d except substituting methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step provided the title compound which was separated by HPLC to give the first eluting diastereoemer as a white solid (144.3 mg, 85.1 MIS (ESJ) 563.2 and the second elutinga diastereomer as a white solid (Il6.9mcg, 10.0%) MIS (ESI): 563.0 Example 274 Preparation of 7 -Methoxvbenzofuran2car-boxvlic acid (S)-3-methvil- -3-oxo I -(thiazole- 2 -sulfonvl)-azePan.4..ylcarbamnoyll-butyl lamide Following, the procedure of Example 75c-d except substituting 7methoxvbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step provided the title compound which was separated by HPLC to give the first eluting, diastereoemer as a white solid (75 mg, MIS (EST) 563.2 and the second eluting diastereomer as a white solid (57 ma, MIS (ESI) 563.0 Exampe 275 Preparation of -Methvbenzofuran-2carboxvlic acid f (S)-3-methvi-1 I 43-oxo- I -(thiazole-2sulfonvi )-azepan-4-ylcarbamoyl bbutvl. amide Following the procedure of Example 75c-d except substituting 3methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by H-PLC to give the first eluting diastereoemer as white solid (69.5 mg, MIS (ESI) 547.2 and the second eluting diastereomer as a white solid (65 mg, MIS (ESI) 547.2 Example 276 Preparation of Benzorblthiotphene-2-arboxvlic acid I (S)-3-methvl- 1-f3--oxo- I-(thiazole-2sulfonvl)-azepan4-vlcarbamgyvL.butvI lamide Following the procedure of Example 75c-d except substituting benzo[b]thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by H-PLC to give the first eluting diastereoemer as a white solid (79.5 233 mg. MS (ESI) 549.3 and the second eluting diastereomer as a white solid (50.5 ma, 31 MS (ESI) 549.2 Example 277 Preparation of 1-Methyl-I H-indole-2-carboxylic acid f(S)-3-methvl- I-r3-oxo- I-(thiazole-2sulfonyl)-zepan-4-vicarbanovl..butIlamide Following the procedure of Example 75c-d except substituting I -methylindole-2carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by HPLC to give the first eluting diastereoemer as a white solid mg, MIS(ESI) 563.2 and the second eluting diastereomer as a white solid' (57 mg, MIS (ESI) 563.0 Example 278 Preparation of Ouinoxaline-2-carboxylic acid 4(S)-3-methvi- I -f 3-oxo- I -(thiazole-2s lonvl)-azepan..4-ylcarbamovli..butvl amide Following the procedure of Example 75c-d except substituting quinoxaline-2carboxylic acid for benzofuran-2-carboxylic acid'in step 75c provided the title compound which was separated by HPLC to give the first eluting diastereoemer as a white solid (126 mg, MIS (ESI) 545.2 and the second eluting diastereomer as a white solid rmg, MS (ESI) 545.2 (M+H) 4 234 Example 279 Preparation of Ouinoline-2-carboxylic acid f 141 -(4-fluoro-benzenesulfonvl)-3-oxoazepan-4-vlcarbamoyll-3-rnethyl-butvl I-amide Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for benzenesulfonyl chloride and 2-quinoline carboxylic acid for benzofuran-2carboxylic acid, the title compound was prepared. The residue was purified by HPLC.

First eluting, diastereomer; MS 555.2; IH-NMR (400Hz, CDC1 3 8.62(d, IH), 8.34-8.23(q, 2H) 8.19-8.17(d, lH), 7.90-7.88(d, IH), 7.88-7.80(m, 3H), 7.66-7.64(t, lH), 7.25-7.07(m, 5.08(m, lH), 4.72 (mn, IH), 4.58-4.53(d, 1H),4.00(m, 1I), 3.46-3.42(d, I1H), 2.47(m, I1H), 2 .27-2.12(rm, 2H), 1.90-1.40(m, 5H), 1.03- 1.01(mn, 6H); and the second eluting diastereomer: MS (M+H 4 555.4.

The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

235

Claims

1. A method of inhibiting a protease comprising administering to a patient in need thereof an effective amount of a compound of Formula I: R N/R N R2 wherein: R' is selected from the group consisting of: R 2 is selected from the group consisting of:- H, CI- 6 alkyl, C 3 6 cylcloalkyl-CO- 6 alkyl, Ar-CO- 6 alkyl, Het-CO- 6 alkyl, R 9 R 9 R 9 S0 2 R 9 R 9 R' NC(O)-, R 9 R 11 R 9 (R")NS0 2 P:OPER\Kb,,\12363490 div.dai 3sdoc.06/ 1/03 237 R 3 is selected from the group consisting of: H, CI- 6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, HetCO- 6 alkyl and ArCO- 6 alkyl; R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring; R 4 is selected from the group consisting of: H, CI. 6 alkyl, C 3 6 cycloalkyl-CO- 6 alkyl, Ar-CO- 6 alkyl, Het-CO- 6 alkyl, R 5 R 5 R 5 S0 2 R 5 R 5 R1 3 and R 5 R" NC(S)-; R 5 is selected from the group consisting of: H, C 1 6 alkyl, C 2 6 alkenyI, C 2 6 alkynyl, C 3 6 cycloalkyl-CO- 6 alkyI, Ar-CO- 6 alkyl, Het-CO. 6 alkyl, halogenated methyl and acetyl; R 6is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO 0 6 alkyl or Het-Co. 6 alkyl; R 7 is selected from the group consisting of: H, C 1 6 alkyl, C 3 6 cycloalkyl-CO-6alkyl, Ar-CO. 6 alkyl, Het-CO- 6 alkyl, R' 0 R' R 1 0 S0 2 R' 0 R' 0 R1 4 and R' 0 R 1 4 NC(S)-; R 8 is selected from the group consisting of: H, C 1 6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, Het-CO- 6 alkyl and Ar-CO- 6 alkyl; R 9 is selected from the group consisting of: C 1 6 alkyl, C 3 6 cycloalkyl-CO. 6 alkyl, Ar- CO- 6 alkyl and Het-CO- 6 alkyl; R1 0 is selected from the group consisting of: CI- 6 alkyl, C 3 6 cycloalkyl-CO. 6 alkyl, Ar- CO. 6 alkyl and Het-CO 0 6 alkyl; R" is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO. 6 alkyl and Het-Co- 6 alkyl; *R 1 2 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO- 6 alkyl and Het-Co- 6 alkyl; R 1 3 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO- 6 alkyl and Het-Co. 6 alkyl; *R1 4 is selected from the group consisting of: H, C 1 6 alkyl, Ar-CO. 6 alkyl and Het-Co. 6 alkyl; P:'OPERKb.\12363490 div~cl~ms.doc-W6l 1/03 -238- R' is selected from the group consisting of:. H, C,. 6 alkyl, Ar-CO. 6 alkyl and Het-Co. 6 alkyl; R" is selected from the group consisting of:- H, C 1 6 alkyl, Ar-CO- 6 alkyl or Het-Co- 6 alkyl; is selected from the group consisting of: H, C,- 6 alkyl, C 3 6 cycloalkyl-CO. 6 alkyl, Ar-CO- 6 alkyl and Het-CO- 6 alkyl; X is selected from the group consisting of: CH 2 S, and 0; Z is selected from the group consisting of: C(O) and CH 2 wherein each C 1 6 alkyl may be optionally substituted by a moiety selected from the group consisting of C(O)R' 2 N(R' 2 2 R' 2 NC(O)0R', C0 2 N(R' 2 2 N(C=NH)N- 2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more Ph- Co- 6 alkyl, Het-CO 0 6 alkyl, C 1 6 alkoxy, Ph-CO 0 6 alkoxy, Het-CO 0 6 alkoxy, OH, (CH 2 6 NR' 5 R' ~516 O(CH 2 16 NR"R C, 6 alkyl, N(R' 7 2 SR' 7 CF 3 NO 2 CN, CO 2 R' 7 CON(R' 7 2 F, Cl, Br or 1; where and R' 6 are H, C I 6 alkyl, Ph-CO- 6 alkyl, naphthyl-CO- 6 alkyl or Het-Co- 6 alkyl; and R "7 is phenyl, naphthyl, or C,- 6 alkyl; and wherein each Het is optionally substituted with one or two. moieties selected from 17 1771 Ar-CO. 6 alkyl, C I 6 alkyI, OR", N(R' 7 2 SR' 7 CF 3 NO 2 CN, CO 2 CON(R' 7 2 F, Cl, Br or 1; where R 1 7 is phenyl, naphthyl, or C,- 6 alkyl; and pharmaceutically acceptable salts, hydrates and solvates thereof.

2. A method according to Claim I wherein in the compound of Formula I R' is R1 0

3. A method according to Claim I wherein in the compound of Formula I R 3 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- PPER\KbW\l2363490.div.cimsdoc-06/l 1/03 -239- hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl.

4. A method according to Claim 3 wherein in the compound of Formula I R 3 is selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl. A method according to Claim 4 wherein in the compound of Formula I R 3 is isobutyl.

6. A method according to Claim 1 wherein in the compound of Formula I R 4 is selected from the group consisting of: R 5 or R 5 S0 2

7. A method according to -Claim 6 wherein in the compound of Formula I R 4 is R 5

8. A method according to Claim 7 wherein in the compound of Formula I R 5 is selected from the group consisting of: Cl.-6alkyl, halogenated methyl, acetyl, Ar-CO-6alkyl and Het-CO-6alkyl, wherein Cl. 6 alkyl may be optionally substituted by a moiety selected 12 12 12 12 form the group consisting of OR 2, C(O)R SR' 2 S(O)R 2 N(R2)2, RINC(O)OR, CO 2 N(R' 2 2 N(C=NH)NH 2 Het, C 3 6 cycloalkyl; and- Ar represents phenyl or naphthyl, optionally substituted by one or more Ph-Co- 1516 6 alkyl, Het-CO-6alkyl, Cl. 6 alkoxy, Ph-CO-6alkoxy, Het-Co.- 6 alkoxy, OH, (CH 2 )l-6NR O(CH 2 )l- 6 NR1 5 R' 6 Cl-6alkyl, OR" 7 N(R" 7 2 SR" 7 CF 3 NO 2 CN, CO 2 R' 7 CON(R'") 2 F, Cl, Br or I; where R' 5 and R' 6 are H, Cl. 6 alkyl, Ph-CO-6alkyl, naphthyl-CO-6alkyl or Het-Co- 6 alkyl; and R 17 is phenyl, naphthyl, or C.. 6 alkyl; and wherein each Het is optionally substituted with one or two moieties selected from Ar-CO-6alkyl, Cl-6alkyl, OR' 7 N(R' 7 2 SR 7 CF 3 NO 2 CN, CO 2 R" 7 CON(R 2 F, Cl, Br and I, where R' 7 is phenyl, naphthyl, or Cl.-6alkyl.

9. A method according to Claim 8 wherein in the compound of Formula I R 5 is selected from the group consisting of: methyl, halogenated methyl, alkoxy substituted methyl, heterocycle substituted methyl; P.'OPER\Kbtn%12363490 &x.dmo-06/11/03 240 butyl, aryl substituted butyl; isopentyl; 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; tetrahydrofuran72-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, alkyl substituted indolyl; pyridinyl, alkyl substituted pyridinyl, 1-oxy-pyridinyl; thiophenyl, alkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3 ,2-b]thiophenyl; isoxazolyl, alkyl substituted isoxazolyl; and oxazolyl. A method according to Claim 8 wherein in the compound of Formula I R 5 is selected from the group consisting of: pentanonyl; naphthylen-2-yl; benzo[1,3]dioxol-5-yl; furan-2-yl; P.'OPER/Kbn\12363490 divcdimos doc.6/11/03 -241 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, pyridin-2-yl, thiophen-3-yl; thieno[3,2-b]thiophene-2-yl; isoxazol-4-yl; and oxazol-4-yl.

11. A method according to Claim 8 wherein in the compound of Formula I R 5 is selected from the group consisting of: tri fluoromethyl, 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 -trifluoromethyl-phenyl)- furan-2-yl, 5 -bromo-fuiran-2-yl, 5 -(4-chloro-phenyl)-ftiran-2-yl; -(2-piperazin-4-carboxylic acid tert-butyl ester-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl- ethoxy)-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6- dimethoxy-benzofuran-2-yl, 5 -fluoro-benzofuran-2-yl, 5 ,6-difluoro-benzofuran-2-yl, 3- methyl-benzofuran-2-yl; ,6-dimethoxy-benzo[b] thiophen-2-yI; N-methyl-indol-2-yl; 1 -oxy-pyridin-2-yl, 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; P:\OPERKbn\12363490.di.claimtdloc.-I 1/03 242 3,5-dimethyl-isoxazol-4-yl; and 5-methyl-2-phenyl oxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-4-yl.

12. A method according to Claim 8 wherein in the compound of Formula I R 5 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 method according to Claim 1 wherein in the compound of Formula I R' is selected from the group consisting of H and naphthalen-2-yl-methyl.

14. A method according to Claim 13 wherein in the compound of Formula I R' is H. A method according to Claim 1 wherein in the compound of Formula I R" is H.

16. A method according to Claim 1 wherein in the compound of Formula I is selected from the group consisting of H and 6,6-dimethyl.

17. A method according to Claim 1 wherein in the compound of Formula I is H.

18. A method according to Claim 1 wherein in the compound of Formula I R" and R"' are both H.

19. A method according to Claim 1 wherein in the compound of Formula I: R 2 is selected from the group consisting of: H, Cl.6alkyl, C 3 6 cylcloalkyl-Co-6alkyl, Ar-Co. 6 alkyl, Het-Co-.alkyl, R 9 R 9 R 9 S0 2 R 9 R 9 R"NC(O)-, R 9 R 9 (R')NSO 2 SC() ,N CandH and P.'OER\Kb,,(I 2363490 divedinmsdmc.0I 1(90 243 R 6 *R 6 is selected from the group consisting of. H, C,- 6 alkyI, Ar-CO- 6 alkyl or Het-C 0 6 alkyl; *R 7 is selected frm the group consisting of: H, C 1 6 alkyl, C 3 6 cycloalkyl-CO- 6 alkyl, Ar-CO. 6 alkyl, Het-CO- 6 alkyl, R' 0 R' 0 R' 0 S0 2 R' 0 WR 1R 4 and WR 1R 4 NC(S)-; R 8 is selected from the group consisting of: H, C,- 6 alkyl, C 26 alkenyl, C 2 6 alkynyl, Het-CO- 6 alkyl and Ar-CO- 6 alkyl; R9 is selected from the group consisting of: C,- 6 alkyl, C 3 6 cycloalkyl-CO- 6 alkyl, Ar- CO. 6 alkyl and Het-CO- 6 alkyl; R1 0 is selected from the group consisting of:- C,- 6 alkyl, C 3 6 cycloalkyl-CO- 6 alkyI, Ar- CO- 6 alkyl and Het-CO. 6 alkyl; Z is selected from the group consisting of: C(O) and CH 2 wherein each C I 6 alkyl may be optionally substituted by a moiety selected from the group consisting of OR' 2 C(O)R' 2 SR' 2 S(O)R' 2 N(R' 2 2 R' 2 NC(O)0R C0 2 N(R' 2 2 N(C=NH)NH 2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more Ph-Co- 6 alkyl, Het-CO- 6 alkyl, C1. 6 alkoxy, Ph-CO- 6 alkoxy, Het-CO- 6 alkoxy, OH, (CH 2 1 6 NR 5 R1 6 O(CH 2 6 NR' 5 C,- 6 alkyl, OR" 7 N(R' 7 2 SR" 7 CF 3 NO 2 CN, C0 2 R' 7 CON(R 7 2 F, Cl, Br or I; where R1 5 and R 1 6 are H, CI. 6 alkyl, Ph-CO- 6 alkyl, naphthyl-CO. 6 alkyl or Het-Co. 6 alkyl; and R'1 7 is phenyl, naphthyl, or C 1 6 alkyl; and wherein each Het is optionally substituted with one or two moieties selected from Ar-CO. 6 alkyI, C,- 6 alkyI, OR' 7 N(R' 7 2 SR' 7 CF 3 NO 2 CN, C0 2 R' 7 CON(R' 7 2 F, Cl, Br or 1; where R'1 7 is phenyl, naphthyl, or C 1. 6 alkyl. A method according to Claim 19 wherein in the compound of Formula I R 2 is selected from the group consisting of: P:)OPER\Kbml2363490.didaimsd.0.6/I 1103 -244- R6 I R 7 AR-CO-6alkyl, R 9 and R 9 and R 8

21. A method according to Claim 20 wherein in the compound of Formula I R 2 is selected from the group consisting of: Ar-0-6alkyl, R 9 and R 9 S0 2

22. A method according to Claim 21 wherein in the compound of Formula I R is R 9 S0 2

23. A method according to Claim 19 wherein in the compound of Formula I R6 is H.

24. A method according to Claim 19 wherein in the compound of Formula IR 7 is R' OOC(O). A method according to Claim 19 wherein in the compound of Formula I R 8 is C 1 6 alkyl.

26. A method according to Claim 25 wherein in the compound of Formula I R 8 is isobutyl.

27. A method according to Claim 19 wherein in the compound of Formula I R 9 is selected from the group consisting of: C 1 s 6 alkyl, Ar-Co-salkyl and Het-Co.- 6 alkyl; wherein each Cl-6alkyl may be optionally substituted by a moiety selected from the group consisting of OR' 2 C(O)R 2 SR' 2 S(O)R' 2 N(R' 2 2 R 2 NC(0)OR 5 CO 2 N(RI 2 2 N(C=NH)NH 2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more Ph-Co- 6 alkyl, Het-CO-6alkyl, Cl-6alkoxy, Ph-Co. 6 alkoxy, Het-CO-6alkoxy, OH, (CH 2 )1. 6 NR 5 R' 6 O(CH 2 )1- 6 NR' 5 R' 6 Cl-6alkyl, OR 7 N(R' 7 2 SR 7 CF 3 NO 2 CN, CO 2 R 7 CON(R 2 F, Cl, Br or I; where and R' 6 are H, Cs 6 alkyl, Ph-Co.- 6 alkyl, naphthyl-Co.salkyl or Het-Co. P;\OPER\Kb,,\I 2363490 di~Iaims doc-06/I11/03 245 6 alkyl; and R 1 7 is phenyl, naphthyl, or C,- 6 alkyl; and wherein each Het is optionally substituted with one or two moieties selected from Ar-CO. 6 alkyl, CI- 6 alkyl, OR N(R' 7 2 SR' 7 CF 3 NO 2 CN, C0 2 R' 7 CON(R' 7 2 F, Cl, Br or 1; where R 1 7 is phenyl, naphthyl, or C,- 6 alkyl.

28. A method according to Claim 27 wherein in the compound of Formula I R 9 is selected from the group consisting of: methyl; ethyl, and CI- 6 alkyl-substituted ethyl; butyl, C 1 6 alkyl-substituted butyl; tert-butyl; isopentyl; phenyl, halogen substituted phenyl, CI- 6 alkoxy phenyl, cyanophenyl; toluyl, Het-substituted toluyl; benzoic acid; naphthylenyl; benzo[ 1,3]dioxolyl; benzo[ I pyridinyl, 1-oxy-pyridinyl, C,- 6 alkyl pyridinyl; thiophene; thiazolyl; 1 H-imidazolyl, C, 6 alkyl substituted imidazolyl; I H-[1I,2,4]triazolyl, C 1 6 alkyl substituted I 1,2,4]triazolyl; and quinolinyl.

29. A method according to Claim 27 wherein in the compound of Formula I R9 is selected from the group consisting of: 2-cyclohexyl-ethyl; 3 -methylbutyl; 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3- chlorophenyl, 4-chiorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 ,4-dimethoxyphenyl, P:\OPER\Kbw(I12363490,divclaimsdoc.06I t/03 246 2-cyanophenyl; 2-benzoic acid; naphthylen-2-yl; benzo[1I,3]dioxol-5-yl; benzo[ 1 ,2,5]oxadiazol-4-yl; pyridin-2-yl, pyridin-3 -yl, I -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; I H-imidazol-2-yl, 1 H-imidazol-4-yl, I-methyl-i H-imidazol-2-yl, 1-methyl-I H- imidazol-4-yl; I H-[1I,2,4]triazol-3-yl, 5-methyl-i H-[1I,2,4]triazol-3-yl; and quinolin-2-yl.

30. A method according to Claim I wherein in the compound of Formula 1: R 0 R4 R' is3 R 2 is selected from the group consisting of: Ar-CO- 6 alkyl, R 9 R 9 S0 2 R 9 and R R 3 is selected from the .group H, CI- 6 alkyl and Ar-CO- 6 alkyl; R 4 is selected from the group consisting of: R 5 R 5 or R 5 S0 2 R 5 is selected from the group consisting of: C 1 6 alkyl, halogenated methyl, Ar-Co- 6 alkyl and Het-CO. 6 alkyl; R6is H; R' is R' 0 0C(O); P)OPER\Kb.\I 2363490 diIinhs d-06/I 1/03 247 R 8 is C I 6 alkyl; R9 is selected from the group consisting of: C,- 6 alkyI, Ar-CO. 6 alkyl and Het-Co. 6 alkyI; R1 0 is selected from the group consisting of: C,- 6 alkyl, Ar-C0. 6 alkyl and Het-Co. 6 alkyl; 'is H; R" is H; is H; Z is selected from the group consisting of C(O) and CH 2 wherein each CI- 6 alkyl may be optionally substituted by a moiety selected from the group consisting of OR' 2 C(O)R' 2 SR' 2 S(O)R' 2 N(R' 2 2 R' 2 NC(O)0R C0 2 N(R' 2 2 N(C=NH)NH 2 Het, C 3 6 cycloalkyl and Ar; Ar represents phenyl or naphthyl, optionally substituted by one or more Ph-Co- 6 alkyl, Het-CO. 6 alkyl, C 1 6 alkoxy, Ph-CO. 6 alkoxy, Het-CO- 6 alkoxy, OH, (CH 2 6 NR1 5 R" 6 O(CH,)1. 6 NR' 5 C,- 6 alkyl, OR" 7 N(R' 7 2 SR' 7 CF 3 NO 2 CN, CO 2 R' 7 CON(R' 7 2 F, Cl, Br or 1; where R' 5 and R 1 6 are H, C 1 6 alkyl, Ph-CO- 6 alkyl, naphthyl-CO- 6 alkyl or Het-Co. 6 alkyl; and R 1 7 is phenyl, naphthyl,- or C I 6 alkyl; and wherein each Het is optionally substituted with one or two moieties selected from Ar-CO- 6 alkyl, C,- 6 alkyl, OR' 7 N(R' 2 SR' 7 CF 3 NO 2 CN, C0 2 R' 7 CON(R' 7 2 F, Cl, Br or 1; where R 1 7 is phenyl, naphthyl, or CI- 6 alkyl.

31. A method according to Claim 30 wherein in the compound of Formnula 1: R 2 is selected from the group consisting of:- Ar-CO- 6 alkyl, R 9 R'S0 2 R 3 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, I -hydroxyethyl, toluyl, naphthalen-2-ylmethyl; benzyloxymnethyl, and hydroxymethyl; is R 5 R 5 is selected from the group consisting of: methyl, halogenated methyl, alkoxy substituted methyl, heterocycle substituted methyl; butyl, aryl substituted butyl; isopentyl; HOPER\Kb,,nA2363490 div.lhi,-,do-06I 1/03 248 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; fuiranyl, halogen substituted furanyl, aryl substituted furanyl; tetrahydrofuran-2-yl; benzofuranyl, alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, alkyl substituted benzofuranyl; benzo thiophenyl, alkoxy substituted benzo[b]thiophenyl; quinolinyl; quinoxalinyl; 1,8 naphthyridinyl; indolyl, alkyl substituted indolyl; pyridinyl, alkyl substituted pyridinyl, I -oxy-pyridinyl; thiophenyl, alkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3,2-b]thiophenyl; isoxazolyl, alkyl substituted isoxazolyl; and oxazolyl; R 9 is selected from the group consisting of-. methyl; ethyl, and C 1 6 alkyl-substituted ethyl; butyl, C 1 6 alkyl-substituted butyl; tert-butyl; isopentyl; phenyl, halogen substituted phenyl, C 1 6 alkoxy phenyl, cyanophenyl; toluyl, Het-substituted toluyl; benzoic acid; P;OPER\Kb,,,\2363490 ivdajmdc-WI 103 249 naphthylenyl; benzo[1 ,3]dioxolyl; benzo[ 1 pyridinyl, 1-oxy-pyridinyl, C 1 6 alkyl pyridinyl; thiophene; thiazolyl; I H-imidazolyl, C! 6 alkyl substituted imidazolyl; 1 H-[1I,2,4]triazolyl, C I 6 alkyl substituted 1 1,2,4]triazolyl; and quinolinyl.

32. A method according to Claim 30 wherein in the compound of Formula I R 5 is selected from the, group, consistinglof. 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-yI, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl;, quinoxalin-2-yl; 1,8 naphthyridin-2-yl; indol-3-yl, pyridin-2-yl, thiophen-3-yl; thieno[3 ,2-b]thiophene-2-yl; isoxazol-4-yl; and oxazol-4-yl.

33. A method according to Claim 30 wherein in the compound of Formula I R 5 is selected from the group consisting of: tri fluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl, 2-thiophenyl-methyl; P;'OPERKbm\12363490.div.chaims.doc.06/ 11/03 -250- 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; -nitro- furan-2-yl, 5 -(4-nitrophenyl)-furan-2-yl, 5-(3 -trifluoromethyl-phenyl)- furan-2-yl, 5 -bromo-furan-2-yl, 5-(4-chloro-phenyl)-furan-2-yl; -(2-piperazin-4-carboxylic acid tert-butyl ester-ethoxy)benzofuran-2-yl, 5 cyclohexyl-ethoxy)-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl, 5-methoxy-benzo furan- 2-yl, 5,6-dimethoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran- 2-yl, 3-methyl-benzofuran-2-yl; ,6-dimethoxy-benzo [b]thiophen-2-yl; N-methyl-indol-2-yl; I -oxy-pyridin-2-yl, 5 -methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-yl; -tert-butyl-3 -methyl thieno[3 ,2-b]thiophen-2-yl; 3,5-dimethyl-isoxazol-4-yl; and -methyl-2-phenyl oxazol-4-yl, and 2-phenyl-5 -tri fluoromethyl-oxazol-4-yl.

34. A method according to Claim 30 wherein in the compound of Formula I R, is selected from the group consisting of: 2-cyclohexyl-ethyl; 3-methylbutyl; 3,4-dichiorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3- chiorophenyl, 4-chiorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-cyanophenyl; 2-benzoic acid; naphthylen-2-yl; benzo[ I 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- P:'OPER(Kbm,,\2363490.divclain5.doc.0I 1103 -251 pyridin-2-yI, 6-methyl-pyridin-2-yl; thiophene-2-yl; thiazol-2-yl; I H-imidazol-2-yl, I H-imidazol-4-yl, 1-methyl-I H-imidazol-2-yl, 1-methyl-i H- imidazol-4-yl; 1 1,2,4]triazol-3-yl, 5-methyl-I H-[1I,2,4]triazol-3-yl; and quinolin-2-yl. A method according to Claim 30 wherein in the compound of Formula 1: R 2 is R'SO 2 R 3 is isobutyl; R 4 is R 5 C(O); R 5 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 qinolin-2-yl; and R 9 is selected from the group consisting of:- pyridin-2-yl and 1-oxy-pyridin-2-yl.

36. A method according to Claim 35 wherein- in the compound of Formula I R 5 is 3- methyl-benzofuran-2-yl.

37. -A method according to Claim 35 wherein in the compound of Formula I R 9 is 1- oxy-pyridin-2-yl.

38. A method according to Claim I wherein the compound of Formnula I is selected from the group consisting of: -I-I((S)-2-BenzY ocarbonyo4-m-pentnyIl)- 3 -oo-zpn ylcarbarnoyl )carbamic acid benzyl ester; Naphthylene-2-carboxylic acid((S)- I -bny--x-zpn4ycraol--ehl butyllarnide; Benzo[ 1 3 idioxole-5- carboxylic acid 1 -benzy-3-oxo-azepa4ycrbaoyl)- 3 methy1-butyljamide; Benzofuran-2-carboxylic acid -bny- oo zpn4-labnbl--eh butyllamide; Benzo~b]thiophene2carbxylic acid 1-(1 ez13oo-zpn4ycabmy)3 methyI-butyl]amide; Naphthylene-2-sulphonyl ezl3ooaepn4ycraol)3mty-uyl amide; Quinoline-2-carboxylic acid f(S)-I -bny--x-zpn4ycraol--ehl butyllanmide; 252 3,4-dichlorobenzoic acid f(S)-I -benzyl-3-oxo-azepan-4.ylcarbamoyl)-3-methyl- butyl]amide; 4- f (S)-MethyI-2-[(quinoline-2-carbonyl)-aminojpentanoylamino J -3-oxo- I -[2-(3-pyridin-2- yl-phenyl)-acetyllazepanium; 1 2 -Benzyloxycarbonylamino-4-methyl-pentyl).4- f (S)-4-methyi-2-[(2-quirioiline-2- carbonyl )-amino]-pentanoylamino)-3-oxo-azepan ium; I -Benzoyl-4-((S)-2-(benzorl 3 ]dioxole-carbonylamino)-4-methyl-pentanoylmino-3-oxo- azepanium, I -Benzoy- 4 2 -(4fuorobenzoyamino)4methypenanoyIaino)-3oxoazepanium. 3-Ox o-4-((S)-4-methyl-2- 2 -morpholin o.4-y I-ethoxy)-benzofuran-2-carbonyI )amino) pentanoylamino)- I 4 -methyl-pentanoyl)-azepanium; 2 -Morpholin-4-yi-ethoxy)-benzofuran-2-carboxylic acid -benzenesulfonyl-3- oxo-azepan-4-ylcarbamoy)-3methy[.buty]mide; 4-((S)-4-Methyl-2- 2 -morpholino-4-yI-ethoxy)-benzofuran-2carbonyl)amino I pentanoylamino)-.3-oxo-azepane-1I-carboxylic acid phenylamide; 2 -Morpholino-4-yJ-ethoxy)-benzofuranr2-carboxylic acid. ((S)-3-methyl- 1 3-oxo- 1 -42- 3 -pyridin- 2 -yI-phenyl)acetyl-azepan-4ylcarbamoyI I}-butyl)amide;- 2 -Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid f(S)-i -(benzoyl-3-oxo-azepan- 4-ylcarbamoyl)-3-methyl-butyl]amide; 5-(2-Pyri-olidin- I -yI-ethoxy)-benzofuran-2-carboxylic acid I -benzenesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl~amide; 5-(2-Piperidin- 1 -yl-ethoxy)-benzofuran-2-carboxylic acid I -benzenesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyllamide; 2 -Morpholino-4-yi-ethoxy);-benzofuran-2-carboxylic acid ((S)-3-methyl- I- I 3-oxo- 1 3 -pyridin- 2 -yI-phenyl)ethyl]-azepan.4-ylcarbamoyI -butyl)amide; Naphthlene-2-carboxylic acid ((S)-3-methyl- I I 3-oxo- I -[2;-(3-pyridin-2-yi-phenyl)ethyl]- azepan-4-ylcarbamoyl)}-butyl)aniide; 1 Hjndole-2-carboxylic acid ((S)-3-methyl- 1- {3-oxo-lI-[ 2 -(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl }-butyl)amide; 1 H-Indole-2-carboxylic acid 1-(1 -benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyllamide; Benzofuran-2-carboxylic acid -benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3 methyl-butyijamide; 253 Benzofuran-2-carboxylic acid [(S)-3-rnethyl- I1- {3-oxo- 1-[2-(3-pyridin-2-yI-phenyl)ethyl)- azepan-4-ylcarbamoyl)I-butyl)amide; 5-(2-Morpholino-4-yi-ethoxy)-benzofuran-2-carboxylic acid [(S)-3-mnethyl- I-(3-oxo- 1- phenethyl-azepan-4-ylcarbamoyl]-butylJarnide; Naphthylene-2-carboxylic acid [(S)-3-methyl- I -(3-oxo- I -phenethyl-azepan-4- yicarbamoyll-butyl amide; Benzofuran-2-carboxylic acid f (S)-3-methyl- 1 -[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyi]-butyl }-arnide; Naphthylene-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl I-amnide; 5-(2-Morpholino-4-yI-ethoxy)-benzofuran-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I (pyndine-2-sulfonyl)-azepan-4-ycarbamoyl]-butyl)I-amide; 4-((S)-4-Methyl-2- -(2-morpholino-4-y-ethoxy)-benzofuran-2-carbony ]-amino I penranoylamino)-3-oxo-azepane- I -carboxylic acid tert-butyl ester; 4-((S)-4-Methyl-2- {[(5-(2-morpholino-4-yI-ethoxy)-benzofuran-2-carboxylic acid methyl-i -(3-oxo-azepan-4ylcarbanoyl-butyl }axide;, 4-Methyl-pentanoic acid 3-oxo-1I-[2-(3-pyridin-2-yl-phenyl-acetyl]-azepan-4-yl )-amide; ((S)-3-Methyl- 1- {3-oxo- I .2-(3-pyridin-2-yI-phenyl)-acetyl]-azepan-4-ylcarbanoyl I- butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester; (S)-4-Methyl-2-[(naphthyien-2-ylmethyl)-amino)-pentenoic acid [3-oxo-lI-[2-(3-pyridin-2- yi-phenyl)-acetyl]-azepan-4-yl -amide; (S)-3-Methyl- I-[3-oxo- 1 -(pyidine-2-sulfonyl)-azepan-4-ylcarbanoyl]- acid tert-butyl ester; 5-(2-Piperizin- I -yl-ethoxy)-benzofuran-2-carboxylic acid I (S)-3-rnethyl- I -[3-oxo- I (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyI I-amide; 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid (S)-3-metbyl- I -[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide; 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl- 1 3-oxo- I pyiidin-2-yl-phenyl)etbyl]-azepan-4-ylcarbanioyl 1-butyl)amide; {(S)-3-Methyl-lI-[3-oxo-lI-(3-pyridin-2-yl-pbenyl)-ethyI [azepan-4-ylcarbamoyl]- acid tert-butyl ester; 5-(2-piperizin- I -yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl- I I3-oxo- 1 pyridin-2-yl-phenyl)ethyll-azepan-4-ylcarbamoyl }-butyl)amide-, 254 4 -Methyl-2(methy-naphthlen2ylmethyl-amino)pentanoic acid [3-oxo-]I-(pyridine- 2 -sulphonyl)-azepan.4.yi]-amide; 4 -Mehy- 2 (mehylnaphthaen2ymethy]-amno)pentanoc acid 3-oxo- pyridin- 2 -yI-phenyl)yacetyl].azepan-4.yI }-amide; 5-2Mrhln--lehxy-ezfrn2croyic acid methyl ((S)-3-methyl- I-f{3- oxo- 1-[ 2 3 -pyridin-2-yi-phenyI)acetylIJ zepan-4yicarbamoy1 I-butyl)amide; Benzofuran-2-carboxylic acid methyl f (S)-3-methyl- I -[3-oxo- I -(pyn'dine-2-sulfonyl)- azepan. 4 -ylcarbamoyl)3methyl-butyl]-amide 2 2 2 -Trifluoro-N((S-3-methyI- I 3-oxo- I-[ 2 3 -pyridin-2-ylI-pheny)acetylI-azepa-4- ylcarbamoyl)I-butyl)-N-naphthylen.2.ylmethyl..acetamide; 4 -[(S)-(Methanesulphonyl-naphthylen.2 ylmethyl-amino)-4-methy I 1 -lmiJ3- oxo-azepane- 1 -carboxylic acid benzyl ester: Quinoline-2-carboxyljc acid (S)-3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan-4 ylcarbamoyl]-butyl }amide; Quinoline-8-carboxylic acid f(S)-3-methyl- I -[3-oxo- 1 -(pyridine-2-sulfonvl)-azepan-4 ylcarbamoylj-butyl }amide; Quinoline-6-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan-4- yicarbamoyl]-butyl }amide; Quin ol ine-4-carboxylic acid -methyl- [3-oxo- I -(pyridine-2-sulfonyl)-azepan.4 ylcarbamoyl]-butyl) amide; Qu inoline- 3-carboxylic acid f (S)-3-methyl- 1- [3-oxo- I -(pyridine-2-sulfonyl)-azepan-4. ylcarbamoyl]-butyl) amide; lsoquinoline-3-carboxylic acid f (S)-3-methyl- 1 -[3-oxo- I -(pyridine-2-sulfonyl)-azepan.4- ylcarbamoyl)-butyl) amide; Isoquinoline- I -carboxylic acid (S)-3-methyl- 1 -[3-oxo- I -(pyridine-2-sulfonyl)-azepan- ylcarbarnoyl)-butyl }amide; Quinoxaline-2-carboxylic acid (S)-3-methyl- I-[3-oxo-l1-(pyridine-2-sulfonyl)-azepan.4 ylcarbamoyl]-butyl Jamide; Benzo[b]thiophene2caoxylic acid ((S)-3-methyl-l1-f 3-oxo-lI-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoylp-buty) jamide; I 8 -Naphthyridine-2-carboxylic acid ((S)-3-methyl- 1-[3-oxo-l1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyly-butyl }amide; 255 I H-Indole-2-carboxylic acid (S)-3-rnethyl- 1 -[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide; 5-Methoxy-berizofuran-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- 1 -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl )axnide; 5-Bromo-furan-2-carboxylic acid f (S)-3-rnethyl- I [3-oxo- I -(pyridine-2-sulfony! )-azepan- 4-ylcarbamoyljj-butyl) amide; Furan-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan-4- ylIcarbamoyl-butyl) }amide, 5-Nitro-furan-2-carboxylic acid I (S)-3-rnethyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl) amide; 5-(4-Nittro-phenyl )-furan-2-carboxylic acid (S)-3-methyl-l1-[3-oxo- 1-(pyridine-2- sulfonyl)-azepan-4-ylcarbarnoyl]-butyi )amide; 3-Tzifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine- 2-sulfonyl )-azepan-4-ylcarbamoyl ]-butyl amide; Tetrahydro-furan-2-carboxylic acid I (S)-3-methyl- I -[3-oxo- 1 -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl amnide; (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)- azepan-4-yl]-amide; [2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2- sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid (S)-3-rnethyl-1- [3-oxo-l1-(pyridine-2-carbonyl)-azepan-4- ylcarbamnoyl)-3- butyl]-amide; Benzofuran-2-carboxylic acid I (S)-3-methyl- I -[3-oxo- I -oxy-pyridine-2-carbonyl)- azepan-4-ylcarbamoyl)-buryl }amide; 4-((S)-2-tert-Butylcarbonylamino-4-methyl-pentanoylamino)-3-oxo-azepane- I -carboxylic acid benzyl ester; 5,6-Dimethoxy-benzofuran-2-carboxylic acid (S)-3-methyl-lI-[3-oxo-lI-(1-methyl-i H- imidazole-4-sulfonyl)-azepan-4-ylcarbarnoyl)-butyl amide; Benzofuran-2-carboxylic acid (S)-3-rnethyl-lI-[I -(5-methyl-i 1,2,4]tiazole-3-sulfonyl)- 3-oxo-azepan-4-ylcarbaxnoyl)-butyl )aniide; Benzofuran-2-carboxylic acid (S)-3-methyl-l1-[1 -methyl- 1H-imidazole-3-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl )amide; 256 Benzofuran-2-carboxylic acid f (S)-3-methyl- 1 -[1I H-imidazole-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl }amide; Benzofuran-2-carboxylic acid I (S)-3-methyl- I -[3-oxo- I -(thiazoie-2-sulfonyl)-azepan-4- ylcarbamoyll-butyl) amide; Benzofuran-2-carboxylic acid f (S)-3-methyl- 1I 1-methyl- I H-imidazole-4-sulfonyl)-3- oxo-azepan-4-ylcarbarnoyi]-butyl }amide; 4 -Oxy-morpholino-4-yI-ethoxy)-benzofuran-2-carboxylic acid f (S)-3-rnethyl- 1 -[3-oxo- I -(pyridine-2-sulfonyl)-azepan..4-ylcarbamoyl]-butyI I amide; Benzofuran-2-carboxylic acid (S)-3-methyl- I -[3-oxo- 1 -(pyridine- 3-sulfonyl)-azepan-4- ylcarbamoyl]-butyl )axnide; Benzofuran-2-carboxylic acid ((S)-3-methyl- I 3-oxo- 1I-(]I -oxy-pyridine-3-sulfonyl)- azepan-4-ylcarbamoyl]-butyl) amide; Quinoline-3-carboxylic acid 1 -(3.4-dichloro-benzene-sulfonyl)-3-oxo-azepan-4- ylcarbamoyl)]-3D-methyl-butyl }-amide; 5-Hydroxy-benzofuran-2-carboxylic acid (S)-3-methyl- 1-[1 -(1-methyl-i H-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl aniide;. Benzofuran-2-carboxylic acid (S)-3-methyl- I -[3-oxo- I -oxy-pyr-idine-2-sulfonyl)- azepan-4-ylcarbamoyl)]-3-methyl-butyl) -amide; f (S (Benzofuran-2-carbonyl)-amino }-4-methyl-pentanoylamino )-3-oxo-azepane- 1I-sulfonyl)-benzoic acid; (Benzofuran-2-carbonyl)-aminol-4-methyl-pentanoylamino )-3-oxo-azepane- I -sulfonyl)-benzoic acid; Benzo[blthiophene-2-carboxylic acid I (S)-3-methyl- I -[3-oxo- I -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl amide; 5-Bromo-furan-2-carboxylic acid (S)-3-methyl- 1 -[3-oxo- I -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl amide;- 5,6-Dimethoxy-benzofuran-2-carboxylic acid ((S)-3-methyl- I-[3-oxo- 1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl lamide; 1 -Oxy-pyridine-2-carboxylic acid (S)-3-methyl-l1-[3-oxo- I-(pyridine-2-sulfonyl)-azepan- 4-ylcarbainoyl]-butyl I amide; (S)-4-Methyl-2-(pyridine-2-sulfonylarnino)-pentanoic acid [3-oxo-1I-(pyridine-2-sulfonyl)- azepan-4-yli-amide; 257 (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-1I-(pyridine-2-sulfonyl)-azepan-4- yII-arnide; (S)-4-Methyi-2-(3-phenyl-uriedo)-peitaioic acid [3-oxo-lI-(pyridine-2-sulfonyl)-azepan-4- yI]-amide-; Benzofuran-2-carboxylic acid f I [6,6-dimethyl-3-oxo- I (pyridine-sulphonyl)-azepan-4- ylcarbarnoyl 1-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid (S)-3-methyl- I- [3-oxo-l1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-buty amide; Thienof 3 2-blthiophene-2-carboxylic acid (S)-3-methyi- I -[3-oxo- I -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbaxnoylj-butylI jamide; Quinoxaline-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl amnide; Quinoline-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -oxy-pynidine-2-sulfonyl)-azepan- 4-vlcarbanioyl]-butyl) )amide-, Thiophene-3-carboxylic acid (S)-3-methyl- 1 -[3-oxo- 1 -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl lamide; I H-Indole-5-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl )amide; Benzo[ 1,3jdioxole-5-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl )amide; Furan-2-carboxylic acid ((S)-3-methyl- I-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl )arnide; (S)-4-MethyI-2-(2-thiophen-2-yi-acerylanino)-pencanoic acid [3-oxo- I-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-yII-amide; 1 H-Indole-2-carboxylic acid ((S)-3-methyl-l1-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl I}amide; 4-Fluoro- {(S)-3-methyl-l1-f 3-oxo- I-(I -oxy-pyridine-2-sulphonyl)-azepan-4-cabarnoyl- butyl }-benzamide; 5-(2-Morpholin-4-yI-ethoxy)-benzofuran-2-carboxylic acid (S)-3-methvl-lI-[3-oxo-( I-oxy- pyridine2-sulphonyl)-azepan-4-ylcarbaxnoyll- -buty }-amide; Thiophene-2-carboxylic acid (S)-3-methyl- I-[3-oxo-l1-(1 -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl amide; 258 3 -Methyl-benzafui-an-2-carboxylic acid (S)-3-methyl- 1 43-oxo- I -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-utyI I amide; 6-Methyl-N- I (S)-3-methyl- I -[3-oxo- I -oxy-pyridine-2-sulfony)-azepan-4-ycarbamoyj butyl 1-nicotinamide; (S)-4-Methyl-2-(2-th iophen-yI-acetylamino)-pentanoic acid- [3-oxo- I -(pyridine-2- sulfonyl)-azepan..4-yl]-butyl )axnide; 1 H-Indole-6-carboxylic acid (S)-3-methyl- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan-4- ylcarbainoyll-butyl Jamide; Benzo[ 1 3 ldioxole-5-carboxyic acid f (S)-3-methyl- 1- [3-oxo- I -(pyridine-2-sulfony])- azepan-4-ylcarbamoyl)-butyl )amide; 3,4-Dihydro-2H-benzo~bI[1I,4]dioxepine-7-carboxylic acid (S)-3-methyl- I -3-oxo- oxy-pyridine-2-sulfonyl)yazepan-4.yicarbaoylIbutyI I amide; 5-MethyI-thiophene2carboxylic acid f (S)-3-methyl- I-[3-oxo-]1-(1 -oxy-pyridine-2- sulfonyl )-azepan-4-ylcarbamoyl)-butyl amnide; 4 ,5-Dibromo-thiophene-2-carboxylic acid (S)-3-methyl-1- [3-oxo-l1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]ybutyI I amide; 3 ,5-Dimethyl-isoxazole-4-carboxylic acid f(S)-3-methyl-lI-[3-oxo-l1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbarnoylp-butyl }amide; 2 2 -Benzyloxy-acetylamino)-4-methyl-pentanoic acid[ I -(4-methoxy- benzenesulfonyl)-3-oxo-azepan.4.yl]-amide; 3 -Trifluoromethyl-pheny1)-furan.2-carboxylic acid (S)-3-methyl- I-[3-oxo-l1-(1 -oxy- pyridine- 2 -sulfonyl)-azepan-4-ycarbamoyI..butyI I amide; 5-Methyl-2 -phenyi-oxaz'ole-4-carboxylic acid I (S)-3-methyl- 1-f 3-oxo- 1 -oxy-pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyl]..butyI I}amide; Ben~zofuran-2-carboxylic acid 14 1 3 4 -dimethoxy-benzenesulfony)-3-oxo-azepn 4-ylcarbamoyl]-butyl I -amnide; Benzofuran-2-carboxylic acid 1 1-(4-bromo-benzenesulfonyl)-3-oxo-azepan-.4. ylcarbalnoyll-3-methyk-butyl I -amide; Benzofuran-2-carboxylic acid 1-[1 -(benzo[ 1,2,5]oxadiazole-4-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyk..butyl }-am ide; Benzofuran-2-carboxylic acid 1-[l -(3,5-dimethyl-oxazole-4 -sulfonyl)-3-oxo-azepan- 4 -ylcarbamoyll-3-methyl-butyl I -amide; 259 3 -Methyl-benzofuran-2carboxylic acid (S)-3-methyl- I-[3-oxo-lI-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyly-butyl )amide; Thieno[3,2-b~thiophene-2-carIboxylic acid i(S)-3-rnethyl- I-[3-oxo- 1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyly-butyl }amide; 5-rert-ButyI-3-methyI-thieno[3,2bthiophene2-caboxylic acid I(S)-3-methyl- I -[3-oxo- I (pyridine-2-sufonyazepa-4ycrboyl]butyI I amide; 5-Methyl-2-phenyl-oxazole4carboxylic acid (S)-3-methyl- I-[3-oxo-lI-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl].butyI I amide; 2 -PhenyI-5-trifluoromethyl-oxazole.4carboxylic acid I (S)-3-methyl- I -[3-oxo- I -(pyridine- 2 -sulfonyl)-azepan-4.ylcarbamoyl]-butyl }amide; Quinoline-2-carboxylic acid 1 -methanesulfonyl-3-oxo-azepan-4ylcarbamoyl)-3 methyl-butyl)-amide; 1-Methyl-I H-indole-2-carboxylic acid I-(1 -methanesulfonyl-3-oxo-azepa..z4. ylcarbamoyl)-3-methyi-butyl)-amide; Furan-2-carboxylic acid I -methanesulfonyl-3-oxo-azepan..4.ylcarbamoyl)-3 methyl-butylcarbamoyly-methyl 1-amide;- 5-Methoxy-benzofuran-2-carboxylic acid -methanesulfonyl-3-oxo-azepanA.. ylcarbamoyl)-3-methyl-butyl].amide; Quinoxaline-2-carboxylic acid 1-(1 -methanesulfonyI-3-oxo-azepan-4ylcaramoyl)y3 methyl-butyl)-amide; 4 -Chloro-phenyI)-furan-2-carboxylic acid (S)-3-methyl-l1-[3-oxo-lI-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]ybutyI amide; 2 2 -(4-Methoxy-phenyI)-acetylamino).4-methyl-pentanoic acid (I -methanesulfonyl-3- oxo-azepan-4-yl)-amide; Quinoline-2-carboxylic acid f(S)-I 2 -cyano-benzenesufony)-3-oxoaepan-4- ylcarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-I H-indole -2-carboxylic acid (fl(S)-I -(2-cyano-benzenesulfonyl)-3-oxo. azepan- 4 -ylcarbaxoyly3methyl-buryl }-amide; Furan-2-carboxylic acid Q{ 1 I 2 -cyano-benzenesulfonyl)-3-oxo-azepan.4. ylcarbamoyl]-3-methy1-butylcarbamoyI 1-methyl)-amide; 2-carboxylic acid I 1-[I1 2 -cyano-benzenesulfonyl)y3-oxo- azepan-4-ylcarbamoyl 1-3-methyl-butyl )-amide; 260 Quinoxaline-2-carboxylic acid I I- [I -(2-cyano-benzenesulfonyl)-3-oxo-azepan-4- ylcarbarnoyll-3-methyl-butyl }-amide; (2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid []1-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; Quinoline-2-carboxylic acid 141 -(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- yicarbamoyl]-3-methyl-butyl I -amide; I-Methyl-I H-indole-2-carboxylic acid 1(S)-I-fl -(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyI -amide: Furan-2-carboxylic acid 1-[1 -(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyI I -rnethyl)-amide; 5-Methoxy-benzofuran-2-carboxylic acid 1-fl-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Qui'noxaline-2-carboxylic acid I I-f -(4-methoxy-benzenesulfonyl )-3-oxo-azepan-4- ylcarbamoyll-3-methyl-butvl }-Arnide; [2-(4-Methoxy-phenyl )-acetylarnino)-4-methyl-pentanoic acid [1 -(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; I1-Methyl- I H-indole-2-carboxylic acid I -(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoylj-3-methyl-butyl)I-arnide; Furan-2-carboxylic acid I- I -(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylIcarbarroyl] -3-methyl-buty lcarbarnoy 1) -methyl)-amide; 5-Methoxy-benzofuran-2-carboxylic acid f 1-fl-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl 1-amide;. Quinoxaline-2-carboxylic acid I 1-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl)I-amide; [2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [1 -(4-fluoro- benzenesulfonyl)3-oxo-azepan-4-y7j-amide; Benzofuran-2-carboxylic acid- 1-[f1 -(3-chloro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl -amide; 5-Methoxy-benzofuran-2-carboxylic acid-( -[1-(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl)}-amide; 7-Methoxy-benzofuran-2-carboxylic acid- I- -II -(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbanioylj-3-methyl-butyl)I-aniide; 261 5,6-Dimethoxy-benzofuran-2-carboxylic acid-( -f 1-(3-chioro-benzenesulphonyl)-3- oxo-azepan-4-yicarbamoyi]-3-methyl-butyI I -amide; 3-Methyi-benzofuran-2-carboxyiic acid- I-[i -(3-chioro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyll-3-rnethyl-butyl I -amide; Benzo[bIthiophene-2-carboxylic acid-({ -(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-yicarbamoyl]-3-methyl.butyl)J-amide; i-Methyl-i H-indole-2-carboxyiic acid- f I -(3-chloro-benzenesuilphonyl)-3-oxo- azepan-4-ylcarbamoyll-3-niethyl-butyl }-amide; Quinoxaline-2-carboxyiic acid- f 1-ri -(3-chioro-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyi-butyi }-aniide; Benzofuran-2-carboxylic acid- f 1-ri -(2-fluoro-benzenesulphonyi)-3-oxo-azepan-4- ylcarbamnoyll-3-methyl-buryl }-amide;, 5-Methoxy-benzofuran-2-carboxylic acid-fj(S)- l-(2-fluoro-benzenesuiphonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyi }-amide;! 7 -Methoxy-benzofuran-2-carboxylic acid-fJ(S)- I 1-(2-fluoro-benzenesulphonyi)-3-oxo- azepan-4-ylcarbamoyl-3-methyl-butyI }-axnide;- ,6-Dimethoxy-benzofuran-2-carboxylic acid-f 1I -(2-fiuoro-benzenesuiphonyl)-3- oxo-azepan-4-yicarbamoyl]-3-methyl-butyl)-amide; 5-MethyI-benzofuran-2-carboxyiic acid- (S)-1-r1 -(2-fluoro-benzenesuiphonyl)-3-oxo- azepan-4-ylcarbamoyi]-3-rnethyl-butyl )-amide:... Benzo(btthiophene-2-carboxylic acid-fI(S)- I- -[1-(2-fluoro-benzenesuiphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 1-Methyl-i H-indole-2-carboxyiic acid- f I -(2-fiuoro-benzenesuiphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl I -amide; (S)-4-Methyl-2-( I-oxy-pyridine-2-suifonyiamino)-pentanoic acid [3-oxo-l1-(pyridine-2- sulfonyl)-azepan-4-yl]-amide; Quinoxaline-2-carboxylic acid- 14[1 -(2-fiuoro-benzenesuiphonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxyiic acid-fI (S)-3-methyi- I -[3-oxo- I -(thiophene-2- suifonyl)-azepan-4-yicarbamoyl]-butyl 1-amide; 7-Methoxy-benzofuran-2-carboxylic acid- f (S)-3-methyl- 1 -[3-oxo- I -(thiophene-2- sulfonyl)-azepan-4-ylcarbamoyl].butyl -amnide; 262 6 -Dimethoxy-benzofuran-2-.carboxylic acid- I (S)-3-methyl- I -[3-oxo- I -(thiophene-2- sulfonyl)-azepan-4-ylcarbamoylp-butyl 1-amide; 3 -Methyl-benzofuran-2-carboxylic acid-f ((S)-3-methyl- I -[3-oxo- I -(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyiy-butyl J-amide; Benzo[blthiophene-2-carboxylic acid- f (S)-3-methyl- I -[3-oxo- I -(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyly-butyl -amnide; I -Methyl-I -H-indole-2-carboxylic acid-f (S)-3-methyl- I -[3-oxo- I -(thi ophene-2-sulfonyh)- azepan-4-ylcarbarnoyl]-butyl 1-amide; Quinoxaline-2-carboxylic acid- f (S)-3-methyl- I -[3-oxo- 1 -(thiophene-2-sulfonyl)-azepan-4- ylcarbanmoyII-butylI-aiide; Ben zofuran-2-carboxy lic acid- f I 4 -chloro-benzenesulphonyly3-oxo-azepan.4- ylcarbamoyl]-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid-f((S)- I 4 -chloro-benzenesulphonyl)-3-oxo. azepan-4-ylcarbamoyl-3-methyv-butyl -amide; 7 -Methoxy-benzofuiran-2-carboxylic acid- (S 1 -(4-chloro-benzenesulphonyl )-3-oxo- azepan- 4 -ylcarbamoylj[3-methyl-butyl }-amide;- 6 -Dimethoxy-benzofuran-2-arboxylic acid- J(S)-I -(4-chloro-benzenesulphonyl)-3- oxo-azepan-4-ylcarbamoyl ]-3-methyl-butyl)I-arnide; 3 -Methyl-benzofuran-2-carboxylic acid- -[I1 -(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamovlI-3methyl-butyI I -aride; Benzofb] chiophene-2-carboxylic acid- I -f 1-(4-chloro-benzenesulphonyl)-3-oxo. azepan-4-ylcarbamoyl-3-methyl.butyI I -amide; I -Methyl- I H-indole-2-carboxylic acid-fI(S)-I 1-(4-chloro-benzenesulphonyl)-3-oxo. azepan-4-ylcarbamoyll-3-methyl.butyl }-amide; Quinoxal ine-2-carboxylic acid- I 4 -chloro-benzenesulphonyl)-3-oxo-azepan4 ylcarbamnoyll-3-methyl..butyl }-amide; Benzofuran-2-carboxylic acid-f((S)-I 3 -rnethoxy-benzenesuphony)3-oxo-azepan-4- ylcarbarnoyll-3-rnethyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxyuic acid-f((S)- I 1-( 3 -niethoxy-benzenesulphonyl)-3-oxo. azepan-4-ylcarbamoyII-3-methyl-buty) }-amide; 7 -Methoxy-benzofuran-2-carboxylic acid-fI(S)-I I 3 -methoxy-benzenesulphonyl)-3-oxo. azepanA4-ylcarbamoyl-3-methyl-butyl)}-arnide; 263 5,6-Dimethoxy-benzofuran-2-carboxylic acid-({ -(3-methoxy-benzenesulphonyl)-3- oxo-azepan-4-ylcarbarnoyl]-3-methyl-butyl I -amide; 3-Methyl-benzofuran-2-carboxylic acid- f I -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Benzo[bjthiophene-2-carboxylic acid- f I I -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl I -amide; I-Methyl-I I--indole-2-carboxylic acid-({ 1-[1 -(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Quinoxaline-2-carboxylic acid- I -(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4- ylcarbaxnoylj-3-methyl-butyl }-amide; Benzofuran-2-carboxylic acid- (S)-3-methyl- 1 -(3-oxo- I -(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl 1-amide; Benzofuran-2-carboxylic acid f (S)-3-rnethyl- 1 ,4-tridueterio)-3-oxo- I -(pyridine-2- sulfonyl)-azepan-4-ylcarbanoyl3-butyl I amide; Benzofuran-2-carboxylic acid (S)-2-methyl-l1-[3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl -amnide; Benzofuran-2-carboxylic acid [3-oxo- I-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-propyl }-amide; Benzofuran-2-carboxylic acid (S)-2-cyclohexyl-l1-[3-oxo-lI-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl ]-ethyl }-amide; Benzofuran-2-carboxylic acid 1- [3-oxo- I-(pyridine-2-sulfonyl)-azepan-4- ylcarbarnoyll-ethyl )-arnide; Benzofuran-2-carboxylic acid (S)-3-methanesulfinyl- 1- 3-oxo-l1-(pyridine-2-sulfonyl)- azepan-4-ylcarbarnoyl)-propyl )-axnide; Benzofuran-2-carboxylic acid [3-oxo-lI-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- methyl )-axnide; Benzofuran-2-carboxylic acid I-(3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-pentyl }-amide; Benzofuran-2-carboxylic acid 1- [3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbaxnoyll-butyl }-amide; Benzofuran-2-carboxylic acid (S)-2-methyl- I-[3-oxo-l1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll-propyl I -amide: 264 Benzofuran-2-carboxylic acid (S)-2-hydroxy- I -[3-oxo- I -(pyridine-2-sulfonyl)-azepan.4- ylcarbamoyl]-propyl }-amide; Benzofuran-2-carboxylic acid f I- [3-oxo- I -(pyridine-2-sul fonyl)-azepan-4- y lcarbamoyl]-2-phenyl-ethyl) -amide; 1 -(Benzofuran-2-carbonyl)-pyrrolidine-2carboxylic acid [3 -oxo- I -(pyridine-2-sulfonyl)- azepan-4-yi]-amide; 3 .4-Dimethoxy-N- 14 1 4 -methoxv-benzenesufony)-3-oxoepan-4-ylcaramoyj.. 3-methyl-butyl }-benzamide; Benzo[bjthiophene-2-carboxylic I 4 -imethoxy-benzenesulfonyl)-3.oxo- azepan-4-ylcarbamoyl]-3-methyj..butyl)}-amide; Benzo[ I 3 ldioxole-5-carboxylic acid f 4 -fluoro-benzenesulfonvl)-3-oxozepan.4- yicarbamoyl]-3methyl-butyl }-amide;, 2 2 -Benzyloxy-acetylamino-4-methyI-pentanoic acid[ I -(4-fluoro-benzenesulfonyl)-3- oxo-azepan-4-yi]-amide; Benzofbjthiophene-2-carboxylic acid- I 1-( 4 -fluoro-benzenesulfonyl)-3-oxo-azepan. 4-vi carbamoyl]-3.methyl-butyl)I-amide;- Benzofuran-2-carboxylic acid I(S)-I -(1-benzoyI- 3 -oxo-azepan--ycarbamoyl)p3-methy... butyl }-amide; (S--ehl2(unln-8sloyaio-etni acid [3-oxo- 1 -(pyridine-2- sulfonyl)-azepan-4-yI]-amide; 4 -Methyl-2-(naphthylene-2-sulfonyamino)pentanoic acid [3-oxo-l1-(pyridine-2- sulfonyl)-azepan-4-ylj-amide; Benzofuran-2-carboxylic acid- I I 4 -fluoro-benzenesulfonyl)-3oxoazepan4yI carbamoyl ]-3-methyl-butyl) -amide; N- I- I-( 4 -Fluoro-benzenesulfonyl)-3-oxo-azepan-4ylcarbamoyI 1-3-methyl-butyl 3.4-dimethoxy-benzamide; Cyclohexanecarboxylic acid 1-(ri 4 -fluoro-benzenesulfonyl)-3-oxo-azepan-4. ylcarbamoyl -3-methyl-butvl }-amide; 2 2 -Benzyloxy-acetylaniino).4-methyl-pentanoic acid[ I -(methanesulfonyl)-3-oxo- azepan-4-yi)-amide; Benzo[b]Lhiophene-2-carboxylic acid- I -methanesulfonyl-3-oxo-azepan-4-y carbamoyl)-3-methyl-butyl]yamide; 265 Benzo[ 1,3)dioxole-5-carboxyiic acid- I -methanesulfonyl-3-oxo-azepan-4-yI carbamoyl)-3-methyl-butyi]-amide; Benzofuran-2-carboxylic acid- I -methanesulfonyl-3-oxo-azepan-4-yI carbamoyl)-3- methyl-butyi]-amide; N- I -Methanesulfonyi)-3-oxo-azepan-4-ylcarbamoyl -3-methyl-butyl -3,4- dimethoxy-benzarnide; (S)-2-(2-Benzyloxy-acetylamino)-4-methy-pentanoic acid[ 1 -(2-cyano-benzerisulfonyl)-3- oxo-azepan-4-yiI-amide; 1-(2-Cyano-benzenesulfonyi)-3-oxo-azepan-4-ylcarbamoyl -3-methy I-butyl methanesuifonyl- I -benzamide; Benzo[bljthiophene-2-carboxylic acid- 1-[rI -(2-cyano--benzenesulfonyl)-3-oxo-azepan- 4-yl carbamoyl)-3-methyl-butyl]-amide; Benzof 1 ,3]dioxole-5-carboxyiic acid-fI 1-ri -(2-cyano-benzenesuifonyl )-3-oxo-azepan- 4-ylcarbamoyl)-3-methyl-butyl]-amide; (S)-4-Methyl-2-[4-oxo-4-((4-phenoxy-phenyl)-butyrviarino)}-pentanoic acid [3-oxo- 1- (pyridine-2-sulfonyl)Lazepan-4-yl]-;amide; N-f -(2-cyano-benzenesuifonyl)-3-oxo-azepan-4-ylcarbanoyl)}-3-methyl-butyl 3.4-dimethoxy-benzamide; Cyciohexanecarboxylic acid If(S)- I -(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl I -3-methyl-butyl -amide; 4-MethansulfonyI-N- If(S)- I- [4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methyl-butyl-benzamide; 4-Methansulfonyl-N- If(S)- I -[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- metbyl-butyl-benzamide; (S)-3-Methyi- I -[3-oxo- I -(pyridine-2-suifonyi)-azepan-4-ylcarbamoyl]-butycarbanoyI carbamnic acid benzyl ester; (S)-2-[5-(4-Methoxy-phenyl)-pentanoylanniol-4-rnethyl-pentanoic acid [3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-yiI-anide; (S)-2-[2-(3-Benzyloxy-4-rnethoxy-phenyl)-acetyiamnio]-4-methypentanoic acid [3-oxo- 1 (pyridine-2-sulfonyl)-azepan-4-yI]-amide; 5,6-Difluoro-benzofuran-2-carboxyiic acid I (S)-3-metbyi- I -[1I -(pyridine-2-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl-butyl) )amide; 266 (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid [3-oxo-1I-(pyridine-2-sulfonyl)- azepan-4-yIj-amide; Benzofuran-2-carboxylic acid f (S)-3-methyl- I -[1I -(6-methyl-pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl)-butyl }arnide; 5-Methoxy-benzofuran-2-carboxylic acid f (S)-3-methyl- 1 -[1I -(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl].butyl }anmide; 3-Methyl-benzofuran-2-carboxylic acid (S)-3-methyl- I-[I -(6-methyl-pyridine-2- sulfonyI)-3-oxo-azepan-4-ylcarbamoy!]-butyl jamide; 7-Methoxy-benzofuran-2-carboxylic acid (S)-3-methyl-1- [1 -(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbanioyl]-butyl) amnide; 6 -Dimethoxy-benzo~b~thiophene-2-carboxylhc acid ((S)-3-methyl- 1-[i -(pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl ]-butyl amide; I -Benzyl-5-oxo-pyrrolidine-2-carboxylic acid I (S)-3-methyl- I- I 3-oxo-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl) amide; (S)-l1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid (S)-3-methyl- 1- {3-oxo-(pyridine-2- sulfonyI)-azepan-4-ylcarbamoy3-butyI amide; Benzofuran-2-carboxyli'c acid I (S)-2-cyclopropyl- 1 -[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl)-ethyl]-amide; Benzofuran-2-carboxylic acid f (S)-3-methylsulfanyil1-[3-oxo-l1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-propyll-amide; Benzofuran-2-carboxylic acid~ (S)-2-naphthylen-2-y]- 1- [3-oxo- I -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-ethyl]-amide; Thieno[3,2-b~thiophene-2-carboxylic acid (S)-3-methyl- I I[ -(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl amide; Thiieno[3,2-b]thiophene-2-carboxylic acid ((S)-3-methyl- 141 -(3-methyl-pyridine-- sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl )axnide; 3-Metbyl-benzofuran-2-carboxylic acid (S)-3-inethyl- 1-El-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4.ylcarbamoyll-butyl }anide; 5-Methoxy-benzofuran-2-carboxylic acid (S)-3-methyl- 1-11I -(3-rnethyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbaxnoyl]-butyl }aride; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl- I -[3-oxo- 1 -oxy-pyridine-2- sulfonyl )-azepan-4-ylcarbamoyl)-butyl }amide; 267 3 -TrifluoromethyI-phenyl)-furan.2-carboxylic acid I (S)-2-cyclohexyl- I1- f 3-oxo- I1- (pyridine- 2 -sulfonyl)-azepan-4.ylcarbamoylp-ethyl j -amide; 5-(4-Chioro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl- 3-oxo- I -(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-ethyI }-amide; Benzofuran-2-carboxylic acid f (S)-3-methyl- 1 -[6-rnethyl-3-oxo- I -(pyridine-sulphonyl)- azepan-4-ylcarbaxnoyl]-buryl }-aniide; 4 -Chloro-phenyl)-furan-2-carboxylic acid f (S)-2-cyclohexyl- I -[3-oxo- I -oxy- pyridine- 2 -suifonyl)-azepan-4.yicarbarnoyly-ethyI -amide; 3 -Trifluoromethyl-phenyl)-furan2carboxylic acid{( (S)-2-cyclohexyl- I -[3-oxo- I -(I1- oxy-pyridine- 2 -sulfonyl)-azepan.4-ylcarbamoylI-ethy }-amide; 5-Fluoro-benzofuran-2-carboxylic acid (S )-3-rnethyl-1- [3-oxo-lI-(pyridine-2-sulfonyl)- azepan-4-yicarbarnoyl]-butyl 1-amide; 6 -Dimethoxy-benzofuran-2-carboxy1 ic acid({ (S)-2-cyclohexyl-1- [3-oxo- I -oxy- pyridine- 2 -sulfonyl)-azepan-4-ylcarbamoyly-ethyl }-amide; 5,5-Bis-( 4 -methoxy-phenyl)-pent-4-enoic acid 4 (S)-3-metbyl- I1- [3-oxo-lI-(pyridine-2-sulfonyl)-azepan.4ylcarbamoyl])}-butyl)}-amide; Quinoline-8-carboxylic acid f (S)-2-naphthylen-2-yi- 1-[3-oxo- I1- (pyridine- 2 -sulfonyl)-azepan4ylcarbamoyl)-ethyl].amide; Naphthylene-lI-carboxylic acid f (S)-2-naphthylen-2-yl-1- [3-oxo- 1- (pyridine- 2 -sulfony1)-azepan-4-ycarbamoy)ethyI]-amide; Quinoline-8-carboxylic acid I4(S)-i -[3-oxo- I -(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyfl-2-pheny..ethyl) -amide; Naphthyridine-2-carboxylic acid f (S)-3-methyl- 1- [3-oxo- 1 -(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyI I}-amide; Naphtbylene- I -carboxylic acid f I -[3-oxo- I -(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2phe nyl-ethyl }-amide; 3-Methylbenzofuran-2-carboxylic acid 4 (S)-3-methyl-1- [3-oxo- 1 -(cyclohexyl-proprionyl)-azepan-4-ylcarbamoy]-butyI I-amide; 3 -Methylbenzofuran-2-carboxylic acid I (S)-3-methyl-1I- [3-oxo- I 4 -methyl-pentanoyl)-azepan..4.ylcarbamoyl]pbutyl 1-arnide; 3-Methylbenzofuran-2-carboxylic acid I (S)-3-methyl- I -[3-oxo- 1 -oxy-pyridine-2- carbonyl)-azepan-4-ylcarbamoylj-butyl -amnide; (S)-Acetylaxino-4-methyl-pentanoic acid [3-oxo-]I-(pyridine-2-sulfonyl)- azepan-4-yJ]-amide; Quinoline-2-carboxylic acid f 1-[3-oxo- I1-(pyridine-2-sulfonyl)-azepan- 4 -ylcarbamoyl]-pentyl }-amide; Benzofuran-2-carboxylic acid I (S)-3-methyl- I -[3-oxo I -(cyclohexyl-proprionyl )-azepan-4-ylcarbamoyl I-butyI }-amide; Ben zofuran-2-carboxy li c acid (S)-3-methyl- I1- [3-oxo- I 4 -rnethyl-pentanoyl)-azepan-4ylcarbamoyly-butyI -amide; Quinoline-2-carboxylic acid I-[3-oxo-1 -(pyridine-2 -sulfonyI)-azepan.4-ylcarbamoy1]-2phenyi-ethy) 1-amide: Benzofuran-2-carboxylic acid({ (S)-2-benzyloxy-lI-[3-oxo- I -(pyridine-2- sulIfonyl )-azepane-4-ylcarbamoyl )ethyl)} -amide; Benzofuran-2-carboxylic acid f (S)-2-hydroxy- I [3-oxo- I -(pyridine-2- sulIfon y I)-azepane-4-ylIcarbamnoyl]I.-ethyl I -amide; -Met hoxvbenzofuran2carboxyl ic acid f (S)-3-methyl- I I -(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl I amide; 7 -Methoxvbenzofuran.2-carboxylic acid (S)-3-methyl-lI-[3-oxo-l1-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyly-butyl }amide; 3 -Methylbenzofuran-2-carboxylic acid (S)-3-methy[- I-[3-oxo-l1-(thiazole-2-sulfonyl)- azepan-4-v icarbamoyl]-butyl }amide; Benzo[bjthiophene-2.carboxylic acid (S)-3-methyl- I -[3Y-oxo- 1 -(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl )amide; 1-Methyl-I H-indole-2-carboxylic acid ((S)-3-methyl- 1-[3-oxo-l1-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]ybutyl }amide; Quinoxaline-2-carboxylic acid f (S)-3-methyl- I -[3-oxo- I -(thiazole-2-sulfonyl )-azepan-4- ylcairbamoyl]-butyl )amide; and Quinoline-2-carboxylic acid I [1-(4-fluoro-benzenesulfony I)-3-oxo-azepan-4- ylcarbamoylI-3-methyl-butyI }-amide. P.'OPERKb/I 2363490 dicIimsdo-0I U03 -270-

39. A method according to any one of Claims 1 to 38 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease.

40. A method according to Claim 39 wherein said protease is a cysteine protease.

41. A method according to Claim 40 wherein said cysteine protease is cathepsin K.

42. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound of Formula I as defined in any one of Claims 1 to 38.

43. A method according to Claim 42 wherein said disease is osteoporosis.

44. A method according to Claim 42 wherein said disease is periodontitis. A method according to Claim 42 wherein said disease is gingivitis.

46. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound of Formula I as defined in any one of Claims 1 to 38.

47. A method according to Claim 46 wherein said disease is osteoarthritis.

48. A method according to Claim 46 wherein said disease is rheumatoid arthritis.

49. Use of a compound of Formula I as defined in 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. P:OPER\Kbm\l 2363490.div.clims doc06/I 1/03 -271 A use according to Claim 49 wherein said protease is a cysteine protease.

51. A use according to Claim 50 wherein said cysteine protease is cathepsin K.

52. Use of a compound of Formula I as defined in any one of Claims 1 to 38 in the manufacture of a medicament for use in treating a disease characterized by bone loss.

53. A use according to Claim 52 wherein said disease is osteoporosis.

54. A use according to Claim 52 wherein said disease is periodontitis. A use according to Claim 52 wherein said disease in gingivitis.

56. Use of a compound of Formula I as defined in 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.

57. A use according to Claim 56 wherein said disease is osteoarthritis.

58. A use according to Claim 56 wherein said disease is rheumatoid arthritis.

59. A method of inhibiting a protease according to Claim 1, substantially as hereinbefore described.

60. A method of treating a disease characterised by bone loss according to Claim 42, substantially as hereinbefore described.

61. A method of treating a disease characterised by excessive cartilage or matrix degradation according to Claim 46, substantially as hereinbefore described. P:OPERkKbmll2363490 di.c1ims.dc.06d 1/03 272

62. Use of a compound according to any one of Claims 49, 52 or 56, substantially as hereinbefore described. DATED this 6th day of November, 2003 SmithKline Beecham Corporation By DAVIES COLLISON CAVE Patent Attorneys for the Applicants