NZ522965A - Protease inhibitors - Google Patents

Protease inhibitors

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Publication number
NZ522965A
NZ522965A NZ522965A NZ52296501A NZ522965A NZ 522965 A NZ522965 A NZ 522965A NZ 522965 A NZ522965 A NZ 522965A NZ 52296501 A NZ52296501 A NZ 52296501A NZ 522965 A NZ522965 A NZ 522965A
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New Zealand
Prior art keywords
methyl
oxo
azepan
amide
butyl
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NZ522965A
Inventor
Robert W Marquis
Yu Ru
Daniel F Veber
Maxwell D Cummings
Scott K Thompson
Dennis S Yamashita
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Smithkline Beecham Corp
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Publication of NZ522965A publication Critical patent/NZ522965A/en

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • A—HUMAN NECESSITIES
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Abstract

The application discloses both the compound and the process for the synthesis of IA. For compound IA : R1 is selected from the group consisting of (see below); R2 is selected from the group consisting of: C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, R9C(O)-, R9SO2-, R9R11NC(O)- and R9SO2R11NC(O)-; R3 is C1-6 alkyl; R4 is R5C(O)-; R5 is Het-C0-6alkyl; R9 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl and Het-C0-6alkyl; R11 is selected from the group consisting of H, C1-6alkyl, ArC0-6alkyl, and Het-C0-6alkyl; R' is H; R'' is H; R''' is H; R'''' is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl; n is an integer from 1 to 5; Pharmaceutically acceptable salts, hydrates and solvates thereof are also included. The compound can be used in pharmaceutical compositions to treat diseases characterized by bone loss, for example, osteoporosis, periodontis, gingivitis, osteoarthritis, rheumatoid arthritis or excessive cartilage or matrix degradation. The compound can also be used in the manufacture of a medicament to treat parasitic infection such as, schistosomiasis, malaria, trypsanoma brucei, pneumocystis carinii, trypsanoma cruzi and Crithidia fusiculata.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 522965 <br><br> 522965 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> PROTEASE INHIBITORS <br><br> FIELD OF THE INVENTION <br><br> This invention relates in general to 4-amino-azepan-3-one protease inhibitors, 5 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 10 cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis. <br><br> BACKGROUND OF THE INVENTION <br><br> Cathepsins are a family of enzymes which are part of the papain superfamily of 15 cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, 20 D., et al., (1996) J. Biol. Chem. 271,2126-2132. <br><br> 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. <br><br> Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated 25 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 30 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 <br><br> 1 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458. <br><br> 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 5 crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodelling at discrete foci throughout life. These 10 foci, or remodelling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement. <br><br> Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface. 15 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 20 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. <br><br> Several published studies have demonstrated that inhibitors of cysteine proteases 25 are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. J., 1980,192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-AIa-CHN2) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al., 30 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 <br><br> 2 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al, Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Everts, et al., J. Cell. Physiol, 1992,150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269,1106, Inaoka, et al., 5 Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, etal., 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. <br><br> 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 10 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 15 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. <br><br> Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 20 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 25 therein. <br><br> 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 30 cysteine proteases cathepsins B, H and L. International Patent Application No. <br><br> 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-lpconvertase. Alkoxymethyl and mercaptomethyl ketones have also been described as <br><br> 3 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479). <br><br> Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al., 5 Biochem. J., 1968,107,103, Garker et al., Biochem. J., 1974,139,555, Gray et al., <br><br> 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. <br><br> 10 Antipain and leupeptin are described as reversible inhibitors of cysteine protease in <br><br> McConnell et al., /. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and Grinde, Biochem. Biophys. Acta,, 701, 328). <br><br> 15 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent <br><br> Nos.4,749,792 and 4,638,010. <br><br> 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 <br><br> 20 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. <br><br> 25 We have now discovered a novel class of 4-amino-azepan-3-one compounds which are protease inhibitors, most particularly of cathepsin K. <br><br> SUMMARY OF THE INVENTION <br><br> An object of the present invention is to provide 4-amino-azepan-3-one carbonyl 30 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 <br><br> 4 <br><br> 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, or at least to provide the public with a useful choice. <br><br> Accordingly, in the first aspect, this invention provides a compound according to Formula IA, as defined below. <br><br> In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula IA and a pharmaceutical^ acceptable carrier, diluent or excipient. <br><br> In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula IA. <br><br> Also described herein is 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 particular cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K. <br><br> 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, <br><br> such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis. <br><br> DETAILED DESCRIPTION OF THE INVENTION <br><br> Described herein are compounds of Formula I: <br><br> H <br><br> z <br><br> R' <br><br> I <br><br> wherein: <br><br> Rl is selected from the group consisting of: <br><br> Intellectual Property Office of NZ <br><br> 26 FEB 2004 <br><br> 5 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> R2 is selected from the group consisting of: H, Ci_galkyl, Cg.gcycloalkyl-CQ. galkyl, Ar-Co-galkyl, Het-C0_6alkyl, R9C(0)-, R9C(S)-, R9S02-, R90C(0)-, <br><br> MO) ,^N <br><br> R^HNQO)-, R9RnNC(S)-, R9(Rl 1)NS02-R6 <br><br> R7^ Y ^ <br><br> R , and R9S02RnNC(0)-; <br><br> R3 is selected from the group consisting of: H, Ci_6alkyl, C3-6cycloalkyl-Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC().galkyl and ArCo_6alkyl; <br><br> R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring; <br><br> R^ is selected from the group consisting of: H, Cj.galkyl, Cg.gcycloalkyl-15 C0.6alkyl, Ar-C0„6alkyl, Het-C0-6alkyl, R5C(0)-, R5C(S)-, R5S02-, R50C(0)-, R5Rl2NC(0&gt;, and R5R12NC{S)-; <br><br> r5 is selected from the group consisting of: H, Cj.galkyl, C2-6alkenyl, C2-6alkynyl, C3_gcycloalkyl-Co-6alkyl, Ar-Co_6alkyl and Het-CQ-^alkyl; <br><br> R^ is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6aIkyI, and Het-20 Cp-galkyl; <br><br> R^ is selected from the group consisting of: H, Cj.galkyl, C3_6cycIoalkyl~ C0.6alkyl, Ar-Co-galkyl, Het-C0-6alkyl, r10C(o&gt;, r10C(S)-, r10SO2-, r10OC(O)-, r10r13NC(O&gt;, and r10r13NC(S)-; <br><br> R^ is selected from the group consisting of: H, C j .galley 1, C2-6alkenyl, <br><br> 6 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> C2-6alkynyl, HetCg^galkyl and ArCo-galkyl; <br><br> R^ is selected from the group consisting of: Cj.galkyl, C3_5cycloalkyl-Co_6alkyl, Ar-C0.6aUcyl and Het-Cg-galkyl; <br><br> RlO is selected from the group consisting of: C^galkyl, C3_gcycloaLkyl-Co-6alkyl&gt; 5 Ar-C()-6aIkyl and Het-C()_galkyl; <br><br> Rl 1 is selected from the group consisting of: H, C]_galkyl, Ar-Co_6alkyl, and Het-C0.6alkyl; <br><br> R^2 is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, and Het-C0.6alkyl; <br><br> 10 Rl3 is selected from the group consisting of: H, Cgalley 1, Ar-Co-6alkyl, and Het- <br><br> C0_6alkyl; <br><br> R' is selected from the group consisting of: H, C^galkyl, Ar-Co-6alkyl, and Het-Co-eaiky1; <br><br> R" is selected from the group consisting of: H, C^.galkyl, Ar-Co-galkyl, or Het- <br><br> 15 Co_6alkyl; : <br><br> R"' is selected from the group consisting of: H, Cj.gallcyl, C3_gcycloalkyl-Co_6alkyl, Ar-CQ-galkyl, and Het-Co-galkyl; <br><br> R"" is selected from the group consisting of: Ci-6aUcyl, C3_gcycloalkyl-Co_6alkyl C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl and ArCg-galkyl; <br><br> 20 X is selected from the group consisting of: CH2, S, and O; <br><br> Z is selected from the group consisting of: C(O) and CH2; <br><br> n is an integer from 1 to 5; <br><br> and pharmaceutical^ acceptable salts, hydrates and solvates thereof. <br><br> O <br><br> R' <br><br> r-N- <br><br> 1 3 <br><br> 25 In compounds of Formula !, when Rl is R <br><br> R^ is selected from the group consisting of: H, Ci-galkyl, C3-6cycloalkyl-Co-6alkyl,C2-6alkenyl, C2-6alkynyl, Het-Co_galkyl and Ar-CQ.galkyl; <br><br> is preferably selected from the group consisting of: H, C3-6cycloalkyl-30 Co-galkyl, C2-6alkenyl, Ar-Co-galkyl, and Ci_6alkyl; <br><br> R^ is more preferably selected from the group consisting of: <br><br> 7 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, <br><br> cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl. <br><br> R3 is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl. <br><br> R3 is most preferably isobutyl. <br><br> R^ is selected from the group consisting of: H, C^.galkyl, C3_gcycloalkyl-Co-galkyl, Ar-C0_6alkyl, Het-Co_6alkyl, R5C(0)-, R5C(S)-, R5S02-, R50C(0)-, R5R13NC(0)-, and R5R13NC(S&gt;. <br><br> R^ is preferably selected from the group consisting of: R^OC(O)-, R^C(O)- and R5S02-. <br><br> R^ is most preferably R^C(O)-. <br><br> In some embodiments, R^ is preferably methanesulfonyl. <br><br> R^ is selected from the group consisting of: H, Cj.galkyl, C2_galkenyl, C2_6alkynyl, C3_gcycloalkyl-Co_6alkyl, Ar-Co-6alkyl or Het-Co-galkyl. <br><br> Preferably R^ is selected from the group consisting of: Cj.galkyl, Ar-CQ.galkyl and Het-Co-6alkyl. <br><br> More preferably, and especially when R^ is R^C(O)-, R^ is selected from the group consisting of: <br><br> methyl, especially halogenated methyl, more especially trifluoromethyl, especially C^.galkoxy substituted methyl, more especially phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl; <br><br> ethyl, especially piperidin-1 -yl-ethyl; <br><br> butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; <br><br> isopentyl; <br><br> cyclohexyl; <br><br> pentanonyl, especially 4-pentanonyl; <br><br> butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4-methoxyphenyl)-but-3-enyl; <br><br> acetyl; <br><br> phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or C^.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> methoxy-phenyl, especially phenyl substituted with one or more Cj.galkyl sulfonyl groups, more especially 4-methanesulfonyl-phenyl; <br><br> benzyl; <br><br> naphthalenyl, especially naphthylen-2-yl; <br><br> 5 benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; <br><br> furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-nitro-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-furan-2-yl,more especially halogen substituted furanyl, even more especially 5-bromo-furan-2-yl, more especially aryl substituted furanyl, even more especially 5-{4-chloro-phenyl)-furan-2-yl, more especially Cj.galkyl substituted furanyl, even more especially 3-methyl-furan-2~yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; <br><br> tetrahydrofuranyl, tetrahydrofuran-2-yl; <br><br> benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-15 morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-l-yl-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially Cj.galkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especially Cj.galkyl substituted 20 benzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; also 5-fluoro-3-methyl-benzofuran-2-yl, 6-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; <br><br> naphtho[2,l-b]-furanyl, especially naphtho[2,l-b]-furan-2-yl, alkyl substituted 25 naphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; <br><br> benzo[fe]thiophenyl, especially benzo[£&gt;]thiophen-2-yl; especially Cj.galkoxy substituted benzo[b]thiophenyl, more especially 5,6-dimethoxy- benzo[i?Jthiophen-2-yl; <br><br> quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and . quinolin-8-yl; <br><br> 30 quinoxalinyl, especially quinoxalin-2-yl; <br><br> 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; <br><br> indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially C\_ galkyl substituted indolyl, more especially N-methyl-indoI-2-yl; <br><br> 9 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C^.galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; <br><br> furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Cj.galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; <br><br> thiophenyl, especially thiophen-3-yl, also thiophen-2-yI, especially Chalky I substituted thiophenyl, more especially 5-methyl-thiophen-2-yland 5-methyI-thiophen-3-yl, especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; <br><br> thieno[3,2-£&gt;]thiophene, especially thieno[3,2-fe]thiophene-2-yl, more especially Cj.galkyl substituted thieno[3,2-&amp;]thiophene-2-yl, more especially 5-/er/-butyl-3-methyl-thieno[3,2~i&gt;]thiophene-2-yl; <br><br> isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; <br><br> oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl. <br><br> When R4 is R^S02, R5 is preferably pyridin-2-yl or l-oxo-pyridin-2-yl. <br><br> R'is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, and Het-co-6aikyi- <br><br> Preferably R' is selected from the group consisting of: H and naphthaIen-2-yl- <br><br> methyl. <br><br> Most preferably R' is H. <br><br> R"is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het-C0-6alkyl. <br><br> Most preferably R" is H. <br><br> R'"is selected from the group consisting of: H, C^galkyl, C3_6cycloalkyl-Co-6alkyl, and Het-CQ.galkyl. <br><br> R'" is preferably selected from the group consisting of: H and Cj.galkyl. <br><br> 10 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> R'" is more preferably selected from the group consisting of: H, methyl and 6,6-dimethyl. <br><br> R'" is still more preferably selected from the group consisting of: H and 6,6-dimethyl. <br><br> 5 Most preferably R'" is H. <br><br> R' 0 ,N„ <br><br> R4 |^R" <br><br> In compounds of Formula I, when R* is <br><br> 10 R^ is selected from the group consisting of: Ci-6alkyl, C3-6cycloalkyl-Co-6alkyl; C2-6alkenyl, C2-6alkynyl, Het-CQ-galkyi and Ar-Co_6alkyI. <br><br> R^ is preferably Ci-6alkyl. <br><br> R^ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclohexylmethyl, and toluyl. <br><br> 15 R"" is selected from the group consisting of: Ci_6alkyl, C3_6cycloalkyl- <br><br> Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCQ-galkyl and ArCp-galkyl; <br><br> R"" is preferably Ci-galkyl; <br><br> R"" is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl. <br><br> 20 R"" is most preferably methyl. <br><br> In such compounds, R', R", R'", R4, and R^ are as described above wherein 0 <br><br> R4^ <br><br> R3 <br><br> In compounds of Formula I, when R^ is <br><br> 25 <br><br> 11 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 11 is preferably an integer of from 1 to 5; and R, R , R , R4, and R^ are as described above wherein <br><br> O <br><br> Rl is R <br><br> n is most preferably 3. <br><br> The ring may be unsubstituted or substituted with one or more of Cl-6alkyl, C3_6cycl°alkyl-Cg_6alkyl, C2-6alkenyI, C2-6alkynyl, HetCo_6alkyl, ArCQ-galkyl, or halogen. <br><br> The ring is preferably unsubstituted. <br><br> H, C^galkyl, C3_6cycloalkyl-C0-6aIkyl, Ar-C0-6alkyl, Het-Co.6alkyl, R9C(0)-, R9C(S)-, <br><br> 10 <br><br> In compounds of Formula I, R^ is selected from the group consisting of: <br><br> R9S02-, R90C(0)-, R^^NCCO)-, R9RnNC(S)-, R9RnNS02-, <br><br> n6 <br><br> 15 <br><br> 20 <br><br> Even more preferably, R^ is selected from the group consisting of: Ar-Q)-6alky], R9C(0)-, and R9SQ2. <br><br> Most preferably R^ is R9SC&gt;2. <br><br> 25 <br><br> In such embodiments: <br><br> 12 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> R.6 is selected from the group consisting of: H, C^alkyl, Ar-Co-6aIkyl, or Het-Co-6alkyl, preferably H. <br><br> R7 is selected from the group consisting of: H, Cj.galkyl, C3_6Cydoalkyl-C0.6alkyl, Ar-C0_6alkyl, Het-C0.6alkyl, rl0c(o)-, r10c(s)-, r10so2-, r10OC(O)-, r10r14nC(0)-, r10r14nc(s)-, r7 is preferably r10OC(O). <br><br> R^ is selected from the group consisting of: H, C]_6alkyl, C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl and ArCo_6alkyl; preferably C^galkyl, more preferably isobutyl. <br><br> R^ is selected from the group consisting of: C^.galkyl, C3_6cycloalkyl-Co_6alkyl, Ar-Co-6alkyl, and Het-Co-6aIkyl. <br><br> R^ is preferably selected from the group consisting of: C|_galkyl, Ar-CQ.galkyl, and Het-Co_galkyl. <br><br> More preferably, is selected from the group consisting of: <br><br> methyl; <br><br> ethyl, especially Cj.galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; <br><br> butyl, especially C^gbutyl, more especially 3-methylbutyl; <br><br> terr-butyl, particularly when is R^OC(O); <br><br> isopentyl; <br><br> phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially Cj.galkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially Cj.galkyl substituted phenyl, more especially 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially C^.galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; <br><br> toluyl, especially Het-substituted toluyl, more especially 3-{pyridin-2-yl)toluyl; naphthylene, especially naphthyl-2-ene; <br><br> benzoic acid, especially 2-benzoic acid; <br><br> benzo[l,3]dioxolyl, especially benzo[l,3]dioxol~5-yl; <br><br> benzo[l,2,5]oxadiazolyl, especially benzo[l,2,5]oxadiazol-4-yl; <br><br> 13 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> pyridinyl, especially pyridin-2-yl, pyridin-3-yI, especially 1-oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridiii-3-yl; especially C j .galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; <br><br> thiophenyl, especially thiophenyl-2-yl; <br><br> thiazolyl, especially thiazol-2-yI; <br><br> lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, more especially Cj.galkyl substituted imidazolyl, even more especially l-methyl-lH-imidazol-2-yl, 1-methyl-lH-imidazol-4-yl, and l,2-dimethyl-lH-imidazol-4-yl; <br><br> triazolyl, especially lH-[l,2,4]triazolyl, more especially lH-[l,2,4]triazol-3-yl, especially C^galkyl substituted lH-[l,2,4]triazolyl, more especially 5-methyl-lH-[l,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl. <br><br> WhenR2 is R.9sc&gt;2, R^ is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl. <br><br> When R2 is r9s02RHnC(0)-, R^ is preferably Ar-Cg.galkyl, more preferably Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl. <br><br> When R2 is R^C(O)-, R^ is preferably selected from the group consisting of Cj.galkyl, C3.gcycloalkyl-C0_6a.lkyl, and Het-Cg-galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl. <br><br> Rl 1 is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, and Het-Co_6alkyl. <br><br> When R2 is R9S02R1 ^CCO)-, R11 is preferably H. <br><br> When R2 is Ar-Co_galkyl, R2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl. <br><br> When R2 is Cj.galkyl, R2 is preferably selected from 1-propyl, 1-butyl, and 1- <br><br> pentyl. <br><br> 14 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> When r2 is Het-CQ_galkyl, Het-Cp-gaLkyl is preferably Het-methyl, and Het in Het-methyl is preferably selected from the group consisting of: <br><br> pyridinyl, especially pyridin-2-yl, especially Cj.galkylpyridinyl, more especially 6-methyl-pyridin-2-yl; <br><br> thiophenyl, especially thiophene-2-yl, more especially thiophen-2-yl or benzo[b]thiophen-2-yl; <br><br> thiazolyl, especially thiazol-4-yl such as l-(2-morpholin-4-yl-thiazol-4-yl), and 1-(isothiazol-3-yl); <br><br> lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especially Cj.galkyl substituted imidazolyl, more especially l-methyl-lH-imidazoI-2yl; <br><br> triazolyl, especially 3H-[l,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl, especially Cj.galkyl substituted 3H-[l,2,3]triazolyl, more especially 3-phenyl-3H-[l,2,3]triazolyl -4-yl; <br><br> quinolinyl, especially quinolin-2-yl, quinolin-2-yl; <br><br> furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-ethyl-furan- <br><br> 2-yl; <br><br> thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, especially Cj.galkyl substituted thieno[3,2-b]thiophenyl, especially 3,4-dimethyl-thieno[3,2-b]thiophene-2-yl. <br><br> is also preferably: <br><br> H; <br><br> toluyl; <br><br> aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl. Compounds of Formula I where R" and R'" are both H are preferred. <br><br> More preferred are compounds of Formula I wherein: <br><br> R1 is <br><br> 15 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> R' ° <br><br> r-N- <br><br> RJ <br><br> R^ is selected from the group consisting of: Ar-Co-6alkyl, R^C(O)-, R^SC^, <br><br> R6 <br><br> .N„ <br><br> r7/ <br><br> R^R1 iNC(O)-, and R° ; <br><br> R-3 is selected from the group consisting of: H, Ci-6alkyl, C3_6cycloalkyl-5 Co-6alkyl and Ar-Cg-galkyl; <br><br> R4 is selected from the group consisting of: R^OC(O)-, R^C(O)- and R^SC^-; R5is selected from the group consisting of: Cj.galkyl, Ar-C^galkyl and Het-C0_6alkyl; <br><br> R6 is H; <br><br> 10 R7 is R10OC(O); <br><br> R^ is Cj_6alkyl; <br><br> R^ is selected from the group consisting of: C^.galkyl, Ar-CQ.galky] and Het-C0-6alkyl; <br><br> R*0 is selected from the group consisting of: Cj.galkyl, Ar-Cg-galkyl and Het-15 C0.6alkyl; <br><br> R'isH; <br><br> R"is H; <br><br> R'" is H; and <br><br> Z is selected from the.group consisting of: C(O) and CH2. <br><br> 20 <br><br> Even more preferred are such compounds of Formula I wherein R^ is selected from the group consisting of: Ar-C()-6alkyl, R^C(O)-, R^S02- <br><br> Yet more preferred are compounds of Formula I wherein: <br><br> 25 R1 is <br><br> O <br><br> R4' <br><br> R' -N <br><br> R3 <br><br> R^ is selected from the group consisting of: Ar-Co-6alkyl, R^C(O)- and R^SC^; <br><br> 16 <br><br> WO 01/95911 <br><br> PCT/U SO1/19062 <br><br> R3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, <br><br> 1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl; R4 is R5C(0)-; <br><br> 5 R^ is selected from the group consisting of: <br><br> methyl, especially halogenated methyl, more especially tiifluoromethyl, especially C^.galkoxy substituted methyl, more especially phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl; ethyl, especially piperidin-1 -yl-ethyl; <br><br> 10 butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; <br><br> isopentyl; <br><br> cyclohexyl; <br><br> pentanonyl, especially 4-pentanonyl; <br><br> butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4-15 methoxyphenyl)-but-3-enyl; <br><br> acetyl; <br><br> phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or C^.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-20 methoxy-phenyl, especially phenyl substituted with one or more Cj_galkyl sulfonyl groups, more especially 4-methanesulfonyl-phenyl; <br><br> benzyl; <br><br> naphthalenyl, especially naphthylen-2-yl; <br><br> benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; <br><br> 25 furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-nitro-furan- <br><br> 2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-furan-2-yl,more especially halogen substituted furanyl, even more especially 5-bromo-furan-2-yl, more especially aryl substituted furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl, more especially Cj.galky] substituted furanyl, even more especially 3-methyl-furan-2-yl, 4-methyl-furan-2- <br><br> 30 yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; <br><br> tetrahydrofuranyl, especially tetrahydrofuran-2-yl; <br><br> benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- <br><br> 17 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- l-yl-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially C^.galkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yI, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especially C^_galkyl substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; also 5-fluoro~3-methyl-benzofuran-2-yl, 6-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; <br><br> naphtho[2,l-b]-furanyl, especially naphtho[2,l-b]-furan-2-yl, alkyl substituted naphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; <br><br> benzo[/&gt;]thiophenyl, especially benzo[&amp;]thiophen-2-yl; especially C^.galkoxy substituted benzo[Z?]thiophenyl, more especially 5,6-dimethoxy- benzo[i&gt;]thiophen-2-yl; <br><br> quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; <br><br> quinoxalinyl, especially quinoxalin-2-yl; <br><br> 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; <br><br> indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially C|. galkyl substituted indolyl, more especially N-methyl-indol-2-yl; <br><br> pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially Cj.galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; <br><br> furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C^galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; <br><br> thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, especially Cj.galkyl substituted thiophenyl, more especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3-yl, especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; <br><br> thieno[3,2-&amp;]thiophene, especially thieno[3,2-fo]thiophene-2-yl, more especially Cj_galkyl substituted thieno[3,2-Z?]thiophene-2-yl, more especially 5-rer/-butyl-3-methyl-thieno[3,2-£&gt;]thiophene-2-yl; <br><br> isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; <br><br> 18 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazoIyl, especially lH-benzoimidazol-5-yl. <br><br> R^ is selected from the group consisting of: <br><br> methyl; <br><br> ethyl, especially Chalky 1-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; <br><br> butyl, especially C^.gbutyl, more especially 3-methylbutyl; <br><br> tert-butyl, particularly when r2 is R^OC(O); <br><br> isopentyl; <br><br> phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C^galkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C^galkyl substituted phenyl, more especially 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cj.galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; <br><br> toluyl, especially Het-substituted toluyl, more especially 3- (pyridin-2-yl)toluyl; naphthylene, especially naphthyl-2-ene; <br><br> ' benzoic acid, especially 2-benzoic acid; <br><br> benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; <br><br> benzo[l,2,5]oxadiazolyl, especially benzo[l,2,5]oxadiazol-4-yl; <br><br> pyridinyl, especially pyridin-2-yI, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially C^galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; <br><br> thiophenyl, especially thiophenyl-2-yl; <br><br> thiazolyl, especially thiazol-2-yl; <br><br> lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, more especially C^galkyl substituted imidazolyl, even more especially l-methyl-lH-imidazol-2-yl, 1-methyl-lH-imidazol-4-yl, and l,2~dimethyl-lH-imidazol-4-yl; <br><br> 19 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> triazolyl, especially lH-[l,2,4]triazolyl, more especially lH-[l,2,4]triazol-3-yl, especially Cj.galkyl substituted lH-[l,2,4]triazolyl, more especially 5-methyl-lH-[l,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially C^galkyl substituted isoxazolyl, 5 more especially 3,5-dimethyl- isoxazol-4-yl. <br><br> R'isH; <br><br> R" is H; and R'" is H. <br><br> 10 <br><br> More preferred are compounds of Formula I wherein: R* is <br><br> R4/ <br><br> R3 <br><br> 15 R2 is R9S02; <br><br> R^ is isobutyl; <br><br> R4 is R5C(0); <br><br> r5 is selected from the group consisting of: 3-methy]-benzofuran-2-yl, thieno[3,2-Z&gt;]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl, preferably 20 3-methyl-benzofuran-2-yl; <br><br> R^ is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl, preferably l-oxy-pyridin-2-yl. <br><br> R' is H; and R'" is H; <br><br> 25 <br><br> Most preferred is such compound wherein: R^ is 3-methyl-benzofuran-2-yl; and R9 is l-oxy-pyridin-2-yl. <br><br> 20 <br><br> As indicated above, in a first aspect the present invention provides compounds of Formula IA: <br><br> R" <br><br> N <br><br> R! <br><br> 0 <br><br> \ <br><br> R' <br><br> IA <br><br> wherein: <br><br> Rl is selected from the group consisting of: <br><br> R' O <br><br> R' O <br><br> , and <br><br> R <br><br> R^ is selected from the group consisting of: Cj.galkyl, Ar-Co_galkyl, Het-C0_6alkyl, R9C(0&gt;, R9S02-, R9RuNC(0&gt;, andR9S02RnNC(0)-; <br><br> R3 is Ci_6alkyl; <br><br> R4 is R5C(0)-; <br><br> R5 is Het-Co-6alkyl; <br><br> R9 is selected from the group consisting of: C^galkyl, C3_6cycloalkyl-C{)_6alkyl, Ar-C0_6alkyl and Het-Co-galkyl; <br><br> rH is selected from the group consisting of: H, Ci-6alkyl, Ar-Co-6alkyl and Het-C^galkyl, preferably H; <br><br> R'isH; R"is H; <br><br> R'" is H; <br><br> Intellectual Propen Office of NZ <br><br> 26 FEB 2004 <br><br> 21 <br><br> RECEIVE <br><br> R""is selected from the group consisting of: Ci-6alkyl, C3_6cycloalkyl-Co_6alkyl C2-6aIkenyl, C2-6alkynyl, HetCo_galkyl and ArCo_galkyl; and n is an integer from 1 to 5, preferably n is 3; <br><br> and pharmaceutical^ acceptable salts, hydrates and solvates thereof. <br><br> In embodiment IA, when R* is <br><br> R3 is preferably selected from the group consisting of: but-2-yl and isobutyl. <br><br> R3 is most preferably isobutyl. <br><br> Preferably, R5 is selected from the group consisting of: <br><br> piperidin-ethyl, especially piperidin-l-yl-ethyl; <br><br> benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; <br><br> furanyl, especially furan-2-yl, especially aryl substituted furanyl, such as 5-(3-trifluoromethyl-phenyl)-furan-2-yl, more especially Cj.galkyl substituted furanyl, even more especially 3-methyl-furan-2~yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; <br><br> benzofuranyl, especially benzofuran-2-yl, especially Cj.galkoxy substituted benzofuranyl, more especially 5-methoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2-yl, especially Cj_galkyl substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3 ^-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; also 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; <br><br> naphtho[2,l-b3-furanyl, especially naphtho[2, l-b]-furan-2-yl, Cj_galkyl substituted naphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; <br><br> benzo[fc]thiophenyl, especially benzo[&amp;]thiophen-2-yl; <br><br> O <br><br> quinolinyl, especially quinolin-2-yl; <br><br> Intellectual Property Office of NZ <br><br> 22 <br><br> 26 FEB 20(W <br><br> RECEIVE <br><br> quinoxalinyl, especially quinoxalin-2-yl; <br><br> pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yl and l-oxy-pyridin-3-yl; <br><br> furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Cj.galkyl substituted furo[3,2-b]-pyridin-2-yl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; <br><br> thiophenyl, especially thiophen-3-yl, and thiophen-2-yl, Cj.galkyl substituted thiophenyl, especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3-yl; and thieno [3,2-Z&gt;] thiophene, especially thieno[3,2-&amp;]thiophene-2-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl. <br><br> is more preferably selected from the group consisting of: 3-methyl-benzofuran-2-yl,thieno[3,2-&amp;]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl. <br><br> In embodiment IA, when R* is <br><br> R3 is preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, <br><br> isobutyl and t-butyl. <br><br> R"" is selected from the group consisting of: Ci-6alkyl, C3-6cycloalkyl-Co-6alkyl, C2-6a3kenyl, C2-6alkynyl, HetCo_6a]kyl and ArC^galkyl; <br><br> R""is preferably Ci-galkyl; <br><br> R"" is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl. <br><br> Most preferably R"" is methyl. <br><br> In such compounds, R' and R^ are as described above wherein <br><br> B' O <br><br> Intellectual Property Office of NZ <br><br> 23 <br><br> 2 6 FEB 2004 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> O <br><br> 5 n is an integer of from 1 to 5; preferably 3; and <br><br> R and R^ are as described above wherein <br><br> O <br><br> The cyclic ring may be unsubstituted or substituted with one or more of Ci_6alkyl, 10 C3_(5cycloalkyl-Co_6alkyl, C2~6alkenyl, C2-6alkynyl, HetCg-galkyl, ArCg-galkyl, or halogen. <br><br> The cyclic ring is preferably unsubstituted. <br><br> In embodiment IA, R2- is selected from the group consisting of: <br><br> 15 <br><br> C^alkyl, Ar-C0_6alkyl, Het-Co^alkyl, R9C(0)-, R9S02-, R9R! ^0(0)-, and R9S02RUNC(0)-. <br><br> More preferably R2 is selected from the group consisting of: Ar-C()-6alkyl, 20 R9C(0)-, R9S02, and R9R* lNC(0)-. <br><br> Even more preferably, R2 is selected from the group consisting of: Ar-Co-6alkyl, R9C(0)-, and R9S02. <br><br> 25 Most preferably R2 is R9S02. <br><br> 24 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> In such embodiment: <br><br> R9 is selected from the group consisting of: C^.gaLkyi, C3_gcycloalkyl-Co_(5alkyl, Ar-Co-galkyl, and Het-Cg-galkyl. <br><br> R9 is preferably selected from the group consisting of: C^galkyl, Ar-Cg-galkyl, 5 and Het-Cg-galkyl. <br><br> More preferably, R9 is selected from the group consisting of: <br><br> ethyl, especially C^galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; <br><br> propyl, especially prop-l-yl; <br><br> isopentyl; <br><br> 10 butyl, especially but-l-yl; <br><br> phenyl, especially halogen substituted phenyl, more especially 3-fluorophenyl, 4~ fluorophenyl, 2-chlorophenyl; especially Cj.galkyl substituted phenyl, more especially 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cj.galkyl sulfonyl substituted phenyl, more especially 4-methanesuIfonyl phenyl, and 2-methanesulfonyl phenyl; <br><br> 15 pyridinyl, especially pyridin-2-yl, 1-oxy-pyridinyl, more especially 1-oxy-pyridin- <br><br> 2-yl; <br><br> lH-imidazolyl, especially lH-imidazol-2-yl Cj.galkyl substituted imidazolyl, especially l-methyl-lH-imidazol-2-yl; and isoxazolyl, especially isoxazol-4-yl, C^.galkyl substituted isoxazolyl, especially <br><br> 20 3,5-dimethyl- isoxazol-4-yl. <br><br> When R2 is R9SC&gt;2, R9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl. <br><br> 25 When R2 is R^SC^Rl iNC(O)-, R9 is preferably Ar-Cg-galkyl, more preferably <br><br> Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, 4-fluoro phenyl. <br><br> When R2 is R9C(0)-, R9 is preferably selected from the group consisting of <br><br> 30 C]_galkyl, c3.gcycloalkyl-Co_galkyl, and Het-Cg.galkyl, more preferably l-oxy-pyridin-2-yl, 2-cyclohexyl ethyl, and isopentyl. <br><br> When R2 is R9SC&gt;2Rl iNC(O)-, Rl 1 is selected from the group consisting of: <br><br> 25 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> H, Cj_galkyl, Ar-CQ.galkyl and Het-C()-6alkyl- Preferably in such embodiment, R.H is H. <br><br> R2 may suitably be selected from the group consisting of: <br><br> Ci.galkyl, Ar-Co-galkyl and Het-C()-6alkyl, preferably C^galkyl and Het-5 Co-6alkyl, <br><br> When R2 is Ax-Cg-galkyl, R2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl. <br><br> 10 When R2 is Cj.galkyl, R2 is preferably selected from l-propyl, 1-butyl, and 1-pentyl. <br><br> When R2 is Het-Cg-galkyl, Het-CQ.galkyl is preferably Het-methyl, and Het in Het-methyl is preferably selected from the group consisting of: <br><br> pyridinyl, especially pyridin-2-yl, Cj.galkylpyridinyl, especially 6-methyl-pyridin- <br><br> 15 2-yl; <br><br> thiophenyl, especially thiophene-2-yl; <br><br> benzo[b]thiophen-2-yl; <br><br> thiazolyl, especially thiazol-4-yl such as isothiazol-3-yl; <br><br> lH-imidazolyl, especially lH-imidazol-2-yl, C^.galkyl substituted imidazolyl, <br><br> 20 especially l-methyl-lH-imidazol-2yl; <br><br> triazolyl, especially 3H-fl,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl, especially Cj.galkyl substituted 3H-[l,2,3]triazolyl, more especially 3-phenyl-3H-[l,2,3]triazolyl -4-yl; <br><br> quinolinyl, especially quinolin-2-yl, quinolin-2-yl; <br><br> 25 furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-ethyl-furan- <br><br> 2-yl; <br><br> thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, Cj.galkyl substituted thieno[3,2-b]thiophene-2-yI, especially 3,4-dimethyl-thieno[3,2-b]thiophene-2-yl. <br><br> 30 The compounds of embodiment IA have the same uses described throughout this specification for compounds of Formula I. The compounds of embodiment IA may be formulated into pharmaceutical compositions and used in methods of treatment as described for compounds of Formula I throughout this specification. <br><br> 26 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Compounds of Formula I selected from the following group are particularly preferred embodiments of the present invention: <br><br> Example Chemical Name <br><br> No. <br><br> 1 {(S)-1-[ lr((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl}carbamic acid benzyl ester; <br><br> 2 Naphthylene-2-carboxylic acid[(S)-1 -(1 -benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; <br><br> 3 Benzo[l,3]dioxole-5-carboxylie acid [(S)-l-(l-benzyl-3-oxo-azepan-4-y]carbamoyl)-3-methyl-butyl]amide; <br><br> 4 Benzofuran-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; <br><br> 5 Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-b\ityl]amide; <br><br> 6 Naphthylene-2-sulphonyl [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; <br><br> 7 Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; <br><br> 8 3,4-dichlorobenzoic acid [(S)-1 -(1 -benzyl-3-oxo-azepan-4-yIcarbamoyl)-3-methyl-butyl]amide; <br><br> 9 4-{(S)-Methyl-2-[(quinoline-2-carbonyl)-amino]pentanoylamino)-3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]azepanium; <br><br> 10 l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{(S)-4-methyl-2-[(2-quinoiline-2-carbonyl)-amino]-pentanoylamino)-3-oxo-azepanium; <br><br> 11 l-Benzoyl-4-((S)-2-(benzo[l,3]dioxole-carbonylamino)-4-methyl-pentanoylamino)-3-oxo-azepamum; <br><br> 12 l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium; <br><br> 13 3-Oxo-4-((S)-4-methyl-2-{[5-(2-morpholino-4-yI-ethoxy)-benzofuran-2-carbonyl] amino} -pentanoylamino)-1 -(4-methyl-pentanoyl)-azepanium; <br><br> 27 <br><br> PCT/USO1/19062 <br><br> 5-(2-MorphoIin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- <br><br> (l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- <br><br> butyl]amide; <br><br> 4~((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino} -pentanoylamino)-3-oxo-azepane- 1-carboxylic acid phenylamide; <br><br> 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbaraoyl }-butyl)amide; <br><br> 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; <br><br> 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- <br><br> (l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- <br><br> butyi]amide; <br><br> 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-y lcarbamoy 1} -butyl) amide; <br><br> Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide; lH_Indole-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-phenethyl-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 28 <br><br> PCT/US01/19062 <br><br> Naphthylene-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-phenethyl-azepan-4-ylcarbamoyl]-butyI} amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- <br><br> 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Naphthylene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 5-(2-Morpholrno-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)- <br><br> 3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 4-((S)-4-Methyl-2- {[(5-(2-morphoHno-4-yl-ethoxy)-benzofuran-2-. carbonyl]-amino }-pentanoylamino)-3-oxo-azepane-1 -carboxylic acid tert-butyl ester; <br><br> 4-((S)-4-Methyl-2- {[(5-(2-morpholino-4-y l-ethoxy)-benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 4-Methyl-pentanoic acid {3-oxo-l-[2-(3-pyridin-2-yl-phenyl-acetyl]-azepan-4-yl} -amide; <br><br> ((S)-3-Methyl-1- {3-oxo- l-[2-(3-pyridin-2-y l-phenyl)-acety 1]-azepan-4-ylcarbamoyl} -butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester; <br><br> (S)-4-Methyl-2-[(naphthylen-2-ylmethyl)-amino]-pentenoic acid [3-oxo- l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-yl }-amide; <br><br> 4-[2-(2-{(S)-3-Methyl-l-[3-oxo-l-(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyIcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester; <br><br> 5-(2-Piperizin-l-yl-ethoxy)-benzofuraii-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyl}-amide; <br><br> 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-y]carbamoyl]-butyl} amide; <br><br> 29 <br><br> PCT/US01/19062 <br><br> 5-(2-CyclohexyI-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-bu tyl)amide; <br><br> 4-[2-(2-{(S)-3-Methyl-l-[3-oxo-l-(3-pyridin-2-yl-phenyl)-ethyl [azepan-4-ylcarbamoyl]-butylcarbamoyl} -benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxyIic acid tert-butyl ester; <br><br> 5-(2-piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)araide; <br><br> (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-aniino)pentanoic acid [3-oxo-l-(pyridine-2-sulphony])-azepan-4-yl]-aniide; (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid {3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-yl}-amide; <br><br> 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl-l-{ 3-oxo-1 - [2-(3-pyridin-2-yl-phenyl)a.cetyl]-azepan-4-ylcarbamoyl} -butyl)amide; Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; <br><br> 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl}-butyl)-N-naphthylen-2-ylmethyl-acetamide; <br><br> 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoylamino]-3-oxo-azepane-1-carboxylic acid benzyl ester; <br><br> Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Quinoline-8-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}aniide; Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 30 <br><br> PCT/US01/19062 <br><br> Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridiiie-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Isoquinoline-l-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 1 H-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoy l]-buty 1} amide; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(py ridine-2-sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl] amide; <br><br> Tetrahydro-furan-2-carboxylic acid {(S)-3-methy 1-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepaii-4-ylcarbamoyl]-butyl} amide; (S)-4-Methyl-2-(2-phenoxy~acetylamino)-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; <br><br> 31 <br><br> \ <br><br> PCT/US01/19062 <br><br> (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylie acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-carbonyl)-azepan-4-ylcarbamoyl)-3-butyl]-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2~carbonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 4-((S)-2-tert-ButyIcarbonylamino-4-methyl-pentanoylainino)-3-oxo-azepane-1-carboxylic acid benzyl ester; 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(1-methy 1- lH-imidazole-4-sulfony l)-azepan-4-ylcarbamoyl] -butyl} amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[ 1,2,4]triazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1 -[ 1 -(lH-imidazole-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; Benzofuran-2-carboxylic acid {(S)-3-metbyl-l-[3-oxo-l-(thiazoJe- <br><br> 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 5-(4-Oxy-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- <br><br> 3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Quinoline-3-carboxylic acid {(S)-l-(3,4-dichloro-benzene-sulfonyl)-3-oxo~azepan-4-ylcarbamoyl)]-3-methyl-butyl}-amide; <br><br> 32 <br><br> PCT/US01/19062 <br><br> 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- <br><br> pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl}- <br><br> amide; <br><br> 2-(4- {(S)-2- {(Benzofuran-2-carbonyl)-amino} -4-methy 1-pentanoylamino}-3-oxo-azepane-l-sulfonyl)-benzoic acid; <br><br> 3-(4- {(S)-2- {(Benzofuran-2-carbony l)-amii&gt;o]-4-methyl-pentanoylamino} -3-oxo-azepane- l-sulfonyl)-benzoic acid; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI} amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyi)-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepaii-4-yl]-amide; (S)-4-Methyl-2-(3-phenyl-uriedo)-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid {(S)-.l-[6,6-dimethyl-3-oxo-1 (pyridine-sulphonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- <br><br> l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- <br><br> butyl} amide; <br><br> 33 <br><br> PCT/US01/19062 <br><br> Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- <br><br> l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- <br><br> butyl}amide; <br><br> Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Quinoline-2-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l~(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Thiophene-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l- [3-oxo-1-( 1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide; <br><br> Benzo[ 1,3]dioxole-5-carboxylic acid {(S)-3-methyl- l-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-y lcarbamoyl]-butyl} amide; (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide; lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 4-Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]-butyl}-benzamide; <br><br> 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-( l-oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]- -buty}-amide; <br><br> Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-butyl}amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1-(l-oxy-pyridine-2-sulfonyl)-azepaii-4-ylcarbamoyl]-butyl}amide; <br><br> 6-Methyl-N- {(S)-3-methyl-1 -[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-nicotinamide; (S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-oxo-l-(pyridine-2-sulfoiiyl)-azepan-4-yl]-butyl}amide; <br><br> 34 <br><br> PCT/US01/19062 <br><br> lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 3.4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl] butyl Jamide; <br><br> 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 4.5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- <br><br> butyl Jamide; <br><br> 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo- <br><br> l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- <br><br> butyl Jamide; <br><br> (S)-2-(2-Benzyloxy-acetylamino)-4-niethyl-pentanoic acid[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyljamide; <br><br> 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide; <br><br> Benzoforan-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyI-butyl}-amide; <br><br> 35 <br><br> PCT/USO1/19062 <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI} amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- <br><br> 1-(pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 5-ferf-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> Quinoline-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; l-Methyl-lH-indole-2-caiboxylic acid [(S)-l-(l-methanesulfonyl- <br><br> 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Furan-2-carboxyIic acid {[(S)-l-(l-methanesulfonyI-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; <br><br> QuinoxaIine-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid (l-methanesulfonyl-3-oxo-azepan-4-yl)-amide; Quinoline-2-carboxylic acid {[(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> 1-Methyl-lH-indole-2-carboxyIic acid {[(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> 36 <br><br> PCT/USO1/19062 <br><br> Furan-2-carboxylic acid ({(S)-l-[l-(2-cyano-benzenesulfonyl)-3- <br><br> oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)- <br><br> amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfoiiyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> Quinoxaline-2-carboxylic acid {(S)-l-[l-(2-cyano- <br><br> benzenesuifonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; Quinoline-2-carboxylic acid {[(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> l-Methyl-lH-indole-2-carboxyIic acid {[(S)-l-[l-(4-methoxy- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Furan-2-carboxylic acid ({(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcaxbamoyI}-methyl)-amide; <br><br> 5-Methoxy-benzofuran-2-carboxyIic acid {[(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> Qmnoxaline-2-carboxylic acid {[(S)-l-[l-(4-methoxy- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; l-Methyl-lH-indole-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> 37 <br><br> PCT/USO1/19062 <br><br> Furan-2-carboxylic acid ({(S)-l-[l-(4-fluoro-benzenesulfonyl)-3- <br><br> oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)- <br><br> amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-l-[l-(4-fluoro- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Quinoxaline-2-carboxylic acid {[(S)-l-[l-(4-fluoro- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid- {(S)-1-[ l-(3-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid- {(S)-1 - [1 -(3-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 1 -Methyl- lH-indole-2-carboxylic acid- {(S)-1 -[l-(3-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 38 <br><br> PCT/US01/19062 <br><br> Quinoxaline-2-carboxylic acid-{(S)-l-[l-(3-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid-{ (S)-l-[l-(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 7-Methoxy-benzofuraxi-2-carboxylic acid-{ (S)-l-[l-(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-buty][}- <br><br> amide; <br><br> 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{ (S)-l-[l-(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 5-Methy l-benzofuran-2-carboxylic acid- {(S)-1 - [ l-(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzo[b]thiophene-2-carboxylic acid- {(S)-1 - [ 1 -(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> l-Methyl-lH-indole-2-carboxylic acid-{(S)-l-[l-(2-fluoro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> (S)-4-Methyl-2-(l-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; Quinoxaline-2-carboxylic acid- {(S)-1 - [ l-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 39 <br><br> PCT/US01/19062 <br><br> 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3- <br><br> oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}- <br><br> amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid-{ (S)-3-methyl-l-[3-oxo-l- <br><br> (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> Benzo[b]thiophene-2-carboxyIic acid-{(S)-3-methyl-l-[3-oxo-l- <br><br> (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyIj-butyl}-amide; <br><br> l-Methyl-l-H-indole-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- <br><br> (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> Quinoxaline-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- <br><br> (thiophene-2-sulfonyl)-azepan-4-y]carbamoyl]-butyl}-amide; <br><br> Benzofiiran-2-carboxylic acid- {(S)-1 - [ l-(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyI]-3-methyl-butyI}- <br><br> amide; <br><br> 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 5,6-Dimethoxy-benzofuran-2-carboxylic acid- {(S)-1 - [ 1 -(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 1 -Methyl- lH-indole-2-carboxylic acid- {(S)-1 -[ 1 -(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyl}~ <br><br> amide; <br><br> 40 <br><br> PCT/US01/19062 <br><br> Quinoxaline-2-carboxylic acid-{(S)-l-[l-(4-chloro- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-.amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-yIcarbamoyl]-3-methyl-butyl} -amide; <br><br> 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[ 1 -(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-y lcarbamoy l]-3-methy 1-butyl} -amide; <br><br> 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-buty 1} -amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-tl-(3-methoxy- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-y lcarbamoy l]-3-methy 1-butyl} -amide; <br><br> l-Methyl-lH-indole-2-carboxylic acid-{ (S)-1 -[l-(3-methoxy- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} <br><br> amide; <br><br> Quinoxaline-2-carboxylic acid-{(S)-l-[l-(3-methoxy- <br><br> benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} <br><br> amide; <br><br> Benzofuran-2-carboxylic acid-{ (S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(2,2',4-tridueterio)-3-oxo-l-(pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide; <br><br> 41 <br><br> PCT/US01/19062 <br><br> Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide; Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-ethyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methanesulfInyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide; Benzofuran-2-carboxylic acid {[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-methyl}-ainide; <br><br> Benzofuran-2-carboxyIic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfony l)-azepan-4-y lcarbamoy l]-pentyl} -amide; Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-2-methy 1-1-[3-oxo-1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide; Benzofuran-2-carboxylic acid {(S)-2-hydroxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide; l-(Benzofuraxi-2-carbonyl)-pyrrolidine-2-carboxylic acid [3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-benzamide; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-imethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> Benzo[l,3]dioxole~5-carboxylic acid {(S)-l-[l-(4-fluoro- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3methyl-butyl}- <br><br> amide; <br><br> 42 <br><br> PCT/USO1/19062 <br><br> (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl—butyl}-amide; <br><br> (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyI]-3-methyl-butyl}-amide; <br><br> N- {(S)-l-[l-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4- <br><br> ylcarbamoyl} -3-methyl-butyl} -3,4-dimethoxy-benzamide; <br><br> Cyclohexanecarboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)- <br><br> 3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-amide; <br><br> (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[ 1 - <br><br> (methanesulfonyI)-3-oxo-azepan-4-yl]-amide; <br><br> Benzo[b]thiophene-2-carboxylic acid-{(S)-l-(l-methanesulfonyl- <br><br> 3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide; <br><br> Benzo[l,3]dioxole-5-carboxylic acid-{(S)-l-(l-methanesulfonyl-3- <br><br> oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide; <br><br> Benzofuran-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo- <br><br> azepan-4-yl carbamoyl)-3-methyl-butyl]-amide; <br><br> N-[(S)-1-(1 -Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl} -3- <br><br> methyl-butyl} -3,4-dimethoxy-benzamide; <br><br> (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[ l-(2- <br><br> cyano-benzensulfonyl)-3-oxo-azepan-4-yl]-amide; <br><br> N- {(S)-1 -[l-(2-Cy ano-benzenesulfonyl)-3-oxo-azepan-4- <br><br> y lcarbamoy 1} -3-methyl-butyl} -4-methanesulfonyl-1 -benzamide; <br><br> 43 <br><br> PCT/US01/19062 <br><br> Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide; <br><br> Benzo[l,3]dioxole-5-carboxylic acid-{(S)-l-[l-(2-cyano- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]- <br><br> amide; <br><br> (S)-4-Methyl-2-[4-oxo-4-((4-phenoxy-phenyl)-butyrylamino}- <br><br> pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; <br><br> N-{(S)-l-[(l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4- <br><br> ylcarbamoyl}-3-methyl-butyl}-3,4-dimethoxy-benzamide; <br><br> Cyclohexanecarboxylic acid {(S)-l-[l-(4-methoxy- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}- <br><br> amide; <br><br> 4-Methansulfonyl-N- {(S)- l-[4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3-methyl-butyl-benzaraide; <br><br> 4-Methansulfonyl-N- {(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3-methyl-butyl-benzamide; <br><br> ({(S)-3-Methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylcarbamoyl}-carbamic acid benzyl ester; (S)-2-[5-(4-Methoxy-phenyl)-pentanoylanmio]-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-ainide; (S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; <br><br> 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-y lcarbamoy l]-butyl} amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 44 <br><br> PCT/USO1/19062 <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyI-l-[l-(6- <br><br> methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- <br><br> butyljamide; <br><br> 7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {{S)-3-methyl-l-[l-(pyridme-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> (R)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl-l-{3-oxo-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl) amide; <br><br> (S)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl-1 - {3-oxo-(pyridine-2-sulfonyl)-azepan-4-y lcarbamoy 1]-butyl} amide; <br><br> Benzofuran-2-carboxylic acid {(S)-2-cyclopropyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Benzofuran-2-caxboxylic acid {(S)-3-methylsulfanyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-propyl]-amide; Benzofuran-2-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1 - [ l-(6-methyl-pyridme-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl Jamide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl Jamide; <br><br> 45 <br><br> PCT/US01/19062 <br><br> 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide; <br><br> 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxyIic acid{ (S)-2-cyclohexyl-1- {3-oxo-1-(pyridine-2-sulfony l)-azepan-4-ylcarbamoyl]-ethyl}-amide; <br><br> 5-(4-Chloro-phenyl)-furan-2-carboxylic acid{ (S)-2-cyclohexyl-1 -{3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulphonyl)-azepan-4-ylcarbamoyl]-butyl} -amide; 5-(4-Chloro-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; <br><br> 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-1- [3-oxo-1 -(1-oxy-py ridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; <br><br> 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid{ (S)-2-cyclohexyl-1-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethylj-amide; <br><br> 5,5-Bis-(4-methoxy-phenyl)-pent-4-enoic acid {(S)-3-methyl~l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]}-butyl}-amide; <br><br> Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Naphthylene-1-carboxylic acid {(S)-2-naphthylen-2-y 1-1-[3-oxo-1-(pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide; Naphthyridine-2-carboxyIic acid {(S)-3-methyI-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 46 <br><br> PCT/US01/19062 <br><br> Naphthylene-1-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide; 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(cyclohexyl-proprionyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(4-methyl-pentanoyl)-azepan-4-ylcarbamoyl]-butyl} -amide; <br><br> 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; (S)-Acetylamino-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; <br><br> Quinolme-2-carboxylic acid {l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl}-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo -1- (cy clohexy 1-propriony 1)-azepan-4-y lcarbamoy l]-butyl} -amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(4-methyI-pentanoyl)-azepan-4-ylcarbamoyI]-butyl}-amide; Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide; Benzofuran-2-carboxylic acid{ (S)-2-benzyloxy- l-[3-oxo-1-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-amide; Benzofuran-2-carboxylic acid{(S)-2-hydroxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl }-amide; . 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 3-Methylbenzofiiran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyI)-azepan-4-y lcarbamoy l]-butyl} amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-y lcarbamoy l]-buty 1} amide; l-Methyl-lH-indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide; <br><br> 47 <br><br> PCT/US01/19062 <br><br> Quinoxaline-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-1 -(thiazole- <br><br> 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Quinoline-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfonyl)- <br><br> 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> The following compounds are also particularly preferred embodiments of the present invention: <br><br> Benzofuran-2-carboxylic acid {(S)~l~[-(3~fluoro-benzensulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide; (S)-4-methyl-2-(3-piperidin-l-yl-propanoylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid {(S)-1 - [-(4-ethyl-benzensulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-1-butyl}- amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-1 - {3-oxo-1 -[ 1 -(1 -oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; <br><br> Benzo[l,3]-dioxole-5-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[ 1 -oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl} -butyl)-amide; ~ ~ <br><br> 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(3-cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> Benzo[l,3]-dioxole-5-carboxylic acid {(S)-l-[l-(3-cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> Benzo[l,3]-dioxole-5-carboxylic acid {(S)-l-[l-(4~methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide Benzofuran-2-carboxylic acid [(S)-l-[3-oxo-l-(ethanesulfonyl-azepan-4-ylcarbamoyl)-3-methyl-l-butyl]- amide; <br><br> 48 <br><br> PCT/US01/19062 <br><br> 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methy 1-1-[3-oxo-1-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 5-Fluoro-3-methyl-benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(R)-3-methyl-l-[3-oxo-l-(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide; 3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-l-[-3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbarnoy l]-3-methy 1-butyl} -amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 3-methyl-furan-2-carboxylic acid {(S)-l-[l-(3-fluoro- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Quinoline-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> Quinoxaline-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3 -oxo-azepaxi-4-ylcarbamoyl]-3-methyl-butyl} -amide; <br><br> 49 <br><br> PCT/USO1/19062 <br><br> Thiophene-2-carboxylic acid {(S)-1 - [ l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> 5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-ethanesuIfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyI]-amide; 3-Methyl-benzofuran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-yIcarbamoyl)-3-methyl-butyl]-amide; Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-yIcarbamoyl)-3-methy]-butyl]-amide; 3-Methyl-furan-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Quinoline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; <br><br> Quinoxaline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 5-Methyl-thiophene-2-carboxyIic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-1 -sulfonyl)-azepan-4-y lcarbamoy 1]-3-methyl-1 -butyl} -amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1 -butyl }-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methy 1-1 -butyl} -amide; 3-Methyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl3-3-methyl-1 -butyl} -amide; <br><br> 50 <br><br> PCT/US01/19062 <br><br> 2,5-Dimethyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-1-(propane- l-sulfonyl)-azepan-4-ylcarbamoyI]-3-methyl-1 -butyl} -amide; <br><br> Quinoxaline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; Thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- 1-butyl} -amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; <br><br> 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(1 -oxy -pyridine-2-sulfonyl)-azepan-4-ylcarbamoy 1] -butyl} -amide; <br><br> 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> l-methyl-naphtho[2,l-b]-furan-2-carboxylic acid {(S)-3-metliyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-1 -(1 -oxy-pyridine-2-sulfony l)-azepan-4-ylcarbamoy 1]-butyl}-amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {l,3-dimethyl-l-[3-oxo-l-(l-oxyrpyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> 51 <br><br> PCT/USO1/19062 <br><br> Benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin- <br><br> 2-ylmethyl-azepan-4-ylcarbamoyl]-butyl}-arQide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-qumolin-2-ylmethyI-azepajQ-4-yIcarbamoyl]-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl)-amide; Benzofuran-2-carboxylic acid ((S)-3-methyH-{3-oxo-l-[l-toluene-2-sulfonylamino)-methanoy l]-azepan-4-y lcarbamoy 1} -butyl)-amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[ l-toIuene-2-sulfonylamino)-methanoylJ-azepan-4-ylcarbamoyl }-butyl)-amide; <br><br> Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- <br><br> toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}- <br><br> butyl)-amide; <br><br> Benzofuran-2-carboxylic acid ((S)-3-methyI-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl]-azepaii-4-ylcarbamoyl}-butyl)-amide; <br><br> Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chIoro-benzenesulfonylamino)-methanoyl]-azspan-4-ylcarbamoyl} -butyl)-amide; <br><br> Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fIuoro- <br><br> benzenesulfonylaimno)-methanoyl]-azepaj)-4-ylcarbamoyl}-butyl)- <br><br> amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; . <br><br> Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro-benzenesuIfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; <br><br> 52 <br><br> PCT/US01/19062 <br><br> Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-4-sulfonylamino)-methanoyl]-azepan-4-y lcarbamoy 1} -butyl)-amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-t l-toluene-4-sulfonylamino)-methanoyI]-azepan-4-y lcarbamoy 1} -butyl)-amide; <br><br> Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyI}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridia-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; <br><br> Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6- <br><br> methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}- <br><br> amide; <br><br> Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro- <br><br> phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro- <br><br> phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 2,4-Dimethylfuran-3-carboxylic acid {(S)-l-[l-(2-fluoro- <br><br> phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Quinoxaline-2-carboxylic acid {(S)-l-[l-(2-fluoro- <br><br> phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-btityl}- <br><br> amide; <br><br> Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro- <br><br> phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 53 <br><br> PCT/US01/19062 <br><br> Quinoline-2-carboxylic acid {(S)-l-[l-(2-fluoro- <br><br> phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> 4-Methyl-thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> 5-Methoxy-benzofuraa-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyI)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> 4-Methyl-furan-2-carboxylic acid {(S)-1- [l-(2-fluoro- <br><br> pheny lcarbamoy l)-3-oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl} - <br><br> amide; i <br><br> Benzofuran-2-carboxylic acid [(S)-l-(l-butyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; <br><br> Benzofuran-2-carboxylic acid [(S)-l-(l-propyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-benzyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-morpholin-4-yl-thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide; <br><br> Benzofurati-2-carboxylic acid {(S)-l-[l-(5-ethyl-furan-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(3,4-dimethyl-thieno[3,2-b]thiophene-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(3-phenyl- <br><br> 3H-[l,2,3]triazol-4-ylmethyl)-azepan-4-ylcarbamoyl]-butyl}- <br><br> amide; <br><br> Benzofuran-2-carboxylic acid [(S)-l-[l-(isothiazol-3-ylmethyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-thiophen-2-ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide; <br><br> 54 <br><br> PCT/US01/19062 <br><br> Benzofuran-2-carboxylic acid [(S)-l-(l-benzo[b]thiophen-2-ylmethyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-pentyl-azepan-4-ylcarbamoyl)-butyl]-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazol-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-buty}-amide; <br><br> 1-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl}-amide; <br><br> 2-Oxy-pyridine-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl} -amide; lH-Benzoimidazole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepari-4-ylcarbamoyl]-butyl}-amide; 4-{(S)-2-[(l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}- l-methyl-3-oxo-l-pentyl-azepanium; Benzofuran-2- carboxylic acid {(S)-l-[l-(l,2-dimethyl-l H -imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; <br><br> Benzofuran-2- carboxylic acid {(S)-l-[l-(l-methyl-l H - <br><br> imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl- <br><br> butyl}-amide; <br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methanesulfonyl- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(2-methanesulfonyl- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- <br><br> amide; <br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-isoxazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoy l]-3 -methyl-butyl} -amide; <br><br> 3-Methyl-benzofuran-2-carboxylic acid {(lS,2R)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclopentyl }-amide; and <br><br> 55 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 381 Furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyH-[-3-oxo-1- <br><br> (l-oxy-pyridine-2-sulfonyl)-azepan-4-y lcarbamoy l]-buty I} -amide. <br><br> Particularly preferred compounds of embodiment IA are Example Nos. 280 to 381 in the list herein above. <br><br> 5 Specific representative compounds of the present invention are set forth in <br><br> Examples 1-381. <br><br> Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds of the present invention are configurationally more stable at the carbon center alpha to the ketone. <br><br> 0 The present invention includes deuterated analogs of the inventive compounds. A <br><br> representative example of such a deuterated compound is set forth in Example 192. A 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. <br><br> 5 Where possible the present invention includes quaternary salts of the inventive compounds. A representative example of such a quaternary salt is set forth in Example 373. A representative synthetic route for the quaternary salts of the present invention is set forth in Scheme 6, below. <br><br> :0 Definitions <br><br> 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 <br><br> :5 such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans <br><br> 10 (E) isomers are within the scope of this invention: In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as <br><br> 56 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> being included within this invention whether existing in equilibrium or predominantly in one form. <br><br> 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 5 other occurrence, unless specified otherwise. <br><br> 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). <br><br> 10 "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 15 enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors. <br><br> The term "amino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, 20 tryptophan, tyrosine and valine. <br><br> "Ci-galkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Ci_6alkyl may be optionally substituted by a moiety selected from the group consisting of: OR*4, C(0)Rl4, SR^4, 25 S(0)R14, NR142, R14NC(0)0R5, C02R14, C02NR142, N(C=NH)NH2, Het, C3_ gcycloalkyl, and Ar; where R^ is selected from the group consisting of: H, Cj.galkyl, C2_6alkenyl, C2-6alkynyl, C3_6cycloalkyl-Co-6alkyl, Ar-C^galkyl and Het-Cg-galkyl; and R*4 is selected from the group consisting of: H, C^galkyl, Ar-Co-6alkyl, and Het-C0-6alkyl; <br><br> 30 "C3_6cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane. <br><br> "C2_6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2_galkenyl <br><br> 57 <br><br> WO 01/95911 PCT/US01/19062 <br><br> includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included. <br><br> "C2-6alkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2-6 alkynyl includes acetylene, 1-5 propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. <br><br> "Halogen" means F, CI, Br, and I. <br><br> "Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-Cg-galkyl; C]_galkoxy; Ph-Cg-galkoxy; Het-C().galkoxy; OH, (CH2)i_ 10 6NR15R16; 0(CH2)i_6NR15R16; Cl^alkyl, OR17, N(R17)2, SR17, CF3, N02, CN, C02R17, CON(R17), F, CI, Br or I; where R15 and R16 are H, C^alkyl, Ph-C0-6alkyl, naphthyl-Co-galkyl °r Het-C^galkyl; and R*7 is phenyl, naphthyl, or C^galkyl. <br><br> As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic 15 heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The 20 heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C0_6Ar, Ci_6alkyl, OR17, N(R17)2, SR17, CF3, N02, CN, C02R17, CONOR*7), F, CI, Br and I, where R*7 is phenyl, naphthyl, or Cj-galkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-25 oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo[b]thiophenyl, thieno[3,2-30 &amp;]thiophenyl, benzo[l,3]dioxolyl, 1,8 naphthyridinyl, pyranyl, tetrahydrofuranyl, <br><br> tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are available by routine <br><br> 58 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> chemical synthesis and are stable. The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur. <br><br> Here and throughout this application the term Cq denotes the absence of the substituent group immediately following; for instance, in the moiety ArCg-galkyl, when C 5 is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo_6alkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0. <br><br> 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 10 benzyloxycarbonyl radical. <br><br> Certain reagents are abbreviated herein. m-CPBA refers to 3-chloroperoxybenzoic acid, EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide, DMF refers to dimethyl formamide, DMSO refers to dimethyl sulfoxide, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran. <br><br> 15 <br><br> Methods of Preparation <br><br> 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 (1) with a base such as sodium hydride and 5-bromo-l-pentene provides the diene 2. Treatment of 2 with 20 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 25 azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon. Acylation of 5 with an acid such as Cbz-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. 30 Coupling of 6 with Cbz-leucine may be effected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7. <br><br> 59 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Scheme 1 <br><br> O N h <br><br> O N <br><br> &gt;; t o <br><br> oh d, e f, g <br><br> ~ XVN—3 <br><br> O <br><br> oh <br><br> r o o • <br><br> h, i <br><br> QrVV* <br><br> Cl- <br><br> Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 2,6-diisopropylphenylimido 5 neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, toluene c.) m-CPBA, CH2C12; d.) NaN3, CH3OH, H,0, NH.C1; e.) 10% Pd/C, HL,, f.) Cbz-leucine, EDC, CH.C1,; g.) HCl, EtOAc; h.) Cbz-leucine, EDC, CH^; i.) pyridine sulfur trioxide complex, DMSO, TEA. <br><br> 10 Compounds of the general formula I wherein R1 and R2 are amides may be prepared in the general fashion outlined in Scheme 2. Aikylation of N-Cbz allyl amine (8) with a base such as sodium hydride and 5-bromo-l-pentene provides the diene 9. Treatment of 9 with bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride olefin metathesis catalyst developed by Grubbs provides the azepine 10. Epoxidation of 10 with standard oxidizing 15 agents common to the art such as m-CPBA provide the epoxide 11. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine. Acylation of 12 with N-Boc- <br><br> 60 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> leucine and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13. Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HCl or TFA provides intermediate 14. <br><br> 5 Acylation of 14 may be effected with a carboxylic acid in the presence of a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15. <br><br> 10 " Scheme 2 <br><br> 13 14 15 <br><br> Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) <br><br> ,bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CH,C12; c.) /n-CPBA, 15 CHjCljj d.) NaN3, CH3OH, HA NH4C1; e.) propanediol, CH3OH, TEA; f.) Boc-leucine, EDC, CEL,C12; g.) 10% Pd/C, H2; h.) RjCOjH, EDC, CH3C1, or R.COC1, CR,C12; i.) HCl/ EtOAc; j.) RjCOjH, EDC, CHjCl,; k.) pyridine sulfur trioxide complex, DMSO, TEA. <br><br> 61 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> Compounds of the general formula I wherein R2 is an alkyl, urea or sulphonamide group and R1 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. <br><br> 15 <br><br> Scheme 3 <br><br> oh <br><br> oh nh3+ci- <br><br> R^N ^ ) O <br><br> C,d <br><br> RI^N ) O <br><br> 13 <br><br> 16 <br><br> 17 <br><br> f. b e,b oh <br><br> - - <br><br> r1"'YN o rVV ° <br><br> nh,+c h ^ <br><br> 18 <br><br> m- y o <br><br> 19 <br><br> 9H H 5 <br><br> o rNrrW* <br><br> &gt;Ns_J ° <br><br> R&gt;6 <br><br> , f o o <br><br> k-n. ) o <br><br> R'I <br><br> 20 <br><br> 21 <br><br> Reagents and conditions: a.) R,CHO, NaBH(OAc)3; b.) HCl; c.) RoC02H, EDC, CR,C12; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R,S02CI, TEA, CH2C12. <br><br> 62 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 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. <br><br> The individual diastereomers of benzofuran-2-carboxylic acid {(S)-3-methyl-l-5 [(2,2',4-trideuterio)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide 31 and 32 may be prepared as outlined in Scheme 4. Alkylation of allyl-carbamic acid benzyl ester 22 with 5-bromo-l-pentene in the presence of a base such as sodium hydride provides the diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride developed by Grubbs provides the 2,3,4,7-tetrahydro-azepine-l-lO carboxylic acid benzyl ester 24. Epoxidation of azepine 24 may be effected with standard oxidizing agents common to the art such as m-CPBA to provide epoxide 25. Nucleophilic epoxide ring opening of 25 may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown). <br><br> 63 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Scheme 4 <br><br> 31 32 <br><br> Reagents and Conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 5 bis(tricyclohexylphosphine)benzylidine ruthenium (TV) dichloride, CH2C12; c.) m-CPBA, CHjCl,; d.) NaN3, CHjOH, H20, NH4CI; e.) 1,3-propanedithiol, TEA, methanol; f.) N-Boc-leucine, EDC, CHjClj-, g.) 10% Pd/C, H,; h.) 2-pyridinesulphonyl chloride, TEA, CH2C12; i.) 4 N HCl/dioxane, methanol; j.) benzofuran-2-carboxylic acid, EDC, CH2C12; k.) pyridine sulfur trioxide complex, DMSO, TEA; 1.) CD,OD;D2Q (10:1), TEA; m.) HPLC separation. <br><br> 64 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> The intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1,3-propanedithioI and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water. Acylation of 26 may be effected with an 5 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 CH2C12 followed by removal of the fert-butoxycarbonyl protecting group under acidic conditions provides 28. Coupling 10 of 28 with benzofuran-2-carboxylic acid may be effected with a coupling agent such as <br><br> 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 CD30D:D20 at reflux provides the deuterated analog as a mixture of diastereomers which are separated by 15 HPLC to provide the deuterated compounds 31 and 32. <br><br> Compounds of the general formula I may also be prepared as outlined in Scheme 5. The amine of compound 12 may be protected with with di-terf-butyldicarbonate to provide the N-Boc derivative 33 (Scheme 2). Removal of the benzyloxycarbonyl protecting group may be effected by treatment of 33 with hydrogen gas in the presence of a catalyst such as 20 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 fert-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 25 presence of a coupling agent common to the art such as HBTU or polymer supported EDC provides the alcohol intermediate 37. Removal of the terj-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 30 to the art such as pyridine sulfur trioxide complex in DMSO and triethylamine or the Dess-Martin periodinane to provide the ketone 40. <br><br> 65 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> Scheme 5 <br><br> — &gt;rYtSro3 — &gt;rVtS <br><br> ° o <br><br> 12 33 34 <br><br> 39 40 <br><br> 5 Reagents and Conditions: (a) Di-tert-butyldicarbonate, THF; (b) EL,, 10% Pd/C, EtOAc; (c) 2-pyridylsulfonyl chloride, TEA ; (d) HCl, EtOAc; (e) N-Boc-cylohexylalanine, P-EDC, CHjC12; (f) HCl, CHjCIj; (g) benzofuran-2-carboxylic acid, P-EDC, CH,C12; (h) Dess-Martin periodinane, methylene chloride. <br><br> 10 The quaternized, 4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 6. The skilled artisan will understand from Scheme 6 how to make any of the quaternized, 4-amino-azepan-3-one compounds of the present invention. Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent 15 deprotection of the N-Boc group under acidic conditions provides the amine salt 16. Treatment of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate <br><br> 66 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Quaternization of the amine of 17 may be effected by treatment with an alkylating agent such as iodomethane to provide the quaternary amine salt 41. <br><br> 5 Scheme 6 <br><br> J- J- <br><br> IH a &lt;1 V a'b ?H H f 0 o <br><br> R1 <br><br> 16 <br><br> 13 <br><br> Reagents and conditions: a.) R,CHO, NaBH(OAc)3; b.) HCl; c.) RjC02H, EDC, CH^Cl,; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) iodomethane <br><br> 10 <br><br> The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience). 15 Coupling methods to form amide bonds herein are generally well known to the art. <br><br> The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally 20 illustrative of the technique and are incorporated herein by reference. <br><br> 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 &amp; Sons, New York (1981). The term "amino 25 protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and c, d r <br><br> R1 <br><br> 17 <br><br> O <br><br> R1 <br><br> rN <br><br> H <br><br> Y^NAR2 o H <br><br> 41 <br><br> 67 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 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. <br><br> 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 5 hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, <br><br> maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations 0 such as Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts. Quaternary ammonium salts are prepared by treating a parent amine compound with an excess of alkyl halide, such as methyl iodide. 5 This invention also provides a pharmaceutical composition which comprises a . <br><br> 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 0 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 ;5 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. <br><br> Alternately, these compounds may be encapsulated, tableted or prepared in an 0 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 <br><br> 68 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the 5 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. <br><br> 10 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. <br><br> Schemes 1-4 above, the skilled artisan will appreciate that the present invention includes all <br><br> 15 <br><br> Novel Intermediates <br><br> Referring to the methods of preparing the compounds of Formula I set forth in novel intermediates required to make the compounds of Formula I. In particular, the present invention provides the compounds of Formula II; <br><br> ,2 <br><br> 20 <br><br> R' <br><br> II <br><br> wherein: <br><br> Rl is selected from the group consisting of: <br><br> 25 <br><br> O <br><br> O <br><br> o <br><br> 69 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> R' 0 <br><br> R <br><br> ;and s ^ " <br><br> is selected from the group consisting of: H, Cj.galkyl, Cg.gcycloalkyl-CQ.galkyl, Ar-5 C0_6alkyl, Het-C0.6alkyl, R9C(0)-, R9C(S)-, R9S02-, R90C(0)-, <br><br> l/NyUL-CIO) <br><br> R9R! iNCCO)-, R9R11NC(S)-, R9(R! 1)NS02- ^ <br><br> r6 <br><br> R Y. <br><br> 8 <br><br> R ; andR9S02RnNC(0)- ; <br><br> R^ is selected from the group consisting of: H, Cl-6alkyl, C3-6cycloalkyl-10 Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCo-6alkyl and ArCo-6alkyl; <br><br> R^ and R' may be connected to form a pyrrolidine, piperidine or morpholine ring; R4 is selected from the group consisting of: H, C^.galkyl, C3_6cycloalkyl-C0.6alkyl, Ar-C0_6alkyl, Het-CQ.galkyl, R5C(0)-, R5C(S)-, R5S02-, R50C(0)-, R5Rl2NC(0)-, and R5R12NC(S)-; <br><br> 15 R^ is selected from the group consisting of: H, Cj_galkyl, C2-6alkenyl, <br><br> C2-6alkynyl, c3_gcycloalkyl-CQ_galkyl, Ar-CQ-6alkyl and Het-CQ.galkyl; <br><br> R^ is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, or Het-Co-6alkyi; <br><br> r7 is selected from the group consisting of: H, C^alkyl, Cg.gcycloalkyl-20 C0_6alkyl, Ar-C0_6alkyl, Het-C0_6alkyl, r10C(o)-, rloc(S)-, r10SO2-, r10OC(O)-, r10r13NC(0)-, and r10r13NC(S)-; <br><br> r8 is selected from the group consisting of: H, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, HetCo-6alkyl and ArCo-6alkyl; <br><br> R9 is selected from the group consisting of: C^galkyl, Cg.gcycloalkyl-Co-galkyl, 25 Ar-Co-galkyl and Het-Cp-galkyl; <br><br> R^® is independently selected from the group consisting of: Cj.galkyl, <br><br> 70 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> C3_6cycloalkyl-C()-6alkyl&gt; Ar-Co-6aIkyl and Het-Co_6alkyl; <br><br> is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, andHet- <br><br> co^aikyi; <br><br> is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyI, andHet- <br><br> 5 Cg-galkyl; <br><br> is selected from the group consisting of: H, C j.galkyl, Ar-Co-6alkyl, and Het- <br><br> Co-6alkyi; <br><br> R' is selected from the group consisting of: H, Cj.^alkyl, Ar-Co-6alkyl, and Het- <br><br> Co^aikyi; <br><br> 10 R" is selected from the group consisting of: H, Cj_galkyl, Ar-Co-6alkyl, or Het- <br><br> C0_6alkyl; <br><br> R'" is selected from the group consisting of: H, C^.galkyl, C3_gcycloalkyl-C0_6alkyl, Ar-CQ.galkyl, and Het-C().galkyl; <br><br> R"" is selected from the group consisting of: Ci-6alkyl, C3_6cycloalkyl-Co_6alkyl 15 C2-6alkenyl, C2-6alkynyl, HetC().gatkyl and ArCp-galkyl; <br><br> n is an integer of from 1 to 5; <br><br> and salts, hydrates and solvates thereof. <br><br> With reference to embodiment IA, the present invention includes the novel 20 intermediates of Formula HA: <br><br> IIA <br><br> wherein: <br><br> 25 Rl is selected from the group consisting of: <br><br> 71 <br><br> R.2 is selected from the group consisting of: Cj.galkyl, Ar-C^galkyl, Het-C^galkyl, R9C(0)-, R9S02-, It^R^NCCO)-, and R9S02RnNC(0)-; <br><br> R3 is C^alkyl; <br><br> R4 is R5C(0)-; <br><br> R5 is Het-C0-6alkyl; <br><br> R9 is selected from the group consisting of: Cj.galkyl, C3_6cycloalkyl-Co_6alkyl, Ar-C0_6alkyl and Het-C^galkyl; <br><br> Rll is selected from the group consisting of: H, Ci-galkyl, Ar-Co-galkyl and Het-Co-galkyl, preferably H; <br><br> R'isH; * <br><br> R" is H; ; <br><br> R'" is H; <br><br> R"" is selected from the group consisting of: Ci-6alkyl, C3.6cycloalkyl-CQ_galkyl, C2-6alkenyl, C2-6alkynyl, HetCo-galkyl and ArC^gallcyl, preferably Ci-galiyl; and n is an integer from 1 to 5, preferably n is 3; <br><br> and pharmaceutically acceptable salts, hydrates and solvates thereof. <br><br> The following compounds are preferred novel intermediates: [(S)-l(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester; <br><br> (S)-2-Amino-4-methyl-pentanoic acid (l-benzyl-3-hydroxy-azepan-4-yl)-amide; (S)-2-Amino-4-methyl-pentanoic acid{ 3-hydroxy- l-[2-(3-pyridin-2-yl-phenyI)-acetyl]-azepan-4-yl}-amide; <br><br> {(S)-l-[4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepan-l-ylmethyl]-3-methyl-butyl}-carbamic acid benzyl ester; <br><br> (S)-2-Aimno-4-methyl-pentanoic acid-(l -benzoyl-3-hydroxy-azepan-4-yl)-amide; <br><br> Intellectual Proper Office of NZ <br><br> / Z <br><br> 2 6 FEB 200^ <br><br> receive <br><br> (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(4-methyl-pentanoyl)-azepan-4-yl]-amide; <br><br> (S)-2-Amino-4-methyl-pentanoic acid (l-benzenesulfonyl-3-hydroxy-azepan-4-yl)- <br><br> amide; <br><br> thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-hydroxy-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbarnoyl]-butyl}amide; <br><br> thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; <br><br> 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-batyl}amide; <br><br> quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-solfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; and quinoxaline-2-carboxylic acid {(S)-3-methy 1-1 - [ 3-hydroxy-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide. <br><br> Referring to Schemes 1-6 herein above, the present invention provides a process for the synthesis of compounds of Formula (IA) comprising the step of oxidizing the appropriate compound of Formula (IIA) with an oxidant to provide the compound of Formula (IA) as a mixture of diastereomers. Preferably the oxidant is sulphur trioxide pyridine complex in DMSO and triethylamine. <br><br> synthesis of deuterated compounds of Formxila (IA). Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound of Formula (IA) as a mixture of diastereomers is added to the synthesis. Preferably, the deuterating agent is CD30D:D20 (10:1) in triethylamine. <br><br> The process further comprises the step of separating the diastereomers of Formula (IA) by separating means, preferably by high pressure liquid chromatography (HPLC). <br><br> Referring to Scheme 6, the present invention also provides a process for the synthesis of quaternary salts of the 4-amino-azepan-3-one compounds of Formula (IA). <br><br> Process for Synthesis of Inventive Compounds <br><br> Referring to Scheme 4, the present invention also provides a process for the <br><br> 73 <br><br> Intellectual Property <br><br> Office of NZ 2 6 FEB 2DW <br><br> Utility of the Present Invention <br><br> The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine 5 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. <br><br> 10 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 fiisiculata; as well as in schistosomiasis, malaria, tumor metastasis, <br><br> metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage 15 loss, including osteoporosis, gingival disease including gingivitis and periodontitis, <br><br> arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; <br><br> hypercalcemia of malignancy, and metabolic bone disease. <br><br> Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be 20 effectively treated with the compounds of this invention. <br><br> Also described herein are 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. In particular, described herein are 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. Also particularly described are methods for treating diseases in which cysteine proteases are implicated, including infections by Pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fiisiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, <br><br> Intellectual Proper.; 74 Office of N2 <br><br> 2 6 FEB 2004 <br><br> receivi <br><br> muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, <br><br> most particularly diseases of excessive bone or cartilage loss, including osteoporosis, <br><br> gingival disease including gingivitis and periodontitis, arthritis, more specifically, <br><br> osteoarthritis and rheumatoid arthritis, Paget' s disease, hypercalcemia of malignancy, and 5 metabolic bone disease. <br><br> Also described is a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., alendronate), 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. <br><br> 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 15 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 20 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. <br><br> The compounds of this invention may also be administered orally to the patient, in 25 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. <br><br> 30 No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention. <br><br> Intellectual Prcoen., Office of NZ <br><br> 26 FEB 2004 RECEIVE <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Biological Assays <br><br> 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. <br><br> 5 <br><br> Determination of cathepsin K proteolytic catalytic activity <br><br> 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 10 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 15 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II <br><br> fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product. <br><br> Inhibition studies <br><br> 20 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 25 curves were linear, apparent inhibition constants (KiiQpp) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140): <br><br> v = VmA / [Ka(l + I/Kit app) +A] (1) <br><br> 30 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. <br><br> 76 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give kQbs according to equation 2: <br><br> 5 [AMC] = vsst+(vo- vss) [1 - exp (-k0bst)]/k0bs (2) <br><br> where [AMC] is the concentration of product formed over time t, \&gt;o is the initial reaction velocity and is the final steady state rate. Values for k0bs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate 10 constant (k0bs I inhibitor concentration or k0bs f [I]) describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201). <br><br> Human Osteoclast Resorption Assay 15 Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4°C). The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice The cell suspension was mixed frequently. <br><br> 20 The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 <br><br> min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber. <br><br> Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were remoyed from their stock bottle and placed into 5 mL of fresh medium (this washes 25 away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium. <br><br> The beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 30 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. <br><br> 77 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 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 1.5xlO^/mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 5 mL aliquots of the cell suspension (per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37°C for 30 min. 10 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a'48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium 15 cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water. <br><br> The TRAP positive osteoclasts were enumerated by bright-field microscopy and 20 were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope. <br><br> General <br><br> Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, 25 respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. cdci3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and cd3od is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q -- quartet, m = multiplet, dd = doublet of doublets, dt = 30 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 <br><br> 78 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm-*). Mass spectra were taken on either VG 70 FE, PE Syx API EI, 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 5 analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius. <br><br> 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. <br><br> 10 Where indicated, certain of the materials were purchased from the Aldrich <br><br> Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfleld, New Jersey, and Advanced Chemtech, Louisville, Kentucky. <br><br> Examples <br><br> 15 In the following synthetic examples, temperature is in degrees Centigrade (°C). <br><br> Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These Examples are given to illustrate the invention, not to limit its scope. Reference is made to the claims for <br><br> 20 what is reserved to the inventors hereunder. <br><br> 79 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 1 <br><br> Preparation of {(S)-l-ri-ffS)-2-Benzyloxycarbonvlamino-4-methvl-pentanoviy3-oxo-azepan-4-vlcarbamovllcarbamic acid benzyl ester <br><br> 5 <br><br> a.) Allyl-pent-4-enyl-carbamic acid tert-butyl ester <br><br> 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 tert-butyl N-allylcarbamate (6.0 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 10 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 x's), brine, dried (MgS04), filtered and concentrated to give 10 grams of the title compound as an oil: MS(EI) 226 (M+H*). <br><br> 15 <br><br> b.) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid fert-butyl ester <br><br> To a solution of compound of Example la (4.5 g) in benzene was added the 2,6-diisopropylphenylimidoneophylidene molybdenum bis(J-butoxide) (600 mg). The reaction was heated to reflux for 1.5 hours whereupon the reaction was concentrated in vacuo. 20 Chromatography (50% CH,Cl2:hexanes) of the residue gave 3.92 g of the product: <br><br> c.) 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid tert-butyl ester <br><br> To a solution of the compound of Example lb (3.0 g, 15.2 mmol) in CH2CI2 was added m-CPBA (7.8 g, 45.6 mmol). The mixture was stirred overnight at room temperature 25 whereupon it was partitioned between CH2C12 and staurated K^COj. The organic layer was washed with sat. NaHCOs, water, brine, dried (MgS04), filtered and concentrated to give 3.11 g of the title compound as an oil: MS(EI) 214 (M+-H+). <br><br> d.) 4-Azido-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester <br><br> 30 To a solution of the epoxide from Example lc ( 3.92 g, 20 mmol) in methanol'.water (180 mL of an 8:1 solution) was added nh4ci (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 <br><br> 80 <br><br> WO 01/95911 PCT/US01/19062 <br><br> solvent was removed in vacuo and the remaining solution was diluted with ethyl acetate and washed with water, brine dried (Na2SC&gt;4), filtered and concentrated. Column chromatography (40% ethyl acetate:hexanes) of the residue provided 3.43 g of the title compound. <br><br> 5 <br><br> e.) 4-Amino-3-hydroxy-azepane-1-carboxylic acid Zert-butyl ester <br><br> 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 10 analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo. Column chromatography of the residue (25% methanokdichloromethane) provided 2.57 g of the title compound: MS(EI) 231 (M+H+). <br><br> f.) 4-((S)-2-benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane-15 1-carboxylic acid tert butyl ester <br><br> To a solution of the amino alcohol of Example le (160 mg, 0.70 mmol) in CH2CI2 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 20 IN HCl, sat. K2CO3, water, brine, dried (MgSC&gt;4), filtered and concentrated. Column chromatography of the residue (3% methanokdichloromethane) gave 200 mg of the title compound: MS(EI) 478 (M+H+), 500 (M+Na+). <br><br> g.) [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)~3-methyl-butyl]-carbamic acid benzyl 25 ester <br><br> A solution of the compound of Example If (200 mg, 0.42 mmol) in methanol (5 mL) was added 4M HCl 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 (M+H+). ' <br><br> 30 <br><br> 81 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> h-) {(S)-1 - [4-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carbonyl]-3-methy 1-butyl }carbamic acid benzyl ester <br><br> To a solution of the amine salt of Example lg (168 mg, 0.42 mmol) in CH2CI2 was added EDC (81 mg), HOBt (57 mg), triethylamine (0.09 mL) and Cbz-leucine (111 5 mg). The reaction was stirred until complete by TLC analaysis. Workup followed by column chromatography (5% CH30H:CH2Cl2) provided 159 mg of the title compound: MS (EI) 625 (M+H+). <br><br> i.) {(S)-l-[4-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-3~oxo-10 azepane-l-carbonyl]-3-methyl-butyl}carbamic acid benzyl ester <br><br> To a solution of the alcohol of Example lh (130 mg, 0.21 mmol) in DMSO was added TEA (0.17 mL) and pyridine sulfur trioxide 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, 15 dried (MgSO^, filtered and concentrated. Column chromatography of the residue (5% <br><br> CH30H:CH2C12) provided 100 mg of the title compound as a mixture of diastereomers: 'H NMR (CDC13): 8 1.0 (m, 12H), 1.5-2.1 ( m, 8H), 2.2 ( m, 4H), 3.0 (m, IH), 3.5 (d, LH). 3.6 (d, IH), 4.01 (m, IH), 4.5 (m, 2H), 4.7 (m, IH), 5.0 ( m, 5H), 7.3 (m, 10H): MS (EI) 623(M+H+), 645 (M+Na+). Separation of the diastereomers by HPLC provided 20 diastereomer 1 :MS (EI) 623 (M+H+), 645 (M+Na+) and diastereomer 2: MS (ES) 623 (M+H+), 645 (M+Na+). <br><br> 82 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 2 <br><br> Preparation of Naphthvlene-2-carboxvlic acidlYSM-H -benzvl-3-oxo-azepan-4-vlcarbamovlV3-methvl-butvll amide <br><br> 5 <br><br> a.) Allyl-pent-4-enyl-carbamic acid benzyl ester <br><br> To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added benzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon 5-10 bromo-l-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 (MgSCfy), filtered and concentrated. Column chromatography of the residue (10% ethyl acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(EI) 15 : 260 (M+H+). <br><br> b.) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid benzyl ester <br><br> To a solution of compound of Example 2a (50 g) in dichloromethane was added bis(tricyclohexylphosphine)benzy!idine ruthenium (IV) dichloride (5.0 g). The reaction 20 was heated to reflux until complete as determined by TLC analysis. The reaction was concentrated in vacuo. Column chromatography of the residue (50% dichloromethane:hexanes) gave 35 g of the title compound: MS(EI) 232 (M+H+). <br><br> c.) 8-Oxa-3-aza-bicyclo[5.LO]octane-3-carboxylic acid benzyl ester <br><br> 25 Following the general procedure of Example lc except substituting the compound of Example 2b the title compound was prepared: MS(EI) 248 (M+H+), 270 (M+Na+). <br><br> d.) 4-azido-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a solution of the epoxide from Example 2c (2.0 g, 8.1 mmol) in methanol:water 30 (8:1 solution) was added NH4C1 (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). The reaction was heated to 40°C until complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The <br><br> 83 <br><br> WO 01/95911 PCT/US01/19062 <br><br> organic layer was washed with sat. NaHC03, water, brine dried (MgS04), filtered and concentrated. Column chromatography (20% ethyl acetate:hexanes) of the residue provided 1.3 g of the title compound: MS(EI) 291 (M+H+) plus 0.14 g of trans-4-hy droxy-3.-azido-hexahydro- lH-azepine <br><br> 5 <br><br> e.) 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester <br><br> 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 (1.1 mL, 11.37 mL). The reaction was stirred until complete consumption of the starting material was observed 10 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 (M+H+). <br><br> f.) 4-((S)-2-terf-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan-15 1-carboxylic acid benzyl ester <br><br> To a solution of the amino alcohol of Example 2e (720 mg, 2.72 mmol) in CH2CI2 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 20 IN HCl, sat. K2CO3, water, brine, dried (MgSQ4), filtered and concentrated. Column chromatography of the residue (3% methanol:dichloromethane) gave 1.0 g of the title compound: MS(EI) 478 (M+H+). <br><br> g.) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert 25 butyl ester <br><br> 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 30 to provide 0.82 g of the title compound: MS(EI) 344 (M+H+). <br><br> 84 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> h.) [(S)-l-(l-Benzyl-3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester <br><br> To a solution of the compound of Example 2g (0.69 g, 2.01 mmol) in CH2CI2 was added benzaldehyde (0.32 mL, 3.01 mmol) followed by sodium triacetoxyborohydride 5 (0.85 g, 4.02 mmol). The reaction was stirred until complete as determined by TLC <br><br> 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. NaHCC&gt;3, water, brine, dried (Na2SC&gt;4), filtered and concentrated. Column chromatography of the residue (5% methanol: dichloromethane) gave 800 mg of the title 10 compound: MS(ES) 434 (M+H+). <br><br> i.) (S)-2-Amino-4-methyl-pentaiioic 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 HCl in dioxane (15 mL). The reaction was stirred at room temperature overnight 15 whereupon it was concentrated in vacuo to give 800 mg of the title compound: MS(ES) 334 (M+H+). <br><br> j.) Naphthylene-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> 20 To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH2C12 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. NaHCC&gt;3, water, brine, dried (Na2SC&gt;4), filtered and concentrated. Column 25 chromatography of the residue (5% methanol:dichloromethane) gave 0.14 g of the title compound: MS(EI) 488 (M+H+). <br><br> k.) Naphthylene-2-carboxylic acid[(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butylj-amide <br><br> 30 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 (CDC13): 8 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 (m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 (m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 12H); MS(EI): 486 <br><br> 85 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> (M+H\100%). Separation of the diastereomers by HPLC provided diastereomer 1: MS (EI) 486.3 (M+H+), and diastereomer 2: MS (ES) 486.3 (M+H+). <br><br> Example 3 <br><br> 5 <br><br> Preparation of BenzoF 1.31dioxole-5-carboxvlic acid r(S)-l-(l-benzvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl--butvHamide a.) Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-10 ylcarbamoyI)-3-methyl-butyl]amide <br><br> Following the general procedure of Example 2j except substituting piperonylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 482 (M+H+). <br><br> b.) Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-15 ylcarbamoyI)-3-methyl-butyl]amide <br><br> Following the general procedure of Example li except substituting the compound of Example 3a the title compound was prepared: 'H NMR (CDC13): 8 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 (m, 2H),,2.9 (m, IH), 3.0 (m, IH). 3.2 (d, IH), 3.5 (q, IH), 3.7 (m, 2H), 4.7 ( . m, IH), 5.2 ( m, IH), 6.0 (s, 2H), 6.8 (m, 2H).7.2 (m, 6H); MS(EI): 480 (M+H\100%). 20 The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MS (EI) 480.3 (M+H+), 959.6 2M+H+) and diastereomer 2: MS (EI) 480.3 (M+H+), 959.6 2M+H+). <br><br> 86 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> Example 4 <br><br> Preparation of Benzofuran-2-carboxvlic acid f(S)-1 -(l-benzvl-3-oxo-azepan-4-ylcarbamovlV3-methvl-butvllamide <br><br> 5 <br><br> a.) Benzofuran-2-carboxylic acid [(S)-l-(l~benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the general procedure of Example 2j except substituting benzofuran-2-carboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 478 10 (M+H+). <br><br> b.) Benzofuran-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methy 1-butyl] amide <br><br> Following the general procedure of Example li except substituting the compound 15 of Example 4a the title compound was prepared: 476 MS(EI): 492 (M+H*,100%). The diastereomers were separated by preparative scaleHPLC. Lyophilisation of the eluents provided diastereomer 1: MS (EI) 476.4 (M+H+), 951.6 (M+H+) and diastereomer 2: MS (EI) 476.4 (M+H+), 951.6 2M+H+). <br><br> 20 Example 5 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid r(S)-l-(l-benzvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvllamide <br><br> 25 a.) Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4~ ylcarbamoyl)-3-methy 1-butyl] amide <br><br> 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 (M+H+). <br><br> 30 <br><br> 87 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-benzyI-3-oxo-azepan-4-yIcarbamoyl)-3-methyl-butyl]amide <br><br> Following the general procedure of Example li except substituting the compound of Example 5a the title compound was prepared: 'H NMR (CDC13): 8 1.0 ( m, 6H), 1.5-2.1 ( 5 m, 5H), 2.2 (m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 (m, IH), 5.2 (m, IH), 7.2-8.4 (m, 10H): MS(EI): 492 (M+H\100%) <br><br> The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MS (EI) 492.4 (M+H+), 983.7 2M+H+) and 10 diastereomer 2: MS (EI) 492.4 (M+H+), 983.7 2M+H+). <br><br> Example 6 <br><br> Preparation of Naphthvlene-2-sulphonvl rfS)-l-(l-benzvl-3-oxo-azepan-4-vlcarbamovl)-3-15 methvl-butvll-amide a.) Naphthylene-2-sulphonyl [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH2CI2 was 20 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 (Na2SC&gt;4), filtered and concentrated. Column chromatography of the residue (10% methanohdichloromethane) provided 52 mg of the title compound: MS(EI) 524 (M+H+). <br><br> 25 <br><br> b.) Naphthylene-2-sulphonyl [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyI)-3-methyl-butyl]-amide <br><br> Following the general procedure of Example li except substituting the compound of Example 6a the title compound was prepared:: 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 30 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (dd, IH). 3.3 (m, IH), 3.6 (m, 2H), 3.7 ( m, IH), 4.7 (m, IH), 5.3 ( m, IH), 7.2-8.4 (m, 12H): MS(EI): 522 (M+H\100%) <br><br> 88 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 7 <br><br> Preparation of Ouinoline-2-carboxvlic acid IYSV1 -(1 -benzvl-3-oxo- azetian-4-vlcarbamovl)-3-methvl-butvnamide <br><br> 5 <br><br> a.) Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the general procedure of Example 2j except substituting 2-quinolinecarboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 10 489 (M+H+). <br><br> b.) Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methy 1-butyl]amide <br><br> Following the general procedure of Example li except substituting the compound 15 of Example 7a the title compound was prepared: 'H NMR (CDC13): 5 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, IH), 5.2 (m, IH), 7.2-8.4 (m, 11H); MS(EI): 487 (M+H\100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MS (EI) 492.4 (M+H+), 983.7 2M+H+) and diastereomer 2: MS (EI) 492.4 (M+H+), 20 983.7 2M+H+). <br><br> Example 8 <br><br> Preparation of 3.4-dichlorobenzoic acid r(S)-l-(l-benzvl-3-oxo-azepan-4-vlcarbamovl&gt;3-25 methvl-butvllamide a.) 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl~3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the general procedure of Example 2j except substituting 3,4-30 dichlorbenzoic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 506 (M+-H+). <br><br> 89 <br><br> WO 01/95911 PCT/US01/19062 <br><br> b.) 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl-3-oxo-azepan~4-ylcarbamoyl)-3-methyl-butyljamide <br><br> Following the general procedure of Example li except substituting the compound of Example 8a the title compound was prepared: JH NMR (CDC13): 5 1.0 ( m, 6H), 1.5-2.1 ( 5 m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 (m, 2H), 5.2 (m, IH), 7.2-8.4 (m, 8H); MS(EI): 504 (M\100%). <br><br> Example 9 <br><br> 10 Preparation of 4-{ (SVMethvl-2-f(Quirioline-2-carbonvlVamino]pentanovlaminol-3-oxo-l-r2-(3-PYridin-2-vl-phenvlVacetvllazepanium a.) 4-((S)-2-fer£-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-1-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepanium <br><br> 15 To a solution of the compound of Example 2g (0.5g, 1.46 mmol) in CH2CI2 was added EDC (307 mg, 1.60 mmol), HOBt (216 mg, 1.60 mmol) and 3-(2-pyridyl)phenyl acetic acid (341 mg, 1.60 mmol). 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 (M+H+). <br><br> 20 <br><br> b.) 4-((S)-Amino-4-methyl-pentanoylamino)~3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepanium <br><br> To a solution of the compound of Example 9a (1.3 g) dissolved in methanol (20 mL was added 4M HCl in dixoane (20 mL). The reaction was stirred until complete by TLC 25 analysis whereupon it was concentrated in vacuo to give 1.1 g of the title compound: MS (EI) 439 (M+H+). <br><br> c.) 4- {(S)-Methyl-2-[(quinoline-2-carbonyl)-amino]pentanoylamino }-3-hydroxy-1-[2-(3-pyridin-2-yl-phenyl)-acetyl]azepamum 30 Following the procedure of Example 7a except substituting the compound of <br><br> Example 9b the title compound was prepared: MS(EI) 594 (M+H+). <br><br> 90 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> d.) 4-{(S)-Methyl-2-[(quinoline-2-carbonyl)-amino]pentanoylamino}-3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]azepanium <br><br> Following the procedure of Example li except substituting the compound of Example 9c the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.4 (dd, IH). 3.8 (m, 3H), 4.1 (m, 2H), 4.7 (m, 3H), 5.4 ( m, IH), 7.2-8.4 (m, 14H); MS(EI): 592 (M+H+,100%) . <br><br> Example 10 <br><br> Preparation of l-((S)-2-Benzvloxvcarbonvlamino-4-methvl-pentvlV4-f (S)-4-methvl-2-\(2-quinoiline-2-carbonvlVaminol-pentanovlamLnoV3-oxo-azepanium a.) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-((S)-2-terf-butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepanium <br><br> Following the procedure of Example 2h except substituting Cbz-leucinal for benzaldehyde the title compound was prepared: MS(EI) 577 (M+H+). <br><br> b.) 4-((S)~2-Amino-4-methy-pentanoylamino)-l-((S)-2-terf-benzylxycarbonylamino-4-methyl-pentyl)-3-hydroxy-azepanium <br><br> Following the procedure of Example 2i except substituting the compound of Example 10a the title compound was prepared: MS(EI) 477 (M+H+). <br><br> c.) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{(S)-4-methyl-2-[(2-quinoiline-2-carbonyl)-amino]-pentanoylamino)-3-hydroxy-azepanium <br><br> Following the procedure of Example 7a except substituting the compound of Example 10b the title compound was prepared: MS(EI) 632 (M+H+). <br><br> d.) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{(S)-4-methyl-2-[(2-quinoiline-2-carbonyl)-amino]-pentanoylamino)-3-oxo-azepanium <br><br> Following the procedure of Example li except substituting the compound of Example 10c the title compound was prepared: 'H NMR (CDCl.,): 8 1.0 ( m, 12H), 1.5-2.1 (m, 10H), <br><br> 91 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 2.2 ( m, 4H), 2.9 (m, IH), 3.4 (M, 2H). 3.7 (m, IH), 4.7 ( m, 2H), 5.2 ( m, 3H), 7.2 (m, 4H), 7.5 (m, IH), 7.6 (m, IH), 7.7 (m, IH), 8.1 (m, IH), 8.2 (m, 2H), 8.5 (m, IH); MS(EI): 630 (M+H\100%) . <br><br> 5 Example 11 <br><br> Preparation of 1 -Benzovl-4-((S)-2-fbenzo f 1.31 dioxole-carbonvlamin oV4-methvl-pentanovlamino)-3-oxo-azepanium <br><br> 10 a.) l-Benzoyl-4-((S)-2-rert-butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepanium <br><br> Following the procedure of Example 9a except substituting benzoic acid for 3-(2-pyridyl)phenyl acetic acid the title compound was prepared: MS(EI) 448(M+H+). <br><br> 15 b.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-l-benzoyl-3-hydroxy-azepanium Following the procedure of Example 2i except substituting the compound of Example 1 la the title compound was prepared: MS(EI) 348 (M+H+). <br><br> c.) l-Benzoyl-4-((S)-2-(benzo[l,3]dioxole-carbonylamino)-4-methyl-pentanoylamino)-20 3-hydroxy-azepanium <br><br> Following the procedure of Example 2j except substituting the compound of Example lib for the compound of Example 2j and piperonylic acid for 2-naphthoic acid the title compound was prepared: MS(EI) 496 (M+H+). <br><br> 25 d.) l~Benzoyl-4-((S)-2-(benzo[l,3]dioxole-carbonylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium <br><br> Following the procedure of Example li except substituting the compound of Example 11c the title compound was prepared: 'H NMR (CDC13): § 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 (m, IH), 30 5.2 ( m, IH), 6.0 (s, 2H), 7.2-8.4 (m, 8H); MS(EI): 494 (M+EF, 70%). <br><br> 92 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 12 <br><br> Preparation of l-Benzovl-4-f(S)-2-f4-fluoro-benzov1amino)-4-methyl-pentanovlamino)-3-oxo-azepanium a.) l-BenzoyM-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-hydroxy-azepanium <br><br> Following the procedure of Example 11c except substituting 4-fluorobenzoic acid for piperonylic acid the title compound was prepared: MS(EI) 470 (M+H+). <br><br> b.) l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium <br><br> Following the procedure of Example li except substituting the compound of Example 12a the title compound was prepared: !H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (dd, IH). 3.6 (m, IH), 4.0 (m, 2H), 4.7 ( m, IH), 5.2 (m, IH), 7.2-8.4 (m, 9H); MS(EI): 468 (M+H*, 10%). <br><br> Example 13 <br><br> Preparation of 3-Oxo-4-((S)-4-methvl-2-i r5-(2-morpholino-4-vl-ethoxv)-benzofuran-2-carbonvllammo&gt;-pentanovlamino)~l-f4-methvl-pentanovl)-azepanium a.) 4-((S)-2-£err-butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-l-(4-methyl-pentanoyl)-azepanium <br><br> 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 (M+H+). <br><br> b.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-l-(4-methyl-pentanoyl)-azepanium <br><br> Following the procedure of Example 2i except substituting the compound of Example 13a the title compound was prepared: MS(EI) 342 (M+H+). <br><br> 93 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> c.) 3-Hydroxy-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino }-pentanoylamino)- l-(4-methyl-pentanoyl)-azepanium <br><br> To a solution of the compound of Example 13b (200 mg, 0.53 mmol) in dichloromethane was added EDC (111 mg, 0.58 mmol), HOBt (78 mg, 0.58 mmol), TEA 5 (0.11 mL, 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 (5% methanol: dichloromethane) provided 160 mg of the title compound: MS(EI) 615 (M+H+). <br><br> 10 d.) 3-Oxo-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyI]amino} -pentanoylamino)-1 -(4-methyl-pentanoyl)-azepanium <br><br> Following the procedure of Example li except substituting the compound of Example 13d the title compound was prepared: 'H NMR (CDC13): 5 1.0 ( m, 12H), 1.5-2.1 (m, 8H), 2.2 (m, 2H), 2.3 (m, IH), 2.4-2.5 (m, 2H), 2.6 (m 5H), 2.7 (m, 2H), 2.9 (m, IH), 15 3.4 (m, IH), 3.7 (m, 4H), 4.1 (m, 2H), 4.5-4.6 (m, 2H), 5.2 ( m, IH), 7.2-8.4 (m, 4H): <br><br> MS(EI): 613 (M+H\100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1 and diastereomer 2. <br><br> 20 <br><br> Example 14 <br><br> Preparation of 3-Oxo-4-((S)-4-methvl-2-{ r5-(2-morpholino-4-vl-ethoxv)-benzofuran-2-carbonvllamino 1-pentanovlaminoVl-benzenesulphonvl-azepanium a.) l-Benzenesulphonyl-4~((S)-2-fert-butoxycarbonylamino-methyl-pentanoylamino)-25 3-hydroxy-azepanium <br><br> To a solution of the amine of Example 2g (0.5 g, 1.46 mmol) in dichloromethane was added triethylamine (0.4 mL, 2.92 mmol) followed by benzenesulphonyl chloride (0.28 mL, 2.18 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (10% 30 methanol:dichloromethane) provided 450 mg of the title compound: MS(EI) 484 (M+H+). <br><br> 94 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> b.) 4-((S)-2-Amino-methyl-pentanoylamino) l-benzenesulphonyl-3-hydroxy-azepanium <br><br> Following the procedure of Example 2i except substituting the compound of Example 14a the title compound was prepared: MS(EI) 384 (M+H+). <br><br> c.) 3-Hydroxy-4-((S)-4-methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino} -pentanoylamino)-1 -benzenesulphonyl-azepanium <br><br> Following the procedure of Example 13c except substituting the compound of Example 14b the title compound was prepared: MS(EI) 657 (M+H+), <br><br> d.) 3-Oxo-4-((S)-4-methyl-2- {[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyljamino }-pentanoylamino)-1-benzenesulphonyl-azepanium <br><br> Following the procedure of Example li except substituting the compound of Example 14c the title compound was prepared: "H NMR (CDC13): 5 1.0 ( m, 6H), 1.5-2.1 15 (m, 5H), 2.2 (m, 2H), 2.4 (m, IH), 2.7 (m, 4H), 2.8 (m, 2H), 3.5 (m, IH), 3.8 (m, 4H), 4.0 (m, IH), 4.1 (m, 2H), 4.4 (m, IH), 4.5 (m, IH), 4.7 (m, IH), 5.1 ( m, IH), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, 3H), 7.7 (m, 2H): MS(EI): 655 (M+H+,100%) . <br><br> Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 45:55 20 CH3CN:20 mm khpo4 (pH 7 buffer) 60 min. gradient 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (Rj = 44.6 mins. and 45.9 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 50:50 ch3cn: mm khpo4 (pH 7 buffer)gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation of the eluents provided 25 diastereomer 1 (anal. Rf = 44.6 mins.) and diastereomer 2 (anal. Rt = 45.9 mins). <br><br> 95 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 15 <br><br> Preparation of 4-((S1-4-Methvl-2-([5-(2-mnrpholino-4-vl-ethoxvs)-benzofaran-2-carboDvllaminol-pentanovIaminoVS-oxo-azepane-l-carboxvlic acid phenylamide <br><br> 5 <br><br> a-) [(S)-l-(3-Hydroxy-l-phenylcarbamoyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester <br><br> To a solution of the amine of Example 2g (0.5 g, 1.46 mmol) in dichloromethane (20 mL) was added phenyl isocyanate (0.24 mL, 2.18 mmol). The reaction was stirred at 10 room temperature until complete as determined by TLC analysis. Workup and column chromatography (5% methanokdichloromethane) provided 578 mg of the title compound: MS (EI) 463 (M+H+). <br><br> b.) 4-((S)-2-Amino-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid 15 phenyl amide <br><br> Following the procedure of Example 2i except substituting the compound of Example 15a the title compound was prepared: MS(EI) 363 (M+H+). <br><br> c.) 3-Hydroxy-4-((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-20 carbonyl]amino}-pentanoylamino)-azepane-l-carboxylic acid phenylamide <br><br> Following the procedure of Example 13c except substituting the compound of Example 15b the title compound was prepared: MS(EI) 636 (M+H+). <br><br> d.) 4-((S)-4-Methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino}-25 pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide <br><br> Following the procedure of Example li except substituting the compound of Example 15c the title compound was prepared: 'H NMR (CDCI3):): 5 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 3.0 (m, 2H), 3.1 (m, IH), 3.8 (m, IH), 3.9 (m, 4H), 4.2 (m, IH), 4.3 (m, 2H), 4.9 (m, 2H), 5.2 ( m, IH), 7.2-8.4 (m, 9H): MS(EI): 634 30 (M+ir,100%) <br><br> Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH3CN:20 mM KHPO4 (pH 7 buffer) isocratic, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV <br><br> 96 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> detection at 215 nM) showed two peaks (Rt = 27.3 mins. and 30.1 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 50:50 CH3CN: 20 mM KHPO4 (pH 7 buffer) gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHC03:ethyl 5 acetate extraction provided diastereomer 1 (anal. Rt = 27.3 mins.) and diastereomer 2 (anal. Rt = 30.1 mins). <br><br> Example 16 <br><br> 10 Preparation of 5-(2-Morpho1ino-4-v1-ethoxvVbenzofuran-2-carboxvlic acid ((SV3-methvl-l-(3-oxo-l-r2-(3-Dvridin-2-vl-phenvl)acetvll-azepan-4-vlcarbamovl)-butvDamide a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> 15 Following the procedure of Example 13c except substituting the compound of <br><br> Example 9b the title compound was prepared: MS(EI) 712 (M+H+). <br><br> b.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l~[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> 20 Following the procedure of Example li except substituting the compound of <br><br> Example 16c the title compound was prepared: 'H NMR (CDC13): ): 8 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 2.8 (m, 2H), 2.9 (m, IH), 3.5 (m, IH), 3.7 (m, 4H), 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 ( m, IH), 7.2-8.0 (m, 13H), 8.5 (m, IH); MS(EI): 710 (M+H\100%) MS(EI). <br><br> 25 <br><br> Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH3CN:20 mM KHPO4 (pH 7 buffer) isocratic, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV 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 CH3CN: 20 mM 30 KHPO4 (pH 7 buffer) gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHC03-.ethyl acetate extraction provided diastereomer 1: MS(EI) 710.3 (M+H+) (anal. Rt = 33.9 mins.) and diastereomer 2: MS(EI) 710.3 (M+H+) (anal. Rt = 37.9 mins). <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 17 <br><br> Preparation of 5-f2-Morpholino-4-vl-ethoxv')-benzofuraD-2-carboxvlic acid rfSM-fbenzovl-5 3-oxo-azepan-4-vlcarbamovlV3-methvl-butvnamide a.) 5-(2-Morpholino-4~yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyI-butyl]amide <br><br> Following the procedure of Example 13c except substituting the compound of 10 Example lib the title compound was prepared: MS(EI) 621 (M+H+). <br><br> b.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3-oxo-azepan-4-ylcarbamoyI)-3-methyl-butyl]amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 17a the title compound was prepared: 'H NMR (CDCl,): 8 1.0 (m, 6H), 1.5-2.1 ( m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 2.9 (m, 2H), 3.0 (m, IH), 3.7 (m, 5H), 4.0 (m, IH), 4.1 (m, 2H), 4.7 (m, 2H), 5.4 ( m, IH), 7.2-8.4 (m, 1 IH): MS(EI): 619 (M+H\100%) <br><br> Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 55:45 20 CH3CN:20 mM KHPO4 (pH 7 buffer) 30 min. gradient, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (Rt = mins. 13.5 and 17.6 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 45:55 CH3CN: mM KHPO4 (pH 7 buffer) 60 min. gradient, 15 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the 25 eluents by NaHC03:ethyl acetate extraction provided diastereomer 1 (anal. Rt = 13.5 mins.) and diastereomer 2 (anal. Rt = 17.6 mins). <br><br> 98 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 18 <br><br> Preparation of 5-('2-Pvrrolidin-l-vl-ethoxvVbenzofuran-2-carboxvlic acid IYS&gt;1-(1-benzenesulfonvl-3-oxo-a2epan-4-vlcarbamovlV3-methvl-butvnamide <br><br> 5 <br><br> a.) 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl~butyl]amide <br><br> Following the procedure of Example 14c except substituting 5-(2-pyrrolidin-l-yl-ethyloxy)-benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-10, carboxylic acid the title compound was prepared: MS(EI) 641 (M+H+). <br><br> b.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 18a the title compound was prepared: 'H NMR (CDC13): 5 1.0 ( m, 6H), 1.5-2.1 (m, 9H), 2.2 ( m, 2H), 2.5 (m, IH), 2.7 (m, 4H), 3.0 (m, 2H), 3.4 (m, IH), 4.0 (m, IH), 4.1 (m, 2H), 4.5 (m, IH), 4.6 (m, IH), 5.0 (m, IH), 7.2-8.4 (m, 11H): MS(EI): 639 (M+H\100%). <br><br> 20 Example 19 <br><br> Preparation of 5-f2-Piperidin-]-vl-ethoxvVbenzofuran-2-carboxvlic acid TCSVl-f 1-benzenesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvllamide <br><br> 25 a.) 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the procedure of Example 14c except substituting 5-(2-piperidin-l-yl-ethyloxy)-benzofuran-2-carboxylic acid for 5-(2-moipholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 655 (M+H+). <br><br> 30 <br><br> 99 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the procedure of Example li except substituting the compound of Example 18a the title compound was prepared: 'H NMR (CDC13): 5 1.0 ( m, 6H), 1.5-2.1 5 (m, 11H), 2.2 (m, 2H), 2.5 (m, 5H), 2.7 (m, 2H), 3.5 (m, IH), 4.0 (m, IH), 4.1 (m, 2H), 4.5 (m, IH), 4.6 (m, IH), 5.0 (m, IH), 7.2-8.4 (m, 11H): MS(EI): 653 (M+1T,100%) . <br><br> Example 20 <br><br> 10 Preparation of 5-(2-Morpholino-4-vl-ethoxvVbenzofuran-2-carboxvlic acid ((SV3-methvl-l-( 3-oxo-l-r2-(3-pvridin-2-vl-ohenvl)ethvll-azepan-4-vlcarbamovl)-butvl'l amide a.) 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid methoxy methyl amide <br><br> To a solution of 3-(2-pyridyl)phenyl acetic acid (lg) in dichloromethane was added 15 N, O-dimethylhydroxylamine hydrochloride (0.92 g), triethylamine (1.3 mL), HOBt (0.96 g) and EDC (1.1 g). The reaction was stirred until complete. Workup and column chromatography (40% .ethyl acetate:hexanes provided 1.1 g of the title compound: MS(EI) 257 (M+H+). <br><br> 20 b.) 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde <br><br> To a solution of 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid methoxy methyl amide (0.2 g) of Example 20a in THF was added LAH (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. <br><br> 25 <br><br> c-) ((S)-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-ethyl]-azepan-4-ylcarbamoyl}-3-methyl-butyl)-carbamic acid tert butyl ester <br><br> Following the general procedure of Example 2g except substituting 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde for benzaldehyde the title compound 30 was prepared: MS(EI) 525 (M+H+). <br><br> 100 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> d.) (S)-2-Amino-4-methyl-pentanoic acid- {3-hydroxy- l-[2-(3-pyridin-2-yl-phenyl)-ethy 1]-azepan-4-yl }-amide <br><br> Following the procedure of Example 2i except substituting the compound of Example 20c the title compound was prepared. <br><br> 5 <br><br> e.) 5-(2-Morpholino-4-yl-ethoxy)~benzofuran-2-carboxylic acid ((S)-3-methyl-l-(3hydroxy—l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> Following the procedure of Example 13c except substituting the compound of Example 20d the title compound was prepared. <br><br> 10 <br><br> f.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxy-1 -[2-(3-pyridin-2-yl-phenyl)ethyl] -azepan-4-ylcarbamoyl} -butyl)amide <br><br> Following the procedure of Example li except substituting the compound of Example 20e the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 15 (m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 2.8 (m, 6H), 3.1 (m, IH), 3.3 (m, IH), 3.5 (m, IH), 3.7 (m, 4H), 4.2 (m, 3H), 4.6 (m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 13H), 8.6 (m, IH); MS(EI): 696 (M+H\ 80%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 696 (M+H\ 100%), and the slower eluting diastereomer; MS(EI): 20 696 (M+fT, 100%). <br><br> Example 21 <br><br> Preparation of Naphthlene-2-carboxvlic acid (YS)-3-methvl-l-(3-oxo-l-r2-(3-pvridin-2-vl-25 phenvl)ethvll-azepan-4-vlcarbamovn-bvitvl)amide a.) Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yI-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> Following the procedure of Example 20f except substituting 2-naphthoic acid for 5-30 (2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 579 (M+H+). <br><br> 101 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> b.) Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> Following the procedure of Example li except substituting the compound of Example 21b the title compound was prepared: 'H NMR (CDC13): S 1.0 ( m, 6H), 1.5-2.1 5 (m, 6H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, IH), 3.4 (d, IH). 3.5 (m, IH), 4.7 ( m, IH), 5.0 ( m, IH), 6.8-7.2 (m, 6H), 7.3 (m, IH), 7.5 (m, 2H), 7.9 ( m, 6H), 8.2 (M, IH), 8.7 (m, IH): MS(EI):577 (M+H\100%). <br><br> 10 <br><br> Example 22 <br><br> Preparation of lH-Indole-2-carboxvlic acid f(S)-3-methvl-l-{3~oxo-l-r2-f3-pvridin-2-vl-phenvBethvn-azepan-4-vlcarbamovli-butvl')amide a.) ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl~phenyl)ethyl]-azepan-4-15 ylcarbamoyl} -butyl) amide <br><br> Following the procedure of Example 20f except substituting lH-indole-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 568 (M+H+). <br><br> 20 b.) ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl }-butyI)amide <br><br> Following the procedure of Example li except substituting the compound of Example 22b the title compound was prepared:: !H NMR (CDC13): ): 8 1.0 (m, 6H), 1.5-2.1 ( m, 5H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m," IH), 3.4 (d, IH). 3.5 (m, IH), 4.7 ( m, 25 IH), 5.0 (m, IH), 6.8-7.2 (m, 6H), 7.0-7.9 (m, 12H), 8.7 (m, IH), 9.5 (m, IH): MS(EI) 566 (M+H+,100%) <br><br> 102 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 23 <br><br> Preparation of lH-Indole-2-carboxvHc acid [YS)-l-(l-benzenesulfonvl-3-oxo-azepan-4-ylcarbamovl)-3-methvl-butv11amide <br><br> 5 <br><br> a.) lH-IndoIe-2-carboxyIic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl] amide <br><br> Following the procedure of Example 2j except substituting the compound of Example 14b and substituting lH-indole-2-carboxylic acid for naphthoic acid the title 10 compound was prepared: MS(EI) 527 (M+H+). <br><br> b.) lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 23b the title compound was prepared: 'H NMR (CDCl,): 8 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (dd, IH). 3.9 (m, IH), 4.5 (dd, 2H), 4.7 (m, IH), 5.0 (m, IH), 7.2-7.6 (m, 10H). 9.5 (b, IH); MS(EI): 525 (M+H+, 10%). <br><br> Example 24 <br><br> 20 <br><br> Preparation of Benzofuran-2-carboxvlic acid r(S)-l-(l-benzenesulfonvl-3-oxo-azepan-4-ylcarbamovl)-3-methvl-butvn amide a.) Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4-25 ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the procedure of Example 23a except substituting benzofuran-2-carboxylic acid for lH-indole 2-carboxylic acid the title compound was prepared: MS(EI) 528 (M+H+). <br><br> 30 b.) Benzofiiran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide <br><br> Following the procedure of Example li except substituting the compound of Example 24b the title compound was prepared: 'H NMR (CDC13): S 1.0 (m, 6H), 1.5-2.1 <br><br> 103 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 5 <br><br> (m, 5H), 2.2 (m, 2H), 2.6 (m, IH), 3.5 (d, IH). 4.1 (m, IH), 4.7 (m, 2H), 5.0 ( m, IH), 7.2-7.2 (m, 10H). <br><br> Example 25 <br><br> Preparation of Benzofuran-2-carboxvlic acid [f SV3-methvl-1-13-oxo-1-1" 2-f3-pvridin-2-vl-phenvl)ethvll-azepan-4-vlcarbamovII-butvDamide a.) Benzofaran-2-carboxylic acid [(S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl- <br><br> 10 phenyl)ethyl]-azepan-4-ylcarbamoyl }-butyl)amide <br><br> Following the procedure of Example 20e except substituting benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic the title compound was prepared: MS(EI) 569 (M+H+). <br><br> 15 b.) Benzofuran-2-carboxylic acid [(S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl} -butyl)amide <br><br> Following the procedure of Example li except substituting the compound of Example 25b the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 5H), 3.0 (m, IH). 3.3 (m, IH), 3.5 (m, IH), 4.7 (m, IH), 5.2 <br><br> 20 (m, IH), 7.2-7.7 (m, 14H), 8.7 (m, IH); MS(EI): 567 (M+H\100%) <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 656 (M+H\100%), and the slower eluting diastereomer; MS(EI): 656 (M+H+,100%). <br><br> 25 Example 26 <br><br> Preparation of 5-(2-MorDholino-4-vl-ethoxvVbenzofuran-2-carboxvlic acid r(SV3-methvl-l-(3-oxo-1 -phenethvl-azepan-4-vlcarbamovll -butyl 1 amide <br><br> 30 Following the procedures of Examples 20c-f except substituting phenylacetaldehyde for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde of Example 20c the title compound was prepared: 'H NMR (CDC13): 5 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.4 (m, IH), 2.6 (m,4H), 2.7 (m, 6H), 3.0 (m, IH), 3.3 (dd, IH), 3.5 <br><br> 104 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> (q, IH), 3.7 ( m, 4H). 4.2 (m, 2H), 4.7 (m,lH), 5.0 ( m, IH), 7.2-7.2 (m, 11H); MS(EI): 619 (M+IT, 80%) <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 619 (M+H\100%), and the slower eluting diastereomer; MS(EI): 5 619 (M+H+,100%). <br><br> Example 27 <br><br> Preparation of Naphthvlene-2-carboxvlic acid [YS)-3-methvl-l-(3-oxo-l-phenethvl-azepan-10 4-vlcarbamovl'l-butvl \ amide <br><br> Following the procedures of Examples 2h-k except substituting phenylacetaldehyde for benzaldehyde of Example 2h the title compound was prepared: 'H NMR (CDC13): S 1.0 (m, 6H), 1.5-2.1 ( m, 5H), 2.2 (m, 2H), 2.4 (m, IH), 2.7 (m, 4H), 3.0 (m, IH), 3.7 (d, IH), 3.5 (q, IH), 4.7 (m, IH), 5.1 (m, IH), 6.9 -7.2 (m, 7H), 7.5 (m, 2H), 7.9 (m, 4H) 8.4 (m, IH); MS(EI): 500 (M+H+,100%) . <br><br> Example 28 <br><br> 20 Preparation of Benzofuran-2-carboxvlic acid US)-3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvlVazepan-4-vlcarbamovI"l-butvl I amide a.) (S)-2-Amino-4-methyI-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> 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 (M+H+). <br><br> b.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-30 azepan-4-ylcarbamoyl]-butyl Jamide <br><br> To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.15 g) in dichloromethane was added TEA (0.11 mL), HOBt (49 mg), EDC (69 mg) and benzofuran-2-carboxylic acid (58 mg). The <br><br> 105 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> reaction was stirred until complete. Workup and column chromatography (5% methanokethyl acetate) provided the title compound: MS(EI) 529 (M+H+). <br><br> c.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-5 ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 28b the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (dd, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, IH), 8.0 ( m, 2H), 8.7 (m, IH); MS(EI): 527 10 (M+tf, 40%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR: 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.7 (d, IH); 4.0 (d, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, IH), 8.0 (m,2H), 8.7 (m, IH); MS(EI): 527 (M+H\ 100%), and the slower eluting diastereomer; 15 'HNMR: 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.7 (d, IH); 4.0 (d, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, IH), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 527 (M+H\ 100%). <br><br> Example 29 <br><br> 20 <br><br> Preparation of Naphthvlene-2-carboxvlic acid f (SV3-methvl-1 -f3-oxo-1 -(pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvl 1 amide a.) Naphthylene-2-carboxylic acid {(S)-3-methyl-l-t3-hydroxy-l-(pyridine-2-sulfonyl)-25 azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 28b except substituting 2-naphthoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 539 (M+H+). <br><br> b.) Naphthylene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-30 azepan-4-ylcarbamoyl]-butyl Jamide <br><br> Following the procedure of Example li except substituting the compound of Example 29a the title compound was prepared: !H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.7 (m, IH), 3.7 (dd, IH). 4.0 (m, IH), 4.7 ( m, 2H), 5.0 (m, IH), <br><br> 106 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 7.2-7.3 (m, 2H), 7.5 (m, 3H), 7.9 (m, 6H), 8.3 (m, IH), 8.4 (m, IH); MS(EI): 537 (M+H\ 50%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 537 (M+H+, 100%), and the slower eluting diastereomer; MS(EI): 537 (M+H\ 100%). <br><br> Example 30 <br><br> Preparation of 5-(2-Morpholino-4-vl-ethoxvVbenzofuran-2-carboxvlic acid (fSV3-methvl-l-r3-oxo-l-fDvridine-2-sulfonvl')-azepan-4-vlcarbamovl'i-butvllamide a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 13c except substituting the compound of Example 28a the title compound was prepared: MS(EI) 658 (M+H+). <br><br> b.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 29a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.5 (m, 4H). 3.7 (m, 6H), 4.1 (m, IH), 4.5 (m, 2H), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 4H), 7.4 (m, 2H), 8.0 (m, 2H), 8.7 (m, IH), 8.7 (m, IH); MS(EI): 656 (M+IT,100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 656 (M+HT, 100%), and the slower eluting diastereomer; MS(EI): 656 (M+tT, 100%). <br><br> 107 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 31 <br><br> Preparation of 4-(YS)-4-Methvl-2-{ r(5-(2-morpholino-4-vl-ethoxv)-benzofuran-2-carbonvri-aminol-pentanov1amiTioV3-oxo-azepane-l-carboxvlic acid tert-butyl ester <br><br> 5 <br><br> a.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-1 -carboxylic acid ferf-butyl ester <br><br> To a solution of the compound of Example If (0.89 g) in ethyl acetate:methanol (30 mL of a 2:1 mixture) was added 10 % Pd/C and a balloon of hydrogen gas was attached. 10 The reaction was stirred until complete by TLC analysis whereupon it was filtered and concentrated to provide the title compound (0.57 g). <br><br> b.) 4-((S)-4-Methyl-2-{ [(5-(2-morpholino-4~yl-ethoxy)-benzofuran-2-carbonyl]-amino}-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid /erf-butyl ester <br><br> 15 Following the procedure of Example 13c except substituting the compound of <br><br> Example 31a the title compound was prepared. <br><br> c.) 4-((S)-4-Methyl-2~{[(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]-amino}-pentanoylamino)-3-oxo-azepane-1-carboxylic acid tert-butyl ester <br><br> 20 Following the procedure of Example li except substituting the compound of <br><br> Example 31b the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5 (m, 9H), 1.7 (m, 5H), 2.2 (m, 2H), 2.5 (m, 5H), 2.7 (m, 2H), 3.5 (m , IH). 3.8 (m, 4H), 4.1 (m, 3H), 4.2 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 5H); MS(EI): 615 (M+HM00%) . <br><br> 25 Example 32 <br><br> Preparation of 4-f(S)-4-Methvl-2-f r(5-f2-morpholino-4-vl-ethoxv)-benzofuran-2-carboxvlic acid r(S)-3-methvI-l-(3-oxo-azepan-4-ylcarbamovll-butvl)amide <br><br> 30 To a solution of the compound of Example 31c in THF (5 mL) was added 1M HCl in ether (5 mL). Th reaction was stirred overnight whereupon it was concentrated to provide the tide compound: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 2.7 (m, 4H), 3.2 (dd, 3H). 3.7 (m, 6H), 4.0 (m, 3H), 4.5 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 6H); MS (EI): 515 (M+IT,100%) . <br><br> Example 33 <br><br> Preparation of 4-Methyl-pentanoic acid 13-oxo-l-r2-(3-pvridin-2-vl-phenvl-acetvn-azepan-4-vll-amide a.) 3-Hydroxy-4-(4-methyl-pentanoylamino)-azepane-l-carboxylic acid tert-butyl ester Following the procedure of Example If except substituting 4-methylpentanoic acid for Cbz-leucine the title compound was prepared: MS(EI) 329 (M+H+). <br><br> b.) 4-Methyl pentanoic acid (3-hydroxy-azepan-4~yl)-amide <br><br> To a solution of the compound of Example 33a (200 mg) in methanol (5 mL) was added 4M HCl dioxane (5 mL). The reaction was stirred until complete whereupon it was concentrated to provide the title compound (132 mg): MS(EI) 229 (M+H+). <br><br> c.) 4-Methyl-pentanoic acid {3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl-acetyl]-azepan-4-yl} amide <br><br> Following the procedure of Example 9a except substituting the compound of Example 33b the title compound was prepared: MS(EI) 424 (M+H+). <br><br> d.) 4-Methyl-pentanoic acid {3-oxo-l~[2-(3-pyridin-2-yl-phenyl-acetyl]-azepan-4-yl}-amide <br><br> Following the procedure of Example li except substituting the compound of Example 33c the title compound was prepared: 'H NMR (CDC13) 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 2.9 (m, IH), 3.5 (m, IH), 3.7 (m, 2H), 4.1 (m, 3H), 4.6 (m, IH), 5.3 (m, IH), 7.2-8.0 (m, 7H), 8.7 (m, IH); MS(EI): 422 (M+H\100%) . <br><br> 109 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 34 <br><br> Preparation of (fSV3-Methvl-l-(3-oxo-l-r2-(3-pvridin-2-vl-phenyl)-acetvll-azepan-4-vlcarbamovll-butvl)-naphthvlene-2-methvl-carbamic acid tert-butyl ester <br><br> 5 <br><br> a.) (S)-4-Methyl-2-[naphthalene-2-ylmethyl)-amino]-pentanoic acid methyl ester <br><br> To a solution of leucine methyl ester hydrochloride (0.5 g) in dichlormethane was added triethylamine (0.9 mL), 2-naphthaldehyde (0.43 g) and sodium triacetoxyborohydride (0.87 g). The mixture was stirred until complete. Workup and column chromatography 10 (5% ethyl acetate:dich!oromethane) provided 0.4 g of the title compound: MS(EI) 286 (M+H+). <br><br> b.) (S)-2-(ferf-Butoxycarbonyl-naphthlen-2-ylmethyl-amino)-4-metyhyl pentanoic acid methyl ester <br><br> 15 To a solution of the compound of Example 34a (0.35 g) in dichloromethane was added di-ferf-butyldicarbonate (0.29 g). After 2 hours at room temperature triethylamine was added and the reaction heated to reflux. Upon completion, the reaction was concentrated and the residue was purified by column chromatography (50% hexane:dichloromethane) to provide 0.17 g of the title compound: MS(EI) 386 (M+H+). <br><br> 20 <br><br> c.) (S)-2-(fert-Butoxycarbonyl-naphthlen-2-ylmethyl-amino)-4-methyl pentanoic acid <br><br> To a solution of the compound of Example 34b (0.17 g) in THF:methanol (15 mL . of a 2:1 solution) was added LiOH (0.019 g). The reaction was stirred overnight whereupon it was concentrated to provide the title compound . <br><br> 25 d.) 4-[(S)-tert-butoxycarbonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoylamino]-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a sloution of the compound of Example 2e (0.11 g) in dichloromethane was added EDC (0.08 g), HOBt (0.06 g) and the acid of Example 34c. Upon completion the reaction was worked up and chromatographed (5% methanol:dichloromethane) to provide 30 the title compound (0.18 g): MS(EI) 618 (M+H+). <br><br> 110 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> e-) t(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-naphthylen-2-ylmethyl carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 34d (0.17 g) in ethyl acetate methanol (20:10 mL) was added 10% Pd/C. A balloon of hydrogen was attached and the reaction 5 was stirred until complete consumption of the starting material. The reaction was filtered and concentrated to provide the title compound (0.10g): MS(ET) 484 (M+H+). <br><br> f.) ((S)-3-Methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-y]-pheny])-acetylJ-azepan-4-ylcarbamoy 1}-butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester <br><br> 10 Following the procedure of Example 9a except substituting the compound of <br><br> Example 34e the title compound was prepared: MS(EI) 679 (M+H+). <br><br> g.) ((S)-3-Methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4- ■ yIcarbamoyl}-butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester <br><br> 15 Following the procedure of Example li except substituting the compound of <br><br> Example 34f the title compound was prepared: : 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 16H), 2.7 (m, IH), 3.2 (m, IH). 3.7 (m, 3H), 4.0 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.2-7.3 (m, 16H), 8.6 (m, IH); MS(EI): 677 (M+H\100%) . <br><br> 20 Example 35 <br><br> Preparation of ("S)-4-Methvl-2-r(naphthvlen-2-vlmethv1Vaminol-pentenoic acid r3-oxo-l-["2-G-pvridin-2-vI-phenvl)-acetvD-azepan-4-vll-amide <br><br> 25 To a solution of the compound of Example 34g (20 mg) in THF was added 1M HCl in ether. The reaction was stirred until complete consumption of the starting material whereupon it was concentrated to provide the title compound: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (m, 5H), 4.0 (m, IH), 4.7 (m, 2H), 4.4 (m, IH), 7.2-8.0 (m, 16H), 8.7 (m, IH); MS(EI): 577 (M+H\100%) . <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 36 <br><br> Preparation of 4-\2-(2-\CS&gt;3-Methvl-l-r3-oxo-l-(pvidine-2-sulfonvl&gt;azepan-4-vlcarbamovn-butvlcarbamovll-benzofuran-5-vloxvVethvll-piperazine-l-carboxvlic acid 5 fert-butvl ester a.) 4-[2-(2-{(S)-3-Methyl-l-[3-hydroxy-l-(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester To a solution of the compound of Example 28a (0.15 g) in dichloromethane was 10 added EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 4-[2-(2-carboxy- <br><br> benzofuran-5-yloxy)-ethyl]-piperazine-1 -carboxylic acid tarf-butyl ester. The reaction was stirred until complete. Work up and column chromatography (10 % methanol: ethyl acetate) provided the title compound (0.10 g): MS(EI) 757 (M+H+). <br><br> 15 b.) 4-[2-(2-{ (S)-3-Methyl-l-[3-oxo-l-(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester <br><br> Following the procedure of Example li except substituting the compound of Example 36a the title compound was prepared: "H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 14H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (m, 2H), 3.5 (m, 4H). 3.7 (m, 6H), 4.1 (m, IH), 4.5 20 (m, 2H), 4.7 (m, 2H), 5.0 (m, IH), 7.0-7.6 (m, 6H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 755 (M+H+,100%). <br><br> Example 37 <br><br> 25 Preparation of 5-f2-Piperizin-1 -vl-ethoxv)-benzofuran-2-carboxvlic acid {fSV3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovl")-3-butvn-amide <br><br> The compound of Example 36b (0.02 g) was dissolved in 4M HCl in dioxane. The reaction was stirred until complete whereupon it was concentrated to provide the title 30 compound: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-1.7 (m, 7H), 2.7 (m, 2H), 3.3 (M, 2H), 3.5 (m , IH). 3.8 (m, 5H), 4.1 (m, 3H), 4.7 (m, 4H), 5.0 (m, IH), 7.0-7.3 (m, 2H), 7.4 (m, 6H), 8.0 (m, 2H), 8.7 (m, IH): MS(EI): 655 (M+H+,100%). <br><br> 112 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 38 <br><br> Preparation of 5-(2-CvcIohexvl-ethoxy Vbenzofuran-2-carboxvlic acid {fSI^-methvl-l-rS-oxo-l-fpvridine-2-sulfonvl1-azepaii-4-vlcarbamovll-butvl) amide <br><br> 5 <br><br> a.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> To a solution of the compound of Example 28a (0.15 g) in dichloromethane was added EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 5-(2-cyclohexyl-ethoxy)-10 benzofuran carboxylic acid (0.01 g). The reaction was stirred until complete by TLC analysis. Workup and column chromatography (100% ethyl acetate) provided the title compound (0.15 g): MS(EI) 655 (M+H+). <br><br> b.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-15 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 38a the title compound was prepared: MS(EI) 653 (M+H+). <br><br> 20 <br><br> Example 39 <br><br> Preparation of 5-&lt;'2-Cvclohexvl-ethoxv')-benzofuran-2-carboxvlic acid (YS)-3-methvl-l-(3-oxo-l-r2-(3-pvridin-2-vl-phenvl)ethvl1-azepan-4-vlcarbamovl)-butvl)amide a.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1 - {3-25 hydroxy-1 - [2-(3-pyridin-2-yl-pheny l)ethy 1] -azep an-4-ylcarbamoyl} -butyl) amide <br><br> To a solution of the compound of Example 20d (0.15 g) in dichloromethane was added EDC (0.06 g), HOBt (0.04 g), triethylamine (0.14 mL) and 5-(2-cyclohexyl-ethoxy)-benzofuran carboxylic acid (0.09 g). The reaction was stirred until complete by TLC analysis. Workup and column chromatography (100% ethyl acetate) provided the title 30 compound (0.10 g): MS(EI) 695 (M+H+). <br><br> 113 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> Following the procedure of Example li except substituting the compound of Example 39a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 5 (m, 18H), 2.2 (m, 2H), 2.7 (m, 3H), 3.2 (m, IH), 3.5 (m, IH). 3.9 (m, 4H), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 13H), 8.7 (m, IH): MS(EI): 693 (M+IT,100%) <br><br> Example 40 <br><br> 10 Preparation of 4-r2-f2-f(S)-3-Methvl-l-r3-oxo-l-f3-pvridin-2-vI-phenvl)-ethvl fazepan-4-vlcarbamovn-butvlcarbamoYl)-benzofurap-5-vloxvVethvll-piperazine-l-carboxvlic acid te/t-butvl ester a.) 4-[2-(2-{(S)-3-Methyl-l-[3-hydroxy-l-(3-pyridin-2-yl-phenyI)-ethyl [azepan-4-15 ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester <br><br> To a solution of the compound of Example 20d (0.15 g) in dichloromethane was added EDC (0.06 g), HOBt (0.04 g), triethylamine (0.14 mL) and 4-[2-(2-carboxy-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester (0.12 g). The 20 reaction was stirred until complete by TLC analysis. Workup and column chromatography (10% methanokethyl acetate) provided the title compound (0.09 g): MS(EI) 797 (M+H+). <br><br> b.) 4-[2-(2-{(S)-3-Methyl-l-[3-oxo-l-(3-pyridin-2-yl-phenyl)-ethyl [azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid <br><br> 25 tert-butyl ester <br><br> Following the procedure of Example li except substituting the compound of Example 40a the title compound was prepared: MS(EI) 795.9 (M+H+). <br><br> 114 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 41 <br><br> Preparation of 5-(2-piperizin-l-vl-ethoxvVbenzofuran-2-carboxvlic acid ((S)-3-methvI-l-{3-oxo-l-r2-G-Pvridin-2-vl-phenvr)ethvn-azepan-4-vlcarbamovl)-butv1)amide <br><br> 5 <br><br> Following the procedure of Example 37 except substituting the compound of Example 40b the title compound was prepared: 'H NMR (€DC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 3.4-3.6 (m, 19H), 4.5 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m, IH), 7.4 (m, IH), 7.5 (m, 2H), 7.7 (m, 2H), 7.8 (m, IH), 8.1 (m, 2H), 8.4 (m, IH), 8.7 (m, 10 IH); MS(EI): 695 (M+H\ 70%). <br><br> Example 42 <br><br> Preparation of (S)-4-Methvl-2-(methvl-naphthalen-2-vlmethvl-amino)pentanoic acid T3-15 oxo-1 -Cpvridine-2-sulphonvl)-azepan-4-vn -amide a.) 4-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-3-hydroxy-azepane-1-carboxylic acid benzyl ester <br><br> To a solution of the compound of Example 2e (0.35 g)in dichloromethane was 20 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 (5% methanol;dichloromethane) provided 0.6 g of the title compound: MS(EI) 492 (M+H+). <br><br> b.) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-methyl-carbamic acid 25 tert-butyl ester <br><br> To a solution of the compound of Example 42a (0.6 g) in methanokethyl acetate (10:20 mL) 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+). <br><br> 30 <br><br> c.) {(S)-l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 42b (0.2 g) in dichloromethane was added triethylamine (0.16 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was <br><br> 115 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> stirred until complete. Workup and column chromatography (5% methanol:ethyl acetate) provided the title compound (0.23 g): MS(EI) 499 (M+H+). <br><br> d.) (S)-4-Methyl-2-methylamino-pentanoic acid [3-hydroxy-l-(2-pyridine-2-sulfonyl)-5 azepan-4-yl]-amide <br><br> 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. <br><br> Concentration provided the title compound: MS(EI) 399 (M+H+). <br><br> 10 e.) (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-hydroxy-l-(pyridine-2-sulphonyl)-azepan-4-yl]-amide <br><br> 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 (0.11 g). The reaction was stirred until complete. Workup and 15 column chromatography (5% methanol ethyl acetate) provided the title compound (0.03 g): MS(EI) 539 (M+H+). <br><br> f.) (S)-4-Methyl-2-(methyl~naphthalen-2-ylmethyl-amino)pentanoic acid [3-oxo-l-(pyridine-2-sulphonyl)-azepan-4-yl]-amide 20 Following the procedure of Example li except substituting the compound of <br><br> Example 42e the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 2.6 (m, IH), 3.3 (m, IH), 3.7 (m, 2H), 4.1 (m, IH), 4.7 (m, IH), 5.2 (m, IH), 7.2-8.0 (m, 10H), 8.7 (m, IH); MS(EI): 537 (M+H\100%) . <br><br> 25 Example 43 <br><br> Preparation of (S)-4-Methvl-2-(methvl-naphthalen-2-vlmethv1-aminolpentanoic acid (3-oxo-l-r2-r3-pvridin-2-vl-phenvl)-acetvn-azepan-4-vll-amide <br><br> 30 a.) ' ((S)-l-{3-Hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl}-3-methyl-butyl)-methyl-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 42b (0.25 g) was added 3-(2-pyridyl)phenyl acetic acid (0.16 g), HOBt (0.12 g) and EDC (0.15 g). The reaction was <br><br> 116 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> stirred until complete. Workup and column chromatography (5% methanol:ethyl acetate) provided the title compound (0.24 g): MS(EI) 553 (M+H+). <br><br> b.) (S)-4-Methyl-2-methylamino-pentanoic acid {3-hydroxy-l-[2-(3-pyridin-2-yl-5 phenyl)-acetyl]-azepan-4-yl}-amide <br><br> Following the procedure of Example 42d except substituting the compound of Example 43a the title compound was produced: MS(EI) 453 (M+H+). <br><br> c.) (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid {3-oxo-l-[2-10 (3-pyridin-2-yI-phenyl)-acetyl]-azepan-4-yl}-amide <br><br> Following the procedures of Examples 42e-f except substituting the compound of Example 43b the title compound was produced: "H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 3.0 (m, 1H), 3.5 (m, IH), 3.7 (m, 4H), 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.2-8.0 (m, 15H), 8.7 (m, IH); MS(EI): 591 (M+H+,100%) . <br><br> 15 <br><br> 20 <br><br> Example 44 <br><br> Preparation of 5-(2-Mon&gt;holino-4-vl-ethoxv)-benzofuran-2-carboxvlic acid methyl (CSV3-methvl-l-l3-oxo-l-r2-f3-pvridin-2-vl-phenvl)acetvll-azepan-4-vlcarbamovll-butyl)ainide a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide <br><br> To a solution of the compound of Example 43b (0.1 g) in dichloromethane was added 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid (0.06 g), HOBt (0.026 25 g), TEA (0.07 mL) and EDC (0.04 g). The reaction was stirred until complete. Workup and chromatography (20% methanol:ethyl acetate) provided the title compound (0.07 g): MS(EI) 726 (M+H+). <br><br> b.) 5-(2-Morpholino-4-yI-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl-30 1 - {3-oxo-1 -[2-(3-pyridin-2-yl-phenyl)acetyl] -azepan-4-ylcarbamoyl} -buty l)amide <br><br> Following the procedure of Example li except substituting the compound of Example 44a the title compound was prepared: 'H NMR (CDC13):): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 2.7 (m, 4H), 2.8 (m, 2H), 2.9 (m, IH), 3.5 (m, 1H\ 3.7 (m, 4H), <br><br> 117 <br><br> WO 01/95911 PCT/US01/19062 <br><br> 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 (m, IH), 7.2-8.0 (m, 12H), 8.5 (m, IH); MS(EI): 724 (M+ffjOO^o) . <br><br> Example 45 <br><br> 5 <br><br> Preparation of Benzofaran-2-carfaoxvlic acid methvl ffS")-3-methvl-l-r3-oxo-l-fpyridine-2-sulfonvl')-azepari-4-vlcarbamovlV3-methvl-butvn-amide a.) Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-10 sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> To a solution of the compound of Example 42d (0.1 g) in dichloromethane was added benzofuran-2-carboxylic acid (0.04 g), TEA (excess), HOBt (0.03 g), and EDC (0.04 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.04 g): MS(EI) 542.9 (M+H+). <br><br> 15 <br><br> b.) Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> Following the procedure of Example li except substituting the compound of Example 45a the title compound was prepared: 'H NMR (CDC13): 6 1.0 (m, 6H), 1.5-2.1 20 (m, 8H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (m, IH), 3.7 (m, 2H), 4.1 (m, IH), 4.7 (m, IH), 5.2 (m, IH), 7.2-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 541 (M+H\ 10%). <br><br> Example 46 <br><br> 25 Preparation of 2.2,2-Trifluoro-N-ffS)-3-methvl-l-{3-oxo-1 -f2-f 3-pvridin-2-vl-phen vlV acetvll-azepan-4-vlcarbamovll-butvl)-N-naphthvlen-2-vlmethvl-acetamide a.) (S)-4-Methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoic acid methyl ester <br><br> 30 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 g). 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. <br><br> 118 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) (S)-4-Methyl-2-[naphthylen-2-ylrnethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoic acid lithium salt <br><br> To a solution of the compound of Example 46a (0.49 g) in THFrwater (3 mL of a 2:1 solution) was added lithium hydroxide monohydrate (0.06 g). The reaction was stirred 5 overnight whereupon it was concentrated to provide the title compound (0.46 g): MS(EI) 366(M+H+). <br><br> c.) 3-Hydroxy-4-{(S)-4-methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoylamino}-azepane-1-carboxylic acid benzyl ester <br><br> 10 To a solution of the compound of Example 2e (0.29 g) in dichloromethane was added EDC (0.24 g), HOBt (0.16 g) and the compound of Example 46b (0.46 g). The reaction was stirred until complete. Workup and column chromatography (5% methanoliethyl acetate) provided the title compound (0.25 g): MS(EI) 614 (M+H+). <br><br> 15 d.) 2,2,2-Trifluoro-N-[(S)-l-(3-hydroxy-azepan-ylcarbamoyl)-3-methyl-butyl]-N-naphthIen-2-ylmethyl-acetamide <br><br> Following the procedure of Example 42b except substituting the compound of Example 46c the title compound was produced: MS(EI) 480 (M+H+). <br><br> 20 e.) 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl} -butyl)-N-naphthylen-2-ylmethyl-acetamide <br><br> Following the procedure of Example 43a except substituting the compound of Example 46d the title compound was produced: MS(EI) 675 (M+H+). <br><br> 25 f.) 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl}-butyl)-N-naphthylen-2-ylmethyl-acetairiide <br><br> Following the procedure of Example li except substituting the compound of Example 46e the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.2 (m, IH), 3.7 (m, 3H), 4.1 (m, IH), 4.5 (m, 2H), 4.7 <br><br> 30 (m, 2H), 5.2 (m, IH), 7.2-8.0 (m, 14H), 8.7 (m, IH): MS(EI): 673 (M+H\100%). <br><br> 119 <br><br> WO 01/95911 PCT/USO 1/19062 <br><br> Example 47 <br><br> Preparation of 4-IYSy("Methanesulphonvl-naphthvlen-2-vlmethvl-amino'&gt;-4-methvl-pentanovlaininol-3-oxo-azepane-l-carboxvlic acid benzvl ester <br><br> 5 <br><br> a.) (S)-2-(Methanesulfonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoic acid methyl ester <br><br> To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added triethylamine (0.36 mL) and methansulfonyl chloride (0.16 mL). The reaction was 10 stirred at room temperature until complete. Workup and chromatography (20% ethyl acetateihexanes) provided the title compound (0.24 g). <br><br> b.) (S)-2-(Methanesulfonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoic acid lithium salt <br><br> 15 Following the procedure of Example 46b except substituting the compound of <br><br> Example 47a the title compound was prepared: MS(EI) 348 (M+H+). <br><br> c.) 4-[(S)-(Methanesulphonyl-naphthylen-2-yImethyl-amino)-4-methyl-pentanoylamino]-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> 20 Following the procedure of Example 46c except substituting the compound of <br><br> Example 47b the title compound was prepared: MS(EI) 596 (M+H+). <br><br> d.) 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoylaminoj-3-oxo-azepane- 1-carboxylic acid benzyl ester <br><br> 25 Following the procedure of Example li except substituting the compound of <br><br> Example 47c the title compound was prepared: *H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 3.0 (m, IH), 3.5 (m, IH), 4.1 (m, IH), 4.5 (m, 3H), 4.7 (m, IH), 5.2 (m, 3H), 7.2-8.0 (m, 13H); MS(EI): 596 (M+3H\100%) . <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 48 <br><br> Preparation of Ouinoline-2-carboxvlic acid (CSV3-methvl-l-r3-oxo-l-('pvridme-2-sulfonvlV a2epan-4-vlcarbamovll-butvl) amide <br><br> 5 <br><br> a.) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 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 10 (M+H+). <br><br> b.) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 48a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.1 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0-7.2 (m, IH), 7.3 (m, IH), 7.5 (m, IH), 7.7 (m, IH), 7.8 (m, 3H), 8.1 (m, IH), 8.3 (m, 2H), 8.7 (m, 2H); MS(EI): 538 (M+H\100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 20 diastereoemer; MS(EI): 538 (M+H+,100%), and the slower eluting diastereomer; MS(EI): . 538 (M+H\100%). <br><br> Example 49 <br><br> 25 Preparation of Ouinoline-8-carboxvlic acid f (S")-3-methvl-l-r3-oxo-l-Cpvridine-2-suIfonvlV azepan-4-vicarbamovll-butvl I amide a.) Quinoline-8-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide 30 Following the procedure of Example 28b except substituting quinoIine-8-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+). <br><br> 121 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> b.) Quinoline-8-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 49a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH),.3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.5 (m, 4H), 7.6 (m, IH), 7.7 (m, 3H), 8.2 (m, IH), 8.6 (m, IH), 8.7 (m, IH), 8.9 (m, IH); MS(EI): 538 (M+H+,l00%) . <br><br> Example 50 <br><br> Preparation of Ouinoline-6-carboxvlic acid f (SV3-methvl-1 -f3-oxo-1 -('pvridine-2-sulfonv]')-azepan-4-vlcarbamo vll -butyl 1 ami de a.) Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3~hydroxy-l-(pyridine-2-sulfonyl)-15 azepan-4-ylcarbamoyl]-butyl} amide •' &lt; <br><br> 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 (M+H+). <br><br> 20 b.) Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 50a the title compound was prepared: 'H NMR (CDCl3): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0 25 (m, 2H), 7.5 (m, 2H), 7.9 (m, 2H), 8.0 (m, 3H), 8.2 (m, IH), 8.7 (m, IH), 8.9 (m, IH); MS(EI): 538 (M+1T,100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 538 (M+H\100%). <br><br> 30 <br><br> 122 <br><br> WO 01/95911 PCT/USO 1/19062 <br><br> Example 51 <br><br> Preparation of Ouinoline-4-carboxvlic acid lfS')-3-methvl-l-r3-oxo-l-Cpvridirie-2-sulfonvl')-azepan-4-vIcarbamovll-butvl&gt;axnide <br><br> 5 <br><br> a.) Quinoline-4-carboxylic acid {(S)-3-methyl-1 -[3-hydroxy-1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 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 10 (M+H+). <br><br> b.) Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 51a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 &lt;m, IH), 6.5-7.2 (m, 2H), 7.4 (m, 2H), 7.5 (m, IH), 7.7 (m, IH), 7.9 (m, 2H), 8.0 (m, IH), 8.2 (m, IH), 8.7 (m, IH), 8.9 (m, IH); MS(EI): 538 (M+H\100%) <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 20 diastereoemer; MS(EI): 538 (M+H\100%), and the slower eluting diastereomer; MS(EI): 538 (M+HV00%). <br><br> Example 52 <br><br> 25 Preparation of Ouinoline-3-carboxvlic acid f(S)-3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-hutv1 \ amide a.) Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide 30 Following the procedure of Example 28b except substituting quinoline-3-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(E1) 540 (M+H+). <br><br> 123 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-y lcarbamoy l]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 52a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 5 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m 2H), 7.5 (m, IH), 7.6 (m, IH), 7.7-7.9 (m, 4H), 8.1 (m, IH), 8.5 (m, IH), 8.6 (m, IH), 9.3 (m, IH); MS(EI): 538 (M+H\100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H\100%), and the slower eluting diastereomer; MS(EI): 10 538 (M+H+,100%). <br><br> Example 53 <br><br> Preparation of Isoauinoline-3-carboxvlic acid ITS)-3-methv 1-l-r3-oxo-1 -fpvridine-2-15 sulfonvn-azepan-4-vlcarbamovIl-butvll amide a.) Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl) azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting isoquinoline-3-20 carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+). <br><br> b.) Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 25 Following the procedure of Example li except substituting the compound of <br><br> Example 53a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0 (m, IH). 7.5 (m, IH), 7.7 (m, 2H), 7.9 (m, 4H), 8.7 (m, 3H), 9.2 (m, IH); MS(EI): 538 (M+HU00%) . <br><br> 30 <br><br> 124 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 54 <br><br> Preparation of Isoquinoline-l-carboxvlic acid USyS-methvl-l-B-oxo-l-fpvridine^-sulfonvlVazepan-4-vlcarbamovll -butyl} amide <br><br> 5 <br><br> a.) Isoquinoline-1-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting isoquinoline-1-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 10 540 (M+H+). <br><br> b.) Isoquinoline-l-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 54a the title compound was prepared: !H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.3 (m, IH), 7.5 (m, IH), 7.7-8.0 (m, 6H), 8.7 (m, 3H), 9.5 (m, IH); MS(EI): 538 (M+H+,100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 20 diastereoemer; MS(EI): 537 (M+,100%), and the slower eluting diastereomer; MS(EI): 537 (M\100%). <br><br> Example 55 <br><br> 25 Preparation of Ouinoxaline-2-carboxvlic acid f(S)-3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvl)anaide a.) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide 30 Following the procedure of Example 28b except substituting quinoxaline-2- <br><br> carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 541 (M+H+). <br><br> 125 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> b.) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 55a the title compound was prepared: "HNMR (CDClj): 5 1.0 (m, 6H), 1.5-2.1 5 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7..0-7.2 (m, 2H), 7.5 (m, IH), 7.7 (m, 3H), 8.2 (m, 2H), 8.3 (m, IH), 8.7 (m, IH), 9.5 (m, IH); MS(EI): 539 (M+Er;30%). <br><br> Example 56 <br><br> 10 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid ((S)-3-methvl-l-r3-oxo-l-('pvridine-2-sulfonvl)-azepan-4-vlcarbamovl1-butvllamide a.) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-15 sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide <br><br> 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 (M+H+). <br><br> 20 b.) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI}amide <br><br> Following the procedure of Example li except substituting the compound of Example 56a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.8-25 7.2 (m, IH), 7.5 (m, 3H), 8.0 (m, 6H), 8.7 (m, IH); MS(EI): 543 (M+H\ 60%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 3.8 (m,lH), 4.1 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.4-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 543 (M+H+,100%), and the slower eluting diastereomer; 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 30 IH), 3.8 (m,lH), 4.1 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.4-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 543 (M+H+,100%). <br><br> 126 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 57 <br><br> Preparation of l,8-Naphthvridine-2-carboxvlic acid ((S)-3-methvl-l-r3-oxo-l-fpvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvl}amide <br><br> 5 <br><br> a.) l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting l,8-naphthyridine-2-carboxylic acid for benzofuran-2-carboxyhc acid the title compound was prepared: MS(EI) 10 541 (M+H+). <br><br> b.) l,8-Naphthyridine-2-carboxylic acid {(S)-3-methy 1-1-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting the compound of 15 Example 57a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m, IH), 7.6 (m, 2H), 7.9 (m, 2H), 8.3 (m, IH), 8.4 (m, 2H), 8.5 (m, 2H), 9.2 (m, IH); MS(EI): 539 (M+HT,100%) <br><br> 20 Example 58 <br><br> Preparation of lH-Indole-2-carboxvlic acid (fSV3-methvl-l-f3-oxo-1 -fpyridine-2-sulfon vl)-azepan-4-vlcarbamovll-butvl) amide <br><br> 25 a.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting lH-indole-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 528 (M+H+). <br><br> 30 <br><br> b.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 58a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 <br><br> 127 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.8 (m, IH), 7.1 (m, IH), 7.3 (m, 3H), 7.4 (m, IH), 7.5 (m, IH), 7.6 (m, IH), 8.0 (m, 2H), 8.7 (m, IH), 9.4 (b, IH); MS(EI): 526 (M+H\ 80%). <br><br> 5 Example 59 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovl1-butvl I amide <br><br> 10 a.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide <br><br> Following the procedure of Example 28b except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 559 (M+H+). <br><br> 15 <br><br> b.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 59a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 20 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, 4H). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0 (m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 557 (M+H+, 70%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.7 (m, 4H). 4.0 (d, IH), 4.7 (m, 2H), 5.0 (d, IH), 7.0 (m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 25 8.7 (d, IH); MS(EI): 557 (M+H\l00%), and the slower eluting diastereomer; MS(EI): 557 (M+H\100%). <br><br> 128 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 60 <br><br> Preparation of 5-Bromo-furan-2-carboxvlic acid f ("S)-3-methvI-l-r3-oxo-l-Cpvridine-2-sulfonvlVazepan-4-vlcarbamovll-biitvT \ amide <br><br> 5 <br><br> a.) 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide ^ <br><br> 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 (M+H+). <br><br> 10 <br><br> b.) 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 60a the title compound was prepared: 'H NMR (CDC1,): S 1.0 (m, 6H), 1.5-2.1 15 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, 1H), 6.5 (m, IH), 6.7 (m, IH), 7.1 (m, 2H), 7.5 (m, IH), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 555 (M-kFP, 60%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 555 (M+H\100%), and the slower eluting diastereomer; MS(EI): 20 555 (M+H\100%). <br><br> Example 61 <br><br> Preparation of Furan-2-carboxvlic acid \ (SV3-methvl- l-B-oxo-1 -(pvridine-2-sulfonvl')-25 azepan-4-vlcarbamovll-butvl) amide a.) Furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 2-furoic acid for 30 benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 479 (M+H+). <br><br> 129 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfony])-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 61a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 5 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.5 (m, IH), 7.2 (m, 3H), 7.5 (m, 2H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 477 (M+tT, 50%). <br><br> Example 62 <br><br> 10 Preparation of 5-Nitro-furan-2-carboxvlic acid {('S)-3-methvl-l-r3-oxo-l-fpvridme-2-sulfonvl)-azepan-4-vlcarbamovn-butvl) amide a.) 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl]amide <br><br> 15 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 (M+H+). <br><br> b.) 5-Nitro-faran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 20 Following the procedure of Example li except substituting the compound of <br><br> Example 62a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7, (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m, IH), 7.3 (m, IH), 7.5 (m, IH), 7.9 (m, 2H), 8.7 (m, IH); MS(EI): 522 (M+lT, 80%). <br><br> 25 <br><br> 130 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 63 <br><br> Preparation of 5-f4-Nitro-phenvls)-furan-2-carboxvlic acid f fS)-3-m&amp;thvl-l-r3-oxo-l-fpvridine-2-sulfonvI")-azepan-4-vlcarbamovll-butvl}aroide <br><br> 5 <br><br> a.) 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-metbyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 5-(4-nitrophenyl)-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 600 10 (M+H+). <br><br> b.) 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting the compound of 15, Example 63a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.9 (m, IH), 7.2 (m, IH), 7.5 (m, 2H), 7.9-8.0 (m, 4H), 8.5 (m, IH), 8.6 (m, IH); MS(EI): 598 (M+KT, 80%). <br><br> 20 Example 64 <br><br> Preparation of 5-f3-Trifluoromethvl-phenvl)-furan-2-carboxvlic acid lfS)-3-methyl-l-f3-oxo- l-rpvridine-2-sulfonvl')-azepan-4-vlcarbamovn-butvl) amide <br><br> 25 a.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-y!carbamoyl] -butyl} amide <br><br> Following the procedure of Example 28b except substituting 5-[3-{trifhioromethyl)phenyl]-2-furoic acid for benzofiiran-2-carboxylic acid the title compound was prepared: MS(E1) 623 (M+H+). <br><br> 30 <br><br> b.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting the compound of Example 64a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 <br><br> 131 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.1 . (m, IH), 7.5 (m, 3H), 8.0 (m, 4H) 8.7 (m, IH); MS(EI): 621 (M+IT, 80%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 621 (M+H\100%), and the slower eluting diastereomer; MS(EI): 5 621 (M+H\100%). <br><br> Example 65 <br><br> Preparation of Tetrahvdro-furan-2-carboxvlic acid f(S)-3-methvl-l-r3-oxo-l-(pvridine-2-10 sulfonvlVazepan-4-vlcarbamovll-butvl) amide a.) Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-1 -f3-hydroxy-1 -(pyridinej2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting tetrahydrofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 483 (M+H+). <br><br> b.) Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 20 Following the procedure of Example li except substituting the compound of <br><br> Example 65a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 12H), 2.7 (m, IH), 3.8 (m, 3H). 4.0 (m, IH), 4.5 (m, 2H), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, IH), 7.5 (m, IH), 7.9 (m, 2H), 8.7 (m, IH). MS(EI): 481 (M+tT, 80%). <br><br> 25 Example 66 <br><br> Preparation of (S)-4-Methvl-2-f2-phenoxv-acetvlamino)-pentanoic acid r3-oxo-fpvridine-2-sulfonvl)-azepan-4-vn-amide <br><br> 30 a.) (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-hydroxy-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example 28b except substituting phenoxyacetic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(E1) 519 (M+H+). <br><br> 132 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> b.) (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2-sulfony])-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substituting the compound of Example 66a the title compound was prepared: 'H NMR (CDC1,): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.5 (m, 3H), 4.7 (m, IH), 5.1 (m, IH), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 517 (M+H+, 60%). <br><br> Example 67 <br><br> Preparation of (S&gt;2-r2-f4-Fluoro-phenoxv)-acetvlaminol-4-methvl-pentanoic acid T3-oxo-rpvridine-2-sulfonvl)-azepan-4-vll-amide a.) (S)-2-[2-(4-FIuoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-hydroxy-15 (pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example 28b except substituting 4-fluorophenoxyacetic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 537 (M+H+). <br><br> 20 b.) (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substituting the compound of Example 67a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.6 (d, IH). 4.0 (m, IH), 4.5 (, 3H), 4.8 (m, IH), 5.1 25 (m, IH), 7.0 (m, 4H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 535 (M+H\ 50%). <br><br> 133 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 68 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(pyridine-2-carbonvD-azeDan-4-vIcarbamovlV3- hutvll-amide <br><br> 5 <br><br> a.) {(S)-l-[3-Hydroxy-1 -(pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl} -carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 2g (0.25 g) in dichloromethane was added picolinic acid (0.09g), EDC (0.14 g) and HOBt (0.10 g). The reaction was stirred 10 until complete. Workup and column chromatography (5% methanolrethyl acetate) provided the title compound (0.35 g). <br><br> b.) (S)-2-Amino-4-methylpentanoic acid [3-hydroxy-l-(pyridine-2-carbonyl)-azepan-4-yl]-amide <br><br> 15 To a solution of the compound of Example 68a (0.34 g) in methanol (6 mL) was added 4M HCl in dioxane (6 mL). The reaction was stirred until complete whereupon it was concentrated to provide the title compound (0.34 g): MS(EI) 349 (M+H+). <br><br> c.) Benzofiiran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-carbonyl)-20 azepan-4-ylcarbamoyl)-3- butyl]-amide <br><br> Following the procedure of Example 28b except substituting the compound of Example 68b the title compound was prepared: MS(EI) 493 (M+H+). <br><br> d.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-carbonyl)-25 azepan-4-ylcarbamoyl)-3- butyl]-amide <br><br> Following the procedure of Example li except substituting the compound of Example 68c the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.7 (m, IH), 4.7 (m, 4H), 5.0 (m, IH), 7.0-7.5 (m, 8H), 8.2 (m, IH); MS(EI): 491 QVT,100%). <br><br> 30 <br><br> 134 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 69 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(SV3-methyl-l-r3-oxo-l-(l-oxv-pvridine-2-carbonvlVazepan-4-vlcarbamovll-butvl) amide <br><br> 5 <br><br> Following the procedures of Examples 68a-d except substituting picolinic acidN-oxide for picolinic acid of Example 68c the title compound was prepared: 'H NMR (CDClj): S 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (d, IH). 4.0 (m, IH), 4.7 (m, 3H), 5.5 (m, IH), 7.0 (m, 2H), 7.2-7.5 (m, 7H), 8.1 (m, 2H); MS(EI): 507 (M+, 10 20%). <br><br> Example 70 <br><br> Preparation of 4-((S)-2-te&gt;t-Butvlcarbonvlamino-4-methvl-pentanovlamino)-3-oxo-azepane-15 1-carboxvlic acid benzvl ester <br><br> Following the procedure of Example 92j, except substituting 4-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid benzyl ester for benzofuran-2-carboxylie acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-(pyridine-20 2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methy 1-butyl }-amide, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 476.2; iH-NMR (400 MHz, CDC13): • 7.40-6.95(m, 7H), 5.25-4.60(m, 4H), 4.40-4.06(m, 2H), 3.70-3.58(t, IH), 2.70-2.50(m, IH), 2.25-1.30(m, 1 6H); and the second eluting diastereomer:, 1.00-0.85(d, 6H); and the second eluting diastereomer: MS (M+H+) 476.2. <br><br> 25 <br><br> Example 71 <br><br> Preparation of 5.6-Dimethoxvbenzofuran-2-carboxylic acid ( fS)-3-methvl-l-[3-oxo-l-( 1-methyl-lH-imidazole-4-suIfonyl)-azepan-4-y]carbamoyl1-butvl) amide <br><br> 30 a.) {(S)-l-t3-Hydroxy-l-(l-methyl-lH-imidazole-2-sulfonyl)-azepan-4-ylcarbamoyl}-3-methyl-butyl}-carbamic acid tert-butyl ester <br><br> To a solution of the amine of Example 2g in methylene chloride (5ml) was added pyridine (92jiL, 1.14mmol) followed by l-methylimidazole-4-sulfonylchIoride (0.112g, <br><br> 135 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 0.623mmol). The reaction was allowed to stir for I6h at room temperature. The solution was then washed with saturated aqueous NaHC03, water and brine. The product was purified by column chromatography (silica gel: methanol/ methylenechloride) to yield the title compound as a white solid (0.172g, 68%); 'HNMR (400MHz, CDC13) 8 7.6 (d, IH), 5 7.5 (d, IH), 6.6 (d, IH), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H); MS(ESI): 488.2 (M+HT <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(l-methyl-lH-imidazole-2-sulfonyl)-azepan-4-yl]-amide <br><br> To a solution of the compound of Example 7 la (0.172g, 0.353mmol) in minimal MeOH was added 4M HCl in dioxane (lOmL) and stirred for 4h at room temperature. The 10 reaction mixture was concentrated and azeotroped with toulene (2x's) to yield the title compound as an off white solid: MS(ESI): 388.2 (M+H)+ <br><br> c.) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-methyl-lH-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide <br><br> 15 To a stirring solution of the compound of Example 7 lb (0.137g, 0.353 mmol), 5,6- <br><br> dimethoxybenzofuran-2-carboxylic acid (0.86g, 0.388mmol), triethylamine (246 mL, 1.77 mmol) and 1-hydroxybenzotriazole (O.Olg, 0.070mmol) in DMF (5mL) was added l-(3-dimethylaminopropyl)3-ethyIcarbodimide hydrochloride (0.074g, 0.388mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed 20 successively with saturated aqueous sodium bicarbonate, water (2x's), and saturated brine. The organic layer was dried over Na,S04, filtered and concentrated. The product was purified by column chromatography (silica gel; methanol/dichloromethane) to yield the title compound as a white solid (0.088g, 42%): MS(ESI): 592.1 (M+H)+ <br><br> 25 d.) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyM-[3-oxo-l-(l-methyl-lH-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide <br><br> Oxalyl chloride (52|iL, 0.596mmol) chloride was cooled to -78°. To this was added dimethyl sulfoxide (106jiL, 1.49mmol) in methylene chloride dropwise. After stirring for 15min at -78°, the alcohol in methylene chloride was added slowly and allowed to stir for 30 lh when Et3N (416|xL,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 MgS04, filtered and concentrated. The product was purified by column chromatography (silica gel: methanol/methylene <br><br> 136 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> chloride) to yield the title compound as white solid (0.068g, 78%): 'H NMR (400MHz, CDC13) 5 6.8-7.6 (m, 14H), 4 (d, 12H), 1 (d, 12H); MS(ESI): 590.1 (M+H)+ <br><br> Example 72 <br><br> 5 <br><br> Preparation of Benzofiiran-2-carboxvIic acid I fSV3-methvl-l-n-f5-methvl-lH-ri.2.41triazole-3-sulfonvl)-3-oxo-azepaii-4-vlcarbamovll-butvllamide a.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid 10 benzyl ester <br><br> To a stirring solution of the compound of Example 2f (3.5 g, 7.33 mmol) in EtOAc (0.5 mL) was added 4M HCl in dioxane (12.8 mL). The mixture was stirred for lh at room temperature. The reaction mixture was then concentrated and azeotroped with toluene (2x20 mL) to yield the title compound as a pale yellow oil (3.13g, 100%): MS(ESI) 378.4 15 (M+H)+ <br><br> b.) 4-{(S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a stirring solution of the compound of Example 72a (3.13g, 7.57mmol), 20 benzofuran-2-carboxylic acid (1.35g, 8.32mmol), triethylamine (1.17ml, 8.25mmol) and 1-hydroxybenzotriazole (0.2g, 1.48mmol) in DMF (30mL) was added l-(3-dimethylaminopropyl)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 (2X), and brine. The organic layer was 25 dried over Na^SO,, filtered and concentrated. The product was purified by column chromatography (silica gel; ethylacetate/dichloromethane) to yield the title compound (3.7g, 93%). 'HNMR (400MHz, CDC13) 5 6.8-7.7 (m, 12H), 5.35 (s, 2H), 1.0 (d, 6H): MS(ESI): 522 (M+H)+ <br><br> 30 c.) Benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> To a solution the compound of Example 72b (2.6 g, 4.9 mmol) in EtOAc (150 mL) was added 10% palladium on carbon (1.3 g) and stirred at room temperature for 64 h under <br><br> 137 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> a 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%): !H NMR (400MHz, CDCy 5 6.8-7.7(m, 7H), 1.02 (d, 6H); MS(ESI) 388 (M+H)+ <br><br> 5 d.) Benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[l,2,4]triazole-3-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide <br><br> To a stirring solution of the compound of Example 72c (O.lOOg, 0.25mmol) and triethylamine (35jnL, 0.25mmol) in methylene chloride (2mL) was added 5-methyl-lH-1,2,4-triazolesulfonylchloride (0.043g, 0.25mmol). The reaction was allowed to stir for 10 10 min and washed with saturated aqueous NaHC03, water and saturated brine. The organic layer was dried over Na2S04, filtered and concentrated. The compound was purified by column chromatography (silica gel; ethylacetate/ hexane) to yield the title compound as a pale yellow oil (0.111, 84%): MS(ESI) 532.73 (M+H)+ <br><br> 15 e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[l,2,4]triazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl] -butyl} amide <br><br> To a stirring solution of the compound of Example 72d (0.108g,, 0.206mmol) in dimethylsulfoxide (2mL) was added triethylamine (172]nL, 1.23mmol) followed by sulfur trioxide pyridine (0.116g, 0.718mmol) and stirred for 16h at room temperature. The 20 reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na1S04, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.08g, '81%): 'HNMR (400MHz, CDC13) 6 7.1-7.7 (m, 7H), 2.65 (s, 3H), 1.0 (d, 6H); MS(ESI): 552.71 (M+Na)+ <br><br> 25 <br><br> 138 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 73 <br><br> Preparation of Benzofuran-2-carboxvlic acid I (SV3-methvl-1 -1"!-(" 1-methvl-1 H-imidazole-3-sulfonvIV3-oxo-az&amp;pan-4-vlcarbamovn-butvl) amide <br><br> 5 <br><br> a.) Benzofuran-2-carboxylic acid {(S)-3-methyl -1 -[ 1 -(1 -methyl-lH-imidazole-3-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide <br><br> To a stirring solution of the compound of Example 72c (O.lOOg, 0.25mmol) and triethylamine (35|JiL, 0.25mmol) was added 1-methylimidazole sulfonyl chloride (0.046g, 10 0.255mmol). The reaction was allowed to stir for lOmin and washed with saturated aqueous NaHC05, water and saturated brine. The organic layer was dried over Na2S04, filtered and concentrated. The compound was purified by column chromatography (silica gel; ethylacetate /hexane) to yield the title compound as a pale yellow oil (0.113g, 82%): 'HNMR (400 MHz, CDCy 8 6.9-7.7 (m, 9H), 3.9 (2s, 3H), 1.0 (d, 6H); MS(ESI): 531.8 15 (M+H)+ <br><br> b.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l~[l-(l-methyl-lH-imidazole-3-sulfonyl)-3-oxo-azepan-4-y lcarbamoy l]-butyl} amide <br><br> To a stirring solution of the compound of Example 73a (0.085g, 0.159mmol) in 20 dimethylsulfoxide was added triethylamine (133pL, 0.95mmol) followed by sulfurtrioxide pyridine (0.08g, 0.5mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na^SO,,, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a 25 white solid (0.072g, 83%). MS(ESI): 529.76 (M+H)+ <br><br> 139 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 74 <br><br> Preparation of Benzofuran-2-carboxvlic acid (fS)-3-methvl-141 -f lH-imidazole-2-sulfonvl')-3-oxo-azepan-4-vlcarbamovll-butvl 1 amide <br><br> 5 <br><br> a.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo-azepan-4-ylcarbaraoyl]-butyl}amide <br><br> To a stirring solution of the compound of Example 72c (O.lOOg, 0.25mmol) and triethylamine (35joL, 0.25mmol) was added 2-imidazolesulfonyl chloride (0.046g, 10 0.255mmol). The reaction was allowed to stir for lOmin and washed with saturated aqueous NaHC03, water and saturated brine. The organic layer was dried over Na2S04, filtered and concentrated. The compound was purified by column chromatography (silica gel; ethylacetate/hexane) to yield the title compound as a pale yellow oil (0.113g, 82%): <br><br> 'HNMR (400MHz, CDC13) 6 7.1-7.7 (m, 9H), 4.8 (s, IH), d, 6H); MS(ESI): 517.76 (M+H)+ <br><br> 15 <br><br> b.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-suIfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide <br><br> To a stirring solution of the compound of Example 74a (0.107g, 0.206mmol) in dimethylsulfoxide (2mL) was added triethylamine (172]xL, 1.23mmol) followed by 20 sulfurtrioxide pyridine (0.115g, 0.718mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na2S04, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.09g, 85%); MS(ESI): 515.84 (M+H)+ <br><br> 25 <br><br> 140 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 75 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-fthiazoIe-2-sulfonvl)-azepati-4-vlcarbamovll-butvI)amide <br><br> 5 <br><br> a.) {(S)-1- [3-Hydroxy-1 -(thiazole-2-sulfonyl)-azepan-4-yIcarbamoyl} -3-methyl-butyl }-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 2g (2.50g, 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 10 shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (2.50 g, 5.10 mmol, 70%); MS: 490.91 (M+H)+. <br><br> b.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hyroxy-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl] -butyl} -amide <br><br> 15 To a solution of the compound of Example 75b (0.15 g, 0.45 mmol) in CH2C12 (20 <br><br> mL) was added benzofuran-2-carboxylic acid (0.109 g, 0.172 mmol), 1-hydroxybenzotriazole (0.106 g, 0.762mmol), and P-EDC (0.85g, lmmol/g) in CH,C12 (10 mL) . After shaking at room temperature overnight, the solution was treated with tisamine (0.589g, 3.75mmol/g). After shaking for another 2hr, the solution was filtered and 20 concentrated to yield the title compound as a white solid (166.7 mg, 70%); MS (ESI): 535.3 (M+H)+. <br><br> c.) Benzofuran-2-carboxylic acid{S}-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyI]-buty 1}-amide 25 To a stirring solution of the compound of Example 75c (166.7 mg, 0.313 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (265.5 mg, 0.626 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 (2x). The organic phases were 30 combined, washed with saturated brine, dried (MgS04), filtered and concentrated. The residue was purified by HPLC (50:50 ethanol: hexane, 20mL/min, 25min, WhelkO-l(R,R) 21x250mm column, UV detection at 280 nm and 305 nm) to yield the first elution as a <br><br> 141 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> white sohd (84.8mg, 50.8 %). MS (ESI): 533.2 (M+H)+ and the second elution as a white solid (50.1mg, 30.0%) MS: 533.2 (M+H*). <br><br> Example 76 <br><br> 5 <br><br> Preparation of Benzofuran-2-carboxvIic acid ((S)-3-methvl-l-ri-(l-methvl-lH-imidazole-4-sulfonvl)-3-oxo-azepan-4-vlcarbamovn-butvI) amide a.) {(S)-1- [3-Hydroxy-1 -(1-methyl- lH-imidazole-2-sulfonyl)-azepan-4-ylcarbamoyl} -10 3-methyl-butyl}-carbamic acid tert-butyl ester <br><br> To a solution of the amine of Example 2g in methylenechloride (5ml) was added pyridine (92jiL, 1.14mmol) followed by l-methylimidazole-4-sulfonylchloride (0.112g, 0.623mmol). The reaction was allowed to stir for 16h at room temperature. The solution was then washed with saturated aqueous NaHC03, water and brine. The product was 15 purified by column chromatography (silica gel: methanol/ methylenechloride) to yield th'e title compound as a white solid (0.172g, 68%): 'HNMR (400MHz, CDC13) 8 7.6 (d, IH),-7.5 (d, IH), 6.6 (d, IH), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H); MS(ESI): 488.2 (M+H)+ <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-1-( i-methyl-lH-imidazole-2-sulfonyl)-azepan-4-yl]-amide <br><br> 20 To a solution of the compound of Example 76a (0.172g, 0.353mmol) in minimal <br><br> MeOH was added 4M HCl in dioxane (lOmL) 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 (M+H)+ <br><br> 25 c.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide <br><br> To a stirring solution of the compound of Example 72c (0.2g, 0.471mmol), benzofuran-2-carboxylic acid (0.084 g, 0.388 mmol), triethylamine (72|jL, 0.517mmol) and 1-hydroxybenzotriazole (0.012 g, 0.088 mmol) in DMF (5 mL) was added l-(3-30 dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.099g, 0.515mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2x's), and saturated brine. The organic layer was dried over Na2S04, filtered and concentrated. The product was <br><br> 142 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> purified by column chromatography (silica gel; methanol/dichloromethane) to yield the title compound as a white solid (0.226g, 90%): 'HNMR (400MHz, CDC13) 8 6.9-8.1 (m, 18H), 3.75 (2s, 6H), 1 (d, 12H); MS(ESI): 531.80(M+H)+' <br><br> 5 d.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-iinidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide <br><br> To a stirring solution of the compound of Example 76a (0.226 g, 0.426mmol) in dimethylsulfoxide (2mL) was added triethylamine (355jiL, 2.55mmol) followed by sulfur trioxide pyridine (0.238g, 1.48mmol) and stirred for 16h at room temperature. The reaction 10 mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na2S04, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.168g, 76%): 'HNMR (400MHz, CDC13) 8 7.1-7.7 9m, 18H), 3.7 (2s, 6H), 0.9 (d, 12H); MS (ESI): 529.80 (M+H)+ <br><br> 15 <br><br> 20 <br><br> Example 77 <br><br> Preparation of 5-(4-Oxv-morpholino-4-vI-ethoxv)-benzofuran-2-carboxvlic acid l(S)-3-meth vl-1 -13-oxo-1 -(pvridine-2-sulfon vl)-azepan-4-vlcarbamovn-butvl) amide <br><br> To a solution of the compound of Example 30b (0.01 g) in dichloromethane (2 mL) was added m-CPBA (0.008 g). The reaction was stirred overnight. Workup and column chromatography (30% methanol :dichloromethane) provided the title compound: 'H NMR (CDClj): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 4H), 2.7 (m, IH), 2.8 (m 2H), 25 3.7 (m, 4H), 3.8 (q, IH). 4.0 (m, 3H), 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, 3H), 7.4 (m, 2H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 671 (M+,100%). <br><br> 143 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> Example 78 <br><br> Preparation of Benzofuran-2-carboxvlic acid I fSV3-methvI-1 ~r3-oxo-l -(pvridine-3-sulfonvD-azepan-4-vlcarbamovll-butvl) amide <br><br> 5 <br><br> a.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a solution of 4-((S)-2-terf-butoxycarbonylarnino-4-methyl-pentanoylamino)-3-hydroxy-azepan-1-carboxylic acid benzyl ester of Example 2f (4.0 g) in methanol (20 mL) 10 was added 4M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 2 hours whereupon it was concentrated to provide the title compound (3.8 g): MS(EI) 378 (M+H+). <br><br> b.) 4-{ (S)-2-[(Benzofuran-2-carbonyl)-arnino]-4-methyl-pentanoylamino} -3-hydroxy-15 azepane-l-carboxylic acid benzyl ester <br><br> To a solution of 4-((S)-2-amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid benzyl ester of Example 78a (3.2 g) in dichloromethane (200 mL) was added EDC (1.48 g), HOBt (1.05 g), TEA (1.29 mL) and benzofuran-2-carboxylic acid. The reaction was stirred until complete. Workup and column chromatography (2% 20 methanol:dichloromethane) provided the title compound (3.78 g): MS(EI) 521 (M+H+). <br><br> c.) Benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> To a solution of 4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-25 pentanoylamino }-3-hydroxy-azepane-l-carboxylic acid benzyl ester of Example 78b (1.6 g) in methanolrethyl 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 provide the title compound (1.16 g): MS (EI) 387 (M+H+). <br><br> 30 d.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.3 g) in dichloromethane was added triethylamine (0.17 mL) followed by 3-pyridinesulfonyl chloride (0.25 g). The reaction was <br><br> 144 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (5% methanoliethyl acetate) provided 0.32 g of the title compound: MS(EI) 528 (M+H+). <br><br> e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide of Example 78d the tide compound was prepared: NMR (CDCI3): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (d, IH). 4.0 (m, IH), 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, 2H), 7.2-7.5 (m, 6H), 8.1 (m, IH), 8.9-9.0 (m, 2H); MS(EI): 526 (M+,100%). <br><br> Example 79 <br><br> Preparation of Benzofuran-2-carboxvlic acid f('SV3-methvl-l-r3-oxo-l-n-oxv-Pvridine-3-sulfonvlVazepan-4-vlcarbamovll-butvl) amide a.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-3~ sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> To a solution of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 78d (0.05g) in dichloromethane was added m-CPBA (0.05 g). The reacrton was stirred overnight. <br><br> Workup and column chromatography (10% methanol:dichloromethane) provided the title compound (0.03 g): MS(EI) 544 (M+H+). <br><br> b.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyljamide of Example 79a the title compound was prepared: 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (d, IH). 4.0 (m, IH), 4.5 (m, IH), 4.7 (m, IH), 5.0 (m, IH), 7.2-7.5 (m, 7H), 8.1-8.2 (m, 2H). MS(EI): 542 (M+, 50%). <br><br> 145 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example SO <br><br> Preparation of Ouinolme-3-carboxvlic acid ((SV 1 -f3.4-dichloro-benzene-sulfonvD-3-oxo-azep an-4-vie arb amo vP "1 - 3 -meth vl -butyl) - ami de <br><br> 5 <br><br> Following the procedures of Example 75a-d except substituting 3,4-dichlorosulfonyl 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(CDCI3, 400 MHz) 5 9.34 (s, IH), 8.61 (s, IH), 8.14 (m, IH), 7.81 (m, 3H), 7.60 (m, 10 3H), 7.19 m, 2H), 5.09 (m, IH), 4.88 (m, IH), 4.50 (m, IH), 3.92 (m, IH), 3.51 (m, IH), 2.57 (m, IH), 2.23 (m, 2H), 1.60 (m, 5H), 1.01 (m, 6H). <br><br> Example 81 <br><br> 15 Prepeoaration of 5-Hvdroxv-benzofuran-2-carboxvlic acid f(S)-3-methvl-l-ri-(l-methvl-lH-imidazole-4-sulfonvl)-3-oxo-azepan-4-vlcarbamovll-butvllamide a.) 5-Hydroxy-benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide 20 To a stirring solution of the compound of Example 76b (0.1 g, 0.235 mmol), 5- <br><br> hydroxybenzofuran-2-carboxylic acid(0.046g, 0.256mmol), triethylamine (36 |iL, 0.258 mmol) and 1-hydroxybenzotriazole (0.006g, 0.044mmol) in DMF (5mL) was added l-(3-dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.05g, 0.26mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed successively 25 with saturated aqueous sodium bicarbonate, water (2X), and saturated brine. The organic layer was dried over Na2S04, filtered and concentrated. The product was purified by column chromatography (silica gel; methanol/dichloromethane) to yield the title compound as a white solid (0.129g, 100%). 'HNMR (400MHz, CDC13) 8 6.8-8 (m, 16H), 3.6 (2s, 6H), 0.85 (d, 12H). <br><br> 30 MS(ESI): 547.88(M+H)+' <br><br> 146 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> b.) 5-Hydroxy-benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Oxalyl chloride (13 |JL, 0.149 mmol) chloride was taken to -78°. To this was added dimethyl sulfoxide (28 flL, 0.394mmol) in methylene chloride dropwise. After stirring for 5 15min at -78 °, the alcohol of Example 8 la in methylene chloride was added slowly and allowed to stir for lh when Et3N (7 |iL, 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 MgS04, <br><br> filtered and concentrated. The product was purified by column chromatography (silica gel: 10 methanol/methylene chloride) to yield the title compound as white solid (0.021g, 78%): MS(ESI) 545.9(M+H)+' <br><br> Example 82 <br><br> 15 Preparation of Benzofuran-2-carboxvlic acid \ (SV3-methvl-1 -f3-oxo-l-(" 1 -oxv-pvridine-2-sulfonvD-azepan-4-vlcarbamovl)l-3-methvl-butvll-amide a.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl}-amide 20 To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-aizepan-4- <br><br> ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.10 g) in dichloromethane was added triethylamine (0.07 mL) followed by 2-pyidinesulphonylchloride N-oxide. The reaction was stirred at room temperature overnight. Workup and chromatography (10% methanol:dichloromethane) provided the title compound (0.01 g): MS(EI) 544 (M+H+). <br><br> 25 <br><br> 147 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl} -amide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-5 ylcarbamoyl)]-3-methyl-butyl)-amide of Example 82a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (rn, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 -7.5 (m, 9H), 8.1-8.2 (m, 2H). MS(EI): 542 (M+, 20%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting <br><br> 10 diastereoemer; 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.8 (d, IH). 4.0 (d, IH), 4.7 (m, IH), 4.8 (d, IH), 5.0 (m, IH), 7.0 -7.5 (m, 9H), 8.1-8.2 (m, 2H); MS(EI): 542 (M+,100%), and the slower eluting diastereomer; MS(EI): 542 (M+H+,100%). <br><br> 15 Example 83 <br><br> Preparation of 2-(4-{ (SV2-IrBenzofqran-2-carbonvl')-aminol-4-methvl-pentanovlamino)-3-oxo-azepane-1 -sulfonvl)-benzoic acid <br><br> 20 a.) 2-(4-{ (S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-l-sulfonyl)-benzoic acid methyl ester <br><br> Following the procedure of Example 75a-c, except substituting 2-carboxymethylsulphonyl chloride for 2-thiazolesulfonyl chloride, the title compound was prepared: MS (M+H+ ) = 585.56, M+Na+ = 607.76, 2M+H+ = 1170.48. <br><br> 25 <br><br> b.) 2-(4-{(S)-2-[(Benzofuran-2-caxbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane- l-sulfonyl)-benzoic acid <br><br> 2-(4- {(S)-2- [(benzofuran-2-carbony l)-amino]-4-methyl-pentanoylamino} -3-hydroxy-azepane-l-sulfonyl)-benzoic acid methyl ester (compound 83a, 180 mg, 0.309 <br><br> 30 mmol) was dissolved in 5:1 MeOH/water (6 ml) LiOH (14 mg, 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 HCl (adjusted to pH=2), extracted with EtOAc (3 x 10 ml), dried with MgS04, filtered, concentrated, and chromatographed (silica gel, 1% acetic acid/ <br><br> 148 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 4% MeOH/ CH2C12) to yield the title compound as a white solid (48 mg, 27%): M+H+ = 572.2 <br><br> c.) 2-(4-{(S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-oxo-5 azepane-l-sulfonyl)-benzoic acid <br><br> Following the procedure of Example 75d, except substituting 2-(4-{(S)-2-[(benzofuran-2-carbonyl)-arnino]-4-methyl-pentanoylamino }-3-hydroxy-azepane-l -sulfonyl)-benzoic acid for benzofuran-2-carboxylie acid {(S)-3-methyl-l-[3-hydroxy-1-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide, the title compound was prepared: 10 MS (M+H+): 570.2 (M+H+). ]H NMR(400Hz,CDCl3-CD3OD): 5 8.05-7.95 (m, IH), 7.70-7.15 (m, 8H), 5.15-5.00 (m,lH), 4.95-4.75 (m, 2H), 4.15-4.00 (m, IH), 3.65 (d, IH), 2.85-2.70 (m, IH), 2.25-2.05 (m, 2H), 1.90-1.70 (m, 4H), 1.60-1.45 (m, IH), 0.95 (d, 6H). <br><br> Example 84 <br><br> 15 <br><br> Preparation of 3-(4-((SV2-IflBenzofuran-2-carbonvT)-amino]-4-methvl-pentanovlaminol-3-oxo-azepane- 1-sulfonvlVbenzoic acid <br><br> Following the procedure of Example 83, except substituting 3-20 carboxymethylbenzenesulphonyl chloride for 2-carboxymethylbenzenesulfonyl chloride, the title compound was prepared: MS 570.2 (M+H+); ^H NMR (400Hz,CDCl3-CD3OD): 6 8.46 (d,lH), 8.31-8.25 (m,lH), 8.00-7.97 (m,lH), 7.70-7.62 (m, 2H), 7.55-7.46 (m, IH), 7.45-7.35 (mflH), 7.30-7.25 (m, IH), 5.10-5.05 (m,lH), 4.95-4.78 (m,lH), 4.75-4.55 (q,lH), 4.00 (d,lH), 3.5 (d, IH), 2.60-2.40 (m, 2H), 2.25-2.15 (m,lH), 1.95-1.70 (m, 25 4H), 1.55-1.40 (m,lH), 0.98 (t, 6H). <br><br> 149 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 85 <br><br> Preparation of Benzofblthiophene-2-carboxvlic acid ((S)-3-methvI-l-r3-oxo-l-fl-oxv-Pvridine-2-sulfonylVazepan-4-vlcarbamovl"l-butvl \ amide <br><br> 5 <br><br> a.) {(S)-1 -[3-Hydroxy-1-( 1 -oxy-pyridine-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl-carbamic acid fert-butyl ester <br><br> To a solution of [(S)-1 -(3-hydroxy-azepan-4-ylcarbamoy])-3-methyl-butylJ-carbamic acid tert butyl ester of Example 2g (2.5 g) in dichloromethane (100 mL) and 10 saturated sodium bicarbonate was added freshly prepared 2-pyidinesulphonyl chloride N-oxide (prepared by bubbling chlorine gas through a solution of 2-mercaptopyridine-N-oxidein 9M HCl 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 1 hour. Workup and column chromatography (10% 15 methanol:dichloromethane) provided the title compound (2.0 g): MS(EI) 500 (M+H+). <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-1-(1-oxy-pyyridine-sulfonyl)-azepan-4-yl]-amide <br><br> To a solution of {(S)-l-[3-hydroxy-l-(l-oxy-pyridine-suIfonyl)-azepan-4-20 ylcarbamoyl3-3-methyl-butyl-carbamic acid ferr-butyl ester of Example 85a (2.0 g) in methanol (20 mL) was added 4M HCl 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 g):MS(EI) 400 (M+H+). <br><br> 25 c.) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(l-oxy-pyyridine-sulfonyl)-azepan-4-yl]-amide of Example 85b (0.25 g) in dichloromethane (12 mL) was added triethylamine (0.12 mL), EDC (0.11 g), HOBt (0.077 g) and 30 benzo[b]thiophene-2-carboxylie acid. The reaction was stirred until complete. Workup and column chromatography (10% methanol: dichloromethane) provided the title compound (0.26 g): MS (EI) 560 (M+H+). <br><br> 150 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> d.) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl-1- [3-hydroxy-1-( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-5 ylcarbamoyl]-butyl} amide of Example 85c the title compound was prepared: 'H NMR (CDC1,): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.5 (m, 4H), 7.8 (m, 3H), 8.1-8.2 (m, 2H). MS(EI): 558 (ivr,100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 10 diastereoemer; MS(EI): 558 (MM 00%), and the slower eluting diastereomer; MS(EI): 558 (M+,l 00%). <br><br> Example 86 <br><br> 15 Preparation of 5-Bromo-furan-2-carboxvlic acid {(SV3-methvl-l-f3-oxo-l-fl-oxv-Pvridine-2-sulfom'l&gt;azepan-4-vlcarbamovl"l-butyl 1 amide a. 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 20 Following the procedure of Example 85c except substituting 5-bromo-2-furoic acid for benzo[b]thiophene-2-carboxyIic acid the title compound was prepared: MS(EI) 574 (M+H+). <br><br> b.) 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-25 sulfonyl)-azepan-»4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting 5-bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 86a the title compound was prepared: 'H NMR (CDCI3): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 30 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, 2H), 7.4 (m, 2H), 8.1-8.2 (m, 2H); MS(EI): 570 (MM 00%). <br><br> 151 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> The diastereomeric mixture Was separated by-'HPLC to provide the faster eluting <br><br> \ <br><br> diastereoemer; MS (EI): 572 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 572 (M+H+,100%). <br><br> Example 87 <br><br> Preparation of 5,6-Dimethoxvbenzofuran-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(l-oxv-pvridine-2-sulfonvl)-azeDan-4-vlcarbamovn-butvl I amide a.) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting 5,6-dimethoxybenzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS (EI) 604 (M+H+). <br><br> b.) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting 5,6-dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1- [3-hydroxy-l-( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 87a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, 7H). 4.0 (m, IH), 4.7 (m, IH), <br><br> 4.8 (m, IH), 5.0 (m, IH), 7.0-7.5 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 602 (MM00%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 602 (MM00%), and the slower eluting diastereomer; MS(EI): 602 (M+,l 00%). <br><br> 152 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 88 <br><br> Preparation of l-Oxv-pvridine-2-carboxvlic acid (fS&gt;3-methvl-1 -13-oxo-1 -(pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvl)amide a.) l-Oxy-pyridine-2-carboxyIic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> 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 (M+H+). <br><br> b.) l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4~ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting l-oxy-pyridine-2-carboxylic acid {(S)-3-methyI-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 88a the title compound was prepared: 'HNMR (CDC13): 6 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.1 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.5 (m, 3H), 7.9 (m 2H), 8.3-8.4 (m, 2H), 8.6 (m, IE); MS(EI): 503 (1^,100%) . <br><br> Example 89 <br><br> Preparation of (SV4-Methvl-2-fpyridine-2-sulfonylamino')-pentanoic acid D-oxo-l-(pvridme-2-sulfonvl)-azepan-4-vn-amide a.) (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.25 g) in dichloromethane was added triethylamine (0.27 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirred until complete. Workup and column chromatography (5% methanokdichloromethane) provided the title compound (0.09 g): MS(EI) 525 (M+H+). <br><br> 153 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-1 -(pyridine-2-sulfonyl)-az£pan-4-yl]-amide <br><br> Following the procedure of Example li except substituting (S)-4-methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- <br><br> 5 yl]-amide of Example 89a the title compound was prepared: lH NMR (CDC13); 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4.7 (m, IH), 5.0 (m, IH), 5.5 (m, IH), 7.0 (m IH), 7.5 (m, 2H), 7.9 (m 3H), 8.6 (m, 2H). MS(EI): 523 (M+,100%). <br><br> 0 Example 90 <br><br> Preparation of (SV2-(3-Benzvl-ureido')-4-methvl-pentanoic acid r3-oxo-l-(pvridine-2-sulfonvlVazepan-4-vll-amide <br><br> 5 a.) (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-1 -(pyridine-2- . sulfonyl)-azepan-4~yl]-amide <br><br> To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyyridine-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.25 g) in dichloromethane was added triethylamine (0.17 mL) and benzyl isocyanate (0.088g). The reaction was stirred until <br><br> O complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.12 g). <br><br> b.) (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> 15 Following the procedure of Example li except substituting (S)-2-(3-benzyl-ureido)- <br><br> 4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 89a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, 3H), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.2 (, 5H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 515 (M\ 60%). <br><br> 10 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 516 (M+H\100%), and the slower eluting diastereomer; MS(EI): 516 (M+fT,100%). <br><br> 154 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 91 <br><br> Preparation of (S)-2~f3-Phenvl-uriedo')-4-methvl pentanoic acid r3-oxo-l-fpvridine-2-suIfonyl)-azepan-4-vll-amide <br><br> 5 <br><br> a.) (S)-2-(3-Phenyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example 90a except substituting phenyl isocyante for benzyl isocyanate the title compound was prepared:: MS(EI) 503 (M+H+). <br><br> 10 <br><br> b.) (S)-2-(3-Phenyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substituting (S)-2-(3-phenyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of 15 Example 91a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.0-7.9 (m, 8H), 8.6 (m, IH). MS(EI): 501 (M*, 60%). <br><br> 20 <br><br> Example 92 <br><br> Preparation of Benzofuran-2-carboxvlic acid (fSVl-[6.6-dim&amp;thvl-3-oxo-l(mridin&amp;-sulphonvlVazepan-4-vlcarbamovl1-3-methvl-butvll-amide a.) Allyl-(2,2-dimethyl-pent-4-enylidene)-amine 25 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 allylamine on rotavapor provided 3.76 g of the title compound as clear liquid (yield 100%). ^H-NMR (400 MHz, cdci3): • 30 7.52(s, IH), 5.99-5.90(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). <br><br> 155 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) Allyl-(2,2-dimethyl-pent-4-enyl)-amine <br><br> Allyl-(2,2-dimethyl-pent-4-enylidene)-amine of Example 92a (3.76g, 25mmol) was diluted in 5ml MeOH. To the solution NaBIfy (0.95g, 25mmol) was added at 0°C. After addition the mixture was stirred at r.t. for 5h. Methanol was removed on rotavapor and the 5 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 (M+H+): 154.0; <br><br> 2 4 <br><br> H-NMR (400 MHz, CDC13): 5.93-5.76(m, 2H), 5.29-4.99(m, 4H), 3.22(d, 2H), 2.34(s, 2H), 2.01 (d, 2H), 0.94(s, 6H). <br><br> 10 c.) Pyridine-2-sulfonic acid allyl-(2,2-dimethyl-pent-4-enyl)-amide <br><br> Allyl-(2,2-dimethyl-pent-4-enyl)-amine (0.43 g, 2.8 mmol) and NMM (0.57g, 5.6mmol) were mixed in 30 mL CH2CI2. 2-pryridinesulphonyl 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. overnight. Washed by 10% NaHC03 and the brine. Purified by column 15 chromatography gave 0.6 g colorless oil in 13% yield. MS (M+H+): 295.2; ^H-NMR (400 MHz, CDCI3): • 8.71-8.70(d, IH), 7.98-7.86(m, 2H), 7.48-7.46(m, IH), 5.88-5.77(m, IH), 5.55-5.45(m, IH), 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) <br><br> 20 d.) .3,3-Dimethyl- l-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro- lH-azepine <br><br> Pyridine-2-sulfonic acid allyl-(2,2-dimethyl-pent-4-enyl)-amide (0.6g, 2mmol) was diluted in CH2CI2 (50ml) After carefully degass by Ar, Grubbs catalyst (0.17g, 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 25 (5%-20% E/H) to give 0.47g of the title compound in 87% yield. MS (M+H+): 267.0; 1H-NMR (400 MHz, CDCI3): • 8.70-8.69(d, IH), 7.96-7.88(m, 2H), 7.49-7.46(m, IH), 5.81-5.70(m, 2H), 3.93-3.92(d, 2H), 3.26(s, 2H), 2.13-2.12(d, 2H), 1.00(s, 6H) <br><br> e.) 5,5-Dimethyl-3-(pyridine-2-sulfony 1)-8-oxa-3-aza-bicy clo[5.1.0] octane 30 To the solution of the compound of Example 92d (1.2 g, 4.5 mmol) in 50 mL <br><br> CH2CI2 was added NaHC03 (2.4 g, 13.5 mmol) and then MCPBA (1.2 g, 13.5 mmol) in portions. The reaction was stirred at r.t. for 4h before it was worked up by washing with 15% NaOH, saturated K2CO3, brine and dried (Na2S04) to give l.Og crude product in 79 <br><br> 156 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> % yield ( good enough for next reaction without further purification.) MS (M+H+): 283.0; iH-NMR (400 MHz, CDC13): • 8.68-8.67(d, IH), 8.03-7.87(m, 2H), 7.49-7.40(m, IH), 4.44-3.89(q, IH), 3.62-3.59(d, IH), 3.50(m, IH), 3.00(m, IH), 2.78-2.62(m, 2H), 2.12-2.06(m, IH), 1.52-1.46(q, IH), 1.20(s, 3H), 0.89(s, 3H). <br><br> 5 <br><br> f.) 4-Azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol 5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane from <br><br> Example 92e (1.2 g, 4.3 mmol) was dissolved in the mixture of 7 ml MeOH and 1 ml H2O. NaN3 (0.83 g, 13 mmol) and nh4ci (0.7 g, 13 mmol) were added to the solution. The 10 resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHC03 and brine. Purified on column chromatography gave 0.4g 4-azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol (yield 29%); MS (M+H+): 326.2; iH-NMR (400 MHz, cdci3): • 8.68-8.67(m, IH), 8.05-7.90(m, 2H), 7.53-7.50(m, IH), 3.75-3.60(m, 3H), 3.49-3.30(m, 3H), 1.73-1.66(m, IH), 1.56-15 1.52(d, IH), 1.07(s, 3H), 0.99(s, 3H) <br><br> g.) 4-Amino-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-oI 4-Azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol from Example 92f (0.4 <br><br> g, 1.23 mmol) was dissolved in THF (50 ml) and H2O (0.2 ml). ppi13 (0.48 g, 1.85 mmol) 20 was added to this solution. The reaction mixture was stirred at 45°C over night. TLC <br><br> showed no starting material left. THF was evaporated, azeotroped with toluene (2x's). The resulting thick oil was dissolved in MeOH, treated with HCl in ether to adjust pH to acidic. More ether was added and the solution turned cloudy. 0.22 g white precipitate of the title compound was collected. (45% yield); ^H-NMR (400 MHz, CD3OD): • 8.68(m, IH), 8.10-25 7.93(m, 2H), 7.62(m, IH), 3.90(m, IH), 3.68(m,lH), 3.40~2.90(m, 4H), 1.82(m, IH), 1.53(d, IH), 1.05(s, 6H) <br><br> h.) {(S)-l-[3-Hydroxy-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-yIcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester <br><br> 30 4-Amino-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt from Example <br><br> 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 high vacuum. The <br><br> 157 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> residue was diluted with EtOAc and washed with H20,10% NaHC03 and brine. Purification by column chromatography gave 0.22 g of the title compound (72% yield); MS (M+H+): 512.9; 1H-NMR (400 MHz, CDCI3): • 8.68-8.67(d, IH), 7.97-7.88(m, 2H), 7.69-7.64(m, IH), 6.62-6.53(m, IH), 5.06-5.00(m, IH), 4.03-3.18(m, 7H), 1.80-1.42(m, 5 15H), 1.04-0.92(m, 12H). <br><br> i.) Benzofuran-2-carboxylic acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methy 1-butyl} -amide <br><br> To {(S)-l-[3-Hydroxy-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-10 ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester of Example 92h (0.22g, <br><br> 0.43mmol) was added HCl/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t. for 2h before solvents and excess amount of HCl was removed on rotavapor. The resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The 15 mixture was stirred at r.t. overnight. DMF was then removed and the residue was re-dissolved in EtOAc (50 ml), washed with 10% NaHC03 (50 ml x 2) and brine (50 ml). Evaporation of the solvent gave crude product 0.26 g. Purification by column chromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8; iH-NMR (400 MHz, CDCI3): • 8.66-8.63(m, IH), 7.94-7.1 l(m, 10H), 4.72(m, IH), 4.01-20 2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H). <br><br> j.) Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> To a solution of benzofuran-2-carboxylic acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-25 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide from Example 92i <br><br> (100 mg, 0.18mmol) in 2 ml CH2C12, was added Dess-Martin reagent (76 mg, 0.18 mmol) at r.t.. The solution was stirred for 2h when 20 ml CH2C1, was added and then washed with NaHC03 and brine. Purification by column chromatograghy (50% ethyl acetate in hexane) gave 70 mg of the title compound in 70% yield. MS (M+H+): 555.4; 1H-NMR (400 MHz, 30 CDC13): • 8.68~8.67(d, IH), 7.97-7.93(m, 2H), 7.69-7.28(m, 6H), 7.32-6.92(m, 2H), 5.24(m, IH), 4.79-4.69(m, 2H), 3.80-3.71(m, 2H), 2.54-2.50(d, IH), 1.92-1.76(m, 4H), 1.45-1.40(m, 4H), 1.01-0.91(m, 9H). <br><br> 158 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS (M+H+): 555.2, and the slower eluting diastereomer; MS (M+H+): 555.2. <br><br> 5 Example 93 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid ((S)-3-methvl-1 -[3-oxo-1 -(1-oxv-pvridine-2-sulfonvI)-azepan-4-vlcarbamovll-butvl) amide <br><br> 10 a.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting 5-methoxybenzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 574 (M+H+). <br><br> b.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide <br><br> Following the procedure of Example li except substuting 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-1- [3-hydroxy-1 -(1 -oxy-pyridine-2-suIfony l)-azepan-4-20 ylcarbamoyl]-butyl Jamide of Example 93a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, 4H). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.6 (m, 8H) 8.0-8.2 (m, 2H); MS(EI): 572 (M*, 30%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 25 diastereoemer; 'HNMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.7 (s, 3H), 3.8 (d, IH). 4.0 (d, IH), 4,7 (m, IH), 4.8 (d, IH), 5.0 (m, IH), 7.4-8.6 (m, 8H) 8.0-8.2 (m, 2H); MS(EI): 573 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 573 (M+H\100%). <br><br> 159 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 94 <br><br> Preparation of Thienof3.2-blthiophene-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(l-oxv-pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvn amide a.) Thieno[3,2-b]thiophene-2-carboxyIic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 85c except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzo[b]tbiophene-2-carboxylic acid the title compound was prepared: MS(EI) 566 (M+H+). <br><br> b.) Thieno[3,2-b]thiophene-2-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methy 1-1 -[3-hydroxy-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide of Example 94a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-7.5 (m, 6H), 7.7 (d, IH), 8.0-8.2 (m, 2H). MS(EI): <br><br> 564 (MM 00%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.8 (d, IH). 4.0 (d, IH), 4,5 (m, IH), 4.7 (d, IH), 5.0 (m, IH), 7.4-7.5 (m, 6H), 7.7 (d, IH), 8.0-8.2 (m, 2H); MS(EI): 565 (M+HM00%) and the slower eluting diastereomer; MS(EI): <br><br> 565 (M+HM00%). <br><br> 160 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 95 <br><br> « <br><br> Preparation of Ouinoxaline-2-carboxvlic acid l(SV3-methvl-l-f3-oxo-l-('l-oxv-pvridine-2-sulfonvl Vazepan-4-vlcarbamovll-butvl 1 amide <br><br> 5 <br><br> a.) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting quinoxaline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: 10 MS(EI) 556 (M+H+). <br><br> b.) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yl carbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting quinoxaline-2-carboxylic 15 acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 95a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-7.5 (m, 2H), 7.9 (m, IH), 8.0-8.4 (m, 4H, 9.6 (d, IH); MS(EI): 554 (M+,100%) . 20 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 555 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 555 (M+H\100%). <br><br> Example 96 <br><br> 25 <br><br> Preparation of Ouinoline-2-carboxvlic acid f (S)-3-methvl- 1-r3-oxo-l-f l-oxv-pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butvl) amide a.) QuinoIine-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-30 sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 85c except substituting quinoline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 555 (M+H+). <br><br> 161 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> b.) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substuting quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-5 butyl Jamide of Example 96a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.6 (m, 10H); MS(EI): 553 (M+,100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 554 (M+H\100%) and the slower eluting diastereomer; MS(EI): 10 554 (M+Ht,100%). <br><br> Example 97 <br><br> Preparation of Thiophene-3-carboxvlic acid i (SV3-methvl-1 - [3-oxo-1 -f 1 -oxv-Pvridine-2-15 sulfonvlVa2epan-4-vlcarbamovll-butvl 1 amide a.) Thiophene-3-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 85c except substituting thiophene-3-20 carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 510 (M+H+). <br><br> b.) Thiophene-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> 25 Following the procedure of Example li except substuting thiophene-3-carboxylic acid {(S)-3-methyl~l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide of Example 97a the title compound was prepared: 'H NMR (CDCi,): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 4H), 7.8 (m, IH), 8.1-8.2 (m, 2H); MS(EI): 508 (M+, 80%). <br><br> 30 <br><br> 162 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 98 <br><br> Preparation of lH-Indole-5-carboxvlic acid jfSV3-methvl-l-r3-oxo-l-(T-oxv-pvridine-2-sulfonvlV azepan-4-vlcarbamovn-butv] 1- amide <br><br> 5 <br><br> a.) lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting lH-indole-5-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: 10 MS(EI) 543 (M+). <br><br> b.) lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-suIfonyl)-azepan-4-y lcarbamoy 1]-butyl} amide <br><br> Following the procedure of Example li except substuting of lH-indole-5-15 carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 98a the title compound was prepared: 'H NMR (CDCla): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 8.6 (b, IH); MS(EI): 541 (M+,100%) . <br><br> 20 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 542 (M+H\80%) and the slower eluting diastereomer; MS(EI): 542 (M+H\80%). <br><br> 25 <br><br> Example 99 <br><br> Preparation of Benzol"! .31dioxole-5-carboxylie acid f (SV3-methyl-l-r3-oxo- 1-f 1 -oxv-pvridine-2-sulfonvl)-azepan-4-ylcarbamovil-butvl) amide a.) Benzotl,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-30 pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting Benzo[l,3]dioxole-5-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 548 (M+). <br><br> 163 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-5 ylcarbamoyl]-butyl} amide of Example 99a the title compound was prepared: 'H NMR (CDCy: 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4.5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 6.0 (s, 2H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); <br><br> MS(EI): 546 (M+,100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting <br><br> 10 diastereoemer; MS (EI): 547 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 547 (M4-H\100%). <br><br> Example 100 <br><br> 15 Preparation of Furan-2-carbbxvlic acid ) CSV 3-methvl-1 -[3-oxo-1 -(1 -oxv-pvridine-2-sulfonvl)-azet)an-4-vlcarbam6vn-butvl I amide a.) Furan-2-carboxylic acid {(S)-3-methy 1-1-[3-hydroxy-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 20 Following the procedure of Example 85c except substituting furoic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 494 (M+). <br><br> b.) Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 25 Following the procedure of Example li except substuting furan-2-carboxylic acid <br><br> {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 100a the title compound was prepared: !H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 492 (^,100%) . <br><br> 30 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer MS(EI): 493 (M+H\100%) and the slower eluting diastereomer; MS(EI): 493 (M+H\100%). <br><br> 164 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 101 <br><br> Preparation of rSV4-Methvl-2-(2-thiophen-2-vl-acetvlamiiio)-pentanoic acid r3-oxo-l-(l-oxv-pvridine-2-sulfonvl)-azepan-4-vn-amide <br><br> 5 <br><br> a.) (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-hydroxy-l-(l-oxy~ pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example 85c except substituting thiophene-2-acetic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> 10 <br><br> b.) (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substuting (S)-4-methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-15 azepan-4-yl]-amide of <br><br> Example 101a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, 3H); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 522 (M+, 20%). <br><br> 20 Example 102 <br><br> Preparation of lH-Indole-2-carboxvlic acid {(SV3-methvl-l-r3-oxo-l-(l-oxv-pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvl)amide <br><br> 25 a.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting lH-indole-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS (EI) 543 (M+). <br><br> 30 <br><br> b.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide <br><br> Following the procedure of Example li except substuting lH-indole-2-carboxylic acid {(S)-3-methy 1-1 - [3-hydroxy-1-( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- <br><br> 165 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> butyl}amide of Example 102a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH),7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 9.4 (b, IH); MS(EI): 541 <br><br> or,ioo%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 542 (M+tT,100%) and the slower eluting diastereomer; MS(EI): 542 (M+H\100%). <br><br> Example 103 <br><br> Preparation of 4-FIuoro-((SVS-methvl-l-rS-oxo-l-d-oxv-pvridine-l-sulphonvlVazepan^-carbamovll -butvl \ -benzamide a.) 4-Fluoro-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulphonyI)-azepan-4-15 carbamoyl]-butyl }-benzamide <br><br> Following the procedure of Example 85c except substituting 4-fluorobenzoic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 522 (M+). <br><br> 20 b.) 4-Fluoro-{ (S)-3-methyl-1- [3-oxo-1 -(1 -oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]-butyl}-benzamide <br><br> Following the procedure of Example li except substuting 4-fluoro-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]-butyl}-benzamide of Example 103a the title compound was prepared: *H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 25 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH),7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS(EI): 520 (M+,100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 521 (M+H\100%) and the slower eluting diastereomer MS(EI): 521 (M+H+,100%). <br><br> 30 <br><br> 166 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 104 <br><br> Preparation of 5-f2-Moinholin-4-yl-ethoxv)-berizofuran-2-carboxvlic acid (fS)-3-methvl-l-r3-oxo-n-oxv-pvridine2-sulphonvl")-azepaii-4-vlcarbamovll-butv)-amide <br><br> 5 <br><br> a.) 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-(l-oxy-pyridine2-sulphonyI)-azepan-4-ylcarbamoyl]-buty }-amide <br><br> Following the procedure of Example 85c except substituting 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title 10 compound was prepared: MS(EI) 673 (M+). <br><br> b.) 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]-buty}-amide <br><br> Following the procedure of Example li except substuting 5-(2-morpholin-4-yl-15 ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-(l-oxy-pyridine2- <br><br> sulphonyl)-azepan-4-ylcarbamoyl]-buty}-amide of Example 104a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m; 2H), 2.5 (m, 4H), 2.7 (m, 3H), 3.7 (m, 4H); 3.9 (m, IH), 4,5 (m, 3H), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS(EI): 671 (M+,100%) . <br><br> 20 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 672 (M+H\100%) and the slower eluting diastereomer MS(EI): 672 (M+H\100%). <br><br> 25 <br><br> Example 105 <br><br> Preparation of Thiophene-2-carboxvlic acid f fS)-3-methvl-1 - r3-oxo-l -f 1 -oxv-pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butvn amide a.) Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-30 sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide <br><br> 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) 510 (M+). <br><br> 167 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting thiophene-2-carboxylic acid {(S)-3-methyl-1 -[3-hydroxy-1-( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-5 butyl}amide of Example 105a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 508 (M+,100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 509 (M+H\100%) and the slower eluting diastereomer MS(EI): 10 509 (M+H\100%). <br><br> Example 106 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid l("SV3-methvl-l-r3-oxo-l-fl-oxv-15 pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvl 1 amide a.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting 3-methylbenzofuran-2-20 carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 558 (M+). <br><br> b.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 25 Following the procedure of Example li except substuting 3-methylbenzofuran-2- <br><br> carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 106a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); 30 MS(EI): 556 (M\100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (t, IH), 3.8 (d, IH); 4.1 (d, IH), 4,7 (m, IH), 4.7 (d, IH), 5.0 (m, IH), 7.0 (m, 2H), 7.3 <br><br> 168 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> 5 <br><br> (m, 2H), 7.4 (m, 4H), 8.1 (d, IH), 8.2 (d, IH); MS(EI): 557 (M+HM00%) and the slower eluting diastereomer MS(EI): 557 (M+H\100%). <br><br> Example 107 <br><br> Preparation of 6-Methvl-N-((Sy3-methvl-l-r3-oxo-l-(l-oxv-pvridrne-2-sulfonv1Va?.epan-4-vlcarbamovll-butvl l-nicotinamide a.) 6-Methyl-N-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine~2-sulfonyl)-azepan-4-10 y lcarbamoy l]-butyl} -nicotinamide <br><br> Following the procedure of Example 85c except substituting 6-methylnicotinic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 519 (M+). <br><br> 15 b.) 6-Methyl-N-{ (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -nicotinamide <br><br> Following the procedure of Example li except substuting of 6-methyl-N-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-nicotinamide Example 107a the title compound was prepared:: 'H NMR (CDCL,): 8 1.0 20 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 3H), 9.0 (m, IH); MS(EI): 517 (M+,100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 518 (M+H+,100%) and the slower eluting diastereomer MS(EI): 25 518 (M+H+,100%). <br><br> 169 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 108 <br><br> Preparation of fS)-4-Methvl-2-f2-thiophen-vl-acetv1aminoVpentanoic acid-r3-oxo-l-fpvridine-2-sulfonvl)-azepaxi-4-vll-butv1) amide <br><br> 5 <br><br> a.) (S)-4-Methyl~2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl] -butyl} amide <br><br> 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 10 (M+H+). <br><br> b.) (S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-oxo-1 -(pyridine-2-suIfonyl)-azepan-4-yl]-butyl} amide <br><br> Following the procedure of Example li except substuting (S)-4-methyl-2-(2-15 thiophen-yl-acetylamino)-pentanoic acid-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-butyl Jamide of Example 108a the title compound was prepared: MS(ESI) 506.8 (M+H+). <br><br> Example 109 <br><br> 20 Preparation of lH-Indole-6-carboxvlic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyi)-azepan-4-vlcarbamovll-butvl 1 amide a.) 1 H-In dole-6-carb oxy lie acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 25 Following the procedure of Example 28b except substituting lH-indole-6- <br><br> carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 527 (M+H+). <br><br> b.) lH-Indole-6-carboxylic acid {(S)-3-methyH-[3-oxo-l-(pyridine-2-sulfonyl)-30 azepan-4-ylcarbamoyl]-butyl Jamide <br><br> Following the procedure of Example li except substuting lH-indole-6-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide of Example 109a the title compound was prepared: MS(EI) 525 (M+H+). <br><br> 170 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 110 <br><br> Preparation of Benzori.31dioxole-5-carboxvlic acid f(S)-3-methvl-l -r3-oxo-1 -(pvridine-2-sulfonvl)-azepan-4-vlcarbamovl1-hntvl 1 amide <br><br> 5 <br><br> a.) Benzo[1.3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting piperonylic acid for benzofuran-2-carboxylic acid the tide compound was prepared: MS(EI) 532.7 (M+H+). <br><br> 10 <br><br> b.) Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI} amide <br><br> Following the procedure of Example li except substuting benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-15 ylcarbamoyl]-butyl} amide of Example 110a the title compound was prepared: MS(EI) 530.8 (M+H+). <br><br> Example 111 <br><br> 20 Preparation of 3.4-Dihvdro-2H-benzorbiri.41dioxepine-7-carboxvlic acid ffS)-3-methvl-l-r3-oxo-l-d-oxv-pvridine-2-sulfonYD-azepan-4-vlcarbamovll-butvllamide a.) 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-1 -(1 -oxy-pyridine-2-sulfony l)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 25 Following the procedure of Example 85c except substituting 3,4-dihydro-2H-l,5- <br><br> benzodioxepine-7-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS (EI) 576 (M+). <br><br> b.) 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-oxo-30 l-( l^-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting 3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-1 -[3-hydroxy-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 111a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 4H), 2.5 (d, 3H), 2.7 <br><br> 171 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4.2 (m, 4H), 4,5*(t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 575 (M+H+,100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 575 (M+H\100%) and the slower eluting diastereomer MS(EI): 5 575 (M+HT,100%). <br><br> Example 112 <br><br> Preparation of 5-Methvl-thiophene-2-carboxvlic acid ((SV3-methvl-l-r3-oxo-1 -(1-oxv-10 pyridine-2-sulfonvlVazeDan-4-vlcarbamovll-butvl}amide a.) 5-Methyl-thiophene-2-carboxylic acid {(S)-3 -methyl-1 -[3-hydroxy-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI}amide <br><br> Following the procedure of Example 85c except substituting 5-methyl thiophene-2-15 carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 524 (M+). <br><br> b.) 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 20 Following the procedure of Example li except substuting 5-methyl-thiophene-2- <br><br> carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-y lcarbamoy 1] -butyl} amide of Example 112a the title compound was prepared: 'HNMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 4H), 8.1-8.2 (m, 2H); 25 MS (EI): 523 (M+IT, 100%) . <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 523 (M+Hf,100%) and the slower eluting diastereomer MS(EI): 523 (M+H\100%). <br><br> 172 <br><br> WO 01/95911 PCT/USO 1/19062 <br><br> Example 113 <br><br> Preparation of 4.5-Dibromo-thiophene-2-carboxvlic acid f (SV3-methvl-1 -[3-oxo-1 -f 1 -oxv-pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvl) amide <br><br> 5 <br><br> a.) 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l~[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 85c except substituting 4,5-dibromo-thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound 10 was prepared: MS(EI) 668 (M+). <br><br> b.) 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> **Following the procedure of Example li except substuting 4,5-dibromo-15 thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 113a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 2H); MS(EI): 665 (M+ET,100%). <br><br> 20 <br><br> Example 114 <br><br> Preparation of 3.5-Dimethvl-isoxazole-4-carboxvlic acid ((SV3-methvl-l-r3-oxo-l-Cl-oxv-pvridine-2-sulfon vlVazepan-4-vlcarbamovn -butyl} amide a.) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 85c except substituting 3,5-dimethyl-isoxazole-4-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound 30 was prepared: MS(EI) 524 (M+H+). <br><br> 173 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-1 -[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting 3,5-dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl~l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-5 ylcarbamoyl]-butyl} amide of Example 114a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, 3H), 2.6 (m, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 521 (M\100%). <br><br> 0 Example 115 <br><br> Preparation of (S")-2-f2-Benzvloxv-acetvlamino)-4-methvl-pentanoic acidll-f4-methoxv-benzenesulfonvlV3-oxo-azepan-4-vll-amide <br><br> 5 a.) {(S)-l-[3-Hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid-ferr-butyl ester • <br><br> [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid-ferr-butyl ester (compound 2g, 0.8 g, 2.33 mmol) was dissolved in 1,2-dichloroethane (DCE, 20 ml). Then, morpholinemethyl polystyrene resin beads (1.26 g, 3.7 mmol/g, Nova) were ,0 added and the solution was shaken for 5 minutes. Then, p-methoxybenzenesulfonyl chloride (0.48 g, 2.33 mmol) 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 10 ml), then CHL,C12 (10 ml). The combined organics were concentrated in vacuo, and used in the next reaction without further purification: M+H+ = 514.2. <br><br> :5 <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-yl]-amide-HCl salt <br><br> {(S)-l-[3-Hydroxy-l-(4-methoxy-benzenesulfonyI)-azepan-4-ylcarbamoyl]-3-methyl-butyl} -carbamic acid-tert-butyl ester (compound 207a, 0.59 g, 1.15 mmol) was tO dissolved in CH2C12 (8 ml), then a solution of 4 M HCl 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+H* = 413.8. <br><br> 174 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> c.) (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-yl]-amide <br><br> (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(4-methoxy-benzenesulfonyl)-5 azepan-4-y 1]-amide-HCl salt (crude product from reaction mixture of 115b) was dissolved in MeOH (10 ml) and was treated with carbonate-polystyrene resin beads (1.75 g, 2.63 mmol/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 mmol/g, 0.91 mmol, 10 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 (O.lg, 3.66 mmol/g, 0.366 mmol) was added and the reaction mixture was shaken for 1.5 h. The reaction mixture was then filtered, washed with DCE (2x10 ml) and CH,C12 (10 ml), and the combined organics were concentrated in vacuo. The 15 crude product was used in the next reaction without further purification: M+H1" = 562.2. <br><br> d.) (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan- 4-yl]-amide <br><br> (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy-l-(4-20 methoxy-benzenesulfonyl)-azepan-4-yl]-amide (compound 207c, 0.24 g, 0.44 mmol) was dissolved in CH.,^ (5 ml), then Dess-Martin periodinane (0.3 g, 0.7 mmol) was added and the reaction was stirred for 30 min. The reaction was diluted with CH2C12 (20 ml), then was extracted with aqueous 10% Na2S205 (10 ml), then aqueous 10% NaHC03 (10 ml), water (10 ml), brine (10 ml). The combined organics were concentrated in vacuo. The residue 25 was purified by HPLC (50:50 Ethanol: hexanes, 20mL/min, 25min, WhelkO-l(R.R) <br><br> 21x250mm column, UV detection at 280nm and 305nm) to yield the first elution as a white solid (47 mg, 43 %): MS 560.4 (M+H+).1H NMR (400Hz,CDCl3): 8 7.73 (d, 2H), 7.40-7.30 (m, 5H), 7.05 (d, 2H), 3.99 (s, 2H), 3.88 (s, 3H), 2.28-2.10 (m, 2H), 0.95 (t, 6H) and second eluting diastereomer: MS 560.2 (M+H+). <br><br> 30 <br><br> 175 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 116 <br><br> Preparation of 5-G-Trifhioromethvl-phenvD-furan-2-carboxvlic acid KS")-3-methvl-l-r3-oxo-l-fl-oxv-pvridine-2-suIfonyr)-azepan-4-vlcarbamovl"l-butvI}aiiiide <br><br> 5 <br><br> a.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 85c except substituting 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title 10 compound was prepared: MS(EI) 638 (M+). <br><br> b.) 5-(3-Trifluoromethyl-:phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting 5-(3-trifluoromethyl-15 phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- <br><br> sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 116a the title compound was prepared: 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.1 (m, IH), 4,7 (t, IH), 4.8 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 9H), 8.1-8.2 (m, 2H); MS(EI): 637 (M+H\ 100%). <br><br> 20 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 637 (M+H+, 100%) and the slower eluting diastereomer MS(EI): 637 (M+H\ 100%) . <br><br> 25 <br><br> Example 117 <br><br> Preparation of 5-Methvl-2-phenvl-oxazole-4-carboxvlic acid f (S)-3-methvl-l-[3-oxo-l-f 1-oxv-pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butv1lamide a.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-30 oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 85c except substituting 5-methyl-2-phenyl-oxazole-4-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 585 (M+). <br><br> 176 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substuting 5-methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-5 azepan-4-ylcarbamoyl]-butyl} amide of Example 117a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H); MS(EI): 584 (M+H+, 100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 10 diastereoemer: MS(EI): 584 (M+H+, 100%) and the slower eluting diastereomer MS(EI): 584 (M+RT, 100%) . <br><br> Example 118 <br><br> 15 Preparation of Benzofuran-2-carboxvIic acid KSVl-f l-f3.4-dimethoxv-benzenesulfonvl&gt;3-oxo-azepan-4-vlcaTbamovll-batvn-amide a.) Benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} -amide <br><br> 20 To a solution of benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy- <br><br> benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide of Example 78c (0.175 g) in dichloromethane was added triethylamine (0.1 mL) and 3,4-dimethoxybenzenesulfonyl chloride (0.12 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dicloromethane) provided the title compound (0.21 g): 25 MS(EI) 587 (M+). <br><br> b.) Benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} -amide <br><br> Following the procedure of Example li except substuting benzofuran-2-carboxylic 30 acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}-amide of Example 118a the title compound was prepared:: :H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, IH), 3.5 (d, IH); 3.7 (t, 6H), 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 8H); MS(EI): 586 (M+lT, 100%). <br><br> 177 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 119 <br><br> Preparation of Benzofuran-2-carboxvlic acid I fSM-1" 1 -(4-bromo-benzenesulfonvl')-3-oxo-azepan-4-vlcarbamovn-3-methvl-but\'l^ -amide <br><br> 5 <br><br> a.) Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methy 1-butyl} -amide <br><br> Following the procedure of Example 118a except substituting 4-bromobenzenesulfonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the title 10 compound was prepared: MS(EI) 606 (M+). <br><br> b.) Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic 15 acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide of Example 119a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, IH), 3.5 (d, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 9H); MS(E1): 604 (M+, 100%). <br><br> 20 Example 120 <br><br> Preparation of Benzofuran-2-carboxvlic acid I CSV l-ri-fbenzor 1.2.51oxadiazole-4-sulfonvl)-3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvl 1 -amide <br><br> 25 a.) Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole-4-sulfonyl)-3-hy droxy-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide <br><br> Following the procedure of Example 118a except substituting benzofurazan-4-sulfonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the title compound was prepared: MS(EI) 569 (M+). <br><br> 30 <br><br> b.) Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> Following the procedure of Example li except substituting Benzoforan-2-carboxylic acid {(S)-1 -[ l-(benzo[ 1,2,5]oxadiazole-4-sulfonyl)-3-hydroxy-azepan-4- <br><br> 178 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> ylcarbamoyl]-3-methyl-butyl}-amide of Example 120a the title compound was prepared: 'H NMR (CDClj): 6 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, IH), 3.7 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); MS(EI): 568 (M+H+, 100%). <br><br> 5 Example 121 <br><br> Preparation of Benzofuran-2-carboxvHc acid I fSVl-Fl-C3.5-dimethv1-oxazole-4 -sulfonvlV <br><br> 3-oxo-azepan-4-vlcarbamovH-3-methvl-butvl) -amide <br><br> 10 a.) Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> Following the procedure of Example 118a except substituting 3,5-dimethyloxazole- <br><br> 4-sulphonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the title compound was prepared: MS(EI) 546 (M+)- <br><br> 15 <br><br> b.) Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)- l-[l-(3,5-dimethyl-oxazole-4-sulfonyl)-3-hydroxy-azepan-4-20 ylcarbamoyl]-3-methyl-butyl}-amide of Example 121a the title compound was prepared: 'H NMR (CDC1J: 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.4 (d, 3H), 2.7 (t, 3H), 3.6 (d, IH), 4.1 (m, IH), 4.4 (t, IH), 4.7 (m, IH), 5.2 (m, IH), 7.4-8.0 (m, 5H); MS(EI): 544 (M+, 100%). <br><br> 25 Example 122 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid I &lt;S)-3-methvl-l-f3-oxo-1 -fpvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvl \ amide <br><br> 30 a.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> 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 (M+). <br><br> 179 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> b.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide <br><br> Following the procedure of Example li except substituting 3-methylbenzofuran-2-5 carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- <br><br> ylcarbamoyl]-butyl} amide of Example 122a the title compound was prepared: 'H NMR (CDClj): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, IH), 3.8 (m, IH), 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 7H); 8.7 (m, IH); MS(EI): 540 (M\ 100%). <br><br> 10 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, IH), 3.8 (d, IH); 4.1 (d, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 7H); 8.7 (m, IH); MS(EI): 541 (M+H\100%) and the slower eluting diastereomer MS(EI): 541 (M+H\ 100%). <br><br> 15 <br><br> 20 <br><br> Example 123 <br><br> Preparation of Thienor3,2-blthiophene-2-carboxvlic acid {(S)-3-methyI-l-r3-oxo-l-(pyridine-2-sulfonvl'l-azeDan-4-vlcarbamovl"l-butvl \ amide a.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 28b except substituting thieno[3,2-bjthiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was 25 prepared: MS(EI) 550 (M+). <br><br> b.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting thieno[3,2-b]thiophene-30 2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- <br><br> ylcarbamoyl]-butyl}amide of Example 123a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (m, IH); MS(EI): 548 (M+, 100%). <br><br> 180 <br><br> WO 01/95911 PCT/US01/19062 <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: 'HNMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.7 (t, IH), 3.8 (d, IH); 4.1 (d, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (d, IH); MS(EI): 549 (M-fH\100%) and the slower eluting diastereomer MS(EI): 549 (M+H\ 100%). <br><br> 5 <br><br> 10 <br><br> Example 124 <br><br> Preparation of 5-ferf-ButvI-3-methvI-thienor3.2-blthiophene-2-carboxvlic acid l(S)-3-methvl- l-f3-oxo-l-f pyridine-2-sulfonvl)-azepan-4-vIcarbamovll-butvl) amide a.) 5-fe?t-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 5-tert-butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title 15 compound was prepared: MS (EI) 620 (M+). <br><br> b.) 5-rerr-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting 5-ferf-butyl-3-methyl-20 thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- <br><br> sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 124a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.45 (s, 9H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.4 (d, 3H), 2.7 (m, IH), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 4H); 8.7 (m, IH); MS(EI): 618 (M+, 100%). <br><br> 181 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 125 <br><br> Preparation of 5-Methvl-2-phenvl-oxazole-4-carboxvlic acid -f (S)-3-methvl-l-l"3-oxo-l-("PYridine-2-sulfonvD-azepan-4-vlcarbamovll-butvllamide <br><br> 5 <br><br> a.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 28b except substituting 5-methyl-2-phenyl-oxazole-4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was 10 prepared: MS(EI) 569 (M+). <br><br> b.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide <br><br> Following the procedure of Example li except substituting 5-methyl-2-phenyl-15 oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 125a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, IH), 2.6 (m, 3H), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (m, IH); MS(EI): 567 (M+, 100%). <br><br> 20 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 568 (M+H\100%) and the slower eluting diastereomer MS(EI): 568 (M+H\100%) <br><br> 25 <br><br> Example 126 <br><br> Preparation of 2-Phenvl-5-trifluoromethvl-oxazole-4-carboxvlic acid (fS)-3-methvl-l-[3-oxo-1 -(pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvl) amide a.) 2-Phenyl-5-trifluoromethyl-oxazoIe-4-carboxylic acid {(S)-3-methyl-l-[3-hydrox-l-30 (pyridine-2~sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 2-phenyl-5-trifluoromethyl-oxazoler4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 623 (M+). <br><br> 182 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> b.) 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydrox-l-(pyridine-2-5 sulfonyl)-azepan-4-ylcarbamoyI]-butyl Jamide of Example 126a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (m, IH); MS(EI): 621 (M+, 100%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting 10 diastereoemer: MS(EI): 622 (M+H\100%) and the slower eluting diastereomer: MS(EI): 622 (M+H\100%). <br><br> Example 127 <br><br> 15 Preparation of Ouinoline-2-carboxvlic acid lYSVl-(l-methanesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvll-amide <br><br> Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and 2-quinoline carboxylic acid for benzofuran-2-20 carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 475.2; ^H-NMR (400 MHz, CDCI3): • 8.65(d, IH), 8.35-8,28(q, 2H), 8.20-8.18(d, IH), 7.91-7.89(d, IH), 7.80-7.78(t, IH), 7.67-7.65(t, IH), 7.10(d, IH), 5.08(m, IH), 4.73 (m, IH), 4.56-4.51(d, IH), 4.00(m, IH), 3.67-3.62(d, IH), 2.91(s, 3H), 2.70(m, IH), 2.32-2.10(m, 2H), 1.95-1.40(m, 5H), 1.02-1.00(m, 6H); and the 25 second eluting diastereomer: MS (M+H+): 475.2 <br><br> Example 128 <br><br> Preparation of l-Methvl-lH-indole-2-carboxvlic acid IYS)-l-(l-methanesulfonvl-3-oxo-30 azepan-4-ylcarbamovI)-3-methvI-butvll-amide <br><br> Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and N-methylindole-2-carboxylic acid for <br><br> 183 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 477.2; ^H-NMR (400 MHz, cdci3): • 7.65-7.63(d, IH), 7.39-7.33(m, 2H), 7.17-7.14(1, IH), 6.98-6.95(m, 2H), 6.65(d, IH), 5.08(m, IH), 4.68 (m, IH) 4.56-4.52(d, IH), 4.03(m, 4H), 3.67-3.63(d, IH), 2.92(s, 3H), 5 2.71(m, IH), 2.32-2.10(m, 2H), 1.95-1.40(m, 5H), 1.02-1.00(d, 6H); and the second eluting diastereomer: MS (M+H+): 477.2 <br><br> Example 129 <br><br> 0 Preparation of Furan-2-carboxvlic acid (lYSVl-fl-methanesulfonvl-S-oxo-azepan-^-vlcarbamovl&gt;3-methvI-butvlcarbarriovn-methyl)-amide <br><br> Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine for benzofuran-5 2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 471.2; ^H-NMR (400 MHz, cdci3): • 7.50(m, IH), 7.15(m, IH), 7.05(m, IH), 6.90(d, IH), 6.55(m, 2H), 5.08(m, IH), 4.55 (m, 2H), 4.12(m, 2H), 4.05(m, IH), 3.70(d, IH), 2.92(s, 3H), 2.75(m, IH), 2.20-1.40(m, 7H), 0.95 (m, 6H); and the second eluting diastereomer: MS (M+H+): 471.4. <br><br> 0 <br><br> Example 130 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid [("SVl-(1-methanesulfonvl-3-oxo-azepan-4-vlcarbamovlV3-methvl-butvIl-amide <br><br> :5 <br><br> 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; MS (M+H+): 494.2; ^H-NMR (400 MHz, cdci3): • 10 7.42-7.40(d, 2H), 7.08-6.94(m, 4H), 5.10(m, IH), 4.71(m, IH), 4.56-4.52(d, IH), 4.02(m, IH), 3.86(s, 3H), 3.68-3.63(d, IH), 2.92(s, 3H), 2.72(m, IH), 2.30-1.15(m, 2H), 1.95-1.40(m, 5H), 0.99 (d, 6H); and the second eluting diastereomer: MS (M+H+): 494.2. <br><br> 184 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 131 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid r("S)-l-fl-methanesulfonvl-3-oxo-azepan-4-vlcarbamovD-3-methvl-butvll-amidp. <br><br> 5 <br><br> Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran-2-carboxyIic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 476.2; 1»-NMR (400 MHz, CDCI3): • 9.66(s, 10 IH), 8.38(d, IH), 8.20-8.18(m, 2H), 7.88(m, 2H), 7.01(d, IH), 5.10(m, IH), 4.77(m, IH), 4.57-4.52(d, IH), 4.08-4.00(m, IH), 3.69-3.64(d, IH), 2.92(s, 3H),2.71(m, IH), 2.42-2.15(m, 2H), 1.95-1.42(m, 5H), 1.02-1.01(d, 6H); and the second eluting diastereomer: MS (M+H+): 476.2. <br><br> 15 Example 132 <br><br> Preparation of 5-(4-Chloro-phenvlVfuran-2-carboxvlic acid {(SV3-methvl-l-[3-oxo-l-(pvridine-2-sulfonvl)-azetian-4-vlcarbamovl1-butvl} amide <br><br> 20 a.) 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyM-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 5-(4-chlorophenyl)-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 590 <br><br> (M+H+). <br><br> 25 <br><br> b.) 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting 5-(4-chloro-pheny 1)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-30 ylcarbamoyl]-butyl Jamide of Example 132a the title compound was prepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH), 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.7 (m, IH), 7.2 (m, IH), 7.3 (m, 2H), 7.5 (m, IH), 7.7 (m, 2H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 587 (M+, 80%) <br><br> 185 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 587 (M+H\100%) and the slower eluting diastereomer: MS(EI): 587 (M+H+,100%). <br><br> 5 Example 133 <br><br> Preparation of fS")-2-r2-(4-Methoxv-phenvD-acetvlamino)-4-methvl-pentanoic acid (1-methanesulfonvl-3-oxo-azepan-4-viVamide <br><br> 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 (M+H+): 468.2; ^H-NMR (400 MHz, CDCI3): • 7.19-7.17(d, 2H), 6.90-6.88(d, 3H), 5.83-5.81(d, IH), 5.00(m, IH), 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, IH), 2.22-2.10(m, 2H), 1.99( m, IH), 1.62-1.35(m, 4H), 0.90-0.88(d, 6H); and the second eluting diastereomer: MS (M+H+): 468.2. <br><br> Example 134 20. <br><br> Preparation of Ouinoline-2-carboxvlic acid f IYS)-l-ri-(2-cvano-benzenesulfonvD-3-oxo-azepan-4-vlcarbamovll -3-methvl-butvl) -amide <br><br> Following the procedure of Example 75, except substituting 2-cyanobenzenesulfonyl chloride for thiazole-2-sulfonyl chloride and quinoIine-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 562.2; ^H-NMR (400 MHz, CDCI3): • 8.65(d, 1H), 8.48-8.40(q, 2H), 8.25-8.10(q, 2H), 7.91-7.65(m, 6H); and the second eluting diastereomer:, 7.12(d, IH), 5.10(m, IH), 4.73 (m, IH) 4,61-4.56(d, lH),4.20(m, lH),3.73-3.68(d, IH), 2.80(m, IH), 2.27(m, 2H), 1.91-1.40(m, 5H), 1.03-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+): 562.2. <br><br> 186 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 135 <br><br> Preparation of 1-Methvl-lH-indole -2-carboxvlic acid irfSVl-ri-Q-cvano-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovn-3-methvl-butvll-amide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl 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 HPLC. First eluting diastereomer, MS (M+H+): 564.2; ^H-NMR 10 (400 MHz, CDCI3): • 8.13(d, 1H), 7.89(d, 1H), 7.77-7.67(m, 3H), 7.38-7.16(m, 4H), 6.97(s, IH), 6.70(d, IH), 5.05(m, IH), 4.70-4.60 (m, IH), 4.55-4.50(d, IH), 4.07(m, IH), 4.05(s, 3H), 3.76-3.71(d, IH), 2.75(m, IH), 2.30(m, 2H), 2.00-1.45(m, 5H), 1.00(d, 6H); and the second eluting diastereomer: MS (M+H+) 564.2. <br><br> 15 Example 136 <br><br> Preparation of Furan-2-carboxvlic acid (f fS)-l-ri-f2-cvano-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvlcarbamovl)-methvlVamide <br><br> 20 Following the procedure of Example 75, except substituting 2- <br><br> cyanophenylsulfonyl 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 (M+H+): 558.2; ^H-NMR (400 MHz, CDCI3): • 8.14-8.12(d, IH), 7.91-7.90(d, IH), 7.80-7.72(m, 2H), 7.48(s, IH), 7.14(d, 25 2H), 6.98(d, IH), 6.80(d, IH), 6.52-6.51(t, IH), 5.03(m, IH), 4.60-4.53 (m, 2H), 4.17-4.14(m, 3H), 3.74-3.69(d, IH), 2.80(m, IH), 2.25(m, 2H), 2.00-1.40(m, 5H), 1.03-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+) 558.2. <br><br> 187 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> Example 137 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid ((SM-ri-(2-cvano-benzenesulfonvD-3-oxo-azepan-4-y]carbamovll-3-methvl-butvI)-amide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2-carboxyUc acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 581.4; ^H-NMR <br><br> 10 (400 MHz, CDCI3): • 8.15-8.13(d, IH), 7.92-7.90(d, IH), 7.81-7.74(m, 2H), 7.42-7.40(m, 2H), 7.08-7.03(m, 3H), 6.96(d, IH), 5.10(m, IH), 4.72-4.60 (m, 2H), 4.17 (d, IH), 3.85(s, 3H), 3.75-3.70(d, IH), 2.83-2.76(t, IH), 2.27(m, 2H), 1.92-1.51(m, 5H), 1.02-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+) 581.2. <br><br> Preparation of Ouinoxaline-2-carboxvlic acid f (SV1 -I" 1 -("2-c vano-benzenesulfon vlV 3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide cyanophenylsulfonyl 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 (M+H+): 563.2; ^H-NMR (400 MHz, CDCI3): • 9.65(s, IH), 8.40(m, IH), 8.22-8.10(m, 3H), 7.90-7.22(m, 5H), 7.00(d, IH), 25 5.10(m, IH), 4.75(m, IH), 4.65-4.60(d, IH), 4.20-4.10(m, IH), 3.72-3.70(d, IH), 2.70(m, IH), 2.38(m, 2H), 1.95-1.40(m, 5H), 1.02(d, 6H); and the second eluting diastereomer: MS (M+H+) 563.2. <br><br> 15 <br><br> Example 138 <br><br> 20 <br><br> Following the procedure of Example 75, except substituting 2- <br><br> 188 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 139 <br><br> Preparation of (SV2-r2-f4-Methoxv-phenvl')-acetv]amino')-4-methvl-pentanoic acid fl-(2-cvano-benzenesulfonvD-3-oxo-azepan-4-v11-amida <br><br> 5 <br><br> 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 (M+H+): 555.2; iH-NMR (400 MHz, cdci3): • 10 8.14-8.12(d, IH), 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, IH), 5.02(m, IH), 4.59-4.55(d, IH), 4.45-4.42(m, IH), 4.18-4.15(m, IH), 3.82(s, 3H), 3.72-3.67(d, IH), 3.53(s, 2H), 2.82-2.79(t, IH), 2.22(m, 2H), 1.92( m, IH), 1.60-1.30(m, 4H), 0.91-0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 555.2. <br><br> 15 Example 140 <br><br> Preparation of Ouinoline-2-carboxvlic acid {r(S)-l-ri-f4-methoxv-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvI) -amide <br><br> 20 Following the procedure of Example 75, except substituting 4- <br><br> methoxybenzenesulfonyl 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 (M+H+): 567.2; *H-NMR (400 MHz, cdci3): • 8.72-8.61(d, IH), 8.35-8.28(q, 2H) 8.21-8.18(d, IH), 7.91-7.60(m, 25 5H), 7.10-6.99(m, 3H), 5.05(m, IH), 4.73 (m, IH) 4,59-4.52(d, lH),4.00(m, IH), 3.88(s, 3H), 3.45-3.38(d, IH), 2.42(m, IH), 2.30-1.35 (m, 7H), 1.03-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+) 567.2. <br><br> 189 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 141 <br><br> Preparation of 1-Methyl-lH-indole-2-carboxvlic acid &lt; IYS")-l-ri-(4-methoxv-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl}-amide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methyl-indole-2-carboxylic acid for benzofuran-2-caiboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 569.2; ^H-NMR 10 (400 MHz, cdci3): • 7.78-7.72(d, 2H), 7.70-7.65(d, IH), 7.42-7.30(m, 2H), 7.17-7.14(t, IH), 7.05-6.95(m, 4H), 6.65(d, IH), 5.05(m, IH), 4.70-4.50 (m, 2H), 4.03(s, 3H), 3.88(s, 3H), 3.45-3.40(d, IH), 2.45(m, IH), 2.30-2.10(m, 2H), 1.90-1.35(m, 6H); and the second , eluting diastereomer:, 1.00(d, 6H); and the second eluting diastereomer: MS (M+H+) 569.2. <br><br> 15 <br><br> 20 <br><br> Example 142 <br><br> Preparation of Furan-2-carboxvlic acid (((SVl-ri-(4-methoxv-benzenesulfonvl')-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvlcarbamovll-methvD-amide <br><br> Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl 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 (M+H+): 563.2; ^H-NMR (400 25 MHz, cdci3): • 7.74-7.72(d, 2H), 7.47 (s, IH), 7.15-6.99(m, 4H), 6.91(d, IH), 6.70(d, IH), 6.52-6.5l(m, IH), 5.01(m, IH), 4.53-4.49 (m, 2H), 4.17-4.14(m, 2H), 4.00-3.90(m, IH), 3.88(s, 3H), 3.45-3.41(d, IH), 2.47(m, IH), 2.17(m, 2H), 1.85-1.40(m, 5H), 0.95(m, 6H); and the second eluting diastereomer: MS (M+H+) 563.2. <br><br> 190 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 143 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid f r.fS)-l-l"l-('4-methoxv-benzenesulfonvI)-3-oxo-azepan-4-vlcarhamovn-3-methvl-butvl)-amide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl 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; MS 10 (M+H+): 586.2; *H-NMR (400 MHz, CDC13): • 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(m, 2H), 4.05-4.00(m, IH), 3.89(s, 3H), 3.86(s, 3H), 3.45-3.40(d, IH), 2.50-2.40(m, IH), 2.30-2.10(m, 2H), 1.90-1.35(m, 5H), 1.01(m, 6H); and the second eluting diastereomer; MS (M+H+) 586.2. <br><br> 15 Example 144 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid {r(S)-l-ri-(4-methoxv-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvn-amide <br><br> 20 Following the procedure of Example 75, except substituting 4- <br><br> methoxyphenylsulfonyl 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 (M+H+): 568.2; ^H-NMR (400 MHz, cdci3): • 9.66(s, IH), 8.40-8.35(m, IH), 8.19(m, 2H), 7.88(m, 2H), 7.75-25 7.73(d, 2H), 7.02-6.90(m, 3H), 5.10-5.05(m, IH), 4.75(m, IH), 4.60-4.55(d, IH), 4.05-3.95(m, IH), 3.89(s, 3H), 3.45-3.41(d, IH), 2.45(m, IH), 2.30-2.10(m, 2H), 1.95-1.40(m, 5H), 1.04-1.02(d, 6H); and the second eluting diastereomer: MS (M+H+) 568.2. <br><br> 191 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 145 <br><br> Preparation of fS)-2-\2-(4-Methoxv-DhenvlVacetvIamino')-4-methvl-pentanoic acid ri-C4— methoxv-benzenesuIfonvr)-3-oxo-azeDan-4-vn-amide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl chloride for thiazole-2-suIfonyl 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 (M+H+): 560.4; ^H-NMR 10 (400 MHz, CDC13): • 7.74-7,71(d, 2H), 7.19-7.17(d, 2H), 7.01-6.99(d, 2H), 6.90-6.88(d, . 2H), 6.85(d, IH), 5.81(d, IH), 4.99(m, IH), 4.55-4.44(m, 2H), 3.97(m, IH), 3.88(s, 3H), 3.81(s, 3H), 3.53(s, 2H), 3.43-3.38(d, IH), 2.43(t, IH), 2.14(m, 2H), 1.85-1.35(m, 5H), 0.90-0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 560.2. <br><br> 15 Example 146 <br><br> Preparation of l-Methvl-lH-indoIe-2-carboxvlic acid f r(S)-l-ri-f4-fluoro-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvn-amide <br><br> 20 Following the procedure of Example 75, except substituting 4- <br><br> fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methyl-indole-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 557.2; ^H-NMR (400 MHz, cdci3): • 7.84-7.80(m, 2H), 7.66-7.65(d, IH), 7.40-7.14(m, 5H), 6.95(m, 2H), 25 6.65-6.63(d, IH), 5.07(m, IH), 4.68-4.55 (m, 2H), 4.04(s, 3H), 3.48-3.43(d, IH), 2.49(m, IH), 2.25(m, 2H), 1.89-1.38(m, 6H); and the second eluting diastereomer:, 1.01(d, 6H); and the second eluting diastereomer: MS (M+H+) 557.4. <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 147 <br><br> Preparation of Furan-2-carboxvlic acid ClfSVl-f l-(4-fluoro-benzenesulfonvlV3-oxo-azepan-4-vlcaTbamovl1-3-methvl-butvlcarbamovll-metbvlVamide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for thiazoIe-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 (M+H+): 551.4; ^H-NMR (400 10 MHz, CDC13): 7.81(m, 2H), 7.48(s, IH), 7.27-7.16(m, 3H), 7.05(m, IH), 6.90(d, IH), <br><br> 6.52(m, 2H), 5.00(m, IH), 4.60-4.48 (m, 2H), 4.14(m, 2H), 4.00-3,90(d, IH), 3.48-3.44(d, IH), 2.50(m, IH), 2.20(m, 2H), 1.90-1.40(m, 5H), 0.95(m, 6H); and the second eluting diastereomer: MS (M+H+) 551.2. <br><br> 15 Example 148 <br><br> Preparation of 5-Methoxvbenzofaran-2-carboxvlic acid 11"fS)-l-ri-C4-fluoro-benzenesulfonvl)-3-oxo-azepan-4-yIcarbamovll-3-methvl-butvI}-amide <br><br> 20 Following the procedure of Example 75, except substituting 4- <br><br> fluorophenylsulfonyl 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; MS (M+H+): 574.2; ^H-NMR (400 MHz, cdci3): • 7.84-7.81(m, 2H), 7.42-7.40(m, 2H), 7.27-7.22(m, 2H), 7.08-7.04(m, 25 3H), 6.93(d, IH), 5.10-5.02(m, IH), 4.69-4.55(m, 2H), 4.05-4.00(m, IH), 3.86(s, 3H), 3.47-3.43(d, IH), 2.49(m, IH), 2.24(m, 2H), 1.90-1.40(m, 5H), 1.01(m, 6H); and the second eluting diastereomer: MS (M+H+): 574.2 <br><br> 193 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 149 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid f 1YSV1 -fl-(4-fluoro-benzenesulfonvl&gt;3-oxo-azepan-4-vlcarbamovll-3-methvl-butv11 -ami de <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl 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 (M+H+): 556.2; 1H-NMR 10 (400 MHz, CDC13): • 9.66(s, IE), 8.40-8.35(d, IH), 8.21-8.18(m, 2H), 7.90-7.81(m, 4H), 7.27-7.22(m, 2H), 6.97(d, IH), 5.10-5.02(m, IH), 4.75(m, IH), 4.59-4.55(d, IH), 4.05-4.39(m, IH), 3.48-3.44(d, IH), 2.49(m, IH), 2.32-2.10(m, 2H), 1.90-1.40{m, 5H), 1.03-1.02(d, 6H); and the second eluting diastereomer. MS (M+H+) 556.2. <br><br> 15 Example 150 <br><br> Preparation of fS)-2-f2-C4-Methoxv-DhenvlVacetvlamino')-4-methvl-pentanoic acid \l-(4-fluoro-benzenesulfonvlV3-oxo-azepan-4-vll-amide <br><br> 20 Following the procedure of Example 75, except substituting 4- <br><br> fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyI)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 548.2; ^H-NMR (400 MHz, cdci3): • 7.83-7.80(m, 2H), 7.27-7.17(m, 4H), 6.90-6.88(d, 3H), 5.85(d, IH), 25 4.98(m, IH), 4.55-4.43(m, 2H), 4.00-3.97(m, IH), 3.81(s, 3H), 3.53(s, 2H), 3.45-3.41(d, IH), 2.48(t, IH), 2.17-2.14(m, 2H), 1.90-1.30(m, 5H), 0.90-0.88(d, 6H); and the second eluting diastereomer: MS (M+H+): 548.4. <br><br> 194 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 151 <br><br> Preparation of Benzofaran-2-carboxvlic acid-i(S~)-l-ri-(3-chloro-benzenesulphonvlV3-oxo-azepan-4-YlcarbamovH-3-methvI-hutvB-amide <br><br> 5 <br><br> a.) {(S)-l-[l-(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 2g (2.50g, 7.29mmol) in DCE (100ml) was added P-NMM (4.0g) and 3-chlorobenzenesulphonyl chloride (1.85g, 8.75mmol). 10 After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (3.13g, 83.3%). MS: 539.78 (M+Na)+. <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-chloro-benzenesulfonyl)-3-hydroxy-15 azepan-4-yl]-amide <br><br> To a stirring solution of the compound of Example 151a (l.Og, 1.93mmol) in methnol (10 ml) was added HCl (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-C03 (2.85g, 20 2.63mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.59 g, 1.42 mmol, 95%). MS: 417.86 (M+H)\ <br><br> c.) Benzofuran-2-carboxylic acid- {(S)- l-[l-(3-chloro-benzenesulphonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> 25 To a solution of the compound of Example 151b (0.14 g, 0.33 mmol) in CH2C12 (20 <br><br> mL) was added benzofuran-2-carboxylic acid (0.81,0.50 mmol), 1-hydroxybenzotriazole (0.77 g, 0.57 mmol), and P-EDC (0.67g, 1 mmol/g) in CHjCl^ (10 mL). After shaking at room temperature overnight, the solution was treated with tisamine (0.45 g, 3.75 mmol/g). After shaking for another 2 hr, the solution was filtered and concentrated to yield the title 30 compound as a white solid (122 mg, 65%). MS (ESI): 562.2 (M+H)+. <br><br> 195 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> d.) Benzofuran-2-carboxylic acid-{(S)-l~[l-(3-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyI}-amide <br><br> To a stirring solution of the compound of Example 151c (122 mg, 0.22 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (185 mg, 0.44 mmol). After 5 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 layer was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgS04), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (62.7 10 mg, 51.6%), MS (ESI): 560.2 (M+H)+and the second eluting diastereomer as a white solid (40.2 mg, 33.1 %). MS (ESI): 560.2 (M+H)+ <br><br> Example 152 <br><br> 15 Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid-l(S)-l-ri-(3-chloro-benzsnesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the procedure of Example 151c-d, except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylie acid of Example 151c 20 provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (64.4 mg, 50.3%): MS (ESI): 590.2 (M+H)+ and the second eluting distereomer as a white solid (44.4 mg, 34.7%): MS (ESI): 590.2 (M+H)+ <br><br> Example 153 <br><br> 25 Preparation of 7-Methoxvbenzofuran-2-carboxvlic acid-( (SVl-fl-(3-chloro-benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvll-amide <br><br> Following the procedure of Example 151c-d except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151c 30 provided the title compound which was separated by HPLC to give first eluting diastereomer as a white solid (51.1mg, 39.9%), MS (ESI): 590.2 (M+H)+ and the second eluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 590.2 (M+H)+ <br><br> 196 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 154 <br><br> Preparation of 5.6-Dimethoxvbenzofaran-2-carboxvlic acid-KSM-IT-G-chloro-benzenesulphonvl")-3-oxo-azepan-4-vl carbamoyl! -3-methvl-butyl} -amide <br><br> 5 Following the procedure of Example 15 lc-d except substituting 5,6- <br><br> dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151c provided the title compound which was separated by HPLC to give first eluting diastereomer as a white solid (51.1mg, 39.9%), MS (ESI): 622.2 (M+H)+ and the second eluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 622.2 (M+H)+ <br><br> 10 Example 155 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid-f (S)-l-ri-(3-chloro-benzenesulphonvl)-3-oxo-azepan-4-vlcarbamoyl"l-3-methvl-butyn-aimde <br><br> 15 Following the procedure of Example 15 lc-d except substituting 3- <br><br> methylbenzofuran-2-carboxyIic 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 (78.6mg, 63.1%), MS (ESI): 574.2 (M+H)+ and the second eluting diastereomer as a white solid (40.7mg, 32.6%). MS (ESI): 574.2 (M+H)+ <br><br> 20 Example 156 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-ifSM-IT-G-chloro-benzenesulphonvlV3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvl'&gt;-amide <br><br> 25 Following the procedure of Example 15 lc-d except substituting benzo[b]thiophene- <br><br> 2-carboxylic 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 (41.0 mg, 32.8%), MS (ESI): 576.2 (M+H)+ and the second eluting diastereomer as a white solid (31.0 mg, 24.8%). MS (ESI): 576.4 (M+H)+ <br><br> 30 <br><br> 197 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 157 <br><br> Preparation of l-Methvl-lH-indole-2-carboxvlic acid-( (S)-l-ri-f3-chloro-benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the procedure of Example 15 lc-d except substituting l-methylindole-2-carboxylic 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 mg, 22.9%), MS (ESI): 573.2 (M+H)+ and the second eluting diastereomer as a white solid (28.5mg, 22.9%). MS (ESI): 573.2 (M+H)+ <br><br> Example 158 <br><br> Prepaxation of Ouinoxaline-2-carboxvlic acid-{(S)-l-fl-(3-chloro-benzenesulphonvD-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl I -amide <br><br> Following the procedure of Example 15 lc-d except substituting quinoxaline-2-carboxylic 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 (63.1 mg, 50.8%), MS (ESI): 572.2 (M+H)+ and the second eluting distereomer as a white solid (43.2 mg, 34.8%), MS (ESI): 572.2 (M+H)+ <br><br> Example 159 <br><br> Preparation of Benzofuran-2-carboxvlic acid-f (S)-l-ri-(2-fluoro-benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvl)-amide a.) {(S)-l-[l-(2-Fluoro-benzenesulfonyI)-3-hydroxy-azepan-4-ylcarbamoyI]-3-methyI-butylj-carbamic acid ten-butyl ester <br><br> To a solution of the compound of Example 2g (1.03 g, 3.00 mmol) in DCE (20 ml) was added P-NMM (1.65 g, 3.64 mmol/g) and 2-fluorobenzenesulphony 1 chloride (0.70 g, 3.60 mmol). After shaking at room temperature overnight, the solution was filtered. The <br><br> 198 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> filtrate was concentrated to yield the title compound as white solid (1.13 g, 75.1%): MS: 523.88 (M+Na)+. <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [l-(2-fluoro-benzenesulfonyl)-3-hydroxy-5 azepan-4-yl]-amide <br><br> To a stirring solution of the compound of Example 159a (1.13 g, 2.25 mmol) in methnol (15 ml) was added HCl (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-C03 (5.70 g, 2.63 10 mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.868g, 2.16mmol, 96%): MS: 401.96 (M+H)+. <br><br> c.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> 15 To a solution of the compound of Example 159b (0.11 g, 0.26 mmol) in CH,C12 (10 <br><br> mL) was added benzofuran-2-carboxylic acid (64.7 mg, 0.39 mmol), 1-hydroxybenzotriazole (61. lg, 0.45 mmol), and P-EDC (0.53 g, 1 mmol/g) in CH2C12 (10 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 20 concentrated to yield the title compound as a white solid (103.5 mg, 70%): MS (ESI) 546.2 (M+H)+ <br><br> d.) Benzofuran-2-carboxylic acid-{(S)-l-fl-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> 25 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 (2x). The organic phases were 30 combined, washed with saturated brine, dried (MgS04), 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)+ <br><br> 199 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> Example 160 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid-i (S)-l-IT-(2-fluoro-5 benzenesulphonvI")-3-oxo-azepan-4-vlcarhamov11-3-methvl-butvl}-amide <br><br> Following the procedure of Example 159c-d, except substituting 5-methoxybenzofuran-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 10 diastereomer as a white solid (48.3 mg, 59.2%) MS (ESI): 574.2 (M+H)+ and the second eluting diastereomer as a white solid (24.2mg, 29.6%) MS (ESI): 574.2 (M+H)+ <br><br> Example 161 <br><br> Preparation of 7-Methoxvbenzofuran-2-carboxvIic acid-i (S)-l-f l-(2-fluoro-15 benzenesulphonvD-3-oxo-azepan-4-ylcarbamovn-3-methvl-butvll-amide <br><br> Following the procedure of Example 159c-d except substituting 7-methoxybenzofuran-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 20 - diastereomer as a white solid (47.7 mg, 58.5%): MS (ESI) 574.2 (M+H)+ and the second eluting diastereomer as a white solid (27.7 rag, 33.9%). <br><br> Example 162 <br><br> Preparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acid-iCSVl-ri-(2-fluoro-25 benzen&amp;sulphonvl)-3-oxo-azepari-4-v]carbamovll-3-methvl-butvB-amide <br><br> Following the procedure of Example 159c-d except substituting 5,6-dimethoxybenzofiiran-2-carboxylic acid for benzofuran-2-carboxy]ic acid in step 159c provided the title compound which was separated by HPLC to give the first eluting 30 diastereomer: MS (ESI) 606.4 (M+H)+ and the second eluting diastereomer as a white solid MS(ESI) 606.4 (M+H*). <br><br> 200 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 163 <br><br> Preparation of 3-Methvlbenzofiiran-2-carboxvlic acid-((SM-ri-f2-fluoro-benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl}-amide <br><br> 5 <br><br> Following the procedure of Example 159c-d except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 160c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (50.5 mg, 63.7%): MS (ESI) 558.2 and the second elutinfg 10 diastereoemer as a white solid (20.6 mg); MS 558.2 (M+H)+. <br><br> Example 164 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-{(S)-l-l"l-(2-fluoro-15 benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvll-amide <br><br> Following the procedure of Example 159c-d except substituting benzo[b]thiophene-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 20 solid (52.5 mg, 65.9%): MS (ESI) 560.2 (M+H)+ and the second eluting diastereomer as a white solid (20.7mg, 26.0%): MS(ESI) 560.2 (M+H)+. <br><br> Example 165 <br><br> 25 Preparation of l-Methvl-lH-indole-2-carboxvlic acid~j(S)-l-ri-(2-fluoro-benzenesulphonvl")-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> Following the procedure of Example 159c-d except substituting l-methyIindoIe-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compound 30 which was separated by HPLC to give the first eluting diastereomer as a white solid (51.4 mg, 64.9%): MS (ESI) 557.2 (M+H)+ and the seond eluting diastereoemer as a white solid (21.0 mg, 26.5%): MS 557.2 (M+H)+. <br><br> 201 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 166 <br><br> Preparation of CSV4-Methvl-2-(l-oxv-pvridiTie-2-sulfonvlaminoVpentanoic acid f3-oxo-l-fpvridine-2-sulfonvI)-azepan-4-vll-amide <br><br> 5 a.) (S)-4-Methyl-2-(l-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> To a solution of the compound of Example 28a (0.1 g) in dichlorormethane (10 mL) and saturated NaHC03 was added 2-pryridinesulfonyl chloride N-oxide (0.9 mL) in a dropwise fashion over 3 minutes. The reaction was stirred at room temperature for 30 0 minutes. Workup and columnn chromatography provided 9.2 mg of the title compound: MS (ESI) 541 (M+H*). <br><br> b.) (S)-4-Methyl-2-(l~oxy-pyridine-2-sulfonylammo)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substituting the compound of 5 Example 166a the title compound was prepared: MS (ESI) 539 (M+H+)- <br><br> Example 167 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid-{ (SV1 -I"! -(2-fluoro-benzenesuk&gt;honvIV3-oxo-0 azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> Following the procedure of Example 159c-d except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compound which was purified by HPLC to give the first eluting diastereomer as a white solid (49.7 5 mg, 62.9%): MS (ESI) 556.2 (M+H)+ and the second eluting diastereomer as a white solid (19.9 mg, 25.1%): MS 556.4 (M+H)+. <br><br> Example 168 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid-{(SV3-msthvl-l-("3-oxo-l-i0 (thiophene-2-sulfonvlVazepan-4-vlcarbamovll-butvn-amide <br><br> Following the procedure of Example 75a-d except substituting 2-thiophensulfonyl chloride for 2-thiazolesupfonyl chloride of Example 75a and 5-methoxybenzofuran-2- <br><br> 202 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was purified by HPLC to give the first eluting diastereomer as a white solid (71 mg, 65%): MS (ESI) 562.2 (M+H)+ and the second eluting diastereomer as a white solid (21.6 mg, 20.0%) MS (ESI): 562.2 (M+H)+. <br><br> Example 169 <br><br> Preparation of 7-Methoxvbenzofuran-2-carboxvlic acid-{(S)-3-methvl-l-f3-oxo-l-(thiophene-2-sulfonvl")-azepan-4~vlcarbamovn-butvll-amide <br><br> Following the procedure of Example 168 except substituting 7-methoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which ws purified by HPLC to give the first eluting diastereomer as a white solid (88 mg, 80%): MS (ESI) 562.2 (M+H)+ and the second eluting diastereomer as a white solid (18 mg, 16%) MS (ESI): 562.2 (M+H)+. <br><br> Example 170 <br><br> Preparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acid-l(SV3-methvl-l-r3-oxo-l-(thiophene-2-sulfonvl)-azepan-4-vlcarbamovn-butvl}-amide <br><br> Following the procedure of Example 168 except substituting 5,6-dimethoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was purified by HPLC to give the first eluting diastereomer MS (ESI) 594.2 (M+H)"1" and the second eluting diastereomer. <br><br> Example 171 <br><br> Preparation of 3-Methvlbenzofaran-2-carboxvlic acid-{(S)-3-methvl-l-r3-oxo-l-(thiophene-2-sulfonvl"&gt;-azepan-4-vlcarbamovll-butvll-amide <br><br> Following the procedure of Example 168 except substituting 3-methybenzofuran-2-carboxylic 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, 83%): MS (ESI) 546.2 (M+H)+ and the second eluting diastereomer as a white solid (16 mg, 15%): MS (ESI) 546.2 (M+H)+. <br><br> 203 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> 10 <br><br> Example 172 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-i fS)-3-methvl-l-f3-oxo-l-(thiophene-2-sulfonvlVazepan-4-vlcarbamovll-butv1)-amide. <br><br> Following the procedure of Example 168 except substituting benzo[b]thiophene-2-carboxylic 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, 41%): MS (ESI) 548.4 (M+H)+ and the second eluting diastereomer as a white solid (33.4 mg, 31.5%): MS (ESI) 548.2 (M+H)+. <br><br> Example 173 <br><br> Preparation of 1 -Methyl-1 H-indole-2-carboxvlic acid- (CS)-3-methvl- 1-f3-oxo-1 -(thiophene-2-sulfonvlVazepan-4-vlcarbamovll-butvl)-amide <br><br> 15 Following the procedure of Example 168 except substituting l-methylindole-2- <br><br> carboxylic 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 mg, 34.0%): MS (ESI) 545.2 (M+H)+ and the second eluting diastereomer as a white solid (45.8 mg, 43%): MS (ESI) 545.2 (M+H)+. <br><br> 20 <br><br> Example 174 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid-f fS)-3-methvl-1 -f3-oxo-1 -(thiophene-2-sulfonvl)-azepan-4-vlcarbamovll-butvl)-amide <br><br> 25 Following the procedure of Example 168 except substituting quinoxaline-2- <br><br> carboxylic 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 (60 mg, 56%): MS (ESI) 544.4 (M+H)+ and the second eluting diastereomer as a white solid (38.7 mg, 37%): MS (ESI) 544.4 (M+H)+ <br><br> 30 <br><br> 204 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 175 <br><br> Preparation of Benzofuran-2-carboxvlic acid-(fSVl-ri-C4-chloro-benzenesuIphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl) -amide <br><br> 5 <br><br> a-) {(S)-l-[l-(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid terr-butyl ester <br><br> To a solution of the compound of Example 2g (2.50 g, 7.29mmol) in DCE (100 ml) was added P-NMM (4.0g) and 4-chlorobenzenesulphonyl chloride (1.85g, 8.75mmol). 10 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, 83.3%). MS: 539.78 (M+Na)+. <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-chloro-benzenesulfonyl)-3-hydroxy-15 azepan-4-yl]-amide <br><br> To a stirring solution of the compound of example 175a (1.0 g, 1.93mmol) in methnol (10 ml) was added HCl (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-COa (2.85 g, 20 2.63 mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.59 g, 1.42 mmol, 95%): MS: 417.86 (M+H)\ <br><br> c.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulphonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> 25 To a solution of the compound of Example 175b (0.14 g, 0.335 mmol) in CH2C12 <br><br> (20 mL) was added benzofuran-2-carboxylic acid (0.81, 0.50 mmol), 1-hydroxybenzotriazole (0.77g, 0.569mmol), and P-EDC (0.67g, lmmol/g) in CH2C12 (10 mL). After shaking at room temperature overnight, the solution was treated with tisamine (0.446 g, 3.75 mmol/g). After shaking for another 2 hr, the solution was filtered and 30 concentrated to yield the title compound as a white solid (122.2 mg, 65%). MS (ESI): 562.2 (M+H)+. <br><br> 205 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> d.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl} -amide <br><br> To a stirring solution of the compound of Example 175c (122.2mg, 0.217mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (184.8mg, 0.436mmol). After 5 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 (2x). The organic phases were combined, washed with saturated brine, dried (MgS04), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid 10 (62.7mg, 51.6 %): MS (ESI) 560.2 (M+H)+and the second elution as a white solid (32.7mg, 26.9 %): MS (ESI) 560.2 (M+H)+. <br><br> Example 176 <br><br> 15 • Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid-f(S)-l-ri-(4-chloro-benzenesulphon vl V3-oxo-azepan-4-vlcarbamovll -3 -methyl-butyl)-ami de <br><br> Following the procedure of Example 175c-d except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c 20 provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (64.4 mg, 50%): MS (ESI) 590.2 (M+H)+ and the second eluting diastereoemer as a white solid (32.2 mg, 25.2%): MS (ESI) 590.0 (M+H)+. <br><br> Example 177 <br><br> 25 <br><br> Preparation of 7-Methoxybenzofuran-2-carboxvIic acid-{(S")-l-ri-(4-chloro-benzenesulphonvl V3-oxo-azepan-4-vlcarbamovn-3-methvl-butvl 1 -amide <br><br> Following the procedure of Example 175c-d except substituting 7-30 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 (51.1 mg, 40%): MS (ESI) 590.2 (M+H)+ and the second eluting diastereoemer as a white solid (41 mg, 32%): MS (ESI) 590.2 (M+H)+. <br><br> 206 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 178 <br><br> Preparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acid-{(S)-l-fl-(4-chloro-5 benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the procedure of Example 175c~d except substituting 5,6-dimethoxybenzofuran-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 10 diastereomer: MS (ESI) 622.2 (M-t-H)"1" and the second eluting diastereoemer: MS (ESI) 622.2 (M+H)+. <br><br> Example 179 <br><br> 15 Preparation of 3-Methvlbenzofuran-2-carboxvlic acid-{ (S)-l-lT-(4-chloro-benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the procedure of Example 175c-d except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c 20 provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (78.6 mg, 63%): MS (ESI) 574.2 (M+H)+ and the second eluting diastereoemer as a white solid (27.6 mg, 22%): MS (ESI) 574.2 (M+H)+. <br><br> Example 180 <br><br> Preparation of Benzorblthiophene-2-carboxylic acid- f f S)-1 -I" 1 -f4-chloro-benzenesulphonvlV3-oxo-azepan-4-vlcarbamoyll-3-methvl-butvll-amide <br><br> Following the procedure of Example 175c-d except substituting benzo[b]thiophene-30 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 (41 mg, 33%): MS (ESI) 576.2 (M+H)+ and the second eluting diastereoemer as a white solid (32.6 mg, 26%): MS (ESI) 576.2 (M+H)+. <br><br> 207 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 181 <br><br> Preparation of l-Methvl-lH-indole-2-carboxvlic acid-i (S")-l-lT-(4-chIoro-5 benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the procedure of Example 175c-d except substituting l-methylindole-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 (28.5 10 mg, 23%): MS (ESI) 573.2 (M+H)+ and the second eluting diastereoemer as a white solid (38.5 mg, 31%): MS (ESI) 573.2 (M+H)+. <br><br> Example 182 <br><br> 15 Preparation of Ouinoxaline-2-carboxvlic acid-f (S&gt;l-ll-f4-chloro-benzenesulphonvD-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvn-amide <br><br> Following the procedure of Example 175c-d except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound 20 which was separated by HPLC to give the first eluting diastereomer as a white solid (63 mg, 51%): MS (ESI) 572.2 (M+H)+ and the second eluting diastereoemer as a white solid (44.5 mg, 36%): MS (ESI) 572.2 (M+H)+. <br><br> Example 183 <br><br> Preparation of Benzofiiran-2-carboxvlic acid-i (S)-l-ri-f3-methoxv-benzenesuiphonvD-3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvll-amide a.) {(S)-l-[l-(3-Methoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-30 methyl-butyl }-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 2g (1.60g, 4.66mmol) in DCE (50ml) was added P-NMM (2.56g, 3.64mmol/g ) and 3-methoxy-benzenesulphonyl chloride (1.15g, 5.59mmol). After shaking at room temperature for over night, the solution was <br><br> 208 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> filtered. The filtrate was concentrated to yield the title compound as white solid (1.70g, 71.1%): MS 535.8 (M+Na)\ <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-methoxy-benzenesulfonyl)-3-hydroxy-5 azepan-4-yl3-amide <br><br> To a stirring solution of the compound of example 183a (1.70 g, 3.31mmol) in methnol (22 ml) was added HCl (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-C03 (5.02 g, 2.63 10 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, 96%): MS 413.90 (M+H)+. <br><br> c.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> 15 To a solution of the compound of Example 183b (0.11 g, 0.26 mmol) in CH2C12 (10 <br><br> mL) was added benzofuran-2-carboxylic acid (64.69mg, 0.399 mmol), 1-hydroxybenzotriazole (61.lg, 0.452mmol), and P-EDC (0.532g, lmmol/g) in CH2CL, (10 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 20 concentrated to yield the title compound as a white solid (103.5 mg, 70%): MS (ESI) 558.2 (M+H)+. <br><br> d.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> 25 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 (2x). The organic phases were 30 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)+ <br><br> 209 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 184 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid-i (S)-l-fl-(3-methoxv-5 benzenesulphonvlV3-ox.o-azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> Following the procedure of Example 183c-d except substituting 5-methoxybenzofuran-2-carboxylic 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 (33 mg, 31%): MS (ESI) 586.2 (M+H)+ and the second eluting diastereoemer as a white solid (35.2 mg, 32%): MS (ESI) 586.2 (M+H)+. <br><br> Example 185 <br><br> 15 Preparation of 7-Methoxvbenzofuran-2-carboxvlic acid-1 (SVl-H -(3-methoxv-benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvIl-amide <br><br> Following the procedure of Example 183c-d except substituting 1-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c 20 provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (41 mg, 38%); MS (ESI) 586.4 (M+H)+ and the second eluting diastereoemer as a white solid (39.5 mg, 36%): MS (ESI) 586.2 (M+H)+. <br><br> Example 186 <br><br> Preparation of 4.5-Dimethoxvbenzofuran-2-carboxvlic acid-i fS&gt;l-ri-(3-methoxv-benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> Following the procedure of Example 183c-d except substituting 5,6-30 dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MS (ESI) 618.4 (M+H)+ and the second eluting diastereoemer. <br><br> 210 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 187 <br><br> Preparation of 3-MethvIbenzofuran-2-caiboxvlic acid-1 fSVl-ri-f3-methoxv-benzenesulphonvD-3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvl}-amide <br><br> 5 <br><br> Following the procedure of Example 183c-d except substituting 3-methylbenzofuran-2-carboxylic 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 (76 mg, 72%): MS (ESI) 570.2 (M+H)+ and the second 10 eluting diastereoemer as a white solid (23.2 mg, 22%): MS (ESI) 570.2 (M+H)+. <br><br> Example 188 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-f (S)-l-ri-(3-methoxv-15 benzenesulphon vl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl I -amide <br><br> Following the procedure of Example 183c-d except substituting benzo[b]thiophene-2-carboxylic 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 20 solid (37 mg, 35%): MS (ESI) 572.2 (M+H)+and the second eluting diastereoemer as a white solid (31 mg, 29%): MS (ESI) 572.2 (M+H)+. <br><br> Example 189 <br><br> 25 Preparation of l-Methvl-lH-indole-2-carboxvlic acid-( CSV 1-[1 -(3-methoxv-benzenesulphonvl)-3-oxo-azepan-4-vlcarbamQvn-3-methvl-butvn-amide <br><br> Following the procedure of Example 183c-d except substituting l-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound 30 which was separated by HPLC to give the first eluting diastereomer as a white solid (34 <br><br> mg, 32%): MS (ESI) 569.2 (M+H)+ and the second eluting diastereoemer as a white solid (38 mg, 38%): MS (ESI) 569.4 (M+H)+ <br><br> 211 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 190 <br><br> Preparation of Quinoxaline-I (S)-1 -11 -f3-methoxv-benzenesulphonvlV3-oxo-azepan-4-ylcarbamovl"l-3-methvl-butvl l-amide <br><br> 5 <br><br> Following the procedure of Example 183c-d except substituting quinoxaline-2-carboxylic 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, 67%): MS (ESI) 568.2 (M+H)+ and the second eluting diastereoemer as a white solid 10 (27 mg, 24%); MS (ESI) 568.2 (M+H)+. <br><br> Example 191 <br><br> Preparation of Benzofuran-2-carboxvlic acid-{fS)-3-methvI-l-r3-oxo-l-(thiophene-2-sulfonvl)-azepan-4-vlcarbamovn-butvl 1 -amide <br><br> 15 Following the procedure of Example 168 except substituting benzofuran-2- <br><br> carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which ws purified by HPLC to give the first eluting diastereomer as a white solid (76 mg, 73%): MS (ESI) 532.2 (M+H)+ and the second eluting diastereomer as a white solid (25 mg, 23%) MS (ESI): 532.2 (M+H)+. <br><br> 20 <br><br> Example 192 <br><br> Preparation of Benzofuran-2-carboxvlic acid ((SV3-methv1-l-rC2.2'.4-trideuterioV3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvIlamide <br><br> 25 <br><br> To a solution of benzofuran-2-carbox.ylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 28c (0.03 g) in D20:CD30D (0.4:4 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 <br><br> 30 redissolved in the same mixture and heated to reflux overnight. The reaction was concentrated and the residue purified by column chromatography (5% methanol:dichloromethane) to provide the title compound (0.02 g): 'HNMR: 8 1.0 (m, 6H), <br><br> 212 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 1.5-2.2 (m, 6H), 2.7 (m, IH), 4.1 (m, IH), 4.7 (m, 2H), 7.4-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 529 (M\ 45%). <br><br> The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 530 (M+H+,100%) and the slower eluting diastereomer: MS(EI): 5 530 (M+HU00%). <br><br> Example 193 <br><br> Preparation of Benzofuran-2-carboxvlic acid l(SV2-methvl-l-[3-oxo-l-('pvridirie-2-10 sulfonvl)-azepan-4-vlcarbamovJ1-butvl}-amide a.) 4-tert-Butoxycarbonylamino-3-hydroxy-azepane-l-carboxylicacid benzyl ester <br><br> To a stirring solution of compound of Example 2e (1.04 g, 3.92mmol) in THF was added di-tert-butyldicarbonate (0.864 g). After stirring at room temperature for 30 minutes, 15 the reaction mixture was diluted with diethylether and extracted with saturated NaHCOs The organic layer was dried over anhydrous Na2S04, filtered, concentrated, and purified by silica gel column to give the title compound as a yellow oil (0.963 g, 2.64 mmol, 67%). MS (ESI): 365.03 (M+H)+. <br><br> 20 b.) (3-Hydroxy-azepan-4-yl)-carbamic acid tert-butyl ester <br><br> To a solution of compound of Example 193a (0.963g, 2.64mmol) in ethyl acetate (16 ml) was added 10% palladium on carbon (500 mg). 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, 2.29mmol, 87%): MS(ESI): 231.92 25 (M+H)\ <br><br> c.) [3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4~yl]-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 193b (0.53, 2.29 mmol) in dichloromethane (20 ml) was added triethylamine (232 mg) and pyridine-2-sulfonyl 30 chloride (410 mg, 2.32 mmol). After stirring at room temperature for 30 minutes, the . mixture was washed with saturated NaHC03 The. organic layer was dried, filtered, concentrated and purified on a silica gel column to give the tide compound as a solid ( 0.58 g, 1.57 mmol, 68%): MS(ESI): 372.95 (M+H)+. <br><br> 213 <br><br> WO 01/95911 PCT/US01/19062 <br><br> d.) 4-Amino- l-(pryidine-2-sulfonyl)-azepan-3-ol <br><br> To a stirring solution of the compound of Example 193c (0.583 g, 1.57mmol) in ethyl acetate (0.5 ml) was added HCl (4M in dioxane, 3.9 ml). After stirring the reaction 5 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 (M+H)+. <br><br> 10 e.) {(S)-l-[3-Hydroxy-l-(pryidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-meth-butyl}-carhamic acid tert-butyl ester <br><br> To a solution of the compound of example 193d (19 mg, 0.070 mmol) in CHjClj was added N-Boc-isoleucine (24.5 mg, 0.10 mmol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in CH,C12 . After shaking at room temperature 15 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 (M+H)+. <br><br> f.) (S)-2-Amino-3-methyl-penatanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-20 4-yl]-amide <br><br> To a stirring solution of the compound of example 193e (34 mg, 0.07 mmol) in CH2C12 (0.50 ml) was added HCl (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 25 methanol. After four hours of shaking, the mixture was filtered and concentrated to give the title compound as a solid.: MS(ESI) 384.9 (M+H)+. <br><br> g.) Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide <br><br> 30 To a solution of the compound of example 193f (27 mg, 0.070 mmol) in CHjCl., <br><br> 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 CH2C12 . After shaking at room temperature overnight, the mixture was treated with PS-Trisamine. After shaking for <br><br> 214 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> another 2 hours, the mixture was filtered and concentrated to yield the title compound as a solid: MS (ESI) 528.9 (M+H)+. <br><br> h.) Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-5 4-ylcarbamoyl]-butyl}-amide <br><br> To a stirring solution of the compound of example 193g (37 mg, 0.07 mmol) in CHjClj (0.5 ml) was added Dess-Martin reagent (45 mg, 0.105 mmol). After stirring for 30 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 10 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): MS (ESI) 526.91 (M+H)\ <br><br> 15 Example 194 <br><br> Preparation of Benzofuran-2-carboxvlic acid l(S)-l-r3-oxo-l~(pvridine-2-sulfonvD-azepan-4-vlcarbamo vll -propyl) -amide <br><br> 20 Following the procedure of Example 193e-h, except substituting N-Boc-alpha- <br><br> aminobutyric acid in step 193e the title compound was purified to yield two diastereomers as solids (first eluting: 5 mg, second eluting: 5 mg) MS(ESI) 543.8 (M+H)+. <br><br> Example 195 <br><br> 25 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S)-2-cvcIohexyl-l-r3-oxo-l-('pvridine-2-sulfonvl)-azepan-4-vlcarbamovn -ethyl} -amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-30 cyclohexylalanine 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(ESI): 566.87 (M+H)\ <br><br> 215 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 196 <br><br> Preparation of Benzofuran-2-carboxvlic acid ((SV 1 -D-oxo-1 -("pvridine-2-sulfonviyazepan-4-vlcarbamovll-ethvl 1-amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-alanine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 5.5 mg, second eluting: 5 mg). <br><br> Example 197 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S)-3-methanesulfinvl-l-r3-oxo-l-(pvridine-2-sulfonylVazepan-4-vlcarbamovl"i-propvl 1 -amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-L-methionine for step 1(f), the title compound was purified to yield two diastereomers as solids (first eluting: 3 mg, second eluting: 3 mg). MS(ESI): 560.7 (M+H)+. <br><br> Example 198 <br><br> Preparation of Benzofuran-2-carboxvlic acid ir3-oxo-l-fpyridine-2-sulfonvlVazepan-4-vlcarbamovll-methvl )-amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-glycine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 3mg,second eluting: 3 mg). MS(ESI): 470.81 (M+H)+. <br><br> 216 <br><br> WO 01/95911 " PCT/US01/19062 <br><br> Example 199 <br><br> Preparation of Benzofurati-2-carboxvlic acid {(Syi-r3-oxo-l-(Dvridine-2-sulfonvD-azepan-4-vlcarbamovll-pentvl) -amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-norleucine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4 mg, second eluting: 5 mg). MS(ESI): 526.85 (M+H)". <br><br> Example 200 <br><br> Preparation of Benzofuran-2-carboxvlic acid l(SVl-f3-oxo-l-(pvridine-2-sulfonviyazepan-4-vlcarbamovll-hutvl 1-amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-norvaline for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 7.5 mg, second eluting: 3.5 mg). MS(ESI): 512.8 (M+H)+. <br><br> Example 201 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(Sy2-methvl-l-f3-oxo-l-(pvridine-2-sulfonviyazepan-4-vlcarbamovll-propvl) -amide <br><br> 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 mg, second eluting: 4.5 mg). MS(ESI): 512.8 (M+H)+. <br><br> 217 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 202 <br><br> Preparation of Benzofaran-2-carboxvlic acid ((Sy2-hvdroxv-l-r3-oxo-l-(pvridine-2-sulfonviyazepaD-4-vlcarbamovIl -propyl) -amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-L-threonine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 3 mg, second eluting: 3 mg). <br><br> Example 203 <br><br> Preparation of Benzofuran-2-carboxvIic acid ffS)-l-f3-oxo-l-(pyridine-2-sulfonvl)-azepan-4-vlcarbamovll -2-phenvl-ethvl) -amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-phenylalanine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting:5mg, second eluting: 5mg). MS(ESI): 560.8 (M+H)+. <br><br> Example 204 <br><br> Preparation of l("Benzofuran-2-carbonvlVpvrrolidine-2-carboxvlic acid r3-oxo-l~(pvridine-2-sulfonvl)-azepan-4-vll -amide <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-L-proline for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4 mg, second eluting: 5mg). MS(ESI): (M+H)+. <br><br> Example 205 <br><br> Preparation of 3.4-Dimethoxv-N- l(S)-l-r l-(4-imethoxv-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamovll -3-methvl-butvl }-benzamide <br><br> Following the procedure of Example 115, except substituting 3,4-dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. <br><br> 218 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> The residue was purified by HPLC. First eluting diastereomer: MS 576.4(M+H+). ^ H NMR (500 MHz,CDCl3): 8 7.68 (d, 2H),7.00 (d,lH), 6.89 (s, 2H),3.84 (s, 3H),3.77 (s, 6H), 2.38 (t,lH), 0.94 (d, 6H): MS 576.4 (M+H+). <br><br> 5 Example 206 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-USVl-l" l-(4-imethoxv-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl}-amide <br><br> 10 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 (M+H+).^H NMR (500 MHz,CDCl3): 8 7.80-7.68 (m, 5H), 7.38-7.34 (m, 2H), 7.01-6.93 (m, 4H), 3.83 (s, 3H), 2.38 (t, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 572.2 (M+H+). <br><br> 15 <br><br> Example 207 <br><br> Preparation of Benzori31dioxole-5-carboxvlic acid ((SVl-ri-("4-fluoro-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovn-3methYl-butvll-aimde <br><br> 20 <br><br> Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4-methylenedioxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer, MS 548.2 25 (M+H+); lE NMR (400Hz,CDCl3): 5 7.85-7.78 (m, 2H), 7.38-7.20 (m, 4H), 7.05 (d, IH), 2.52-2.40 (m,lH), 1.0 (d, 6H). Second eluting diastereomer: MS 548.2 (M+H+). <br><br> 219 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 208 <br><br> Preparation of (S)-2-f2-Benzyloxy-acetvIamino)-4-methvl-pentanoic acidri-(4-fluoro-benzenesulfonvlV3-oxo-azepan-4-yll-amide <br><br> 5 <br><br> Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 548.2 (M+H+).1h NMR (400Hz,CDCl3-CD3C&gt;D) 6 7.88-7.80 (m, 2H), 7.45-7.30 (m, 10 5H), 7.30-7.20 (m, 2H), 4.00 (s, 2H), 2.60-2.48 (m,lH), 0.96 (t, 6H): MS 548.2 (M+H+). <br><br> Example 209 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-US')-1-1" l-(4-fluoro-benzenesulfonvl')-15 3-oxo-azepan-4-vl carbamovll-3-methvl-butvl 1 -amide <br><br> Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzo[b]thiophenecarbonyl chloride for benzyloxyacetyl chloride, the title compound was 20 prepared. The residue was purified by HPLC. First eluting diastereomer: MS 560.2 (M+H+).lH NMR (500 MHz,CDCl3): 8 7.80-7.72 (m, 5H).7.37-7.34 (m, 2H), 7.33-7.15 (m, 4H), 2.43 (t, IH), 0.96 (d, 6H). Second eluting diastereomer: MS 560.2 (M+H+). <br><br> Example 210 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S')-l-ri-benzovl-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl {-amide a.) Benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-hydroxy-azepan-4-ylcarbamoyl]-30 3-methyl-butyl }-amide <br><br> To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.2 g) in dichloromethane was added benzoic acid (0.12 g), HOBt (0.07 g) and EDC (0.99 g). The reaction was stirred until <br><br> 220 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.2 g): ]H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (in, 6H), 2.7 (m, IH), 3.8 (m,lH), 4.1 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.0-7.7 (m, 10H), 8.7 (m, IH); MS(EI): 492 (M+IT, 100%). <br><br> 5 <br><br> b.) Benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-10 amide of Example 210a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 3.7 (m,lH), 4.0 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.4-8.0 (m, 8H); MS(EI): 490 (M+H+, 100%). <br><br> 15 <br><br> Example 211 <br><br> Preparation of (S)-4-Methvl-2-(quinoline-8-sulfonvlamino)-pentanoic acid r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vll-amide a.) (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-hydroxy-1-20 (pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example 89a except substituting 8-quinolinesulfonyl chloride for 2-pyridinesulfonyl chloride the title compound was prepared: MS(EI) 576 (M+H+). <br><br> 25 b.) (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substituting (S)-4~methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 211a the title compound was prepared: 'H NMR (CDC13): 80.5-0.8 30 (m, 6H), 1.4-1.8 (m, 7H), 2.5 (m, IH), 3.5-3.9 (m, 3H), 4.4 (m, IH), 4.6 (m, IH), 5.5 (m, IH), 6.7 -7.0 (m, 2H), 7.5 (m, 3H), 8.0 (m, 2H), 8.3 (m, 2H), 8.6 (m, IH), 9.0 (m, IH); MS(EI): 674 (M+H+, 100%). <br><br> 221 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 212 <br><br> Preparation of (S)-4-Methvl-2-(naphthvlene-2-sulfonvlamino)-pentanoic acid 13-0X0-1-("pvridine-2-sulfonvlVazepan-4-vll-amide <br><br> 5 <br><br> a.) (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example 89a except substituting 2-naphthylenesulfonyl chloride for 2-pyridinesulfonyl chloride the title compound was prepared: MS(EI) 575 10 (M+H+). <br><br> b.) (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Example li except substituting (S)-4-methyl-2-15 (naphthylene-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 212a the title compound was prepared: 'H NMR (CDC13): 5 0.5-0.8 (m, 6H), 1.4-1.8 (m, 7H), 2.5 (m, IH), 3.5-3.9 (m, 3H), 4.5 (m, IH), 4.6 (m, IH), 5.5 (m, IH), 6.7 (m, IH), 7.5-8.0 (m, 9H), 8.5-8.6 (m, 2H); MS(EI): 673 (M+H\ 100%). <br><br> 20 Example 213 <br><br> Preparation of Benzofuran-2-carboxvlic acid-((S)-l-F l-(,4-fluoro-benzenesulfonvlV3-oxo-azepan-4-vl carbamovll-3-methvl-butvl 1-amide <br><br> 25 Following the procedure of Example 115, except substituting 4- <br><br> fluorobenzenesulphonyl 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: MS 544.2.(M+H+).^H NMR (500 MHz,CDCl3): 5 7.79-7.77 (m, 2H), 7.61 (d, IH), 7.46-7.38 30 (m, 3H), 7.25-7.06 (m, 5H), 2.43 (t, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 544.4 (M+H+). <br><br> 222 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 214 <br><br> Preparation of N-l(S&gt;l-ri-(4-Fluoro-benzenesulfonvD-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvl}-3.4-dimethoxv-benzamjde <br><br> 5 <br><br> Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl 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 564.2.(M+H+). *H 10 NMR (500 MHz,CDCl3): 8 7.80-7.76 (m, 2H),7.19 (t, 2H),7.05 (d, IH), 6.88 (s, 2H), 6.78 (d, IH), 6.53 (s, IH), 3.77 (s, 6H), 2.43 (t, IH), 0.94 (d, 6H). Second eluting diastereomer: MS 546.2 (M+H+). <br><br> 15 <br><br> Example 215 <br><br> Preparation of Cyclohexanecarboxylic acid l(SVl-ri-r4-fluoro-benzenesulfonvl')-3-oxo-azepan-4-vlcarbamovl 1 -3-methvl-butyl \ -ami de <br><br> Following the procedure of Example 115, except substituting 4-20 fluorobenzenesulphonyl 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 510.4.(M+H+).lH NMR (400Hz,CDCl3): 8 7.83-7.80 (m, 2H), 7.27-7.20 (m, 2H), 6.92 (d, IH), 6.95 (d, IH). 2.50 (t, IH), 1.90-1.20 (m, 15H), 0.94 (t, 6H). Second eluting 25 diastereomer: MS 510.2 (M+H+). <br><br> Example 216 <br><br> Preparation of (S)-2-('2-Benzvloxv-acetv1aminoV4-methvl-pentanoic acidl"!-30 (methanesulfonvl)-3-oxo-azepan-4-vn-amide <br><br> Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The <br><br> 223 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M+H+).*H NMR (500 MHz,CDCl3): 5 7.37-7.24 (m, 4H), 6.93-6.91 (m, 2H), 5.02-5.00 (m, IH), 2.88 (s, 3H), 2.70 (t, IH), 0.92 (t, 6H). Second eluting diastereomer: MS 468.2 (M+H+). <br><br> 5 Example 217 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-lCSV1 -(1 -methanesulfonvl-3-oxo-azepan-4-vl carbamovlV3-methvl-butvl1-amide <br><br> 10 Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl 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 (M+H+^H NMR (500 MHz,CDCl3): 5 7.83-7.78 (m, 3H),7.42-7.37 (m, 2H),6.94 (d, IH), 6.75 (d, IH), 2.89 (s, 3H), 2!68 (t, IH), 15 0.97 (d, 6H). Second eluting diastereomer: MS 480.2 (M+H+). <br><br> Example 218 <br><br> Preparation of Benzor 1.31dioxole-5-carboxvlic acid-l(SV l-d-methanesulfonvl-3-oxo-20 azepan-4-vl carbamovD-S-methvl-butvll-amide <br><br> 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 25 HPLC. First eluting diastereomer: MS 468.2 (M+H+).1H NMR (500 MHz,CDCI3): 5 7.31-7.24 (m, 2H), 6.91 (d, IH), 6.00 (s, 2H), 2.89 (s, 3H), 2.67 (t, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 468.2 (M+H+). <br><br> 224 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 219 <br><br> Preparation of Benzofuran-2-carboxvlic acid-l(SVl-(l-methanesulfonvl-3-oxo-azepan-4-vl carbamovlV3-methvl-hutvn-amide <br><br> 5 <br><br> Following the procedure of Example 115, except substituting methanesulphonyl 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: MS 464.2 (M+H+^H NMR (500 MHz,CDCl3): 8 10 7.64 (d, IH), 7.51-7.37 (m, 3H), 7.29-7.28 (m, IH), 2.89 (s, 3H), 2.67 (t, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 464.2 (M+H+). <br><br> Example 220 <br><br> 15 Preparation ofN-l"(SVl-(l-MethanesulfonvlV3-oxo-azepan-4-vlcarbamovl 1 -3-methvl-butvl 1-3.4-dimethoxv-benzamide <br><br> Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4-dimethoxybenzoyl chloride for 20 benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 484.2 (M+H+).*H NMR (500 MHz,CDCl3): 8 6.94-6.88 (m, 3H), 6.58-6.55 (m, 2H), 3.80 (s, 6H), 2.89 (s, 3H), 0.95 (d, 6H). Second eluting diastereomer: MS 484.2 (M+H+). <br><br> 25 Example 221 <br><br> Preparation of (SV2-('2-Benzvloxv-acetvlaminoV4-methvl-pentanoic acidfl-(2-cvano-benzensulfonvl)-3-oxo-azepan-4-vn-amide <br><br> 30 Following the procedure of Example 115, except substituting 2- <br><br> cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M+H+).lH NMR (500 MHz,CDC13): 8 8.10 (d, IH), 7.86 (d, IH), 7.76-7.70 (m, 2H), <br><br> 225 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 7.35-7.31 (m, 5H), 6.93 (d, 2H), .4.61-4.47 (m, 4H), 2.77 (t, IH), 0.92 (t, 6H). Second eluting diastereomer: MS 555.2 (M+H+). <br><br> Example 222 <br><br> 5 <br><br> Preparation of N-f(SM-f l-(2-Cvano-benzenesulfonvl')-3-oxo-azetian-4-vlcarbamovl}-3-methvl-butvl l-4-methanesulfonvl-l -benzamide <br><br> Following the procedure of Example 115, except substituting 2-10 cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 4- <br><br> methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 589.2 (M+H+^H NMR (500 MHz,CDCl3): 5 8.10 (d,lH), 7.96 (s, 4H), 7.88 (d, IH), 7.78-7.71 (m, 2H), 3.05 (s, 3H), 2.79 (t, IH), 0.97 (t, 6H). Second eluting diastereomer: MS 589.2 15 (M+H+). <br><br> Example 223 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid-f fSVl-ri-C2-cvano-benzenesulfonvl')-20 3-oxo-azepan-4-vl carbamovD-3-methvl-butvll-amide <br><br> Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzo[b]thiophene-2-carbonyl chloride for benzyloxyacetyl chloride, the title compound 25 was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 567.2 (M+H+).!h NMR (500 MHz,CDCl3): 8 8.10 (d, IH), 7.86-7.70 (m, 6H), 7.37-7.30 (m, 2H), 2.76 (t, IH), 0.98 (d; 6H). Second eluting diastereomer: MS 567.2 (M+H+). <br><br> 226 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 224 <br><br> Preparation of Benzori.31dioxole-5-carboxvlic acid-((S)-l-fl-(2-cvano-benzenesulfonv0-3-oxo-azepan-4-vlcarbamovlV3-methvl-butvll-amide <br><br> Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl 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 (M+H+). *H NMR (500 10 MHz,CDCI3): 6 8.11 (d, IH), 7.87 (d, IH), 7.76-7.71 (m, 2H), 7.31-7.24 (m, 2H), 6.00 (s, 2H), 2.77 (t, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 555.4 (M+H+). <br><br> 15 Preparation of (SV4-Methvl-2-r4-oxo-4-((4-phenoxv-pherivl')-butvrvlamino}-Dentanoic acid r3-oxo-l-(pvridme-2-sulfonvlVazeoan-4-vl1-amide <br><br> Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for thiaxole-2-sulfonyl chloride and 4-phenoxyphenyl-carboxylic acid for 20 benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+) 635.4; XH-NMR (400 MHz, CDC13): * 8.69(d, IH), 7.99-7.94(m, 4H), 7.53-7.39(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, IH), 3.85-3.80(d, IH), 3.33(m, 2H), 2.70-2.64(m, 3H), 2.20-1.40(m, 6H); and the second eluting diastereomer:, 0.96-0.92(m, 6H); 25 and the second eluting diastereomer: MS (M+H+) 635.4. <br><br> Preparation of ISM (SVl-IY 1-f 2-cvano-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamovl 1-3-30 roethvl-butvl I-3.4-dimethoxv-benzamide <br><br> Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4- <br><br> 5 <br><br> Example 225 <br><br> Example 226 <br><br> 227 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 571.4 (M+H+).lH NMR (500 MHz,CDCl3): 8 8.10 (d, IH), 7.87 (d, IH), 7.76-7.70 (m, 2H), 6.98 (s, 2H), 6.89 (s, 2H), 3.79 (s, 6H), 2.76 (t, IH), 0.96 (d, 6H). Second eluting diastereomer: MS 571.4 5 (M+H+). <br><br> Example 227 <br><br> Preparation of Cyclohexanecarboxylic acid {(SVl-fl-(4-methoxv-benzenesulfonvl')-3-oxo-10 azepan-4-vlcarbamovl 1 -3-methvl-butvl 1 -amide <br><br> Following the procedure of Example 115, except substituting cyclohexylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 522.4 (M+H+^H NMR (500 15 MHz,CDCl3): 8 7.70 (d, 2H), 6.97 (d, 2H), 2.40 (t, IH), 1.90-1.20 (m, 16H), 0.92 (d, 6H). Second eluting diastereomer: MS 522.4 (M+H+). <br><br> Example 228 <br><br> 20 Preparation of 4-Methansulfonvl-N- {(SV1 -14-methoxv-benzenesulfonvlV3-ox o-azepan-4-carbamovll-3-methvl-butvl-benzamide <br><br> Following the procedure of Example 115, except substituting 4-methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound was 25 prepared. The residue was purified by HPLC. First eluting diastereomer: MS 594.2 (M+H+).lH NMR (500 MHz,CDCl3): 8 7.96 (s, 4H), 7.69 (d, 2H), 7.25 (d,lH), 6.98 (d,3H), 3.85 (s, 3H), 3.04 (d, 3H), 2.42 (t, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 594.2 (M+H+). <br><br> 228 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 229 <br><br> Preparation of 4-Methansulfonvl-N-i CSVl-r4-fluoro-benzenesuIfonvlV3-oxo-azepan-4-carbamovll-3-methvl-butvl--betizamide <br><br> 5 <br><br> Following the procedure of Example 115, except substituting 4-fluorophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and substituting 4-methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 582.2 10 (M+H+). % NMR (500 MHz,CDCl3): 5 7.94 (s, 4H), 7.80-7.77 (m, 2H), 7.25-7.19 (m, 3H), 7.00 (d, IH), 3.04 (s, 3H), 0.96 (d, 6H). Second eluting diastereomer: MS 582.2 (M+H+). <br><br> 15 <br><br> Example 230 <br><br> Preparation of (i (S&gt;3-Methvl- l-B-oxo-1 -(pvridine-2-sulfonvl'l-azepan-4-vlcarbamovll-butylcarbamovl )-carbamic acid benzyl ester <br><br> Following the procedure of Example 75, except substituting 2-pyridylsulfonyl 20 chloride for benzenesulfonyl chloride and N-carbobenzyloxycarbonyl-glycine for benzofuran-2-carboxylic acid, the title compound was prepared, The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 574.2; ^H-NMR (400 MHz, cdci3); • 8.60(d, IH), 7.97-7.90(m, 2H), 7.50(m, IH), 7.42-7.25(m, 5H), 6.90(m, IH), 6.42(m, IH), 5.38(m, IH), 5.18-5.10(m, 4H), 4.78-4.72(d, IH), 4.50(m, IH), 4.12-4.05(m, IH), 3.95-25 3.85(m, 2H), 2.72(m, IH), 2.25-2.10(m, 2H), 1.90-1.40(m, 5H), 0.92(m, 6H); and the second eluting diastereomer: MS (M+H+) 574.2. <br><br> 229 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 231 <br><br> Preparation of (S')-2-[5-(4-Methoxv-phenvlVpentanovlamniol -4-methvl-pentanoi c acid F3-oxo-1 -(pyridine-2-sulfonvl)-azepan-4-vl 1 -ami de <br><br> 5 <br><br> 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 diastereomer; MS (M+H+): 573.4; *H-NMR (400 MHz, cdci3): • 10 8.59(d, IH), 7.97-7.94(m, 2H), 7.53(m, IH), 7.09-7.07(d, 2H), 6.89-6.81(m, 3H), 5.90(m, IH), 5.12(m, IH), 4.79-4.74(d, IH), 4.48(m, IH), 4.12(m, IH), 3.86-3.81(d, IH), 3.79(s, 3H), 2.69(m, IH), 2.59-2.57(m, 2H), 2.23-2.10(m, 3H), 1.75-1.45(m, 10H), 0.96-0.95(m, 6H); and the second eluting diastereomer: MS (M+H+) 573.4. <br><br> 15 Example 232 <br><br> Preparation of (SV2-r2-("3-Benzvloxv-4-methoxv-phenvlVacetvlamnio1-4-methvlpentanoic acid r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vll-amide <br><br> 20 Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and (3-benzyIoxy-4-methoxy-phenyl)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 637.4; iH-NMR (400 MHz, CDC13): • 8.69(d, IH), 7.98-7.91(m, 2H), 7.53-7.30(m, 6H); and the second eluting diastereomer:, 25 6.89-6.82(m, 4H), 5.82(m, IH), 5.14-5.07(m, 3H), 4.78-4.73(d, IH), 4.43(m, IH), 4.09(m, IH), 3.89(s, 3H), 3.82(d, IH), 3.49(s, 2H), 2.69(m, IH), 2.14(m, 2H), 1.82-1.40(m, 5H), 0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 637.4. <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 233 <br><br> Preparation of 5.6-DifIuoro-benzofuran-2-carboxvlic acid I(S&gt;3-methvl-l-fl-("pvridine-2-sulfonvlV3-oxo-azepan-4-vlcarbamovl1-butvl 1 amide a.) 5,6-Difhioro-benzofuran-2-caiboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 28b except substituting 5,6-difluorobenzofuran-2-carboxylic acid for bernzofuran-2-carboxylic acid provided the title compound: MS (M+H+): 564 <br><br> b.) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting the compound of Example 233a provided the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 562; and the second eluting diastereomer: MS (M+H+) 562. <br><br> Example 234 <br><br> Preparation of rS)-4-Metfavl-2-(5-oxo-hexanovlamino&gt;pentanoic acid r3-oxo-l-(pvridine-2-sulfonvlVazepan-4-vn-amide <br><br> 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 tide compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 495.4 (M+H+); Second eluting diastereomer: MS 495.4 (M+H+). <br><br> 231 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 235 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(SV3-methvl- 1-F1 -(6-methvl-pvridine-2-sulfonvl)-3-oxo-azepan-4-vlcarbamovl1-butv1 } amide <br><br> 5 <br><br> a.) 6-methyl-pyridine-2-sulphonyl chloride <br><br> The title compound was prepared in a similar fashion as that described in Example 85a for the preparation of 2-pyridinesulfonyl chloride-N-oxide. <br><br> 10 b.) {(S)-l-[3-Hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl }-carbamic acid rert-butylester <br><br> To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid Jen-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-2-15 sulphonyl chloride (6.44 mL of a 0.13 g/mL solution in 9M HCl). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (1.2 g). <br><br> c.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-20 sulfonyl)-azepan-4-yl]-amide <br><br> To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 235a (1.2 g) in methanol (20 mL) was added 4M HCl in diopxane (20 mL). The reaction was stirred until complete whereupon it was concentrated to provide the title compound (1 g). <br><br> 25 <br><br> d.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)~3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 28b except substituting (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-sUlfonyl)-azepan-4-yl]-amide of 30 Example 235c the title compound was prepared: MS(EI) 542 (M+). <br><br> 232 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl Jamide <br><br> Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-niethyl-pyridine-2-sulfonyl)-3-hydroxy-azepaii-4-ylcarbamoyl]-butyl}amide of Example 235d the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, IH), 4.1 (m, IH), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 8H); MS(EI); 540 (M\ 100%). <br><br> Example 236 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid lfSV3-methvl-l-ri-f6-methvl-pvridine-2-sulfonvl)-3-oxo-azepan-4-vlcarbamovn-butvl \ amide a.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 235c for (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28b the title compound was prepared: MS(EI) 572 (M+). <br><br> b.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methy]-l-[l-(6-methyl-pyridine-2-su]fony])-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide of Example 236a the title compound was prepared: 'H NMR (CDClj): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, IH), 3.8 (s, 3H); 4.1 (m, IH), 4,7 (m, 2H), 5.3 (m, IH), 7.4-8.0, (m, 7H); MS(EI): 570 (M+, 100%). <br><br> 233 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 237 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid ((S)-3-methvl-l-ri-r6-methvl-pyridme-2-stilfonvlV3-oxo-azepan-4-vlc arbamovri-butvl 1 amide <br><br> 5 <br><br> a.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyL} amide <br><br> Following the procedure of Example 236a except substituting 3-metbylbenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid the title compound was 10 prepared: MS(EI) 556 (M+). <br><br> b.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl~pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide i <br><br> Following the procedure of Example li except substituting 3-methylbenzofuran-2-15 carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- . ylcarbamoyl]-butyl Jamide of Example 237a the title compound was prepared: 'H NMR ! (CDCIj): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, IH), 3.8 (s, IH); 4.3 (m, IH), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H); MS(EI): 564 (M\ 100%). <br><br> 20 Example 238 <br><br> Preparation of 7-Methoxvbenzofuran-2-carboxvlic acid (fSV3-methvl-l-fl-(pyridine-2-sulfonvl)-3-oxo-azepan-4-vlcarbamovn-butvl}amide <br><br> 25 a.) 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 559 (M+H+). <br><br> 30 <br><br> b.) 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li except substituting 7-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- <br><br> 234 <br><br> WO 01/95911 PCT/US01/19062 <br><br> ylcarbamoyl]-butyl}amide of Example 238a the title compound was prepared: MS(EI) 557 (M+H+). <br><br> Example 239 <br><br> 5 <br><br> Preparation of 5.6-Dimethoxv-benzofblthiophene-2-carboxvlic acid f (S)-3-methvl-l-[l-('pvridine-2-sulfonvlV3-oxo-azepan-4-vlcarbamovll-butvllamide a.) 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-10 pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcaTbamoyl]-butyl} amide <br><br> Following the procedure of Example 28b except substituting 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 604 (M+). <br><br> 15 b.) 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyxidine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl Jamide of Example 239a the title compound was 20 prepared: MS (EI) 602.9 (M+H+). <br><br> Example 240 <br><br> Preparation of (R)-l-Benzvl-5-oxo-pvrrolidine-2-carboxvlic acid i(SV3-methvl-l--f3-oxo-25 (pyridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvl Jamide <br><br> Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for thiazole-2-sulfonyl chloride and (R)-l-benzyl-5-oxo-pyrrolidine-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was 30 purified by HPLC. First eluting diastereomer; MS (M+H+): 584.4; iH-NMR (400 MHz, cdci3): • 8.69(d, IH), 7.99-7.92(m, 2H), 7.52(m, IH), 7.32-7.22(m, 5H), 6.92(d, IH), 6.38(d, IH), 5.15-5.08(m, 2H), 4.80-4.75(d, IH), 4.47-4.44(m, IH), 4.14-4.10(m, IH), 3.89-3.80(m, 3H), 2.75-2.63(m, 2H), 2.46-1.44(m, 10H), 0.95(d, 6H); and the second eluting diastereomer: MS (M+H+) 584.4. <br><br> 235 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 241 <br><br> Preparation of (S")-l-Benzvl-5-oxo-pvrrolidine-2-carboxvlic acid I(S)-3-methvl-l-f3-oxo-5 fpyridine-2-sulfonvl')-azepan-4-vlcarbamovll-butvl 1 amide <br><br> Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and (S)-l-benzyl-5-oxo-pyrrolidine-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was 0 purified by HPLC. First eluting diastereomer; MS (M+H+): 584.4; *H-NMR (400 MHz, CDC13): • 8.69(d, IH), 7.98-7.92(m, 2H), 7.52(m, IH), 7.32-7.22(m, 5H), 6.92(d, IH), 6.38(d, IH), 5.22-5.18(d, IH), 5.10(m, IH), 4.80-4.75(d, IH), 4.51(m, IH), 4.12-4.08 (m, IH), 3.91-3.79(m, 3H), 2.71-1.38(m, 12H), 0.97(d, 6H); and the second eluting diastereomer: MS (M+H+): 584.4. <br><br> 5 <br><br> Example 242 <br><br> Preparation of Benzofuran-2-carboxvlic acid ((SV2-cvclopropvl-1 -f3-oxo-l-(pyridine-2-suIfonvl")-azepan-4-vlcarbamovl)-ethvl1-amide <br><br> ;0 <br><br> Following the procedure of Example 193e-h except substituting N-Boc-cyclopropylalanine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 8 mg, second eluting: 8 mg): MS(ESI): 525 (M+H)+. <br><br> 15 Example 243 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S)-3-methvlsulfanvl-143-0X0-1 -(pvridine-2-sulfonyl)-azepan-4-vlcarbamovl)-propyn-amide <br><br> 10 Following the procedures of Examples 193e-g except substituted N-Boc-L- <br><br> methionine in step 193e. The oxidation of Example 193g was performed by adding sulfur trioxide-pyridine complex (34mg, 0.211 mmol ) and triethylamine ( 0.077 ml) to the alcohol intermediate in DMSO solvent (0.200 ml). After stirring at room temperature for two hours, the mixture was diluted with water and extracted with ethyl acetate. The organic <br><br> 236 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> layer was dried, filtered, concentrated, and purified by HPLC to yield two diastereomers of the title compound as solids (first eluting: 8mg, second eluting: 5 mg). MS(ESI): 545 (M-fH)+. <br><br> 5 Example 244 <br><br> Preparation of Benzofiiran-2-carboxvIic acid l(S)-2-naphthvlen-2-vl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovlVethvll-amide <br><br> Following the procedure of Example 193e-h except substituting except substituting N-(t-butoxycarbonyI)-3-(2-naphthyl)-L-alanine, the title compound was purified to yield two diastereomers as solids (first eluting: 5.3 mg, second eluting: 3.3 mg): MS(ESI): 610.8 (M+H)\ <br><br> 15 Example 245 <br><br> Preparation of Thienor3.2-blthiophene-2-carboxvlic acid ((SV3-methvl-l-[l-(6-methvl-Pvridine-2-sulfonvlV3-oxo-a2epan-4-vlcarbamovll-butvllaTOide <br><br> 20 a.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methy 1- 1-f 1 -(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example 236a except substituting thieno[3,2-b]thiophene-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 564 (M+). <br><br> b.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-30 ylcarbamoyl]-butyl jamide of Example 245a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 2.7 (m, IH), 3.8 (s, IH); 4-1 (m, IH), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H); MS(EI): 562 (M\ 100%). <br><br> 237 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 246 <br><br> Preparation of Thienor3,2-blthiophene-2-carboxvlic acid ((S)-3-methvl-l-ri-(3-methvl-Pvridme-2-sulfonvl")-3-oxo-azepan-4-vIcarbamovIl-butvl)amide <br><br> 5 <br><br> a.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(3-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> Following the procedure of Examples 235b-c except substituting 3-methyl-pyridine-2-sulfonyl chloride for 6-methyl-pyridine-2-sulfonyl chloride the title compound 10 was prepared: MS(EI) 399 (M+). <br><br> b.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyI]-butyl} amide <br><br> To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy- l-(3-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 246a (0.25 g) in dichloromethane was added thieno[3,2-b]thiophene (0.10 g), triethylamine (0.12 mL), HOBt (0.085 g) and EDC (0.12 g). The reaction was stinred until complete. Workup and column chromatography (5% methanol: dichloromethane) provided the title compound (0.18 g): MS(EI) 564 (M+). <br><br> c.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methy]-l-[ 1 -(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoylj-butyl}amide of Example 245a the title compound was prepared: 'H NMR (CDCy: 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 3.0 (m, IH), 3.8 (s, 3H); 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 5H), 8.4 (m, IH); MS(EI): 562 (M\ 100%). <br><br> 238 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 247 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid ((SV3-methvl-l-r 1 -(3-methvl-Pvridine-2-sulfonvlV3-oxo-azepan-4-vlcarbamovll-butvl I amide <br><br> 5 <br><br> a.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyI]-butyl}amide <br><br> Following the procedure of Example 246c except substituting 3-methylbenzofuran-2-carboxylic acid for thieno[3,2-b]thiophene the title compound was prepared: MS(EI) 556 10 (M+). <br><br> b.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl3-butyl}amide <br><br> Following the procedure of Example li except substituting 3-methylbenzofuran-2-15 carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-buty 1} amide of Example 247a the title compound was prepared: 'H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 2.6 (m, 3H), 3.0 (m, IH), 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H), 8.4 (m, IH); MS(EI): 554 (M+, 100%). <br><br> 20 Example 248 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid ICS)-3-methvl-l-ri-f3-methvl-pvridine-2-sulfonvl)-3-oxo-azepan-4-vlcarbamovll-butvl) amide <br><br> 25 a.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example 246c except substituting 5-methoxybenzofuran-2-carboxylic acid for thieno[3,2-b]thiophene the title compound was prepared: MS(EI) 572 (M+). <br><br> 30 <br><br> b.) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide <br><br> Following the procedure of Example li except substituting 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- <br><br> 239 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> ylcarbamoyl]-butyl Jamide of Example 247a the title compound was prepared: "H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 3.0 (m, IH), 3.8 (s, 3H); 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H), 8.4 (m, IH); MS(EI): 570 (M+, 100%). <br><br> 5 Example 249 <br><br> Preparation of 5.6-Difluoro-benzofuran-2-carboxvIic acid ICS)-3-methvi-1 -f3-oxo-1 -(1 -oxv-Dvridine-2-sulfoDvl)-azepan-4-vlcarbamovll-butvl 1 amide <br><br> 0 a.) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l~oxy-pyridine-2-suIfonyl)-azepan-4-ylcarbamoyI]-butyl} amide <br><br> Following the procedure of Example 85c exept substituting 5,6-difluorobenzofuran-2-carboxylic acid for benzo[b]thiophene-2-caiboxylic acid the title compound was prepared: MS(ESI) 580.9 (M+H+). <br><br> 5 <br><br> b.) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide <br><br> Following the procedure of Example li exept substituting the compound of Example 249a the title compound was prepared: MS(ESI) 578.87 (M+H+). <br><br> :o <br><br> Example 250 <br><br> Preparation of 5-(3-Trifluoromethvl-phenvl')-furan-2-carboxvlic acid{(S)-2-cvclohexvl-l-{3-oxo-l-&lt;'pvridine-2-su).fonvl)-azepan-4-vlcarbamovll-ethvl ? -amide <br><br> :5 <br><br> a.) 4-((S)-2-f&lt;?Jt-Butoxycarbonylamino-3-cyclohexyl-proprionylamino)-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a solution of the compound of Example 2e (3.2 g, 12.2 mmol) in DMF (35 mL) was added N-Boc-cyclohexylalanine (3.3 g), HOBt (1.8 g) and EDC (2.56 g). The reaction 10 was stirred until complete. Workup and column chromatography of the residue (65% hexanes:ethyl acetate) provided 5.5 g of the title compound. <br><br> 240 <br><br> WO 01/95911 PCT/US01/19062 <br><br> b.) [(S)-Cyclohexyl-l-(3-hydroxy-azepan-4-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester <br><br> 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 5 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. <br><br> c.) {(S)-2-Cyclohexyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester <br><br> 10 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 (1 g). 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% 15 methanol:dichloromethane) of the residue provided 1.0 g of the title compound: MS (ESI) 525 (M+H*). <br><br> d.) (S)-2-Amino-3-cyclohexyl-N-[3-hydroxy-(pyridine-2-sulfonyl)-azepan-4-yl]-proprionamide <br><br> 20 To a solution of the compound of Example 250c (1.0 g) in methanol (10 mL) was added HCl (10 mL of 4M HCl 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. <br><br> 25 e.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-{3-hydroxy-l-(pyridine-2-sulfonyI)-azepan-4-ylcarbamoyI]-ethyl}-amide <br><br> To a solution of the compound of Example 250d (0.20 g, 0.4 mmol) in DMF (0.5 mL) was added diisopropylethylamine (0.16 mL), HOBt (0.06 g), EDC (0.084 g) and 5-[3-(trifluoromethyl)phenyl]-2-furoic acid (0.11 g).). The reaction was stirred until complete 30 consumption of the starting material. Workup and column chromatography 4% methanohdichloromethane) provided 0.23 g of the title compound. <br><br> 241 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> f.) 5-(3-Trifluoromethyl-phenyl)-ftiran-2-carboxylic acid {(S)-2-cyclohexyl-1 - {3-oxo-l-(pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-ethyl}-amide <br><br> 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 disatereomer (52 mg): MS (ESI) 661.4 and the second eluting diastereomer (45.8 mg): MS (ESI) 661.6. <br><br> Example 251 . <br><br> Preparation of 5-(4-Chloro-phenvl)-furan-2-carboxvlic acidl(S)-2-cvclohexvl-l-l3-oxo-l-(pvridine-2-sulfon vl)-azepan-4-vlcarbamovn-eth yl) -amide <br><br> Following the procedures of Example 250e-f except substituting 5-(4-chlorophenyl)-2-furoic 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 (57 mg): MS (ESI) 627.4 and the second eluting diastereomer (53 mg): MS (ESI) 627.4. <br><br> Example 252 <br><br> Preparation of Benzofuran-2-carboxvlic acid i(S)-3-methvl-l-r6-methvl-3-oxo-l-(pvridine-suiphonvlVazepan-4-vlcarbamovll-butvn-amide <br><br> 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 (M+H+): 541.2; iH-NMR (400 MHz, CDC13): • 8.71-8.66(m, IH), 7.98-7.93(m, 2H), 7.91(d, IH), 7.67-7.29(m, 5H), 7.15-6.92(m, 2H), 5.28-5.20(m, IH), 4.82-4.47(m, 2H), 3.97-3.78(m, IH), 3.65-2.98(m, IH), 2.37-2.34(m, IH), 2.20-1.55(m, 3H), 1.22-1.19(m, 3H), 1.00-0.86(m, 9H). <br><br> 242 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 253 <br><br> Preparation of 5-(4-Chloro-phenvl)-faran-2-carboxvlic acidf (S)-2-cvclohexvl-l-F3-oxo-l-&lt;"l-oxv-pvridine-2-sulfonvl)-azeDan-4-vIcarbamovl'l-ethvl)-amide <br><br> 5 <br><br> Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c and substituting 5-(4-chlorophenyI)-2-furoic acid for 5-[3-(trifhioromethyl)phenyl]-2-furoic acid of Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided 10 the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2. <br><br> Example 254 <br><br> 15 Preparation of 5-(3-Trifluoromethvl-phenvl&gt;furan-2-carboxvIic acidf (S")-2-cvclohexvl-l-r3-oxo-l-n-oxv-pvridine-2-sulfonvl)-azepan-4-ylcarbamoyl"]-ethvl)-amide <br><br> Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c the title compound was 20 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. <br><br> Example 255 <br><br> 25 Preparation of 5-Fluoro-benzofuraii-2-carboxvlic acid f CSV3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl1-azepan-4-vlcarbamovn-butvn-amide a.) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide 30 Following the procedure of Example 28b except substituting 5-fluorobenzofuran-2- <br><br> carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS (ESI) 547 (M+H+). <br><br> 243 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide <br><br> Following the procedure of Example li except substituting the compound of Example 255a the title compound was prepared: MS(ESI) 544.9 (M+H+). <br><br> 5 <br><br> Example 256 <br><br> Preparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acidf (S)-2-cvclohexvl-1-["3-oxo-1 -d-oxY-pyridine-2-sulfonvl'&gt;-azepan-4-vlcarbamovll-ethvl l-amide <br><br> 10 <br><br> Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c and substituting 5,6-dimethoxybenzofuran-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 15 provided the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2. <br><br> Example 257 <br><br> 20 Preparation of 5.5-Bis-(4-methoxy-phenvD-pent-4-enoic acid \fSV3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azenan-4-vlcarbamovlll-butvl}-amide <br><br> 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 25 for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+) 677.4; *H-NMR (400 MHz, CDC13): • 8.69(d, IH), 7.98-7,92(m, 2H), 7.53-7.50(m, IH), 7.27-6.77(m, 10H), 6.00-5.87(m, 2H), 5.08(m, IH), 4.76-4.72(d, IH), 4.48(m, IH), 4.08(m, IH), 3.83(s, 3H), 3.78(s, 3H), 2.70-1.35(m, 12H), 0.91(d, 6H); and the second eluting diastereomer: MS (M+H+) 30 677.4. <br><br> 244 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 258 <br><br> Preparation of Ouinoline-8-carboxvlic acid f(SV2-naphthvlen-2-vl-l-r3-oxo-l-(pvridine-2-sulfonvD-azepan-4-vlcarbamovlVethvll-amide <br><br> 5 <br><br> a.) 4-Amino-1 -(pyridine-2-sulfonyl)-azepan-3-ol <br><br> To a solution of the compound of Example 193c (1.5 g) in methanol (10 mL) was added HCl (10 mL of 4M HCl in dioxane). The reaction was stirred until complete by TLC analysis whereupon it was concentrated to provide 1.2 g of the title compound as a white 10 solid. <br><br> b.) . {(S)-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-napthylene-2-yl-ethyl}-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 258a (225 mg) in dichloromethane was 15 added TEA (0.15 mL), HOBt (99 mg), EDC (140 mg) and N-Boc-L-2-naphthylalanine (230 mg). The reaction was stirred until complete. Workup and column chromatography of the residue (3% methanol:dichloromethane) provided 0.35g of the title compound: MS(ESI) 569 (M+H+). <br><br> 20 c.) (S)-2-Amino-N-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-3-naphthylen-2-yl-proprionamide <br><br> To a solution of the compound of Example 258b (0.35 g) in methanol (5 mL) was added HCl (5 mL of 4M HCl in dioxane). The reaction was stirred until complete by TLC analysis whereupon it was concentrated to provide 0.31 g of the title compound as a white 25 solid. <br><br> d.) Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-hydroxy-l-(pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide <br><br> To a solution of the compound of Example 258c (131 mg) in dichloromethane was 30 added TEA, HOBt (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 (5% methanokdichloromethane) provided 0.35g of the title compound: MS(ESI) 574 (M+H+). <br><br> 245 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> e.) Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide <br><br> Following the procedure of Example li except substituting the compound of Example 258d the title compound was prepared. <br><br> Example 259 <br><br> Preparation of Naphthylene-1-carboxylic acid ((SV2-naphthvlen-2-vI-l-r3-oxo-l-(pvridiDe-2-sulfonyl&gt;azepan-4-vIcarbamovD-ethvn-amide <br><br> Following the procedures of Examples 258d-e except substituting 1-naphthoic acid for quinoline-8-carboxylic acid the title compound was prepared. <br><br> Example 260 <br><br> Preparation of Ouinoline-8-carboxvlic acid f fS V1 -f3-oxo-1 -fpvridine-2-sulfonvlVazepan-4-vlcarbamovll-2-phenvl-ethvl ] -amide <br><br> Following the procedures of Examples 258a-e except substituting N-Boc-phenylalanine for N-Boc-L-2-naphthylalanine the title compound was prepared. <br><br> Example 261 <br><br> Preparation of Naphthvridine-2-carboxvlic acid ((SV3-methvl-l-r3-oxo-l-fpvridine-2-suIfonvr)-azepan-4-vIcarbamovl~l-butyll-amide <br><br> Following the procedure of Example 28b-c exept subsituting l,6-naphthyridine-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared. <br><br> 246 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 262 <br><br> Preparation of Naphthvlene-l-carboxvlic acid fCSVl-r3~oxo-l-('pvridiiie-2-sulfonvl'l-azepan-4-vlcarbamovl1-2-phenvl-ethvn-amide <br><br> Following the procedure of Example 260 except substituting 1-naphthoic acid for quinoline-8-carboxylic acid the title compound was prepared. <br><br> 10 <br><br> Example 263 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid IfS)-3-methvl-l-r3-oxo-l-(cvclohexvl-proprionvl)-azepan-4-vlcarbamovI'i-butvl 1 -amide a.) 4-{(S)-2-[(3-Methylbenzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-15 hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a solution of the compound of Example 72a (1.2 g, 2.67 mmol) was added EDC (0.56 g), HOBt (0.36 g), TEA (0.67 g) and 3-methylbenzofuran-2-carboxylic acid (0.47 g). The reaction was stirred until complete consumption of the starting material was observed. Workup and colum chromatography (4:1 hexanes:ethyl acetate) provided 1.05 g of the title 20 compound: MS (ESI) 536 (M+H+). <br><br> b.) 3-Methylbenzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide <br><br> Following the procedure of Example 2g except substituting the compound of 25 Example 263a the title compound was prepared: MS (ESI) 402 (M+H+). <br><br> c.) 3-MethyIbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(cyclohexyl-proprionyl)-azepan-4-y lcarbamoy l]-butyl} -amide <br><br> Following the procedure of Example 263a except substituting the compound of 30 Example 263b and 3-cyclohexylpropionic acid for 3-methylbenzofuran-2-carboxylic acid the title compound was prepared: MS (ESI) 540 (M+H*). <br><br> 247 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> d.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(cyclohexyl-proprionyl)-azepan-4-ylcarbamoyl]-butyl}-amide <br><br> Following the procedure of Example li except substituting the compound of Example 263c the title compound was prepared: MS (ESI) 538 (M+H*). <br><br> Example 264 <br><br> Preparation of 3-Methvlbenzofaran-2-carboxylic acid {(S)-3-methvl-l-r3-oxo-l-(4-methvl-pentanovlVazepan-4-vlcarbamovn-butvll-amide <br><br> 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+). <br><br> Example 265 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid ((SV3-methvl-l-r3-oxo-l-(l-oxv-pvridine-2-carbonvlVazepan-4-vlcarbamovll-butvl}-amide <br><br> Following the procedures of Example 263c-d except substituting picolinic acid N-oxide for 3-cyclohexylpropionic acid the title compound was prepared: MS (ESI) 498 (M+H+). <br><br> Example 266 <br><br> Preparation of (S)-Acetv1amino-4-methvl-pentanoic acid r3-oxo-l-fovridine-2-sulfonvl)-azepan-4~vl"l-amide <br><br> Following the procedure of Example 75c-d except substituting acetic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by HPLC to give the first eluting diastereoemer: MS (M+H+) 425.2; *H-NMR (400Hz, cdci3): • 8.69(d, IH), 7.96-7.94(m, 2H), 7.53-7.52(m, IH), 7.05(m, IH), 5.92(m, IH), 5.08(m, IH), 4.69-4.53(m, 2H), 4.05-3.90(m, 2H), 2.80(m, IH), 2.25-2.12(m, 2H), 1.64(s, <br><br> 248 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 3H), 1.90-1.40(m, 5H), 0.95(m, 6H); and the second eluting distereomer: MS (M+H+): 425.2 <br><br> Example 267 <br><br> 5 <br><br> Preparation of Ouinoline-2-carboxvlic acid {(SVl-r3-oxo-l-(pvridine-2-salfonvlVazepan-4-vlcarbamovll-pentvH-amide a.) 4-((S)-2-terf-Butoxycarbonylamino-hexanoylamino)-3-hydroxy-azepane-l-10 carboxylic acid benzyl ester <br><br> To a stirring solution of compound of the amino alcohol of Example 2e (200 mg, 0.74mmol) in DMF (4 ml) was added N-Boc-norleucine (175 mg, 0.76mmol), EDC-HC1 (145 mg, 0.76mmol), and 1-hydroxybenzotriazole (21 mg, 0.16mmol). Reaction allowed to proceed overnight at room temperature. The following morning the mixture was diluted 15 with ethyl acetate, washed with sat. NaHC03, H20, and brine. Dried on MgS04, filtered and purified by column chromatography to give 300 mg of the title compound: MS(ESI) 478.11 (M+H)+. <br><br> b.) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester 20 To a solution of compound of Example 267a (300 mg, 0.6 3mmol) in ethyl acetate <br><br> (5 ml) was added 10% palladium on carbon (160 mg) and H2 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 (M+H)\ <br><br> 25 <br><br> c.) {(S)-l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl}-carbamic acid tert-butyl ester <br><br> 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-2-30 sulfonyl chloride (83mg, 0.47 mmol). After stirring at room temperature for 1 hr the mixture was washed with saturated NaHC03 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 (M+H)+. <br><br> 249 <br><br> WO 01/95911 PCT/US01/19062 <br><br> d.) (S)-2-Amino-hexanoic acid {3-hydroxy- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> To a stirring solution of the compound of Example 267c (142mg, 0.29mmol) in 5 ethyl acetate was added HCl (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 10 (M+H)+. <br><br> e.) Quinoline-2-carboxylic acid {(S)-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl] -pentyl} -amide <br><br> To a solution of the compound of Example 267d (104 mg, 0.27mmol) in CH2C12 15 was added quinaldic acid (47mg, 0.27 mmol), 1-hydroxybenzotriazole (7.4, .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. NaHC03, H20, dried on MgS04, and filtered to obtain 172mg crude product: MS(ESI) 539.90 (M+H)\ <br><br> 20 f.) Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl} -amide <br><br> 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 25 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 (M+H)\ <br><br> 250 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 268 <br><br> Preparation of Benzofuran-2-carboxvlic acid f (SV3-methvl-l-f3-oxo-1 -fcvclohexvl-proprionvlVazepan-4-vlcarbamovll-butvll-amide <br><br> 5 <br><br> Following the procedures of Example 263a-d except substituting benzofuran-2-carboxylic acid for 3-methylbenzofuran-2-carboxylic acid of Example 263a the title compound was prepared: MS(ESI) 524 (M+H4). <br><br> 10 Example 269 <br><br> Preparation of Benzofuran-2-carboxvlic acid i(S')-3-methvl-l-r3-oxo-l-('4-methvl-pentanovD-azepan-4-vlcarbamovll-butvn-amide <br><br> 15 Following the procedures of Example 263a-d except substituting benzofuran-2- <br><br> carboxylic acid for 3-methylbenzofuran-2-carboxylic acid of Example 263a and 5-methyl pentanoic aicd for cyclohexyl propionic acid the title compound was prepared: MS(ESI) 484 (M+H4). <br><br> 20 Example 270 <br><br> Preparation of OuinoIine-2-carboxvlic acid i CSV 1 43-oxo-1 -(pvridine-2-sulfonvlV azepan-4-vlcarbamovll -2-phenvl-ethvl I -amide <br><br> Following the procedure of Example 267a-f except substituting N-Boc-25 phenylalanine for N-Boc-norleucine in step 267a the title compound was prepared. <br><br> Separation of the mixture by HPLC provided two diastereomers as solids (first eluting: 20.5 mg; second eluting: 27 mg ): MS(ESI) 571.95 (M+H)+. <br><br> 251 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 271 <br><br> Preparation of Benzofuran-2-carboxvlic acidf CSV 2-benzvloxv-l~r3-oxo-l-fpvridine-2-sulfonvl)-azepane-4-vlcarbamovI"l-ethvl)-amide <br><br> 5 <br><br> Following the procedure of Example 193e-h, except substituting N-Boc-O-benzyl-L-serine in step 193e the title compound was prepared as a mixture of distereoemers. To a solution of benzofuran-2-carboxylic acid {(S)-2-benzyloxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-amide (90 mg) in ethyl acetate (2 mL) was added 10 10% Pd/C (50 mg). 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)-2-15 hydroxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-amide were also isolated as described below in Example 272. <br><br> Example 272 <br><br> 20 Preparation of Benzofiiran-2-carboxvlic acid ((S")-2-hvdroxv-1-r3-oxo-l-(pvridine-2-sulfonvl)-azepane-4-vlcarbamovll-ethvll-amide <br><br> The title compound was obtained as discussed above in Example 271. <br><br> Purification of the mixture by HPLC provided the two diastereomers in solid form (first 25 eluting: 1.6 mg; second eluting 2.1 mg): MS(ESI): 500.9 (M+H)+. <br><br> Example 273 <br><br> Preparation of 5-Methoxvbenzofuran-2-carboxvlic acid I (S)-3-meth vl-1 -f3-oxo-1 -(thiazole-30 2-sulfonvl)-azepan-4-vlcarbamovll-butvl \ amide <br><br> • Following the procedure of Example 75c-d except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by HPLC to give the first eluting <br><br> 252 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> diastereoemer as a white solid (144.3 mg, 85.1%): MS (ESI) 563.2 (M+H)+ and the second eluting diastereomer as a white solid (16.9mg, 10.0%) MS (ESI): 563.0 (M+H)+ <br><br> Example 274 <br><br> 5 <br><br> Preparation of 7-Methoxvbenzofuran-2-carboxvlic acid ( f S)-3-methvl-1 -T3-oxo-l-fthiazole-2-sulfonvl)-azepan-4-vlcarbamovll-butvl) amide <br><br> Following the procedure of Example 75c-d except substituting 7-10 methoxybenzofuran-2-carboxylic 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 (75 mg, 47%): MS (ESI) 563.2 (M+H)+ and the second eluting diastereomer as a white solid (57 mg, 35%): MS (ESI) 563.0 (M+H)+ <br><br> 15 Example 275 <br><br> Preparation of 3-Methvlbenzofuran-2-carboxvlic acid (CS)-3-methvl-l-r3-oxo-l-rthiazole-2-sulfonvll-azepaD-4-vlcarbamovll-butvl} amide <br><br> 20 Following the procedure of Example 75c-d except substituting 3- <br><br> methylbenzofuran-2-carboxylic 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 (69.5 mg, 42%): MS (ESI) 547.2 (M+H)+and the second eluting diastereomer as a white solid (65 mg, 40%): MS (ESI) 547.2 (M+H)+ <br><br> 25 <br><br> Example 276 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid i fSV3-methvl-1 -f3-oxo-1 -(thiazole-2-sulfonvl)-azepan-4-vlcarbamovP-butvl I amide <br><br> 30 <br><br> 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 tide compound which was separated by HPLC to give the first eluting diastereoemer as a white solid (79.5 <br><br> 253 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> mg, 48%): MS (ESI) 549.3 (M+H)+ and the second eluting diastereomer as a white solid (50.5 mg, 31%): MS (ESI) 549.2 (M+H)+ <br><br> Example 277 <br><br> 5 <br><br> Preparation of l-Methvl-lH-indole-2-carboxvlic acid ((S)-3-methvl-l-r3-oxo-l-('thiazole-2-sulfonvl)-azepan-4-vlcarbamovll-butvI} amide <br><br> Following the procedure of Example 75c-d except substituting l-methylindole-2-10 carboxylic 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 (75 mg, 47%): MS (ESI) 563.2 (M+H)+ and the second eluting diastereomer as a white solid (57 mg, 35%): MS (ESI) 563.0 (M+H)+ <br><br> 15 Example 278 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid ((SV3-methyl-143-oxo-1 -(thiazole-2-sulfonvD-azepan-4-vlcarbamovll-butvl) amide <br><br> 20 Following the procedure of Example 75c-d except substituting quinoxaline-2- <br><br> carboxylic 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, 77%): MS (ESI) 545.2 (M+H)+ and the second eluting diastereomer as a white solid (25 mg, 15%): MS (ESI) 545.2 (M+H)+ <br><br> 25 <br><br> 254 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 279 <br><br> Preparation of Ouinoline-2-carboxvlic acid (T("SI-1 -F1 -(4-fluoro-b&amp;nzenesulfonvl")-3-oxo-azepan-4-vlcarbamovll-3-methvl-hutvn-amide <br><br> 5 <br><br> Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for benzenesulfonyl chloride and 2-quinoline carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. <br><br> First eluting diastereomer; MS (M+H+): 555.2; ^H-NMR (400Hz, CDC13): • 8.62(d, IH), 10 8.34-8.23(q, 2H) 8.19-8.17(d, IH), 7.90-7.88(d, IH), 7.88-7.80(m, 3H), 7.66-7.64(t, IH), 7.25-7.07(m, 3H), 5.08(m, IH), 4.72 (m, IH), 4.58-4.53(d, lH),4.00(m, IH), 3.46-3.42(d, IH), 2.47(m, IH), 2.27-2.12(m, 2H), 1.90-1.40(m, 5H), 1.03-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+): 555.4. <br><br> 15 Example 280 <br><br> Preparation of Benzofuran-2-carboxvlic acid IfSM-r-G-fluoro-benzensulfonvD-S-oxo-azepan-4-vlcarbamovn-3-methvl-1 -butyl I- amide <br><br> 20 a.) Allyl-pent-4-enyl-carbamic acid benzyl ester <br><br> To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added allyl-carbamic acid benzyl ester (7.3 g, 38.2 mriiol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 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 25 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^, filtered and concentrated. Column chromatography of the residue (10% ethyl acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(ES) 260 (M+H+). <br><br> 255 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> b.) 2,3,4,7-Tetrahydro-azepine- 1-carboxylic acid benzyl ester <br><br> To a solution of compound of Example 280a (50 g) in dichloromethane was added bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (5.0 g). The reaction was heated to reflux until complete as determined by TLC analysis. The reaction was 5 concentrated in vacuo. Column chromatography of the residue (50% <br><br> dichloromethane:hexanes) gave 35 g of the title compound: MS(ES) 232 (M+H+). <br><br> c.) 8-C)xa-3-aza-bicyclo[5.1.0]octaiie-3-carboxylic acid benzyl ester <br><br> To a solution of the compound of Example 280b (35 g, 1.5 mol) in CH2C12 was 0 added m-CPBA (78 g, 0.45 mol). The mixture was stirred overnight at room temperature whereupon it was filtered to remove the solids. The filtrate was washed with saturated water and saturated NaHCO, (several times). The organic layer was dried (MgSO^), filtered and concentrated to give 35 g of the title compound which was of sufficient purity to carry on to the next step: MS(ES) 248 (M+-H+), 270 (M+Na+), <br><br> 5 <br><br> d.) 4-Azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester <br><br> To a solution of the epoxide from Example 280c (2.0 g, 8.1 mmol) in methanol:water (8:1 solution) was added NH4C1 (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). The reaction was heated to 40°C until complete consumption of the ,0 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. NaHC03, water, brine dried (MgS04), filtered and concentrated. Column chromatography (20% ethyl acetate:hexanes) of the residue provided 1.3 g of the title compound: MS(ES) 291 (M+H+) plus 0.14 g of trans-4-5 hydroxy-3-azido-hexahydro-lH-azepine e.) 4-Amino-3-hydroxy-azepane-l-carboxylic acid benzyl ester <br><br> To a solution of the azido alcohol of Example 280d (1.1 g, 3.79 mmol) in methanol was added triethyamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 i0 mmoL). 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(ES) 265 (M+H+). <br><br> 256 <br><br> WO 01/95911 <br><br> I <br><br> PCT/USO 1/19062 <br><br> f.) 4-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan-l-carboxylic acid benzyl ester <br><br> To a solution of the amino alcohol of Example 280e (720 mg, 2.72 mmol) in 5 CH2C12 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 HCl, sat. KjC03, water, brine, dried (MgS04), filtered and concentrated. Column chromatography of the residue (3% methanol:dichloromethane) gave 1.0 g of the 10 title compound: MS(ES) 478 (M+H+). <br><br> g-) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester <br><br> To a solution of the compound of Example 280f (1.0 g) and 10% Pd/C (catalytic) in 15 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 to provide 0.82 g of the title compound: MS(ES) 344 (M+H+). <br><br> 20 h.) (S)-2-Amino-4-methyl-pentanoic acid [l-(3~fluoro-benzenesulfonyl)-3-hydroxy-azepan-4-yl]-amide <br><br> To a solution of the compound of Example 280g (0.2 g) in dichloroethane (20 mL) was added p-NMM (0.32 g) and 3-fluorobenzenesulfonyl chloride (0.11 g). The reaction was stirred until complete as determined by MS analysis whereupon it was filtered, 25 concentrated. The residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL) was added. The reaction was maintained at room temperature until complete consumption of the starting material whereupon it was concentrated. The residue was dissolved in methanol whereupon p-carbonate resin was added. The mixture was shaken at room temperature for 4 hours then filtered and concentrated to provide 0.64 g of the title 30 compound. <br><br> 257 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> i.) Benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesuIfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]3-methyl-butyl}-amide <br><br> To a solution of the compound of Example 280h (0.15 g) in CH2C12 was added benzofuran-2-carboxylic acid (0.56 mmol), HOBt (0.09 mg), and p-EDC (0.75 mg). The 5 reaction was stirred overnight whereupon trisamine (0.50 g) was added and stirred an additional 1.5 hours. The reaction was filtered and concentrated to provide the title compound. <br><br> j.) Benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-10 4-ylcarbamoyl]3-methyl-butyl}-amide <br><br> To a solution of the compound of Example 280i (0.3 mmol) in CH2C12 was added Dess-Martin periodinane (0.25 g). The reaction was stirred until complete as determined by MS analysis. Workup and HPLC chromatography provided diastereomer 1: MS(ES) 543.2 (M+H)+ and diastereomer 2: MS(ES) 543.2 (M+H)+. <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> Example 281 <br><br> Preparation of (S~)-4-Methvl-2-f3-piperidin-l-vl-propanovlamino)-pentanoic acid B-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vll-aniide <br><br> Following the general procedures of Examples 280h-j except substituting 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride and 1-piperidinepropionoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 521.9 (M+H)+. <br><br> Example 282 <br><br> Preparation of Benzofuran-2-carboxvlic acid (CSV 1 -["-f4-ethvl-benzensulfonvB-3-oxo-azepan-4-vlcarbamovll-3-methvl-l-butvll- amide <br><br> Following the general procedures of Examples 280h-j except substituting 4-ethylnezenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride the title compound was <br><br> 258 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> prepared: Separation of the diastereomers provided diastereomer 1 MS(ES) 554.4 (M+H)+ and distereomer 2 MS(ES) 554.4 (M+H)+. <br><br> Example 283 <br><br> 5 <br><br> Preparation of 5-G-Trifluoromethvl-phenvlVfuran-2-carboxvlic acid (YS)-3-methvl-l-f 3-oxo-l-ri-(l-oxv-pvridin-2-vD-inethanovl'l-azepan-4-vlcarbaniovl)-butvl)-amide a.) 4-((S)-2-Amino-4-methyI-pentanoyIamino)-3-hydroxy-azepane-l-carboxyIic acid 10 benzyl ester <br><br> To a solution of the compound of Example 280f (7.32 g) in methanol was added 4M HCl in dioxane (38 mL). The reaction was stirred until complete whereupon it was concentrated to give 6.9 g of the title compound as a white solid. <br><br> 15 b.) 3-Hydroxy-4-[(S)-4-methyl-2-({ l-[5-(3-trifluoromethyl-phenyl)-ftiran-2-yl]-methanoyl}-amino)-pentanoylamino]azepane-l-carboxylic acid benzyl ester <br><br> To a solution of the compound of Example 283a (1.2 g) in dichloromethane was added TEA (0.93 mL), EDC (0.56 g), HOBt (0.36 g) and 5-[3-(trifluoromethyl) phenyl]-2-furoic acid (0.68 g). The reaction was stirred at room temperature until complete as 20 determined by TLC analysis. Workup and column chromatography provided 1.35 g of the title compound: MS (ES) 616 (M+H)+. <br><br> c.) 5-[3-(Trifluoromethyl)phenyl]-furan-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide 25 To a solution of the compound of Example 283b (1.3 g) in ethyl acetate methanol <br><br> (20 mL of an 8:1 mixture) was added 10% Pd\C. The mixture was stirred under a balloon of hydrogen gas until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered and concentrated to provide 0.96 g of the title compound which was used directly in the following reaction with no further purification. <br><br> 30 <br><br> 259 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> d.) 5-(3-Trifhioromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-1 -[ l-( 1 -oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl} -butyl)-amide <br><br> To a solution of the compound of Example 283c (0.3 g) in dichloromethane was added TEA (0.22 mL), EDC (0.13 g), HOBt (0.8 g) and picolinic acid N-oxide (0.09 g). <br><br> 5 The reaction was stirred at room temperature until complete as determined by TLC <br><br> analysis. Workup and column chromatography provided 0.16 g of the title compound: MS (ES) 603 (M+H)+. <br><br> e.) 5-(3-Trifluoromethyl-phenyl)-ftiran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-10 [l-(l-oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide <br><br> To a solution of the compound of Example 283d (0.15 g) in DMSO (1.5 mL) was added TEA (0.37 mL) and pyridine sulfur trioxide complex (0.21 g). The reaction was stirred until complete as determined by LCMS. Workup and column chromatography (10% methanol:dichloromethane) provided 0.12 g of the title compound: MS (ES) 601 (M+H)+. 15 The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. <br><br> Example 284 <br><br> 20 Preparation of Benzon.31-dioxole-5-carboxvlic acid ((SV3-methvl-1 -f 3-oxo-1 -[ 1 -oxv-t&gt;vridin-2-vl)-methanovll-azepan-4-vlcarbamovll-butvi)-amide <br><br> Following the general procedures of Examples 283b-e except substituting piperonylic acid for 5-[3-(trifluoromethyl) phenyl]-2-furoic acid the title compound was 25 prepared: MS(ES) 511 (M+H)+. <br><br> The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. <br><br> 260 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 285 <br><br> Preparation of 5-(3-Trifluoromethyl-phenvlVfuran-2-carboxvlic acid {(SM-IT-O-cvclohexvl-proDanovIV 3-oxo-azepan-4-vlcarhamov11 -3-methvl-butvl ?-amide <br><br> 5 <br><br> Following the general procedures of Examples 283b~e except substituting 3-cyclohexylpropionic acid for picolinic acid N-oxide the title compound was prepared: MS(ES) 618 (M+H)+. <br><br> The diastereomers were separated by HPLC to provide diastereomer 1 and 10 diastereomer 2. <br><br> Example 286 <br><br> 15 Preparation of Benzon.31-dioxole-5-carboxvlic acid ((SVl-ri-(3-cvclohexvl-propanovlV3-oxo-azepan-4-vlcarbamovll-3-methvI-butvl) -amide <br><br> Following the general procedures of Examples 283b-e except substituting 3-cyclohexylpropionic acid for picolinic acid N-oxide and piperonylic acid for 5-[3-20 (trifluoromethyl) phenyl]-2-furoic acid the title compound was prepared: MS(ES) 528 (M+H)+. <br><br> The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. <br><br> 25 Example 287 <br><br> Preparation of 5-("3-Trifluoromethvl-phenvD-furan-2-carboxvlic acid {(SV 1-1" l-(4-methvl-pentanovIV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> 30 Following the general procedures of Examples 283b-e except substituting 4- <br><br> methyl-pentanoic acid for picolinic acid N-oxide the title compound was prepared: MS(ES) 578 (M+H)+. <br><br> 261 <br><br> WO 01/95911 PCT/US01/19062 <br><br> The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. <br><br> Example 288 <br><br> 5 <br><br> Preparation of Benzori.31-dioxole-5-carboxvlic acid US')-l-ri-&lt;'4-methvl-pentanovl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvl) -amide <br><br> Following the general procedures of Examples 2S3b-e except substituting 4-10 methyl-pentanoic acid for picolinic acid N-oxide and piperonylic acid for 5-[3- <br><br> (trifluoromethyl) phenyl]-2-furoic acid the title compound was prepared: MS(ES) 488 (M+H)+. <br><br> The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. <br><br> 15. <br><br> 20 <br><br> 25 <br><br> Example 289 <br><br> Preparation of Benzofuran-2-carboxvlic acid ((S~) 1 - T3-oxo-1 -(propane-1 -sulfonvD-azepan-4-vlcarbamovll -3-methvl-1 -butvl \ - amide <br><br> Following the general procedures of Examples 280h-j except substituting propanesulfonyl chloride for 3-fluorosulfonyl chloride the title compound was prepared. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 491.2 (M+H)+ and diastereomer 2: MS(ES) 491.2 (M+H)+. <br><br> Example 290 <br><br> Preparation of Benzofuran-2-carboxvlic acid rfSM-r3-oxo-l-(ethanesulfonvl-azepan-4-vlcarbamovl')-3-methvl-l-butvll- amide <br><br> 30 <br><br> Following the general procedures of Examples 280h-j except substituting ethanesulfonyl chloride for 3-fluorobenzenesulfonyl chloride the title compound was prepared. <br><br> 262 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 477.4 (M+H)* and diastereomer 2: MS(ES) 477.4 (M+H)+. <br><br> 5 Example 291 <br><br> Preparation of 5-Fluoro-benzofuraD-2-carboxvIic acid {rS~)-3-methvl-l-f3-oxo-l-fl~oxv-pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butvl 1 -amide <br><br> 10 a.) {(S)-l-[3-Hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methy 1-butyl }-carbamic acid terf-butyl ester <br><br> Generation of 2-pyridmesulfonylchloride-N-oxide: To a 0°C solution of 2-mercaptopyridine-N-oxide (2.23 g, 17.55 mmol) in 9M HCl (33 mL) was bubbled chlorine gas for approximately 90 minutes. The dissolved chlorine was removed under vacuum at 15 0°C. <br><br> To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid Terr butyl ester of Example 280g (2.5 g, 7.28 mmol) in CH2C12 (100 mL) and sat. NaHC03 (400 mL) was added the solution of 2-pyridinesulfonylchloride-N-oxide (27 mL, 102 mg/mL) dropwise in portions. As the addition proceeds additional sat. NaHC03 is 20 added in order to maintain the pH at approximately 8-9. Upon complete addition of the sulfonylchloride the reaction is stirred for an additional hour whereupon the organic layer was removed and washed with brine. The organic layer was evaporated and the residue chromatographed (5% methanohdichloromethane) to provide 2.5 g of the title compound: MS (ES) 500 (M+tf). <br><br> 25 <br><br> b.) (S)-2-Ammo-4-methyl-pentanoic acid-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> To a solution of {(S)-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-30 ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester of Example 291a (2.0 g) in methanol (20 mL) was added 4 M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 1.5 hours whereupon it was concentrated to provide 1.8 g of the title compound: MS (ES) 400 (M+H+). <br><br> 263 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> c.) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyI-l-[3-hydroxy-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide <br><br> To a solution of the compound of Example 291b (0.30 g) in CH2CL, was added 5-5 fluoro-benzofuran-2-carboxylic acid (0.11 g), EDC (0.13 g), HOBt (0.086 g), and TEA (0.22 mL). The reaction was stirred until complete as determined by LCMS whereupon it was diluted with ethyl acetate and washed with water, sat. K^COj, IN HCl, brine, dried (MgS04), filtered and concentrated. Column chromatography (10% methanol: dichloromethane) of the residue provided 0.27 g of the title compound: MS(ES) 563 10 (M+H)\ <br><br> d.) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine- <br><br> 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide <br><br> To a solution of the compound of Example 291c (0.19 g) in DMSO (1.5 mL) was 15 added sulfur trioxide pyridine complex (0.26 g). The reaction was stirred until complete as determined by LCMS whereupon it was diluted with ethyl acetate and washed with sat. NaHC03, brine dried, filtered and concentrated. Column chromatography of the residue provided 0.15 g of the title compound as a mixture of diastereomers: MS(ES) 561 (M-t-H)+. Separation of the diastereomers by HPLC provided diastereomer 1 and 20 diastereomer 2. <br><br> Example 292 <br><br> Preparation of 5-Fluoro-3-methvl-benzofuran-2-carboxvlic acid f (SV3-methvl- 1-f3-oxo-1-25 fl-oxv-pvridine-2-sulfonv]Va2epan-4-vlcarbamovll-butvll-amide <br><br> Following the general procedure of Examples 29 lc-d except substituting 5-fluoro- <br><br> 3-methyl benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MSQBS) 575 (M+H)\ <br><br> 30 Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> 264 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 293 <br><br> Preparation of 6-Fhioro-3-methvl-benzofuran-2-carboxvlic acid IfSV3-methvl-l-r3-oxo-l-f l-oxv-pvridine-2-sulfonvl)-azepan-4-vlcarbamo vll-butvl) -amide <br><br> 5 <br><br> Following the general procedure of Examples 29 lc-d except substituting 6-fluoro-3-methyl benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 575 (M+H)+. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1 and 10 diastereomer 2. <br><br> Example 294 <br><br> Preparation of 3-MethvI-benzofuran-2-carboxvlic acid ((Rl-S-methvI-l-fS-oxo-i-d-oxv-15 pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvU-amide <br><br> Following the general procedures of Examples 280f-i except substituting N-Boc-D-leucine for N-Boc-L-leucine, 2-pyridinesulfonylchloride N-oxide for 3-fluorobenzenesulfonyl chloride and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-20 2-carboxylic acid the title compound was prepared: MS(ES) 556 (M+H)+. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> 265 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 295 <br><br> Preparation of 3-Methvl-furor3.2-bl-pvridine-2-carboxvlic acid lfSV3-methvI-l-r-3-oxo-l-(l-oxv-pvridine-2-suIfonvD-azepan-4-ylcarbamovn-butvl l-amide <br><br> 5 <br><br> Following the general procedure of Examples 29lc-d except substituting 3-methyl-furo[3,2-b]-pyridine-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 558 (M-t-H)+. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1 and 10 diastereomer 2. <br><br> Example 296 <br><br> Preparation of 5-Methoxv-benzofuran-2-carboxvlic acid {(SVl-f 1-G-fluoro-15 benzenesulfonvl')-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl}-amide <br><br> Following the general procedure of Examples 280h-j except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. <br><br> 20 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 574.5 <br><br> (M+H)+ and diastereomer 2 574.5 (M+H)+. <br><br> Example 297 <br><br> 25 Preparation of 3-Methvl-benzofuran-2-carboxvlic acid {("SVl-ri-G-fluoro-benzenesulfon.vl)-3-oxo-azepan-4-vIcarbamov]]-3-methv1-bntvi?-amide <br><br> Following the general procedure of Examples 280h-j except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound 30 as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 557.4 (M+H)+ and diastereomer 2 557.4 (M+H)+. <br><br> 266 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 298 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid ICSVl-ri-(3-fluoro-benzenesulfonvlV 5 3-oxo-azepan-4-vlcarbamovll -3-methvl-butvl 1 -amide <br><br> Following the general procedure of Examples 280h-j except substituting benzo[b]thiophene-2-carboxylic acid_for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 559-4 <br><br> (M+H)+ and diastereomer 2 559.4 (M+H)+. <br><br> Example 299 <br><br> 15 Preparation of 3-Methvl-furan-2-carboxvlic acid ICS1-1 -1" 1 -(3-fluoro-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovn-3-methvl-butvl)-amide <br><br> Following the general procedure of Examples 280h-j except substituting 3-methyl-furan-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a 20 mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.2 (M+H)+ and diastereomer 2 507.4 (M+H)+. <br><br> 267 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 300 <br><br> Preparation of Ouinoline-2-carboxvlic acid ((SVl-ri-CS-fluoro-benzenesulfonvD-S-oxo-azepan-4-vlcarbamovll-3-methvl-butvl) -ami de <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting quinoline-2-carboxylic acid for benzoforan-2-carboxylic acid provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 554.2 10 (M+H)+ and diastereomer 2 MS(ES) 545.2 (M+H)\ <br><br> Example 301 <br><br> Preparation of Thienor3.2-blthiophene-2-carboxvlic acid (fSM-ri-(3-fluoro-15 benzenesulfonvlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the general procedure of Examples 280h-j except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. <br><br> 20 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 565.2 <br><br> (M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)\ <br><br> Example 302 <br><br> 25 Preparation of Ouitioxaline-2-carboxvlic acid US~)-l-IT-(3-fluoro-benzenesulfonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvll-amide <br><br> Following the general procedure of Examples 280h-j except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title 30 compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 555.4 (M+H)+ and diastereomer 2 MS(ES) 555.4 (M+H)\ <br><br> 268 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 303 <br><br> Preparation of Thiophene-2-carboxvlic acid l(SVl-ri-f3-fluoro-benzenesulfonvD-3-oxo-azepan-4-vlcarbamovH-3-methv1-hutvB-amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting thiophene-2-carboxyIic acid for benzofuran-2-carboxyIic acid provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 509.4 10 (M+H)+ and diastereomer 2 MS(ES) 509.2 (M+H)+. <br><br> Example 304 <br><br> Preparation of 5-Methvl-thiophene-2-carboxvlic acid (fSVl-T l-G-fluoro-benzenesulfonvD-15 3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl}-amide <br><br> Following the general procedure of Examples 280h-j except substituting 5-methyl-thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. <br><br> 20 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 523.2 <br><br> (M+H)+ and diastereomer 2 MS(ES) 523.4 (M+H)+. <br><br> 269 <br><br> WO 01/95911 PCT/USO 1/19062 <br><br> Example 305 <br><br> Preparation of 5-Methoxv-benzofuran-2-carboxvlic acid [YSyi-(l-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvl7-amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1: MS(BS) 507.4 <br><br> (M+H)+ and diastereomer 2 MS(ES) 507.4 (M+H)\ <br><br> Example 306 <br><br> 15 Preparation of 3-Methvl-benzofuran-2-carboxvlic acid ["CSV 1 -(l-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvn-amide <br><br> Following the general procedure of Examples 280h-j except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride <br><br> 20 for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 491.2 (M+H)+ and diastereomer 2 MS(ES) 491.2 (M+HT. <br><br> 25 Example 307 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid r(SVl-d-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovlV3-methvl-butvn-amide <br><br> 30 Following the general procedure of Examples 280h-j except substituting benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> 270 <br><br> WO 01/95911 <br><br> PCT/USO1/19062 <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 493.4 (M+H)+ and diastereomer 2 MS(ES) 493.4 (M+H)+. <br><br> Example 308 <br><br> 5 <br><br> Preparation of 3-Methvl-furan-2-carboxvlic acid IYS)-l-fl-ethanesuIfonvl-3-oxo-azepan-4-vlcarbamovlV3-methvl-butvll-amide <br><br> Following the general procedure of Examples 280h-j except substituting 3-methyl-10 furan-2-carboxyIic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 441.2 (M+H)+ and diastereomer 2 MS(ES) 441.2 (M+H)+. <br><br> 15 Example 309 <br><br> Preparation of OuinoIine-2-carboxvlic acid rfS")-l-("l-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovlV3-methvI-butvU-amide <br><br> 20 Following the general procedure of Examples 280h-j except substituting quinoline- <br><br> 2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 488.2 (M+H)+ and diastereomer 2 MS(ES) 488.2 (M+H)\ <br><br> 25 <br><br> Example 310 <br><br> Preparation of Thienor3.2-blthiophene-2-carboxvlic acid ITS')-1 -fl-ethanesulfonvl-3-oxo-azepan^-vlcarbamovD-S-methvl-butvll-amide <br><br> 30 <br><br> Following the general procedure of Examples 280h-j except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and <br><br> 271 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 499.4 (M+H)+ and diastereomer 2 MS(ES) 499.4 (M+H)+. <br><br> Example 311 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid ffS)-1 -fl-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-methvl-butvll-amide <br><br> Following the general procedure of Examples 280h-j except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 489.2 (M+H)+ and diastereomer 2 MS(ES) 489.2 (M+H)+. <br><br> Example 312 <br><br> Preparation of Thiophene-2-carboxvlic acid IYSM-(l-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovlV3-methvI-butvll-amide <br><br> Following the general procedure of Examples 280h-j except substituting thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 443.4 (M+H)+ and diastereomer 2 MS(ES) 443.2 (M+H)+. <br><br> 272 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 313 <br><br> Preparation of 5-Methvl-thiophene-2-carboxvlic acid rfSM-fl-ethanesulfonvl-3-oxo-azepan-4-vlcarbamovl)-3-metfavl-butvll-amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting 5-methyl-thiophene-2-carboxylic acid for benzoforan-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 457.2 <br><br> (M+H)+ and diastereomer 2 MS(ES) 457.4 (M+H)+. <br><br> Example 314 <br><br> 15 Preparation of 5-Methoxv-benzofuran-2-carboxvlic acid {(SVl-r3-oxo-l-fpropane-l-sulfonvl)-azepan-4-vlcarbamovn-3-methvl-1-butyl)- amide <br><br> Following the general procedure of Examples 280h-j except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and 1- <br><br> 20 propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 521.4 (M+H)+ and diastereomer 2 MS(ES) 521.2 (M+H)+. <br><br> 273 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 315 <br><br> Preparation of 3-Methyl-benzofuran-2-carboxylic acid {(S)-1-[3-oxo-1 -(propane-1-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl}- amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 505.4 <br><br> (M+H)+ and diastereomer 2 MS(ES) 505.2 .(M+H)\ <br><br> Example 316 <br><br> 15 Preparation of Benzorblthiophene-2-carboxvlic acid ICS)-1 -1"3-oxo-1 -("propane-1 -sulfonvl)-azepan-4-vIcarbamovll-3-methvl- 1-butvl 1 - amide <br><br> Following the general procedure of Examples 280h-j except substituting benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and 1- <br><br> 20 propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.4 (M+H)+ and diastereomer 2 MS(ES) 507.4 (M+Hf. <br><br> 274 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 317 <br><br> Preparation of 3-MethvI-furan-2-carboxvlic acid lfS')-l-T3-oxo-l-fpropane-l-sulfonvl')-azepan-4-vlcarbamovn-3-methvl- 1-butvl} - amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting 3-methyl-furan-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 455.2 <br><br> (M+H)+ and diastereomer 2 MS(ES) 455.4 (M+H)+. <br><br> Example 318 <br><br> 15 Preparation of 2,5-Dimethvl-benzofuran-2-carboxvlic acid {fSM-B-oxo-l-fpropane-l-sulfonvlVazepan-4-vlcarbamovn-3-methvl-l-butvl}- amide <br><br> ■ I <br><br> Following the general procedure of Examples 280h-j except substituting 2,5-dimethyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and 1- <br><br> 20 propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 469.4 (M+H)+ and diastereomer 2 MS(ES) 469.2 (M+H)\ <br><br> 275 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 319 <br><br> Preparation of Ouinoline-2-carboxvlic acid KSVl-re-oxo-l-fpropane-l-sulfonvD-azepan^-vlcarbamovll-3-methvI- 1-butvl 1 - amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 565.2 ' 10 (M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)+. <br><br> Example 320 <br><br> Preparation of Thienor3.2-blthiophene-2-carboxvlic acid {(SV l-r3-oxo-l-fpropane-l-15 sulfonvlVazepan-4-vlcarbamovll-3-methvl-1 -butvl) - amide <br><br> Following the general procedure of Examples 280h-j except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound 20 as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 513.2 (M+H)+ and diastereomer 2 MS(ES) 513.2 (M+H)\ <br><br> 276 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 321 <br><br> Preparation of Qm'nnxaline-2-carboxvlic acid HSVl-B-oxo-l-lpropane-l-sulfonvD-azepan-4-vlcarbamovll-3-methvl-l-butvlI- amide <br><br> Following the general procedure of Examples 280h-j except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 503.4-(M+H)+ and diastereomer 2 MS(ES) 503.4 (M+H)+. <br><br> Example 322 <br><br> Preparation of Thiophene-2-carboxvlic acid F CSV 1-F3-oxo-1 -(propane-1 -sulfonvlVazepan-4-vlcarbamovl1-3-methvl- 1-butvl 1- amide <br><br> Following the general procedure of Examples 280h-j except substituting thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 457.4 (M+H)+ and diastereomer 2 MS(ES) 457.4 (M+H)+. <br><br> 277 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 323 <br><br> Preparation of 5-Methvl-thioDhene-2-carboxvlic acid {(SVl-B-oxo-l-fpropane-l-sulfonvl)-azepan-4-vlcarbamovll-3-methvl-l-butvl&gt;- amide <br><br> 5 <br><br> Following the general procedure of Examples 280h-j except substituting 5-methyl-thiophene-2-carboxylie acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 471.4 <br><br> (M+H)+ and diastereomer 2 MS(ES) 471.4 (M+H)+. <br><br> Example 324 <br><br> 15 Preparation of 5-Methoxv-3-methvl-benzofuran-2-carboxvlic acid l(SV3-methvl-l-r3-oxo-l-d-oxv-pvridine-2-sulfonvl)-azepan-4-vlcarbamovll-butvl&gt;-amide <br><br> Following the general procedure of Examples 29 lc-d except substituting 5-methoxy-3-methyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid 20 provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 565.2 (M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)\ <br><br> 25 <br><br> Example 325 <br><br> Preparation of 3.5-Dimethvl-benzofuran-2-carboxvlic acid /(S)-3-methvl- l-f~3-oxo-1 -fl-oxv-pvridine-2-sulfonvl')-azepan-4-vlcarbamovll-butvll-amide <br><br> Following the general procedure of Examples 29 lc-d except substituting 3,5-30 dimethyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 571 (M+H)+. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> 278 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 326 <br><br> Preparation of 3-Ethvl-benzofuran-2-carboxvlic acid f fSV3-methvl-l-r3-oxo-l-(l-oxy-5 pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butvll-amide <br><br> Following the general procedure of Examples 29lc-d except substituting 3-ethyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 571 (M+H)\ <br><br> 10 Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> Example 327 <br><br> ,15 Preparation of 4-Methoxv-3-methvl-benzofuran-2-carboxvlic acid (CSV3-methvl-l-f3-oxo-l-('l-oxv-pvridine-2-sulfonvlVazepan-4-vlcarbamovll-butvlVamide <br><br> Following the general procedure of Examples 29 lc-d except substituting 4-methoxy-3-methyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid 20 provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)\ Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> 25 <br><br> . Example 328 <br><br> Preparation of l-Methvl-naphthol"2.1-b"l-furan-2-carboxvlic acid USV3-methvl-l-r3-oxo-l-(l-oxv-pvridine-2-sulfonvl&gt;azepan-4-vlcarbamovll-butvll-amide <br><br> Following the general procedure of Examples 29 lc-d except substituting 1-methyl-30 naphtho[2,l-b]-furan-2-carboxylic acid for 5-fIuoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 607 (M+H)+. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> 279 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> Example 329 <br><br> Preparation of 6-Methoxv-3-methvl-benzofuran-2-carboxvlic acid I('SV3-methvl-l-r3-oxo-5 l-(l-oxv-Pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butvl}-amide <br><br> Following the general procedure of Examples 291c-d except substituting 6-methoxy-3-methyl-benzofuran-2-carboxylip acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. 0 Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. <br><br> Example 330 <br><br> 5 Preparation of 3-Methvl-benzofuran-2-carboxvlic acid f 1.3-dimethvl-l-r3-oxo-l-("l-oxv-pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butvl]-amide a.) 4-(2-fert-Butoxycarbonylamino-2,4-dimethyl-pentanoylamino)-3-hydroxy-. azepane-l-carboxylic acid benzyl ester <br><br> 0 To a solution of N-[(l,l-dimethylethoxy)carbonyl]-2-methyl-(d,l)-leucine (3.0g) in methlene chloride was added EDC (2.34g), HOBt (1.65g), Et3N (1.7 ml) and the compound of Example 280e (3.23 g). After stirring at room temperature over night the mixture was washed with 0.1N HCl, Sat. NaHC03, H2O, Brine. The organic layer was concentrated and residue was purified by flash column chromatography eluting with CH2CI2 : CH3OH 5 (95:5) to give the title compound as a white solid (4.0g, 66.6%). MS: 492.4 (M+H)+ <br><br> b.) [l-(3-Hydroxy-azepan-4-ylcarbamoyl)-l,3-dimethyl-butyl]-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 330(a) (3.04 g, 8.00 mmol) in ethyl 0 acetate (50 mL) was added 10% palladium on carbon (1.5 g). After stirring at room temperature under a hydrogen atmosphere for 16 h, the mixture was filtered through celite. The filtrate was concentrated to yield the title compound as a yellow oil (1.97 g, 100%). MS (ESI): 358.4 (M+H)+ <br><br> 280 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> c.) {1 - [3-Hydroxy-1 -(1-hy droxy-pyridine-2-sulfonyl)-azepan-4-y lcarbamoy 1]-1,3-dimethyl-buty 1} -carbamic acid tert-butyl ester <br><br> 2-Mercaptane N-oxide (1.25g) was disolved in concentrated HCl (5.5ml). After. <br><br> 5 cooled to 0°C water (3ml) was added. CI2 gas was bubbled through this solution for 1.5h. Water solution was extacted with cold CH2CI2 then the combined organic layer was washed with Sat.NaHCC&gt;3, brine. To a solution of the compound of Example 330b (1.20 g) and Et3N (1.3 ml) in DCE (10 ml) was added the sulfonyl chloride which was freshly prepared above at 0°C. Stirring was kept for lh then the reaction mixture was washed with 10 brine, dried over Na2S04, concentrated and purified through flash column chromatograpghy eluting with CH2CI2: CH3OH (95:5). The filtrate was concentrated to yield the title compound as white solid (1.2 g, 70%). MS: 515.4 (M+H)\ <br><br> d.) 2-Amino-2,4-dimethyl~pentanoic acid [3-hydroxy-l-(hydroxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide <br><br> 15 To a stirring solution of the compound of Example 330c (l.Og, 2.04 mmol) in methanol (10ml) was added HCl (4M in Dioxane) (10 ml). After stirring at room temperature for 3hr, the solution was concentrated to get white solide. To a solution of the white solid (0.81g, 1.53mmol, 75%) in methnol (30ml) was added P-C03 (2.9g, 2.63mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the 20 title compound as white solid (0.57g, 1.45mmol, 95%). MS: 415.4 (M+H)+. <br><br> e.) 3-Methyl-benzofuran-2-carboxylic acid {1,3 -dimethyl-1 - [3-hydroxy-1 - (1 ~oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide <br><br> To a solution of the compound of Example 330d (0.150 g, 0.448 mmol) in CH2C12 25 (20 mL) was added 3-methyl benzofuran-2-carboxylic acid (0.109 g), 1- <br><br> hydroxybenzotriazole (0.106g, 0.762mmol), and P-EDC (0.85g, Immol/g) in CHjC12 (10 mL) . After shaking at room temperature for over night, the solution was treated with tisamine (0.589g, 3.75mmol/g). After shaking for another 2hr, the solution was filtered and concentrated to yield the title compound as a white solid (166.7mg, 70%). MS (ESI): 30 573.2(M+H)+. <br><br> 281 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> f.) 3-Methyl-benzofuran-2-carboxylic acid{ l,3-dimethyl-l-[3-oxo-l-(oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide <br><br> To a stirring solution of the compound of Example 330e (140.7mg, 0.245mmol) in DMSO (2mL) was added Py-S03 (155.7mg, 0.98mmol) and Et3N (0.27ml, 1.96mmol). After stirring at room temperature for 2 h. Sat. NaHC03 and ethyl acetate was added to quench the reaction. Organic layer was washed with brine, dried over Na^S04 and concentrated.The residue was purified through flash column chromatograghy eluting with CH2CI2 :CH30H (95:5) to yield the title compound as a white solid (69.9mg, 50.8 %). MS (ESI): 571.2(M+H)+ . <br><br> Example 331 <br><br> Preparation of Benzofuran-2-carboxvlic acid r(S)-3-methvl-l-r3-oxo-l-quinoIin-2-vlmethvl-azepan-4-vlcarbamovn-butvll-amide a.) [(S)-l-(3-Hydroxy-l-quinoline-2-ylmethyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 280g (1.0 g) in CH2C12 was added a-quinoline carbaldehyde (0.68 g) and NaBH(OAc)3 (1.2 g). Workup and column chromatography (6% methanol: dichloromethane) provided 1.4 g of the title compound: MS(ES) 485 (M+H)\ <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid (3-hydroxy-l-quinolin-2-methyl-azepan-4~yl)-amide <br><br> To a solution of the compound of Example 331a (1.4 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred until complete whereupon the reaction was concentrated to provide 1.3 g of the title compound: MS(ES) 385 (M+H)\ <br><br> 282 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> c. ) Benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-hydroxy-l-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl} -amide <br><br> Following the general procedure of Example 291c except substituting the compound of Example 331b and benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-5 carboxylic acid the title compound was prepared: MS(ES) 545 (M+H)\ <br><br> d.) Benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin~2-ylmethyl-azepan-4-y lcarbamoy l]-butyl}-amide <br><br> Following the general procedure of Example 291d except substituting the 10 compound of Example 331c the title compound was prepared: MS(ES) 543 (M+H)+. <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid f&lt;"S)-3-methvl-l-f3-oxo-l-quinolin-15 2-vlmethvI-azepan-4-vlcarbamovI1-butyl}-amide <br><br> Following the procedure of Example 33 lc-d except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid r(SV3-methvl-l-r3-oxo-l-auinolin-2-vlmethyl-azepan-4-vlcarbamovll-butvl)-amide <br><br> Following the procedure of Example 33 lc-d except substituting benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 541 (M+H)+. <br><br> Example 332 <br><br> prepared: MS(ES) 541 (M+H)+. <br><br> 20 <br><br> Example 333 <br><br> 25 <br><br> 283 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 334 <br><br> Preparation of Benzofuran-2-carboxvlic acid (YSy3-methvl-1-( 3-oxo-l-fl-toluene-2-sulfonvlamino)-methanovll-azepan-4-vlcarbamovl)-butvlt-amide <br><br> 5 <br><br> a.) ((S)-l-{3~Hydroxy-l-[l-(toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-3-methyl-butyl)-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 280g (1.0 g) in CH2C12 was added o-toluenesulfonyl isocyanate (0.68 g). The reaction was stirred until complete consumption 10 of the starting material was observed. Workup and column chromatography (6% <br><br> methanolrdichloromethane) provided 1.28 g of the title compound: MS(ES) 541 (M+H)+. <br><br> b.) (S)-2-Amino-4-methyl-pentanoic acid {3-hydroxy-l-[l-(toluene-2-sulfonylamino)-methanoyl]-azepan-4-yl}-amide <br><br> 15 Following the procedure of Example 283a except substituting the compound of <br><br> Example 334a the title compound was prepared: MS(ES) 441 (M+HTT. <br><br> c.) Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-l-[l-toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide <br><br> 20 Following the procedure of Example 280i except substituting the compound of <br><br> Example 334b the title compound was prepared: MS(ES) 585 (M+H)+. <br><br> d.) Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3~oxo-l-[l~toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide <br><br> 25 Following the procedure of Example 29Id except substituting the compound of <br><br> Example 334c the title compound was prepared: MS(ES) 583 (M+H)+. <br><br> 284 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 335 <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid f("SV3-methvl-l-f3-oxo-l-ri-toluene-2-sulfonvlamino')-methanovll-azepan-4-vlcarbamovn-btttvlVamide <br><br> 5 <br><br> Following the procedures of Example 334c-d except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+. <br><br> 10 Example 336 <br><br> Preparation of Benzofblthiophene-2-carboxvlic acid (YS)-3-methvl-l-l3-oxo-Hl-toluene-2-sulfonvlamino)-methanovll-azepan-4-vlcarbamovn-butvlVamide <br><br> 15 Following the procedures of Example 334c-d except substituting <br><br> Benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 599 (M+H)+. <br><br> 20 <br><br> Example 337 <br><br> Preparation of Benzofuran-2-carboxvlic acid (YSV 3-methvl-1-(3-oxo-1-[2-chloro-benzenesulfonvlamino')-methanovn-azepan-4-vlcarbamovll-butvl')-amide <br><br> Following the procedures of Example 334a-d except substituting 2-25 chlorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 603 (M+H)+. <br><br> 285 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 338 . <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid (~(SV3-methvl-l-{3-oxo-l-r2-chloro-benzenesulfonvlamino)-methaDovll-azepan-4-vlcarbamovll-butvl&gt;-amide <br><br> Following the procedures of Example 334a-d except substituting 2-chlorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 617 (M+H)+. <br><br> Example 339 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid (YSy3-methvl-l-f3-oxo-l-r2-chloro-benzenesulfonvlamLno")-methanovll-azeDan-4-vlcarbamovl)-butvl)-amide <br><br> Following the procedures of Example 334a-d except substituting 2-chlorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 619 (M+H)\ <br><br> Example 340 <br><br> Preparation of Benzofuran-2-carboxvlic acid ((SV3-methvl-l-{3-oxo- 1-14-fluoro-benzenesulfonvlainino)-methanovll-azepan-4-vlcarbamovl}-butvl)-amide <br><br> Following the procedures of Example 334a-d except substituting 4-fluorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 587 (M+H)+. <br><br> 286 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 341 <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid &lt;YS")-3-methvl-1 - f 3-oxo-1 -r4-fluoro-benzenesulfonvlaminoVmethanovll-azepan^-vlcarbamovll-butvlVamide <br><br> Following the procedures of Example 334-d except substituting 4-fluorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 601 (M+H)+. <br><br> Example 342 <br><br> Preparation of Benzol~b"lthiophene-2-carboxvlic acid (fS&gt;3-methvl-1-{3-oxo-1-[4-fluoro-benzenesulfonvlamino)-methanovi'l-azepan-4-vIcarbamovl)-butvlVamide <br><br> Following the procedures of Example 334a-d except substituting 4-fluorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 603 (M+H)+. <br><br> Example 343 <br><br> Preparation of Benzofuran-2-carboxvlic acid (&lt;SV3-methvl- 1-f 3-oxo-1 - T l-toIuene-4-sulfonvlaminoVmethanovll-azepan-4-vlcarbamovl}-butvl)-amide <br><br> Following the procedures of Example 334a-d except substituting p-toluenesulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 583 (M+H)+. <br><br> 287 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 344 <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid ffS)-3-methvl-l-(3~oxo-l-["l-toluene-4-sulfonvlamino')-methanovll-azepan-4-vlcarbamoyl}-butvl')-amide <br><br> 5 <br><br> Following the procedures of Example 334a-d except substituting p-toluenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid_for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+. <br><br> 10 Example 345 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid (CSV3-methvl-1- (3-oxo-1-T1 -toluene-4-sulfonvlamino')-methanovll-azepan-4-vlcarbamovl}-butvlVamide <br><br> 15 Following the procedures of Example 334a-d except substituting p-toluenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+. <br><br> 20 <br><br> Example 346 <br><br> Preparation of Benzofuran-2-carboxylic acid f (SV3-methvl-l-ri-(6-methvl-pvridin-2-vlmethvl)-3-oxo-azepan-4-v1carbamovl1-buty])-amide <br><br> Following the general procedures of Example 331a-d except substituting 6-25 methylpyridine-2-aldehyde for a-quinoline carbaldehyde the title compound was prepared: MS(ES) 491 (M+H)+. <br><br> The diastereomers were separated by HPLC to provide diastereoemr 1 and diastereomer 2. <br><br> 288 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 347 <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid ffS)-3-methvl-l-ri-("6-methyl-pvridin-2-vlmethvIV3-oxo-azepan-4-vlcarbamovl1-butvl&gt;-amide <br><br> 5 <br><br> Following the general procedures of Example 331a-d except substituting 6-methylpyridine-2-aldehyde for a-quinoline carbaldehyde and 3-methyl-benzofuran-2-carboxylic acid for benzofuran carboxylic acid the title compound was prepared: MS(ES) 505 (M+H)+. <br><br> 10 The diastereomers were separated by HPLC to provide diastereoemr 1 and diastereomer 2. <br><br> Example 348 <br><br> 15 Preparation of Benzo[b"lthiophene-2-carboxvlic acid \ (SV3-methvl- 1-T1-C6-methvl-pvridin- <br><br> 2-vlmethvl)-3-oxo-azepan-4-vlcarbamov1'l-butvll-amide <br><br> Following the general procedures of Example 331a-d except substituting 6-methylpyridine-2-aldehyde for a-quinoline carbaldehyde and benzo[b]thiophene-2-20 carboxylic acid for benzofuran carboxylic acid the title compound was prepared: MS(ES) 507 (M+H)+. <br><br> The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. <br><br> 25 Example 349 <br><br> Preparation of Benzorblthiophene-2-carboxvlic acid f (SVl-fl-f2-fluoro-phenvlcarbamovlV <br><br> 3-oxo-azepan-4-vlcarbamovl'l-3-methvl-butv]?-amTde <br><br> 30 a.) {(S)-l-[l-(2-fluorophenylcarbamoyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl }-carbamic acid tert-butyl ester <br><br> To a solution of the compound of Example 280g (0.1 gm, 0.29mmol) dissolved in THF was added 2-flurophenyl isocyanate (32 ml, 0.29 mmol) and stirred for lhr. THF was <br><br> 289 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> removed in vaccuo and the compound was directly used in the next step: MS(ES): 481.02(M+H)+. <br><br> b.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid 5 (2-fluoro-phenyl)-amide <br><br> To a solution of the compound of Example 349a (1.96 g, 4.1 mmol) dissolved in MeOH was added 4M HCl/ dioxane (5ml, 20.3 mmol) and allowed to stir at RT for 2hr. Excess reagent was removed in vaccuo and azeotroped with toluene to yield 1.84gm of the product. <br><br> 10 <br><br> c.) Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> To a solution of the compound of Example 349b (0.11 g, 0.28 mmol) dissolved in dichloromethane were added P-EDC (0.35 g, 1.8 mmol/g), HOBT (0.06 g, 0.49 mmol) and 15 2-benzothiophene carboxylic acid (0.077 gm, 0.432 mmol). The reaction mixture was shaken for 16 hr. The reaction was continued for one more hour by the addition of trisamine(0.38 gm, 3.7 mmol/g), followed by the filtration of the product. The product was purified on a silica gel column to yield 112.5 mg of the product: MS(ES): 541.2(M+H)+. <br><br> 20 d.) Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide <br><br> To a solution of the compound of example 349c (0.112 g, 0.2 mmol) was dissolved in dichloromethane followed by the addition of Dess-Martin periodinane (0.175 g, 0.41 mmol). The reaction was stirred for lhr followed whereupon it was washed with Na2S203, 25 NaHC03 and brine. The compound was purified on a silica gel column to yield 78 mg of the product as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS (ES) 539 (M+H)+ and diastereomer 2: 539 MS(ES) (M+H)+. <br><br> 290 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 350 <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid i(SI-l-ri-(2-fluoro-phenvlcarbamovl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvl)-amide <br><br> 5 <br><br> Following the general procedures of example 349c-d except substituting 3-methyl-benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 537 10 (M+H)+ and diastereomer 2: MS(ES) 537 (M+H)+. <br><br> Example 351 <br><br> Preparation of 2.4-Dimethv1ftiran-3-carboxvlic acid ICS)-l-Tl-Q-fluoro-phenvlcarbamovD-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl) -amide <br><br> 15 <br><br> Following the general procedures of example 349c-d except substituting 2,4-dimethylfuran-3-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 501 20 (M+H)+ and diastereomer 2: MS(ES) 501 (M+H)+. <br><br> Example 352 <br><br> Preparation of Ouinoxaline-2-carboxvlic acid f (SV 1 -T1 -(2-fluoro-phenvlcarbamovlV3-oxo-25 azepan-4-vlcarbamovn-3-methvl-butvl 1 -amide <br><br> Following the general procedures of example 349c-d except substituting quinoxaline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> 30 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 535 <br><br> (M+H)+ and diastereomer 2: MS(ES) 535 (M+H)+. <br><br> 291 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> Example 353 <br><br> Preparation of Thienor3.2-b1thiophene-2-carboxvlic acid (("SVl-[T-f2-fluoro-phenvlcarbamovl)-3-oxo-azeDan-4-vIcarbamovll-3-methvl-butvll-amide <br><br> 5 <br><br> Following the general procedures of example 349c-d except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 545 10 (M+H)+ and diastereomer 2: MS(ES) 545 (M+H)+- <br><br> Example 354 <br><br> Preparation of Ouinoline-2-carboxvlic acid ((SV 1-f l-f2-fluoro-phenvlcarbamovl&gt;3-oxo-15 azepan-4-vlcarbamovll-3-methvl-butyl|-amide <br><br> Following the general procedures of example 349c-d except substituting quinoline-2-carboxylic acid_for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> 20 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 534 <br><br> (M+H)+ and diastereomer 2: MS(ES) 534 (M+H)+. <br><br> Example 355 <br><br> 25 Preparation of 4-Methvl-thiophene-2-carboxvlic acid l(S)-l-ri-f2-fluoro-phenvlcarbamovlV3-oxo-azeDan-4-vlcarbamovn-3-methvl-butvll-amide <br><br> Following the general procedures of example 349c-d except substituting 4-methyl-thiophene-2-carboxylic acid for benzo[b]thiophene-2~carboxylic acid the title compound 30 was prepared. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 503 (M+H)+ and diastereomer 2: MS(ES) 503 (M+H)+. <br><br> 292 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 356 <br><br> Preparation of 5-Methoxv-benzofuran-2-carboxvlic acid {CSVl-ri-f2-fluoro-phenvlcarbamovlV3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> 5 <br><br> Following the general procedures of example 349c-d except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 553 10 (M+H)+ and diastereomer 2: MS(ES) 553 (M+H)+. <br><br> Example 357 <br><br> Preparation of 4-Methvl-furan-2-carboxvlic acid l(S&gt;l-ri-(2-fluoro-phenvlcarbamovD-3-15 oxo-azepan-4-vlcarbamovn-3-methvl-butvl 1 -amide <br><br> Following the general procedures of example 349c-d except substituting 4-methyl-furan-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. <br><br> 20 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 487 <br><br> (M+H)+ and diastereomer 2: MS(ES) 487 (M+H)+. <br><br> Example 358 <br><br> 25 Preparation of Benzofuran-2-carboxvlic acid IYSyi-d-butvl-3-oxo-azepan-4-vlcarbamoviy 3-methvl-butvll-amide <br><br> Following the general procedure of Examples 331a-d except substituting butyraldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation <br><br> 30 of the diastereomers by HPLC provided diastereomer 1: MS(ES) 441.9 (M+H)+ and diastereomer 2: MS(ES) 441.9 (M+H)+. <br><br> 293 <br><br> WO 01/95911 <br><br> PCT/USO 1/19062 <br><br> Example 359 <br><br> Preparation of Benzofuran-2-carboxvlic acid ITSM-fl -propyl-3-oxo-azepan-4-vlcarbamovlV3-methvl-butvll-amide <br><br> 5 <br><br> Following the general procedure of Examples 331a-d except substituting propionaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 428 (M+H)+ and diastereomer 2: MS(ES) 428 (M+H)\ <br><br> 10 <br><br> Example 360 <br><br> Preparation of Benzofuran-2-carboxylic acid {(S)-l-[l-( 494.2)-3-oxo-azepan-4-y lcarbamoy l]-3-methy 1-butyl} -amide <br><br> 15 <br><br> Following the general procedure of Examples 331a-d except substituting 2-fluorobenzaldeyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) (M+H)+ and diastereomer 2: MS(ES) 494.2 (M-t-H)+. <br><br> 20 <br><br> Example 361 <br><br> Preparation of Benzofuran-2-carboxvlic acid ((SV3-methvl-l-fl-(2-morpholm-4-vl-thiazol-4-vlmethvl")-3-oxo-azepan-4-vlcarbamovll-butvll-amide <br><br> Following the general procedure of Examples 331a-d except substituting 2-morpholin-4-yl-thiazole-4-carbaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 568.2 (M+H)+ and diastereomer 2: MS(ES) 568.4 (M+H)\ <br><br> 294 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 362 <br><br> Preparation of Benzofuran-2-carboxvlic acid (fSVl-ri-r5-ethvl-furaxi-2-vlmethvlV3-oxo-azepan-4-vIcarbamovll-3-methvl-butvll-amide <br><br> 5 <br><br> Following the general procedure of Examples 331a-d except substituting 5-ethyl-2-furaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 549.4 (M+H)+ and diastereomer 2: MS(ES) 549.4 (M+H)+. <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Example 363 <br><br> Preparation of Benzofuran-2-carboxvlic acid ICSVl-Tl-(3.4-dimethvl-thienor3.2-blthiophene-2-vlmethvl')-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvn-amide <br><br> Following the general procedure of Examples 331a-d except substituting 3,4-diemethylthieno[b]thiophene-2-carboxaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 566.2 (M+H)+ and diastereomer 2: MS(ES) 566.2 (M+H)\ <br><br> Example 364 <br><br> Preparation of Benzofuran-2-carboxvlic acid f CSV3-methvl-1 ~r3-oxo-1 -f3-phenvl-3H-n.2.31triazol-4-vlmethvl')-azepan-4-vlcarbamovl"l-butvH-amide <br><br> Following the general procedure of Examples 331a-d except substituting 2-phenyl-2H-pyrazole-3-carbaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 543.2 (M+H)+ and diastereomer 2: MS(ES) 543.4 (M+H)+. <br><br> 30 <br><br> 295 <br><br> 10 <br><br> WO 01/95911 PCT/USO 1/19062 <br><br> Example 365 <br><br> Preparation of Benzofuran-2-carboxvlic acid rCSVl-ri-fisothiazol-3-vlmethvl-3-oxo-azepan-4-vlcarbamovD-3-methvl-butvl 1 -amide <br><br> 5 <br><br> Following the general procedure of Examples 331a-d except substituting isothiazole-3-carbaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 483.1 (M+H)+ and diastereomer 2: MS(ES) 483.1 (M+H)+. <br><br> Example 366 <br><br> Preparation of Benzofuran-2-carboxvlic acid I"(SV3-methvl- 1-f3-oxo-l-thiophen-2-vlmethvl-azepan-4-vlcarbamovl')-butvll-amide <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Following the general procedure of Examples 331a-d except substituting thiophene-2-carbaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 582 (M+H)+ and diastereomer 2: MS(ES) 582 (M+H)\ <br><br> Example 367 <br><br> Preparation of Benzofuran-2-carboxvlic acid F(SV3-methvl-1 -("3-oxo-1 -thiophen-2-vlmethvl-azepan-4-vlcarbamovD-butvll-amide <br><br> Following the general procedure of Examples 331a-d except substituting benzo[b]thiophene-2-carbaldehyde for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 546 (M+H)* and diastereomer 2: MS(ES) 546 (M+H)+. <br><br> 30 <br><br> 296 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 368 <br><br> Preparation of Benzofuran-2-carboxvlic acid rfS)-3-methvl-l-(3-oxo-l-pentvl-azepan-4-vlcarbamovD-butvIl-amide <br><br> Following the general procedure of Examples 331a-d except substituting pentanal for a-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 556 (M+H)+ and diastereomer 2: MS(ES) 556 (M+H)+. <br><br> Example 369 <br><br> Preparation of Benzofuran-2-carboxvlic acid {(S)-3-methvl-l-ri-fl-methvl-lH-imidazol-2-vlmethvl)-3-oxo-azepan-4-vlcarbamovIl-butvl-amide <br><br> Following the general procedure of Examples 331a-d except 'substituting 3-methyl-3H-imidazole-4-carbaldehyde for a-quinoline carbaldehyde the title compound was prepared: MS(ES) 480.4 (M+H)+. <br><br> Example 370 <br><br> Preparation of l-Oxv-pvridine-2-carboxvlic acid I CSV3-methvl-1 -f3-oxo-l-(pvridine-2-sulfonvl")-azepan-4-vlcarbamovl 1-butvll-amide <br><br> Following the procedure of Example 280h-j except substituting l-oxy-pyridine-2-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1 (ESMS: M+H* = 504.2) and diastereomer 2 (ESMS: M+H+ = 504.2). <br><br> 297 <br><br> WO 01/95911 PCT/US01/19062 <br><br> Example 371 <br><br> Preparation of 2-Oxv-pvridine-3-carboxvlic acid (fS')-3-methvl-l-f3-oxo-l-&lt;/pvridine-2-sulfonvD-azepan-4-vlcarbamovl 1-butvlV-am <br><br> 5 <br><br> Following the procedure of Example 280h-j except substituting 2-oxy-pyridine-3-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1 (ESMS: M+EP = 504.2) and diastereomer 2 10 (ESMS: M+H+ = 504.2). <br><br> Example 372 <br><br> Preparation of lH-Benzoimidazole-5-carboxvlic acid ((Sy3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamovIl-butvl}-amide <br><br> 15 <br><br> Following the procedure of Example 280h-j except substituting 1H-benzoimidazole-5-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the tide compound. Separation of the diastereomers by HPLC gave diastereomer 1 (ESMS: M+HT 20 = 504.2) and diastereomer 2 (ESMS: M+H~ = 504.2). <br><br> Example 373 <br><br> Preparation of 4-((SV2-rCl-Benzofran-2-vl-methanovlVaminol-4-methvl-25 pentanoylamino I - l-methvl-3-oxo- 1-pentvl-azepanium <br><br> A solution of the compound of Example 368 in neat methyl iodide was heated at reflux for 48 hours whereupon the mixture was concentrated to provide the title compound: MS(ES) 471.6 (M+H)+. <br><br> 30 <br><br> 298 <br><br> WO 01/95911 PCT/USO1/19062 <br><br> Example 374 <br><br> Preparation of Benzofuran-2- carboxylic acid (CS')-l-ri-('1.2-dimethvl-l H -imidazole-4-sulfonvl")-3-oxo-azepan-4-vlcarbamoyll-3-methvl-butvl}-amide <br><br> 5 <br><br> Following the procedure of Example 280h-j except substituting 1,2-dimethyl-l H -imidazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound: MS(ES) 544.4 (M+H)+. <br><br> 10 Example 375 <br><br> Preparation of Benzofuran-2- carboxylic acid (CSVl-Fl-d-methyl-1 H -imidazoIe-4-sulfonvf)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl)-amide <br><br> 15 Following the procedure of Example 280h-j except substituting 1-methyl-1 H - <br><br> imidazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound: MS(ES) 530.2 (M+H)+. <br><br> 20 <br><br> Example 376 <br><br> Preparation of Benzofaran-2- carboxylic acid f (SI-l-H-d-methyl-l H -imidazole-4-sulfonvl")-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvl}-amide <br><br> Following the procedure of Example 280h-j except substituting 4-methanesulfonyl-25 benzenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 604.2 (M+H)+ and diastereomer 2: MS(ES) 604.2 (M+H)+. <br><br> 299 <br><br> WO 01/95911 <br><br> PCT/US01/19062 <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> Example 377 <br><br> Preparation of Benzofuran-2-carboxvlic acid ffSVl-ri-(2-metbanesuIfonvl-benzenesulfonvlV3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvn-amide <br><br> Following the procedure of Example 280h-j except substituting 2-methanesulfonyl-benzenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 604.2 (M+H)+ and diastereomer 2: MS(ES) 604.2 (M+H)+. <br><br> Example 378 <br><br> Preparation of Benzofuran-2-carboxvlic acid ffSVl-ri-f3.5-dimethvl-isoxazole-4-sulfonvl)-3-Qxo-azepan-4-vlcarbamov 11-3-methvl-butvl)-amide <br><br> Following the procedure of Example 280h-j except substituting 3,5-dimethyl-isoxazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 545.2 (M+H)+ and diastereomer 2: MS(ES) 545.2 (M+H)+. <br><br> Example 379 <br><br> Preparation of 3-Methvl-benzofuran-2-carboxvlic acid (dS.2RV2-methvl-l-r3-oxo-l-("pvridine-2-sulfonvl')-azepan-4-vlcarbamovD-biitv11-amide a.) 3-Methyl-benzofuran-2-carboxylic acid {(lS,2R)-2-methyl-l-[3-hydroxy-l-{pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide <br><br> Following the general proceures of Example 280f-i except substituting N-Boc-allo-isoleucine for N-Boc-leucine and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl 30 chloride and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared. <br><br> 300 <br><br></p> </div>

Claims (2)

    <div class="application article clearfix printTableText" id="claims"> <p lang="en"> WO 01/95911<br><br> PCT/US01/19062<br><br> b.) 3-Methyl-benzofuran-2-carboxylic acid {(lS,2R)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfony])-azepan-4-ylcarbamoyl]-butyl}-arnide<br><br> Following the general procedure of Example 29 Id except substituting the compound of Example 105b the title compound was prepared. Separation of the 5 diastereomers by HPLC provided diastereomer 1: MS(ES) 541 (M+H)+ and diastereomer 2: MS(ES) 541 (M+H)\<br><br> Example 380<br><br> 10 Preparation of 3-Methvl-benzofuran-2-carboxvlic acid 1143-0X0-1-Cpvridine-2-sulfonvD-azepan-4-vlcarbamov31-cvclopentvl }-amide<br><br> Following the general procedures of Examples 379a-b except substituting N-Boc-cycloleucine for N-Boc-allo-leucine the title compound was prepared: MS(ES) 539 15 (M+H)+.<br><br> Example 381<br><br> Preparation of Furor3,2-bl-pvridine-2-carboxvlic acid {fS)-3-methvl-l-r-3-oxo-1-fl-oxv-20 pvridine-2-sulfonvlVazepan-4-vlcarbamovn-butvl}-amide<br><br> Following the general procedure of Examples 291c-d except substituting furo [3,2-b]-pyridine-2-carboxylic acid for 5-fluoro-benzofuran-2~carboxylic acid provided the title compound as a mixture of diastereomers: MSQES) 587 (M+H)+.<br><br> 25 Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 544.2<br><br> (M+H)+ and diastereomer 2: MS(ES) 544.2 (M+H)+.<br><br> 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 30 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 folly set forth.<br><br> 301<br><br> WO 01/95911 PCT/USO1/19062<br><br> We claim:<br><br> 1. A compound of Formula IA:<br><br> 5<br><br> 10<br><br> R:<br><br> IA<br><br> wherein:<br><br> Rl is selected from the group consisting of:<br><br> O<br><br> R'<br><br> r-n-<br><br> R3 • R * ) n -<br><br> R2 is selected from the group consisting of: Cj.galkyl, Ar-Cg-galkyl, Het-C0_6alkyl, R9C(0)-, R9S02-, R9R* ^0(0)-, and R9S02RnNC(0)-;<br><br> 15 R-3 is Ci_6alkyl;<br><br> R4 is R5C(0)-,<br><br> R^ is Het-Co_6alkyl;<br><br> R9 is selected from the group consisting of: Cj.galkyl, C3_6cycloalkyl-Co-6alkyl&gt; Ar-Co_6alkyl and Het-C()-6alkyl;<br><br> 20 Rl 1 is selected from the group consisting of: H, Cj.galkyl, Ar-CQ-6alkyl, and Het-<br><br> C0.6alkyl;<br><br> R'is H;<br><br> R" is H;<br><br> R'" is H;.<br><br> 25 R"" is selected from the group consisting of: Ci_6alkyl, C3_6cycloalkyl-Co-6alkyl<br><br> C?-6alkenyl, C2-6alkynyl, HetCo-6alkyl and ArCo_6alkyl;<br><br> 302<br><br> n is an integer from 1 to 5;<br><br> and pharmaceutically acceptable salts, hydrates and solvates thereof.<br><br> O<br><br> 2. A compound according to Claim 1 wherein Rl is<br><br> R<br><br> 3. A compound according to Claim 1 or 2 wherein R3 is selected from the group consisting of: isobutyl and but-2-yl.<br><br> 4. A compound according to Claim 3 wherein is isobutyl.<br><br> 5. A compound according to any one of claims 1 to 4 wherein R5 is selected from the group consisting of:<br><br> piperidinyl-ethyl;<br><br> benzo[l,3]dioxolyl;<br><br> furanyl, aiyl substituted furanyl, C^alkyl substituted furanyl; benzofuranyl, C^galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, Cj.galkyl substituted benzofuranyl;<br><br> napththo[2,l-b]-furanyl, C^.galkyl substituted napththo[2,l-b]-furanyl;<br><br> benzo[&amp;]thiophenyl;<br><br> quinolinyl;<br><br> quinoxalinyl;<br><br> I<br><br> 1-oxy-pyridinyl;<br><br> furo[3,2-b]-pyridinyl, C^galkyl substituted furo[3,2-b]-pyridinyl;<br><br> thiophenyl, Cj^alkyl substituted thiophenyl;<br><br> thieno[3,2-&amp;]thiophenyl; and lH-benzoimidazol-5-yl.<br><br> 6. A compound according to any one of claims 1 to 4 wherein R5 is selected from the group consisting of:<br><br> piperidin-l-yl-ethyl;<br><br> benzo[l,3]dioxol-5-yl,<br><br> 303<br><br> ?6 FEB 200&lt;i<br><br> RECEIVE<br><br> furan-2-yl;<br><br> benzoforan-2-yl;<br><br> napththo[2,l-b]-foran-2-yl benzo[&amp;]thiophen-2-yl;<br><br> quinolin-2-yl;<br><br> quinoxalin-2-yl;<br><br> l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl;<br><br> furo[3,2-b]-pyridin-2-yl;<br><br> thiophene-2-yl;<br><br> thieno[3,2-fc]thiophene-2-yl; and lH-benzoimidazol-5-yl.<br><br> 7. A compound according to any one of claims 1 to 4 wherein R5 is selected from the group consisting of:<br><br> 5-(3-trifluoromethyl-phenyl)-furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, 2,4-dimethyl-furan-2-yl;<br><br> 5-methoxy-benzofura-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl;<br><br> 1 -methyl-naphtho[2, l-b]-furan-2-yl;<br><br> 5-methyl-thiophen-2-yl, and 3-methyl-furo[3^b]pyridin-2-yl.<br><br> 8. A compound according to any one of claims 1 to 4 wherein R5 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.<br><br> R' O<br><br> 9. A compound according to Claim 1 wherein R* is<br><br> R3<br><br> 10. A compound according to Claim 9 wherein R"" is Ci_6alkyl.<br><br> Intellectual Property Office of NZ<br><br> 2 6 FEB 2004<br><br> 304<br><br> RECEIVE1<br><br> 11. A compound according to Claim 10 wherein Ci_6alkyl is methyl.<br><br> FV 0<br><br> r4/<br><br> 12. A compound according to Claim 1 wherein R* is 5 13. A compound according to Claim 12 wherein n is 3. .<br><br> 14. A compound according to any one of claims 1 to 13 wherein R9 is selected from the group consisting of:<br><br> ethyl, and C3_6cycloalkyl-substituted ethyl;<br><br> 10 propyl;<br><br> butyl;<br><br> isopentyl;<br><br> phenyl, especially halogen substituted phenyl, C^galkyl substituted phenyl, Cj.galkylsulfonyl substituted phenyl;<br><br> 15 pyridinyl, Cj.galkyl substituted pyridinyl;<br><br> 1-oxy-pyridinyl; and isoxazolyl, Cj.galkyl substituted isoxazolyl.<br><br> 15. A compound according to any one of claims 1 to 13 wherein R9 is selected from the group consisting of:<br><br> cyclohexyl-ethyl;<br><br> prop-l-yl but-l-yl;<br><br> 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 25 4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl;<br><br> pyridin-2-yl, l-oxy-pyridin-2-yl;<br><br> l,2-dimethyl-lH-imidazol-2-yl, l-methyl-lH-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl.<br><br> 16. A compound according to any one of claims 1 to 13 wherein R2 is selected from the group consisting of: Ci^alkyl, Ar-Co-6alkyl and Het-Co-6alkyl.<br><br> Intellectual Proper: 305 Office of NZ<br><br> 2 6 FEB 2004 receive<br><br> 17. A compound according to Claim 16 wherein is selected from the group consisting of: Cj.galkyl and Het-CQ-galkyl.<br><br> 5 18. A compound according to Claim 17 wherein Cj.galkyl and Het-Co_galkyl are selected from the group consisting of: Het-substituted methyl and pentyl.<br><br> 19. A compound according to Claim 18 wherein Het-substituted methyl is selected from the group consisting of:<br><br> 10 quinolin-2-ylmethyl;<br><br> 6-methyl-pyridin-2-ylmethyl;<br><br> 2-morpholin-4-yl-thiazol-4-ylmethyl;<br><br> 5-ethyl-furan-2-ylmethyl;<br><br> 3,4dimethyl-thieno[3,2-b]thiophene-2-ylmethyl; 15 3-phenyl-3H-[l,2,3]triazol-4-ylmethyl;<br><br> isothiazol-3-ylmethyl;<br><br> thiophen-2-ylmethyl;<br><br> benzo[b]thiophen-2-ylmethyl; and l-methyl-lH-imidazol-2-ylmethyl.<br><br> 20<br><br> 20. A compound according to any one of claims 1 to 13 wherein R2 is selected from the group consisting of: Ar-Co-6alkyl, R9C(0)-, R9S02, and R9RuNC(0)-.<br><br> 21. A compound according to Claim 20 wherein R^ is selected from the group 25 consisting of: Ar-Co-6aUjyl&gt; R^C(O)-, and R9S02-<br><br> 22. A compound according to Claim 21 wherein R^ is R9S02.<br><br> 23. A compound according to Claim 22 wherein R® is selected from the group 30 consisting of: C^galkyl, Ar-C^galkyl and Het-Co-gaUcyl.<br><br> 24. A compound according to Claim 1 wherein:<br><br> JnteHectual Propert<br><br> Office of NZ 306 2 6 FEB 2004<br><br> receive<br><br> WO 01/95911<br><br> PCT/US01/19062<br><br> O<br><br> R2 is R9S02; and R-* is isobutyl;<br><br> 5 R9 is selected from the group consisting of: Cj.galkyl, Ar-CQ.^alkyl and Het-<br><br> C0-6alkyl.<br><br> 25. A compound according to Claim 24 wherein:<br><br> is selected from the group consisting of: 10 piperidinyl-ethyl;<br><br> benzo[l,3]dioxolyl;<br><br> furanyl, aryl substituted furanyl, C^galkyl substituted furanyl; benzofuranyl, C^galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C^.galkyl substituted benzofuranyl; 15 napththo[2,l-b]-furanyl, Cj.gaLkyl substituted napththo[2,l-b]-furanyl;<br><br> benzo[fc]thiophenyl;<br><br> quinolinyl;<br><br> quinoxalinyl;<br><br> 1-oxy-pyridinyl;<br><br> 20 furo[3,2-b]-pyridinyl, Cj.galkyl substituted furo[3,2-b]-pyridinyl;<br><br> thiophenyl, Cj_galkyl substituted thiophenyl;<br><br> thieno [3,2-&amp;]thiophenyl; and lH-benzoimidazol-5-yl; and R9 is selected from the group consisting of:<br><br> 25 ethyl, c3_gcycloalkyl-substituted ethyl;<br><br> propyl;<br><br> butyl;<br><br> isopentyl;<br><br> halogen substituted phenyl, C^galkyl substituted phenyl, Cj.galkylsulfonyl 30 substituted phenyl;<br><br> pyridinyl, C^.galkyl substituted pyridinyl;<br><br> 307<br><br> WO 01/95911<br><br> PCT/US01/19062<br><br> 1-oxy-pyridinyl; and isoxazolyl, Cj.galkyl substituted isoxazolyl.<br><br> 26. A compound according to Claim 24 wherein: is selected from the group 5 consisting of:<br><br> piperidin- 1-yl-ethyl;<br><br> benzo [ 1,3]dioxol-5-yl;<br><br> furan-2-yl;<br><br> benzoforan-2-yl;<br><br> 10 napththo[2,l-b]-furan-2-yl benzo [b] thiophen-2-y 1;<br><br> quinolin-2-yl;<br><br> quinoxalin-2-yl;<br><br> l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl;<br><br> 15 furo[3,2-b]-pyridin-2-yl;<br><br> thiophene-2-yl;<br><br> thieno[3,2-£&gt;]thiophene-2-yl; and lH-benzoimidazol-5-yl.<br><br> 20 27. A compound according to Claim 24 wherein R^ is selected from the group consisting of:<br><br> 5-(3-triflouromethyl-phenyl)-furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2~yl, 2,4-dimethyl-furan-2-yl;<br><br> 5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 25 3,5-dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofiiran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl;<br><br> l-methyl-naphtho[2,l-b]-furan-2-yl;<br><br> 5-methyl-thiophen-2-yl, and 30 3-methyl-furo[3,2b]pyridin-2-yl.<br><br> 28. A compound according to Claim 24 wherein R9 is selected from the group consisting of:<br><br> 308<br><br> WO 01/95911 PCT/US01/19062<br><br> cyclohexyl-ethyl;<br><br> prop-l-yl but-l-yl;<br><br> 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 5 4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl;<br><br> pyridin-2-yl, l-oxy-pyridin-2-yl;<br><br> l,2-dimethyl-lH-imidazol-2-yl, l-methyl-lH-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl.<br><br> 10 29. A compound according to Claim 24 wherein:<br><br> is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2-b]thiophen-2-y 1, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, or quinolin-2-yl; and<br><br> 15 R9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.<br><br> 30. A compound according to Claim 29 wherein r5 is 3-methyl-benzofuran-2-yl.<br><br> 31. A compound according to Claim 30 wherein R9 is l-oxy-pyridin-2-yl.<br><br> 32. A compound according to Claim 1 selected from the group consisting of: Benzofuran-2-carboxylic acid { (S)-1 -[-(3-fluor o-benzensulfony l)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-1 -butyl} -amide; (S)-4-methyl-2-(3-piperidin-l-yl-propanoylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyI)-azepan-4-yI]-amide;<br><br> Benzofuran-2-carboxylie acid {(S)-l-[-(4-ethyl-benzensulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-1- {3-oxo-l-[l-(l-oxy-pyridin-2~yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amxde;<br><br> Benzo [ l,3]-dioxole-5-carboxyIic acid ((S)-3-methyl-1- {3-oxo-1- [1-oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;<br><br> 309<br><br> WO 01/95911<br><br> PCT/US01/19062<br><br> 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(3-<br><br> cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-<br><br> amide;<br><br> Benzofl ,3]-dioxole-5-carboxylic acid {(S)- l-[l-(3-cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-(3-Trifluoromethyl-phenyl)-fiuran-2-carboxylic acid {(S)-l-[l-(4-methyl~ pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzof1,3]-dioxole-5-carboxylic acid {(S)-1- [ 1 -(4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- 1-butyl}- amide; Benzofuran-2-carboxylic acid [(S)-l-[3-oxo-l-(ethanesulfonyl-azepan-4-ylcarbamoyl)-3-methyl-1 -butyl]- amide;<br><br> 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;<br><br> 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;<br><br> 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(R)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-l-[-3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepaii-4-ylcarbamoyl]-3-methyl-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 3-methyl-furan-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Quinoline-2-carboxylic acid {(S)-1 -[l-(3-fluoro-benzenesuIfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;<br><br> 310<br><br> WO 01/95911<br><br> PCT/US01/19062<br><br> Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Quinoxaline-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Thiophene-2-carboxylic acid {(S)-1-[l-(3-fluoro-benzenesuIfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-etharvesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> 3-Methyl-benzofuran-2-carboxylic acid [(S)-1-( l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> 3-Methyl-furan-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-<br><br> 4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> Quinoline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfony 1-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> Quinoxaline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> Thiophene-2-caiboxylic acid [(S)-l~(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> 5-Methyl-thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 5-Methoxy-benzofuran-2-caxboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyI)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfoiiyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-arnide; Benzo[b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;<br><br> 311<br><br> WO 01/95911<br><br> PCT/USO1/19062<br><br> 3-Methyl-furan-2-carboxylic acid {(S)-1 -[3-oxo- l-(propane- 1-sulfonyl)-azepan-4-ylcarbamoyl]-3-methy 1-1 -butyl} -amide; 2,5-Dimethyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-<br><br> 4-ylcarbamoyl]-3-methyl-l-butyl}-amide;<br><br> Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; Quinoxaline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane- 1-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1 -butyl} -amide;<br><br> Thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;<br><br> 5-Methyl-thiophene-2-carboxylic acid {(S)-1 -[3-oxo-1 -(propane-1 -sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;<br><br> 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide; 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI}-amide;<br><br> 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methy 1-1 -[3-oxo-1 -(1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;<br><br> 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1 - [3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; l-methyl-naphtho[2,l-b]-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-<br><br> 1 -(1 -oxy-pyridine-2-suIfonyI)-azepan-4-y lcarbamoy l]-buty I }-amide;<br><br> 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {l,3-dimethyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyl-azepan-4-y lcarbamoyl]-butyl} -amide; 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide;<br><br> 312<br><br> WO 01/95911<br><br> PCT/US01/19062<br><br> Benzo [b]thiophene-2-carboxylic acid [(S)-3-methyl-1 - [3-oxo- l-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide;<br><br> Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-2-suIfonylamino)-methanoyl]-azepan-4-ylcarbamoyl} -butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;<br><br> Benzo [b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-<br><br> toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-<br><br> amide;<br><br> Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{ 3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyI-l-{3-oxo-l-[2-chloro-benzenesuIfonylamino)-methanoyl]-azepan-4-ylcarbamoyI}-butyl)-amide;<br><br> Benzo[b]thiophene-2-carboxylie acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;<br><br> Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro-*<br><br> benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{ 3-oxo-1-[4-fluoro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyI)-amide;<br><br> Benzo [b]thiophene-2-carboxylic acid ((S)-3-methyl-1-{ 3-oxo-1 -[4-fluoro-<br><br> benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyI)-amide;<br><br> Benzofaran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-4-<br><br> sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;<br><br> 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-1-[ 1-<br><br> toluene-4-sulfonylamino)-methanoyl3-azepan-4-ylcarbamoyl}-butyl)-<br><br> amide;<br><br> Benzo[b]thiophene-2-carboxylie acid ((S)-3-methyl-l-{3-oxo-l-[l-<br><br> toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-<br><br> amide;<br><br> 313<br><br> WO 01/95911<br><br> PCT/US01/19062<br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-1-[ 1 -(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-aniide;<br><br> 3-Methyl-benzofuran-2-carboxyIic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 2,4-Dimethylfuran-3-carboxylic acid {(S)-l-[l-(2-fIuoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyI-butyl}-amide; Quinoxaline-2-carboxylic acid {(S)-1 -[ 1 -(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyI]-3-methyl-butyl}-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Quinoline-2-carboxylic acid {(S)-l-[l-(2-.fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]~3-methyl-butyl}-amide;<br><br> 4-Methyl-thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;<br><br> 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-pheny]carbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 4-Methyl-furan-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid [(S)-l-(l-butyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyI-butyl]-amide;<br><br> Benzofuran-2-carboxylic acid [(S)-l-(l-propyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;<br><br> Benzofuran-2-carboxylic acid {(S)-1 -[1 -(2-fiuoro-benzy])-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;<br><br> Benzofaran-2-caTboxylic acid {(S)-3-methyl-l-[l-(2-morpholin-4-yl-thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;<br><br> 314<br><br> WO
  1. 01/95911<br><br> PCT/USO1/19062<br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(5-ethyl-furan-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;<br><br> Benzofuran-2-carboxyIic acid {(S)-l-[l-(3,4-dimethyl-thieno[3,2-&amp;]thiophene-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;<br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(3-phenyl-3H-[l,2,3]triazol-4-y]methyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid [(S)-l-[l-(isothiazol-3-ylmethyl-3-oxo-azepan-4-y lcarbamoy l)-3-methyl-butyl} -amide;<br><br> Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-thiophen-2-ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide;<br><br> Benzofuran-2-carboxylic acid [(S)-l-(l-benzo[b]thiophen-2-ylmethyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl- l-(3-oxo- l-pentyl-azepan-4-ylcarbamoyl)-butyl]-amide;<br><br> Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[l-( 1 -methyl- lH-imidazol-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-buty}-amide;<br><br> 1-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl }-amide;<br><br>
  2. 2-Oxy-pyridine-3-carboxylic acid {(S)-3-methyl-1 -[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl}-amide; lH-Benzoimidazole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 4-{(S)-2-[(l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}-l-xnethyl-3-oxo-l-pentyl-azepanium;<br><br> Benzofuran-2- carboxylic acid {(S)-l-[l-(l,2-dimethyH H -imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2- carboxylic acid {(S)-l-[l-(l-methyl-l H -imidazole-4-sulfonyl)-3-oxo-azepaii-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methanesulfonyl-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(2-methanesulfonyl-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;<br><br> 315<br><br> Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-isoxazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoy l]-3-methyl-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(lS,2R)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {l-[3-oxo-l-(pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-cyclopentyl}-amide; and<br><br> Furo[3,2-b]-pyridine-2-carboxylicacid {(S)-3-methyl-l-[-3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide.<br><br> 33. A phannaceutical composition comprising a compound according to any one of Claims 1 to 32 and a pharmaceutically acceptable carrier, diluent or excipient.<br><br> Intellectual Property Office of NZ<br><br> 2 6 FEB 2004<br><br> receive<br><br> 10<br><br> 15<br><br> \<br><br> \<br><br> X,<br><br> X,<br><br> 34. A compound of Formula IIA:<br><br> R\ /RM N<br><br> OH<br><br> R,n/ N<br><br> \<br><br> 20<br><br> HA<br><br> wherein:<br><br> R* is selected from the group consisting of:<br><br> ,4/<br><br> &gt;4/<br><br> R' O<br><br> i<br><br> N&gt;<br><br> R<br><br> ,4/<br><br> , and<br><br> 25<br><br> ) n .<br><br> R2 is selected from the group consisting of: Cj.galkyl, Ar-CQ.galkyl, Het-Co-6alkyl, r9C(0)-, r9sc&gt;2-, R^^ncco)-, and r9s02R11NC(0&gt;;<br><br> 317<br><br> intellectual Property Office of NZ<br><br> 2 6 FES 2004<br><br> receive<br><br> R3 is Ci-6alkyl;<br><br> R4isR5C(0)-,<br><br> R5 is Het-Co-6alkyl;<br><br> 5 R9 is selected from the group consisting of: Cj.galkyl, C3_6cycloaIkyl-CQ_6alkyl,<br><br> Ar-Co-galkyl and Het-Co_6alkyl;<br><br> R*1 is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6aIkyl, and Het-C0_6alkyl;<br><br> R'isH;<br><br> 10 R" is H;<br><br> R" is H;<br><br> R"" is selected from the group consisting of: Ci_6alkyl, C3_6cycloalkyl-Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCo_6alkyl and ArCo_6alkyl; and n is an integer from l'to 5;<br><br> 15 and salts, hydrates and solvates thereof.<br><br> 35. A process for the synthesis of a compound according to Claim 1 comprising the step of oxidizing a corresponding compound of Claim 34'with an oxidant to provide the compound of Formula (IA) as a mixture of diastereomers.<br><br> 20<br><br> 36. The process of Claim 35 wherein the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine.<br><br> 37. The process of Claim 35 further comprising the step of separating the diasteromers 25 by separating means.<br><br> 38. The process of Claim 37 wherein said separating means is high presssure liquid chromatography (HPLC).<br><br> 39. The process of Claim 35 further comprising the step of deuterating said diastereomers with a deuterating agent.<br><br> intellectual Property Office of NZ<br><br> 318<br><br> 26 FEB 2004<br><br> receiv r ' CI<br><br> 40. The process of Claim 39 wherein said deuterating agent is CD3OD: D2O (10:1) in triethylamine.<br><br> 41. Use of a compound according to any one of Claims 1 to 32 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.<br><br> 42. , A use according to Claim 41 wherein said protease is a cysteine protease.<br><br> 43. A use according to Claim 42 wherein said cysteine protease is cathepsin K.<br><br> 44. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a disease characterized by bone loss.<br><br> 45. A use according to Claim 44 wherein said disease is osteoporosis.<br><br> 46. A use according to Claim 44 wherein said disease is periodontitis.<br><br> 47. A use according to Claim 44 wherein said disease is gingivitis.<br><br> 48. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation.<br><br> 49. A use according to Claim 48 wherein said disease is osteoarthritis.<br><br> 50. A use according to Claim 48 wherein said disease is rheumatoid arthritis.<br><br> 51. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a parasitic disease.<br><br> 1<br><br> c 1<br><br> Intellectual Property<br><br> Office of NZ<br><br> 319 26 FEB 2004<br><br> receive<br><br> 52. A use according to Claim 51 wherein said disease is selected from the group consisting of: schistosomiasis, malaria, and infections by Pneumocystis caiinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata.<br><br> 53. A compound as claimed in claim 1 substantially as herein described with reference to any one of Examples 1 to 279.<br><br> 54. A process as claimed in claim 35 substantially as herein described with reference to any example thereof.<br><br> 320<br><br> Intellectual Property Office of NZ<br><br> 2 6 FEB 2004<br><br> RECEIVE<br><br> </p> </div>
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