BG107327A - Protease inhibitors - Google Patents

Abstract

The present invention provides 4-amino-azepan-3-one protease inhibitors and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, novel intermediates of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and peridontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease, hypercalcaemia or malignancy; and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention. 65 claims

Description

HA PROTEASE INHIBITORS

Technical field

The invention generally relates to 4-amino-azepan-3-one protease inhibitors, especially such inhibitors of cysteine and serine proteases, in particular compounds that inhibit cysteine proteases, in particular compounds that inhibit cysteine proteases of the superfamily papain, and more particularly compounds that inhibit cysteine proteases from the cathepsin family, and most particularly compounds that inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are involved, in particular pain Rooms associated with excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.

BACKGROUND OF THE INVENTION

Cathepsins are a family of enzymes that are part of the papain superfamily of cysteine proteases. The cathepsins B, H, L, N, and S. have been described in the literature. Recently, the cathepsin K polypeptide and complementary DNA encoding this polypeptide are disclosed in U.S. Pat. No. 5,501,969 (called cathepsin O). Recently expressed, purified and characterized cathepsin K. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F. H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.

In the literature, cathepsin K is referred to differently as cathepsin O or cathepsin 02. The designation cathepsin K is considered most appropriate.

Cathepsins function in the normal physiological process of protein degradation in animals, including humans, for example in the destruction of connective tissue. Increased levels of these enzymes in the body, however, can cause pathological conditions that lead to illness. Thus, cathepsins have been implicated as agents of various disease states, including, but not limited to, infections with pneumocystis carinii, t / ypsanoma cruzi, trypsanoma brucei brucei and Crithidia fusiculata; as well as schistosomiasis, malaria, tumor metastases, metachromatic leukodystrophy, muscular dystrophy, amitrophy and more. See International Patent Application WO 94/04172, published March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 A1 and the references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, are involved in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.

Cathepsin K is thought to play a role in causing disease with extreme bone and cartilage loss. The bone is made up of a protein matrix that includes crystals of hydroxyapatite with a spindle-shaped or flat shape. Type I collagen is the major structural protein of bone, accounting for about 90% of the protein matrix. The remaining 10% of the matrix consists of a number of non-collagen proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Throughout life, skeletal bone undergoes remodeling of individual foci. These foci or sites of remodeling undergo a cycle consisting of a bone resorption phase followed by a bone replacement phase.

Bone resorption is performed by osteoclasts, which are polynucleated cells of hematopoietic origin. The osteoclasts adhere to the bone surface and form a highly compacted area, followed by extensive wrinkling of the membrane on their upper (i.e., absorbent) surface. This creates a closed extracellular compartment on the bone surface that is acidified by proton pumps in the swollen membrane and in which the osteoclast secretes proteolytic enzymes. Low pH in the compartment results in dissolution of the hydroxyapatite crystals on the bone surface, while proteolytic enzymes break down the protein matrix. In this way, a resorption cavity or well is formed. At the end of this phase of the cycle, the osteoblasts build a new protein matrix that subsequently mineralizes. In some conditions such as osteoporosis and Paget's disease, the normal balance between bone resorption and buildup is impaired and there is a net loss of bone in each cycle. Ultimately, this causes the bone to weaken and can lead to an increased risk of fracture with minimal trauma.

Some published studies indicate that cysteine protease inhibitors are effective in inhibiting osteoclast-mediated bone resorption and indicate the essential role of cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. J., 1980, 192, 365, disclose a series of protease inhibitors in the murine bone-organ culture system and indicate that cysteine protease inhibitors (e.g., leipeptin, Z-Phe-Ala-CHN ₂ ) prevent bone resorption while serine protease inhibitors are ineffective. Delaisse, et al., Biochem. Biophys. Really.

Refs., 1984, 125, 441, reveal that E-64 and leipeptin are also effective in preventing bone resorption in vivo, as measured by the acute change in serum calcium in rats with a calcium deficiency diet. Lerner, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in murine cranial arches. Other studies, such as those of 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 have also reported a relationship between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, et al., Biochem. Biophys. Really. Commun., 1995, 206, 89 and Shi, et al., FEBS Lett., 1995, 357, 129 reveal that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease, present in these cells.

The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide effective treatment for diseases with extreme bone loss, including but not limited to osteoporosis, gum disease such as gingivitis and periodontitis, Paget disease, hypercalcaemia due to malignant disease, and metabolic disease . It has also been demonstrated that cathepsin K levels are elevated in chondroclasts of the osteoarthritic synovial sheath. Thus, selective inhibition of cathepsin K may also be useful for the treatment of cartilage or matrix ultimate destruction diseases, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that break down the surrounding matrix.

Thus, selective inhibition of cathepsin K may also be useful for the treatment of some neoplastic diseases.

Some cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, discloses some vinylsulfones that irreversibly inhibit cysteine proteases, such as cathepsins B, L, S, 02 and cruzain. Other classes of compounds such as aldehydes, nitriles, α-ketocarbonyl compounds, halomethyl ketones, diazomethyl-ketones, (acyloxy) methyl ketones, ketomethylsulfonium salts and epoxysuccinyl compounds that inhibit cysteine proteases have also been reported. See Palmer, supra, and the sources cited there.

U.S. Pat. No. 4,518,528 discloses peptidylfluoromethyl ketones as irreversible cysteine protease inhibitors. International Patent Application Publication No. W094 / 04172 and European Patent Application Nos. EP 0 525 420 A1, EP 0 603 873 A1, and EP 0 611 756 A2 disclose alkoxymethyl- and mercaptomethylketones that inhibit the cysteine proteases cathepsin B, H, and Int. patent application No. PCT / US94 / 08868 and

European Patent Application EP 0 623 592 A1 describes alkoxymethyl- and mercaptomethyl ketones that inhibit cysteine protease 1E-1convertase. Alkoxymethyl- and mercaptomethylketones are also described as inhibitors of the serine protease kininogenase (International Patent Application PCT / GB91 / 01479).

Azapeptides which are intended to deliver the azaamino acid to the active sites of serine proteases and which have a well cleaved group are disclosed by Elmore et al.,

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

Gray et al., Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984,

259, 4279, Powers et al., J. Biol. Chem., 1984, 259, 4288 and are known to inhibit serine proteases. In addition, J. Med. Chem., 1992, 35, 4279 discloses some azapeptide esters such as cysteine protease inhibitors.

Antipain and leipeptin have been described as reversible cysteine protease inhibitors in McConnell et al., J. Med. Chem., 33, 86; and have also been disclosed as serine protease inhibitors in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogues are also known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and Grinde, Biochem. Biophys. Acta, 701, 328).

1,3-Diamidopropanones are also described as' analgesic agents in US Patent Nos. 4,749,792 and 4,638,010.

Thus, a structurally diverse set of protease inhibitors has been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals and especially in humans, since they suffer from a number of disadvantages. These disadvantages include lack of selectivity, cytotoxicity, poor solubility and too fast plasma clearance. Therefore, there is a need for methods of treating diseases caused by pathological levels of proteases, in particular cysteine proteases, in particular cathepsins, most notably cathepsin K, and novel inhibitory compounds useful in such methods.

We have now discovered a new class of 4-amino-azepan-3-ones compounds that are protease inhibitors and most specifically cathepsin K.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide 4-aminoazepan-3-one carbonyl protease inhibitors, especially such cysteine and serine protease inhibitors, in particular such compounds that inhibit cysteine proteases, in particular such compounds that inhibit cysteine proteases from papain superfamily, and more particularly such compounds that inhibit the cysteine proteases of the cathepsin family, and most particularly such compounds that inhibit cathepsin K and which are useful for treating diseases that may be therapeutically modified by altering the activity of such proteases.

Accordingly, as a first aspect, the invention provides a compound of formula I.

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

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

In another aspect, this invention provides a method of treating diseases in which the disease pathology can be therapeutically modified by inhibiting proteases, especially cysteine and serine proteases, in particular cysteine proteases, in particular cysteine proteases from the papain superfamily , and in particular the cysteine proteases of the cathepsin family, most notably cathepsin K.

In a certain aspect, the compounds of this invention are particularly useful for the treatment of diseases characterized by extreme bone loss such as osteoporosis and gum disease, such as gingivitis and periodontitis, or extreme loss of cartilage or matrix degradation such as osteoarthritis and rheumatoid arthritis. Detailed description of the invention

The present invention provides compounds of formula I:

wherein:

R ¹ is selected from the group consisting of:

R ² is selected from the group consisting of: H, C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, Ar-C ₀ . ₆ alkyl,

HE ₀ . ₆ alkyl, R ⁹ C (O) -,

R ⁹ OC (O) -,

R ⁹ R ⁿ NC (O) -, R ⁹ R ⁿ NC (S) -,

R ⁹ SO ₂ R ¹¹ NC (O) -;

R ³ is selected from the group consisting of:

H,

With _b6 alkyl, C _{3. 6} cycloalkyl-So_ ₆ alkyl, C _{2. 6} alkenyl, C ₂ . ₆ alkynyl, No _{(C0. 6alkyl} and

AgSO. ₆ alkyl;

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

R ⁴ is selected from the group consisting of: H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar-C0-6 alkyl, H 1 -C0-6 alkyl, R ⁵ C (O) -, R ⁵ C (S) - , R ⁵ SO 2 -, R ⁵ OC (O) -, R ⁵ R ¹² NC (O) -, and R ⁵ R ¹² NC (S) -;

R ⁵ is selected from the group consisting of: H, C 1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, Sz_ ₆ cycloalkyl-Co. ₆ alkyl, Ar-C ₀ . ₆ alkyl and HetC ₀ . ₆ alkyl;

R ⁶ is selected from the group consisting of: H, C 1-6 alkyl, C 1 -C 5. ₆ alkyl and HbO- ₆ alkyl;

R ⁷ is selected from the group consisting of: H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, H 2 -C 6 alkyl, R ¹⁰ C (O) -, R ¹⁰ C (S) -, R ¹⁰ SO 2 -, R ¹⁰ OC (O) -, R ¹⁰ R ¹³ NC (O) -, and R ¹⁰ R ¹³ NC (S) -;

R ⁸ is selected from the group consisting of: H, C 1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H ₁ C ₀ . ₆ alkyl and C ₁ -C ₆ alkyl;

R ⁹ is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C 1 -C 4 alkyl and H 1: -Co. ₆ alkyl;

R ¹⁰ is selected from the group consisting of: alkyl, Sz_ ₆ cycloalkyl-C _{0. 6} alkyl, Ar-C ₀ . ₆ alkyl and H 2 _{O 0} . ₆ alkyl;

R ¹¹ is selected from the group consisting of: H, _b6 alkyl, Ar-C _{0. 6} alkyl and C ₁ -C ₆ alkyl;

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

R is selected from the group consisting of: H, _b6 alkyl, Ar-C _{0. 6} alkyl and HbO- ₆ alkyl;

R 1 is selected from the group consisting of: H, C 1-6 alkyl, Ar-C ₀ . ₆ .

alkyl and Het-Co-alkyl;

R is selected from the group consisting of: H, C 1. ₆ alkyl, Ar-So_ ₆ alkyl or HE1-Co. ₆ alkyl;

R 1 is selected from the group consisting of: H, C 1-6 alkyl, C 3-6 cycloalkyl-Co. ₆ alkyl, C 1 -C ₆ alkyl and C 1 -C ₆ alkyl;

R is selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl-C ₀ . ₆ alkyl C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H ₁ C ₀ . ₆ alkyl and ArC ₀ . ₆ alkyl;

X is selected from the group consisting of: CH ₂ , S and O;

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

η is an integer from 1 to 5;

and their pharmaceutically acceptable salts, hydrates and solvates.

R

In compounds of formula I, when R e,

R ^{1 * 3} is selected from the group consisting of: H, C 1-6 alkyl, C ₃ . ₆ cycloalkyl-Co-alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, NeC ₀ . ₆ alkyl and ArC ₀ . ₆ alkyl;

with

R is preferably selected from the group consisting of: H, C3. ₆ cycloalkyl-Co. ₆ alkyl, C ₂ . ₆ alkenyl, Ar-C ₀ . ₆ alkyl and C 1-6 alkyl;

with

R is more preferably selected from the group consisting of:

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

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

R is most preferably isobutyl.

R ⁴ is selected from the group consisting of: H, C 1-6 alkyl, C 3. 6cycloalkyl-C0-6alkyl, At-Co-alkyl, Het-Co-alkyl, R ⁵ C (O) -, R ⁵ C (S) -, R ⁵ SO 2 -, R ⁵ OC (O) -, R ⁵ R ¹³ NC (O) - and R ⁵ R ¹³ NC (S) -.

R ⁴ is preferably selected from the group consisting of: R ⁵ OC (O) -, R ⁵ C (O) -, and R ⁵ SO ₂ -.

R ⁴ is most preferably R ⁵ C (O) -.

In some embodiments, R ⁴ is preferably methanesulfonyl.

R ⁵ is selected from the group consisting of: H, C 1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C3. ₆ cycloalkyl-Co_alkyl, Ar-Co. ₆ alkyl or H ₂ Cl ₆ alkyl.

Preferably R ⁵ is selected from the group consisting of: C 1-6 alkyl, C ₁ -C ₆ -alkyl and H ₁ -C ₆ -alkyl.

More preferably, and especially when R ⁴ is R ⁵ C (O) -, R ⁵ is selected from the group consisting of:

methyl, in particular halogenated methyl, in particular trifluoromethyl, in particular C 1-6 alkoxy-substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxy-methyl, in particular heterocycle-substituted methyl, in particular 2-thiophenylmethyl;

ethyl, in particular piperidin-1-yl-ethyl;

butyl, in particular aryl-substituted butyl, in particular

4- (4-methoxy) phenyl-butyl;

isopentyl;

cyclohexyl;

pentanoyl, in particular 4-pentanoyl;

butenyl, in particular aryl-substituted butenyl, more preferably 4,4-bis (4-methoxyphenyl) -but-3-enyl;

acetyl;

phenyl, in particular phenyl substituted by one or more halogen atoms, more particularly 3,4-dichlorophenyl and 4fluorophenyl, in particular phenyl substituted by one or more aryloxy or C 1-4 alkoxy groups, in particular 3, 4-dimethoxyphenyl, 3-benzyloxy-4-methoxy-phenyl, in particular phenyl substituted with one or more C1-4 alkylsulfonyl groups, more preferably 4-methanesulfonyl-phenyl;

benzyl;

naphthalenyl, in particular naphthylen-2-yl; benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;

furanyl, in particular furan-2-yl, in particular substituted furanyl, such as 5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5 (3-trifluoromethyl-phenyl) -furan-2-yl, in particular halogen-substituted furanyl, even more particularly 5-bromo-furan-2-yl, in particular aryl-substituted furanyl, even more particularly 5- (4-chloro-phenyl) -furan-2-yl, in particular C 1-6 alkyl substituted furanyl, even more particularly 3-methyl-furan-2-yl, 4-methylfuran-2-yl, 2,5-dimethyl-furan-2- yl and 2,4-dimethyl-furan-3-yl-;

tetrahydrofuranyl, tetrahydrofuran-2-yl;

benzofuranyl, in particular benzofuran-2-yl and substituted benzofuranyl, in particular 5- (2-piperazine-4-carboxylic acid tributyl ester-ethoxy) benzofuran-2-yl, 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-yl, 5- (2-piperazin-1-ylethoxy) benzo-furan-2-yl, 5- (2-cyclohexyl-ethoxy) -benzofuran-2-yl; in particular C1-4alkoxy-substituted benzofuranyl, more preferably 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl,

5,6-dimethoxy-benzofuran-2-yl, in particular halogen-substituted benzofuranyl, in particular 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, in particular C 1-6 alkyl substituted benzofuranyl, most notably 3-methyl-benzofuran-2-yl, 3,5-dimethylbenzofuran-2-yl and 3-ethyl-benzofuran-2-yl; and 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 -2yl and 6-methoxy-3-methyl-benzofuran-2-yl;

naphtho [2,1-6] -furanyl, in particular naphtho [2,1- f] -furan-2-yl, alkyl-substituted naphtho [2,1- b] furanyl, in particular 1-methylnaphtho [2,1 - /]] - furan-2-yl;

benzo [b] thiophenyl, in particular benzo [b] thiophen-2-yl; optionally C 1-4 alkoxy-substituted benzo [b] thiophenyl, more preferably 5,6-dimethoxy-benzo [b] thiophen-2-yl;

quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;

quinoxalinyl, in particular quinoxalin-2-yl;

1,8 naphthyridinyl, in particular 1,8 naphthyridin-2-yl; indolyl, in particular indol-2-yl, in particular indol-6-yl, indol-5-yl, in particular C 1-6 alkyl-substituted indolyl, more preferably N-methyl-indol-2-yl;

pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, in particular C 1-6 alkyl-substituted pyridinyl, more preferably 2-methyl-pyridin-5-yl and oxy-pyridinyl, - especially 1-oxy-pyridin-2-yl and 1-oxy-pyridin-3-yl;

furo [3,2-b] - pyridinyl, in particular furo [3,2-b]] - pyridin-2-yl, C 1-6 Hn-saMecTeH furo [3,2-b] - pyridinyl, in particular especially 3-methylfuro [3,2-b] pyridin-2-yl;

thiophenyl, in particular thiophen-3-yl, and also thiophen-2yl, in particular C 1-4 alkyl-substituted thiophenyl, in particular 514 methyl-thiophen-2-yl and 5-methyl-thiophen-3-yl , in particular halogen-substituted thiophenyl, in particular 4,5-dibromothiophen-2-yl;

thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl, in particular C 1-6 alkyl-substituted thieno [3,2-0] thiophen-2-yl, more particularly 5-tert-butyl-3-methyl-thieno [3,2-b] thiophen-2-yl;

isoxazolyl, in particular isoxazol-4-yl, in particular C 1-6 alkyl-substituted isoxazolyl, in particular 3,5-dimethylisoxazol-4-yl;

oxazolyl, in particular oxazol-4-yl, in particular 5methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4yl; and

1H-benzoimidazolyl, in particular 1H-benzoimidazol-5-yl.

When R ⁴ is R ⁵ SC> 2, R ⁵ is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.

R 1 is selected from the group consisting of: H, C 1-6 alkyl, ArC ₀ . ₆ alkyl and HECO. ₆ alkyl.

Preferably R 1 is selected from the group consisting of: H and naphthalen-2-yl-methyl.

Most preferably R 'is H.

R is selected from the group consisting of: H, C 1-6 alkyl, ArC ₀ . ₆ alkyl and H 1: -C ₀ . ₆ alkyl.

Most preferably R is H.

R 1 is selected from the group consisting of: H, C 1-6 alkyl, C 3. cycloalkyl-So_ ₆ alkyl and HE1: -So.balkil.

R 1 is preferably selected from the group consisting of: H and C 1-6 alkyl.

R 1 is more preferably selected from the group consisting of: H, methyl and 6,6-dimethyl.

R 1 is even more preferably selected from the group consisting of: H and 6,6-dimethyl.

Most preferably R 'is H.

R 'I

XX.

In compounds of formula I, when R is

R is selected from the group consisting of: Sweet, C _3-6 cycloalkyl-C ₀ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, HEB ₀ . ₆ alkyl and C ₁ -C ₆ alkyl.

a

R is preferably C1-4 alkyl.

R is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, pem-butyl, cyclohexylmethyl and toluyl.

R is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ cycloalkyl-Co. ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, HetCO-alkyl and ArCO-alkyl;

R is preferably C1-4 alkyl;

R is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and pem-butyl.

R is most preferably methyl.

In such compounds, R ', R, R', R ⁴ and R ⁵ are as described

above at

In compounds of formula I, when

η is preferably an integer from 1 to 5; and

R ', R, R', R ⁴ and R ⁵ are as described above, where

η is most preferred 3.

The ring may be unsubstituted or substituted by one or more C 1-6 alkyl, C 3-3. ₆ cycloalkyl-So_ ₆ alkyl, C _{2. 6} alkenyl, C ₂ . ₆ alkynyl, H1-Co. ₆ alkyl, Ar-Cd. ₆ alkyl or halogen.

The ring is preferably unsubstituted.

In compounds of formula I, R 'is selected from the group consisting of: H, C 1-6 alkyl, C 3-3. ₆ cycloalkyl-C _0-3 alkyl, C ₁ -C ₆ alkyl, HetC ₀ . ₆ alkyl, R ⁹ C (O) -, R ⁹ C (S) -,

R ⁹ R ⁿ NC (S) -, R ⁹ R ⁿ NSO ₂ -,

and R ⁹ SO ₂ R ⁿ NC (O) -.

More preferably, R is selected from the group consisting of:

Ar-C ₀ . ₆ alkyl, R ⁹ C (O) -, R ⁹ SO ₂ , R ⁹ R ⁿ NC (O) - and

More preferably, R is selected from the group consisting of: Ar-C ₀ . ₆ alkyl, R ⁹ C (O) - and R ⁹ SO ₂ .

Most preferably R ² is R ⁹ SO ₂ .

In such embodiments:

R ⁶ is selected from the group consisting of: H, C 1-4 alkyl, Ar C ₀ . ₆ alkyl or H 1: -Co. ₆ alkyl, preferably H.

R ⁷ is selected from the group consisting of: H, Sbalkil, C3-6 cycloalkyl-Co-alkyl, Ar-So.6alkil, HE1: -C (). 6 alkyl, R ¹⁰ C (O) -, R ¹⁰ C ( S) -, R ¹⁰ SO2-, R ¹⁰ OC (O) -, R ¹⁰ R ^{14 NC (O) -, R 1o} R ¹⁴ NC (S) -, R ⁷ is preferably R ¹⁰ OC (O).

R ⁸ is selected from the group consisting of: H, _b6 alkyl, C _{2. 6} alkenyl, C ₂ . ₆ alkynyl, HEB ₀ . ₆ alkyl and Ar-C ₀ . ₆ alkyl; preferably C1-4alkyl, more preferably isobutyl.

Fr.

R is selected from the group consisting of: _b6 alkyl, C _{3. 6} cycloalkyl-C ₀ . ₆ alkyl, Ar-C ₀ . ₆ alkyl and HEB ₀ . ₆ alkyl.

Q

R is preferably selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and No (-CO ₆ alkyl.

More preferably, R ⁹ is selected from the group consisting of: methyl;

ethyl, in particular C _x . ₆ alkyl-substituted ethyl, more preferably 2-cyclohexyl-ethyl;

propyl;

butyl, in particular C ^ butyl, more particularly 3-methylbutyl;

9 tert-butyl, in particular when R is R OC (O);

isopentyl;

phenyl, in particular halogen-substituted phenyl, more preferably 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, in particular C 1-4 -alkoxy, phenyl, especially phenyl in particular 3methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, in particular cyanophenyl, in particular 2-cyanophenyl; in particular C 1-4 alkyl-substituted phenyl, in particular 4-ethyl-phenyl, 2-methylphenyl, 4-methylphenyl, in particular C 1-4-alkylsulfonyl-substituted phenyl, in particular 4-methanesulfonylphenyl and 2methanesulfonylphenyl;

toluyl, in particular Het-substituted toluyl, in particular

3- (pyridin-2-yl) toluyl;

naphthylene, in particular naphthyl-2-ene;

benzoic acid, in particular 2-benzoic acid; benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl; benzo [1,2,5] oxadiazolyl, in particular benzo [1,2,5] oxadiazol-4-yl;

pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, in particular 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; in particular C 1-6 alkylidinyl, more preferably 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl;

thiophenyl, in particular thiophenyl-2-yl;

thiazolyl, in particular thiazol-2-yl;

1H-imidazolyl, in particular 1H-imidazol-2-yl, 1Himidazol-4-yl, in particular C 1-6 alkyl-substituted imidazolyl, even more particularly 1-methyl-1H-imidazol-2-yl, 1 -methyl-1H-imidazol-4-yl and 1,2-dimethyl-1H-imidazol-4-yl;

triazolyl, in particular 1H- [1,2,4] triazolyl, more preferably 1H- [1,2,4] triazol-3-yl, in particular C 1-6 alkyl-substituted

1H- [1,2,4] triazolyl, in particular 5-methyl-1H- [1,2,4] triazol-3yl; and isoxazolyl, especially isoxazol-4-yl, more especially Cl _b6 alkyl-substituted isoxazolyl, more especially 3,5-dimethylisoxazol-4-yl.

When R ² is R ⁹ SO ₂ , R ⁹ is most preferably selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.

When R ² is R ⁹ SO ² R ⁿ NC (O) -, R ⁹ is preferably Ar-CO. ₆ alkyl, more preferably Ar, most preferably substituted phenyl such as 2-methylphenyl, 4-methylphenyl, 2-chlorophenyl and 4-fluorophenyl.

When R ² is R ⁹ C (O) -, R ⁹ is preferably selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl-Co. ₆ alkyl and N 1 -C 1 -C ₆ alkyl, more preferably 1-oxy-pyridin-2-yl, cyclohexylethyl and 3methylbutyl.

R ¹¹ is selected from the group consisting of: H, C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and H 1: -Co. ₆ alkyl.

When R ² is R ⁹ SO ₂ R ^H NC (O) -, R ¹¹ is preferably H.

When R ² is Ag-Co. ₆ alkyl, R ² is preferably phenyl, optionally substituted phenyl, in particular halogen-substituted phenyl, even more particularly 2-fluorobenzyl.

2

When R is C 1-6 alkyl, R is preferably selected from 1-propyl, 1-butyl and 1-pentyl.

When R ² is HEEC ₀ . ₆ alkyl, HEEC ₀ . ₆ alkyl is preferably Het-methyl and Het in Het-methyl is preferably selected from the group consisting of:

pyridinyl, in particular pyridin-2-yl, in particular Cj. ₆ . alkylpyridinyl, in particular 6-methyl-pyridin-2-yl;

thiophenyl, in particular thiophen-2-yl, in particular thiophen-2-yl or benzo [b] thiophen-2-yl;

thiazolyl, in particular thiazol-4-yl such as 1- (2-morpholin-4-ylthiazol-4-yl) and 1- (isothiazol-3-yl);

1H-imidazolyl, in particular 1H-imidazol-2-yl, 1Himidazol-4-yl, in particular C ₁ . ₆ alkyl-substituted imidazolyl, in particular 1-methyl-1H-imidazol-2-yl;

triazolyl, in particular 3H- [1,2,3] triazolyl, more particularly 3H- [1,2,3] triazol-4-yl, in particular C 1-6 alkyl-substituted 3H- [1,2,3] triazolyl, in particular 3-phenyl-3H- [1,2,3] triazolyl-4-yl;

quinolinyl, in particular quinolin-2-yl, quinolin-2-yl;

furanyl, in particular furan-2-yl, in particular substituted furanyl, such as 5-ethyl-furan-2-yl;

thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl, especially C 1-6 alkyl-substituted thieno [3,2-0] thiophenyl, in particular

3,4-dimethyl-thieno [3,2-b] thiophen-2-yl.

R ² is also preferred:

H;

toluyl;

aryl-substituted ethyl, in particular 2-phenylethyl, 2- [3- (pyridin2-yl) phenyl] ethyl.

Compounds of formula I are preferred in which R "and R" are both H.

More preferred are compounds of formula I in which:

9

R is selected from the group consisting of: Ar-C ₀ -alk, R C (O) -,

R ⁹ SO ₂ , R ⁹ R ^u NC (O) - and ^R ;

R is selected from the group consisting of: H, C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl and Ar-C ₀ . ₆ alkyl;

R ⁴ is selected from the group consisting of: R ⁵ OC (O) -, R ⁵ C (O) -, and R ⁵ SO ₂ -;

R ⁵ is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and H 2 _{O 0} . ₆ alkyl;

R ⁶ is H;

R ⁷ is R ¹⁰ OC (O);

R ^s is C 1-6 alkyl;

R ⁹ is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and H 1 -Co. ₆ alkyl;

R ¹⁰ is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and H 2 _{O 0} . ₆ alkyl;

R'eH;

R is H;

R 'is H; and

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

Even more preferred are those compounds of formula I, 'Y in which R is selected from the group consisting of: Ar-C 1-6 alkyl,

R ⁹ C (O) -, R ⁹ SO ₂ .

Even more preferred are compounds of formula I in which:

R ¹ is

? 9

R 2 is selected from the group consisting of: C 1 -C 6 alkyl, R C (O) and R ⁹ SO ₂ ;

a

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

R ⁴ is R ⁵ C (O) -;

R ° is selected from the group consisting of:

methyl, in particular halogenated methyl, in particular trifluoromethyl, in particular C 1-4 alkoxy-substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxy-methyl, in particular heterocycle methyl substituted, in particular 2-thiophenylmethyl;

ethyl, in particular piperidin-1-yl-ethyl;

butyl, in particular aryl-substituted butyl, in particular

4- (4-methoxy) phenyl-butyl;

isopentyl;

cyclohexyl;

pentanoyl, in particular 4-pentanoyl;

butenyl, in particular aryl-substituted butenyl, more preferably 4,4-bis (4-methoxyphenyl) -but-3-enyl;

acetyl;

phenyl, in particular phenyl substituted by one or more halogen atoms, more particularly 3,4-dichlorophenyl and 4fluorophenyl, in particular phenyl substituted by one or more aryloxy or C 1-4 alkoxy groups, in particular 3, 4-dimethoxyphenyl, 3-benzyloxy-4-methoxy-phenyl, in particular phenyl substituted with one or more C1-4 alkylsulfonyl groups, more preferably 4-methanesulfonyl-phenyl;

benzyl;

naphthalenyl, in particular naphthylen-2-yl; benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl; furanyl, in particular furan-2-yl, in particular substituted furanyl, such as 5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5 (3-trifluoromethyl-phenyl) -furan-2-yl, in particular halogen-substituted furanyl, even more particularly 5-bromo-furan-2-yl, in particular aryl-substituted furanyl, even more particularly 5- (4-chloro-phenyl) -furan-2-yl, in particular C 1-6 alkyl-substituted furanyl, even more particularly 3-methyl-furan-2-yl, 4-methylfuran-2-yl, 2,5-dimethyl-furan-2 -yl and 2,4-dimethyl-furan-3-yl;

tetrahydrofuranyl, in particular tetrahydrofuran-2-yl;

benzofuranyl, in particular benzofuran-2-yl and substituted benzofuranyl, in particular 5- (2-piperazine-4-carboxylic acid tert-N-butyl ester-ethoxy) benzofuran-2-yl, 5- (2morpholino-4- yl-ethoxy) -benzofuran-2-yl, 5- (2-piperazin-1-ylethoxy) -benzofuran-2-yl, 5- (2-cyclohexyl-ethoxy) -benzofuran-2yl; in particular C1-4alkoxy-substituted benzofuranyl, more preferably 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl,

5,6-dimethoxy-benzofuran-2-yl, in particular halogen-substituted benzofuranyl, in particular 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, in particular C 1-6 alkyl -substituted benzofuranyl, most notably 3-methyl-benzofuran-2-yl, 3,5-dimethylbenzofuran-2-yl and 3-ethyl-benzofuran-2-yl; and 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;

naphtho [2,1-6] -furanyl, in particular naphtho [2,1 -?] - furan-2-yl, alkyl-substituted naphtho [2,1 -?] - furanyl, in particular 1-methylnaphtho [2,1-b] furan-2-yl;

benzo [b] thiophenyl, in particular benzo [b] thiophen-2-yl; optionally C 1-6 alkoxy-substituted benzo [b] thiophenyl, more preferably 5,6-dimethoxy-benzo [b] thiophen-2-yl;

quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;

quinoxalinyl, in particular quinoxalin-2-yl;

1,8 naphthyridinyl, in particular 1,8 naphthyridin-2-yl;

indolyl, in particular indol-2-yl, in particular indol-6-yl, indol-5-yl, in particular C 1-6 alkyl-substituted indolyl, more preferably N-methyl-indol-2-yl;

pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, in particular C 1-6 alkyl-substituted pyridinyl, more preferably 2-methyl-pyridin-5-yl and oxy-pyridinyl, - especially 1-oxy-pyridin-2-yl and 1-oxy-pyridin-3-yl;

furo [3,2 - /?] - pyridinyl, especially furo [3,2 - b] - pyridin-2-yl, _b6 alkyl substituted furo [3,2- £] pyridinyl, especially 3 -methylfuro [3,2-b] pyridin-2-yl;

thiophenyl, in particular thiophen-3-yl, and also thiophen-2-yl, in particular C 1-6 alkyl-substituted thiophenyl, in particular 5-methyl-thiophen-2-yl and 5-methyl-thiophen-3-yl, especially halogen-substituted thiophenyl, in particular 4,5-dibromothiophen-2-yl;

thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl, more particularly C ₁ . ₆ alkyl-substituted thieno [3,2-b] thiophen-2-yl, more preferably 5-7,7 H -butyl-3-methyl-thieno [3,2-6] thiophen-2-yl;

isoxazolyl, in particular isoxazol-4-yl, in particular (3µ ₆ alkyl-substituted isoxazolyl, more particularly 3,5-dimethylisoxazol-4-yl;

oxazolyl, in particular oxazol-4-yl, in particular 5methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4yl; and

1H-benzoimidazolyl, in particular 1H-benzoimidazol-5-yl.

R ⁹ is selected from the group consisting of:

methyl;

ethyl, in particular C ₁ . ₆ alkyl-substituted ethyl, more preferably 2-cyclohexyl-ethyl;

propyl;

butyl, in particular C 1-4 butyl, in particular 3methylbutyl;

Q mpem-butyl, in particular when R 'is R OC (O); isopentyl;

phenyl, in particular halogen-substituted phenyl, more preferably 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, in particular C, 4-chloro-phenyl, in particular in particular 3methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, in particular cyanophenyl, in particular 2-cyanophenyl; in particular Ομ ₆ alkyl-substituted phenyl, in particular 4-ethyl-phenyl, 2-methylphenyl, 4-methylphenyl, in particular C 1-6 alkylsulfonyl-substituted phenyl, in particular 4-methanesulfonylphenyl and 2methanesulfonylphenyl;

toluyl, in particular Het-substituted toluyl, in particular

3- (pyridin-2-yl) toluyl;

naphthylene, in particular naphthyl-2-ene;

benzoic acid, in particular 2-benzoic acid; benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl; benzo [1,2,5] oxadiazolyl, in particular benzo [1,2,5] oxadiazol-4-yl;

pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, in particular 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; in particular C 1-6 alkylpyridinyl, more preferably 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl;

thiophenyl, in particular thiophenyl-2-yl;

thiazolyl, in particular thiazol-2-yl;

1H-imidazolyl, in particular 1H-imidazol-2-yl, 1Himidazol-4-yl, more particularly C 1-6 alkyl-substituted imidazolyl, even more particularly 1-methyl-1H-imidazol-2-yl, 1 -methyl-1H-imidazol-4-yl and 1,2-dimethyl-1H-imidazol-4-yl;

triazolyl, in particular 1H- [1,2,4] triazolyl, more particularly 1H- [1,2,4] triazol-3-yl, in particular C 1-6 alkyl-substituted 1H- [1,2,4] triazolyl, in particular 5-methyl-1H- [1,2,4] triazol-3yl; and isoxazolyl, in particular isoxazol-4-yl, in particular C 1-6 alkyl-substituted isoxazolyl, in particular 3,5-dimethyl isoxazol-4-yl.

R 'is H;

R is H; and

R '' is N.

More preferred are compounds of formula I in which:

Re

R27

R ² e R ⁹ SO ₂ ;

R is isobutyl;

R ⁴ e R ⁵ C (O);

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

R ⁹ is selected from the group consisting of: pyridin-2-yl and 1-oxypyridin-2-yl, preferably 1-oxy-pyridin-2-yl.

R 'is H; and

R 'is H;

Most preferred are compounds in which:

R ⁵ is 3-methyl-benzofuran-2-yl

Q

R is 1-oxy-pyridin-2-yl.

An embodiment (IA) of the present invention provides compounds of formula IA:

where:

R ¹ is selected from the group consisting of:

R

and

R '/ N.

) n

R ² is selected from the group consisting of: C 1-6 alkyl, C ¹ -C 6 alkyl, C ¹ -C 6 alkyl, R ⁹ C (O) -, R ⁹ SO 2 -, R ⁹ R ¹¹ NC (O) - and

R ⁹ SO ₂ R ⁿ NC (O) -;

Λ

R is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H 1? C ₀ . ₆ alkyl and C ₁ -C ₀ alkyl; preferably C 1-6 alkyl;

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

R ⁴ is R ⁵ C (O) -;

R ⁵ is selected from the group consisting of: C ₁ . ₆ alkyl and Het-C ₀ . ₆ alkyl; preferably HEB ₀ . ₆ alkyl;

R ⁹ is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C ₁ -C ₆ alkyl and H ₁ -C ₆ alkyl;

R is selected from the group consisting of H; C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and H 1: -C ₀ . ₆ alkyl; preferably N.

R'eH;

R is H;

R 1 is selected from the group consisting of: H and C 1-6 alkyl, preferably H;

R is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H 1: -C ₀ . ₆ alkyl and C 1 -C ₆ alkyl; and η is an integer from 1 to 5, preferably 3;

and their pharmaceutically acceptable salts, hydrates and solvates.

Ο

R

In the embodiment ΙΑ, when R ¹ is a

R is preferably C1-4 alkyl;

R is more preferably selected from the group consisting of: but-2-yl and isobutyl.

with

R is most preferably isobutyl.

R ⁴ is R ⁵ C (O) -.

R ⁵ is selected from the group consisting of: _b6 alkyl and Het-C _{0. 6} alkyl, preferably C 1 -C 4 alkyl;

More preferably, R ⁵ is selected from the group consisting of: piperidin-ethyl, in particular piperidin-1-yl-ethyl; benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl; furanyl, in particular furan-2-yl, in particular aryl substituted furanyl, such as 5- (3-trifluoromethyl-phenyl) -furan-2-yl, in particular C 1-4 alkyl-substituted furanyl, even more preferably 3 - methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethylfuran-2-yl and 2,4-dimethyl-furan-3-yl;

benzofuranyl, in particular benzofuran-2-yl, in particular C 1-4 alkoxy-substituted benzofuranyl, in particular 5-methoxybenzofuran-2-yl, in particular halogen-substituted benzofuranyl, in particular 5-fluoro-benzofuran -2-yl, in particular C 1-6 alkyl substituted benzofuranyl, most notably 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl and 3-ethyl-benzofuran-2-yl; and also 5fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl and 6-methoxy-3-methylbenzofuran-2 -il;

naphtho [2,1-b] furanyl, in particular naphtho [2,1- b] furan-2-yl, Sfalkyl-substituted naphtho [2,1- b] furanyl, in particular 1-methylnaphtho [ 2,1- f]] - furan-2-yl;

benzo [b] thiophenyl, in particular benzo [b] thiophen-2-yl;

quinolinyl, in particular quinolin-2-yl;

quinoxalinyl, in particular quinoxalin-2-yl;

pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, pyridin-5-yl and oxy-pyridinyl, in particular 1-oxy-pyridin-2-yl and 1-oxy-pyridin-3-yl;

furo [3,2-b] -pyridinyl, in particular furo [3,2-0] -pyridin-2-yl, Sfalkyl-substituted furo [3,2-0] -pyridin-2-yl, in particular 3-methylfuro [3,2-b] pyridin-2-yl;

thiophenyl, in particular thiophen-3-yl and thiophen-2-yl, Sfalkyl substituted thiophenyl, in particular 5-methyl-thiophen-2-yl and 5-methylthiophen-3-yl; and thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl; and 1H-benzoimidazolyl, in particular 1H-benzoimidazol-5-yl.

R ⁵ is more preferably 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.

R '

lx

In embodiment IA, when R is

R 3 is selected from the group consisting of: Sfalkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C 3-6 alkenyl, C 3-6 alkynyl, N 3 CO 4 alkyl and Ar-C ₀ . ₆ alkyl.

R is preferably Salkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl and Ar-C ₀ . ₆ alkyl.

R ³ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, cyclohexylmethyl and toluyl.

R is selected from the group consisting of: -C ₆ alkyl, Sz_ ₆ cycloalkyl-C _{0. 6} alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H 1 -C ₀ . ₆ alkyl and Ar-C ₀ .

₆ alkyl;

R is preferably C _b6 alkyl;

R is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl.

Most preferably R is methyl.

In such compounds, R 'and R ⁴ are as described above at

In embodiment IA, when R ¹ is

η is an integer from 1 to 5; preferably 3 and

R 'and R ⁴ are as described above in

The cyclic ring may be unsubstituted or substituted by one or more C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C ₂ . ₆ alkenyl, C 1-4 alkynyl, H 1: Co. ₆ alkyl, Ag-Co. ₆ alkyl or halogen.

The cyclic ring is preferably unsubstituted.

In an embodiment, ΙΑ R is selected from the group consisting of: C _1-6 alkyl, Ar-C ₀ . ₆ alkyl, Het-Co-alkyl, R ⁹ C (O) -, R ⁹ SO 2 -, R ⁹ R ⁿ NC (O) -, and R ⁹ SO ² R ⁿ NC (O) -.

More preferably, R is selected from the group consisting of: Ar-C ₀ . ₆ alkyl, R ⁹ C (O) -, R ⁹ SO ₂ and R ⁹ R ⁿ NC (O) -.

More preferably, R ² is selected from the group consisting of: Ar-C 1-6 alkyl, R ⁹ C (O) -, and R ⁹ SO 2.

Most preferably R is R SO ₂ .

In such an embodiment:

R ⁹ is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, Ag-Co. ₆ alkyl and H 1: -C ₀ . ₆ alkyl.

R ⁹ is preferably selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and Het-Co-alkyl.

η

More preferably, R is selected from the group consisting of:

ethyl, in particular C1-6 alkyl-substituted ethyl, more preferably 2-cyclohexyl-ethyl;

propyl, in particular prop-1-yl;

isopentyl;

butyl, especially but-1-yl;

phenyl, especially halogen-substituted phenyl, in particular 3fluorophenyl, 4-fluorophenyl, 2-chlorophenyl; in particular C ₃ . ₆ alkyl-substituted phenyl, in particular 4-ethyl-phenyl, 2-methylphenyl, 4-methylphenyl, in particular C 1-6 alkylsulfonyl substituted phenyl, in particular 4-methanesulfonylphenyl and 2methanesulfonyl phenyl;

pyridinyl, in particular pyridin-2-yl, 1-oxy-pyridinyl, more particularly 1-oxy-pyridin-2-yl;

1H-imidazolyl, in particular 1H-imidazol-2-yl, C 1-6 alkyl substituted imidazolyl, in particular 1-methyl-1H-imidazol-2-yl and isoxazolyl, in particular isoxazol-4-yl, C 1-6 alkyl- substituted isoxazolyl, in particular 3,5-dimethyl-isoxazol-4-yl.

When R ² is R ⁹ SO ₂ , R ⁹ is most preferably selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.

When R ² is R ⁹ SO ² R ¹¹ NC (O) -, R ⁹ is preferably Ar-CO. ₆ alkyl, more preferably Ar, most preferably substituted phenyl such as 2-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 4-fluorophenyl.

When R ² is R ⁹ C (O) -, R ⁹ is preferably selected from the group consisting of C 1-6 alkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl and HEB ₀ . ₆ alkyl, more preferably 1-oxy-pyridin-2-yl, 2-cyclohexylethyl and isopentyl.

When R ² is R ⁹ SO ² R ⁿ NC (O) -, R ¹¹ is selected from the group consisting of: H, C 1-6 alkyl, Ar-CO. ₆ alkyl and H 1 -C ₀ . ₆ alkyl. Preferably in such an embodiment R ¹¹ is H.

R ² may be suitably selected from the group consisting of: _b6 alkyl, Ar-Co. ₆ alkyl and HEB ₀ . ₆ alkyl, preferably C _x . ₆ alkyl and HECO. _6- alkyl

When R is Ar-C ₀ . ₆ alkyl, R is preferably phenyl, optionally substituted phenyl, in particular halogen-substituted phenyl, even more particularly 2-fluorobenzyl.

When R ² is C 1-6 alkyl, R ² is preferably selected from 1 propyl, 1-butyl and 1-pentyl.

When R ² is He 1 -C ₀ . ₆ alkyl, HOC ₀ . ₆ alkyl is preferably Het-methyl and Het in Het-methyl is preferably selected from the group consisting of:

pyridinyl, in particular pyridin-2-yl, C 1-6 alkylpyridinyl, in particular 6-methyl-pyridin-2-yl;

thiophenyl, in particular thiophen-2-yl;

benzo [b] thiophen-2-yl;

thiazolyl, in particular thiazol-4-yl such as isothiazol-3-yl;

1H-imidazolyl, in particular 1H-imidazol-2-yl, C 1-6 alkyl substituted imidazolyl, in particular 1-methyl-1H-imidazol-2-yl;

triazolyl, in particular 3H- [1,2,3] triazolyl, more particularly 3H- [1,2,3] triazol-4-yl, in particular C 1-6 alkyl-substituted 3H- [1,2,3] triazolyl, in particular 3-phenyl-3H- [1,2,3] triazolyl-

4-yl;

quinolinyl, in particular quinolin-2-yl, quinolin-2-yl;

furanyl, in particular furan-2-yl, in particular substituted furanyl, such as 5-ethyl-furan-2-yl;

thieno [3,2-6] thiophene, in particular thieno [3,2- b] thiophen-2-yl, C 1-6 alkyl-substituted thieno [3,2- b] thiophen-2-yl, in particular 3,4-dimethyl-thieno [3,2-6] thiophen-2-yl.

The compounds of embodiment IA have the same use described in this specification for the compounds of formula I. The compounds of embodiment IA can be formulated in pharmaceutical compositions and used in treatment methods as described in the specification for compounds of formula I.

The compounds of formula I selected from the following group are particularly preferred embodiments of the present invention: Ex. Chemical name

No.

{(S) -1- [1- (S) -2-Benzyloxycarbonylamino-4-methylpentanoyl] -3-oxo-azepan-4-ylcarbamoyl} carbamic acid, benzyl ester;

Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

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

Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

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

Naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azepan-4ylcarbamoyl) -3-methyl-butyl] amide;

Quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

3,4-Dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azepane-

4-ylcarbamoyl) -3-methyl-butyl] amide;

4- {(S) -Methyl-2 - [(quinoline-2-carbonyl) -amino] pentanoylamino} -3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepane;

1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentyl) -4 - {(S) -4methyl-2 - [(2-quinoline-2-carbonyl) -amino] -pentanoylamino} -3-oxo-azepane;

1-Benzoyl-4 - ((S) -2- (benzo [1,3] dioxole-carbonylamino) -4-methyl-pentanoylamino) -3-oxo-azepane;

1-Benzoyl-4 - ((S) -2- (4-fluoro-benzoylamino) -4-methylpentanoylamino) -3-oxo-azepane;

3-Oxo-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -1- (4-methylpentanoyl) ) -azepane;

5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

4 - ((S) -4-Methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) -benzofuran-

2-carbonyl] amino} -pentanoylamino) -3-oxo-azepane-1-carboxylic acid phenylamide;

5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide;

5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azepan-4-ylcarbamoyl) -3methyl-butyl] -amide;

5- (2-Pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide ;

5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

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

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

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

1H-Indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-

3- oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

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

5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azepan-4-ylcarbamoyl) -butyl] -amide;

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

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

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

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

4 - ((S) -4-Methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] -amino} -pentanoylamino) -3-oxoazepane-1-carboxylic acid mpem-butyl ester;

4 - ((S) -4-Methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxoazepane) -4-ylcarbamoyl] -butyl} amide;

4-Methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin-2-ylphenyl-acetyl] -azepan-4-yl} -amide;

((S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepan-4-ylcarbamoyl} -butyl) -naphthylene-2-methyl -carbamic acid tert-butyl ester (S) -4-Methyl-2 - [(naphthylen-2-ylmethyl) -amino] -pentenoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ) -acetyl] azepan-4-yl} -amide;

4- [2- (2 - {(S) -3-Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -butylcarbamoyl} -benzofuran-538 yloxy) -ethyl ] -piperazine-1-carboxylic acid tert-butyl ester;

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

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

5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) ethyl] -azepane -4-ylcarbamoyl} -butyl) amide;

4- [2- (2 - {(S) -3-Methyl-1- [3-oxo-1- (3-pyridin-2-yl-phenyl) -ethyl [azepan-4-ylcarbamoyl] -butylcarbamoyl} - benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester;

5- (2-Piperazin-1-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide;

(S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] amide;

(S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepan-4 -yl} -amide;

5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide;

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

2,2,2-Trifluoro-N - ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-ylcarbamoyl} -butyl) -N-naphthyl-2-ylmethyl-acetamide;

4 - [(S) - (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methylpentanoylamino] -3-oxo-azepane-1-carboxyl! benzyl ester;

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

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

Quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide;

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

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

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

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

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

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

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

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

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

5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4yl carbamoyl] -butyl} amide;

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

(S) -4-Methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azepan-4-yl] -amide;

(S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methylpentanoic acid [-3-oxo- (pyridine-2-sulfonyl) -azepan-4yl] amide;

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

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

4 - ((S) -2-tert-Butylcarbonylamino-4-methylpentanoylamino) -3-oxo-azepane-1-carboxylic acid benzyl ester

5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-methyl-1H-imidazole-4-sulfonyl) -azepane-

4-yl carbamoyl] -butyl} amide;

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

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

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

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

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

5- (4-Oxy-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl carbamoyl] -butyl} amide;

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

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

5-Hydroxy-benzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-

4-yl carbamoyl] -butyl} amide;

Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-

1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl) -3-methyl-butyl} -amide;

2- (4 - {(S) -2 - {(Benzofuran-2-carbonyl) -amino} -4-methylpentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid;

3- (4 - {(S) -2 - {(Benzofuran-2-carbonyl) -amino} -4-methylpentanoylamino} -3-oxo-azepan-1-sulfonyl) -benzoic acid;

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

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

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

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

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

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

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

Benzofuran-2-carboxylic acid {(S) -1- [6,6-dimethyl-3oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

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

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

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

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

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

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

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

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

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

4-fluoro- {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-carbamoyl] -butyl} -benzamide;

5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine-2-sulfonyl) -azepan-4- ylcarbamoyl] -butyl} amide;

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

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

6- Methyl-N - {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -nicotinamide;

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

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

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

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

113 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide ;

114 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-yl carbamoyl] -butyl } amide;

115 (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4yl] amide;

116 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-

4-yl carbamoyl] -butyl} amide;

117 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide;

118 Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} amide;

119 Benzofuran-2-carboxylic acid {(S) -1- [1- (4-6-methylbenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

121 Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyloxazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

122 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

Thieno [3,2-6] thiophene-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

5-tert-Butyl-3-methyl-thieno [3,2-0] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) azepane -4-ylcarbamoyl] -butyl} amide;

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

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

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

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

Furan-2-carboxylic acid {[(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butylcarbamoyl] methyl} amide;

5-Methoxy-benzofuran-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

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

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

134 Quinoline-2-carboxylic acid {[(S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

136 furan-2-carboxylic acid ({(S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl carbamoyl} -methyl) -amide;

137 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

138 Quinoxaline-2-carboxylic acid {(S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

140 Quinoline-2-carboxylic acid {[(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

142 furan-2-carboxylic acid ({(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylcarbamoyl} -methyl) -amide;

143 5-Methoxy-benzofuran-2-carboxylic acid {[(S) -1- [1- (4methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide;

144 Quinoxaline-2-carboxylic acid {[(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

145 (S) -2- [2- (4-Methoxy-phenyl) -acetylamino] -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4yl] amide;

146 1-Methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide;

147 Furan-2-carboxylic acid ({(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylcarbamoyl} -methyl) amide;

148 5-Methoxy-benzofuran-2-carboxylic acid {[(S) -1- [1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

149 Quinoxaline-2-carboxylic acid {[(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

150 (S) -2- [2- (4-Methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4yl] amide;

151 Benzofuran-2-carboxylic acid - {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

152 5-Methoxy-benzofuran-2-carboxylic acid - {(S) -1- (1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-1-butyl} -amide;

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

154 5,6-Dimethoxy-benzofuran-2-carboxylic acid - {(S) -1- [1 (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

155 3-Methyl-benzofuran-2-carboxylic acid - {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

156 Benzo [b] thiophene-2-carboxylic acid - {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

158 Quinoxaline-2-carboxylic acid - {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

159 Benzofuran-2-carboxylic acid - {(S) -1- 1- (2-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

160 5-Methoxy-benzofuran-2-carboxylic acid - {(S) -1- (1- (2fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide;

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

162 5.6-Dimethoxy-benzofuran-2-carboxylic acid - {(S) -1- [1 (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

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

Benzo [b] thiophene-2-carboxylic acid - {(S) -1- [1- (2-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

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

Quinoxaline-2-carboxylic acid - {(S) -1- [1- (2-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

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

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

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

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

1-Methyl-1-N-indole-2-carboxylic acid - {(S) -3-methyl-1 [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

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

175 Benzofuran-2-carboxylic acid - {(S) -1- [1- (4-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

176 5-Methoxy-benzofuran-2-carboxylic acid - {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

177 7-Methoxy-benzofuran-2-carboxylic acid - {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

178 5,6-Dimethoxy-benzofuran-2-carboxylic acid - {(S) -1- [1 (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

179 3-Methyl-benzofuran-2-carboxylic acid - {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide;

180 Benzo [b] thiophene-2-carboxylic acid - {(S) -1- [1- (4-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

181 1-Methyl-1H-indole-2-carboxylic acid - {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

182 Quinoxaline-2-carboxylic acid - {(S) -1- [1- (4-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

183 Benzofuran-2-carboxylic acid - {(S) -1- [1- (3-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

184 5-Methoxy-benzofuran-2-carboxylic acid - {(S) -1- [1- (3methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

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

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

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

Benzo [b] thiophene-2-carboxylic acid - {(S) - [1- (3-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

Quinoxaline-2-carboxylic acid {(S) -1- [1- (3-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

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

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

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

Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1 (pyridin-2-sulfonyl) -azepan-4-yl carbamoyl] -ethyl} -amide;

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

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

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

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

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

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

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

1- (Benzofuran-2-carbonyl) -pyrrolidine-2-carboxylic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] amide;

3,4-Dimethoxy-N - {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -benzamide;

Benzo [b] thiophene-2-carboxylic acid - {(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

Benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide;

(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4yl] amide;

Benzo [b] thiophene-2-carboxylic acid - {(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

(S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl] amide;

(S) -4-Methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl] amide; Benzofuran-2-carboxylic acid - {(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

N - {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -3,4-dimethoxy-benzamide; Cyclohexanecarboxylic acid {(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (methanesulfonyl) -3-oxo-azepan-4-yl] amide;

Benzo [b] thiophene-2-carboxylic acid - [(S) -1- (1methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

Benzo [1,3] dioxole-5-carboxylic acid - [(S) -1- (1methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

Benzofuran-2-carboxylic acid - [(S) -1- (1methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

B1 - {[(S) -1- (1-Methanesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -

3-methyl-butyl} -3,4-dimethoxy-benzamide;

(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4yl] amide;

N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -4-methanesulfonyl-1-benzamide; Benzo [b] thiophene-2-carboxylic acid - ((S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

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

N - {(S) -1 - [(1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -3,4-dimethoxy-benzamide;

Cyclohexanecarboxylic acid {(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

4- Methanesulfonyl-N - {(S) -1- [4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl} -benzamide;

4-Methanesulfonyl-N - {(S) -1- [4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl} -benzamide;

({(S) -3-Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl} -carbamic acid benzyl ester (S) -2- [5- (4- Methoxy-phenyl) -pentanoylamino] -4-methylpentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4yl] amide;

232 (S) -2- [2- (3-Benzyloxy-4-methoxy-phenyl) -acetylamino] -4-methylpentanoic acid [3-oxo-1- (pyridin-2-sulfonyl) azepan-4-yl] amide;

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

234 (S) -4-Methyl-2- (5-oxo-hexanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] amide;

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

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

237 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide;

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

1- [1- (pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide;

239 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -

3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} amide;

240 (H) -1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -

3-methyl-1- [3-oxo- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide;

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

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

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

244 Benzofuran-2-carboxylic acid {(S) -2-naphthylen-2-yl-1 [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] ethyl} amide;

245 Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1 [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl } amide;

246 Thieno [3,2-d] thiophene-2-carboxylic acid {(S) -3-methyl-1 [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] - butyl} amide;

247 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide;

248 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridin-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide;

249 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide;

250 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepane-

4-ylcarbamoyl] -ethyl} amide;

251 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} amide;

Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [6-methyl-

3- oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-

4-ylcarbamoyl] -ethyl} amide;

5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl ] -ethyl} amide;

5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-

1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-

4-ylcarbamoyl] ethyl} amide;

5,5-Bis- (4-Methoxy-phenyl) -pent-4-enoic acid {(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide;

Quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl carbamoyl] ethyl} amide;

Naphthylene-1-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] ethyl} amide;

Quinoline-8-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-

2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} amide;

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

Naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-

-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} amide;

3-Methyl benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] butyl} amide;

3-Methyl benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (4-methyl-pentanoyl) -azepan-4-ylcarbamoyl] butyl} amide;

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

(S) -Acetylamino-4-methyl-pentanoic acid [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-yl] amide;

Quinoline-2-carboxylic acid {1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide;

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

Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-

1- (4-methyl-pentanoyl) -azepan-4-ylcarbamoyl] -butyl} amide;

Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-

2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} amide;

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

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

5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

274 7-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

275 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

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

277 1-Methyl-1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide;

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

279 Quinoline-2-carboxylic acid {[(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

The following compounds are also particularly preferred embodiments of the present invention:

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

281 (S) -4-Methyl-2- (3-piperidin-1-yl-propanoyl amino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4yl] amide;

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

283 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;

Benzo [1,3] -dioxole-5-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1-oxy-pyridin-2-yl) -methanoyl] -azepan-4-ylcarbamoyl} - butyl) amide;

5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;

Benzo [1,3] -dioxole-5-carboxylic acid {(S) -1- [1- (3cyclohexyl-propanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide;

5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl] -

3-methyl-butyl} amide;

Benzo [1,3] -dioxole-5-carboxylic acid {(S) -1- [1- (4methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

Benzofuran-2-carboxylic acid [(S) -1- [3-oxo-1 (ethanesulfonyl-azepan-4-ylcarbamoyl) -3-methyl-1-butyl] amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide;

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

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

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

295 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridin-2-sulfonyl) - azepan-4-ylcarbamoyl] -butyl} -amide;

296 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- (1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide;

297 3-Methyl-benzofuran-2-carboxylic acid} (S) -1- (1- (3-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;

298 Benzo [b] thiophene-2-carboxylic acid {(S) -1- (1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

299 3-Methyl-furan-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

300 Quinoline-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

301 Thieno [3,2-5] thiophene-2-carboxylic acid {(S) -1- [1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide;

302 Quinoxaline-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

303 Thiophene-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

304 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

5-Methoxy-benzofuran-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

3-Methyl-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

Benzo [b] thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

3-Methyl-furan-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

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

Thieno [3,2-b] thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

Quinoxaline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

Thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

5-Methyl-thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

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

3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [3-oxo- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide;

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

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

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

Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide; Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide;

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

Thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide; 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide;

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

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

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

327 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide;

328 1-Methyl-naphtho [2,1-6] -furan-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;

329 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide;

330 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide;

331 Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] -butyl] amide;

332 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] butyl} amide;

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

334 Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4-yl carbamoyl} -butyl) amide;

335 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4ylcarbamoyl} -butyl) amide;

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

337 Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- [2-chloro-benzenesulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide;

338 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [2-chloro-benzenesulfonylamino) -methanoyl] -azepane-

4-ylcarbamoyl} -butyl) amide;

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

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

341 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [4-fluoro-benzenesulfonylamino) -methanoyl] azepan-4-ylcarbamoyl} -butyl) amide ;

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

343 Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- [1-toluene-4-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide;

344 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepan-4ylcarbamoyl} -butyl) amide;

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

346 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide;

3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide;

Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide;

Benzo [b} thiophene-2-carboxylic acid <(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-yl-carbamoyl] -3-methylbutyl} amide;

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

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

Quinoxaline-2-carboxylic acid <(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

Quinoline-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

4- Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

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

4-Methyl-furan-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

Benzofuran-2-carboxylic acid [(S) -1- (1-butyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

Benzofuran-2-carboxylic acid [(S) -1- (1-propyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide;

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

Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (2morpholin-4-yl-thiazol-4-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide;

Benzofuran-2-carboxylic acid {(S) -1- [1- (5-ethyl-furan-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide;

Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethylthieno [3,2-b] thiophen-2-ylmethyl) -3-oxo-azepan-4ylcarbamoyl] -3-methyl-butyl } amide;

Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (3-phenyl-3H- [1,2,3] triazol-4-ylmethyl) -azepan-4-ylcarbamoyl] -butyl} amide;

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

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

Benzofuran-2-carboxylic acid [(S) -1- (1-benzo [b] thiophen-2-ylmethyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide;

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

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

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

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

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

4 - {(S) -2 - [(1-Benzofuran-2-yl-methanoyl) -amino] -4-methylpentanoyl amino} -1-methyl-3-oxo-1-pentyl-azepane Benzofuran-2-carboxylic acid {(S) -1- (1- (1,2-Dimethyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide;

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

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

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

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

379 3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide;

380 3-Methyl-benzofuran-2-carboxylic acid {1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] cyclopentyl} amide;

381 Furo [3,2-6] -pyridine-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] - butyl} amide.

Individual representative compounds of the present invention are presented in Examples 1-381.

Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds of the present invention are more stable at the carbon center α relative to the ketone in the configuration ratio.

The present invention includes deuterated analogs of the inventive compounds. A representative example of such a deuterated compound is shown in Example 192. A representative synthesis pathway for the deuterated compounds of the present invention is shown in Scheme 4 below. The deuterated compounds of the present invention exhibit superior chiral stability compared to that of the proton isomer.

Wherever possible, the present invention includes quaternary salts of the compounds disclosed. A representative example of such a quaternary salt is shown in Example 373. A representative synthesis route for the quaternary salt of the present invention is shown in Scheme 6 below.

Definitions

The present invention includes all the hydrates, solvates, complexes and prodrugs of the compounds of this invention.

Prodrugs are all covalently linked compounds which release the in vivo active drug of formula I. If a compound of the present invention contains a chiral center or other form of isomer center, any such isomer or isomers, including enantiomers and diastereomers, are intended to be encompassed herein. . Compounds of the invention containing a chiral center can be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using known methods, and the single enantiomer can be used alone. In cases where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are included in the invention. In cases where the compounds may exist in a tautomeric form, such as keto-enol tautomers, it is contemplated in the invention that each tautomeric form be involved, whether it exists in equilibrium or preferably in one form.

The value of each substituent in each case of Formula I or in any of its sub-formulas is independent of its meaning or of that of any other substituents, in any other case, unless otherwise indicated.

To describe the compounds of the present invention, abbreviations and symbols commonly used in peptide articles and chemical articles are commonly used. Generally, the abbreviations of amino acids follow the NACC-Nomenclature Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).

Proteases are enzymes that catalyze the cleavage of the amide bonds of peptides and proteins by nucleophilic substitution of the amide bond, ultimately resulting in hydrolysis. Such proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. The compounds of the present invention can bind more strongly to the enzyme than to the substrate and are not cleaved at all after enzymatically catalyzed attack by the nucleophile. Therefore, they competitively protect proteases from recognizing and hydrolyzing natural substrates and thus act as inhibitors.

The term amino acid, as used herein, refers to the D- or L-isomers of alanine, arginine, aspartic, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline. , serine, threonine, tryptophan, tyrosine and valine.

C 1-6 alkyl as used herein is intended to encompass substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and propyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and their simple aliphatic isomers. C 1-6 alkyl may be optionally substituted by a group selected from the group consisting of: OR ¹⁴ , C (O) R ¹⁴ , SR ¹⁴ , S (O) R ¹⁴ , NR ¹⁴ 2, R ¹⁴ NC (O) OR ^5, CO2R ^14, CO2NR ¹⁴ 2, N (C = NH) NH _2, Het, Sz_ ₆ cycloalkyl and Ar; wherein R ⁵ is selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, and C 1 -C 6 alkyl; and R ¹⁴ is selected from the group consisting of: H, C 1-6 alkyl, Ar-CO. ₆ alkyl and H 1 -C ₀ . ₆ alkyl;

Sz_ ₆ cycloalkyl as applied herein is meant to encompass substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.

C ₂ . ₆ alkenyl as used herein means an alkyl group having 2 to 6 carbons in which one carbon-carbon single bond is replaced by a carbon-carbon double bond. C ₂ . ₆ alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and some isomeric pentanes and hexanes. Both cis and trans isomers are included.

C ₂ . ₆ alkynyl means an alkyl group having 2 to 6 carbons in which one carbon-carbon single bond is substituted is a carbon-carbon triple bond. C ₂ _b alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

Halogen means F, Cl, Br and J.

Ar or aryl is phenyl or naphthyl optionally substituted with one or more Ry-C _{0. 6} alkyl; He ₁ -C ₀ . ₆ alkyl; C1-6 alkoxy; Pb-C ₀ . ₆ alkoxy; NAC ₀ . ₆ alkoxy; OH, (CH ₂ ) ₁ . ₆ NR ¹⁵ -R ¹⁶ ; (□ (CH 2 NR 4 R ¹⁶ ; C 1-4 alkyl, OR ¹⁷ , N (R ¹⁷ ) 2, SR ¹⁷ , CF 3, NO ₂ , CN, CO ₂ R ¹⁷ , CON (R ¹⁷ ), F, Cl, Br or J; wherein R ¹⁵ and R ¹⁶ are H, Srbalkil, P11-C _{0. 6} alkyl, naphthyl-C _{0. 6} alkyl or HE1-C _{0. 6} alkyl; and R is phenyl, naphthyl or jam.

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 heterocyclic ring, which is saturated or unsaturated and consisting 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 be optionally oxidized and the nitrogen heteroatom may be quaternized, and includes any bicyclic group in which each of the heterocycle ring defined above enes is fused to a benzene ring. The heterocyclic ring may be attached to any one heteroatom or carbon atom which results in the formation of a stable structure, and may optionally be substituted by one or two groups selected from C ₀ . ₆ Ar, C 1-6 alkyl, OR ¹⁷ , N (R ¹⁷ ) 2, SR ¹⁷ , CF 3, NO ₂ , CN, CO ₂ R ¹⁷ , CON (R), F, Cl, Br and J, where R is phenyl, naphthyl or C 1-6 alkyl. Examples of such heterocycles are the following: , oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzofuranyl, thiol, benzofuranyl, thiol, benzofuranyl, thiol, benzofuranyl, thiol , benzo [1 , 3] dioxolyl, pyrimidine, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazole, thiamorpholin sulfoxide, triazolyl, thiazole; be obtained by routine chemical synthesis and are resistant. The term heteroatom as used herein refers to oxygen, nitrogen and sulfur.

Here, as in the entire application, the term C ₀ denotes the absence of an immediate next substituent group; for example in the AgCO group. ₆ alkyl, when C is 0, the substituent is Ar, for example phenyl. Conversely, when the group ArC ₀ . ₆ alkyl is identified as a specific aromatic group, for example phenyl, it is to be understood that the value of C is 0.

Some radical groups here are given abbreviations. t-Bu refers to the tertiary butyl radical, Boc refers to the tert 75 butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical and Cbz refers to the benzyloxycarbonyl radical.

Some of the reagents here are given with abbreviations. m-CPBA refers to 3-chlororegoxybenzoic acid, EDC refers to Nethyl-B1 '(dimethylaminopropyl) -carbodiimide, DMF refers to dimethylformamide, DMSO refers to dimethylsulfoxide, TEA refers to triethylamine, TFA refers to trifluoroacetic acid THF refers to tetrahydrofuran.

Methods of preparation

The compounds of general formula I may be prepared in a manner analogous to those set out in Schemes 1, 2 and 3. The alkylation of m / S is (S) -7-butyl-N-allylcarbamate (1) with a base such as sodium hydride and 5bromo-1- pentene yields diene 2. Treatment of 2 or 2,6diisopropylphenylimidoneophilidene molybdenum bls (tert-butoxide) or with bis (tricyclohexylphosphine) benzylidene (IV) dichloride olefin exchange catalysts developed by Grubbs 3 gives azatecaphthalates m-CPBA gives epoxide 4. Opening of the nucleophilic the epoxy ring may be carried out with a reagent such as sodium azide to give the azido-alcohol (not shown), which can be reduced to the amino-alcohol 5 under customary conditions such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst like palladium on charcoal. The acylation of 5 with an acid such as Cbz-leucine in the presence of a coupling reagent such as N-ethyl-L1 '(dimethylaminopropyl) carbodiimide (EDC) followed by removal of the BOC protecting group in acidic medium affords the amine salt 6. The binding of 6 to Cbz- leucine may be carried out with a binder such as

N-ethyl-N (dimethylaminopropyl) -carbodiimide to give the intermediate alcohol (not shown), which is oxidized with an oxidant such as a pyridine-sulfotrioxide complex in dimethyl sulfoxide and triethylamine to give ketone 7.

Scheme 1

Reagents and Conditions: a.) NaH, 5-bromo-1-pentene, DMF; B.) A catalyst for 2,6-diisopropylphenylimidoneophilidene molybdenum bis (/ l /? -Butoxide) or bis (tricyclohexylphosphine) benzylidene (IV) dichloride, toluene c.) M-CPBA, CH ₂ Cl ₂ ; d.) NaN ₃ , CH ₃ OH, H ₂ O, NH ₄ C1; e.) 10% Pd / C, H ₂ , f.) Cbz-leucine, N-ethyl (dimethylaminopropyl) carbodiimide (EDC), CH ₂ Cl ₂ ; g.) HCl, EtOAc; h.) Cbz-leucine, EDC, CH ₂ C1 ₂ ; i.) Pyridine-sulfur trioxide complex, DMSO, TEA.

Compounds of general formula I, wherein R and R are amides, can be prepared by the general method shown in Scheme 2. Alkylation of N-Cbz allylamine (8) with a base such as sodium hydride and 5-bromo-1-pent gives diene 9. Treatment of 9 with bis (tricyclohexylphosphine) benzylidene ruthenium (1U) dichloride olefin exchange catalyst developed by Grubbs gives azepine

10. The epoxidation of 10 with standard conventional oxidants such as m-CPBA gives epoxide 11. The opening of the nucleophilic epoxy ring can be accomplished with a reagent such as sodium azide to give an azidoalcohol (not shown) which can be reduced to the amino alcohol 12 with a reducing reagent such as propandiol in the presence of triethylamine. The acylation of 12 with N-Boc-leucine and a binding reagent such as N-ethyl-N '(dimethylaminopropyl) -carbodiimide, followed by removal of the protective Cbz group under hydrogenolysis conditions gives the amine 13. The binding of 13 to the carboxylic acid is effected by a binder reagent such as N, N-N (dimethylaminopropyl) -carbodiimide, and subsequent removal of the labile in acidic medium an N-Boc protecting group with an acid such as HCl or trifluoroacetic acid affords intermediate 14. The acylation of 14 can be carried out with carboxylic acid in the presence of a conventional binder such as N-ethyl N (dimethylaminopropyl) -carbodiimide yields an intermediate alcohol (not shown) which is oxidized with an oxidant such as a pyridine sulfur trioxide complex in dimethyl sulfoxide and triethylamine to give ketone.

Reagents and Conditions: a.) NaH, 5-bromo-1-pentene, DMF; B.) The bis (tricyclohexylphosphine) catalyst benzylidene (1U) dichloride, CH ₂ Cl ₂ ; c.) / n-CPBA, CH ₂ Cl ₂ ; d.) NaN ₃ , CH ₃ OH, H ₂ O,

NH ₄ C1; e.) Propandiol, CH ₃ OH, TEA; f.) Boc-leucine, EDC, CH ₂ Cl ₂ ; g.) 10% Pd / C, H ₂ ; h.) R 2 CO 4, EDC, CH ₂ Cl ₂ or R ₂ COQ, CH ₂ Cl ₂ ; i.) HCl / EtOAc; j.) R ₂ CO ₂ H, EDC, CH ₂ C1 ₂ ; k.) pyridine sulfur trioxide complex, DMSO, TEA.

Compounds of general formula I, in which R is an alkyl, urea or sulfonamide group and R ¹ is an amide, can be prepared by the general method given in Scheme 3. The reductive amination of 13 can be accomplished by treatment with an aldehyde followed by reducing reagent such as sodium triacetoxyborohydride. Subsequent release of the N-Boc group in acidic medium yields the amine salt 16. The coupling of 16 with an acid chloride or a carboxylic acid in the presence of a conventional binder such as EDC, followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfotrioxide complex gives ketone 17. On the other hand, treatment of amine 13 with isocyanate followed by release of the N-Boc group yields the amine salt 18. Acylation and oxidation give ketone 19. Further derivatization of amine 13 may be effected vein by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20. Acylation and oxidation provides the ketone 21.

Scheme 3

Reagents and conditions: a.) RqCHO, NaBH (OAc) ₃ ; b.) HCl; c.) R ₂ CO ₂ H, EDC, CH ₂ C1 ₂ ; d.) Pyridine-sulfur trioxide complex, DMSO, TEA; e.) RxNCO, base; f.) RjSO ^ l, TEA, CH ₂ C1 ₂ .

The deuterated compound of Example 192 can be conveniently prepared according to Scheme 4. Those skilled in the art will be able to understand from Example 192 and Scheme 4 how to obtain deuterated compounds of the present invention.

Separate diastereomers of benzofuran-2-carboxylic acid {(S) -3-methyl-1 - [(2,2 ', 4-tridutero) -3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amides 31 and 32 can be prepared as shown in Scheme 4. The alkylation of allylcarbamic acid benzyl ester 22 with 5-bromo-1-pentene in the presence of a base such as sodium hydride gives diene 23. Treatment of diene 23 with bis (tricyclohexylphosphine) benzylidine ruthenium (1H) dichloride, developed by Grubbs, gives the benzyl ester of 2,3,4,7-tetrahydro-azepine-1-carboxylic acid 24.

The epoxidation of azepine 24 can be accomplished with conventional, standard oxidizers such as m-CPBA to give epoxide 25. The opening of the nucleophilic epoxy ring of 25 can be accomplished with a reagent such as sodium azide to give azido alcohol (not shown).

Scheme 4

30

32

Reagents and Conditions: a.) NaH, 5-bromo-1-pentene, DMF; B.) Bis (tricyclohexylphosphine) benzylidene (1U) dichloride,

CH ₂ Cl ₂ ; c.) / n-CPBA, CH ₂ Cl ₂ ; d.) NaN ₃ , CH ₃ OH, H ₂ O, NH ₄ C1; e.) 1,3 Propanedithiol, TEA, methanol; f.) N-Boc-leucine, EDC, CH ₂ Cl ₂ ; g.) 10% Pd / C, H ₂ ; h.) 2-Pyridinesulfonyl chloride, TEA, CH ₂ Cl ₂ ; i.) 4 Ν HCl / dioxane, methanol; j.) Benzofuran-2-carboxylic acid, EDC, CH ₂ Cl ₂ ; k.) Pyridine-sulfur trioxide complex, dimethyl sulfoxide,

TEA; 1.) CD ₃ OD; D ₂ O (10: 1), TEA; (w) separation by HPLC.

The intermediate azidoalcohol may be reduced to the amino alcohol 26 under conventional conditions such as 1,3propanedithiol and triethylamine in methanol or triphenylphosphine in tetrahydrofuran and water. The acylation of 26 can be accomplished with an acid such as N-Boc-leucine in the presence of a binder such as EDC. Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd / C yields the amine 27. Treatment of the amine 27 with 2-pyridinesulfonyl chloride in the presence of triethylamine or saturated sodium bicarbonate solution and CH ₂ Cl ₂ and subsequent removal of mpemobutoxy a protecting group in an acidic medium gives 28. The coupling of 28 with benzofuran-2-carboxylic acid can be accomplished with a binding reagent such as EDC to give the intermediate alcohol 29. The alcohol 29 can be oxidized is an oxidizing agent 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 CD ₃ OD: D ₂ O at boiling affords the deuterated analogue in the form of a mixture of diastereomers which are separated by HPLC to give the deuterated compounds 31 and 32.

Compounds of general formula I can also be prepared as shown in Scheme 5. The amine of compound 12 can be protected with di-tert-butyldicarbonate to give the NBoc derivative 33 (Scheme 2). Removal of the benzyloxycarbonyl protecting group can be accomplished by treating 33 with hydrogen gas in the presence of a catalyst as 10% Pd / C to give amine 34. Treatment of amine 34 with sulfonyl chloride as 2-pyridinesulfonyl chloride in the presence of a base such as N-methylmorpholine or triethylamine gives the sulfonamide derivative 35. Removal of the tert-butoxycarbonyl protecting group may be carried out with acid as hydrochloric acid to give intermediate 36. Coupling of 36 with an acid such as N-Boc-cycle lohexylalanine in the presence of a conventional binder such as HBTU or EDC with a polymeric backbone gives the alcohol intermediate 37. Removal of the (n) 7-butoxycarbonyl protecting group in an acidic medium gives the amine 38. The coupling of 38 with an acid such as benzofuran-2-carboxy an acid in the presence of a binder such as HBTU or EDC with a polymeric backbone gives the alcohol 39. The alcohol 39 may be oxidized by a customary oxidizing agent such as a pyridine sulfur trioxide complex in dimethyl sulfoxide and triethylamine or periodinin. Dess-Martin to obtain ketone 40.

Figure 5

Reagents and conditions:

(a) Di-tert-butyldicarbonate, tetrahydrofuran; (B) H ₂ ,

10% Pd / C, EtOAc; (c) 2-pyridylsulfonyl chloride, TEA;

(d) HCl, EtOAc; (e) N-Bocylohexylalanine, P-EDC, CH ₂ C1 ₂ ; (f) HC1, CH ₂ C1 _2; (g) benzofuran

2-carboxylic acid, P-EDC, CH ₂ C1 ₂ ; (h) Periodontin of DessMartin, methylene chloride.

The quaternized 4-amino-azepan-3-ones compounds of the present invention can be conveniently prepared according to the invention

Scheme 6. Those skilled in the art will understand from Scheme 6 how to obtain the quaternized 4-amino-azepan-3-ones compounds of the present invention. The reductive amination of 13 can be accomplished by treatment with an aldehyde followed by a reducing reagent such as sodium triacetoxyborohydride. Subsequent release of the N-Boc group in acidic medium yields the amine salt 16. Treatment of 16 with acid chloride or with carboxylic acid in the presence of a conventional binder such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as the pyridine sulfotrioxide complex gives the ketone 17. The quaternization of the amine of 17 can be accomplished by treatment with an alkylating reagent such as iodomethane to give the quaternary amine salt 41.

Figure 6

17

Reagents and conditions: a.) R4 CHO, NaBH (OAc) ₃ ; b.) HCI; c.)

R ₂ CO ₂ H, EDC, CH ₂ C1 ₂ ; d.) Pyridine-sulfur trioxide complex, dimethyl sulfoxide, TEA; e.) Iodomethane

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

Coupling methods for the preparation of amide bonds are generally known in the art. Peptide Synthesis Methods Exposed 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, III., 1984, are generally illustrative of the method and are incorporated herein by reference.

Methods for the synthesis of the compounds of this invention often employ protecting groups to mask the reactive groups or to reduce adverse side effects. Such protecting groups are generally described in Green, T. W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term amino protecting groups, as known in the art, generally refers to the groups Boc, acetyl, benzoyl, Fmoc and Cbz and derivatives thereof. Methods for protecting and deprotecting and for replacing one amino protecting group with another group are known.

The acid addition salts of the compounds of formula I are prepared in a standard manner in a suitable solvent of the starting compound and an excess of acid such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanes. Some of the compounds form internal or amphoteric salts that may be acceptable. The cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide containing the appropriate cation; or with a suitable organic amine. Cations such as Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺⁺ , Mg ^++, and NH ₄ ⁺ are distinct examples of cations involved in pharmaceutically acceptable salts. Halides, sulfates, phosphates, alkanoates (such as acetate and trifluoroacetate), benzoates and sulfonates (such as mesylate) are examples of anions involved in pharmaceutically acceptable salts. Quaternary ammonium salts are prepared by treating the starting amine compound with an excess of alkyl halide, such as methyl iodide.

This invention also provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of formula I may be used for the manufacture of medicaments, and the pharmaceutical compositions of the compounds of formula I prepared as described above may be formulated as solutions or lyophilized powders for parenteral administration. The powders may be processed by the addition of a suitable diluent or other pharmaceutically acceptable carrier immediately before use. The liquid composition may be a buffered isotonic aqueous solution. Exemplary suitable diluents are normal isotonic saline, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such a composition is particularly suitable for parenteral administration but can also be used for oral administration or placed in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

On the other hand, these compounds can be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to improve or stabilize the composition or to facilitate its preparation. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut butter, olive oil, saline and water. The carrier may also include a sustained release substance such as glyceryl monostearate or glyceryl distearate, alone or with wax. The amount of solid carrier varies, but preferably is between about 20 mg and about 1 g per unit dose, the pharmaceutical compositions are prepared following conventional pharmaceutical methods including grinding, mixing, granulation and compression, where necessary for the tablet forms; or grinding, mixing and filling with hard gelatin capsules. When using a liquid carrier, the preparation will be in the form of a syrup, elixir, emulsion or aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly orally or in a soft gelatin capsule.

For rectal administration, the compounds of this invention may also be mixed with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and formulated as suppositories.

New intermediates

Referring to the methods of preparing the compounds of formula I set forth in Schemes 1-4 above, one skilled in the art may appreciate that the present invention includes all new intermediates necessary for the preparation of the compounds of formula I. In particular, the present invention provides the compounds of formula I:

where:

R ¹ is selected from the group consisting of:

R ² is selected from the group consisting of cycloalkyl-C ₀ . ₆ alkyl,

R ⁹ C (S) -,

Ar-So_ ₆ alkyl,

R ⁹ OC (O) -, from: H, C 1-4 alkyl, C ₃ . ₆ Het-C.balkyl, R ⁹ C (O) -,

R ⁹ R ⁿ NC (O) -, R ⁹ R ⁿ NC (S) -, se

R ⁹ (R ⁿ ) NSO ² R ⁹ SO ² R ⁿ NC (O) -;

R is selected from the group consisting of:

H,

Calkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, HetCo-alkyl and

Ar-CO-alkyl;

R and R 'may be linked to form a pyrrolidine, piperidine or morpholine ring;

R ⁴ is selected from the group consisting of: H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar-Co-alkyl, H 1 -C 6 alkyl, R ⁵ C (O) -, R ⁵ C ( S) -, R ⁵ SO 2 -, R ⁵ OC (O) -, R ⁵ R ¹² NC (O) -, and R ⁵ R ¹² NC (S) -;

R ⁵ is selected from the group consisting of: H, C 1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C _3-6 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl and HetC ₀ . ₆ alkyl;

£

R is selected from the group consisting of: H, C 1-6 alkyl, Ar-C ₀ . ₆ alkyl or Het-Co-alkyl;

-y

R is selected from the group consisting of: H, C1-6alkyl, C3. ₆ cycloalkyl-C ₀ . ₆ alkyl, Ar-C ₀ . ₆ alkyl, NHSO. ₆ alkyl, R ¹⁰ C (O) -, R ¹⁰ C (S) -, R ¹⁰ SO ₂ -, R ¹⁰ OC (O) -, R ¹⁰ R ¹³ NC (O) -h R ¹⁰ R ¹³ NC (S ) -;

Q

R is selected from the group consisting of: H, C 1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H 1 -C ₀ 6 ^{alkyl and} Ar-Co. ₆ alkyl;

R ⁹ is selected from the group consisting of: C ₁ . ₆ alkyl, C3. ₆ cycloalkyl-C ₀ . ₆ alkyl, Ar-C0-6alkyl and Het-C0-6alkyl;

R ¹⁰ is independently selected from the group consisting of: C 1-6 alkyl, C 3-3. ₆ cycloalkyl-C _0-3 alkyl, Ar-C ₀ . ₆ alkyl and H 1 -C ₀ . ₆ alkyl;

R ¹¹ is selected from the group consisting of: H, C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and H 1 -C ₀ . ₆ alkyl; -

R is selected from the group consisting of: H, C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and C 1 -C 10 alkyl;

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

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

R is selected from the group consisting of: H, C ₁ -alk, At-Cq. ₆ alkyl or C ₁ -C ₆ alkyl;

R 'is selected from the group consisting of: H, alkyl, Sz_ ₆ cycloalkyl-C _{0. 6} alkyl, C ₁ -C ₆ alkyl and Het-C 0 alkyl;

R is selected from the group consisting of: alkyl, Sz_ ₆ cycloalkyl-C _{0. 6} alkyl C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, HepC ₀ . ₆ alkyl and ArC ₀ . ₆ alkyl;

η is an integer from 1 to 5;

and their pharmaceutically acceptable salts, hydrates and solvates.

In connection with embodiment A, the present invention includes the new intermediates of formula PA:

where:

R ¹ is selected from the group consisting of:

and

O) n

R is selected from the group consisting of: C 1-6 alkyl, C 1 -C ₆ alkyl, H 1 -C0. ₆ alkyl, R ⁹ C (O) -, R ⁹ SO 2 -, R ⁹ R ⁿ NC (O) -, and R ⁹ SO ² R ⁿ NC (O) -;

R ³ is C 1-6 alkyl;

R ⁴ is R ⁵ C (O) -;

R ⁵ is He 1 -C ₀ . ₆ alkyl;

R ⁹ is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ . cycloalkyl-C ₀ . ₆ alkyl, C ₁ -C ₆ alkyl and H 1: -C ₀ . ₆ alkyl;

R ¹¹ is selected from the group consisting of: H, C 1-6 alkyl, Ar-Co. ₆ . alkyl and HECO. ₆ alkyl;

R'eH;

R is H;

R 'is H;

R is selected from the group consisting of C ^ alkyl, C ₃ _b_ cycloalkyl-C _{0. 6} alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, H ₁ C ₀ . ₆ alkyl and ArC ₀ . ₆ alkyl;

η is an integer from 1 to 5, preferably η is 3;

and their pharmaceutically acceptable salts, hydrates and solvates.

The following compounds are preferred new intermediates:

[(S) -1 (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] carbamic acid benzyl ester;

(S) -2-Amino-4-methyl-pentanoic acid (1-benzyl-3-hydroxy-azepan-4-yl) -amide;

(S) -2-Amino-4-methyl-pentanoic acid {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-yl} -amide;

{(S) -1- [4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxyazepan-1-ylmethyl] -3-methyl-butyl} -carbamic acid, benzyl ester;

(S) -2-Amino-4-methyl-pentanoic acid (1-benzoyl-3-hydroxy-azepan-4-yl) -amide;

(S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4methylpentanoyl) -azepan-4-yl] -amide;

(S) -2-Amino-4-methyl-pentanoic acid (1-benzenesulfonyl3-hydroxy-azepan-4-yl) -amide;

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

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

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

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

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

and

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

Method for the synthesis of the compounds of the invention

Referring to Schemes 1-6 above, the present invention provides a method for the synthesis of compounds of formula (I), comprising the step of oxidizing the corresponding compound of formula (II) with an oxidant to obtain the compound of formula (I) in the form of a mixture of diastereomers. Preferably, the oxidant is a sulfur trioxide pyridine complex in dimethyl sulfoxide and triethylamine.

Referring to Scheme 4, the present invention also provides a method for the synthesis of deuterated compounds is Formula (I). In particular, when looking for a deuterated isomer, in the synthesis after the oxidation step, an additional step of deuterating the protonated isomer with a deuterating reagent is included to obtain the deuterated compound of Formula (I) in the form of a mixture of diastereomers. Preferably, the deuterating reagent is CD ₃ OD: D ₂ O (10: 1) in triethylamine.

The method further comprises the step of separating the diastereomers of formula (I) by separation methods, preferably by high pressure liquid chromatography (HPLC).

Referring to Scheme 6, the present invention also provides a method for the synthesis of quaternary salts of 4amino-azepan-3-one compounds of formula (I).

Usefulness of the invention

The compounds of formula I are useful as protease inhibitors, in particular as cysteine and serine protease inhibitors, in particular as cysteine protease inhibitors, even more particularly as cysteine protease inhibitors of the papain superfamily, and more particularly as The cysteine protease inhibitors of the cathepsin family, most notably as cathepsin K. inhibitors. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and memory formulations. compounds.

The present compounds are useful for the treatment of cysteine protease-mediated diseases, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei and Crithidia fusiculata; as well as schistosomiasis, malaria, tumor metastases, metachromatic leukodystrophy, muscular dystrophy, amitrophy; and in particular diseases involving cathepsin K, most notably diseases with extreme bone and cartilage loss including osteoporosis, gum disease including gingivitis and periodontitis, arthritis, in particular osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia due to malignancy and metabolic bone disease.

Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that break down the surrounding matrix, and some tumors and metastatic neoplasia can be effectively treated with the compounds of this invention.

The present invention also provides methods of treating diseases caused by pathological levels of proteases, in particular cysteine and serine proteases, in particular cysteine proteases, even more particularly cysteine proteases of the papain superfamily, and more particularly cysteine proteases from the cathepsin family, which methods include administering to an animal, especially a mammal, and most specifically to a person in need thereof, a compound of the present invention. The present invention more specifically provides methods of treating diseases caused by pathological levels of cathepsin K, which methods include administering to an animal, particularly a mammal, and most specifically to a person in need thereof a cathepsin K inhibitor comprising a compound of the present invention. The present invention particularly provides methods of treating diseases in which cysteine proteases are involved, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei and Crithidia fusiculata; as well as schistosomiasis, malaria, tumor metastases, metachromatic leukodystrophy, muscular dystrophy, amitrophy; and in particular cathepsin K-mediated diseases, most notably diseases of extreme bone and cartilage loss including osteoporosis, gum disease including gingivitis and periodontitis, arthritis, especially osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia due to malignancy and metabolic bone disease.

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

For acute therapy, parenteral administration of a compound of Formula I is preferred. An intravenous infusion of the compound in a 5% solution of dextrose in water or normal saline or a similar formulation with suitable excipients is most effective, although a single intramuscular injection is useful. A typical parenteral dose will be from about 0.01 to about 100 mg / kg; preferably between 0.1 and 20 mg / kg, in a manner that maintains the plasma drug concentration at a value effective to inhibit cathepsin K. The compounds are administered one to four times daily in an amount to give a total daily dose of about 0.4 to about 400 mg / kg per day. The exact amount of a compound of the invention that is therapeutically effective and the pathway in which such compound is best administered are readily determined by one of ordinary skill in the art by comparing blood reagent levels with the concentration needed to produce a therapeutic effect.

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

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

Biological analyzes

The compounds of this invention can be tested by one of several biological assays to determine the concentration of a compound required to produce a pharmacological effect.

Determination of Cathepsin K proteolytic catalytic activity

All cathepsin K assays were performed with a human recombinant enzyme. Standard assay conditions for the determination of kinetic constants use a fluorogenic peptide substrate, usually Cbz-Phe-Arg-AMC, and determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock solutions with concentrations of 10 or 20 µM in dimethyl sulfoxide with a final substrate concentration of 20 μΜ were prepared for the analysis. All samples analyzed are with

10% dimethyl sulfoxide content. Independent experiments have found that this amount of dimethyl sulfoxide does not affect the enzyme activity or the kinetic constants. All assays were performed at room temperature, and the fluorescence of the substance (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II plaque reader. Product development curves were obtained in 20 to 30 minutes following the formation of the AMC product.

Inhibition assay

Potential inhibitors were evaluated using the development curve method. The assays were performed in the presence of different concentrations of the test compound. The reactions are initiated by the addition of an enzyme to the buffered solutions of inhibitor and substrate. Data analysis was performed according to one of two methods, depending on the appearance of development curves in the presence of inhibitors. For those compounds whose developmental curves are linear, apparent inhibition constants (K _iapp ) are calculated according to Equation 1 (Brandt et al., Biochemitsry, 1989, 28,140):

v = V _m A / [K _a (l + I / K _{i> app} ) + A] (1) where v is the reaction rate with maximum velocity V _m , A is the substrate concentration at Michaelis constant K _a and I is the inhibitor concentration.

For those compounds whose developmental curves show a downward inhibition characteristic over time, the data from the individual data groups were analyzed to obtain k _obs according to Equation 2:

[AMC] = v _ss t + (v ₀ -v _ss ) [l-exp (-k _ob j)] / k _obs (2) where [AMC] is the product concentration obtained for time t, v ₀ is the initial reaction rate and is the final speed in steady state. The values for k _obs were then analyzed as a linear function of the inhibitor concentration to obtain the apparent second order rate constant (/ < _{o /} "/ inhibitor concentration or & _ο & / [1])> describing the time-dependent inhibition. The overall discussion of this kinetic processing has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201).

Resorption analysis of human osteoclasts

Aliquots of osteoclastoma-derived cell suspensions were removed from storage where they were stored under liquid nitrogen and warmed rapidly at 37 ° C and washed once in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). ). The medium was aspirated and replaced with mouse anti-HLA-DR antibody diluted 1: 3 in RPMI-1640 medium and incubated for 30 minutes on ice. The cell suspension was stirred periodically.

The cells were washed twice with cold medium RPMI-1640 by centrifugation (1000 rpm, 5 minutes at 4 ° C) and then transferred to a sterile 15 mL capacity centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber.

A sufficient number of magnetic beads (5 per mononuclear cell) coated with goat anti-mouse IgG were removed from the bottle in which they were stored and placed in 5 mL of fresh medium (thus washing away the toxic azide preservative). The medium was removed by magnetizing the pearls and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was stirred periodically. Cell-coated beads were magnetically released, and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh cell medium was added to the cell-coated beads to displace any engaging osteoclasts. This washing process was repeated 10 times. Covered cells were discarded.

The osteoclasts were counted in a counting chamber using a plastic disposable pasteur pipette to load the sample chamber. The cells were pelleted by centrifugation and the osteoclast density was adjusted to 1.5 x 10 ⁴ / mL in EMEM medium supplemented with 10% fetal bovine serum and 1.7 g / L sodium bicarbonate. Aliquots of 3 mL of the cell suspension (treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube was added 3 mL of appropriate treatment (diluted to 50 μΜ in EMEM medium). Appropriate carrier controls, a positive control (87MEM1 diluted to 100 pg / mL) and an isotype control (IgG2a diluted to 100 pg / mL) are also included. The tubes were incubated at 37 ° C for 30 minutes.

Aliquots of 0.5 mL of cells were seeded on sterile dentin sections in a 48-well plate and incubated at 37 ° C for 2 hours. Each processing is screened four times. The sections were washed in alternate six-fold warm PBS (10 mL / well in a 6-well plate) and then fresh treated or control and incubated at 37 ° C for 48 hours. The sections were then washed in phosphate-buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 minutes, then washed in water and incubated in buffer for 5 minutes at 37 ° C. The sections were then washed in cold water and

100 incubated in cold acetate buffer / durable red garnet for 5 minutes at 4 ° C. Excess buffer was aspirated and sections were air-dried after washing with water.

TRAP positive osteoclasts are enumerated by bright-field microscopy and then removed from the dentin surface by ultrasonic treatment. Well volumes were determined using a Nikon / Lasertec ILM21W confocal microscope.

Total

Nuclear magnetic resonance spectra were recorded at 250 or 400 MHz using a Bruker AM 250 or Bruker AC 400 spectrometer, respectively. CDC1 ₃ is deuterochloroform, DMSO-d ₆ is hexadeutrodimethylsulfoxide and CD ₃ OD is tetradeuteromethanol. The chemical shifts are given in parts per million (d) relative to the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, b = doublet, 1 = triplet, μ = quartet, w = multiplet, dd = doublet of doublets, dt = doublet of triplets, arp = apparent, bj = wide. J represents the NMR coupling constant measured in Hz. Constant-wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and infrared spectra with Fourier transform (FTIR) were recorded on a Nicolet Impact 400 D. infrared spectrometer. IR and FTIR spectra were recorded in transmission mode and position given in backwave numbers (cm ' ¹ ). The mass spectra were taken on either a VG 70 FE, PE Syx API III, or a VG ZAB HF instrument using ionization by fast atom bombardment (FAB) or electrospray (ES). Elemental analysis was obtained from a Perkin-Elmer 240C elemental analyzer. The melting points were taken from a melting point apparatus

101

Thomas-Hoover and have not been adjusted. All temperatures are given in degrees Celsius.

Analtech GF and E. silica gel were used for thin layer chromatography. Flash and gravity chromatography were performed on E. Merck Kieselgel 60 silica gel (230-400 mesh).

Some of the materials (where indicated) were purchased from Aldrich Chemical Co., Milwaukee, Wis., Chemical Dynamics Corp., South Plainfield, N.J. and Advanced Chemtech, Louisville, Kentucky.

Examples of carrying out the invention

In the following synthesis examples, the temperature is in degrees (° C). Unless otherwise stated, all starting materials were obtained from commercial sources. It is believed that without further elaboration, the person skilled in the art can make full use of the present invention using the foregoing description. The examples are given to illustrate the invention but not to limit its scope. Claims have been made of what is claimed by the inventors.

Example 1

Preparation of {(5) -1- [1 - ((S) -2-benzyloxycarbonylamino-4-methylpentanoyl) -3-oxo-azepan-4-ylcarbamoyl} carbamic acid, benzyl ester

a.) Allyl-pent-4-enyl-carbamic acid tert-butyl ester

To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed with hexanes) in dimethylformamide (30 mL) was added dropwise pem-butyl N-allylcarbamate (6.0 g, 38.2 mmol). The mixture was stirred at room temperature for approximately 10 minutes and then 5-bromo-pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction mixture was heated to 40 ° C for about 2 hours and then the reaction mixture was partitioned between ethyl acetate and water. The organic layer is washed with

102 water (2 x) and brine, dried (MgSO ₄ ), filtered and concentrated to give 10 g of the title compound as an oil: MS (EI) 226 (M + H ⁺ ).

b. ) 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid tert-butyl ester

To a solution of the compound of Example 1a (4.5 g) in benzene was added 2,6-diisopropylphenylimidoneophilidic molybdenum 6nc (tbutoxide) (600 mg). The reaction mixture was heated to reflux for 1.5 hours and then the reaction mixture was concentrated in vacuo. Chromatography (50% CH ₂ C12: hexanes) on the residue gave 3.92 g of the product:

c. ) 8-Oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid tert-butyl ester

To a solution of the compound of Example 1b (3.0 g, 15.2 mmol) in CH ₂ Cl ₂ was added m-CPBA (7.8 g, 45.6 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH ₂ Cl ₂ and saturated K ₂ CO _{3 solution} . The organic layer was washed with saturated NaHCO ₃ solution, water and brine, dried (MgSO ₄ ), filtered and concentrated to give 3.11 g of the title compound as an oil: MS (EI) 214 (M + H ⁺ ).

d. ) 4-Azido-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester

To a solution of the epoxide of Example 1c (3.92 g, 20 mmol) in methanol: water (180 mL of a solution in 8: 1) was added NH ₄ C1 (3.18 g, 60 mmol) and sodium azide (3.9 g, 60 mmol). . The reaction mixture was heated to 40 ° C until TLC analysis showed complete exhaustion of the starting epoxide. The bulk of the solvent was removed in vacuo and the remaining solution was diluted with ethyl acetate and evaporated.

103 washes with water and brine, dried (Na ₂ SO4), filtered and concentrated. Column chromatography (40% ethyl acetate-hexanes) on the residue gave 3.43 g of the title compound.

e. ) 4-Amino-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester

To a solution of the azido-alcohol of Example Id (3.4 g) and 10% Pd / C (catalytic amount) in ethyl acetate: methanol (2: 1 solution) was placed a hydrogen balloon. The reaction mixture was stirred until complete exhaustion of the starting material was established by TLC analysis. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo. Column chromatography of the residue (25% methanol: dichloromethane) afforded 2.57 g of the title compound: MS (EI) 231 (M + H ⁺ ).

f. ) 4 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid pem-butyl ester

To the solution of the amino alcohol of Example 1e (160 mg, 0.70 mmol) in CH ₂ Cl ₂ was added EDC (134 mg), HOBt (94 mg) and Cbzleucine (185 mg). The reaction mixture was kept at room temperature until complete exhaustion of the starting material was established by TLC analysis. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl, saturated K ₂ CO _{3 solution} , water and brine, dried (MgSO ₄ ), filtered and concentrated. Column chromatography of the residue (3% methanol: dichloromethane) afforded 200 mg of the title compound: MS (EI) 478 (M + H ⁺ ), 500 (M + Na ⁺ ).

Mr Rücker ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] carbamic acid benzyl ester

To 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).

104

The reaction mixture was stirred at room temperature for about 2 hours and then the solvent was removed in vacuo to give 168 mg of the title compound: MS (EI) 378 (M + H ⁺ ).

h. ) {(S) -1- [4 - ((S) -2-Benzyloxycarbonylamino-4-methylpentanoylamino) -3-hydroxy-azepane-1-carbonyl] -3-methyl-butyl} carbamic acid, benzyl ester

To a solution of the amine salt of Example 1g (168 mg, 0.42 mmol) in CH ₂ Cl ₂ was added EDC (81 mg), HOBt (57 mg), triethylamine (0.09 mL) and Cbz-leucine (111 mg). The reaction mixture was stirred until the reaction was complete according to TLC analysis. The workup followed by column chromatography (5% CH ₃ OH: CH ₂ Cl ₂ ) gave 159 mg of the title compound: MS (EI) 625 (M + H ⁺ ).

i. ) {(S) -1- [4 - ((S) -2-Benzyloxycarbonylamino-4-methylpentanoylamino) -3-oxo-azepane-1-carbonyl] -3-methylbutyl} carbamic acid, benzyl ester

To a solution of the alcohol of Example 1h (130 mg, 0.21 mmol) in dimethyl sulfoxide was added TEA (0.17 mL) and pyridine sulfate trioxide (97 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for about 2 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated. Column chromatography of the residue (5% CH ₃ OH: CH ₂ Cl ₂ ) gave 100 mg of the title compound as a mixture of diastereomers: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 12H), 1.5 -2.1 (m, 8H), 2.2 (m, 4H), 3.0 (m, 1H), 3.5 (d, 1H), 3.6 (d, 1H), 4.01 (m, 1H), 4.5 (m, 2H). 4.7 (m, 1H), 5.0 (m, 5H), 7.3 (m, 10H); MS (EI) 623 (M + H ⁺ ), 645 (M + Na ⁺ ). Separation of diastereomers by HPLC

105 gave diastereomer 1: MS (EI) 623 (M + H ⁺ ), 645 (M + Na ⁺ ) and diastereomer 2: MS (ES) 623 (M + H ⁺ ), 645 (M + Na ⁺ ).

Example 2

Preparation of naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

a. ) Allyl-pent-4-enyl-carbamic acid, benzyl ester

Benzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) was added dropwise to a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in dimethylformamide. The mixture was stirred at room temperature for approximately 10 minutes and then 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction mixture was heated to 40 ° C for about 4 hours and then partitioned between dichloromethane and water. The organic layer was washed with water (2 x) and brine, dried (MgSO ₄ ), filtered and concentrated. Column chromatography of the residue (10% ethyl acetate: hexanes) afforded 10.3 g of the title compound as an oil: MS (EI) 260 (M + H ⁺ ).

b. ) 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid, benzyl ester

To a solution of the compound of Example 2a (50 g) in dichloromethane was added bis (tricyclohexylphosphine) benzylidene ruthenium (GI) dichloride (5.0 g). The reaction mixture was heated to reflux, which was determined by TLC analysis. The reaction mixture was concentrated in vacuo. Column chromatography of the residue (50% dichloromethane: hexanes) afforded 35 g of the title compound: MS (EI) 232 (M + H ⁺ ).

c. ) 8-Oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid, benzyl ester

Following the general method of Example 1c with the exception of using the compound of Example 2b, a

106 title compound: MS (EI) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).

d. ) 4-Azido-3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To a solution of the epoxide of Example 2c (2.0 g, 8.1 mmol) in methanol: water (8: 1 solution) was added NH ₄ Cl (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). The reaction mixture was heated at 40 ° C until complete exhaustion of the starting epoxide was detected by TLC analysis. The bulk of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and buffer at pH 4. The organic layer was washed with saturated NaHCO ₃ solution, water and brine and dried (MgSO ₄ ), filtered and concentrated. Column chromatography (20% ethyl acetate: hexanes) of the residue gave 1.3 g of the title compound: MS (EI) 291 (M + H ⁺ ) plus 0.14 g of trans-4-hydroxy-3-azidohexahydro-1H-azepine

e. ) 4-Amino-3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To a solution of the azidoalcohol 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 mixture was stirred until complete exhaustion of the starting material was established by TLC analysis and then the reaction mixture was concentrated in vacuo. Column chromatography of the residue (20% methanol: dichloromethane) afforded 0.72 g of the title compound: MS (EI) 265 (M + H ⁺ ).

f. ) 4 - ((S) -2-igret-Butoxycarbonylamino-4-methyl-pentanoylamino) 3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To the solution of the amino alcohol of Example 2e (720 mg, 2.72 mmol) in CH ₂ Cl ₂ was added EDC (521 mg), HOBt (368 mg) and N-Bocleucine (630 mg). The reaction mixture was kept at room temperature until TLC analysis showed complete exhaustion

107 starting material. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl, saturated K ₂ CO _{3 solution} , water and brine, dried (MgSO ₄ ), filtered and concentrated. Column chromatography of the residue (3% methanol: dichloromethane) afforded 1.0 g of the title compound: MS (EI) 478 (M + H ⁺ ).

Mr Rücker ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl) carbamic acid tert-butyl ester

To a solution of the compound of Example 2f (1.0 g) and 10% Pd / C (catalytic amount) in ethyl acetate: methanol (2: 1 solution) was placed a hydrogen balloon. The reaction mixture was stirred until complete exhaustion of the starting material was established by TLC analysis. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo to give 0.82 g of the title compound: MS (EI) 344 (M + H ⁺ ).

h. ) [(S) -1- (1-Benzyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methylbutyl] -carbamic acid tert-butyl ester

To a solution of the compound of Example 2g (0.69 g, 2.01 mmol) in CH ₂ Cl ₂ was added benzaldehyde (0.32 mL, 3.01 mmol), followed by sodium triacetoxyborohydride (0.85 g, 4.02 mmol). The reaction mixture was stirred until the reaction was complete, which was determined by TLC analysis, and then a few drops of water were added to the reaction mixture to destroy excess sodium triacetoxyborohydride. The mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution, water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. Column chromatography of the residue (5% methanol: dichloromethane) afforded 800 mg of the title compound: MS (ES) 434 (M + H ⁺ ).

i. (S) -2-Amino-4-methyl-pentanoic acid (1-benzyl-3-hydroxyazepan-4-yl) -amide

108

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 mixture was stirred at room temperature overnight and then concentrated in vacuo to give 800 mg of the title compound: MS (ES) 334 (M + H ⁺ ).

j. ) Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxyazepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH ₂ Cl ₂ was added triethylamine (0.17 mL, 1.22 mmol), EDC (103.5 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and 2 -Naphthoic acid (93 mg, 0.54 mmol). The reaction mixture was stirred until the reaction was complete according to TLC analysis. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ solution, water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. Column chromatography of the residue (5% methanol: dichloromethane) afforded 0.14 g of the title compound: MS (EI) 488 (M + H ⁺ ).

k. ) Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Example 1 with the exception that the compound of Example 1 is replaced by that of Example 2j, the title compound is obtained: Ή NMR (CDCl ₃ ): δ

l. 0 (m, 6Η), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H), 3.4 (m, 1H), 3.7 (m, 2H) , 4.7 (m, 1H), 5.2 (m, 1H), 7.2-8.4 (m, 12H); MS (EI): 486 (M + H ^& lt ^{; +} & gt ^; , 100%). Separation of diastereomers by HPLC gave diastereomer 1: MS (EI) 486.3 (M + H ⁺ ) and diastereomer 2: MS (ES) 486.3 (M + H ⁺ ).

109

Example 3

Preparation of benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

a. ) Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 2j with the exception that 2-naphthoic acid is replaced with piperic acid, the title compound is obtained: MS (ES) 482 (M + H ⁺ ).

b. ) Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-yl-carbamoyl) -3-methyl-butyl] amide

Following the general method of Example 1 with the exception of using the compound of Example 3, the title compound was obtained: NMR (CDCl 3): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.0 (m, 1H), 3.2 (d, 1H),

3.5 (q, 1H), 3.7 (m, 2H), 4.7 (m, 1H), 5.2 (m, 1H), 6.0 (s, 2H), 6.8 (m, 2H), 7.2 (m, 6H); MS (EI): 480 (M + H ^& lt ^{; +} & gt ^; , 100%). The diastereomers were separated by preparative HPLC. Lyophilization of the eluent afforded 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 ⁺ ).

Example 4

Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-benzyl -

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

a.) Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxyazepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 2j with the exception that 2-naphthoic acid is replaced by benzofuran-2-carboxylic acid, the title compound is obtained: MS (ES) 478 (M + H ⁺ ).

110

b.) Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 1 with the exception that the compound of Example 4a was used, the title compound was obtained: 476 MS (EI): 492 (M + H ⁺ , 100%). The diastereomers were separated by preparative HPLC. Lyophilization of the eluent gives diastereomer 1: MS (EI)

476.4 (M + H ⁺ ), 951.6 (M + H ⁺ ) and diastereomer 2: MS (EI) 476.4 (M + H ⁺ ), 951.6 (M + H ⁺ ).

Example_5

Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

a. ) Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 2j with the exception that 2-naphthoic acid is replaced with benzothiophene-2-carboxylic acid, the title compound is obtained: MS (ES) 494 (M + H ⁺ ).

b. ) Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 1 with the exception that using the compound of Example 5a, the title compound was obtained: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H), 3.4 (m, 1H),

3.7 (m, 2H), 4.7 (m, 1H), 5.2 (m, 1H), 7.2-8.4 (m, 10H): MS (EI): 492 (M + H ⁺ , 100%).

The diastereomers were separated by preparative HPLC. Lyophilization of the eluent gives diastereomer 1: MS (EI)

492.4 (M + H ⁺ ), 983.7 2M + H ⁺ ) and diastereomer 2: MS (EI) 492.4 (M + H ⁺ ), 983.7 2M + H ⁺ ).

Ill

Example 6 Preparation of Naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azepane-4-carbamoyl) -3-methyl-butyl] -amide

a. ) Naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-hydroxy-azepan-4ylcarbamoyl) -3-methyl-butyl] -amide

To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH ₂ Cl ₂ was added triethylamine (0.24 mL, 1.72 mmol) and 2 naphthalenesulfonyl chloride (122 mg, 0.54 mmol). The reaction mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. The reaction mixture was worked up, dried (Na ₂ SO ₄ ), filtered and concentrated. Column chromatography of the residue (10% methanol: dichloromethane) afforded 52 mg of the title compound: MS (EI) 524 (M + H ⁺ ).

b. ) Naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azepan-4ylcarbamoyl) -3-methyl-butyl] -amide

Following the general procedure of Example li except substituting the compound of Example 6, prepare the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (dd, 1H), 3.3 (m, 1H) ,

3.6 (m, 2H), 3.7 (m, 1H), 4.7 (m, 1H), 5.3 (m, 1H), 7.2-8.4 (m, 12H): MS (EI): 522 (M + H ⁺ , 100) %).

Example 7

Preparation of quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

a.) Quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxyazepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 2j with the exception that 2-naphthoic acid is replaced by 2-quinolinecarboxylic acid

112 acid, to give the title compound: MS (ES) 489 (M + H ⁺ ).

B.) Quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-yl carbamoyl) -3-methyl-butyl] amide

Following the general method of Example 1 with the exception that using the compound of Example 7a, the title compound was obtained: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H), 3.4 (m, 1H),

3.7 (m, 2H), 4.7 (m, 1H), 5.2 (m, 1H), 7.2-8.4 (m, 11H); MS (EI): 487 (M + H ^& lt ^{; +} & gt ^; , 100%). The diastereomers were separated by preparative HPLC. Lyophilization of the eluent afforded diastereomer 1: MS (EI) 492.4 (M + H ⁺ ), 983.7 2M + H ⁺ ) and diastereomer 2: MS (EI) 492.4 (M + H ⁺ ), 983.7 2M + H ⁺ ).

Example 8

Preparation of 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-yl-carbamoyl) -3-methyl-butyl] amide

a. ) 3,4-Dichlorobenzoic acid [(S) -1- (1-benzyl-3-hydroxyazepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Example 2j with the exception that 2-naphthoic acid is replaced by 3,4-dichlorobenzoic acid, the title compound is obtained: MS (ES) 506 (M + H ⁺ ).

b. ) 3,4-Dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general procedure of Example li except substituting the compound of Example 8a the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H), 3.4 (m, l H),

3.7 (m, 2H), 4.7 (m, 2H), 5.2 (m, 1H), 7.2-8.4 (m, 8H); MS (EI): 504 (M ⁺ , 100%).

113

Preparation of 4 - {(S) -methyl-2 - [(quinoline-2-carbonyl) amino] pentanoylamino} -3-oxo-1- [2- (3-pyridin-2-yl-phenyl) acetyl] azepane

a. ) 4 - ((S) -2- (trans) -1-Butoxycarbonylamino-4-methyl-pentanoylamino) 3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane

To a solution of the compound of Example 2g (0.5 g, 1.46 mmol) in CH ₂ Cl ₂ was added EDC (307 mg, 1.60 mmol), HOBt (216 mg, 1.60 mmol) and 3- (2-pyridyl) phenylacetic acid (341 mg, 1.60 mmol). The reaction mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. Workup and column chromatography (2% methanol: dichloromethane) gave the title compound: MS (ES) 539 (M + H ⁺ ).

b. ) 4 - ((S) -Amino-4-methyl-pentanoylamino) -3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane

To a solution of the compound of Example 9a (1.3 g) dissolved in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred until completion of the reaction by TLC analysis and then concentrated in vacuo to give 1.1 g of the title compound: MS (EI) 439 (M + H ⁺ ).

c. ) 4 - {(S) -Methyl-2 - [(quinoline-2-carbonyl) -amino] pentanoylamino} 3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepane

Following the procedure of Example 7a with the exception of using the compound of Example 9b, the title compound was obtained: MS (EI) 594 (M + H ⁺ ).

d. ) 4 - {(S) -Methyl-2 - [(quinoline-2-carbonyl) -amino] pentanoylamino} 3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepane

Following the procedure of Example li with the exception of using the compound of Example 9c,

114 compound the title: NMR (CDC1 _3): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.4 (dd, 1H), 3.8 (m, 3H),

4.1 (m, 2H), 4.7 (m, 3H), 5.4 (m, 1H), 7.2-8.4 (m, 14H); MS (EI): 592 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 10

Preparation of 1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentyl) 4 - {(S) -4-methyl-2 - [(2-quinoline-2-carbonyl) -amino] -pentanoylamino} 3- oxo-azepane

a. ) 1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentyl) -4 - ((S) -2 / iret-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy azepane

Following the procedure of Example 2h with the exception that benzaldehyde is replaced by Cbz-leucinal, the title compound is obtained: MS (EI) 577 (M + H ⁺ ).

b. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -1 - ((S) -2-tertbenzyloxycarbonylamino-4-methyl-pentyl) -3-hydroxy-azepane

Following the procedure of Example 2i with the exception of using the compound of Example 10a, the title compound was obtained: MS (EI) 477 (M + H ⁺ ).

c. 1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentyl) -4 - {(S) -4methyl-2 - [(2-quinoline-2-carbonyl) -amino] -pentanoylamino} -3-hydroxy droxy azepane

Following the procedure of Example 7a with the exception that the compound of Example 10b was used, the title compound was obtained: MS (EI) 632 (M + H ⁺ ).

d. ) 1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentyl) -4 - {(S) -4methyl-2 - [(2-quinoline-2-carbonyl) -amino] -pentanoylamino} -3-oxazepane

Following the procedure of Example li with the exception of using the compound of Example 10c,

115 title compound: ³ H NMR (CDCl 3): δ 1.0 (m, 12H), 1.5-2.1 (m, 10H), 2.2 (m, 4H), 2.9 (m, 1H), 3.4 (m, 2H) ), 3.7 (m, 1H), 4.7 (m, 2H), 5.2 (m, 3H), 7.2 (m, 4H), 7.5 (m, 1H), 7.6 (m, 1H), 7.7 (m, 1H) , 8.1 (m, 1H), 8.2 (m, 2H), 8.5 (m, 1H); MS (EI): 630 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 11

Preparation of 1-benzoyl-4 - ((S) -2- (benzo [1,3] dioxocarbonylamino) -4-methyl-pentanoylamino) -3-oxo-azepane

a. ) 1-Benzoyl-4 - ((S) -2-tert-butoxycarbonylamino-4-methylpentanoylamino) -3-hydroxy-azepane

Following the procedure of Example 9a with the exception that 3- (2-pyridyl) phenylacetic acid is replaced by benzoic acid, the title compound is obtained: MS (EI) 448 (M + H ⁺ ).

b. ) 4- ((S) -2-Amino-4-methyl-pentanoylamino) -1-benzoyl-3-hydroxyazepane

Following the procedure of Example 2i with the exception of using the compound of Example 11a, the title compound was obtained: MS (EI) 348 (M + H ⁺ ).

c. ) 1-Benzoyl-4 - ((S) -2- (benzo [1,3] dioxole-carbonylamino) -4-methylpentanoylamino) -3-hydroxy-azepane

Following the procedure of Example 2j with the exception that the compound of Example 2j is replaced by that of Example lib and 2 the naphthoic acid is replaced with piperic acid, the title compound is obtained: MS (EI) 496 (M + H ⁺ ).

d. ) 1-Benzoyl-4 - ((S) -2- (benzo [1,3] dioxole-carbonylamino) -4-methylpentanoylamino) -3-oxo-azepane

Following the procedure of Example 1 with the exception that the compound of Example 1 2 is used, is obtained

116 title compound: ² H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H) ), 3.4 (m, 1H),

3.7 (m, 2H), 4.7 (m, 1H), 5.2 (m, 1H), 6.0 (s, 2H), 7.2-8.4 (m, 8H); MS (EI): 494 (M + H ^& lt ^{; +} & gt ^; , 70%).

Example 12

Preparation of 1-benzoyl-4 - ((S) -2- (4-fluoro-benzoylamino) -4-methylpentanoylamino) -3-oxo-azepane

a. ) 1-Benzoyl-4 - ((S) -2- (4-fluoro-benzoylamino) -4-methylpentanoylamino) -3-hydroxy-azepane

Following the procedure of Example 11c with the exception that piperronic acid is replaced with 4-fluorobenzoic acid, the title compound is obtained: MS (EI) 470 (M + H ⁺ ).

b. ) 1-Benzoyl-4 - ((S) -2- (4-fluoro-benzoylamino) -4-methylpentanoylamino) -3-oxo-azepane

Following the procedure of Example 1 with the exception that using the compound of Example 12a, the title compound was obtained: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (dd, 1H), 3.6 (m, 1H), 4.0 (m, 2H), 4.7 (m, 1H), 5.2 (m, 1H). 7.2-8.4 (m, 9H); MS (EI): 468 (M + H ^& lt ^{; +} & gt ^; , 10%).

Example 13

Preparation of 3-oxo-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-ylethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino) -1- (4methyl -pentanoyl) -azepane

a.) 4 - ((S) -2-yl-Butoxycarbonylamino-4-methyl-pentanoylamino) 3-hydroxy-1- (4-methyl-pentanoyl) -azepane

Following the procedure of Example 9a with the exception that 3- (2-pyridyl) phenylacetic acid is replaced by isocapronic

117 acid, to give the title compound: MS (EI) 442 (M + H ⁺ ).

b. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-1- (4-methylpentanoyl) -azepane

Following the procedure of Example 2i with the exception of using the compound of Example 13a, the title compound was obtained: MS (EI) 342 (M + H ⁺ ).

c. 3-Hydroxy-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -1- (4- methylpentanoyl) -azepane

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 (0.11 mL, 0.79 mmol) and 5- (2- morpholine-4-ylethyloxy) benzofuran-2-carboxylic acid. The reaction mixture was stirred at room temperature until completion of the reaction according to TLC analysis. Treatment and column chromatography (5% methanol: dichloromethane) afforded 160 mg of the title compound: MS (EI) 615 (M + H ⁺ ).

d. 3-Oxo-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -1- (4- methylpentanoyl) -azepane

Following the procedure of Example 1 with the exception that using the compound of Example 13d, the title compound was obtained: NMR (CDCl 3): δ 1.0 (m,

12H), 1.5-2.1 (m, 8H), 2.2 (m, 2H), 2.3 (m, 1H), 2.4-2.5 (m, 2H), 2.6 (m 5H), 2.7 (m, 2H), 2.9 ( m, 1H), 3.4 (m, 1H), 3.7 (m, 4H), 4.1 (m, 2H), 4.5-

4.6 (m, 2H), 5.2 (m, 1H), 7.2-8.4 (m, 4H): MS (EI): 613 (M + H ⁺ , 100%). The diastereomers were separated by preparative HPLC. Lyophilization of the eluent gives diastereomer 1 and diastereomer 2.

118

Example 14

Preparation of 3-oxo-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-ylethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino) -1-

a. 1-Benzenesulfonyl-4 - ((S) -2-7-yl-butoxycarbonylamino-methylpentanoylamino) -3-hydroxy-azepane

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 benzenesulfonyl chloride (0.28 mL, 2.18 mmol). The reaction mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. Workup and column chromatography (10% methanol: dichloromethane) gave 450 mg of the title compound: MS (EI) 484 (M + H ⁺ ).

b. ) 4 - ((S) -2-Amino-methyl-pentanoylamino) -1-benzenesulfonyl-3-hydroxy-azepane

Following the procedure of Example 2i with the exception of using the compound of Example 14a, the title compound was obtained: MS (EI) 384 (M + H ⁺ ).

c. 3-Hydroxy-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -1-benzenesulfonyl-azepane

Following the procedure of Example 13c with the exception of using the compound of Example 14b, the title compound was obtained: MS (EI) 657 (M + H ⁺ ).

d. 3-Oxo-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -1-benzenesulfonyl-azepane

Following the procedure of Example li with the exception of using the compound of Example 14c,

119 compound the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, 1H), 2.7 (m, 4H), 2.8 (m, 2H) , 3.5 (m, 1H), 3.8 (m, 4H), 4.0 (m, 1H), 4.1 (m, 2H), 4.4 (m, 1H), 4.5 (m, 1H), 4.7 (m, 1H). 5.1 (m, 1H), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, 3H), 7.7 (m, 2H): MS (EI): 655 (M + H ⁺ , 100%) .

Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 45:55 CH ₃ CN: 20 mm CHPO ₄ (pH 7 buffer) 60 min gradient 1 mL / minute; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (R _t = 44.6 minutes and 45.9 minutes). The diastereomers were separated by preparative HPLC (40:60 to 50:50 CH ₃ CN: mm CHPO ₄ (buffer pH 7) gradient, 12 mL / minute, 60 minutes; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 PM). Lyophilization of the eluents gave diastereomer 1 (analytical R _t = 44.6 minutes) and diastereomer 2: (analytical R _t = 45.9 minutes).

Example 15

Preparation of 4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -3-oxo-azepane-1-carboxylic acid phenylamide

a.) [(S) -1- (3-Hydroxy-1-phenylcarbamoyl-azepan-4-ylcarbamoyl) -3methyl-butyl] -carbamic acid pem-butyl ester

To a solution of the amine of Example 2g (0.5 g, 1.46 mmol) in dichloromethane (20 mL) was added phenylisocyanate (0.24 mL, 2.18 mmol). The reaction mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. Treatment and column chromatography (5% methanol: dichloromethane) afforded 578 mg of the title compound: MS (EI) 463 (M + H ⁺ ).

120

b. ) 4 - ((S) -2-Amino-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid phenylamide

Following the procedure of Example 2i with the exception of using the compound of Example 15a, the title compound was obtained: MS (EI) 363 (M + H ⁺ ).

c. 3-Hydroxy-4 - ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] amino} -pentanoylamino) -azepane-1-carboxylic acid phenylamide

Following the procedure of Example 13c with the exception that the compound of Example 15b was used, the title compound was obtained: MS (EI) 636 (M + H ⁺ ).

d. ) 4 - ((S) -4-Methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino) -3-oxo-azepan-1- carboxylic acid phenylamide

Following the procedure of Example 1 with the exception of using the compound of Example 15c, the title compound was obtained: ¹ H NMR (CDCl 3):? Δ 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, 1H),

3.8 (m, 1H), 3.9 (m, 4H), 4.2 (m, 1H), 4.3 (m, 2H), 4.9 (m, 2H), 5.2 (m, 1H), 7.2-8.4 (m, 9H) : MS (EI): 634 (M + H ^& lt ^{; +} & gt ^; , 100%).

Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH ₃ CN: 20 mM CHPO ₄ (pH 7 buffer) isocratic, 1 mL / minute; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (R _t = 27.3 minutes and 30.1 minutes). The diastereomers were separated by preparative HPLC (40:60 to 50:50 CH ₃ CN: 20 mM CHPO ₄ (pH 7 buffer) gradient, 12 mL / minute, 60 minutes; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilization and desalination of the eluents by extraction with NaHCO3: ethyl acetate gives a diastereomer

121 (analytical R _t = 27.3 minutes) and diastereomer 2: (analytical R _t = 30.1 minutes).

Example 16

Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2- phenyl) appetyl] -azepan-4-ylcarbamoyl} -butyl) amide

a. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-ylphenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 13c with the exception of using the compound of Example 9b, the title compound was obtained: MS (EI) 712 (M + H ⁺ ).

b. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 1 with the exception that using the compound of Example 16c, the title compound was obtained: ¹ H NMR (CDCl 3):? Δ 1.0 (1H, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 4H), 2.8 (t, 2H), 2.9 (t, 1H), 3.5 (t, 1H), 3.7 (t, 4H), 3.9 (t, 3H) ), 4.3 (t, 2H), 4.7 (t, 2H), 5.4 (t, 1H), 7.2-8.0 (t, 13H), 8.5 (t, 1H); MS (EI): 710 (M + H ⁺ , 100%).

Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH ₃ CN: 20 mM CHPO ₄ (pH 7 buffer) isocratic, 1 mL / minute; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (R _t = 33.9 minutes and 37.9 minutes). The diastereomers were separated by preparative HPLC (40:60 to 45:55 CH ₃ CN: 20 mM CHPO ₄ (pH 7 buffer) gradient, 12 mL / minute, 60 minutes; inertsil ODS-3 column 250 x 20 mm; UV

122 detection at 215 nM). Lyophilization and desalination of the eluents by extraction with NaHCO ₃ : ethyl acetate gave diastereomer 1: MS (EI) 710.3 (M + H ⁺ ) (analytical Rt = 33.9 minutes) and diastereomer 2: MS (EI) 710.3 (M + H ⁺ ) (analytical R _t = 37.9 minutes).

Example 17

Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

a. ) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-hydroxy-azepan-4-ylcarbamoyl) -3methyl-butyl] -amide

Following the procedure of Example 13c with the exception that the compound of Example lib was used, the title compound was obtained: MS (EI) 621 (M + H ⁺ ).

b. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide

Following the procedure of Example 1 with the exception of using the compound of Example 17a, the title compound was obtained: NMR (CDCl ₃ ): δ 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, 1H),

3.7 (m, 5H), 4.0 (m, 1H), 4.1 (m, 2H), 4.7 (m, 2H), 5.4 (m, 1H), 7.2-8.4 (m, 11H): MS (EI): 619 (M + H ⁺ , 100%).

Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 55:45 CH ₃ CN: 20 mM CHPO ₄ (pH 7 buffer) 30 min gradient, 1 mL / minute; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (R _t = MHHyTH 13.5 and 17.6 minutes). The diastereomers are separated by preparative

123

HPLC (40:60 to 45:55 CH ₃ CN: mM KHPO ₄ (pH 7 buffer) 60 min gradient, 15 mL / min, 60 min; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilization and desalination of the eluents by extraction with NaHCO ₃ : ethyl acetate gave diastereomer 1 (analytical R _t = 13.5 minutes) and diastereomer 2: (analytical R _t = 17.6 minutes).

Example 18

Preparation of 5- (2-pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

a. ) 5- (2-Pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the procedure of Example 14c with the exception that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid is replaced by 5- (2-pyrrolidin-1-yl-ethyloxy) -benzofuran2- carboxylic acid, to obtain the title compound: MS (EI) 641 (M + H ⁺ ).

b. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide

Following the procedure of Example 1 with the exception that using the compound of Example 18a, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 9H ), 2.2 (m, 2H), 2.5 (m, 1H), 2.7 (m, 4H), 3.0 (m, 2H),

3.4 (m, 1H), 4.0 (m, 1H), 4.1 (m, 2H), 4.5 (m, 1H), 4.6 (m, 1H), 5.0 (m, 1H), 7.2-8.4 (m, 11H) : MS (EI): 639 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 19

Preparation of 5- (2-piperidin-1-yl-ethoxy) -benzofuran-2124 carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

a. ) 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3methyl-butyl] amide

Following the procedure of Example 14c with the exception that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid is replaced by 5- (2-piperidin-1-yl-ethyloxy) -benzofuran2- carboxylic acid, to obtain the title compound: MS (EI) 655 (M + H ⁺ ).

b. ) 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azepan-4-yl carbamoyl) -3-methyl-butyl ] amide

Following the procedure of Example 1 with the exception that using the compound of Example 18a, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, IN ), 2.2 (m, 2H), 2.5 (m, 5H), 2.7 (m, 2H), 3.5 (m, 1H), 4.0 (m, 1H), 4.1 (m, 2H), 4.5 (m, 1H) , 4.6 (m, 1H), 5.0 (m, 1H), 7.2-8.4 (m, 11H): MS (EI): 653 (M + H ⁺ , 100%).

Example 20

Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide

a.) 5- (2-Morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid methoxy methylamide

To a solution of 3- (2-pyridyl) phenylacetic acid (1 g) in dichloromethane was added N, N-dimethylhydroxylamine hydrochloride (0.92 g), triethylamine (1.3 mL), HOBt (0.96 g) and EDC (1.1 g). The reaction mixture was stirred until the reaction was complete. Treatment and column chromatography (40% ethyl acetate:

125 hexanes) afforded 1.1 g of the title compound: MS (EI) 257 (M + H ⁺ ).

b. 5- (2-Morpholin-4-yl-ethyloxy) benzofuran-2-carbaldehyde

To a solution of 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid methoxymethylamide (0.2 g) of Example 20a in tetrahydrofuran was added lithium aluminum hydride (2.0 mL of 1 M solution in tetrahydrofuran). The reaction mixture was stirred until complete depletion of the starting material. Treatment gave 160 mg of the title compound.

c. ) ((S) - {3-Hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -ethyl] -azepan-4-ylcarbamoyl} -3-methyl-butyl) -carbamic acid tert-butyl ester

Following the general method of Example 2g with the exception that benzaldehyde is replaced by 5- (2-morpholin-4-ylethyloxy) benzofuran-2-carbaldehyde, the title compound is obtained: MS (EI) 525 (M + H ⁺ ).

d. (S) -2-Amino-4-methyl-pentanoic acid {{3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -ethyl] azepan-4-yl} -amide

Following the procedure of Example 2i with the exception of using the compound of Example 20c, the title compound was obtained.

e. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-ylphenyl) ) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 13c with the exception that the compound of Example 20d was used, the title compound was obtained.

f. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxy-1- [2- (3-pyridin-2-yl) -phenyl) ethyl] azepan-4-ylcarbamoyl} -butyl) amide

126

Following the procedure of Example 1 with the exception that using the compound of Example 20f, the title compound was obtained: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 3H), 2.7 (m, 4H), 2.8 (m, 6H), 3.1 (m, 1H), 3.3 (m, 1H), 3.5 (m, 1H), 3.7 (m, 4H) , 4.2 (m, 3H), 4.6 (m, 1H), 5.2 (m, 1H), 7.2-8.4 (m, 13H), 8.6 (m, 1H); MS (EI): 696 (M + H ^& lt ^{; +} & gt ^; , 80%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 696 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 696 (M + H ⁺ , 100%).

Example 21

Preparation of naphthalene-2-carboxylic acid ((B) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} butyl) amide

a. ) Naphthalene-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1 [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 20f with the exception that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid is replaced by 2-naphthoic acid, the title compound is obtained: MS (EI ) 579 (M + H ⁺ ).

b. ) Naphthalene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 1 with the exception that using the compound of Example 21b, the title compound was obtained: NMR (CDCl 3): δ 1.0 (m,

6H), 1.5-2.1 (m, 6H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, 1H), 3.4 (d, 1H).

3.5 (m, 1H), 4.7 (m, 1H), 50 (m, 1H), 6.8-7.2 (m, 6H), 7.3 (m, 1H), 7.5 (m, 2H), 7.9 (m, 6H) , 8.2 (m, 1H), 8.7 (m, 1H): MS (EI): 577 (M + H ⁺ , 100%).

127

Example 22

Preparation of 1H-indole-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl } bo: til) amide

a. ) ((S) -3-Methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) ethyl] azepan-4-yl carbamoyl} -butyl) amide

Following the procedure of Example 20f with the exception that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid is replaced by 1H-indole-2-carboxylic acid, the title compound is obtained : MS (EI) 568 (M + H ⁺ ).

b. ) ((S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 1 with the exception that using the compound of Example 22b, the title compound was obtained: ² H NMR (CDCl 3):? Δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, 1H), 3.4 (d, 1H).

3.5 (m, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 6.8-7.2 (m, 6H), 7.0-7.9 (m, 12H),

8.7 (m, 1H), 9.5 (m, 1H): MS (EI): 566 (M + H ⁺ , 100%).

Example 23

Preparation of 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-carbamoyl) -3-methyl-butyl] amide

a. ) 1H-Indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the procedure of Example 2j with the exception that using the compound of Example 14b and replacing the naphthoic acid with 1H-indole-2-carboxylic acid, the title compound was obtained: MS (EI) 527 (M + H) ⁺ ).

b. ) 1H-Indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

128

Following the procedure of Example 1 with the exception of using the compound of Example 23b, the title compound was obtained: ^] H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (dd, 1H), 3.9 (m, 1H),

4.5 (dd, 2H), 4.7 (m, 1H), 5.0 (m, 1H), 7.2-7.6 (m, 10H). 9.5 (b, 1H); MS (EI): 525 (M + H ^& lt ^{; +} & gt ^; , 10%).

Example 24

Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

a. ) Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the procedure of Example 23a with the exception that 1H-indole-2-carboxylic acid is replaced by benzofuran-2carboxylic acid, the title compound is obtained: MS (EI) 528 (M + H ⁺ ).

b. ) Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the procedure of Example 1 with the exception that using the compound of Example 24b, the title compound was obtained: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.6 (m, 1H), 3.5 (d, 1H), 4.1 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.2 (m, 10H).

Example 25

Preparation of benzofuran-2-carboxylic acid [(S) -3-methyl-1 {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} butyl) amide

a.) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-hydroxy- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} butyl) amide

129

Following the procedure of Example 20f with the exception that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid is replaced by benzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 569 (M + H ⁺ ).

B.) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [2 (3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} - butyl) amide

Following the procedure of Example li except substituting the compound of Example 25b the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 5H), 3.0 (m, 1H). 3.3 (t, 1H),

3.5 (m, 1H), 4.7 (m, 1H), 5.2 (m, 1H), 7.2-7.7 (m, 14H), 8.7 (m, 1H); MS (EI): 567 (M + H ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 656 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 656 (M + H ⁺ , 100%).

Example_26

Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azepan-4-ylcarbamoyl) -butyl] -amide

Following the procedures of Examples 20c-f except that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carbaldehyde of Example 20c except substituting phenylacetaldehyde, the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (t, 1H), 2.6 (t, 4H), 2.7 (t, 6H) , 3.0 (t, 1H), 3.3 (dd, 1H), 3.5 (q, 1H), 3.7 (t, 4H), 4.2 (t, 2H),

4.7 (m, 1H), 5.0 (m, 1H), 7.2-7.2 (m, 1H); MS (EI): 619 (M + H ⁺ , 80%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 619

130 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 619 (M + H ⁺ , 100%).

Example 27

Preparation of naphthylene-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-stained-4-ylcarbamoyl) -butyl] amide

Following the procedures of Examples 2h-k with the exception that the benzaldehyde of Example 2h is replaced by phenyl acetaldehyde, the title compound is obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5- 2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, 1H), 2.7 (m, 4H), 3.0 (m, 1H), 3.7 (d, 1H), 3.5 (q, 1H), 4.7 (m, 1H), 5.1 (m, 1H), 6.9-7.2 (m, 7H), 7.5 (m, 2H), 7.9 (m, 4H) 8.4 (m, 1H); MS (EI): 500 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 28

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Examples 14a-b with the exception that the benzenesulfonyl chloride of Example 14a is replaced by 2-pyridinesulfonyl chloride, the title compound is obtained: MS (EI) 385 (M + H ⁺ ).

b. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (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 reaction mixture was stirred until the reaction was complete. Treatment and column chromatography (5% methanol:

131 ethyl acetate) gave the title compound: MS (EI) 529 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception that using the compound of Example 28b, the title compound was obtained: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (w, 1H), 3.7 (dd, 1H), 4.0 (w, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (t, 3H), 7.4 (t, 4H), 7.6 (t, 1H), 8.0 (t, 2H), 8.7 (t, 1H) ; MS (EI): 527 (M + H ⁺ , 40%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; ^X H NMR: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (d, 1H); 4.0 (d, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H) ; MS (EI): 527 (M + H ⁺ , 100%) and the slower eluting diastereomer; NMR: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H),

2.2 (m, 2H), 2.7 (t, 1H), 3.7 (d, 1H); 4.0 (d, 1H), 4.7 (t, 2H), 5.0 (t, 1H), 7.2-7.3 (t, 3H), 7.4 (t, 4H), 7.6 (t, 1H), 8.0 (t, 2H) , 8.7 (m, 1H); MS (EI): 527 (M + H ⁺ , 100%).

Example 29

Preparation of naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a.) Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced with 2-naphthoic acid, the title compound is obtained: MS (EI) 539 (M + H ⁺ ).

132

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

Following the procedure of Example 1 with the exception that using the compound of Example 29a, the title compound was obtained: H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (dd, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 2H), 7.5 (m, 3H), 7.9 (m, 6H), 8.3 (m, 1H), 8.4 (m, 1H) ; MS (EI): 537 (M + H ^& lt ^{; +} & gt ^; , 50%).

, The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 537 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 537 (M + H ⁺ , 100%).

Example 30

Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) azepan-4- ylcarbamoyl] -butyl} amide

Following the procedure of Example 13c with the exception of using the compound of Example 28a, the title compound was obtained: MS (EI) 658 (M + H ⁺ ).

b. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl ] -butyl} amide

Following the procedure of Example li except substituting the compound of Example 29a, the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.5 (m, 4H), 3.7 (m, 6H) ,

4.1 (m, 1H), 4.5 (m, 2H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 4H), 7.4

133 (m, 2H), 8.0 (m, 2H), 8.7 (m, 1H), 8.7 (m, 1H); MS (EI): 656 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 656 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 656 (M + H ⁺ , 100%).

Example 31

Preparation of 4 - ((S) -4-methyl-2 - ([(5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carbonyl] -amino} -pentanoylamino) -3-oxo-azepane-1carboxyl acid tert-butyl ester

a. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid tert-butyl ester

To a solution of the compound of Example If (0.89 g) in ethyl acetate: methanol (30 mL of 2: 1 mixture) was added 10% Pd / C and a hydrogen gas balloon. The reaction mixture was stirred until completion of the reaction according to TLC analysis and then filtered and concentrated to give the title compound (0.57 g).

b. ) 4 - ((S) -4-Methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] -amino)} -pentanoyl amino) -3-hydroxy- azepan-1 carboxylic acid tert-butyl ester

Following the procedure of Example 13c with the exception of using the compound of Example 31a, the title compound was obtained.

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

Following the procedure of Example 1 with the exception of using the compound of Example 31b, the title compound was obtained: NMR (CDCl 3): δ 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

134 (m, 1H). 3.8 (m, 4H), 4.1 (m, 3H), 4.2 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H),

7.2-7.3 (m, 5H); MS (EI): 615 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example_32

Preparation of 4 - ((S) -4-methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3 -oxo-azepan-4 To a solution of the compound of Example 31c in tetrahydrofuran (5 mL) was added IM HCl in ether (5 mL) The reaction mixture was stirred overnight and then concentrated to give the compound indicated in title: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 3.2 (dd, 3H), 3.7 ( m, 6H), 4.0 (m, 3H), 4.5 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 6H); MS (EI): 515 (M + H ⁺ , 100%) .

Preparation of 4-methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin2-yl-phenyl-apetyl] -azepan-4-yl} -amide

a. 3-Hydroxy-4- (4-methyl-pentanoylamino) -azepane-1-carboxylic acid tert-butyl ester

Following the procedure of Example If with the exception that Cbz-leucine is replaced by 4-methylpentanoic acid, the title compound is obtained: MS (EI) 329 (M + H ⁺ ).

b. ) 4-Methyl pentanoic acid (3-hydroxy-azepan-4-yl) -amide

To a solution of the compound of Example 33a (200 mg) in methanol (5 mL) was added 4M HCl dioxane (5 mL). The reaction mixture was stirred until the reaction was complete and then concentrated to give the title compound (132 mg): MS (EI) 229 (M + H ⁺ ).

c. ) 4-Methyl-pentanoic acid {3-hydroxy-1- [2- (3-pyridin-2-ylphenyl-acetyl] -azepan-4-yl} -amide

135

Following the procedure of Example 9a with the exception that the compound of Example 3b was used, the title compound was obtained: MS (EI) 424 (M + H ⁺ ).

d.) 4-Methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin-2-ylphenyl-acetyl] -azepan-4-yl} -amide

Following the procedure of Example 1 with the exception that the compound of Example 3 3c was used, the title compound was obtained: NMR (CDCl ₃ ) δ 1.0 (m, 6H),

1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 3.5 (w, 1H), 3.7 (m, 2H), 4.1 (t, 3H) , 4.6 (m, 1H), 5.3 (m, 1H), 7.2-8.0 (m, 7H), 8.7 (m, 1H); MS (EI): 422 (M + H ⁺ , 100%).

Example 34

Preparation of ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) appetyl] -azepan-4-ylcarbamoyl} -butyl) -naphthylene-2-methylcarbamic acid tert-butyl ester

a. ) (S) -4-Methyl-2- [naphthalen-2-ylmethyl) -amino] -pentanoic acid methyl ester

To a solution of leucinmethyl ester hydrochloride (0.5 g) in dichloromethane was added triethylamine (0.9 mL), 2-naphthaldehyde (0.43 g) and sodium triacetoxyborohydride (0.87 g). The mixture was stirred until the reaction was complete. Treatment and column chromatography (5% ethyl acetate: dichloromethane) afforded 0.4 g of the title compound: MS (EI) 286 (M + H ⁺ ).

b. (S) -2- (tert-1-Butoxycarbonyl-naphthalen-2-ylmethyl-amino) -4-methylpentanoic acid methyl ester

To a solution of the compound of Example 34a (0.35 g) in dichloromethane was added dimethylbutyl dicarbonate (0.29 g). After 2 hours at room temperature, triethylamine was added and the reaction mixture was heated to reflux. After completion of the reaction, the reaction mixture was concentrated and the residue was concentrated

136 was purified by column chromatography (50% hexane: dichloromethane) to give 0.17 g of the title compound: MS (EI) 386 (M + H ⁺ ).

c. (S) -2- (tert-Butoxycarbonyl-naphthalen-2-ylmethyl-amino) -4-methyl pentanoic acid

To a solution of the compound of Example 34b (0.17 g) in tetrahydrofuran: methanol (15 mL of a 2: 1 solution) was added LiOH (0.019 g). The reaction mixture was stirred overnight and then concentrated to give the title compound.

d. ) 4 - [(S) -Tre / 71-Butoxycarbonyl-naphthalen-2-ylmethyl-amino) -4-methyl-pentanoyl amino] -3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To a solution 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 of the addition, the reaction mixture was treated and chromatographed (5% methanol: dichloromethane) to give the title compound (0.18 g): MS (EI) 618 (M + H ⁺ ).

e. ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] naphthylen-2-ylmethyl carbamic acid tert-butyl ester

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 hydrogen balloon was attached and the reaction mixture was stirred until complete exhaustion of the starting material. The reaction mixture was filtered and concentrated to give the title compound (0.10 g): MS (EI) 484 (M + H ⁺ ).

f. ) ((S) -3-Methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepan-4-ylcarbamoyl} -butyl) -naphthylene-2- methyl-carbamic acid mpem-butyl ester

137

Following the procedure of Example 9a with the exception of using the compound of Example 34f, the title compound was obtained: MS (EI) 679 (M + H ⁺ ).

g.) ((S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] azepan-4-ylcarbamoyl} -butyl) -naphthylene- 2-methyl-carbamic acid tert-butyl ester

Following the procedure of Example 1 with the exception of using the compound of Example 34f, the title compound was obtained: NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.2 (m, 16H), 2.7 (m, 1H), 3.2 (m, 1H), 3.7 (m, 3H), 4.0 (m, 1H),

4.7 (m, 2H), 5.2 (m, 1H), 7.2-7.3 (m, 16H), 8.6 (m, 1H); MS (EI): 677 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 35

Preparation of (S) -4-Methyl-2 - ((naphthylen-2-ylmethyl) -amino] ~ pentanoic acid {3-oxo-1- (2- (3-pyridin-2-yl-phenyl) -etethyl] To a solution of the compound of Example 34g (20 mg) in tetrahydrofuran was added IM HCl in ether The reaction mixture was stirred until complete depletion of the starting material and then concentrated to give the title compound: ^T H NMR (CDC1 ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (m, 5H), 4.0 (m, 1H), 4.7 (m , 2H), 4.4 (m, 1H), 7.28.0 (m, 16H), 8.7 (m, 1H); MS (EI): 577 (M + H ⁺ , 100%).

Example 36

Preparation of 4- (2- (2 - {(S) -3-methyl-1- (3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl} -benzofuran-5-yloxy) -ethyl n-piperazine-1-carboxylic acid tert-butyl ester

a.)

4- [2- (2 - {(S) -3-Methyl-1- [3-hydroxy-1- (pyridin-2-sulfonyl) azepan-4-ylcarbamoyl] -butylcarbamoyl} -benzofuran-5-yloxy) ethyl ] -Piperazine-1-carboxylic acid tert-butyl ester

138

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 4- [2- (2-carboxy-benzofuran-5-yloxy) - ethyl] -piperazine-1-carboxylic acid tert-butler. The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (10% methanol: ethyl acetate) afforded the title compound (0.10 g): MS (EI) 757 (M + H ⁺ ).

b.) 4- [2- (2 - {(S) -3-Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl} -benzofuran-5 -yloxy) -ethyl] piperazine-1-carboxylic acid tert-butyl ester

Following the procedure of Example 1 with the exception that using the compound of Example 36a, the title compound was obtained: ^T H NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 14H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (m, 2H), 3.5 (m, 4H),

3.7 (m, 6H), 4.1 (m, 1H), 4.5 (m, 2H), 4.7 (m, 2H), 5.0 (m, 1H), 7.0-7.6 (m, 6H), 8.0 (m, 2H) , 8.7 (m, 1H); MS (EI): 755 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 37

Preparation of 5- (2-piperizin-1-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-butyl} -amide

The compound of Example 36b (0.02 g) was dissolved in 4M HCl in dioxane. The reaction mixture was stirred until complete dissolution and then concentrated to give the title compound: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-1.7 (m, 7H), 2.7 ( m, 2H), 3.3 (m, 2H), 3.5 (m, 1H). 3.8 (m, 5H), 4.1 (m, 3H), 4.7 (m, 4H), 5.0 (m, 1H), 7.0-7.3 (m, 2H), 7.4 (m, 6H), 8.0 (m, 2H) , 8.7 (m, 1H): MS (EI): 655 (M + H ⁺ , 100%).

Preparation of 5- (2-cyclohexy-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4139 ylcarbamoyl] - butyl} amip

a. ) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide

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) -benzofuran carboxylic acid (0.01 g). . The reaction mixture was stirred until the reaction was complete according to TLC analysis. Workup and column chromatography (100% ethyl acetate) gave the title compound (0.15 g): MS (EI) 655 (M + H ⁺ ).

b. ) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using the compound of Example 38a, the title compound was obtained: MS (EI) 653 (M + H ⁺ ).

Example 39

Preparation of 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] azepan-4-ylcarbamoyl} -butyl) amide

a.) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) ) ethyl] -azepan4-yl-carbamoyl} -butyl) amide

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 mixture was stirred until the reaction was complete according to TLC analysis. Processing and the column

140 chromatography (100% ethyl acetate) afforded the title compound (0.10 g): MS (EI) 695 (M + H ⁺ ).

b.) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide

Following the procedure of Example I, with the exception of using the compound of Example 39a, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 18H), 2.2 (m, 2H), 2.7 (m, 3H), 3.2 (m, 1H), 3.5 (m, 1H).

3.9 (m, 4H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 13H), 8.7 (m, 1H):

MS (EI): 693 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 40

Preparation of 4- [2- (2 - {(S) -3-methyl-1- [3-oxo-1- (3-pyridin-2-ylphenyl) -ethyl [azepan-4-ylcarbamoyl] -butylcarbamoyl} - benzofuran5-yloxy) -ethyl] -piperazine-1-carboxylic acid third) 4- [2- (2 - {(S) -3-Methyl-1- [3-hydroxy-1- (3-pyridin-2-yl) -phenyl) -ethyl [azepan-4-ylcarbamoyl] -butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-1-carboxylic acid tert-butyl ester

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-1-carboxylic acid tert-butyl ester (0.12 g). The reaction mixture was stirred until the reaction was complete according to TLC analysis. Workup and column chromatography (10% methanol: ethyl acetate) gave the title compound (0.09 g): MS (EI) 797 (M + H ⁺ ).

b.) 4- [2- (2 - {(S) -3-Methyl-1- [3-oxo-1- (3-pyridin-2-yl-phenyl) -ethyl [azepan-4-ylcarbamoyl] - butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-1-carboxylic acid tert-butyl ester

141

Following the procedure of Example 1 with the exception that using the compound of Example 40a, the title compound was obtained: MS (EI) 795.9 (M + H ⁺ ).

Example 41

Preparation of 5- (2-piperizin-1-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-ylphenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 37 with the exception of using the compound of Example 40b, the title compound was obtained: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 3.4-3.6 (m, 19H), 4.5 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H, 7.2 (m, 1H), 7.4 (m, 1H) ), 7.5 (m, 2H), 7.7 (m, 2H), 7.8 (m, 1H), 8.1 (m, 2H), 8.4 (m, 1H), 8.7 (m, 1H); MS (EI): 695 (M + H ⁺ , 70%).

Example 42

Preparation of (S) 4-Methyl-2- (methyl-naphthalen-2-ylmethylamino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

a. ) 4 - [(S) -2- (tert-Butoxycarbonyl-methyl-amino) -4-methylpentanoylamino] -3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To a solution of the compound of Example. 2e (0.35 g) in dichloromethane was added N-methyl-N-Boc-leucine (0.36 g), HOBt (0.2 g) and EDC (0.28 g). The reaction mixture was stirred until the reaction was complete. Treatment and column chromatography (5% methanol: dichloromethane) afforded 0.6 g of the title compound: MS (EI) 492 (M + H ⁺ ).

b. ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -methylcarbamic acid pem-butyl ester

142

To a solution of the compound of Example 42a (0.6 g) in methanol: ethyl acetate (10:20 mL) was added 10% Pd / C and a hydrogen balloon was attached. The reaction mixture was stirred overnight and then filtered and concentrated to give 0.50 g of the title compound: MS (EI) 358 (M + H ⁺ ).

c. ) {(S) -1- [3-Hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -methyl-carbamic acid tert-butyl ester

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 mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: ethyl acetate) afforded the title compound (0.23 g): MS (EI) 499 (M + H ⁺ ).

d. ) (S) -4-Methyl-2-methylamino-pentanoic acid [3-hydroxy-1- (2-pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of the compound of Example 42c (0.23 g) in methanol (3.0 mL) was added 4M HCl in dioxane (3.0 mL). The reaction mixture was stirred until the reaction was complete. Concentration gave the title compound: MS (EI) 399 (M + H ⁺ ).

e. ) (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of the compound of Example 42d (0.05 g) in dichloromethane was added triethylamine (0.07 mL), 2-naphthaldehyde (0.05 g) and sodium triacetoxyborohydride (0.11 g). The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol ethyl acetate) gave the title compound (0.03 g): MS (EI) 539 (M + H ⁺ ).

143

f.) (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception of using the compound of Example 42f, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 5H), 2.6 (m, 1H), 3.3 (m, 1H), 3.7 (m, 2H),

4.1 (m, 1H), 4.7 (m, 1H), 5.2 (m, 1H), 7.2-8.0 (m, 10H), 8.7 (m, 1H); MS (EI): 537 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 43

Preparation of (S) -4-Methyl-2- (methyl-naphthalen-2-ylmetstamino) pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) acetyl] -azepan-4 -or} -amide

a. ) ((S) -1- {3-Hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-ylcarbamoyl} -3-methyl-butyl) -methyl-carbamic acid tert-butyl ester

To a solution of the compound of Example 42b (0.25 g) was added 3- (2-pyridyl) phenylacetic acid (0.16 g), HOBt (0.12 g) and EDC (0.15 g). The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: ethyl acetate) afforded the title compound (0.24 g): MS (EI) 553 (M + H ⁺ ).

b. ) (S) -4-Methyl-2-methylamino-pentanoic acid {3-hydroxy-1- [2 (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-yl} -amide

Following the procedure of Example 42d with the exception that using the compound of Example 43a, the title compound was obtained: MS (EI) 453 (M + H ⁺ ).

c. ) (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane -4-yl} amide

144

Following the procedures of Examples 42e-f except substituting the compound of Example 43b, the product of the ^title:] H NMR (CDC1 _3): δ 1.0 (m, 6H), 1.5-2.1 (m , 5H), 2.2 (m, 5H), 3.0 (m, 1H), 3.5 (m, 1H), 3.7 (m, 4H), 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.2-8.0 (m, 15H), 8.7 (m, 1H); MS (EI): 591 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 44

Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide

a. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-) ylphenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide

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 g), TEA (0.07 mL). and EDC (0.04 g). The reaction mixture was stirred until the reaction was complete. Workup and chromatography (20% methanol: ethyl acetate) afforded the title compound (0.07 g): MS (EI) 726 (M + H ⁺ ).

b. 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-) ylphenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) amide

Following the procedure of Example 1 with the exception of using the compound of Example 44a, the title compound was obtained: ^] H NMR (CDCl ₃ ): δ 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, 1H),

3.5 (m, 1H), 3.7 (m, 4H), 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 (m, 1H), 7.2-8.0 (m, 12H) , 8.5 (m, 1H); MS (EI): 724 (M + H ^& lt ^{; +} & gt ^; , 100%).

145

Example 45

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

a. ) Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Benzofuran-2-carboxylic acid (0.04 g), TEA (excess), HOBt (0.03 g) and EDC (0.04 g) were added to a solution of the compound of Example 42d (0.1 g) in dichloromethane. The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: dichloromethane) gave the title compound (0.04 g): MS (EI) 542.9 (M + H ⁺ ).

b. ) Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example I, with the exception of using the compound of Example 45a, the title compound was obtained: ³ H NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 8H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (m, 1H), 3.7 (m, 2H),

4.1 (m, 1H), 4.7 (m, 1H), 5.2 (m, 1H), 7.2-8.0 (m, 8H), 8.7 (m, 1H); MS (EI): 541 (M + H ^& lt ^{; +} & gt ^; , 10%).

Example 46

Preparation of ___ of 2,2,2-trifluoro-1 H [- ((S) -3-methyl-1- {3-oxo-1- (2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4- ylcarbamoyl} -butyl) -naphthalen-2-ylmethyl-appetite, l

a.) (S) -4-Methyl-2- [naphthylen-2-ylmethyl- (2,2,2-trifluoro-acetyl) amino] -pentanoic acid methyl ester

To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added potassium carbonate (catalytic

146 trifluoroacetic acid (0.44 g). The reaction mixture was stirred at room temperature for 1 hour and then concentrated and chromatographed (20% ethyl acetate: hexane) to give the title compound.

B.) (S) -4-Methyl-2- [naphthylen-2-ylmethyl- (2,2,2-trifluoro-acetyl) amino-pentanoic acid lithium salt

To a solution of the compound of Example 46a (0.49 g) in tetrahydrofuran: water (3 mL of a 2: 1 solution) was added lithium hydroxide monohydrate (0.06 g). The reaction mixture was stirred overnight and then concentrated to give the title compound (0.46 g): MS (EI) 366 (M + H ⁺ ).

e.) 3-Hydroxy-4 - {(S) -4-methyl-2- [naphthylen-2-ylmethyl- (2,2,2trifluoro-acetyl) -amino] -pentanoylamino} -azepane-1-carboxylic acid, benzyl ester

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 mixture was stirred until the reaction was complete. Treatment and column chromatography (5% methanol: ethyl acetate) afforded the title compound (0.25 g): MS (EI) 614 (M + H ⁺ ).

d. ) 2,2,2-Trifluoro-N - [(S) -1- (3-hydroxy-azepan-ylcarbamoyl) -3-methyl-butyl] -N-naphthalen-2-ylmethyl-acetamide

Following the procedure of Example 42b with the exception that the compound of Example 46c was used, the title compound was obtained: MS (EI) 480 (M + H ⁺ ).

e. ) 2,2,2-Trifluoro-N - ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-ylcarbamoyl } -butyl) -1H-naphthylen-2ylmethyl-acetamide

147

Following the procedure of Example 43a with the exception of using the compound of Example 46d, the title compound was obtained: MS (EI) 675 (M + H ⁺ ).

f.) 2,2,2-Trifluoro-N - ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane -4-ylcarbamoyl} -butyl) -1H-naphthylen-2ylmethyl-acetamide

Following the procedure of Example 1 with the exception of using the compound of Example 46e, the title compound was obtained: NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.7 (m, 3H),

4.1 (m, 1H), 4.5 (m, 2H), 4.7 (m, 2H), 5.2 (m, 1H), 7.2-8.0 (m, 14H), 8.7 (m, 1H): MS (EI): 673 (M + H ⁺ , 100%).

Example 47

Preparation of 4 - [(S) - (methanesulfonyl-naphthalen-2-ylmethyl-amino) 4-methyl-pentanoylamino] -3-oxo-azepane-1-carboxylic acid,

pentanoic acid methyl ester

To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added triethylamine (0.36 mL) and methanesulfonyl chloride (0.16 mL). The reaction mixture was stirred at room temperature until the reaction was complete. Treatment and chromatography (20% ethyl acetate: hexanes) gave the title compound (0.24 g).

b.) (S) -2- (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methylpentanoic acid, lithium salt

Following the procedure of Example 46b with the exception that using the compound of Example 47a, the title compound was obtained: MS (EI) 348 (M + H ⁺ ).

148

c. ) 4 - [(S) - (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methylpentanoylamino] -3-hydroxy-azepane-1-carboxylic acid, benzyl ester

Following the procedure of Example 46c with the exception of using the compound of Example 47b, the title compound was obtained: MS (EI) 596 (M + H ⁺ ).

d. ) 4 - [(S) - (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methylpentanoylamino] -3-oxo-azepane-1-carboxylic acid, benzyl ester

Following the procedure of Example 1 with the exception that the compound of Example 47c was used, the title compound was obtained: NMR (CDCl 3): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 3.0 (m, 1H), 3.5 (m, 1H), 4.1 (m, 1H),

4.5 (m, 3H), 4.7 (m, 1H), 5.2 (m, 3H), 7.2-8.0 (m, 13H); MS (EI): 596 (M + 3H ^&lt; ⁺ & gt ^; , 100%).

Example 48

Preparation of quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-2-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

b. ) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example li except substituting the compound of Example 48a the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m,

149

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.1 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.0-7.2 (m, 1H), 7.3 (m, 1H), 7.5 (m, 1H), 7.7 (m, 1H), 7.8 (m, 3H) , 8.1 (m, 1H), 8.3 (m, 2H), 8.7 (m, 2H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%).

Example 49

Preparation of quino.-pin-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] carbamoyl] -butyl} amide

a. ) Quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-8-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

b. ) Quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using the compound of Example 49a, the title compound was obtained: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.5 (m, 4H), 7.6 (m, 1H), 7.7 (m, 3H), 8.2 (m, 1H), 8.6 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 50

Preparation of quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide a.) Quinoline-6 -carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

150

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-6-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

B.) Quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example li except substituting the compound of Example 50a the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H) ,

4.7 (m, 2H), 5.0 (m, 1H), 7.0 (m, 2H), 7.5 (m, 2H), 7.9 (m, 2H), 8.0 (m, 3H), 8.2 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%).

Example 51

Preparation of quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) Quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-4-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

b. ) Quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using the compound of Example 51a, the title compound was obtained: ¹ H NMR (CDCl 3): δ 1.0 (m,

151

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 6.5-7.2 (m, 2H), 7.4 (m, 2H), 7.5 (m, 1H), 7.7 (m, 1H), 7.9 (m, 2H) , 8.0 (m, 1H), 8.2 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%).

Example 52

Preparation of quinoline-3-carboxylic acid {(B) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl-butyl} -amide

a. ) Quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-3-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

b. ) Quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception that using the compound of Example 52a, the title compound was obtained: * H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 1H) , 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.2 (m 2H), 7.5 (m, 1H), 7.6 (m, 1H), 7.7-7.9 (m, 4H), 8.1 (m, 1H). 8.5 (m, 1H), 8.6 (m, 1H), 9.3 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%).

152

Example 53

Preparation of isoquinoline-3-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) Isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by isoquinoline 3-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

b. ) Isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using the compound of Example 53a, the title compound was obtained: NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.0 (m, 1H). 7.5 (m, 1H), 7.7 (m, 2H), 7.9 (m, 4H), 8.7 (m, 3H), 9.2 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 54

Preparation of isoquinoline-1-carboxylic acid {(R) -3-methyl-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) Isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-hydroxy1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced with isoquinoline-1-carboxylic acid, the title compound is obtained: MS (EI) 540 (M + H ⁺ ).

b. ) Isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example li with the exception of using the compound of Example 54a,

153 compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H) ),

4.7 (m, 2H), 5.0 (m, 1H), 7.3 (m, 1H), 7.5 (m, 1H), 7.7-8.0 (m, 6H), 8.7 (m, 3H), 9.5 (m, 1H) ; MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 537 (M ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 537 (M ⁺ , 100%).

Preparation of quinoxaline-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b is the exception that benzofuran-2-carboxylic acid is replaced by quinoxaline-2 carboxylic acid to give the title compound: MS (EI) 541 (M + H ⁺ ).

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

Following the procedure of Example li except substituting the compound of Example 55a the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (w,

6H), 1.5-2.1 (m, 5H), 2.2 (t, 2H), 2.7 (t, 1H), 3.7 (d, 1H), 4.0 (t, 1H),

4.7 (t, 2H), 5.0 (t, 1H), 7.0-7.2 (t, 2H), 7.5 (t, 1H), 7.7 (t, 3H), 8.2 (t, 2H), 8.3 (t, 1H) , 8.7 (m, 1H), 9.5 (m, 1H); MS (EI): 539 (M + H &lt; ⁺ &gt;,

30%).

Example 56

Preparation of benzo [b] thiophene-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] 154

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

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 545 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception that using the compound of Example 56a, the title compound was obtained: 1 H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 6.8-7.2 (m, 1H), 7.5 (m, 3H), 8.0 (m, 6H), 8.7 (m, 1H); MS (EI): 543 (M + H ^& lt ^{; +} & gt ^; , 60%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; ^T H NMR (CDC1 _3): δ 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, 1H), 7.4-8.0 (m, 8H), 8.7 (m, 1H); MS (EI): 543 (M + H ⁺ , 100%) and the slower eluting diastereomer; 1.0 (m, 6H),

1.5-2.2 (m, 6H), 2.7 (w, 1H), 3.8 (m, 1H), 4.1 (t, 1H), 4.7 (t, 2H), 5.1 (t, 1H), 7.4-8.0 (t, 8H), 8.7 (m, 1H); MS (EI): 543 (M + H ⁺ , 100%).

Example 57

Preparation of 1,8-naphthyridine-2-carboxylic acid {(S) -3methyl-1- (3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

a.) 1,8-Naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

155

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 1,8 naphthyridine-2-carboxylic acid, the title compound is obtained: MS (EI) 541 (M + H ⁺ ).

B.) 1,8-Naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example li except substituting the compound of Example 57a the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H) ,

4.7 (m, 2H), 5.0 (m, 1H), 7.2 (m, 1H), 7.6 (m, 2H), 7.9 (m, 2H), 8.3 (m, 1H), 8.4 (m, 2H), 8.5 (m, 2H), 9.2 (m, 1H); MS (EI); 539 (M + H ⁺ , 100%).

Example 58

Preparation of 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. 1H-Indole-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 1H-indole-2-carboxylic acid, the title compound is obtained: MS (EI) 528 (M + H ⁺ ).

b. 1H-Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl carbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception that the compound of Example 58a was used, the title compound was obtained: NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (t, 1H),

4.7 (t, 2H), 5.0 (t, 1H), 6.8 (t, 1H), 7.1 (t, 1H), 7.3 (t, 3H), 7.4 (t, 1H), 7.5 (t, 1H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H), 9.4 (b, 1H); MS (EI): 526 (M + H ⁺ , 80%).

156

Example 59

Preparation of 5-methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

a. 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5methoxybenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 559 (M + H ⁺ ).

b. 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using the compound of Example 59a, the title compound was obtained: ^] H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 4H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.0 (m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 557 (M + H ^& lt ^{; +} & gt ^; , 70%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; ² H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (t, 4H), 4.0 (d, 1H), 4.7 (m, 2H), 5.0 (d, 1H), 7.0 (m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (d, 1H); MS (EI): 557 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 557 (M + H ⁺ , 100%).

Example 60

Preparation of _5-bromo-fluoro-2-carboxylic acid {{(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] carbamoyl] 157

a. 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5-bromo-2-furoic acid, the title compound is obtained: MS (EI) 558 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception that using the compound of Example 60a, the title compound was obtained: R NMR (CDCl ₃ ): δ 1.0 (m, 6Η), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 6.5 (m, 1H), 6.7 (m, 1H), 7.1 (m, 2H), 7.5 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 555 (M + H ^& lt ^{; +} & gt ^; , 60%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 555 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 555 (M + H ⁺ , 100%).

Example 61

Preparation of furan-2-carboxylic acid {(B) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced with 2-furoic acid, the title compound is obtained: MS (EI) 479 (M + H ⁺ ).

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

158

Following the procedure of Example 1 with the exception that using the compound of Example 61a, the title compound was obtained: ^] H NMR (CDCl 3): δ 1.0 (1H, 6H), 1.5-2.1 (m, 5H) , 2.2 (t, 2H), 2.7 (t, 1H), 3.7 (d, 1H), 4.0 (t, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 6.5 (m, 1H), 7.2 (m, 3H), 7.5 (m, 2H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 477 (M + H ⁺ , 50%).

Example 62

Preparation of 5-nitro-furan-2-carboxylic acid {(R) -3-methyl1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

a. 5-Nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5-nitro-2-furoic acid, the title compound is obtained: MS (EI) 524 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception that using the compound of Example 62a, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.2 (m, 1H), 7.3 (m, 1H), 7.5 (m, 1H), 7.9 (m, 2H), 8.7 (m, 1H); MS (EI): 522 (M + H ^& lt ^{; +} & gt ^; , 80%).

Example 63

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

159

a. ) 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5- (4-nitrophenyl) -2-furoic acid, the title compound is obtained: MS (EI) 600 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception that using the compound of Example 63a, the title compound was obtained: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (t, 1H),

4.7 (t, 2H), 5.0 (t, 1H), 6.9 (t, 1H), 7.2 (t, 1H), 7.5 (t, 2H), 7.9-8.0 (t, 4H), 8.5 (t, 1H) , 8.6 (t, 1H); MS (EI): 598 (M + H ⁺ , 80%).

Example 64

Preparation of 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ___ {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4yl carbamoyl] -butyl } amide

a. ) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4yl carbamoyl] -butyl } amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5- [3 (trifluoromethyl) phenyl] -2-furoic acid, the title compound is obtained: MS (EI) 623 ( M + H ⁺ ).

b. ) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

160

Following the procedure of Example 1 with the exception that using the compound of Example 64a, the title compound was obtained: Ή NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 7.1 (m, 1H), 7.5 (m, 3H), 8.0 (m, 4H) 8.7 (m, 1H); MS (EI): 621 (M + H ^& lt ^{; +} & gt ^; , 80%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 621 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 621 (M + H ⁺ , 100%).

Example 65

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

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

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by tetrahydrofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 483 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception that using the compound of Example 65 a, the title compound was obtained: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.2 (m, 12H ), 2.7 (m, 1H), 3.8 (w, 3H), 4.0 (t, 1H), 4.5 (t, 2H),

4.8 (m, 1H), 5.0 (m, 1H), 7.0 (m, 1H), 7.5 (m, 1H), 7.9 (m, 2H), 8.7 (m, 1H). MS (EI): 481 (M + H ⁺ , 80%).

161

Example 66

Preparation of (S) -4-Methyl-2- (2-phenoxy-apetylamino) -pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

a. ) (S) -4-Methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-hydroxy- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by phenoxyacetic acid, the title compound is obtained: MS (EI) 519 (M + H ⁺ ).

b. ) (S) -4-Methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception that using the compound of Example 66a, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) ), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.5 (m, 3H), 4.7 (m, 1H), 5.1 (m, 1H), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS (EI): 517 (M + H ^& lt ^{; +} & gt ^; , 60%).

Example_67

Preparation of (S) -2- [2- (4-fluoro-phenoxy) -ethyl-ethylamino] -4-methylpentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

a. ) (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-hydroxy- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced with 4fluorophenoxyacetic acid, the title compound is obtained: MS (EI) 537 (M + H ⁺ ).

b. ) (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

162

Following the procedure of Example li except substituting the compound of Example 67a the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.6 (d, 1H), 4.0 (m, 1H) ,

4.5 (, 3H), 4.8 (m, 1H), 5.1 (m, 1H), 7.0 (m, 4H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS (EI): 535 (M + H ^& lt ^{; +} & gt ^; , 50%).

Example 68

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] -3-butyl} amide

a. ) {(S) -1- [3-Hydroxy-1- (pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 2g (0.25 g) in dichloromethane was added picolinic acid (0.09 g), EDC (0.14 g) and HOBt (0.10 g). The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: ethyl acetate) gave the title compound (0.35 g) ·

b. (S) -2-Amino-4-methylpentanoic acid [3-hydroxy-1- (pyridine2-carbonyl) -azepan-4-yl] -amide

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 mixture was stirred until the reaction was complete and then concentrated to give the title compound (0.34 g): MS (EI) 349 (M + H ⁺ ).

c. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] -3-butyl} -amide

Following the procedure of Example 28b with the exception that using the compound of Example 68b, the title compound was obtained: MS (ED) 493 (M + H ⁺ ).

163

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

Following the procedure of Example 1 with the exception that using the compound of Example 68c, the title compound was obtained: ² H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.5 (m, 1H), 3.7 (m, 1H), 4.7 (m, 4H), 5.0 (m, 1H), 7.0-7.5 (m, 8H), 8.2 (m, 1H) ); MS (EI): 491 (M ⁺ , 100%).

Example 69

Preparation of benzofuran-2-carboxylic acid {(B) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedures of Examples 68a-d with the exception that the picolinic acid of Example 68c is replaced by the picolinic acid N-oxide, the title compound is obtained: ^X H NMR (CDCl 3): δ 1.0 (m, 6H ), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H), 4.0 (m, 1H), 4.7 (m, 3H), 5.5 (m, 1H), 7.0 (m, 2H), 7.2-7.5 (m, 7H), 8.1 (m, 2H); MS (EI): 507 (M ⁺ , 20%).

Example 70

Preparation of 4 - ((S) -2-tert-butylcarbonylamino-4-methylpentanoylamino) -3-oxo-azepane-1-carboxylic acid benzyl ester

Following the procedure of Example 92j with the exception that benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6 dimethyl-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] The 3-methylbutyl} -amide is replaced by 4 - ((S) -2-tert-butoxycarbonylamino-4methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 476.2; ^! H NMR (400 MHz, CDCl ₃ ): 7.40164

6.95 (m, 7H), 5.25-4.60 (m, 4H), 4.40-4.06 (m, 2H), 3.70-3.58 (t, 1H), 2.70-2.50 (m, 1H), 2.25-1.30 (m, 16H) ); and a second eluting diastereomer: 1.00-0.85 (d, 6H); and a second eluting diastereomer: MS (M + H ⁺ ) 476.2.

Example 71

Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-methyl-1H-imidazole-4-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide

a. ) {(S) -1- [3-Hydroxy-1- (1-methyl-1H-imidazole-2-sulfonyl) -azepan4-ylcarbamoyl} -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the amine of Example 2g in methylene chloride (5 ml) was added pyridine (92 µL, 1.14 mmol), followed by 1-methylimidazole-4-sulfonyl chloride (0.112 g, 0.623 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature. The solution was subsequently washed with saturated aqueous NaHCO ₃ , water and brine. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give the title compound as a white solid (0.172 g, 68%): ^T H NMR (400 MHz, CDCl ₃ ) δ 7.6 (d, 1H), 7.5 (d, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H); MS (ESI): 488.2 (M + H) &lt; ⁺ & gt ^; .

b. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-methyl-1H-imidazole-2-sulfonyl) -azepan-4-yl] -amide

To a solution of the compound of Example 71a (0.172 g, 0.353 mmol) in a minimal amount of MeOH was added 4M HCl in dioxane (10 mL) and stirred for 4 hours at room temperature. The reaction mixture was concentrated and azeotroped with toluene (2 x) to give the title compound as an off-white solid: MS (ESI): 388.2 (M + H) ⁺ .

165

c. ) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl1- [3-hydroxy-1- (1-methyl-1H-imidazole-4-sulfonyl) -azepan-4ylcarbamoyl] -butyl} amide

To a stirred solution of the compound of Example 7lb (0.137 g, 0.353 mmol), 5,6-dimethoxybenzofuran-2-carboxylic acid (0.86 g, 0.388 mmol), triethylamine (246 mL, 1.77 mmol) and 1hydroxybenzotriazole (0.01 g, 0.070 mmol) ) in dimethylformamide (5 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.074 g, 0.388 mmol). After stirring at room temperature for 16 hours, the solution was diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate solution, water (2 x) and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.088 g, 42%): MS (ESI): 592.1 (M + H) ⁺ .

d. ) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl1- [3-oxo-1- (1-methyl-1H-imidazole-4-sulfonyl) -azepan-4ylcarbamoyl] -butyl} amide

Oxalyl chloride (52 µL, 0.596 mmol) was cooled to -78 ° C. Dimethyl sulfoxide (106 pL, 1.49 mmol) in methylene chloride was added dropwise. After stirring for 15 minutes at -78 ° C, alcohol in methylene chloride was slowly added and stirred for 1 hour, with Et ₃ N (416 pL,

2.98 mmol). The solution was then brought to room temperature, quenched with water and extracted with methylene chloride. The organic layer was separated and washed with brine, dried over MgSO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give

166 title compound as a white solid (0.068 g, 78%): ^T H NMR (400 MHz, CDCl ₃ ) δ 6.8-7.6 (m, 14H), 4 (d, 12H), 1 ( d, 12H); MS (ESI): 590.1 (M + H) &lt; ⁺ & gt ^; .

Example 72

Preparation of benzofuran-2-carboxylic acid {(B) -3-methyl-1 [1- (5-methyl-1-H- [1,2,4] triazole-3-sulfonyl) -3-oxo-azepane- 4ylcarbamoyl] -butyl} amide

a. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a stirred 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 1 hour at room temperature. The reaction mixture was then concentrated and azeotroped with toluene (2 x 20 mL) to give the title compound as a pale yellow oil (3.13 g, 100%): MS (ESI) 378.4 (M + H) ⁺

b. ) 4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methylpentanoylamino} -3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a stirred solution of the compound of Example 72a (3.13 g, 7.57 mmol), benzofuran-2-carboxylic acid (1.35 g, 8.32 mmol), triethylamine (1.17 ml, 8.25 mmol) and 1-hydroxybenzotriazole (0.2 g, 1.48 mmol) in dimethylformamide (30 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.6 g, 8.33 mmol). After stirring at room temperature for 16 hours, the solution was diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate, water (2 x) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; ethyl acetate / dichloromethane) to give

167 the title compound (3.7 g, 93%). ² H NMR (400 MHz, CDCl ₃ ) δ 6.8-7.7 (m, 12H), 5.35 (s, 2H), 1.0 (d, 6H): MS (ESI): 522 (M + H) ⁺ .

c. ) Benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4ylcarbamoyl) -3-methyl-butyl] -amide

To a solution of 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 hours under hydrogen atmosphere. The mixture was then filtered through celite and the filtrate concentrated to give the title compound as a white solid (1.92 g, 100%): ¹ H NMR (400 MHz, CDCl 3) δ 6.8-7.7 (m, 7H ), 1.02 (d, 6H); MS (ESI) 388 (M + H) ⁺ .

d. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-H- [1,2,4] triazole-3-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] butyl} amide

To a stirred solution of the compound of Example 72c (0.100 g, 0.25 mmol) and triethylamine (35 pL, 0.25 mmol) in methylene chloride (2 mL) was added 5-methyl-1H-1,2,4-triazolesulfonyl chloride (0.043 g, 0.25 mmol). The reaction mixture was stirred for 10 minutes and washed with saturated aqueous NaHCO ₃ , water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The compound was purified by column chromatography (silica gel; ethyl acetate / hexane) to give the title compound as a pale yellow oil (0.111, 84%): MS (ESI) 532.73 (M + H) ⁺

e. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-

168

1H- [1,2,4] triazole-3-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

To a stirred solution of the compound of Example 72d (0.108 g, 0.206 mmol) in dimethyl sulfoxide (2 mL) was added triethylamine (172 pL, 1.23 mmol), followed by sulfur trioxide pyridine (0.116 g, 0.718 mmol) and stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water (x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the compound of the title as a white solid (0.08 g, 81%): ^T H NMR (400 MHz, CDCI3) δ 7.1-7.7 ( m, 7H), 2.65 (s, 3H), 1.0 (d, 6H); MS (ESI): 552.71 (M + Na) &lt; ⁺ &gt;.

Example 73

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1CD1-methyl-1H-imidazole-3-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} amide

a.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- (1- (1-methyl-1H-imidazole-3-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] butyl} amide

To a stirred solution of the compound of Example 72c (0.100 g, 0.25 mmol) and triethylamine (35 pL, 0.25 mmol) was added 1methylimidazole sulfonyl chloride (0.046 g, 0.255 mmol). The reaction mixture was stirred for 10 minutes and washed with saturated aqueous NaHCO ₃ , water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The compound was purified by column chromatography (silica gel; ethyl acetate / hexane) to give

169 the title compound as a pale yellow oil (0.113 g, 82%): ^X H NMR (400 MHz, CDCl ₃ ) δ 6.9-7.7 (m, 9H), 3.9 (2s, 3H), 1.0 (d , 6H); MS (ESI): 531.8 (M + H) &lt; ⁺ & gt ^; .

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

To a stirred solution of the compound of Example 73a (0.085 g, 0.159 mmol) in dimethyl sulfoxide was added triethylamine (133 pL, 0.95 mmol), followed by sulfur trioxide-pyridine complex (0.08 g, 0.5 mmol) and stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water (x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the title compound as a white solid (0.072 g, 83%). MS (ESI): 529.76 (M + H) ⁺ .

Example 74

Preparation of benzofuran-2-carboxylic acid {(R) -3-methyl-1 [1- (1H-imylazole-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

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

To a stirred solution of the compound of Example 72c (0.100 g, 0.25 mmol) and triethylamine (35 pL, 0.25 mmol) was added 2-imidazolesulfonyl chloride (0.046 g, 0.255 mmol). The reaction mixture was stirred for 10 minutes and washed with saturated aqueous NaHCO ₃ , water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and filtered

170 concentrates. The compound was purified by column chromatography (silica gel; ethyl acetate / hexane) to give the title compound as a pale yellow oil (0.113 g, 82%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.1-7.7 (m , 9H), 4.8 (s, 1H), d, 6H); MS (ESI): 517.76 (M + H) &lt; ⁺ & gt ^; .

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

To a stirred solution of the compound of Example 74a (0.107 g, 0.206 mmol) in dimethyl sulfoxide (2 mL) was added triethylamine (172 pL, 1.23 mmol) followed by sulfur trioxide pyridine complex (0.115 g, 0.718 mmol) and stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water (x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the title compound as a white solid (0.09 g, 85%); MS (ESI): 515.84 (M + H) ⁺ .

Example 75

Preparation of benzofuran-2-carboxylic acid {(B) -3-methyl-1 [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a.) {(S) -1- [3-Hydroxy-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl} -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 2g (2.50 g, 7.29 mmol) in 1,2-dichloroethane (100 mL) was added P-NMM (4.0 g) and thioazole-2 sulfonyl chloride (1.6 g, 8.75 mmol). After shaking at room temperature, the solution was filtered overnight. The filtrate was concentrated to give the title compound as a white solid (2.50 g, 5.10 mmol, 70%); MS: 490.91 (M + H) ⁺ .

171

b. ) Benzofuran-2-carboxylic acid {(5) -3-methyl-1- [3-hydroxy1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

To a solution of the compound of Example 75b (0.15 g, 0.45 mmol) in CH ₂ Cl ₂ (20 mL) was added benzofuran-2-carboxylic acid (0.109 g, 0.172 mmol), 1-hydroxybenzotriazole (0.106 g, 0.762 mmol) and P-EDC (0.85 g, 1 mmol / g) in CH ₂ Cl ₂ (10 mL). After shaking at room temperature overnight, the solution was treated with trisamine (0.589 g, 3.75 mmol / g). After shaking for another 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (166.7 mg, 70%); MS (ESI): 535.3 (M + H) ⁺ .

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

To a stirred 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 hours, a solution of sodium thiosulfate (2 mL of 10% solution in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous phase was extracted with dichloromethane (2 x). The organic phases are combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC (50:50 ethanol: hexane, 20 mL / minute, 25 minutes, WhelkO-1 (R, R) 21 x 250 mm column, UV detection at 280 nm and 305 nm) to give the first eluate as a white solid (84.8 mg, 50.8%). MS (ESI): 533.2 (M + H) ⁺ and a second eluate as a white solid (50.1 mg, 30.0%) MS: 533.2 (M + H ⁺ ).

172

Example 76

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (1-methyl-1-H-imidazol-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} amide

a. ) <(S) -1- [3-Hydroxy-1- (1-methyl-1H-imidazole-2-sulfonyl) -azepan-4-ylcarbamoyl} -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the amine of Example 2g in methylene chloride (5 ml) was added pyridine (92 pL, 1.14 mmol), followed by 1-methylimidazole4-sulfonyl chloride (0.112 g, 0.623 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature. The solution was subsequently washed with saturated aqueous NaHCO ₃ , water and brine. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give the title compound as a white solid (0.172 g, 68%): 1 ^. H NMR (400 MHz, CDCl ₃ ) δ 7.6 (d, 1H), 7.5 (d, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H) ); MS (ESI): 488.2 (M + H) &lt; ⁺ & gt ^; .

b. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-methyl-1H-imidazole-2-sulfonyl) -azepan-4-yl] -amide

To a solution of the compound of Example 76a (0.172 g, 0.353 mmol) in a minimal amount of MeOH was added 4M HCl in dioxane (10 mL) and stirred for 4 hours at room temperature. The reaction mixture was concentrated and azeotroped with toluene (2 x) to give the title compound as an off-white solid. MS (ESI): 388.2 (M + H) ⁺ .

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

173

To a stirred solution of the compound of Example 72c (0.2 g, 0.471 mmol), benzofuran-2-carboxylic acid (0.084 g, 0.388 mmol), triethylamine (72 pL, 0.517 mmol) and 1-hydroxybenzotriazole (0.012 g, 0.088 mmol) in dimethylformamide (5 mL) was added 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.099 g, 0.515 mmol). After stirring at room temperature for 16 hours, the solution was diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate solution, water (2 x) and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.226 g, 90%): 1 ^. H NMR (400 MHz, CDCl ₃ ) δ 6.9-8.1 (m, 18H), 3.75 (2s, 6H), 1 (d, 12H); MS (ESI): 531.80 (M + H) &lt; ⁺ & gt ^; .

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

To a stirred solution of the compound of Example 76a (0.226 g, 0.426 mmol) in dimethyl sulfoxide (2 mL) was added triethylamine (355 pL, 2.55 mmol), followed by sulfur trioxide pyridine (0.238 g, 1.48 mmol) and stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water (x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the compound of the title as a white solid (0.168 g, 76%): ^T H NMR (400 MHz, CDCI3) δ 7.1-7.7 9m , 18H), 3.7 (2s, 6H), 0.9 (d, 12H); MS (ESI): 529.80 (M + H) &lt; ⁺ & gt ^; .

174

Example_77

Preparation of 5- (4-oxy-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4- ylcarbamoyl] -butyl} amide

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 mixture was stirred overnight. Workup and column chromatography (30% methanolchloromethane) gave the title compound: ² H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 ( m, 4H), 2.7 (m, 2H), 3.7 (m, 4H),

3.8 (q, 1H), 4.0 (m, 3H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0 (m, 3H), 7.4 (m, 2H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS (EI): 671 (M ⁺ , 100%).

Example 78

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (pyridine-3-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To a solution of 4 - ((S) -2-tert-butoxycarbonylamino-4methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 2f (4.0 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound (3.8 g): MS (EI) 378 (M + H ⁺ ).

b. ) 4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methylpentanoylamino} -3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a solution of 4 - ((S) -2-amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example

175

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 mixture was stirred until the reaction was complete. Workup and column chromatography (2% methanol: dichloromethane) gave the title compound (3.78 g): MS (EI) 521 (M + H ⁺ ).

c. ) Benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4ylcarbamoyl) -3-methyl-butyl] -amide

To a solution of 4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 78b (1.6 g) in methanol: ethyl acetate (50 mL: 100 mL) was added 10% Pd / C. The reaction mixture was stirred under a hydrogen balloon for 2 hours and then filtered and concentrated to give the title compound (1.16 g): MS (EI) 387 (M + H ⁺ ).

d. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy1- (pyridine-3-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

To a solution of benzofuran-2-carboxylic acid [(S) -1- (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 mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. Treatment and column chromatography (5% methanol: ethyl acetate) afforded 0.32 g of the title compound: MS (EI) 528 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-hydroxy-1- (pyridine-3-sulfonyl) -azepan-4-ylcarbamoyl ] 176 Butyl} amide of Example 78d, the title compound was obtained: ^] H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H), 4.0 (m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0 (m, 2H), 7.2- 7.5 (m, 6H), 8.1 (m, 1H), 8.9-9.0 (m, 2H); MS (EI): 526 (M ⁺ , 100%).

Example 79

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-3-sulfonyl) -azepan-4-ylcarbamoyl] -

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

To a solution of benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (pyridine-3-sulfonyl) -azepan-4ylcarbamoyl] -butyl} amide of Example 78d (0.05 g) in dichloromethane rn-CPBA (0.05 g) was added. The reaction mixture was stirred overnight. Workup and column chromatography (10% methanol: dichloromethane) gave the title compound (0.03 g): MS (EI) 544 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-hydroxy-1- (1-oxy-pyridine-3-sulfonyl) -azepane -4-ylcarbamoyl] butyl} amide of Example 79a, gave the title compound: NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m,

2H), 2.5 (w, 1H), 3.5 (d, 1H), 4.0 (m, 1H), 4.5 (m, 1H), 4.7 (m, 1H), 5.0 (t, 1H), 7.2-7.5 (t , 7H), 8.1-8.2 (m, 2H). MS (EI): 542 (M ⁺ , 50%).

Example 80

Preparation of quinoline-3-carboxylic acid {(S) -1- (3,4-dichlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl)] - 3-methyl-butyl} amide

177

Following the procedures of Example 75a-d with the exception that the thioazole-2-sulfonyl chloride of Example 75a is replaced by 3,4-dichlorosulfonyl chloride and benzofura-2carboxylic acid is replaced by the quinoline-3-carboxylic acid, the title compound is obtained for title: ² H NMR (CDCl ₃ , 400 MHz) δ 9.34 (s, 1H), 8.61 (s, 1H), 8.14 (m, 1H), 7.81 (m, 3H), 7.60 (m, 3H), 7.19 m, 2H), 5.09 (m, 1H), 4.88 (m, 1H), 4.50 (m, 1H), 3.92 (m, 1H), 3.51 (m, 1H), 2.57 (m, 1H), 2.23 (m , 2H), 1.60 (m, 5H), 1.01 (m, 6H).

Example 81

Preparation of 5-hydroxy-benzofuran-2-carboxylic acid {(S) 3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4ylcarbamoyl] -butyl} amide

a.) 5-Hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-hydroxy-azepan-4ylcarbamoyl] -butyl } amide

To a stirred solution of the compound of Example 76b (0.1 g, 0.235 mmol), 5-hydroxybenzofuran-2-carboxylic acid (0.046 g, 0.256 mmol), triethylamine (36 pL, 0.258 mmol) and 1hydroxybenzotriazole (0.006 g, 0.044 mmol) in dimethylformamide (5 mL) was added 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.05 g, 0.26 mmol). After stirring at room temperature for 16 hours, the solution was diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate solution, water (2 x) and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.129 g, 100%). ² H NMR (400 MHz, CDCl ₃ ) δ 6.8-8 (m, 16H),

3.6 (2s, 6H), 0.85 (d, 12H).

178

MS (ESI): 547.88 (M + H) &lt; ⁺ & gt ^; .

b.) 5-Hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4ylcarbamoyl] -butyl } amide

Oxalyl chloride (13 µL, 0.149 mmol) was adjusted to -78 ° C. Dimethyl sulfoxide (28 µL, 0.394 mmol) in methylene chloride was added dropwise. After stirring for 15 minutes at -78 ° C, the alcohol of Example 81a in methylene chloride was slowly added and stirred for 1 hour, with Et ₃ N (7 pL, 0.05 mmol) added. The solution was brought to room temperature and quenched with water and extracted with methylene chloride. The organic layer was separated and washed with brine, dried over MgSO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give the title compound as a white solid (0.021 g, 78%): MS (ESI) 545.9 (M + H) ⁺ .

Example 82 Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl)] - 3-methyl-butyl } -amide

a.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (1-oxy-pyridine-2-sulfonyl) -azepan-4-yl carbamoyl)] -3-methylbutyl} -amide

To a solution of benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide of Example 78c (0.10 g) in dichloromethane was added triethylamine (0.07 mL). followed by 2-pyridinesulfonyl chloride-L1-oxide. The reaction mixture was stirred at room temperature overnight. Treatment and chromatography (10% methanol: dichloro179 methane) afforded the title compound (0.01 g): MS (EI) 544 (M + H ⁺ ).

b.) {(S) -3-Methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl)] - 3-methyl-butyl} -amide

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane -4-ylcarbamoyl)] 3-methyl-butyl} -amide of Example 82a, the title compound was obtained: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H). 7.0-7.5 (m, 9H), 8.1-8.2 (m, 2H). MS (EI): 542 (M ⁺ , 20%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; ^X H NMR (CDCl ₃ ); δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.8 (d, 1H), 4.0 (d, 1H), 4.7 (w, 1H) ), 4.8 (d, 1H), 5.0 (m, 1H), 7.0-7.5 (m, 9H), 8.1-8.2 (1H, 2H); MS (EI): 542 (M ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 542 (M + H ⁺ , 100%).

Example 83

Preparation of 2- (4 - {(S) -2 - {(benzofuran-2-carbonyl) -amino} -4methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid

a.) 2- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methylpentanoylamino} -3-hydroxy-azepane-1-sulfonyl) -benzoic acid methyl ester

Following the procedure of Example 75a-c with the exception that 2-thiazolesulfonyl chloride is replaced by 2carboxymethylsulfonyl chloride, the title compound is obtained: MS (M + H ⁺ ) = 585.56, M + Na ⁺ = 607.76, 2M + H ⁺ = 1170.48.

180

b. ) 2- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methylpentanoylamino} -3-hydroxy-azepane-1-sulfonyl) -benzoic acid

2- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methylpentanoylamino-} -3-hydroxy-azepane-1-sulfonyl) -benzoic acid methyl ester (compound 83a, 180 mg , 0.309 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 hours. The mixture was then quenched with water and 6 N HCl (adjusted to pH = 2), extracted with EtOAc (3 x 10 ml), dried with MgSO ₄ , filtered, concentrated and chromatographed (silica gel, 1% acetic acid). acid / 4% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (48 mg, 27%): M + H ⁺ = 572.2.

c. ) 2- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methylpentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid

Following the procedure of Example 75d with the exception that benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } The amide is replaced by 2- (4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methylpentanoyl-amino} -3-hydroxy-azepane-1-sulfonyl) -benzoic acid, the title compound was obtained: MS (M + H ⁺ ): 570.2 (M + H ⁺ ). ^! H NMR (400 Hz, CDCl3-CD3OD): δ 8.05-7.95 (m, 1H), 7.70-7.15 (m, 8H), 5.15-5.00 (m, 1H), 4.95-4.75 (m, 2H), 4.154. 00 (m, 1H), 3.65 (d, 1H), 2.85-2.70 (m, 1H), 2.25-2.05 (m, 2H), 1.90-1.70 (m, 4H), 1.60-1.45 (m, 1H). 0.95 (d, 6H).

Example 84

Preparation of 3- (4 - {(S) -2 - {(benzofuran-2-carbonyl) -amino] -4methyl-pentanoylamino} 3-oxo-azepane-1-sulfonyl) -benzoic acid

181

Following the procedure of Example 83 with the exception that 2-carboxymethylbenzenesulfonyl chloride is replaced by 3carboxymethylbenzenesulfonyl chloride, the title compound is obtained: MS 570.2 (M + H ⁺ ); ^X H NMR (400 Hz, CDCl _{3 3} CD ₃ OD): δ 8.46 (d, 1H), 8.31-8.25 (m, 1H), 8.00-7.97 (m, 1H), 7.70-7.62 (m, 2H), 7.55 -7.46 (m, 1H), 7.45-7.35 (m, 1H), 7.30-7.25 (m, 1H), 5.105.05 (m, 1H), 4.95-4.78 (m, 1H), 4.75-4.55 (q. 1H), 4.00 (d, 1H), 3.5 (d, 1H), 2.60-2.40 (m, 2H), 2.25-2.15 (m, 1H), 1.95-1.70 (m, 4H), 1.55-1.40 (m. 1H), 0.98 (t, 6H).

Example 85

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

a. ) {(S) -1- [3-Hydroxy-1- (1-oxy-pyridine-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl-carbamic acid tert-butyl ester

To a solution of [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3methyl-butyl] -carbamic acid tert-butyl ester of Example 2g (2.5 g) in dichloromethane (100 mL) and saturated sodium solution bicarbonate was added freshly prepared 2-pyridinesulfonyl chloride N-oxide (obtained by passing chlorine gas through a solution of 2 mercaptopyridine-N-oxide in 9M HCl for about 90 minutes. Removal of excess chlorine in vacuo gave 2-pyridylsulfonyl sulfonylsulfonyl sulfide. The reaction mixture was stirred at room temperature for 1 hour. Workup and column chromatography (10% methanol: dichloromethane) gave the title compound (2.0 g): MS (EI) 500 (M + H ⁺ ).

b. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-oxypyridine-sulfonyl) -azepan-4-yl] -amide

To a solution of {(S) -1- [3-hydroxy-1- (1-oxy-pyridinesulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl-carbamate

182 Acid m / xw-butyl ester of Example 85a (2.0 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated to give the title compound (1.8 g): MS (EI) 400 (M + H ⁺ ).

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

To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-sulfonyl) -azepan-4-yl] -amide from

Example 85b (0.25 g) in dichloromethane (12 mL) was added triethylamine (0.12 mL), EDC (0.11 g), HOBt (0.077 g) and benzo [b] thiophene-2-carboxylic acid. The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (10% methanol: dichloromethane) gave the title compound (0.26 g): MS (E1) 560 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception of using benzo [b] thiophene-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) ) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 85c, to give the title compound: NMR (CDCl3): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H),

4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.5 (m, 4H), 7.8 (m, 3H), 8.1-8.2 (m, 2H) .. MS (EI): 558 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 558 (M ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 558 (M ⁺ , 100%).

183

Example 86

Preparation of 5-bromo-furan-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-

a. 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5-bromo-2-furoic acid, the title compound is obtained: MS (EI) 574 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception of using 5-bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) ) -azepan-4-ylcarbamoyl] -butyl} -amide from Example 86a to give the title compound: ¹ H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H),

4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0 (m, 2H), 7.4 (m, 2H), 8.1-8.2 (m, 2H); MS (EI): 570 (M ^&lt; ^{+ &gt;} , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 572 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 572 (M + H ⁺ , 100%).

Example 87

Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-piripin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

184

a. ) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5,6 dimethoxybenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 604 (M + H ⁺ ).

b. ) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2) -sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 87a, gave the title compound: ² H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.7 (m, 1H), 3.8 (m, 7H), 4.0 (m, 1H),

4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0-7.5 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 602 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 602 (M ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 602 (M ⁺ , 100%).

Example 88

Preparation of 1-oxy-pyridine-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (- pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] a.) 1-oxy- Pyridine-2-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

185

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by picolinic acid N-oxide, the title compound is obtained: MS (EI) 505 (M + H ⁺ ).

B.) 1-Oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using 1-oxy-pyridine-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} amide of Example 88a, the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.1 (m, 1H ),

4.7 (m, 2H), 5.0 (m, 1H), 7.5 (m, 3H), 7.9 (m 2H), 8.3-8.4 (m, 2H), 8.6 (m, 1H); MS (EI): 503 (M ⁺ , 100%).

Example .89

Preparation of (S) -4-Methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

a. ) (S) -4-Methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (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 mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: dichloromethane) gave the title compound (0.09 g): MS (EI) 525 (M + H ⁺ ).

b. ) (S) -4-Methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception of the use of (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentane

186 The acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide of Example 89a, gave the title compound:

NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H),

3.8 (q, 1H), 4.0 (m, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 5.5 (m, 1H), 7.0 (m 1H), 7.5 (m, 2H), 7.9 ( m 3H), 8.6 (m, 2H), MS (EI): 523 (M ⁺ , 100%).

Example 90

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

a. ) (S) -2- (3-Benzyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (pyridin-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 mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: dichloromethane) gave the title compound (0.12 g).

b. (S) -2- (3-Benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1 (pyridin-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception of using (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane -4-yl] -amide of Example 89a, gave the title compound: NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 ( m, 1H), 3.8 (q, 1H), 4.0 (m, 3H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.2 (, 5H), 7.5 ( m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS (EI): 515 (M ⁺ , 60%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 516

187 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 516 (M + H ⁺ , 100%).

Example 91

Preparation of (S) -2- (3-Phenyl-ureido) -4-methyl pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

a. ) (S) -2- (3-Phenyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 90a with the exception that the benzylisocyanate is replaced by phenylisocyanate, the title compound is obtained: MS (EI) 503 (M + H ⁺ ).

b. ) (S) -2- (3-Phenyl-ureido) -4-methyl-pentanoic acid [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception of using (S) -2- (3-phenyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane -4-yl] -amide of Example 91a the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H ), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.0-7.9 (m, 8H),

8.6 (m, 1H). MS (EI): 501 (M ⁺ , 60%).

Preparation of benzofuran-2-carboxylic acid {{(S) -1- [6,6 dimethyl-3-oxo-1 (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

a.) Allyl- (2,2-dimethyl-pent-4-enylidene) -amine

2,2-Dimethyl-4-pentenal (2.8 g, 25 mmol) was dissolved in 15 mL of benzene. Allylamine (2.85 g, 50 mmol) was added to this solution. Several molecular sieves are used to absorb the water obtained during the reaction. The mixture was stirred at room temperature overnight. Removing

188 solvent and an excess of allylamine on a rotary evaporator afforded 3.76 g of the title compound as a clear liquid (100% yield). ^! H NMR (400 MHz, CDCl3): 7.52 (s, 1H), 5.99-5.90 (m, 1H), 5.80-5.70 (m, 1H), 5.15-4.99 (m, 4H), 4.01-3.99 (m, 2H) ), 2.17 (d, 2H), 1.06 (s, 6H).

b). Allyl- (2,2-dimethyl-pent-4-enyl) -amine

The allyl- (2,2-dimethyl-pent-4-enylidene) -amine of Example 92a (3.76 g, 25 mmol) was diluted with 5 ml of MeOH. NaBH ₄ (0.95 g, 25 mmol) was added to the solution at 0 ° C. After the addition, the mixture was stirred at room temperature for 5 hours. The methanol was removed on a rotary evaporator and the residue partitioned between EtOAc and 20% NaOH. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give 2.26 g of the title compound: MS (M + H ⁺ ): 154.0; ^! H NMR (400 MHz, CDCl ₃ ): 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).

C.) Pyridine-2-sulfonic acid allyl- (2,2-dimethyl-pent-4-enyl) amide

Allyl- (2,2-dimethyl-pent-4-enyl) -amine (0.43 g, 2.8 mmol) and NMM (0.57 g, 5.6 mmol) were combined in 30 mL of CH ₂ Cl ₂ . To the solution, which was cooled in an ice-water bath, was slowly added 2-pyridinesulfonyl chloride. After the addition, the reaction mixture was stirred overnight at room temperature. Wash with 10% NaHCO ₃ and brine. Purification by column chromatography afforded 0.6 g of a colorless oil in 73% yield. MS (M + H ⁺ ): 295.2; 1 H NMR (400 MHz, CDCl ₃ ):? 8.71-8.70 (d, 1H), 7.98-7.86 (m, 2H), 7.48-7.46 (m, 1H), 5.88-5.77 (m, 1H), 5.55- 5.45 (m, 1H), 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).

189

d. ) 3,3-Dimethyl-1- (pyridine-2-sulfonyl) -2,3,4,7-tetrahydro-1 Nazepine

Pyridine-2-sulfonic acid allyl- (2,2-dimethyl-pent-4enyl) -amide (0.6 g, 2 mmol) was diluted with CH ₂ Cl ₂ (50 ml). After careful degassing with Ar under argon protection, a Grubbs catalyst (0.17 g, 0.2 mmol) was added. The mixture was refluxed for 2 hours before the solvent was removed on a rotary evaporator. The crude product was purified by column chromatography (5% -20% E / H) to give 0.47 g of the title compound in 87% yield. MS (M + H ⁺ ): 267.0; NMR (400 MHz, CDC1 _3): · 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).

e. ) 5,5-Dimethyl-3- (pyridine-2-sulfonyl) -8-oxa-3-azabicyclo [5.1.0] octane

To a solution of the compound of Example 92d (1.2 g, 4.5 mmol) in 50 mL of CH ₂ Cl ₂ was added NaHCO ₃ (2.4 g, 13.5 mmol) and then in portions-MCPBA (1.2 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 4 hours before being treated by washing with 15% NaOH, saturated K ₂ CO _{3 solution} and brine and dried (Na ₂ SO ₄ ) to give 1.0 g of crude product in 79% yield (good enough for use in the next reaction without further purification) MS (M + H ⁺ ): 283.0; ^! H NMR (400 MHz, CDCl ₃ ):? 8.68-8.67 (d, 1H), 8.03-7.87 (m, 2H), 7.49-7.40 (m, 1H), 4.443.89 (q, 1H), 3.62-3.59 (d, 1H), 3.50 (m, 1H), 3.00 (m, 1H), 2.78-2.62 (m, 2H), 2.12-2.06 (m, 1H), 1.52-1.46 (q, 1H), 1.20 (s , 3H), 0.89 (s, 3H).

f. 4-Azido-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol

The 5,5-Dimethyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane of Example 92e (1.2 g, 4.3 mmol) was dissolved in a mixture of 7

190 ml MeOH and 1 ml H ₂ O. NaN ₃ (0.83 g, 13 mmol) and NH ₄ Cl (0.7 g, 13 mmol) were added to the solution. The resulting mixture was refluxed overnight. After removal of MeOH, the residue was diluted with EtOAc and washed with 10% NaHCO ₃ and brine. Purification by column chromatography gave 0.4 g of 4-azido-6,6 dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol (29% yield); MS (M + H ⁺ ): 326.2; ^! H NMR (400 MHz, CDCl ₃ ):? 8.68-8.67 (m, 1H), 8.05-

7.90 (m, 2H), 7.53-7.50 (m, 1H), 3.75-3.60 (m, 3H), 3.49-3.30 (m, 3H),

1.73-1.66 (m, 1H), 1.56-1.52 (d, 1H), 1.07 (s, 3H), 0.99 (s, 3H).

Mr Rücker 4-Amino-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol

The 4-Azido-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol of Example 92f (0.4 g, 1.23 mmol) was dissolved in tetrahydrofuran (50 ml) and H ₂ O (0.2 ml ). PPh ₃ (0.48 g, 1.85 mmol) was added to this solution. The reaction mixture was stirred at 45 ° C overnight. TLC indicated that no starting material remained. The tetrahydrofuran was evaporated in an azeotropic mixture with toluene (2 x). The resulting thick oil was dissolved in MeOH and treated with HCl in ether to adjust to acidic pH. More ether was added and the solution was cloudy. 0.22 g of a white precipitate was isolated from the title compound (45% yield); ¹ H NMR (400 MHz, CD ₃ OD): ·

8.68 (m, 1H), 8.10-7.93 (m, 2H), 7.62 (m, 1H), 3.90 (m, 1H), 3.68 (m, 1H).

3.40-2.90 (m, 4H), 1.82 (m, 1H), 1.53 (d, 1H), 1.05 (s, 6H).

h. ) {(S) -1- [3-Hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid

4-Amino-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol hydrochloride salt of Example 92 g (0.22 g, 0.6 mmol) was dissolved in 5 ml of dimethylformamide. 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 room temperature overnight. Dimethylformamide is removed in deep vacuum. The residue was diluted with EtOAc and washed with H ₂ O, 10% NaHCO ₃ and brine. Purification by column chromatography afforded 0.22 g of the title compound (72% yield); MS (M + H ⁺ ): 512.9; ^X H NMR (400 MHz, CDCl ₃ ):? 8.68-8.67 (d, 1H), 7.977.88 (m, 2H), 7.69-7.64 (m, 1H), 6.62-6.53 (m, 1H), 5.06- 5.00 (m, 1H), 4.03-3.18 (m, 7H), 1.80-1.42 (m, 15H), 1.04-0.92 (m, 12H).

i.) Benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6 dimethyl-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

To {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester of Example 92h (0.22 g, 0.43 mmol) was added HCl / dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at room temperature for 2 hours before the solvents and excess HCl were removed on a rotary evaporator. The resulting white solid was dissolved in 5 ml of dimethylformamide. 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol) were added to the solution. The mixture was stirred at room temperature overnight. The dimethylformamide was then removed and the residue redissolved in EtOAc (50 ml) and washed with 10% NaHCO ₃ (50 ml x 2) and brine (50 ml). Evaporation of the solvent gave 0.26 g of crude product. Purification by column chromatography afforded the title compound 0.15 g in 63% overall yield; MS (M + H ⁺ ): 556.8; ^! H NMR (400 MHz, CDCl ₃ ); · 8.66-8.63 (m, 1H), 7.94-7.11 (m, 10H), 4.72 (m, 1H), 4.01-2.98 (m, 7H),

1.78-1.39 (m, 5H), 1.02-0.85 (m, 12H).

192

j.) Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-6,6-dimethyl-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} - amide

To a solution of benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide of Example 92i (100 mg, 0.18 mmol) in 2 ml of CH ₂ Cl ₂ at room temperature was added Dess-Martin reagent (76 mg, 0.18 mmol). The solution was stirred for 2 hours with 20 ml of CH ₂ Cl _{2 added.} and then washed with NaHCO ₃ and brine. Purification by column chromatography (50% ethyl acetate in hexane) afforded 70 mg of the title compound in 70% yield. MS (M + H ⁺ ): 555.4; NMR (400 MHz, CDC1 _3): · 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, 1H), 4.79-4.69 (m, 2H), 3.80-3.71 (m, 2H), 2.54-

2.50 (d, 1H), 1.92-1.76 (m, 4H), 1.45-1.40 (m, 4H), 1.01-0.91 (m, 9H).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (M + H ⁺ ):

555.2 and the slower eluting diastereomer; MS (M + H ⁺ ): 555.2.

Example 93

Receiving. 5- Methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-N- [3-oxogl- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a.) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 574 (M + H ⁺ ).

193

b.) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 5-methoxybenzofuran-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 93a to give the title compound: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H ), 2.7 (m, 1H), 3.8 (m, 4H), 4.0 (m, 1H),

4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 8H) 8.0-8.2 (m, 2H); MS (EI): 572 (M ⁺ , 30%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; ^! H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (s, 3H), 3.8 (d, 1H) , 4.0 (d, 1H), 4.7 (m, 1H), 4.8 (d, 1H), 5.0 (m, 1H), 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%).

Example 94

Preparation of thieno [3,2-d] thiophene-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] - butyl} amide

a.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl ] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by thieno [3,2b] thiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 566 (M + H ⁺ ).

194

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

Following the procedure of Example 1, it is this exception that uses thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (1-oxy-pyridine) 2-sulfonyl) -azepan-4ylcarbamoyl] -butyl} amide of Example 94a the title compound the ^title:! H NMR (CDCl3): δ 1.0 (1H, 6H), 1.5-2.1 (1H, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (t, 1H) ,

4.5 (t, 1H), 4.7 (t, 1H), 5.0 (t, 1H), 7.4-7.5 (t, 6H), 7.7 (d, 1H), 8.0-8.2 (t, 2H). MS (EI): 564 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; ^X H NMR (CDCI 3): δ 1.0 (m, 6H), 1.5-2.1 (1H, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.8 (d, 1H), 4.0 (d, 1H) ), 4.5 (m, 1H), 4.7 (d, 1H), 5.0 (m, 1H), 7.4-7.5 (m, 6H),

7.7 (d, 1H), 8.0-8.2 (m, 2H); MS (EI): 565 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 565 (M + H ⁺ , 100%).

Example 95

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

a. ) Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid, the title compound is obtained: MS (EI) 556 (M + H ⁺ ).

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

195

Following the procedure of Example 1 with the exception of using quinoxaline-2-carboxylic acid {(S) -3-methyl-1 [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane -4-yl-carbamoyl] butyl} amide of Example 95a, gave the title compound: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m , 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4- 7.5 (m, 2H), 7.9 (m, 1H), 8.0-8.4 (m, 4H, 9.6 (d, 1H); MS (EI): 554 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 555 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 555 (M + H ⁺ , 100%).

Example 96

Preparation of quinoline-2-carboxylic acid {($) - 3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -

a. ) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by quinoline-2-carboxylic acid, the title compound is obtained: MS (EI) 555 (M + H ⁺ ).

b. ) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} amide of Example 96a the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m,

196

2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 10H); MS (EI): 553 (M ^&lt; ^{+ &gt;} , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 554 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 554 (M + H ⁺ , 100%).

Example 97

Preparation of Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl] amide

a. ) Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by thiophene-3 carboxylic acid, the title compound is obtained: MS (EI) 510 (M + H ⁺ ).

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

Following the procedure of Example 1 with the exception of using thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] butyl} amide of Example 97a, gave the title compound: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H) , 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m , 4H), 7.8 (m, 1H), 8.1-8.2 (m, 2H); MS (EI): 508 (M ⁺ , 80%).

Example 98

Preparation of 1H-indole-5-carboxylic acid {(B) -3-methyl-1- [3oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

197

a. 1H-Indole-5-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 1H-indole5-carboxylic acid, the title compound is obtained: MS (EI) 543 (M ⁺ ).

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

Following the procedure of Example 1 with the exception of using 1H-indole-5-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (1-oxy-pyridine-2-sulfonyl) - azepan-4-ylcarbamoyl] butyl} amide of Example 98a, gave the title compound: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 8.6 ( b, 1H); MS (EI): 541 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 542 (M + H ⁺ , 80%) and the slower eluting diastereomer; MS (EI): 542 (M + H ⁺ , 80%).

Example 99

Preparation of benzo [1,3] dioxole-5-carboxylic acid {(S) -3methyl-1- [3-oxo-1 (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

a.) Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl } amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by

198 benzo [1,3] dioxole-5-carboxylic acid, to give the title compound: MS (EI) 548 (M ⁺ ).

B.) Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl } amide

Following the procedure of Example 1 with the exception of using benzo [1,3] dioxole-5-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2 -sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 99a, to give the title compound: NMR (CDCl ₃ ): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H),

4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 6.0 (s, 2H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 546 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer; MS (EI): 547 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 547 (M + H ⁺ , 100%).

Example 100

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

a. ) furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by furoic acid, the title compound is obtained: MS (EI) 494 (M ⁺ ).

b. ) furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxypyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

199

Following the procedure of Example 1 with the exception that furan-2-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] butyl} amide of Example 100a, gave the title compound: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H) , 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 492 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer MS (EI): 493 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 493 (M + H ⁺ , 100%).

Example 101

Preparation of (S) -4-Methyl-2- (2-thiophen-2-yl-acetylamino) pentanoic acid [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-yl] -gamide

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

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by thiophene-2-acetic acid, the title compound is obtained.

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

Following the procedure of Example 1 with the exception of the use of (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) pentanoic acid [3-hydroxy-1- (1-oxy-pyridine) 2-sulfonyl) azepan-4-yl] -amide of Example 101a, the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6Η), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (m, 3H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 522 (M ⁺ , 20%).

200

Example 102

Preparation of 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

a. 1H-Indole-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 1H-indole2-carboxylic acid, the title compound is obtained: MS (EI) 543 (M ⁺ ).

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

Following the procedure of Example 1 with the exception that using 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (1-oxy-pyridine-2-sulfonyl) - azepan-4-ylcarbamoyl] butyl} amide of Example 102a, gave the title compound: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 9.4 ( b, 1H); MS (EI): 541 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 542 (M + H ⁺ , 100%) and the slower eluting diastereomer; MS (EI): 542 (M + H ⁺ , 100%).

Example 103

Preparation of 4-fluoro - {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-carbamoyl] -butyl} -benzamide

a.) 4-Fluoro - {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-carbamoyl] -butyl} -benzamide

201

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 4fluorobenzoic acid, the title compound is obtained: MS (EI) 522 (M ⁺ ).

B.) 4-Fluoro - {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepane-4-carbamoyl] -butyl} -benzamide

Following the procedure of Example 1 with the exception that 4-fluoro - {(S) -3-methyl-1- [3-hydroxy-1- (1-oxypyridine-2-sulfonyl) -azepan-4- is used carbamoyl] -butyl} -benzamide of Example 103a the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H),

3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS (EI): 520 (M ^&lt; ^{+ &gt;} , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 521 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 521 (M + H ⁺ . 100%).

Example 104

Preparation of 5- (2-morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine-2-sulfonyl) -azepan-4- ylcarbamoyl] -butyl} -amide

a.) 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid, the title compound is obtained : MS (EI) 673 (M ⁺ ).

202

B.) 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 1 with the exception of using 5- (2-morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (1 -Oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 104a, gave the title compound: ² H NMR (CDCl ₃ ): δ 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, 1H), 4.5 (m, 3H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H): MS ( EI): 672 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 672 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 672 (M + H ⁺ , 100%).

Example 105

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

a. ) Thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by thiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 510 (M ⁺ ).

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

Following the procedure of Example 1 with the exception that thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} amide 203 from Example 105a, the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 508 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 509 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 509 (M + H ⁺ . 100%).

Example 106

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

a. 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 3methylbenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 558 (M ⁺ ).

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

Following the procedure of Example 1 with the exception of using 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) - azepan-4-ylcarbamoyl] -butyl} -amide from Example 106a to give the title compound: ² H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H ), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS (EI): 556 (M ⁺ , 100%).

204

The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: ^H} NMR (CDC1 _3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 ( s, 3H), 2.7 (t, 1H), 3.8 (d, 1H); 4.1 (d, 1H), 4.7 (t, 1H), 4.7 (d, 1H), 5.0 (t, 1H), 7.0 (t, 2H), 7.3 (t, 2H), 7.4 (t, 4H) , 8.1 (d, 1H), 8.2 (d, 1H); MS (EI): 557 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 557 (M + H ⁺ , 100%).

Example 107

Preparation of 6-methyl-N - {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -nicotinamide

a. 6-Methyl-1 - {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -nicotinamide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 6methyl nicotinic acid, the title compound is obtained: MS (EI) 519 (M ⁺ ).

b. 6-Methyl-N - {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -nicotinamide

Following the procedure of Example 1 with the exception of using 6-methyl-N '[- {(S) -3-methyl-1- [3-hydroxy-1- (1-oxypyridine-2-sulfonyl) - azepan-4-ylcarbamoyl] -butyl} -nicotinamide of Example 107a, the title compound was obtained: ^] H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m , 2H), 2.6 (s, 3H), 2.7 (t, 1H), 3.8 (q, 1H); 4.0 (t, 1H), 4.5 (t, 1H), 4.7 (t, 1H), 5.0 (t, 1H), 7.4-8.0 (t, 3H), 8.1-8.2 (t, 3H), 9.0 ( m, 1H); MS (EI): 517 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 518 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 518 (M + H ⁺ . 100%).

205

Example 108

Preparation of (S) -4-Methyl-2- (2-thiophen-yl-apetylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -butyl } amide

a. ) (S) -4-Methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by thiophene-2-acetic acid, the title compound is obtained: MS (ESI) 508.8 (M + H ⁺ ).

b. ) (S) -4-Methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -butyl} amide

Following the procedure of Example 1 with the exception of using (S) -4-methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) ) -azepan-4-yl] butyl} amide of Example 108a, to give the title compound: MS (ESI) 506.8 (M + H ⁺ ).

Example 109

Preparation of 1H-indole-6-carboxylic acid {(B) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

a. 1H-Indole-6-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 1H-indole-6carboxylic acid, the title compound is obtained: MS (EI) 527 (M + H ⁺ ).

b. 1H-Indole-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception that 1H-indole-6-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (pyridine-2-sulfonyl) -azepan-4- is used of ylcarbamoyl] 206 butyl} amide of Example 109a, to give the title compound: MS (EI) 525 (M + H ⁺ ).

Example 110

Preparation of benzo [1,3] dioxole-5-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

a. ) Benzo [1.3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced with piperic acid, the title compound is obtained: MS (EI) 532.7 (M + H ⁺ ).

b. ) Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [3 oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using benzo [1,3] dioxole-5-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) - azepan-4-ylcarbamoyl] -butyl} -amide of Example 110a, to give the title compound: MS (EI) 530.8 (M + H ⁺ ).

Example 111

Preparation of N, 4-dihydro-2H-benzo [b] [1,4] dioxepine-7carboxylic acid {(B) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} amide

a.) 3,4-Dihydro-2H-benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine) -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 3,4-dihydro-2H-1,5-benzodioxepine-7-carboxylic acid, the title compound is obtained: MS (EI) 576 (M ⁺ ).

207

B.) 3,4-Dihydro-2H-benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine) -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 1 with the exception of using 3,4-dihydro-2H-benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl-1- [3 -Hydroxy-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide to give the title compound: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 4H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.2 (m, 4H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.48.0 (m, 5H), 8.1-8.2 ( m, 2H); MS (EI): 575 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 575 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 575 (M + H ⁺ , 100%).

Example 112

Preparation of 5-methyl-thiophene-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

a. 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5-methylthiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 524 (M ⁺ ).

b. 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example I with the exception of using 5-methyl-thiophene-2-carboxylic acid {(S) -3208 methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2- sulphonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 112a to give the title compound: ^] H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 4H), 8.1-8.2 (m, 2H); MS (EI): 523 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 523 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 523 (M + H ⁺ . 100%).

Example 113

Preparation of 4,5-dibromothiophene-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

a. ) 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 4,5-dibromo-thiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 668 ( M ⁺ ).

b. ) 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 4,5-dibromothiophene-2-carboxylic acid {(S) -3methyl-1 - [3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) azepan-4-ylcarbamoyl] -butyl} amide of Example 113a the title compound the ^title:! H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H),

209

4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 2H); MS (EI): 665 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 114

Preparation of 3,5-dimethyl-isoxazole-4-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4yl carbamoyl] -butyl} amide

a. ) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1 [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxyl. acid is replaced by 3,5dimethyl-isoxazole-4-carboxylic acid to give the title compound: MS (EI) 524 (M + H ⁺ ).

b. ) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl } amide

Following the procedure of Example 1 with the exception of the use of 3,5-dimethyl-isoxazole-4-carboxylic acid {(S) 3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine). 2-sulfonyl) -azepan-4-yl carbamoyl] -butyl} amide of Example 114a the title compound the ^title:! H NMR (CDCl ₃ ): δ 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, 1H ),

3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 521 (M ⁺ , 100%).

Example_115

Preparation of (S) -2- (2-Benzyloxy-acetylamino) -4-methylpentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4yl] -amide

210

a. ) {(S) -1- [3-Hydroxy-1- (4-methoxy-benzenesulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester [(8) -1- (3-Hydroxy- azepan-4-ylcarbamoyl) -3-methyl-butyl] carbamic acid pem-butyl ester (compound 2g, 0.8 g, 2.33 mmol) was dissolved in 1,2-dichloroethane (DCE, 20 ml). Morpholinmethylpolystyrene resin beads (1.26 g, 3.7 mmol / g, Nova) were then added and the solution was shaken for 5 minutes. The p-methoxybenzenesulfonyl chloride (0.48 g, 2.33 mmol) was then dissolved in 1,2-dichloroethane (10 ml) and this solution was added to the reaction mixture. The latter was shaken overnight, filtered and washed with 1,2-dichloroethane (2 x 10 ml) and then with CH ₂ Cl ₂ (10 ml). The combined organic phases were concentrated in vacuo and used in the next reaction without further purification: M + H ⁺ = 514.2.

b. ) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4methoxy-benzenesulfonyl) -azepan-4-yl] -amide-hydrochloride salt {(S) -1- [3-Hydroxy] 1- (4-Methoxy-benzenesulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester (compound 207a, 0.59 g, 1.15 mmol) was dissolved in CH ₂ Cl ₂ (8 ml), then a solution of 4 M HCl in dioxane (8 ml) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, azeotroped twice with toluene (10 ml) in vacuo and used in the next reaction without further purification: M + H ⁺ = 413.8.

c. (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azepan-4-yl] -amide (S) -2- Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4methoxy-benzene-sulfonyl) -azepan-4-yl] -amide-hydrochloride salt

211 (crude product of 115b reaction mixture) was dissolved in MeOH (10 ml) and treated with carbonate-polystyrene resin beads (1.75 g, 2.63 mmol / g, 4.6 mmol) and shaken for 2 hours, filtered was washed with MeOH (10 ml) and the combined organic phases were concentrated in vacuo. The product was then dissolved in 1,2-dichloroethane (2 ml) and morpholinemethylpolystyrene resin grains (0.25 g, 3.77 mmol / g, 0.91 mmol, Nova) were added and the reaction mixture was shaken for 5 minutes. Benzylacetyl chloride (0.081 g, 0.44 mmol) was then added and the reaction mixture was shaken overnight. Grains of trisaminpolystyrene (0.1 g, 3.66 mmol / g, 0.366 mmol) were added and the reaction mixture was shaken for 1.5 h. It was filtered, washed with 1,2-dichloroethane (2 x 10 ml) and CH ₂ Cl ₂ (10 ml) and the combined organic phases were concentrated in vacuo. The crude product was used in the following reaction without further purification: M + H ⁺ = 562.2.

d.) (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-yl] -amide (8) - 2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azepan-4-yl] -amide (compound 207c, 0.24 g, 0.44 mmol) was dissolved in CH ₂ Cl ₂ (5 ml) then Dess-Martin periodinine (0.3 g, 0.7 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (20 ml) and then extracted with 10% aqueous Na ₂ S ₂ O ₅ (10 ml) and then with 10% aqueous NaHCO ₃ (10 ml). with water (10 ml) and brine (10 ml). The combined organic phases were concentrated in vacuo. The residue was purified by HPLC (50:50 ethanol: hexanes, 20 mL / minute, 25 min, WhelkO-1 (R, R) column 21 x 250 mm, UV detection at 280 nm and 305 nm) to give the first eluate under white solid form (47 mg, 43%): MS 560.4 (M + H ⁺ ).

212 ^J H NMR (400 Hz, CDCl ₃ ): δ 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 the second eluting diastereomer: MS 560.2 (M + H ⁺ ).

Preparation of 5- (3-trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -methyl-1- (3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepane- 4-tert-carbamoyl] -butyl amide

a.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane -4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5- (3-trifluoromethyl-phenyl) -furan-2-carboxylic acid, the title compound is obtained: MS ( EI) 638 (M ⁺ ). B_) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using 5- (3-trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1 -Oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 116a, gave the title compound: ^T H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m , 5H), 2.2 (t, 2H), 2.6 (d, 3H), 2.7 (t, 1H), 3.8 (q, 1H); 4.1 (t, 1H), 4.7 (t, 1H), 4.8 (t, 1H), 5.0 (t, 1H), 7.4-8.0 (t, 9H), 8.1-8.2 (t, 2H); MS (EI): 637 (M + H ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 637 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 637 (M + H ⁺ . 100%).

213

Example 117

Preparation of 5-methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-

a. 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5-methyl-2-phenyl-oxazole-4-carboxylic acid, the title compound is obtained: MS (EI) 585 (M ⁺ ).

b. ) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (- 1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 5-methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy) -pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 117a, to give the title compound: Ή NMR (CDCl 3): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H);

4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H); MS (EI): 584 (M + H ^& lt ^{; +} & gt ^; , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 584 (M + H ⁺ , 100%) and the slower eluting diastereomer M8 (E1): 584 (M + H ⁺ . 100%).

Example 118

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} amide

214

a. ) Benzofuran-2-carboxylic acid {(S) -1- (1- (3,4-dimethoxybenzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide

To a solution of benzofuran-2-carboxylic acid {(S) -1- (1 (3,4-dimethoxy-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), and the reaction mixture was stirred until completion of the reaction. : MS (EI) 587 (M ⁺ ).

b. ) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 1 with the exception of the use of benzofuran-2-carboxylic acid {(S) -1- (1- (3,4-dimethoxy-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl} butyl} -amide of Example 118a, gave the title compound: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.5 (d, 1H); 3.7 (t, 6H), 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 8H); MS (EI): 586 (M + H ⁺ , 100%).

Example 1.19

Preparation of benzofuran-2-carboxylic acid {(S) -1- (1- (4-bromo-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

a.) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-6pOMobenzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 118a with the exception that 3,4-dimethoxybenzenesulfonyl chloride is replaced by

4-bromobenzenesulfonyl chloride to give the title compound: MS (EI) 606 (M ⁺ ).

215

b.) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-6poMobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -1- (1- (4bromo-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl } -amide of Example 119a, afforded the title compound: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.5 (d , 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.48.0 (m, 9H); MS (EI): 604 ( M ⁺ , 100%).

Example 120

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1 (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamo] 3-methyl-butyl Damide

a. ) Benzofuran-2-carboxylic acid {(S) -1- [1 (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-hydroxy-azepan-4ylcarbamoyl] -3-methyl-butyl} -amide

Following the procedure of Example 118a with the exception that 3,4-dimethoxybenzenesulfonyl chloride is replaced by benzofurazan-4-sulfonyl chloride, the title compound is obtained: MS (EI) 569 (M ⁺ ).

b. ) Benzofuran-2-carboxylic acid {(S) -1- [1 (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl-butyl} -amide

Following the procedure of Example 1 with the exception of the use of benzofuran-2-carboxylic acid {(S) -1- (l (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-hydroxy-azepane -4ylcarbamoyl] -3-methyl-butyl} -amide of Example 120a, gave the title compound: ^X H NMR (CDCl ₃ ): δ 1.0 (m,

216

6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.7 (m, 1H); 4.1 (m, 1H), 4.7 (m, 2H),

5.2 (m, 1H), 7.4-8.0 (m, 8H); MS (EI): 568 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 121 Preparation of Benzofuran-2-Carboxylic Acid ...... {(S) -1- [1- (3.5-dimethyl-oxazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl- butyl} -amide

a. ) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyloxazole-4-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 118a with the exception that 3,4-dimethoxybenzenesulfonyl chloride is replaced by

3,5-dimethyloxazole-4-sulfonyl chloride, the title compound was obtained: MS (EI) 546 (M ⁺ ).

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

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -1- (1- (3,5-dimethyl-oxazole-4-sulfonyl) -3-hydroxy-azepan-4- of ylcarbamoyl] -3methyl-butyl} -amide of Example 121a, to give the title compound: ³ H NMR (CDCl 3): δ 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, 1H), 4.1 (m, 1H), 4.4 (t, 1H), 4.7 (m, 1H), 5.2 (m, 1H) , 7.4-8.0 (m, 5H); MS (EI): 544 (M ⁺ , 100%).

Example 122

Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

a.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

217

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced with 3methylbenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 542 (M ⁺ ).

B.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4ylcarbamoyl] -butyl} amide of Example 122a, gave the title compound: ¹ H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (d , 3H), 2.7 (m, 1H), 3.8 (m, 1H),

4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 7H); 8.7 (m, 1H); MS (EI): 540 (M ^&lt; ^{+ &gt;} , 100%).

The diastereomeric mixture was separated by HPLC to provide the faster eluting ^{diastereomer:!} H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (t, 1H), 3.8 (d, 1H) ; 4.1 (d, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 7H);

8.7 (m, 1H); MS (EI): 541 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 541 (M + H ⁺ , 100%).

Example 123 Preparation of Thieno [3.2-6] Thiophene-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-47ylcarbamoyl] r butyl} amide

a.) Thieno [3,2-5] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by thieno [3,2218

B] Thiophene-2-carboxylic acid, to give the title compound: MS (EI) 550 (M ⁺ ).

B.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception of using thieno [3,2-5] thiophene-2-carboxylic acid {(S) -3methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) ) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 123a to give the title compound: H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (m, 1H); 4.1 (m, 1H),

4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (m, 1H); MS (EI): 548 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.7 (t , 1H), 3.8 (d, 1H); 4.1 (d, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (d, 1H); MS (EI): 549 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 549 (M + H ⁺ , 100%).

Example 124

Preparation of 5-tert-butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridin-2su) Piponyl) -azepian-4-ylcarbamoyl] -butyl} amide

a.) 5-N-N-Butyl-3-methyl-thieno [3,2-0] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine) -2-sulfonyl) azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5-tert-butyl 3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid, the compound is obtained in the title: MS (EI) 620 (M ⁺ ).

219

b.) 5- (7-Tert-Butyl-3-methyl-thieno [3,2-d] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 1 with the exception of using 5-777 N- (77-butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (pyridine-2sulfonil) azepan-4-ylcarbamoyl] -butyl} amide of Example 124a, the title compound the ^title:! H NMR (CDCl ₃ ): δ 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, 1H) , 3.8 (m, 1H); 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 4H);

8.7 (m, 1H); MS (EI): 618 (M ⁺ , 100%).

Example 125

Preparation of 5-methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-p-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide

a. 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5-methyl-2-phenyl-oxazole-4-carboxylic acid, the title compound was obtained: MS (EI) 569 (M ⁺ ).

b. 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (- pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 5-methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridin-2 -sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 125a, gave the title compound: Ή NMR (CDCl ₃ ): δ 1.0 (m,

220

6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, 1H), 2.6 (m, 3H), 3.8 (m, 1H);

4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (m, 1H); MS (EI): 567 (M ⁺ , 100%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 568 (M + H ⁺ , 100%) and the slower eluting diastereomer MS (EI): 568 (M + H ⁺ . 100%).

Example 126

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4ylcarbamoyl] -butyl} amide

a. 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid, the title compound was obtained: MS (EI) 623 (M ⁺ ).

b. 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 1 with the exception of using 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridin-2 -sulfonyl) azepan-4-ylcarbamoyl] -butyl} -amide of Example 126a, to give the title compound: ¹ H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (m, 1H); 4.1 (m, 1H),

4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (m, 1H); MS (EI): 621 (M ^&lt; ^{+ &gt;} , 100%).

221

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 622 (M + H ⁺ , 100%) and the slower eluting diastereomer: MS (EI): 622 (M + H ⁺ , 100%).

Example 127

Preparation of quinoline-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amyl

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with 2-quinolinecarboxylic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 475.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 8.65 (d, 1H), 8.35-8.28 (q, 2H), 8.20-8.18 (d, 1H), 7.91-7.89 (d, 1H), 7.80-7.78 ( t, 1H), 7.67-7.65 (t, 1H), 7.10 (d, 1H), 5.08 (m, 1H), 4.73 (m, 1H), 4.56-

4.51 (d, 1H), 4.00 (m, 1H), 3.67-3.62 (d, 1H), 2.91 (s, 3H), 2.70 (m, 1H), 2.32-2.10 (m, 2H), 1.95-1.40 ( m, 5H), 1.02-1.00 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 475.2.

Example 128 Preparation of 1-methyl-1H-indole-2-carboxylic acid [(S) -1- (1methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with N-methyl-indole-2-carboxylic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 477.2; ^! 1 H NMR (400 MHz, CDCl ₃ ):? 7.65-7.63 (d, 1H), 7.39-7.33 (m, 2H), 7.17-7.14 (t, 1H), 6.98-

6.95 (m, 2H), 6.65 (d, 1H), 5.08 (m, 1H), 4.68 (m, 1H) 4.56-4.52 (d, 1H), 4.03 (m, 4H), 3.67-3.63 (d, 1H) ), 2.92 (s, 3H), 2.71 (m, 1H), 2.32-2.10 (m,

222

2H), 1.95-1.40 (m, 5H), 1.02-1.00 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 477.2.

Example 129

Preparation of furan-2-carboxylic acid 1 [(5) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butylcarbamoyl] methyl} -amide

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with N- (2-furan-carbonyl) glycine, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 471.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 7.50 (m, 1H, 7.15 (m, 1H), 7.05 (m, 1H), 6.90 (d, 1H), 6.55 (m, 2H), 5.08 (m. 1H), 4.55 (m, 2H), 4.12 (m, 2H), 4.05 (m, 1H), 3.70 (d, 1H), 2.92 (s, 3H).

2.75 (m, 1H), 2.20-1.40 (m, 7H), 0.95 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 471.4.

Example 130

Preparation of 5-methoxybenzofuran-2-carboxylic acid [(S) -1 (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 494.2; ^! 1 H NMR (400 MHz, CDCl ₃ ):? 7.42-7.40 (d, 2H), 7.08-6.94 (m, 4H), 5.10 (m, 1H), 4.71 (m, 1H), 4.56-4.52 (d, 1H) ), 4.02 (m, 1H), 3.86 (s, 3H), 3.68-3.63 (d, 1H), 2.92 (s, 3H), 2.72 (m, 1H), 2.30-1.15 (m, 2H), 195- 1.40 (m, 5H), 0.99 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 494.2.

223

Example 131

Preparation of quinoxaline-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amip

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 476.2; ^T H NMR (400 MHz, CDC1 _3): · 9.66 (s, IH ), 8.38 (d, IH), 8.20-8.18 (m, 2H), 7.88 (m, 2H), 7.01 (d, IH), 5.10 (m, 1H), 4.77 (m, 1H), 4.57-4.52 (d, 1H), 4.08-4.00 (m, 1H), 3.69-3.64 (d, 1H), 2.92 (s, 3H), 2.71 (m , 1H), 2.42-2.15 (m, 2H), 1.95-1.42 (m, 5H), 1.02-1.01 (d, 6H); and a second eluting diastereomer: MS (M + H ⁺ ):

476.2.

Example 132

Preparation of 5- (4-chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide

a. ) 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(3) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5- (4-chlorophenyl) -2-furoic acid, the title compound is obtained: MS (EI) 590 (M + H ⁺ ).

b. ) 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(BDZ-methyl1- [3-oxo-1- (- pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception that 5- (4-chloro-phenyl) -furan-2-carboxylic acid is used

224 {(S) -3-Methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide of Example 132a, the title compound was obtained: NMR (CDCI3 ): δ 1.0 (m,

6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),

4.7 (m, 2H), 5.0 (m, 1H), 6.7 (m, 1H), 7.2 (m, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.7 (m, 2H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 587 (M ⁺ , 80%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (E1): 587 (M + H ⁺ , 100%) and the slower eluting diastereomer: MS (EI): 587 (M + H ⁺ , 100%).

Example 133

Preparation of (S) -2- [2- (4-Methoxy-phenyl) -apetylamino] -4-methylpentanoic acid (1-methanesulfonyl-3-oxo-azepan-4-yl) -amide

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 4-methanesulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 2- (4-methoxyphenyl) -acetic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 468.2; ^T H NMR (400 MHz, CDCI3): · 7.19-7.17 ( d, 2H), 6.90-6.88 (d, H), 5.83-5.81 (d, 1H), 5.00 (m, IH), 4.53-4.40 (m , 2H), 4.03-3.99 (m, 1H), 3.81 (s, 3H), 3.66-3.61 (d, 1H), 3.53 (s, 2H), 2.91 (s, 3H), 2.73 (t, 3H). 2.22-2.10 (m, 2H), 1.99 (m, 1H), 1.62-1.35 (m, 4H), 0.90-0.88 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 468.2.

Example 134 Preparation of Quinoline-2-Carboxylic Acid {] (S) -1- [1- (2-Thianobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 2-cyanobenzene225 sulfonyl chloride and benzofuran-2-carboxylic acid is replaced by quinoline-2-carboxylic acid, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 562.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 8.65 (d, 1H), 8.48-8.40 (q, 2H), 8.25-8.10 (q, 2H), 7.91-

7.65 (m, 6H); and a second eluting diastereomer: 7.12 (d, 1H), 5.10 (m, 1H), 4.73 (m, 1H) 4.61-4.56 (d, 1H), 4.20 (m, 1H), 3.73-3.68 (d, 1H) , 2.80 (m, 1H), 2.27 (m, 2H), 1.91-1.40 (m, 5H), 1.03-1.01 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 5.62.2.

Example 135

Preparation of 1-methyl-1H-indole -2-carboxylic acid {[(S) -1 [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by N-methyl-indole-2-carboxylic acid to give the compound indicated in the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 564.2; ^! 1 H NMR (400 MHz, CDCl 3):? 8.13 (d, 1H), 7.89 (d, 1H), 7.77-7.67 (m, 3H), 7.38-7.16 (m, 4H), 6.97 (s, 1H), 6.70 (d, 1H), 5.05 (m, 1H), 4.70-

4.60 (m, 1H), 4.55-4.50 (d, 1H), 4.07 (d, 1H), 4.05 (s, 3H), 3.76-3.71 (d, 1H), 2.75 (m, 1H), 2.30 (m. 2H), 2.00-1.45 (m, 5H), 1.00 (d, 6H); and a second eluting diastereomer: ms (m + H ⁺ ) 564.2.

Example 136 Preparation of Furan-2-Carboxylic Acid ({(S) -1- [1- (2-Cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl carbamoyl} -methyl) -amide

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 2226 cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by N- (2-furan-carbonyl) -glycine to give the compound indicated in the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ):

558.2; ^! 1 H NMR (400 MHz, CDCl ₃ ): δ 8.14-8.12 (d, 1H), 7.91-7.90 (d, 1H), 7.80-7.72 (m, 2H), 7.48 (s, 1H), 7.14 (d, 2H) ), 6.98 (d, 1H), 6.80 (d, 1H), 6.52-6.51 (t, 1H), 5.03 (m, 1H), 4.60-4.53 (m, 2H), 4.17-4.14 (m, 3H).

3.74-3.69 (d, 1H), 2.80 (m, 1H), 2.25 (m, 2H), 2.00-1.40 (m, 5H), 1.03-1.01 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 558.2.

Example 137

Preparation of 5-methoxybenzofuran-2-carboxylic acid {(S) 1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with 5-methoxybenzofuran-2-carboxylic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ):

581.4; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15-8.13 (d, 1H), 7.92-7.90 (d,

1H), 7.81-7.74 (m, 2H) 7.42-7.74 (m, 2H), 7.08-7.03 (m, 3H), 6.96 (d, 1H).

5.10 (m, 1H), 4.72-4.60 (m, 2H), 4.17 (d, 1H), 3.85 (s, 3H), 3.75-3.70 (d,

1H), 2.83-2.76 (t, 1H), 2.27 (m, 2H), 1.92-1.51 (m, 5H), 1.92-1.51 (m, 5H), 1.02-1.01 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ )

5.12.

Preparation of quinoxaline-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl227

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 563.2; ^! H NMR (400 MHz, CDCl ₃ ):? 9.65 (s, 1H), 8.40 (m, 1H), 8.22-8.10 (m, 3H), 7.90-7.22 (m, 5H), 7.00 (d, 1H). 5.10 (m, 1H), 4.75 (m, 1H), 4.65-4.60 (d, 1H), 4.20-

4.10 (m, 1H), 3.72-3.70 (d, 1H), 2.70 (m, 1H), 2.38 (m, 2H), 1.95-1.40 (m, 5H), 1.02 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ )

563.2.

Example 139

Preparation of (S) -2- [2- (4-Methoxy-phenyl) -attetylamino) -4-methylpentanoic acid [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4yl] -amide

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 2- (4-methoxyphenyl) -acetic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 555.2; ^T H NMR (400 MHz, CDCI3): · 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, 1H), 5.02 (m, 1H), 4.59-4.55 (d, 1H), 4.45-4.42 (m, 1H), 4.18-4.15 (m, 1H), 3.82 (s , 3H), 3.72-3.67 (d, 1H), 3.53 (s, 2H), 2.82-2.79 (t, 1H), 2.22 (m, 2H), 1.92 (m, 1H), 1.60-1.30 (m, 4H) ); and second eluting diastereomer: MS (M + H ⁺ ) 555.2.

Example 140

Preparation of quinopine-2-carboxylic acid {[(S) -1- [1- (4methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl228

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with 4-methoxybenzenesulfonyl chloride and benzofuran-2-carboxylic acid, substituting 2-quinoline carboxylic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 567.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 8.72-8.61 (d, 1H), 8.35-8.28 (q, 2H) 8.21-8.18 (d, 1H), 7.91-7.60 (m, 5H), 7.10-6.99 (m, 3H), 5.05 (m, 1H), 4.73 (m, 1H) 4.59-4.52 (d, 1H), 4.00 (m, 1H), 3.88 (s, 3H), 3.45-3.38 (d, 1H) , 2.42 (m, 1H), 2.30-

1.35 (m, 7H), 1.03-1.01 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 567.2.

Example 141 Preparation of 1-Methyl-1H-Indole-2-carboxylic acid {[(S) -1 [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 Follow the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid being replaced by N-methyl-indole-2-carboxylic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 569.2; ² H NMR (400 MHz, CDCl ₃ ):? 7.78-7.72 (d, 2H), 7.70-7.65 (d, 1H), 7.42-7.30 (m, 2H), 7.17-7.14 (t, 1H), 7.05- 6.95 (m, 4H), 6.65 (d, 1H), 5.05 (m, 1H), 4.70-4.50 (m, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 3.45-3.40 (d. 1H), 2.45 (m, 1H), 2.30-2.10 (m, 2H), 1.90-1.35 (m, 6H) and a second eluting diastereomer: 1.00 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 569.2.

Example 142

Preparation of furan-2-carboxylic acid ({(S) -1- [1- (4-methoxy229 benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylcarbamoyl} -methyl) -amide

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by N- (2-furan-carbonyl) -glycine to give the title compound in the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 563.2; ² H NMR (400 MHz, CDCl ₃ ):? 7.74-7.72 (d, 2H), 7.47 (s, 1H), 7.15-6.99 (m, 4H), 6.91 (d, 1H).

6.70 (d, 1H), 6.52-6.51 (m, 1H), 5.01 (m, 1H), 4.53-4.49 (m, 2H), 4.17-4.14 (m, 2H), 4.00-3.90 (m, 1H). 3.88 (s, 3H), 3.45-3.41 (d, 1H), 2.47 (m, 1H),

2.17 (m, 2H), 1.85-1.40 (m, 5H) 0.95 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 563.2.

Example 143

Preparation of 5-methoxybenzofuran-2-carboxylic acid {] (S) 1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 5-methoxybenzofuran-2-carboxylic acid to give the compound indicated in. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 586.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 7.75-7.73 (d, 2H), 7.42-7.40 (m, 2H), 7.08-6.99 (m, 5H), 6.91 (d, 1H), 5.05 (m. 1H), 4.70-4.55 (m, 2H), 4.05-4.00 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.45-3.40 (d, 1H), 2.50-2.40 (m. 1H), 2.30-2.10 (m, 2H), 1.90-1.35 (m, 5H), 1.01 (m, 6H): and a second eluting diastereomer: MS (M + H ⁺ ) 586.2.

Example 144

Preparation of quinoxaline-2-carboxylic acid {[(S) -1- [1- (4230 methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3Z-methyl Following the procedure of Example 75, except that thiazole-2-sulfonyl chloride is replaced by 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid to give the title compound. The residue was purified by HPLC. The first elution is a diastereomer; MS (M + H ⁺ ): 568.2; ^X H NMR (400 MHz, CDCl ₃ ):? 9.66 (s, 1H), 8.40-8.35 (m, 1H), 8.19 (m, 2H), 7.88 (m, 2H), 7.75-7.73 (d, 2H) , 7.02-6.90 (m, 3H), 5.10-5.05 (m, 1H), 4.75 (m, 1H), 4.60-4.55 (d, 1H), 4.05-3.95 (m, 1H), 3.89 (s, 3H) , 3.45-3.41 (d, 1H),

2.45 (m, 1H), 2.30-2.10 (m, 2H), 1.95-1.40 (m, 5H), 1.04-1.02 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 568.2.

Example 145

Preparation of (S) -2- [2- (4-Methoxy-phenyl) -apetylamino) -4-methylpentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-yl] -amide

Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid, substituting 2- (4-methoxyphenyl) -acetic acid to give the compound indicated in the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 560.4; ^T H NMR (400 MHz, CDCI3): · 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 , 1H), 5.81 (d, 1H), 4.99 (m, 1H), 4.55-4.44 (m, 2H), 3.97 (m, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.53 ( s, 2H), 3.43-3.38 (d, 1H), 2.43 (t, 1H), 2.14 (m, 2H), 1.85-1.35 (m, 5H), 0.90-0.89 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 560.2.

231

Example 146

Preparation of 1-methyl-1H-indole-2-carboxylic acid {[(S) -1- [1 (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 75 with the exception of replacing thiazole-2-sulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid being replaced by N-methyl-indole-2-carboxylic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 557.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 7.84-7.80 (m, 2H), 7.66-7.65 (d, 1H), 7.40-7.14 (m, 5H), 6.95 (m, 2H), 6.65-6.63 ( d, 1H), 5.07 (m, 1H),

4.68-4.55 (m, 2H), 4.04 (s, 3H), 3.48-3.43 (d, 1H), 2.49 (m, 1H), 2.25 (m, 2H), 1.89-1.38 (m, 6H); and a second eluting diastereomer: 1.01 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 557.4.

Preparation of furan-2-carboxylic acid ({(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylcarbamoyl} -methyl) -amide

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by N- (2-furan-carbonyl) glycine to give the compound indicated in the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 551.4; ^T H NMR (400 MHz, CDC1 _3): 7.81 (m, 2H), 7.48 (s, IH) , 7.27-7.16 (m, H), 7.05 (m, IH) , 6.90 (d, IH), 6.52 ( m, 2H), 5.00 (m, 1H), 4.60-4.48 (m, 2H), 4.14 (m, 2H), 4.00-3.90 (d, 1H), 3.48-3.44 (d, 1H), 2.50 (m. 1H), 2.20 (m, 2H), 1.90-1.40 (m, 5H), 0.95 (m, 6H): and a second eluting diastereomer: MS (M + H ⁺ )

551.2.

232

Preparation of 5-methoxybenzofuran-2-carboxylic acid {] (S) ~ 1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amyl

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 5-methoxybenzofuran-2-carboxylic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 574.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 7.84-7.81 (m, 2H), 7.42-7.40 (m, 2H), 7.27-7.22 (m, 2H), 7.08-7.04 (m, 3H), 6.93 ( d, 1H), 5.10-5.02 (w, 1H), 4.69-4.55 (m, 2H), 4.05-4.00 (m, 1H), 3.86 (s, 3H), 3.47-3.43 (d, 1H).

2.40 (m, 1H), 2.24 (m, 2H), 1.90-1.40 (m, 5H), 1.01 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 574.2.

Example 149

Preparation of quinoxaline-2-carboxylic acid {[(S) -1- [1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 556.2; ^! H NMR (400 MHz, CDCl3):? 9.66 (s, 1H), 8.40-8.35 (d, 1H), 8.21-8.18 (m, 2H), 7.90-

7.81 (m, 4H), 7.27-7.22 (m, 2H), 6.97 (d, 1H), 5.10-5.02 (m, 1H), 4.75 (m, 1H), 4.59-4.55 (d, 1H), 4.05- 4.39 (m, 1H), 3.48-3.44 (d, 1H), 2.49 (m, 1H), 2.32-2.10 (m, 2H), 1.90-1.40 (m, 5H), 1.03-1.02 (d, 6H): and second eluting diastereomer: MS (M + H ⁺ ) 556.2.

233

Example 150

Preparation of (S) -2- [2- (4-Methoxy-phenyl) -acetylamino) -4-methylpentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4yl] -amide

Following the procedure of Example 75 with the exception that replacing thiazole-2-sulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 2- (4-methoxyphenyl) -acetic acid to give the title compound the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 548.2; ^X H NMR (400 MHz, CDCl ₃ ):? 7.83-7.80 (m, 2H), 7.27-7.17 (m, 4H), 6.90-6.88 (d, 3H), 5.85 (s, 1H), 4.98 (m. 1H), 4.55-4.43 (m, 2H), 4.00-3.97 (m, 1H), 3.81 (s, 3H), 3.53 (s, 2H), 3.45-3.41 (d, 1H), 2.48 (t, 1H) , 2.17-2.14 (t, 2H), 1.90-

1.30 (m, 5H), 0.90-0.88 (d, 6H) and second eluting diastereomer: MS (M + H ⁺ ): 548.4.

Example 151

Preparation of benzofuran-2-carboxylic acid - {(S) -1- [1- (3x-turo-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

a.) {(S) -1- [1- (3-Chloro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 2 g (2.50 g, 7.29 mmol) in 1,2-dichloroethane (100 ml) was added P-NMM (4.0 g) and 3-chlorobenzenesulfonyl chloride (1.85 g, 8.75 mmol). After shaking at room temperature, the solution was filtered overnight. The filtrate was concentrated to give the title compound as a white solid (3.13 g, 83.3%). MS: 539.78 (M + Na) &lt; ⁺ &gt;.

234

b. ) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-chlorobenzenesulfonyl) -3-hydroxy-azepan-4-yl] -amide

HCl (4M in dioxane) (10 ml) was added to a stirred solution of the compound of Example 151a (10 g, 1.93 mmol) in methanol (10 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of the white solid (0.68 g, 1.50 mmol, 78%) in methanol (37 ml) was added P-CO ₃ (2.85 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.59 g, 1.42 mmol, 95%). MS: 417.86 (M + H) ⁺ .

c. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

To a solution of the compound of Example 15 lb (0.14 g, 0.33 mmol) in CH ₂ Cl ₂ (20 mL) was added benzofuran-2-carboxylic acid (0.81, 0.50 mmol), 1-hydroxybenzotriazole (0.77 g, 0.57 mmol) and P-EDC (0.67 g, 1 mmol / g) in CH ₂ Cl ₂ (10 mL). After shaking at room temperature overnight, the solution was treated with trisamine (0.45 g, 3.75 mmol / g). After shaking for another 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (122 mg, 65%). MS (ESI): 562.2 (M + H) ⁺ .

d. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

To a stirred solution of the compound of Example 151c (122 mg, 0.22 mmol) in dichloromethane (4 mL) was added a reagent of DessMartin (185 mg, 0.44 mmol). After stirring at room

235 temperature for 2 hours was added successively to a solution of sodium thiosulphate solution (2 mL of 10% solution in water) and saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was extracted with dichloromethane (2 x). The organic phases are combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluted diastereomer as a white solid (62.7 rag, 51.6%), MS (ESI): 560.2 (M + H) ⁺ and the second eluted diastereomer as a white solid ( 40.2 mg, 33.1%). MS (ESI): 560.2 (M + H) ⁺ .

Example 152

Preparation of 5-methoxybenzofuran-2-carboxylic acid - {(8) 1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 151c-d with the exception that the benzofuran-2-carboxylic acid of Example 151c is replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluted diastereomer as a white solid (64.4 mg, 50.3%); MS (ESI): 590.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (44.4 mg, 34.7%): MS (ESI): 590.2 (M + H) ⁺ .

Example 153

Preparation of 7-methoxybenzofuran-2-carboxylic acid - {(S) 1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 Follow the procedure of Example 151c-d with this except that the benzofuran-2-carboxylic acid of Example 151c is replaced by 7-methoxybenzofuran-2-carboxylic acid,

236 afforded the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (51.1 mg, 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) ⁺ .

Example 154

Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-zepan-4-ylcarbamoyl] -3 Following the procedure of Example 151c -d with the exception that the benzofuran-2-carboxylic acid of Example 151c is replaced by 5,6-dimethoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting diastereomer under white solid (51.1 mg, 39.9%), MS (ESI): 622.2 (M + H) ⁺ and the second eluting diastereomer as white solid (36.7 mg, MS (ESI):

622.2 (M + H) ⁺ .

Example 155

Preparation of 3-methylbenzofuran-2-carboxylic acid - {(S) -1 [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 151c-d with the exception that the benzofuran-2-carboxylic acid of step 151c is replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluted diastereomer as a white solid (78.6 mg, 63.1%), MS (ESI): 574.2 (M + H) ⁺ and the second eluted diastereomer as a white solid (40.7 mg, 32.6%). MS (ESI): 574.2 (M + H) ⁺ .

237

Example 156

Preparation of benzo [b] thiophene-2-carboxylic acid - {(S) -1- (1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 151c-d with the exception that the benzofuran-2-carboxylic acid of step 151c is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving 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) ⁺ .

Example 157

Preparation of 1-methyl-1H-indole-2-carboxylic acid - {(S) -1- (1 (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure from Example 151c-d with the exception that the benzofuran-2-carboxylic acid of step 151c is replaced by 1-methyl-indole-2-carboxylic acid, the title compound is separated, which is separated by HPLC to give the first eluting agent. diastereomer as white solid (28.5 mg, 22.9%), MS (ESI): 573.2 (M + H) ⁺ and the second eluting diastereomer as white solid (28.5 mg, 22.9%). ): 573.2 ( + H) ^+.

Example153

Preparation of quinoxaline-2-carboxylic acid - {(B) -1- (1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 151c-d with the exception that the benzofuran-2-carboxylic acid of step 151c is replaced by quinoxaline-2-carboxylic acid,

238 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 diastereomer under white solid form (43.2 mg, 34.8%), MS (ESI): 572.2 (M + H) ⁺ .

Example 159

Preparation of benzofuran-2-carboxylic acid - {(S) -1- [1- (2fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

a. ) {(S) -1- [1- (2-Fluoro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 2 g (1.03 g, 3.00 mmol) in 1,2-dichloroethane (20 ml) was added P-NMM (1.65 g, 3.64 mmol / g) and 2-fluorobenzenesulfonyl chloride (0.70 g, 3.60 mmol). . After shaking at room temperature, the solution was filtered overnight. The filtrate was concentrated to give the title compound as a white solid (1.13 g, 75.1%): MS: 523.88 (M + Na) ⁺ .

b. ) (S) -2-Amino-4-methyl-pentanoic acid [1- (2-fluoro-benzenesulfonyl) -3-hydroxy-azepan-4-yl] -amide

HCl (4M in dioxane) (15 ml) was added to a stirred solution of the compound of Example 159a (1.13 g, 2.25 mmol) in methanol (15 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of the white solid (1.11 g, 2.60 mmol, 75%) in methanol (50 ml) was added P-CO 3 (5.70 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound under

239 white solid form (0.868 g, 2.16 mmol, 96%): MS: 401.96 (M + H) ⁺ .

c. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (2-fluorobenzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

To a solution of the compound of Example 159b (0.11 g, 0.26 mmol) in CH ₂ Cl ₂ (10 mL) was added benzofuran-2-carboxylic acid (64.7 mg, 0.39 mmol), 1-hydroxybenzotriazole (61.1 g, 0.45 mmol) and P -EDC (0.53 g, 1 mmol / g) in CH ₂ Cl ₂ (10 mL). After shaking at room temperature overnight, the solution was treated with trisamine (0.35 g, 3.75 mmol / g). After shaking for another 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (103.5 mg, 70%): MS (ESI) 546.2 (M + H) ⁺ .

d. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (2-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

Dess-Martin reagent (164.7 mg, 0.39 mmol) was added to a stirred solution of the compound of Example 159c (103.5 mg, 0.19 mmol) in dichloromethane (4 mL). After stirring at room temperature for 2 hours, a solution of sodium thiosulphate (2 mL of 10% solution in water) and saturated aqueous sodium bicarbonate (2 mL) was added sequentially to the solution. The aqueous phase was extracted with dichloromethane (2 x). The organic phases are combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give 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 (20.7 mg , 20.0%) MS (ESI) 544.4 (M + H) ⁺ .

240

Example 160

Preparation of 5-methoxybenzofuran-2-carboxylic acid - {(8) -

1- [1- (2-Fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 159c-d with the exception that the benzofuran-2-carboxylic acid of step 159c is replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC yielding first eluting diastereomer as white solid (48.3 mg, 59.2%) MS (ESI): 574.2 (M + H) ⁺ and second eluting diastereomer as white solid (24.2 mg, 29.6%) MS (ESI) ): 574.2 (M + H) ⁺ .

Example 161

Preparation of 7-methoxybenzofuran-2-carboxylic acid - {(8) 1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 Following the procedure of Example 159c-d with this except that the benzofuran-2-carboxylic acid of step 159c is replaced by 7-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting 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 mg, 33.9%).

Example 162

Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(5) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl-butyl} -amide

Following the procedure of Example 159c-d with the exception that benzofuran-2-carboxylic acid from step 159c

241 is replaced by 5,6-dimethoxybenzofuran-2-carboxylic acid to give the title compound which is separated by HPLC to give the first eluting diastereomer: MS (ESI) 606.4 (M + H) ⁺ and the second eluting diastereomer as a white solid MS (ESI) 606.4 (M + H ⁺ ).

Example 163

Preparation of 3-methylbenzofuran-2-carboxylic acid - {(S) -1 (1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 159c-d with the exception that the benzofuran-2-carboxylic acid of step 160c is replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC affording the first eluting diastereomer as a white solid (50.5 mg, 63.7%): MS (ESI) 558.2 and the second eluting diastereomer as a white solid (20.6 mg); MS 558.2 (M + H) ⁺ .

Example 164

Preparation of benzo [b] thiophene-2-carboxylic acid - {(S) -1- (1- (2fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 159c- d with the exception that the benzofuran-2-carboxylic acid of step 159c is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting diastereomer in the form of a white solid (52.5 mg, 65.9%): MS (ESI) 560.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (20.7 mg, 26.0%): MS (ESI) 560.2 (M + H) ⁺ .

242

Example 165 Preparation of 1-methyl-1H-indole-2-carboxylic acid - {(S) -1- [1 (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] 2 H 2-methyl butyl} -amide

Following the procedure of Example 159c-d with the exception that the benzofuran-2-carboxylic acid of step 159c is replaced by 1-methyl-indole-2-carboxylic acid, the title compound is obtained, which is separated by HPLC , giving the first eluting diastereomer as a white solid (51.4 mg, 64.9%): MS (ESI) 557.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (21.0 mg, 26.5%); MS 557.2 (M + H) ⁺ .

Example 166

Preparation of (S) -4-Methyl-2- (1-oxy-pyridine-2-sulfonylamino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] amide

a. ) (S) -4-Methyl-2- (1-oxy-pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of the compound of Example 28a (0.1 g) in dichloromethane (10 mL) and saturated NaHCO ₃ was added dropwise over 3 minutes 2-pyridine-sulfonyl chloride-N-oxide (0.9 mL). The reaction mixture was stirred at room temperature for 30 minutes. Treatment and column chromatography gave 9.2 mg of the title compound: MS (ESI) 541 (M + H ⁺ ).

b. ) (S) -4-Methyl-2- (1-oxy-pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception that using the compound of Example 166a, the title compound was obtained: MS (ESI) 539 (M + H ⁺ ).

243

Example 167 Preparation of -quinoxaline-2-carboxylic acid - {(S) -1- [1- (2 = fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 159c-d with the exception that the benzofuran-2-carboxylic acid of step 159c is replaced by quinoxaline-2-carboxylic acid, the title compound is purified, which is purified by HPLC affording the first eluting agent. diastereomer as a white solid (49.7 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) ⁺ .

Example 168

Preparation of 5-methoxybenzofuran-2-carboxylic acid - {(8) 3-methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 75a-d with the exception that the 2-thiazolesulfonyl chloride of Example 75a is replaced with 2-thiophenesulfonyl chloride and the benzofuran-2-carboxylic acid of step 75c is replaced by the 5-methoxybenzofuran-2 carboxylic acid, indicated in the title, 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 substance (21.6 mg, 20.0%) MS (ESI): 562.2 (M + H) ⁺ .

Example 169

Preparation of 7-methoxybenzofuran-2-carboxylic acid - {(8) 3-methyl-1- (3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

244

Following the procedure of Example 168 with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by 7methoxybenzofuran-2-carboxylic acid, the title compound is obtained which is purified by HPLC to give the first eluting diastereomer under white solid form (88 mg, 80%): MS (ESI) 562.2 (M + H) ⁺ and the second eluting diastereomer as white solid (18 mg, 16%) MS (ESI): 562.2 (M + H) ⁺ .

Example 170

Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 168 with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by 5,6 dimethoxybenzofuran-2-carboxylic acid, the title compound is purified, which is purified by HPLC to give the first elution diastereomer MS (ESI) 594.2 (M + H) ⁺ and the second eluting diastereomer.

Example 171

Preparation of 3-methylbenzofuran-2-carboxylic acid - {(S) -3methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] Following the procedure of Example 168 with this except that 5-methoxybenzofuran-2-carboxylic acid is replaced by 3methylbenzofuran-2-carboxylic acid, the title compound is purified, which is 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) ⁺ .

245

Example 172

Preparation of benzo [b] thiophene-2-carboxylic acid - {(S) -3methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] Following the procedure of Example 168 hereby except that 5-methoxybenzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained, which is 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) ⁺ .

Example 173

Preparation of 1-methyl-1H-indole-2-carboxylic acid - {(S) -3methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 168 with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by 1methyl-indole-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting white solid diastereomer (35.8 mg, 34.0%): MS (ESI) 545.2 (M + H) ⁺ and the second eluting white solid diastereomer (45.8 mg, 43%): MS (ESI) 545.2 (M + H) ⁺ .

Example 174

Preparation of quinoxaline-2-carboxylic acid - <(S) -3-methyl-1 [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 168 with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give

246 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) ⁺ .

Example 175

Preparation of benzofuran-2-carboxylic acid - {(B) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3_-methyl.) {(8) -1- [1 - (3-Chloro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 2g (2.50 g, 7.29 mmol) in 1,2-dichloroethane (100 ml) was added P-NMM (4.0 g) and 4-chlorobenzenesulfonyl chloride (1.85 g, 8.75 mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to give the title compound as a white solid (3.13 g, 83.3%). MS: 539.78 (M + Na) &lt; ⁺ &gt;.

b.) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-chlorobenzenesulfonyl) -3-hydroxy-azepan-4-yl] -amide

HCl (4M in dioxane) (10 ml) was added to a stirred solution of the compound of Example 175a (1.0 g, 1.93 mmol) in methanol (10 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of the white solid (0.68 g, 1.50 mmol, 78%) in methanol (37 ml) was added P-CO ₃ (2.85 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.59 g, 1.42 mmol, 95%): MS: 417.86 (M + H) ⁺ .

247

c. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

To a solution of the compound of Example 175b (0.14 g, 0.335 mmol) in CH ₂ Cl ₂ (20 mL) was added benzofuran-2-carboxylic acid (0.81, 0.50 mmol), 1-hydroxybenzotriazole (0.77 g, 0.569 mmol) and P -EDC (0.67 g, 1 mmol / g) in CH ₂ Cl ₂ (10 mL). After shaking at room temperature overnight, the solution was treated with trisamine (0.446 g, 3.75 mmol / g). After shaking for an additional 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (122.2 mg, 65%). MS (ESI): 562.2 (M + H) ⁺ .

d. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (4-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

Dess-Martin reagent (184.8 mg, 0.436 mmol) was added to a stirred solution of the compound of Example 175c (122.2 mg, 0.217 mmol) in dichloromethane (4 mL). After stirring at room temperature for 2 hours, a solution of sodium thiosulphate (2 mL of 10% solution in water) and saturated aqueous sodium bicarbonate solution (2 mL) was added sequentially to the solution. The aqueous phase was extracted with dichloromethane (2 x). The organic phases are combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluting diastereomer as a white solid (62.7 mg, 51.6%); MS (ESI) 560.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (32.7 mg, 26.9%): MS (ESI) 560.2 (M + H) ⁺ .

Example 176

Preparation of 5-methoxybenzofuran-2-carboxylic acid - {(8) 1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3248

Following the procedure of Example 175c-d with the exception that the benzofuran-2-carboxylic acid of step 175c is replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC yielding first eluting diastereomer as a white solid (64.4 mg, 50%): MS (ESI) 590.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (32.2 mg, 25.2%): MS ( ESI) 590.0 (M + H) ⁺ .

Example 177

Preparation of 7-methoxybenzofuran-2-carboxylic acid - {(8) 1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 175c-d with the exception that the benzofuran-2-carboxylic acid of step 175c is replaced by 7-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC yielding first eluting diastereomer as a white solid (51.1 mg, 40%): MS (ESI) 590.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (41 mg, 32%): MS ( ESI) 590.2 (M + H) ⁺ .

Example 178 Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl } -amide

Following the procedure of Example 175c-d with the exception that the benzofuran-2-carboxylic acid of step 175c is replaced by 5,6-dimethoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluting diastereomer: MS

249 (ESI) 622.2 (M + H) ⁺ and the second eluting diastereomer: MS (ESI)

622.2 (M + H) ⁺ .

Example 179

Preparation of 3-methyl benzofuran-2-carboxylic acid - {(S) -1 [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 175c-d with the exception that the benzofuran-2-carboxylic acid of step 175c is replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give first eluting diastereomer as a white solid (78.6 mg, 63%): MS (ESI) 574.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (27.6 mg, 22%): MS ( ESI) 574.2 (M + H) ⁺ .

Example 180

Preparation of benzo [b] thiophene-2-carboxylic acid - {(S) -1- (1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amyl

Following the procedure of Example 175c-d with the exception that the benzofuran-2-carboxylic acid of step 175c is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluting diastereomer as a white solid (41 mg, 33%): MS (ESI) 576.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (32.6 mg, 26%): MS (ESI) 576.2 (M + H) ⁺ .

Example 181

Preparation of 1-methyl-1H-indole-2-carboxylic acid - {(5) -1- [1 (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl250

Following the procedure of Example 175c-d with the exception that the benzofuran-2-carboxylic acid of step 175c is replaced by 1-methyl-indole-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluting diastereomer as a white solid (28.5 mg, 23%): MS (ESI) 573.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (38.5 mg, 31%): MS (ESI) 573.2 (M + H) ⁺ .

Example 182

Preparation of quinoxaline-2-carboxylic acid (S) -! - ^^?

x-poro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 175c-d except that benzofuran-2-carboxylic acid from step 175c is replaced by quinoxalin-2- carboxylic acid to give the title compound 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 diastereomer as a white solid (44.5 mg, 36%): MS (ESI) 572.2 (M + H) ⁺ .

Example 183

Preparation of benzofuran-2-carboxylic acid - {(5) -1- [1- (3methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

a.) {(S) -1- [1- (3-Methoxy-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 2g (1.60 g, 4.66 mmol) in 1,2-dichloroethane (50 ml) was added P-NMM (2.56 g, 3.64 mmol / g) and 3-methoxy-benzenesulfonyl chloride (1.15 g, 5.59 mmol) ). After shaking at room temperature overnight,

The solution was filtered. The filtrate was concentrated to give the title compound as a white solid (1.70 g, 71.1%): MS 535.8 (M + Na) ⁺ .

b. ) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-methoxybenzenesulfonyl) -3-hydroxy-azepan-4-yl] -amide

HCl (4M in dioxane) (22 ml) was added to a stirred solution of the compound of Example 183a (1.70 g, 3.31 mmol) in methanol (22 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of this white solid (1.19 g, 2.64 mmol, 80%) in methanol (50 ml) was added P-CO ₃ (5.02 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (1.03 g, 2.49 mmol, 96%): MS

413.90 (M + H) ⁺ .

c. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (3-methoxybenzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

To a solution of the compound of Example 183b (0.11 g, 0.26 mmol) in CH _{2 C} 12 (10 mL) was added benzofuran-2-carboxylic acid (64.69 mg, 0.399 mmol), 1-hydroxybenzotriazole (61.1 g, 0.452 mmol) and P -EDC (0.532 g, 1 mmol / g) in CH ₂ Cl ₂ (10 mL). After shaking at room temperature overnight, the solution was treated with trisamine (0.355 g, 3.75 mmol / g). After shaking for an additional 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (103.5 mg, 70%): MS (ESI) 558.2 (M + H) ⁺ .

d. ) Benzofuran-2-carboxylic acid - {(S) -1- [1- (3-methoxy-

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

To a stirred solution of the compound of Example 183c (103 mg, 0.19 mmol) in dichloromethane (4 mL) was added a reagent of DessMartin (157 mg, 0.37 mmol). After stirring at room temperature for 2 hours, a solution of sodium thiosulphate (2 mL of 10% solution in water) and saturated aqueous sodium bicarbonate solution (2 mL) was added sequentially to the solution. The aqueous phase was extracted with dichloromethane (2 x). The organic phases are combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluting diastereomer as a white solid (76.2 mg, 73.6%): MS (ESI: 556.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (24.1 mg , 23.3%): MS (ESI) 556.2 (M + H) ⁺ .

Example 184

Preparation of 5-methoxybenzofuran-2-carboxylic acid - {(8) 1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC yielding the first eluting diastereomer as a white solid (33 mg, 31%): MS (ESI) 586.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (35.2 mg, 32%): MS ( ESI) 586.2 (M + H) ⁺ .

Example 185

Preparation of 7-methoxybenzofuran-2-carboxylic acid - {(8) 1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3253 methyl-butyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by 7-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC affording the first eluting diastereomer as a white solid (41 mg, 38%); MS (ESI) 586.4 (M + H) ⁺ and the second eluting diastereomer as a white solid (39.5 mg, 36%): MS (ESI) 586.2 (M + H) ⁺ .

Example 186

Preparation of 4,5-dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by 5,6-dimethoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluting diastereomer: MS (ESI) 618.4 (M + H) ⁺ and the second eluting diastereomer.

Example 187

Preparation of 3-methylbenzofuran-2-carboxylic acid tert - {(S) -1 [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-t-butyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC yielding first eluting diastereomer as a white solid (76 mg, 72%): MS (ESI) 570.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (23.2 mg, 22%): MS ( ESI) 570.2 (M + H) ⁺ .

254

Example 188 Preparation of benzo (b) thiophene-2-carboxylic acid - {(S) -1- (1- (3methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluting diastereomer as a white solid (37 mg, 35%): MS (ESI) 572.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (31 mg, 29%): MS (ESI) 572.2 (M + H) ⁺ .

Example 189

Preparation of 1-methyl-1H-indole-2-carboxylic acid - {(S) -1- (1 (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by 1-methyl-indole-2-carboxylic acid to give the title compound which is separated by HPLC. giving the first eluting diastereomer as a white solid (34 mg, 32%): MS (ESI) 569.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (38 mg, 38%): MS (ESI) 569.4 (M + H) ⁺ .

Example 190 Preparation of Quinoxaline - {(S) -1- (1- (3-Methoxy-benzenesulfonyl) -oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

Following the procedure of Example 183c-d with the exception that the benzofuran-2-carboxylic acid of step 183c is replaced by quinoxaline-2-carboxylic acid, the title compound is obtained, which is separated by

255

HPLC yielding the first eluting diastereomer as a white solid (71 mg, 67%): MS (ESI) 568.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (27 mg, 24%) : MS (ESI) 568.2 (M + H) ⁺ .

Example 191

Preparation of benzofuran-2-carboxylic acid {(B) -3-methyl-1 [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 168 with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by benzofuran-2-carboxylic acid, the title compound is purified, which is purified by HPLC to give the first eluting diastereomer under white solid (76 mg, 73%): MS (ESI) 532.2 (M + H) ⁺ and the second eluting diastereomer as white solid (25 mg, 23%) MS (ESI): 532.2 (M + H) ⁺ .

Example 192

Preparation of Benzofuran-2-carboxylic acid {(S) -3-methyl-1 ^[(2,2, 4-trideutero) -3-oxo-1- (pyridine-2-sulfonyl) -azepan-4ylcarbamoyl] -butyl } amide

To a solution of benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide of Example 28c (0.03 g) in D ₂ O: CD ₃ OD (0.4: 4 mL) was added triethylamine (0.04 mL). The reaction mixture was heated to reflux for 2 hours and then concentrated and dried in vacuo. The residue was redissolved in the same mixture and heated to reflux overnight. The reaction mixture was concentrated and the residue purified by column chromatography (5% methanol: dichloromethane) to give the title compound (0.02 g): 1 ^. H NMR: δ

256

1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 7.48.0 (m, 8H), 8.7 (m, 1H); MS (EI): 529 (M ⁺ , 45%).

The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer: MS (EI): 530 (M + H ⁺ , 100%) and the slower eluting diastereomer: MS (EI): 530 (M + H ⁺ , 100%).

Example 193

Preparation of benzofuran-2-carboxylic acid {(B) -2-methyl-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

a. ) 4-7 Pre-Butoxycarbonylamino-3-hydroxy-azepane-1 carboxylic acid benzyl ester

To a stirred solution of the compound of Example 2e (1.04 g, 3.92 mmol) in tetrahydrofuran was added di-tert-butyl dicarbonate (0.864 g). After stirring at room temperature for 30 minutes, the reaction mixture was diluted with diethyl ether and extracted with saturated NaHCO _{3 solution} . The organic layer was dried over anhydrous Na ₂ SO ₄ , 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) &lt; ⁺ & gt ^; .

b. ) (3-Hydroxy-azepan-4-yl) -carbamic acid tert-butyl ester

To a solution of the compound of Example 193a (0.963 g, 2.64 mmol) 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 filtrate was concentrated to give the title compound (0.529 g, 2.29 mmol, 87%): MS (ESI): 231.92 (M + H) ⁺ .

c. ) [3-Hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -carbamic acid tert-butyl ester

257

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 chloride (410 mg, 2.32 mmol). After stirring at room temperature for 30 minutes, the mixture was washed with saturated NaHCO ₃ solution. The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound as a solid (0.58 g, 1.57 mmol, 68%): MS (ESI):

372.95 (M + H) ⁺ .

d. 4-Amino-1- (pyridine-2-sulfonyl) -azepan-3-ol

HCl (4M in dioxane, 3.9 ml) was added to a stirred solution of the compound of Example 193c (0.583 g, 1.57 mmol) in ethyl acetate (0.5 ml). After stirring the reaction mixture for 30 minutes at room temperature, the mixture was concentrated to give a white solid. The solid was treated with NaOH and then extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give a yellow solid (0.35 g, 1.28 mmol, 81%): MS (ESI) 272.93 (M + H) ⁺ .

e. ) {(S) - 1- [3-Hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 193d (19 mg, 0.070 mmol) in CH ₂ Cl ₂ was added N-Boc-isoleucine (24.5 mg, 0.10 mmol), 1hydroxybenzotriazole (16.1 mg, 0.12 mmol) and P-EDC (140 mg, 0.14 mmol) in CH ₂ C1 _2. After shaking at room temperature overnight, the mixture was treated with PS-Trisamine. After shaking for an additional 2 hours, the mixture was filtered and concentrated to give the title compound as a solid. MS (ESI) 484.97 (M + H) ⁺ .

258

f. (S) -2-Amino-3-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a stirred solution of the compound of Example 193e (34 mg, 0.07 mmol) in CH ₂ Cl ₂ (0.50 ml) was added HCl (4M in dioxane) (0.165 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated to give a white solid. This white solid was azeotroped with toluene and then treated with MP-carbonate (0.35 mmol) in methanol. After 4 hours of shaking, the mixture was filtered and concentrated to give the title compound as a solid: MS (ESI) 384.9 (M + H) ⁺ .

Mr Rücker ) Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-hydroxy-

1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

To a solution of the compound of Example 193f (27 mg, 0.070 mmol) in CH ₂ Cl ₂ was added 2-benzofurancarboxylic acid (17.0 mg, 0.106 mmol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmol) and P-EDC (140 mg , 0.14 mmol) in CH ₂ C1 _2. After shaking at room temperature, the mixture was treated with PStrisamine overnight. After shaking for an additional 2 hours, the mixture was filtered and concentrated to give the title compound as a solid: MS (ESI) 528.9 (M + H) ⁺ .

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

To a stirred solution of the compound of Example 193 g (37 mg, 0.07 mmol) in CH ₂ Cl ₂ (0.5 ml) was added Dess-Martin reagent (45 mg, 0.105 mmol). After stirring for 30 minutes, a solution of sodium thiosulfate (10% solution in water, 0.50 ml) and saturated aqueous sodium bicarbonate solution (0.50 ml) was added successively to the reaction mixture. Then the mixture was stirred

259 was extracted with dichloromethane (2 fold). The organic layer was dried, filtered and concentrated. The residue was purified by HPLC to give the two diastereomers of the title compound as solids (first eluting diastereomer: 7 mg, second eluting diastereomer: 5.5 mg): MS (ESI) 526.91 (M + H) ⁺ .

Example 194

Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -propyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e using N-Boc-alpha-aminobutyric acid, the title compound was purified to give two diastereomers as solids (first eluting diastereomer: 5 mg, second eluting diastereomer: 5 mg) MS (ESI) 543.8 (M + H) ⁺ .

Example 195

Preparation of benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-cyclohexylalanine was used, the title compound was purified to give two diastereomers as solids (first eluting diastereomer : 4.5 mg second eluting diastereomer: 4.5 mg): MS (ESI): 566.87 (M + H) ⁺ .

Example 196

Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -a.cepan-4-ylcarbamoyl] -ethyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-alanine was used, the title compound was purified to give

260 two diastereomers in the form of solids (first eluting diastereomer: 5.5 mg, second eluting diastereomer: 5 mg).

An example. 197

Preparation of benzofuran-2-carboxylic acid {(S) -3methanesulfinyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -propyl} -amide

Following the procedure of Example 193e-h with the exception that in step 1 (f) using N-Boc-L-methionine, the title compound was purified to give two diastereomers in the form of solid substances (first eluting diastereomer: 3 mg, second eluting diastereomer: 3 mg). MS (ESI): 560.7 (M + H) ⁺ .

Example 198

Preparation of benzofuran-2-carboxylic acid {[3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -methyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-glycine was used, the title compound was purified to give two diastereomers as solids (first eluting diastereomer : 3 mg, second eluting diastereomer: 3 mg). MS (ESI): 470.81 (M + H) ⁺ .

Example 199

Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-norleucine was used, the title compound was purified to give two diastereomers in the form of solids (the first eluting diastereomer : 4 mg, second eluting diastereomer: 5 mg). MS (ESI): 526.85 (M + H) ⁺ .

261

Example 200

Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e it was used with N-Boc-norvaline, the title compound was obtained, which was purified to give two diastereomers as solids (first eluting diastereomer: 7.5 mg, second eluting diastereomer:

3.5 mg). MS (ESI): 512.8 (M + H) ⁺ .

Example 201

Preparation of benzofuran-2-carboxylic acid {(S) -2-methyl-1 [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl J-propyl} amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-valine was used, the title compound was purified to give two diastereomers in the form of solids (the first eluting diastereomer : 6 mg, second eluting diastereomer: 4.5 mg). MS (ESI): 512.8 (M + H) ⁺ .

Example 202

Preparation of benzofuran-2-carboxylic acid {(S) -2-hydroxy] [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl carbamoyl] -propyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-L-threonine was used, the title compound was purified to give two diastereomers as solids (first eluting diastereomer: 3 mg, second eluting diastereomer: 3 mg) ·

262

Example 203

Preparation of benzofuran-2-carboxylic acid <(S) -1- [3-oxo-1 (pyrylin-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-phenylalanine was used, the title compound was purified to give two diastereomers in the form of solids (the first eluting diastereomer : 5 mg, second eluting diastereomer: 5 mg). MS (ESI): 560.8 (M + H) ⁺ .

Example 204

Preparation of 1- (Benzofuran-2-carbonyl) pyrrolidine-2-carboxylic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 193e-h with the exception that using step 193e using N-Boc-L-proline, the title compound was purified to give two diastereomers as solids (first eluting diastereomer: 4 mg, second eluting diastereomer: 5 mg). MS (ESI): (M + H) &lt; + & gt ^; .

Example 205

Preparation of 3,4-dimethoxy-L1 - {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -benzamide

Following the procedure of Example 115 with the exception that benzyloxyacetyl chloride is replaced by 3,4-dimethoxybenzoyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 576.4 (M + H ⁺ ). ^! H NMR (500 MHz, CDCl ₃ ): δ 7.68 (d, 2H), 7.00 (d, 1H), 6.89 (s, 2H), 3.84 (s, 3H), 3.77 (s, 6H), 2.38 (t. 1H), 0.94 (d, 6H): MS 576.4 (M + H ⁺ ).

Example 206

Preparation of benzo [b] thiophene-2-carboxylic acid - {(S) -1- (1- (4263 methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl7

Following the procedure of Example 115 with the exception that benzyloxyacetyl chloride is replaced by 2-thiophene-carbonyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS

572.2 (M + H ⁺ ). ^X H NMR (500 MHz, CDCl ₃ ): δ 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, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 572.2 (M + H ⁺ ).

Example 207

Preparation of benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1 (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride is replaced by 3,4methylenedioxybenzoyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS 548.2 (M + H ⁺ ); ^X H NMR (400 Hz,

CDCl ₃ ): δ 7.85-7.78 (m, 2H), 7.38-7.20 (m, 4H), 7.05 (d, 1H), 2.52-2.40 (m, 1H), 1.0 (d, 6H). Second eluting diastereomer: MS 548.2 (M + H ⁺ ).

Example 208

Preparation of (S) -2- (2-Benzyloxy-acetylamino) -4-methylpentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4 Following the procedure of Example 115 with the exception that 4 -methoxybenzenesulfonyl chloride is replaced by 4-fluorobenzenesulfonyl chloride to give the title compound. The residue was purified by HPLC. First eluting

264 Diastereomer: MS 548.2 (M + H ⁺ ). ^! H NMR (400 Hz, CDCl3-CD3OD) δ

7.88-7.80 (m, 2Η), 7.45-7.30 (m, 5H), 7.30-7.20 (m, 2H), 4.00 (s, 2H), 2.60-2.48 (t, 1H), 0.96 (t, 6H): MS 548.2 (M + H ^& lt ^{; +} & gt ^; ).

Example 209

Preparation of benzo (b) thiophene-2-carboxylic acid - {(S) -1- (1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 115 c except that 4-methoxybenzenesulfonyl chloride was replaced with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl benzo (b] thiophenecarbonyl, prepare the title. The residue was purified by HPLC. First eluting diastereomer: MS 560.2 (M + H ^{+ X} H NMR (500 MHz,

CDCI3): δ 7.80-7.72 (m, 5H) .7.37-7.34 (m, 2H), 7.33-7.15 (m, 4H), 2.43 (t, 1H), 0.96 (d, 6H). Second eluting diastereomer: MS 560.2 (M + H ⁺ ).

Example 210

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide a.) Benzofuran-2-carboxylic acid {(8) -1- (1-benzoyl-3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

To a solution of benzofuran-2-carboxylic acid ((S) -1- (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 mixture was stirred until completion of the reaction The workup and column chromatography (5% methanolchloromethane) gave the title compound (0.2 g): ^X H NMR (CDC1 ₃ ) : δ 1.0 (m, 6H), 1.5-2.2

265 (m, 6H), 2.7 (m, 1H), 3.8 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.0-7.7 (m, 10H) , 8.7 (m, 1H); MS (EI): 492 (M + H ^& lt ^{; +} & gt ^; , 100%).

b.) Benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-oxoazepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide from Example 210a, gave the title compound: ^X H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.7 (m, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H); MS (EI): 490 (M + H ^& lt ^{; +} & gt ^; , 100%).

Example 211

Preparation of (S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

a. ) (S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 89a with the exception that 2-pyridinesulfonyl chloride is replaced by 8-quinolinsulfonyl chloride, the title compound is obtained: MS (EI) 576 (M + H ⁺ ).

b. ) (S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception of using (S) -4-methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane -4-yl] -amide of Example 211a the title compound the ^title:! H NMR (CDCl3): δ 0.5-0.8 (m, 6H), 1.4-1.8 (m, 7H), 2.5 (m, 1H), 3.5-3.9 (m, 3H), 4.4 (m, 1H), 4.6 ( m, 1H), 5.5 (m, 1H), 6.7-7.0 (m, 2H), 7.5 (m, 3H), 8.0 (m, 2H), 8.3 (m, 2H), 8.6 (m, 1H), 9.0 (m, 1H); MS (EI): 674 (M + H ^& lt ^{; +} & gt ^; , 100%).

266

Example 212

Preparation of (S) -4-Methyl-2- (naphthylene-2-sulfonylamino) pentanoic acid [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl] amide.

a. ) (S) -4-Methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 89a with the exception that 2-pyridinesulfonyl chloride is replaced by 2-naphthylenesulfonyl chloride, the title compound is obtained: MS (EI) 575 (M + H ⁺ ).

b. ) (S) -4-Methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 1 with the exception of using (S) -4-methyl-2- (naphthylene-2-sulfonylamino) pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- 4-yl] -amide of Example 212a, the title compound the ^title:! H NMR (CDCl ₃ ): δ 0.5-0.8 (m, 6Η), 1.4-1.8 (m, 7H), 2.5 (m, 1H), 3.5-3.9 (m, 3H), 4.5 (m, 1H), 4.6 (m, 1H), 5.5 (m, 1H), 6.7 (m, 1H), 7.5-8.0 (m, 9H), 8.5-8.6 (m, 2H); MS (EI): 673 (M + H ^& lt ^{; +} & gt ^; , 100%).

Preparation of benzofuran-2-carboxylic acid - {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride is replaced by 2benzofurancarbonyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 544.2 (M + H ⁺ ). 1 H NMR (500 MHz, CDCl ₃ ): δ 7.79-7.77 (m, 2H), 7.61 (d, 1H), 7.46-7.38 (m, 3H), 7.25-7.06

267 (m, 5H), 2.43 (t, 1H), 0.95 (d, 6H). Second eluting diastereomer: MS 544.4 (M + H ⁺ ).

Example 214

Preparation of N - {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxoazepan-4-ylcarbamoyl] -3-methyl-butyl} -3,4-dimethoxy-benzamide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride is replaced by 3,4 dimethoxybenzoyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 564.2 (M + H ⁺ ). ^! H NMR (500 MHz, CDCl ₃ ): δ 7.80-7.76 (m, 2H), 7.19 (t, 2H), 7.05 (d, 1H), 6.88 (s, 2H), 6.78 (d, 1H), 6.53 ( s, 1H), 3.77 (s, 6H), 2.43 (t, 1H), 0.94 (d, 6H). Second eluting diastereomer: MS 546.2 (M + H ⁺ ).

Example 215

Preparation of Cyclohexanecarboxylic Acid __ {(S) -1- [1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-carbamoyl] -3-methyl Following the procedure of Example 115, except that 4-methoxybenzenesulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride are replaced by cyclohexylcarbonyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 510.4 (M + H ⁺ ). ¹ H NMR (400 Hz, CDCl 3): δ 7.83-7.80 (m, 2H), 7.27-7.20 (m, 2H), 6.92 (d, 1H), 6.95 (d, 1H). 2.50 (t, 1H), 1.90-1.20 (m, 15H), 0.94 (t, 6H). Second eluting diastereomer: MS 510.2 (M + H ⁺ ).

Example 216

Preparation of (S) -2- (2-Benzoxy-acetylamino) -4-methyl268 pentanoic acid [1- (methanesulfonyl) -3-oxo-azepan-4-yl] -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by methanesulfonyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M + H ⁺ ). ¹ H NMR (500 MHz, CDCl 3): δ 7.37-

7.24 (m, 4H), 6.93-6.91 (m, 2H), 5.02-5.00 (m, 1H), 2.88 (s, 3H), 2.70 (t, 1H), 0.92 (t, 6H). Second eluting diastereomer: MS 468.2 (M + H ⁺ ).

Example 217

Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl) -3-methyl-butyl] -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by methanesulfonyl chloride and benzyloxyacetyl chloride is replaced by benzo [b] thiophenecarbonyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 480.2 (M + H ⁺ ). ^} H NMR (500 MHz, CDC1 _3): δ 7.83-

7.78 (m, 3H), 7.42-7.37 (m, 2H), 6.94 (d, 1H), 6.75 (d, 1H), 2.89 (s, 3H).

2.68 (t, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 480.2 (M + H ⁺ ).

Example 218

Receiving. benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl) -3-methyl-butyl] -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by methanesulfonyl chloride and benzyloxyacetyl chloride is replaced by piperinylcarbonyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M + H ⁺ ). ¹ H NMR (500 MHz, CDCl 3); δ 7.31269

7.24 (m, 2H), 6.91 (d, 1H), 6.00 (s, 2H), 2.89 (s, 3H), 2.67 (t, 1H), 0.95 (d, 6H). Second eluting diastereomer: MS 468.2 (M + H ⁺ ).

Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by methanesulfonyl chloride and benzyloxyacetyl chloride is replaced by 2-benzofurancarbonyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 464.2 (M + H ⁺ ). Ή NMR (500 MHz, CDCl ₃ ): δ 7.64 (d, 1H), 7.51-7.37 (m, 3H), 7.29-7.28 (m, 1H), 2.89 (s, 3H), 2.67 (t, 1H). 0.97 (d, 6H). Second eluting diastereomer: MS 464.2 (M + H ⁺ ).

Example_220 Ishsarbamoyl) -Z2Hgetylg5u11iH-_ZLgDIMethoxy2.benzamide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by methanesulfonyl chloride and benzyloxyacetyl chloride is replaced by 3,4-dimethoxybenzoyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 484.2 (M + H ⁺ ). ^X H NMR (500 MHz, CDCl ₃ ): δ 6.946.88 (1H, 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 ⁺ ).

Example 221

Preparation of (S) -2- (2-Benzyloxy-acetylamino) -4-methylpentanoic acid [1- (2-cyano-benzenesulfonyl) -3_-oxo-azepang4d

270

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 2-cyanophenylsulfonyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M + H ⁺ ). ^X H NMR (500 MHz, CDCl ₃ ): δ 8.10 (d, 1H), 7.86 (d, 1H), 7.76-7.70 (m, 2H), 7.35-7.31 (m, 5H), 6.93 (d, 2H) , 4.61-4.47 (m, 4H), 2.77 (t, 1H), 0.92 (t, 6H). Second eluting diastereomer: MS 555.2 (M + H ⁺ ).

Example 222

Preparation of N - {(S) -1- [1- (2-Thiano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -4-methanesulfonyl-1-benzamide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride is replaced by 4methanesulfonylbenzoyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 589.2 (M + H ⁺ ). ^! H NMR (500 MHz, CDCl ₃ ): δ 8.10 (d, 1H), 7.96 (s, 4H), 7.88 (d, 1H), 7.78-7.71 (m, 2H), 3.05 (s, 3H), 2.79 ( t, 1H), 0.97 (t, 6H). Second eluting diastereomer: MS

589.2 (M + H ⁺ ).

Example 223

Preparation of benzo [b] thiophene-2-carboxylic acid - {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 115 c this exception, that 4-methoxybenzenesulfonyl chloride is replaced by 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride is replaced by benzo [b] thiophene-2-carbonyl chloride gives the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 567.2 (M + H ⁺ ). ¹ H NMR (500

271

MHz, CDCl ₃ ): δ 8.10 (d, 1H), 7.86-7.70 (m, 6H), 7.37-7.30 (m, 2H), 2.76 (t, 1H), 0.98 (d, 6H). Second eluting diastereomer: MS 567.2 (M + H ⁺ ).

Example 224

Preparation of benzo [1,3] dioxole-5-carboxylic acid-S8) -1- [1,1g (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride is replaced by piperronyloyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M + H ⁺ ). NMR (500 MHz, CDCl3): δ 8.11 (d, 1H), 7.87 (d, 1H), 7.76-7.71 (m, 2H), 7.31-7.24 (m, 2H), 6.00 (s, 2H), 2.77 ( t, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 555.4 (M + H ⁺ ).

Preparation of (S) -4-Methyl-2- [4-oxo-4- (4-phenoxy-phenyl) butyrylamino] -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) azepan-4-yl ] -amide

Following the procedure of Example 75 with the exception that thioxole-2-sulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 4-phenoxyphenyl-carboxylic acid to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ) 635.4; ^! H NMR (400

MHz, CDCl3): · 8.69 (d, 1H), 7.99-7.94 (m, 4H), 7.53-7.39 (m, 3H), 7.23-

6.95 (m, 7H), 6.20 (d, 1H), 5.07 (m, 1H), 4.77-4.72 (d, 1H), 4.46 (m, 1H).

4.13-4.09 (m, 1H), 3.85-3.80 (d, 1H), 3.33 (m, 2H), 2.70-2.64 (m, 3H),

272

2.20-1.40 (m, 6H); and the second eluting diastereomer: 0.96-0.92 (m, 6H); and the second eluting diastereomer: MS (M + H ⁺ ) 635.4.

Example 226

Preparation of N - {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azedane Following the procedure of Example 115 with the exception of replacing 4-methoxybenzenesulfonyl chloride with 2cyanophenylsulfonyl chloride and benzyloxyacetylacetyl, 4Dimethoxybenzoyl chloride, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer: MS 571.4 (M + H ⁺ ). ^X H NMR (500 MHz,

CDCl ₃ ): δ 8.10 (d, 1H), 7.87 (d, 1H), 7.76-7.70 (m, 2H), 6.98 (s, 2H), 6.89 (s, 2H), 3.79 (s, 6H), 2.76 (t, 1H), 0.96 (d, 6H). Second eluting diastereomer: MS 571.4 (M + H ⁺ ).

methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the procedure of Example 115 with the exception that benzyloxyacetyl chloride is replaced by cyclohexylcarbonyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 522.4 (M + H ⁺ ). ^X H NMR (500 MHz, CDCl ₃ ): δ 7.70 (d, 2H), 6.97 (d, 2H), 2.40 (t, 1H), 1.90-1.20 (m, 16H), 0.92 (d, 6H). Second eluting diastereomer: MS 522.4 (M + H ⁺ ).

Example 228

Preparation of 4-methanesulfonyl-N - {(S) -1 - [(4-methoxybenzamide)

273

Following the procedure of Example 115 with the exception that benzyloxyacetyl chloride is replaced by 4-methanesulfonylbenzoyl chloride, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer: MS 594.2 (M + H ⁺ ). NMR (500 MHz, CDC1 _3): δ 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, 1H), 0.95 (d, 6H). Second eluting diastereomer: MS 594.2 (M + H ⁺ ).

Example 229

Preparation of 4-Methanesulfonyl-N - {(S) -1- [4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl} -benzamide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 4-fluorophenylsulfonyl chloride and benzyloxyacetyl chloride is replaced by 4methanesulfonylbenzoyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 582.2 (M + H ⁺ ). ^T H NMR (500 MHz, CDC1 _3): δ 7.94 (s, 4H ), 7.80-7.77 (m, 2H), 7.25-7.19 (m, H), 7.00 (d, IH) , 3.04 (s, 3H) , 0.96 (d, 6H). Second eluting diastereomer: MS 582.2 (M + H ⁺ ).

Example 230

Preparation of {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) azepan-4-yl-carbamoyl] -butylcarbamoyl} -carbamic acid, benzyl ester

Following the procedure of Example 75 with the exception that benzenesulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by Ncarbobenzyloxycarbonyl-glycine to give the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 574.2; ^! H NMR (400

274

MHz, CDCl-): · 8.60 (d, 1H), 7.97-7.90 (m, 2H), 7.50 (m, 1H), 7.42-7.25 (m, 5H), 6.90 (m, 1H), 6.42 (m. 1H), 5.38 (m, 1H), 5.18-5.10 (m, 4H),

4.78-4.72 (d, 1H), 4.50 (m, 1H), 4.12-4.05 (m, 1H), 3.95-3.85 (m, 2H), 2.72 (m, 1H), 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.

Example 231 Preparation of (S) -2- [5- (4-Methoxy-phenyl) -pentanoylamino] -4methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4 Following the procedure of Example 75 with the exception that benzenesulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 5- (4methoxyphenyl) pentanoic acid, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 573.4; 1 H NMR (400 MHz, CDCl 3):? 8.59 (d, 1H), 7.97-7.94 (m, 2H), 7.53 (m, 1H), 7.09-7.07 (d, 2H), 6.89-6.81 (m, 3H) ), 5.90 (m, 1H), 5.12 (m, 1H), 4.79-4.74 (d, 1H),

4.48 (m, 1H), 4.12 (m, 1H), 3.86-3.81 (d, 1H), 3.79 (s, 3H), 2.69 (m, 1H), 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 second eluting diastereomer: MS (M + H ⁺ ) 573.4.

Example 232

Preparation of (S) -2- [2- (3-Benzyloxy-4-methoxy-phenyl) acetylamino] -4-methylpentanoic acid [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 75 with the exception that benzenesulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by (3-benzyloxy-4methoxy-phenyl) acetic acid, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 637.4; ^! H NMR (400

275

MHz, CDCl ₃ ): · 8.69 (d, 1H), 7.98-7.91 (m, 2H), 7.53-7.30 (m, 6H); and a second eluting diastereomer: 6.89-6.82 (m, 4H), 5.82 (m, 1H), 5.145.07 (m, 3H), 4.78-4.73 (d, 1H), 4.43 (m, 1H), 4.09 (m , 1H), 3.89 (s, 3H),

with. 82 (d, 1H), 3.49 (s, 2H), 2.69 (m, 1H), 2.14 (m, 2H), 1.82-1.40 (m, 5H), 0.89 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 637.4.

Example 233

Preparation of 5,6-Pifluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azepan-4i. bicarbamoyl] -butyl} amide

a. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-

1- [1- (pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5,6 difluorobenzofuran-2-carboxylic acid, the title compound is obtained: MS (M + H ⁺ ): 564.

b. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-

1- [1- (Pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using the compound of Example 233a, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 562; and second eluting diastereomer: MS (M + H ⁺ ) 562.

Example 234

Preparation of (S) -4-Methyl-2- (5-oxo-hexanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 115 with the exception that 4-methoxybenzenesulfonyl chloride is replaced by 2pyridinesulfonyl chloride and benzyloxyacetyl chloride is replaced by 5276 oxo-hexanoyl chloride to give the title compound. The residue was purified by HPLC. First eluting diastereomer: MS 495.4 (M + H ⁺ ); Second eluting diastereomer: MS 495.4 (M + H ⁺ ).

Example 235

Preparation of benzofuran-2-carboxylic acid {(5) -3-methyl-1 [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -

a. 6-Methyl-pyridine-2-sulfonyl chloride

The title compound was prepared in a similar manner to that described in Example 85a for the preparation of 2-pyridinesulfonyl chloride-L [-oxide.

b. ) {(S) -1- [3-Hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

To a solution of [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3methyl-butyl] -carbamic acid tert-butyl ester of Example 2g (1.0 g) in dichloromethane (20 mL) was added a saturated solution of sodium bicarbonate (50 mL). To this solution was added 6-methylpyridine-2-sulfonyl chloride (6.44 mL of 0.13 g / mL solution in 9M HCl). The reaction mixture was stirred until the reaction was complete. Treatment and column chromatography. (5% methanol: dichloromethane) gave the title compound (1.2 g).

c. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azepan-4-yl] -amide of Example 235a (1.2 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred until complete

277 reaction and then concentrated to give the title compound (1 g).

d. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 28b with the exception of using (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy- (6-methyl-pyridine-2-sulfonyl) -azepan-4-yl ] -amide from Example 235c, the title compound was obtained: MS (EI) 542 (M ⁺ ).

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

Following the procedure of Example 1 with the exception of using benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane -4ylcarbamoyl] -butyl} amide of Example 235d, gave the title compound: ^X H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H). 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 1H), 5.3 (m, 1H), 7.4-8.0 (m, 8H); MS (EI); 540 (M ⁺ , 100%).

Example 236

Preparation of 5-methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} amide

a.) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1 (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5methoxybenzofuran-2-carboxylic acid and (S) -2-amino-4-methyl pentanoic acid [3-hydroxy-1- (pyridine) Of Example 28b was replaced by (S) -2-amino-4-methylpentanoic acid (3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) azepane, 2-sulfonyl) -azepan-4278 yl] -amide -4-yl] -amide of Example 235c, the title compound was obtained: MS (EI) 572 (M ⁺ ).

B.) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1 (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 5-methoxybenzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy- of azepan-4ylcarbamoyl] -butyl} amide from Example 236a, the title compound was obtained: Ή NMR (CDCl ₃ ): δ 1.0 (m, 6Η), 1.5-2.2 (m, 6H), 2.6 (m, 3H) , 2.7 (m, 1H), 3.8 (s, 3H); 4.1 (m, 1H),

4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0, (m, 7H); MS (EI): 570 (M ^&lt; ^{+ &gt;} , 100%).

Example 237

Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide

a. ) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 236a with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 556 (M ⁺ ).

b. 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 3-methylbenzofuran-2-carboxylic acid {(S) -3279 methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy -azepan-4-ylcarbamoyl] -butyl} -amide from Example 237a to give the title compound: ^T H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H ), 2.7 (m, 1H), 3.8 (s, 1H); 4.1 (m, 1H),

4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H); MS (EI): 564 (M ⁺ , 100%).

Example 238

Preparation of 7-methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butylamide

a. 7-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 7methoxybenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 559 (M + H ⁺ ).

b. 7-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception of using 7-methoxybenzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy- of azepan-4-ylcarbamoyl] -butyl} -amide of Example 238a, the title compound was obtained: MS (EI) 557 (M + H ⁺ ).

Example 239

Preparation of 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid D8) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azepan-4ylcarbamoyl] -butyl} amide

280

a. ) 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4ylcarbamoyl ] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5,6-dimethoxybenzo [b] thiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 604 ( M ⁺ ).

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

Following the procedure of Example 1 with the exception of using 5,6-dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine) The 2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide of Example 239a gave the title compound: MS (EI) 602.9 (M + H ⁺ ).

Example 240

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

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by (R) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 584.4; ^! H NMR (400 MHz, CDCl ₃ ):? 8.69 (d, 1H), 7.99-7.92 (m, 2H),

7.52 (m, 1H), 7.32-7.22 (m, 5H), 6.92 (d, 1H), 6.38 (d, 1H), 5.15-5.08 (m, 2H), 4.80-4.75 (d, 1H), 4.47- 4.44 (m, 1H), 4.14-4.10 (m, 1H), 3.89-3.80

281 (m, 3H), 2.75-2.63 (m, 2H), 2.46-1.44 (m, 10H), 0.95 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 584.4.

Example 241

Preparation of (S) -1-Benzyl-5-oxo-pyrrolidine727carbamic acid {(S) -3-methyl-1- [3-oxo (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 75 with the exception that benzenesulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by (S) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid, the compound is obtained. indicated in the title. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 584.4; ^! H NMR (400 MHz, CDCl ₃ ):? 8.69 (d, 1H), 7.98-7.92 (m, 2H), 7.52 (m, 1H), 7.32-7.22 (m, 5H), 6.92 (d, 1H). 6.38 (d, 1H), 5.22-5.18 (d, 1H), 5.10 (m, 1H), 4.80-

4.75 (d, 1H), 4.51 (m, 1H), 4.12-4.08 (m, 1H), 3.91-3.79 (m, 3H), 2.71-1.38 (m, 12H), 0.97 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 584.4.

Example 242

Preparation of benzofuran-2-carboxylic acid {(S) -2cyclopropyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

Following the procedure of Example 193e-h with the exception that in step 193e N-Boc-cyclopropylalanine was used, the title compound was purified to give two diastereomers as solids (first eluting diastereomer : 8 mg, second eluting diastereomer: 8 mg): MS (ESI): 525 (M + H) ⁺ .

Example 243

Preparation of benzofuran-2-carboxylic acid <(S) -3282 methyl sulfanyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -propyl} -amide

The procedures of Examples 193e-g are followed except that in step 193e N-Boc-L-methionine is used. The oxidation of the compound of Example 193g was carried out by adding to the alcohol intermediate in dimethyl sulfoxide solvent (0.200 ml) sulfur trioxide-pyridine complex (34 mg, 0.211 mmol) and triethylamine (0.077 ml). After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, concentrated and purified by HPLC to give two diastereomers of the title compound as solids (first eluting diastereomer: 8 mg, second eluting diastereomer: 5 mg). MS (ESI): 545 (M + H) ⁺ .

Preparation of benzofuran-2-carboxylic acid {(S) -2-naphthalen-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

Following the procedure of Example 193e-h with the exception that using N- (tert-butoxycarbonyl) -3- (2 naphthyl) -E-alanine, the title compound was purified to give two diastereomers below solid form (first eluting diastereomer: 5.3 mg, second eluting diastereomer: 3.3 mg): MS (ESI): 610.8 (M + H) ⁺ .

Example 245

Preparation of Thieno [3,2-6] Thiophene-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4ylcarbamoyl] -butyl } amide

283

a. ) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl ] butyl} amide

Following the procedure of Example 236a with the exception that 5-methoxybenzofuran-2-carboxylic acid is replaced by thieno [3,2-b] thiophene-2-carboxylic acid, the title compound is obtained: MS (EI) 564 (M ⁺ ).

b. ) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl ] butyl} amide

Following the procedure of Example 1 with the exception of using thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) ) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide of Example 245a, the title compound was obtained: NMR (CDCl3): δ 1.0 (m,

6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 2.7 (m, 1H), 3.8 (s, 1H); 4.1 (m, 1H),

4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H); MS (EI): 562 (M ⁺ , 100%).

Example 246

Preparation of thieno] 3,2-d] thiophene-2-carboxylic acid {(S) -3methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4ylcarbamoyl] - butyl} amide

a. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (3-methyl-pyridine-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Examples 235b-c with the exception that 6-methyl-pyridine-2-sulfonyl chloride is replaced by 3-methyl-pyridine-2-sulfonyl chloride, the title compound is obtained: MS (EI) 399 (M ⁺ ).

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

284

To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (3-methyl-pyridine-2-sulfonyl) -azepan-4-yl] -amide of Example 246a (0.25 g) in dichloromethane was added thieno [3,2-6] thiophene (0.10 g), triethylamine (0.12 mL), HOBt (0.085 g) and EDC (0.12 g). The reaction mixture was stirred until the reaction was complete. Workup and column chromatography (5% methanol: dichloromethane) gave the title compound (0.18 g): MS (EI) 564 (M ⁺ ).

c.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (3methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl ] butyl} amide

Following the procedure of Example 1 with the exception of using thieno [3,2-5] thiophene-2-carboxylic acid {(S) -3methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) ) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide of Example 245a to give the title compound: ^T H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H) , 2.6 (m, 3H) 3.0 (m, 1H), 3.8 (s, 3H); 4.1 (m, 2H),

4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 5H), 8.4 (m, 1H); MS (EI): 562 (M ⁺ , 100%).

Example 247

Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4ylcarbamoyl J-butyl} amide

a.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 246c with the exception that thieno [3,2-6] thiophene is replaced by 3methylbenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 556 (M ⁺ ).

285

b.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception that using 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy- of azepan-4ylcarbamoyl] -butyl} amide from Example 247a, the title compound was obtained: * H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H ), 2.6 (m, 3H), 3.0 (m, 1H), 4.1 (m, 2H),

4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H), 8.4 (m, 1H); MS (EI): 554 (M ⁺ , 100%).

Example 248

Preparation of 5-methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide

a. 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 246c with the exception that thieno [3,2-b] thiophene is replaced by 5methoxybenzofuran-2-carboxylic acid, the title compound is obtained: MS (EI) 572 (M ⁺ ).

b. ) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception that using 5-methoxybenzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy- azepan-4-ylcarbamoyl] -butyl} amide of Example 247a the title compound the ^title:! H NMR (CDCl3): δ 1.0 (m,

286

6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 3.0 (m, 1H), 3.8 (s, 3H); 4.1 (m, 2H),

4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H), 8.4 (m, 1H); MS (EI): 570 (M ^&lt; ^{+ &gt;} , 100%).

Example 249

Preparation of 5,6-difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-

a. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(3) -3-methyl-

1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 85c with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5,6difluorobenzofuran-2-carboxylic acid, the title compound is obtained: MS (ESI) 580.9 (M + H ⁺ ).

b. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-

1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide

Following the procedure of Example 1 with the exception that the compound of Example 249a was used, the title compound was obtained: MS (ESI) 578.87 (M + H ⁺ ).

Preparation of 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] - ethyl} -amide

a.) 4- ((S) -2-tert-Butoxycarbonyl amino-3-cyclohexylpropionylamino) -3-hydroxy-azepane-1-carboxylic acid, benzyl ester

To a solution of the compound of Example 2e (3.2 g, 12.2 mmol) in dimethylformamide (35 mL) was added N-Boc-cyclohexylalanine

287 (3.3 g), HOBt (1.8 g) and EDC (2.56 g). The reaction mixture was stirred until the reaction was complete. Treatment and column chromatography of the residue (65% hexanesethyl acetate) afforded 5.5 g of the title compound.

b. ) [(S) -Cyclohexyl-1- (3-hydroxy-azepan-4-ylcarbamoyl) -ethyl] -carbamic acid tert-butyl ester

To a solution of the compound of Example 250a (5.5 g) in ethyl acetate: methanol (185 mL: 40 mL) was added 10% Pd / C. This mixture was stirred under a hydrogen atmosphere until complete exhaustion of the starting material was established. The reaction mixture was filtered and concentrated to give 3.75 g of the title compound.

c. ) {(S) -2-Cyclohexyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 250b (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 dropwise 2pyridinesulfonyl chloride (0.55 g in 5 mL of dichloromethane). The mixture was stirred for 20 minutes and then the organic layer was separated and washed with water and brine, dried, filtered and concentrated. Column chromatography (2% methanol: dichloromethane) of the residue gave 1.0 g of the title compound: MS (ESI) 525 (M + H ⁺ ).

d. (S) -2-Amino-3-cyclohexyl-L- [3-hydroxy- (pyridine-2-sulfonyl) -azepan-4-yl] -propionamide

HCl (10 mL 4M HCl in dioxane) was added to a solution of the compound of Example 250c (1.0 g) in methanol (10 mL). The reaction mixture was stirred until complete depletion of the starting material and then concentrated. The residue was evaporated

288 was azeotroped with toluene then washed with ether to give 0.95 g of the title compound.

e. ) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl } -amide

To a solution of the compound of Example 250d (0.20 g, 0.4 mmol) in dimethylformamide (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 mixture was stirred until complete depletion of the starting material. Treatment and column chromatography (4% methanol: dichloromethane) afforded 0.23 g of the title compound.

f. ) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

Following the procedure of Example 75d with the exception of using the compound of Example 250f, the title compound was obtained. Separation of diastereomers by HPLC gave the first eluting diastereomer (52 mg): MS (ESI) 661.4 and the second eluting diastereomer (45.8 mg): MS (ESI) 661.6.

Example 251

Preparation of 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] ] -ethyl} -amide

Following the procedures of Example 250e-f with the exception that 5- [3- (trifluoromethyl) phenyl] -2-furoic acid of Example 250e is replaced by 5- (4-chlorophenyl) -2-furoic acid, the title compound. Separation of the diastereomers by HPLC gave the first elution

289 diastereomer (57 mg): MS (ESI) 627.4 and the second eluting diastereomer (53 mg): MS (ESI) 627.4.

Example 252

Preparation of benzofuran-2-carboxylic acid {(B) -3-methyl-1 [6-methyl-3-oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 92 with the exception that 2,2-dimethyl-4-pentenyl is replaced by 2-methyl-4-pentenyl, the title compound is obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ): 541.2; ¹ H NMR (400 MHz, CDCl ₃ ):? 8.71-8.66 (m, 1H), 7.98-

7.93 (m, 2H), 7.91 (d, 1H), 7.67-7.29 (m, 5H), 7.15-6.92 (m, 2H), 5.28-5.20 (m, 1H), 4.82-4.47 (m, 2H). 3.97-3.78 (m, 1H), 3.65-2.98 (m, 1H), 2.37-

2.34 (m, 1H), 2.20-1.55 (m, 3H), 1.22-1.19 (m, 3H), 1.00-0.86 (m, 9H).

Example 253

Preparation of 5- (4-chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-N- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane4 -ylcarbamoyl] -ethyl} -amip

Following the procedures of Example 250c-f with the exception that the 2-pyridinesulfonyl chloride of Example 250c is replaced by 2-pyridinesulfonyl chloride-T4-oxide and 5- [3- (trifluoromethyl) phenyl] -2-furoic acid of Example 250e. substituted with 5 (4-chlorophenyl) -2-furoic acid to give the title compound. Separation of diastereomers by HPLC gave the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2.

Example 254

Preparation of 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4- ylcarbamoyl] -ethyl} -amide

290

Following the procedures of Example 250c-f with the exception that the 2-pyridinesulfonyl chloride of Example 250c is replaced by 2-pyridinesulfonyl chloride-N-oxide, the title compound is obtained. Separation of diastereomers by HPLC gave the first eluting diastereomer: MS (ESI) 677.2 and the second eluting diastereomer: MS (ESI) 677.4.

Example 255

Preparation of 5-fluoro-benzofuran-2-carboxylic acid <(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

a. ) 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b with the exception that benzofuran-2-carboxylic acid is replaced by 5fluorobenzofuran-2-carboxylic acid, the title compound is obtained: MS (ESI) 547 (M + H ⁺ ).

b. ) 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 1 with the exception that using the compound of Example 255a, the title compound was obtained: MS (ESI) 544.9 (M + H ⁺ ).

Example 256

Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyrilin-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} - amide

Following the procedures of Example 250c-f with the exception that the 2-pyridinesulfonyl chloride of Example 250c is

291 is replaced by 2-pyridinesulfonyl chloride-L1-oxide and 5- [3 (trifluoromethyl) phenyl] -2-furoic acid of Example 250e is replaced by 5,6-dimethoxybenzofuran-2-carboxylic acid to give the title compound. Separation of diastereomers by HPLC gave the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2.

Example 257

Preparation of 5,5-bis- (4-methoxy-phenyl) -pent-4-enoic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 75 with the exception that thiazole-2-sulfonyl chloride is replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 5,5-bis (4-methoxy-phenyl) -pent-4- enoic acid, the title compound was obtained. The residue was purified by HPLC. First eluting diastereomer; MS (M + H ⁺ ) 677.4; ^! H NMR (400 MHz, CDCl ₃ ):? 8.69 (d, 1H), 7.98-7.92 (m, 2H),

7.53-7.50 (m, 1H), 7.27-6.77 (m, 10H), 6.00-5.87 (m, 2H), 5.08 (m, 1H), 4.76-4.72 (d, 1H), 4.48 (m, 1H). 4.08 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 2.70-1.35 (m, 12H), 0.91 (d, 6H); and second eluting diastereomer: MS (M + H ⁺ ) 677.4.

Example 258

Preparation of quinoline-8-carboxylic acid {(S) -2-naphtylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

a.) 4-Amino-1- (pyridine-2-sulfonyl) -azepan-3-ol

HCl (10 mL 4M HCl in dioxane) was added to a solution of the compound of Example 193c (1.5 g) in methanol (10 mL).

292

The reaction mixture was stirred until the reaction was complete by TLC analysis and then concentrated to give 1.2 g of the title compound as a white solid.

b. ) {(S) - 1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-naphthylen-2-yl-ethyl} -carbamic acid tert-butyl ester

To a solution of the compound of Example 258a (225 mg) in dichloromethane was added TEA (0.15 mL), HOBt (99 mg), EDC (140 mg) and N-Boc-L-2-naphthylanine (230 mg). The reaction mixture was stirred until the reaction was complete. Treatment and column chromatography of the residue (3% methanol: dichloromethane) afforded 0.35 g of the title compound: MS (ESI) 569 (M + H ⁺ ).

c. (S) -2-Amino-N- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -

3-Naphthyl-2-yl-propionamide

To a solution of the compound of Example 258b (0.35 g) in methanol (5 mL) was added HCl (5 mL 4M HCl in dioxane). The reaction mixture was stirred until the reaction was complete by TLC analysis and then concentrated to give 0.31 g of the title compound as a white solid.

d. ) Quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

To a solution of the compound of Example 258c (131 mg) in dichloromethane was added TEA, HOBt (39 mg), EDC (55 mg) and quinoline-8-carboxylic acid (51 mg). The reaction mixture was stirred until the reaction was complete. Treatment and column chromatography of the residue (5% methanol: dichloromethane) afforded 0.35 g of the title compound: MS (ESI) 574 (M + H ⁺ ).

293

e.) Quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

Following the procedure of Example li with the exception of using the compound of Example 258d, the title compound was obtained.

Example 259

Preparation of naphthylene-1-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] ethyl} -amide

Following the procedures of Examples 258d-e with the exception that quinoline-8-carboxylic acid is replaced by 1 naphthoic acid, the title compound is obtained.

Example 260

Preparation of quinoline-8-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide

Following the procedures of Examples 258a-e with the exception that N-Boc-L-2-naphthylalanine is replaced by N-Bocphenylalanine, the title compound is obtained.

Example 261

Preparation of naphthyridine-2-carboxylic acid {(S) -3-methyl-

1- [3-Oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 28b-c with the exception that benzofuran-2-carboxylic acid is replaced by

1,6-Naphthyridine-2-carboxylic acid to give the title compound.

Example 262

Preparation of naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide

294

Following the procedure of Example 260 with the exception that quinoline-8-carboxylic acid is replaced by 1-naphthoic acid, the title compound is obtained.

Example 263

Preparation of 3-methylbenzofuran2-carboxylic acid {(1S) -3methyl-1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] -butyl} -amide

a. ) 4 - {(S) -2 - [(3-Methylbenzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1-carboxylic acid, benzyl ester

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 3methylbenzofuran-2-carboxylic acid (0.47 g). The reaction mixture was stirred until complete exhaustion of the starting material was established. Treatment and column chromatography (4: 1 hexanes: ethyl acetate) afforded 1.05 g of the title compound: MS (ESI) 536 (M + H ⁺ ).

b. ) 3-Methylbenzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the procedure of Example 2g with the exception of using the compound of Example 263a, the title compound was obtained: MS (ESI) 402 (M + H ⁺ ).

c. 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 263a with the exception that using the compound of Example 263b and 3methylbenzofuran-2-carboxylic acid was replaced by 3cyclohexylpropionic acid, the title compound was obtained: MS (ESI) 540 (M + H ⁺ ) .

295

d.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 1 with the exception that the compound of Example 263c was used, the title compound was obtained: MS (ESI) 538 (M + H ⁺ ).

Example 264

Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (4-methyl-pentanoyl) -azepan-4-ylcarbamoyl] butyl] -amide

Following the procedures of Example 263c-d with the exception that 3-cyclohexylpropionic acid is replaced by 4methylpentanoic acid, the title compound is obtained: MS (ESI) 498 (M + H ⁺ ).

Example 265

Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedures of Example 263c-d with the exception that 3-cyclohexylpropionic acid is replaced by picolinic acid oxide, the title compound is obtained: MS (ESI) 498 (M + H ⁺ ).

Example 266

Preparation of (S) -acetylamino-4-methyl-pentanoic acid [2L oxo-1- (pyridin-2-sulfonyl) -azepan-4-yl] -amide

Following the procedure of Example 75c-d with the exception that the benzofuran-2-carboxylic acid of step 75c is replaced with acetic acid, the title compound is separated, which is separated by HPLC to give the first eluting diastereomer: MS ( M + H ⁺ ) 425.2; 7 NMR (400 Hz,

296

CDC1 ( ₃ ): · 8.69 (d, 1H), 7.96-7.94 (m, 2H), 7.53-7.52 (m, 1H), 7.05 (m, 1H), 5.92 (m, 1H), 5.08 (m, 1H) , 4.69-4.53 (m, 2H), 4.05-3.90 (m, 2H), 2.80 (m, 1H), 2.25-2.12 (m, 2H), 1.64 (s, 3H), 1.90-1.40 (m, 5H) , 0.95 (m, 6H); and the second eluting diastereomer: MS (M + H ⁺ ): 425.2

Example 267

Preparation of quinoline-2-carboxylic acid {(S) -1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide

a. ) 4 - ((S) -2-tert-Butoxycarbonylamino-hexanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a stirred solution of the amino alcohol of Example 2e (200 mg, 0.74 mmol) in dimethylformamide (4 ml) was added N-Bocnorleucine (175 mg, 0.76 mmol), EDC-HCl (145 mg, 0.76 mmol) and 1hydroxybenzotriazole (21 mg, 0.16 mmol). The reaction was allowed to proceed overnight at room temperature. The following morning, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ , H ₂ O and brine. It was dried over MgSO ₄ , filtered and purified by column chromatography to give 300 mg of the title compound: MS (ESI) 478.11 (M + H) ⁺ .

b. ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester

To a solution of the compound of Example 267a (300 mg, 0.63 mmol) in ethyl acetate (5 ml) was added 10% palladium on carbon (160 mg) and H ₂ from a filled balloon. After stirring the solution at room temperature for 48 hours, the mixture was filtered through celite. The filtrate was concentrated to give the title compound (crude, 161 mg, 0.47 mmol): MS (ESI): 344.19 (M + H) ⁺ .

c. ) {(S) -1- [3-Hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -carbamic acid tert-butyl ester

297

To a solution of the compound of Example 267b (161 mg, 0.47 mmol) in dichloromethane (6 ml) was added triethylamine (0.065 ml, 0.47 mmol) and pyridine-2-sulfonyl chloride (83 mg, 0.47 mmol). After stirring at room temperature for 1 hour, the mixture was washed with saturated NaHCO ₃ solution. The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound (142 mg, 0.29 mmol): MS (ESI): 485.10 (M + H) ⁺ .

d. ) (S) -2-Amino-hexanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide

HCl (4M in dioxane) (0.760 ml, 3.0 mmol) was added to a stirred solution of the compound of Example 267c (142 mg, 0.29 mmol) in ethyl acetate. After stirring the reaction mixture for 1 hour at room temperature, the mixture was concentrated to give a white solid. The solid was azeotroped with toluene twice with a rotary evaporator, then treated with resin bound carbonate (1.47 mmol) in methanol and shaken. After 4 hours, the suspension was filtered and concentrated to give 104 mg of crude product: MS (ESI) 385.08 (M + H) ⁺ .

e. ) Quinoline-2-carboxylic acid {(S) -1- [3-hydroxy-1- (pyridine-

2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide

To a solution of the compound of Example 267d (104 mg, 0.27 mmol) in CH ₂ Cl ₂ was added quinalic acid (47 mg, 0.27 mmol), 1-hydroxybenzotriazole (7.4, 0.055 mmol) and EDC-HCl (52 mg, 0.27 mmol) ) in dimethylformamide (2 ml). After stirring at room temperature overnight, the mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ solution and H ₂ O, dried over MgSO ₄ and filtered to give 172 mg of crude product: MS ( ESI) 539.90 (M + H) ⁺ .

298

f.) Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide

To a stirred solution of the compound of Example 267e (172 mg crude, 0.32 mmol) in 1 ml dimethyl sulfoxide was added sulfur trioxide-pyridine complex (260 mg, 1.6 mmol)) and triethylamine (0.88 ml, 3.2 mmol). After stirring at room temperature for two hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, concentrated and purified by HPLC to give two diastereomers of the title compound as solids (first: 40 mg: second: 43 mg): MS (ESI) 537.86 (M + H) ⁺ .

Example 268

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedures of Example 263a-d with the exception that the 3-methylbenzofuran-2-carboxylic acid of Example 263a is replaced by benzofuran-2-carboxylic acid, the title compound is obtained: MS (ESI) 524 (M + H ⁺ ).

Example 269 [3-Oxo-1- (4-methyl-pentanoyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedures of Example 263a-d with the exception that 3-methylbenzofuran-2-carboxylic acid of Example 263a is replaced by benzofuran-2-carboxylic acid and cyclohexylpropionic acid is replaced by 5-methyl pentanoic acid, the compound is obtained. cited under title: MS (ESI) 484 (M + H ⁺ ).

299

Example 27Q

Preparation of quinoline-2-carboxylic acid {(S) -1- [3-oxo-1 Following the procedure of Example 267a-f with the exception that the N-Boc-norleucine from step 267a is replaced by N-Bocphenylalanine, obtains the title compound. Separation of the mixture by HPLC afforded two diastereomers in the form of solids (first eluting diastereomer:

20.5 mg; second eluting diastereomer: 27 mg): MS (ESI) 571.95 (M + H) ⁺ .

Preparation of benzofuran-2-carboxylic acid {(S) -2-benzyloxy-N - [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 Following the procedure of Example 193e-h except that in step 193e uses N-Boc-O-benzyl-E-serine to give the title compound as a mixture of distereomers. To a solution of benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -ethyl} -amide (90 mg) in ethyl acetate (2 mL) was added 10% Pd / C (50 mg). After the hydrogenolysis of approximately 50% of the starting benzyl ether, the reaction mixture was filtered and concentrated. Purification of this 4-component mixture by HPLC gave 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) ) ⁺ . In addition, two separate diastereomers of benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1 - (- pyridine-2-sulfonyl) -azepane300 are also isolated

4-ylcarbamoyl] -ethyl} -amide, as described below in Example

272

Example 272

Preparation of benzofuran-2-carboxylic acid {(S) -2-hydroxy- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide

The title compound was obtained as described above in Example 271. Purification of the mixture by HPLC gave the two diastereomers in solid form (first eluting diastereomer: 1.6 mg; second eluting diastereomer

2.1 mg): MS (ESI): 500.9 (M + H) ⁺ .

Example 273

Preparation of 5-methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] Following the procedure of Example 75c-d with the exception that the benzofuran-2-carboxylic acid of step 75c is replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting diastereomer as a white solid MS (144.3 mg, 85.1%): MS (ESI) 563.2 (M + H) ⁺ and the second eluting diastereomer as a white solid (16.9 mg, 10.0%) MS (ESI): 563.0 (M + H) ⁺

Example 274

Preparation of 7-methoxybenzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] Following the procedure of Example 75c-d with the exception that the benzofuran-2-carboxylic acid of step 75c is replaced by 7-methoxybenzofuran-2-carboxylic acid,

301 gave the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (75 mg, 47%): MS (ESI) 563.2 (M + H) ⁺ and the second eluting diastereomer under white solid form (57 mg, 35%): MS (ESI) 563.0 (M + H) ⁺ .

Preparation of 3-methylbenzofuran-2-carboxylic acid 1 (S) 2S 2 methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] Following the procedure of Example 75c-d with the exception that the benzofuran-2-carboxylic acid of step 75c is replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting diastereomer as a white solid substance (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) ⁺ .

Example_276

Preparation of benzo [b] thiophene-2-carboxylic acid (S-XL methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] Following the procedure of Example 75c-d with this except that the benzofuran-2-carboxylic acid of step 75c is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained, which is separated by HPLC to give the first eluting diastereomer as a white solid substance (79.5 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) ⁺ .

Example_277

Preparation of 1-methyl-1H-indole-2-carboxylic acid {(S) -3302 butyl} _amide

Following the procedure of Example 75c-d with the exception that the benzofuran-2-carboxylic acid of step 75c is replaced by 1-methyl-indole-2-carboxylic acid, the title compound is obtained, which is separated by HPLC giving the first eluting diastereomer 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) ⁺ .

Example 278 Preparation of Quinoxaline-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the procedure of Example 75c-d with the exception that the benzofuran-2-carboxylic acid of step 75c is replaced by quinoxaline-2-carboxylic acid, the title compound is obtained, which is separated by HPLC affording the first eluting agent. diastereomer as white solid (126 mg, 77%): MS (ESI) 545.2 (M + H) ⁺ and the second eluting diastereomer as white solid (25 mg, 15%): MS (ESI) 545.2 (M + H) ⁺ .

Example 279

Preparation of quinoline-2-carboxylic acid {(S) -1- [1- (4fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the procedure of Example 75 with the exception that benzenesulfonyl chloride is replaced by 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 2quinoline-carboxylic acid, the title compound is obtained. The residue was purified by HPLC. First

303 eluting diastereomer; MS (M + H ⁺ ): 555.2; ¹ H NMR (400 Hz, CDCl ₃ ): .8.62 (d, 1H), 8.34-8.23 (q, 2H) 8.19-8.17 (d, 1H), 7.90-7.88 (d, 1H), 7.88-7.80 (m , 3H), 7.66-7.64 (t, 1H), 7.25-7.07 (m, 3H), 5.08 (m, 1H),

4.72 (m, 1H), 4.58-4.53 (d, 1H), 4.OO (m, 1H), 3.46-3.42 (d, 1H), 2.47 (m, 1H), 2.27-2.12 (m, 2H). 1.90-1.40 (m, 5H), 1.03-1.01 (m, 6H); and second eluting diastereomer: MS (M + H ⁺ ): 555.4.

Example 280 Preparation of Benzofuran-2-Carboxylic Acid __ {(S) -1 - (- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide

a. ) Allyl-pent-4-enyl-carbamic acid benzyl ester

Allylcarbamic acid benzyl ester (7.3 g, 38.2 mmol) was added dropwise to a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in dimethylformamide. The mixture was stirred at room temperature for approximately 10 minutes and then 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction mixture was heated to 40 ° C for about 4 hours and then partitioned between dichloromethane and water. The organic layer was washed with water (2 x) and brine, dried (MgSO ₄ ), filtered and concentrated. Column chromatography of the residue (10% ethyl acetate: hexanes) afforded 10.3 g of the title compound as an oil: MS (ES) 260 (M + H ⁺ ).

b. ) 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid, benzyl ester

To a solution of the compound of Example 280a (50 g) in dichloromethane was added bis (tricyclohexylphosphine) benzylidene ruthenium (1H) dichloride (5.0 g). The reaction mixture was heated to reflux, which was determined by TLC analysis. The reaction mixture was concentrated in vacuo. Column chromatography of the residue (50% dichloromethane: hexanes) afforded 35 g of the title compound: MS (ES) 232 (M + H ⁺ ).

304

c. ) 8-Oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid benzyl ester

To a solution of the compound of Example 280b (35 g, 1.5 mol) in CH ₂ Cl ₂ was added m-CPBA (78 g, 0.45 mol). The mixture was stirred overnight at room temperature and then filtered to remove solids, the filtrate was washed with water and saturated NaHCO ₃ solution (several times). The organic layer was dried (MgSO ₄ ), filtered and concentrated to give 35 g of the title compound, which was sufficiently pure to be used in the next step: MS (ES) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).

d. ) 4-Azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a solution of the epoxide of Example 280c (2.0 g, 8.1 mmol) in methanol: water (8: 1 solution) was added NH ₄ Cl (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). The reaction mixture was heated to 40 ° C until complete exhaustion of the starting epoxide was detected by TLC analysis. The bulk of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and buffer pH 4. The organic layer was washed with saturated NaHCO ₃ solution, water and brine and dried (MgSO ₄ ), filtered and concentrated. Column chromatography (20% ethyl acetate: hexanes) of the residue gave 1.3 g of the title compound: MS (ES) 291 (M + H ⁺ ) plus 0.14 g of trans-4-hydroxy-3-azidohexahydro-1H-azepine.

e. ) 4-Amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a solution of the azidoalcohol of Example 280d (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 mmol). The reaction mixture was stirred until complete depletion by TLC analysis

305 starting material and then the reaction mixture was concentrated in vacuo. Column chromatography of the residue (20% methanol: dichloromethane) afforded 0.72 g of the title compound: MS (ES) 265 (M + H ⁺ ).

f. ) 4 - ((S) -2 - [? Ret-Butoxycarbonylamino-4-methyl-pentanoylamino) -

3-Hydroxy-azepane-1-carboxylic acid benzyl ester

To a solution of the amino alcohol of Example 280f (720 mg, 2.72 mmol) in CH ₂ Cl ₂ was added EDC (521 mg), HOBt (368 mg) and N-Bocleucine (630 mg). The reaction mixture was kept at room temperature until complete exhaustion of the starting material was established by TLC analysis. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl, saturated K ₂ CO _{3 solution} , water and brine, dried (MgSO ₄ ), filtered and concentrated. Column chromatography of the residue (3% methanol: dichloromethane) afforded 1.0 g of the title compound: MS (ES) 478 (M + H ^b ).

Mr Rücker ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester

To a solution of the compound of Example 280f (1.0 g) and 10% Pd / C (catalytic) in ethyl acetate: methanol (2: 1 solution) was placed a hydrogen balloon. The reaction mixture was stirred until complete exhaustion of the starting material was established by TLC analysis. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to give 0.82 g of the title compound: MS (ES) 344 (M + H ⁺ ). j.) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-fluorobenzenesulfonyl) -3-hydroxy-azepan-4-yl] -amide

To a solution of the compound of Example 280g (0.2 g) in dichloroethane (20 mL) was added p-NMM (0.32 g) and 3fluorobenzenesulfonyl chloride (0.11 g). The reaction mixture was stirred until completion of the reaction, which was determined by MS

306 analysis and then filtered and concentrated. The residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL) was added. The reaction mixture was kept at room temperature until complete depletion of the starting material and then concentrated. The residue was dissolved in methanol and then a carbonate resin was added. The mixture was shaken at room temperature for 4 hours, then filtered and concentrated to give 0.64 g of the title compound.

i. ) Benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] 3-methylbutyl} -amide

To a solution of the compound of Example 280h (0.15 g) in CH ₂ Cl ₂ was added benzofuran-2-carboxylic acid (0.56 mmol), HOBt (0.09 mg) and p-EDC (0.75 mg). The reaction mixture was stirred overnight, then trisamine (0.50 g) was added and stirred for an additional 1.5 hours. The reaction mixture was filtered and concentrated to give the title compound.

j. ) Benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl-butyl} amide

To a solution of the compound of Example 280i (0.3 mmol) in CH ₂ Cl ₂ was added periodontin of Dess-Martin (0.25 g). The reaction mixture was stirred until completion of the reaction, which was determined by MS analysis. Treatment and HPLC chromatography gave diastereomer 1: MS (ES) 543.2 (M + H) ⁺ and diastereomer 2: MS (ES)

543.2 (M + H) ⁺ .

Example 28.1

Preparation of (S) -4-Methyl-2- (3-piperidin-1-yl-propanoylamino) 307 amide

Following the general procedures of Examples 280h-j with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 2-pyridinesulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 1-piperidine-propionic acid, the title compound 52 is obtained (MS) 52 (MS). (M + H) ⁺ .

Example 282

Preparation of benzofuran-2-carboxylic acid <X8) -1 - [- (4-ethylbenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-meths-1-butyl} amide

Following the general procedures of Examples 280h-j with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 4-ethylbenzenesulfonyl chloride, the title compound is obtained: Separation of diastereomers yields diastereomer 1 MS (ES) 554.4 (M + H) ⁺ 554.4 (M + 55o.4) 2: MS (ES) 554.4 (M + H) ⁺ .

Example 283

Preparation of 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

a. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a solution of the compound of Example 280f (7.32 g) in methanol was added 4M HCl in dioxane (38 mL). The reaction mixture was stirred until the reaction was complete and then concentrated to give 6.9 g of the title compound as a white solid.

b. 3-Hydroxy-4 - [(S) -4-methyl-2 - ({1- [5- (3-trifluoromethyl-phenyl) -furan-2-yl] -methanoyl} -amino) -pentanoyl amino] azepane -1 Carboxylic acid benzyl ester

308

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 mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. Treatment and column chromatography afforded 1.35 g of the title compound: MS (ES) 616 (M + H) ⁺ .

c. ) 5- [3- (Trifluoromethyl) phenyl] -furan-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

To a solution of the compound of Example 283b (1.3 g) in ethyl acetate: methanol (20 mL of 8: 1 mixture) was added 10% PdC. The mixture was stirred under a hydrogen gas bubble until complete exhaustion of the starting material was established by TLC analysis. The reaction mixture was filtered and concentrated to give 0.96 g of the title compound, which was used directly in the next reaction without further purification.

d. 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [1- (1-oxy-pyridin-2-yl) - methanoyl] azepan-4-ylcarbamoyl} -butyl) -amide

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 N-oxide of picolinic acid (0.09 g). The reaction mixture was stirred at room temperature until completion of the reaction, which was established by TLC analysis. Treatment and column chromatography gave 0.16 g of the title compound: MS (ES) 603 (M + H) ⁺ .

e. 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1- (1-oxy-pyridin-2-yl) - methanoyl] azepan-4-yl carbamoyl} -butyl) -amide

309

To a solution of the compound of Example 283d (0.15 g) in dimethylsulfoxide (1.5 mL) was added TEA (0.37 mL) and pyridine sulfate trioxide complex (0.21 g). The reaction mixture was stirred until the reaction was complete, which was determined by LCMS. Treatment and column chromatography (10% methanol: dichloromethane) afforded 0.12 g of the title compound: MS (ES) 601 (M + H) ⁺ .

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 284

Preparation of benzo [1,3] -dioxole-5-carboxylic acid ((S) -3methyl-1- {3-oxo-1 - [- oxy-pyridin-2-yl) -methanoyl] -azepan-4ylcarbamoyl} - butyl) -amide

Following the general procedures of Examples 283b-e with the exception that 5- [3- (trifluoromethyl) phenyl] -2-furoic acid is replaced by piperic acid, the title compound is obtained: MS (ES) 511 ( M + H) ⁺ .

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 285

Preparation of 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl -butyl} -amide

Following the general procedures of Examples 283b-e with the exception that picolinic acid N-oxide is replaced by 3cyclohexylpropionic acid, the title compound is obtained: MS (ES) 618 (M + H) ⁺ .

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

310

Example 286

Preparation of benzo [1,3] -dioxole-5-carboxylic acid {(S) -1- [1 (3-tert-ethoxypropanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} - amide

Following the general procedures of Examples 283b-e, with the exception that picolinic acid N-oxide is replaced with 3cyclohexylpropionic acid and 5- [3- (trifluoromethyl) phenyl] -2-furoic acid is replaced by piperic acid, the compound is obtained. cited under title: MS (ES) 528 (M + H) ⁺ .

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 287

Preparation of 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl -butyl} -amide

Following the general procedures of Examples 283b-e with the exception that picolinic acid N-oxide is replaced by 4-methyl-pentanoic acid, the title compound is obtained: MS (ES) 578 (M + H) ⁺ .

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 288

Preparation of benzo [1,3] -dioxole-5-carboxylic acid {(S) -1- [1 (4-methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

Following the general procedures of Examples 283b-e, with the exception that picolinic acid N-oxide is replaced with 4methyl-pentanoic acid and 5- [3- (trifluoromethyl) phenyl] -2-furoic acid is replaced by piperic acid the title compound: MS (ES) 488 (M + H) ⁺ .

311

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 289 Preparation of Benzofuran-2-Carboxylic Acid {{8) 1- [3-Oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} _-amide

Following the general procedures of Examples 280h-j with the exception that 3-fluorosulfonyl chloride is replaced by propanesulfonyl chloride, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 491.2 (M + H) ⁺ and diastereomer 2: MS (ES)

491.2 (M + H) ⁺ .

Example 290

Preparation of benzofuran-2-carboxylic acid [(S) -1- [3-oxo-1 (ethanesulfonyl-azepan-4-ylcarbamoyl) -3-methyl-1-butyl] -amide

Following the general procedures of Examples 280h-j with the exception that 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 477.4 (M + H) ⁺ and diastereomer 2: MS (ES) 477.4 (M + H) ⁺ .

Example 291

Preparation of 5-fluoro-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

a.) {(5) -1- [3-Hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

312

Preparation of 2-pyridinesulfonyl chloride-N-oxide: To a solution of 2-mercaptopyridine-N-oxide (2.23 g, 17.55 mmol) in 9M HCl (33 mL) at 0 ° C was bubbled chlorine gas for about 90 minutes. The dissolved chlorine was removed in vacuo at 0 ° C.

To a solution of [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3methyl-butyl] -carbamic acid tert-butyl ester of Example 280g (2.5 g, 7.28 mmol) in CH ₂ Cl ₂ (100 mL ) and a saturated solution of NaHCO ₃ (400 mL) was added dropwise a solution of 2-pyridinesulfonyl chloride-N-oxide (27 mL, 102 mg / mL). An additional saturated solution of NaHCO ₃ was added during the addition to maintain the pH at about 8-9. When the addition of the sulfonyl chloride is complete, the reaction mixture is stirred for another hour and then the organic layer is removed and washed with brine. The organic layer was evaporated and the residue chromatographed (5% methanol: dichloromethane) to give 2.5 g of the title compound: MS (ES) 500 (M + H ⁺ ).

b. ) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-yl] -amide

To a solution of {(S) -1- [3-hydroxy-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester of Example 291a ( 2.0 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated to give 1.8 g of the title compound: MS (ES) 400 (M + H ⁺ ).

c. 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} - amide

313

To a solution of the compound of Example 29 lb (0.30 g) in CH ₂ Cl ₂ was added 5-fluoro-benzofuran-2-carboxylic acid (0.11 g), EDC (0.13 g), HOBt (0.086 g) and TEA (0.22 mL ). The reaction mixture was stirred until completion of the reaction, which was determined by LCMS, then diluted with ethyl acetate and washed with water, saturated K ₂ CO _{3 solution} , 1N HCl and brine, dried (MgSO ₄ ). , filtered and concentrated. Column chromatography (10% methanol: dichloromethane) of the residue gave 0.27 g of the title compound: MS (ES) 563 (M + H) ⁺ .

d.) 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} - amide

To a solution of the compound of Example 29 lc (0.19 g) in dimethylsulfoxide (1.5 mL) was added sulfur trioxide pyridine complex (0.26 g). The reaction mixture was stirred until completion of the reaction, which was determined by LCMS, then diluted with ethyl acetate and washed with saturated NaHCO ₃ solution and brine, dried, filtered and concentrated. Column chromatography of the residue gave 0.15 g of the title compound as a mixture of diastereomers: MS (ES) 561 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Preparation of 5-fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 5-fluoro-3-methyl benzofuran-2-carboxylic acid,

314 obtains the title compound as a mixture of diastereomers: MS (ES) 575 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 293

Preparation of 6-fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 6-fluoro-3-methyl benzofuran-2-carboxylic acid, the title compound is obtained. in the form of a mixture of diastereomers: MS (ES) 575 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 294

Preparation of ...... 3-Methyl-benzofuran-2-carboxylic acid {(R) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general procedures of Examples 280f-i with the exception that N-Boc-L-leucine is replaced by N-Boc-D-leucine, 3-fluorobenzenesulfonyl chloride is replaced by 2-pyridinesulfonyl chloride-1-oxide and benzofuran-2-carboxyl acid is replaced by 3-methyl-benzofuran-2-carboxylic acid to give the title compound: MS (ES) 556 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 295

Preparation of 3-methyl-furo [.3,2-6] -pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-triidin-2- sulfonyl) -azepan-4315

N -carbamoyl] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 3-methyl-furo [3,2-6] -pyridine-2-carboxylic acid, the title compound as a mixture of diastereomers: MS (ES) 558 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 296

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

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 5methoxy-benzofuran-2-carboxylic acid, the title compound is obtained as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 574.5 (M + H) ⁺ and diastereomer 2: 574.5 (M + H) ⁺ .

Example 297

Preparation of 3-methyl-benzofuran-2-carboxylic acid {(S) -1 [1- (3-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 3methyl-benzofuran-2-carboxylic acid, the title compound is obtained in the form of a mixture of diastereomers.

316

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 557.4 (M + H) ⁺ and diastereomer 2: 557.4 (M + H) ⁺ .

Example 298

Preparation of benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the general method of Examples 280h- With the exception that benzofuran-2-carboxylic acid is replaced by benzo (b) thiophene-2-carboxylic acid, the title compound is obtained in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 559.4 (M + H) ⁺ and diastereomer 2: 559.4 (M + H) ⁺ .

Example 299

Preparation of 3-methyl-furan-2-carboxylic acid {(S) -1- (1- (3fluoro-benzene-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylamide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 3methyl-furan-2-carboxylic acid, the title compound is obtained as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 507.2 (M + H) ⁺ and diastereomer 2: 507.4 (M + H) ⁺ .

Example 300

Preparation of quinoline-2-carboxylic acid {(S) -1- (1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

317

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-2-carboxylic acid, the title compound is obtained as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 554.2 (M + H) ⁺ and diastereomer 2: MS (ES)

545.2 (M + H) ⁺ .

Example 301

Preparation of Thieno [3,2-0] Thiophene-2-carboxylic acid {(S) -1- [1 (3-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by thieno [3,2-b] thiophene-2-carboxylic acid, the title compound is obtained as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 565.2 (M + H) ⁺ and diastereomer 2: MS (ES)

565.2 (M + H) ⁺ .

Example 302

Preparation of quinoxaline-2-carboxylic acid {(S) -1- [1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid, the title compound is obtained as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 555.4 (M + H) ⁺ and diastereomer 2: MS (ES)

555.4 (M + H) ⁺ .

318

Example 303

Preparation of thiophene-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by thiophene-2-carboxylic acid, the title compound is obtained as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 509.4 (M + H) ⁺ and diastereomer 2: MS (ES)

509.2 (M + H) ⁺ .

Example 304

Preparation of 5-methyl-thiophene-2-carboxylic acid {(S) -1- [1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the general method of Examples 280h- With the exception that benzofuran-2-carboxylic acid is replaced by 5methyl-thiophene-2-carboxylic acid, the title compound is obtained in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 523.2 (M + H) ⁺ and diastereomer 2: MS (ES)

523.4 (M + H) ⁺ .

Example 305

Preparation of 5-methoxy-benzofuran-2-carboxylic acid [(S) 1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Examples 280h-j except that benzofuran-2-carboxylic acid is replaced by 5methoxy-benzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is obtained by ethanesulfonyl chloride

319 the title compound as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 507.4 (M + H) ⁺ and diastereomer 2: MS (ES)

507.4 (M + H) ⁺ .

Example 306

Preparation of 3-methyl-benzofuran-2-carboxylic acid [(S) -1 (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 3methyl-benzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride to give the title compound the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 491.2 (M + H) ⁺ and diastereomer 2: MS (ES)

491.2 (M + H) ⁺ .

Example 307

Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride to give the title compound , in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 493.4 (M + H) ⁺ and diastereomer 2: MS (ES)

493.4 (M + H ⁺ ).

320

Example 308

Preparation of N-methyl-furan-2-carboxylic acid [(S) -1- (1 ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide Following the general method of Examples 280h -j with the exception that benzofuran-2-carboxylic acid is replaced by 3methyl-furan-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride, the title compound is obtained in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 441.2 (M + H) ⁺ and diastereomer 2: MS (ES)

441.2 (M + H) ⁺ .

Example 309

Preparation of quinoline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide Following the general method of Examples 280h-j with this exception that benzofuran-2-carboxylic acid is replaced by quinoline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride to give the title compound as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 488.2 (M + H) ⁺ and diastereomer 2: MS (ES)

488.2 (M + H) ⁺ .

Example 310

Preparation of Thieno [3.2-L] Thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by thieno [3,2-b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride

321 the title compound as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 499.4 (M + H) ⁺ and diastereomer 2: MS (ES)

499.4 (M + H) ⁺ .

Example 311

Preparation of quinoxaline-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride, the title compound is obtained a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 489.2 (M + H) ⁺ and diastereomer 2: MS (ES)

489.2 (M + H) ⁺ .

Example 312

Preparation of thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride, the title compound is obtained a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 443.4 (M + H) ⁺ and diastereomer 2: MS (ES)

443.2 (M + H) ⁺ .

Example 313

Preparation of 5-methyl-thiophene-2-carboxylic acid [(S) -1- (1 322 ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amip

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 5methyl-thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by ethanesulfonyl chloride to give the title compound the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 457.2 (M + H) ⁺ and diastereomer 2: MS (ES)

457.4 (M + H) ⁺ .

Example 314

Preparation of 5-methoxy-benzofuran-2-carboxylic acid {(S) 1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 5methoxy-benzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride to give the title compound , in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 521.4 (M + H) ⁺ and diastereomer 2: MS (ES)

521.2 (M + H) ⁺ .

Example 315

Preparation of 3-methyl-benzofuran-2-carboxylic acid <(S) -1 [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 3-methyl-benzofuran-2-carboxylic acid and 3-fluorobenzene323 sulfonyl chloride is replaced by 1-propanesulfonyl chloride to give the compound, the title, in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 505.4 (M + H) ⁺ and diastereomer 2: MS (ES)

505.2 (M + H) ⁺ .

Example 316

Preparation of benzo [b] thiophene-2-carboxylic acid {(S) -1- [3oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1 butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride to give the compound, in the title, in the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 507.4 (M + H) ⁺ and diastereomer 2: MS (ES)

507.4 (M + H) ⁺ .

Example 317

Preparation of 3-methyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-yl carbamoyl] -3-methyl-1-butylE-amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 3-methyl-furan-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride to give the compound indicated in the title compound , in the form of a mixture of diastereomers.

324

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 455.2 (M + H) ⁺ and diastereomer 2: MS (ES)

455.4 (M + H) ⁺ .

Example 318 of 2,5-Dimethyl-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3methyl-1-butyl} - amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by

2,5-Dimethyl-benzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride are replaced by 1-propanesulfonyl chloride to give the title compound as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 469.4 (M + H) ⁺ and diastereomer 2: MS (ES)

469.2 (M + H) ⁺ .

Example 319

Preparation of quinoline-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-yl carbamoyl] -3-methyl-1-butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by quinoline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride, the title compound is obtained the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 565.2 (M + H) ⁺ and diastereomer 2: MS (ES)

565.2 (M + H) ⁺ .

Example 320

Preparation of thieno [3,2- f] thiophene-2-carboxylic acid {(S) -1- [3325 oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1 -butylTamid

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by thieno [3,2-b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride; obtains the title compound as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 513.2 (M + H) ⁺ and diastereomer 2: MS (ES)

513.2 (M + H) ⁺ .

Example 321

Preparation of quinoxaline-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride to give the title compound the form of a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 503.4 (M + H) ⁺ and diastereomer 2: MS (ES)

503.4 (M + H) ⁺ .

Example 322

Preparation of thiophene-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide

Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride

326 is replaced by 1-propanesulfonyl chloride to give the title compound as a mixture of diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 457.4 (M + H) ⁺ and diastereomer 2: MS (ES)

457.4 (M + H) ⁺ .

Example 323

Preparation of 5-methyl-thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1 Following the general method of Examples 280h-j with the exception that benzofuran-2-carboxylic acid is replaced by 5methyl-thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced by 1-propanesulfonyl chloride to give the title compound as the title diastereomers.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 471.4 (M + H) ⁺ and diastereomer 2: MS (ES)

471.4 (M + H) ⁺ .

Example 324

Preparation of 5-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 5-methoxy-3-methyl-benzofuran-2-carboxylic acid, the title compound is obtained , in the form of a mixture of diastereomers: MS (ES) 587 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 565.2 (M + H) ⁺ and diastereomer 2: MS (ES)

565.2 (M + H) ⁺ .

327

Example 325

Preparation of 3,5-dimethyl-benzofuran-2-carboxylic acid {(S) -3-Methyl-1- (3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 3,5-dimethyl-benzofuran-2-carboxylic acid, the title compound is obtained under form of mixture of diastereomers: MS (ES) 571 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 326

Preparation of 3-ethyl-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 3-ethyl-benzofuran-2-carboxylic acid, the title compound is obtained as diastereomer mixture: MS (ES) 571 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 327

Preparation of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 4-methoxy-3-methyl-benzofuran-2-carboxylic acid,

328 to give the title compound as a mixture of diastereomers: MS (ES) 587 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 328

Preparation of 1-methyl-naphtho [2,1-b] -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 1-methyl-naphtho [2,1-6] -furan-2-carboxylic acid, the title compound as a mixture of diastereomers: MS (ES) 607 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Preparation of 6-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by 6-methoxy-3-methyl-benzofuran-2-carboxylic acid, the title compound is obtained , in the form of a mixture of diastereomers: MS (ES) 587 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1 and diastereomer 2.

Example 330

Preparation of 3-methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide

329

a. ) 4- (2-tert-1-Butoxycarbonylamino-2,4-dimethyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester

To a solution of N - [(1,1-dimethylethoxy) carbonyl] -2-methyl (cC) -leucine (3.0 g) in methylene chloride was added EDC (2.34 g), HOBt (1.65 g), Et ₃ N (1.7 ml). ) and the compound of Example le (3.23 g). After stirring at room temperature overnight, the mixture was washed with 0.1N HCl, saturated NaHCO ₃ solution, H ₂ O and brine. The organic layer was concentrated and the residue purified by flash column chromatography eluting with CH ₂ Cl ₂ : CH ₃ OH (95: 5) to give the title compound as a white solid (4.0 g, 66.6%). MS: 492.4 (M + H) ⁺ .

b. ) [1- (3-Hydroxy-azepan-4-ylcarbamoyl) -1,3-dimethyl-butyl] -carbamic acid tert-butyl ester

To a solution of the compound of Example 330 (a) (3.04 g, 8.00 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (1.5 g). After stirring at room temperature under hydrogen for 16 hours, the mixture was filtered through celite. The filtrate was concentrated to give the title compound as a yellow oil (1.97 g, 100%). MS (ESI):

358.4 (M + H) ⁺ .

c. ) {- [3-Hydroxy-1- (1-hydroxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -1,3-dimethyl-butyl} -carbamic acid tert-butyl ester

2-Mercaptan-N-oxide (1.25 g) was dissolved in concentrated HCl (5.5 ml). After cooling to 0 ° C, water (3 ml) was added. Through the solution for 1.5 hours passed C1 ₂ gas. The aqueous solution was extracted with cold CH ₂ Cl ₂ then mixed

The 330 organic layers were washed with saturated NaHCO ₃ solution and brine. To a solution of the compound of Example 330b (1.20 g) and Et ₃ N (1.3 ml) in 1,2-dichloroethane (10 ml) was added the freshly prepared sulfonyl chloride prepared above at 0 ° C. Stirring was maintained for 1 hour, after which the reaction mixture was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography eluting with CH ₂ Cl ₂ : CH ₃ OH (95: 5 ). The filtrate was concentrated to give the title compound as a white solid (1.2 g, 70%). MS:

515.4 (M + H) ⁺ .

d. ) 2-Amino-2,4-dimethyl-pentanoic acid [3-hydroxy-1- (hydroxy-pyridine-2-sulfonyl) -azepan-4-yl] -amide

HCl (4M in dioxane) (10 ml) was added to a stirred solution of the compound of Example 3O3 (1.0 g, 2.04 mmol) in methanol (10 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of this white solid (0.81 g, 1.53 mmol, 75%) in methanol (30 ml) was added P-CO ₃ (2.9 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.57 g, 1.45 mmol, 95%). MS: 415.4 (M + H) < + &gt;.

e. 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

To a solution of the compound of Example 330d (0.150 g, 0.448 mmol) in CH ₂ Cl ₂ (20 mL) was added 3-methyl-benzofuran-2-carboxylic acid (0.109 g), 1-hydroxybenzotriazole (0.106g, 0.762 mmol) and P -EDC (0.85 g, 1 mmol / g) in CH ₂ Cl ₂ (10 mL). Next

331 shaking at room temperature overnight was treated with trisamine (0.589 g, 3.75 mmol / g). After shaking for an additional 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (166.7 mg, 70%). MS (ESI): 573.2 (M + H) ⁺ .

f.) 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-oxo-1- (oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

To a stirred solution of the compound of Example 30Oe (140.7 mg, 0.245 mmol) in dimethyl sulfoxide (2 mL) was added PySO ₃ (155.7 mg, 0.98 mmol) and Et ₃ N (0.27 mL, 1.96 mmol). After stirring at room temperature for 2 hours, a saturated solution of NaHCO ₃ and ethyl acetate were added to deactivate the reaction mixture. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography eluting with CH ₂ Cl ₂ : CH ₃ OH (95: 5) to give the title compound as a white solid (69.9 mg, 50.8%). MS (ESI): 571.2 (M + H) ⁺ .

Example 313 Preparation of benzofuran-2-carboxylic acid [(S) -3-methyl-1 [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] -butyl} -amide

a.) [(S) -1- (3-Hydroxy-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl) 3-methyl-butyl] -carbamic acid tert-butyl ester

To a solution of the compound of Example 280g (1.0 g) in CH ₂ Cl ₂ was added α-quinolinecarbaldehyde (0.68 g) and NaBH (OAc) ₃ (1.2 g). Treatment and column chromatography (6% methanol: dichloromethane) gave 1.4 g of the title compound: MS (ES) 485 (M + H) ⁺ .

332

b. (S) -2-Amino-4-methyl-pentanoic acid (3-hydroxy-1-quinoline-

2-methyl-azepan-4-yl) -amide

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 mixture was stirred until the reaction was complete and then concentrated to give 1.3 g of the title compound: MS (ES) 385 (M + H) ⁺ .

c. ) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-hydroxy-

1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] -butyl} -amide

Following the general method of Example 291c with the exception of using the compound of Example 33 lb and benzofuran-2-carboxylic acid in place of 5-fluorobenzofuran-2-carboxylic acid, the title compound was obtained: MS (ES (ES ) 545 (M + H) ⁺ .

d. ) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] -butyl} -amide

Following the general method of Example 29Id with the exception that the compound of Example 332c was used, the title compound was obtained: MS (ES) 543 (M + H) ⁺ .

Preparation of 3-methyl-benzofuran-2-carboxylic acid [(S) -3methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 331c-d with the exception that benzofuran-2-carboxylic acid is replaced by 3methyl-benzofuran-2-carboxylic acid, the title compound is obtained: MS (ES) 541 (M + H) ⁺ .

Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -3333 methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] butyl} -amide

Following the procedure of Example 33 lc-d with the exception that benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained: MS (ES) 541 (M + H) ⁺ .

Example 334

Preparation of benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) -amide

a. ) ((S) -1- {3-Hydroxy-1- [1- (toluene-2-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -3-methyl-butyl) -carbamic acid tert-butyl ester

To a solution of the compound of Example 280g (1.0 g) in CH ₂ Cl ₂ was added o-toluenesulfonyl isocyanate (0.68 g). The reaction mixture was stirred until complete exhaustion of the starting material was established. Treatment and column chromatography (6% methanol: dichloromethane) afforded 1.28 g of the title compound: MS (ES) 541 (M + H) ⁺ .

b. (S) -2-Amino-4-methyl-pentanoic acid {3-hydroxy-1- [1- (toluene-2-sulfonylamino) -methanoyl] -azepan-4-yl} -amide

Following the procedure of Example 280g, with the exception that the compound of Example 334a was used, the title compound was obtained: MS (ES) 441 (M + H) ⁺ .

c. ) Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-

- [1 - (That luen-2-sulfonyl amino) -methanoyl] -azepan-4yl carbamoyl} -butyl) -amide

Following the procedure of Example 280i with the exception of using the compound of Example 334b, the title compound was obtained: MS (ES) 585 (M + H) ⁺ .

d.) Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1 (toluene-2-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} butyl) -amide

Following the procedure of Example 29 Id with the exception of using the compound of Example 334c, the title compound was obtained: MS (ES) 583 (M + H) ⁺ .

Example 335

Preparation of 3-methyl-benzofuran-2-carboxylic acid ((S) -3methyl-1- {3-oxo-1- [1- (toluene-2-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) - amide

Following the procedures of Example 334c-d with the exception that benzofuran-2-carboxylic acid is replaced by 3methyl-benzofuran-2-carboxylic acid, the title compound is obtained: MS (ES) 597 (M + H) ⁺ .

Preparation of benzo [b] thiophene-2-carboxylic acid ((S) -3ylcarbamoyl} -butyl) -amide

Following the procedures of Example 334c-d with the exception that benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained: MS (ES) 599 (M + H) ⁺ .

Example 337

Preparation of benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [2- (chloro-benzenesulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) -amide

-> p

5

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by 2chlorobenzenesulfonylisocyanate, the title compound is obtained: MS (ES) 603 (M + H) ⁺ .

Example 338

Preparation of 3-methyl-benzofuran-2-carboxylic acid ((S) -3methyl-1- (3-oxo-1- [2- (chloro-benzenesulfonylamino) -methanoyl] azepan-4-ylcarbamoyl} -butyl) -amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by 2-chlorobenzenesulfonylisocyanate and benzofuran-2-carboxylic acid is replaced by 3-methyl-benzofuran-2-carboxylic acid, the title compound is obtained MS (ES) 617 (M + H) ⁺ .

Example 339

Benzo [b] thiophene-2-carboxylic acid ((S) -3methyl-1- {3-oxo-1- [2- (chloro-benzenesulfonylamino) -methanoyl] azepan-4-yl carbamoyl} -butyl) -amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by 2-chlorobenzenesulfonylisocyanate and benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the compound is obtained MS (ES) 619 (M + H) ⁺ .

Example 340

Preparation of benzofuran-2-carboxylic acid ((R) -3-methyl-1 {3-oxo-1- [4- (fluoro-benzenesulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) -amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by 4336 fluorobenzenesulfonylisocyanate, the title compound is obtained: MS (ES) 587 (M + H) ⁺ .

Example 341

Preparation of 3-methyl-benzofuran-2-carboxylic acid ((S) -3methyl-N- {3-oxo-1- [4- (fluoro-benzenesulfonylamino) -methanoyl] azepan-4-ylcarbamoyl} -butyl) -amide

Following the procedures of Example 334-d with the exception that o-toluenesulfonylisocyanate is replaced by 4fluorobenzenesulfonylisocyanate and benzofuran-2-carboxylic acid is replaced by 3-methyl-benzofuran-2-carboxylic acid, the title compound is obtained MS (ES) 601 (M + H) ⁺ .

Example 342

Preparation of benzo [b] thiophene-2-carboxylic acid ((S) -3methyl-1- {3-oxo-1- [4- (fluoro-benzenesulfonylamino) -methanoyl] azepan-4-yl carbamoyl} -butyl) - amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by 4fluorobenzenesulfonylisocyanate and benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained MS (ES) 603 (M + H) ⁺ .

Example 343

Preparation of benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1- (toluene-4-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) -amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by p-toluenesulfonylisocyanate, the title compound is obtained: MS (ES) 583 (M + H) ⁺ .

337

Example 344

Preparation of 3-methyl-benzofuran-2-carboxylic acid ((S) -3methyl-1- {3-oxo-1- [1- (toluene-4-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) - amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by p-toluenesulfonylisocyanate and benzofuran-2-carboxylic acid is replaced by 3-methyl-benzofuran-2-carboxylic acid to give the title compound: MS (ES) 597 (M + H) ⁺ .

Example 345

Preparation of benzo [b] thiophene-2-carboxylic acid ((S) -3methyl-1- {3-oxo-1- [1- (toluene-4-sulfonylamino) -methanoyl] -azepan-4yl carbamoyl} -butyl) -amide

Following the procedures of Example 334a-d with the exception that o-toluenesulfonylisocyanate is replaced by rtoluenesulfonylisocyanate and benzofuran-2-carboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid to give the title compound MS (ES) 597 (M + H) ⁺ .

Example 346

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] Following the general procedures of Example 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 6methylpyridin-2-aldehyde, the title compound is obtained: MS (ES) 491 (M + H) ⁺ .

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

338

Example 347

Preparation of 3-methyl-benzofuran-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide

Following the general procedures of Example 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 6methylpyridin-2-aldehyde and benzofuran carboxylic acid is replaced by 3-methyl-benzofuran-2-carboxylic acid, the compound specified in title: MS (ES) 505 (M + H) +.

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 348

Preparation of benzo [b] thiophene-2-carboxylic acid {(S) -3methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide

Following the general procedures of Example 331a-d with the exception that cs-quinolinecarbaldehyde is replaced by 6methylpyridin-2-aldehyde and benzofurancarboxylic acid is replaced by benzo [b] thiophene-2-carboxylic acid, the title compound is obtained : MS (ES) 507 (M + H) +.

The diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.

Example 349

Preparation of benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl.) {(8) -1 - [1- (2-Fluorophenylcarbamoyl) -3-hydroxy-azepan-4ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester

339

To a solution of the compound of Example 280g (0.1 g, 0.29 mmol) dissolved in tetrahydrofuran was added 2fluorophenylisocyanate (32 ml, 0.29 mmol) and stirred for 1 hour. The tetrahydrofuran was removed in vacuo and the compound used directly in the next step: MS (ES): 481.02 (M + H) +.

b. ) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid (2-fluoro-phenyl) -amide

To a solution of the compound of Example 349a (1.96 g, 4.1 mmol) dissolved in MeOH was added 4M HCl / dioxane (5 ml, 20.3 mmol) and allowed to stir at room temperature for 2 hours. The excess reagent was azeotropically removed with toluene in vacuo to give 1.84 g of product.

c. ) Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

To a solution of the compound of Example 349b (0.11 g, 0.28 mmol) dissolved in dichloromethane was added P-EDC (0.35 g, 1.8 mmol / g), HOBT (0.06 g, 0.49 mmol) and 2-benzothiophene carboxylic acid (0.077 g, 0.432 mmol). The reaction mixture was shaken for 16 hours. The reaction was maintained for another hour by adding trisamine (0.38 g, 3.7 mmol / g), after which the product was filtered. It was purified on a silica gel column to give 112.5 mg of the product: MS (ES): 541.2 (M + H) ⁺ .

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

The compound of Example 349c (0.112 g, 0.2 mmol) was dissolved in dichloromethane and then Dess-Martin periodinine (0.175 g, 0.41 mmol) was added. The reaction mixture was stirred for 1 hour and then washed with Na ₂ S ₂ O ₃ , NaHCO ₃ and brine.

340

The compound was purified on a silica gel column to give 78 mg of the product as a mixture of diastereomers. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 539 (M + H) ⁺ and diastereomer 2: 539 MS (ES) (M + H) ⁺ .

Example 350

Preparation of 3-methyl-benzofuran-2-carboxylic acid _ {_ (5) -1 [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 3-methyl-benzofuran-2-carboxylic acid, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 537 (M + H) ⁺ and diastereomer 2: MS (ES) 537 (M + H) ⁺ .

Example 351

Preparation of 2,4-dimethylfuran-3-carboxylic acid {(S) -1- [1 (2-fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylamide

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 2,4-dimethylfuran-3-carboxylic acid, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 501 (M + H) ⁺ and diastereomer 2: MS (ES) 501 (M + H) ⁺ .

Example 352

Preparation of quinoxaline-2-carboxylic acid {(S) -1- [1- (2fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

341

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by quinoxaline-2-carboxylic acid, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 535 (M + H) ⁺ and diastereomer 2: MS (ES) 535 (M + H) ⁺ .

Example 353

Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1 (2-fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoid] -3-methylbutyl} -amide

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by thieno [3,2-b] thiophene-2-carboxylic acid, the title compound is obtained .

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 545 (M + H) ⁺ and diastereomer 2: MS (ES) 545 (M + H) ⁺ .

Example 35..4

Preparation of quinoline-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by quinoline-2-carboxylic acid, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 534 (M + H) ⁺ and diastereomer 2: MS (ES) 534 (M + H) ⁺ .

342

Example 355

Preparation of 4-methylthiophene-2-carboxylic acid {(S) -1- [1- (2fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl Following the general procedures of Example 349c-d with this exception, that benzo [b] thiophene-2-carboxylic acid is replaced by 4-methyl-thiophene-2-carboxylic acid, gives the title compound.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 503 (M + H) ⁺ and diastereomer 2: MS (ES) 503 (M + H) ⁺ .

Example 356

Preparation of 5-methoxy-benzofuran-2-carboxylic acid {(S) 1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepan-4-yl carbamoyl] -3methyl-butyl} -amide

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 5-methoxy-benzofuran-2-carboxylic acid, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 553 (M + H) ⁺ and diastereomer 2: MS (ES) 553 (M + H) ⁺ .

Example 357

Preparation of 4-methyl-furan-2-carboxylic acid {(S) -1- [1- (2fluoro-phenyl-carbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutylamide

Following the general procedures of Example 349c-d with the exception that benzo [b] thiophene-2-carboxylic acid is replaced by 4-methyl-furan-2-carboxylic acid, the title compound is obtained.

343

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 487 (M + H) ⁺ and diastereomer 2: MS (ES) 487 (M + H) ⁺ .

Example 358

Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-butyl 3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by butyraldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 441.9 (M + H) ⁺ and diastereomer 2: MS (ES) 441.9 (M + H) ⁺ .

Example 359 Preparation of Benzofuran-2-carboxylic acid [(S) -1- (1-propyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced with propionaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 428 (M + H) ⁺ and diastereomer 2: MS (ES) 428 (M + H) ⁺ .

Example 360

Preparation of benzofuran-2-carboxylic acid {(S) -1- (1- (494.2) 3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 2fluorobenz aldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) (M + H) ⁺ and diastereomer 2: MS (ES)

494.2 (M + H) ⁺ .

344

Example 361

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (2-morpholin-4-yl-thiazol-4-yl methyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} - amide

Following the general method of Examples 3a-d with the exception that α-quinolinecarbaldehyde is replaced by 2-morpholine-4-yl-thiazole-4-carbaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 568.2 (M + H) ⁺ and diastereomer 2: MS (ES) 568.4 (M + H) ⁺ .

Example 362

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (5-ethyl-furan-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 5-ethyl-2furaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 549.4 (M + H) ⁺ and diastereomer 2: MS (ES) 549.4 (M + H) ⁺ .

Example 363

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethyl-thieno [3,2-b] thiophen-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -3- methyl-butyl} -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 3,4-dimethylthieno [b] thiophene-2-carboxaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 566.2 (M + H) ⁺ and diastereomer 2: MS (ES) 566.2 (M + H) ⁺ .

345

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1-ylcarbamoyl] -butyl} -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 2-phenyl-2Hpyrazole-3-carbaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 543.2 (M + H) ⁺ and diastereomer 2: MS (ES) 543.4 (M + H) ⁺ .

Example 365

Preparation of benzofuran-2-carboxylic acid [(S) -1- [1 (isothiazol-3-ylmethyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl} -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by isothiazole-3carbaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 483.1 (M + H) ⁺ and diastereomer 2: MS (ES)

483.1 (M + H) ⁺ .

Example 366

Preparation of benzofuran-2-carboxylic acid [(B) -3-methyl-1 (3-oxo-1-thiophen-2-ylmethyl-azepan-4-ylcarbamoyl) -butyl] -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by thiophene-2carbaldehyde, the title compound is obtained.

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 582 (M + H) ⁺ and diastereomer 2: MS (ES) 582 (M + H) ⁺ .

346

Example 367 Preparation of Benzofuran-2-Carboxylic Acid [(S) -3-Methyl-1 (3-oxo-1-thiophen-2-ylmethyl-azepan-4-ylcarbamoyl) -butyl] -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by benzo [b] thiophene-2-carbaldehyde, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 546 (M + H) ⁺ and diastereomer 2: MS (ES) 546 (M + H) ⁺ .

Example 368

Preparation of benzofuran-2-carboxylic acid [(B) -3-methyl-1 (3-oxo-1-pentyl-azepan-4-ylcarbamoyl) -butyl] -amide

Following the general method of Examples 331a-d, with the exception that α-quinolinecarbaldehyde is replaced by pentane, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 556 (M + H) ⁺ and diastereomer 2: MS (ES) 556 (M + H) ⁺ .

Example 369

Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-t-1 [1- (1-methyl-1-H-imidazol-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] - butyl} -amide

Following the general method of Examples 331a-d with the exception that α-quinolinecarbaldehyde is replaced by 3-methyl-3H-imidazole-4-carbaldehyde, the title compound is obtained: MS (ES) 480.4 (M + H) ⁺ .

Example 370

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

347

Following the procedure of Example 280h-j with the exception that 2-benzofuran-2-carboxylic acid is replaced by

1-oxy-pyridine-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride are replaced by 2-pyridinesulfonyl chloride to give the title compound. Separation of diastereomers by HPLC gave diastereomer 1: (ESMS: M + H ⁺ = 504.2) and diastereomer 2: (ESMS: M + H ⁺ = 504.2).

Example 371

Preparation of 2-oxy-pyridine-3-carboxylic acid {(S) -3methyl-1- [3-oxo-1 - (- pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butylamide

Following the procedure of Example 280h-j with the exception that 2-benzofuran-2-carboxylic acid is replaced by

2- Oxy-pyridine-3-carboxylic acid and 3-fluorobenzenesulfonyl chloride are replaced by 2-pyridinesulfonyl chloride to give the title compound. Separation of diastereomers by HPLC gave diastereomer 1: (ESMS: M + H ⁺ = 504.2) and diastereomer 2: (ESMS: M + H ⁺ = 504.2).

Example 372

Preparation of 1H-benzoimidazole-5-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butylamide

Following the procedure of Example 280h-j, with the exception that 2-benzofuran-2-carboxylic acid is replaced by 1H-benzoimidazole-5-carboxylic acid and 3-fluorobenzenesulfonyl chloride is substituted with the 2-compound to give the compound the title. Separation of diastereomers by HPLC gave diastereomer 1: (ESMS: M + H ⁺ = 504.2) and diastereomer 2: (ESMS: M + H ⁺ = 504.2).

348

Example 3.73 Preparation of 4 - {(S) -2 - [(1-benzofuran-2-yl-methanoyl) -amino] -4methyl-pentanoylamino} -1-methyl-3-oxo-1-pentyl-azepane

A solution of the compound of Example 368 in pure methyl iodide was heated at reflux for 48 hours and then the mixture was concentrated to give the title compound: MS (ES) 471.6 (M + H) ⁺ .

Example 374

Preparation of benzofuran-2-carboxylic acid {(S) -1- (1- (1,2-dimethyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 280h-j with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 1,2dimethyl-1H-imidazole-4-sulfonyl chloride to give the title compound: MS (ES) 544.4 (M + H) ⁺ .

Example 375

Preparation of benzofuran-2-carboxylic acid __ {(S) -1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 280h-1 with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 1methyl-1H-imidazole-4-sulfonyl chloride, the title compound is obtained: MS (ES) 530.2 (M + H) ⁺ .

Example 376

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

Following the procedure of Example 280h-j with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 4methanesulfonylbenzenesulfonyl chloride, the compound is obtained,

349 referred to in the title. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 604.2 (M + H) ⁺ and diastereomer 2: MS (ES) 604.2 (M + H) ⁺ .

Example 377

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (2methanesulfonyl-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} -amide

Following the procedure of Example 280h-j with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 2methanesulfonylbenzenesulfonyl chloride, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 604.2 (M + H) ⁺ and diastereomer 2: MS (ES) 604.2 (M + H) ⁺ .

Example 378

Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-isoxazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3m.ethyl-butyl} - amide

Following the procedure of Example 280h-1 with the exception that 3-fluorobenzenesulfonyl chloride is replaced by 3,5-dimethyl-isoxazole-4-sulfonyl chloride, the title compound is obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 545.2 (M + H) ⁺ and diastereomer 2: MS (ES) 545.2 (M + H) ⁺ .

Example_372

Preparation of 3-methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4ylcarbamoyl] -butide} -amide

a.) 3-Methyl-benzofuran-2-carboxylic acid {(18,2K) -2-methyl-1 [3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide

350

Following the general procedures of Example 280f-1 with the exception that N-Boc-leucine is replaced by N-Boc-allo-isoleucine, 3-fluorobenzenesulfonyl chloride with 2-pyridinesulfonyl chloride and benzofuran-2-carboxylic acid is replaced by 3-methylbenzoisobenzoate. 2-carboxylic acid, the title compound was obtained.

B.) 3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-Methoxy-1 [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide

Following the general method of Example 29Id with the exception that using the compound of Example 105b, the title compound was obtained. Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 541 (M + H) ⁺ and diastereomer 2: MS (ES) 541 (M + H) ⁺ .

Example 380 Preparation of 3-methyl-benzofuran-2-carboxyl. {1- [3-Oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -cyclopentyl} -amide

Following the general procedures of Examples 3-79a-b with the exception that N-Boc-allo-leucine is replaced by N-Boc-cyclo-leucine, the title compound is obtained: MS (ES) 539 (M + H) + .

Example 381

Preparation of furo [3,2-6] -pyridine-2-carboxylic acid {(S) -3methyl-1 - [- 3-oxo-1- (1-oxy-pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl ] -butyl} -amide

Following the general method of Examples 291c-d with the exception that 5-fluoro-benzofuran-2-carboxylic acid is replaced by furo [3,2-b] -pyridine-2-carboxylic acid,

351 the title compound as a mixture of diastereomers: MS (ES) 587 (M + H) ⁺ .

Separation of diastereomers by HPLC gave diastereomer 1: MS (ES) 544.2 (M + H) ⁺ and diastereomer 2: MS (ES)

544.2 (M + H) ⁺ .

The above specification and the examples fully disclose how to prepare and use the compounds of the present invention. However, the invention is not limited to the individual embodiments described above, but includes all modifications thereof within the scope of the following claims. References to journals, patents, and other publications cited herein cover the present state of the art and are incorporated herein by reference as set forth herein in their entirety.

Claims (65)

Patent Claims 1. A compound of formula IA: wherein: R ¹ is selected from the group consisting of: R is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ . alkyl, HTC ₀ . ₆ alkyl, R ^{7 * 9} C (O) -, R ⁹ SO 2 -, R ⁹ R ⁿ NC (O) -, and R ⁹ SO ² R ⁿ NC (O) -; α R is C _1-6 alkyl; R ⁴ is R ⁵ C (O) -; R ⁵ is He 1 -C ₀ . ₆ alkyl; R ⁹ is selected from the group consisting of: Sweet, C 3-6 cycloalkyl-C ₀ . ₆ alkyl, Ar-C ₀ . ₆ alkyl and HTC ₀ . ₆ alkyl; R is selected from the group consisting of: H, Rock, Ar-C0-6alkyl and Het-C0-6alkyl; R'eH; R is H; 353 R 'is Η; R is selected from the group consisting of: C 1-6 alkyl, C _3-6 . cycloalkyl-alkyl, C ^ alkenyl, C ₂ .balkinil, Ne1S _{0. 6} alkyl and ArC ₀ . ₆ alkyl; η is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof. The compound of claim 1, wherein R ¹ is a The compound of claim 1, wherein R is selected from the group consisting of: isobutyl and but-2-yl. The compound of claim 3, wherein R is isobutyl. The compound of claim 1, wherein R ⁵ is selected from the group consisting of: piperidinyl-ethyl; benzo [1,3] dioxolyl; furanyl, aryl-substituted furanyl, C 1-6 alkyl-substituted furanyl; benzofuranyl, C 1-6 alkoxy-substituted benzofuranyl, halogen-substituted benzofuranyl, C 1-6 alkyl-substituted benzofuranyl; petroleum [2,1 - &] - furanyl, C ₁ . ₆ alkyl-substituted naphtho [2,1-6] furanyl; benzo [O] thiophenyl; quinolinyl; quinoxalinyl; 1-oxy-pyridinyl; 354 furo [3,2-0] -pyridinyl, C 1-6 alkyl-substituted furo [3,2-b] pyridinyl; thiophenyl, C 1-6 alkyl-substituted thiophenyl; and thieno [3,2-0] thiophenyl; and 1H-benzoimidazol-5-yl. The compound of claim 1, wherein R ⁵ is selected from the group consisting of: piperidin-1-yl-ethyl; benzo [1,3] dioxol-5-yl; furan-2-yl; benzofuran-2-yl; petroleum [2,1 - &] - furan-2-yl; benzo [6] thiophen-2-yl; quinolin-2-yl; quinoxalin-2-yl; 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; furo [3,2-b] -pyridin-2-yl; thiophen-2-yl; thieno [3,2-b] thiophen-2-yl; and 1H-benzoimidazol-5-yl. The compound of claim 1, wherein R ⁵ is selected from the group consisting of: 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-2yl; 5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3-ethylbenzofuran-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- silt; 355 1-methyl-naphtho [2,1-5] -furan-2-yl; 5-methyl-thiophen-2-yl 3-methyl-furo [3,2-6] -pyridin-2-yl. The compound of claim 1, wherein R ⁵ is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno [3,2b] thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxaline -2-yl and quinolin-2-yl. The compound of claim 1, wherein R ¹ is The compound of claim 9, wherein R is C 1-6 alkyl. The compound of claim 10, wherein C 1-6 alkyl is methyl. The compound of claim 1, wherein R ¹ is The compound of claim 12, wherein η is 3. The compound of claim 1, wherein R ⁹ is selected from the group consisting of: ethyl and C ₃ . ₆ cycloalkyl-substituted ethyl; propyl; butyl; isopentyl; phenyl, especially halogen-substituted phenyl, C 1-6 alkyl-substituted phenyl, C ₁ . ₆ alkylsulfonyl-substituted phenyl; 356 pyridinyl, C 1-6 alkyl-substituted pyridinyl, 1- oxy-pyridinyl; and isoxazolyl, C 1-6 alkyl-substituted isoxazolyl. The compound of claim 1, wherein R ⁹ is selected from the group consisting of: cyclohexyl-ethyl cycle; prop-1-yl; but-1-yl; 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methanesulfonylphenyl and 2methanesulfonylphenyl; pyridin-2-yl, 1-oxy-pyridin-2-yl; 1,2-dimethyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl. The compound of claim 1, wherein R is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl, HEC ₆ alkyl. The compound of claim 16, wherein R ² is selected from the group consisting of: C 1-6 alkyl and H 2 _{O 0} . ₆ alkyl. The compound of claim 17, wherein C 1-6 alkyl and H 1 -C ₀ . ₆ alkyl are selected from the group consisting of: Het-substituted methyl and pentyl. The compound of claim 18, wherein the Het substituted methyl is selected from the group consisting of: quinolin-2-ylmethyl; 6-methyl-pyridin-2-ylmethyl; 2-morpholin-4-yl-thiazol-4-ylmethyl; 5-ethyl-furan-2-ylmethyl; 3,4-dimethyl-thieno [3,2-6] thiophen-2-ylmethyl; 357 3-phenyl-3H- [1,2,3] triazol-4-ylmethyl; isothiazol-3-ylmethyl; thiophen-2-ylmethyl; benzo [b] thiophen-2-ylmethyl; and 1-methyl-1H-imidazol-2-yl methyl; The compound of claim 1, wherein R is selected from the group consisting of: Ar-C 1-4 alkyl, R ⁹ C (O) -, R ⁹ SO ₂ and R ⁹ R ⁿ NC (O) -. The compound of claim 20, wherein R is selected from the group consisting of: Ar-Cd. ₆ alkyl, R ⁹ C (O) -h R ⁹ SO ₂ . 2 Q The compound of claim 21, wherein R is R SO ₂ . The compound of claim 22, wherein R ⁹ is selected from the group consisting of: C ₁ . ₆ alkyl, Ar-C ₀ . ₆ alkyl and H 1? ₆ alkyl. The compound of claim 1, wherein: Re R ² is R ⁹ SO ₂ ; and a R is isobutyl; R ⁹ is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl and Het-C _1-6 alkyl. The compound of claim 24, wherein: R ⁵ is selected from the group consisting of: piperidinyl-ethyl; benzo [1,3] dioxolyl; 358 furanyl, aryl-substituted furanyl, C]. ₆ alkyl-substituted furanyl; benzofuranyl, C]. ₆ alkoxy-substituted benzofuranyl, halogen-substituted benzofuranyl C 1-6 alkyl-substituted benzofuranyl; naphtho [2,1- b] furanyl, C 1-6 alkyl-substituted naphtho [2,1- b] furanyl; benzo [S] thiophenyl; quinolinyl; quinoxalinyl; 1-oxy-pyridinyl; furo [3,2-6] -pyridinyl, C 1-6 alkyl-substituted furo [3,2-b] pyridinyl; thiophenyl, C 1-6 alkyl-substituted thiophenyl; and thieno [3,2-0] thiophenyl; and 1H-benzoimidazol-5-yl; and R ⁹ is selected from the group consisting of: ethyl, C _3-6 cycloalkyl-substituted ethyl ,; propyl; butyl; isopentyl; halogen-substituted phenyl, _b6 alkyl-substituted phenyl, C ^ alkylsulfonyl-substituted phenyl; pyridinyl, C 1-6 alkyl-substituted pyridinyl, 1-oxy-pyridinyl; and isoxazolyl, C 1-6 alkyl-substituted isoxazolyl. The compound of claim 24, wherein: R ⁵ is selected from the group consisting of: piperidin-1-yl-ethyl; 359 benzo [1,3] dioxol-5-yl; furan-2-yl; benzofuran-2-yl; petroleum [2,1 - &] - furan-2-yl; benzo [1,2] thiophen-2-yl; quinolin-2-yl; quinoxalin-2-yl; 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; furo [3,2-6] -pyridin-2-yl; thiophen-2-yl; thieno [3,2-6] thiophen-2-yl; and 1H-benzoimidazol-5-yl. The compound of claim 24, wherein: R ⁵ is selected from the group consisting of: 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; 5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3-ethylbenzofuran-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- silt; 1-methyl-naphtho [2,1-0] -furan-2-yl; 5-methyl-thiophen-2-yl; and 3-methyl-furo [3,2-6] -pyridin-2-yl. The compound of claim 24, wherein: R ⁹ is selected from the group consisting of: cyclohexyl-ethyl; prop-1-yl; but-1-yl; 360 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methanesulfonylphenyl and 2methanesulfonyl phenyl; pyridin-2-yl, 1-oxy-pyridin-2-yl; 1,2-dimethyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl. The compound of claim 24, wherein: R ³ is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl or quinolin-2 -or. R ⁹ is selected from the group consisting of: pyridin-2-yl and 1-oxypyridin-2-yl. The compound of claim 29, wherein R ⁵ is 3-methylbenzofuran-2-yl. The compound of claim 30, wherein R ⁹ is 1-oxypyridin-2-yl. A compound according to claim 1 selected from the group consisting of: Benzofuran-2-carboxylic acid {(S) -1 - [- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; (S) -4-Methyl-2- (3-piperidin-1-yl-propanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] amide; Benzofuran-2-carboxylic acid {(S) -1 - [(4-ethylbenzenesulfonyl) -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; 361 Benzo [1,3] -dioxole-5-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-oxy-pyridin-2-yl) -methanoyl] -azepan-4-ylcarbamoyl} -butyl amide; 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide ; Benzo [1,3] -dioxole-5-carboxylic acid {(S) -1- [1- (3cyclohexyl-propanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl-butyl} amide; Benzo [1,3] -dioxole-5-carboxylic acid {(S) -1- [1- (4-methylpentanoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Benzofuran-2-carboxylic acid {(S) 1- [3-oxo-1- (propane-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; Benzofuran-2-carboxylic acid [(S) -1- [3-oxo-1 (ethanesulfonyl-azepan-4-ylcarbamoyl) -3-methyl-1-butyl] amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide; 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide ; 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide ; 362 3-Methyl-benzofuran-2-carboxylic acid {(1) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide; 3-Methyl-furo [3,2-6] -pyridine-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl ] -butyl} amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; Benzo [b] thiophene-2-carboxylic acid {(S) -1- (1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; 3-Methyl-furan-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Quinoline-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Thieno [3,2-5] thiophene-2-carboxylic acid {(S) -1- (1- (3fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; Quinoxaline-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Thiophene-2-carboxylic acid {(S) -1- (1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; 363 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide; 3-Methyl-benzofuran-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide; Benzo [b] thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide; 3-Methyl-furan-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide; Quinoline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide; Thieno [3,2-b] thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide; Quinoxaline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide; Thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide; 5-Methyl-thiophene-2-carboxylic acid [(S) -1- (methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methylbutyl] amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-oxo- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; 364 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; Benzo [b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; 3-Methyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; 2.5-Dimethyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide; Thieno [3,2-6] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; Quinoxaline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; Thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide; 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [3-oxo-1 (propane-1-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-1-butyl} amide; 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; 3.5-Dimethyl-benzofuran-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide; 365 3- Ethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide; 4- Methoxy-3-methyl-benzofuran-2-carboxylic acid] (S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-yl carbamoyl] - butyl} amide; 1-Methyl-naphtho [2,1- b] -furan-2-carboxylic acid {(S) -3methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4yl carbamoyl] -butyl} amide; 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) 3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide; Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] -butyl] amide; 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] butyl} amide; Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl] butyl} amide; Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1 [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4yl carbamoyl} -butyl) amide; 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide; 366 Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4ylcarbamoyl} -butyl) amide; Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1 [2-chloro-benzenesulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide; 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [2-chloro-benzenesulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide; Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino) -methanoyl] -azepan-4yl carbamoyl} -butyl) amide; Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1 [4-fluoro-benzenesulfonylamino) -methanoyl] -azepan-4yl carbamoyl} -butyl) amide; 3- Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [4-fluoro-benzenesulfonylamino) -methanoyl] -azepane- 4-ylcarbamoyl} -butyl) amide; Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino) -methanoyl] -azepan-4yl carbamoyl} -butyl) amide; Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1 [1-toluene-4-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide; 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1 {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepan-4-ylcarbamoyl} -butyl) amide; Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepan-4ylcarbamoyl} -butyl) amide; 367 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- (1- (6methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide; 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1 [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4yl carbamoyl] -butyl} amide; Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6methyl-pyridin-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] butyl} amide; Benzo [b} thiophene-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-yl-carbamoyl] -3-methylbutyl} amide; 3- Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide; 2,4-Dimethylfuran-3-carboxylic acid {(S) -1- [1- (2fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; Quinoxaline-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (2fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; Quinoline-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; 4- Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; 368 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- (1- (2fluoro-phenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; 4-Methyl-furan-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Benzofuran-2-carboxylic acid [(S) -1- (1-butyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide; Benzofuran-2-carboxylic acid [(S) -1- (1-propyl-3-oxoazepan-4-ylcarbamoyl) -3-methyl-butyl] amide; Benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluorobenzyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide; Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (2morpholin-4-yl-thiazol-4-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide; Benzofuran-2-carboxylic acid {(S) -1- [1- (5-ethyl-furan-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide; Benzofuran-2-carboxylic acid {(S) -1- (1- (3,4-dimethylthieno [3,2-b] thiophen-2-ylmethyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl- butyl} amide; Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1 (3-phenyl-3H- [1,2,3] triazol-4-ylmethyl) -azepan-4ylcarbamoyl] -butyl } amide; Benzofuran-2-carboxylic acid {(S) -1- [1- (isothiazol-3-ylmethyl-3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide; Benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-thiophen-2-ylmethyl-azepan-4-ylcarbamoyl) -butyl] amide; Benzofuran-2-carboxylic acid [(S) -1- (1-benzo [b] -thiophen-2-ylmethyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] amide; 369 Benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1pentyl-azepan-4-ylcarbamoyl) -butyl] amide; Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1methyl-1H-imidazol-2-ylmethyl) -3-oxo-azepan-4ylcarbamoyl] -butyl} amide; 1- (Oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide; 2- Oxy-pyridine-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide; 1H-Benzoimidazole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide; 4 - {(S) -2 - [(1-Benzofuran-2-yl-methanoyl) -amino] -4-methylpentanoylamino} -1-methyl-3-oxo-1-pentyl-azepane Benzofuran-2-carboxylic acid {(S) -1- [1- (1,2-dimethyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3methyl-butyl} amide; Benzofuran-2-carboxylic acid {(S) -1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; Benzofuran-2-carboxylic acid {(S) -1- [1- (4methanesulfonyl-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide; Benzofuran-2-carboxylic acid {(S) -1- (1- (2methanesulfonyl-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide; 370 Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethylisoxazole-4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methylbutyl} amide; 3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide; 3-Methyl-benzofuran-2-carboxylic acid {1- [3-oxo-1 (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] cyclopentyl} amide; and Furo [3,2-b] -pyridine-2-carboxylic acid {(S) -3-methyl-1 [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl } amide. 33. A pharmaceutical composition comprising a compound of any one of claims 1 to 32 and a pharmaceutically acceptable carrier, diluent or excipient. The use of the compounds of claim 1 for the preparation of a protease inhibitor medicament, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 32. The use of claim 34, wherein said protease is selected from the group consisting of cysteine protease and serine protease. The use of claim 35, wherein said protease is a cysteine protease. The use of claim 36, wherein said cysteine protease is cathepsin K. 38. Use for the treatment of a disease characterized by bone loss, including inhibition of said bone loss 371 by administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 32. The use of claim 38, wherein said disease is osteoporosis. The use of claim 38, wherein said disease is periodontitis. The use of claim 38, wherein said disease is gingivitis. Use of the compounds of claim 1 for the preparation of a medicament for the treatment of a disease characterized by end-cartilage or matrix degradation, comprising inhibiting said end-cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 32. The use of claim 42, wherein said disease is osteoarthritis. The use of claim 42, wherein said disease is rheumatoid arthritis. Use for the treatment of a disease caused by a parasite by administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 32. The use of claim 45, wherein said disease is selected from the group consisting of: schistosomiasis, malaria and infections with pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei and Crithidia fusiculata. 47. Compound of formula PA: 372 where: R ¹ is selected from the group consisting of: R is selected from the group consisting of: C 1-6 alkyl, Ar-C ₀ . ₆ alkyl, Het-Co-alkyl, R ⁹ C (O) -, R ⁹ SO 2 -, R ⁹ R ⁿ NC (O) -, and R ⁹ SO ² R ^H NC (O) -; R is C}. ₆ alkyl; R ⁴ is R ⁵ C (O) -; R ⁵ is He 1 -Co. ₆ alkyl; R ⁹ is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ . cycloalkyl-C ₀ . ₆ alkyl, L 2 -C ₀ . ₆ alkyl and HEB ₀ alkyl; R ¹¹ is selected from the group consisting of: H, C 1-6 alkyl, Ar-C ₀ . ₆ . alkyl and Het-Co-alkyl; R'eH; R is H; R '' is H; 373 R is selected from the group consisting of: C 1-6 alkyl, C ₃ . ₆ . cycloalkyl-C ₀ . ₆ alkyl, C 1-6 alkenyl, C ₂ . ₆ alkynyl, H 1: CO. ₆ alkyl and ArC ₀ . ₆ alkyl; and η is an integer from 1 to 5; and its salts, hydrates and solvates. 48. A method for the synthesis of a compound according to claim 1, characterized in that it comprises the step of oxidizing the corresponding compound of claim 47 with an oxidant to obtain the compound of formula (A) in the form of a mixture of diastereomers. The method of claim 48, wherein the oxidant is a sulfur trioxide-pyridine complex in dimethyl sulfoxide and triethylamine. 50. The method of claim 48, further comprising the step of separating the diastereomers by a separation method. 51. The method of claim 50, wherein said separation method is high pressure liquid chromatography (HPLC). The method of claim 48, further comprising the step of deuterating said diastereomers with a deuterating agent. The method of claim 52, wherein said deuterating agent is CD ₃ OD: D ₂ O (10: 1) in triethylamine. Use of a compound according to any one of claims 1 to 32 for the manufacture of a protease inhibiting drug selected from the group consisting of cysteine protease and serine protease. 374 The use of claim 54, wherein said protease is a cysteine protease. The use of claim 55, wherein said cysteine protease is cathepsin K. Use of a compound according to any one of claims 1 to 32 for the manufacture of a medicament for the treatment of a disease characterized by bone loss. The use of claim 57, wherein said disease is osteoporosis. The use of claim 57, wherein said disease is periodontitis. The use of claim 57, wherein said disease is gingivitis. Use of a compound according to any one of claims 1 to 32 for the manufacture of a medicament for the treatment of a disease characterized by extreme cartilage or matrix degradation. The use of claim 61, wherein said disease is osteoarthritis. < The use of claim 61, wherein said disease is rheumatoid arthritis. Use of a compound of any one of claims 1 to 32 for the manufacture of a medicament for the treatment of a disease caused by parasites. The use of claim 64, wherein said disease is selected from the group consisting of: schistosomiasis, malaria and infections with pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei and Crithidia fusiculata.