HUP0301231A2 - Protease inhibitors, pharmaceutical compositions containing them and their use - Google Patents

Abstract

For the compounds of the general formula (IA) of the invention - in the formula of which R1 means a group of the general formula; R2 is a C1-C6 alkyl group, Ar-(C0-6 alkyl) group, Het-(C0-6 alkyl) group, R9C(O)-, R9SO2-, R9R11NC(O)- or R9SO2R11NC(O)- group of general formula; R3 is an alkyl group having 1 to 6 carbon atoms; R4 is a group with the general formula R5C(O); R5 is Het-(C0-C6 alkyl); R9 is C1-6 alkyl, (C3-6 cycloalkyl)-(C0-6 alkyl), Ar-(C0-6 alkyl) and Het-(C0-6 alkyl); R11 means a hydrogen atom, a C1-6 alkyl group, an Ar -(C0-6 alkyl) group and a Het-(C0-6 alkyl) group; R' is a hydrogen atom; R< is a hydrogen atom; R<' is a hydrogen atom; R<< is a C1-6 alkyl group, (C3-6 cycloalkyl)-(C0-6 alkyl) group, C2-6 alkenyl group, C2-6 alkynyl group, Ar-(C0-6 alkyl) group and Het -(C0-C6 alkyl)- group; and the value of n is 1,2, 3, 4 or 5 and their pharmaceutically acceptable salts, hydrates and solvates. The invention also includes pharmaceutical preparations containing compounds of general formula (I) as active ingredients and the medicinal use of the compounds. The compounds and pharmaceutical preparations according to the invention are particularly well suited for the treatment of diseases in which cysteine proteases play a significant role, especially for the treatment of excessive bone and cartilage loss diseases such as osteoporosis, periodontitis and arthritis. HE

Description

The invention relates to 4-amino-3-oxo-azepane protease inhibitors, in particular to inhibitors of cysteine and serine proteases, more particularly to compounds which inhibit cysteine proteases, further narrowly to compounds which inhibit cysteine proteases of the papain superfamily, further narrowly to compounds which inhibit cysteine proteases of the cathepsin family, and most narrowly to compounds which inhibit cathepsin K. The compounds are particularly useful for the treatment of diseases in which cysteine proteases play a significant role, in particular for the treatment of diseases involving excessive bone and cartilage loss, such as osteoporosis, periodontitis and arthritis.

Cathepsins are a family of enzymes belonging to the papain superfamily of cysteine proteases. Cathepsins B, H, L, N, and S have previously been described in the literature. Recently, U.S. Patent No. 5,501,969 described the cathepsin K polypeptide and the cDNA encoding such a polypeptide (in the referenced patent, the enzyme is referred to as cathepsin 0). The expression, purification, and characterization of cathepsin K were first described in 1996 [Bossard, MJ, et al., J. Biol. Chem., 271, 12517-12524 (1996); Drake, FH, et al., J. Biol. Chem., 271, 12511-12516 (1996); Bromme, D., et al. _t J. Biol. Chem., 271, 2126-2132 (1996)].

Cathepsin K is known by various names in the literature2

They were chosen, such as cathepsin 0 or cathepsin 02. The most suitable designation was cathepsin K.

Cathepsins are involved in the normal physiological process of protein degradation in animals, including humans, such as the degradation of connective tissue. However, increased levels of the enzymes can result in pathological conditions that cause disease. Thus, cathepsins may play a role in various diseases, such as, among others, infections caused by pneumocystis carinii, trypsinoma cruzi, trypsinoma brucei brucei and Crithidia fusiculata; as well as schistosomiasis, malaria, tumor metastasis, leukodystrophia metachromatica, dystrophia muscularum, amyotrophia, etc. (see, for example, International Patent Application WO 94/04172 and European Patent Application 0 603 873). Two bacterial cysteine proteases (gingipains) from P. gingivallis are involved in the pathogenesis of gingivitis [Potempa, J., et al., Perspectives in Drug Discovery and Design, 2, 445-458 (1994)].

Cathepsin K is believed to play a crucial role in diseases associated with excessive bone and cartilage loss. Bone consists of a protein matrix embedded with spindle-shaped or lamellar hydroxyapatite crystals. Type I collagen is the primary structural protein of bone, accounting for approximately 90% of the structural protein. The remaining 10% of the matrix is made up of a number of noncollagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone is

It undergoes transformation in discrete foci throughout life. The foci, or transformation units, undergo a cycle consisting of a phase of bone resorption followed by a phase of bone replacement.

Bone resorption is carried out by osteoclasts, multinucleated cells of haematopoietic origin. Osteoclasts adhere to the bone, form a tight junction, and then forcefully rupture the membrane at their apical surface (i.e., their resorbing surface). This results in the formation of a closed extracellular chamber on the bone surface, which is acidified by proton pumps in the ruptured membrane and into which the osteoclast secretes proteolytic enzymes. The low pH of the chamber dissolves the hydroxyapatite crystals on the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna or cavity is formed. At the end of this phase of the cycle, the osteoblasts deposit a new protein matrix, which is then mineralized. In serious diseases such as osteoporosis or Paget's disease, the normal balance between bone resorption and bone formation is disrupted, with each cycle eventually ending in bone loss. Overall, this leads to a weakening of the bone, which significantly increases the risk of fracture even with minimal trauma.

Several published studies have demonstrated that inhibitors of cysteine proteases effectively inhibit osteoclast-mediated bone resorption and that cysteine proteases play an essential role in the process of bone resorption. For example, Delaisse describes a series of protease inhibitors that work in a mouse bone organ culture system and suggests that inhibitors of cysteine proteases (e.g. leupeptin, ZPhe-Ala-CHN2) inhibit bone resorption, while serine protease inhibitors were ineffective [Delaisse et al., Biochem. J., 192, 365 (1980)]. Delaisse also describes

[Delaisse et al., Biochem. Biophys. Res. Commun., 125, 441 (1984)], that both E-64 and leupeptin were effective in inhibiting bone resorption in vivo, as measured by acute changes in serum calcium in rats fed a calcium-deficient diet. Lerner describes that the endogenous cysteine protease inhibitor cystatin inhibits PTH-stimulated bone resorption in mouse calvaria [Lerner et al., J. Bone Min. Res., Ί_, 433 (1992)]. Other publications also report a relationship between cysteine protease inhibitor inhibition and bone resorption [see, for example: Delaisse et al., Bone, j3, 305 (1987); Hill et al., J. Cell Biochem., 56, 118 (1994); and Everts et al., J. Cell Physiol., 150, 221 (1992)]. The cysteine protease cathepsin K is known to be highly expressed in osteoclasts and may be the primary cysteine protease in these cells [Tezuka et al., J. Biol. Chem., 269, 1106 (1994); Inaoka et al., Biochem. Biophys. Res. Common., 206, 89 (1995); and Shi et al., FEBS Lett., 357, 129 (1995)].

The very intense and selective expression of cathepsin K in osteoclasts strongly suggests that the enzyme plays an essential role in bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases associated with excessive bone loss, including osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, malignant hypercalcemia, and metabolic bone disease. It has also been demonstrated that cathepsin K is present in increased amounts in chondroclasts of osteoarthritic synovium. Accordingly, inhibition of cathepsin K may be useful in the treatment of diseases of excessive cartilage or matrix degradation, including osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express proteolytic enzymes that degrade the surrounding matrix in high amounts. Thus, selective inhibition of cathepsin K can also be used to treat certain neoplastic diseases.

A number of cysteine protease inhibitors are known. Palmer describes certain vinyl sulfones [Palmer J., Med. Chem., 38, 3193 (1995)] which irreversibly inhibit cysteine proteases such as cathepsin B, L, S, O2 and cruzain. Other classes of compounds useful for inhibiting cysteine proteases are also known, such as aldehydes, nitriles, α-ketocarbonyl compounds, (halomethyl) ketones, (diazomethyl ketones, [(acyloxy)methyl] ketones, ketomethyl sulfonium salts and epoxy succinyl compounds [see, for example, Palmer J., Med. Chem., 38, 3193 (1995) and references therein].

U.S. Patent No. 4,518,528 describes peptidyl (fluoromethyl) ketones as irreversible inhibitors of cysteine proteases. International Patent Application WO 94/041726 · ··« · · ··· • · · · · · · · · ··»·« · · «· · International Patent Application No. 0 623 592 and European Patent Application No. 0 623 592 describe (alkoxymethyl) and (mercaptomethyl) ketones that inhibit the IL-Ιβ convertase cysteine protease. (Alkoxymethyl) and (mercaptomethyl) ketones have also been previously reported as inhibitors of the serine protease kininogenase in International Patent Application No. PCT/GB91/01479.

Azapeptides with good leaving groups designed to deliver the aza-amino acid to the active site of serine proteases have been described in several places [Elmore et al., Biochem. , 107, 103 (1968); Garker et al., Biochem. J., 139, 555 (1974); Gray et al., Tetrahedron, 33, 837 (1977); Gupton et al., J. Biol. Chem., 259, 4279 (1984); and Powers et al., J. Biol. Chem., 259, 4288 (1984)], and which compounds are known to inhibit serine proteases. In addition, certain azapeptide esters have been described to function as inhibitors of cysteine proteases [J. Med. Chem., 35, 4279 (1992)].

Antipaint and leupeptin are described by McConnell as reversible inhibitors of cysteine proteases [McConnell et al., J. Med. Chem., 33, 86 (1990)], while Umezawa describes the same compounds as serine protease inhibitors [Meth. Enzym., 45, 678]. Synthetic analogues of these compounds are well-known cysteine protease inhibitors [Barrett, Biochem. J. , 201, 189; and

Grinds, Biochem. Biophys Acta, 701, 328].

1,3-Diamidoacetone derivatives have also been described previously as analgesics (U.S. Patent Nos. 4,749,792 and 4,638,010).

Based on the above, it can be seen that cysteine protease inhibitors with a wide variety of structures have been identified in the past. However, the known inhibitors have not proven to be suitable as therapeutic agents for use in animals, especially humans, due to certain disadvantageous characteristics. Such disadvantageous characteristics include, among others, the following: lack of selectivity, cytotoxicity, poor solubility, and excessively rapid plasma clearance. There is a significant need for methods and pharmaceutical compositions suitable for the treatment of diseases caused by proteases, more specifically cysteine proteases, including cathepsins, especially cathepsin K, and for novel inhibitor compounds useful therein.

We have identified a new class of 4-amino-3-oxo-azepane compounds that are protease inhibitors, specifically cathepsin K inhibitors.

One aspect of the present invention relates to 4-amino-3-oxo-azepanecarbonyl protease inhibitors, in particular inhibitors of cysteine and serine proteases, more particularly to compounds that inhibit cysteine proteases, further narrowed to compounds that inhibit cysteine proteases of the papain superfamily, further narrowed to compounds that inhibit cysteine proteases of the cathepsin family, and most narrowly to compounds that inhibit cathepsin K. The compounds of the invention can be used to treat diseases that can be therapeutically modified by altering the activity of said proteases.

Accordingly, one aspect of the invention is the compounds of formula (I).

Another object of the invention is pharmaceutical compositions comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to intermediates useful in the preparation of compounds of general formula (I).

The invention further includes a method for treating diseases whose pathology can be therapeutically modified by proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, more narrowly papain family cysteine proteases, more narrowly cathepsin family cysteine proteases, and most narrowly cathepsin K inhibition.

According to one preferred embodiment of the invention, the compounds of the invention are particularly useful for the treatment of diseases associated with bone loss, such as osteoporosis, gingival diseases, such as gingivitis and periodontitis, and diseases of excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.

One aspect of the present invention is compounds of general formula (I)

(I) — in the formula of which

R ³ · means

group of general formula;

R is hydrogen, C1-6 cycloalkyl)-(C0-6 alkyl, C3-6 alkyl, Ar-(C0-6 alkyl), Het-(C0-6 al9 9 9 9 krl), RC(O)-, RC(S)-, R SO ₂ -, ROC(O)-,

11 9 11 9 11

RR NC(O)-, RR NC(S)-, R (R )NSO ₂ - group with general formula, group with formula,

R ⁶ ,N .Z.

r ⁷ γ

R ⁶ or R ⁹ is a group of general formula SO2R ¹¹ NC(O) -;

R represents a hydrogen atom, a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group or an Ar-(C0-6 alkyl) group;

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

R represents hydrogen, alkyl group of 1-6 carbon atoms, (C3-6 cycloalkyl)-(C0-6 alkyl)-group, Ar-(C0-6 alkyl)-group, Het-(C0-6 alkyl)-group, RC(O)-, RC(S)-, R SO ₂ -, ROC(O)-,

12 -3 Ί 2

a group of general formula R R NC(O)- and R R NC(S)-;

R ⁵ represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a (C 3-6 cycloalkyl)-(C 0-6 alkyl) group, an Ar-(C 0-6 alkyl) group and an Het-(C 0-6 alkyl) group;

R ⁶ represents a hydrogen atom, a C 1-6 alkyl group, an Ar-(C 0-6 alkyl) group and an Het-(C 0-6 alkyl) group;

R represents a hydrogen atom, a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group, a Het-(C0-6 alkyl) group, R ¹⁰ C(O)-, R ¹⁰ C(S)-, R ¹⁰ SO2-, R ¹⁰ OC(O)-,

13 10 13

R R NC(O)- and R R NC(S)- groups; g

R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,

Hep-(C0-6 alkyl)-group and Ar-(C0-6 alkyl)-group

- 11 alkyl)-group; 9

R represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and an Het-(C0-6 alkyl) group;

R ¹⁰ is a C 1-6 alkyl group, a (C 3-6 cycloalkyl)-(C 0-6 alkyl) group, an Ar-(C 0-6 alkyl) group and an Het-(C 0-6 alkyl) group;

R represents hydrogen, C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl);

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R' represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R' represents a hydrogen atom, a C1-C6 alkyl group, a (C3-C6 cycloalkyl)-(C0-C6 alkyl) group, an Ar-(C0-C6 alkyl) group and an Het-(C0-C6 alkyl) group;

R'"' represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, an Ar-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group;

X represents a methylene group, a sulfur or an oxygen atom;

Z is a carbonyl or methylene group; and n is 1, 2, 3, 4 or 5 - and pharmaceutically acceptable salts, hydrates and solvates thereof.

In the compounds of general formula (I), if R is a group of general formula O R' II _r 4/ D ³ “, then

R represents a hydrogen atom, a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and an Ar-(C0-6 alkyl) group;

R preferably represents a hydrogen atom, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C1-6 alkyl group and an Ar-(C0-6 alkyl) group;

R is more preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, cyclopropyl

-methyl-, cyclohexylmethyl-, 2-(methylsulfinyl)ethyl·-, 1-hydroxyethyl-, tolyl-, (2-naphthyl)methyl-, (benzyloxy)methyl- and hydroxymethyl-groups.

R is more preferably tolyl, isobutyl and cyclohexylmethyl.

R is most preferably isobutyl. 4

R represents hydrogen, C1-6 alkyl, (C3-6 cycloalkyl)-(C0-6 alkyl), Ar-(C0-6 alkyl), Het-(C0-6 alkyl)5 5 5 5 5 13

-group, R 0(0)-, RC(S)-, R SO ₂ -, ROC(O)-, RR NC(O)- and 5 13

R R NC(S)- group with general formula. 4 5 5 5

R is preferably a group of the general formula RC(0)-, R SO ₂ - and R OC(0)-.

5

R is most preferably a group of the general formula R C(0)-.

In some embodiments, R is preferably mesyl (methylsulfonyl).

R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (C3-6 cycloalkyl)-(C0-6 alkyl), Ar-(C0-6 alkyl) or Het-(C0-6 alkyl).

Preferably, R is a C1-C6 alkyl group, Ar-(C0-C6 alkyl) group and Het-(C0-C6 alkyl) group. , „ 4 5

More preferably — and especially when R is a group of general formula R C(O)5 — R is:

methyl group, especially halogenated methyl group, even in«*4 · ♦ * ♦ * *

- 14 - .1..:.. ..* *-’’·.· more trifluoromethyl group, especially methyl group substituted by alkoxy group, more preferably phenoxymethyl, (4-fluorophenoxy)methyl group, especially methyl group substituted by heterocyclic group, more preferably (2-thienyl)methyl group;

ethyl group, especially (1-piperidinyl)ethyl group;

butyl, especially aryl-substituted butyl, more particularly 4-(4-methoxyphenyl)butyl;

isopentyl swept;

cyclohexylswept;

pentanonyl group, especially 4-pentanonyl group;

butenyl, especially aryl-substituted butenyl, more particularly 4,4-bis(4-methoxyphenyl)but-3-enyl;

acetylene brush;

phenyl, especially phenyl substituted with one or more halogen atoms, more preferably 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or C1-6 alkoxy groups, more preferably 3,4-dimethoxyphenyl, 3-(benzyloxy)-4-methoxyphenyl, especially phenyl substituted with one or more sulfonyl groups, more preferably 4-mesylphenyl;

benzyl group;

naphthyl group, especially 2-naphthyl group;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl;

furyl group, especially 2-furyl group, especially subs4* · * · -'4 * · . « ··« «4 »··

- 15 - Λ ./’·.·%>· titrated furyl group, for example 5-nitro-2-furyl-, 5-(4-nitrophenyl)-2-furyl-, 5-[3-(trifluoromethyl)phenyl]-2-furyl-group, more preferably furyl group substituted with a halogen atom, more preferably 5-bromo-2-furyl-group, more preferably furyl group substituted with an aryl group, more preferably 5-(4-chlorophenyl)-2-furyl-group, more preferably furyl group substituted with an alkyl group having 1-6 carbon atoms, more preferably 3-methyl-2-furyl-, 4-methyl-2-furyl-, 2,5-dimethyl-2-furyl- and 2,4-dimethyl-3-furyl-group;

tetrahydrofuryl group, 2-tetrahydrofuryl group;

benzofuranyl group, especially 2-benzofuranyl group, and substituted benzofuranyl group, more particularly 5-{2-[4--(tert-butoxycarbonyl)-1-piperazinyl]-ethoxy}-2-benzofuranyl-, 5-(2-morpholinoethoxy)-2-benzofuranyl-, 5-[2-(1-piperazinyl)-ethoxy]-2-benzofuranyl-, 5-(2-cyclohexylethoxy)-2-benzofuranyl-; in particular benzofuranyl substituted with 1-6 C alkoxy, more particularly 7-methoxy-2-benzofuranyl, 5-methoxy-2-benzofuranyl, 5,6-dimethoxy-2-benzofuranyl, in particular benzofuranyl substituted with halogen, more particularly 5-fluoro-2-benzofuranyl, 5,6-difluoro-2-benzofuranyl, in particular benzofuranyl substituted with 1-6 C alkyl, most particularly 3-methyl-2-benzofuranyl, 3,5-dimethyl-2-benzofuranyl and 3-ethyl-2-benzofuranyl; also 5-fluoro-3-methyl-2-benzofuranyl, 6-fluoro-3-methyl-2-benzofuranyl, 5-methoxy-3-methyl-2-benzofuranyl, 4-methoxy-3-methyl-2-benzofuranyl and 6-methoxy-3-methyl-2

-benzofuranyl group.

naphtho[2,1-b]furanyl, especially naphtho[2,1-b]furan-2-yl, alkyl-substituted naphtho[2,1-b]furanyl, especially 1-methylnaphtho[2,1-b]furan-2-yl;

benzo[b]thienyl, especially benzo[b]thiophen-2-yl; especially benzo[b]thienyl substituted with 1-6C alkoxy, more particularly 5,6-dimethoxybenzo[b]thiophen-2-yl;

quinolyl group, especially 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl and 8-quinolyl groups;

quinoxalinyl group, especially 2-quinoxalinyl group;

1,8-naphthyridinyl, especially 1,8-naphthyridin-2-yl;

indolyl, especially 2-indolyl, especially 6-indolyl, 5-indolyl, especially C1-C6 alkyl substituted indolyl, more preferably N-methyl-2-indolyl;

pyridyl, especially 2-pyridyl, 3-pyridyl, 5-pyridyl, especially pyridyl substituted with C1-6 alkyl, more particularly 2-methyl-5-pyridyl, and 1-oxy-2-pyridyl and 1-oxy-3-pyridyl;

thienyl group, especially 3-thienyl group, and 2-thienyl group, especially alkyl-substituted thienyl group, more particularly 5-methyl-2-thienyl and 5-methyl-3-thienyl group, especially halogen-substituted thienyl group, more particularly 4,5-dibromo-2-thienyl group;

thieno[3,2-b]thienyl group, especially thieno[3,2-b]thiophen-2-yl group, more especially alkyl-substituted thieno17

[3,2-h]thiophen-2-yl, more preferably 5-tert-butyl-3-methylthieno[3,2-b]thiophen-2-yl;

isoxazolyl, especially 4-isoxazolyl, especially C1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-4-isoxazolyl;

oxazolyl group, especially 4-oxazolyl group, more especially 5-methyl-2-phenyl-4-oxazolyl-, 2-phenyl-5-(trifluoromethyl)-4-oxazolyl group; and ΙΗ-benzimidazolyl group, especially ΙΗ-5-benzimidazolyl group.

5

When R is a group of the general formula R SO2-, R ⁵ is preferably a 2-pyridyl or 1-oxy-2-pyridyl group.

R' represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and an Het-(C0-C6 alkyl) group.

Preferably, R' represents a hydrogen atom and a (2-naphthyl)methyl group.

Most preferably, R' is hydrogen.

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group, and an Het-(C0-C6 alkyl) group.

Most preferably, R is hydrogen.

R' represents a hydrogen atom, a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group.

R' preferably represents a hydrogen atom and an alkyl group having 1 to 6 carbon atoms.

R' is more preferably hydrogen or 6,6-dimethyl.

R' is most preferably hydrogen.

In the compounds of general formula (I), when R ¹ is

R’ is a group with the general formula O, then 3

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and an Ar-(C0-6 alkyl) group.

R is preferably an alkyl group having 1-6 carbon atoms. 3

R more preferably represents methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclohexylmethyl and tolyl.

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and an Ar-(C0-6 alkyl) group.

R is preferably an alkyl group having 1-6 carbon atoms.

R" is more preferably methyl, ethyl, propyl, butyl, isobutyl and tert-butyl.

R is most preferably methyl.

5

In these compounds, R', R, R', R and R are as defined above, where R is

group with a general formula.

In those compounds of general formula (I) in which

n is preferably 1, 2, 3, 4 or 5, and R' is

R”, R” ', R and R are

as defined above, where R ¹ is a group of the general formula.

Most preferably, n is 3.

The ring may optionally be substituted with one or more C1-6 alkyl groups, (C3-6 cycloalkyl)-(C0-6 alkyl) groups, C2-6 alkenyl groups, C2-6 alkynyl groups, Het-(C0-6 alkyl) groups, Ar-(C0-6 alkyl) groups and/or halogen atoms.

The ring is preferably unsubstituted. 2

In the compounds of general formula (I), R represents a hydrogen atom, a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl)-group, an Ar-(C0-6 alkyl)-group, a Het-(C0-6 alkyl)-group, RC(O)-,

9 9 9119 11

RC(S)-, R so ₂ -, ROC(O)-, RR NC(O)-, RR NC(S)-,

11L J

R (R )NSO2- group of general formula,, ^r6 Γ I _r 7/ XZ X . group of formula, ” and R^SC^R^NC (O) - group of general formula. 2

Preferably, R is Ar-(0-6 C alkyl)-group,

R ⁶ r ⁷ γ 9 9 911 Ae

A group with the general formula RC(0)-, R SO ₂ -, RR NC(O)- and R.

More preferably, R is Ar-(C0-C6 alkyl)9 9

-group, R C(0)- and R SO2- group.

9

Most preferably, R is a group of the general formula R SO ₂ -.

In such solutions:

R ⁶ represents a hydrogen atom, a C 1-6 alkyl group, an Ar-(C 0-6 alkyl) group and a Het-(C 0-6 alkyl) group, preferably a hydrogen atom.

R represents hydrogen, alkyl having 1-6 carbon atoms, (C3-6 cycloalkyl)-(C0-6 alkyl)-group, Ar-(C0-6 alkyl)-group, Het-(C0-6 alkyl)-group, R ¹⁰ C(O)-, R ¹⁰ C(S)-, R ¹⁰ SO ₂ ~, R ¹⁰ OC(O)-, R ¹⁰ R ¹⁴ NC(O)- and 10 14 7

R R is a group of general formula NC(S)-, preferably R is 10

R 0C(0)~ group of general formula, g

R represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and an Ar-(C0-6 alkyl) group, preferably a C1-6 alkyl group, more preferably an isobutyl group.

R represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group. 9

R is preferably C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl).

And more preferably R means:

methyl group;

ethyl, especially ethyl substituted with C1-6 alkyl, more preferably 2-cyclohexylethyl;

propyl brushed;

butyl, especially butyl substituted with C1-6 alkyl, more preferably 3-methylbutyl;

9 tert-butyl, especially when R is a group of the general formula R OC(O)-;

isopentyl group;

phenyl group, especially halogen-substituted phenyl group, especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C1-C6 alkoxy-substituted phenyl group, especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, especially 2-cyanophenyl; especially C1-C6 alkyl-substituted phenyl group, especially 4-ethylphenyl, 2-methylphenyl, 4-methylphenyl; especially phenyl substituted with C1-6 alkylsulfonyl, more particularly 4-(methylsulfonyl)phenyl and 2-(methylsulfonyl)phenyl;

tolyl, especially tolyl substituted with Het, more particularly 3-(2-pyridyl)tolyl;

naphthyl group, especially 2-naphthyl group;

carboxyphenyl group, especially 2-carboxyphenyl group;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl;

benzo[1,2,5]oxadiazolyl, especially benzo[1,2,5]oxadiazol-4-yl;

pyridyl group, especially 2-pyridyl, 3-pyridyl group, especially 1-oxypyridyl group, more particularly 1-oxy-2-pyridyl, 1-oxy-3-pyridyl group; especially (C1-6 alkyl)pyridyl group, more particularly 3-methyl-2-pyridyl, 6-methyl-2-pyridyl group;

thienyl group, especially 2-thienyl group;

thiazolyl, especially 2-thiazolyl;

1H-imidazolyl group, especially 1H-2-imidazolyl, 1H-4-imidazolyl, more preferably imidazolyl group substituted with 1-6 C alkyl group, most preferably 1-methyl-1H-2-imidazolyl, 1-methyl-1H-4-imidazolyl and 1,2-dimethyl-1H-4-imidazolyl;

triazolyl, especially 1H-1,2,4-triazolyl, especially 1H-1,2,4-triazol-3-yl, more preferably 1H-1,2,4-triazolyl substituted with C1-6 alkyl, most preferably 5-methyl-1H-1,2,4-triazol-3-yl; and isoxazolyl, especially 4-isoxazolyl, especially isoxazolyl substituted with C1-6 alkyl, most preferably 3,5-dimethyl-4-isoxazolyl.

When R is a group of the general formula R SO2-, 9 then R is most preferably a 2-pyridyl and 1-oxy-2-pyridyl group. . 9 9 11

If R means R SO2R NC(O)- of general formula 9 .

group, R preferably represents Ar-(C0-C6 alkyl), more preferably Ar-, most preferably substituted phenyl, for example 2-methylphenyl, 4-methylphenyl, 2-chlorophenyl and 4-fluorophenyl.

9

If R is a group of general formula R C(0)-, 9

R preferably represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group, more preferably 1-oxy-2-pyridyl, cyclohexylmethyl and 3-methylbutyl groups.

R represents hydrogen, C1-C6 alkyl, Ar-(C0-C6 alkyl) and Het-(C0-C6 alkyl). 9 9 11

When R is a group of the general formula R SO2R NC(O)-, R ¹¹ is preferably a hydrogen atom.

If R is Ar-(C0-C6 alkyl), 2

R preferably represents a phenyl group, especially a substituted phenyl group, more preferably a phenyl group substituted with a halogen atom, in particular a 2-fluorobenzyl group.

. 2 2

When R is an alkyl group having 1-6 carbon atoms, R is preferably 1-propyl, 1-butyl and 1-pentyl.

When R is Het-(C0-6 alkyl), the Het-(C0-6 alkyl) is preferably Het-methyl, where in the Het-methyl Het is preferably pyridyl, especially 2-pyridyl, especially (C1-6 alkyl)pyridyl, more preferably 6-methyl-2-pyridyl;

thienyl group, especially 2-thienyl group, more preferably 2-thienyl or benzo[b]thiophen-2-yl-c]thiophen-2-yl group;

thiazolyl, especially 4-thiazolyl, such as 1-(2-morpholino-4-thiazolyl) and 1-(3-isothiazolyl);

1H-imidazolyl, especially 1H-2-imidazolyl and 1H-4-imidazolyl, especially imidazolyl substituted with a C1-6 alkyl group, more preferably 1-methyl-1H-2-imidazolyl;

triazolyl, especially 3H-1,2,3-triazolyl, more particularly 3H-1,2,3-triazol-4-yl, especially 3H-1,2,3-triazolyl substituted with C1-6 alkyl, more particularly 3-phenyl-3H-1,2,3-triazol-4-yl;

quinolyl group, especially 2-quinolyl group;

furyl, especially 2-furyl, especially substituted furyl, such as 5-ethyl-2-furyl;

thieno[3,2-b]thienyl, especially thieno[3,2-b]thiophen-2-yl, especially thieno[3,2-b]thienyl substituted with a C1-6 alkyl group, especially 3,4-dimethylthieno[3,2-b]thiophen-2-yl.

.

R is also preferably hydrogen;

swept away;

aryl-substituted ethyl, especially 2-phenylethyl, 2-[(3-(2-pyridyl)phenyl]ethyl.

Preferred compounds of formula (I) are those in which R and R' are each hydrogen.

Even more preferred are those compounds of formula (I) in which R 1 is

group of general formula;

9

R is Ar-(C0-C6 alkyl)-group, R is C(0)~,

^R6

R ⁷ \

911 ήβ

R SO2-, R R NC(O)- and R group of general formula;

R represents a hydrogen atom, a C1-C6 alkyl group and an Ar-(C0-C6 alkyl) group;

5 5 5

R is a group of the general formula RC(O)-, RSO2- and ROC(O)-;

R ⁵ represents a C 1-6 alkyl group, an Ar-(C 0-6 alkyl) group and an Het-(C 0-6 alkyl) group;

R ⁶ represents a hydrogen atom; 7 10

R is a group of general formula R 0C(0)-; θ

R is a C1-C6 alkyl group; 9

R is C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl);

R is C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl);

R' represents a hydrogen atom;

R represents a hydrogen atom;

R' is hydrogen; and

Z represents a carbonyl or methylene group.

Even more preferred are those compounds of general formula (I) in which R is Ar-(C0-6 alkyl), R C(0)- or R SO2-.

Even more preferred are those compounds of general formula (I) in which

R ¹ meaning

group of general formula;

9

R is Ar-(C0-C6 alkyl)-group, R is C(O)- or 9

R is a group with general formula SO2-;

R represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, cyclopropylmethyl, cyclohexylmethyl, 2-(methylsulfinyl)ethyl, 1-hydroxyethyl, butyl, (2-naphthyl)methyl, (benzyloxy)methyl and hydroxymethyl;

₅

R is a group of the general formula RC(O)~;

R ^{3 4 5} represents a methyl group, especially a halogenated methyl group, more preferably a trifluoromethyl group, especially a methyl group substituted with an alkoxy group, more preferably a phenoxymethyl, (4-fluorophenoxy)methyl group, especially a methyl group substituted with a heterocyclic group, more preferably a (2-thienyl)methyl group;

ethyl group, especially (1-piperidinyl)ethyl group;

butyl, especially aryl-substituted butyl, more particularly 4-(4-methoxyphenyl)butyl;

isopentyl group;

cyclohexylswept;

pentanonyl group, especially 4-pentanonyl group;

butenyl, especially aryl-substituted butenyl, more particularly 4,4-bis(4-methoxyphenyl)but-3-enyl;

acetylene brush;

phenyl, especially phenyl substituted with one or more halogen atoms, more preferably 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more C1-6 alkoxy groups, more preferably 3,4-dimethoxyphenyl, 3-(benzyloxy)-4-methoxyphenyl, especially phenyl substituted with one or more C1-6 alkylsulfonyl groups, more preferably 4-mesylphenyl;

benzyl benzoate;

naphthyl group, especially 2-naphthyl group;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl;

furyl group, especially 2-furyl group, especially substituted furyl group, for example 5-nitro-2-furyl, 5-(4-nitrophenyl)-2-furyl, 5-[3-(trifluoromethyl)phenyl]-2-furyl group, more preferably furyl group substituted by halogen atom, more preferably 5-bromo-2-furyl group, more preferably furyl group substituted by aryl group, more preferably 5-(4-chlorophenyl)-2-furyl group, more preferably furyl group substituted by C1-6 alkyl group, in particular 3-methyl-2-furyl, 4-methyl-2-furyl, 2,5-dimethyl-2-furyl and 2,4-dimethyl-3-furyl group;

benzofuranyl group, especially 2-benzofuranyl group, and substituted benzofuranyl group, especially 5-{2-[4-(tert-butoxycarbonyl)-1-piperazinyl]-ethoxy}-2-benzofuranyl-, 5-(2- -morpholinoethoxy)-2-benzofuranyl-, 5-[2-(1-piperazinyl)-ethoxy]-2-benzofuranyl-, 5-(2-cyclohexylethoxy)-2-benzofuranyl- group; especially benzofuranyl group substituted with 1-6 C alkoxy group, especially 7-methoxy-2-benzofuranyl-, 5-methoxy-2-benzofuranyl-, 5,6-dimethoxy-2-benzofuranyl group, especially benzofuranyl group substituted with halogen atom, especially 529

-fluoro-2-benzofuranyl, 5,6-difluoro-2-benzofuranyl, especially benzofuranyl substituted with 1-6 C alkyl, especially 3-methyl-2-benzofuranyl, 3,5-dimethyl-2-benzofuranyl and 3-ethyl-2-benzofuranyl; furthermore 5-fluoro-3-methyl-2-benzofuranyl, 6-fluoro-3-methyl-2-benzofuranyl, 5-methoxy-3-methyl-2-benzofuranyl, 4-methoxy-3-methyl-2-benzofuranyl and 6-methoxy-3-methyl-2-benzofuranyl;

naphtho[2,1-b]furanyl, especially naphtho[2,1-b]furan-2-yl, alkyl-substituted naphtho[2,1-b]furanyl, especially 1-methylnaphtho[2,1-b]furan-2-yl;

benzo[b]thienyl, especially benzo[b]thiophen-2-yl; especially benzo[b]thienyl substituted with 1-6 C alkoxy, more particularly 5,6-dimethoxybenzo[b]thiophen-2-yl;

quinolyl group, especially 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl and 8-quinolyl groups;

quinoxalinyl group, especially 2-quinoxalinyl group;

1,8-naphthyridinyl group, especially 1,8-naphthyridin-2-

-il-group;

indolyl group, especially 2-indolyl group, especially 6-indolyl-, 5-indolyl group, especially indolyl group substituted with C1-C6 alkyl group, more especially N-methyl-2-indolyl-group

- 30 ports;

pyridyl, especially 2-pyridyl, 3-pyridyl, 5-pyridyl, especially pyridyl substituted with C1-6 alkyl, more particularly 2-methyl-5-pyridyl, and 1-oxy-2-pyridyl and 1-oxy-3-pyridyl;

furo[3,2-b]pyridyl, especially furo[3,2-b]pyridin-2-yl, furo[3,2-b]pyridyl substituted with C1-6 alkyl, especially 3-methylfuro[3,2-b]pyridin-2-yl;

thienyl group, especially 3-thienyl group, and 2-thienyl group, especially alkyl-substituted thienyl group, more particularly 5-methyl-2-thienyl and 5-methyl-3-thienyl group, especially halogen-substituted thienyl group, more particularly 4,5-dibromo-2-thienyl group;

thieno[3,2-b]thienyl, especially thieno[3,2-b]thiophen-2-yl, more preferably alkyl-substituted thieno[3,2-b]thiophen-2-yl, more preferably 5-tert-butyl-3-methyl-thieno[3,2-b]thiophen-2-yl;

isoxazolyl, especially 4-isoxazolyl, especially C1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-4-isoxazolyl;

oxazolyl group, especially 4-oxazolyl group, more particularly 5-methyl-2-phenyl-4-oxazolyl-, 2-phenyl-5-(trifluoromethyl)-4-oxazolyl group; and 1H-benzimidazolyl group, especially 1H-5-benzimidazolyl group;

R represents a methyl group;

ethyl, especially ethyl substituted with C1-6 alkyl, more preferably 2-cyclohexylethyl;

butyl, especially C1-C6 alkyl substituted butyl, more preferably 3-methylbutyl;

tert-butyl group, especially when R is 9

R 0C(0)- is a group with the general formula;

isopentyl group;

phenyl group, especially halogen-substituted phenyl group, especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C1-C6 alkoxy-substituted phenyl group, especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, especially 2-cyanophenyl; especially C1-C6 alkyl-substituted phenyl group, especially 4-ethylphenyl, 2-methylphenyl, 4-methylphenyl; especially 1-6 .L ·:·. .»· ·-* ···· phenyl substituted with a carbon alkylsulfonyl group, more particularly 4-(methylsulfonyl)phenyl and 2-(methylsulfonyl)phenyl;

tolyl, especially tolyl substituted with Het, more particularly 3-(2-pyridyl)tolyl;

naphthyl group, especially 2-naphthyl group;

carboxyphenyl group, especially 2-carboxyphenyl group;

benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl;

benzo[1,2,5]oxadiazolyl, especially benzo[1,2,5]oxadiazol-4-yl;

pyridyl group, especially 2-pyridyl, 3-pyridyl, especially 1-oxypyridyl, more particularly 1-oxy-2-pyridyl, 1-oxy-3-pyridyl; especially (C1-6 alkyl)pyridyl, more particularly 3-methyl-2-pyridyl, 6-methyl-2-pyridyl;

thienyl group, especially 2-thienyl group;

thiazolyl, especially 2-thiazolyl;

IJZ-imidazolyl group, especially ΙΉ-2-imidazolyl-, 1H-4-imidazolyl-, more preferably imidazolyl group substituted with 1-6 carbon alkyl groups, most notably 1-methyl-1H-2-imidazolyl-, 1-methyl-1H-4-imidazolyl- and 1,2-dimethyl-1H-4-imidazolyl- 33

-group;

triazolyl group, especially 1H-1,2,4-triazolyl group, especially 1H-1,2,4-triazol-3-yl group, more preferably 1H-1,2,4-triazolyl group substituted with a C1-C6 alkyl group, most preferably

5-methyl-1H-1,2,4-triazol-3-yl; and isoxazolyl, especially 4-isoxazolyl, especially C1-6 alkyl substituted isoxazolyl, more preferably 3,5-dimethyl-4-isoxazolyl;

R' represents a hydrogen atom;

R is hydrogen; and

R' represents a hydrogen atom.

Even more preferred are those compounds of formula (I) in which R is

group of general formula;

9

R is a group of general formula R SO ₂ -;

R is isobutyl;

5

R is a group of the general formula RC(O)-;

R ⁵ is 3-methyl-2-benzofuranyl-, thieno[3,2-b]thiophen-2-

-yl, 5-methoxy-2-benzofuranyl, 2-quinoxalinyl and 2-quinolyl groups, preferably 3-methyl-2-benzofuranyl group;

R is 2-pyridyl or 1-oxy-2-pyridyl, preferably 1-oxy-2-pyridyl;

R' is hydrogen; and

R' represents a hydrogen atom.

Most preferred are those compounds in which R5 is 3-methyl-2-benzofuranyl; and QR is 1-oxy-2-pyridyl.

One aspect of the present invention [IA.] is directed to compounds of general formula (IA)

— in the formula of which

R ¹ meaning

group of general formula;

R is a C1-C6 alkyl group, Ar-(C0-C6 alkyl) group, Het-(C0-C6 alkyl) group, 9 9 911 9 11

a group of the general formula RC(O)-, R SO ₂ -, RR NC(O)- or R ⁹ SO ₂ R NC (O)-;

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6

- 35 } ♦* ♦*% ***

Λ* * 94 ti» ♦*» alkenyl group, C2-6 alkynyl group, Het-(C0-6 alkyl) group or Ar-(C0-6 alkyl) group, preferably C1-6 alkyl group; 3

R and R' can be linked to form a pyrrolidine, piperidine or morpholine ring; 4 5

R is a group of the general formula RC(O)~;

R ⁵ is a C 1-6 alkyl group or a Het-(C 0-6 alkyl) group, preferably a Het-(C 0-6 alkyl) group;

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and an Het-(C0-6 alkyl) group; 11

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R' represents a hydrogen atom;

R represents a hydrogen atom;

R' represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom;

R is a C1-C6 alkyl group, a (C3-C6 cycloalkyl)-(C0-C6 alkyl) group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group; and n is 1, 2, 3, 4 or 5, preferably 3 — and pharmaceutically acceptable salts, hydrates and sol- 36

their sins are formed.

In solution IA, if R means

group with general formula; then 3

R is preferably an alkyl group having 1-6 carbon atoms;

R is more preferably 2-butyl or isobutyl;

q

R is most preferably isobutyl;

5

R is a group of the general formula RC(O)-;

R is a C1-6 alkyl group or a Het-(C0-6 alkyl) group, preferably a Het-(C0-6 alkyl) group;

R is more preferably a piperidylethyl group, especially a (1-piperidyl)ethyl group;

benzo[1,3-]dioxolyl, especially benzo[1,3]dioxol-5-yl;

furyl group, especially 2-furyl group, especially substituted furyl group, for example 5-nitro-2-furyl, 5-(4-nitrophenyl)-2-furyl, 5-[3-(trifluoromethyl)phenyl]-2-furyl group, more particularly furyl group substituted with a halogen atom, more particularly 5-bromo-2-furyl group, more particularly furyl group substituted with an aryl group, more particularly

5-(4-chlorophenyl)-2-furyl, more particularly furyl substituted with C1-6 alkyl, specifically 3-methyl-2-furyl, 4-methyl-2-furyl, 2,5-dimethyl-2-furyl and 2,4-dimethyl-3-furyl;

benzofuranyl, especially 2-benzofuranyl, and substituted benzofuranyl, especially 5-{2-[4-(tert-butoxycarbonyl)-1-piperazinyl]-ethoxy}-2-benzofuranyl, 5-(2-morpholinoethoxy)-2-benzofuranyl, 5-[2-(1-piperazinyl)-ethoxy]-2-benzofuranyl, 5-(2-cyclohexylethoxy)-2-benzofuranyl; in particular benzofuranyl substituted with 1-6 C alkoxy, more particularly 7-methoxy-2-benzofuranyl, 5-methoxy-2-benzofuranyl, 5,6-dimethoxy-2-benzofuranyl, in particular benzofuranyl substituted with halogen, more particularly 5-fluoro-2-benzofuranyl, 5,6-difluoro-2-benzofuranyl, in particular benzofuranyl substituted with 1-6 C alkyl, most particularly 3-methyl-2-benzofuranyl, 3,5-dimethyl-2-benzofuranyl and 3-ethyl-2-benzofuranyl; also 5-fluoro-3-methyl-2-benzofuranyl, 6-fluoro-3-methyl-2-benzofuranyl, 5-methoxy-3-methyl-2-benzofuranyl, 4-methoxy-3-methyl-2-benzofuranyl and 6-methoxy-3-methyl-2-benzofuranyl groups;

naphtho[2,1-b]furanyl, especially naphtho[2,1-b]furan-2-yl, alkyl-substituted naphtho[2,1-b]furanyl, especially 1-methylnaphtho[2,1-b]furan-2-yl;

benzo[b]thienyl, especially benzo[b]thiophen-2-yl; especially benzo[b]thienyl substituted with 1-6C alkoxy, more particularly 5,6-dimethoxybenzo[b]thiophen-2-yl;

quinolyl group, especially 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl and 8-quinolyl groups;

quinoxalinyl group, especially 2-quinoxalinyl group;

pyridyl, especially 2-pyridyl, 3-pyridyl, 5-pyridyl, especially pyridyl substituted with C1-6 alkyl, more particularly 2-methyl-5-pyridyl, and 1-oxy-2-pyridyl and 1-oxy-3-pyridyl;

furo[3,2-b]pyridyl, especially furo[3,2-b]pyridin-2-yl, furo[3,2-b]pyridyl substituted with C1-6 alkyl, especially 3-methylfuro[3,2-b]pyridin-2-yl;

thienyl, especially 3-thienyl, and 2-thienyl, especially alkyl-substituted thienyl, especially 5-methyl-2-thienyl and 5-methyl-3-thienyl, especially halogen-substituted thienyl, especially 4,5-dibromo-2-thienyl;

thieno[3,2-b]thienyl group, especially thieno[3,2-b]ti

thieno[3,2-b]thiophen-2-yl, more preferably alkyl-substituted thieno[3,2-b]thiophen-2-yl, more preferably 5-tert-butyl-3-methyl-thieno[3,2-b]thiophen-2-yl; and

1H-benzimidazolyl group, especially 1H-5-benzimidazolyl group;

R ⁵ is more preferably 3-methyl-2-benzofuranyl, thieno[3,2-b]thiophen-2-yl, 5-methoxy-2-benzofuranyl, 2-quinoxalinyl and 2-quinolyl.

In solution IA, if R ¹ means

R'O

R4

R3 is a group with the general formula, then 3

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and an Ar-(C0-6 alkyl) group;

R is preferably an alkyl group having 1-6 carbon atoms; 3

R is more preferably methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclohexylmethyl and tolyl;

R’’ is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and Ar-(C0-6 alkyl)40

-group;

R is preferably an alkyl group having 1-6 carbon atoms;

R is more preferably methyl, ethyl, propyl, butyl, isobutyl and tert-butyl;

R is most preferably methyl.

In these compounds, the

In a group of general formula R' and R have the meanings defined above.

_ i

In solution IA, if R means

a group of the general formula; then n is 1, 2, 3, 4 or 5, preferably 3; and

R' and R mean the

in a group of general formula as defined above.

The ring may optionally be substituted with one or more C1-6 alkyl groups, (C3-6 cycloalkyl)-(C0-6 alkyl) groups, C2-6 alkenyl groups, C2-6 alkynyl groups, Het-(C0-6 alkyl) groups, Ar-(C0-6 alkyl) groups and/or halogen atoms.

The ring is preferably unsubstituted.

In Solution IA, R is a C1-C6 alkyl group, Ar-(C0-C6 alkyl) group, Het-(C0-C6 alkyl) group, RC(0)-, RSO2-, RRNC(O)- and RSO2RNO(0)-.

More preferably, R is Ar-(C0-6 alkyl)9 99 11

-group, R C(0)-, R SO2- and R R NC(O)- group.

Even more preferably, R is Ar-(C0-C9,9 alkyl), R is O(O)- and R is S0 ₂ ~.

Most preferably, R is a group of the general formula RSO2-.

In such solutions: 9

R represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and an Het-(C0-6 alkyl) group.

R preferably represents a C1-6 alkyl group, an Ar-(C0-6 alkyl) group and an Het-(C0-6 alkyl) group.

, 9

More preferably, R is:

ethyl group, especially ethyl group substituted with alkyl group of 1-6 carbon atoms, more especially 2-cyclohexylethyl group:

propyl group, especially 1-propyl group;

isopentyl swept;

butyl group, especially 1-butyl group;

phenyl, especially halogen-substituted phenyl, especially 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl; phenyl substituted with C1-6 alkyl, especially 4-ethylphenyl, 2-methylphenyl, 4-methylphenyl; phenyl substituted with C1-6 alkylsulfonyl, especially 4-(methylsulfonyl)phenyl and 2-(methylsulfonyl)phenyl;

pyridyl group, especially 2-pyridyl, 1-oxypyridyl group, more preferably 1-oxy-2-pyridyl group;

1H-imidazolyl, especially 1H-2-imidazolyl, more preferably 1-methyl-1H-2-imidazolyl; and isoxazolyl, especially 4-isoxazolyl, especially isoxazolyl substituted with 1-6 C alkyl, more preferably 3,5-dimethyl-4-isoxazolyl.

9

When R is a group of the general formula R SO2-, then R is most preferably a 2-pyridyl and 1-oxy-2-pyridyl group. 9 9 11

When R is a group of the general formula R SO2R NC(O)- 9 , R is preferably an Ar-(C0-C6 alkyl) group, more preferably an Ar- group, most preferably a substituted phenyl group, such as 2-methylphenyl, 4-methylphenyl, 2-chlorophenyl and 4-fluorophenyl. . 9 . 9

If R is a group of general formula R C(0)~, 9

R preferably represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group, more preferably 1-oxy-2-pyridyl, cyclohexylmethyl and isopentyl groups.

9 11

When R is a group of the general formula R SO2R NC(O)-, R ¹¹ is hydrogen, C 1-6 alkyl, Ar-(C 0-6 alkyl) and Het-(C 0-6 alkyl). In this embodiment, R is preferably hydrogen.

R is suitably C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl), preferably C1-6 alkyl and Het-(C0-6 alkyl).

When R is Ar-(C0-C6 alkyl), R is preferably phenyl, especially substituted phenyl, more preferably halogen-substituted phenyl, most preferably 2-fluorophenyl.

2

When R is an alkyl group having 1-6 carbon atoms, R is preferably 1-propyl, 1-butyl and 1-pentyl. 2

When R is Het-(C0-6 alkyl), the Het-(C0-6 alkyl) is preferably Het-methyl, where in the Het-methyl Het is preferably pyridyl, especially 2-pyridyl, especially (C1-6 alkyl)pyridyl, more preferably 6-methyl-2-pyridyl;

thienyl group, especially 2-thienyl group;

benzo[b]thiophen-2-yl group;

thiazolyl group, especially 4-thiazolyl group and 3-isothiazolyl group;

1H-imidazolyl, especially 1H-2-imidazolyl, imidazolyl substituted with C1-6 alkyl, more preferably 1-methyl-1H-2-imidazolyl;

triazolyl, especially 3H-1,2,3-triazolyl, more particularly 3H-1,2,3-triazol-4-yl, especially 3H-1,2,3-triazolyl substituted with C1-6 alkyl, more particularly 3-phenyl-3H-1,2,3-triazol-4-yl;

quinolyl group, especially 2-quinolyl group;

furyl, especially 2-furyl, especially substituted furyl, such as 5-ethyl-2-furyl;

thieno[3,2-b]thienyl, especially thieno[3,2-b]thiophen-2-yl, especially thieno[3,2-b]thienyl substituted with C1-6 alkyl, especially 3,4-dimethylthieno[3,2-b]thiophen-2-yl.

The compounds of Embodiment IA can be utilized in the same way as the compounds of Formula (I). The compounds of Embodiment IA can be formulated into pharmaceutical compositions in the same way and used in the same treatment methods as the compounds of Formula (I).

The compounds of general formula (I) listed in the following group are particularly preferred embodiments of the invention:

Example number Chemical name 1. benzyl-[(S)-1-{1-[(S)-2-{[(benzyloxy)- -carbonyl]-amino}-4-methylpentanoyl]-3-oxo-4- -azepanyl}-carbamoyl]-carbamate 2. W-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -naphthalene carboxamide 3. N—{ (S) -1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-benzo[1,3]dioxole-5- -carboxamide 4. N-{ (S) -1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 5. N-{ (S) -1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2- -carboxamide 6. N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -naphthalenesulfonamide 7. N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

(sequel)

Example number Chemical name 8. N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-3,4-dichlorobenzamide 9. 4-{[(S)-4-methyl-2-{[(2-quinolyl)carbonyl]- -amino}-pentanoyl]-amino}-3-oxo-1-{2-[3-(2- -pyridyl)phenyl]-acetyl}-azepane 10. 1-[(S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentyl]-4-{[(S)-4-methyl-2-{[(2-quinolyl)carbonyl]amino}-pentanoyl]amino}-3-oxoazepane 11. l-benzoyl-4-[{(S)-2-[(benzo[1,3]dioxolyl- -carbonyl)-amino]-4-methyl-pentanoyl}-amino]-3- -oxo-azepane 12. l-benzoyl-4-[{(S)-2-[(4-fluorobenzoyl)amino]- -4-methylpentanoyl}-amino]-3-oxo-azepane 13. 3-OXO-4-[{(S)-4-methyl-2-[{[5-(2-morpholino- -ethoxy)-2-benzofuranyl]-carbonyl}-amino]- -pentanoyl}-amino]-1-(4-methylpentanoyl) - -azepane 14. N-[(S)-1-{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

- 47 (continued)

Example number Chemical name 15. N-phenyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholino- -ethoxy)-2-benzofuranyl]-carbonyl}-amino]- -pentanoyl}-amino]-3-oxo-l-azepanecarboxamide 16. N—[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-acetyl}-4-azepanyl]-carbamoyl]-butyl]- -5-(2-morpholinoethoxy)-2-benzofurancarboxamide 17. 2V— { (S) -1- [ (1-benzoyl-3-oxo-4-azepanyl) - -carbamoyl]-3-methylbutyl}-5-(2-morpholino- -ethoxy)-2-benzofurancarboxamide 18. N- [(S)— 1—{ [1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-pyrrolidinyl)ethoxy]-2-benzofurancarboxamide 19. N- [(S)— 1—{ [1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-piperidyl)ethoxy]-2-benzofurancarboxamide 20. N- [(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-5- -(2-morpholinoethoxy)-2-benzofurancarboxamide 21. N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-2- -naphthalene carboxamide

(sequel)

Example number Chemical name 22. N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-1H- -2-indolecarboxamide 23. N-[(S) -1-{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-1H-2-indolecarboxamide 24. N- [ (S) — 1—{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide 25. N- [(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-2- -benzofurancarboxamide 26. N-{(S)-3-methyl-1-[(3-oxo-1-phenethyl-4-azepanyl)carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide 27. N-{(S)-3-methyl-1-[(3-oxo-1-phenethyl-4- -azepanyl)-carbamoyl]-butyl}-2- -naphthalene carboxamide 28. 7J-{ (S) -3-methyl-1- [ { 3-oxo-1- [ (2-pyridyl) - -sulfonyl]-4-azepanyl}-carbamoyl·]-butyl}-2- -benzofurancarboxamide

(sequel)

Example number Chemical name 29. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-2- -naphthalene carboxamide 30. N- {(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5- -(2-morpholinoethoxy)-2-benzofurancarboxamide 31. tert-butyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholino- -ethoxy)-2-benzofuranyl]-carbonyl}-amino]- -pentanoyl}-amino]-3-oxo-l-azepanecarboxylate 32. 2N-{(S)-3-methyl-1-[(3-oxo-4-azepanyl)- -carbamoyl]-butyl}-5-(2-morpholinoethoxy)-2- -benzofurancarboxamide 33. N- [3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4- -azepanyl]-4-methylpentanamide 34. tert-butyl-N- [(S)-3-methyl-1-{ [3-oxo-1-{2—[3—(2 — -pyridyl)-phenyl]-acetyl}-4-azepanyl]- -carbamoyl}-butyl]-N- [(2-naphthyl)-methyl]- -carbamate 35. N- [3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]-(S)-4-methyl-2-{[(2-naphthyl)methyl]amino}-pentenamide

(sequel)

Example number Chemical name 36. tert-butyl-4-{2-[{2-[{(S)-3-methyl-1-[{3-oxo-1- [(2-pyridyl)sulfonyl]-4-azepanyl}- -carbamoyl]-butyl}-carbamoyl]-5-benzofuranyl}- -oxy]-ethyl}-1-piperazinecarboxylate 37. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[2-(1-piperazinyl)ethoxy]-2-benzofurancarboxamide 38. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide 39. N- [(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-5- -(2-cyclohexylethoxy)-2-benzofurancarboxamide 40. tert-butyl-4-[2—{[2 — { [(S)-3-methyl-1-{ [3-oxo-1- -{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]- -carbamoyl}-butyl]-carbamoyl}-5-benzofuranyl]- -oxy}-ethyl]-1-piperazinecarboxylate 41. N- [(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)- -phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-5- -[2-(1-piperazinyl)-ethoxy]-2- -benzofurancarboxamide

sequel

Example number Chemical name 42. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl} - (S)-4-methyl-2-{N-methyl-W-[(2- -naphthyl)methyl]amino}pentanamide 43. N-[3-oxo-1-{2-[3-(2-pyridyl)-phenyl]-acetyl}-4- -azepanyl]-(S)-4-methyl-2-{N-methyl-N-[(2- -naphthyl)methyl]amino}pentanamide 44. M-methyl-N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2- -pyridyl)-phenyl]-acetyl}-4-azepanyl]- -carbamoyl}-butyl]-5-(2-morpholinoethoxy)-2- -benzofurancarboxamide 45. N-methyl-N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide 46. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-N- [(2-naphthyl)methyl]-2,2,2-trifluoroacetamide 47. benzyl-4-{[(S)-2-{N-mesyl-N-[(2-naphthyl)-methyl]- -amino}-4-methylpentanoyl]-amino}-3-oxo-1- -azepanecarboxylate

(sequel)

Example number Chemical name 48. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinolinecarboxamide 49. W-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-8-quinolinecarboxamide 50. W-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-6- -quinoline carboxamide 51. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4-quinolinecarboxamide 52. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-3-quinolinecarboxamide 53. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -isoquinolinecarboxamide 54. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1-isoquinolinecarboxamide

sequel

Example number Chemical name 55. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-2-quinoxalinecarboxamide 56. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -benzo[b]thiophene-2-carboxamide 57. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-1,8- -naphthyridine-2-carboxamide 58. N-{(5)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1H- -2-indolecarboxamide 59. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl)-5- -methoxy-2-benzofurancarboxamide 60. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-furancarboxamide 61. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-furancarboxamide

(sequel)

Example number Chemical name 62. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5- -nitro-2-furancarboxamide 63. N~ {(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5- -(4-nitrophenyl)-2-furancarboxamide 64. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide 65. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-tetrahydrofurancarboxamide 66. N- {3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-4-methyl-2-[(2-phenoxyacetyl)- -amino]pentanamide 67. N- {3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[2-(4-fluorophenoxy)acetyl]amino}pentanamide 68. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)carbonyl]-4-azepanyl}-carbamoyl]-3-butyl}-2-benzofurancarboxamide

(sequel

Example number Chemical name 69. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-3-butyl}-2- -benzofurancarboxamide 70. benzyl-4- [ { (S)-2-[(tert-butoxycarbonyl)- -amino]-4-methylpentanoyl}-amino]-3-oxo-1- -azepanecarboxylate 71. N-{ (5) - 3-methyl-1- [ {3-oxo-1- [ (1-methyl-121-4- -imidazolyl)-sulfonyl]-4-azepanyl}- -carbamoyl]-butyl}-5,6-dimethoxy-2- -benzofurancarboxamide 72. N-{(S)-3-methyl-1-[{3-oxo-1-[(5-methyl-1H-1,2, 4- -triazol-3-yl)sulfonyl]-4-azepanyl}- -carbamoyl]butyl}-2-benzofurancarboxamide 73. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-3- -imidazolyl)sulfonyl]-4-azepanyl}- -carbamoyl]butyl}-2-benzofurancarboxamide 74. N- { (S) - 3-methyl-1- [ {3-oxo-1- [ (1ff-2-imidazolyl) - -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -2- -benzofurancarboxamide 75. N- {(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

(sequel)

Example number Chemical name 76. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4- -imidazolyl)sulfonyl]-4-azepanyl}- -carbamoyl]-butyl}-2-benzofurancarboxamide 77. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[2- -(4-oxymorpholino)ethoxy]-2- -benzofurancarboxamide 78. N-{(S)-3-methyl-1-[{3-oxo-1-[(3-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-2- -benzofurancarboxamide 79. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-3-pyridyl)- -sulfonyl]-4-azepanyl)carbamoyl]butyl}-2- -benzofurancarboxamide 80. N- {(S)-[{1-[(3,4-dichlorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-3- -quinolinecarboxamide 81. N- { (S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4- -imidazolyl)sulfonyl]-4-azepanyl}- -carbamoyl]-butyl}-5-hydroxy-2- -benzofurancarboxamide

(sequel)

Example number Chemical name 82. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2- -benzofurancarboxamide 83. 2-{[ 4 — {[(S)-2-{[(2-benzofuranyl)carbonyl]- -amino}-4-methylpentanoyl]amino}-3-oxo-1- -azepanyl]sulfonyl}-benzoic acid 84. 3-{[4—{[(S)-2-{[(2-benzofuranyl)carbonyl]- -amino}-4-methylpentanoyl]amino}-3-oxo-1- -azepanyl]sulfonyl}-benzoic acid 85. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -benzo[b]thiophene-2-carboxamide 86. N- { (S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} - 5- -bromo-2-furancarboxamide 87. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5,6- -dimethoxy-2-benzofurancarboxamide 88. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}carbamoyl]butyl}-1- -oxy-2-pyridinecarboxamide

(sequel)

Example number Chemical name 89. N- {3-oxo-1-[(2-pyridyl)-sulfonyl]-4- -azepanyl}-(S)-4-methyl-2-{[(2-pyridyl)- -sulfonyl]-amino}-pentanamide 90. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-2-(3-benzylureido)-4-methyl- -pentanamide 91. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-2-(3-phenylureido)-4-methyl- -pentanamide 92. N-{(S)-3-methyl-1-[{6,6-dimethyl-3-oxo-1-[(2- -pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide 93. N- {(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5- -methoxy-2-benzofurancarboxamide 94. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -thieno[3,2-b]thiophene-2-carboxamide 95. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2- -quinoxalinecarboxamide

(sequel)

Example number Chemical name 96. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2- -quinoline carboxamide 97. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -thiophene carboxamide 98. N-[(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1H- -5-indolecarboxamide 99. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -benzo[1,3]dioxole-5-carboxamide 100. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2- -furancarboxamide 101. N-{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4- -azepanyl}- (S)-4-methyl-2-{[(2-thienyl)-acetyl]- -amino}-pentanamide 102. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1H- -2-indolecarboxamide

(sequel)

Example number Chemical name 103. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-4- -fluorobenzamide 104. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5- -(2-morpholinoethoxy)-2-benzofurancarboxamide 105. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2- -thiophene carboxamide 106. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -methyl-2-benzofurancarboxamide 107. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-6- -methylnicotinamide 108. N- [{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-butyl]-(S)-4-methyl-2-{[(2-thienyl)- -acetyl]-amino}-pentanamide 109. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1H- -6-indolecarboxamide

(sequel)

Example number Chemical name 110. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -benzo[1,3]dioxole-5-carboxamide 111. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carboxamide 112. N-{(Sj-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5- -methyl-2-thiophenecarboxamide 113. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4,5-dibromo-2-thiophenecarboxamide 114. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3,5-dimethyl-4-isoxazolecarboxamide 115. N-{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-2-{[2-(benzyloxy)acetyl]amino}-4-methylpentanamide 116. N- { (S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-[3- -(trifluoromethyl)-phenyl]-2-furancarboxamide

(sequel)

Example number Chemical name 117. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5- -methyl-2-phenyl-4-oxazolecarboxamide 118. N—{(S)-[{1-[(3,4-dimethoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]butyl}-2- -benzofurancarboxamide 119. N-{(S) — [ {1— [(4-bromophenyl)sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 120. N-(S)-{1-[{1-[(benzo[1,2,5]oxadiazol-4-yl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide 121. N-(S)-{1-[{1-[(3,5-dimethyl-4-oxazolyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide 122. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3- -methyl-2-benzofurancarboxamide 123. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -thieno[3,2-b]thiophene-2-carboxamide

(sequel)

Example number Chemical name 124. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5- -tert-butyl-3-methylthieno[3,2-b]thiophene-2- -carboxamide 125. N-{(Sj-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-5- -methyl-2-phenyl-4-oxazolecarboxamide 126. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-phenyl-5-(trifluoromethyl)-4-oxazolecarboxamide 127. N- { (S)-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide 128. W-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-1-methyl-1H-2- -indole carboxamide 129. N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2-furancarboxamide 130. N- { (S)-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-5-methoxy-2- -benzofurancarboxamide

(continued) .· ·*’· ·**·

Example number Chemical name 131. N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 132. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5- -(4-chlorophenyl)-2-furancarboxamide 133. N-(1-Mesyl-3-oxo-4-azepanyl)-(S)-{2-[2-(4- -methoxyphenyl)acetyl]amino}-4-methyl- -pentanamide 134. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinolinecarboxamide 135. 2V-{ (S) -1- [ {1- [ (2-cyanophenyl) -sulfonyl] -3-oxo- -4-azepanyl}-carbamoyl]-3-methyl-butyl}-1- -methyl-1H-2-indolecarboxamide 136. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -furancarboxamide 137. N-{ (S) -1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide

(sequel)

Example number Chemical name 138. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 139. N-{1-[(2-cyanophenyl)sulfonyl]-3-OXO-4-azepanyl}-(S)-{2-[2-(4-methoxyphenyl)acetyl]- -amino]-4-methylpentanamide 140. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinolinecarboxamide 141. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-1- -methyl-1H-2-indolecarboxamide 142. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl} - 2- -furancarboxamide 143. N- {(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 144. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide

(sequel

Example number Chemical name 145. 2V— {1— [ (4-methoxyphenyl) -sulfonyl] -3-oxo-4-azepanyl}-(S)-{2-[2-(4-methoxyphenyl)-acetyl]- -amino}-4-methylpentanamide 146. N-{(Sj-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-1- -methyl-1H-2-indolecarboxamide 147. N-{(5)-1-[ {1 —[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-2- -furancarboxamide 148. N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 149. N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 150. N-{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-{2-[2-(4-methoxyphenyl)acetyl]- -amino}-4-methylpentanamide 151. N- {(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide

(sequel)

Example number Chemical name 152. N- {(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 153. N—{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-7- -methoxy-2-benzofurancarboxamide 154. N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-5,6- -dimethoxy-2-benzofurancarboxamide 155. N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-3- -methyl-2-benzofurancarboxamide 156. N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[b]thiophene-2-carboxamide 157. N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-1- -methyl-1H-2-indolecarboxamide 158. N-{(S)-1-[{1—[(3-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide

(sequel)

Example number Chemical name 159. N- { (S) -1- [ {1- [(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl} -2- -benzofurancarboxamide 160. N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 161. N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-7- -methoxy-2-benzofurancarboxamide 162. N—{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-5,6- -dimethoxy-2-benzofurancarboxamide 163. N- {(Sj -1-[{1—[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methyl-2-benzofurancarboxamide 164. N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[b]thiophene-2-carboxamide 165. N- { (Sj-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-1- -methyl-1.H-2-indolecarboxamide

(sequel

Example number Chemical name 166. Λ7-{ 3-oxo-l - [ (2-pyridyl) -sulfonyl] -4- -azepanyl}(S)-4-methyl-2-{[(1-oxy-2-pyridyl)- -sulfonyl]amino}-pentanamide 167. N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 168. N-{(S)—1-[{1—[(2-thienyl)sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methylbutyl}-5-methoxy- -2-benzofurancarboxamide 169. N-{(S)—1—[{1—[(2-thienyl)sulfonyl]-3-OXO-4- -azepanyl}-carbamoyl]-3-methylbutyl}-7-methoxy- -2-benzofurancarboxamide 170. N-{(S)—1-[{1—[(2-thienyl)sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methylbutyl}-5,6- -dimethoxy-2-benzofurancarboxamide 171. N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methylbutyl}-5-methyl- -2-benzofurancarboxamide 172. N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-OXO-4- -azepanyl}-carbamoyl]-3-methylbutyl}- benzo[b]thiophene-2-carboxamide

(sequel)

Example number Chemical name 173. N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methyl-butyl}-1-methyl- -177-2-indolecarboxamide 174. TV-{ (S)-1-[{1-[ (2-thienyl)-sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 175. N—{(S)-1-[{1—[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 176. N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 177. N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-7- -methoxy-2-benzofurancarboxamide 178. N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-5,6- -dimethoxy-2-benzofurancarboxamide 179. N-{(5)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-3- -methyl-2-benzofurancarboxamide

(sequel)

Example number Chemical name 180. W-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- benzo[b]thiophene-2-carboxamide 181. N- { (S) -1- [ {1- [(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-1- -methyl-1-[2-indolecarboxamide 182. N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 183. N- { (S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 184. N-{(S)-1-[{1—[(3-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 185. N- {(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl} -7- -methoxy-2-benzofurancarboxamide 186. N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl]carbamoyl]-3-methylbutyl}- -5,6-dimethoxy-2-benzofurancarboxamide

(sequel)

Example number Chemical name 187. N- { (S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-3- -methyl-2-benzofurancarboxamide 188. N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}benzo[b]thiophene-2-carboxamide 189. N-{(S)-1-[{1-[(3-Methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-1- -methyl-1H-2-indolecarboxamide 190. N-{(S)-1-[{1-[(3-Methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2- -quinoxalinecarboxamide 191. N—{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4- -azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 192. N~{(S)-3-methyl-1-[{(2,2',4-trideuterio)-3-oxo- -1-[(2-pyridyl)sulfonyl]-4-azepanyl}- -carbamoyl]butyl}-2-benzofurancarboxamide 193. 2V—{ (S) -2-methyl-1- [ { 3-oxo-1- [ (2-pyridyl) -sulfonyl] -4-azepanyl}-carbamoyl]-butyl)-2-benzofurancarboxamide

(sequel)

Example number Chemical name 194. N- { (S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}carbamoyl]propyl}-2- -benzofurancarboxamide 195. N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-2- -benzofurancarboxamide 196. N- { (S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}carbamoyl]ethyl}-2- -benzofurancarboxamide 197 . N-{(S)-3-mesyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]propyl}-2-benzofurancarboxamide 198. N-{(S)-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl]carbamoyl]methyl}-2- -benzofurancarboxamide 199. N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}carbamoyl]pentyl}-2- -benzofurancarboxamide 200. N- {(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}carbamoyl]butyl}-2- -benzofurancarboxamide

(continued) · ·· · * ♦ * ·> .1.

Example number Chemical name 201. N-{(S)-2-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]propyl}-2- -benzofurancarboxamide 202. N-{(S)-2-hydroxy-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]propyl}-2-benzofurancarboxamide 203. N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-carbamoyl]-2-phenylethyl}-2- -benzofurancarboxamide 204. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-1-[(2-benzofuranyl)carbonyl]-2- -pyrrolidinecarboxamide 205. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]-3-methylbutyl} -3,4-dimethoxybenzamide 206. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[b]thiophene-2-carboxamide 207. N-{(S) -1- [ {1- [(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl]carbamoyl]-3-methylbutyl}- -benzo[1,3]dioxole-4-carboxamide

(sequel)

Example number Chemical name 208. N-{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4- -azepanyl}-(S)-2-{[2-(benzyloxy)acetyl]- -amino}-4-methylpentanamide 209. N-{(S)-1-[{1—[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[b]thiophene-2-carboxamide 210. N- { (Sj -1- [(1-benzoyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 211. N-{1-[(2-pyridyl)sulfonyl]-3-ΟΧΟ-4- -azepanyl}-(S)-2-{[(8-quinolyl)sulfonyl]- -amino}-4-methylpentanamide 212. 1-[(2-pyridyl)sulfonyl]-3-oxo-4- -azepanyl}-(S)-2-{[(2-naphthyl)sulfonyl]- -amino}-4-methylpentanamide 213. N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 214. N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-3,4- -dimethoxybenzamide

(continued) •J <.'· .:..... · _Λ ·

Example number Chemical name 215. N-{(S)-1-[{1—[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- -cyclohexanecarboxamide 216. N-(1-mesyl-3-oxo-4-azepanyl)-(S)-2-{[2- -(benzyloxy)acetyl]amino}-4-methyl- -pentanamide 217. N- { (S) -1- [(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2- -carboxamide 218. N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-benzo[1,3]dioxole-5-carboxamide 219. 27-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2— benzofurancarboxamide 220. N—{(Sj-1-[(1-mesyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-3,4-dimethoxy- -benzamide 221. 77-{1- [ (2-cyanophenyl) -sulfonyl] -3-oxo-4- -azepanyl}-(S)-2-{[2-(benzyloxy)-acetyl]- -amino}-4-methylpentanamide

(continued) .i .:.

Example number Chemical name 222. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-4- -mesylbenzamide 223. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[b]thiophene-2-carboxamide 224. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[1,3]dioxole-5-carboxamide 225. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}(S)-4-methyl-2-{4-oxo-4-[(4-phenoxy- -phenyl)butyryl]amino}pentanamide 226. N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo- -4-azepanyl}carbamoyl]-3-methylbutyl]-3,4- -dimethoxybenzamide 227. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}- -cyclohexanecarboxamide 228. N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-4- -mesylbenzamide

(sequel)

Example number Chemical name 229. N- { (S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-4- -mesylbenzamide 230. benzyl-2\7- [ { (S) -3-methyl-1 - [ { 3-oxo-1 - [ (2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]- -butyl}-carbamoyl]-carbamate 231. N- {3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-2-{5-[(4-methoxyphenyl)- -pentanoyl]amino]-4-methylpentanamide 232. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-2-[2-{[3-(benzyloxy)-4-methoxy- -phenyl]acetyl}amino]-4-methylpentanamide 233. N- {(S)-3-methyl-1-[{1—[(2-pyridyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]butyl}-5,6- -difluoro-2-benzofurancarboxamide 234. N- {3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-[(5-oxohexanoyl)- -amino]pentanamide 235. N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide

(sequel

Example number Chemical name 236. N- {(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-5-methoxy-2-benzofurancarboxamide 237. N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-3-methyl-2-benzofurancarboxamide 238. N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-7-methoxy-2-benzofurancarboxamide 239. N-{(S)-3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]butyl}-5,6- -dimethoxybenzo[b]thiophene-2-carboxamide 240. N-{(S)-3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]butyl}(R)-1- -benzyl-5-oxo-2-pyrrolidinecarboxamide 241. N-{(S)-3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3- -oxo-4-azepanyl}carbamoyl]butyl}(S)-1- -benzyl-5-oxo-2-pyrrolidinecarboxamide 242. 2N-{(S)-2-cyclopropyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-2-benzofurancarboxamide

(sequel)

Example number Chemical name 243. N-{ (S') -3- (methylthio) -1- [ { 3-oxo-1- [ (2-pyridyl) -sulfonyl] -4-azepanyl}-carbamoyl]-propyl}-2-benzofurancarboxamide 244. N-{(S)-2-(2-naphthyl)-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-2- -benzofurancarboxamide 245. N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}carbamoyl]- -butyl}-thieno[3,2-b]thiophene-2-carboxamide 246. N-{(S)-3-methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide 247. N-{(S)-3-methyl-1-[{1—[(3-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-3-methyl-2-benzofurancarboxamide 248. N-{(S)-3-methyl-1-[{1-[(3-methyl-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-5-methoxy-2-benzofurancarboxamide 249. N- {(S)-3-methyl-1-[{1—[(1-oxy-2-pyridyl) - -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -butyl}-5,6-difluoro-2-benzofurancarboxamide

(sequel)

Example number Chemical name 250. N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-5-[3- -(trifluoromethyl)-phenyl]-2-furancarboxamide 251. N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-5-(4- -chlorophenyl)-2-furancarboxamide 252. 2N-{ (5) -3-methyl-1- [ { 6-methyl-3-oxo-1- [ (2- -pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide 253. N- { (S)-2-cyclohexyl-1-[{1-[(1-oxy-2-pyridyl)- -sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]- -ethyl}-5-(4-chlorophenyl)-2-furancarboxamide 254. N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(1-oxy-2- -pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]- -ethyl}-5-[3-(trifluoromethyl)phenyl]-2- -furancarboxamide 255. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5- -fluoro-2-benzofurancarboxamide

(continued) ί .· ··· ··* ··· eL, »»»„ »»· * _w · ',·*

Example number Chemical name 256. N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(1-oxy-2- -pyridyl)sulfonyl]-4-azepanyl}carbamoyl]- -ethyl}-5,6-dimethoxy-2-benzofurancarboxamide 257. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl]-5,5-bis(4-methoxyphenyl)pent-4-enamide 258. N-{(S)-2-(2-naphthyl)-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-8- -quinoline carboxamide 259. N-{(S)-2-(2-naphthyl)-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-l- -naphthalene carboxamide 260. N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-carbamoyl]-2-phenylethyl}-8- -quinolinecarboxamide 261. N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-naphthyridinecarboxamide 262. N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}carbamoyl]-2-phenylethyl}-1- -naphthalene carboxamide

(sequel)

Example number Chemical name 263. N-[(S)-3-methyl-1-{[3-oxo-1-(cyclohexylpropionyl)-4-azepanyl]carbamoyl}-butyl]-3-methyl-2-benzofurancarboxamide 264. N-[(S)-3-methyl-1-{[3-oxo-1-(4-methylpentanoyl)-4-azepanyl]carbamoyl}-butyl]-3-methyl-2-benzofurancarboxamide 265. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -methyl-2-benzofurancarboxamide 266. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-(acetylamino)-4-methyl- -pentanamide 267. N-{1-[{3-oxo-l-[(2-pyridyl)sulfonyl]-4- -azepanyl}-carbamoyl]-pentyl}-2- -quinolinecarboxamide 268. N-[(S)-3-methyl-1-{[3-oxo-1-(cyclohexylpropionyl)-4-azepanyl]carbamoyl}-butyl]-2-benzofurancarboxamide 269. N-[(S)-3-methyl-1-{[3-oxo-1-(4-methylpentanoyl)-4-azepanyl]carbamoyl}-butyl]-2-benzofurancarboxamide

(sequel)

Example number Chemical name 270. N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-carbamoyl]-2-phenylethyl}-1- -quinolinecarboxamide 271. N-{(5)-2-(benzyloxy)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]- -ethyl}-2-benzofurancarboxamide 272. N-{(S)-2-hydroxy-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-ethyl}-2- -benzofurancarboxamide 273. 2N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5- -methoxy-2-benzofurancarboxamide 274. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-7- -methoxy-2-benzofurancarboxamide 275. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -methyl-2-benzofurancarboxamide 276. N—{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

(sequel)

Example number Chemical name 277. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-l- -methyl-1H-2-indolecarboxamide 278. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinoxalinecarboxamide 279. N-{(S) -1- [ {1- [(4-fluorophenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2— quinoxalinecarboxamide

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

Example number Chemical name 280. N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 281. N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4- -azepanyl}-(S)-4-methyl-2-{[3-(1-piperidyl)- -propionyl]-amino}-pentanamide

(sequel)

Example number Chemical name 282. N-{(S) -1-[{1—[(4-ethylphenyl)sulfonyl]-3-oxo- -4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 283. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}-carbamoyl]-butyl}-5-[3- -(trifluoromethyl)phenyl]-2-furancarboxamide 284. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl} -benzo[1,3]dioxole-5-carboxamide 285. N- [(S)— 1—{[1-(3-cyclohexylpropionyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide 286. N-[(S)— 1—{[1-(3-cyclohexylpropionyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]- -benzo[1,3]dioxole-5-carboxamide 287. N- [(S)-1-{[1-(4-methylpentanoyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide 288. N- [(S)— 1—{[1-(4-methylpentanoyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]- -benzo[1,3]dioxole-5-carboxamide

(sequel

Example number Chemical name 289. N- [(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide 290. N- [(S)-1-{ [1-(ethylsulfonyl)-3-OXO-4- -azepanyl]carbamoyl}-3-methylbutyl]-2- -benzofurancarboxamide 291. N- { (S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl} - 5- -fluoro-2-benzofurancarboxamide 292. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl]carbamoyl]butyl}-5- -fluoro-3-methyl-2-benzofurancarboxamide 293. N~{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-6- -fluoro-3-methyl-2-benzofurancarboxamide 294. N-{(R)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -methyl-2-benzofurancarboxamide 295. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -methylfuro[2,3-b]pyridine-2-carboxamide

(sequel)

Example number Chemical name 296. 2V-{ (S) -1- [ {1- [ (3-fluorophenyl) -sulfonyl] -3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methoxy-2-benzofurancarboxamide 297. N- { (S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl} -3- -methyl-2-benzofurancarboxamide 298. N-{ (S)-1-[{1—[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}- -benzo[b]thiophene-2-carboxamide 299. N- { (S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-3- -methyl-2-furancarboxamide 300. N-{ (S) -1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -quinolinecarboxamide 301. N-{ (S) -1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}- -thieno[3,2-b]thiophene-2-carboxamide 302. N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl} -2- -quinoxalinecarboxamide

(sequel)

Example number Chemical name 303. N-{ (S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2- -thiophenecarboxamide 304. 2V-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3- -oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5- -methyl-2-thiophenecarboxamide 305. N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]-5-methoxy- -2-benzofurancarboxamide 306. N- [(S) -1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-benzofurancarboxamide 307. N- [ (S) -1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]benzo[b]thiophene-2-carboxamide 308. Δ7- [ (S) — 1—{ [1-(ethylsulfonyl)-3-oxo-4-azepanyl]-carbamoyl}-3-methylbutyl]-3-methyl- -2-furancarboxamide 309. N-[(S) -1- {[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinolinecarboxamide

(sequel

Example number Chemical name 310. N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]- -thieno[3,2-b]thiophene-2-carboxamide 311. N- [(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinoxalinecarboxamide 312. N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]-2- -thiophenecarboxamide 313. N- [(S)-1-{ [1-(ethylsulfonyl)-3-OXO-4- -azepanyl]carbamoyl}-3-methylbutyl]-5-methyl- -2-thiophenecarboxamide 314. N- [(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide 315. N- [(S)-1-{[1-(propylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]-3-methyl- -2-benzofurancarboxamide 316. N-[(S)— 1—{[1-(propylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]- -benzo[b]thiophene-2-carboxamide

(sequel

Example number Chemical name 317. N- [(S)— 1—{ [1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-furancarboxamide 318. N- [(Sj-1-{[1-(propylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]-2,5- -dimethyl-2-furancarboxamide 319. N- [(S)-1-{ [1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinolinecarboxamide 320. N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4- -azepanyl]carbamoyl}-3-methylbutyl]- -thieno[3,2-b]thiophene-2-carboxamide 321. N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinoxalinecarboxamide 322. N- [(S)-1-{[1-(propylsulfonyl)-3-OXO-4- -azepanyl]carbamoyl}-3-methylbutyl]-2- -thiophenecarboxamide 323. N- [(S)-1-{[1-(propylsulfonyl)-3-OXO-4- -azepanyl]carbamoyl}-3-methylbutyl]-5-methyl- -2-thiophenecarboxamide

(sequel)

Example number Chemical name 324. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl]-5- -methoxy-3-methyl-2-benzofurancarboxamide 325. N-{(Sj-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3,5- -dimethyl-2-benzofurancarboxamide 326. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -ethyl-2-benzofurancarboxamide 327. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl} - 4- -methoxy-3-methyl-2-benzofurancarboxamide 328. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl]-1- -methyl-naphtho[2,1-b]furan-2-carboxamide 329. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-6- -methoxy-3-methyl-2-benzofurancarboxamide 330. N-{1,3-dimethyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3- -methyl-2-benzofurancarboxamide

*♦ (continued

Example number Chemical name 331. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)- -methyl]-4-azepanyl}-carbamoyl]-butyl}-2- -benzofurancarboxamide 332. N-{ (S') -3-methyl-1- [ { 3-oxo-1- [ (2-quinolyl) - -methyl]-4-azepanyl}-carbamoyl]-butyl}-3-methyl- -2-benzofurancarboxamide 333. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)- -methyl]-4-azepanyl}-carbamoyl]-butyl}- -benzo[b]thiophene-2-carboxamide 334. N-{ (S') -3-methyl-1 - [ { 3-oxo-1 - [ { [ (2-tolyl) - -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-2-benzofurancarboxamide 335. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)- -sulfonyl]-amino]-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-3-methyl-2- -benzofurancarboxamide 336. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)- -sulfonyl]amino]carbonyl]-4-azepanyl} -carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

sequel

Example number Chemical name 337. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-2-benzofurancarboxamide 338. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-3-methyl-2- -benzofurancarboxamide 339. N- { (S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide 340. N- { (S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-2-benzofurancarboxamide 341. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-3-methyl-2- -benzofurancarboxamide 342. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide

(sequel)

Example number Chemical name 343. N- { (S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-2-benzofurancarboxamide 344. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)- -sulfonyl]-amino}-carbonyl]-4-azepanyl}- -carbamoyl]-butyl}-3-methyl-2- -benzofurancarboxamide 345. N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)- -sulfonyl]amino}carbonyl]-4-azepanyl} -carbamoyl]butyl}benzo[b]thiophene-2-carboxamide 346. N- { (S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2- -pyridyl)-methyl]-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide 347. N- { (S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2- -pyridyl)-methyl]-4-azepanyl}-carbamoyl]- -butyl}-3-methyl-2-benzofurancarboxamide 348. N-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2- -pyridyl)-methyl]-4-azepanyl}-carbamoyl]- -butyl}-benzo[b]thiophene-2-carboxamide

(sequel)

Example number Chemical name 349. N—{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)- -carbamoyl]-4-azepanyl}-carbamoyl]-butyl}- -benzo[b]thiophene-2-carboxamide 350. N—{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-3-methyl-2-benzofurancarboxamide 351. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)- -carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-2,4- -dimethyl-3-furancarboxamide 352. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)- -carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-2- -quinoxalinecarboxamide 353. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)- -carbamoyl]-4-azepanyl}-carbamoyl]-butyl}- -thieno[3,2-b]thiophene-2-carboxamide 354. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinolinecarboxamide 355. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-4-methyl-2-thiophenecarboxamide

- 97 (continued)

Example number Chemical name 356. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)- -carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-5- -methoxy-2-benzofurancarboxamide 357. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)- -carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-4- -methyl-2-furancarboxamide 358. N- { (S)-1-[(1-butyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl} -2- -benzofurancarboxamide 359. N-{(S)-1-[(1-propyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 360. N- [(S)— 1—{[1-(2-fluorobenzyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide 361. N- { (S)-3-methyl-1-[{3-oxo-1-[(2-morpholino-4- -thiazolyl)-methyl]-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide 362. N-{(S)-3-methyl-1-[{3-oxo-1-[(5-ethyl-2-furyl)- -methyl]-4-azepanyl}-carbamoyl]-butyl}-2- -benzofurancarboxamide

(sequel)

Example number Chemical name 363. N-{(S)-3-methyl-1-[{3-oxo-1-[(3,4-dimethylthieno[3,2-b]thiophen-2-yl)methyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide 364. N-{(S)-3-methyl-1-[{3-oxo-1-[(3-phenyl-3H-1,2,3- -triazol-4-yl)-methyl]-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide 365. 2V-{ (S) - 3-methyl-l - [ { 3-oxo-l - [ (3-isothiazolyl) - -methyl]-4-azepanyl}-carbamoyl]-butyl}-2- -benzofurancarboxamide 366. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thienyl)-methyl]- -4-azepanyl}-carbamoyl]-butyl}-2- -benzofurancarboxamide 367. N-{(S)-3-methyl-1-[{3-oxo-1-[(benzo[b]thiophen-2- -yl)-methyl]-4-azepanyl}-carbamoyl]-butyl}-2- -benzofurancarboxamide 368. N-{(S)-1-[(1-pentyl-3-oxo-4-azepanyl)- -carbamoyl]-3-methylbutyl}-2- -benzofurancarboxamide 369. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-2- -imidazolyl)-methyl]-4-azepanyl}-carbamoyl]- -butyl}-2-benzofurancarboxamide

(sequel)

Example number Chemical name 370. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-1- -oxy-2-pyridinecarboxamide 371. N-{(Sj-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-2- -oxy-3-pyridinecarboxamide 372. N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1H- -5-benzimidazole carboxamide 373. 4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino}- -4-methylpentanoyl]-amino}-1-methyl-3-oxo-1- -pentyl azepanium 374. 2V— { (S) - 3-methyl-1- [ { 3-oxo-1- [ (1,2-dimethyl-1H-4- -imidazolyl)-sulfonyl]-4-azepanyl}- -carbamoyl]-butyl}-2-benzofurancarboxamide 375. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4- -imidazolyl)sulfonyl]-4-azepanyl}- -carbamoyl]butyl}-2-benzofurancarboxamide 376. N-[(S)-1-{[1-{[4-(methylsulfonyl!)phenyl]sulfonyl}-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

(continued) ••t ·**· ·**« ** ** - ooo - Example number Chemical name 377. N- [(S)— 1—{ [ 1— {[2-(methylsulfonyl)phenyl]- -sulfonyl}-3-oxo-4-azepanyl]carbamoyl}-3- -methylbutyl]-2-benzofurancarboxamide 378. N- { (S)-3-methyl-1-[{3-oxo-1-[(3,5-dimethyl-4- -isoxazolyl)sulfonyl]-4-azepanyl}- -carbamoyl]butyl}-2-benzofurancarboxamide 379. N-{(IS,2R)-2-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide 380. N-{1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]cyclopentyl}-3-methyl-2-benzofurancarboxamide 381. N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)- -sulfonyl]-4-azepanyl}-carbamoyl]-butyl} -furo[3,2-b]pyridine-2-carboxamide

Among the compounds of Solution 1A, the compounds of Examples 280-381 listed above are particularly preferred.

Representative individual compounds of the invention are described in Examples 1-381.

Compared to five- and six-membered ring compounds, the invention * - 101 - : .· ··:.··.:··.

« seven-membered ring compounds are more configurationally stable at the carbon atom alpha to the keto group.

The invention also includes deuterated analogs of the compounds of the invention. A representative example of such deuterated compounds is described in Example 192. A representative method for preparing deuterated compounds of the invention is shown in Scheme 4 below. Compared to the protonated isomers, the deuterated compounds of the invention have significantly improved chiral stability.

Where possible, the invention also includes quaternary salts of the compounds of the invention. A representative example of such quaternary salts is described in Example 192. A representative method for preparing quaternary salts of the invention is shown in Scheme 6 below.

Definitions

The invention includes all hydrates, solvates, complexes and prodrugs of the compounds of the invention. Prodrugs include covalently bound compounds which are converted in vivo to an active compound of formula (I). Where a compound of the invention contains a chiral center or other form of an isomeric center, the invention includes all possible forms of such isomer or isomers, including enantiomers and diastereomers. Compounds of the invention containing a chiral center may be used as racemic mixtures, enantiomers or diastereomers.

- As a mixture enriched in 102 omers, or racemic mixtures can be separated using methods well known in the art, and a single enantiomer can be used alone. In cases where the compounds have an unsaturated carbon-carbon double bond, the cis or (Z)-isomers and the trans or {E}-isomers are both within the scope of the invention. In cases where the compounds are present in tautomeric forms, such as keto-enol tautomers, all tautomeric forms are within the scope of the invention, regardless of whether the tautomeric mixtures are in the form of an equilibrium mixture or in a form enriched in one of the tautomers.

Unless otherwise indicated, the meanings of identical substituents or subsubstituents occurring at any position in general formula (I) are independent of each other.

In describing the compounds of the invention, abbreviations and symbols customary in the field of peptides and general chemistry are used. The abbreviations of amino acids are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Eur. J. Biochem., 158, 9 (1984)].

Proteases are enzymes that catalyze the cleavage of the amide bond of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis. Such proteases include, but are not limited to, cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. The compounds of the invention can bind to the enzyme more strongly than

103 substrate, and the bond is usually not cleaved after enzyme-catalyzed attack by the nucleophile. The compounds therefore competitively inhibit proteases from recognizing and hydrolyzing the natural substrate, thereby exerting their effect as inhibitors.

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

The term C1-6 alkyl as used herein refers to substituted and unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terebutyl, pentyl, isopentyl, neopentyl and hexyl groups, as well as simple aliphatic isomers thereof. Any C1-6 alkyl group optionally includes -OR, -C(O)R, -SR, 14 14 14 5 14 14

-S(0)R , -NR ~N(R )C(O)OR, -COOR , -COONR ₂ may be substituted with a group of the general formula, -N(C=NH)NH ₂ , Het, C3-6 cycloalkyl and Ar groups, where R ⁵ represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, Ar-(C0-6 alkyl) group and Het-(C0-6 alkyl) group; and R represents a hydrogen atom, a C1-6 alkyl group, Ar-(C0-6 alkyl) group and Het-(C0-6 alkyl) group.

As used herein, C3-6 cycloalkyl

The term group 104 refers to substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

The term "C2-6 alkenyl" as used herein refers to alkyl groups having from 2 to 6 carbon atoms in which one carbon-carbon single bond is replaced by one carbon-carbon double bond. Examples of alkenyl groups having from 2 to 6 carbon atoms include, but are not limited to, groups derived from the following compounds: ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene, and the various isomers pentene and hexene. The definition includes both cis and trans isomers.

The term C2-6 alkynyl as used herein refers to alkyl groups having from 2 to 6 carbon atoms in which a carbon-carbon single bond is replaced by a carbon-carbon triple bond. Examples of C2-6 alkynyl groups include, but are not limited to, groups derived from the following compounds: acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and the simple isomers of pentyne and hexyne.

The term halogen atom refers to fluorine, chlorine, bromine and iodine atoms.

Ar or aryl represents a phenyl or naphthyl group optionally substituted with one or more phenyl-(C0-6 alkyl)-, Hep-(C0-6 alkyl)-, C1-6 alkoxy-, phenyl-(C0-6 alkoxy)-, Hep-(C0-6 alkoxy)-, C1-6 alkyl-, hydroxy-, -(CH2)i-6 ^-

105

-NR ¹⁵ R ¹⁶ , -O(CH2)i-6-NR ¹⁵ R ¹⁶ , -OR ¹⁷ , -N(R ¹⁷ )2, -SR ¹⁷ group, trifluoromethyl-, nitro-, cyano group,

17

-COOR, -CON(R), a fluorine, chlorine, bromine or iodine atom; where R and R are hydrogen, C1-6 alkyl, phenyl-(C0-6 alkyl), naphthyl-(C0-6 alkyl) or Het-(C0-6 alkyl) groups; and

R represents a phenyl, naphthyl group or a C1-C6 alkyl group.

The abbreviation or term "Het" or "heterocyclic group" as used herein refers to a stable 5-7 membered monocyclic group, a stable 7-10 membered bicyclic heterocyclic group, or a stable 11-18 membered tricyclic heterocyclic group, which is saturated or unsaturated, and which consists of carbon atoms and one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms are optionally oxidized, and the nitrogen atom may be optionally quaternized. In addition, the definition also includes any bicyclic group in which the heterocyclic groups as defined above are fused to a benzene ring. The heterocyclic group may be linked through any heteroatom or carbon atom that results in the formation of a stable structure. The heterocyclic group may optionally be substituted by one or two groups selected from the following substituents: Ar, C1-6 alkyl, 17 17 17

-OR, -N(R)2, -SR group, trifluoromethyl, nitro, cyano group, -CO2R, -CON(R)2 group, fluorine, chlorine, bromine and/or iodine atom, where in the general formulas , , . 17 R means phenyl, naphthyl or alkyl group with 1-6 carbon atoms. Examples of such heterocyclic groups include, but are not limited to, piperidyl, piperazinyl, 2-oxo-piperazinyl, 2-oxo-piperidyl, 2-oxo-pyrrolidinyl, 2-oxo-azepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, 1-oxypyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolyl, quinoxalinyl, isoquinolyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, benzofuranyl, thienyl, benzo[b]thienyl, thieno[3,2-b]thienyl, benzo[1,3-]dioxolyl, 1,8-naphthyridinyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl groups, which groups can be prepared by conventional chemical syntheses and are stable. The term heteroatom as used herein refers to oxygen, nitrogen and sulfur atoms.

A C0 alkyl group means that there is no alkyl group in the given molecular moiety. Thus, the Ar-(C0 alkyl) group is equivalent to the Ar group, for example, the phenyl group. A single aromatic group, for example, the phenyl group, means an Ar-(C0-6 alkyl) group in which the alkyl group has 0 carbon atoms.

107

Certain groups are indicated by abbreviations in the specification. The abbreviation t-Bu denotes the tertiary butyl group (tert-butyl group), the abbreviation Boc or BOC denotes the tert-butoxycarbonyl group, the abbreviation Fmoc denotes the fluorenylmethoxycarbonyl group, the abbreviation Ph denotes the phenyl group, while the abbreviation Cbz or CBZ denotes the benzyloxycarbonyl group.

Some reagents are also abbreviated in this specification. m-CPBA is 3-chloroperbenzoic acid, EDC or EDCI is N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide, DMF is N,27-dimethylformamide, DMSO is dimethyl sulfoxide, TEA is triethylamine, TFA is trifluoroacetic acid, and THF is tetrahydrofuran.

108 <·

Production processes

The compounds of general formula (I) are generally classified as 1., 2.

and prepared according to the methods shown in Scheme 3.

Reaction scheme 1

Reagents and conditions: a.) sodium hydride, 5-bromo-l-pentene, DMF; b.) {[(2,6-diisopropylphenyl)imido]neophilidene}-molybdenum bis(tert-butoxide) or [bis(tricyclohexylphosphine)benzylidine]-ruthenium(IV) dichloride catalyst, toluene; c.) 3-chloroperbenzoic acid, methylene dichloride; d. ) sodium azide, methanol, water, ammonium chloride; e.) 10 wt% palladium/carbon catalyst, hydrogen gas; f.) Cbz-leucine, EDC, methylene dichloride;

109

g.) HCl, ethyl acetate; h.) Cbz-leucine, EDC, methylene dichloride; i.) pyridine/sulfur trioxide complex, DMSO, triethylamine.

Alkylation of tert-butyl-N-allyl carbamate 1 with base and 5-bromo-l-pentene affords diene 2. Compound 2 is reacted with the Grubbs-developed {[(2,6-diisopropylphenyl)imido]neophilidene}-molybdenum bis(tert-butoxide) or [bis(tricyclohexylphosphine)benzylidine]ruthenium(IV) dichloride olefin metathesis catalyst to afford azepine 3. Compound 3 is epoxidized with standard oxidizing agents commonly used in the art, such as 3-chloroperbenzoic acid, to afford epoxide 4. Nucleophilic epoxide ring opening, for example with sodium azide, yields an azido alcohol not shown in the scheme, which can then be reduced to the amino alcohol of formula 5 by hydrogenation under conditions conventional in the art, for example with 1,3-dimercaptopropane in methanol or in the presence of a catalyst, such as palladium on carbon. Compound 5 is acylated with an acid, such as Cbz-leucine, in the presence of a coupling agent, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), and the BOC protecting group is removed under acidic conditions to give the amino salt of formula 6. The compound of formula 6 is coupled with Cbz-leucine in the presence of a coupling agent, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), to give an intermediate alcohol not shown in the reaction scheme, which is oxidized to the ketone of formula 7 with an oxidizing agent, such as pyridine/sulfur trioxide complex in dimethyl sulfoxide and triethylamine.

Reaction scheme 2

f.s

14 15

Reagents and conditions: a.) sodium hydride, 5-bromo-l-pentene, DMF; b.) [bis(tricyclohexylphosphine)benzylidine]ruthenium(IV) dichloride catalyst, methylene dichloride; c. ) 3-chloroperbenzoic acid, methylene dichloride; d.) sodium azide, methanol, water, ammonium chloride; e.) dimercaptopropane, methanol, triethylamine; f.) Boc-leucine, EDC, methylene dichloride; g.) 10 wt% palladium/carbon catalyst, hydrogen gas; h. ) RiCOOH, EDC, methylene dichloride or RiCOCl, methylene dichloride; i.) HCl, ethyl acetate;

j.) RiCOOH,

EDC, methylene dichloride; k.) pyridine/sulfur trioxide

Ill complex, DMSO, triethylamine.

Those compounds of general formula (I) in which 1 2

R and R are part of an amide group, and can be prepared according to the procedure of Scheme 2. Alkylation of 2N-Cbz-allylamine 8 with base and 5-bromo-1-pentene affords diene 9. Reaction of compound 9 with the [bis(tricyclohexylphosphine)benzylidine]ruthenium(IV) dichloride olefin metathesis catalyst developed by Grubbs affords azepine 10. Epoxidation of compound 10 with standard oxidizing agents commonly used in the art, such as 3-chloroperbenzoic acid, affords epoxide 11. Nucleophilic epoxide ring opening, for example with sodium azide, yields an azido alcohol not shown in the scheme, which can then be reduced to the amino alcohol of formula 12 with a reducing agent commonly used in the art, such as 1,3-dimercaptopropane in the presence of triethylamine. Compound of formula 12 is acylated with N-Boc-leucine in the presence of a coupling agent, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), followed by removal of the Cbz protecting group under hydrogenolytic conditions to give the amine of formula 13. Compound 13 is coupled with a carboxylic acid in the presence of a coupling agent, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), and the acid-labile 7\7-Boc protecting group is removed with an acid, such as hydrochloric acid or trifluoroacetic acid, to give an intermediate 14.

112 is obtained. The intermediate of general formula 14 is acylated with a carboxylic acid in the presence of a coupling agent, for example N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), to give an intermediate alcohol not shown in the reaction scheme, which is oxidized to the ketone of formula 15 with an oxidizing agent, for example pyridine/sulfur trioxide complex in dimethyl sulfoxide and triethylamine.

Reaction scheme 3

Reagents and conditions: a.) RiCHO, NaBH(0Ac)3; b.) hydrogen chloride; c.) R2COOH, EDC, methylene dichloride; d.) pyridine/sulfur trioxide complex, DMSO, triethylamine; e.) RiNCO, base; f.)

R1SO2CI, triethylamine, methylene dichloride

113

Those compounds of general formula (I) in which 2 1

R is alkyl, carbamido or sulfonamido, and R is amido, can be prepared according to the procedure of Scheme 3. Reductive amination of compound 13 can be carried out by reaction with an aldehyde followed by a reducing agent, such as sodium [triacetoxyhydridoborate] (1—). The Af-Boc protecting group is then removed under acidic conditions to give the amine salt 16. Compound 16 is coupled with a carboxylic acid in the presence of an acid chloride or a coupling agent commonly used in the art, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, and the alcohol intermediate not shown in the scheme is then oxidized with an oxidizing agent, such as pyridine/sulfur trioxide complex in dimethyl sulfoxide and triethylamine to give ketone 17. Alternatively, the amine 13 is reacted with an isocyanate and the N-Boc protecting group is removed to give the amine salt 18. Acylation and oxidation of the latter compound affords the ketone 19. Further transformations of the amine 13 include reaction with a sulfonyl chloride and removal of the N-Boc protecting group to give the amine salt 20. Acylation and oxidation of the latter compound affords the ketone 21.

114

Reaction scheme 4

í 1 h __________ y । í ___________ oo 22 ²³ o .o Ϊ —- cu° _Y »c3 cl.o _y »^_ oo 25 26 1 OH oh Xo 1 H j ·· ^{Λ Λ} _{_2_} „ Α-γ , _N ) ^{o H / VW h} a° 27 28 ? 1 DHD j? 1, m ^D —D— Cí° Cí ^& 31 Reagents and conditions: a.) sodium hydride 0u° _Y O 0 24 H s^NH, A ^f ' ^{9 NH} 2 * H íS \ ö ^H oM 30 _D h rh ) S ^H oA^ 32 , 5-bromo-l-pentene

DMF; b.)

[bis (tricyclohexylphosphine)benzylidine] ruthenium (IV) dichloride catalyst, methylene dichloride; c.) 3-chloroperbenzoic acid, methylene dichloride; d. ) sodium azide, methanol, water, ammonium chloride; e.) dimercaptopropane, methanol, triethylamine; f.) N-Boc-leucine, EDC, methylene dichloride; g.) 10 wt% palladium/carbon catalyst, hydrogen gas; h. ) [(2-pyridyl)sulfonyl] chloride, triethylamine, methylene dichloride; i.) 4 M HCl/dioxane, methanol; j.) 2-benzofurancarboxylic acid, EDC, methylene dichloride; k.) pyridine/sulfur trioxide complex, DMSO, triethylamine; 1.) CD3OD/D2O (10:1), triethylamine; m.) HPLC separation

The deuterated compound of Example 192 can be readily prepared by the method of Scheme 4. Knowing Example 192 and Scheme 4, one skilled in the art can deuterate any of the compounds of the invention.

The individual diastereomers of N-{(S)-3-methyl-1-[{(2,2',4-trideuterio)-3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide of formulae 31 and 32 can be prepared according to Scheme 4.

Alkylation of benzyl-V-allyl carbamate 22 with 5-bromo-1-pentene in the presence of a base, such as sodium hydride, affords diene 23. Compound 23 can be reacted with the [bis(tricyclohexylphosphine)benzylidine]ruthenium(IV) dichloride olefin metathesis catalyst developed by Grubbs to afford benzyl-2,3,4,7-tetrahydro-1-azepinecarboxylate 24. Azepine 24 can be prepared by standard oxidizing agents commonly used in the art, such as

- 116 - ΪΛ. ’JVV

Epoxidation with 3-chloroperbenzoic acid gives the epoxide of formula 25. Nucleophilic epoxide ring opening with, for example, sodium azide yields the azido alcohol not shown in the scheme, which can then be reduced to the amino alcohol of formula 26 with a reducing agent commonly used in the art, such as triethylamine in methanol and 1,3-dimercaptopropane. Compound of formula 26 is acylated with N-Boc-leucine in the presence of a coupling agent, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), and the Cbz protecting group is removed with hydrogen gas in the presence of a 10% palladium/carbon catalyst to give the amine of formula 27. Compound 27 can be reacted with [(2-pyridyl)sulfonyl] chloride in the presence of triethylamine or saturated aqueous sodium bicarbonate solution and methylene chloride, followed by removal of the (tert-butoxycarbonyl) protecting group under acidic conditions to give intermediate 28. Intermediate 28 is acylated with 2-benzofurancarboxylic acid in the presence of a coupling agent, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), to give intermediate alcohol 29, which is oxidized to ketone 30 with an oxidizing agent, such as pyridine/sulfur trioxide complex in dimethyl sulfoxide and triethylamine. The ketone of formula 30 is a mixture of diastereomers. The ketone of formula 30 is reacted with triethylamine in a CD3OD/D2O mixture at reflux temperature to obtain the deuterated analogue as a mixture of diastereomers, which is separated by HPLC into the deuterated compounds of formula 31 and 32.

- 117 Reaction scheme 5

Reagents and conditions: a.) di(tert-butyl)dicarbonate, tetrahydrofuran; b.) hydrogen gas, 10 wt% palladium/carbon catalyst, ethyl acetate; c.) [(2-pyridyl)sulfonyl]chloride, triethylamine; d.) hydrogen chloride, ethyl acetate; e. ) N-Boc-cyclohexylalanine, P-EDC, methylene dichloride; f.) hydrogen chloride, methylene dichloride; g. ) 2-benzofurancarboxylic acid, P-EDC, methylene dichloride; h.) Dess-Martin periodane, methylene dichloride.

The compounds of general formula (I) can also be prepared by the method according to reaction scheme 5. By protecting the amino group of the compound of formula 12 with di(tert-butyl)dicarbonate, the compound of formula 33 is obtained.

- 118 - .S. .?<

The ΛΖ-Boc derivative is obtained (Scheme 2). The [(benzyloxy)carbonyl] protecting group can be removed by reacting compound 33 with hydrogen gas in the presence of a catalyst, such as 10% palladium on carbon. The amine 34 thus obtained can be reacted with a sulfonyl chloride, such as [(2-pyridyl)sulfonyl] chloride, in the presence of a base, such as N-methylmorpholine or triethylamine, to produce the sulfonamide derivative 35. Compound 36 is coupled with an acid, such as N-Boc-cyclohexylalanine, in the presence of a coupling agent, such as [2-(1H-1-benzotriazolyl)-ΔΓ,N,Ν', W'-tetramethyluronium]-(hexafluorophosphate) (HBTU) or polymer-supported N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (P-EDC), to give the alcohol intermediate 37. Removal of the (tert-butoxycarbonyl)-protecting group under acidic conditions gives the amine 38. Compound 38 is coupled with 2-benzofurancarboxylic acid in the presence of a coupling agent, such as [2-(1H-1-benzotriazolyl)-N, N, N', N'-tetramethyluronium]-(hexafluorophosphate) (HBTU) or polymer-supported N-ethyl-2V'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (P-EDC), to give alcohol 39, which is oxidized to ketone 40 with an oxidizing agent, such as pyridine/sulfur trioxide complex in dimethyl sulfoxide and triethylamine or Dess-Martin periodane.

- 119 Reaction scheme 6

Reagents and conditions: a.) RiCHO, NaBH(OAc) ₃ ; b.) hydrogen chloride; c.) R2COOH, EDC, methylene dichloride; d.) pyridine/sulfur trioxide complex, dimethyl sulfoxide, triethylamine; e.) methyl iodide.

The quaternized 4-amino-3-oxo-azepane compounds of the invention can be prepared easily by the method of Scheme 6. Based on Scheme 6, one skilled in the art will readily understand how to prepare the quaternized 4-amino-3-oxo-azepane compounds of the invention. The reductive amination is carried out by reacting the compound of formula 13 with an aldehyde, followed by reduction with a reducing agent, such as sodium [triacetoxyhydridoborate] (1-). Removal of the W-Boc protecting group under acidic conditions provides the amine salt of formula 16. The compound of formula 16 is coupled with an acid chloride or a coupling agent commonly used in the art, such as N-ethyl-ΔΓ'-[3-(dimethylamino)propyl] 120

-carbodiimide (EDC) is reacted with a carboxylic acid, followed by oxidation of the alcohol intermediate not shown in the reaction scheme with an oxidizing agent, such as pyridine/sulfur trioxide complex, to produce the ketone of general formula 17. The tertiary (cyclic) amino group of compound of general formula 17 is quaternized by reaction with an alkylating agent, such as methyl iodide, to yield the quaternary amine salt of general formula 41.

The starting materials used in the solutions according to the invention are commercially available amino acids or compounds that can be easily prepared by commonly used methods well known to those skilled in the art [see, for example: Compendium of Organic Synthetic Methods, Vol. IVI (Wiley-Interscience)].

Coupling methods for forming amide bonds are generally known in the art. Methods for peptide synthesis are also well known [see, for example, Bodansky et al., The Practice of Peptide Synthesis, Springer-Verlag, Berlin (1984); E. Gross and J. Meienhofer, The Peptides, 1, 1-284 (1979); and J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd Ed., Pierce Chemical Co., Rockford, Ill., USA (1984)].

In carrying out the processes for preparing the compounds of the invention, protecting groups are often used to mask reactive functional groups or to minimize unwanted side reactions. Suitable protecting groups are provided by

121 is described, inter alia, in Green, T. W., Protective Groups In Organic Chemistry, John Wiley & Sons, New York (1981). The term amino-protecting group generally refers to the following groups: tert-butoxycarbonyl (Boc), acetyl, benzoyl, fluorenylmethoxycarbonyl (Fmoc), (benzyloxy)carbonyl (Cbz), and derivatives thereof known in the art. Methods for forming and removing protecting groups, and for replacing one amino-protecting group with another amino-protecting group, are generally known.

Acid addition salts of compounds of formula (I) may be prepared by reacting the parent compound with an excess of an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid, in a suitable solvent according to standard procedures. Certain compounds also form acceptable inner salts or zwitterions. Cationic salts are prepared by reacting the parent compound with an excess of a hydroxide, carbonate or alkanolate containing the appropriate cation, or with a suitable organic amine. Specific examples of cations present in pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium and ammonium ions. Specific examples of anions in pharmaceutically acceptable salts include, but are not limited to, halides, sulfates, phosphates, alkanoates (e.g., acetates and trifluoroacetates), benzoates, and sulfonates (e.g., mesylates).

122

Quaternary ammonium salts can be prepared by reacting the parent amine compound with an excess of an alkyl halide, such as methyl iodide.

The 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) can also be used to prepare a pharmaceutical composition. Pharmaceutical compositions comprising compounds of formula (I) prepared according to the invention can be formulated as solutions or lyophilized powders for parenteral administration. The powders are prepared by adding a suitable diluent or other pharmaceutically acceptable carrier immediately before use to form a formulation suitable for administration. The liquid composition may be, for example, a buffered, isotonic, aqueous solution. Examples of suitable diluents include, but are not limited to, normal, isotonic sodium chloride solution, standard 5% aqueous dextrose solution or buffered sodium or ammonium acetate solution. Such a preparation is particularly suitable for parenteral administration, but may also be used for oral administration or for use in inhalers or in an aerosol device for insufflation suitable for the delivery of specific doses. In some cases, it may also be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively, the compounds can be encapsulated, tableted

123 and can be formulated into emulsions or syrups suitable for oral administration. In order to improve or stabilize the formulation or to facilitate the preparation of the composition, pharmaceutically acceptable solid or liquid carriers can be used. Solid carriers include, but are not limited to, starch, lactose, calcium sulfate dihydrate, gypsum, magnesium stearate or stearic acid, talc, pectin, acacia gum, agar or gelatin. Liquid carriers include, but are not limited to, sugar syrup, peanut oil, olive oil, sodium chloride solution and water. The carrier may also contain a delayed release agent, such as glyceryl monostearate or glyceryl distearate, optionally together with a wax. The amount of solid carrier varies but is preferably between about 20 mg and about 1 g per dosage unit. The pharmaceutical compositions may be prepared by methods conventionally employed in the pharmaceutical art, for example, by grinding, mixing, granulating and, if necessary, compressing in the case of tablets, or by grinding, mixing and filling in the case of capsules. When a liquid carrier is used, the composition may be in the form of, for example, a syrup, elixir, emulsion or aqueous or non-aqueous suspension. The liquid composition may be administered directly orally or may be filled into a soft gelatin capsule.

In preparing compositions suitable for rectal administration, the compounds of the invention are combined with carriers such as cocoa butter, glycerin, gelatin, or polyethylene glycols.

124 kai is combined, then the mixture is melted in cone molds.

New intermediates

In connection with the preparation processes of the compounds of general formula (I) shown in Schemes 1-4, it will be apparent to the person skilled in the art that the invention also encompasses novel intermediates for the preparation of the compounds of general formula (I). In particular, the invention relates to the compounds of general formula (II)

— in the formula of which

R is significant

R'O

group of general formula;

R is hydrogen, C1-6 cycloalkyl)-(C0-6 alkyl, C3-6 alkyl, Ar-(C0-6 alkyl), Het-(C0-6 alkyl)

9 9 9 kil)-group, RC(O)-, RC(S)-, R SO ₂ -, ROC(O)-,

11 9 11 9 11

RR NC(O)-, RR NC(S)-, R (R )NSO ₂ - group of general formula, group of formula _r ,

HUF ⁶

N. -Z.

r ⁷ γ n or R ⁹ SO ₂ R ¹¹ NC (O) - group with the general formula;

R represents hydrogen, C1-6 alkyl, (C3-6 cycloalkyl)-(C0-6 alkyl), C2-6 alkenyl, C2-6 alkynyl, Het-(C0-6 alkyl) or Ar-(C0-6 alkyl);

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

R represents hydrogen, alkyl group of 1-6 carbon atoms, (C3-6 cycloalkyl)-(C0-6 alkyl)-group, Ar-(C0-6 alkyl)-group, Het-(C0-6 alkyl)-group, RC(O)-, RC(S)-, R SO ₂ -, R OC(O)-,

a group of general formula R R NC(O)- and R R NC(S)-;

R represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and an Het-(C0-6 alkyl) group;

R ⁶ represents a hydrogen atom, a C 1-6 alkyl group, an Ar-(C 0-6 alkyl) group and a Het-(C 0-6 alkyl·) group;

- 126 - :?<··::

R is hydrogen, C1-6 alkyl, (C3-6 cycloalkyl)-(C0-6 alkyl), Ar-(C0-6 alkyl), Het-(C0-6 alkyl), ^R10 C(O)-, ^R10 C(S)-, ^R10 _SO2- , ^R10 OC(O)-,

13 10 13

R R NC(O)- and R R NC(S)- groups; θ

R represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group and an Ar-(C0-6 alkyl) group;

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and an Het-(C0-6 alkyl) group;

R ¹⁰ is a C 1-6 alkyl group, a (C 3-6 cycloalkyl)-(C 0-6 alkyl) group, an Ar-(C 0-6 alkyl) group, and an Het-(C 0-6 alkyl) group;

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R represents a hydrogen atom, a C1-C6 alkyl group, Ar-

-(C0-6 alkyl)-group and Het-(C0-6 alkyl)-group;

R' is hydrogen, C1-6 alkyl, Ar127

-(C0-6 alkyl)-group and Het-(C0-6 alkyl)-group;

R represents a hydrogen atom, a C1-C6 alkyl group, an Ar-(C0-C6 alkyl) group and a Het-(C0-C6 alkyl) group;

R' represents a hydrogen atom, a C1-C6 alkyl group, a (C3-C6 cycloalkyl)-(C0-C6 alkyl) group, an Ar-(C0-C6 alkyl) group, and an Het-(C0-C6 alkyl) group;

R" is a C1-C6 alkyl group, a (C3-C6 cycloalkyl)-(C0-C6 alkyl) group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an Ar-(C0-C6 alkyl) group, and a Het-(C0-C6 alkyl) group; and n is 1, 2, 3, 4 or 5 — and pharmaceutically acceptable salts, hydrates and solvates thereof.

In connection with solution IA, the invention includes the novel intermediates (HA) of general formula (IIA) — in the formula of which

R ¹ meaning

128

group with general formula; 2

R is a C1-C6 alkyl group, Ar-(C0-C6 alkyl) group, Het-(C0-C6 alkyl) group, 9 9 9 11 9 11

a group of the general formula RC(O)-, R SO ₂ -, RR NC(O)- or R SO ₂ R NC(O)-;

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Het-(C0-6 alkyl) group or an Ar-(C0-6 alkyl) group, preferably a C1-6 alkyl group;

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

5

R is a group of the general formula RC(O)-;

R ⁵ represents a C 1-6 alkyl group or a Het-(C 0-6 alkyl) group, preferably a Het-(C 0-6 alkyl) group;

R represents a C1-6 alkyl group, a C3-6 cycloalkyl-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group;

R represents hydrogen, C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl);

R' represents a hydrogen atom;

129

R represents a hydrogen atom;

R' represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom;

R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, an Ar-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group; and n is 1, 2, 3, 4 or 5, preferably 3 - and pharmaceutically acceptable salts, hydrates and solvates thereof.

Among the new intermediates, the following compounds are preferred:

benzyl N-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate;

N-(1-benzyl-3-hydroxy-4-azepanyl)-(S)-2-amino-4-methylpentanamide;

N-[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]-(S)-2-amino-4-methylpentanamide;

benzyl N-[(S)-1-{[4-{[(S)-2-amino-4-methylpentanoyl]amino}-3-hydroxy-1-azepanyl]methyl}-3-methylbutyl]carbamate;

- N-(1-benzoyl-3-hydroxy-4-azepanyl)-(Sj-2-amino-4-methylpentanamide;

N-[3-hydroxy-1-(4-methylpentanoyl)-4-azepanyl]-(S)-2-amino-4-methylpentanamide;

N- [1-(phenylsulfonyl)-3-hydroxy-4-azepanyl]-(S)-2-amino- 130 - .L<’· %?

-4-methylpentanamide;

N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide;

N—{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide;

N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide;

N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide;

N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinolinecarboxamide; and

N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinoxalinecarboxamide.

Process for preparing the compounds of the invention

In connection with the above reaction schemes 1-6, the invention relates to a process for the preparation of compounds of general formula (I), in which a corresponding compound of general formula (II) is oxidized with an oxidizing agent, thereby obtaining the compound of general formula (I) in the form of a mixture of diastereomers. The oxidizing agent is preferably dimethylsulfoxide.

131 oxide sulfur trioxide/pyridine complex and triethylamine.

In connection with Scheme 4, the invention relates to a process for the preparation of deuterated compounds of formula (I). If a deuterated compound is required, the above process for the preparation of compounds of formula (I) is supplemented by a further step following the oxidation step, in which the protonated isomer is reacted with a deuterating agent to obtain the deuterated compound of formula (I) as a mixture of diastereomers. The deuterating agent is preferably a 10:1 volume CD3OD/D2O mixture in triethylamine.

The process according to the invention may further comprise the step of separating the diastereomers of the compounds of general formula (I) by separation techniques, preferably by high-pressure liquid chromatography (HPLC).

In connection with Scheme 6, the invention also provides a process for the preparation of quaternary salts of 4-amino-3-oxo-azepane compounds of formula (I).

Use of the compounds of the invention

The compounds of general formula (I) are useful as protease inhibitors, especially inhibitors of cysteine and serine proteases, more particularly as compounds which inhibit cysteine proteases, more narrowly as compounds which inhibit cysteine proteases of the papain family, more narrowly as compounds which inhibit cysteine proteases of the cathepsin family, and in the narrowest sense as compounds which inhibit cysteine proteases of the cathepsin family.

132 compounds that inhibit cathepsin K. The invention also provides useful compositions and preparations of the compounds, including pharmaceutical compositions and pharmaceutical preparations of the compounds.

The compounds of the invention can be used to treat diseases in which cysteine proteases may play a role, such as, but not limited to, infections caused by pneumocystis carinii, trypsinoma cruzi, trypsinoma brucei brucei and Crithidia fusiculata; as well as schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amyotrophy; and in particular for the treatment of diseases in which cathepsin K plays a role, in particular diseases associated with excessive bone loss, such as, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, malignant hypercalcemia and metabolic bone disease.

Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, the compounds of the invention may also be useful in the treatment of certain tumors and metastatic neoplasias.

The invention also relates to a method for treating diseases caused by pathological concentrations of proteases, in particular cysteine and serine proteases, more particularly cysteine proteases, more specifically cysteine proteases of the papain family, more specifically cysteine proteases of the cathepsin family.

- 133 J..:..

for the treatment of diseases caused by pathological concentrations of cathepsin K, comprising administering to an animal, particularly a mammal, more particularly a human, in need of such treatment a compound of the invention. More particularly, the invention relates to a method for the treatment of diseases caused by pathological concentrations of cathepsin K, comprising administering to an animal, particularly a mammal, more particularly a human, in need of such treatment a cathepsin K inhibitor, including a compound of the invention. The invention also relates to a method for the treatment of diseases in which cysteine proteases may play a role, such as, but not limited to, infections caused by pneumocystis carinii, trypsinoma cruzi, trypsinoma brucei brucei and Crithidia fusiculata; and schistosomiasis, malaria, tumor metastasis, leukodystrophia metachromatica, dystrophia muscularum, amyotrophia; and in particular for the treatment of diseases in which cathepsin K plays a role, primarily diseases associated with excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, malignant hypercalcemia, and metabolic bone disease.

The invention also provides a method for treating osteoporosis or inhibiting bone loss, comprising administering to a patient internally an effective amount of a compound of formula (I) alone or in combination with other bone resorption inhibitors, such as bisphosphonates (e.g. alendronate), hormone replacement therapy, antiestrogens, or other agents.

- 134 in combination with nec or calcitonin. Treatment with a compound of the invention and an anabolic agent, such as the bone morphogenic protein iproflavone, may also be used to prevent bone loss or increase bone mass.

For acute therapy, parenteral administration of a compound of formula (I) is preferred. Intravenous infusion of the compound in 5% aqueous dextrose or saline is most effective, but intramuscular bolus injection may also be used. The parenteral dose is typically from about 0.01 mg/kg to about 100 mg/kg, preferably from 0.1 mg/kg to 20 mg/kg, administered in such a manner that the plasma concentration of the active ingredient is cathepsin K inhibitory. The compounds are administered one to four times daily in amounts such that the total daily dose is from about 0.4 mg/kg/day to about 400 mg/kg/day. The precise amount of a compound of the invention that is considered therapeutically effective can be readily determined by one skilled in the art by comparing the concentration required for therapeutic effect with the blood concentration of the active ingredient.

The compounds of the invention can also be administered to the patient orally, in which case the compound is used in an amount such that the concentration of the active ingredient is sufficient to inhibit bone resorption or to achieve the other indications mentioned above. The pharmaceutical composition containing the compound can be administered orally according to the patient's condition.

- 135 *·*, *»4 ,·» w is administered at an oral dose of between about 0.1 mg/kg and about 50 mg/kg. Preferably, the oral dose is between about 0.5 mg/kg and about 20 mg/kg.

No unacceptable toxicological effects are expected to occur when the compounds of the invention are administered according to the methods of the invention.

Biological tests

The compounds of the invention were tested in a number of biological assays to determine the concentration of the compounds required to achieve a given pharmacological effect.

Determination of the proteolytic catalytic activity of cathepsin K

For cathepsin K, all assays were performed with human recombinant enzyme. To determine kinetic constants, a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, was used under standard assay conditions and measurements were performed in 100 mM sodium acetate (pH 5.5) containing 20 mM cysteine and 5 mM EDTA. Stock solutions of substrate were prepared in 10 mM or 20 mM dimethyl sulfoxide. A final substrate concentration of 20 μΜ was used in the assays. All assays contained 10% dimethyl sulfoxide. In independent experiments, it was observed that this concentration of dimethyl sulfoxide did not affect enzyme activity or kinetic constants.

- 136 -

All assays were performed at ambient temperature. Product fluorescence (excitation at 360 nm; emission at 460 nm) was monitored using a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product formation curves were recorded 20-30 min after the formation of the AMC product.

Inhibition! tests

Potential inhibitors were evaluated using the progress curve method. The assays were performed in the presence of different concentrations of the test compound. The reactions were initiated by adding the enzyme to buffered solutions of the inhibitor and substrate. The data were analyzed according to one of two methods, depending on the shape of the progress curves obtained in the presence of the inhibitors.

For compounds with linear progression curves, the apparent inhibition constants (Ki, _a pp) were calculated using equation 1 [Brandt et al., Biochemistry, 28, 140 (1989)]:

Equation 1 v = V _m A/[K _a (l + I/Ki, _app ) + A] where va is the rate of reaction with maximum rate V _m , A is the substrate concentration with K _the Michelis constant, and I is the inhibitor concentration.

For compounds whose process curves show a downward slope corresponding to time-dependent inhibition, the data obtained for individual compositions were analyzed according to equation 2:

Equation 2

[AMC] = v _ss t + (vq ' ^v ss) [1 - exp (-k _obs t) ]/k _obs where [AMC] at is the concentration of product formed over time, vq is the initial reaction rate, and v _{ss is} the final equilibrium rate. The k _obs values thus calculated were then analyzed as a linear function of inhibitor concentration to determine the second-order rate constant describing the time-dependent inhibition (k _o b _s /inhibitor concentration or k _o b _s /[I]). A full discussion of the kinetic treatment has been previously described in detail [Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 61, 201 (1988)].

Human osteoclast resorption assay

Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, rapidly warmed to 37 °C, and washed once in RPMI-1640 medium by centrifugation at 1000 rpm for 5 min at 4 °C. The medium was aspirated, replaced with murine anti-HLA-DR antibody diluted 1:3 in RPMI-1640 medium, and incubated on ice for 30 min. The cell suspension was mixed frequently.

The cells were centrifuged at 1000 rpm at 4 °C.

• 9 · 9 · 9 9 ·· »· *· ten were washed twice in cold RPMI1640 medium by centrifugation for 5 minutes and then placed in a sterile 15 ml centrifuge tube. The number of mononuclear cells was determined in a modified Neubaier counting chamber.

A sufficient number (5/mononuclear cell) of goat anti-mouse IgG-coated magnetic beads were removed from the storage container and the beads were placed in 5 ml of fresh medium (this wash removed the toxic azide preservative). The beads were fixed on a magnet, the medium was removed and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated on ice for 30 min. The suspension was frequently mixed. The cells coating the beads were fixed on a magnet and the remaining cells (i.e. the osteoclast-rich fraction) were decanted into a sterile 50 ml centrifuge tube. Fresh medium was added to the bead-coated cells to remove any remaining osteoclasts. The latter step was repeated ten times. The bead-coated cells were set aside.

Osteoclast numbers were determined in a counting chamber, using a large-bore disposable Pasteur pipette to fill the chamber with the sample. Cells were pelleted by centrifugation and then adjusted to a density of 1.5× ¹⁰⁴ /ml in EMEM medium supplemented with 10% fetal bovine serum and 1.7 g/l sodium bicarbonate. 3 ml aliquots of the cell suspension per treatment were decanted into 15 ml centrifuge tubes139 with needles. The cells were pelleted by centrifugation. 3 ml of the appropriate treatment (diluted to a concentration of 50 μΜ in EMEM medium) was added to each tube. Appropriate vehicle controls, a positive control (87MEM diluted to 100 μρ/μl) and an isotype control (IgG2a diluted to 100 μg/ml) were also used during the study. The tubes were incubated for 30 minutes at 37 °C.

Cells were plated in 0.5 ml aliquots onto sterile dentin slices in 48-well plates. All treatments were performed in quadruplicate. The slices were washed six times with warm PBS (10 ml/well in a 6-well plate), then placed in fresh treatment or control and incubated for 48 hours at 37 °C. The slices were then washed in phosphate-buffered saline, fixed for 5 minutes in 2% glutaraldehyde in 0.2 M sodium cacodylate, washed with water and incubated in buffer for 5 minutes at 37 °C. The slices were then washed in cold water and incubated in cold acetate buffer/fast garnet red for 5 minutes at 4 °C. Excess buffer was aspirated off, the slices were washed with water, and then air-dried.

TRAP-positive osteoclasts were counted using a brightfield microscope and then removed from the dentin surface using ultrasound. Cavity volume was determined using a Nikon/Lasertec ILM21W confocal microscope.

140

General experimental part

Nuclear magnetic resonance spectra were recorded on a Bruker AM 250 (250

MHz) or Bruker AC 400 (400 MHz) spectrometer. CDCl3 represents deutero-chloroform, DMSO-dg represents hexadeutero-dimethylsulfoxide, and CD3OD represents tetradeutero-methanol. The chemical shifts (δ) relative to the tetramethylsilane internal standard in the direction of lower field strength are given in parts per million (ppm). The abbreviations used in the NMR spectra data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. AJ represents the NMR coupling constant in Hertz (Hz). Continuous infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolat Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in propagation mode, and the positions of the bands are given as the reciprocal of the wavenumber (in cm ¹ ). Mass spectra were recorded using the fast atom bombardment (FAB) or electron scattering (ES) ionization technique on a VG 70 FE, PE Syx API III, or VG ZAB HF instrument. Elemental analyses were performed on a Perkin-Elmer 240C elemental analyzer. Melting points were determined using a Thomas-Hoover melting point meter; melting points are uncorrected. All temperatures are given in degrees Celsius (°C).

For thin layer chromatography studies Analtech

- 141 Silica Gel GF and E. Merck Silica Gel 60 F254 thin layer plates were used. Flash and gravity chromatography separations were performed on E. Merck Kieselgel (230-400 mesh) silica gel.

Some of the compounds specifically noted in the examples were purchased from Aldrich Chemical Co., Milwaukee, Wisconsin, United States; Chemical Dynamics Corp., South Plainfield, New Jersey, United States; and Advanced Chemtech, Louisville, Kentucky, United States.

EXAMPLES

In the following preparation examples, all temperatures are given in degrees Celsius (°C). Unless otherwise indicated, all starting materials were obtained from commercial sources. It is believed that one skilled in the art will be able to practice the invention to its fullest extent using the above description without further elaboration. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention. The scope of the invention is defined by the appended claims.

142

Example 1

Preparation of benzyl-[(S)-1-{1-[(S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentanoyl]-3-oxo-4-azepanyl}carbamoyl]carbamate

a.) tert-Butyl-N-allyl-N-pent-4-enylcarbamate

To a suspension of 3.05 g (76.33 mmol) of 60% sodium hydride dispersion in mineral oil, washed with hexane, in 30 ml of N,N-dimethylformamide was added dropwise 6.0 g (38.2 mmol) of tert-butyl-N-allyl carbamate. The mixture was stirred at room temperature for about 10 minutes, and then 6.78 ml (57.24 mmol) of 5-bromo-1-pentene was added dropwise. The reaction mixture was heated at 40 °C for about 2 hours, then partitioned between ethyl acetate and water. The organic phase was washed twice with water, then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. 10 g of the title compound was obtained as an oil. MS (ES) 226 (M+H ⁺ ).

b.) tert-Butyl-2,3,4,7-tetrahydro-1-azepinecarboxylate

To a benzene solution of 4.5 g of the product of Example 1a was added 600 mg of {[(2,6-diisopropylphenyl)imido]neophilidene}-molybdenum bis(tert-butoxide). The reaction mixture was heated at reflux for 1.5 hours and then concentrated in vacuo. The residue was chromatographed using a 50:50 methylene chloride/hexane solvent mixture as eluent. 3.92 g of product was obtained.

c.) tert-Butyl-8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate

3.0 g (15.2 mmol) of the product of Example 1b in methylenedichloro

To a solution of 143 was added 7.8 g (45.6 mmol) of 3-chloroperbenzoic acid. The reaction mixture was stirred overnight at room temperature and then partitioned between methylene chloride and saturated aqueous potassium carbonate solution. The organic phase was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give 3.11 g of the title compound as an oil. MS (ES) 214 (M + H ⁺ ) .

d.) tert-Butyl-4-azido-3-hydroxy-l-azepanecarboxylate

To a solution of 3.92 g (20 mmol) of the product of Example 1c in 180 ml of 8:1 methanol/water was added 3.18 g (60 mmol) of ammonium chloride and 3.9 g (60 mmol) of sodium azide. The reaction mixture was heated at 40 °C until the starting epoxide was completely converted by thin layer chromatography. Most of the solvent was removed in vacuo, then the remaining solution was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 40:60 ethyl acetate/hexane solvent as eluent. 3.43 g of the title compound was obtained.

e.) tez ^, c-Butyl-4-amino-3-hydroxy-l-azepanecarboxylate

3.4 g of the azido-alcohol of Example 1 and a catalytic amount of 10% by weight palladium/carbon catalyst prepared in a 2:1 volume ethyl acetate/methanol solvent mixture

The reaction mixture was placed under a balloon pressure of hydrogen for 144 t. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography using a 25:75 volume methanol/methylene dichloride solvent mixture as eluent. 2.57 g of the title compound were obtained. MS (ES) 231 (M + H ⁺ ).

(E.) tert-Butyl-4-{[(S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-1-azepanecarboxylate

To a solution of 160 mg (0.70 mmol) of the product of Example 1 in methylene chloride were added 134 mg of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), 94 mg of 1-hydroxybenzotriazole (HOBt) and 185 mg of N-[(benzyloxy)carbonyl]leucine (Cbz-leucine). The reaction mixture was kept at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then diluted with ethyl acetate, the solution was washed with 1 M hydrochloric acid solution, saturated aqueous potassium carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 3:97 methanol/methylene chloride solvent mixture as eluent to give 200 mg of the title compound. MS (ES) 478 (M + H ⁺ ), 500 (M + Na ⁺ ).

145

g.) Benzyl {(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate

To a solution of 200 mg (0.42 mmol) of the product of Example 1f.) in 5 ml of methanol was added 5 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for about 2 hours, then the solvent was removed in vacuo. 168 mg of the title compound was obtained. MS (ES) 378 (M + H ⁺ ).

h.) Benzyl-(S)-1-{[4-(S)-{[2-{[(benzyloxy)carbonyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-1-azepanyl]carbonyl}-3-methylbutyl]carbamate

To a solution of 168 mg (0.42 mmol) of the product of Example 1 in methylene chloride was added 81 mg of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 57 mg of 1-hydroxybenzotriazole, 0.09 ml of triethylamine and 111 mg of N-[(benzyloxy)carbonyl]leucine. The reaction mixture was stirred until the starting compound was completely converted according to thin layer chromatography analysis. After work-up, the crude product was subjected to column chromatography using a 5:95 volume methanol/methylene dichloride solvent mixture as eluent. 159 mg of the title compound was obtained. MS (ES) 625 (M + H ⁺ ).

i.) Benzyl-[(S)-1-{1-[(S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentanoyl]-3-oxo-4-azepanyl}carbamoyl]carbamate

To a solution of 130 mg (0.21 mmol) of the product of Example 1h in dimethyl sulfoxide was added 0.17 ml of triethylamine and 97 mg (0.62 mmol) of pyridine/sulfur trioxide complex. The

The reaction mixture was stirred at room temperature for about 2 hours and then partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 5:95 (v/v) methanol/methylene dichloride solvent mixture as the eluent. 100 mg of the title compound was obtained as a mixture of diastereomers. H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 12H) , 1.5-2.1 (m, 8H) , 2.2 (m, 4H) ,

3.0 (m, IH), 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 (ES) 623 (M +

H ⁺ ), 645 (M + Na ⁺ ). After separation of the diastereomers using HPLC: Diastereomer 1: MS (ES) 623 (M + H ⁺ ), 645 (M + Na ⁺ ); and Diastereomer 2: MS (ES) 623 (M + H ⁺ ), 645 (M + Na ⁺ ).

Example 2

Preparation of N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-naphthalenecarboxamide

a.) Benzyl-N-allyl-N-pent-4-enylcarbamate

To a suspension of 1.83 g (76.33 mmol) of a 90% by weight dispersion of sodium hydride in mineral oil in N,2N-dimethylformamide was added dropwise 7.3 g (38.2 mmol) of benzyl N-allyl carbamate. The mixture was stirred at room temperature for about 10 minutes, and then 6.78 ml (57.24 mmol) of 5-bromo-l-pentene was added dropwise. The reaction mixture was heated at 40 °C for about 4 hours and then partitioned

147 was partitioned between methylene chloride and water. The organic phase was washed twice with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 10:90 (v/v) ethyl acetate/hexane mixture as eluent. 10.3 g of the title compound was obtained as an oil. MS (ES) 260 (M + H ⁺ ).

b.) Benzyl-2,3,4,7-tetrahydro-l-azepinecarboxylate g To a solution of the product of Example 2a in methylene chloride was added 5.0 g of bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride. The reaction mixture was heated at reflux temperature until the starting compound was completely converted according to thin layer chromatography analysis, and then concentrated in vacuo. The residue was chromatographed using a 50:50 volume methylene chloride/hexane solvent mixture as eluent. 35 g of the title compound were obtained. MS (ES) 232 (M + H ⁺ ).

c.) Benzyl-8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate

The title compound was prepared according to the general procedure of Example 1e, except that the starting material was the product of Example 2c. MS (ES) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).

d.) Benzyl 4-azido-3-hydroxy-l-azepanecarboxylate

To a solution of 2.0 g (8.1 mmol) of the product of Example 2c in 8:1 methanol/water was added 1.29 g (24.3 mmol) of ammonium chloride and 1.58 g (24.30 mmol) of sodium azide. The reaction mixture was heated to 40 °C .: .··. .*·, .··. .··

- 148 until the starting epoxide was completely converted according to thin layer chromatography analysis. Most of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic phase was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 20:80 (v/v) ethyl acetate/hexane mixture as eluent. 1.3 g of the title compound [MS (ES) 291 (M + H ⁺ ) ] and 0.14 g of trans-4-hydroxy-3-azido-hexahydro-1H-azepine were obtained.

e.) Benzyl 4-amino-3-hydroxy-l-azepanecarboxylate

To a solution of 1.1 g (3.79 mmol) of the azido alcohol from Example 2d in methanol was added 1.5 ml (11.37 mmol) of triethylamine and 1.1 ml (11.37 mmol) of 1,3-dimercaptopropane. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then concentrated in vacuo and the residue was subjected to column chromatography using a 20:80 (v/v) methanol/methylene dichloride solvent mixture as eluent. 0.72 g of the title compound was obtained. MS (ES) 265 (M + H ⁺ ).

f.) Benzyl 4-[{(S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl]amino]-3-hydroxy-1-azepanecarboxylate

To a solution of 720 mg (2.72 mmol) of the product of Example 2e in methylene chloride was added 521 mg of N-ethyl-N’-[3-(dimethyl

149

-amino)-propyl]-carbodiimide hydrochloride (EDC), 368 mg of 1-hydroxybenzotriazole (HOBt) and 630 mg of N-[(benzyloxy)-carbonyl]-leucine (Cbz-leucine). The reaction mixture was kept at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then diluted with ethyl acetate, the solution was washed with 1 M hydrochloric acid solution, saturated aqueous potassium carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography, using a 3:97 volume methanol/methylene dichloride solvent mixture as the eluent. 1.0 mg of the title compound was obtained. MS (ES) 478 (M+H ⁺ ).

g.) tert-Butyl-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate

A solution of 1.0 g of the compound of Example 2f and a catalytic amount of 10% palladium on carbon catalyst in 2:1 ethyl acetate/methanol was placed under a balloon pressure of hydrogen. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then filtered to remove the catalyst and the filtrate was concentrated in vacuo to give 0.82 g of the title compound. MS (ES) 344 (M + H ⁺ ).

h.) tert-Butyl-{(S)-1-[(1-benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate

0.69 g (2.01 mmol) of the product of Example 2g methylenediamine

To a 150% chloride solution, 0.32 ml (3.01 mmol) of benzaldehyde was added first, followed by 0.85 g (4.02 mmol) of sodium [triacetoxyhydridoborate](1—) reagent. The reaction mixture was allowed to stir until the starting compound was completely converted according to thin-layer chromatography analysis. Subsequently, a few drops of water were added to the reaction mixture to destroy the excess of sodium [triacetoxyhydridoborate] (1—) reagent, and then it was diluted with ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography, using a 5:95 volume methanol/methylene dichloride solvent mixture as eluent. 800 mg of the title compound were obtained. MS (ES) 434 (M + H ⁺ ).

i.) N-(1-Benzyl-3-hydroxy-4-azepanyl)-(S)-2-amino-4-methylpentanamide

To a solution of 800 mg of the product of Example 2h in 15 ml of methanol was added 15 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo to give 800 mg of the title compound. MS (ES) 334 (M + H ⁺ ).

j.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-naphthalenecarboxamide

To a solution of 200 mg (0.49 mmol) of the product of Example 21 in methylene chloride was added 0.17 ml (1.22 mmol) of triethylamine, 103.5 mg of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), 73 mg (0.54 mmol) of 1-hydroxybenzoic acid, and 100 mg (0.12 mmol) of 1-hydroxybenzoic acid.

151 triazole (HOBt) and 93 mg (0.54 mmol) 2-naphthoic acid. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 5:95 (v/v) methanol/methylene dichloride solvent mixture as eluent. 0.14 g of the title compound was obtained. MS (ES) 488 (M + H ⁺ ) .

k.) N-{ (S)-1-[(1-Benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl]-2-naphthalenecarboxamide

The title compound was prepared according to the general procedure of Example 11, except that instead of the product of Example 1h, the product of Example 2j was used as the starting compound. H-NMR (CDCl ₃ ) δ (ppm): 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, 12H). MS (ES): 486 (M + H ⁺ , 100 +). After separation of the diastereomers using HPLC: Diastereomer 1: MS (ES) 486.3 (M + H ⁺ ); and Diastereomer 2: MS (ES) 486.3 (M + H ⁺ ).

Example 3 Preparation of N-((S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}benzo[1,3]dioxole-5-carboxamide

- 152 a.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the general procedure of Example 2j, except that piperonyl acid was used as the starting compound instead of 2-naphthoic acid. MS (ES) 482 (M + H ⁺ ).

b.) N-{(S)-1-[(1-Benzyl-3-oxo-4-azepanyl)-carbamoyl]-3-methyl-butyl}-benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the general procedure of Example 11, except that the starting material was the product of Example 3a. H-NMR (CDCl3) δ (ppm): 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 (ES): 480 (M + H ⁺ , 100 %). The diastereomers were separated by preparative HPLC and the eluates were lyophilized. Diastereomer 1: MS (ES) 480.3 (M + H ⁺ ), 959.6 (2M + H ⁺ ); and Diastereomer 2: MS (ES) 480.3 (M + H ⁺ ), 959.6 (2M + H ⁺ ).

Example 4

Preparation of N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

a.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 2j, except that 2-benzofurancarboxylic acid was used as the starting compound instead of 2-naphthoic acid. MS (ES) 478 (M + H).

b.) N-{(S)-1-[(1-Benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 11, except that the starting material was Example 4a. MS (ES): 492 (M + H ⁺ , 100%). The diastereomers were separated by preparative HPLC and the eluates were lyophilized. Diastereomer 1: MS (ES) 476.4 (M + H ⁺ ), 951.6 (M + H ⁺ ); and Diastereomer 2: MS (ES) 476.4 (M + H ⁺ ), 951.6 (2M + H ⁺ ).

Example 5

Preparation of N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}benzo[b]thiophene-2-carboxamide

a.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 2j, except that benzothiophene-2-carboxylic acid was used as the starting compound instead of 2-naphthoic acid. MS (ES) 494 (M + H).

b.) N-{(S)-1-[(1-Benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 11, except that the starting material was the product of Example 5a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 492 (M + H ⁺ , 100%). The diastereomers were separated by preparative HPLC, and the eluates were lyophilized. Diastereomer 1: MS (ES) 492.4 (M + H), 983.7 (2M + H); and Diastereomer 2: MS (ES) 492.4 (M + ^H ), 983.7 (2M + H).

Example 6

Preparation of N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-naphthalenesulfonamide

a.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-naphthalenesulfonamide

To a solution of 200 mg (0.49 mmol) of the product of Example 2i in methylene chloride was added 0.24 ml (1.72 mmol) of triethylamine and 122 mg (0.54 mmol) of [(2-naphthyl)sulfonyl] chloride. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then worked up, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 10:90 (v/v) methanol/methylene chloride solvent mixture as eluent. 52 mg of the title compound was obtained. MS (ES) 524 (M + H ⁺ ).

b.) N-{(S)-1-[(1-Benzyl-3-oxo-4-azepanyl)-carbamoyl]-3-methyl-butyl}-2-naphthalenesulfonamide

The title compound was prepared by the general procedure of Example 11.

- 155 was prepared in the same way, except that the product of Example 6a was used as the starting compound. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 522 (M + H ⁺ , 100 %).

Example 7

Preparation of N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

a.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

The title compound was prepared according to the general procedure of Example 2j, except that 2-quinolinecarboxylic acid was used as the starting compound instead of 2-naphthoic acid. MS (ES) 489 (M + H ⁺ ).

b.) N-{(S)-1-[(1-Benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

The title compound was prepared according to the general procedure of Example 11, except that the starting material was the product of Example 7a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 487 (M + H ⁺ , 100%). The diastereomers were separated by preparative HPLC, and the eluates were lyophilized. Diastereomer 1: MS (ES) 492.4 (M + H ⁺ ), 983.7 (M + H ⁺ ) ; and dia 2 ** « ·· fr wt ·

- 156 - 2 ^: O ^S *>

stereoisomer: MS (ES) 492.4 (M + H ⁺ ), 983.7 (2M + H ⁺ ).

Example 8

Preparation of N-{(S)-1-[(1-benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-3,4-dichlorobenzamide

a.) N-{(S)-1-[(1-Benzyl-3-hydroxy-4-azepanyl)-carbamoyl]-3-methylbutyl}-3,4-dichlorobenzamide

The title compound was prepared according to the general procedure of Example 2j, except that 2,3-dichlorobenzoic acid was used as the starting compound instead of 2-naphthoic acid. MS (ES) 506 (M + H ⁺ ).

b.) N-{(S)-1-[(1-Benzyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-3,4-dichlorobenzamide

The title compound was prepared according to the general procedure of Example 11, except that the starting material was the product of Example 8a. ¹ H-NMR (CDCl3) δ (ppm): 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, 2H), 5.2 (m, 1H), 7.2-8.4 (m, 8H). MS (ES): 504 (M ⁺ , 100%).

Example 9

Preparation of 4-{[(S)-4-methyl-2-{[(2-quinolyl)carbonyl]amino}-pentanoyl]amino}-3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-azepane

a.) 4-[{(S)-2-[(tert-Butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]acetyl}azepane

To a solution of 0.5 g (1.46 mmol) of the product of Example 2g in methylene chloride was added 307 mg (1.60 mmol) of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), 216 mg (1.60 mmol) of 1-hydroxybenzotriazole (HOBt) and 341 mg (1.60 mmol) of 2-[3-(2-pyridyl)phenyl]acetic acid. The reaction mixture was stirred at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then worked up and the residue was subjected to column chromatography using a 2:98 volume methanol/methylene dichloride solvent mixture as eluent to give the title compound. MS (ES) 539 (M+H ⁺ ).

b.) 4-{[(S)-2-Amino-4-methyl-pentanoyl]-amino]-3-hydroxy-1-{2-

-[3-(2-pyridyl)phenyl]acetyl}-azepane

To a solution of 1.3 g of the product of Example 9a in 20 ml of methanol was added 20 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then concentrated in vacuo to give 1.1 g of the title compound. MS (ES) 439 (M + H ⁺ ).

c.) 4-{[(S)-4-Methyl-2-{[(2-quinolyl)carbonyl]amino)pentanoyl]amino)-3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]acetyl}-azepane

The title compound was prepared according to the general procedure of Example 7a, except that the starting material was 158 -

The product of Example 9b was used as the starting compound in this case. MS (ES) 594 (M + H ⁺ ).

d.) 4-{[(S)-4-Methyl-2-{[(2-quinolyl)carbonyl]amino}-pentanoyl]amino}-3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-azepane

The title compound was prepared according to the general procedure of Example 11, except that the starting material was the product of Example 9c. H-NMR (CDCl3) δ (ppm): 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 (ES): 592 (M + H ⁺ , 100%).

Example 10

Preparation of 1-[(S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentyl]-4-{[(S)-4-methyl-2-{[(2-quinolyl)carbonyl]amino}-pentanoyl]amino}-3-oxoazepane

a. ) 1-[(S) -2-{[(Benzyloxy)carbonyl]amino}-4-methylpentyl]-

-4-[{(S)-2-[(tert-butoxycarbonyl)amino]-4-methyl-

-pentanoyl}-amino]-3-hydroxyazepane

The title compound was prepared according to the procedure of Example 2h, except that instead of benzaldehyde, N-[(benzyloxy)carbonyl]leucine was used as the starting compound. MS (ES) 577 (M + H ⁺ ).

b.) 1-[(S)-2-{[(Benzyloxy)carbonyl]amino}-4-methylpentyl]-

-4-[(S)-2-amino-4-methylpentanoyl)amino]-3-hydroxyazepane

The title compound was prepared according to the procedure of Example 2i.

was prepared as described above, except that the starting compound in this case was the product of Example 10a. MS(ES) 477 (M + H ⁺ ).

c.) 1-[(S)-2-{[(Benzyloxy)carbonyl]amino}-4-methylpentyl]-4-{[(S)-4-methyl-2-{[(2-quinolyl)carbonyl]amino}-pentanoyl]amino}-3-hydroxyazepane

The title compound was prepared according to the procedure of Example 7a, except that the starting material was Example 10b. MS (ES) 632 (M + H ⁺ ).

d.) 1-[(S)-2-{[(Benzyloxy)carbonyl]amino}-4-methylpentyl]-4-{[(S)-4-methyl-2-{[(2-quinolyl)carbonyl]amino}-pentanoyl]amino}-3-oxoazepane

The title compound was prepared according to the procedure of Example 10c, except that the starting compound in this case was the product of Example 10c. H-NMR (CDCl3) δ (ppm): 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 (ES) :

630 (M+H ⁺ , 100%).

Example 11

Preparation of l-benzoyl-4-[{(S)-2-[(benzo[1,3]dioxolylcarbonyl)amino]-4-methylpentanoyl}amino]-3-oxoazepane

a.) l-Benzoyl-4-[{(S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxyazepane

- 160

The title compound was prepared according to the procedure of Example 9a, except that benzoic acid was used as the starting compound instead of 2-[3-(2-pyridyl)phenyl]acetic acid. MS (ES) 448 (M + H ⁺ ).

b.) l-Benzoyl-4-[(S)-2-amino-4-methylpentanoyl)amino]-3-hydroxyazepane

The title compound was prepared according to the procedure of Example 2i, except that the starting material was Example 11a. MS(ES) 348 (M + H ⁺ ).

c.) l-Benzoyl-4-[{(S)-2-[(benzo[1,3]dioxolylcarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxyazepane

The title compound was prepared according to the procedure of Example 2j, except that the starting compound was the product of Example 11b instead of the product of Example 2i, and piperonyl acid instead of 2-naphthoic acid. MS (ES) 496 (M + H ⁺ ).

d. ) l-Benzoyl-4-[{(S)-2-[(benzo[1,3]dioxolylcarbonyl)amino]-

-4-methylpentanoyl}-amino]-3-oxo-azepane

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 11c. H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 494 (M + H ⁺ , 70 %).

- 161

Example 12

Preparation of l-benzoyl-4-[{(S)-2-[(4-fluorobenzoyl)amino]-4-methylpentanoyl}amino]-3-oxoazepane

a.) l-Benzoyl-4-[{(S)-2-[(4-fluorobenzoyl)amino]-4-methylpentanoyl}amino]-3-hydroxyazepane

The title compound was prepared according to the procedure of Example 11c, except that 4-fluorobenzoic acid was used as the starting compound instead of piperonyl acid. MS (ES) 470 (M + H ⁺ ).

b.) l-Benzoyl-4-[{(S)-2-[(4-fluorobenzoyl)-amino]-4-methylpentanoyl}-amino]-3-oxo-azepane

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 12a. H-NMR (CDCl3) δ (ppm): 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 (ES): 468 (M + H ⁺ , 10%).

Example 13

Preparation of 3-OXO-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]pentanoyl}-amino]-1-(4-methylpentanoyl)azepane

a.) 4-[{(S)-2-[(tert-Butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxy-1-(4-methylpentanoyl)azepane

The title compound was prepared according to the procedure of Example 9a, except that the starting compound was 162 -

Isocaproic acid was used instead of 2-[3-(2-pyridyl)phenyl]acetic acid in this case. MS (ES) 442 (M + H).

b.) 4-{[(S)-2-Amino-4-methylpentanoyl]amino}-3-hydroxy-1-(4-methylpentanoyl)azepane

The title compound was prepared according to the procedure of Example 2i, except that the starting material was Example 13a. MS (ES) 342 (M + H ⁺ ).

c.) 3-Hydroxy-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-1-(4-methylpentanoyl)-azepane

To a solution of 200 mg (0.53 mmol) of the product of Example 13b in methylene chloride was added 111 mg (0.58 mmol) of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), 111 mg (0.58 mmol) of 1-hydroxybenzotriazole (HOBt), 0.11 ml (0.79 mmol) of triethylamine and 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid. The reaction mixture was stirred until the starting compound was completely converted according to thin layer chromatography analysis. After work-up, the residue was subjected to column chromatography, eluting with a 5:95 volume methanol/methylene chloride solvent mixture. 160 mg of the title compound was obtained. MS (ES) 615 (M + H ). d.) 3-OXO-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-1-(4-methylpentanoyl)-azepane

The title compound was prepared according to the procedure of Example 13d, except that the starting compound was the product of Example 13d. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES) :

613 (M + H ⁺ , 100%). The diastereomers were separated by preparative HPLC and the eluates were lyophilized to obtain diastereomer 1 and diastereomer 2.

Example 14

Preparation of 3-OXO-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]pentanoyl}-amino]-1-(phenylsulfonyl)azepane

a.) 4-[{(S)-2-[(tert-Butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxy-1-(phenylsulfonyl)azepane

To a solution of 0.5 g (1.46 mmol) of the amine of Example 2g in methylene chloride was added first 0.4 ml (2.92 mmol) of triethylamine, then 0.28 ml (2.18 mmol) of (phenylsulfonyl) chloride. The reaction mixture was stirred at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then worked up and the residue was subjected to column chromatography, eluting with a 10:90 volume methanol/methylene dichloride solvent mixture. 450 mg of the title compound was obtained. MS (ES) 484 (M + H ⁺ ).

b.) 4-{[(S)-2-Amino-4-methylpentanoyl]amino}-3-hydroxy-1-(phenylsulfonyl)azepane

164

The title compound was prepared according to the procedure of Example 2i, except that the starting material was Example 14a. MS (ES) 384 (M + H ⁺ ).

c.) 3-Hydroxy-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-1-(phenylsulfonyl)-azepane

The title compound was prepared according to the procedure of Example 13c, except that the starting material was Example 14b. MS (ES) 657 (M + H ⁺ ).

d.) 3-OXO-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-1-(phenylsulfonyl)-azepane

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 14c. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 655 (M + H ⁺ , 100 %).

Analysis of the diastereomeric mixture by analytical HPLC {40:60 —> 45:55 v/v acetonitrile/[20 mM KHPO4 (pH 7 buffer)] 60 min solvent gradient, 1 ml/min; inertsil ODS-3 column, 4.6 x 250 mm; UV detection at 215 nm} showed two peaks (Rt - 44.6 min and 45.9 min). The diastereo

165 were separated using preparative HPLC {40:60 -> 50:50 v/v acetonitrile/[20 mM KHPO4 (pH 7 buffer)] 60 min solvent gradient, 12 ml/min; inertsil ODS-3 column, 20 χ 250 mm; UV detection at 215 nm}. The eluates were lyophilized: 1st diastereomer (anal. Rt = 44.6 min); 2nd diastereomer (anal. Rt = 45.9 min).

Example 15

Preparation of N-phenyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl]amino]pentanoyl}amino]-3-oxo-1-azepanecarboxamide

a.) tert-Butyl-[(S)-1-{[3-hydroxy-1-(phenylcarbamoyl)-4-azepanyl]carbamoyl}-3-methylbutyl]carbamate

To a solution of 0.5 g (1.46 mmol) of the product of Example 2g in 20 ml of methylene chloride was added 0.24 ml (2.18 mmol) of phenyl isocyanate. The reaction mixture was stirred at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then worked up and the crude product was subjected to column chromatography using a 5:95 (v/v) methanol/methylene chloride solvent mixture as eluent. 578 mg of the title compound was obtained. MS (ES) 463 (M + H ⁺ ).

b. ) N ^L -Phenyl-4-{[ (S)-2-(aminomethyl)-pentanoyl]-amino}-3-

-hydroxy-1-azepanecarboxamide

The title compound was prepared according to the procedure of Example 2i, except that the starting compound in this case was the product of Example 15a.

We used 166. MS (ES) 363 (M + H ⁺ ).

c.) N-Phenyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-3-hydroxy-1-azepanecarboxamide

The title compound was prepared according to the procedure of Example 13c, except that the starting material was Example 15b. MS (ES) 636 (M + H ⁺ ).

d.) N-Phenyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-3-oxo-1-azepanecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 15c. 1H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 634 (M + H ⁺ , 100 %).

The diastereomeric mixture was analyzed by analytical HPLC {40:60 v/v acetonitrile/[20 mM KHPO4 (pH 7 buffer)] isocratic solvent mixture, 1 ml/min; Inertsil ODS-3 column, 4.6 χ 250 mm; UV detection at 215 nm) showed two peaks (Rt = 27.3 min and 30.1 min). The diastereomers were separated by preparative HPLC {40:60 —> 50:50 v/v acetonitrile/[20 mM KHPO4 (pH 7 buffer)] 60 min solvent gradient, 12 ml/min; Inertsil ODS-3 column, 20 χ 250 mm; UV detection at 215 nm}. The eluates were lyophilized

- 167 .i .··. .'· j .· ··: .··. :·· ··««·· ·« ·· ·· and desalted by NaHCO3/ethyl acetate extraction: 1st diastereomer (anal. Rt = 27.3 min); 2nd diastereomer (anal. Rt = 30.1 min).

Example 16

Preparation of H-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]carbamoyl)butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

a.) N-[(S)-3-Methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]acetyl)-4-azepanyl]carbamoyl)butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 13c, except that the starting material was Example 9b. MS (ES) 712 (M + H ⁺ ).

b.) N-[(S)-3-Methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl)-4-azepanyl]carbamoyl)butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 16a, except that the starting material was the product of Example 16a. ^Ή-ΝΜΗ (CDCl3) δ (ppm): 1.0 (m, 6H) , 1.5-2.1 (m, 5H) , 2.2 (m, 2H) , 2.7 (m, 4H) , 2.8 (m, 2H) , 2.9 (m, 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, 13H), 8.5 (m, 1H). MS (ES) : 710 (M +

H ⁺ , 100%).

The diastereomeric mixture was analyzed by analytical HPLC {40:60 v/v acetonitrile/[20 mM KHPO4 (pH 7 buffer)] isocratic solvent mixture, 1 mL/min; Inertsil ODS-3 column, 4.6 χ 250 mm; UV detection at 215 nm}, showing two peaks (Rt = 33.9 min and 37.9 min). The diastereomers were separated by preparative HPLC {40:60 -> 45:55 v/v acetonitrile/[20 mM KHPO4 (pH 7 buffer)] 60 min solvent gradient, 12 mL/min; Inertsil ODS-3 column, 20 χ 250 mm; UV detection at 215 nm}. The eluates were lyophilized and desalted by NaHCO3/ethyl acetate extraction: 1st diastereomer MS (ES) 710.3 (M + H ⁺ ), (anal. Rt = 33.9 min); 2nd diastereomer MS (ES) 710.3 (M + H ⁺ ), (anal. Rt = 37.9 min).

Example 17

Preparation of N-{(S)-1-[(1-benzoyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

a.) N-{(S) -1-[(1-Benzoyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 13c, except that the starting material was Example 11b. MS (ES) 621 (M + H ⁺ ).

b.) N-{(S)-1-[(1-Benzoyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 17a. H-NMR (CDCl ₃ ) δ (ppm): 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 (ES) 619 (M + H ⁺ , 100 %).

The diastereomeric mixture was determined by analytical HPLC {40:60 —>

Analysis of the 55:45 acetonitrile/[20 mM KHPO4 (pH 7 buffer)] 30 min solvent gradient, 1 ml/min; Inertsil ODS-3 column, 4.6 x 250 mm; UV detection at 215 nm} showed two peaks (Rt = 13.5 min and 17.6 min). The diastereomers were separated using preparative HPLC {40:60 —> 45:55 acetonitrile/[20 mM KHPO4 (pH 7 buffer)] 60 min solvent gradient, 12 ml/min; Inertsil ODS-3 column, 20 χ 250 mm; UV detection at 215 nm}. The eluates were lyophilized and desalted by NaHCO3/ethyl acetate extraction: 1. diastereomer (anal. Rt = 13.5 min); Diastereomer 2 (anal. Rt = 17.6 min).

Example 18

Preparation of N-[(S)-1-{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-pyrrolidinyl)ethoxy]-2-benzofurancarboxamide

a.) N— [(S)-1-{[1-(Phenylsulfonyl)-3-hydroxy-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-pyrrolidinyl)ethoxy]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 14c, except that instead of 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid,

170 in this case 5-[2-(1-pyrridinyl)ethoxy]-2-benzofurancarboxylic acid was used. MS (ES) 641 (M + H ⁺ ).

b.) N- [(S)-1-{[1-(Phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-pyrrolidinyl)ethoxy]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 18a. H-NMR (CDCl ₃ ) δ (ppm): 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, UH). MS (ES): 639 (M + H ⁺ , 100 %).

Example 19

Preparation of N- [(S)-1~{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-piperidyl)ethoxy]-2-benzofurancarboxamide

a.) N- [(S)-1-{[1-(Phenylsulfonyl)-3-hydroxy-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-piperidyl)ethoxy]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 14c, except that instead of 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid, 5-[2-(1-piperidyl)ethoxy]-2-benzofurancarboxylic acid was used as the starting compound. MS (ES) 655 (M + H ⁺ ).

171

b.) N-[(S)-1-{[1-(Phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[2-(1-piperidyl)ethoxy]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 18a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m,

UH) , 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, UH). MS (ES): 653 (M + H ⁺ , 100 %).

Example 20

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

a.) N-Methyl-N-methoxy-5-(2-morpholinoethoxy)-2-benzofurancarboxamide To a solution of 2-[3-(2-pyridyl)phenyl]acetic acid in methylene dichloride, 0.92 g N, O-dimethylhydroxylamine hydrochloride, 1.3 ml triethylamine, 0.96 g 1-hydroxybenzotriazole (HOBt) and 1.1 g N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride were added. The reaction mixture was stirred until the starting compound was completely converted. After working up the reaction mixture, the crude product thus obtained was subjected to column chromatography, using a 40:60 volume ethyl acetate/hexane solvent mixture as the eluent. 1.1 g of the title compound was obtained. MS (ES) 257 (M+H ⁺ ).

172

b.) 5-(2-Morpholine-ethoxy)-2-benzofurancarbaldehyde

To a solution of 0.2 g of N-methyl-N-methoxy-5-(2-morpholinoethoxy)-2-benzofurancarboxamide (product of Example 20a) in tetrahydrofuran was added 2.0 ml of 1 M lithium aluminum hydride solution in tetrahydrofuran. The reaction mixture was stirred until the starting compound was completely converted. After workup, 160 mg of the title compound was obtained.

c.) tert-Butyl-{[(S)-3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-3-methylbutyl]carbamate

The title compound was prepared according to the procedure of Example 2g, except that instead of benzaldehyde, 5-(2-morpholinoethoxy)-2-benzofurancarbaldehyde was used as the starting compound. MS (ES) 525 (M + H ⁺ ).

d.) N-[3-Hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl)-4-azepanyl]-(S)-2-amino-4-methylpentanamide

The title compound was prepared according to the procedure of Example 2i, except that the starting compound in this case was the product of Example 20c.

e.) N-[(S)-3-Methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 13c, except that the starting compound in this case was the product of Example 20d.

173

f. ) N-[(S)-3-Methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 20e. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m,

5H) , 2.2 (m, 2H) , 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 (ES): 696 (M + H ⁺ , 80 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 696 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 696 (M + H ⁺ , 100%)].

Example 21

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-2-naphthalenecarboxamide

a.) N-[(S)-3-Methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-2-naphthalenecarboxamide

The title compound was prepared according to the procedure of Example 20f, except that 2-naphthoic acid was used as the starting compound instead of 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid. MS (ES) 579 (M + H ⁺ ).

174

b.) N-[(S)-3-Methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)-phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-2-naphthalenecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 21b. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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), 5.0 (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 (ES): 577 (M + H ⁺ , 100 %).

Example 22

Preparation of N~[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-ΙΗ-2-indolecarboxamide

a.) N-[(S)-3-Methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 20f, except that 1Jf-2-indolecarboxylic acid was used as the starting compound instead of 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid. MS (ES) 568 (M + H ⁺ ).

b.) N-[(S)-3-Methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)-phenyl]-ethyl}-4-azepanyl]-carbamoyl}-butyl]-ΙΗ-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 22b.

We used 175. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 566 (M+H ⁺ , 100 %).

Example 23

Preparation of N- [(S)-1-{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]-carbamoyl}-3-methylbutyl]-ΙΗ-2-indolecarboxamide a.) N- [(S)-1-{[1-(phenylsulfonyl)-3-hydroxy-4-azepanyl]-carbamoyl}-3-methylbutyl]-ΙΗ-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 2j, except that instead of naphthoic acid, ΙΗ-2-indolecarboxylic acid was used as the starting compound. MS (ES) 527 (M + H ).

b.) N-[(S)-1-{[1-(Phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-ΙΗ-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 23b. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 525 (M + H ⁺ , 100 %).

Example 24

Preparation of N-[(S)-1-{[1-(phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

176

a.) N-[(S)-1-{[1-(Phenylsulfonyl)-3-hydroxy-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 23, except that 2-benzofurancarboxylic acid was used as the starting compound instead of 1H-2-indolecarboxylic acid. MS (ES) 528 (M + H).

b.) N-[(S)-1-{[1-(Phenylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 24b. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-2-benzofurancarboxamide

a.) N-[(S)-3-Methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 20e, except that instead of 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid, 2-benzofurancarboxylic acid was used as the starting compound. MS (ES) 569 (M + H ⁺ ).

177

b.) N-[(S)-3-Methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 25b. ^X H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H) , 1.5-2.1 (m, 5H) , 2.2 (m, 2H) , 2.7 (m, 5H) , 3.0 (m, 1H) , 3.3 (m, 1H) , 3.5 (m, 1H) , 4.7 (m, 1H) , 5.2 (m, 1H) , 7.2-7.7 (m, 14H) , 8.7 (m, 1H) . MS (ES) : 567 (M + H ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 656 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 656 (M + H , 100%)].

Example 26

Preparation of N-{(S)-3-methyl-1-[(3-oxo-1-phenethyl-4-azepanyl)carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 26c-f, except that phenylacetaldehyde was used instead of 5-(2-morpholinoethoxy)-2-benzofurancarbaldehyde as in Example 20c. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, 1H), 2.6 (m, 4H), 2.7 (m, 6H), 3.0 (m, 1H), 3.3 (dd, 1H), 3.5 (q, 1H), 3.7 (m, 4H), 4.2 (m, 2H), 4.7 (m, 1H), 5.0 (m, 1H), 7.2-7.2 (m, UH). MS (ES): 619 (M + H ⁺ , 80 %).

The diastereomeric mixture was selected using HPLC.

- 178 -

el, resulting in the isolation of a faster eluting diastereomer [MS (ES) 619 (M + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES) 619 (M + H , 100 %)].

Example 27 Preparation of N-{(S)-3-methyl-1-[(3-oxo-1-phenethyl-4-azepanyl)carbamoyl]butyl}-2-naphthalenecarboxamide

The title compound was prepared according to the procedure of Examples 2h-k, except that phenylacetaldehyde was used instead of benzaldehyde in Example 20h. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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(ES): 500 (M + H ⁺ , 100 %).

Example 28

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide

The title compound was prepared according to the procedure of Example 14a-b, except that [(2-pyridyl)sulfonyl] chloride was used instead of (phenylsulfonyl) chloride in Example 14a. MS (ES) 385 (M + H ⁺ ).

- 179 b.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.15 g of N-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide (product of Example 28a) in methylene chloride was added 0.11 ml of triethylamine, 49 mg of 1-hydroxybenzotriazole, 69 mg of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 58 mg of 2-benzofurancarboxylic acid. The reaction mixture was stirred until the starting compound was completely converted. After work-up, the crude title compound obtained was subjected to column chromatography, eluting with a 5:95 volume methanol/ethyl acetate solvent mixture. MS (ES) 529 (M + H ⁺ ).

c.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide The title compound was prepared according to the procedure of Example li, except that the product of Example 28b was used as the starting compound. ¹ H-NMR (CDCl3) δ (ppm): 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, 3H) , 7.4 (m, 4H) , 7.6 (m,

1H), 8.0 (m, 2H), 8.7 (m, 1H). MS (ES): 527 (M + H ⁺ , 40 %).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [ ^1H -NMR (CDCl3) δ (ppm): 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

- 180 -

(m, 2H), 8.7 (m, 1H). MS (ES): 527 (M + H ⁺ , 100 %) ], and a slower eluting diastereomer [ ¹ H-NMR (CDCl3) δ (ppm): 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 (ES) :

527 (M + H ⁺ , 100%)] was isolated.

Example 9

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-naphthalenecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-

-azepanyl}-carbamoyl]-butyl}-2-naphthalenecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 2-naphthoic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 539 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-

-azepanyl}-carbamoyl]-butyl}-2-naphthalenecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 29a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 537 (M + H ⁺ , 50 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 537 (Μ + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES) 537 (M + H , 100 %)].

Example 30

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

a.) N-{(S) -3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 13c, except that the starting material was Example 28a. MS (ES) 658 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 29a. H-NMR (CDCl3) δ (ppm): 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 (m, 2H), 8.0 (m, 2H), 8.7 (m, 1H), 8.7 (m, 1H). MS (ES): 656 (M + H ⁺ , 100%).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereo- 182 -

because [MS (ES) 656 (Μ + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES) 656 (M + H ⁺ , 100 %)] were isolated.

Example 31

Preparation of tert-butyl 4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]pentanoyl}-amino]-3-oxo-l-azepanecarboxylate

a.) tert-Butyl-4-{[(S)-2-amino-4-methylpentanoyl]-amino]-3-hydroxy-1-azepanecarboxylate

To a solution of 0.89 g of the product of Example If in 20 ml of a 2:1 ethyl acetate/methanol solvent mixture was added 10% palladium/carbon catalyst, and the flask was connected to a balloon containing hydrogen gas. The reaction mixture was stirred until the starting compound was completely converted as determined by thin layer chromatography. The reaction mixture was then filtered and concentrated. 0.57 g of the title compound was obtained.

b.) tert-Butyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-3-hydroxy-l-azepanecarboxylate

The title compound was prepared according to the procedure of Example 13c, except that the starting compound in this case was the product of Example 31a.

c.) tert-Butyl-4-[{(S)-4-methyl-2-[{[5-(2-morpholinoethoxy)-2-benzofuranyl]carbonyl}-amino]-pentanoyl}-amino]-3-oxo-l-azepanecarboxylate

- 183

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 31b. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5 (m, 9H), 1.7 (m, 5H), 2.2 (m, 2H), 2.5 (m, 5H), 2.7 (m, 2H), 3.5 (m, 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 (ES): 615 (M + H ⁺ , 100 %).

Example 32

N-{(S)-3-methyl-1-[(3-oxo-4-azepanyl)carbamoyl]butyl}-5-

Preparation of -(2-morpholinoethoxy)-2-benzofurancarboxamide

To a solution of the product of Example 31c in 5 ml of tetrahydrofuran was added 5 ml of 1 M hydrogen chloride in diethyl ether. The reaction mixture was stirred overnight and then concentrated to give the title compound. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 515 (M + H ⁺ , 100 %).

Example 33

Preparation of N-[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]-4-methylpentanamide

a.) tert-Butyl-3-hydroxy-4-[(4-methylpentanoyl)amino]-1-azepanecarboxylate

The title compound was prepared according to the procedure of Example 1f, with the difference that instead of N-[(benzyloxy)carbonyl]leucine as the starting compound,

- 184

In this case, 4-methylpentanoic acid was used. MS (ES) 329 (M + H ⁺ ).

b.) N-(3-Hydroxy-4-azepanyl)-4-methylpentanamide

To a solution of 200 mg of the product of Example 33a in 5 mL of methanol was added 5 mL of 4 M hydrochloric acid in dioxane. The reaction mixture was stirred until the starting material was completely converted. The reaction mixture was then concentrated to give 132 mg of the title compound. MS (ES) 229 (M + H ⁺ ).

c.) N-[3-Hydroxy-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]-4-methylpentanamide

The title compound was prepared according to the procedure of Example 9a, except that the starting material was Example 33b. MS (ES) 424 (M + H ⁺ ).

d. ) N-[3-Oxo-1-{2-[3-(2-pyridyl)-phenyl]-acetyl)-4-azepanyl]-4-methyl-1-pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 33c. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 4.1 (m, 3H), 4.6 (m, 1H), 5.3 (m, 1H), 7.2-8.0 (m, 7H), 8.7 (m, 1H). MS (ES): 422 (M + H ⁺ , 100 %).

185

X ·**» **· *’ **

Example 34

tert-Butyl-N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)-phenyl]-acetyl}-4-azepanyl]-carbamoyl}-butyl]-N- [(2-naphthyl)

-methyl]carbamate production

a.) Methyl-(S)-4-methyl-2-{[(2-naphthyl)methyl]amino}pentanoate

To a solution of 0.5 g of leucine methyl ester hydrochloride in methylene chloride was added 0.9 ml of triethylamine, 0.43 g of 2-naphthalenecarbaldehyde and 0.87 g of sodium [triacetoxyhydridoborate](1-). The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume ethyl acetate/methylene dichloride solvent mixture as the eluent. 0.4 g of the title compound was obtained. MS (ES) 286 (M + H ⁺ ).

b.) Methyl-(S)-2-{N-(tert-butoxycarbonyl)-N-[(2-naphthyl)methyl]amino}-4-methylpentanoate

To a solution of 0.35 g of the product of Example 34a in methylene chloride was added 0.29 g of di(tert-butyl)dicarbonate. The reaction mixture was stirred at room temperature for 2 hours, then triethylamine was added and heated to reflux. After the reaction was complete, the reaction mixture was concentrated. The residue was purified by column chromatography using a 50:50 hexane/methylene chloride solvent mixture as eluent. 0.17 g of the title compound was obtained. MS (ES) 386 (M + H ⁺ ).

- 186 -

c.) (S)-2-{N-(tert-Butoxycarbonyl)-N-[(2-naphthyl)methyl]amino]-4-methylpentanoic acid

To a solution of 0.17 g of the product of Example 34b in 15 ml of a 2:1 tetrahydrofuran/methanol solvent mixture was added 0.019 g of lithium hydroxide. The reaction mixture was stirred overnight and then concentrated to give the title compound.

d.) Benzyl 4-{[(S)-{N-(tert-butoxycarbonyl)-N-[(2-naphthyl)methyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-1-azepanecarboxylate

To a solution of 0.11 g of the product of Example 2e in methylene chloride was added 0.08 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.06 g of 1-hydroxybenzotriazole, and to the resulting mixture was added the product of Example 34c. After the reaction was complete, the reaction mixture was worked up and the crude product thus obtained was chromatographed using a 5:95 volume methanol/methylene chloride solvent mixture as the eluent. 0.18 g of the title compound was obtained. MS (ES) 618 (M + H ⁺ ).

e.) tert-Butyl-N- { (S)-1-[(3-hydroxy-4-azepanyl)-carbamoyl]-3-methyl-butyl}-N- [(2-naphthyl)-methyl]-carbamate

To a solution of 0.17 g of the product of Example 34d in 30 ml of a 2:1 ethyl acetate/methanol mixture was added 10% palladium on carbon and the flask was connected to a balloon containing hydrogen gas. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then

187 was filtered and solidified. 0.10 g of the title compound was obtained. MS (ES) 484 (M + H ⁺ ).

f.) tert-Butyl-N- [(S)-3-methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)-phenyl]-acetyl}-4-azepanyl]-carbamoyl}-butyl]-N-[(2-naphthyl)-methyl]-carbamate

The title compound was prepared according to the procedure of Example 9a, except that the starting material was Example 34e. MS (ES) 679 (M + H ⁺ ).

g.) tert-Butyl-N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]carbamoyl}-butyl]-N- [(2-naphthyl)methyl]carbamate

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 34f. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 677 (M + H ⁺ , 100%).

Example 35

Preparation of N-[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]-(S)-4-methyl-2-{[(2-naphthyl)methyl]amino}pentenamide mg 34g. To a solution of the product of Example 1 in tetrahydrofuran was added 1 M diethyl ether hydrogen chloride solution. The reaction mixture was stirred until the starting compound

188 was completely converted. The reaction mixture was then concentrated to give the title compound. 1 H-NMR (CDCl3) δ (ppm): 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), 7.2-8.0 (m, 16H), 8.7 (m, 1H). MS(ES): 577 (M + H ⁺ , 100 %).

Example 36 Preparation of tert-butyl 4-{2-[{2-[{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}carbamoyl]-5-benzofuranyl}oxy]ethyl}-1-piperazinecarboxylate a.) tert-Butyl 4-{2-[{2-[{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}carbamoyl]-5-benzofuranyl}oxy]ethyl}-1-piperazinecarboxylate

To a solution of 0.15 g of the product of Example 28a in methylene chloride was added 0.07 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.05 g of 1-hydroxybenzotriazole, and then tert-butyl-4-{2-[(2-carboxy-5-benzofuranyl)oxy]ethyl}-1-piperazinecarboxylate was added to the mixture thus obtained. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up, and the crude product thus obtained was subjected to column chromatography, using a 10:90 volume methanol/ethyl acetate solvent mixture as the eluent. 0.10 g of the title compound was obtained. MS (ES) 757 (M + H ).

189

b.) tert-Butyl-4-{2-[{2-[{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}carbamoyl]-5-benzofuranyl}oxy]ethyl}-1-piperazinecarboxylate

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 36a. H-NMR (CDC1 ₃ ) δ (ppm): 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-?, 6 (m, 6H), 8.0 (m, 2H), 8.7 (m, 1H). MS (ES): 755 (M + H ⁺ , 100 %).

Example 37

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[2-(1-piperazinyl)ethoxy]-2-benzofurancarboxamide

0.02 g of the product of Example 36b was dissolved in 4 M hydrochloric acid in dioxane. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up to give the title compound. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-1.7 (m, 7H), 2.7 (m, 2H), 3.3 (Μ, 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 (ES): 655 (M + H ⁺ , 100 %).

190

Example 38

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide

To a solution of 0.15 g of the product of Example 28a in methylene chloride was added 0.07 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.05 g of 1-hydroxybenzotriazole, 0.11 ml of triethylamine and 0.01 g of 5-(2-cyclohexylethoxy)-2-benzofurancarboxylic acid. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using ethyl acetate as eluent. 0.15 g of the title compound was obtained. MS (ES) 655 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 38a. MS (ES) 653 (M + H ⁺ ).

191

Example 39

N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl]butyl]-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide

a.) N- [(S)-3-Methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]ethyl]-4-azepanyl]carbamoyl]butyl]-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide

To a solution of 0.15 g of the product of Example 20d in methylene chloride was added 0.06 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.04 g of 1-hydroxybenzotriazole,

0.14 ml of triethylamine and 0.09 g of 5-(2-cyclohexylethoxy)-2-benzofurancarboxylic acid. The reaction mixture was allowed to stir until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using ethyl acetate as eluent. 0.10 g of the title compound was obtained. MS (ES) 695 (M + H ⁺ ).

b.) N-[(S)-3-Methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl]-4-azepanyl]carbamoyl]butyl]-5-(2-cyclohexylethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 39a. ^X H-NMR (CDCl3) δ (ppm): 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,

192

1H). MS (ES): 693 (M + H ⁺ , 100 %).

Example 40

Preparation of tert-butyl-4-[2-{[2-{[(Sj-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]carbamoyl}-5-benzofuranyl]oxy}-ethyl]-1-piperazinecarboxylate

a.) tert-Butyl-4-[2-{[2-([(S)-3-methyl-1-{[3-hydroxy-1-(2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]carbamoyl}-5-benzofuranyl]oxy}-ethyl]-1-piperazinecarboxylate

To a solution of 0.15 g of the product of Example 20d in methylene chloride was added 0.06 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.04 g of 1-hydroxybenzotriazole, 0.14 ml of triethylamine and 0.12 g of tert-butyl-4-{2-[(2-carboxy-5-benzofuranyl)oxy]ethyl}-1-piperazinecarboxylate. The reaction mixture was stirred until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 10:90 volume methanol/ethyl acetate solvent mixture as eluent. 0.09 g of the title compound was obtained. MS (ES) 797 (M + H ⁺ ).

b.) tert-Butyl-4-[2-{[2-{[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]carbamoyl}-5-benzofuranyl]oxy}-ethyl]-1-piperazinecarboxylate

193

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 40a. MS (ES) 795.9 (M + H).

Example 41

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]ethyl}-4-azepanyl]carbamoyl}-butyl]-5-[2-(1-piperazinyl)ethoxy]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 37, except that the starting compound in this case was the product of Example 40b. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES) :

695 (M+H', 70%).

Example 42

Preparation of N-{3-oxo-l-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{N-methyl-N- [(2-naphthyl)methyl]-amino}-pentanamide a.) Benzyl-4-[{(S) -2-[N- (tert-butoxycarbonyl)-N-methylamino]-4-methylpentanoyl}-amino]-3-hydroxy-l-azepanecarboxylate 0.35 g of the product of Example 2e in methylene dichloride was added 0.36 g of N- (tert-butoxycarbonyl)-N-methylleucine, 0.2 g of 1-hydroxybenzotriazole and 0.28 g of N-ethyl-N'- [3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction

194 The mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume methanol/methylene dichloride solvent mixture as the eluent. 0.6 g of the title compound was obtained. MS (ES) 492 (M + H ).

b.) tert-Butyl-N-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl)-N-methylcarbamate

To a solution of 0.6 g of the product of Example 42a in 30 ml of a 1:2 methanol/ethyl acetate solvent mixture was added 10% palladium on carbon and the flask was connected to a balloon containing hydrogen gas. The reaction mixture was stirred until the starting material was completely converted. The reaction mixture was then filtered and concentrated to give 0.50 g of the title compound. MS (ES) 358 (M + H ⁺ ).

c.) tert-Butyl-N- {(S)-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-3-methylbutyl}-N-methylcarbamate

To a solution of 0.2 g of the product of Example 42b in methylene chloride was added 0.16 ml of triethylamine and 0.15 g of [(2-pyridyl)sulfonyl] chloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume methanol/ethyl acetate solvent mixture as the eluent. 0.23 g of the title compound was obtained. MS (ES) 499 (M + H ⁺ ).

195

d.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-(methylamino)pentanamide

To a solution of 0.23 g of the product of Example 42c in 3.0 mL of methanol was added 3.0 mL of 4M hydrochloric acid in dioxane. The reaction mixture was stirred until the starting material was completely converted. The reaction mixture was concentrated to give the title compound. MS (ES) 399 (M + H ⁺ ).

e.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{N-methyl-17- [ (2-naphthyl) -methyl] -amino}-pentanamide

To a solution of 0.05 g of the product of Example 42d in methylene chloride was added 0.07 ml of triethylamine, 0.05 g of 2-naphthalenecarbaldehyde and 0.11 g of sodium [triacetoxyhydridoborate](1—). The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume methanol/ethyl acetate solvent mixture as the eluent. 0.03 g of the title compound was obtained. MS (ES) 539 (M + H ).

f.) N-{3-Oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{N-methyl-W-[(2-naphthyl)-methyl]-amino}-pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 42e. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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,

- 196 - ..··„··..·

1H). MS (ES): 537 (M + H ⁺ , 100 %).

Example 43

Preparation of N-[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]-(S)-4-methyl-2~ {N-methyl-N- [(2-naphthyl)methyl]amino}-pentanamide

a.) tert-Butyl-N- [(S)-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)-phenyl]-acetyl}-4-azepanyl]-carbamoyl}-3-methyl-butyl]-N-methylcarbamate

To a solution of 0.25 g of the product of Example 42b were added 0.16 g of 2-[3-(2-pyridyl)phenyl]acetic acid, 0.12 g of 1-hydroxybenzotriazole and 0.15 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume methanol/ethyl acetate solvent mixture as the eluent. 0.24 g of the title compound was obtained. MS (ES) 553 (M + H ⁺ ).

b.) N-[3-Hydroxy-1-{2-[3-(2-pyridyl)-phenyl]-acetyl}-4-azepanyl]-(S)-4-methyl-2-{N-methyl-N- [(2-naphthyl)-methyl]-amino}-pentanamide

The title compound was prepared according to the procedure of Example 42d, except that the starting material was Example 43a. MS (ES) 453 (M + H ⁺ ).

197

c.) N-[3-Oxo-1-{2-[3-(2-pyridyl)-phenyl]-acetyl}-4-azepanyl]-(S)-4-methyl-2-{N-methyl-N-[(2-naphthyl)-methyl]-amino}-pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 43b. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 591 (M + H ⁺ , 100%).

Example 44

Preparation of N-methyl-N- [(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]carbamoyl)butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

a.) N-Methyl-N-[(S)-3-methyl-1-{[3-hydroxy-1-{2-[3-(2-pyridyl)phenyl]acetyl}-4-azepanyl]carbamoyl}-butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

To a solution of 0.1 g of the product of Example 43b in methylene chloride was added 0.06 g of 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid, 0.026 g of 1-hydroxybenzotriazole, 0.07 ml of triethylamine and 0.04 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 20:80 volume methanol/ethyl acetate solvent mixture as eluent.

198 wt. 0.07 g of the title compound was obtained. MS (ES) 726 (M + H).

b.) N-Methyl-N-[(S)-3-methyl-1-{[3-oxo-1-{2-[3-(2-pyridyl)phenyl]acetyl)-4-azepanyl]carbamoyl}-butyl]-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 44a. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 724 (M + H ⁺ , 100 %).

Example 45

Preparation of N-methyl-N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-Methyl-N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.1 g of the product of Example 42d in methylene chloride was added 0.04 g of 2-benzofurancarboxylic acid, an excess of triethylamine, 0.03 g of 1-hydroxybenzotriazole and 0.04 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography.

- 199 was chromatographed using a 5:95 volume methanol/ethyl acetate solvent mixture as eluent. 0.04 g of the title compound was obtained. MS (ES) 542.9 (M + H ).

b.) N-Methyl-N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 45a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 541 (M + H ⁺ , 10 %).

Example 46

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-N-[(2-naphthyl)methyl]-2,2,2-trifluoroacetamide

a.) Methyl-(S)-4-methyl-2-{N- [(2-naphthylmethyl)-N- (2,2,2-trifluoroacetyl)amino}-pentanoate

To a solution of 0.5 g of the product of Example 34a in methylene chloride was added a catalytic amount of potassium carbonate and 0.44 g of trifluoroacetic acid. The reaction mixture was stirred at room temperature for one hour and then concentrated. The crude title compound obtained as a residue was chromatographed using a 20:80 (v/v) ethyl acetate/hexane solvent mixture as eluent.

200

b.) Lithium-(S)-4-methyl-2-{N- [(2-naphthylmethyl)-N- (2,2,2-trifluoroacetyl)amino}-pentanoate

To a solution of 0.49 g of the product of Example 46a in 3 ml of a 2:1 tetrahydrofuran/water mixture was added 0.06 g of lithium hydroxide monohydrate. The reaction mixture was stirred overnight and then concentrated to give 0.46 g of the title compound. MS (ES) 366 (M + H ⁺ ).

c.) Benzyl-3-hydroxy-4-{[(S)-4-methyl-2-{N- [(2-naphthylmethyl)-N-(2,2,2-trifluoroacetyl)amino}-pentanoyl]-amino}-1-azepanecarboxylate

To a solution of 0.29 g of the product of Example 2e in methylene dichloride were added 0.24 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.16 g of 1-hydroxybenzotriazole and 0.46 g of the product of Example 46b. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography, eluting with a 5:95 volume methanol/ethyl acetate solvent mixture. 0.25 g of the title compound was obtained. MS (ES) 614 (M + H ⁺ ).

d.) N-{(S)-1-[(3-Hydroxy-1-azepanyl)carbamoyl]-3-methylbutyl}-N- [(2-naphthyl)methyl]-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure of Example 42b, except that the starting material was Example 46c. MS (ES) 480 (M + H ⁺ ).

201

e.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-N- [(2-naphthyl)methyl]-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure of Example 43a, except that the starting compound was the product of Example 46d. MS (ES) 675 (M + H ⁺ ).

f.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-N-[(2-naphthyl)-methyl]-2,2,2-trifluoroacetamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 46e. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 673 (M + H ⁺ , 100 %).

Example 47

Preparation of benzyl-4-{[(S)-2-{N-mesyl-N- [(2-naphthyl)-methyl]-amino}-4-methyl-pentanoyl]-amino}-3-oxo-l-azepanecarboxylate a.) Methyl-(S)-2-{N-mesyl-N- [(2-naphthyl)-methyl]-amino}-4-methylpentanoate

To a solution of 0.5 g of the product of Example 34a in methylene chloride was added 0.36 ml of triethylamine and 0.16 ml of mesyl chloride. The reaction mixture was stirred at room temperature until the starting compound was completely converted.

202

The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 20:80 (v/v) ethyl acetate/hexane solvent mixture as the eluent. 0.24 g of the title compound was obtained.

b.) Lithium-(S)-2-(N-mesyl-N-[(2-naphthyl)methyl]amino)-4-methylpentanoate

The title compound was prepared according to the procedure of Example 46b, except that the starting material was Example 47a. MS (ES) 348 (M + H ⁺ ).

c.) Benzyl-4-{[(S)-2-{N-mesyl-N-[(2-naphthyl)-methyl]-amino)-4-methyl-pentanoyl]-amino)-3-hydroxy-l-azepanecarboxylate

The title compound was prepared according to the procedure of Example 46c, except that the starting material was Example 47b. MS (ES) 596 (M + H ⁺ ).

d.) Benzyl-4-{[(S)-2-{N-mesyl-N-[(2-naphthyl)-methyl]-amino)-4-methyl-pentanoyl]-amino)-3-oxo-1-azepanecarboxylate

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 47c. H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 596 (M + 3H ⁺ , 100%).

203

Example 48

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinolinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 2-quinolinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 540 (M + H ⁺ ).

b.) W-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 48a.

we plowed 1 . H-NMR (CDCl3) δ (ppm): 1.0 (m, 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 (ES): 538 (M + H ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 538 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 538 (M + H ⁺ , 100%)].

Example 49

Preparation of N-{(S)-3-methyl-1-[(3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-8-quinolinecarboxamide

204

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-8-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that instead of 2-benzofurancarboxylic acid, 8-quinolinecarboxylic acid was used as the starting compound. MS (ES) 540 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-8-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 49a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 538 (M + H ⁺ , 100 %).

Example 50

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-6-quinolinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-6-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 6-quinolinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 540 (M + H ⁺ ).

205

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-6-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 50a. 1H-NMR (CDCl3) δ (ppm): 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 (ES) :

538 (M+H ⁺ , 100%).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 538 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 538 (M + H ⁺ , 100%)].

Example 51

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4-quinolinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 4-quinolinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 540 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-4-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 51a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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) , 6.57.2 (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 (ES): 538 (M + H ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 538 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 538 (M + H ⁺ , 100%)].

Example 52

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-quinolinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 3-quinolinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 540 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl)-carbamoyl]-butyl}-3-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 52a. ¹ H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m,

207

5R) , 2.2 (in, 2H) , 2.7 (m, 1H) , 3.7 (d, 1H) , 4.0 (m, 1H) , 4.7 (m, 2H), 5.0 (m, IE), 7.2 (m, 2H) , 7.5 (m, 1H) , 7.6 (m, 1H) ,

7.7-7.9 (m, 4H), 8.1 (m, IE), 8.5 (m, IE), 8.6 (m, IB), 9.3 (m, IE). MS (ES): 538 (M + E ⁺ , 100 %).

The diastereomeric mixture was separated using BPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 538 (M + E ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 538 (M + E ⁺ , 100%)].

Example 53

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-isoquinolinecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-isoquinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 3-isoquinolinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 540 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3-isoquinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product 1 of Example 53a. E-NMR (CDCl3) δ (ppm): 1.0 (m, 6E), 1.5-2.1 (m,

5E), 2.2 (m, 2H), 2.7 (m, ÍR), 3.7 (d, ÍR), 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, ÍR), 7.0 (m, ÍR), 7.5 (m, ÍR), 7.7 (m, 2H),

208

7.9 (m, 4H), 8.7 (m, 3H), 9.2 (m, 1H). MS (ES) : 538 (M + H ⁺ ,

100%).

Example 54

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1-isoquinolinecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1-isoquinolinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 1-isoquinolinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 540 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1-isoquinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 54a.

Ί was used. H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 538 (M + H ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES) 537 (M ⁺ , 100%)] and a slower eluting diastereomer [MS (ES) 537 (M ⁺ , 100%)].

209

Example 55

Preparation of γ-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinoxalinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 2-quinoxalinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 541 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product 1 of Example 55a. H-NMR (CDCl3) δ (ppm): 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), 7.0-7.2 (m, 2H), 7.5 (m, 1H), 7.7(m,

3H), 8.2 (m, 2H), 8.3 (m, 1H), 8.7 (m, 1H), 9.5 (m, 1H). MS (ES): 539 (M + H ⁺ , 30 %).

Example 56

Preparation of N—{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 28b.

210 was prepared, with the difference that instead of 2-benzofurancarboxylic acid, benzo[b]thiophene-2-carboxylic acid was used as the starting compound. MS (ES) 545 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl)-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 56a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 543 (M + H ⁺ , 60 %).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [ H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.8 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H), 8.7 (m, 1H). MS (ES): 543 (M + H ⁺ , 100 %) ] , and a slower eluting diastereomer [ ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.8 (m,1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H), 8.7 (m, 1H). MS (ES): 543 (M + H ⁺ , 100 %)] was isolated.

Example 57

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl)-1,8-naphthyridine-2-carboxamide

211

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1,8-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure of Example 28b, except that 1,8-naphthyridine-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 541 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl]-carbamoyl]-butyl}-1,8-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 57a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES) :

539 (M+H ⁺ , 100%).

Example 58

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1g-2-indolecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 1H-2-indolecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 528 (M + H ⁺ ).

- 212 -

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-ΙΗ-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product 1 of Example 58a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m,

5H) , 2.2 (m, 2H) , 2.7 (m, 1H) , 3, ? (d, 1H) , 4.0 (m, 1H), 4.7 (m, 2H) , 5, 0 (m, 1H) , 6.8 (m, 1H) , 7.1 (m, 1H) , 7.3 (m, 3H) , 7.4 (m, 1H) , 7, 5 (m, 1H) , 7.6 (m, 1H) , 8.0 (m, 2H) , 8.7 (m,

1H), 9.4 (b, 1H). MS(ES): 526 (M + H ⁺ , 80 %).

Example 59

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 559 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 59a. ^X H-NMR (CDCl3) δ (ppm): 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 (ES): 557 (M + H ⁺ , 70%).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (m, 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 (ES): 557 (M + H ⁺ , 100 %) ] , and a slower eluting diastereomer [MS (ES): 557 (M + H ⁺ , 100 %)] was isolated.

Example 60

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-furancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-bromo-2-furancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 479 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-furancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 60a. H-NMR (CDCl3) δ (ppm): 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) , 6.5 (m, 1H) , 6.7 (m, 1H) , 7.1 (m, 2H),

7.5 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H). MS (ES): 555 (M + H ⁺ , 60 %) The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 555 (M + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES): 555 (M + H ⁺ , 100 %)].

Example 61

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 2-furancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 479 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 61a. H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m,

215

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), 7.2 (m, 3H), 7.5 (m, 2H) ,

8.0 (m, 2H), 8.7 (m, 1H). MS (ES): 477 (M + H ⁺ , 50 %).

Example 62

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-nitro-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[(3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-nitro-2-furancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-nitro-2-furancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 524 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl]-5-nitro-2-furancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 62a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 522 (M + H ⁺ , 80 %).

216

Example 63

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-5-(4-nitrophenyl)-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-5-(4-nitrophenyl)-2-furancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-(4-nitrophenyl)-2-furancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 600 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-5-(4-nitrophenyl)-2-furancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 63a. H-NMR (CDCl ₃ ) δ (ppm): 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), 6.9 (m, 1H), 7.2 (m, 1H), 7.5 (m, 2H),

7.9-8.0 (m, 4H), 8.5 (m, 1H), 8.6 (m, 1H). MS (ES): 598 (M + H ⁺ , 80 %).

217

Example 64

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl)-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 623 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was the product of Example 64a. H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 621 (M + H ⁺ , 80 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 621 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 621 (M + H ⁺ , 100%)].

218

Example 65

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-tetrahydrofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-tetrahydrofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 2-tetrahydrofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 483 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-tetrahydrofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 65a. ^X H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H) , 1.5-2.2 (m, 12H) , 2.7 (m, 1H) , 3.8 (m, 3H) , 4.0 (m, 1H) , 4.5 (m, 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 (ES): 481 (M + H ⁺ , 80 %).

Example 66

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-[(2-phenoxyacetyl)amino]-pentanamide a.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-[(2-phenoxyacetyl)amino]-pentanamide

The title compound was prepared according to the procedure of Example 28b, except that the starting material was

In this case, 2-phenoxyacetic acid was used instead of 2-benzofurancarboxylic acid as compound 219. MS (ES) 519 (M + H ⁺ ).

b.) N- {3-Oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-[(2-phenoxyacetyl)amino]pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 66a. H-NMR (CDCl3) δ (ppm): 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 (ES): 517 (M + H ⁺ , 60 %) -

Example 67

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[2-(4-fluorophenoxy)acetyl]amino}-pentanamide a.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[2-(4-fluorophenoxy)acetyl]amino}-pentanamide

The title compound was prepared according to the procedure of Example 28b, except that 2-(4-fluorophenoxy)acetic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 537 (M + H ⁺ ). b.) N-{3-Oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[2-(4-fluorophenoxy)acetyl]amino}pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 67a.

We used 220. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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 (m, 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 (ES): 535 (M + H ⁺ , 50 %).

Example 68

Preparation of H-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]-3-butyl}-2-benzofurancarboxamide

a.) tert-Butyl-{(S)-1-[{3-hydroxy-1-[(2-pyridyl)-carbonyl]-4-azepanyl}-carbonyl]-3-methyl-butyl}-carbamate

To a solution of 0.25 g of the product of Example 2g in methylene chloride were added 0.09 g of picolinic acid, 0.14 g of 2\7-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.10 g of 1-hydroxybenzotriazole. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 (v/v) methanol/ethyl acetate solvent mixture as eluent. 0.35 g of the title compound was obtained.

b.) N-{3-hydroxy-1-[(2-pyridyl)carbonyl]-4-azepanyl}(S)-2-

-amino-4-methylpentanamide

To a solution of 0.34 g of the product of Example 68a in 6 ml of methanol was added 6 ml of 4 M hydrochloric acid in dioxane. The reaction mixture was stirred until the starting material was completely converted and then concentrated. 0.34 g of the title compound was obtained. MS (ES) 349 (M + H ⁺ ).

221

c.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]-3-butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that the starting material was Example 68b. MS (ES) 493 (M + H ⁺ ).

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]-3-butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 68c. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 491 (M ⁺ , 100 %) -

Example 69

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]-3-butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 68a-d, except that picolinic acid N-oxide was used instead of picolinic acid as in Example 68c. H-NMR (CDCl3) δ (ppm): 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 (ES): 507 (M ⁺ , 20%).

222

Example 70

Preparation of benzyl 4-[{(S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-oxo-1-azepanecarboxylate

The title compound was prepared according to the procedure of Example 92j, except that benzyl 4-[{(Sj-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxy-1-azepanecarboxylate was used instead of 2N-{(S)-1-[{3-hydroxy-6,6-dimethyl-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-3-methylbutyl]-2-benzofurancarboxamide. The residue was purified by HPLC. + 1

First eluting diastereomer: MS (M + H ) : 476.2; H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.40-6.95 (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). Second eluting diastereomer: ¹ H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.00-0.85 (d, 6H); MS (Μ + H ⁺ ) 476.2.

Example 71

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl]-5,6-dimethoxy-2-benzofurancarboxamide

a. ) tert-Butyl-N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-methyl-1H-2-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}carbamate

To a solution of the amine of Example 2g in 5 ml of methylene chloride was added first 92 μΐ (1.14 mmol) of pyridine, then 0.112 g (0.623 mmol) of [(1-methyl-4-imidazolyl)sulfonyl] chloride. The reaction mixture was stirred at room temperature for 16 hours.

223 was stirred. The solution was then washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and the product was purified by silica gel column chromatography using methanol/methylene dichloride as eluent. The title compound was obtained as a white solid (0.172 g, 68% yield). H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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) ⁺ .

b.) N-{3-Hydroxy-1-[(1-methyl-1H-2-imidazolyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide

To a solution of 0.172 g (0.353 mmol) of the product of Example 71a in a minimum amount of methanol was added 10 mL of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 4 h, then concentrated and the residue was azeotroped twice with toluene to give the title compound as an off-white solid. MS (ESI): 388.2 (M + H) ⁺ .

c.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5,6-dimethoxy-2-benzofurancarboxamide

To a solution of 0.137 g (0.353 mmol) of the product of Example 71b, 0.86 g (0.388 mmol) of 5,6-dimethoxy-2-benzofurancarboxylic acid, 2.46 ml (1.77 mmol) of triethylamine and 0.01 g (0.070 mmol) of 1-hydroxybenzotriazole in 5 ml of N,N-dimethylformamide was added 0.074 g (0.388 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride with stirring. The reaction mixture was

The mixture was stirred at room temperature for 224 h, then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate, twice with water, and finally with saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained as a residue was purified by column chromatography on silica gel using methanol/methylene dichloride as eluent. The title compound was obtained as a white solid (0.088 g, 42%). MS (ESI): 592.1 (M + H) ⁺ .

d.) N-{(S)-3-Methyl-l-[{3-oxo-l-[(l-methyl-lH-4-imidazolyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5,6-dimethoxy-2-benz ofurancarboxamide μΐ (0.596 mmol) oxalyl dichloride was cooled to -78 °C, then 106 μΐ (1.49 mmol) dimethyl sulfoxide in methylene dichloride was added dropwise. The mixture was stirred for 15 minutes at -78 °C, then the alcohol in methylene dichloride was slowly added, the mixture was stirred for one hour, then 416 μΐ (2.98 mmol) triethylamine was added. The solution was then warmed to room temperature, then the reaction was stopped by adding water. The aqueous mixture was extracted with methylene chloride, the organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using a methanol/methylene chloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.068 g (78 % yield). ¹ H-NMR (400 MHz, CDCl3) δ (ppm): 6.8-7.6 (m, 14H) , 4 (d, 12H) , 1 (d, 12H) . MS (ESI): 590.1 (M + H) ⁺ .

Example 72

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) Benzyl 4-{[(S)-2-amino-4-methylpentanoyl]amino}-3-hydroxy-1-azepanecarboxylate

To a solution of 3.5 g (7.33 mmol) of the product of Example 2f in 0.5 ml of ethyl acetate was added 12.8 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for one hour, then concentrated, and the residue was azeotroped twice with 20 ml of toluene. The title compound was obtained as a pale yellow oil in an amount of 3.13 g (100% yield). MS (ESI): 378.4 (M + H) ⁺ .

b.) Benzyl 4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-1-azepanecarboxylate

To a solution of 3.13 g (7.57 mmol) of the product of Example 72a, 1.35 g (8.32 mmol) of 2-benzofurancarboxylic acid, 1.17 ml (8.25 mmol) of triethylamine and 0.2 g (1.48 mmol) of 1-hydroxybenzotriazole in 30 ml of N,N-dimethylformamide was added 1.6 g (8.33 mmol) of N-ethyl-N'-[3-(dimethylamino)

226

-propyl]-carbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, and the solution was washed successively with saturated aqueous sodium bicarbonate solution, twice with water, and finally with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column using ethyl acetate/methylene dichloride as eluent. 3.7 g of the title compound was obtained in 93% yield. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.8-7.7 (m, 12H), 5.35 (s, 2H), 1.0 (d, 6H). MS (ESI): 522 (M+H) ⁺ .

c.) N-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 2.6 g (4.9 mmol) of the product of Example 72b in 150 ml of ethyl acetate was added 1.3 g of 10% palladium/carbon catalyst, and the mixture was stirred at room temperature under a hydrogen atmosphere for 64 hours. The reaction mixture was then filtered through a pad of Celite, and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 1.92 g (100% yield). H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.8-7.7 (m, 7H),

1.02 (d, 6H). MS (ESI) 388 (M + H) ⁺ .

d.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

0.100 g (0.25 mmol) of the product of Example 72c and 35 μΐ

- 227 (0.25 mmol) of triethylamine in 2 ml of methylene chloride was added with stirring to a solution of 0.043 g (0.25 mmol) of [(5-methyl-1H-1,2,4-triazol-3-yl)sulfonyl] chloride. The reaction mixture was stirred for 10 min and then washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using ethyl acetate/hexane as eluent. The title compound was obtained as a pale yellow oil in an amount of 0.111 g (84% yield). MS (ESI): 532.73 (M+H) ⁺ .

e.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(5-methyl-1H-1,2,4-triazol-3-yl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-benz of uranium carboxamide

To a stirred solution of 0.108 g (0.206 mmol) of the product of Example 72d in 2 ml of dimethyl sulfoxide was added first 172 μΐ (1.23 mmol) of triethylamine, then 0.116 g (0.718 mmol) of sulfur trioxide/pyridine complex. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, then washed twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.08 g (81 % yield). ^X H-NMR

228 (400 MHz, CDCl 3 ) δ (ppm): 7.1-7.7 (m, 7H), 2.65 (s, 3H), 1.0 (d, 6H). MS (ESI): 552.71 (M + Na) ⁺ .

Example 73

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-3-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-methyl-1H-3-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a stirred solution of 0.100 g (0.25 mmol) of the product of Example 72c and 35 μΐ (0.25 mmol) of triethylamine was added 0.046 g (0.255 mmol) of [(1-methyl-1H-3-imidazolyl)sulfonyl] chloride. The reaction mixture was stirred for 10 min and then washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using ethyl acetate/hexane as the eluent. The title compound was obtained as a pale yellow oil in an amount of 0.113 g (82% yield). ^H-NMR (400 MHz, CDCl 3 ) δ (ppm): 6.9-7.7 (m, 9H), 3.9 (2s, 3H), 1.0 (d, 6H). MS (ESI): 531.8 (M + H) ⁺ .

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-methyl-1H-3-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

229

To a stirred solution of 0.085 g (0.159 mmol) of the product of Example 73a in dimethyl sulfoxide was added first 133 μΐ (0.95 mmol) of triethylamine, followed by 0.08 g (0.5 mmol) of sulfur trioxide/pyridine complex. The reaction mixture was stirred at room temperature for 16 h, then diluted with ethyl acetate and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.072 g (83 % yield). MS (ESI): 529.76 (M + H) ⁺ .

Example 4 Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1H-2-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1H-2-imidazolyl)sulfonyl]-4-azepanyl]carbamoyl]butyl]-2-benzofurancarboxamide

To a stirred solution of 0.100 g (0.25 mmol) of the product of Example 72c and 35 μΐ (0.25 mmol) of triethylamine was added 0.046 g (0.255 mmol) of [(2-imidazolyl)sulfonyl] chloride. The reaction mixture was stirred for 10 minutes and then washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic phase was

230 was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using ethyl acetate/hexane as the eluent. The title compound was obtained as a pale yellow oil and 0.113 g (82 % yield). '''H-NMR (400 MHz, CDCl3) δ (ppm): 7.1-7.7 (m, 9H) , 4.8 (s, 1H) , d, 6H) . MS (ESI): 517.76 (M + H) ⁺ .

b.) N-{(S)-3-Methyl-l-[{3-oxo-l-[(ΙΗ-2-imidazolyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide To a solution of 0.107 g (0.206 mmol) of the product of Example 74a in 2 ml of dimethyl sulfoxide, 172 μΐ (1.23 mmol) of triethylamine and then 0.115 g (0.718 mmol) of sulfur trioxide/pyridine complex were added with stirring. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.09 g (85% yield). MS (ESI): 515.84 (M + H) ⁺ .

Example 75

N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

- 231 -

preparation of a.) tert-Butyl-{(S)-[{3-hydroxy-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]-3-methylbutyl}carbamate

To a solution of 2.50 g (7.29 mmol) of the product of Example 2g in 100 mL of dichloroethane (DCE) was added 4.0 g of P-NMMet and 1.6 g (8.75 mmol) of [(2-thiazolyl)sulfonyl] chloride. The reaction mixture was shaken overnight and the solution was filtered. 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) ⁺ .

b.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.15 g (0.45 mmol) of the product of Example 75b in 20 ml of methylene chloride was added 0.109 g (0.172 mmol) of 2-benzofurancarboxylic acid, 0.106 g (0.762 mmol) of 1-hydroxybenzotriazole and 0.85 g (1 mmol/g) of P-EDC {polymer-supported N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride} in 10 ml of methylene chloride. The reaction mixture was shaken overnight, and then 0.589 g (3.75 mmol/g) of tisamine was added to the solution. The mixture was shaken for a further 2 hours, after which the solution was filtered and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 166.7 mg (70% yield). MS (ESI): 535.3 (M + H) ⁺ .

c.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

166.7 mg (0.313 mmol) of the product of Example 75c in 4 ml of

- 265.5 mg (0.626 mmol) of Dess-Martin reagent was added to a solution of 232 in ethylene dichloride while stirring. The reaction mixture was stirred for 2 hours at room temperature, then 2 ml of 10% by weight aqueous sodium thiosulfate solution and 2 ml of saturated aqueous sodium bicarbonate solution were added simultaneously to the solution. The aqueous mixture was extracted twice with methylene dichloride, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by HPLC [50:50 ethanol/hexane; 20 ml/min; 25 min; WhelkO-1(R,R) 21 χ 250 mm column; UV detection at 280 nm and 305 nm] was used. The first eluting fractions gave 84.8 mg of a white solid in 50.8% yield. MS (ESI): 533.2 (M + H) ⁺ . The second eluting fractions gave 50.1 mg of a white solid in 30.0% yield. MS: 533.2 (M + H) ⁺ .

Example 76 Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) tert-Butyl-{(S) -[{3-hydroxy-l-[(l-methyl-lH-2-imidazolyl)-sulfonyl]-4-azepanyl}-carbamoyl]-3-methyl-butyl}-carbamate To a solution of the amine of Example 2g. prepared in 5 ml of methylene dichloride, 92 μΐ (1.14 mmol) of pyridine was first added, followed by 0.112 g (0.623 mmol) of [(l-methyl-4-imidazolyl)-sulfonyl]

-chloride. The reaction mixture was stirred at room temperature for 16 hours.

The mixture was stirred at room temperature, and the solution was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. The crude product was purified by silica gel column chromatography using methanol/methylene dichloride as eluent to afford the title compound as a white solid (0.172 g, 68% yield). H-NMR (400 MHz, CDCl3) δ (ppm): 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) ⁺ .

b.) N-{3-Hydroxy-1-[(1-methyl-1H-2-imidazolyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide

To a solution of 0.172 g (0.353 mmol) of the product of Example 76a in a minimum amount of methanol was added 10 mL of 4 M hydrochloric acid in dioxane. The reaction mixture was stirred at room temperature for 4 h, then concentrated and the residue was azeotroped twice with toluene to give the title compound as an off-white solid. MS (ESI): 388.2 (M + H) ⁺ .

c.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.2 g (0.471 mmol) of the product of Example 72c, 0.084 g (0.388 mmol) of 2-benzofurancarboxylic acid, 72 μΐ (0.517 mmol) of triethylamine and 0.012 g (0.088 mmol) of 1-hydroxybenzotriazole in 5 ml of N, N-dimethylformamide was added 0.099 g (0.515 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride while stirring. The reaction mixture was stirred for 16 hours.

The mixture was stirred at room temperature for 234 h, then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate, twice with water, and finally with saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.266 g (90% yield). H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.9-8.1 (m, 18H), 3.75 (2s, 6H), 1 (d, 12H). MS (ESI): 531.80 (M+H) ⁺ .

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-m.ethyl-1H-4-imidazolyl)-sulfonyl]-4-azepanyl]-carbamoyl]-butyl]-2-benz ofurancarboxamide

To a stirred solution of 0.226 g (0.426 mmol) of the product of Example 76a in 2 ml of dimethyl sulfoxide was added first 355 μΐ (2.55 mmol) of triethylamine, then 0.238 g (1.48 mmol) of sulfur trioxide/pyridine complex. The reaction mixture was stirred at room temperature for 16 h, then diluted with ethyl acetate and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.168 g (76% yield). H-NMR

235 (400 MHz, CDCl ₃ ) δ (ppm): 7.1-7.7 (m, 18H), 3.7 (2s, 6H), 0.9 (d, 12H). MS (ESI): 529.80 (M + H) ⁺ .

Example 77

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[2-(4-oxymorpholino)ethoxy]-2-benzofurancarboxamide

To a solution of 0.01 g of the product of Example 30b in 2 ml of methylene chloride was added 0.008 g of 3-chloroperbenzoic acid, and the reaction mixture was stirred overnight. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 30:70 volume methanol/methylene chloride solvent mixture as eluent. ¹ H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H) ,

1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 4H), 2.7 (m, 1H), 2.8 (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 (ES): 671 (M ⁺ , 100 %).

Example 78

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) Benzyl 4-[(S)-(2-amino-4-methylpentanoyl)amino]-3-hydroxy-1-azepanecarboxylate

4.0 g of benzyl-4-[{(S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxy-1-azepam according to Example 2f

- To a solution of 236 pancarboxylate in 20 ml methanol was added 20 ml 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. 3.8 g of the title compound was obtained. MS (ES) 378 (M + H ⁺ ). b.) Benzyl-4-{[(S)-2-{[(2-benzofuranyl)-carbonyl]-amino}-4-methyl-pentanoyl]-amino}-3-hydroxy-1-azepanecarboxylate

To a solution of 3.2 g of benzyl 4-[(S)-(2-amino-4-methylpentanoyl)amino]-3-hydroxy-1-azepanecarboxylate from Example 78a in 200 ml of methylene chloride was added 1.48 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 1.05 g of 1-hydroxybenzotriazole, 1.29 ml of triethylamine and 2-benzofurancarboxylic acid. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 2:98 volume methanol/methylene chloride solvent mixture as eluent. 3.78 g of the title compound was obtained. MS (ES) 521 (M + H ⁺ ).

c.) N-{(S)-1-[(3-Hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 1.6 g of benzyl 4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-1-azepanecarboxylate from step 78b in 150 ml of a 1:2 methanol/ethyl acetate solvent mixture was added 10% palladium on carbon. The reaction mixture was stirred under a balloon-pressure hydrogen atmosphere for 2 h, then filtered and the filtrate was concentrated. 1.16 g of the title compound was obtained. MS (ES) 387 (M + H ⁺ ).

237

d.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.3 g of Ν-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 78c in methylene dichloride was added first 0.17 ml of triethylamine and then 0.25 g of [(2-pyridyl)sulfonyl]chloride. The reaction mixture was stirred at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography, using a 5:95 volume methanol/ethyl acetate solvent mixture as eluent. 0.32 g of the title compound was obtained. MS (ES) 528 (M + H ⁺ ).

e.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{{S)-3-methyl-1-[{3-hydroxy-1-[(3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide from Example 78d. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 526 (M ⁺ , 100 %).

.· ··· *··* ί·.

- 238 - .........

Example 79

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.05 g of N-{(S)-3-methyl-1-[{3-hydroxy-1-[(3-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-2-benzofurancarboxamide from Example 78d in methylene chloride was added 0.05 g of 3-chloroperbenzoic acid. The reaction mixture was stirred overnight. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 10:90 volume methanol/methylene chloride solvent mixture as the eluent. 0.03 g of the title compound was obtained. MS (ES) 544 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-3-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide from Example 79a. ^X H-NMR (CDC1 ₃ ) δ (ppm): 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), 4.5 (m, 1H), 4.7 (m, 1H) , 5.0 (m, 1H), 7.2-7.5 (m, 7H), 8.1-8.2 (m, 2H). MS (ES) : 542 (M ⁺ , 50 %).

- 239 -

Example 80

Preparation of N-{(S)-[{1-[(3,4-dichlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-3-quinolinecarboxamide

The title compound was prepared according to the procedure of Examples 75a-d, except that in this case [(3,4-dichlorophenyl)sulfonyl] chloride was used instead of [(2-thiazole)sulfonyl] chloride and 3-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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 N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-hydroxy-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-hydroxy-2-benzofurancarboxamide

To a solution of 0.1 g (0.235 mmol) of the product from step 76b, 0.046 g (0.256 mmol) of 5-hydroxy-2-benzofurancarboxylic acid, 36 μΐ (0.258 mmol) of triethylamine and 0.006 g (0.044 mmol) of 1-hydroxybenzotriazole in 5 ml of N, N-dimethylformamide was added 0.05 g (0.26 mmol) of N-ethyl-N’-[3-(dimethyl- 240 -

-amino)-propyl]-carbodiimide hydrochloride. The reaction mixture was stirred for 16 hours at room temperature, then the solution was diluted with ethyl acetate, then washed successively with saturated aqueous sodium bicarbonate solution, twice with water, and finally with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid and in an amount of 0.129 g (100% yield). H-NMR (400 MHz, CDCl 3 ) δ (ppm): 6.8-8 (m, 16H), 3.6 (2s, 6H), 0.85 (d, 12H). MS (ESI): 547.88 (M + H) ⁺ .

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-methyl-1H-4-imidazolyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-hydroxy-2-benzofurancarboxamide μΐ (0.149 mmol) oxalyl dichloride was cooled to -78 °C, then a solution of 28 μΐ (0.394 mmol) dimethyl sulfoxide in methylene dichloride was added dropwise. The mixture was stirred for 15 minutes at -78 °C, then a solution of the alcohol of Example 81a in methylene dichloride was slowly added, the mixture was stirred for one hour, then 7 μΐ (0.05 mmol) triethylamine was added. The solution was then warmed to room temperature, then the reaction was stopped by adding water. The aqueous mixture was extracted with methylene chloride, the organic phase was separated, saturated aqueous sodium chloride241

-solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product obtained as a residue was purified by chromatography on a silica gel column, using a methanol/methylene dichloride solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 0.021 g (78 % yield). MS (ESI): 545.9 (M + H) ⁺ .

Example 82

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N—{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.10 g of N-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 78c in methylene chloride was added first 0.07 ml of triethylamine, then [(2-pyridyl)sulfonyl]chloride-N-oxide. The reaction mixture was stirred overnight at room temperature, then worked up, and the crude product thus obtained was subjected to column chromatography, using a 10:90 volume methanol/methylene chloride solvent mixture as eluent. MS (ES) 544 (M + H ⁺ ).

b.) N—{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was obtained according to the procedure of Example 11.

242 was prepared in the same way, with the difference that in this case the starting compound was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide according to Example 82a. ^H-NMR (CDCl3) δ (ppm): 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 (ES): 542 (M ⁺ , 20%).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [ ^1H -NMR (CDCl3) δ (ppm): 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 (m, 1H), 4.8 (d, 1H), 5.0 (m, 1H), 7.0-7.5 (m, 9H), 8.1-8.2 (m, 2H). MS (ES): 542 (M ⁺ , 100 %)], and a slower eluting diastereomer [MS (ES): 542 (M + H ⁺ , 100 %)] was isolated.

Example 83

Preparation of 2-{[4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino]-3-oxo-1-azepanyl]sulfonyl}benzoic acid

a.) Methyl 2-{[4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino]-4-methylpentanoyl]amino]-3-hydroxy-1-azepanyl]sulfonyl]benzoate

The title compound was prepared according to the procedure of Examples 75a-c, except that {[2-(methoxycarbonyl)phenyl]sulfonyl} chloride was used instead of [(2-thiazolyl)sulfonyl] chloride. MS

243

4* Ψ (M+H ) = 585.56, Μ + Na = 607.76, 2M + Η = 1170.48.

b.) 2-{[4-{[(S)-2-{[(2-Benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-1-azepanyl]sulfonyl}-benzoic acid

180 mg (0.309 mmol) of methyl 2-{[4—{[(S)-2-{[(2-benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino}-3-hydroxy-l-azepanyl]sulfonyl}benzoate (product of Example 83a) was dissolved in 6 ml of a 5:1 methanol/water solvent mixture, and then 14 mg (0.34 mmol) of lithium hydroxide was added to the solution. The reaction mixture was refluxed for 6 hours with stirring, then the reaction was stopped by adjusting the pH to 2 with 6 M hydrochloric acid. The aqueous mixture was extracted three times with 10 ml of ethyl acetate, the organic solutions were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel using a 1:4:95 (v/v) acetic acid/methanol/methylene dichloride solvent mixture as eluent to afford the title compound as a white solid (48 mg, 27%). M + H ⁺ = 572.2.

c.} 2-{[4—{[(S)-2-{[(2-Benzofuranyl)-carbonyl]-amino}-4-methyl-pentanoyl]-amino}-3-oxo-l-azepanyl]-sulfonyl}-benzoic acid The title compound was prepared according to the procedure of Example 75c, except that instead of N-{(5)-3-methyl-l-[{3-hydroxy-l-[(2-thiazolyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide, 2-{[4—{[(S)-2-{[(2-benzofuranyl)-carboxamide] was used as the starting compound.

244 bonyl]-amino}-4-methyl-pentanoyl]-amino}-3-hydroxy-1-azepanyl]-sulfonyl}-benzoic acid was used. MS (M + H ): 570.2 (M + + Ί

H ). H-NMR (400 MHz, CDCl3 + CD3OD) δ (ppm): 8.05-7.95 (m, 1H), 7.70-7.15 (m, 8H), 5.15-5.00 (m, 1H), 4.95-4.75 (m, 2H), 4.15-4.00 (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-{[(2-benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino}-3-oxo-1-azepanyl]sulfonyl}-benzoic acid

The title compound was prepared according to the procedure of Example 83, except that {[3-(methoxycarbonyl)phenyl]sulfonyl} chloride was used instead of {[2-(methoxycarbonyl)phenyl]sulfonyl} chloride. MS 570.2 (M + H ⁺ ). ¹ H-NMR (400 MHz, CDCl3 + CD3OD) δ (ppm): 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), 5.10-5.05 (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 N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

245

a.) tert-Butyl-{(S)-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbonyl]-3-methylbutyl}carbamate

To a solution of 2.5 g of tert-butyl {(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate from Example 2g in 100 ml of methylene chloride was added saturated aqueous sodium bicarbonate solution, and then freshly prepared [(2-pyridyl)sulfonyl]chloride N-oxide was added to the mixture {the latter reagent was prepared by bubbling chlorine gas into a solution of 2-mercaptopyridine N-oxide in 9 M hydrochloric acid for about 90 minutes, and then removing the excess chlorine in vacuo to obtain [(2-pyridyl)sulfonyl]chloride N-oxide}. The reaction mixture was stirred at room temperature for one hour, then worked up, and the crude product was subjected to column chromatography using a 10:90 (v/v) methanol/methylene dichloride solvent mixture as eluent. 2.0 g of the title compound was obtained. MS (ES) 500 (M + H ⁺ ).

b.) N-{3-Hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}- (S) -2-amino-4-methylpentanamide

To a solution of 2.0 g of tert-butyl {(S)-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbonyl]-3-methylbutyl}carbamate from Example 85a in 20 ml of methanol was added 20 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. 1.8 g of the title compound was obtained as a residue. MS (ES) 400 (M + H ⁺ ).

- 246 -

c.) N—{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

To a solution of 0.25 g of N-{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}- (S)-2-amino-4-methylpentanamide from Example 85b in 12 ml of methylene chloride was added 0.12 ml of triethylamine, 0.11 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.077 g of 1-hydroxybenzotriazole and benzo[b]thiophene-2-carboxylic acid. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 10:90 volume methanol/methylene chloride solvent mixture as the eluent. 0.26 g of the title compound was obtained. MS (ES) 560 (M+H ⁺ ).

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide The title compound was prepared according to the procedure of Example li, with the difference that in this case the starting compound was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide according to Example 85c.

¹ H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 558 (M ⁺ , 100 %).

The diastereomeric mixture was selected using HPLC.

- 247 -

el, resulting in the isolation of a faster eluting diastereomer [MS (ES): 558 (M ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES): 558 (M ⁺ , 100 %)].

Example 86

Preparation of H-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5-bromo-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5-bromo-2-furancarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 574 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-bromo-2-benzofurancarboxamide from Example 86a. H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 570 (M ⁺ , 100 %) .

- 248 The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 572 (M + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES): 572 (M + H ⁺ , 100 %)].

Example 87

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5,6-dimethoxy-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5,6-dimethoxy-2-benzofurancarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 604 (M + H ⁺ ).

b.) N- {(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl]-5,6-dimethoxy-2-benzofurancarboxamide from Example 87a. ¹ H-NMR (CDCl3) δ (ppm): 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

- 249 -

(m, 2H). MS (ES): 602 (M ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 602 (M ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES): 602 (M ⁺ , 100 %)].

Example 88

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1-oxy-2-pyridinecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1-oxy-2-pyridinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that picolinic acid N-oxide was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 505 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-1-oxy-2-pyridinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl]-1-oxy-2-pyridinecarboxamide from Example 88a. H-NMR (CDCl ₃ ) δ (ppm): 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

- 250 1H). MS (ES): 503 (M ⁺ , 100 %).

Example 89

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-pyridyl)sulfonyl]amino}-pentanamide a.) N- {3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-pyridyl)sulfonyl]-amino}-pentanamide

To a solution of 0.25 g of N-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}- (S)-2-amino-4-methylpentanamide from Example 28a in methylene chloride was added 0.27 ml of triethylamine and 0.15 g of [(2-pyridyl)sulfonyl] chloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume methanol/methylene chloride solvent mixture as eluent. 0.09 g of the title compound was obtained. MS (ES) 525 (M + H ⁺ ).

b.) N-{3-Oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-pyridyl)sulfonyl]amino}pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-pyridyl)sulfonyl]amino}pentanamide from Example 89a. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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)

- 251 -

8.6 (m, 2H). MS (ES): 523 (M ⁺ , 100 %) .

Example 90

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-(3-benzylureido)-4-methylpentanamide

a.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-(3-benzylureido)-4-methylpentanamide

To a solution of 0.25 g of V-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide from Example 28a in methylene chloride was added 0.17 ml of triethylamine and 0.088 g of benzyl isocyanate. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 5:95 volume methanol/methylene chloride solvent mixture as the eluent. 0.12 g of the title compound was obtained.

b.) N-{3-Oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}(S)-2-

-amino-4-methyl-pentanamide

The title compound was prepared according to the procedure of Example li, except that the starting compound in this case was N-{3~-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide from Example 90a. H-NMR (CDCl ₃ ) δ (ppm): 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 (ES) :515 (M ⁺ , 60 %) .

- 252 The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 516 (M + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES): 516 (M + H ⁺ , 100 %)].

Example 91

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-(3-phenylureido)-4-methylpentanamide

a.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-

-(3-phenylureido)-4-methylpentanamide

The title compound was prepared according to the procedure of Example 90a, except that phenyl isocyanate was used as the starting compound instead of benzyl isocyanate. MS (ES) 503 (M + H ⁺ ).

b.) N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-(3-phenylureido)-4-methylpentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-(3-phenylureido)-4-methylpentanamide from Example 91a. H-NMR (CDCl3) δ (ppm): 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 (ES): 501 (M ⁺ , 60%).

·< rih

- 253 - **'·

Example 92

Preparation of N-{(S)-3-methyl-1-[{6,6-dimethyl-3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-Allyl-N-(2,2-dimethylpent-4-enylidene)amine

2.8 g (25 mmol) of 2,2-dimethyl-4-pentenal was dissolved in 15 ml of benzene. 2.85 g (50 mmol) of allylamine was added to the solution. A small amount of molecular sieves was added to the reaction mixture to bind the water formed during the reaction. The reaction mixture was stirred overnight at room temperature, then the solvent and excess allylamine were removed using a rotary evaporator. The title compound was obtained as a clear liquid and in an amount of 3.76 g (100 % yield). H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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.) N-Allyl-N-(2,2-dimethylpent-4-enyl)amine

3.76 g (25 mmol) of the product of Example 92a, V-allyl-N-(2,2-dimethylpent-4-enylidene)-amine, was diluted with 5 ml of methanol. The solution was cooled to 0 °C, and then 0.95 g (25 mmol) of sodium [tetrahydridoborate] (1—) reagent was added. The reaction mixture was stirred at room temperature for 5 h, then the methanol was removed by rotary evaporation. The residue was partitioned between ethyl acetate and 20% aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. 2.26 g of the title compound were obtained. MS (M + H ⁺ ): 154.0.

- 254 -

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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.) N-Allyl-N-(2,2-dimethylpent-4-enyl)-2-pyridinesulfonamide To 10 ml of methylene chloride were added 0.43 g (2.8 mmol) of N-allyl-N-(2,2-dimethylpent-4-enyl)amine and 0.57 g (5.6 mmol) of N-methylmorpholine. The resulting solution was placed in an ice bath, and then [(2-pyridyl)sulfonyl]chloride was slowly added. The reaction mixture was stirred at room temperature overnight, then washed with 10% by weight aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. After purification by column chromatography, 0.6 g of a colorless oil was obtained in 73% yield. MS (M + H ⁺ ): 295.2. ¹ H-NMR (400 MHz, CDCl3) δ (ppm): 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).

d.) 3,3-Dimethyl-1-[(2-pyridyl)-sulfonyl]-2,3,4,7-tetrahydro-1H-azepine

0.6 g (2 mmol) of N-allyl-N-(2,2-dimethylpent-4-enyl)-2-pyridinesulfonamide was diluted with 50 ml of methylene chloride. After the solution was carefully deaerated with argon, 0.17 g (0.2 mmol) of Grubbs catalyst was added under an argon atmosphere. The reaction mixture was refluxed for 2 hours, and the solvent was removed by rotary evaporation. The crude product obtained as a residue was purified by column chromatography, using as eluent

255

A 5:95 to 20:80 ethyl acetate/hexane solvent gradient was used. 0.47 g of the title compound was obtained in 87% yield. MS (M + H ⁺ ): 267.0. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.70-8.69 (d, 1H), 7.96-7.88 (m, 2H), 7.49-7.46 (m, 1H), 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-[(2-pyridyl)-sulfonyl]-8-oxa-3-aza-bicyclo[5.1.0]octane

To a solution of 1.2 g (4.5 mmol) of the product of Example 92d in 50 ml of methylene chloride was added first 2.4 g (13.5 mmol) of sodium bicarbonate, then 1.2 g (13.5 mmol) of 3-chloroperbenzoic acid in portions. The reaction mixture was stirred at room temperature for 4 h, then washed with 15% by weight sodium hydroxide solution, saturated aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. 1.0 g of crude product was obtained in 79% yield, which was pure enough to be used in the next reaction without further purification. MS (M + H) ⁺ : 283.0. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.68-8.67 (d, 1H), 8.03-7.87 (m, 2H), 7.49-7.40 (m, 1H), 4.44-3.89 (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-3-hydroxy-1-[(2-pyridyl)-sulfonyl]-azepane

1.2 g (4.3 mmol) of 5,5-dimethyl-3-[(2-pi

256 ridyl)-sulfonyl]-8-oxa-3-azabicyclo[5.1.0]octane was dissolved in a mixture of 7 ml of methanol and 1 ml of water. To the solution were added 0.83 g (13 mmol) of sodium azide and 0.7 g (13 mmol) of ammonium chloride. The reaction mixture was refluxed overnight, and then the methanol was removed. The residue was diluted with ethyl acetate, then washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. After purification by column chromatography, 0.4 g of 4-azido-6,6-dimethyl-3-hydroxy-1-[(2-pyridyl)-sulfonyl]-azepane was obtained in a yield of 29%.

+ 1

MS (M+H): 326.2. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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-i.66 (m, 1H), 1.56-1.52 (d, 1H), 1.07 (s, 3H), 0.99 (s, 3H).

g.) 4-Amino-6,6-dimethyl-3-hydroxy-1-[(2-pyridyl)sulfonyl]azepane

0.4 g (1.23 mmol) of 4-azido-6,6-dimethyl-3-hydroxy-1-[(2-pyridyl)sulfonyl]-azepane from Example 92f was dissolved in 50 ml of tetrahydrofuran and 0.2 ml of water. 0.48 g (1.85 mmol) of triphenylphosphine was added to the solution, and the reaction mixture was stirred overnight at 45 °C. Thin-layer chromatography analysis performed at this time showed that the starting compound was no longer present in the reaction mixture. The tetrahydrofuran was evaporated and the residue was azeotroped twice with toluene. The thick oil thus obtained was dissolved in methanol, and the solution was acidified with a solution of hydrogen chloride in diethyl ether. Diethyl ether was added to the solution,

- The solution became cloudy at 257 °C. The white solid was filtered off to give 0.22 g of the title compound. H-NMR (400 MHz, CD ₃ OD) δ (ppm): 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.) tert-Butyl N -{ (S)-1-[{3-hydroxy-6,6-dimethyl-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-3-methyl-butyl}-carbamate

0.22 g (0.6 mmol) of 4-amino-6,6-dimethyl-3-hydroxy-1-[(2-pyridyl)sulfonyl]-azepane hydrochloride from Example 92g was dissolved in 5 ml of N,N-dimethylformamide. To the resulting solution were added 0.22 g (0.9 mmol) of N-Boc-Leu-OH and 0.34 g (0.9 mmol) of [2-(1H-1-benzotriazolyl)-N,N,N',N'-tetramethyluronium]— —(hexafluorophosphate) (HBTU), followed by 0.24 g (2.4 mmol) of N-methylmorpholine. The reaction mixture was stirred overnight at room temperature, and then the N,N-dimethylformamide was removed under high vacuum. The residue was diluted with ethyl acetate and the solution was washed with water, 10% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. After purification by column chromatography, 0.22 g of the title compound was obtained in 72% yield. MS (M + H ): 512.9. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.68-8.67 (d, 1H), 7.97-7.88 (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 .· ··; :..

- 258 - ......... ’····..·

i.) N-{(S)-3-Methyl-1-[{6,6-dimethyl-3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To 0.22 g (0.43 mmol) of tert-butyl-N-{(S)-1-[{3-hydroxy-6,6-dimethyl-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-3-methylbutyl}carbamate from Example 92h was added 20 ml (80 mmol) of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 2 hours, and the excess hydrogen chloride was removed by rotary evaporation. The resulting white solid was dissolved in 5 ml of N,N-dimethylformamide. To the solution were added 84 mg (0.52 mmol) of 2-benzofurancarboxylic acid, 0.2 g (0.52 mmol) of [2-(lfl-1-benzotriazolyl)-N, N, N', N'-tetramethyluronium]-(hexafluorophosphate) and 0.2 g (2 mmol) of N-methylmorpholine. The reaction mixture was stirred overnight at room temperature, and then the N, N-dimethylformamide was removed. The residue was dissolved in 50 ml of ethyl acetate, and the solution was washed twice with 50 ml of 10% by weight aqueous sodium bicarbonate solution and 50 ml of saturated aqueous sodium chloride solution. The solvent was evaporated to give 0.26 g of crude product. After purification by column chromatography, 0.15 g of the title compound was obtained in 63% yield. MS (M + H ⁺ ): 556.8. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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).

259

j.) N-{(S)-3-Methyl-1-[{6,6-dimethyl-3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 100 mg (0.18 mmol) of N-{(S)-3-methyl-1- [ {6,6-dimethyl-3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide from Example 921 in 2 ml of methylene chloride at room temperature was added 76 mg (0.18 mmol) of Dess-Martin reagent. The reaction mixture was stirred for 2 hours, then 20 ml of methylene chloride was added, and the solution was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. After purification by column chromatography using a 50:50 volume ethyl acetate/hexane solvent mixture, 70 mg of the title compound was obtained in 70% yield. 8.68-8.67 (d, 1H), 7.97-7.93 (m, 2H), 7.69-7.28 (m, 6H), 7.32-6.92 (m, 2H), 5.24 (m, 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 using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 555.2 (M + H ⁺ ) ] and a slower eluting diastereomer [MS (ES): 555.2 (M + H ⁺ )].

Example 93

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

260

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 574 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl]-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-methoxy-2-benzofurancarboxamide from Example 93. H-NMR (CDC1 ₃ ) He (ppm): 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 (ES): 572 (M ⁺ , 30 %).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [ ^1H -NMR ( _CDCl3 ) δ (ppm): 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 (ES): 573 (M + H ⁺ , 100 %)], and a slower eluting diastereomer [MS (ES): 573 (M + H ⁺ , 100 %)] is isolated

- 261 tons.

Example 94

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 85c, except that instead of benzo[b]thiophene-2-carboxylic acid, thieno[3,2-b]thiophene-2-carboxylic acid was used as the starting compound. MS (ES) 566 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[(3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide from Example 94.

H-NMR (CDC1 ₃ ) δ (ppm): 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, 6H), 7.7 (d, 1H), 8.0-8.2 (m, 2H), MS (ES): 564 (M ⁺ , 100%).

The diastereomeric mixture was selected using HPLC.

- 262 el, resulting in a faster eluting diastereomer [ ¹ H-NMR (CDCl ₃ ) δ (ppm): 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), 4.5 (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 (ES): 565 (M + H ⁺ , 100%)], and a slower eluting diastereomer [MS (ES): 565 (M + H ⁺ , 100%)] was isolated.

Example 95

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinoxalinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]-butyl)-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 2-quinoxalinecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 556 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}Ί-2-quinoxalinecarboxamide was used as the starting compound. H-NMR (CDCl ₃ ) δ (ppm):

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),

- 263 - .........’*-··..*

7.4-7.5 (m, 2H), 7.9 (m, 1H), 8.0-8.4 (m, 4H, 9.6 (d, 1H)). MS (ES): 554 (M ⁺ , 100%).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 555 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 555 (M + H , 100%)].

Example 96

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinolinecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]-butyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 2-quinolinecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 555 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl)-carbamoyl]-butyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-quinolinecarboxamide from Example 96a. ^Ή-ΝΜΚ (CDCl ₃ ) δ (ppm): 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), 7.4-8.6 (m, 10H). MS (ES): 553 (M ⁺ , 100%).

264

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 554 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 554 (M + H , 100%)].

Example 97

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl)-3-thiophenecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)-carbamoyl]-butyl)-3-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 3-thiophenecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 510 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was 27-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-thiophenecarboxamide from Example 97a. H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 508 (M ⁺ , 80 %).

'1 ’,·’*···’·.· :λ’ ·♦· ···· Λ. ·_· · ·

- 265 - -

Example 98

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-ΙΗ-5-indolecarboxamide a.) N-{(S) -3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]-carbamoyl]-butyl}-1H-5-indolecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 177-5-indolecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 543 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-ΙΗ-5-indolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1H-5-indolecarboxamide from Example 98a. H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 541 (M ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 542 (M + H ⁺ , 80%)] and a slower eluting diastereomer [MS (ES): 542 (M + H ⁺ , 80%)].

266

Example 99

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[1,3]dioxole-5-carboxamide

a.) N—{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the procedure of Example 85c, except that benzo[b]thiophene-2-carboxylic acid was used as the starting compound instead of benzo[1,3]dioxole-5-carboxylic acid. MS (ES) 548 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl)-benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-benzo[1,3]dioxole-5-carboxamide from Example 99a. 1H-NMR (CDCl3) δ (ppm): 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 (ES): 546 (M ⁺ , 100 %) .

The diastereomer mixture was separated using HPLC, resulting in a faster eluting diastereomer [MS (ES) : 547 (M + H + , 100 %) ] and a slower eluting diastereomer [MS (ES) : 547 (M + H ⁺ , 100 %) ] .

- 267 diastereomers [MS (ES): 547 (M + H ⁺ , 100%)] were isolated.

Example 100

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-furancarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 2-furancarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 494 (M + H ⁺ ).

b.) N—{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example li, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-furancarboxamide from Example 100a. “H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 492 (M ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 493 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 493 (M + H ⁺ , 100%)].

268

Example 101

Preparation of N-{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-thienyl)acetyl]amino}-pentanamide a.) N-{3-Hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-thienyl)acetyl]amino}-pentanamide

The title compound was prepared according to the procedure of Example 85c, except that 2-(2-thienyl)acetic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid.

b. ) N-{3-Oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}(S)-

-4-methyl-2-{[(2-thienyl)-acetyl]-amino}-pentanamide

The title compound was prepared according to the procedure of Example li, except that the starting compound in this case was N-{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(2-thienyl)acetyl]amino}-pentanamide from Example 101a. ^X H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 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 (ES) : 522 (M ⁺ , 20 %).

Example 102

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1H-2-indolecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1H-2-indolecarboxamide

- 269 The title compound was prepared according to the procedure of Example 85c, except that instead of benzo[b]thiophene-2-carboxylic acid, 1-indolecarboxylic acid was used as the starting compound. MS (ES) 543 (M + H ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-ΙΗ-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 102a, except that the starting compound used in this case was 27-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-ΙΗ-2-indolecarboxamide from Example 102a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES): 541 (M ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 542 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 542 (M + H ⁺ , 100%)].

Example 103

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4-fluorobenzamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl]-carbamoyl]-butyl]-4-fluorobenzamide

The title compound was prepared according to the procedure of Example 85c, except that the starting material was

- 270 benzo[b]thiophene-2-carboxylic acid was replaced by 4-fluorobenzoic acid in this case. MS (ES) 522 (M + H ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-4-fluorobenzamide

The title compound was prepared according to the procedure of Example 103a, except that the starting compound used in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4-fluorobenzamide from Example 103a.

^H-NMR (CDCl3) δ (ppm): 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 (ES): 520 (M ⁺ , 100 %) .

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 521 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 521 (M + H ⁺ , 100%)].

Example 104

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that the starting material was

- 271 Instead of benzo[b]thiophene-2-carboxylic acid, 5-(2-morpholinoethoxy)-2-benzofurancarboxylic acid was used as compound. MS (ES) 673 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 104a, except that the starting compound used in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(2-morpholinoethoxy)-2-benzofurancarboxamide from Example 104a. ¹ H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES) : 671 (M ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 672 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 672 (M + H ⁺ , 100%)].

Example 105

Preparation of N-{(<S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-thiophenecarboxamide

a.) N—{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-thiophenecarboxamide

- 272 The title compound was prepared according to the procedure of Example 85c, except that 2-thiophenecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 147 (M + H ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl]-carbamoyl]-butyl]-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 105a, except that the starting compound used in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-2-thiophenecarboxamide from Example 105a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 508 (M ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 509 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 509 (M + H ⁺ , 100%)].

Example 106

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-3-methyl-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide .ί .··. .·\ *·

- 273 - ' ” ~ The title compound was prepared according to the procedure of Example 85c, except that instead of benzo[b]thiophene-2-carboxylic acid, 3-methyl-2-benzofurancarboxylic acid was used as the starting compound. MS (ES) 558 (M + H ⁺ ) .

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example li, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide from Example 106a. 1H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 556 (M ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [ ^1H -NMR ( _CDCl3 ) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.1 (m, 2H), 2.6 (s, 3H), 2.7 (t, 1H), 3.8 (d, 1H). 4.1 (d, 1H), 4.7 (m, 1H), 4.7 (d, 1H), 5.0 (m, 1H), 7.0 (m, 2H), 7.3 (m, 2H), 7.4 (m, 4H), 8.1 (d, 1H), 8.2 (d, 1H). MS (ES): 557 (M + H ⁺ , 100 %)], and a slower eluting diastereomer [MS (ES): 557 (M + H ⁺ , 100 %)] was isolated.

- 274 -

Example 107

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-6-methylnicotinamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]-butyl}-6-methylnicotinamide

The title compound was prepared according to the procedure of Example 85c, except that 6-methylnicotinic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 519 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-6-methylnicotinamide

The title compound was prepared according to the procedure of Example 107a, except that the starting compound used in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-6-methylnicotinamide from Example 107a. H-NMR (CDC1 ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 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, 3H), 8.1-8.2 (m, 3H), 9.0 (m, 1H). MS (ES): 517 (M ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 518 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 518 (M + H ⁺ , 100%)].

♦I. -. .·% ri·. ri* : ,* ... ·..· ·..

_ »*·*··* . _t '*-*** - 275 - .-..

Example 108

Preparation of N- [ {3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-butyl]-(S)-4-methyl-2-{[(2-thienyl)acetyl]-amino}-pentanamide a.) N- [{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-butyl]-(S)-4-methyl-2-{[(2-thienyl)acetyl]-amino]-pentanamide

The title compound was prepared according to the procedure of Example 28b, except that 2-(2-thienyl)acetic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ESI): 508.8 (M + H) ⁺ .

b.) N-[{3-Oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl]-butyl]-(S)-4-methyl-2-{[(2-thienyl)-acetyl]-amino}-pentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-butyl]-(S)-4-methyl-2-{[(2-thienyl)acetyl]amino}-pentanamide from Example 108a. MS (ESI): 506.8 (M + H) ⁺ .

Example 109

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-ΙΗ-6-indolecarboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1H-6-indolecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that instead of 2-benzofurancarboxylic acid, 1H-

- 276 -6-indolecarboxylic acid was used. MS (ES) 527 (Μ + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-ΙΗ-6-indolecarboxamide

The title compound was prepared according to the procedure of Example 109a, except that the starting compound used in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl]-ΙΗ-6-indolecarboxamide from Example 109a. MS (ESI): 525 (M + H) ⁺ .

Example 110

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[1,3]dioxole-5-carboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the procedure of Example 28b, except that piperonyl acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 532.7 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl)-benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the procedure of Example 110a, except that 2N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}benzo[1,3]dioxole-5-carboxamide from Example 110a was used as the starting compound.

277 glazed. MS (ES) 530.8 (Μ + Η).

Example 111

Preparation of Ν-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carboxamide a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carboxamide

The title compound was prepared according to the procedure of Example 85c, except that instead of benzo[b]thiophene-2-carboxylic acid, 3,4-dihydro-2H-1,5-benzodiazepine-7-carboxylic acid was used as the starting compound. MS (ES) 576 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3,4-dihydro-2/1-benzo[b][1,4]dioxepin-7-carboxamide from Example 11a. ^X H-NMR (CDCl ₃ ) δ (ppm): 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), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H). MS (ES): 575 (M + H ⁺ , 100 %).

- 278

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 575 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 575 (M + H , 100%)].

Example 112

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-thiophenecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5-methyl-2-thiophenecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 524 (M + H ⁺ ). b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-thiophenecarboxamide The title compound was prepared according to the procedure of Example li, except that 112a was used as the starting compound. 2N-{(5)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-thiophenecarboxamide according to example was used. ¹ H-NMR (CDCl 3 ) δ (ppm): 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 (ES): 523 (M + H ⁺ , 100 %).

279

The diastereomeric mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 523 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 523 (M + H ⁺ , 100%)].

Example 113

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-4,5-dibromo-2-thiophenecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-4,5-dibromo-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 4,5-dibromo-2-thiophenecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 668 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-4,5-dibromo-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-4,5-dibromo-2-thiophenecarboxamide from Example 113a. H-NMR (CDCl ₃ ) δ (ppm): 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

- 280 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 2H). MS (ES): 665 (M + H ⁺ , 100 %).

Example 114

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3,5-dimethyl-4-isoxazolecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3,5-dimethyl-4-isoxazolecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 3,5-dimethyl-4-isoxazolecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 524 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-3,5-dimethyl-4-isoxazolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{{S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3,5-dimethyl-4-isoxazolecarboxamide from Example 114a. ^Ή-ΝΜΗ (CDCI3) δ (ppm): 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

- 281 - —·:·· .···-··..· (ES): 521 (M ⁺ , 100 %).

Example 115

Preparation of N-{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-2-{[2-(benzyloxy)acetyl]amino}-4-methylpentanamide

a.) tert-Butyl-N-{(S)-1-[{3-hydroxy-l-[(4-methoxyphenyl)-sulfonyl]-4-azepanyl}-carbamoyl]-3-methylbutyl}-carbamate 0.8 g (2.33 mmol) of tert-butyl-{(S)-1-[(3-hydroxy-4-azepanyl)-carbamoyl]-3-methylbutyl}-carbamate from Example 2g was dissolved in 20 ml of 1,2-dichloroethane. 1.26 g (3.7 mmol/g) morpholine methyl polystyrene resin beads (Nova) were added to the solution, and the mixture was shaken for 5 minutes. Subsequently, a solution of 0.48 g (2.33 mmol) of [(4-methoxyphenyl)-sulfonyl] chloride in 10 ml of 1,2-dichloroethane was added to the mixture. The reaction mixture was shaken overnight, then filtered, the filtrate was washed twice with 10 mL of 1,2-dichloroethane and 10 mL of methylene chloride, the organic solutions were combined and concentrated in vacuo. The residue was used in the next reaction without further purification. M + H ⁺ = 514.2.

b.) N— {3-Hydroxy-1-[(4-methoxy-phenyl)-sulfonyl]-4-azepanyl}-

- (S)-2-amino-4-methylpentanamide hydrochloride

0.59 g (1.15 mmol) of tert-butyl N-{(5)-1-[{3-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-4-azepanyl}carbamoyl]-3-methylbutyl}carbamate from Example 115a was dissolved in 8 ml of methylene chloride. 8 ml of 4 M dioxane hydrogen chloride was added to the solution.

- 282 - ..··„··..· rogen chloride solution, after which the reaction mixture was stirred for 4 hours at room temperature and then concentrated in vacuo. The residue was azeotropically distilled twice with 10 ml of toluene and then used in the next reaction without further purification. M + H ⁺ = 413.8.

c.) 27-{1-[(4-Methoxyphenyl)sulfonyl]-3-hydroxy-4-azepanyl}(S)-2-{[2-(benzyloxy)acetyl]amino)-4-methylpentanamide

The crude product N-{3-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide hydrochloride from the reaction mixture of Example 115b was dissolved in 10 mL of methanol, and 1.75 g (2.63 mmol/g, 4.6 mmol) of carbonate polystyrene beads was added to the solution. The reaction mixture was shaken for 2 h, then filtered, and the filtrate was washed with 10 mL of methanol. The organic solutions were combined and concentrated in vacuo. The product was dissolved in 2 mL of 1,2-dichloroethane, and 0.25 g (3.77 mmol/g, 0.91 mmol) of morpholine methyl polystyrene beads (Nova) was added. The reaction mixture was shaken for 5 min, then 0.081 g (0.44 mmol) of [(benzyloxy)acetyl] chloride was added. The reaction mixture was shaken overnight, then 0.1 g (3.66 mmol/g, 0.366 mmol) of trisamine polystyrene beads were added, the reaction mixture was shaken for 1.5 h, then filtered. The filtrate was washed twice with 10 mL of 1,2-dichloroethane and 10 mL of methylene chloride, the organic solutions were combined, then concentrated in vacuo. The crude product obtained as a residue was used in the next reaction without further purification. M + H ⁺ = 562.2.

- 283 d.) N-{1-[(4-Methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl)-(S)-2-{[2-(benzyloxy)acetyl]amino)-4-methylpentanamide

0.24 g (0.44 mmol) of N-{1-[(4-methoxyphenyl)sulfonyl]-3-hydroxy-4-azepanyl}-(S)-2-{[2-(benzyloxy)acetyl]amino}-4-methylpentanamide from Example 115c was dissolved in 5 ml of methylene chloride, followed by the addition of 0.3 g (0.7 mmol) of Dess-Martin periodinane. The reaction mixture was stirred for 30 min, then diluted with 20 ml of water, and the solution was washed with 10 ml of 10% w/w aqueous sodium thiosulfate solution, 10 ml of 10% w/w aqueous sodium bicarbonate solution, 10 ml of water, and 10 ml of saturated aqueous sodium chloride solution. The organic solutions were combined and concentrated in vacuo. The residue was purified by HPLC [50:50 ethanol/hexane; 20 mL/min; 25 min; WhelkO-1(R,R) 21 χ 250 mm column; UV detection at 280 nm and 305 nm]. The first eluting fractions gave 47 mg of a white solid in 43% yield. MS (ESI): 560.4 (M + H). ^X H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). The second eluting diastereomer was then isolated. MS: 560.2 (M + H) ⁺ .

Example 116

N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl)-5-[3-(trifluoromethyl)phenyl]-2

-production of furancarboxamide

- 284 a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5-(trifluoromethyl)-2-furancarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 638 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the procedure of Example 116a, except that the starting compound used in this case was N-{(E)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide from Example 116a. H-NMR (CDCl3) δ (ppm): 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), 4.1 (m, 1H), 4.7 (t, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 9H), 8.1-8.2 (m, 2H). MS (ES): 637 (M + H ⁺ , 100%).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 637 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 637 (M + H ⁺ , 100%)].

- 285 -

Example 117

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5-methyl-2-phenyl-4-oxazolecarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 585 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide from Example 117a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m,

1H), 3.8 (g, 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 (ES) : 584 (M +

H ⁺ , 100%).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereo286 [MS (ES) : 584 (Μ + H ⁺

100%)], and a slower eluting diastereomer [MS (ES): 584 (M + H, 100%)] was isolated.

Example 118

Preparation of N-{(S)-[{1-[(3,4-dimethoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) N-{(S)-£{1-[(3,4-Dimethoxyphenyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.175 g of N-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 78c in methylene dichloride, 0.1 ml of triethylamine was added first, followed by 0.12 g of [(3,4-dimethoxyphenyl)sulfonyl] chloride. The reaction mixture was stirred at room temperature until the starting compound was completely converted. The reaction mixture was then worked up, and the crude product thus obtained was subjected to column chromatography, eluting with a 5:95 volume methanol/ethyl acetate solvent mixture. 0.21 g of the title compound was obtained. MS (ES) 587 (M + H ⁺ ).

b.) N-{(S)-[{1-[(3,4-Dimethoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-[{1-[(3,4-dimethoxyphenyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide from Example 118a. 1H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.5

- 287 (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 (ES): 586 (M + H ⁺ , 100 %).

Example 119

Preparation of N-{(S)-[{!-[(4-bromophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl]-2-benzofurancarboxamide a.) N-{(S)-[(1-[(4-bromophenyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 118a, except that [(4-bromophenyl)sulfonyl] chloride was used as the starting compound instead of [(3,4-dimethoxyphenyl)sulfonyl] chloride. MS (ES) 606 (M ⁺ ).

b.) N-{(S)-[{1-[(4-Bromophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 119a, except that the starting compound in this case was N-{(S)-[{1-[(4-bromophenyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]1 from Example 119a.

-3-methylbutyl}-2-benzofurancarboxamide was used. H-NMR (CDCl ₃ ) δ (ppm): 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), 7.4-8.0 (m, 9H). MS (ES): 604 (M ⁺ , 100 %).

288

Example 120 Preparation of N-(S)-{!-[{!-[(benzo[1,2,5]oxadiazol-4-yl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

a.) N-(S)-{1-[{1-[(Benzo[1,2,5]oxadiazol-4-yl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 118a, except that [(4-benzofuranyl)sulfonyl] chloride was used as the starting compound instead of [(4-dimethoxyphenyl)sulfonyl] chloride. MS (ES) 569 (M ⁺ ).

b.) N- (S) -{1-[{1-[(Benzo[1,2,5]oxadiazol-4-yl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-(S)-{1-[{1-[(benzo[1,2,5]oxadiazol-4-yl)-sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 120a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 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 (ES): 568 (M + H ⁺ , 100 %).

Example 121

N-(S)-{!-[{!-[(3,5-dimethyl-4-oxazolyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

Production of 289

a.) N-(S)-{1-[{1-[(3,5-Dimethyl-4-oxazolyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 118a, except that [(3,5-dimethyl-4-oxazolyl)sulfonyl] chloride was used as the starting compound instead of [(3,4-dimethoxyphenyl)sulfonyl] chloride. MS (ES) 546 (M ⁺ ).

b.) N- (S) -{1-[{1-[(3,5-Dimethyl-4-oxazolyl)-sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methyl-butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-(S)-{1-[{1-[(3,5-dimethyl-4-oxazolyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 121a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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 (ES): 544 (M ⁺ , 100%).

Example 122

Preparation of N~{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

290

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 3-methyl-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 542 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide from Example 122a. ^X H-NMR (CDC1 ₃ ) δ (ppm): 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 (ES): 540 (M ⁺ , 100 %).

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomer [ ^1H -NMR ( _CDCl3 ) δ (ppm): 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, 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 (ES): 541 (M + H ⁺ , 100 %)], and a slower eluting diastereomer [MS (ES): 541 (M + H ⁺ , 100 %)] was isolated.

291

Example 123

Preparation of N—{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 28b, except that instead of 2-benzofurancarboxylic acid, thieno[3,2-b]thiophene-2-carboxylic acid was used as the starting compound. MS (ES) 550 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide from Example 123a. H-NMR (CDCl3) δ (ppm): 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 (ES): 548 (M ⁺ , 100 %) .

The diastereomeric mixture was separated using HPLC, resulting in a faster eluting diastereomeric [H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2

292 (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 (ES): 549 (M + H ⁺ , 100 %)], and a slower eluting diastereomer [MS (ES): 549 (M + H ⁺ , 100 %)] was isolated.

Example 124

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl)-5-tert-butyl-3-methylthieno[3,2-b]thiophene-2-carboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-tert-butyl-3-methylthieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 28b, except that instead of 2-benzofurancarboxylic acid, 5-tert-butyl-3-methylthieno[3,2-b]thiophene-2-carboxylic acid was used as the starting compound. MS (ES) 620 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-tert-butyl-3-methyl-thieno[3, 2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 11, with the difference that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-tert-butyl-3-methyl-thieno[3,2-b]thiophene-2Ί from Example 124a.

-carboxamide was used. H-NMR (CDC1 ₃ ) δ (ppm): 1.0 (m, 6H), 1.45 (s, 9H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.4 (d, 3H), 2.7

- 293 (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 (ES): 618 (M ⁺ , 100 %) .

Example 125

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-methyl-2-phenyl-4-oxazolecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 569 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-5-methyl-2-phenyl-4-oxazolecarboxamide from Example 125a. ¹ H-NMR (CDCl3) δ (ppm): 1.0 (m, 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 (ES): 567 (M ⁺ , 100%).

- 294 The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 568 (M + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ES): 568 (Μ + Η , 100 %)].

Example 126

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-2-phenyl-5-(trifluoromethyl)-4-oxazolecarboxamide

a.) N- {(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-2-phenyl-5-(trifluoromethyl)-4-oxazolecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 2-phenyl-5-(trifluoromethyl)-4-oxazolecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 623 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-2-phenyl-5-(trifluoromethyl)-4-oxazolecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl}-2-phenyl-5-(trifluoromethyl)-4Ί-oxazolecarboxamide from Example 126a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H) , 1.5-2.2 (m, 6H) , 2.2 (m, 2H) , 2.7 (m, 1H) , 3.8, (m,

- 295 1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H), 8.7 (m, 1H). MS (ES): 621 (M ⁺ , 100 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 622 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 622 (M + H , 100%)].

Example 127 Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that mesyl chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 475.2. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M+H ⁺ ): 475.2.

Example 128

Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-1-methyl-1g-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 75.

was prepared as described above, except that in this case mesyl chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-methyl-2-indolecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified using HPLC. First eluting diastereomer: MS (M + H ): 477.2. ^Ή-NMR (400 MHz, CDCl3) δ (ppm): 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, 2H), 1, 95-1, 40 (m, 5H), 1.02-1.00 (d, 6H). Second eluting diastereomer: MS (M+H ⁺ ): 477.2.

Example 129

Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case mesyl chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-[(2-furyl)carbonyl]glycine was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 471.2. 1

H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 471.4.

- 297 -

Example 130 Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case mesyl chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 494.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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), 1.95-1.40 (m, 5H), 0.99 (d, 6H). Second eluting diastereomer: MS (M + H):

494.2.

Example 131

Preparation of N-((S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case mesyl chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 476.2. ¹ H-NMR (400 MHz, CDCl3) δ (ppm): 9.66 (s, 1H), 8.38 (d, 1H), 8.20-8.18 (m, 2H), 7.88 (m, 2H), 7.01 (d, 1H), 5.10 (m, 1H), 4.77 (m, 1H),

- 298 -

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). Second eluting diastereomer: MS (M + H ⁺ ): 476.2.

Example 132

Preparation of γ-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(4-chlorophenyl)-2-furancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5-(4-chlorophenyl)-2-furancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-(4-chlorophenyl)-2-furancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 590 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-(4-chlorophenyl)-2-furancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-carbamoyl]-butyl]-5-(4-chlorophenyl)-2-furancarboxamide from Example 132a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 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,

- 299 -

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 (ES) : 587 (M ⁺ , 80 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ES): 587 (M + H ⁺ , 100%)] and a slower eluting diastereomer [MS (ES): 587 (M + H , 100%)].

Example 133

Preparation of N-(1-mesyl-3-oxo-4-azepanyl)-(S)-{2-[2-(4-methoxyphenyl)acetyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 75, except that in this case mesyl chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-(4-methoxyphenyl)acetic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 468.2. ^X H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.19-7.17 (d, 2H), 6.90-6.88 (d,

3H), 5.83-5.81 (d, 1H), 5.00 (m, 1H), 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, 1H), 2.22-2.10 (m, 2H), 1.99 (m, 1H),

1.62-1.35 (m, 4H), 0.90-0.88 (d, 6H). Second eluting diastereomer: MS (M+H ⁺ ): 468.2.

Example 134

Preparation of N~{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

- 300 -

The title compound was prepared according to the procedure of Example 75, except that [(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ): 562.2. ^X H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.65 (d, 1H), 8.48-8.40 (q, 2H), 8.25-8.10 (q, 2H), 7.91-7.65 (m, 6H). Second eluting diastereomer: MS (M + H ⁺ ): 562.2. X-NMR (400 MHz, CDCl3) δ (ppm): 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).

Example 135

Preparation of N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl)-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-methyl-2-indolecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS 4- I (M + H ): 564.2. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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 (m, 1H) , 4.05 (s, 3H) , 3.76-3.71 (d, 1H) , 2.75 • - 301 - J. .:1. ·· :· (m, 1H), 2.30 (m, 2H), 2.00-1.45 (m, 5H), 1.00 (d, 6H). Second eluting diastereomer: MS (M + H ⁺ ): 564.2.

Example 136

Preparation of N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-[(2-furyl)carbonyl]glycine was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. The first eluting diastereomer:

4--I

MS (M+H): 558.2. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ):

558.2.

Example 137

Preparation of N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case

[(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 581.4. ² H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.15-8.13 (d, 1H), 7.92-7.90 (d, 1H), 7.81-7.74 (m, 2H), 7.42-7.40 (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), 1.02-1.01 (m, 6H). Second eluting diastereomer: MS (M + H ⁺ ):

581.2.

Example 138

Preparation of N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 563.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 563.2.

303

139, example

Preparation of N-{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-{2-[2-(4-methoxyphenyl)acetyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-(4-methoxyphenyl)acetic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ): 555.2. ^X H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.14-8.12 (d, 1H), 7.91-7.89 (d, 1H), 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), 0.91-0.89 (d, 6H). Second eluting diastereomer: MS (M + H ⁺ ): 555.2.

Example 140

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(2-cyanophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 567.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 567.2.

Example 141

Preparation of N~{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(4-methoxyphenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-methyl-2-indolecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 569.2. ¹ H-NMR (400 MHz, CDCl3) δ (ppm): 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). Second eluting diastereomer: MS (M+H ⁺ ): 569.2. 1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.00 (d, 6H).

305

Example 142

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(4-methoxyphenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-[(2-furyl)carbonyl]glycine was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 563.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 563.2.

Example 143

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(4-methoxyphenyl)] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride.

-sulfonyl] chloride, and instead of 2-benzofurancarboxylic acid

- 306 5-methoxy-2-benzofurancarboxylic acid was used. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ) : 586.2. ^H-NMR (400 MHz, CDCl3) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 586.2.

Example 144

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(4-methoxyphenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS + 1 (M + H ) : 568.2. H-NMR (400 MHz, CDCl3) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ):

568.2.

307

Example 145

Preparation of N-{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl)-(S)-{2-[2-(4-methoxyphenyl)acetyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 75, except that [(4-methoxyphenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-(4-methoxyphenyl)acetic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer + 1: MS (M + H): 560.4. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 560.2.

Example 146

Preparation of N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl)-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(4-fluorophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and N-methyl-2-indolecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC.

308. First eluting diastereomer: MS (M + H ⁺ ): 557.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 557.4.

Example 147 Preparation of N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-furancarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(4-fluorophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and ZV-[(2-furyl)carbonyl]glycine was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: ο- ί

MS (M+H): 551.4. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.81 (m,

2H) , 7.48 (s, 1H) , 7.27-7.16 (m, 3H) , 7.05 (m, 1H) , 6.90 (d,

1H) , 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). Second eluting diastereomer: MS (M + H ⁺ ): 551.2.

Example 148

Preparation of N~{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

309

The title compound was prepared according to the procedure of Example 75, except that [(4-fluorophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 574.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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 (m, 1H) , 4.69-4.55 (m, 2H) ,

4.05-4.00 (m, 1H), 3.86 (s, 3H), 3.47-3.43 (d, 1H), 2.49 (m,

1H), 2.24 (m, 2H), 1.90-1.40 (m, 5H), 1.01 (m, 6H). Second eluting diastereomer: MS (M + H ⁺ ): 574.2.

Example 149

Preparation of N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(4-fluorophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 556.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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,

- 310 6H). Second eluting diastereomer: MS (M + H ⁺ ): 556.2.

Example 150

Preparation of N-{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl]-(S)-{2-[2-(4-methoxyphenyl)acetyl]amino]-4-methylpentanamide

The title compound was prepared according to the procedure of Example 75, except that [(4-fluorophenyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 2-(4-methoxyphenyl)acetic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: + 1

MS (M+H): 548.2. H-NMR (400 MHz, CDCl ₃ ) S (ppm): 7.83-7.80 (m, 2H), 7.27-7.17 (m, 4H), 6.90-6.88 (d, 3H), 5.85 (d, 1H), 4.98 (m, 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 (m, 2H) , 1.90-1.30 (m, 5H), 0.90-0.88 (d, 6H). Second eluting diastereomer: MS (M+H ⁺ ): 548.4.

Example 151

Preparation of N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl]-2-benzofurancarboxamide

a.) tert-Butyl-N-{[(S)~1~{[1-[(3-chlorophenyl)sulfonyl]-3-hydroxy-4-azepanyl]carbamoyl]-3-methylbutyl]carbamate

To a solution of 2.50 g (7.29 mmol) of the product of Example 2g in 100 ml of 1,2-dichloroethane was added 4.0 g of P-NMM and 1.85 g (8.75 mmol) of [(3-chlorophenyl)sulfonyl] chloride. The

The reaction mixture was shaken overnight at room temperature and filtered. The filtrate was concentrated to give the title compound as a white solid (3.13 g, 83.3%). MS: 539.78 (M + Na) ⁺ .

b.) N-{1-[(3-Chlorophenyl)sulfonyl]-3-hydroxy-4-azepanyl]-(S)-2-amino-4-methylpentanamide

To a solution of 1.0 g (1.93 mmol) of the product of Example 151a in 10 ml of methanol was added 10 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was allowed to stir at room temperature for 3 h and then concentrated. The residue obtained as a white solid (0.68 g, 1.50 mmol, 78% yield) was dissolved in 37 ml of methanol, 2.85 g (2.63 mmol/g) of P-CO ₃ was added, the reaction mixture was shaken for 2 h, then filtered and the filtrate was concentrated. The title compound was obtained as a white solid (0.59 g, 1.42 mmol, 95% yield). MS: 417.86 (M + H) ⁺ .

c.) N-{(S)-1-[{1-[(3-Chlorophenyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 0.14 g (0.33 mmol) of the product of Example 151b in 20 ml of methylene chloride was added 0.81 g (0.50 mmol) of 2-benzofurancarboxylic acid, 0.77 g (0.57 mmol) of 1-hydroxybenzotriazole and 0.67 g (1 mmol/g) of polymer-supported N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride in 10 ml of methylene chloride. The reaction mixture was shaken overnight at room temperature, then 0.45 g (3.75

312 mmol/g) of tisamine. The reaction mixture was shaken for another 2 hours, then filtered, and the filtrate was concentrated to give the title compound as a white solid (122 mg, 65%). MS (ESI): 562.2 (M + H) ⁺ .

d.) N-{(S)-1-[{1-[(3-Chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 122 mg (0.22 mmol) of the product of Example 151c in 4 ml of methylene chloride was added 185 mg (0.44 mmol) of Dess-Martin reagent. The reaction mixture was stirred at room temperature for 2 hours, then 2 ml of 10% by weight aqueous sodium thiosulfate solution and 2 ml of saturated aqueous sodium bicarbonate solution were simultaneously added to the solution. The aqueous phase was extracted twice with methylene chloride, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by HPLC to give 62.7 mg (51.6% yield) of the faster eluting diastereomer [MS (ESI): 560.2 (M + H ⁺ )] as a white solid and 40.2 mg (33.1% yield) of the slower eluting diastereomer [MS (ESI): 560.2 (M + H ⁺ )].

313

Example 152

Preparation of N~{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that 5-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 151c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 64.4 mg (50.3% yield) [MS (ESI): 590.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 44.4 mg (34.7% yield) [MS (ESI): 590.2 (M + H ⁺ )].

Example 153

Preparation of N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that 7-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 151c. The title compound was isolated by HPLC, which gave a white solid in an amount of 51.1 mg (39.9% yield) with a faster eluting

314 eluting diastereomer [MS (ESI): 590.2 (M + H ⁺ )] and a slower eluting diastereomer [MS (ESI): 590.2 (M + H ⁺ )] were isolated as a white solid in an amount of 36.7 mg (28.7 % yield).

Example 154

Preparation of N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl)-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that 5,6-dimethoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 151c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 51.1 mg (39.9% yield) [MS (ESI): 622.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 36.7 mg (28.7% yield) [MS (ESI): 622.2 (M + H ⁺ )].

Example 155

Preparation of N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that the starting material

- 315 was compound 3-methyl-2-benzofurancarboxylic acid instead of 2-benzofurancarboxylic acid according to Example 151c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 78.6 mg (63.1 % yield) [MS (ESI): 574.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in an amount of 40.7 mg (32.6 % yield) [MS (ESI): 574.2 (M + H ⁺ )].

Example 156

Preparation of N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that benzo[b]thiophene-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 151c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 41.0 mg (32.8% yield) [MS (ESI): 576.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in an amount of 31.0 mg (24.8% yield) [MS (ESI): 576.4 (M + H ⁺ )].

- 316 - FUTURE.

Example 157

Preparation of N-{(S)—1—[{1—[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl)-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that 1-methyl-2-indolecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 151c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 28.5 mg (22.9% yield) [MS (ESI): 573.2 (M + H ⁺ ) ] and a slower eluting diastereomer as a white solid in 28.5 mg (22.9% yield) [MS (ESI): 573.2 (M + H ⁺ )] .

Example 158

Preparation of N-{(S)-1-[{1-[(3-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl)-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 151c-d, except that 2-quinoxalinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 151c. The title compound was separated by HPLC, which gave a white solid (63.1 mg, 50.8%) of a faster eluting diastereomer [MS (ESI): 572.2 (M + H ⁺ ) ] and a white, white,

317 was isolated as a crude material and a slower eluting diastereomer [MS (ESI): 572.2 (M + H ⁺ )] was isolated in an amount of 4 3.2 mg (34.8 % yield).

Example 159

Preparation of N~{ (S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

a.) tert-Butyl-N-{[(S)-1-{[1-[(2-fluorophenyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]-3-methylbutyl}carbamate

To a solution of 1.03 g (3.00 mmol) of the product of Example 2g in 20 ml of 1,2-dichloroethane was added 1.65 g of P-NMM and 0.70 g (3.60 mmol) of [(2-fluorophenyl)sulfonyl] chloride. The reaction mixture was shaken overnight at room temperature and then filtered. The filtrate was concentrated to give the title compound as a white solid (1.13 g, 75.1%). MS: 523.88 (M + Na) ⁺ .

b.) N-{1-[(2-Fluorophenyl)sulfonyl]-3-hydroxy-4-azepanyl}- (S)-2-amino-4-methylpentanamide

To a solution of 1.13 g (2.25 mmol) of the product of Example 159a in 15 ml of methanol was added 15 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue obtained as a white solid (1.11 g, 2.60 mmol, 75% yield) was dissolved in 50 ml of methanol, 5.70 g (2.63 mmol/g) of P-CO3 was added to the solution, the reaction mixture was shaken for 2 hours, then filtered and the filtrate was concentrated. A white solid formed

318 and the title compound was obtained in an amount of 0.868 g (2.16 mmol) (96% yield). MS: 401.96 (M + H) ⁺ .

c.) N-{(S)-1-[{1-[(2-Fluorophenyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 0.11 g (0.26 mmol) of the product of Example 159b in 10 ml of methylene chloride were added 64.7 mg (0.39 mmol) of 2-benzofurancarboxylic acid, 61.1 mg (0.45 mmol) of 1-hydroxybenzotriazole and 0.53 g (1 mmol/g) of polymer-supported N-ethyl-N'- [3-(dimethylamino) -propyl] -carbodiimide hydrochloride in 10 ml of methylene chloride. The reaction mixture was shaken overnight at room temperature, then 0.35 g (3.75 mmol/g) of tisamine was added. The reaction mixture was shaken for another 2 hours, then filtered, and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 103.5 mg (70% yield). MS (ESI): 546.2 (M+H) ⁺ .

d.) N-{(£>)-1-[{1-[(2-Fluorophenyl)sulfonyl]-3-OXO-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 103.5 mg (0.19 mmol) of the product of Example 159c in 4 ml of methylene chloride was added 164.7 mg (0.39 mmol) of Dess-Martin reagent. The reaction mixture was stirred at room temperature for 2 hours, then 2 ml of 10% by weight aqueous sodium thiosulfate solution and 2 ml of saturated aqueous sodium bicarbonate solution were added simultaneously to the solution. The aqueous phase was washed twice with methylene chloride.

319 was extracted, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by HPLC to give 76.2 mg (73.6 % yield) of the faster eluting diastereomer [MS (ESI): 544.2 (M + H ⁺ )] as a white solid and 20.7 mg (20.0 % yield) of the slower eluting diastereomer [MS (ESI): 544.4 (M + H ⁺ )] as a white solid.

Example 160

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that 5-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 48.3 mg (59.2% yield) [MS (ESI): 574.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in an amount of 24.2 mg (29.6% yield) [MS (ESI): 574.2 (M + H ⁺ )].

320

Example 161

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl·)carbamoyl]-3-methylbutyl)-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that 7-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 47.7 mg (58.5% yield) [MS (ESI): 574.2 (M + H ⁺ ) ] and a slower eluting diastereomer as a white solid in an amount of 27.7 mg (33.9% yield) [MS (ESI): 574.2 (M + H ⁺ ) ] .

Example 162

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that 5,6-dimethoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was separated using HPLC, which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 606.4 (M + H ⁺ )] and a slower eluting diastereomer [MS (ESI): 606.4 (M + H )]

Example 163

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that 3-methyl-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 50.5 mg (63.7% yield) [MS (ESI): 558.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in an amount of 20.6 mg [MS (ESI): 558.2 (M + H )].

Example 164

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl]-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that benzo[b]thiophene-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was isolated by HPLC, which gave a white solid and a yield of 52.5

A faster eluting diastereomer [MS (ESI): 560.2 (M + H)] was isolated in 322 mg (65.9 % yield) and a slower eluting diastereomer [MS (ESI): 560.2 (M + ^H )] was isolated as a white solid in 20.7 mg (26.0 % yield).

Example 165

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo~4-azepanyl}carbamoyl]-3-methylbutyl}-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that 1-methyl-2-indolecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 51.4 mg (64.9% yield) [MS (ESI): 557.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 21.0 mg (26.5% yield) [MS (ESI): 557.2 (M + H ⁺ )].

Example 166

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(1-oxy-2-pyridyl)sulfonyl]amino}pentanamide

323 «M»

a.) Ν-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(1-oxy-2-pyridyl)sulfonyl]amino}-pentanamide 0.1 g of the product of Example 28a in 10 ml of methylene chloride and saturated aqueous sodium bicarbonate solution was added dropwise over 3 minutes to 0.9 ml of [(2-pyridyl)sulfonyl] chloride N-oxide. The reaction mixture was stirred at room temperature for 20 minutes, then worked up, and the crude product thus obtained was subjected to column chromatography, which gave 9.2 mg of the title compound. MS (ESI): 541 (M + H) ⁺ .

b.) N-{3-Oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[(1-oxy-2-pyridyl)sulfonyl]amino}-pentanamide The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 166a. MS (ESI): 539 (M + H) ⁺ .

Example 167

Preparation of N-{(S)-1-[{1-[(2-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 159c-d, except that 2-quinoxalinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 159c. The title compound was purified by HPLC to give 49.7 mg (62.9%) of the faster eluting diastereomer [MS (ESI): 556.2 (Μ + Η)] as a white solid and 19.9 mg (25.1%) of the slower eluting diastereomer [MS (ESI): 556.4 (M + H ⁺ )] as a white solid.

Example 168

Preparation of N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 75a-d, except that [(2-thienyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride in Example 75a, and 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid in Step 75c. The crude product was purified by HPLC to give 71 mg (65%) of the faster eluting diastereomer [MS (ESI): 562.2 (M + H)] as a white solid and 21.6 mg (20.0%) of the slower eluting diastereomer [MS (ESI): 562.2 (M + ^H )] as a white solid.

Example 169

Preparation of N~{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl)-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 168.

325 was prepared in the same manner as in the previous experiment, except that 7-methoxy-2-benzofurancarboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The crude product was purified by HPLC to give 88 mg (80%) of the faster eluting diastereomer [MS (ESI): 562.2 (M + H ⁺ )] as a white solid and 18 mg (16%) of the slower eluting diastereomer [MS (ESI): 562.2 (M + H )] as a white solid.

Example 170

Preparation of N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 168, except that 5,6-dimethoxy-2-benzofurancarboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The crude product was purified by HPLC, which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 594.2 (M + H ⁺ )] and a slower eluting diastereomer.

Example 171

N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}~

-carbamoyl]-3-methylbutyl]-5-methyl-2-benzofurancarboxamide preparation

The title compound was prepared according to the procedure of Example 168.

326 was prepared in the same manner as in the previous experiment, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The crude product was purified by HPLC to give 88 mg (83% yield) of the faster eluting diastereomer [MS (ESI): 546.2 (M + H ⁺ )] as a white solid and 16 mg (15% yield) of the slower eluting diastereomer [MS (ESI): 546.2 (M + H )] as a white solid.

Example 172

Preparation of γ-((S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl]-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 168, except that benzo[b]thiophene-2-carboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The crude product was purified by HPLC to give 43.4 mg (41%) of the faster eluting diastereomer [MS (ESI): 548.4 (M + H ⁺ )] as a white solid and 33.4 mg (41%) of the slower eluting diastereomer [MS (ESI): 548.2 (M + H ⁺ )] as a white solid.

- 327 -

Example 173

Preparation of (S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 168, except that 1-methyl-2-indolecarboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The crude product was purified by HPLC to give 35.8 mg (34.0%) of the faster eluting diastereomer [MS (ESI): 545.2 (M + H ⁺ ) ] as a white solid and 45.8 mg (43%) of the slower eluting diastereomer [MS (ESI): 545.2 (M + H ⁺ )] as a white solid.

Example 174

N-{(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}-

-carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide preparation

The title compound was prepared according to the procedure of Example 168, except that 2-quinoxalinecarboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The crude product was purified by HPLC to give 60 mg (56%) of the faster eluting diastereomer [MS (ESI): 544.4 (M + H ⁺ )] as a white solid and 38.7 mg (37%) of the slower eluting diastereomer [MS

328 (ESI): 544.4 (Μ + H ⁺ )] was isolated.

Example 175 Preparation of N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamyl]-3-methylbutyl}-2-benzofurancarboxamide a.) tert-Butyl-N-{[(S)-1-{[1-[(4-chlorophenyl)sulfonyl]-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl)carbamate To a solution of 2.50 g (7.29 mmol) of the product of Example 2g in 100 ml of 1,2-dichloroethane were added 4.0 g of P-NMM and 1.85 g (8.75 mmol) of [(4-chlorophenyl)sulfonyl] chloride. The reaction mixture was shaken overnight at room temperature and then filtered. The filtrate was concentrated to give the title compound as a white solid (3.13 g, 83.3%). MS: 539.78 (M + Na).

b.) N-{1-[(4-Chlorophenyl)sulfonyl]-3-hydroxy-4-azepanyl)-(S)-

- 2 - amino - 4 - me ti 1 -pen tánamí d

To a solution of 1.0 g (1.93 mmol) of the product of Example 175a in 10 ml of methanol was added 10 ml of 4 M hydrochloric acid in dioxane. The reaction mixture was stirred at room temperature for 3 h and then concentrated. The residue obtained as a white solid (0.68 g, 1.50 mmol, 78% yield) was dissolved in 37 ml of methanol, 2.85 g (2.63 mmol/g) of P-CO3 was added, the reaction mixture was shaken for 2 h, then filtered and the filtrate was concentrated. The title compound was obtained as a white solid (0.59 g, 1.42 mmol, 95% yield). MS: 417.86 (M + H) ⁺ .

329

c.) N-{(S)-1-[{1-[(4-Chlorophenyl)sulfonyl]-3-hydroxy-4-

- azepanyl}-carbamoyl]-3-methylbutyl}-2-

-benzofurancarboxamide

To a solution of 0.14 g (0.33 mmol) of the product of Example 175b in 20 ml of methylene chloride was added 0.81 g (0.50 mmol) of 2-benzofurancarboxylic acid, 0.77 g (0.57 mmol) of 1-hydroxybenzotriazole and 0.67 g (1 mmol/g) of polymer-supported N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride in 10 ml of methylene chloride. The reaction mixture was shaken overnight at room temperature, then 0.446 g (3.75 mmol/g) of tisamine was added. The reaction mixture was shaken for another 2 hours, then filtered, and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 122.2 mg (65% yield). MS (ESI): 562.2 (M+H) ⁺ .

d.) N-{(S)-1-[{1-[(4-Chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}-

-carbamoyl]-3-xmethylbutyl}-2-benzofurancarboxamide

To a solution of 122.2 mg (0.217 mmol) of the product of Example 175c in 4 ml of methylene chloride was added 184.8 mg (0.436 mmol) of Dess-Martin reagent. The reaction mixture was stirred at room temperature for 2 hours, then 2 ml of 10% by weight aqueous sodium thiosulfate solution and 2 ml of saturated aqueous sodium bicarbonate solution were simultaneously added to the solution. The aqueous phase was extracted twice with methylene chloride, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated.

330

The residue was purified by HPLC to give 62.7 mg (51.6% yield) of the faster eluting diastereomer [MS (ESI): 560.2 (M + H ⁺ )] as a white solid and 32.7 mg (26.9% yield) of the slower eluting diastereomer [MS (ESI): 560.2 (M + H ⁺ )] as a white solid.

Example 176

Preparation of N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 175c-d, except that 5-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 175c. The title compound was separated by HPLC to give 64.4 mg (50% yield) of the faster eluting diastereomer [MS (ESI): 590.2 (M + H ⁺ )] as a white solid and 32.2 mg (25.2% yield) of the slower eluting diastereomer [MS (ESI): 590.0 (M + H ⁺ )] as a white solid.

Example 177

N~{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl)-7-methoxy-2-benzofurancarboxamide

- 331 - : .* ί..: ⁴ ' *5* «*·» ·♦ ,ι production

The title compound was prepared according to the procedure of Example 175c-d, except that 7-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 175c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 51.1 mg (40% yield) [MS (ESI): 590.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in an amount of 41 mg (32% yield) [MS (ESI): 590.2 (M + H ⁺ )].

Example 178

Preparation of N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 175c-d, except that 5,6-dimethoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 175c. The title compound was separated using HPLC, which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 622.2 (M + H ⁺ )] and a slower eluting diastereomer [MS (ESI): 622.2 (M + H ⁺ )].

- 332 -

Example 179

Preparation of N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 175c-d, except that 3-methyl-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 175c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 78.6 mg (63% yield) [MS (ESI): 574.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 27.6 mg (22% yield) [MS (ESI): 574.2 (M + H ⁺ )].

Example 180

Preparation of N~{(S)-1-[{1-1(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 175c-d, except that benzo[b]thiophene-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 175c. The title compound was isolated by HPLC, which gave a white solid in an amount of 41 mg (33% yield) of a faster eluting compound333

Λ **· ♦· ··· * * 4 · do diastereomer [MS (ESI): 576.2 (M + H )] and a slower eluting diastereomer [MS (ESI): 576.2 (M + H ⁺ ) ] were isolated as a white solid in an amount of 32.6 mg (26 % yield).

Example 181

Preparation of N-{(S)-1-[(1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 175c-d, except that 1-methyl-2-indolecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 175c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in an amount of 28.5 mg (23% yield) [MS (ESI): 57 3.2 (M + H )] and a slower eluting diastereomer as a white solid in an amount of 38.5 mg (31% yield) [MS (ESI): 573.2 (M + H )].

182. Nelda

Preparation of N-{(S)-1-[{1-[(4-chlorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound Ά was prepared according to the procedure of Example 175c—d, except that the starting compound was the 2-benzofurancarboxylic acid of Example 175c.

lyet in this case 2-quinoxalinecarboxylic acid was used. The title compound was separated using HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 63 mg (51 % yield) [MS (ESI): 572.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 44.5 mg (36 % yield) [MS (ESI): 572.2 (M + H ⁺ )].

Example 183

Preparation of K-{(S)-1-[£ 1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

a.) tert-Butyl-N- {[(S)-1-{[1-[(3-methoxyphenyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]-3-methylbutyl}carbamate

To a solution of 1.60 g (4.66 mmol) of the product of Example 2g in 50 ml of 1,2-dichloroethane was added 2.56 g of P-NMM and 1.15 g (5.59 mmol) of [(3-methoxyphenyl)sulfonyl] chloride. The reaction mixture was shaken overnight at room temperature and then 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.) 3?-{1-[(3-Methoxyphenyl)sulfonyl]-3-hydroxy-4-azepanyl}(S)-2-amino-4-methylpentanamide

To a solution of 1.70 g (3.31 mmol) of the product of Example 183a in 22 ml of methanol was added 22 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue obtained as a white solid (1.19 g, 2.64 mmol, 80% yield) was dissolved in 50 ml of methanol, 5.02 g (2.63 mmol/g) of P-CO3 was added to the solution, the reaction mixture was shaken for 2 hours, then filtered and the filtrate was concentrated. The title compound was obtained as a white solid (1.03 g, 2.49 mmol, 96% yield). MS: 413.90 (M + H) ⁺ .

c.) M-{(S)-1-[{1-[(3-Methoxyphenyl)sulfonyl]-3-hydroxy-4-

-azepanyl}-carbamoyl]-3-methylbutyl}-2-

-benzofurancarboxamide

To a solution of 0.11 g (0.26 mmol) of the product of Example 183b in 10 ml of methylene chloride were added 64.69 mg (0.399 mmol) of 2-benzofurancarboxylic acid, 61.1 mg (0.452 mmol) of 1-hydroxybenzotriazole and 0.532 g (1 mmol/g) of polymer-supported N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride in 10 ml of methylene chloride. The reaction mixture was shaken overnight at room temperature, then 0.355 g (3.75 mmol/g) of tisamine was added. The reaction mixture was shaken for another 2 hours, then filtered, and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 103.5 mg (70% yield). MS (ESI): 558.2 (M+H) ⁺ .

d.) N-{(S)-1-[{1-[(3-Methoxyphenyl)sulfonyl]-3-OXO-4-

-azepanyl}-carbamoyl]-3-methylbutyl}-2-

-benzofurancarboxamide

103 mg (0.19 mmol) of the product of Example 183c in 4 ml of methyl

To a solution of 336 ml of ethylene dichloride was added 157 mg (0.37 mol) of Dess-Martin reagent. The reaction mixture was stirred at room temperature for 2 hours, then 2 ml of 10% by weight aqueous sodium thiosulfate solution and 2 ml of saturated aqueous sodium bicarbonate solution were added simultaneously to the solution. The aqueous phase was extracted twice with ethylene dichloride, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by HPLC to give 76.2 mg (73.6% yield) of the faster eluting diastereomer [MS (ESI): 556.2 (M + H)] as a white solid and 24.1 mg (23.3% yield) of the slower eluting diastereomer [MS (ESI): 556.2 (M + ^H )].

Example 184

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl)-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that instead of 2-benzofurancarboxylic acid as in Example 183c, 5-methoxy-2-benzofurancarboxylic acid was used as the starting compound. The title compound was separated using HPLC,

337 which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 586.2 (M + H ⁺ ) ] as a white solid in an amount of 33 mg (31 % yield) and a slower eluting diastereomer [MS (ESI): 586.2 (M + H ⁺ ) ] as a white solid in an amount of 35.2 mg (32 % yield).

Example 185

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that 7-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 183c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 41 mg (38% yield) [MS (ESI): 586.4 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 39.5 mg (36% yield) [MS (ESI): 586.2 (M + H ⁺ )].

338

Example 186

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-4,5-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that 5,6-dimethoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 183c. The title compound was separated using HPLC, which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 618.4 (M + H ⁺ )] and a slower eluting diastereomer.

Example 187

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that 3-methyl-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid of Example 183c. The title compound was separated using HPLC, which resulted in a white solid in an amount of 76 mg (72% yield) of a faster eluting diastereomer [MS (ESI): 570.2 (M + H ⁺ )] and a white solid in an amount of 23.2 mg (22% yield) of the diastereomer [MS (ESI): 570.2 (M + H + )]

A slower eluting diastereomer [MS (ESI): 570.2 (M + H ⁺ )] was isolated (yield 339).

Example 188

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that benzo[b]thiophene-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 183c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 37 mg (35% yield) [MS (ESI): 572.2 (M + H ⁺ ) ] and a slower eluting diastereomer as a white solid in 31 mg (29% yield) [MS (ESI): 572.2 (M + H ⁺ )].

Example 189

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that instead of 2-benzofurancarboxylic acid as in Example 183c, 1-methyl-2-indolecarboxylic acid was used as the starting compound.

- 340. The title compound was separated by HPLC to give a white solid (34 mg, 32% yield) of the faster eluting diastereomer [MS (ESI): 569.2 (M + H ⁺ )] and a white solid (38 mg, 38% yield) of the slower eluting diastereomer [MS (ESI): 569.4 (M + H ⁺ )].

Example 190

Preparation of N-{(S)-1-[{1-[(3-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 183c-d, except that 2-quinoxalinecarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid as in Example 183c. The title compound was separated by HPLC, which resulted in the isolation of a faster eluting diastereomer as a white solid in 71 mg (67% yield) [MS (ESI): 568.2 (M + H ⁺ )] and a slower eluting diastereomer as a white solid in 27 mg (24% yield) [MS (ESI): 568.2 (M + H ⁺ )].

Example 191

(S)-1-[{1-[(2-thienyl)sulfonyl]-3-oxo-4-azepanyl}~

-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide preparation

- 341

The title compound was prepared according to the procedure of Example 168, except that 2-benzofurancarboxylic acid was used instead of 5-methoxy-2-benzofurancarboxylic acid. The title compound was purified by HPLC to give 76 mg (73%) of the faster eluting diastereomer [MS (ESI): 532.2 (M + H ⁺ )] as a white solid and 25 mg (23%) of the slower eluting diastereomer [MS (ESI): 532.2 (M + H ⁺ )] as a white solid.

192, example

Preparation of N-{(S)-3-methyl-1-[{(2,2',4-trideuterio)-3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

To a solution of 0.03 g of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl}-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide from Example 28c in 4.4 ml of a 1:10 volume mixture of D2O/CD3OD was added 0.04 ml of triethylamine. The reaction mixture was refluxed for 2 hours, then concentrated, and the residue was dried in vacuo. The dried residue was redissolved in the same mixture, the solution was refluxed overnight, then concentrated. The residue was purified by column chromatography, eluting with a 5:95 volume mixture of methanol/methylene dichloride. 0.02 g of the title compound was obtained.

- 342 ¹ H-NMR δ (ppm): 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 7.4-8.0 (m, 8H), 8.7 (m, 1H). MS (ES) : 529 (M ⁺ , 45 %).

The diastereomer mixture was separated using HPLC, resulting in the isolation of a faster eluting diastereomer [MS (ESI): 530 (M + H ⁺ , 100 %)] and a slower eluting diastereomer [MS (ESI): 530 (M + H ⁺ , 100 %)].

Example 193

Preparation of N-{(S)-2-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a. ) Benzyl 4-[(tert-butoxycarbonyl)amino]-3-hydroxy-1-azepinecarboxylate

To a stirred solution of 1.04 g (3.92 mmol) of the product of Example 2e in tetrahydrofuran was added 0.864 g of di(tert-butyl)dicarbonate. The reaction mixture was stirred at room temperature for 30 min, then diluted with diethyl ether and extracted with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow oil (0.963 g, 2.64 mmol, 67% yield). MS (ESI): 365.03 (M + H) ⁺ .

b.) tert-Butyl-N-(3-hydroxy-4-azepanyl)-carbamate

343

To a solution of 0.963 g (2.64 mmol) of the product of Example 193a in 16 mL of ethyl acetate was added 500 mg of 10% palladium on carbon. The reaction mixture was stirred at room temperature for 48 h, then filtered through Celite, and the filtrate was concentrated. The title compound was obtained as a residue (0.529 g, 2.29 mmol, 87% yield). MS (ESI): 231.92 (M + H) ⁺ .

c.) tert-Butyl-N-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamate

To a solution of 0.53 g (2.29 mmol) of the product of Example 193b in 20 mL of methylene chloride was added 232 mg of triethylamine and 410 mg (2.32 mmol) of [(2-pyridyl)sulfonyl] chloride. The reaction mixture was stirred at room temperature for 30 min and then washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a solid (0.58 g, 1.57 mmol, 68%). MS (ESI): 372.95 (M + H) ⁺ .

d. ) 4-Thinino-3-hydroxy-1-[(2-pyridyl)sulfonyl]azepane

To a solution of 0.583 g (1.57 mmol) of the product of Example 193c in 0.5 ml of ethyl acetate was added 3.9 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 30 min and then concentrated. The white solid obtained as a residue was treated with sodium hydroxide and extracted with ethyl acetate. The

344 The organic phase was dried, filtered and the filtrate was concentrated to give a residue of 0.35 g (1.28 mmol) of yellow solid in 81% yield. MS (ESI): 272.93 (M + H) ⁺ .

e.) tert-Butyl-N-{(S)-1-[{3-hydroxy-1-[(2-pyridyl)-sulfonyl]-4-azepanyl}-carbamoyl]-2-methyl-butyl}-carbamate mg (0.070 mmol) To a solution of the product of Example 193d in methylene dichloride was added 24.5 mg (0.10 mmol) of N-(tert-butoxycarbonyl)-isoleucine, 16.1 mg (0.12 mmol) of 1-hydroxybenzotriazole and 140 mg (0.14 mmol) of polymer-supported N-ethyl-Δ7'-[3-(dimethylamino)-propyl]-carbodiimide hydrochloride (P-EDC) in methylene dichloride. The reaction mixture was shaken overnight at room temperature, then PS-Trisamine was added. The mixture was shaken for another 2 hours, then filtered and the filtrate was concentrated to give the title compound as a solid. MS (ESI): 484.97 (M + H) ⁺ .

f.) N~ {3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl]-(S)-2-amino-3-methyl-pentanamide mg (0.07 mmol) To a solution of the product of Example 193e in 0.50 ml of methylene chloride was added 0.165 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The white solid obtained as a residue was azeotropically distilled with toluene, and then 0.35 mmol) of MP-carbonate in methanol was added. The mixture was shaken for 4 hours, then filtered, and the filtrate was concentrated. The title compound was obtained as a solid. MS (ESI): 384.9 (M +

345

H) ⁺ .

g.) N~{(S)-2-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)-sulfonyl]-4-azepanyl)-carbamoyl]-butyl)-2-benzofurancarboxamide mg (0.070 mmol) To a solution of the product of Example 193f. in methylene dichloride was added 17.0 mg (0.106 mmol) of 2-benzofurancarboxylic acid, 16.1 mg (0.12 mmol) of 1-hydroxybenzotriazole and 140 mg (0.14 mmol) of polymer-supported N-ethyl-N'-[3-(dimethylamino)-propyl]-carbodiimide hydrochloride (P-EDC) in methylene dichloride. The reaction mixture was shaken overnight at room temperature, then PS-Trisamine was added. The mixture was shaken for another 2 hours, then filtered and the filtrate was concentrated to give the title compound as a solid. MS (ESI): 528.9 (M + H) ⁺ .

g.) N-{(S)-2-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide mg (0.07 mol) of the product of Example 193g. To a solution of 0.5 ml of methylene chloride was added 45 mg (0.105 mol) of Dess-Martin reagent. The reaction mixture was stirred at room temperature for 30 minutes, then 0.50 ml of 10% by weight aqueous sodium thiosulfate solution and 0.50 ml of saturated aqueous sodium bicarbonate solution were added simultaneously to the solution. The aqueous phase was extracted twice with methylene chloride, the organic solutions were combined, dried, filtered, and the filtrate was concentrated. The residue was purified by HPLC to give the faster eluting diastereomer of the title compound as a solid (7 mg) [MS (ESI): 526.91 (M +

346

H ⁺ ) ] and the slower eluting diastereomer of the title compound was obtained as a solid and in an amount of 7 mg [MS (ESI): 526.91 (M + H ⁺ ) ] .

Example 194

Preparation of N-{(S)-1-[(3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]propyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)-alpha-aminobutyric acid was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (5 mg) [MS (ESI): 543.8 -J(M + H)], and the slower eluting diastereomer of the title compound was obtained as a solid (5 mg) [MS (ESI): 543.8 (M + H ⁺ )].

Example 195

Preparation of N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that N-(tert-butoxycarbonyl)cyclohexylalanine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (4.5 mg) [MS (ESI): 566.87 (M + H ⁺ )], and the faster eluting diastereomer of the title compound was isolated as a solid (4.5 mg).

The slower eluting diastereomer of the title compound was obtained in 347% [MS (ESI): 566.87 (M + H ⁺ )].

Example 196 Preparation of N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-2-benzofurancarboxamide

The title compound Ά was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)alanine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (5.5 mg) and the slower eluting diastereomer of the title compound was obtained as a solid (5 mg).

Example 197

Preparation of N~{IS)-3-mesyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]propyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)-L-methionine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (3 mg) [MS (ESI): 560.7 (M + H ⁺ )], and the slower eluting diastereomer of the title compound was obtained as a solid (3 mg) [MS (ESI):

- 348,560.7 (M + H ⁺ ) ] .

Example 198

Preparation of Ν-{(S)-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]methyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that N-(tert-butoxycarbonyl)glycine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (3 mg) [MS (ESI): 470.81 (M + H ⁺ ) ] and the slower eluting diastereomer of the title compound was obtained as a solid (3 mg) [MS (ESI): 470.81 (M + H ⁺ )].

Example 199

Preparation of N~{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]pentyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)-norleucine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (4 mg) [MS (ESI): 526.85 (M + H)] and the slower eluting diastereomer of the title compound was obtained as a solid (5 mg) [MS (ESI): 526.85 (M + ^H )].

349

Example 200

Preparation of N-{(S)-1-[(3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)-norvaline was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (7.5 mg) [MS (ESI): 512.8 (M + H ⁺ )] and the slower eluting diastereomer of the title compound was obtained as a solid (3.5 mg) [MS (ESI): 512.8 (M + H ⁺ )].

Example 201

Preparation of N-{(S)-2-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]propyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 193e-h, except that N-(tert-butoxycarbonyl)valine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (6 mg ₎ [MS (ESI): 512.8 (M + H ⁺ )] and the slower eluting diastereomer of the title compound was isolated as a solid (4.5 mg) [MS (ESI): 512.8 (M + H ⁺ )].

350

J..:.

Example 202

Preparation of N—{(S)-2-hydroxy-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]propyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that N-(tert-butoxycarbonyl)-L-threonine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (3 mg) and the slower eluting diastereomer of the title compound was also obtained (3 mg).

Example 203

Preparation of N~{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]-2-phenylethyl)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that N-(tert-butoxycarbonyl)phenylalanine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (5 mg) [MS (ESI): 560.8 (M + H ⁺ )], and the slower eluting diastereomer of the title compound was obtained as a solid (5 mg) [MS (ESI): 560.8 (M + H ⁺ )].

- 351 - J..:'. ^: '.C

Example 204

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-1-[(2-benzofuranyl)carbonyl]-2-pyrrolidinecarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that N-(tert-butoxycarbonyl)-L-proline was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (4 mg) and the slower eluting diastereomer of the title compound was obtained as a solid (5 mg).

Example 205

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-OXO-4-azepanyl}carbamoyl]-3-methylbutyl)-3,4-dimethoxybenzamide

The title compound was prepared according to the procedure of Example 115, except that (3,4-dimethoxybenzoyl) chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 576.4 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS 576.4 (M + H ⁺ ).

352

Example 206

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 115, except that [(benzyloxy)acetyl] chloride was replaced by [(2-thienyl)carbonyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 572.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl·}-benzo[1,3]dioxole-4-carboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(4-methoxyphenyl)sulfonyl] chloride was replaced by [(4-fluorophenyl)sulfonyl] chloride and [3,4-(methylenedioxy)benzoyl] chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 548.2 (M + 4- 1

H ). h-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.85-7.78 (m, 2H), 7.38353

-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 N-{1~[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-2-{[2-(benzyloxy)acetyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 115, except that [(4-fluorophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 548.2 (M + H ). H-NMR (400 MHz, CDCl ₃ + CD 3 OD) δ (ppm): 7.88-7.80 (m, 2H), 7.45-7.30 (m, 5H), 7.30-7.20 (m, 2H), 4.00 (s, 2H), 2.60-2.48 (m, 1H), 0.96 (t, 6H). Second diastereomer eluting with thickener: MS 548.2 (M + H).

Example 209

Preparation of N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(4-fluorophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride, and [(benzo[b]thiophen-2-yl)carbonyl] chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC.

.*· ···. »* ··

- 354. First eluting diastereomer: MS 560.2 (M + H ⁺ ) . ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 H-{(S)-1-[(1-benzoyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

a.) N-{(S)-1-[(1-Benzoyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 0.2 g of N-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 78c in methylene dichloride was added 0.12 g of benzoic acid, 0.07 g of 1-hydroxybenzotriazole and 0.99 g of N-ethyl-Ar ^f -[3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography, using a 5:95 volume methanol/methylene dichloride solvent mixture as the eluent. 0.2 g of the title compound was obtained. ¹ H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.2 (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 (ES): 492 (M + H ⁺ , 100 %).

b.) N- {(S)-1-[(1-Benzoyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was

- 355 In this case, the compound used was N-{(S)-1-[(1-benzoyl-3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide from Example 210a. H-NMR (CDCl3) δ (ppm): 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 (ES): 490 (M + H ⁺ , 100%).

Example 211

Preparation of N-{1-[(2-pyridyl)sulfonyl]-3-oxo-4-azepanyl]-(S)-2-{[(8-quinolyl)sulfonyl]amino]-4-methylpentanamide a.) N-{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl]-(S)-2-{[(8-quinolyl)sulfonyl]amino]-4-methylpentanamide

The title compound was prepared according to the procedure of Example 89a, except that [(8-quinolyl)sulfonyl] chloride was used instead of [(2-pyridyl)sulfonyl] chloride. MS (ES) 576 (M + H ⁺ ).

b.) N-{1-[(2-Pyridyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-2-{[(8-quinolyl)sulfonyl]amino]-4-methylpentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl]-(S)-2-{[(8-quinolyl)sulfonyl]amino}-4-methylpentanamide from Example 211a. ^H-NMR (CDCl3) δ (ppm): 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 (ES): 674 (M + H ⁺ , 100 %).

- 356 -

Example 212

Preparation of (2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-2-{[(2-naphthyl)sulfonyl]amino}-4-methylpentanamide a.) N-{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl)-(S)-2-{[(2-naphthyl)sulfonyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 89a, except that [(2-naphthyl)sulfonyl] chloride was used instead of [(2-pyridyl)sulfonyl] chloride. MS (ES) 575 (M + H ⁺ ).

b.) N-{1-[(2-Pyridyl)sulfonyl]-3-oxo-4-azepanyl}-(S)-2-{[(2-naphthyl)sulfonyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}-(S)-2-{[(2-naphthyl)sulfonyl]amino}-4-methylpentanamide from Example 212a. ^H-NMR (CDC1 ₃ ) δ (ppm): 0.5-0.8 (m, 6H), 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 (ES): 673 (M + H ⁺ , 100 %).

Example 213

Preparation of N-{(S)-1-[(1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(4-fluoro]] was substituted for [(4-methoxyphenyl)sulfonyl] chloride.

357

-phenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was replaced by [(2-benzofuranyl)carbonyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 544.2 (M + H ). ''H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.79-7.77 (m, 2H) , 7.61 (d,

1H) , 7.46-7.38 30 (m, 3H) , 7.25-7.06 (m, 5H) , 2.43 (t, 1H) ,

0.95 (d, 6H). Second eluting diastereomer: MS 544.2 (M+H ⁺ ).

Example 214

Preparation of N-{(S)-1-({1-((4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-3,4-dimethoxybenzamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(4-methoxyphenyl)sulfonyl] chloride was replaced by [(4-fluorophenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was replaced by (3,4-dimethoxybenzoyl) chloride. The crude product obtained as a residue was purified by HPLC. First eluted diastereomer: MS 564.2 (M + H ). H-NMR (500 MHz, CDCl3) δ (ppm): 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

N-{(S)—1-((1-((4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}

-carbamoyl]-3-methylbutyl}cyclohexanecarboxamide preparation

358

The title compound was prepared according to the procedure of Example 115, except that in this case [(4-methoxyphenyl)sulfonyl] chloride was replaced by [(4-fluorophenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was replaced by (cyclohexylcarbonyl) chloride. The crude product obtained as a residue was purified by HPLC+ 1 needles. First eluting diastereomer: MS 510.4 (M + H). H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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 N-(1-mesyl-3-oxo-4-azepanyl)-(S)-2-{[2-(benzyloxy)acetyl]amino)-4-methylpentanamide

The title compound was prepared according to the procedure of Example 115, except that mesyl chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 ⁺ ).

359

Example 217 Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case mesyl chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(benzo[b]thiophen-2-yl)carbonyl] chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 480.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case mesyl chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and (piperonylcarbonyl) chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified using HPLC. First eluting diastereomer: MS 468.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl3) δ (ppm): 7.31-7.24 (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 ⁺ ).

- 360 -

Example 219 Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbufyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case mesyl chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(4-methoxyphenyl)sulfonyl] chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 464.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl3) δ (ppm): 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 Preparation of N-{(S)-1-[(1-mesyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-3,4-dimethoxybenzamide

The title compound was prepared according to the procedure of Example 115, except that in this case mesyl chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and (3,4-dimethoxybenzoyl) chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified using HPLC. First eluting diastereomer: MS 484.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl3) δ (ppm): 6.94-6.88 (m, 3H), 6.58-6.55 (m, 2H), 3.80 (s, 6H), 2.89 (s, 3H), 0.95 (d, 6H). Second eluting diastereomer: MS 484.2 (M + H ⁺ ).

361

Example 221 Preparation of N-{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}-(£)-2-{[2-(benzyloxy)acetyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 115, except that [(2-cyanophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M + H ⁺ ). ^X H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-4-mesylbenzamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(2-cyanophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was used instead of (4-mesylbenzoyl) chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 589.2 (M + H ⁺ ). ^X H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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,

362

6H). Second eluting diastereomer: MS 589.2 (M + H ⁺ ).

Example 223 Preparation of N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl)benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(2-cyanophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride, and [(benzo[b]thiophen-2-yl)carbonyl] chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 567.2 (M + H ). -''H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl)benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(2-cyanophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was used instead of (piperonylcarbonyl) chloride. The crude product obtained as a residue was purified by HPLC.

363 needles. First eluting diastereomer: MS 555.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 ⁺ ).

Example 225 Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{4-oxo-4-[(4-phenoxyphenyl)butyryl]amino}pentanamide

The title compound was prepared according to the procedure of Example 75, except that [(2-pyridyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 4-phenoxybenzoic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 635.4. ¹ H-NMR (400 MHz, CDCl3) δ (ppm): 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), 2.20-1.40 (m, 6H). Second eluting diastereomer: MS 4-Ί (M+H): 635.4. H-NMR (400 MHz, _CDCl3 ) δ (ppm): 0.96-0.92 (m, 6H).

Example 226

Preparation of N-{(S)-1-[{1-[(2-cyanophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-3,4-dimethoxybenzamide

The title compound was prepared according to the procedure of Example 115.

364 was prepared in the same way, except that in this case [(2-cyanophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was used instead of (3,4-dimethoxybenzoyl) chloride. The crude product obtained as a residue was purified using HPLC. First eluting diastereomer: MS 571.4 (M + H ⁺ ). 1 H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 ⁺ ).

Example 227

Preparation of N-{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}cyclohexanecarboxamide

The title compound was prepared according to the procedure of Example 115, except that (cyclohexylcarbonyl) chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 522.4 (M + H). H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 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 ⁺ ).

365

Example 228

Preparation of N~{(S)-1-[{1-[(4-methoxyphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutoxyl}-4-mesylbenzamide

The title compound was prepared according to the procedure of Example 115, except that (4-mesylbenzoyl) chloride was used instead of [(benzyloxy)acetyl] chloride. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS 594.2 (M + H ⁺ ). ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.96 (s, 4H), 7.69 (d, 2H), 7.25 (d, 1H), 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 N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-4-mesylbenzamide

The title compound was prepared according to the procedure of Example 115, except that in this case [(4-fluorophenyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was used instead of (4-mesylbenzoyl) chloride. The crude product obtained as a residue was purified using HPLC. First eluting diastereomer: MS 582.2 (M + H ⁺ ). 1H-NMR (500 MHz, CDCl3) δ (ppm): 7.94 (s, 4H), 7.80-7.77 (m, 2H), 7.25-7.19 (m, 3H), 7.00 (d, 1H), 3.04 (s, 3H), 0.96 (d, 6H). Second eluting diastereomer: MS 582.2 (M + H ⁺ ).

366

Example 230

Preparation of benzyl N-[{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}carbamoyl]carbamate

The title compound was prepared according to the procedure of Example 75, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of (phenylsulfonyl) chloride and N-[(benzyloxy)carbonyl]glycine was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ) : 574.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M + H ⁺ ): 574.2.

Example 231

N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}(S)-2-{5-

Preparation of -[(4-methoxyphenyl)pentanoyl]amino}-4-methylpentanamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of (phenylsulfonyl) chloride and 5-(4-methoxyphenyl)pentanoic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ) : 573.4. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.59 (d, 1H) ,

- 367 - .:.. ..· ·..· ·..·

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), 2.13-2.10 (m, 3H), 1.75-1.45 (m,

10H), 0.96-0.95 (m, 6H). Second eluting diastereomer:

MS (M+H ⁺ ): 573.4.

Example 232

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-[2-{[3-(benzyloxy)-4-methoxyphenyl]acetyl}amino]-4-methylpentanamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of (phenylsulfonyl) chloride and 2-[3-(benzyloxy)-4-methoxyphenyl]acetic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 637.4. ² H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.69 (d, 1H), 7.98-7.91 (m, 2H), 7.53-7.30 (m, 6H). Second eluting diastereomer + 1: MS (M + H ): 637.4. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.89-6.82 (m, 4H), 5.82 (m, 1H), 5.14-5.07 (m, 3H), 4.78-4.73 (d, 1H), 4.43 (m, 1H), 4.09 (m, 1H), 3.89 (s, 3H), 3.82 (d, 1H), 3.49 (s, 2H), 2.69 (m, 1H), 2.14 (m, 2H), 1.82-1.40 (m, 5H), 0.89 (d, 6H).

368

Example 233

Preparation of N-{(S)-3-methyl-1-[{!-[(2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-5,6-difluoro-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-5,6-difluoro-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5,6-difluoro-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 564 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-5,6-difluoro-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example li, except that the starting material was Example 233a. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ) : 562. Second eluting diastereomer: MS (M + H ⁺ ) : 562.

Example 234

Preparation of ff-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-[(5-oxohexanoyl)amino]pentanamide

The title compound was prepared according to the procedure of Example 115.

369 was prepared in the same way, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of [(4-methoxyphenyl)sulfonyl] chloride and [(benzyloxy)acetyl] chloride was used instead of (5-oxohexanoyl) chloride. The crude product obtained as a residue was purified using HPLC. First eluting diastereomer: MS 495.4 (M + H ⁺ ). Second eluting

Diastereomer: MS 495.4 (M + H).

Example 235

N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-

Preparation of -4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) [(6-Methyl-2-pyridyl)sulfonyl] chloride

The title compound was prepared in a similar manner as described in Example 85a for the preparation of [(2-pyridyl)sulfonyl]chloride N-oxide.

b. ) tert-Butyl-N-{(S)-1-[{3-hydroxy-1-[(6-methyl-2-pyridyl)-sulfonyl]-4-azepanyl]-carbamoyl]-3-methyl-butyl]-carbamate

To a solution of 1.0 g of tert-butyl {(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate from Example 2g in 20 ml of methylene chloride was added 50 ml of saturated aqueous sodium bicarbonate solution. To the resulting mixture was added 6.44 ml of a 0.13 g/ml [(6-methyl-2-pyridyl)sulfonyl] chloride solution prepared in 9 M hydrochloric acid. The reaction mixture was allowed to stir until the starting compound was completely converted. The reaction mixture was then worked up, and the crude product thus obtained was collected in a dark

370 was subjected to flash chromatography using a 5:95 volume methanol/methylene dichloride solvent mixture as eluent. 1.2 g of the title compound was obtained.

c.) N-{3-Hydroxy-1-[(6-methyl-2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide

To a solution of 1.2 g of tert-butyl-N-{(S)-1-[[3-hydroxy-1-[(6-methyl-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-3-methylbutyl}carbamate from Example 235b in 20 ml of methanol was added 20 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then concentrated to give 1 g of the title compound.

d.) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that the starting compound in this case was N-{3-hydroxy-1-[(6-methyl-2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide from Example 235c. MS (ES) 542 (M + H ⁺ ).

e.) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example li, with the difference that the starting compound in this case was N-{(S)-3} from Example 235d.

-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4371

-azepanyl}-carbamoyl]-butyl·}-2-benzofurancarboxamide was used. ^H-NMR (CDCl3) δ (ppm): 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, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 8H). MS (ES): 540 (M ⁺ , 100 %) .

Example 236

Preparation of N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[(1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-methoxybenzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid, and N-{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}(S)-2-amino-4-methylpentanamide was used instead of N-{3-hydroxy-1-[(6-methyl-2-pyridyl)sulfonyl]-4-azepanyl}(S)-2-amino-4-methylpentanamide was used instead of N-{3-hydroxy-1-[(6-methyl-2-pyridyl)sulfonyl]-4-azepanyl}(S)-2-amino-4-methylpentanamide in Example 235c. MS (ES) 572 (M + H ⁺ ) .

b.) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl)-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1—[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-aze372 panyl}-carbamoyl]-butyl}-5-methoxy-2-benzofurancarboxamide from Example 236a. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.0 (m, 6H), 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 (ES) : 570 (M ⁺ , 100 %) ·

Example 237

Preparation of N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 236a, except that 3-methyl-2-benzofurancarboxylic acid was used as the starting compound instead of 5-methoxy-2-benzofurancarboxylic acid. MS (ES) 556 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-butyl}-3-methyl-2-benzofurancarboxamide from Example 237a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 6H), 1.5-2.2 (m,

373

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 (ES) : 564 (M ⁺ , 100

Q, \ O / ·

Example 238

Preparation of N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-7-methoxy-2-benzofurancarboxamide

a. ) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-

-hydroxy-4-azepanyl}-carbamoyl]-butyl]-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 7-methoxy-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 559 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[<1—[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-7-methoxy-2-benzofurancarboxamide from Example 238a. MS (ES) 557 (M + H ⁺ ).

374

Example 239

Preparation of N-{(S)-3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-5,6-dimethoxybenzo[b]thiophene-2-carboxamide

a.) N-{(S)-3-Methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepaniyl}carbamoyl]butyl}-5,6-dimethoxybenzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 604 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]-butyl)-5,6-dimethoxybenzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-5,6-dimethoxybenzo[b]thiophene-2-carboxamide from Example 239a. MS (ES) 602.9 (M + H ⁺ ).

Example 240

Preparation of N-{(S)-3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-OXO-4-azepanyl}carbamoyl]butyl)-(R)-1-benzyl-5-oxo-2-pyrrolidinecarboxamide

The title compound was prepared according to the procedure of Example 75.

375, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and (R)-1-benzyl-5-oxo-2-pyrrolidinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ) : 584.4. ^H-NMR (400 MHz, CDCl3) δ (ppm): 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 (m, 3H), 2.75-2.63 (m, 2H), 2.46-1.44 (m, 10H), 0.95 (d, 6H). Second eluting diastereomer: MS (M+H ⁺ ): 584.4.

Example 241

Preparation of N~{(S) -3-methyl-1-[{1-[(2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl)-(S)-1-benzyl-5-oxo-2-pyrrolidinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of (phenylsulfonyl) chloride and (S)-1-benzyl-5-oxo-2-pyrrolidinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer + 1: MS (M + H ): 584.4. h-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second

6 eluting diastereomers: MS (Μ + Η ⁺ ): 584.4.

Example 242

Preparation of Ν-{(S)-2-cyclopropyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]ethyl)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)cyclopropylalanine was used in the procedure of Example 193e. After purification, the faster eluting diastereomer of the title compound was isolated as a solid (8 mg) [MS (ESI): 525 (M + H ⁺ )], and the slower eluting diastereomer of the title compound was also obtained as a solid (8 mg) [MS (ESI): 525 (M + H ⁺ )].

Example 243

Preparation of H-{(S)-3-(methylthio)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]propyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 193e-g, except that in this case N-(tert-butoxycarbonyl)-L-methionine was used in the procedure of Example 193e. The oxidation according to Example 193, step g, was carried out by adding 34 mg (0.211 mmol) of sulfur trioxide/pyridine complex and 0.077 ml of triethylamine to a solution of the alcohol intermediate in 0.200 ml of dimethyl sulfoxide. The reaction mixture was stirred at room temperature for 2 hours. ,1 ,*·. .··, .··. .'· - 377 - xz.

was stirred, then diluted with water and extracted with ethyl acetate. The organic phase was dried, filtered and the filtrate was concentrated. After purification by HPLC, the faster eluting diastereomer of the title compound was isolated as a solid (8 mg) [MS (ESI): 545 (M + H ⁺ )] and the slower eluting diastereomer of the title compound was obtained as a solid (5 mg) [MS (ESI): 545 (M + H ⁺ )].

Example 244

Preparation of N-{(S)-2-(2-naphthyl)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 193e-h, except that 27-(tert-butoxycarbonyl)-3-(2-naphthyl)-alanine was used. After purification, the faster eluting 4-diastereomer of the title compound was isolated as a solid (5.3 mg) [MS (ESI): 610.8 (M + H)] and the slower eluting diastereomer of the title compound was isolated as a solid (3.3 mg) [MS (ESI): 610.8 (M + ^H )].

Example 245

Preparation of N-{(S)-3-methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide

8

a. ) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl]thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 236a, except that instead of 5-methoxy-2-benzofurancarboxylic acid, thieno[3,2-b]thiophene-2-carboxylic acid was used as the starting compound. MS (ES) 564 (M ⁺ ).

b.) N-{(S)-3-Methyl-1-[{1-[(6-methyl-2-pyridyl)-sulfonyl]-3-oxo-4-azepanyl]-carbamoyl]-butyl]-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example li, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1-((6-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide from Example 245a. ¹ H-NMR (CDCl3) δ (ppm): 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 (ES) : 562 (M ⁺ , 100 %) .

Example 246

Preparation of N-{(S)-3-methyl-1-[{1- [(3-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]butyl]thieno[3,2-b]thiophene-2-carboxamide

a.) N-{3-Hydroxy-1-[(3-methyl-2-pyridyl)sulfonyl]-4-azepanyl]-(S)-2-amino-4-methylpentanamide

- 379 - lx,

The title compound was prepared according to the procedure of Example 235b-c, except that [(3-methyl-2-pyridyl)sulfonyl] chloride was used instead of [(6-methyl-2-pyridyl)sulfonyl] chloride. MS (ES) 399 (M ⁺ ).

b.) N-{(S)-3-Methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide

To a solution of 0.25 g of N-{3-hydroxy-1-[(3-methyl-2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide from Example 246a in methylene chloride was added 0.10 g of thieno[3,2-b]thiophene, 0.12 ml of triethylamine, 0.085 g of 1-hydroxybenzotriazole and 0.12 g of N-ethyl-2N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography, using a 5:95 volume methanol/methylene dichloride solvent mixture as the eluent. 0.18 g of the title compound was obtained. MS (ES) 564 (M ⁺ ).

c.) N-{(S)-3-Methyl-1-[{1-[(3-methyl-2-pyridyl)-sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-butyl}-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide from Example 246b.

- 380 -

we applied. ¹ H-NMR (CDC1 ₃ ) δ 6H) , 2.6 (m, 3H) 3.0 (m, 1H) , (m, 2H) , 5.3 (m, 1H) , 7.4-8.0 562 (M ⁺ , 100 %).

(ppm): 1.0 (m, 6H), 1.5-2.2 (m,

3.8 (s, 3H), 4.1 (m, 2H), 4.7 (m, 5H), 8.4 (m, 1H). MS (ES) :

Example 247

Preparation of N-{(S)-3-methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 246c, except that 3-methyl-2-benzofurancarboxylic acid was used instead of thieno[3,2-b]thiophene-2-carboxylic acid. MS (ES) 556 (M ⁺ ).

b.) N-{(S)-3-Methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3-methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-butyl}-3-methyl-2-benzofurancarboxamide 1 from Example 247a. H-NMR (CDCl3) δ (ppm): 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 (ES) :

- 381,554 (M ⁺ , 100%).

Example 248

Preparation of N-{(S)-3-methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

a.) N~{(S)-3-Methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 246c, except that 5-methoxy-2-benzofurancarboxylic acid was used instead of thieno[3,2-b]thiophene-2-carboxylic acid. MS (ES) 572 (M).

b.) (S)-3-Methyl-1-[{1-[(3-methyl-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was N-{(S)-3~-methyl-1-[{1-[(3-methyl-2-pyridyl)-sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-butyl}-5-methoxy-2-benzofurancarboxamide from Example 248a. H-NMR (CDCl3) δ (ppm): 1.0 (m, 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 (ES) : 570 (M ⁺ , 100 %).

382

Example 249

Preparation of N-{(S)-3-methyl-1-[{1-[(1-oxy-2-pyridyl)sulfonyl]-3-oxo-4-azepaniyl}carbamoyl]butyl}-5,6-difluoro-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{1-[(1-oxy-2-pyridyl)sulfonyl]-3-hydroxy-4-azepanyl}carbamoyl]butyl}-5,6-difluoro-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 85c, except that 5,6-difluoro-2-benzofurancarboxylic acid was used as the starting compound instead of benzo[b]thiophene-2-carboxylic acid. MS (ES) 580.9 (M + H ⁺ ).

b.) N-{(S)-3-Methyl-1-({1-[(1-oxy-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]butyl}-5,6-difluoro-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 249a. MS (ESI): 578.87 (M + H) ⁺ .

Example 250

Preparation of N-{(5)-2-cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]ethyl)-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

a.) Benzyl 4-[{(S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionyl)amino]-3-hydroxy-1-azepanecarboxylate

3.2 g (12.2 mmol) of the product of Example 2e in 35 ml of N,N-di-

To a solution of 383 in methylformamide were added 3.3 g of N-(tert-butoxycarbonyl)cyclohexylalanine, 1.8 g of 1-hydroxybenzotriazole and 2.56 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 65:35 (v/v) hexane/ethyl acetate solvent mixture as the eluent. 5.5 g of the title compound was obtained.

b.) tert-Butyl-N- {(S)-2-cyclohexyl-1-1(3-hydroxy-4-azepanyl)-carbamoyl]-ethyl}-carbamate

To a solution of 5.5 g of the product of Example 250a in 185 ml of ethyl acetate and 40 ml of methanol was added 10% palladium/carbon catalyst. The reaction mixture was stirred under a hydrogen atmosphere until the starting compound was completely converted. The reaction mixture was then filtered and the filtrate was concentrated to give 3.75 g of the title compound.

c.) tert-Butyl-J7-{(S)-2-cyclohexyl-1-[{3-hydroxy-1-[(2-pyridyl)-sulfonyl]-4-azepanyl]-carbamoyl]-ethyl}-carbamate 1.0 g (1.91 mmol) of the product of Example 250b. prepared in 5 ml of methylene chloride was added 10 ml of water and 1 g of sodium bicarbonate. To the mixture thus obtained was added dropwise a solution of 0.55 g of [(2-pyridyl)-sulfonyl]-chloride prepared in 5 ml of methylene chloride. The reaction mixture was stirred for 20 minutes, after which the organic phase was separated, washed with water and saturated aqueous sodium chloride.

384 was washed with water, dried, filtered and concentrated. The residue was subjected to column chromatography using a 2:98 volume methanol/methylene dichloride solvent mixture as eluent. 1.0 g of the title compound was obtained. MS (ESI): 525 (M + H) ⁺ .

d.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-3-cyclohexylpropionamide

To a solution of 1.0 g of the product of Example 250c in 10 ml of methanol was added 10 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred until the starting compound was completely converted and then concentrated. The residue was azeotroped with toluene and washed with diethyl ether to give 0.95 g of the title compound.

e.) N-{(S)-2-Cyclohexyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

To a solution of 0.20 g (0.4 mmol) of the product of Example 250d in 0.5 ml _of N,N-dimethylformamide was added 0.16 ml of N,N-diisopropylethylamine, 0.06 g of 1-hydroxybenzotriazole, 0.084 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.11 g of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 4:96 volume methanol/methylene dichloride solvent mixture as the eluent. 0.23 g of the title compound was obtained.

385

f.) N-{(S)-2-Cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]ethyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the procedure of Example 75d, except that the starting material was Example 250e. The diastereomers were separated by HPLC, which resulted in the isolation of 52 mg of the faster eluting diastereomer [MS (ESI): 661.4] and 45.8 mg of the slower eluting diastereomer [MS (ESI): 661.6].

Example 251

Preparation of N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]ethyl}-5-(4-chlorophenyl)-2-furancarboxamide

The title compound was prepared according to the procedure of Examples 250e-f, except that 5-(4-fluorophenyl)-2-furancarboxylic acid was used instead of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid as in Example 252e. The diastereomers were separated using HPLC, which resulted in the isolation of 57 mg of the faster eluting diastereomer [MS (ESI): 627.4], followed by 53 mg of the slower eluting diastereomer [MS (ESI): 627.4].

386

Example 252

Preparation of N-{(S)-3-methyl-1-[{6-methyl-3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 92, except that 2-methyl-4-pentenal was used instead of 2,2-dimethyl-4-pentenal. The crude product obtained as a residue was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 541.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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 N-{(S)-2-cyclohexyl-1-[{1-[(1-oxy-2-pyridyl)sulfonyl]-3-oxo-4-azepanyl)carbamoyl]ethyl]-5-(4-chlorophenyl)-2-furancarboxamide

The title compound was prepared according to the procedure of Examples 250c-f, except that in this case [(2-pyridyl)sulfonyl] chloride-N-oxide was used instead of [(2-pyridyl)sulfonyl] chloride in Example 250c, and 5-(4-chlorophenyl)-2-furancarboxylic acid was used instead of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid in Example 252e. The diastereomers were separated using HPLC, resulting in a faster eluting diastereo

387 [MS (ESI): 643.4], and then a slower eluting diastereomer [MS (ESI): 643.2] was isolated.

Example 254

Preparation of N-{(S)-2-cyclohexyl-1-[{3-oxo-1-[(1-oxy-2-pyroxydyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the procedure of Examples 250c-f, except that [(2-pyridyl)sulfonyl] chloride N-oxide was used instead of [(2-pyridyl)sulfonyl] chloride as in Example 250c. The diastereomers were separated using HPLC, which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 677.2] and then a slower eluting diastereomer [MS (ESI): 677.4].

Example 255

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide

a.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 5-fluoro-2-benzofurancarboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid. MS (ES) 547 (M +

388

b.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was Example 255a. MS (ESI): 544.9 (M + H) ⁺ .

Example 256

Preparation of N-{(S)-2-cyclohexyl-1-[(3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]ethyl)-5,6-dimethoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 250c-f, except that [(2-pyridyl)sulfonyl] chloride N-oxide was used instead of [(2-pyridyl)sulfonyl] chloride in Example 250c, and 5,6-dimethoxybenzofurancarboxylic acid was used instead of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid in Example 252e. The diastereomers were separated using HPLC, which resulted in the isolation of a faster eluting diastereomer [MS (ESI): 643.4] and then a slower eluting diastereomer [MS (ESI): 643.2].

389

Example 257

Preparation of N~<(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}-5,5-bis(4-methoxyphenyl)pent-4-enamide

The title compound was prepared according to the procedure of Example 75, except that [(2-pyridyl)sulfonyl] chloride was used instead of [(2-thiazolyl)sulfonyl] chloride and 5,5-bis(4-methoxyphenyl)pent-4-enecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 677.4. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting + diastereomer: MS (M + H): 677.4.

Example 258

Preparation of N-{(S)-2-(2-naphthyl)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]ethyl}-8-quinolinecarboxamide a.) 4-Amino-3-hydroxy-1-[(2-pyridyl)sulfonyl]azepane

To a solution of 1.5 g of the product of Example 193c in 10 ml of methanol was added 10 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then concentrated to give a white solid.

The title compound was obtained in the form of 390 and in an amount of 1.2 g.

b.) tert-Butyl-N-{(S)-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-2-(2-naphthyl)ethyl}carbamate

To a solution of 225 mg of the product of Example 258a in methylene chloride was added 0.15 ml of triethylamine, 99 mg of 1-hydroxybenzotriazole, 140 mg of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 230 mg of N-(tert-butoxycarbonyl)-L-(2-naphthyl)alanine. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 3:97 volume methanol/methylene chloride solvent mixture as the eluent. 0.35 g of the title compound was obtained. MS (ESI): 569 (M + H) ⁺ .

c.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-2-amino-3-(2-naphthyl)propionamide

To a solution of 0.35 g of the product of Example 258b in 5 ml of methanol was added 5 ml of 4 M hydrochloric acid in dioxane. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography, and then concentrated. 0.31 g of the title compound was obtained as a white solid.

d.) N-{(S)-2-(2-Naphthyl)-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-8-quinolinecarboxamide

To a solution of 131 mg of the product of Example 258c in methylene chloride was added triethylamine, 39 mg of 1-hydroxybenzotriazole,

391 sol, 55 mg N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide— —hydrochloride and 51 mg 8-quinolinecarboxylic acid. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography, eluting with a 5:95 volume methanol/methylene dichloride solvent mixture. 0.35 g of the title compound was obtained. MS (ESI): 574 (M + H) ⁺ .

e.) N~{(S)-2-(2-Naphthyl)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-8-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting compound in this case was the product of Example 258d.

Example 259

Preparation of N-{(S)-2-(2-naphthyl)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-1-naphthalenecarboxamide

The title compound was prepared according to the procedure of Example 258d-e, except that 1-naphthoic acid was used instead of 8-quinolinecarboxylic acid.

Example 260

Preparation of N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-2-phenylethyl}-8-quinolinecarboxamide

The title compound was prepared according to the procedure of Examples 258a-e, except that N-(tert-buto

392 Instead of xi-carbonyl)-1-(2-naphthyl)-alanine, N-(tert-butoxycarbonyl)-phenylalanine was used in this case.

Example 261

Preparation of N~{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-naphthyridinecarboxamide

The title compound was prepared according to the procedure of Example 28b, except that 1,6-naphthyridine-2-carboxylic acid was used as the starting compound instead of 2-benzofurancarboxylic acid.

Example 262

Preparation of N~{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-2-phenylethyl}-1-naphthalenecarboxamide

The title compound was prepared according to the procedure of Example 260, except that 1-naphthoic acid was used instead of 8-quinolinecarboxylic acid.

Example 263

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-(cyclohexylpropionyl)-4-azepanyl]carbamoyl)butyl]-3-methyl-2-benzofurancarboxamide

a.) Benzyl 4-{[(S)-2-{[(3-methyl-2-benzofuranyl)carbonyl]amino)-4-methylpentanoyl]amino)-3-hydroxy-1-azepanecarboxylate

To a solution of 1.2 g (2.67 mmol) of the product of Example 72a

- 393 - 1 <·· 0.56 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.36 g of 1-hydroxybenzotriazole, 0.67 g of triethylamine and 0.47 g of 3-methyl-2-benzofurancarboxylic acid were added. The reaction mixture was stirred until the starting compound was completely converted. The reaction mixture was then worked up and the crude product thus obtained was subjected to column chromatography using a 1:4 ethyl acetate/hexane solvent mixture as the eluent. 1.05 g of the title compound was obtained. MS (ESI): 536 (M + H) ⁺ .

b.) N- {(S)-1-[(3-Hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 2g, except that the starting material was Example 263a. MS (ESI): 402 (M + H) ⁺ .

c.) 2»Z-[(S)-3-Methyl-1-{[3-hydroxy-1-(cyclohexylpropionyl)-4-azepanyl]carbamoyl}-butyl]-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 263a, except that 3-cyclohexylpropionic acid was used instead of 3-methyl-2-benzofurancarboxylic acid. MS (ESI): 540 (M + H) ⁺ .

d.) N- [(S)-3-Methyl-1-{[3-oxo-1-(cyclohexylpropionyl)-4-azepanyl]carbamoyl}-butyl]-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 11, except that the starting material was

In this case, the product of Example 263c was used as compound 394. MS (ESI): 538 (M + H) ⁺ .

Example 264

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-(4-methylpentanoyl)-4-azepanyl]carbamoyl}-butyl]-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 263c-d, except that 4-methylpentanoic acid was used instead of 3-cyclohexylpropionic acid. MS (ESI): 498 (M + H) ⁺ .

Example 265

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 263c-d, except that picolinic acid N-oxide was used instead of 3-cyclohexylpropionic acid. MS (ESI): 498 (M + H) ⁺ .

Example 266

N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}(S)-(acetyl

-amino)-4-methylpentanamide preparation

The title compound was prepared according to the procedure of Example 75c-d, except that acetic acid was used instead of 2-benzofurancarboxylic acid in Example 75c. The crude product was purified by HPLC.

395. First eluting diastereomer: MS (M + H ): 452.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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). Second eluting diastereomer: MS (M+H): 425.2.

267, example

Preparation of N-{1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]pentyl]-2-quinolinecarboxamide a.) Benzyl 4-[{(S)-2-[(tert-butoxycarbonyl)amino]hexanoyl]amino]-3-hydroxy-1-azepanecarboxylate

To a stirred solution of 200 mg (0.74 mmol) of the amino alcohol compound of Example 2e in 4 ml of N,N-dimethylformamide were added 175 mg (0.76 mmol) of N-(tert-butoxycarbonyl)-norleucine, 145 mg (0.76 mmol) of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 21 mg (0.16 mmol) of 1-hydroxybenzotriazole. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate the next morning, and washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and purified by column chromatography. 300 mg of the title compound was obtained. MS (ESI): 478.11 (M+H) ⁺ .

- 396 - χ :?·>:::·

b.) tert-Butyl-N- { (S) -1- [(3-hydroxy-4-azepanyl)-carbamoyl]-pentyl}-carbamate

To a solution of 300 mg (0.63 mmol) of the product of Example 267a in 5 mL of ethyl acetate was added 160 mg of 10% palladium/carbon catalyst. The flask was connected to a hydrogen-filled balloon and placed under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 48 h, then filtered through a Celite pad, and the filtrate was concentrated. The crude title compound was obtained as a residue (161 mg (0.47 mmol). MS (ESI): 344.19 (M + H) ⁺ .

c.) tert-Butyl-N-{(S)-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]pentyl}carbamate

To a solution of 161 mg (0.47 mmol) of the product of Example 267b in 6 mL of methylene chloride was added 0.065 mL (0.47 mmol) of triethylamine and 83 mg (0.47 mmol) of [(2-pyridyl)sulfonyl] chloride. The reaction mixture was stirred at room temperature for 1 hour and then washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 142 mg (0.29 mmol) of the title compound. MS (ESI): 485.10 (M + H) ⁺ .

d.) N-(3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl]-(S)-2-aminohexanamide

To a stirred solution of 142 mg (0.29 mmol) of the product of Example 267c in ethyl acetate was added 0.760 mL (3.0 mmol) of a 4 M solution of hydrogen chloride in dioxane. The reaction mixture was cooled to room temperature.

The mixture was stirred at room temperature for 397 hours and then concentrated. The white solid obtained as a residue was azeotroped twice with toluene on a rotary evaporator, then 0.47 mmol of resin-bound carbonate in methanol was added and the flask was placed on a shaker. After four hours, the suspension was filtered and the filtrate was concentrated. 104 mg of crude product was obtained as a residue. MS (ESI): 385.08 (M + H) ⁺ .

e.) N-{1-[{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]pentyl}-2-quinolinecarboxamide

To a solution of 104 mg (0.27 mmol) of the product of Example 267d in methylene chloride was added 47 mg (0.27 mmol) of quinaldic acid, 7.4 mg (0.055 mmol) of 1-hydroxybenzotriazole and 52 mg (0.27 mmol) of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride in 2 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. 172 mg of crude product was obtained as a residue. MS (ESI): 539.90 (M + H) ⁺ .

f.) N-{1-[{3-Oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]pentyl)-2-quinolinecarboxamide

To a stirred solution of 172 mg (0.32 mmol) of the crude product of Example 267e in 1 mL of dimethyl sulfoxide was added 260 mg (1.6 mmol) of sulfur trioxide/pyridine complex and 0.88 mL (3.2 mmol) of triethylamine. The reaction mixture was stirred for 2 h.

The mixture was stirred at room temperature, then diluted with water and extracted with ethyl acetate. The organic solutions were combined, dried, filtered and the filtrate was concentrated. The residue was purified by HPLC to give 40 mg of the faster eluting diastereomer [MS (ESI): 537.86] and 43 mg of the slower eluting diastereomer [MS (ESI): 537.86].

Example 268

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-(cyclohexylpropionyl)-4-azepanyl]carbamoyl]butyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 263a-d, except that 2-benzofurancarboxylic acid was used instead of 3-methyl-2-benzofurancarboxylic acid of Example 263a. MS (ESI): 524 (M + H) ⁺ .

Example 269

Preparation of N-[(S)-3-methyl-1-{[3-oxo-1-(4-methylpentanoyl)-4-azepanyl]carbamoyl]butyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 263a-d, except that in this case 2-benzofurancarboxylic acid was used instead of 3-methyl-2-benzofurancarboxylic acid according to Example 263a, and 4-methylpentanoic acid was used instead of 3-cyclohexylpropionic acid. MS

- 399 (ESI): 484 (M + H) ⁺ .

Example 270

Preparation of N-{(S)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-2-phenylethyl}-1-quinolinecarboxamide

The title compound was prepared according to the procedure of Examples 267a-f, except that in this case N-(tert-butoxycarbonyl)-phenylalanine was used instead of N-(tert-butoxycarbonyl)-norleucine as in Example 267a. The diastereomeric mixture was separated using HPLC, which resulted in the isolation of 20.5 mg of the faster eluting diastereomer [MS (ESI): 571.95], followed by 27 mg of the slower eluting diastereomer [MS (ESI): 571.95].

Example 271 Preparation of N-{(S)-2-(benzyloxy)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl]-2-benzofurancarboxamide

The mixture of diastereomers of the title compound was prepared according to the procedure of Example 193e-h, except that in this case N-(tert-butoxycarbonyl)-O-benzyl-L-serine was used in the procedure of Example 193e. To a solution of 90 mg of N-{(S)-2-(benzyloxy)-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]ethyl}-2-benzofurancarboxamide in 2 ml of ethyl acetate was added 50 mg of 10% palladium on carbon catalyst. The starting benzyl4 ,·'

- 400 - ί ··>< *«···<

After hydrogenolysis of approximately 50% of the ether, the reaction mixture was filtered and the filtrate was concentrated. The 4-component mixture was purified by HPLC to give 1 mg of the first eluting diastereomer of the title compound [MS (ESI): 590.94 (M + H) ⁺ ] and 0.3 mg of the second eluting diastereomer of the title compound [MS (ESI): 590.94 (M + H) ⁺ ]. In addition, two individual diastereomers of 2N-((S)-2-hydroxy-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]ethyl]-2-benzofurancarboxamide were isolated as described in Example 272 below.

Example 272

Ά.Ζ Preparation of N-{(S)-2-hydroxy-l-[{3-oxo-l-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]ethyl}-2-benzofurancarboxamide

The title compound was obtained as described in Example 271. The mixture was purified by HPLC to give the faster eluting diastereomer as a solid (1.6 mg) [MS (ESI): 500.9 (M + H ⁺ )] and the slower eluting diastereomer as a solid (2.1 mg) [MS (ESI): 500.9 (M + H ⁺ )].

Example 273

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared by the procedure of Example 75c-d, except that ₅ -methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid in the procedure of Example 75c. The crude title compound was isolated by HPLC. This gave the first eluting diastereomer as a white solid (144.3 mg, 85.1% yield) [MS (ESI): 563.2 (M + H) ⁺ ] and the second eluting diastereomer as a white solid (16.9 mg, 10.0% yield) [MS (ESI): 563.2 (M + H) ⁺ ].

Example 274

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-7-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 75c-d, except that 7-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid in the procedure of Example 75c. The crude title compound was isolated by HPLC. This gave the first eluting diastereomer as a white solid (75 mg, 47% yield) [MS (ESI): 563.2 (M + H) ⁺ ] and the second eluting diastereomer as a white solid (57 mg, 35% yield) [MS (ESI): 563.2 (M + H) ⁺ ].

402

Example 275

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 75c-d, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid in the procedure of Example 75c. The crude title compound was isolated by HPLC. This gave the first eluting diastereomer as a white solid (69.5 mg, 42% yield) [MS (ESI): 547.2 (M + H) ⁺ ] and the second eluting diastereomer as a white solid (65 mg, 40% yield) [MS (ESI): 547.2 (M + H) ⁺ ].

Example 276

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 75c-d, except that benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid in the procedure of Example 75c. The crude title compound was separated by HPLC. This gave the first eluting compound as a white solid (79.5 mg, 48%).

403 diastereomer [MS (ESI): 549.3 (M + H) ⁺ ] and the second eluting diastereomer [MS (ESI): 549.2 (M + H) ⁺ ] were isolated as a white solid in an amount of 50.5 mg (31% yield).

Example 277

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1-methyl-1H-2-indolecarboxamide

The title compound was prepared according to the procedure of Example 75c-d, except that 1-methyl-2-indolecarboxylic acid was used instead of 2-benzofurancarboxylic acid in the procedure of Example 75c. The crude title compound was isolated by HPLC. This gave the first eluting diastereomer as a white solid (75 mg, 47% yield) [MS (ESI): 563.2 (M + H) ⁺ ] and the second eluting diastereomer as a white solid (57 mg, 35% yield) [MS (ESI): 563.0 (M + H) ⁺ ] .

Example 278

Preparation of H-{(S)-3-methyl-1-[{3-oxo-1-[(2-thiazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 75c-d, except that instead of 2-benzofurancarboxylic acid in the procedure of Example 75c,

In 404 cases, 2-quinoxalinecarboxylic acid was used. The crude title compound was separated by HPLC. This gave the first eluting diastereomer as a white solid (126 mg, 77% yield) [MS (ESI): 545.2 (M + H) ⁺ ] and the second eluting diastereomer as a white solid (25 mg, 15% yield) [MS (ESI): 545.2 (M + H) ⁺ ] .

Example 279 Preparation of N-{(S)-1-[{1-[(4-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 75, except that [(2-pyridyl)sulfonyl] chloride was used instead of (phenylsulfonyl) chloride and 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The crude product was purified by HPLC. First eluting diastereomer: MS (M + H ⁺ ): 555.2. H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 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), 4.00 (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). Second eluting diastereomer: MS (M+H ⁺ ): 555.4.

405

Example 280

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide a.) Benzyl-N-allyl-N-pent-4-enylcarbamate

To a suspension of 1.83 g (76.33 mmol) of a 90% by weight dispersion of sodium hydride in mineral oil in N,N-dimethylformamide was added dropwise 7.3 g (38.2 mmol) of benzyl N-allyl carbamate. The mixture was stirred at room temperature for about 10 minutes, and then 6.78 ml (57.24 mmol) of 5-bromo-l-pentene was added dropwise. The reaction mixture was heated at 40 °C for about 4 hours and then partitioned between methylene chloride and water. The organic phase was washed twice with water, then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 10:90 (v/v) ethyl acetate/hexane mixture as eluent to give 10.3 g of the title compound as an oil. MS (ES) 260 (M + H ⁺ ).

b.) Benzyl-2,3,4,7-tetrahydro-l-azepinecarboxylate g 280. To a solution of the product of Example a in methylene dichloride was added 5.0 g of bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride. The reaction mixture was heated at reflux temperature until the starting compound was completely converted according to thin layer chromatography analysis, and then concentrated in vacuo. The residue was chromatographed using a 50:50 volume mixture of methylene dichloride/hexane as eluent. 35 g title

406 compounds were obtained. MS (ES) 232 (M + H ⁺ ).

c.) Benzyl-8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate g (1.5 mol) of the product of Example 280b in methylene chloride was added 78 g (0.45 g) of 3-chloroperbenzoic acid. The reaction mixture was stirred overnight at room temperature, then the solid was filtered off. The filtrate was washed with water and several times with sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. 35 g of the title compound was obtained as a residue, which was pure enough to be used in the next step. MS (ES) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).

d.) Benzyl 4-azido-3-hydroxy-l-azepanecarboxylate

To a solution of 2.0 g (8.1 mmol) of the product of Example 280c in 8:1 methanol/water was added 1.29 g (24.3 mmol) of ammonium chloride and 1.58 g (24.30 mmol) of sodium azide. The reaction mixture was heated at 40 °C until the starting epoxide was completely converted by thin layer chromatography. Most of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic phase was washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 20:80 volume ethyl acetate/hexane solvent mixture as eluent. 1.3 g of the title compound [MS (ES) 291 4 (M + H ) ] and 0.14 g of trans-4-hydroxy-3-azido-hexahydro-1H-aze

We won 407 pins.

e.) Benzyl 4-amino-3-hydroxy-l-azepanecarboxylate

To a solution of 1.1 g (3.79 mmol) of the azido alcohol of Example 280d in methanol was added 1.5 ml (11.37 mmol) of triethylamine and 1.1 ml (11.37 mmol) of 1,3-dimercaptopropane. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then concentrated in vacuo and the residue was subjected to column chromatography using a 20:80 (v/v) methanol/methylene dichloride solvent mixture as the eluent. 0.72 g of the title compound was obtained. MS (ES) 265 (M + H ⁺ ).

f.) Benzyl 4-[{(S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino]-3-hydroxy-1-azepanecarboxylate

To a solution of 720 mg (2.72 mmol) of the product of Example 280e in methylene chloride was added 521 mg of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC), 368 mg of 1-hydroxybenzotriazole (HOBt) and 630 mg of N-[(benzyloxy)carbonyl]leucine (Cbz-leucine). The reaction mixture was kept at room temperature until the starting compound was completely converted according to thin layer chromatography analysis. The reaction mixture was then diluted with ethyl acetate, the solution was washed with 1 M hydrochloric acid solution, saturated aqueous potassium carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to column chromatography using a 3:97 volume ratio of methanol/methylene as the eluent.

408

-dichloride solvent mixture was used. 1.0 mg of the title compound was obtained. MS (ES) 478 (M + H).

g.) t-Butyl-{(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}carbamate

A solution of 1.0 g of the compound of Example 280f and a catalytic amount of 10% palladium on carbon in 2:1 ethyl acetate/methanol was placed under a balloon pressure of hydrogen. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then filtered to remove the catalyst and the filtrate was concentrated in vacuo to give 0.82 g of the title compound. MS (ES) 344 (M + H ⁺ ).

h.) N-{1-[(3-Fluorophenyl)sulfonyl]-3-hydroxy-4-azepanyl}-(S)-2-amino-4-methylpentanamide

To a solution of 0.2 g of the product of Example 280g in 20 ml of methylene chloride were added 0.32 g of P-NMM and 0.11 g of [(3-fluorophenyl)sulfonyl] chloride. The reaction mixture was stirred until the reaction was complete according to MS analysis. The reaction mixture was then filtered and the filtrate was concentrated. The residue was dissolved in 10 ml of methanol and 10 ml of 4 M hydrogen chloride in dioxane were added to the solution. The reaction mixture was kept at room temperature until the starting compound was completely converted and then concentrated. The residue was dissolved in methanol and P-carbonate resin was added. The reaction mixture was shaken for 4 hours at room temperature, then filtered and the

40 g of filtrate was concentrated to give 0.64 g of the title compound.

i .) N-{(S) -1-[{1— C(3-Fluorophenyl)sulfonyl]-3-hydroxy-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 0.15 g of the product of Example 280h in methylene chloride was added 0.56 mmol of 2-benzofurancarboxylic acid, 0.09 mg of 1-hydroxybenzotriazole (HOBt) and 0.75 mg of p-EDC. The reaction mixture was stirred overnight, then 0.50 g of trisamine was added, the reaction mixture was stirred for a further 1.5 hours, then filtered and concentrated. The title compound was obtained as a residue.

j.) N-{(S)—1—[{1—[(3-Fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

To a solution of 0.3 mmol of the product of Example 280i in methylene chloride was added 0.25 g of Dess-Martin periodane. The reaction mixture was stirred until the reaction was complete according to MS analysis. After work-up and HPLC chromatography, the following products were obtained; Diastereomer 1: MS (ES) 543.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 543.2 (M + H) ⁺ .

Example 281

Preparation of N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[3-(1-piperidyl)propionyl]amino}pentanamide

The title compound was prepared according to the procedure of Example 280h-j.

410 was prepared in the same way, except that in this case [(2-pyridyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride and 3-(1-piperidyl)propionic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 521.9 (M + H) ⁺ .

Example 282

Preparation of N~{ (S) -1-[{1-[(4-ethylphenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that [(4-ethylphenyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. After separation of the diastereomers, the following products were obtained; Diastereomer 1: MS (ES) 554.4 (M + H) ⁺ ; Diastereomer 2: MS (ES) 554.4 (M + H) ⁺ .

Example 283 Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl]carbamoyl]butyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

a.) Benzyl 4-{[(S)-2-amino-4-methylpentanoyl]amino]-3-hydroxy-1-azepanecarboxylate

To a solution of 7.32 g of the product of Example 280f in methanol was added 38 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred until the reaction was complete and then concentrated to give

6.9 g of the title compound was obtained as a white solid at 411 °C.

b.) Benzyl-3-hydroxy-4-{[(S)-4-methyl-2-{[(5-[3-(trifluoromethyl)-phenyl]-2-furyl}-carbonyl]-amino}-pentanoyl]-amino}-1-azepanecarboxylate

To a solution of 1.2 g of the product of Example 283a in methylene chloride was added 0.93 ml of triethylamine, 0.56 g of ΛΓ-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (EDC), 0.36 g of 1-hydroxybenzotriazole (HOBt) and 0.68 g of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid. The reaction mixture was stirred until the reaction was complete as determined by thin layer chromatography. After work-up and column chromatography, 1.35 g of the title compound was isolated. MS (ES) 616 (M + H) ⁺ .

c.) N-{(S)-1-[(3-Hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

To a solution of 1.3 g of the product of Example 283b in 20 ml of ethyl acetate/methanol (8:1) was added 10% palladium on carbon and the mixture was placed under a balloon pressure of hydrogen. The reaction mixture was stirred until the starting compound was completely converted by thin layer chromatography. The reaction mixture was then filtered and the filtrate was concentrated to give 0.96 g of the title compound, which was used directly in the next reaction without further purification.

412

d.) 2-{(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl)carbamoyl]butyl)-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

To a solution of 0.3 g of the product of Example 283c in methylene chloride was added 0.22 ml of triethylamine, 0.13 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (EDC), 0.8 g of 1-hydroxybenzotriazole (HOBt) and 0.09 g of picolinic acid I/-oxide. The reaction mixture was stirred at room temperature until the reaction was complete as determined by thin layer chromatography. After work-up and column chromatography, 0.16 g of the title compound was isolated. MS (ES) 603 (M + H) ⁺ .

e.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl)carbamoyl]butyl)-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

To a solution of 0.15 g of the product of Example 283d in 1.5 ml of dimethyl sulfoxide was added 0.37 ml of triethylamine and 0.21 g of pyridine/sulfur trioxide complex. The reaction mixture was stirred until the reaction was complete according to LCMS analysis. After work-up, the crude product obtained as a residue was subjected to column chromatography, eluting with a 10:90 volume methanol/methylene dichloride solvent mixture. This gave 0.12 g of the title compound. MS (ES) 601 (M + H) ⁺ .

The diastereomers were separated by HPLC, and a diastereomer 1 and a diastereomer 2 were isolated.

413

Example 284

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}benzo[1,3]dioxole-5-carboxamide

The title compound was prepared according to the general procedure of Example 283b-e, except that piperonyl acid was used instead of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid. MS (ES) 511 (M + H) ⁺ .

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 285

Preparation of N-[(S)-1-{[1-(3-cyclohexylpropionyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the general procedure of Example 283b-e, except that 3-cyclohexylpropionic acid was used instead of picolinic acid N-oxide. MS (ES) 618 (M + H) ⁺ .

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 286

Preparation of N~ [(S)—1—{[1-(3-cyclohexylpropionyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]benzo[1,3]dioxole-5-carboxamide

The title compound was prepared by the general procedure of Example 283b-e.

414, except that in this case 3-cyclohexylpropionic acid was used instead of picolinic acid AP-oxide and piperonyl acid was used instead of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid. MS (ES) 528 (M + H) ⁺ .

By separating the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 287

Preparation of N-[(S)—1—{[1-(4-methylpentanoyl)-3-oxo-4-azepanyl)carbamoyl)-3-methylbutyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide

The title compound was prepared according to the general procedure of Example 283b-e, except that 4-methylpentanoic acid was used instead of picolinic acid N-oxide. MS (ES) 578 (M + H) ⁺ .

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 288

Preparation of N-[(S)-1-{[1-(4-methylpentanoyl)-3-oxo-4-azepanyl]carbamoyl)-3-methylbutyl]benzo[1,3}dioxole-5-carboxamide

The title compound was prepared according to the general procedure of Example 283b-e, except that 4-methylpentanoic acid was used instead of picolinic acid N-oxide and piperonyl acid was used instead of 5-[3-(trifluoromethyl)phenyl]-2-furancarboxylic acid. MS (ES) 488 (M + H) ⁺ .

415

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 289

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that propanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 491.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 491.2 (M + H) ⁺ .

Example 290

Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 477.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 477.4 (M + H) ⁺ .

416

Example 291

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}-carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide

a.) tert-Butyl-{(S)-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbonyl]-3-methylbutyl}carbamate

Preparation of [(2-Pyridyl)sulfonyl] chloride N-oxide: Chlorine gas was bubbled into a solution of 2.23 g (17.55 mmol) of 2-mercaptopyridine N-oxide in 33 ml of 9 M hydrochloric acid cooled to 0 °C for approximately 90 minutes, then the dissolved chlorine was removed under vacuum at 0 °C.

To a solution of 2.5 g (7.28 mmol) of tert-butyl {(S)-1-[(3-hydroxy-4-azepanyl)carbamoyl]-3-methylbutyl]carbamate from Example 280g in 100 ml of methylene chloride was added 400 ml of saturated aqueous sodium bicarbonate solution, and then 27 ml of freshly prepared (density 102 mg/ml) [(2-pyridyl)sulfonyl]chloride N-oxide was added dropwise. In order to maintain the pH at 8-9, additional saturated aqueous sodium bicarbonate solution was added to the reaction mixture simultaneously with the addition of the reagent. After the addition of the sulfonyl chloride was complete, the reaction mixture was stirred for an additional hour, after which the organic phase was separated, washed with saturated aqueous sodium chloride solution, and evaporated. The residue was chromatographed using a 5:95 methanol/methylene dichloride solvent mixture as eluent. As a result, 2.5 g of the title compound was isolated. MS (ES) 500 (M + H ⁺ ).

- 417 b.) N- {3-Hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}- (S’) -2-amino-4-methylpentanamide

To a solution of 2.0 g of tert-butyl {(S)-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbonyl]-3-methylbutyl}carbamate from Example 291a in 20 ml of methanol was added 20 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. 1.8 g of the title compound was obtained as a residue. MS (ES) 400 (M + H ⁺ ).

c.) N~[(S)-3-Methyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide

To a solution of 0.30 g of the product of Example 291b in methylene chloride was added 0.11 g of 5-fluoro-2-benzofurancarboxylic acid, 0.13 g of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (EDC), 0.086 g of 1-hydroxybenzotriazole (HOBt), and 0.22 mL of triethylamine. The reaction mixture was stirred until complete by LCMS analysis. The reaction mixture was then diluted with ethyl acetate, washed with water, saturated aqueous potassium carbonate solution, 1 M hydrochloric acid solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to column chromatography using a 10:90 methanol/methylene dichloride solvent mixture as eluent to give 0.27 g of the title compound. MS (ES) 563 (M + H) ⁺ .

- 418

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide

To a solution of 0.19 g of the product of Example 291c in 1.5 ml of dimethyl sulfoxide was added 0.26 g of pyridine/sulfur trioxide complex. The reaction mixture was stirred until complete by LCMS analysis. The reaction mixture was then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, filtered, and the filtrate was concentrated. The residue was subjected to column chromatography to give 0.15 g of the title compound as a mixture of diastereomers. MS (ES) 561 (M + H) ⁺ .

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 292

Preparation of N-((S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 5-fluoro-2-benzofurancarboxylic acid was used instead of 5-fluoro-3-methyl-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 575 (M + H) ⁺ .

The diastereomers were separated by HPLC and a 1st diastere<·* - Λ* >♦ ♦*

- 419 - 14:/λ’· diomer and a 2nd diastereomer were isolated.

Example 93

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxox-2-pyridyl)-carbonyl]-4-azepanyl}-carbamoyl]-butyl}-6-fluoro-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 6-fluoro-3-methyl-2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 575 (M + H) ⁺ .

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 294 Preparation of N-{(R)-3-methyl-1-[{3-oxo-1-[(1-oxox-2-pyrroxy)-carbonyl]-4-azepanyl}-carbamoyl]-butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280f-i, except that in this case N-Boc-D-leucine was used instead of N-Boc-L-leucine, [(2-pyridyl)sulfonyl] chloride-N-oxide was used instead of [(3-fluorophenyl)sulfonyl] chloride, and 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 556 (M + H) ⁺ .

The diastereomers were separated by HPLC and a 1st diastereomer was obtained.

- 420 - X'z <

omer and a 2nd diastereomer were isolated.

295, example

Preparation of JZ-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]azepanyl}carbamoyl]butyl}-3-methylfuro[2,3-jb]pyridine-2-carboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 3-methylfuro[2,3-b]pyridine-2-carboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. 1 (ES) 558 (M + H) ⁺ .

The diastereomers were separated by HPLC to isolate a diastereomer 1 and a diastereomer 2.

Example 296

Preparation of Η-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 574.5 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 574.5 (M + H) ⁺ .

421

Example 297

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}-carbamyl]-3-methylbutyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 557.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 557.4 (M + H) ⁺ .

Example 298

Preparation of N~{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl)benzo[2>]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 559.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 559.4 (M + H) ⁺ .

422

Example 299

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl)-3-methyl-2-furancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 3-methyl-2-furancarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 507.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 507.2 (M + H) ⁺ .

Example 300

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 554.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 554.2 (M + H) ⁺ .

423

Example 301

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that thieno[3,2-b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 565.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 565.2 (M + H) ⁺ .

Example 302

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 555.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 555.4 (M + H) ⁺ .

424

Example 303

Preparation of N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo~4-azepanyl}carbamoyl]-3-methylbutyl}-2-thiophenecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-thiophenecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 509.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 509.2 (M + H) ⁺ .

Example 304

Preparation of H-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 5-methyl-2-thiophenecarboxylic acid was used instead of 2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 523.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 523.4 (M + H) ⁺ .

425

Example 305

Preparation of N-[(S)-1—{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 507.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 507.4 (M + H) ⁺ .

Example 306

Preparation of N-[(S)-1~{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 491.2 (M 4. 4+ H); and Diastereomer 2: MS (ES) 491.2 (M + H).

426

Example 307

Preparation of 2?-[(S)-1—{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that benzo[t>]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 493.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 493.4 (M + H) ⁺ .

Example 308

Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl)-3-methylbutyl]-3-methyl-2-furancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 441.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 441.2 (M + H) ⁺ .

427

Example 309 Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinolinecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 488.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 488.2 (M + H) ⁺ .

Example 310

Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that thieno[3,2-b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 499.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 499.4 (M + H) ⁺ .

428

Example 311

Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinoxalinecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 489.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 489.2 (M + H) ⁺ .

Example 312 Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-S-methylbutyl]-2-thiophenecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-thiophenecarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 443.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 443.2 (M + H) ⁺ .

429

Example 313

Preparation of N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 5-methyl-2-thiophenecarboxylic acid was used instead of 2-benzofurancarboxylic acid and ethanesulfonyl chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 457.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 457.4 (M + H) ⁺ .

314, example

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 5-methoxy-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 521.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 521.2 (M + H) ⁺ .

430

Example 315

Preparation of N~ [(S)-1~{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl)-3-methylbutyl]-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 505.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 505.2 (M + H) ⁺ .

Example 316

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl)-3-methylbutyl]-benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 507.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 507.4 (M + H) ⁺ .

431

Example 317

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-furancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 3-methyl-2-furancarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 455.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 455.4 (M + H) ⁺ .

Example 318

Preparation of N— [(S) —1 —{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl·]-2,5-dimethyl-2-furancarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2,5-dimethyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(3-fluorophenyl)sulfonyl] chloride was used instead of [(1-propyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 469.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 469.2 (M + H) ⁺ .

- 432 -

Example 319

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinolinecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 565.2 (M + + + H); and Diastereomer 2: MS (ES) 565.2 (M + H).

Example 320

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that thieno[3,2-b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 513.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 513.2 (M + H) ⁺ .

433

Example 321

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinoxalinecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-quinoxalinecarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 503.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 503.4 (M + H) ⁺ .

Example 322

Preparation of N-[(S)-1~{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-thiophenecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 2-thiophenecarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 457.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 457.4 (M + H) ⁺ .

434

Example 323

Preparation of N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methyl-2-thiophenecarboxamide

The title compound was prepared according to the general procedure of Example 280h-j, except that 5-methyl-2-thiophenecarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(1-propyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The title compound was obtained as a mixture of diastereomers.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 471.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 471.4 (M + H) ⁺ .

Example 324

Preparation of N-{(S)-3-methyl-1-[(3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 5-methoxy-3-methyl-2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 587 (M + H) ⁺ .

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 565.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 565.2 (M + H) ⁺ .

- 435 -

Example 325

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl)carbamoyl]butyl}-3,5-dimethyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 3,5-dimethyl-2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 571 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 326

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl)carbamoyl]butyl)-3-ethyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 3-ethyl-2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 571 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a

Diastereomer 1 and a diastereomer 2 were isolated.

«· * * · t * ♦ * * ’* S 436 - .·<.*·· v. ·. ·«

327, example

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-4-methoxy-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 4-methoxy-3-methyl-2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 587 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 328

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl)carbamoyl]butyl)-1-methylnaphtho[2,1-b]furan-2-carboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 1-methylnaphtho[2,1-b]furan-2-carboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 607 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

437

Example 329

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-6-methoxy-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c-d, except that 6-methoxy-3-methyl-2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. The title compound was obtained as a mixture of diastereomers. MS (ES) 587 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 330

Preparation of N-{1,3-dimethyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

a.) Benzyl 4-[{(S)-2-[(tert-butoxycarbonyl)amino]-2,4-dimethylpentanoyl}amino]-3-hydroxy-1-azepanecarboxylate

To a solution of 3.0 g of N-[(1,1-dimethylethoxy)carbonyl]-2-methyl-D,L-leucine in methylene chloride was added 2.43 g of N-ethyl-N-[3-(dimethylamino)propyl]carbodiimide (EDC), 1.65 g of 1-hydroxybenzotriazole (HOBt), 1.7 ml of triethylamine and 3.23 g of the product of Example 280e. The reaction mixture was stirred at room temperature overnight, then washed with 0.1 M hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution.

438 needles, then the organic phase was concentrated. The residue was purified by flash chromatography using a 95:5 (v/v) methylene chloride/methanol solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 4.0 g (66.6 % yield). MS: 492.4 (M + H) ⁺ .

b.) tert-Butyl 1-[1-[(3-hydroxy-4-azepanyl)carbamoyl]-1,3-dimethylbutyl}carbamate

To a solution of 3.04 g (8.00 mmol) of the product of Example 330a in 50 ml of ethyl acetate was added 1.5 g of 10% palladium/carbon catalyst. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 48 h, then filtered through Celite and the filtrate was concentrated. The title compound was obtained as a residue as a yellow oil in an amount of 1.97 g (100% yield). MS (ESI): 358.4 (M + H) ⁺ .

c.) tert-Butyl-N-fl-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-1,3-dimethylbutyl}carbamate

1.25 g of 2-mercaptan-IV-oxide was dissolved in 5.5 ml of concentrated hydrochloric acid. The solution was cooled to 0 °C, then 3 ml of water was added. Chlorine gas (Cl ₂ ) was bubbled into the resulting solution for 1.5 h, then the aqueous solution was extracted with cold methylene dichloride. The organic solutions were combined, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then the freshly prepared sulfonyl chloride was added at a temperature above 0 °C to 1.20 g of

The product of Example 330b and 1.3 ml of triethylamine were added to 10 ml of diethylamine.

- 439 - ..··«··..· to a solution prepared in chloroethane. The reaction mixture was stirred for one hour, then washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography using a 95:5 (v/v) methylene dichloride/methanol solvent mixture as the eluent. The filtrate was concentrated to give the title compound as a white solid (1.2 g, 70% yield). MS: 515.4 (M + H) ⁺ .

d.) N-{3-Hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-2-amino-2,4-dimethylpentanamide

To a stirred solution of 1.0 g (2.04 mmol) of the product of Example 330c in 10 ml of methanol was added 10 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred for 3 h at room temperature and then concentrated. The residue (0.81 g (1.53 mmol) of a white solid obtained in 75% yield) was dissolved in 30 ml of methanol and 2.9 g (2.63 mmol/g) of P-COg was added to the solution. The reaction mixture was shaken for 2 h, then filtered and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 0.57 g (1.45 mmol) (95% yield). MS: 415.4 (M + H) ⁺ .

e.) N-{1,3-Dimethyl-1-[{3-hydroxy-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

To a solution of 0.105 g (0.448 mmol) of the product of Example 330d in 20 ml of methylene chloride was added 0.109 g of 3-me .: .··. .··. .*· • · ··· ·· ·· ·

I · · · · · · ······« · · *· ··

- A solution of 440 til-2-benzofurancarboxylic acid, 0.106 g (0.762 mmol) 1-hydroxybenzotriazole and 0.85 g (1 mmol/g) P-EDC in 10 ml methylene chloride was added. The reaction mixture was shaken overnight at room temperature, then 0.589 g (3.75 mmol/g) tisamine was added. The reaction mixture was shaken for an additional 3 h, then filtered, and the filtrate was concentrated. The title compound was obtained as a white solid in an amount of 166.7 mg (70 % yield). MS (ESI): 573.2 (M + H) ⁺ .

f.) N-{1,3-Dimethyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

To a stirred solution of 140.7 mg (0.245 mmol) of the product of Example 330e in 2 ml of dimethyl sulfoxide was added 155.7 mg (0.98 mmol) of sulfur trioxide/pyridine complex and 0.27 ml (1.96 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 2 hours, then water and ethyl acetate were added to quench the reaction. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography using a 95:5 methylene chloride/methanol solvent mixture as the eluent. The title compound was obtained as a white solid in an amount of 69.9 mg (50.8% yield). MS (ESI): 571.2 (M+H) ⁺ .

- 441 - J..:.. ..··-··..·

Example 331

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

a.) tert-Butyl-{(S)-1-[{3-hydroxy-1-[(2-quinolyl)-methyl]-4-azepanyl}-carbamoyl]-3-methyl-butyl}-carbamate

To a solution of 1.0 g of the product of Example 280g in methylene chloride was added 0.68 g of a-quinolinecarbaldehyde and 1.2 g of sodium [triacetoxyhydridoborate](1—) reagent. After work-up, the crude product was subjected to column chromatography, using a 6:94 volume methanol/methylene dichloride solvent mixture as the eluent. As a result, 1.4 g of the title compound was isolated. MS (ES) 485 (M + H) ⁺ .

b.) N-{3-Hydroxy-1-[(2-quinolyl)methyl]-4-azepanyl}-(S)-2-amino-4-methylpentanamide

To a solution of 1.4 g of the product of Example 331a in 20 ml of methanol was added 20 ml of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred until complete and then concentrated. The residue yielded 1.3 g of the title compound. MS (ES) 385 (M + H ⁺ ).

c.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-quinolyl)-methyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 291c, except that 2-benzofurancarboxylic acid was used instead of 5-fluoro-2-benzofurancarboxylic acid. MS (ES) 545 (M + H) ⁺ .

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-quinolyl)-methyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide

- 442 - .:· .:·· ··· ·-’ ····

The title compound was prepared according to the general procedure of Example 291d, except that the product of Example 331c was used. MS (ES) 543 (M + H) ⁺ .

Example 332

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)methyl]-4-azepanyl}carbamoyl]butyl)-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 331c-d, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 541 (M + H) ⁺ .

Example 333

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)methyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 331c-d, except that benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 541 (M + H) ⁺ .

Example 334

Preparation of N~{(S) -3-methyl-1-[{3-oxo-1-[{[(2-tolyl)sulfonyl]amino)carbonyl]-4-azepanyl)carbamoyl]butyl}-2-benzofurancarboxamide .1 .··.

- 443 - J. -λ ·-’·

a.) tert-Butyl-N-{(S)-1-[{3-hydroxy-1-[{[(2-tolyl)-sulfonyl]-amino}-acetyl]-4-azepanyl}-carbamoyl]-3-methyl-butyl}-carbamate

To a solution of 1.0 g of the product of Example 280g in methylene chloride was added 0.68 g of [(2-tolyl)sulfonyl]isocyanate. The reaction mixture was stirred until the starting compound was completely converted. After work-up, the crude product was subjected to column chromatography using a 6:94 volume methanol/methylene dichloride solvent mixture as eluent. As a result, 1.28 g of the title compound was isolated. MS (ES) 541 (M + H) ⁺ .

b. ) N-{3-Hydroxy-1-[{[(2-tolyl)sulfonyl]amino)acetyl]-4-

- azepanyl}-(S)-2-amino-4-methylpentanamide

The title compound was prepared according to the procedure of Example 283a, except that the starting material was Example 334a. MS (ES) 441 (M + H ⁺ ).

c.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[{[(2-tolyl)-sulfonyl]-

- amino)carbonyl]-4-azepanyl}carbamoyl]butyl)-2-

-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 280i, except that the starting material was Example 334b. MS (ES) 585 (M + H ⁺ ).

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[{[(2-tolyl)-sulfonyl]-amino)-

- carbonyl]-4-azepanyl)-carbamoyl]-butyl)-2-

-benzofurancarboxamide

- 444 The title compound was prepared according to the procedure of Example 291d, except that the starting material was Example 334c. MS (ES) 583 (M + H ⁺ ).

Example 335

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 334c-d, except that 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 597 (M + H) ⁺ .

Example 336

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 334c-d, except that benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 599 (M + H) ⁺ .

Example 337

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

445

The title compound was prepared according to the procedure of Examples 334a-d, except that [(2-chlorophenyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate. MS (ES) 603 (M + H) ⁺ .

Example 338

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that [(2-chlorophenyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate and 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 617 (M + H) ⁺ .

Example 339

Preparation of N~{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}benzo[±>]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that [(2-chlorophenyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate and benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 619 (M + H) ⁺ .

446

Example 340

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl)-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that [(2-chlorophenyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate. MS (ES) 587 (M + H) ⁺ .

Example 341

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)sulfonyl]amino)carbonyl]-4-azepanyl)carbamoyl]butyl)-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that [(4-fluorophenyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate and 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 601 (M + H) ⁺ .

Example 342 Preparation of γ-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)sulfonyl]amino)carbonyl]-4-azepanyl)carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that in this case [(4-fluoro-phenyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate and benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 603 (M + H) ⁺ .

Example 343

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that [(4-tolyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate. MS (ES) 583 (M + H) ⁺ .

Example 344

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 334a-d, except that [(4-tolyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate and 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 597 (M + H) ⁺ .

Example 345

Preparation of N—{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

- 448 - ··♦ -I·.

The title compound was prepared according to the procedure of Examples 334a-d, except that [(4-tolyl)sulfonyl]isocyanate was used instead of [(2-tolyl)sulfonyl]isocyanate and benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 597 (M + H) ⁺ .

Example 346

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2-pyridyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 6-methyl-2-pyridinecarbaldehyde was used instead of α-quinolinecarbaldehyde. MS (ES) 491 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 347

Preparation of γ-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2-pyridyl)methyl]-4-azepanyl}carbamoyl]butyl]-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 6-methyl-2-pyridinecarbaldehyde was used instead of α-quinolinecarbaldehyde and 3-methyl-2-benzofurancarboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 505 (M + H) ⁺ .

449

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 348

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2-pyridyl)methyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 6-methyl-2-pyridinecarbaldehyde was used instead of α-quinolinecarbaldehyde and benzo[b]thiophene-2-carboxylic acid was used instead of 2-benzofurancarboxylic acid. MS (ES) 507 (M + H) ⁺ .

After separation of the diastereomers by HPLC, a diastereomer 1 and a diastereomer 2 were isolated.

Example 349

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

a.) tert-Butyl-{(S)-1-[{3-hydroxy-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl)carbamoyl]-3-methylbutyl)carbamate 0.1 g (0.29 mmol) of the product of Example 280 g. prepared in tetrahydrofuran was added 32 ml (0.29 mmol) of (2-fluorophenyl)isocyanate. The reaction mixture was stirred for one hour, then the tetrahydrofuran was removed in vacuo. The product obtained as a residue was used directly in the next step. MS (ES) 481.02 (M + H) ⁺ .

450

b.) N-(2-Fluorophenyl)-4-{[(S)-2-amino-4-methylpentanoyl]amino}-3-hydroxy-1-azepanecarboxamide

To a solution of 1.96 g (4.1 mmol) of the product of Example 349a in methanol was added 5 ml (20.3 mmol) of 4 M hydrogen chloride in dioxane. The reaction mixture was stirred for 2 hours at room temperature. The excess reagent was then removed in vacuo and the residue was azeotroped with toluene to give 1.84 g of the desired product.

c.) N-{(S)-3-Methyl-1-[{3-hydroxy-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl)carbamoyl]butyl}benzo[b]thiophene-2-carboxamide

To a solution of 0.11 g (0.28 mmol) of the product of Example 439b in methylene chloride was added 0.35 g (1.8 mmol/g) of P-EDC, 0.06 g (0.49 mmol) of 1-hydroxybenzotriazole (HOBt) and 0.077 g (0.432 mmol) of 3-benzothiphenecarboxylic acid. The reaction mixture was shaken for 16 h, then 0.38 g (3.7 mmol/g) of trisamine was added, the reaction mixture was shaken for one hour, and the product was filtered off. The crude product was purified by column chromatography on silica gel to give 112.5 mg of the title compound. MS (ES) 541.2 (M + H) ⁺ .

d.) N-{(S)-3-Methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide 0.112 g (0.2 mmol) of the product of Example 349c. in methylene chloride was added with 0.175 g (0.41 mmol) of Dess-Martin periodane. The reaction mixture was stirred for one hour *« * ·* »·ί ·· ··· - 451 and then washed with aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The crude product was purified by column chromatography on silica gel, resulting in the isolation of 78 mg of product as a mixture of diastereomers. After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 539 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 539 (M + H) ⁺ .

Example 350

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 3-methyl-2-benzofurancarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 537 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 537 (M + H) ⁺ .

Example 351

Preparation of γ-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-2,4-dimethyl-3-furancarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 2,4-dimethyl-3-furancarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 501 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 501 (M + H) ⁺ .

Example 352

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl)-2-quinoxalinecarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 2-quinoxalinecarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 535 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 535 (M + H) ⁺ .

Example 353

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl)thieno[3,2-b]thiophene-2-carboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that thieno[3,2-b]thiophene-2-carboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 545 (M + _ «··· «9 ···

- 453 (H) ⁺ ; and 2nd diastereomer: MS (ES) 545 (Μ + H) ⁺ .

Example 354

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-2-quinolinecarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 2-quinolinecarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 534 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 534 (M + H) ⁺ .

Example 355

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-4-methyl-2-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 4-methyl-2-thiophenecarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 503 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 503 (M + H) ⁺ .

»Λ ) «ν *)* Ό «4 · » 4 >

- 454 - ·* ^:

Example 356

Preparation of Ν-((S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 5-methoxy-2-benzofurancarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 553 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 553 (M + H) ⁺ .

Example 357

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl)-4-methyl-2-furancarboxamide

The title compound was prepared according to the procedure of Example 349c-d, except that 4-methyl-2-furancarboxylic acid was used instead of benzo[b]thiophene-2-carboxylic acid.

After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 487 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 487 (M + H) ⁺ .

Example 358

Preparation of K-{(S)-1-[(1-butyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl]-2-benzofurancarboxamide

- 455

The title compound was prepared according to the procedure of Examples 331a-d, except that butyraldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 441.9 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 441.9 (M + H) ⁺ .

Example 359

Preparation of N-{(S)-1-[(1-propyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that butyraldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 441.9 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 441.9 (M + H) ⁺ .

Example 360

Preparation of N-[(S)—1—{[1-(2-fluorobenzyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 2-fluorobenzaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) (M + H) ⁺ ; and Diastereomer 2: MS (ES) 494.2 (M + H) ⁺ .

• * •'a ·<_ <·<

— 456 ~~ .’..*»· ’».·

Example 361

Preparation of N-{ (S)-3-methyl-1-[{3-oxo-1-[(2-morpholino-4-thiazolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 2-morpholino-4-thiazolecarbaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 568.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 568.4 (M + H) ⁺ .

Example 362

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(5-ethyl-2-furyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 5-ethyl-2-furfural was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 549.4 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 549.4 (M + H) ⁺ .

Example 363

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(3,4-dimethylthieno[3,2-b]thiophen-2-yl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

457

The title compound was prepared according to the procedure of Examples 331a-d, except that 3,4-dimethylthieno[b]thiophene-2-carbaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 566.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 566.2 (M + H) ⁺ .

Example 364

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(3-phenyl-3H-1,2,3-triazol-4-yl)-methyl]-4-azepanyl}-carbamoyl]-butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 2-phenyl-2H-3-pyrazolecarbaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 543.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 543.4 (M + H) ⁺ .

Example 365

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(3-isothiazolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 3-isothiazolecarbaldehyde was used instead of α-quinolinecarbaldehyde.

458 was used. After separation of the diastereomers by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 483.1 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 483.1 (M + H) ⁺ .

Example 366

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thienyl)methyl]-4-azepanyl}carbamoyl]butyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 2-thiophenecarbaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 582 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 582 (M + H) ⁺ .

Example 367

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(benzo[b]thiophen-2-yl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that benzo[Jb]thiophene-2-carbaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 546 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 546 (M + H) ⁺ .

459

Example 368

Preparation of N-{(S)-1-[(1-pentyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that pentanaldehyde was used instead of α-quinolinecarbaldehyde. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 556 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 556 (M + H) ⁺ .

Example 369

Preparation of N-((S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-2-imidazolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Examples 331a-d, except that 3-methyl-3H-4-imidazolecarbaldehyde was used instead of α-quinolinecarbaldehyde. MS (ES) 480.4 (M + H) ⁺ .

Example 370

Preparation of N~{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1-oxy-2-pyridinecarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that in this case 1-oxy-2-pyridinecarboxylic acid was used instead of 2-benzofurancarboxylic acid, and [(3-fluorophenyl)sulfonyl] chloride was used instead of [(2-pi

460 ridyl)sulfonyl] chloride was used. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 504.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 504.2 (M + H) ⁺ .

Example 371

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-oxy-3-pyridinecarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that 2-oxy-3-pyridinecarboxylic acid was used instead of 2-benzofurancarboxylic acid, and [(2-pyridyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 504.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 504.2 (M + H) ⁺ .

Example 372

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-1H-5-benzimidazolecarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that in this case 1H-5-benzimidazolecarboxylic acid was used instead of 2-benzofurancarboxylic acid and [(3-fluorophenyl)sulfonyl] chloride was used instead of [(2-pyridyl)sulfonyl] chloride. The diastereomers

461

After separation by HPLC, the following products were obtained: Diastereomer 1: MS (ES) 504.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 504.2 (M + H) ⁺ .

Example 373

Preparation of 4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino}-4-methylpentanoyl]amino}-1-methyl-3-oxo-1-pentylazepanium

A solution of the product of Example 368 in neat methyl iodide was refluxed for 48 hours and the reaction mixture was concentrated to give the title compound. MS (ES) 471.6 (M + H) ⁺ .

Example 374

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1,2-dimethyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that [(1,2-dimethyl-ΙΗ-4-imidazolyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. MS (ES) 544.4 (M + H) ⁺ .

Example 375

N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl]carbamoyl]butyl]-2

-production of benzofurancarboxamide

462

The title compound was prepared according to the procedure of Example 280h-j, except that [(1-methyl-1H-4-imidazolyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. MS (ES) 530.2 (M + H) ⁺ .

Example 376

Preparation of N-[(S)-1-{[1-{[4-(methylsulfonyl)phenyl]sulfonyl}-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that [(4-mesylphenyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 604.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 604.2 (M + H) ⁺ .

Example 377

Preparation of N-[(£>)-1-{[1-{[2-(methylsulfonyl)phenyl]sulfonyl}-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that [(2-mesylphenyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. The diastereomers

After separation by HPLC, the following products were obtained:

- 463 was obtained; Diastereomer 1: MS (ES) 604.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 604.2 (M + H) ⁺ .

Example 378

Preparation of N—{ (S)-3-methyl-1-[{3-oxo-1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 280h-j, except that [(3,5-dimethyl-4-isoxazolyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 545.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 545.2 (M + H) ⁺ .

Example 379

Preparation of N—{(1S,2R)-2-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

a.) N-{(IS,2R)-2-Methyl-1-[{3-hydroxy-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 280f-i, except that in this case N-Boc-allo-isoleucine was used instead of N-Boc-leucine, [(2-pyridyl)sulfonyl] chloride was used instead of [(3-fluorophenyl)sulfonyl] chloride, and 3464 was used instead of 2-benzofurancarboxylic acid.

-methyl-2-benzofurancarboxylic acid was used.

b.) N-{(1S,2R)-2-Methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl)-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the procedure of Example 291d, except that the starting material was Example 105b. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 541 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 541 (M + H) ⁺ .

Example 380

Preparation of N-{1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]cyclopentyl)-3-methyl-2-benzofurancarboxamide

The title compound was prepared according to the general procedure of Example 379a-b, except that N-Boc-cycloleucine was used instead of ΔΓ-Boc-allo-leucine. MS (ES) 539 (M + H) ⁺ .

Example 381

Preparation of N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl)carbamoyl]butyl}furo[3,2-b]pyridine-2-carboxamide

The title compound was prepared according to the procedure of Example 291c-d, except that instead of 5-fluoro-2-benzofurancarboxylic acid, furo[3,2-b]pyridin was used.

465 dine-2-carboxylic acid was used. After separation of the diastereomers by HPLC, the following products were obtained; Diastereomer 1: MS (ES) 544.2 (M + H) ⁺ ; and Diastereomer 2: MS (ES) 544.2 (M + H) ⁺ .

The above teachings and examples fully describe the possibilities of preparing and using the compounds of the invention. The specific embodiments do not limit the scope of the invention. The scope of protection is determined by the patent claims.

Claims (65)

1,2-dimethyl-1,2-imidazolyl-, 1-methyl-1,2-imidazolyl group; and 1-butyl group; 1-propyl group; 1-methylnaphtho[2,1-b]furan-2-yl group; 1-oxypyridyl group; and isoxazolyl group, isoxazolyl group substituted with C1-6 alkyl group. 1-oxypyridyl-swept; furo[3,2-b]pyridyl, furo[3,2-b]pyridyl substituted with C1-6 alkyl; thienyl group, thienyl group substituted with a C1-C6 alkyl group; thieno[3,2-b]thienyl group; and ΙΗ-5-benzimidazolyl group; and R represents ethyl, ethyl substituted with a C3-C6 cycloalkyl group; 474 propyl brushed; butyl group; isopentyl swept; phenyl group substituted with a halogen atom, phenyl group substituted with a C1-6 alkyl group, phenyl group substituted with a C1-6 alkylsulfonyl group; pyridyl group, pyridyl group substituted with a C1-C6 alkyl group; 1 *3 R is a group of general formula R; 1,2-dimethyl-1H-2-imidazolyl-, 1-methyl-1H-2-imidazolyl group; and 1-butyl acetate; 1-propyl group; 1-oxypyridyl group; and isoxazolyl group, isoxazolyl group substituted with a C1-C6 alkyl group. 1-methylnaphtho[2,1-b]furan-2-yl group; 1-oxypyridyl group; furo[3,2-b]pyridyl group, furo[3,2-b]pyridyl group substituted with a C1-C6 alkyl group; thienyl group, thienyl group substituted with a C1-6 alkyl group; thieno[3,2-b]thienyl group; and ΙΗ-5-benzimidazolyl group. C1-6 alkyl, Ar-467-(C0-6 alkyl) and Het-(C0-6 alkyl); R' represents a hydrogen atom; R represents a hydrogen atom; R'" represents a hydrogen atom; R is C1-6 alkyl, (C3-6 cycloalkyl)-(C0-6 alkyl), C2-6 alkenyl, C2-6 alkynyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl); and n is 1, 2, 3, 4 or 5 - and pharmaceutically acceptable salts, hydrates and solvates thereof. 1. A compound of general formula (IA) (IA) — in the formula of which group with general formula; 2 R is a C1-C6 alkyl group, Ar-(C0-C6 alkyl) group, Het-(C0-C6 alkyl) group, 9 9 911 911 a group of the general formula RC(O)-, R SO ₂ -, RR NC(O)- or R ⁵ S0 ₂ R NC(0)-; R is an alkyl group having 1-6 carbon atoms; 4 5 R is a group of the general formula RC(O)-; R is a Het-(C0-C6 alkyl) group; 9 R represents a C1-6 alkyl group, a C3-6 cycloalkyl-(C0-6 alkyl) group, an Ar-(C0-6 alkyl) group and a Het-(C0-6 alkyl) group; R means hydrogen atom, 2-pyridyl, 1-oxy-2-pyridyl group; 2-thienyl group; thieno[3,2-b]thiophen-2-yl; and 1H-5-benzimidazolyl. - 475 - 2-quinoxalinyl group; 1-oxy-2-pyridyl, 1-oxy-3-pyridyl group; furo[3,2-b]pyridin-2-yl; 2-quinolyl group; 2-benzofuranyl group; naphtho[2,1-b]furan-2-yl group; benzo[b]thiophen-2-yl group; 2-furyl group; 2 , 9 R means a group with the general formula R SO2-; R is isobutyl; and R is a C1-6 alkyl group, Ar-(C0-6 - 473 - - ·’ · ..··*··..’ alkyl) group and Het-(C0-C6 alkyl) group. (2-thienyl)methyl group; (benzo[b]thiophen-2-yl)methyl group; and (1-methyl-1H-2-imidazolyl)methyl group. 2-pyridyl, 1-oxy-2-pyridyl group; 2-thienylswept; thieno[3,2-b]thiophen-2-yl; and 1-5-benzimidazolyl. 2-quinoxalinyl group; 1-oxy-2-pyridyl, 1-oxy-3-pyridyl group; furo[3,2-b]pyridin-2-yl; 2-quinolyl group; 2-benzofuranyl group; naphtho[2,1-b]furan-2-yl group; 469 benzo[b]thiophen-2-yl group; 2-furyl group; 2. A compound according to claim 1, wherein R is group with a general formula. 3 . R is a C1-C6 alkyl group; 3,5-dimethyl-4-isoxazolyl group. 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-(methylsulfonyl)phenyl, 2-(methylsulfonyl)phenyl; 3-methylfuro[3,2-b]pyridin-2-yl group. (3-isothiazolyl)methyl group; (3-phenyl-3-hydroxy-1,2,3-triazol-4-yl)methyl group; (3,4-dimethylthieno[3,2-b]thiophen-2-yl)methyl group; 3,5-dimethyl-4-isoxazolyl group. 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-(methylsulfonyl)phenyl, 2-(methylsulfonyl)phenyl; 3-methylfuro[3,2-b]pyridin-2-yl group. 3 wherein R is present3 wherein R is an isobutyl group. 3. A compound according to claim 1, wherein the group is isobutyl or 2-butyl. The compound according to claim 4.5 R is a group of the general formula RC(O)-; R is Het-(C0-C6 alkyl)-group; R represents a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, an Ar-(C0-6 - C4-88 alkyl) group and C7-(C0-6 alkyl) group; R ¹¹ represents a hydrogen atom, a C 1-6 alkyl group, an Ar-(C 0-6 alkyl) group and an Het-(C 0-6 alkyl) group; R' represents a hydrogen atom; R represents a hydrogen atom; R' represents a hydrogen atom; R is a C1-6 alkyl group, a (C3-6 cycloalkyl)-(C0-6 alkyl) group, a C2-6 alkenyl group, a C2-6 alkynyl group, an Ar-(C0-6 alkyl) group, and a Het-(C0-6 alkyl) group; and n is 1, 2, 3, 4 or 5 — and salts, hydrates and solvates thereof. 4-{[(S)-2-{[(2-benzofuranyl)carbonyl]amino]-4-methylpentanoyl]amino}-1-methyl-3-oxo-1-pentyl-azepanium; N-{(S)-3-methyl-1-[{3-oxo-1-[(1,2-dimethyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl]carbamoyl]butyl]-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-[(S)-1-{[1-{[4-(methylsulfonyl)phenyl]sulfonyl]-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide; N-[(S)-1-{[1-{[2-(methylsulfonyl)phenyl]sulfonyl}-3-oxo-4-azepanyl]carbamoyl]-3-methylbutyl]-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(1S,2R)-2-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl]carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide; N-{1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]cyclopentyl}-3-methyl-2-benzofurancarboxamide; and Ν-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-furo[3,2-b]pyridine-2-carboxamide. - 486 - 5-methyl-2-thienyl group; and 5-methoxy-2-benzofuranyl, 5-fluoro-2-benzofuranyl, 3-methyl-2-benzofuranyl, 3,5-dimethyl-2-benzofuranyl, 3-ethyl-2-benzofuranyl, 5-fluoro-3-methyl-2-benzofuranyl, 5-methoxy-3-methyl-2-benzofuranyl, 4-methoxy-3-methyl-2-benzofuranyl and 6-methoxy-3-methyl-2-benzofuranyl; 5-[3-(trifluoromethyl)phenyl]-2-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 2,5-dimethyl-2-furyl and 2,4-dimethyl-3-furyl groups; (5-ethyl-2-furyl)methyl group; 5-methyl-2-thienyl group; and 5-methoxy-2-benzofuranyl, 5-fluoro-2-benzofuranyl, 3-methyl-2-benzofuranyl, 3,5-dimethyl-2-benzofuranyl, 3-ethyl-2-benzofuranyl, 5-fluoro-3-methyl-2-benzofuranyl, 5-methoxy-3-methyl-2-benzofuranyl, 4-methoxy-3-methyl-2-benzofuranyl and 6-methoxy-3-methyl-2-benzofuranyl; 5-[3-(trifluoromethyl)phenyl]-2-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 2,5-dimethyl-2-furyl and 2,4-dimethyl-3-furyl groups; 5. A compound according to claim 1, wherein R ^{3 * 5} represents a piperidylethyl group; benzo[1,3-]dioxolyl group; furyl group, aryl-substituted furyl group, C1-6 alkyl-substituted furyl group; benzofuranyl group, benzofuranyl group substituted with a C1-6 alkoxy group, benzofuranyl group substituted with a halogen atom, benzofuranyl group substituted with a C1-6 alkyl group; naphtho[2,1-b]furanyl, naphtho[2,1-b]furanyl substituted with a C1-C6 alkyl group; benzo[b]thienyl group; quinolyl group; quinoxaline swept; (6-methyl-2-pyridyl)methyl group; - 472 - ·«<·«·· .·»..· (2-morpholino-4-thiazolyl)-methyl group; 6. A compound according to claim 1, wherein R represents (1-piperidyl)ethyl; benzo[1,3]dioxol-5-yl group; 7. A compound according to claim 1, wherein R ⁵ meaning 8. A compound according to claim ¹ , wherein R5 is 3-methyl-2-benzofuranyl, thieno[3,2-b]thiophen-2-yl, 5-methoxy-2-benzofuranyl, 2-quinoxalinyl and 2-quinolyl. 9 9 lentese is an Ar-(C0-6 alkyl)-group, R is a group of the general formula C(O)- and R is a group of the general formula SO2. 9. A compound according to claim 1, wherein R ¹ is- 470 The group R3 is a group of general formula. 10. A compound according to claim 9, wherein R'' is C1-C6 alkyl. 11. A compound according to claim 10, wherein the C1-6 alkyl group is methyl. 12. A compound according to claim 1, wherein R ¹ is R' O R ^4/ is a group with the general formula ^L n. 13. A compound according to claim 12, wherein n is 3. 14. A compound according to claim 1, wherein R represents ethyl and ethyl substituted with C3-6 cycloalkyl; propyl group; butyl group; isopentyl swept; phenyl group, especially phenyl group substituted with a halogen atom, phenyl group substituted with a C1-6 alkoxy group, phenyl group substituted with a C1-6 alkylsulfonyl group; pyridyl group, pyridyl group substituted with a C1-C6 alkyl group; 15. A compound according to claim 1, wherein R represents a cyclohexylethyl group; 16. A compound according to claim 1, wherein ^R2 is selected from C1-6 alkyl, Ar-(C0-6 alkyl) and Het-(C0-6 alkyl). 17. A compound according to claim 16, wherein ^R2 is C1-6 alkyl and Het-(C0-6 alkyl). 18. A compound according to claim 17, wherein the C1-6 alkyl group and the Het-(C0-6 alkyl) group are methyl and pentyl groups substituted with Het groups. 19. A compound according to claim 18, wherein the methyl group substituted with Het is (2-quinolyl)methyl; 20. A compound according to claim 1, wherein R is present, z 9 9 is Ar-(0-6 alkyl)-, R C(O)-, R SO2- and R R NC(O)-. 21. A compound according to claim 20, wherein R is- 22. A compound according to claim 21, wherein R is a group of the general formula R SO2-. g 23. A compound according to claim 22, wherein R is selected from the group consisting of C1-6 alkyl, (C3-6 cycloalkyl)-(C0-6 alkyl), Ar-(C0-6 alkyl) and Het-(C0-6 alkyl). 24. A compound according to claim 1, wherein R' is 25. A compound according to claim 24, wherein R represents a piperidylethyl group; benzo[1,3-]dioxolyl group; furyl group, aryl-substituted furyl group, C1-6 alkyl-substituted furyl group; benzofuranyl group, benzofuranyl group substituted with a C1-6 alkoxy group, benzofuranyl group substituted with a halogen atom, benzofuranyl group substituted with a C1-6 alkyl group; naphtho[2,1-b]furanyl, naphtho[2,1-b]furanyl substituted with a C1-C6 alkyl group; benzo[b]thienyl group; quinolyl group; quinoxalinyl group; 26. A compound according to claim 24, wherein R represents (1-piperidyl)ethyl; benzo[1,3]dioxol-5-yl group; 27. A compound according to claim 24, wherein R ⁵ meaning 28. A compound according to claim 24, wherein R represents a cyclohexylethyl group; 29. A compound according to claim 24, wherein R is 3-methyl-2-benzofuranyl, thieno[3,2-b]thiophen-2-yl, 5-methoxy-2-benzofuranyl, 2-quinoxalinyl and 2-quinolyl. 30. A compound according to claim 29, wherein ^R5 is 3-methyl-2-benzofuranyl. 9 31. A compound according to claim 30, wherein R is 1-oxy-2-pyridyl. 32. A compound according to claim 1 selected from the group consisting of: N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide; N-{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}-(S)-4-methyl-2-{[3-(1-piperidyl)propionyl]amino}pentanamide; - N-{(S)-1-[{1-[(4-ethylphenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-benzo[1,3]dioxole-5-carboxamide; - N-[(S)-1-{[1-(3-cyclohexylpropionyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide; N-[(S)-1-{[1-(3-cyclohexylpropionyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]benzo[1,3]dioxole-5-carboxamide; N-[(S)-1-{[1-(4-methylpentanoyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-[3-(trifluoromethyl)phenyl]-2-furancarboxamide; N-[(S')-1-{[1-(4-methylpentanoyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]benzo[1,3]dioxole-5-carboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-fluoro-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-6-fluoro-3-methyl-2-benzofurancarboxamide; N-{(R)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methylfuro[2,3-b]pyridine-2-carboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-ΟΧΟ-4-azepanyl}carbamoyl]-3-methylbutyl}-5-methoxy-2-benzofurancarboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4478 -azepanyl}carbamoyl]-3-methylbutyl}-5-methyl-2-benzofurancarboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-OXO-4-azepanyl}carbamoyl]-3-methylbutyl}benzo[b]thiophene-2-carboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-3-methyl-2-furancarboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinolinecarboxamide; N-{(S')-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}thieno[3,2-b]thiophene-2-carboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-OXO-4-azepanyl}carbamoyl]-3-methylbutyl}-2-quinoxalinecarboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-2-thiophenecarboxamide; N-{(S)-1-[{1-[(3-fluorophenyl)sulfonyl]-3-oxo-4-azepanyl}carbamoyl]-3-methylbutyl}-5-methyl-2-thiophenecarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-benzofurancarboxamide; N-[(S)-l-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]4Ί9 -carbamoyl}-3-methylbutyl]benzo[b]thiophene-2-carboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-furancarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinolinecarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]thieno[3,2-b]thiophene-2-carboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinoxalinecarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-thiophenecarboxamide; N-[(S)-1-{[1-(ethylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methyl-2-thiophenecarboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methoxy-2-benzofurancarboxamide; N- [(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-benzofurancarboxamide W- [(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]benzo[b]thiophene-2-carboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-3-methyl-2-furancarboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2,5-dimethyl-2-furancarboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinolinecarboxamide; - 480 N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]thieno[3,2-b]thiophene-2-carboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-quinoxalinecarboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-thiophenecarboxamide; N-[(S)-1-{[1-(propylsulfonyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-5-methyl-2-thiophenecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3,5-dimethyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-3-ethyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-4-methoxy-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-1-methylnaphtho[2,1-b]furan-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)carbonyl]-4-azepanyl}carbamoyl]butyl}-6-methoxy-3-methyl-2-benzofurancarboxamide; - 481 N-{1,3-dimethyl-1-[{3-oxo-1-[(1-oxy-2-pyridyl)-carbonyl]-4 -azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S')-3-methyl-1-[{3-oxo-1-[(2-quinolyl)methyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide; W-{(S)-3-methyl-1-[{3-oxo-1-[(2-quinolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzo[b]thiophenecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-tolyl)sulfonyl]-amino}-carbonyl]-4-azepanyl}-carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2 -benzofurancarboxamide; N~ {(S)-3-methyl-1-[{3-oxo-1-[{[(2-chlorophenyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl}- 482 - -benzo[b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)sulfonyl]amino]carbonyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)sulfonyl]amino]carbonyl]-4-azepanyl}carbamoyl]butyl]-3-methyl-2-benzofurancarboxamide; N-{(S')-3-methyl-1-[{3-oxo-1-[{[(4-fluorophenyl)sulfonyl]amino]carbonyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl]-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)sulfonyl]amino}carbonyl]-4-azepanyl}carbamoyl]butyl]-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[{[(4-tolyl)sulfonyl]-amino}-carbonyl]-4-azepanyl}-carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2-pyridyl)methyl]-4-azepanyl]carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2-pyridyl)methyl]-4-azepanyl}carbamoyl]butyl}-3-methyl-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(6-methyl-2-pyridyl)methyl]-4-azepanyl}carbamoyl]butyl}benzo[b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4- -azepanyl}-carbamoyl]-butyl}-benzo[b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)-carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-3-methyl-2- -benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)-carbamoyl]-4-azepanyl}-carbamoyl]-butyl}-2,4-dimethyl-3- -furancarboxamide; 2N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-2-quinoxalinecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}thieno[3,2-b]thiophene-2-carboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-2-quinolinecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-4-methyl-2-thiophenecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-5-methoxy-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-fluorophenyl)carbamoyl]-4-azepanyl}carbamoyl]butyl}-4-methyl-2-furancarboxamide; N-{(S')-1-[(1-butyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide; N-{(S)-1-[(1-propyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide; N-[(S)-1-{[1-(2-fluorobenzyl)-3-oxo-4-azepanyl]carbamoyl}-3-methylbutyl]-2-benzofurancarboxamide; 484 N-{(S)-3-methyl-1-[{3-oxo-1-[(2-morpholino-4-thiazolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(5-ethyl-2-furyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(3,4-dimethylthieno[3,2-b]thiophen-2-yl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S')-3-methyl-1-[{3-oxo-1-[(3-phenyl-3H-1,2,3-triazol-4-yl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(3-isothiazolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-thienyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S')-3-methyl-1-[{3-oxo-1-[(benzo[b]thiophen-2-yl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-1-[(1-pentyl-3-oxo-4-azepanyl)carbamoyl]-3-methylbutyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(1-methyl-1H-2-imidazolyl)methyl]-4-azepanyl}carbamoyl]butyl}-2-benzofurancarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]-butyl}-1-oxy-2-pyridinecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4-azepanyl}carbamoyl]butyl}-2-oxy-3-pyridinecarboxamide; N-{(S)-3-methyl-1-[{3-oxo-1-[(2-pyridyl)sulfonyl]-4485 -azepanyl}-carbamoyl]-butyl}-1H-5-benzimidazolecarboxamide; 33. A pharmaceutical composition comprising a compound according to any one of claims 1-32 and a pharmaceutically acceptable carrier, diluent or excipient. 34. A pharmaceutical composition according to claim 33, which is used for inhibiting proteases. 35. The pharmaceutical composition of claim 34, wherein the protease is a cysteine protease or a serine protease. 36. The pharmaceutical composition of claim 35, wherein the protease is a cysteine protease. 37. The pharmaceutical composition of claim 36, wherein the cysteine protease is cathepsin K. 38. A pharmaceutical composition according to claim 33 for the treatment of bone loss diseases by inhibiting bone loss. 39. The pharmaceutical composition of claim 38, wherein the disease is osteoporosis. 40. The pharmaceutical composition of claim 38, wherein the disease is periodontitis. 41. The pharmaceutical composition of claim 38, wherein the disease is gingivitis. 42. A pharmaceutical composition according to claim 33, for treating diseases of excessive bone or cartilage loss by inhibiting excessive bone or cartilage loss. 43. The pharmaceutical composition of claim 42, wherein the disease is osteoarthritis. 44. The pharmaceutical composition of claim 42, wherein the disease is rheumatoid arthritis. 487 45. A pharmaceutical composition according to claim 33 for the treatment of parasitic diseases. 46. The pharmaceutical composition of claim 45, wherein the disease is schistosomiasis, malaria or an infection caused by Pneumocystis carinii, Trypsinoma cruzi, Trypsinoma brucei brucei and Crithidia fusiculata. 47. A compound with the general formula (HA) (HA) — in the formula of which “1 Meaning of R group with general formula; 2 R is a C1-C6 alkyl group, Ar-(C0-C6 alkyl) group, Het-(C0-C6 alkyl) group, 9 9 9 11q 11 a group of the general formula RC(O)-, R SO ₂ -, RR NC(O)- or R ^a SO ₂ R NC(O)-; 48. A process for the preparation of a compound according to claim 1, characterized in that a corresponding compound according to claim 47 is oxidized with an oxidizing agent to obtain the compound of general formula (IA) in the form of a mixture of diastereomers. 49. The process of claim 48, wherein the oxidizing agent is sulfur trioxide/pyridine complex with dimethyl sulfoxide and triethylamine. 50. The process of claim 48, wherein the process comprises separating the diastereomers by separation techniques. 51. The method of claim 50, characterized in that - 489 - It is known that the separation technique is high-pressure liquid chromatography (HPLC). 52. The process of claim 48, further comprising the step of deuterating the diastereomers with deuterating agents. 53. The method of claim 52, wherein the deuterating agent is a 10:1 mixture of CD3OD/D2O in triethylamine. 54. Use of a compound according to any one of claims 1-32 for the preparation of pharmaceutical compositions for use in inhibiting proteases selected from cysteine proteases and serine proteases. 55. The use of claim 54, wherein the protease is a cysteine protease. 56. The use of claim 55, wherein the cysteine protease is cathepsin K. 57. Use of a compound according to any one of claims 1-32 in the preparation of pharmaceutical compositions for the treatment of bone loss diseases. 58. The use of claim 57, wherein the disease is osteoporosis. 59. The use of claim 57, wherein the disease is periodontitis. 60. The use of claim 57, wherein the disease is gingivitis. 61. Use of a compound according to any one of claims 1-32 for the preparation of pharmaceutical compositions for the treatment of excessive bone or cartilage degradation diseases. 62. The use of claim 61, wherein the disease is osteoarthritis. 63. The use of claim 61, wherein the disease is rheumatoid arthritis. 64. Use of a compound according to any one of claims 1-32 for the preparation of pharmaceutical compositions for the treatment of parasitic diseases. 65. The use according to claim 64, wherein the disease is schistosomiasis, malaria or an infection caused by Pneumocystis carinii, Trypsinoma cruzi, Trypsinoma brucei brucei and Crithidia fusiculata.