Protease Inhibitors

专利摘要:
The present invention relates to 4-amino-azepan-3-one protease inhibitors which inhibit proteases comprising cathepsin K and their pharmaceutically acceptable salts, hydrates and solvates, pharmaceutical compositions of such compounds, novel Bone loss or excessive cartilage or matrix degradation, including osteoporosis, comprising inhibiting bone loss or excessive cartilage or matrix degradation by administering to a patient in need of such treatment, an intermediate, and a compound of the invention; Gum disease, including gingivitis and periodontitis; Arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; Pregnancy and calcium; And a method for treating metabolic bone disease.
公开号:KR20010089677A
申请号:KR1020017007989
申请日:1999-12-21
公开日:2001-10-08
发明作者:로버트 웰스 제이알. 마르키스；유 류；다니엘 프랑크 베버；맥스웰 데이빗 큐밍스；케빈 톰슨스코트；데니스 야마시타
申请人:스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스；스미스클라인 비참 코포레이션；
IPC主号:

专利说明:

Protease Inhibitors < RTI ID = 0.0 >
[2] Cathepsins are a group of enzymes that are part of the papain phase and cysteine proteases. Cathepsins B, H, L, N and S are described in the literature. In recent years, cathepsin K polypeptides and cDNAs encoding such polypeptides have been disclosed in US 5,501,969 (here called cathepsin O). Cathepsin K was recently published, purified, and characterized. Bossard, MJ et al. (1996) J. Biol. Chem . 271 , 12517-12524); Darke, FH et al. (1996) J. Biol. Chem . 271 , 12511-12516; Bromme, D et al. (1996) J. Biol. Chem . 271 , 2126-2132.
[3] Cathepsin K has been variously indicated in the literature as cathepsin O or cathepsin O2. The name cathepsin K seems to be more appropriate.
[4] Cathepsin acts on the normal physiological processes of protein degradation in animals, including humans, for example, connective tissue degradation. However, high levels of these enzymes in the body can cause pathological conditions that cause disease. Thus, it is believed that the cathepsins include infections caused by pneumocystis carinii, Cruz Trypanosoma bruce trypanosomiasis, and Cryptidia puficuccata as well as schistosomiasis, malaria, cancer metastasis, familial cerebral mesenchymal rhinorrhoea, muscular dystrophy, Have been implicated as causative factors in a variety of diseases (but not limited to). Reference is made to International Publication No. WO 94/04172, published March 3, 1994, and the references cited therein. See also European patent application EP 0 603 873 A1 and the literature cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the development of gingivitis (Potempa, J. et al. (1994) Perspectives in Drug Discovery & Design , 2 , 445-458).
[5] Cathepsin K is believed to act as a cause of excessive loss of bone or cartilage disease. The bone consists of a protein substrate with incorporated fusiform or plate-like crystals of hydroxyapatite. Type I collagen represents the major structural protein of bone, which constitutes about 90% of the protein substrate. The remaining 10% of the substrate consists of many non-collagen proteins, including osteocalcin, proteoglycans, osteopontin, osteoectin, thrombospondin, fibronectin and bone sialoprotein. Skeletal bone is remodeled in individual foci throughout life. This lesion, the remodeling unit, undergoes a cycle consisting of a bone resorptION phase followed by a bone replacement phase.
[6] Bone resorption is carried out by keel cells, which are multicellular cells of the hematopoietic lineage. The keel cells attach to the bone surface to form a tight seal area, followed by extensive membrane ruffling on its normal (i.e., absorbent) surface. This causes an enclosed extracellular compartment that is acidified by the proton pump in the rupled membrane to form on the bone surface, and the keel cells secrete proteases there. The low pH of this compartment dissolves the hydroxyapatite on the bone surface while the proteolytic enzyme digests the protein substrate. In this way, the absorption lacuna, or cow, is formed. At the end of this cycle, the osteoblasts lay a new protein substrate that is subsequently mineralized. In some disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and bone formation is broken, resulting in a net loss of bone per cycle. Ultimately, this weakens the bones and creates the risk of increased fractures in small trauma.
[7] Several published papers have shown that cysteine protease inhibitors are effective at inhibiting keolocyte mediated bone uptake and point to an important role for cysteine protease in bone resorption. See, e.g., Delaisse et al. , Biochem. J. , 1980 , 192, 365) discloses a series of protease inhibitors in the rat osteoblast system and serine protease inhibitors have no effect whereas cysteine protease inhibitors (e.g. leupeptin, Z-Phe-Ala- CHN ₂ ) inhibited bone resorption. See Delaisse et al. , Biochem. Biophys. Res. Commun ., 1984 , 125, 441) discloses that E-64 and leupeptin are also effective in preventing in vivo bone resorption, which was measured by a sharp change in serum calcium of a calcium deficient diet. Lerner et al., J. Bone Min. Res. , 1992 , 7, 433] discloses that cystatin (endogenous cysteine protease inhibitor) inhibits PTH-stimulated bone resorption in both murine rats. [Delaisse et al., Bone , 1987 , 8, 305], Hill et al . , J. Cell. Biochem ., 1994 , 56, 118] and Everts et al ., J. Cell. Physiol ., 1992 , 150, 221] also report correlations between inhibition of cysteine protease activity and bone resorption. Tezuka et al. , J. BIOl. Chem. , 1994 , 269, 1106], Inaoka et al. , Biochem. Biophys. Res. Commun. , 1995 , 206, 89, and Shi et al., FEBS Lett ., 1995 , 357, 129), under normal conditions, cathepsin K (cysteine protease) is abundantly expressed in keel cells and the main cysteine protease Lt; / RTI >
[8] This rich selective expression of cathepsin K in keel cells suggests that this enzyme is essential for bone resorption. Thus, the selective inhibition of cathepsin K selectively inhibits excessive bone loss disease, including, but not limited to, gum disease such as osteoporosis, gingivitis and periodontal disease, Paget's disease, malignant and calcium metabolism and metabolic bone disease Will provide an effective remedy. Cathepsin K levels were also demonstrated to increase in osteoarthritic synovial cartilage-absorbing cells. Therefore, selective inhibition of cathepsin K will also be useful for treating excessive cartilage or matrix degradation diseases including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic tumor cells also exhibit high levels of proteolytic enzymes that degrade surrounding substrates. Thus, selective inhibition of cathepsin K may also be useful in treating certain tumor diseases.
[9] Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem ., 38, 3193) discloses certain vinyl sulfones that irreversibly inhibit cysteine proteases such as cathepsins B, L, S, O2 and cruzain. Other classes of compounds also inhibit cysteine proteases such as aldehydes, nitriles, alpha-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy) methyl ketones, ketomethylsulfonium salts and epoxysuccinyl compounds. . See Palmer, id and the literature cited therein.
[10] US Patent U.S. Pat. 4,518,528 discloses peptidyl fluoromethyl ketone as an irreversible inhibitor of cysteine protease. Published International Application WO 94/04172, European Patent Application EP 0 525 420 A1, EP 0 603 873 A1 and EP 0 611 756 A2 describe alkoxymethyl ketones and mercaptomethyl ketones which inhibit cysteine protease cathepsins B, H and L Lt; / RTI > International patent application PCT / US94 / 08868 and European patent application EP 0 623 592 A1 describe alkoxymethyl ketones and mercaptomethyl ketones which inhibit cysteine protease IL-1 beta conferase. Alkoxymethyl ketones and mercaptomethyl ketones have also been described as inhibitors of serine protease kininogenases (International Patent Application PCT / GB91 / 01479).
[11] Aza peptides with good leaving groups have been reported to be transported to the active sites of serine proteases, see Elmore et al. , Biochem. J. , 1968 , IO7, IO3], Garker et al. , Biochem. J. , 1974 , 139, 555, Gray et al., Tetrahedron , 1977 , 33, 837, Gupton et al., J. Bio . Chem. , 1984 , 259, 4279 and Powers et al . , J. Bio. Chem ., 1984 , 259, 4288, and are known to inhibit serine proteases. Also, Med. Chem., 1992, 35, 4279) describe certain azapeptide esters as cysteine protease inhibitors.
[12] Antipine and leupeptin are described in McConnell et al . , J. Med. Chem ., 33, 86] and are described as inhibitors of serine proteases in Umezawa et al ., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well known cysteine protease inhibitors (Barrett, Biochem. J. , 201, 189 and Grinde, Biochem. Biophys. Acta ., 701, 328).
[13] ≪ RTI ID = 0.0 > 1,3-diamino-propanone < / RTI > 4,749,792 and 4,638,01O.
[14] Therefore, structurally diverse protease inhibitors have been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because of the various disadvantages. These disadvantages include lack of selectivity, cell destruction by cytotoxins, low solubility and excessively rapid plasma clearance. Therefore, there is a need for a method for treating diseases caused by pathological levels of proteases, particularly cysteine proteases, more particularly cathepsin, most particularly cathepsin K, and novel inhibitor compounds useful in such methods.
[15] The inventors of the present invention have now discovered a novel class of 4-amino-azepan-3-one compounds which are priestase inhibitors, most particularly cathepsin K inhibitors.
[1] The present invention relates generally to inhibiting 4-amino-azepan-3-one protease inhibitors, particularly cysteine and serine protease inhibitors, more particularly compounds inhibiting cysteine proteases, more particularly superfamily cysteine proteases , More particularly compounds that inhibit cathepsin and family cysteine proteases, most particularly compounds that inhibit cathepsin K. Such compounds are particularly useful for the treatment of diseases involving cysteine proteases, particularly bone or cartilage excess diseases such as osteoporosis, periodontitis and arthritis.
[16] SUMMARY OF THE INVENTION
[17] It is an object of the present invention to provide a pharmaceutical composition for the treatment of 4-amino-azepan-3-one carbonyl protease inhibitors, in particular cysteine and serine protease inhibitors, more particularly compounds inhibiting cysteine proteases, more particularly superfamily cysteine proteases , More particularly compounds inhibiting cathepsin and family cysteine proteases, most particularly compounds inhibiting cathepsin K, which inhibit the activity of the protease by altering the activity of the protease, ≪ RTI ID = 0.0 > and / or < / RTI >
[18] Thus, in one aspect, the invention provides compounds of formula (I).
[19] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
[20] In another aspect, the present invention provides intermediates useful for preparing compounds of formula (I).
[21] In yet another aspect, the present invention relates to the use of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, more particularly papain phases and cysteine proteases, more particularly cathepsin and cysteine proteases, The present invention provides a method for treating a disease in which the disease can be alleviated therapeutically.
[22] In a particular aspect, the compounds of the present invention are particularly useful for treating bone disorders such as osteoporosis and diseases characterized by gum disease, such as gingivitis and periodontitis, or by excessive degradation of cartilage or matrix such as osteoarthritis and rheumatoid arthritis .
[23] DETAILED DESCRIPTION OF THE INVENTION
[24] The present invention provides compounds of formula (I) and pharmaceutically acceptable salts, hydrates and solvates thereof.
[25]
[26] (here,
[27] R ¹ is And
[28] ≪ / RTI >
[29] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 9 C (O) -} , R 9 R ⁹ R ¹¹ NC (O) -, R ⁹ R ¹¹ NC (S) -, R ⁹ (R ¹¹ ) NSO ₂ -, R ⁹ SO ₂ -, R ⁹ C And ≪ / RTI >
[30] R ³ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, C _{6 O-alkyl} and _O-6 ArC the group consisting of alkyl,
[31] R ³ and R 'may be connected to form a pyrrolidine (204), piperidine or morpholine ring,
[32] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 5 C (O) -} , R 5 ^{C (S) -, R 5} SO 2 -, R 5 0C (O) - is selected from the group consisting ^{of, -, R 5 R 13 NC} (O) -, and R ⁵ R ¹³ NC (S)
[33] R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl and heteroaryl -C _{O Gt;} is selected from the group consisting of < RTI ID = 0.0 >
[34] R ⁶ is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _{heteroaryl-C O 6} group consisting of alkyl,
[35] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, heteroaryl, -C _0-6 alkyl, R ^lO C (O) -, R ^lO C (S) -, R ¹⁰ SO ₂ -, R ¹⁰ OC (O) -, R ¹⁰ R ¹⁴ NC (O) - and R ¹⁰ R ¹⁴ NC (S) -,
[36] R ⁸ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, _{O-C 6} alkyl, ArC _0-6 group consisting of alkyl,
[37] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-O-C 6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl,
[38] R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-O-C 6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl,
[39] R ¹¹ is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl,
[40] R ¹² is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ alkyl,
[41] R ¹³ is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ group consisting of alkyl,
[42] R ¹⁴ is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ alkyl,
[43] R 'is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ alkyl,
[44] R "is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, or a heteroaryl group consisting of -C _0-6 alkyl,
[45] R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-O-C 6} alkyl, and a heteroaromatic group consisting of -C _0-6 alkyl,
[46] X is selected from the group consisting of CH ₂ , S and O,
[47] Z is selected from the group consisting of C (O) and CH ₂ )
[48] In the compounds of formula (I), R < ¹ > Quot;
[49] R ³ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, -C _{6 O-alkyl, Ar-C O-6} group consisting of alkyl,
[50] R ³ is preferably selected from the group consisting of H, Ar-C _0-6 alkyl and C _1-6 alkyl,
[51] R ³ is more preferably selected from the group consisting of H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, -Ethyl, 1-hydroxyethyl, tolyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl,
[52] R < ³ > is more preferably selected from the group consisting of tolyl, isobutyl and cyclohexylmethyl,
[53] R ³ is most preferably isobutyl.
[54] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl C _O-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 5 C (O) -} , R 5 C ^{(S) -, R 5 SO} 2 -, R 5 0C (O) - is selected from the group consisting of ^{-, R 5 R 13 NC (} O) - , and ^{R 5 R 13 NC (S)} .
[55] R ⁴ is preferably R ⁵ 0C (O) - is selected from the group consisting of ^{-, R 5 C (O)} - and R ⁵ SO _2.
[56] R < ⁴ > is most preferably R < ⁵ > C (O) -.
[57] In some embodiments, R < ⁴ > is preferably methanesulfonyl.
[58] R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl or hetero _{O -C-6} Alkyl < / RTI >
[59] Preferably R ⁵ is selected from C _1-6 alkyl, _{Ar-C O-6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl.
[60] In the case of, - more preferably, R ⁵ is, in particular, R ⁴ R ⁵ C (O)
[61] Methyl, particularly halogenated methyl, more particularly trifluoromethyl, especially alkoxy substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, 2-thiophenyl-methyl;
[62] Butyl, especially aryl substituted butyl, more particularly 4- (4-methoxy) phenyl-butyl;
[63] Isopentyl;
[64] Cyclohexyl;
[65] Pentanonyl, especially 4-pentanonyl;
[66] Butenyl, especially aryl substituted butenyl, more particularly 4,4-bis (4-methoxyphenyl) -but-3-enyl;
[67] Acetyl;
[68] Phenyl, in particular phenyl substituted by one or more halogens, more particularly 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted by one or more alkoxy groups, more particularly 3,4-dimethoxy- Phenyl, 3-benzyloxy-4-methoxy-phenyl, especially phenyl substituted by one or more sulfonyl groups, especially 4-methanesulfonyl-phenyl;
[69] benzyl;
[70] Naphthalenyl, especially naphthylen-2-yl;
[71] Benzo [1,3] dioxolyl, especially benzo [1,3] dioxol-5-yl;
[72] Furanyl, in particular furan-2-yl, in particular 5-nitro-furan-2-yl, 5- (4-nitrophenyl) More particularly a 5-bromo-furan-2-yl, more particularly an aryl-substituted furanyl, even more particularly a 5- ( 4-chloro-phenyl) -furan-2-yl;
[73] Tetrahydrofuran-2-yl;
[74] Benzofuran-2-yl and substituted benzofuranyl, more particularly 5- (2-piperazine-4-carboxylic acid tert-butyl ester-ethoxy) (2-piperazin-1-yl-ethoxy) benzofuran-2-yl, 5- (2- Cyclohexyl-ethoxy) -benzofuran-2-yl; Especially alkoxy substituted benzofuranyl, more particularly 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran- Halogen substituted benzofuranyl, more particularly 5-fluorobenzofuran-2-yl (255), 5,6-difluoro-benzofuran-2-yl, especially alkyl substituted benzofuranyl, -Methyl-benzofuran-2-yl;
[75] Benzo [b] thiophenyl, especially benzo [b] thiophen-2-yl; Particularly alkoxy substituted benzo [bithiophenyl, more particularly 5,6-dimethoxy-benzo [b] thiophen-2-yl;
[76] Quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;
[77] Quinoxalinyl, especially quinoxalin-2-yl;
[78] 1,8-naphthyridinyl, especially 1,8-naphthyridin-2-yl;
[79] Indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially alkyl substituted indolyl, more particularly N-methyl-indol-2-yl;
[80] Pyridinyl, especially pyridin-2-yl, pyridin-5-yl, especially 1-oxy-pyridin-2-yl, especially alkyl substituted pyridinyl, more particularly 2-methyl-pyridin-5-yl;
[81] Thiophenyl, in particular thiophen-3-yl, in particular alkyl-substituted thiophenyl, more particularly 5-methyl-thiophen-2-yl, in particular halogen-substituted thiophenyl, more particularly 4,5- Thiophen-2-yl;
[82] Thieno [3,2-b] thiophenes, especially thieno [3,2-b] thiophen-2-yl, more particularly alkyl substituted thieno [ More particularly 5-tert-butyl-3-methylthieno [3,2-b] thiophen-2-yl;
[83] Isoxazolyl, especially isoxazol-4-yl, especially alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl;
[84] Oxazolyl, especially oxazol-4-yl, more particularly from the group consisting of 5-methyl-2-phenyl-oxazol-4-yl and 2-phenyl-5-trifluoromethyl-oxazol- Is selected.
[85] When R ⁴ is R ⁵ SO ₂ , R ⁵ is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.
[86] R 'is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _{heteroaryl-C O 6} group consisting of alkyl.
[87] Preferably, R ' is selected from the group consisting of H and naphthalen-2-yl-methyl,
[88] Most preferably R < 1 >
[89] R " is selected from the group consisting of H, Ci- ₆ alkyl, Ar- _C0-6 alkyl, and hetero- _C0-6 alkyl.
[90] Most preferably, R " is H.
[91] R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 O-alkyl} and _{O-heterocycloalkyl} -C ₆ group consisting of alkyl.
[92] R " is preferably selected from the group consisting of H and 6,6-dimethyl.
[93] Most preferably R " 'is H.
[94] In the compounds of formula (I), R ² is H, C _1-6 alkyl, C- _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl, heteroaryl, -C _0-6 alkyl, R ^{9 C (O) -, R} 9 C (S) -, R 9 SO 2, R 9 0C (O) -, R 9 R 11 NC (O) -, R 9 R 11 NC (S) -, R 9 R ¹¹ NSO ₂ -, , And ≪ / RTI >
[95] Preferably R ² is _{Ar-C O-6} ^{alkyl, R 9 C (O) -} , R 9 SO 2, R 9 R 11 NC (O) - and ≪ / RTI >
[96] More preferably R ² is _{Ar-C O-6} alkyl, R ⁹ C (O) - is selected from the group consisting of and R ⁹ SO _2,
[97] Most preferably, R ² is R ⁹ SO ₂ .
[98] In such an embodiment:
[99] R ⁶ is H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, or _O-heteroaryl -C ₆ are selected from the group consisting of alkyl and, preferably H.
[100] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 10 C (O) -} , R 10 ^{C (S) -, R 1O} SO 2 -, R 10 OC (O) -, R l0 R 14 NC (O) -, R 10 R 14 NC (S) - is selected from the group consisting of, R ⁷ is Preferably R < ¹⁰ > OC (O).
[101] R ⁸ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, _{O-C 6} alkyl and Ar-C _0-6 group consisting of alkyl, preferably C _1-6 alkyl, more preferably isobutyl.
[102] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl.
[103] R ⁹ is preferably selected from the group consisting of C _1-6 alkyl, _{Ar-C O-6} alkyl and _heteroaryl-O -C ₆ alkyl.
[104] More preferably, R < ⁹ > is
[105] methyl;
[106] Ethyl, especially C _1-6 alkyl-substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[107] Butyl, especially C _1-6 butyl, more particularly 3-methylbutyl;
[108] Particularly when the R ² is R ⁹ 0C (O) tert- butyl;
[109] Isopentyl;
[110] Phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C _{1- 6} alkoxyphenyl, more particularly 3-methoxyphenyl. 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more particularly 2-cyanophenyl;
[111] Tolyl, especially hetero-substituted tolyl, more particularly 3- (pyridin-2-yl) tolyl;
[112] Naphthylene, especially naphthyl-2-ene;
[113] Benzoic acid, especially 2-benzoic acid;
[114] Benzo [1,3] dioxolyl, especially benzo [1,3] dioxol-5-yl;
[115] Benzo [1,2,5] oxadiazolyl, especially benzo [1,2,5] oxadiazol-4-yl;
[116] Especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; Especially C _1-6 alkylpyridinyl, more particularly 3-methyl-pyridin-2-yl, 6-methyl-pyridin-
[117] Thiophenes, especially thiophen-2-yl;
[118] Thiazolyl, especially thiazol-2-yl;
[119] Imidazolyl, especially 1 H-imidazol-2-yl, 1 H-imidazol-4-yl, more especially C _1-6 alkyl substituted imidazolyl, 2-yl, 1-methyl-1H-imidazol-4-yl;
[120] 1H- [1,2,4] triazolyl, particularly 1H- [1,2,4] triazol-3-yl, more particularly C _1-6 alkyl substituted 1H- [1,2,4] triazolyl , More particularly 5-methyl-1H- [1,2,4] triazol-3-yl.
[121] When R ² is R ⁹ SO ₂ , R ⁹ is most preferably selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-yl.
[122] R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl; Preferably selected from the group consisting of C _1-6 alkyl, _{Ar-C O-6} alkyl and _heteroaryl-O -C ₆ alkyl.
[123] Z is selected from the group consisting of C (O) and CH ₂ .
[124] R < ^{2 >} is also preferably
[125] H;
[126] Tolyl;
[127] Aryl substituted ethyl, especially 2-phenylethyl, 2- [3- (pyridin-2-yl) phenyl] ethyl.
[128] Compounds of formula (I) wherein R " and R " 'are both H are preferred.
[129] R ¹ is ego,
[130] R ² is _{Ar-C O-6} ^{alkyl, R 9 C (O) -} , R 9 SO 2, R 9 R 11 NC (O) - and ≪ / RTI >
[131] R ³ is selected from the group consisting of H, C _1-6 alkyl and _O-6 alkyl, Ar-C,
[132] R ⁴ is selected from the group consisting of R ⁵ OC (O) -, R ⁵ C (O) - and R ⁵ SO ₂ ,
[133] R ⁵ is selected from C _1-6 alkyl, _{Ar-O-C 6} alkyl, and -C heterocyclic group consisting of _0-6 alkyl,
[134] R < ⁶ > is H,
[135] R < ⁷ > is R < ¹⁰ > OC (O)
[136] R < ⁸ > is _C1-6alkyl ,
[137] R ⁹ is selected from C _1-6 alkyl, _{Ar-O-C 6} alkyl, and -C heterocyclic group consisting of _0-6 alkyl,
[138] R ¹⁰ is selected from C _1-6 alkyl, _{Ar-O-C 6} alkyl, and -C heterocyclic group consisting of _0-6 alkyl,
[139] R 'is H,
[140] R " is H,
[141] R " 'is H,
[142] (I) wherein Z is selected from the group consisting of C (O) and CH ₂ .
[143] R ² is _{Ar-C O-6} ^{alkyl, R 9 C (O) -} , R 9 are those compounds of formula (I) SO is selected from the group consisting of ₂ is more preferable.
[144] R ¹ is ego,
[145] R ² is _{Ar-C O-6} alkyl, R ⁹ C (O) - is selected from the group consisting of and R ⁹ SO _2,
[146] R ³ is selected from the group consisting of H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, -Hydroxyethyl, toluyl, naphthalene-2-ylmethyl, benzyloxymethyl and hydroxymethyl,
[147] R < ⁴ > is R < ⁵ > C (O)
[148] R < ⁵ > is selected from the group consisting of methyl, especially halogenated methyl, more particularly trifluoromethyl, especially alkoxy substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxy- Especially 2-thiophenyl-methyl;
[149] Butyl, especially aryl substituted butyl, more particularly 4- (4-methoxy) phenyl-butyl;
[150] Isopentyl;
[151] Cyclohexyl;
[152] Pentanonyl, especially 4-pentanonyl;
[153] Butenyl, especially aryl substituted butenyl, more particularly 4,4-bis (4-methoxyphenyl) -but-3-enyl;
[154] Acetyl;
[155] Phenyl, in particular phenyl substituted by one or more halogens, more particularly 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted by one or more alkoxy groups, more particularly 3,4-dimethoxy- Phenyl, 3-benzyloxy-4-methoxy-phenyl, especially phenyl substituted by one or more sulfonyl groups, more particularly 4-methanesulfonyl-phenyl;
[156] benzyl;
[157] Naphthylen-2-yl;
[158] Benzo [1,3] dioxolyl, especially benzo [1,3] dioxol-5-yl,
[159] Furanyl, in particular furan-2-yl, in particular 5-nitro-furan-2-yl, 5- (4-nitrophenyl) More particularly a halogen-substituted furanyl, more particularly 5-bromo-furan-2-yl, more particularly aryl-substituted furanyl, more particularly 5- 4-chloro-phenyl) -furan-2-yl;
[160] Tetrahydrofuran-2-yl;
[161] Benzofuran-2-yl and substituted benzofuranyl, more particularly 5- (2-piperazine-4-carboxylic acid tert-butyl ester-ethoxy) (2-piperazin-1-yl-ethoxy) benzofuran-2-yl, 5- (2- Cyclohexyl-ethoxy) -benzofuran-2-yl; Especially alkoxy substituted benzofuranyl, more particularly 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxybenzofuran- Substituted benzofuranyl, more particularly 5-fluorobenzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especially alkyl substituted benzofuranyl, most especially 3-methyl- Benzofuran-2-yl;
[162] Benzo [b] thiophenyl, especially benzo [b] thiophen-2-yl; Especially alkoxy substituted benzo [b] thiophenyl, more particularly 5,6-dimethoxy-benzo [b] thiophen-2-yl;
[163] Quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;
[164] Quinoxalinyl, especially quinoxalin-2-yl;
[165] 1,8-naphthyridinyl, especially 1,8-naphthyridin-2-yl;
[166] Indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially alkyl substituted indolyl, more particularly N-methyl-indol-2-yl;
[167] Pyridinyl, especially pyridin-2-yl, pyridin-5-yl, especially 1-oxy-pyridin-2-yl, especially alkyl substituted pyridinyl, more particularly 2-methyl-pyridin-5-yl;
[168] Thiophenyl, in particular thiophen-3-yl, in particular alkyl-substituted thiophenyl, more particularly 5-methyl-thiophen-2-yl, in particular halogen-substituted thiophenyl, more particularly 4,5- Thiophen-2-yl;
[169] Thieno [3,2-b] thiophenes, especially thieno [3,2-b] thiophen-2-yl, more particularly alkyl substituted thieno [ , More particularly 5-tert-butyl-3-methyl-thieno [3,2-b] thiophen-2-yl;
[170] Isoxazolyl, especially isoxazol-4-yl, especially alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl;
[171] Oxazolyl, especially oxazol-4-yl, more particularly 5-methyl-2-phenyloxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol- ,
[172] R ⁹ is
[173] methyl;
[174] Ethyl, especially C _1-6 alkyl-substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[175] Butyl, especially C _1-6 butyl, more particularly 3-methylbutyl;
[176] Particularly when the R ² is R ⁹ 0C (O) tert- butyl;
[177] Isopentyl;
[178] Phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C _{1- 6} alkoxyphenyl, more particularly 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more particularly 2-cyanophenyl;
[179] Tolyl, especially hetero-substituted tolyl, more particularly 3- (pyridin-2-yl) tolyl;
[180] Naphthylene, especially naphthyl-2-ene;
[181] Benzoic acid, especially 2-benzoic acid;
[182] Benzo [1,3] dioxolyl, especially benzo [1,3] dioxol-5-yl;
[183] Benzo [1,2,5] oxadiazolyl, especially benzo [1,2,5] oxadiazol-4-yl;
[184] Especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; Particularly C _1-6 alkylpyridinyl, more particularly 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl;
[185] Thiophenes, especially thiophen-2-yl;
[186] Thiazolyl, especially thiazol-2-yl;
[187] Imidazol-2-yl (74), 1H-imidazol-4-yl, more particularly C _1-6 alkyl substituted imidazolyl, more particularly 1-methyl- Imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;
[188] 1H- [1,2,4] triazolyl, particularly 1H- [1,2,4] triazol-3-yl, more particularly C _1-6 alkyl substituted 1H- [1,2,4] triazolyl , More particularly 5-methyl-1H- [1,2,4] triazol-3-yl,
[189] R 'is H,
[190] R " is H,
[191] Very particular preference is given to compounds of the formula (I) in which R " 'is H.
[192] R ¹ is ego,
[193] R ² is R ⁹ SO ₂ ,
[194] R ³ is isobutyl,
[195] R < ⁴ > is R < ⁵ > C (O)
[196] R ⁵ is selected from the group consisting of 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen- 2-yl, preferably 3-methyl-benzofuran-2-yl,
[197] R ⁹ is selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-yl, preferably 1-oxy-pyridin-
[198] R 'is H,
[199] Most preferred are compounds of formula (I) wherein R "'is H.
[200] Compounds of formula (I) selected from the following group are particularly preferred embodiments of the invention.
[201] Example No. Compound No.
[202] 1 {(S) -1- [1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl) carbamic acid benzyl ester
[203] 2 naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl)
[204] -3-methyl-butyl] -amide
[205] 3-benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1- benzyl-3- oxo-azepan-4- ylcarbamoyl)
[206] 4-benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl]
[207] 5-benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4-ylcarbamoyl)
[208] 6 naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-
[209] Methyl-butyl] -amide
[210] 7-quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4-ylcarbamoyl)
[211] 8 3,4-Dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[212] (3-pyridin-2-yl-phenyl) - < / RTI > Acetyl] -azepanium
[213] (S) -2 - [(2-quinoline-2-carbonyl) -amino] -4-methyl- -Pentanoylamino} -3-oxo-azepanium < / RTI >
[214] 11 1-Benzoyl-4 - ((S) -2- (benzo [1,3] dioxole-carbonylamino)
[215] Pentanoylamino) -3-oxo-azepanium < / RTI >
[216] 12 1-Benzoyl-4 - ((S) -2- (4-fluoro-benzoylamino) -4-methyl-pentanoylamino) -3-
[217] 3-oxo-4 - ((S) -4-methyl-2 - {[5- (2-morpholino- Amino) -1- (4-methyl-pentanonyl) -azepanium
[218] 14 Preparation of 5- (2-morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl- 3-methyl-butyl] -amide < / RTI >
[219] Carbonyl] amino} -pentanoylamino) - (4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) 3-oxo-azepane-1-carboxylic acid phenylamide
[220] 16 - (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) Pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[221] Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl- -3-methyl-butyl] -amide
[222] 18 Preparation of 5- (2-pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl- Carbamoyl) -3-methyl-butyl] -amide
[223] To a solution of 19 5- (2-piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1 -benzenesulfonyl- Carbamoyl) -3-methyl-butyl] -amide
[224] 2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3- Pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -
[225] Butyl) -amide
[226] 21 naphthylene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Ylcarbamoyl} -butyl) -amide < / RTI >
[227] 22 1H-Indole-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- (3- Ylcarbamoyl} -butyl) -amide < / RTI >
[228] 23 < 1 > H-indole-2-carboxylic acid [(S) -1- (1 -benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)
[229] 24-Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[230] 25 benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- (3- pyridin- Ylcarbamoyl} -butyl) -amide < / RTI >
[231] 26 Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3- 4-ylcarbamoyl) -butyl] -amide
[232] 27 naphthylene-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-phenethyl-azepan-4- ylcarbamoyl) -butyl]
[233] 28 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[234] 29 naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azetan-4-ylcarbamoyl] amides
[235] 30 Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- Trifluoromethyl-phenyl) -azepan-4-ylcarbamoyl] butyl} amide
[236] 31 4 - ((S) -4-Methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-
[237] Yl] -amino} -pentanoylamino) -3-oxo-azepane-1-carboxylic acid tert-butyl ester
[238] 32 S - ^ - ((S) -4-Methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) -benzofuran- -1- (3-oxo-azepan-4-ylcarbamoyl) butyl] -amide
[239] 33 Preparation of 4-methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin- 2-yl- phenyl) -acetyl] -azepan-
[240] (S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin- -Naphthylene-2-methyl-carbamic acid tert-butyl ester
[241] 35 (S) -4-Methyl-2 - [(naphthylen-2-ylmethyl) -amino] -pentenoic acid { ] -Azepan-4-yl} -amide
[242] 36 Synthesis of 4- [2- (2 - {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Ylmethyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[243] 37 Preparation of 5- (2-piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- ) -Azepan-4-ylcarbamoyl] -3-butyl} -amide
[244] 38 Preparation of 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- Yl-carbamoyl] -butyl} -amide
[245] 39 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S)
[246] (3-oxo-l- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepan-4- ylcarbamoyl} -butyl)
[247] 40 4- [2- (2 - {(S) -3 -methyl-1- [3-oxo- 1- (3-pyridin- ] -Butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[248] (S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridinyl) -piperidin- Yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[249] 42 (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-oxo-1- (pyridine- amides
[250] 43 (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid { Azepan-4-yl} -amide
[251] 44 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylate ((S) -3-
[252] Methyl-1- {3-oxo-1- [2- (3-pyridin-2- yl- phenyl) acetyl] -azepan-4- ylcarbamoyl} -butyl) -amide
[253] 45 benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide
[254] 46 Preparation of 2,2,2-trifluoro-N - ((S) -3-methyl-1- {3-oxo- 1- [2- Yl-carbamoyl} -butyl) -N-naphthylen-2-ylmethyl-acetamide
[255] 47 4 - [(S) - (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3-oxo-azepane- 1 -carboxylic acid benzyl ester
[256] 48 quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
[257] 49 quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
[258] (3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[259] 51 < / RTI > quinoline-4-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl]
[260] 52 quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
[261] 53 isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[262] 54 isoquinoline- 1 -carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[263] 55-quinoxaline-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azetan-4-ylcarbamoyl] amides
[264] 56 benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[265] 57 1, 8-Naphthyridine-2-carboxylic acid {(S) -3-methyl- 1- (3- oxo- 1- (pyridine- 2- sulphonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[266] 58 <i> H-indole-2-carboxylic acid {(S) -3-methyl- -amides
[267] Preparation of 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ ] -Butyl} -amide
[268] 60 S-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [ -Butyl} -amide
[269] 61 Furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (pyridine- 2- sulfonyl)
[270] Yl-carbamoyl] -butyl} -amide
[271] 62 Synthesis of 5-nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [ Butyl} -amide
[272] 63 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[273] Preparation of 64 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] butyl} -amide
[274] 65 tetrahydro- furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides
[275] 66 (S) -4-Methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo (pyridine- 2- sulfonyl)
[276] 67 (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-oxo- (pyridine- ]-amides
[277] 68 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- }-amides
[278] 69 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxypyridine- 2- carbonyl) -azepan-4-ylcarbamoyl] Butyl} -amide
[279] 70 4 - ((S) -2-tert-Butylcarbonylamino-4-methyl-pentanoylamino) -3-oxo-azepane- 1 -carboxylic acid benzyl ester
[280] 71 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [
[281] Methyl-1H-imidazole-4-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[282] 72 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole- Azepan-4-ylcarbamoyl] -butyl} -amide
[283] 73 benzo furan-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- 3 -sulfonyl) -3-oxo-azepan- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[284] 74 benzo furan-2-carboxylic acid {(S) -3-methyl-1- [1- (lH-imidazole- 2- sulfonyl) -3-oxo-azepan- Butyl} -amide
[285] 75 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -amides
[286] 76 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- 4- sulfonyl) -3-oxo-azepan- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[287] 77 &lt; RTI ID = 0.0 &gt; (S) -3-Methyl- 1- [3-oxo- 1- (pyridin- 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[288] 78 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 3- sulfonyl) -azepan-4- ylcarbamoyl] amides
[289] 79 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxypyridine- 3- sulfonyl) Butyl} -amide
[290] 4-ylcarbamoyl)] - 3-methyl-butyl} - (3-methyl-isoxazol- amides
[291] 81 &lt; RTI ID = 0.0 &gt; 5-Hydroxy-benzofuran-2-carboxylic &lt; / RTI &gt; Ylcarbamoyl] butyl} -amide
[292] 82 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[293] 83 2- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino}
[294] -3-oxo-azepan-1-sulfonyl) -benzoic acid
[295] 84 3- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino}
[296] -3-oxo-azepan-1-sulfonyl) -benzoic acid
[297] 85 benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [ Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[298] 86 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-
[299] Di-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[300] 87 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-
[301] Oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide
[302] 88 1-Oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [ Butyl} -amide
[303] 89 (S) -4-Methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-
[304] 90 (S) -2- (3-Benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
[305] 91 (S) -4-Methyl-2- (3-phenyl- ureido) -pentanoic acid [3-oxo-1- (pyridine-
[306] 92 benzo furan-2-carboxylic acid {(S) -1- [6,6-dimethyl-3-oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[307] 93 To a solution of 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[308] 94 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- Yl-carbamoyl] -butyl} -amide
[309] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[310] 96-quinoline-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) Butyl} -amide
[311] 97 thiophene-3-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[312] 98 1H-indole-5-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- ] -Butyl} -amide
[313] 99 benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} -amide
[314] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-
[315] Yl) -azepan-4-ylcarbamoyl] -butyl} -amide
[316] (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [
[317] - pyridine-2-sulfonyl) -azepan-4-yl] -amide
[318] Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (l-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide
[319] (S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-
[320] -4-carbamoyl] -butyl} -benzamide &lt; / RTI &gt;
[321] (S) -3-methyl-1- [3-oxo- (1-oxy-pyridin-2- Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[322] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[323] 1O6 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[324] 4-ylcarbamoyl] -butyl} -methyl-N - {(S) -3-methyl-1- [ } -Nicotinamide
[325] (S) -4-methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [3-oxo- }-amides
[326] (S) -3-methyl-l- [3-oxo-l- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amides
[327] 11O benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [ Yl] -butyl} -amide
[328] Benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl-1- [3- Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -
[329] amides
[330] 112 Preparation of 5-methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[331] 113 Synthesis of 4,5-dibromo-thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- -4-ylcarbamoyl] -butyl} -amide
[332] 114 Preparation of 3,5-dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[333] 115 (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4- methoxy- benzenesulfonyl)
[334] 116 &lt; RTI ID = 0.0 &gt; 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) Trifluoromethyl-phenyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[335] 117 Preparation of 5-methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- -4-ylcarbamoyl] -butyl} -amide
[336] 118 benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl) -butyl}
[337] 119 benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[338] 120 benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4- sulfonyl) -3-oxo-azepan- Yl] -3-methyl-butyl} -amide
[339] 121 benzo furan-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl- oxazole- 4- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[340] 122 Preparation of 3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -Butyl} -amide
[341] 123 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[342] 124 Synthesis of 5-tert-butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3- -Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[343] 125 Synthesis of 5-methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[344] 126 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-
[345] Oxo-l- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[346] 127-quinoline-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl-
[347] 128 1 -Methyl-1 H-indole-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) amides
[348] Methyl-butylcarbamoyl] -methyl} - &lt; / RTI &gt; &lt; RTI ID = 0.0 & -amides
[349] 3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] - &lt; / RTI &gt; amides
[350] 3-methyl-butyl] - amide (prepared as described in Example 1)
[351] 132 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [
[352] (Pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[353] 133 (S) -2- [2- (4-Methoxy-phenyl) -acetylamino] -4- methyl- pentanoic acid (1-
[354] Yl-3-oxo-azepan-4-yl) -amide
[355] 134 quinoline-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-
[356] Ylcarbamoyl] -3-methyl-butyl} -amide
[357] 135 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -1- [1- (2- cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl-butyl} -amide
[358] 136 Furan-2-carboxylic acid ({(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan- Carbamoyl} -methyl) -amide &lt; / RTI &gt;
[359] 137 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] - 3-methyl-butyl} -amide
[360] 138-quinoxaline-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[361] 139 (S) -2- [2- (4-Methoxy-phenyl) -acetylamino] -4-methyl- pentanoic acid [1- (2-cyano-benzenesulfonyl) 4-yl] -amide
[362] 140 quinoline-2-carboxylic acid {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-
[363] Ylcarbamoyl] -3-methyl-butyl} -amide
[364] 141 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -1- [1- (4- methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[365] 142 furan-2-carboxylic acid ({(S) -1- [l- (4-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[366] 143 Preparation of 5-methoxy-benzofuran-2-carboxylic acid {[(S) -1- [1- (4- methoxy- benzenesulfonyl) -3-oxo-azepan- -3-methyl-butyl} -amide
[367] 144 quinoxaline-2-carboxylic acid {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[368] 145 (S) -2- [2- (4-Methoxy-phenyl) -acetylamino] -4-methyl- pentanoic acid [1- (4- methoxy- benzenesulfonyl) 4-yl] -amide
[369] 146 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -1- [1- (4- fluorobenzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[370] 147 furan-2-carboxylic acid ({(S) -1- [1- (4-fluoro- benzenesulfonyl) -3-
[371] - azepan-4-ylcarbamoyl] -3-methyl-butylcarbamoyl} -methyl) -amide
[372] 148 Preparation of 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- (l- [4- fluoro-benzenesulfonyl] -3-oxo-azepan- 3-methyl-butyl} -amide
[373] Yl} carbamic acid {(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan- -amides
[374] 150 Preparation of (S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl- pentanoic acid [1- (4-fluoro-benzenesulfonyl) 4-yl] -amide
[375] 151-benzofuran-2-carboxylic acid {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] amides
[376] Preparation of 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3- -Methyl-butyl} -amide &lt; / RTI &gt;
[377] 3-oxo-azepan-4-ylcarbamoyl] -3 (3-chloro-benzenesulfonyl) -Methyl-butyl} -amide &lt; / RTI &gt;
[378] Preparation of 5,6-dimethoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl)
[379] -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[380] 155 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (3- chlorobenzenesulfonyl) -3-
[381] Oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[382] 156 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3- chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide
[383] 157 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -l- [l- (3-chloro-benzenesulfonyl)
[384] Yl] carbamoyl] -3-methyl-butyl} -amide
[385] -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} - &lt; / RTI &gt; -amides
[386] 159 benzofuran-2-carboxylic acid {(S) -1- [1- (2- fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[387] 160 Preparation of 5-methoxy-benzofuran-2-carboxylic acid {(S) -l- [l- (2- fluoro-benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[388] 161 &lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; 7-Methoxy-benzofuran-2-carboxylic acid {(S) -l- [1- (2- fluoro-benzenesulfonyl) 3-methyl-butyl} -amide
[389] 162 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-
[390] Benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl}
[391] 163 5-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (2- fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide
[392] 164 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2- fluoro- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[393] 165 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -1- [1- (2- fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] 3-methyl-butyl} -amide
[394] 166 (S) -4-Methyl-2- (1-oxy-pyridine- 2- sulfonylamino) -pentanoic acid 3-oxo-1- (pyridine- ]-amides
[395] 167 quinoxaline-2-carboxylic acid {(S) -1- [1- (2- fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[396] 168 Preparation of 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (thiophene-2-sulfonyl) Yl] -butyl} -amide
[397] 169 7-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (thiophene-2-sulfonyl) Yl] -butyl} -amide
[398] 170 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [
[399] -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[400] 171 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiophene- 2- sulfonyl) -azepan- ] -Butyl} -amide
[401] 172 benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- (3-oxo- 1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide
[402] 173 1 -Methyl-1-H-indole-2-carboxylic acid {(S) -3-methyl-1- [ Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[403] 174 quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2- sulfonyl) -amides
[404] 175 benzofuran-2-carboxylic acid {(S) -l- [l- (4-chloro-benzenesulfonyl) -3-oxo-azepan- 4- ylcarbamoyl] -amides
[405] 176 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Methyl-butyl} -amide &lt; / RTI &gt;
[406] 177 7-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [l- (4-chloro-benzenesulfonyl) -3-oxo-azepan- -Methyl-butyl} -amide &lt; / RTI &gt;
[407] 178 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl)
[408] -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[409] 179 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[410] 180 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide
[411] 181 l-Methyl-lH-indole-2-carboxylic acid {(S) -1- [l- (4-chloro-benzenesulfonyl)
[412] Yl] carbamoyl] -3-methyl-butyl} -amide
[413] 182 quinoxaline-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan- -amides
[414] 183 benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[415] 184 5-Methoxy-benzofuran-2-carboxylic acid {(S) -1 - [(3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[416] 185 &lt; / RTI &gt; 7-Methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[417] 186 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl)
[418] -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[419] 187 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[420] 188 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-methoxy-benzenesulfonyl)
[421] Yl] carbamoyl] -3-methyl-butyl} -amide
[422] 189 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -1- [l- (3-methoxy-benzenesulfonyl)
[423] Yl] carbamoyl] -3-methyl-butyl} -amide
[424] 190-quinoxaline-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -methyl- amides
[425] 191 benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (thiophene-2- sulfonyl) -amides
[426] 192 benzofuran-2-carboxylic acid {(S) -3-methyl-1 - [(2,2 ', 4-tridecarterio) -3-oxo-1- (pyridine- Azepan-4-ylcarbamoyl] -butyl} -amide
[427] 193 benzofuran-2-carboxylic acid {(S) -2-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[428] 194 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl}
[429] 195 benzo furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -amides
[430] 196 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -ethyl}
[431] 197 benzofuran-2-carboxylic acid {(S) -3-methanesulfinyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides
[432] 198 benzofuran-2-carboxylic acid {[3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -methyl}
[433] 199 benzo furan-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -pentyl}
[434] 200 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[435] 201 benzo furan-2-carboxylic acid {(S) -2-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azetan-4-ylcarbamoyl] amides
[436] 2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl} -amides
[437] 203-benzylfuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[438] 2O4 1- (Benzofuran-2-carbonyl) -pyrrolidine-2-carboxylic acid [3-oxo-1- (pyridine-
[439] 205 Preparation of 3,4-dimethoxy-N - {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Butyl} -benzamide
[440] 206 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4- methoxy- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[441] 207 benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (4- fluoro- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[442] A solution of 208 (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl)
[443] 209 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4-fluoro- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide
[444] 2-carboxylic acid {(S) -1- [1-benzoyl-3-oxo-azepan-4- ylcarbamoyl] -3-methyl- butyl}
[445] 211 (S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-
[446] Synthesis of (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-
[447] 213 benzofuran-2-carboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[448] 214 N - {(S) -1- [1- (4-Fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl]
[449] -3-methyl-butyl} -3,4-dimethoxy-benzamide
[450] 215 Cyclohexanecarboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan- 4- ylcarbamoyl] -3-methyl- butyl}
[451] 216 (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (methanesulfonyl) -3-oxo-azepan-
[452] 217 benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl-
[453] 218 benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1 -methanesulfonyl-3- oxo-azepan-4- ylcarbamoyl) -amides
[454] 219 benzofuran-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[455] 220 N - [(S) -1- (1 -methanesulfonyl) -3-oxo-azepan-4-ylcarbamoyl} -3-methyl- butyl} -3,4-dimethoxy-benzamide
[456] 221 Preparation of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [l- (2-cyano-benzenesulfonyl)
[457] 222 N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo- Phenyl-1-benzamide
[458] 223 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-cyano- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[459] 224 benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (2-cyano- benzenesulfonyl) -3-oxo-azepan- ] -3-methyl-butyl} -amide
[460] 225 (S) -4-Methyl-2- [4-oxo-4 - ((4-phenoxy- phenyl) -butyrylamino) -pentanoic acid [ ) -Azepan-4-yl] -amide
[461] 226 N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Dimethoxy-benzamide
[462] 227 Cyclohexanecarboxylic acid {(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4- ylcarbamoyl] -3-methyl- butyl}
[463] 228 4-Methanesulfonyl-N - [(S) -1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-
[464] 229 4-Methanesulfonyl-N - [(S) -1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-
[465] 23O {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl]
[466] -Butylcarbamoyl} -carbamic acid benzyl ester
[467] 231 (S) -2- [5- (4-Methoxy-phenyl) -pentanoylamino] -4-methyl-pentanoic acid [3-oxo-1- (pyridine- - yl] -amide
[468] 232 (S) -2- [2- (3-Benzyloxy-4-methoxy-phenyl) -acetylamino] -4- methylpentanoic acid Yl] -amide
[469] 233 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[470] 234 (S) -4-Methyl-2- (5-oxo-hexanoylamino) -pentanoic acid [3-oxo-1- (pyridine-
[471] 235 benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide
[472] 236 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[473] 237 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[474] 238 7-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan- ] -Butyl} -amide
[475] 239 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- 4-ylcarbamoyl] -butyl} -amide
[476] 240 (R) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -4-ylcarbamoyl] -butyl} -amide
[477] 241 (S) -1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -4-ylcarbamoyl] -butyl} -amide
[478] 242 benzofuran-2-carboxylic acid {(S) -2-cyclopropyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -amides
[479] 243 benzofuran-2-carboxylic acid {(S) -3-methylsulfanyl- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl }-amides
[480] 244 benzofuran-2-carboxylic acid {(S) -2-naphthylen-2-yl- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Ethyl} -amide
[481] 245 Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2 -sulfonyl) Yl-carbamoyl] -butyl} -amide
[482] 246 Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [ Yl-carbamoyl] -butyl} -amide
[483] 247 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[484] 248 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[485] 249 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1 -oxi-pyridine- Yl-carbamoyl] -butyl} amide
[486] Preparation of 250 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-oxo- Ylcarbamoyl] -ethyl} -amide &lt; / RTI &gt;
[487] 251 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-oxo-1- (pyridine- Ylcarbamoyl] -ethyl} -amide &lt; / RTI &gt;
[488] 252 benzofuran-2-carboxylic acid {(S) -3-methyl-l- [6-methyl-3-oxo-1- (pyridine- sulfonyl) -azepan-4-ylcarbamoyl] }-amides
[489] 253 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [ Azepan-4-ylcarbamoyl] -ethyl} -amide
[490] 254 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [ Trifluoromethyl-phenyl) -azepan-4-ylcarbamoyl] -ethyl} -amide
[491] Preparation of 5-fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ ] -Butyl} -amide
[492] Preparation of 256 5,6-dimethoxy-benzofuran-2-carboxylic acid {(S) -2-cyclohexyl- 1 - [3-oxo-1- (1-oxy- Ylcarbamoyl] -ethyl} -amide &lt; / RTI &gt;
[493] 257 5,5-Bis- (4-methoxy-phenyl) -pent-4-enoic acid {(S) -3-methyl- Yl-carbamoyl] -butyl} -amide
[494] 258 quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3- oxo- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -ethyl }-amides
[495] 259 naphthylene-1-carboxylic acid {(S) -2-naphthylen-2-yl-l- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Ethyl} -amide
[496] -2-phenyl-ethyl} - amide (prepared as described in Example 1, Step B)
[497] 261 naphthyridine-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[498] 262 naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[499] 263 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] Butyl} -amide
[500] 264 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (4- methyl- pentanoyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[501] 265 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy-
[502] Carbonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[503] 266 (S) -Acetylamino-4-methyl-pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-
[504] 267 quinoline-2-carboxylic acid {1- [3-oxo-1- (pyridine-2- sulfonyl) -azepan-4-ylcarbamoyl] -pentyl}
[505] 268 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (cyclohexyl-propionyl) -azepan-4- ylcarbamoyl] amides
[506] 269 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (4-methyl-pentanoyl) -azetan-4-ylcarbamoyl] amides
[507] -2-phenyl-ethyl} -amide &lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[508] 271 benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -amides
[509] 272 benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridin-
[510] Sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide
[511] 273 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide
[512] 274 7-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide
[513] 275 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[514] 276 benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [ ] -Butyl} -amide
[515] 277 1 -Methyl-1 H-indole-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (thiazole- Yl] -butyl} -amide
[516] 278 quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -amides
[517] 279 quinoline-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[518] Specific representative compounds of the present invention are set forth in Examples 1 to 279.
[519] Compared to the corresponding 5-membered and 6-membered ring compounds, the 7-membered ring compounds of the present invention are more stable in atomic arrangement at the carbon center which is in alpha position to the ketone.
[520] The present invention includes deuterated analogs of the compounds of the present invention. Representative examples of such deuterated compounds are given in Example 192. A representative synthesis method for the deuterated compounds of the present invention is shown in Scheme 4 below. The deuterated compounds of the present invention exhibit superior chiral stability over protonated isomers.
[521] Justice
[522] The present invention includes all hydrates, solvates, complexes and prodrugs of the present invention. Prodrugs are any covalently bonded compounds that release an active parent drug of formula (I) in vivo. It is intended that all such forms of isomers, including enantiomers and diastereomers, be included in the present invention, provided that the chiral centers or other forms of isomeric centers are present in the compounds of the present invention. The compounds of the present invention which contain a chiral center may be used as racemic mixtures (enantiomerically enriched mixtures), or as racemic mixtures by isolation of the racemic mixtures by well known methods. Both of the cis (Z) and trans (E) isomers are included within the scope of the present invention when the compound has a debonding carbon-carbon double bond. When the compound exhibits a tautomeric form such as a keto-enol tautomer, the respective tautomeric forms, whether present in equilibrium or predominantly in any form, are also considered to be within the scope of the present invention .
[523] The meaning of any substituent or formula of one of the compounds of formula (I) is independent of the meaning of the other compounds of formula (I), i.e. the meaning of the substituent, unless otherwise specifically defined.
[524] The abbreviations and symbols commonly used in the field of peptides and chemistry are used herein to describe the compounds of the present invention. In general, amino acid abbreviations are described in Eur. J. Biochem., 158, 9 (1984)]. The IUPAC-IUB Joint Committee on Biochemical Nomenclature follows.
[525] &Quot; Protease " is an enzyme that catalyzes the cleavage of amino bonds of peptides and proteins by nucleophilic substitution at the amide bond moiety and ultimately causes hydrolysis. Such proteases include cysteine proteases, serine proteases, aspartic proteases and metalloproteases. The compounds of the present invention are capable of binding to the enzyme more strongly than the substrate and are therefore not normally segmented even after enzyme-catalyzed attack by nucleophiles. Thus, the compounds of the present invention competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors.
[526] The term " amino acid " as used herein refers to an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, D- or L-isomer.
[527] As used herein, " C _1-6 alkyl " refers to a substituted or unsubstituted alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, Pentyl and hexyl, and the simple aliphatic isomers thereof. C _1-6 alkyl is ^{OR 12, C (O) R} 12, SR 12, S (O) R 12, NR 12 2, R 12 NC (O) OR 5, CO 2 R 12, CO 2 NR 12 2, N (C = NH) NH ₂ , hetero, C _3-6 cycloalkyl and aryl, wherein R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and is selected from the group consisting of heteroaryl -C _0-6 alkyl, R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and _heteroaryl-O -C ₆ alkyl).
[528] As used herein, " C _3-6 cycloalkyl " refers to substituted and unsubstituted cyclopropane, cyclobutane. It is intended to include cyclopentane and cyclohexane.
[529] As used herein, " C _2-6 alkenyl " means an alkyl group having 2 to 6 carbons wherein the carbon-carbon single bond is replaced by a carbon-carbon double bond. C _2-6 alkenyl includes ethylene, 1-propylene, 1-butene, 2-butene, isobutene, and some isomeric pentenes and hexenes. Cis and trans isomers.
[530] &Quot; C _2-6 alkynyl " means an alkyl group having 2 to 6 carbons wherein the carbon-carbon single bond is replaced by a carbon-carbon triple bond. C _2-6 alkynyl includes the simple isomers of acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and pentyne and hexyne.
[531] &Quot; Halogen " means F, Cl, Br and I.
[532] &Quot; Ar " or " aryl " means phenyl or naphthyl, optionally one or more phenyl-C _0-6 alkyl; Heteroaryl -C _{6 O-alkyl;} C _1-6 alkoxy; _{Ph-C O-6} alkoxy; _Heteroaryl-O -C ₆ alkoxy; _{OH, (CH 2) 1-6 NR} 15 R 16; ^{_{O (CH 2) 1-6 NR 15}} R 16; C _1-6 ^{alkyl, OR 17, N (R 17} ) 2, SR 17, CF 3, N0 2, CN, CO 2 R 17, CON (R 17), F, Cl, Br or I (wherein, R ¹⁵ and R ¹⁶ is H, C _1-6 alkyl, phenyl -C _{6 O-alkyl, O-naphthyl} -C ₆ alkyl or a _heteroaryl-O -C ₆ alkyl, R ¹⁷ is phenyl, naphthyl or C _1-6 Phenyl or naphthyl optionally substituted by alkyl).
[533] &Quot; Hetero " or " heterocyclic &quot;, as used herein, is defined as consisting of a carbon atom and one to three heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms are optionally And the nitrogen heteroatom may optionally be quaternized), a saturated or unsaturated 5 to 7 membered stable monocyclic heterocyclic ring, a 7 to 10 membered stable bicyclic heterocyclic ring, or A stable tricyclic heterocyclic ring of 11 to 18 members, and any of these heterocyclic rings includes any bicyclic group fused to the benzene ring. The heterocyclic ring may be bonded to any heteroatom or carbon atom to form a stable structure and is selected from the group _{consisting of} C _0-6 Ar, C _1-6 alkyl, OR ¹⁷ , N (R ¹⁷ ) ₂ , SR ¹⁷ , CF ₃ , NO ₂ , CN, CO ₂ R ¹⁷ , CON (R ¹⁷ ), F, Cl, Br and I wherein R ¹⁷ is phenyl, naphthyl or C _1-6 alkyl. , &Lt; / RTI &gt; Examples of such heterocycles include, but are not limited to, triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl, Oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, Pyridyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thia A benzofuranyl, a benzofuranyl, a benzofuranyl, a thiophenyl, a benzofuranyl, a benzofuranyl, a benzofuranyl, a benzofuranyl, a benzofuranyl, a thiophenyl, a benzofuranyl, thiophenyl, thieno [3,2-b] thiophenyl, benzo [1,3] dioxolyl, 1,8-naphthyridinyl, Carbonyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzoxazolyl, thiazol-morpholinyl sulfoxide include side, thiazol-morpholinyl sulfone, and oxadiazolyl. As used herein, the term heteroatom means oxygen, nitrogen and sulfur.
[534] Throughout this specification, the term C ₀ means that there is no substituent immediately following it. For example, when C is 0 in the ArC _O-6 alkyl moiety, this substituent is Ar, for example, phenyl. Conversely, if ArC _O-6 alkyl is defined as a particular aromatic group, for example, phenyl, then the C value should be understood as zero.
[535] In the present specification, some radical groups are abbreviated. t-Bu refers to a tert-butyl radical, Boc refers to a t-butyloxycarbonyl radical, Fmoc refers to a fluorenylmethoxycarbonyl radical, Ph refers to a phenyl radical, and Cbz refers to a benzyloxycarbonyl radical.
[536] Certain reactants herein are abbreviated. m-CPBA is 3-chloroperoxybenzoic acid, EDC is N-ethyl-N '(dimethylaminopropyl) -carbodiimide, DMF is dimethylformamide, DMSO is dimethylsulfoxide, TEA is preethylamide , TFA means trifluoroacetic acid, and THF means tetrahydrofuran.
[537] Manufacturing method
[538] Compounds of formula (I) can be prepared by methods analogous to those outlined in schemes 1, 2 and 3. Alkylation of tert-butyl N-allylcarbamate (1) with a base such as sodium hydride and 5-bromo-1-pentene gives the diene (2). The diene (2) is reacted with bis (tricyclohexylphosphine) benzylidene ruthenium (IV) which was developed by 2,6-diisopropylphenylimidoneophylidenemolybdenum bis (tert-butoxide) or Grubbs ) Dichloride olefin metathesis catalyst, azepine (3) can be obtained. The epinephrine (3) is epoxidized with a standard oxidizing agent customary in the art, such as m-CPBA, to give the epoxide (4). Nucleophilic epoxide ring opening with a reagent such as sodium azide to give the azido alcohol (not shown), which can be converted into hydrogen gas in the presence of a catalyst such as palladium on carbon, or with 1,3-propanedithiol Can be reduced to aminoalcohol (5) under conditions customary in the art, such as triethylamine and triethylamine. The aminoalcohol (5) is acylated with an acid such as Cbz-leucine in the presence of a coupling agent such as EDC and the BOC protecting group is removed under acidic conditions to give the amine salt (6). Coupling of the amine salt (6) with Cbz-leucine is carried out with a coupling agent such as EDC to give the intermediate alcohol (not shown) which is then oxidized with an oxidizing agent such as a pyridine sulfur trioxide complex in DMSO and triethylamine to give ketone 7) can be obtained.
[539] Scheme 1
[540]
[541] Reagents and conditions: a) NaH, 5-bromo-1-pentene, DMF; b) 2,6-diisopropylphenylimidonephosphoridemolybdenum bis (tert-butoxide) or bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride catalyst, toluene; _{c) m-CPBA, CH 2} Cl 2; d) NaN ₃ , CH ₃ OH, H ₂ O, NH ₄ Cl; e) 10% Pd / C, H ₂ ; f) Cbz-leucine, EDC, CH ₂ Cl ₂ ; g) HCl, EtOAc; h) Cbz- leucine, EDC, CH ₂ Cl _2; i) pyridine sulfur trioxide complex, DMSO, TEA.
[542] Compounds of formula (I) wherein R &lt; ¹ &gt; and R &lt; ² &gt; are amides can be prepared by the general methods outlined in scheme 2. [ Alkylation of N-Cbz allylamine (8) with a base such as sodium hydride and 5-bromo-1-pentene gives the diene (9). Diene 9 is treated with bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride olefin metathesis catalyst developed by Groups to obtain azepine 10. The azepine 10 is epoxidized with a standard oxidizing agent customary in the art, such as m-CPBA, to give the epoxide 11. Nucleophilic epoxide ring-opening with a reagent such as sodium azide leads to azido alcohol (not shown), which is reduced with aminoalcohol (12) using a reducing agent such as propanedithiol in the presence of triethylamine . The amino alcohol (12) is acylated with a coupling agent such as N-Boc-leucine and EDC and the Cbz protecting group is removed under hydrolysis conditions to give amine (13). Coupling of the amine 13 with carboxylic acid is carried out with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HCl or TFA to give intermediate 14. Intermediate 14 is acylated with a carboxylic acid in the presence of a coupling agent customary in the art such as EDC to give an intermediate alcohol (not shown) which is treated with an oxidizing agent such as pyridine sulfur trioxide complex in DMSO and triethylamine The ketone 15 can be obtained by oxidation.
[543] Scheme 2
[544]
[545] Reagents and conditions: a) NaH, 5-bromo-1-pentene, DMF; b) bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride catalyst, CH ₂ Cl ₂ ; _{c) m-CPBA, CH 2} Cl 2; d) NaN ₃ , CH ₃ OH, H ₂ O, NH ₄ Cl; e) propanedithiol, CH ₃ OH, TEA, f) Boc-leucine, EDC, CH ₂ Cl ₂ ; g) 10% Pd / C, H 2; h) R ₁ CO ₂ H, EDC, CH ₂ Cl ₂ or R ₁ COCl, CH ₂ Cl ₂ ; i) HCl / EtOAc; j) R ₂ CO ₂ H, EDC, CH ₂ Cl ₂ ; k) pyridine sulfur trioxide complex, DMSO, TEA.
[546] Compounds of formula (I) wherein R ² is an alkyl, urea or sulfonamide group and R ¹ is an amide can be prepared by the general method outlined in Scheme 3. Amine (13) is treated with aldehyde and treated with a reducing agent such as sodium triacetoxyborohydride to effect reductive amination of amine (13). The N-Boc group is then deprotected under acidic conditions to give amine salt (16). The amine salt 16 is coupled with a carboxylic acid or acid chloride in the presence of a coupling agent conventional in the art such as EDC, and then the intermediate alcohol (not shown) is oxidized with an oxidizing agent such as pyridine sulfur trioxide complex to form ketone 17). Alternatively, treatment of amine (13) with isocyanate and deprotonation of the N-Boc group gives amine salt (18). Acylation and oxidation of the amine salt 18 gives the ketone 19. Treatment of the amine 13 with sulfonyl chloride followed by deprotection of the N-Boc group provides additional derivatization of the amine 13 to give the amine salt 20. This amine salt (20) is acylated and the oxidation on ketone (21) is obtained.
[547] Scheme 3
[548]
[549] Reagents and conditions: a) R ₁ CHO, NaBH (OAc) ₃ ; b) HCl; c) R ₂ CO ₂ H, EDC, CH ₂ Cl ₂ ; d) pyridine sulfur trioxide complex, DMSO, TEA; e) R ₁ NCO, base; f) R ₁ SO ₂ Cl, TEA, CH ₂ Cl ₂ .
[550] The deuterated compounds of Example 192 can be readily prepared according to Scheme 4. Those skilled in the art will appreciate from Example 192 and Scheme 4 how to prepare deuterated compounds of the present invention.
[551] Benzofuran-2-carboxylic acid {(S) -3-methyl-1 - [(2,2 ', 4-tridecarterio) -3-oxo-1- (pyridine- Yl-carbamoyl] -butyl} amide (31 and 32) may be prepared as outlined in Scheme 4. &lt; EMI ID = Allyl-carbamic acid benzyl ester (22) is alkylated with 5-bromo-1-pentene in the presence of a base such as sodium hydride to give the diene (23). Diene 23 was treated with bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride developed by Groups to give 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (24). The epoxidation of the azepine 24 is carried out with standard oxidants customary in the art, such as m-CPBA, to give the epoxide 25. The nucleophilic epoxide ring opening of the epoxide (25) can be carried out with a reagent such as sodium azide to give an azido alcohol (not shown).
[552] Scheme 4
[553]
[554] Reagents and conditions: a) NaH, 5-bromo-1-pentene, DMF; b) bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride, CH ₂ Cl ₂ ; _{c) m-CPBA, CH 2} Cl 2; d) NaN ₃ , CH ₃ OH, H ₂ O, NH ₄ Cl; e) 1,3-propanedithiol, TEA, methanol; f) N-Boc- leucine, EDC, CH ₂ Cl _2; g) IO% Pd / C, H 2; h) 2- pyridine sulfonyl chloride, TEA, CH ₂ Cl _2; i) 4 N HCl / dioxane, methanol; j) benzofuran-2-carboxylic acid, EDC, CH ₂ Cl _2; k) pyridine sulfur trioxide complex, DMSO, TEA; l) CD ₃ OD; D ₂ O (10: 1), TEA; m) HPLC separation.
[555] Reduction of the intermediate azido alcohol under conditions customary in the art such as 1,3-propanedithiol and triethylamine in methanol or reduction of the amino alcohol (26) with triphenylphosphine in tetrahydrofuran and water Can be obtained. Acylation of aminoalcohol (26) can be performed with an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC. The benzyloxycarboxyl protecting group is removed with hydrogen gas in the presence of 10% Pd / C to afford amine (27). Amine 27 is treated with ₂ -pyridine sulfonyl chloride or saturated sodium bicarbonate and CH ₂ Cl ₂ in the presence of saturated sodium bicarbonate and CH ₂ Cl ₂ , or triethylamine, followed by treatment with a tert-butoxycarbonyl protecting group (28) is obtained. Coupling of the compound (28) with benzofuran-2-carboxylic acid with a coupling agent such as EDC is performed to obtain the intermediate alcohol (29). Alcohol (29) is oxidized with an oxidizing agent such as DMSO and sulfur trioxide pyridine complex in triethylamine to give a mixture of ketone diastereomers. The ketone 30 is treated with triethylamine in CD ₃ OD: D ₂ O under reflux to give the hydrogenated analog as a mixture of diastereomers, which is separated by HPLC to give deuterated compounds 31 and 32, .
[556] Compounds of formula (I) may also be prepared by the process outlined in Scheme 5. The amine of compound (12) is protected with di-tert-butyl dicarbonate to give N-Boc derivative (33) (Scheme 2). The N-Boc derivative 33 is treated with hydrogen gas in the presence of a catalyst such as 10% Pd / C to remove the benzyloxycarbonyl protecting group to give the amine 34. Amine (34) is treated with 2-pyridine sulfonyl chloride in the presence of a base such as N-methylmorpholine or triethylamine to give the sulfonamide (35). The tert-butoxycarbonyl protecting group is removed using an acid such as hydrochloric acid to obtain intermediate (36). Intermediate 36 is coupled with an acid such as N-Boc-cyclohexylalanine in the presence of a coupling agent customary in the art, such as HBTU or polymer supported EDC to give alcohol intermediate 37. The tert-butoxycarbonyl protecting group is removed under acidic conditions to give amine (38). The amine 38 is coupled with an acid such as benzofuran-2-carboxylic acid in the presence of a coupling agent conventional in the art, such as HBTU or polymer supported EDC to give alcohol 39. [ Alcohol 39 is oxidized with an oxidizing agent customary in the art, such as pyridine sulfur trioxide complex in DMSO and triethylamine or des-martin periodinane to give ketone 40. [
[557] Scheme 5
[558]
[559] Reagents and conditions: a) di-tert-butyl dicarbonate; b) H ₂ , 10% Pd / C, EtOAc; c) 2-pyridylsulfonyl chloride, TEA; d) HCl, EtOAc; e) N-Boc- cyclohexyl _{alanine, P-EDC, CH 2 Cl} 2; f) HCl, CH ₂ Cl ₂ ; g) benzofuran-2-carboxylic _{acid, P-EDC, CH 2 Cl} 2; h) des-martin ferriodin, methylene chloride.
[560] The starting materials used in the present invention are commercially available or can be prepared by conventional methods well known to those skilled in the art and can be prepared by standard publications such as COMPENDIUM OF ORGANIC SYSTHETIC METHODS, Vol. I-VI (Wiley-Interscience publication) .
[561] Coupling methods for forming amide bonds in the present invention are generally well known in the art. Bodansky et al., The PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979) and J.M. The peptide synthesis methods generally described in Stewart and JDYoung, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984 are generally representative examples of this technique, do.
[562] Synthetic methods for preparing the compounds of the present invention often introduce protecting groups to mask reactive functionalities or minimize undesired side reactions. Such protecting groups are generally described in Green, T. W., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting group" generally refers to Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof, as is known in the art. Protecting and deprotecting methods, and replacing amino protecting groups with other residues are well known.
[563] The acid addition salts of formula (I) can be prepared from the parent compound and the excess acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid, Can be prepared in a suitable solvent. Some of these compounds form acceptable internal salts or amphoteric ions. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent such as a hydroxide, carbonate or alkoxide containing suitable cations or with an appropriate organic amine. Cations such as Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺⁺ , Mg ⁺⁺ and NH ₄ ⁺ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfates, phosphates, alkanoates, benzoates (such as acetate and trifluoroacetate), and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
[564] The present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. Thus, the compounds of formula (I) may be used in the manufacture of medicaments. The pharmaceutical composition of formula (I) prepared by the above method can be formulated as a solution for parenteral administration or as a lyophilized powder. The powder may be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered aqueous solution. Examples of suitable diluents are standard isotonic saline, standard 5% dextrose in water, or sodium acetate or ammonium acetate buffer. Such formulations are particularly suitable for parenteral administration, but may also be used for oral administration or may be contained in a metered dose inhaler or sprayer for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy-cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
[565] Alternatively, such compounds may be encapsulated, tableted, or made into emulsions or syrups for oral administration. To improve or stabilize the composition or to facilitate the preparation of the composition, a pharmaceutically acceptable solid or liquid carrier may be added. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, brine and water. The carrier may contain a sustained release agent such as glyceryl monostearate or glyceryl distearate, either alone or in combination with a wax. The amount of solid carrier varies, but is preferably from about 20 mg to about 1 g per dosage unit. Pharmaceutical formulations include milling, mixing, granulating and (if necessary) squeezing for purification; Or milling, mixing and filling for hard gelatin capsule forms. When liquid carriers are used, the formulations may be in the form of syrups, elixirs, emulsions or aqueous or nonaqueous suspensions. Such liquid preparations can be administered directly orally or they can be filled into soft gelatine capsules.
[566] For rectal administration, the compounds of the present invention may also be formulated into suppositories by mixing with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol.
[567] New intermediate
[568] It will be appreciated by those skilled in the art that the present invention includes all the novel intermediates necessary to prepare the compounds of formula (I), with reference to the methods for preparing the compounds of formula (I) set forth in Schemes 1-4 above. In particular, the present invention provides compounds of formula (II) and pharmaceutically acceptable salts, hydrates and solvates thereof.
[569]
[570] (here,
[571] R ¹ is And &Lt; / RTI &gt;
[572] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 9 C (O) -} , R 9 R ⁹ R ¹¹ NC (O) -, R ⁹ R ¹¹ NC (S) -, R ⁹ (R ¹¹ ) NSO ₂ -, R ⁹ SO ₂ -, R ⁹ C And &Lt; / RTI &gt;
[573] R ³ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, C _{6 O-alkyl} and _O-6 ArC the group consisting of alkyl,
[574] R ³ and R 'may be connected to form a pyrrolidine, piperidine or morpholine ring,
[575] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 5 C (O) -} , R 5 ^{C (S) -, R 5} SO 2 - is selected from the group consisting of and ^{R 5 R 13 NC (S)} , -, R 5 0C (O) -, R 5 R 13 NC (O)
[576] R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl and heteroaryl -C _{O Gt;} is selected from the group consisting of &lt; RTI ID = 0.0 &gt;
[577] R ⁶ is selected from H, C _1-6 alkyl, _{Ar-C O-6} group consisting of alkyl or heteroaryl C _O-6 alkyl.
[578] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, _O-heteroaryl -C ₆ ^{alkyl, R 10 C (O) -} , R 10 C (S) -, R ¹⁰ SO ₂ -, R ¹⁰ OC (O) -, R ¹⁰ R ¹⁴ NC (O) - and R ¹⁰ R ¹⁴ NC (S) -,
[579] R ⁸ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, C _{6 O-alkyl} and _O-6 ArC the group consisting of alkyl,
[580] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-O-C 6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl,
[581] R ^1O is independently selected from the group consisting of C _l-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-O-C 6} alkyl and _heteroaryl-O -C ₆ alkyl,
[582] R ¹¹ is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ group consisting of alkyl,
[583] R ¹² is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and heteroaryl C _O-6 alkyl,
[584] R ¹³ is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _{heteroaryl-C O 6} group consisting of alkyl,
[585] R ¹⁴ is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ alkyl,
[586] R 'is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl and heteroaryl C _O-6 alkyl,
[587] R "is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, or _heteroaryl-O -C ₆ group consisting of alkyl,
[588] R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-O-C 6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl,
[589] X is selected from the group consisting of CH ₂ , S and O,
[590] Z is selected from the group consisting of C (O) and CH ₂ )
[591] The following compounds are preferred novel intermediates:
[592] [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid benzyl ester;
[593] (S) -2-Amino-4-methyl-pentanoic acid (1-benzyl-3-hydroxy-azepan-4-yl) -amide;
[594] (S) -2-Amino-4-methyl-pentanoic acid {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-yl} -amide;
[595] [(S) -1- [4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepan- Benzyl benzoate;
[596] (S) -2-Amino-4-methyl-pentanoic acid (1-benzoyl-3-hydroxy-azepan-4-yl) -amide;
[597] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4-methyl-pentanoyl) -azepan-4-yl] -amide;
[598] (S) -2-Amino-4-methyl-pentanoic acid (1-benzenesulfonyl-3-hydroxy-azepan-4-yl) -amide;
[599] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- Yl-carbamoyl] -butyl} amide;
[600] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) Carbamoyl] -butyl} amide;
[601] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} amide;
[602] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan- &Lt; / RTI &gt;amide;
[603] 2-sulfonyl) -azepan-4-ylcarbamoyl] - (3-methyl- Butyl} amide; And
[604] Carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} amide.
[605] A method for synthesizing the compound of the present invention
[606] Referring to Reaction Schemes 1 to 5 above, the present invention provides a process for the synthesis of a compound of formula (I), which comprises oxidizing a suitable compound of formula (II) with an oxidizing agent to obtain the compound of formula (I) as diastereoisomer . Preferably the oxidizing agent is DMSO and sulfur trioxide pyridine complex in triethylamine.
[607] Referring to Scheme 4, the present invention also provides a method for synthesizing deuterated compounds of formula (I). In particular, if a deuterated isomer is needed, an additional step is added to the synthesis method, after the oxidation step, to deuterate the protonated isomer to deuteration agent to obtain the deuterated compound of formula (I) as a diastereomer mixture. Preferably, the deuteration agent is CD ₃ OD: D ₂ O (10: 1) in triethylamine.
[608] The method further comprises separating the diastereomers of formula (I) by separation means, preferably high pressure liquid chromatography (HPLC).
[609] Utility of the present invention
[610] The compounds of formula (I) are useful as protease inhibitors, particularly cysteine and serine protease inhibitors, more particularly cysteine protease inhibitors, more particularly superfamily cysteine protease inhibitors, and more particularly cathepsin cysteine Protease inhibitors, most particularly cathepsin K inhibitors. The present invention also provides useful compositions and formulations of such compounds, including pharmaceutical compositions and formulations of such compounds.
[611] The present compounds are useful for the treatment and prophylaxis of a variety of infectious diseases including infections caused by pneumocystis carinii, Cruz Trypanosoma brucetrifosoma and Cryptidia puficuccata as well as schistosomiasis, malaria, cancer metastasis, familial cerebral mesodermal rhinorrhoea, muscular dystrophy, Particularly osteoarthritis and rheumatoid arthritis, including osteoporosis, gingivitis and periodontitis, more particularly osteoarthritis and rheumatoid arthritis, Paget's disease, malignancy and calcium &lt; RTI ID = 0.0 &gt; And is useful for treating excessive bone or cartilage loss diseases, including hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia,
[612] Metastatic tumor cells typically exhibit high levels of proteolytic enzymes that degrade surrounding substrates, and certain cancers and metastatic tumors can be effectively treated with the compounds of the present invention.
[613] The present invention also relates to the use of a pathological level of proteases, in particular cysteine and serine proteases, more particularly cysteine proteases, more particularly, superfamily cysteine proteases, and more particularly cathepsin family cysteine proteases Which method comprises administering a compound of the present invention to an animal, particularly a mammal, most particularly a human, in need of such treatment. The present invention particularly provides a method of treating a disease caused by a pathological level of cathepsin K, which method comprises administering to an animal in need of treatment, in particular a mammal, most particularly a human, RTI ID = 0.0 &gt; cathepsin &lt; / RTI &gt; K inhibitor. The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prophylaxis of an infectious disease comprising infection by pneumocystis carinii, Cruz Trypanosoma bruce trypanosomiasis and Cryptidia puficuccata as well as schizophrenia, malaria, cancer metastasis, Osteoarthritis and rheumatoid arthritis, Paget's disease, malignancy and calcium, especially osteoporosis, including osteoporosis, gingivitis and periodontitis, especially diseases involving cysteine protease, (But not limited to) excessive bone or cartilage loss, including, but not limited to, hyperlipidemia, hypercholesterolemia, hypotension,
[614] The present invention also encompasses administering to a patient an effective amount of a compound of formula (I) alone or in combination with other bone resorption inhibitors such as bisphosphonates (i.e., alendronate), hormone replacement therapy, anti-estrogens or calcitonin A method of treating osteoporosis or a method of inhibiting bone loss. In addition, anabolic agents such as the compounds of the present invention and osteogenic proteins, iproflavone can be treated to prevent bone loss or to increase bone mass.
[615] For acute treatment, parenteral administration of a compound of formula (I) is preferred. Intramuscular infusion is also necessary, although intravenous infusion of a compound in 5% dextrose in water or saline, or intravenous infusion of a compound containing a suitable excipient Intravenous injection of a similar formulation is most effective. Typically, the parenteral dose is from about 0.01 to about 100 mg / kg, preferably from 0.1 to 20 mg / kg, to maintain the concentration of the drug in plasma at an effective concentration to inhibit cathepsin K. The compound is taken once to four times a day so that the total daily dose is about 0.4 to about 400 mg / kg / day. The precise amount of the therapeutically effective amount of the compound of the present invention and the most preferable route of administration of such a compound can be easily determined by those skilled in the art by comparing the concentrations required for therapeutical effectiveness with blood levels.
[616] The compounds of the present invention may be orally administered to a patient so that the concentration of the drug is sufficient to inhibit bone resorption or to obtain other therapeutic effects as disclosed herein. Typically, a pharmaceutical composition comprising a compound of the invention is administered in an oral dosage of about 0.1 to about 50 mg / kg, depending on the condition of the patient. Preferably, the oral dose is about 0.5 to about 20 mg / kg.
[617] Administration of the compounds of the present invention according to the present invention is not expected to result in any toxic effects that are unacceptable.
[618] Biological analysis
[619] The compounds of the present invention can be tested in one of a variety of biological assays to determine the concentration of the compound required to have the indicated pharmacological effect.
[620] Measurement of proteolytic catalytic activity of cathepsin K
[621] All assays for cathepsin K are performed with human recombinant enzymes. Standard assay conditions for determining rate constants were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA using a fluorogenic peptide substrate, particularly Cbz-Phe-Arg-AMC. The stock substrate solution was prepared at a concentration of 10 or 20 mM in DMSO and the final substrate concentration was 20 μM in the assay. All analytes contained 10% DMSO. Independent experiments have shown that this level of DMSO has no effect on enzyme activity or rate constants. All analyzes were performed at room temperature. The product fluorescence (excitation at 360 nM, emission at 460 nM) was detected with a Perceptive Biosystems Cytofluor II fluorescent plate reader. The product elapsed curve after AMC product formation was made over 20-30 minutes.
[622] Inhibition study
[623] Potential inhibitors were evaluated using the progressive curve method. Analysis was carried out in the presence of various concentrations of the test compound. The enzyme was added to the buffer solution of inhibitor and substrate to initiate the reaction. Data analysis was performed in one of two ways depending on the shape of the progress curve in the presence of the inhibitor. For compounds where the elapsed curve is a straight line, apparent inhibition constants (K _{i, app} ) were calculated according to Equation 1 (Brandt et al., Biochemistry , 1989 , 28, 140).
[624] _{v = V m A / [K} a (1 + I / K i, app) + A]
[625] (Where v is the velocity of the reaction with the maximum velocity V _m , A is the substrate concentration with the Michaelis constant K _a and I is the concentration of the inhibitor)
[626] For a compound whose downward curve has a time-dependent inhibition characteristic, the data obtained from each set is analyzed and k _obs is obtained according to equation (2).
[627] [AMC] = v _ss t + ( v ₀ - v _ss ) [1 - exp (- k _obs t)] / k _obs
[628] (Where AMC is the concentration of product produced during time t, v ₀ is the initial reaction rate, and v _ss is the rate of the final steady state)
[629] The k _obs value was analyzed as a linear function of the inhibitor concentration to yield an apparent secondary rate constant ( k _obs / inhibitor concentration or k _obs / [ I ]) that describes the time dependent inhibition. A complete discussion of this process is fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol. , 1988 , 61, 201).
[630] Analysis of human keel cell absorption
[631] An aliquot of the cell suspension derived from the keel cell tumor was taken from the liquid nitrogen container and quickly warmed at 37 ° C and washed once in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4 ° C). The medium was aspirated, replaced with a murine anti-HLA-DR antibody, diluted 1: 3 in RPMI-1640 medium and incubated on ice for 30 minutes. The cell suspension was mixed frequently.
[632] Cells were washed twice with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 째 C) and transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber.
[633] Sufficient magnetic beads (5 / mononuclear cells) coated with goat anti-mouse IgG were removed from the reservoir and placed in 5 mL of fresh medium (which rinses the toxic azide preservative). The beads were fixed on a magnet to remove the medium and replaced with a fresh medium.
[634] After mixing the beads with the cells, the suspension was incubated on ice for 30 minutes. The suspensions were mixed frequently. The bead-coated cells were fixed in magnets and the remaining cells (fractions rich in keel cells) were transferred to sterile 50 mL centrifuge tubes. New media was added to the bead-coated cells to remove trapped keel cells. This washing procedure was repeated 10 times. The bead-coated cells were discarded.
[635] Using a large diameter disposable plastic Pasteur pipette, the counting chamber was filled with samples and the keel cells were counted. Cells were centrifuged to pellet and EMEM medium was adjusted to a keel cell concentration of 1.5 x 10 ⁴ / mL and 10% fetal calf serum and 1.7 g / l sodium bicarbonate were added. A 3 mL aliquot (per drug) of cell suspension was transferred to a 15 mL centrifuge tube. These cells were centrifuged and made into pellets. Add 3 mL of appropriate drug to each tube (diluted to 50 uM in EMEM medium). Also included were appropriate vehicle controls, positive controls (87MEM1 diluted to 100 ug / mL), and the reference reference control (diluted to 100 ug / mL with IgG2a). The tubes were incubated at 37 DEG C for 30 minutes.
[636] 0.5 mL of cell aliquots were inoculated onto sterile dentin slices of 48-well plates and incubated at 37 ° C for 2 hours. Each drug was screened four times. Slices were washed 6 times in warm PBS (10 mL / well, 6-well plate) and placed in fresh drug or control and incubated at 37 ° C for 48 hours. The slices were washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium chocodilate), then washed with water and incubated in buffer for 5 minutes at 37 ° C. The slices were washed in cold water and incubated for 5 min at 4 [deg.] C in cold acetate buffer / fast red gard. Excess buffer was removed by suction, and the slice was washed with water and dried.
[637] TRAP-positive keel cells were counted with a bright-field microscope and removed from the dentin surface by ultrasonication. The membrane volume was measured with a Nikon / Laserec ILM21W confocal microscope.
[638] Normal
[639] Nuclear magnetic resonance spectra were recorded at 250 MHz or 400 MHz using a Bruker AM 250 or a Bruker AC 400 spectrometer, respectively. CDCl ₃ is deuterated chloroform, DMSO-d 6 is hexadutridomethylsulfoxide and CD ₃ OD is tetra-dithiomethanol. Chemical shifts were reported in millions of units downfield from internal standard tetramethylsilane. The NMR abbreviations are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, app = apparent br = Broad. J is the NMR coupling constant measured in hertz. The continuous wave infrared (IR) spectrum was recorded with a Perkin-Elmer 683 infrared spectrometer and the Fourier transform infrared (FTIR) spectrum was recorded with a Nicolet Impact 400 D infrared spectrometer. The IR and FTIR spectra were recorded in transmission mode and the band position reported for wave number (cm ^-1 ). Mass spectra were measured with VG 70 FE, PE Syx API III or VG ZAB HF apparatus using fast atom bombardment (FAB) or electrospray ionization technique. Elemental analysis values were obtained using a Perkin-Elmer-240C elemental analyzer. Melting points were measured with a Thomas-Hoover melting point device and were not calibrated. All temperatures were reported in ° C.
[640] Analtech Silica Gel &lt; RTI ID = 0.0 &gt; GF) &lt; / RTI &gt; Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were performed on the Merck Kiegel gel 60 (230-400 mesh) silica gel.
[641] If indicated, the specific material is Aldrich Chemical Co, Milwaukee, Wisconsin. And Chemical Dynamics Corp., South Plainfield, New Jersey. And Advanced Chemtech, Louisville, Kentucky.
[642] In the following synthesis example, the temperature is in 占 폚. Unless otherwise stated, all starting materials were obtained from commercial products. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, fully utilize the invention. These embodiments are for the purpose of illustrating the invention and are not intended to limit the scope thereof.
[643] Example 1
[644] [(S) -1- [1 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentanoyl) -3-oxo-azepan-4-ylcarbamoyl} carbamic acid benzyl ester Produce
[645] a) Allyl-pent-4-enyl-carbamic acid tert -butyl ester
[646] 6.0 g (38.2 mmol) of tert -butyl N-allylcarbamate were added dropwise to a suspension of 3.05 g of NaH in 30 ml of DMF (60% NaH in oil 76.33 mmol, washed with hexane). 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 was heated to 40 &lt; 0 &gt; C for about 2 hours and then the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water (twice) and brine, dried (MgSO ₄ ), filtered and concentrated to afford 10 g of the title compound as an oil: MS (EI) 226 (M + H ⁺ ).
[647] b) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid tert -butyl ester
[648] 600 mg of 2,6-diisopropylphenylimido neophenylidenemolybdenum bis (t-butoxide) was added to a solution of 4.5 g of the compound of Example 1a in benzene. The reaction was heated to reflux for 1.5 hours and then the reaction was concentrated in vacuo. Chromatography of the residue (50% CH ₂ Cl ₂ : hexane) gave 3.92 g of product.
[649] c) 8-Oxa-3-aza-bicyclo [5.1.0] octane-3- carboxylic acid tert -butyl ester
[650] 7.8 g (45.6 mmol) of m-CPBA was added to a solution of 3.0 g (15.2 mmol) of the compound of Example 1b in CH ₂ Cl ₂ . The mixture was stirred at room temperature overnight and then partitioned between CH ₂ Cl ₂ and saturated K ₂ CO ₃ . The organic layer was washed with saturated NaHCO ₃ , water and brine, dried (MgSO ₄ ), filtered and concentrated to give 3.11 g of the title compound as an oil: MS (EI) 214 (M + H ⁺ ).
[651] d) 4-Azido-3-hydroxy-azepane-1-carboxylic acid tert -butyl ester
[652] 3.18 g (60 mmol) of NH ₄ Cl and 3.9 g (60 mmol) of sodium azide were added to a solution of 3.92 g (20 mmol) of the epoxide from Example 1c in methanol: water (8: 1 solution 180 ml) . The reaction was heated to 40 &lt; 0 &gt; C until complete consumption of the starting epoxide was observed by TLC analysis. Remove most of the solvent in vacuo and dilute the residue with ethyl acetate, washed with water and brine, dried (Na ₂ SO _4), filtered, and concentrated. The residue was subjected to column chromatography (40% ethyl acetate: hexane) to obtain 3.43 g of the title compound.
[653] e) 4-Amino-3-hydroxy-azepane-1-carboxylic acid tert -butyl ester
[654] Hydrogen in one baloon was added to 3.4 g of the azido alcohol of Example 1d in ethyl acetate: methanol (2: 1 solution) and a catalytic amount of 10% Pd / C solution. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (25% methanol: dichloromethane) to give 2.57 g of the title compound: MS (EI) 231 (M + H ⁺ ).
[655] f) 4 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1 -carboxylic acid tert -butyl ester
[656] 134 mg of EDC, 94 mg of HOBt and 185 mg of Cbz-leucine were added to a solution of 160 mg (0.70 mmol) of the amino alcohol of Example 1e in CH ₂ Cl ₂ . The reaction was maintained at room temperature until complete consumption of starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate, washed with 1N HCl, saturated K ₂ CO ₃ , water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was subjected to column chromatography (3% methanol: dichloromethane) to obtain 200 mg of the title compound: MS (EI) 478 (M + H ⁺ ), 500 (M + Na ⁺ ).
[657] g) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl- butyl] -carbamic acid benzyl ester
[658] 5 ml of 4M HCl in dioxane was added to a solution of 200 mg (0.42 mmol) of the compound of example 1f in 5 ml of methanol. The reaction was stirred at room temperature for about 2 hours and then the solvent was removed in vacuo to give 168 mg of the title compound: MS (EI) 378 (M + H ^& lt ^{; +} & gt ^; ).
[659] h) {(S) -1- [4 - ((S) -2-Benzyloxycarbonylamino-4-methyl-pentanoylamino) -3- hydroxy- Methyl-butyl} carbamic acid benzyl ester
[660] 81 mg of EDC, 57 mg of HOBt, 0.09 ml of triethylamine and 111 mg of Cbz-leucine were added to a solution of Example 1 g amine salt 168 mg (0.42 mmol) in CH ₂ Cl ₂ . The reaction was stirred until the reaction was complete by TLC analysis. After work-up was purified by column chromatography _{(5% CH 3 OH: CH} 2 Cl 2) to give 159 mg the title compound by: MS (EI) 625 (M + H +).
[661] i) Synthesis of {(S) -1- [4 - ((S) -2-Benzyloxycarbonylamino-4-methyl- pentanoylamino) -3-oxo-azepan- -Butyl} carbamic &lt; / RTI &gt; acid benzyl ester
[662] 0.17 ml of TEA and 97 mg (0.62 mmol) of pyridine sulfur trioxide complex were added to a solution of 130 mg (0.21 mmol) of the alcohol from Example 1h in DMSO. The reaction was stirred at room temperature for about 3 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by column chromatography _{(5% CH 3 OH: CH} 2 Cl 2) to give 100 mg of title compound as a mixture of diastereomers _{^{by: 1 H NMR (CDCl 3)}} : δ1.0 (m, 12H), 1.5 2H), 4.5 (m, 2H), 3.0 (m, 2H), 3.0 (m, 4.7 (m, 1H), 5.0 (m, 5H), 7.3 (m, 10H); MS (EI) 623 (M + H ⁺ ), 645 (M + Na ⁺ ). Diastereomers 1 (MS (EI) 623 ( M + H +), 645 (M + Na +)) parts by the separation of diastereomers by HPLC and diastereomer 2 (MS (ES) 623 ( M + H ⁺ & Gt ^; ), 645 (M + Na &lt; ⁺ &gt;)).
[663] Example 2
[664] Preparation of naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl]
[665] a) Allyl-pent-4-enyl-carbamic acid benzyl ester
[666] Benzylallyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) was added dropwise to a suspension of 1.83 g of NaH (90% NaH 76.33 mmol) in DMF. 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 was heated to 40 &lt; 0 &gt; C for about 4 hours before the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (twice) and brine, dried (MgSO _4), filtered, and concentrated. Column chromatography (10% ethyl acetate: hexane) of the residue gave 10.3 g of the title compound as an oil: MS (EI) 260 (M + H <^+> ).
[667] b) 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester
[668] 5.0 g of bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride was added to a solution of 50 g of the compound of Example 2a in dichloromethane. The reaction was heated to reflux until completion of the reaction was observed by TLC analysis. The reaction was concentrated in vacuo. Column chromatography (50% dichloromethane: hexanes) of the residue gave 35 g of the title compound: MS (EI) 232 (M + H ⁺ ).
[669] c) 8-Oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid benzyl ester
[670] The title compound was prepared following the general method of example 1c, but substituting the compound of example 2b: MS (EI) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).
[671] d) 4-Azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[672] 1.29 g (24.3 mmol) of NH ₄ Cl and 1.58 g (24.30 mmol) of sodium azide were added to a solution of 2.0 g (8.1 mmol) of the epoxide from example 2c in methanol: water (8: 1 solution). The reaction was heated to 40 &lt; 0 &gt; C until complete consumption of the starting epoxide was observed by TLC analysis. Most of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic layer was washed with saturated NaHCO ₃ , water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was subjected to column chromatography (20% ethyl acetate: hexane) to obtain 1.3 g of the title compound (MS (EI) 291 (M + H ⁺ )) and trans-4-hydroxy-3-azido-hexahydro- 0.14 g of azepine was obtained.
[673] e) 4-Amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[674] 1.5 ml (11.37 mmol) of triethylamine and 1.1 ml (11.37 mmol) of 1,3-propanedithiol were added to a solution of 1.1 g (3.79 mmol) of the azido alcohol of Example 2d in methanol. The reaction was stirred until complete consumption of starting material was observed by TLC analysis and then the reaction was concentrated in vacuo. The residue was subjected to column chromatography (20% methanol: dichloromethane) to give 0.72 g of the title compound: MS (EI) 265 (M + H ⁺ ).
[675] f) 4 - ((S) -2- tert -Butoxycarbonylamino-4-methyl-pentanoylamino)
[676] - &lt; / RTI &gt; azepane-1-carboxylic acid benzyl ester
[677] 521 mg of EDC, 368 mg of HOBt and 630 mg of N-Boc-leucine were added to a solution of 720 mg (2.72 mmol) of the amino alcohol of Example 2e in CH ₂ Cl ₂ . The reaction was maintained at room temperature until complete consumption of starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate, washed with 1N HCl, saturated K ₂ CO ₃ , water and brine, dried (MgSO ₄ ), filtered and concentrated. The residue was subjected to column chromatography (3% methanol: dichloromethane) to give 1.0 g of the title compound: MS (EI) 478 (M + H ⁺ ).
[678] g) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl- butyl]
[679] tert -butyl ester
[680] One organism's hydrogen was added to a solution of 1.0 g of the compound from Example 2f and a catalytic amount of 10% Pd / C in ethyl acetate: methanol (2: 1 solution). The reaction was stirred until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo to give 0.82 g of the title compound: MS (EI) 344 (M + H ⁺ ).
[681] h) [(S) -1- ( 1- benzyl-3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[682] 0.32 ml (3.01 mmol) of benzaldehyde was added to a solution of 0.69 g (2.01 mmol) of the compound from Example 2g in CH ₂ Cl ₂ followed by 0.85 g (4.02 mmol) of sodium triacetoxyborohydride. The reaction was stirred until a complete reaction was observed by TLC analysis and a few drops of water were added to remove excess sodium triacetoxyborohydride. The reaction was diluted with ethyl acetate and saturated NaHCO _3, washed with water and brine, dried (Na ₂ SO _4), filtered, and concentrated. The residue was subjected to column chromatography (5% methanol: dichloromethane) to give 800 mg of the title compound: MS (ES) 434 (M + H ⁺ ).
[683] i) (S) -2-Amino-4-methyl-pentanoic acid (l-benzyl-3-hydroxy-azepan-
[684] 15 ml of 4M HCl in dioxane was added to a solution of 800 mg of the compound of Example 2h in 15 ml of methanol. The reaction was stirred overnight at room temperature and then concentrated in vacuo to give 800 mg of the title compound: MS (ES) 334 (M + H ⁺ ).
[685] j) naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azepan- 4- ylcarbamoyl) -3-methyl-
[686] Triamine salt of the ethylamine 0.17 ml (1.22 mmol), subjected to EDC 103.5 mg (0.54 mmol), HOBt 73 mg (0.54 mmol) and 2-naphthoic acid 93 mg (0.54 mmol) in CH ₂ Cl ₂ 200 mg Example 2i (0.49 mmol) in dichloromethane. The reaction was stirred until the reaction was complete by TLC analysis. The reaction was diluted with ethyl acetate and saturated NaHCO _3, washed with water and brine, dried (Na ₂ SO _4), filtered, and concentrated. The residue was subjected to column chromatography (5% methanol: dichloromethane) to give 0.14 g of the title compound: MS (EI) 488 (M + H ⁺ ).
[687] k) Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl-
[688] The title compound was obtained following the general procedure of example 1i but substituting the compound of example 1i for the compound of example 2j: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5 2H), 4.7 (m, 1H), 2.2 (m, 2H), 2.9 (m, 5.2 (m, 1H), 7.2-8.4 (m, 12H): MS (EI): 486 (M + H ⁺ , 100%). Diastereomer 1 (MS (EI) 486.3 (M + H ⁺ ) and diastereoisomer 2 (MS (ES) 486.3 (M + H ⁺ )) was obtained by separation of diastereomers by HPLC.
[689] Example 3
[690] Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl- Produce
[691] a) benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-3- hydroxy-azepan- 4- ylcarbamoyl) -amides
[692] The title compound was obtained following the general procedure of example 2j, but replacing 2-naphthoic acid with piperonylic acid: MS (ES) 482 (M + H ⁺ ).
[693] b) Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-
[694] 3-methyl-butyl] -amide &lt; / RTI &gt;
[695] Example 3a, except that the replacement of the compound, following the general method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.9 (m, 1H), 3.0 (m, , 5.2 (m, IH), 6.0 (s, 2H), 6.8 (m, 2H), 7.2 (m, 6H); MS (EI): 480 (M + H ^& lt ^{; +} & gt ^; , 100%). The diastereomers were separated by preparative scale HPLC. By freeze-drying the eluate diastereomer 1 (MS (EI) 480.3 ( M + H +), 959.6 (2M + H +)) and diastereomer 2 (MS (EI) 480.3 ( M + H +), 959.6 (2M + H ⁺ )).
[696] Example 4
[697] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[698] a) Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[699] Following the general method of example 2j, except substituting 2-naphthoic acid for benzofuran-2-carboxylic acid, the title compound was obtained: MS (ES) 478 (M + H ⁺ ).
[700] b) Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -
[701] 3-methyl-butyl] -amide
[702] The title compound was obtained following the general procedure of example 1i, but substituting the compound of example 4a: 476 MS (EI): 492 (M + H ⁺ , 100%). The diastereomers were separated by preparative scale HPLC. MS (EI) 476.4 (M + H ⁺ ), 951.6 (M + H ⁺ ) and diastereoisomer 2 (MS (EI) 476.4 (M + H ⁺ ), 951.6 2M + H ⁺ )).
[703] Example 5
[704] Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl- Yl) -3-methyl-butyl] -amide &lt; / RTI &gt;
[705] a) benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3- hydroxy-azepan-4- ylcarbamoyl)
[706] Following the general method of example 2j, except substituting 2-naphthoic acid for benzothiophene-2-carboxylic acid the title compound was obtained: MS (ES) 494 (M + H ⁺ ).
[707] b) Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4-ylcarbamoyl)
[708] The title compound was obtained following the general procedure of Example 1i but substituting the compound of Example 5a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, , 7.2-8.4 (m, 10H): MS (EI): 492 (M + H ^& lt ^{; +} & gt ^; , 100%).
[709] The diastereomers were separated by preparative scale HPLC. By freeze-drying the eluate diastereomer 1 (MS (EI) 492.4 ( M + H +), 983.7 (2M + H +)) and diastereomer 2 (MS (EI) 492.4 ( M + H +), 983.7 (2M + H ⁺ )).
[710] Example 6
[711] Preparation of naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl]
[712] a) Synthesis of naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[713] 0.24 ml (1.72 mmol) of triethylamine and 122 mg (0.54 mmol) of 2-naphthalenesulfonyl chloride were added to a solution of 200 mg (0.49 mmol) of the amine salt of Example 2i in CH ₂ Cl ₂ . The reaction was stirred at room temperature until the reaction was complete by TLC analysis. The reaction was worked-up, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was subjected to column chromatography (10% methanol: dichloromethane) to give 52 mg of the title compound: MS (EI) 524 (M + H ⁺ ).
[714] b) Synthesis of naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3- oxo-azepan-4-ylcarbamoyl)
[715] Example 6a according to those conducted in the general procedure of Example 1i except for the substitution of a compound of the titled compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (dd, , 5.3 (m, 1H), 7.2-8.4 (m, 12H): MS (EI): 522 (M + H ⁺ , 100%).
[716] Example 7
[717] Preparation of [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide
[718] a) Preparation of quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl-
[719] Following the general method of example 2j, except substituting 2-naphthoic acid for 2-quinolinecarboxylic acid, the title compound was obtained: MS (ES) 489 (M + H ⁺ ).
[720] b) quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl-
[721] Example 7a, except that the replacement of the compound, following the general method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, , 7.2-8.4 (m, 11H): MS (EI): 487 (M + H ^& lt ^{; +} & gt ^; , 100%). The diastereomers were separated by preparative scale HPLC. By freeze-drying the eluate diastereomer 1 (MS (EI) 492.4 ( M + H +), 983.7 (2M + H +)) and diastereomer 2 (MS (EI) 492.4 ( M + H +), 983.7 (2M + H ⁺ )).
[722] Example 8
[723] Preparation of 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl]
[724] a) Preparation of 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[725] Following the general method of example 2j, except substituting 3,4-dichlorobenzoic acid for 2-naphthoic acid, the title compound was obtained: MS (ES) 506 (M + H ⁺ ).
[726] b) Preparation of 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3- oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl]
[727] The title compound was obtained following the general method of example 1i, except substituting the compound of example 8a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H 2H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, , 7.2-8.4 (m, 8H): MS (EI): 504 (M, 100%).
[728] Example 9
[729] 2- (3-pyridin-2-yl-phenyl) -acetyl (3-methoxyphenyl) ] Preparation of azepanium
[730] a) Preparation of 4 - ((S) -2- tert -butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy- Acetyl] azepanium
[731] 341 mg (1.60 mmol) of EDC 307 mg (1.60 mmol), HOBt 216 mg (1.60 mmol) and 3- (2-pyridyl) phenylacetic acid were added to a solution of 0.5 g (1.46 mmol) of the compound from Example 2g in CH ₂ Cl ₂ Lt; / RTI &gt; The reaction was stirred at room temperature until the reaction was complete by TLC analysis. Worked up, and then column chromatography to give the title compound by _{(2% CH 3 OH CH 2} Cl 2): MS (ES) 539 (M + H +).
[732] b) Preparation of 4 - ((S) -amino-4-methyl-pentanoylamino) -3-hydroxy-1- [2- (3- pyridin-
[733] 20 ml of 4M HCl in dioxane was added to a solution of 1.3 g of the compound of Example 9a in 20 ml of methanol. The reaction was stirred by TLC analysis until the reaction was complete and concentrated in vacuo to give 1.1 g of the title compound: MS (EI) 439 (M + H ⁺ ).
[734] c) Preparation of 4 - {(S) -methyl-2 - [(quinoline-2-carbonyl) -amino] pentanoylamino} -3-hydroxy-1- [2- ) -Acetyl] azepanium
[735] MS (EI) 594 (M + H ^& lt ^{; +} & gt ^; ), was prepared following the general method of example 7a, but substituting the compound of example 9b.
[736] d) Preparation of 4 - {(S) -methyl-2 - [(quinoline-2-carbonyl) -amino] pentanoylamino} -Acetyl] azepanium
[737] The title compound was obtained following the general procedure of example 1i, except substituting the compound of example 9c: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H 2H), 4.7 (m, 3H), 5.4 (m, 1H), 2.2 (m, , 7.2-8.4 (m, 14H): MS (EI): 592 (M + H ^& lt ^{; +} & gt ^; , 100%).
[738] Example 10
[739] (S) -2-r (2-quinoline-2-carbonyl) -amino] - Pentanoylamino} -3-oxo-azepanium &lt; / RTI &gt;
[740] a) 1 - ((S) -2- benzyloxycarbonylamino-4-methyl-pentyl) -4 - ((S) -2- tert - butoxy Brassica
[741] Methyl-pentanoylamino) -3-hydroxy-azepanium &lt; / RTI &gt;
[742] Following the procedure of Example 2h, except substituting benzaldehyde for Cbz-leucine, the title compound was obtained: MS (EI) 577 (M + H ^& lt ^{; +} & gt ^; ).
[743] b) 4 - ((S) -2- amino-4-methyl-pentanoyl-amino) -1 - ((S) -2- tert-benzyloxycarbonylamino-4-methyl-phenyl) -3-hydroxy - azepanium
[744] The title compound was obtained according to the procedure of Example 2i but replacing the compound of Example 10a: MS (EI) 477 (M + H <^+> ).
[745] c) Preparation of 1 - ((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4 - {(S) ] -Pentanoylamino} -3-hydroxy-azepanium &lt; / RTI &gt;
[746] MS (EI) 632 (M + H ^& lt ^{; +} & gt ^; ), was prepared following the general method of example 7a, but substituting the compound of example 10b.
[747] d) Preparation of 1 - ((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4 - {(S) ] -Pentanoylamino} -3-oxo-azepanium
[748] The title compound was obtained following the general procedure of Example 1i but substituting the compound of Example 10c: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 12H), 1.5-2.1 (m, 10H ), 2.2 (m, 4H), 2.9 (m, 1H), 3.4 (m, 2H), 3.7 (m, , 7.5 (m, 1H), 7.6 (m, 1H), 7.7 (m, 1H), 8.1 (m, M + H & lt ^; + & gt ^; , 100%).
[749] Example 11
[750] Preparation of 1-benzoyl-4 - ((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl- pentanoylamino) -3-oxo-azepanium
[751] a) 1-Benzoyl-4 - ((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3- hydroxy-
[752] The title compound was obtained according to the procedure of Example 9a, but replacing 3- (2-pyridyl) phenylacetic acid with benzoic acid: MS (EI) 448 (M + H ⁺ ).
[753] b) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -1- benzoyl-3-hydroxy-
[754] The title compound was obtained following the method of Example 2i but substituting the compound of Example 11a: MS (EI) 348 (M + H <^+> ).
[755] c) Preparation of 1-benzoyl-4 - ((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl- pentanoylamino) -3- hydroxy-
[756] The title compound was obtained by following the general procedure of Example 2j but replacing the compound of Example 2j with the compound of Example 11b: MS (EI) 496 (M + H ⁺ ).
[757] d) Benzyl-4 - ((S) -2- (benzo [1,3] dioxol-
[758] Example 11c except that the replacement of the compound, following the general method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, , 6.0 (s, 2H), 7.2-8.4 (m, 8H); MS (EI): 494 (M + H ^& lt ^{; +} & gt ^; , 70%).
[759] Example 12
[760] Preparation of 1-benzoyl-4 - [(S) -2- (4-fluoro-benzoylamino) -4-methyl-pentanoylamino] -3-oxo-azepanium
[761] a) Preparation of 1-benzoyl-4 - [(S) -2- (4- fluoro-benzoylamino) -4-methyl-pentanoylamino] -3- hydroxy-
[762] The title compound was obtained following the general procedure of example 11c, but replacing piperonal acid with 4-fluorobenzoic acid: MS (EI) 470 (M + H ⁺ ).
[763] b) Preparation of 1-benzoyl-4 - [(S) -2- (4- fluoro-benzoylamino) -4-methyl-pentanoylamino] -3-
[764] Example 12a, except that the replacement of the compound, following the general method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (dd, , 7.2-8.4 (m, 9H): MS (EI): 468 (M + H ^& lt ^{; +} & gt ^; , 10%).
[765] Example 13
[766] ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino ) -1- (4-methyl-pentanonyl) -azepanone &lt; / RTI &gt;
[767] a) Preparation of 4 - ((S) -2- tert -butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy- 1- (4-methyl-pentanonyl)
[768] The title compound was obtained according to the procedure of Example 9a, but replacing 3- (2-pyridyl) phenylacetic acid with iso-caproic acid. MS (EI) 442 (M + H ⁺ ).
[769] b) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3- hydroxy- 1- (4-methyl-pentanonyl)
[770] The title compound was obtained following the procedure of Example 2i but substituting the compound of Example 13a: MS (EI) 342 (M + H ^& lt ^{; +} & gt ^; ).
[771] c) 3-Hydroxy-4 - ((S) -4-methyl-2- { Pentanoylamino) -l- (4-methyl-pentanonyl) -azepan &lt; / RTI &
[772] (Morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid was dissolved in CH ₂ Cl 2 (0.5 mL), HOBt 78 mg (0.58 mmol), EDTA 111 mg Was added to a solution of 200 mg (0.53 mmol) of the compound of example 13b in Cl ₂ . The reaction was stirred at room temperature until the reaction was complete by TLC analysis. After work-up was purified by column chromatography _{(5% CH 3 OH: CH} 2 Cl 2) to give 160 mg the title compound by: MS (EI) 615 (M + H +).
[773] d) Preparation of 3-oxo-4 - ((S) -4-methyl-2- { Nonylamino) -1- (4-methyl-pentanonyl) -azepanone
[774] The title compound was obtained following the general procedure of example 1i except substituting the compound of example 13c: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 12H), 1.5-2.1 (m, 8H ), 2.2 (m, 2H), 2.3 (m, 1H), 2.4-2.5 (m, 2H), 2.6 1H), 3.7 (m, 4H), 4.1 (m, 2H), 4.5-4.6 (m, 2H), 5.2 (m, 1H), 7.2-8.4 (m, 4H); MS (EI): 613 (M + H ^& lt ^{; +} & gt ^; , 100%). The diastereomers were separated by preparative scale HPLC. The eluate was lyophilized to obtain diastereomer 1 and diastereomer 2.
[775] Example 14
[776] ((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino ) -1-benzenesulfonyl-azepan &lt; / RTI &gt;
[777] a) 1-Benzenesulfonyl-4 - ((S) -2- tert -butoxycarbonylamino-4-methyl-pentanoylamino
[778] Oxo-3-hydroxy-azepan
[779] 0.4 ml (2.92 mmol) of triethylamine was added to a solution of 0.5 g (1.46 mmol) of the amine from Example 2g in dichloromethane followed by addition of 0.28 ml (2.18 mmol) of benzenesulfonyl chloride. The reaction was stirred at room temperature until the reaction was complete by TLC analysis. After work-up was purified by column chromatography _{(10% CH 3 OH: CH} 2 Cl 2) to give 450 mg the title compound by: MS (EI) 484 (M + H +).
[780] b) 4 - ((S) -2-Amino-methyl-pentanoylamino) -1- benzenesulfonyl-3-hydroxy-
[781] The title compound was obtained following the procedure of Example 2i but replacing the compound of Example 14a: MS (EI) 384 (M + H <^+> ).
[782] c) 3-Hydroxy-4 - ((S) -4-methyl-2- { Pentanoylamino) -1-benzenesulfonyl-azepanium &lt; / RTI &gt;
[783] MS (EI) 657 (M + H ^& lt ^{; +} & gt ^; ), was prepared following the method of Example 13c, but substituting the compound of Example 14b.
[784] d) Preparation of 3-oxo-4 - ((S) -4-methyl-2- { Nonylamino) -1-benzenesulfonyl-azepanium
[785] Example 14c except that the replacement of the compound, following the general method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.4 (m, 1H), 2.7 (m, 4H), 2.8 1H), 4.1 (m, 2H), 4.4 (m, 1H), 4.5 (m, 7.5 (m, 3H), 7.7 (m, 2H): MS (EI): 655 (M + H ⁺ , 100%).
[786] Analytical HPLC (40:60 to _{45:55 CH 3 CN: 20 mM KHPO} 4 (pH 7 buffer) gradient, 60 min, 1 ml / min; inert silica ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) analysis of the a diastereomeric mixture showed two peaks (R _t = 44.6 min, and 45.9 min). Preparatory scale HPLC (40:60 to _{50:50 CH 3 CN: 20 mM KHPO} 4 (pH 7 buffer) gradient, 2 ml / min, 60 min; inert silica ODS-3 column 250 x 20 mm; UV at 215 nM The diastereoisomers were separated by detection. Freeze-drying the eluate to diastereomers 1 (analysis R _t = 44.6 min) and the part to obtain the stereoisomer 2 (analysis R _t = 45.9 min).
[787] Example 15
[788] Carbonyl] amino} -pentanoylamino) - 3- (4-methyl-2 - {[ Oxo-azepane-1-carboxylic acid phenylamide
[789] a) [(S) -1- ( 3- hydroxy-1-phenylcarbamoyl-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[790] 0.24 ml (2.18 mmol) of phenyl isocyanate are added to a solution of 0.5 g (1.46 mmol) of the amine of Example 2g in 20 ml of dichloromethane. The reaction was stirred at room temperature until the reaction was complete by TLC analysis. After work-up was purified by column chromatography _{(5% CH 3 OH: CH} 2 Cl 2) to give a 578 mg the title compound by: MS (EI) 463 (M + H +).
[791] b) 4 - ((S) -2-Amino-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid phenylamide
[792] The title compound was obtained following the procedure of Example 2i but replacing the compound of Example 15a: MS (EI) 363 (M + H <^+> ).
[793] c) 3-Hydroxy-4 - ((S) -4-methyl-2- { Pentanoylamino) -azepane-1-carboxylic acid phenylamide
[794] The title compound was obtained following the procedure of Example 13c, but substituting the compound of Example 15b: MS (EI) 636 (M + H <^+> ).
[795] e) Preparation of 4 - ((S) -4-methyl-2 - {[5- (2-morpholino- 3-oxo-azepane-1-carboxylic acid phenylamide
[796] The title compound was obtained following the general procedure of example Ii but replacing the compound of example 15c: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.7 (m, 4H), 3.0 (m, 2H), 3.1 (m, , 4.3 (m, 2H), 4.9 (m, 2H), 5.2 (m, 1H), 7.2-8.4 (m, 9H); MS (EI): 634 (M + H ⁺ , 100%).
[797] Analytical HPLC: to _{(40:60 CH 3 CN 20 mM KHPO} 4 (pH 7 buffer) isopropyl greater raetik, 1 ml / min;; inert silica ODS-3 column 4.6 x 250 mm UV detection at 215 nM) diastereomeric mixture (R _t = 27.3 minutes and 30.1 minutes). Preliminary scale HPLC (40-60 to 50:50 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) gradient, 12 ml / min, 60 min; inert silica ODS-3 column 250 x 20 mm; The diastereoisomers were separated by detection. The eluate was lyophilized and desalted by extraction with NaHCO ₃ : ethyl acetate to give diastereomer 1 (analysis R _t = 27.3 min) and diastereomer 2 (analysis R _t = 30.1 min).
[798] Example 16
[799] (S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine -2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[800] a) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) 3-pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[801] Following the procedure of Example 13c, except substituting the compound of Example 9b, the title compound was obtained: MS (EI) 712 (M + H ^& lt ^{; +} & gt ^; ).
[802] b) Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -Pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[803] Example 16a, but replacing in the compound of Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, 4H), 2.8 (m, 2H), 2.9 (m, 4.3 (m, 2H), 4.7 (m, 2H), 5.4 (m, 1H), 7.2-8.0 (m, 13H), 8.5 (m, 1H): MS (EI): 710 (m + H +, 100 %) MS (EI).
[804] Analytical HPLC: to _{(40:60 CH 3 CN 20 mM KHPO} 4 (pH 7 buffer) isopropyl greater raetik, 1 ml / min;; inert silica ODS-3 column 4.6 x 250 mm UV detection at 215 nM) diastereomeric mixture (R _t = 33.9 min and 37.9 min). Preparatory scale HPLC (40:60 to _{45:55 CH 3 CN: 20 mM KHPO} 4 (pH 7 buffer) gradient, 12 ml / min, 60 min; inert silica ODS-3 column 250 x 20 mm; UV at 215 nM The diastereoisomers were separated by detection. Eluate lyophilization, and NaHCO _3: ethyl acetate and desalted by extraction diastereomer 1 (MS (EI) 710.3 ( M + H +), analysis R _t = 33.9 min) and diastereomer 2 (MS (EI) 710.3 (M ⁺ H +), was obtained for analysis R _t = 37.9 min).
[805] Example 17
[806] (S) -1- (Benzoyl-3-oxo-azepan-4-ylcarbamoyl) - benzofuran-2-carboxylic acid 3-methyl-butyl] -amide &lt; / RTI &gt;
[807] A mixture of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl- Yl) -3-methyl-butyl] -amide
[808] Following the procedure of Example 13c, except substituting the compound of Example 11b, the title compound was obtained: MS (EI) 621 (M + H ^& lt ^{; +} & gt ^; ).
[809] b) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl- ) -3-methyl-butyl] -amide
[810] Example 17a, but replacing in the compound of Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, 4H), 2.9 (m, 2H), 3.0 (m, MS (EI): 619 (M + H ^& lt ^{; +} & gt ^; , 100%).
[811] Analytical HPLC (40:60 to _{55:45 CH 3 CN: 20 mM KHPO} 4 (pH 7 buffer) gradient, 30 min, 1 ml / min; inert silica ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) analysis of the a diastereomeric mixture showed two peaks (R _t = 13.5 min, and 17.6 min). Preparative scale HPLC (40:60 to 45:55 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) gradient, 15 ml / min, 60 min; inert silica ODS-3 column 250 x 20 mm; The diastereoisomers were separated by detection. The eluent was lyophilized and desalted by extraction with NaHCO ₃ : ethyl acetate to give diastereomer 1 (analysis R _t = 13.5 min) and diastereomer 2 (analysis R _t = 17.6 min).
[812] Example 18
[813] -Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) 3-methyl-butyl] -amide &lt; / RTI &gt;
[814] a) 5- (2-Pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1 -benzenesulfonyl- Ylcarbamoyl) -3-methyl-butyl] -amide
[815] Carboxylic acid with 5- (2-pyrrolidin-1-yl-ethyloxy) -benzofuran-2-carboxylic acid The title compound was obtained following the procedure of Example 14c, except substituting: MS (EI) 641 (M + H <^+> ).
[816] b) 5- (2-Pyrrolidin-l-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl- Ylcarbamoyl) -3-methyl-butyl] -amide
[817] Example 18a, but replacing in the compound of Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 9H) 2H), 2.2 (m, 2H), 2.5 (m, 1H), 2.7 (m, 4H), 3.0 (m, 4.5 (m, 1H), 4.6 (m, 1H), 5.0 (m, 1H), 7.2-8.4 (m, 11H); MS (EI): 639 (M + H ⁺ , 100%).
[818] Example 19
[819] -Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) 3-methyl-butyl] -amide &lt; / RTI &gt;
[820] a) 5- (2-Piperidin-l-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl- Ylcarbamoyl) -3-methyl-butyl] -amide
[821] Carboxylic acid with 5- (2-piperidin-l-yl-ethyloxy) -benzofuran-2-carboxylic acid The title compound was obtained following the procedure of Example 14c, except substituting: MS (EI) 655 (M + H ^& lt ^{; +} & gt ^; ).
[822] b) 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1 -benzenesulfonyl- Ylcarbamoyl) -3-methyl-butyl] -amide
[823] Example 19a, but replacing in the compound of and has, following the method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 11H) 1H), 2.2 (m, 2H), 2.5 (m, 2H), 2.7 (m, 4.6 (m, 1H), 5.0 (m, 1H), 7.2-8.4 (m, 11H), MS (EI): 653 (M + H ⁺ , 100%).
[824] Example 20
[825] (S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine -2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[826] a) 5- (2-Morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid methoxymethylamide
[827] 0.92 g of N, O-dimethylhydroxylamine hydrochloride, 1.3 ml of triethylamine, 0.96 g of HOBt and 1.1 g of EDC were added to a solution of 1 g of 3- (2-pyridyl) phenylacetic acid in dichloromethane. Stir until the reaction was complete. After work-up, column chromatography (40% ethyl acetate: hexane) gave 1.1 g of the title compound: MS (EI) 257 (M + H ⁺ ).
[828] b) 5- (2-Morpholin-4-yl-ethoxy) benzofuran-2-carbaldehyde
[829] 2.0 ml of LAH (1 M solution in THF) was added to a solution of 0.2 g of 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid methoxymethylamide in Example 20a in THF . The reaction was stirred until the starting material was completely consumed. The work-up was carried out to obtain 160 mg of the title compound.
[830] c) (S) - {3-Hydroxy-1- [2- (3-pyridin- 2- yl- phenyl) -ethyl] -azepan-4-ylcarbamoyl} -Carbamic acid tert -butyl ester
[831] Following the procedure of Example 2g except substituting benzaldehyde for 5- (2-morpholin-4-yl-ethoxy) benzofuran-2-carbaldehyde the title compound was obtained: MS (EI) 525 (M + H & lt ^; + & gt ^; ).
[832] d) (S) -2-Amino-4-methyl-pentanoic acid {3-hydroxy-1- [2- (3-pyridin- amides
[833] Following the procedure of Example 2i but replacing the compound of Example 20c, the title compound was obtained.
[834] e) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) 3-pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[835] Following the procedure of Example 13c, except substituting the compound of Example 20d, the title compound was obtained.
[836] f) Preparation of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3- -Pyridin-2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[837] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 20e: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2H), 2.2 (m, 4H), 2.8 (m, 6H), 3.1 (m, 4.2 (m, 3H), 4.6 (m, 1H), 5.2 (m, 1H), 7.2-8.4 (m, 13H), 8.6 (m, 1H): MS (EI): 696 (M + H +, 80 %).
[838] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer (MS (EI): 696 (M + H ⁺ , 100%)) and the slower eluting diastereomer (MS (EI): 696 M + H & lt ^; + & gt ^; , 100%)).
[839] Example 21
[840] Naphthylene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Gt; &lt; RTI ID = 0.0 &gt; amide &lt; / RTI &gt;
[841] a) Naphthylene-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy- 1- [2- (3- pyridin- Ylcarbamoyl} -butyl) -amide &lt; / RTI &gt;
[842] The title compound was obtained following the procedure of Example 20f but replacing 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid with 2-naphthoic acid: MS EI) 579 (M + H ^& lt ^{; +} & gt ^; ).
[843] b) Naphthylene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Ylcarbamoyl} -butyl) -amide &lt; / RTI &gt;
[844] The title compound was obtained following the general procedure of example Ii except substituting the compound of example 21a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H ), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, , 6.8-7.2 (m, 6H), 7.3 (m, 1H), 7.5 (m, 2H), 7.9 577 (M + H & lt ^; + & gt ^; , 100%).
[845] Example 22
[846] Indole-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Carbamoyl} -butyl) -amide &lt; / RTI &gt;
[847] a) (S) -3-Methyl-1- {3-hydroxy-1- [2- (3- pyridin- 2- yl- phenyl) ethyl] -azepan-4-ylcarbamoyl} )-amides
[848] Following the procedure of Example 20f but replacing 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid with 1H-indole-2-carboxylic acid the title compound : MS (EI) 568 (M + H ^& lt ^{; +} & gt ^; ).
[849] b) (S) -3-Methyl-1- {3-oxo-1- [2- (3- pyridin- -amides
[850] The title compound was obtained following the general procedure of example 1i, except substituting the compound of example 22a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, , 6.8-7.2 (m, 6H), 7.0-7.9 (m, 12H), 8.7 (m, 1H), 9.5 (m, 1H); MS (EI): 566 (M + H ⁺ , 100%).
[851] Example 23
[852] Preparation of 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl]
[853] a) Preparation of lH-indole-2-carboxylic acid [(S) -1- (1 -benzenesulfonyl-3-hydroxy- azepan-4- ylcarbamoyl) -3-methyl- butyl]
[854] The title compound was obtained following the procedure of Example 2j except that naphthoic acid was replaced by 1H-indole-2-carboxylic acid and the compound of Example 14b: MS (EI) 527 (M + H ⁺ ).
[855] b) 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)
[856] The title compound was obtained following the general procedure of example Ii except substituting the compound of example 23a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (dd, IH), 3.9 (m, , 7.2-7.6 (m, 10H), 9.5 (b, 1H): MS (EI): 525 (M + H ⁺ , 10%).
[857] Example 24
[858] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl] -amide
[859] a) Benzofuran-2-carboxylic acid [(S) -1- (1 -benzenesulfonyl-3-hydroxy-azepan- 4- ylcarbamoyl) -3-methyl- butyl]
[860] The title compound was obtained following the method of Example 23a, but substituting benzofuran-2-carboxylic acid for 1H-indole-2-carboxylic acid: MS (EI) 528 (M + H <^+> ).
[861] b) Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl) -3- methyl-
[862] The title compound was obtained following the general procedure of Example 1i but substituting the compound of Example 24a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.6 (m, 1H), 3.5 (d, 10H).
[863] Example 25
[864] 2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Gt; &lt; RTI ID = 0.0 &gt; amide &lt; / RTI &gt;
[865] a) Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy- 1- [2- (3- pyridin- Ylcarbamoyl} -butyl) -amide &lt; / RTI &gt;
[866] Following the procedure of Example 20e but replacing 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid with benzofuran-2-carboxylic acid the title compound was obtained Obtained: MS (EI) 569 (M + H ^& lt ^{; +} & gt ^; ).
[867] b) Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Ylcarbamoyl} -butyl) -amide &lt; / RTI &gt;
[868] The title compound was obtained following the general method of example 1i, except substituting the compound of example 25a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H 1H), 2.2 (m, 2H), 2.7 (m, 5H), 3.0 (m, , 7.2-7.7 (m, 14H), 8.7 (m, 1H); MS (EI): 567 (M + H ⁺ , 100%).
[869] (EI): 656 (M + H ⁺ , 100%) and the more slowly eluting diastereoisomers (MS (EI): 656 M + H & lt ^; + & gt ^; , 100%)).
[870] Example 26
[871] (S) -3-methyl-1- (3-oxo-1-phenethyl-azepan-4-ylmethoxy) Ylcarbamoyl) -butyl] -amide &lt; / RTI &gt;
[872] Following the procedure of Example 20c-f but replacing 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carbaldehyde of Example 20c with phenylacetaldehyde, the title compound to _{^{obtain: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, 1H), 2.6 (m, 4H), 2H), 4.7 (m, 1H), 5.0 (m, 2H), 3.0 (m, (m, 1H), 7.2-7.7 (m, 11H): MS (EI): 619 (M + H ⁺ , 80%).
[873] (EI): 619 (M + H ⁺ , 100%) and the slower eluting diastereomer (MS (EI): 619 M + H & lt ^; + & gt ^; , 100%)).
[874] Example 27
[875] Preparation of naphthylene-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azepan-4- ylcarbamoyl) -butyl] -amide
[876] The title compound was obtained following the method of Example 2h-k except substituting phenylacetaldehyde for benzaldehyde in Example 2h: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5- (M, 2H), 2.4 (m, 1H), 2.7 (m, 4H), 3.0 (m, 1H), 5.1 (m, 1H), 6.9-7.2 (m, 7H), 7.5 (m, 2H), 7.9 M + H & lt ^; + & gt ^; , 100%).
[877] Example 28
[878] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Manufacturing
[879] a) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (pyridine- 2- sulfonyl)
[880] MS (EI): 385 (M + H ^& lt ^{; +} & gt ^; ), was prepared in accordance with the general method of examples 14a-b except that the benzenesulfonyl chloride of example 14a was replaced by 2-pyridine sulfonyl chloride. MS
[881] b) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl }-amides
[882] 69 mg of EDC, 49 mg of HOBt, 0.11 ml of TEA and 58 mg of benzofuran-2-carboxylic acid were added to a solution of (S) -2-amino-4-methyl- pentanoic acid [3-hydroxy -L- (pyridine-2-sulfonyl) -azepan-4-yl] -amide. Stir until the reaction was complete. Worked up, and then column chromatography to give the title compound by a (5% CH ₃ OH-ethyl acetate): MS (EI) 529 ( M + H +).
[883] c) Synthesis of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -amides
[884] Example 28b except for the replacement of the compound of Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, IH), 3.7 (dd, IH), 4.0 (m, ), 7.4 (m, 4H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 527 (M + H ⁺ , 40%).
[885] Part diastereomers is faster eluting with a stereoisomeric mixture separated by _{^{HPLC (1 H NMR (CDCl 3}} ): δ1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H) , 2.7 (t, 1H), 3.7 (d, IH), 4.0 (d, IH), 4.7 (m, 2H), 5.0 (m, ), 7.6 (m, 1H) , 8.0 (m, 2H), 8.7 (m, 1H): MS (EI): 527 (m + H +, 100%)) and the slower eluting diastereomer ⁽¹ H _{NMR (CDCl 3): δ1.0 (} m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (d, 1H), 4.0 (d, 1H ), 7.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 3H), 7.4 1H): MS (EI): 527 (M + H ⁺ , 100%).
[886] Example 29
[887] Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Manufacturing
[888] a) naphthylene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl }-amides
[889] Methyl-benzofuran-2-carboxylic acid was replaced by 2-naphthoic acid, the title compound was obtained following the method of example 28b: MS (EI) 539 (M + H <^+> ).
[890] b) Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [ -amides
[891] Example 29a, but replacing in the compound of Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, IH), 3.7 (dd, IH), 4.0 (m, ), 7.5 (m, 3H), 7.9 (m, 6H), 8.3 (m, 1H), 8.4 (m, 1H); MS (EI): 537 (M + H ⁺ , 50%).
[892] (EI): 537 (M + H ⁺ , 100%) and the more slowly eluting diastereoisomers (MS (EI): 537 M + H & lt ^; + & gt ^; , 100%)).
[893] Example 30
[894] Synthesis of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [ ) -Azepan-4-ylcarbamoyl] -butyl} -amide
[895] a) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridin- -Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[896] The title compound was obtained following the procedure of Example 13c, except substituting the compound of Example 28a: MS (EI) 658 (M + H ^& lt ^{; +} & gt ^; ).
[897] b) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[898] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 30a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2 H), 2.7 (m, 1 H). 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 (EI): 656 (M + H ^& lt ^{; +} & gt ^; , 100%).
[899] (EI): 656 (M + H ⁺ , 100%) and the more slowly eluting diastereoisomers (MS (EI): 656 M + H & lt ^; + & gt ^; , 100%)).
[900] Example 31
[901] 4 - ((S) -4-methyl-2 - {[(5- (2-morpholino-4-yl- ethoxy) -benzofuran- 2- carbonyl] -amino} -pentanoylamino) 3-oxo-azepan-1-carboxylic acid tert- Preparation of butyl esters
[902] a) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1 -carboxylic acid tert -butyl ester
[903] 10% Pd / C and hydrogen in one apparatus were added to a solution of 0.89 g of the compound of Example lf in 30 ml of ethyl acetate: methanol (2: 1 solution). The reaction was stirred until the reaction was complete by TLC analysis and the reaction was filtered and concentrated to give the title compound (0.57 g).
[904] b) Preparation of 4 - ((S) -4-methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-
[905] -Amino} -pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid tert -butyl ester
[906] Following the procedure of Example 13c, except substituting the compound of Example 31a, the title compound was obtained.
[907] c) Preparation of 4 - ((S) -4-methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] -amino} -pentanoylamino ) -3-oxo-azepane-1-carboxylic acid tert -butyl ester
[908] Example 31b, but replacing in the compound of the Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (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, 3.8 (m, 4H), 4.1 (m, 3H), 4.2 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 5H); MS (EI): 615 (M + H ^& lt ^{; +} & gt ^; , 100%).
[909] Example 32
[910] 4-methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) Preparation of 1- (3-oxo-azepan-4-ylcarbamoyl) -butyl] -amide
[911] 5 ml of 1 M HCl in ether was added to a solution of the compound of Example 31c in 5 ml of THF. The reaction was stirred overnight and then concentrated to give the title compound: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 4H), 3.2 (dd, 3H). 3.7 (m, 6H), 4.0 (m, 3H), 4.5 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 6H); MS (EI): 515 (M + H ^& lt ^{; +} & gt ^; , 100%).
[912] Example 33
[913] Preparation of 4-methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-4-yl}
[914] a) 3-Hydroxy-4- (4-methyl-pentanoylamino) -azepane-1-carboxylic acid tert-butyl ester
[915] The title compound was obtained according to the procedure of example 1f but replacing Cbz-leucine with 4-methylpentanoic acid: MS (EI) 329 (M + H ⁺ ).
[916] b) 4-Methylpentanoic acid (3-hydroxy-azepan-4-yl) -amide
[917] 5 ml of 4M HCl in dioxane was added to a solution of 220 mg of the compound of Example 33a in 5 ml of methanol. Stirring was continued until the reaction was complete and concentrated to give 132 mg of the title compound: MS (EI) 229 (M + H ^& lt ^{; +} & gt ^; ).
[918] c) 4-Methyl-pentanoic acid {3-hydroxy-l- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepan-
[919] The title compound was obtained following the method of Example 9a, except substituting the compound of Example 33b: MS (EI) 424 (M + H <^+> ).
[920] d) 4-Methyl-pentanoic acid {3-oxo-l- [2- (3-pyridin- 2- yl- phenyl) -acetyl] -azepan-
[921] Examples are, but replacing the compound of 33c according to the method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDC1 3)}} δ1.0 (m, 6H), 1.5-2.1 (m, 5H), 2H), 2.2 (m, 1H), 2.9 (m, 1H), 3.5 (m, (m, 1 H), 7.2-8.0 (m, 7 H), 8.7 (m, 1 H); MS (EI): 422 (M + H ^& lt ^{; +} & gt ^; , 100%).
[922] Example 34
[923] (S) -3-methyl-1- {3-oxo-1- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepan-4-ylcarbamoyl} Naphthylene-2-methyl-carbamic acid tert- Preparation of butyl esters
[924] a) (S) -4-Methyl-2- [naphthalen-2-ylmethyl) -amino] -pentanoic acid methyl ester
[925] 0.9 ml of triethylamine, 0.43 g of 2-naphthaldehyde and 0.87 g of sodium triacetoxyborohydride were added to a solution of 0.5 g of leucine methyl ester hydrochloride in dichloromethane. Stir until the reaction was complete. After workup, column chromatography (5% ethyl acetate: dichloromethane) gave 0.4 g of the title compound: MS (EI) 286 (M + H ⁺ ).
[926] b) (S) -2- ( tert -Butoxycarbonyl-naphthylen-2-ylmethyl-amino) -4-methylpentanoic acid methyl ester
[927] 0.29 g of di- tert -butyl dicarbonate was added to a solution of 0.35 g of the compound of Example 34a in dichloromethane. After 2 hours at room temperature, triethylamine was added and the reaction was heated to reflux. Upon completion of the reaction, the reaction was concentrated and the residue was purified and chromatographed (50% hexane: dichloromethane) to give 0.17 g of the title compound: MS (EI) 386 (M + H ⁺ ).
[928] c) (S) -2- ( tert -Butoxycarbonyl-naphthylen-2-ylmethyl-amino) -4-methylpentanoic acid
[929] 0.019 g of LiOH was added to a solution of 0.17 g of the compound of Example 34b in 15 ml of THF: methanol (2: 1 solution). The reaction was stirred overnight and concentrated to give the title compound.
[930] d) Preparation of 4 - [(S) -tert -butoxycarbonyl-naphthylen-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3- hydroxy- ester
[931] 0.08 g of EDC, 0.06 g of HOBt and the acid from Example 34c in 0.11 g of the compound of Example 2e in dichloromethane. When the reaction was complete, the reaction was worked up and chromatographed (5% methanol: dichloromethane) gave 0.18 g of the title compound: MS (EI) 618 (M + H ⁺ ).
[932] e) [(S) -1- ( 3- hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] - naphthylene-2-yl-methyl-carbamic acid tert-butyl ester
[933] 10% Pd / C was added to a solution of 0.17 g of the compound of Example 34d in ethyl acetate: methanol (20: 10 ml). Hydrogen was added to one apparatus and stirred until the starting material was completely consumed. The reaction was filtered and concentrated to give 0.10 g of the title compound: MS (EI) 484 (M + H ^& lt ^{; +} & gt ^; ).
[934] f) ((S) -3-Methyl-1- {3-hydroxy- 1- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepan-4-ylcarbamoyl} Butyl) -naphthylene-2-methyl-carbamic acid tert -butyl ester
[935] MS (EI) 679 (M + H ^& lt ^{; +} & gt ^; ), was prepared following the procedure of Example 9a, except substituting the compound of Example 34e.
[936] g) ((S) -3-Methyl-1- {3-oxo-1- [2- (3- pyridin- ) -Naphthylene-2-methyl-carbamic acid tert -butyl ester
[937] Performed according to in Example 1i method, but replacing the compound of Example 34f to give the title _{^{compound: 1 H NMR (CDC1 3)}} : δ 1.0 (m, 6H), 1.5-2.2 (m, 16H), 2H), 5.2 (m, 1H), 7.2-7.3 (m, 1H), 2.7 (m, , 8.6 (m, 1 H); MS (EI): 677 (M + H ^& lt ^{; +} & gt ^; , 100%).
[938] Example 35
[939] (3-oxo-l- [2- (3-pyridin-2-yl-phenyl) -acetyl] - &lt; / RTI &gt; azepan-4-yl} -amide
[940] 1 M HCl in ether was added to a solution of 20 mg of the compound of Example 34g in THF. ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1 H), 3.5 (m, 5 H). 4.0 (m, 1H), 4.7 (m, 2H), 4.4 (m, 1H), 7.2-8.0 (m, 16H), 8.7 (m, 1H); MS (EI): 577 (M + H ^& lt ^{; +} & gt ^; , 100%).
[941] Example 36
[942] 4- [2- (2 - {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl } -Benzofuran-5-yloxy) -ethyl] -piperazine-l-carboxylic acid tert- Preparation of butyl esters
[943] a) 4- [2- (2 - {(S) -3-Methyl-1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Carbamoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-l-carboxylic acid tert -butyl ester
[944] Butyl ester was reacted with 0.07 g of EDC, 0.05 g of HOBt, 0.11 ml of triethylamine and 4- [2- (2-carboxybenzofuran-5-yloxy) -ethyl] -piperazine- Was added to a solution of 0.15 g of the compound of example 28a. The mixture was stirred until the reaction was completed. Workup followed by column chromatography (10% methanol: ethyl acetate) afforded 0.10 g of the title compound: MS (EI) 757 (M + H ^& lt ^{; +} & gt ^; ).
[945] b) Preparation of 4- [2- (2 - {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Benzoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-l-carboxylic acid tert -butyl ester
[946] Example 36a, but replacing in the compound of and has, following the procedure of Example li to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 14H) 2H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (m, 2H), 3.5 (m, 4.7 (m, 2H), 5.0 (m, 1H), 7.0-7.6 (m, 6H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 755 (M + H ^& lt ^{; +} & gt ^; , 100%).
[947] Example 37
[948] Preparation of 5- (2-piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- - azepan-4-ylcarbamoyl] -3-butyl} -amide
[949] 0.02 g of the compound of Example 36b was dissolved in 4M HCl in dioxane. ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-1.7 (m, 7H), 2.7 (m, 2H), 3.3 m, 2 H), 3.5 (m, 1 H). 2H), 7.4 (m, 6H), 8.0 (m, 2H), 7.7 (m, 2H) , 8.7 (m, 1H): MS (EI): 655 (M + H ^& lt ^{; +} & gt ^; , 100%).
[950] Example 38
[951] Preparation of 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[952] a) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- Azepan-4-ylcarbamoyl] -butyl} -amide
[953] 0.07 g of EDC, 0.05 g of HOBt, 0.11 ml of triethylamine and 0.01 g of 5- (2-cyclohexyl-ethoxy) benzofuranecarboxylic acid were added to a solution of 0.15 g of the compound of Example 28a in dichloromethane. The mixture was stirred by TLC analysis until the reaction was completed. Work-up followed by column chromatography (100% ethyl acetate) afforded 0.15 g of the title compound: MS (EI) 655 (M + H ⁺ ).
[954] b) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- Yl-carbamoyl] -butyl} -amide
[955] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 38a: MS (EI) 653 (M + H <^+> ).
[956] Example 39
[957] Preparation of 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl- 1- 3- Phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[958] a) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl- 1- {3-hydroxy- 1- [2- (3- Yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[959] 0.06 g of EDC, 0.04 g of HOBt, 0.14 ml of triethylamine and 0.09 g of 5- (2-cyclohexyl-ethoxy) benzofuranecarboxylic acid were added to a solution of 0.15 g of the compound of Example 20d in dichloromethane. The mixture was stirred by TLC analysis until the reaction was completed. Work-up followed by column chromatography (100% ethyl acetate) afforded 0.10 g of the title compound: MS (EI) 695 (M + H ⁺ ).
[960] b) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl- 1- 3- Yl-phenyl) -ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[961] Example 39a, but replacing in the compound of and has, following the method of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 18H) , 2.2 (m, 2H), 2.7 (m, 3H), 3.2 (m, 1H), 3.5 (m, 1H). 3.9 (m, 4H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 13H), 8.7 (m, 1H): MS (EI): 693 (M + H +, 100 %)
[962] Example 40
[963] 2-yl-phenyl) -ethyl-azepan-4-ylcarbamoyl] - &lt; / RTI & -Butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-1-carboxylic acid tert- Preparation of butyl esters
[964] a) 4- [2- (2 - {(S) -3-Methyl-1- [3-hydroxy- -Bamoyl] -butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-l-carboxylic acid tert -butyl ester
[965] 0.06 g of EDC, 0.04 g of HOBt, 0.14 ml of triethylamine and 0.12 g of 4- [2- (2-carboxy-benzofuran-5-yloxy) -ethyl] -piperazine-1 -carboxylic acid tert- Was added to a solution of 0.15 g of the compound of Example 20d in dichloromethane. The mixture was stirred by TLC analysis until the reaction was completed. After workup and column chromatography (100% ethyl acetate) the title compound was obtained: MS (EI) 797 (M + H ^&
[966] b) 4- [2- (2 - {(S) -3-Methyl-1- [3-oxo-l- (3-pyridin- Yl] -butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[967] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 40a: MS (EI): 795.9 (M + H <^+> ).
[968] Example 41
[969] (S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin- 2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[970] The title compound was obtained following the procedure of Example 37, except substituting the compound of Example 40b: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) (M, 1H), 2.2 (m, 2H), 3.4-3.6 (m, 19H), 4.5 ), 7.5 (m, 2H), 7.7 (m, 2H), 7.8 (m, 1H), 8.1 (m, 2H), 8.4 (m, 1H), 8.7 (m, 1H); MS (EI): 695 (M + H &lt; + &gt;, 70%).
[971] Example 42
[972] (3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-yl] -amide was prepared from (S) -4-methyl- Produce
[973] a) Preparation of 4 - [(S) -2- ( tert -Butoxycarbonyl-methyl-amino) -4-methyl-pentanoylamino] -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[974] 0.36 g of N-methyl-N-Boc-leucine, 0.2 g of HOBt and 0.28 g of EDC were added to a solution of 0.35 g of the compound of Example 2e in dichloromethane. The mixture was stirred until the reaction was completed. Work-up followed by column chromatography (5% methanol: dichloromethane) afforded 0.6 g of the title compound: MS (EI) 492 (M + H ⁺ ).
[975] b) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl- butyl] -methyl-
[976] tert -butyl ester
[977] 10% Pd / C and hydrogen in one apparatus were added to a solution of 0.6 g of the compound of Example 42a in methanol: ethyl acetate (10: 20 ml). The reaction was stirred overnight, then filtered and concentrated to afford 0.50 g of the title compound: MS (EI) 358 (M + H ^& lt ^{; +} & gt ^; ).
[978] c) {(S) -1- [3-Hydroxy-1- (pyridine-2- sulfonyl) -azepan-4-ylcarbamoyl]
[979] -Butyl} -methyl-carbamic acid tert -butyl ester
[980] 0.16 ml of triethylamine and 0.15 g of 2-pyridine sulfonyl chloride were added to a solution of 0.2 g of the compound of Example 42b in dichloromethane. The mixture was stirred until the reaction was completed. Work-up and column chromatography (5% methanol: ethyl acetate) afforded 0.23 g of the title compound: MS (EI) 499 (M + H ⁺ ).
[981] d) (S) -4-Methyl-2-methylamino-pentanoic acid [3-hydroxy-1- (2-pyridine- 2- sulfonyl)
[982] 3.0 ml of 4M HCl in dioxane was added to a solution of 0.23 g of the compound of Example 42c in 3.0 ml of methanol. The mixture was stirred until the reaction was completed. Concentration gave the title compound: MS (EI) 399 (M + H ^& lt ^{; +} & gt ^; ).
[983] e) (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid 3-hydroxy- 1- (pyridine- 2- sulfonyl) -amides
[984] 0.07 ml of triethylamine, 0.05 g of 2-naphthaldehyde and 0.11 g of sodium triacetoxyborohydride were added to a solution of 0.05 g of the compound 42d of Example 42d in dichloromethane. The mixture was stirred until the reaction was completed. Work-up followed by column chromatography (5% methanol: ethyl acetate) afforded 0.03 g of the title compound: MS (EI) 539 (M + H ⁺ ).
[985] f) (3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-yl] -amides
[986] Performed according to in Example 1i, but replacing method of a compound of example 42e gives the title _{^{compound: 1 H NMR (CDC1 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 5H), 2.6 (m, IH), 3.3 (m, IH), 3.7 (m, 7. 2-8.0 (m, 10 H), 8.7 (m, 1 H); MS (EI): 537 (M + H ^& lt ^{; +} & gt ^; , 100%).
[987] Example 43
[988] (3-oxo-l- [2- (3-pyridin-2-yl-phenyl) -acetyl] -acetic acid Yl} -amide &lt; / RTI &gt;
[989] a) ((S) -1- {3-Hydroxy-1- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepan-4-ylcarbamoyl} Butyl) -methyl-carbamic acid tert -butyl ester
[990] 0.16 g of 3- (2-pyridyl) phenylacetic acid, 0.12 g of HOBt and 0.15 g of EDC were added to a solution of 0.25 g of the compound of Example 42b. The mixture was stirred until the reaction was completed. Work-up followed by column chromatography (5% methanol: ethyl acetate) afforded 0.24 g of the title compound: MS (EI) 553 (M + H ⁺ ).
[991] b) (S) -4-Methyl-2-methylamino-pentanoic acid {3-hydroxy- -amides
[992] The title compound was obtained following the procedure of Example 42d but replacing the compound of Example 43a: MS (EI) 453 (M + H ^& lt ^{; +} & gt ^; ).
[993] c) (S) -4-Methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid { - azepan-4-yl} -amide
[994] The title compound was obtained following the procedure of Example 42e-f, except substituting the compound of Example 43b: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 1H), 2.2 (m, 5H), 3.0 (m, 1H), 3.5 (m, , 7.2-8.0 (m, 15 H), 8.7 (m, 1 H); MS (EI): 591 (M + H ^& lt ^{; +} & gt ^; , 100%).
[995] Example 44
[996] Methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3- Pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[997] a) Preparation of methyl 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylate ((S) (3-pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[998] 0.06 g of 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid, 0.026 g of HOBt, 0.07 ml of TEA and 0.04 g of EDC were added to a solution of 0.1 g of the compound of Example 43b in dichloromethane . The mixture was stirred until the reaction was completed. After workup, chromatography (20% methanol: ethyl acetate) gave 0.07 g of the title compound: MS (EI) 726 (M + H ⁺ ).
[999] b) Preparation of methyl 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylate ((S) 3-pyridin-2-yl-phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide
[1000] The title compound was obtained following the procedure of Example 1i, except substituting the compound of Example 44a: ¹ H NMR (CDCl ₃ ) 1.0 (m, 6H), 1.5-2.1 (m, 5H) 3H), 3.9 (m, 3H), 4.3 (m, 2H), 2.2 (m, 2H) (m, 2H), 4.7 (m, 2H), 5.4 (m, 1H), 7.2-8.0 (m, 12H), 8.5 (m, 1H); MS (EI): 724 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1001] Example 45
[1002] Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl -Butyl} -amide &lt; / RTI &gt;
[1003] a) Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan- 3-methyl-butyl} -amide
[1004] 0.04 g of benzofuran-2-carboxylic acid, excess TEA, 0.03 g of HOBt and 0.04 g of EDC were added to a solution of 0.1 g of the compound of Example 42d in dichloromethane. The mixture was stirred until the reaction was completed. After work-up, column chromatography (5% methanol: dichloromethane) gave 0.04 g of the title compound: MS (EI) 542.9 (M + H <^+> ).
[1005] b) Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Methyl-butyl} -amide &lt; / RTI &gt;
[1006] Example 45a, but replacing in the compound of Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 8H) 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (m, 7.2-8.0 (m, 8 H), 8.7 (m, 1 H); MS (EI): 541 (M + H ^& lt ^{; +} & gt ^; , 10%).
[1007] Example 46
[1008] (S) -3-methyl-1- {3-oxo-1- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepane -4-ylcarbamoyl} -butyl) -N-naphthylen-2-ylmethyl-acetamide
[1009] a) (S) -4-Methyl-2- [naphthylen-2-ylmethyl- (2,2,2- trifluoro-acetyl) -amino] -pentanoic acid methyl ester
[1010] A catalytic amount of potassium carbonate and 0.44 g of trifluoroacetic acid were added to a solution of 0.5 g of the compound of Example 34a in dichloromethane. The reaction was stirred at room temperature for 1 hour, then concentrated and chromatographed (20% ethyl acetate: hexane) to give the title compound.
[1011] b) (S) -4-Methyl-2- [naphthylen-2-ylmethyl- (2,2,2-trifluoro-acetyl) -amino] -pentanoic acid lithium salt
[1012] 0.06 g of lithium hydroxide monohydrate was added to a solution of 0.49 g of the compound of Example 46a in 3 ml of THF: water (2: 1 solution). The reaction was stirred overnight and then concentrated to afford 0.46 g of the title compound: MS (EI) 366 (M + H ^& lt ^{; +} & gt ^; ).
[1013] c) Synthesis of 3-hydroxy-4 - {(S) -4-methyl-2- [naphthylen-2-ylmethyl- (2,2,2-trifluoro- - &lt; / RTI &gt; azepane-1-carboxylic acid benzyl ester
[1014] 0.24 g of EDC, 0.16 g of HOBt and 0.46 g of the compound of Example 46b were added to a solution of 0.29 g of the compound of Example 2e in dichloromethane. The mixture was stirred until the reaction was completed. Work-up followed by column chromatography (5% methanol: ethyl acetate) afforded 0.25 g of the title compound: MS (EI) 614 (M + H ⁺ ).
[1015] d) 2,2,2-Trifluoro-N - [(S) -1- (3-hydroxy-azepan-ylcarbamoyl) -3-methyl- butyl] -N- Ylmethyl-acetamide
[1016] The title compound was obtained following the procedure of Example 42b, except substituting the compound of Example 46c: MS (EI) 480 (M + H <^+> ).
[1017] e) 2,2,2-Trifluoro-N - ((S) -3-methyl-1- {3-hydroxy- - azepan-4-ylcarbamoyl} -butyl) -N-naphthylen-2-ylmethyl-acetamide
[1018] The title compound was obtained following the procedure of Example 43a, except substituting the compound of Example 46d: MS (EI) 675 (M + H <^+> ).
[1019] f) 2,2,2-Trifluoro-N - ((S) -3-methyl-1- {3-
[1020] -Acetyl] -azepan-4-ylcarbamoyl} -butyl) -N-naphthylen-2-ylmethyl-acetamide
[1021] Examples are, but replacing in the compound of 46e, Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDC1 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2H (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.7 (m, 1H), 7.2-8.0 (m, 14H), 8.7 (m, 1H); MS (EI): 673 (M + H ⁺ , 100%).
[1022] Example 47
[1023] Preparation of 4 - [(S) - (methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl ester
[1024] a) (S) -2- (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methyl-
[1025] ester
[1026] 0.36 ml of triethylamine and 0.16 ml of methanesulfonyl chloride were added to a solution of 0.5 g of the compound of Example 34a in dichloromethane. Stir at room temperature until the reaction was complete. Chromatography after work-up (20% ethyl acetate: hexanes) gave 0.24 g of the title compound.
[1027] b) (S) -2- (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methyl-pentanoic acid lithium salt
[1028] The title compound was obtained following the procedure of Example 46b, except substituting the compound of Example 47a: MS (EI) 348 (M + H ^& lt ^{; +} & gt ^; ).
[1029] c) Preparation of 4 - [(S) - (methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methyl- pentanoylamino] -3- hydroxy- azepane- 1 -carboxylic acid benzyl ester
[1030] The title compound was obtained following the procedure of Example 46c, except substituting the compound of Example 47b: MS (EI) 596 (M + H ^& lt ^{; +} & gt ^; ).
[1031] d) Preparation of 4 - [(S) - (Methanesulfonyl-naphthylen-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3- oxo- azepane- 1 -carboxylic acid benzyl ester
[1032] Examples are, but replacing in the compound of 47c, Example 1i method to give the title compound according to _{^{a: 1 H NMR (CDC1 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 1H), 7.2 (m, 3H), 7.2 (m, 3H), 7.2 (m, -8.0 (m, 13H); MS (EI): 596 (M + 3H ^& lt ^; + & gt ^; , 100%).
[1033] Example 48
[1034] 2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Produce
[1035] a) Quinoline-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amides
[1036] Methyl-benzofuran-2-carboxylic acid was replaced by quinoline-2-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1037] b) quinoline-2-carboxylic acid {(S) -3-methyl- 1- [3- oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amides
[1038] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 48a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 1H), 7.7 (m, 1H), 7.0 (m, 1H), 7.0 (m, , 7.8 (m, 3H), 8.1 (m, 1H), 8.3 (m, 2H), 8.7 (m, 2H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1039] MS (EI): 538 (M + H ⁺ , 100%) and the more slowly eluting diastereoisomers (MS (EI): 538 M + H & lt ^; + & gt ^; , 100%)).
[1040] Example 49
[1041] 8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Produce
[1042] 8-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amides
[1043] Methyl-benzofuran-2-carboxylic acid was replaced by quinoline-8-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1044] b) quinoline-8-carboxylic acid {(S) -3-methyl- 1- [3- oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amides
[1045] Performed according to in Example 1i method, but replacing the compound of Example 49a to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H) , 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 1H), 8.7 (m, 1H), 7.7 (m, 2H), 5.0 (m, (m, 1 H), 8.7 (m, 1 H), 8.9 (m, 1 H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1046] Example 50
[1047] -6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Produce
[1048] carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amides
[1049] The title compound was obtained following the procedure of Example 28b, but replacing benzofuran-2-carboxylic acid with quinoline-6-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1050] b) quinoline-6-carboxylic acid {(S) -3-methyl- 1- [3- oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[1051] ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 2H), 8.0 (m, 3H), 8.0 (m, 2H), 7.0 (m, (m, 1 H), 8.7 (m, 1 H), 8.9 (m, 1 H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1052] MS (EI): 538 (M + H ⁺ , 100%) and later eluting diastereoisomers (MS (EI): 100%) were obtained by separating the diastereomeric mixture by HPLC M + H & lt ^; + & gt ^; , 100%)).
[1053] Example 51
[1054] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Produce
[1055] a) Quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -amides
[1056] Methyl-benzofuran-2-carboxylic acid was replaced by quinoline-4-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1057] b) Quinoline-4-carboxylic acid {(S) -3-methyl- 1- [3- oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amides
[1058] ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 2H), 7.4 (m, 1H), 4.7 (m, 2H), 5.0 (m, , 7.9 (m, 2H), 8.0 (m, 1H), 8.2 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1059] MS (EI): 538 (M + H ⁺ , 100%) and later eluting diastereoisomers (MS (EI): 100%) were obtained by separating the diastereomeric mixture by HPLC M + H & lt ^; + & gt ^; , 100%)).
[1060] Example 52
[1061] 3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide Produce
[1062] a) Quinoline-3-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -amides
[1063] Methyl-benzofuran-2-carboxylic acid was replaced by quinoline-3-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1064] b) quinoline-3-carboxylic acid {(S) -3-methyl-1- [ amides
[1065] ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 1H), 7.7 (m, 2H), 5.0 (m, 1H), 7.2 (m 2H), 7.5 ), 8.1 (m, IH), 8.5 (m, IH), 8.6 (m, IH), 9.3 (m, IH); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1066] MS (EI): 538 (M + H ⁺ , 100%) and later eluting diastereoisomers (MS (EI): 100%) were obtained by separating the diastereomeric mixture by HPLC M + H & lt ^; + & gt ^; , 100%)).
[1067] Example 53
[1068] 3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide Manufacturing
[1069] a) isoquinoline-3-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridin- 2-
[1070] Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1071] Methyl-benzofuran-2-carboxylic acid was replaced by isoquinoline-3-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1072] b) Synthesis of isoquinoline-3-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -amides
[1073] The title compound was obtained following the procedure of example 1i, except substituting the compound of Example 53a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.0 (m, 1H). 7.5 (m, 1H), 7.7 (m, 2H), 7.9 (m, 4H), 8.7 (m, 3H), 9.2 (m, 1H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1074] Example 54
[1075] [(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide Manufacturing
[1076] a) isoquinoline-1-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine-
[1077] - azepan-4-ylcarbamoyl] -butyl} -amide
[1078] Methyl-benzofuran-2-carboxylic acid was replaced by isoquinoline-1-carboxylic acid following the procedure of Example 28b: MS (EI) 540 (M + H ⁺ ).
[1079] b) Preparation of isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -amides
[1080] ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 1H), 7.7-8.0 (m, 6H), 8.7 (m, 3H), 7.5 (m, , 9.5 (m, 1 H); MS (EI): 538 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1081] MS (EI): 537 (M, 100%) and later eluting diastereoisomers (MS (EI): 537 (M, 100%)) were obtained by separating the diastereomeric mixture by HPLC %)).
[1082] Example 55
[1083] 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide as a colorless solid. Manufacturing
[1084] a) quinoxaline-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl }-amides
[1085] Methyl-benzofuran-2-carboxylic acid was replaced by quinoxaline-2-carboxylic acid. MS (EI) 541 (M + H <^+> ).
[1086] 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - &lt; / RTI &gt; -amides
[1087] ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 2H), 7.0 (m, 2H), 7.5 (m, 1H), 7.7 (m, , 8.3 (m, 1 H), 8.7 (m, 1 H), 9.5 (m, 1 H); MS (EI): 539 (M + H ^& lt ^{; +} & gt ^; , 30%).
[1088] Example 56
[1089] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) Butyl} -amide &lt; / RTI &gt;
[1090] a) benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) Yl] -butyl} -amide
[1091] The title compound was obtained following the procedure of Example 28b, except substituting benzo [b] thiophene-2-carboxylic acid for benzo [f] thiophene-2-carboxylic acid: MS (EI) 545 ⁺ ).
[1092] b) Preparation of benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) ] -Butyl} -amide
[1093] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 56a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.8-7. 2 (m, 1H), 7.5 (m, 3H), 8.0 (m, 6H), 8.7 (m, 1H); MS (EI): 543 (M + H ^& lt ^{; +} & gt ^; , 60%).
[1094] Separating the diastereomeric mixture by HPLC with the faster eluting diastereomer _{^{(1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), (M, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H), 8.7 ^{(m + H +, 100%} )) and the diastereomer that eluted later _{^{(1 H NMR (CDCl 3)}} : δ 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), 8.7 543 (M + H & lt ^; + & gt ^; , 100%)).
[1095] Example 57
[1096] 2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide &lt; / RTI &gt;
[1097] a) 1,8-Naphthyridine-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan- Yl] -butyl} -amide
[1098] The title compound was obtained following the procedure of Example 28b, except substituting 1,8-naphthyridine-2-carboxylic acid for benzofuran-2-carboxylic acid: MS (EI) 541 (M + H ⁺ ).
[1099] b) 1,8-Naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [
[1100] - azepan-4-ylcarbamoyl] -butyl} -amide
[1101] The title compound was obtained following the procedure of example 1i, except substituting the compound of example 57a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). (M, 2H), 8.3 (m, 1H), 8.4 (m, 1H), 7.7 (m, 2 H), 8.5 (m, 2 H), 9.2 (m, 1 H); MS (EI): 539 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1102] Example 58
[1103] Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Preparation of amide
[1104] a) 1H-indole-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide
[1105] The title compound was obtained following the method of Example 28b, except substituting 1-H-indole-2-carboxylic acid for benzofuran-2-carboxylic acid: MS (EI) 528 (M ⁺ ).
[1106] b) lH-Indole-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine-2-sulfonyl)
[1107] -4-ylcarbamoyl] -butyl} -amide
[1108] Example 58a except that replaced by the compound, following the procedure of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 1H), 7.3 (m, 1H), 7.4 (m, 1H), 7.5 (m, (m, 1H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H), 9.4 (b, 1H); MS (EI): 526 (M + H ^& lt ^{; +} & gt ^; , 80%).
[1109] Example 59
[1110] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ -Butyl} -amide &lt; / RTI &gt;
[1111] a) 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1112] The title compound was obtained following the method of Example 28b, except substituting 5-methoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid: MS (EI) 559 (M + H ⁺ ).
[1113] b) A mixture of 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- Yl] -butyl} -amide
[1114] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 59a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 1H), 7.0 (m, 4H), 7.6 (m, 2H), 2.7 (m, (m, 3 H), 8.0 (m, 2 H), 8.7 (m, 1 H); MS (EI): 557 (M + H ^& lt ^{; +} & gt ^; , 70%).
[1115] Diastereomeric mixture portions separated by HPLC by eluting faster stereoisomer _{^{(1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 4.0 (d, 1H), 4.7 (m, 2H), 5.0 (d, 1H), 7.0 (m, 4H), 7.6 (m, 2H), 8.7 ( d, 1H); MS (EI): 557 (M + H +, 100%)) and more diastereomers which late eluting isomer (MS (EI): 557 ( M + H +, 100%)).
[1116] Example 60
[1117] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide &lt; / RTI &gt;
[1118] a) 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) Yl] -butyl} -amide
[1119] 2-carboxylic acid was replaced by 5-bromo-2-furoic acid, the title compound was obtained following the method of Example 28b: MS (EI) 558 (M + H <^+> ).
[1120] b) Preparation of 5-bromo-furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan- ] -Butyl} -amide
[1121] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 60a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 1H), 7.5 (m, IH), 7.0 (m, IH), 4.7 (m, (m, 2 H), 8.7 (m, 1 H); MS (EI): 555 (M + H ^& lt ^{; +} & gt ^; , 60%).
[1122] MS (EI): 555 (M + H ⁺ , 100%) and later eluting diastereoisomers (MS (EI): 555 M + H & lt ^; + & gt ^; , 100%)).
[1123] Example 61
[1124] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Produce
[1125] 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -carbamic acid {(S) -amides
[1126] Methyl-benzofuran-2-carboxylic acid was replaced by 2-furoic acid, MS (EI) 479 (M + H ^& lt ^{; +} & gt ^; ).
[1127] b) furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides
[1128] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 61a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 2H), 8.0 (m, 2H), 8.7 (m, 2H), 5.0 (m, (m, 1 H); MS (EI): 477 (M + H ^& lt ^{; +} & gt ^; , 50%).
[1129] Example 62
[1130] 5-Nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] } -Amide &lt; / RTI &gt;
[1131] a) 5-Nitro-furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide
[1132] Methyl-benzofuran-2-carboxylic acid was replaced by 5-nitro-2-furoic acid, the title compound was obtained following the method of Example 28b: MS (EI) 524 (M + H <^+> ).
[1133] b) 5-Nitro-furan-2-carboxylic acid {(S) -3-methyl- 1- [3- oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[1134] The title compound was obtained following the procedure of example 1i, except substituting the compound of example 62a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 1H), 7.2 (m, 1H), 7.3 (m, 2H), 2.7 (m, (m, 1H), 7.5 (m, 1H), 7.9 (m, 2H), 8.7 (m, 1H); MS (EI): 522 (M + H ⁺ , 80%).
[1135] Example 63
[1136] Furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1137] a) 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 4-ylcarbamoyl] -butyl} -amide
[1138] The title compound was obtained following the procedure of Example 28b, but replacing benzofuran-2-carboxylic acid with 5- (4-nitrophenyl) -2-furoic acid. MS (EI) H ⁺ ).
[1139] b) 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1140] Example 63a except that replaced by the compound, following the procedure of Example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 1H), 7.5 (m, 2H), 7.9-8.0 (m, 4H), 7.2 (m, , 8.5 (m, 1H), 8.6 (m, 1H); MS (EI): 598 (M + H ⁺ , 80%).
[1141] Example 64
[1142] (S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1143] a) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- Azepan-4-ylcarbamoyl] -butyl} -amide
[1144] The title compound was obtained following the procedure of Example 28b but replacing benzofuran-2-carboxylic acid with 5- [3- (trifluoromethyl) phenyl] -2-furoic acid. MS (EI ) 623 (M + H ^& lt ^{; +} & gt ^; ).
[1145] b) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- Yl-carbamoyl] -butyl} -amide
[1146] The title compound was obtained following the procedure of Example 1i but substituting the compound of Example 64a: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H) 2.2 (m, 2 H), 2.7 (m, 1 H), 3.7 (d, 1 H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.1 (m, 1H), 7.5 (m, 3H), 8.0 (m, 4H), 8.7 (m, 1H); MS (EI): 621 (M + H ^& lt ^{; +} & gt ^; , 80%).
[1147] (EI): 621 (M + H ⁺ , 100%) and later eluting diastereoisomers (MS (EI): 621 M + H & lt ^; + & gt ^; , 100%)).
[1148] Example 65
[1149] 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - &lt; / RTI &gt; - Preparation of amide
[1150] a) Tetrahydro-furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
[1151] 2-carboxylic acid was replaced by tetrahydrofuran-2-carboxylic acid, the title compound was obtained following the method of Example 28b: MS (EI) 483 (M + H <^+> ).
[1152] b) Tetrahydro-furan-2-carboxylic acid {(S) -3-methyl-1- [ Butyl} -amide
[1153] ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.2 (m, 12H), 1H), 7.0 (m, 1H), 7.5 (m, 1H), 3.8 (m, (m, 1 H), 7.9 (m, 2 H), 8.7 (m, 1 H). MS (EI): 481 (M + H ^& lt ^{; +} & gt ^; , 80%).
[1154] Example 66
[1155] Preparation of (S) -4-methyl-2- (2-phenoxy-acetylamino) -pentanoic acid 3-oxo- (pyridine-2- sulfonyl) -azepan-4-yl]
[1156] a) (S) -4-Methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-hydroxy- (pyridine- 2- sulfonyl)
[1157] Methyl-benzofuran-2-carboxylic acid was replaced by phenoxyacetic acid. MS (EI) 519 (M + H ^& lt ^{; +} & gt ^; ).
[1158] b) (S) -4-Methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo- (pyridine- 2- sulfonyl)
[1159] The title compound was obtained following the procedure of example 1i, except substituting the compound of example 66a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 1H), 7.0 (m, 1H), 4.5 (m, 3H), 4.7 (m, (m, 3H), 7.3 (m, 2H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS (EI): 517 (M + H ^& lt ^{; +} & gt ^; , 60%).
[1160] Example 67
[1161] (S) -2- [2- (4-fluoro-phenoxy) -acetylamino] -4-methyl- pentanoic acid [3-oxo- (pyridine- 2- sulfonyl) - Preparation of amide
[1162] a) (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-hydroxy- (pyridine- - yl] -amide
[1163] Carboxylic acid was replaced by 4-fluorophenoxyacetic acid, the title compound was obtained following the method of Example 28b: MS (EI) 537 (M + H ^& lt ^{; +} & gt ^; ).
[1164] b) (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl- pentanoic acid [3-oxo- (pyridine- Yl] -amide
[1165] The title compound was obtained following the procedure of example 1i, except substituting the compound of example 67a: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) 1H), 7.0 (m, 1H), 4.5 (m, 3H), 4.8 (m, (m, 4H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS (EI): 535 (M + H ^& lt ^{; +} & gt ^; , 50%).
[1166] Example 68
[1167] 3-methyl-1- [3-oxo-1- (pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] - Preparation of amide
[1168] a) {(S) -1- [ 3- hydroxy-1 (pyridine-2-carbonyl) azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[1169] 0.09 g of picolinic acid, 0.14 g of EDC and 0.10 g of HOBt were added to a solution of 0.25 g of the compound of Example 2g in dichloromethane. The mixture was stirred until the reaction was completed. Workup followed by column chromatography (5% methanol: ethyl acetate) afforded 0.35 g of the title compound.
[1170] b) (S) -2-Amino-4-methylpentanoic acid [3-hydroxy-1- (pyridine-
[1171] 6 ml of 4M HCl in dioxane was added to 0.34 g of the compound of Example 68a in 6 ml of methanol. Stirring was continued until the reaction was complete and concentrated to yield 0.34 g of the title compound: MS (EI) 349 (M + H ^& lt ^{; +} & gt ^; ).
[1172] c) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (pyridine-2- carbonyl) Butyl} -amide
[1173] The title compound was obtained following the procedure of Example 28b, except substituting the compound of Example 68b: MS (EI) 493 (M + H ^& lt ^{; +} & gt ^; ).
[1174] d) Benzofuran-2-carboxylic acid {(S) -3-methyl-l- [3-oxo-1- (pyridine- Butyl} -amide
[1175] Performed according to in Example 1i method, but replacing the compound of Example 68c to give the title _{compound: 1H NMR (CDC1 3):} δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.7 (m, 1H), 4.7 (m, 4H), 5.0 (m, 1H), 7.0-7.5 (m, 8H), 8.2 (m, 1H); MS (EI): 491 (M ^&lt; ⁺ & gt ^; , 100%).
[1176] Example 69
[1177] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Butyl} -amide &lt; / RTI &gt;
[1178] The title compound was obtained following the procedure of Example 68a-d but replacing the picolinic acid of Example 68c with picolinic acid N-oxide: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H). 4.0 (m, 1H), 4.7 (m, 3H), 5.5 (m, 1H), 7.0 (m, 2H), 7.2-7.5 (m, 7H), 8.1 (m, 2H); MS (EI): 507 (M ^&lt; ^{+ &gt;} , 20%).
[1179] Example 70
[1180] 4 - ((S) -2- tert-Butylcarbonylamino-4-methyl-pentanoylamino) -3-oxo-azepane-1-carboxylic acid benzyl ester
[1181] Benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6-dimethyl- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide was reacted with 4 - ((S) -2- tert -butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1 -carboxylic acid benzyl ester The title compound was obtained by following the procedure in Example 92j, except substituting. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 476.2; ^{1 H-NMR (400 MHz,} CDCl 3): δ7.40-6.95 (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, 1 H), 2.25-1.30 (m, 16 H); And second eluting diastereomer: 1.00-0.85 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 476.2.
[1182] Example 71
[1183] 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1 -methyl-1 H- imidazole- Yl-carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1184] a) {(S) -1- [3-Hydroxy-1- (1 -methyl-1 H- imidazole- 2- sulfonyl) -azepan-4-ylcarbamoyl} -Carbamic acid tert -butyl ester
[1185] 92 [mu] l (1.14 mmol) of pyridine was added to the amine solution of Example 2g in 5 ml of methylene chloride followed by the addition of 0.112 g (0.623 mmol) of 1-methylimidazole-4-sulfonyl chloride. The reaction was allowed to stand at room temperature for 16 hours. The solution was washed with saturated aqueous NaHCO ₃ solution, water and brine. Purification of the product by column chromatography (silica gel: methanol / methylene chloride) gave the title compound as a white solid (0.172 g, 68%): ¹ H NMR (400 MHz, CDCl ₃ ) 57.6 (d, 7.5 (d, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H); MS (ESI): 488.2 (M + H) &lt; ⁺ & gt ^; .
[1186] b) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1 -methyl-1 H- imidazole-
[1187] 10 ml of 4M HCl in dioxane was added to a solution of 0.172 g (0.353 mmol) of the compound of Example 71a in a minimal amount of MeOH and stirred at room temperature for 4 hours. The reaction mixture was concentrated and azeotroped with toluene (twice) to give the title compound as a gray solid: MS (ESI): 388.2 (M + H) &lt; ⁺ & gt ^; .
[1188] c) Preparation of 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1 -methyl-1 H- imidazole- - azepan-4-ylcarbamoyl] -butyl} -amide
[1189] 0.074 g (0.388 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to a solution of 0.137 g (0.353 mmol) of the compound of Example 71b, 5,6- dimethoxybenzofuran- Was added to a stirred solution of 0.86 g (0.388 mmol) of 2-carboxylic acid, 246 ml (1.77 mmol) of triethylamine and 0.20 g (0.070 mmol) of 1-hydroxybenzotriazole. After stirring at room temperature for 16 h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate solution, water (twice) and saturated brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. Purification of the product by column chromatography (silica gel; methanol / dichloromethane) gave the title compound as a white solid (0.088 g, 42%): MS (ESI): 592.1 (M + H) <^+> .
[1190] d) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [ - azepan-4-ylcarbamoyl] -butyl} -amide
[1191] 52 [mu] l (0.596 mmol) oxalyl chloride was cooled to -78 &lt; 0 &gt; C. 106 [mu] l (1.49 mmol) of dimethylsulfoxide in methylene chloride was added dropwise thereto. On the -78 ℃ stirred for 15 minutes, then added slowly to the alcohol in methylene chloride was added _{Et 3 N 416 ㎕ (2.98 mmol} ) and stirred for 1 hour. The solution was heated to room temperature and then quenched with water and extracted with methylene chloride. After the organic layer was separated, washed with brine, dried over MgSO _4, filtered and concentrated. Purification of the product by column chromatography (silica gel: methanol / methylene chloride) gave the title compound as a white solid (0.068 g, 78%): ¹ H NMR (400 MHz, CDCl ₃ ) 6.8-7.6 ), 4 (d, 12H), 1 (d, 12H); MS (ESI): 590.1 (M + H) &lt; ⁺ & gt ^; .
[1192] Example 72
[1193] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole- Yl-carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1194] a) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[1195] 12.8 ml of 4M HCl in dioxane was added to a stirred solution of 3.5 g (7.33 mmol) of the compound of Example 2f in 0.5 ml of EtOAc. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and azeotroped with toluene (2 x 20 ml) to give the title compound as a light yellow oil (3.13 g, 100%): MS (ESI) 378.4 (M + H) &lt; ⁺ & gt ^; .
[1196] b) Preparation of 4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[1197] 1.6 g (8.33 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to a solution of 3.13 g (7.57 mmol) of the compound from Example 72a, 1.35 g (8.32 mmol), triethylamine (1.17 ml, 8.25 mmol) and 1-hydroxybenzotriazole (0.2 g, 1.48 mmol). After stirring at room temperature for 16 hours, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate solution, water (twice) and saturated brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. The product was purified by column chromatography (silica gel; ethyl acetate / dichloromethane) to give 3.7 g (93%) of the title compound. _{^{1 HNMR (400MHz, CDCl 3)}} δ 6.8-7.7 (m, 12H), 5.35 (s, 2H), 1.0 (d, 6H): MS (ESI): 522 (M + H) +.
[1198] c) Benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[1199] 1.3 g of 10% palladium on carbon were added to a solution of 2.6 g (4.9 mmol) of the compound from Example 72b in 150 ml EtOAc and stirred at room temperature for 64 hours under a hydrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated to give the title compound as a white solid (1.92 g, 100%): ¹ H NMR (400 MHz, CDCl ₃ ) 6.8-7.7 (m, 7H) , &Lt; / RTI &gt; 1.02 (d, 6H); MS (ESI) 388 (M + H) &lt; ⁺ & gt ^; .
[1200] d) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-l- [l- (5-methyl- lH- [l, 2,4] triazol- - azepan-4-ylcarbamoyl] -butyl} -amide
[1201] 0.043 g (0.25 mmol) of 5-methyl-1H-1,2,4-triazolesulfonyl chloride are added to a solution of 0.l00 g (0.25 mmol) of the compound from Example 72c and 35 (0.25 mmol) of triethylamine in 2 ml of methylene chloride, &Lt; / RTI &gt; After stirring for 10 min, it was washed with saturated aqueous NaHCO ₃ solution, water and saturated brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. The product was purified by column chromatography (silica gel; ethyl acetate / hexane) to give the title compound as a light yellow oil (0.111 g, 84%): MS (ESI) 532.73 (M + H) ⁺ .
[1202] e) Benzofuran-2-carboxylic acid {(S) -3-methyl-l- [l- (5-methyl- lH- [l, 2,4] triazol- Azepan-4-ylcarbamoyl] -butyl} -amide
[1203] 172 [mu] l (1.23 mmol) triethylamine was added to a stirred solution of 0.108 g (0.206 mmol) of the compound from Example 72d in 2 ml dimethylsulfoxide followed by 0.116 g (0.718 mmol) sulfur trioxide- Stir for 16 hours. The reaction mixture was diluted with EtOAc and washed with water (2x). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. Purification of the crude product by column chromatography (silica gel; methanol / methylene chloride) gave the title compound as a white solid (0.08 g, 81%): ¹ H NMR (400 MHz, CDCl ₃ ) 7.1-7.7 7H), 2.65 (s, 3H), 1.0 (d, 6H); MS (ESI): 552.71 (M + Na) &lt; ⁺ & gt ^; .
[1204] Example 73
[1205] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- 3 -sulfonyl) -3-oxo-azepan- Yl] -butyl} -amide &lt; / RTI &gt;
[1206] a) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (1 -methyl-1 H- imidazole- 3 -sulfonyl) -3- hydroxy- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1207] 0.046 g (0.255 mmol) of 1-methylimidazole sulfonyl chloride was added to a stirred solution of 0.100 g (0.25 mmol) of Example 72c and 35 [mu] l (0.25 mmol) of triethylamine. After stirring for 10 minutes, it was washed with a saturated aqueous NaHCO ₃ solution, water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; ethyl acetate / hexane) to thereby give the title compound a yellow oil (0.113 g, 82%) ^{as: 1 HNMR (400 MHz, CDCl} 3) δ6.9-7.7 (m, 9H), 3.9 (2s, 3H), 1.0 (d, 6H); MS (ESI): 531.8 (M + H) &lt; ⁺ & gt ^; .
[1208] b) Benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (1- methyl- IH- imidazole- 3 -sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1209] 133 [mu] l (0.95 mmol) triethylamine was added to a stirred solution of 0.085 g (0.159 mmol) of Example 73a in dimethylsulfoxide followed by 0.08 g (0.5 mmol) sulfur trioxide- Lt; / RTI &gt; The reaction mixture was diluted with EtOAc and washed with water (2x). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. Purification of the crude product by column chromatography (silica gel; methanol / methylene chloride) gave the title compound as a white solid (0.072 g, 83%): MS (ESI): 529.76 (M + H) ⁺ .
[1210] Example 74
[1211] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1H-imidazole- } -Amide &lt; / RTI &gt;
[1212] a) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 H- imidazole- 2- sulfonyl) -3-hydroxy-azepan- ] -Butyl} -amide
[1213] 0.046 g (0.255 mmol) of 2-imidazole sulfonyl chloride was added to a stirred solution of 0.100 g (0.25 mmol) of the compound from Example 72c and 35 [mu] l (0.25 mmol) of triethylamine. After stirring for 10 min, it was washed with saturated aqueous NaHCO ₃ solution, water and saturated brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. The product was purified by column chromatography (silica gel; ethyl acetate / hexane) to give the title compound as a pale yellow oil (0.113 g, 82%): 1 HNMR (400MHz, CDC1 3) δ 7.1-7.7 (m, 9H) , 4.8 (s, 1 H), d, 6 H); MS (ESI): 517.76 (M + H) &lt; ⁺ & gt ^; .
[1214] b) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (lH- imidazole- 2- sulfonyl) -3-oxo-azepan- -Butyl} -amide
[1215] (1.23 mmol) of triethylamine was added to a stirred solution of 0.107 g (0.206 mmol) of the compound of Example 74a in 2 ml of dimethylsulfoxide followed by the addition of 0.115 g (0.718 mmol) of sulfur trioxide-pyridine at room temperature Stir for 16 hours. The reaction mixture was diluted with EtOAc and washed with water (2x). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. Purification of the crude product by column chromatography (silica gel; methanol / methylene, chloride) gave the title compound as a white solid (0.09 g, 85%): MS (ESI): 515.84 (M + H) ⁺ .
[1216] Example 75
[1217] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] Preparation of amide
[1218] a) {(S) -1- [3-Hydroxy-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl} -3-
[1219] Methyl-butyl} -carbamic acid tert -butyl ester
[1220] 4.0 g of P-NMM and 1.6 g (8.75 mmol) of thiazole-2-sulfonyl chloride were added to a solution of 2.50 g (7.29 mmol) of the compound of Example 2g in 100 ml of DCE. After shaking at room temperature overnight, 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) &lt; ⁺ & gt ^; .
[1221] b) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide
[1222] 0.85 g (l mmol / g) of P-EDC in 0.109 g (0.172 mmol) of 1-hydroxybenzotriazole, 0.106 g (0.762 mmol) of 1-hydroxybenzotriazole and 10 ml of CH ₂ Cl ₂ was dissolved in CH ₂ Was added to a solution of 0.15 g (0.45 mmol) of the compound of Example 75b in 20 ml of Cl ₂ . After shaking at room temperature overnight, the solution was treated with 0.589 g (3.75 mmol / g) of thiamine. After shaking for an additional 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (166.7 mg, 70%); MS (ESI): 535.3 (M + H) &lt; ⁺ & gt ^; .
[1223] c) Synthesis of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides
[1224] 265.5 mg (0.626 mmol) of the Des-Martin reagent was added to a stirred solution of 166.7 mg (0. 313 mmol) of the compound of Example 75c in 4 ml of dichloromethane. After stirring at room temperature for 2 hours, 2 ml of a solution of sodium thiosulfate (10% in water) and 2 ml of an aqueous saturated sodium bicarbonate solution were simultaneously added to this solution. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by HPLC (50:50 ethanol: hexane, 20 ml / min, 25 min, WhelkO-1 (R, R) 21x250 mm column, UV detection at 280 nm and 305 nm) water (84.8 mg, 50.8%; MS (ESI): 533.2 (M + H) +) and the second eluate as a white solid (50. 1 mg, 30.0%; MS: 533.2 (M + H +)) to give the .
[1225] Example 76
[1226] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- 4- sulfonyl) -3-oxo-azepan- Yl] -butyl} -amide &lt; / RTI &gt;
[1227] a) {(S) -1- [3-Hydroxy-1- (1 -methyl-1 H- imidazole- 2 -sulfonyl) -Carbamic acid tert -butyl ester
[1228] 92 [mu] l (1.14 mmol) of pyridine was added to a solution of the amine of Example 2g in 5 ml of methylene chloride followed by the addition of 0.112 g (0.623 mmol) of 1-methylimidazole-4-sulfonyl chloride. And the mixture was stirred at room temperature for 16 hours. The solution was washed with a saturated aqueous NaHCO ₃ solution, water and brine. Purification of the product by column chromatography (silica gel: methanol / methylene chloride) gave the title compound as a white solid (0.172 g, 68%): ¹ H NMR (400 MHz, CDCl ₃ ) 7.6 (d, (d, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H); MS (ESI): 488.2 (M + H) &lt; ⁺ & gt ^; .
[1229] b) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1 -methyl-1 H- imidazole-
[1230] 10 ml of 4M HCl in dioxane was added to a solution of 0.172 g (0.353 mmol) of the compound of Example 76a in a minimal amount of MeOH. The reaction mixture was concentrated and azeotroped with toluene (twice) to give the title compound as a white solid. MS (ESI): 388.2 (M + H) &lt; ⁺ & gt ^; .
[1231] c) Synthesis of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1232] 0.099 g (0.515 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to a solution of 0.2 g (0.471 mmol) of the compound from Example 72c, benzofuran- g (0.388 mmol) of triethylamine, 72 μl (0.517 mmol) of triethylamine and 0.012 g (0.088 mmol) of 1-hydroxybenzotriazole. After stirring at room temperature for 16 hours, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate solution, water (twice) and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. Purification of the product by column chromatography (silica gel; methanol / dichloromethane) gave the title compound as a white solid (0.226 g, 90%): ¹ H NMR (400 MHz, CDCl ₃ ) 6.9-8.1 (m, , 3.75 (2s, 6H), 1 (d, 12H); MS (ESI): 531.80 (M + H) &lt; ⁺ & gt ^; .
[1233] d) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (l -methyl-lH- imidazole- 4- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1234] 355 [mu] l (2.55 mmol) of triethylamine was added to a stirred solution of 0.226 g (0.426 mmol) of the compound of Example 76a in 2 ml of dimethylsulfoxide followed by 0.238 g (1.48 mmol) of sulfur trioxide pyridine and the mixture was stirred at room temperature for 16 hours Lt; / RTI &gt; The reaction mixture was washed twice with EtOAc and water. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. Purification of the crude product by column chromatography (silica gel; methanol / methylene chloride) gave the title compound as a white solid (0.168 g, 76%): ¹ H NMR (400 MHz, CDCl ₃ ) 7.1-7.7 ), 3.7 (2s, 6H), 0.9 (d, 12H); MS (ESI): 529.80 (M + H) &lt; ⁺ & gt ^; .
[1235] Example 77
[1236] Synthesis of 5- (4-oxy-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1237] 0.008 g of m-CPBA was added to a solution of 0.01 g of the compound of Example 30b in 2 ml of dichloromethane. The reaction was stirred overnight. ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 6H) 2H), 2.5 (m, 4H), 2.7 (m, 1H), 2.8 (m 2H), 3.7 (m, 4H), 3.8 (q, 1H). 2H), 7.5 (m, 1H), 7.9 (m, 1H), 7.0 (m, 3H) (m, 2 H), 8.6 (m, 1 H); MS (EI): 671 (M ^&lt; ⁺ & gt ^; , 100%).
[1238] Example 78
[1239] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine-3- sulfonyl) -azepan-4- ylcarbamoyl] -butyl} Manufacturing
[1240] a) 4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[1241] 20 ml of 4M HCl in dioxane is added to a solution of 4 - ((S) -2- tert -butoxycarbonylamino-4-methyl-pentanoylamino) -3- hydroxy- Carboxylic &lt; / RTI &gt; acid benzyl ester. The reaction was stirred at room temperature for 2 h and then concentrated to give 3.8 g of the title compound: MS (EI) 378 (M + H ^& lt ^{; +} & gt ^; ).
[1242] b) Preparation of 4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[1243] A solution of 4 - ((S) -2-amino-4-methyl-pentanoylamino) - piperidine of Example 78a, 1.48 g EDC, 1.05 g HOBt, 1.29 ml TEA and benzofuran- 3-hydroxy-azepane-1-carboxylic acid benzyl ester in 30 ml of tetrahydrofuran. The mixture was stirred until the reaction was completed. After work-up, column chromatography (2% methanol: dichloromethane) gave 3.78 g of the title compound: MS (EI) 521 (M + H ⁺ ).
[1244] c) Benzofuran-2-carboxylic acid {(S) -1- (3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl- butyl}
[1245] 10% Pd / C was added to a solution of 4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl-penta Nonylamino} -3-hydroxy-azepane-1-carboxylic acid benzyl ester in 20 ml of tetrahydrofuran. Hydrogen was added to one apparatus and stirred for 2 h, then filtered and concentrated to give 1.16 g of the title compound: MS (EI) 387 (M + H ⁺ ).
[1246] d) Synthesis of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 3- sulfonyl) -azepan-4-ylcarbamoyl] -butyl }-amides
[1247] 0.17 ml of triethylamine are added to a solution of the benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) ] -Amide (0.3 g), followed by the addition of 0.25 g of 3-pyridine sulfonyl chloride. Stir at room temperature until the reaction was complete by TLC analysis. Work-up followed by column chromatography (5% methanol: ethyl acetate) afforded 0.32 g of the title compound: MS (EI) 528 (M + H ⁺ ).
[1248] e) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ -amides
[1249] (S) -3-methyl-1- [3-hydroxy-1- (pyridine-3- sulfonyl) -azepan-4-ylcarbamoyl] - butyl} - according to in example 1i, but replacing method of the amide to give the title _{^{compound: 1 HNMR (CDCl 3):}} δ1.0 (m, 6H), 1.5-2.1 (m, 5H), (M, 2H), 2.5 (m, 1H), 3.5 (d, 1H), 4.0 (m, 2H), 7.2-7.5 (m, 6H), 8.1 (m, 1H), 8.9-9.0 (m, 2H); MS (EI): 526 (M &lt; + &gt;, 100%).
[1250] Example 79
[1251] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Butyl} -amide &lt; / RTI &gt;
[1252] a) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- Yl] -butyl} -amide
[1253] 0.05 g of m-CPBA was added to a solution of the benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine- Yl-carbamoyl] -butyl} -amide in 10 ml of tetrahydrofuran at room temperature. The reaction was stirred overnight. After work-up, column chromatography (10% methanol: dichloromethane) gave 0.03 g of the title compound: MS (EI) 544 (M + H ⁺ ).
[1254] b) Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- ] -Butyl} -amide
[1255] (S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine- carbamoyl] -butyl} - and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m , 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H). 4.0 (m, 1H), 4.5 (m, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.2-7.5 (m, 7H), 8.1-8.2 (m, 2H). MS (EI): 542 (M ^&lt; ^{+ &gt;} , 50%).
[1256] Example 80
[1257] Yl} -carbamic acid {(S) -1- (3,4-dichloro-benzene-sulfonyl) -3-oxo-azepan- Preparation of amide
[1258] Example 75a was prepared as described in example 75a but replacing the thiazole-2-sulfonyl chloride of example 75a with 3,4-dichlorosulfonyl chloride and replacing benzofuran-2-carboxylic acid with quinoline- Therefore, the method of -d to give the title _{^{compound: 1 HNMR (CDCl 3, 400}} MHz) δ 9.34 (s, 1H), 8.61 (s, 1H), 8.14 (m, 1H), 7.81 (m, 3H), 7.60 (m, 3H), 7.19 (m, 2H), 5.09 (m, IH), 4.88 (m, IH), 4.50 m, 1 H), 2.23 (m, 2H), 1.60 (m, 5H), 1.01 (m, 6H).
[1259] Example 81
[1260] Preparation of 5-hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (1 -methyl-1 H- imidazole- 4-ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1261] a) 5-Hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (1-
[1262] -4-sulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide
[1263] 0.05 g (0.26 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to a solution of 0.1 g (0.235 mmol) of the compound from Example 76b, 5-hydroxybenzofuran- Was added to a stirred solution of 0.046 g (0.256 mmol) of carboxylic acid, 36 [mu] l (0.258 mmol) of triethylamine and 0.006 g (0.044 mmol) of 1-hydroxybenzotriazole. After stirring for 16 hours at room temperature, the solution was diluted with EtOAc and washed sequentially with a saturated aqueous sodium bicarbonate solution, water (twice) and saturated brine. The organic layer was dried over Na ₂ SO _4, filtered and concentrated. The product was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.129 g, 100%): ¹ H NMR (400 MHz, CDCl ₃ ) 6.8-8 ), 3.6 (2s, 6H), 0.85 (d, 12H). MS (ESI): 547.88 (M + H) &lt; ⁺ & gt ^; .
[1264] b) 5-Hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (1-methyl-
[1265] -4-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide
[1266] 13 [mu] l (0.149 mmol) oxalyl chloride was added to -78 [deg.] C. 28 [mu] l (0.394 mmol) of dimethylsulfoxide in methylene chloride was added dropwise thereto. On the -78 ℃ stirred for 15 minutes and then added slowly to the alcohol of Example 81a in methylene chloride and added _{Et 3 N 7 ㎕ (0.05 mmol} ) and the mixture was stirred for 1 hour. The solution was brought to room temperature, quenched with water and extracted with methylene chloride. After the organic layer was separated, washed with brine, dried over MgSO _4, filtered and concentrated. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give the title compound as a white solid (0.021 g, 78%): MS (ESI) 545.9 (M + H) <^+> .
[1267] Example 82
[1268] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) 3-methyl-butyl} -amide &lt; / RTI &gt;
[1269] a) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- Yl] -3-methyl-butyl} -amide
[1270] 0.07 ml of triethylamine are added to a solution of the benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) ] -Amide (0.10 g) followed by the addition of 2-pyridine sulfonyl chloride N-oxide. The reaction was stirred overnight at room temperature. After work-up chromatography (10% methanol: dichloromethane), 0.01 g of the title compound were obtained: MS (EI) 544 (M + H ⁺ ).
[1271] b) Synthesis of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -3-methyl-butyl} -amide
[1272] (S) -3-methyl-1- [3-hydroxy-1- (1-oxy- pyridine- 2- The title compound was obtained following the procedure of Example 1i but substituting carbamyl] -3-methyl-butyl} -amide for the title compound: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H) (M, 1H), 4.7 (m, 1H), 4.8 (m, 1H) , 5.0 (m, 1H), 7.0-7.5 (m, 9H), 8.1-8.2 (m, 2H). MS (EI): 542 (M ^&lt; ^{+ &gt;} , 20%).
[1273] Diastereomeric mixture portion is separated by HPLC to faster eluting diastereomers _{^{(1 H-NMR (CDCl 3}} ): δ1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H) , 2.7 (t, IH), 3.8 (d, IH), 4.0 (d, IH), 4.7 (m, IH), 4.8 ), 8.1-8.2 (m, 2H); MS (EI) 542 (M ⁺ , 100%)) and a slower eluting diastereomer (MS (EI) 542 (M ⁺ , 100%)).
[1274] Example 83
[1275] 2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid was prepared from 2- (4 - {(S) -2 - [(benzofuran- Produce
[1276] a) 2- (4 - {(S) -2 - [(Benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3- hydroxy- -Benzoic acid methyl ester
[1277] The title compound was obtained following the procedure of Example 75a-c but replacing 2-thiazo sulphonyl chloride with 2-carboxymethylsulfonyl chloride: MS (M + H ⁺ ) = 585.56, M + Na ⁺ = 607.76, 2M + H ^& lt ^{; +} & gt ^; = 1170.48.
[1278] b) Preparation of 2- (4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4- methyl- pentanoylamino} -3- hydroxy- - benzoic acid
[1279] To a solution of 2- (4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl- pentanoylamino} -3-hydroxy- -Benzoic acid methyl ester (Compound 83a) (180 mg, 0.309 mmol) was dissolved and LiOH (14 mg, 0.34 mmol) was added and the reaction mixture was stirred and refluxed for 6 hours. The reaction mixture was quenched with water and 6N HCl (adjusted to pH = 2) and, EtOAc and extracted with (3 x 10 ml) dried over MgSO _4, filtered, concentrated and then purified by chromatography (silica gel, 1% acetic acid / 4% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (48 mg, 27%): M + H ⁺ = 572.2
[1280] c) Preparation of 2- (4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl- pentanoylamino} -3-oxo-azepan- Benzoic acid
[1281] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Amide was prepared from 2- (4 - {(S) -2 - [(benzofuran-2-carbonyl) -amino] -4-methyl- pentanoylamino} -3-hydroxy-azepane- ) - benzoic acid, the title compound was obtained following the method of Example 75d: MS (M + H <^+> ): 570.2 (M + H <^+> ). _{^{1 HNMR (400Hz, CDCl 3 -CD}} 3 OD): δ 8.05-7.95 (m, 1H), 7.70-7.15 (m, 8H), 5.15-5.00 (m, lH), 4.95-4.75 (m, 2H), 2H), 1.90-1.70 (m, 4H), 1.60-1.45 (m, 1H), 2.85-2.70 (m, ), 0.95 (d, 6H).
[1282] Example 84
[1283] - (benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-oxo-azepane- 1 -sulfonyl) -benzoic acid Produce
[1284] Following the procedure of Example 83 but replacing 2-carboxymethylbenzenesulfonyl chloride with 3-carboxymethylbenzenesulfonyl chloride, the title compound was obtained: MS 570.2 (M + H <^+>); ¹ H NMR (400 Hz, CDCl ₃ -CD ₃ OD): 8.46 (d, 1H), 8.31-8.25 (m, 1H), 8.00-7.97 (m, 1H), 7.70-7.62 ), 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), 1.95-1.70 (m, 4H), 1.55-1.40 (m, 1H), 4.00 (d, 1H) (m, 1H), 0.98 (t, 6H).
[1285] Example 85
[1286] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- Gt; &lt; RTI ID = 0.0 &gt; [baramoyl] -butyl} -amide
[1287] a) {(S) -1- [ 3- hydroxy-1 (1-oxy-pyridine-sulfonyl) azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert- Butyl ester
[1288] 2-pyridinesulfonyl chloride N-oxide (prepared by bubbling chlorine gas through 2-mercaptopyridine-N-oxide in 9M HCl for about 90 min. Removal of excess chlorine under vacuum 2-pyridinesulfonyl chloride-N-oxide) was obtained in analogy to example 2g from [(S) -1- (3-hydroxy-azepan-4- ylcarbamoyl ) -3-methyl-butyl] -carbamic acid tert- butyl ester (2.5 g). The reaction was stirred at room temperature for 1 hour. After work-up, column chromatography (10% methanol: dichloromethane) gave 2.0 g of the title compound: MS (EI) 500 (M + H ⁺ ).
[1289] b) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-sulfonyl)
[1290] 20 ml of 4M HCl in dioxane is added to a solution of {(S) -1- [3-hydroxy-1- (1-oxy- pyridine- sulfonyl) -azepan- Yl] -3-methyl-butyl} -carbamic acid tert -butyl ester in 20 ml of tetrahydrofuran. The reaction was stirred at room temperature for 1.5 h and then concentrated to give 1.8 g of the title compound: MS (EI) 400 (M + H ^& lt ^{; +} & gt ^; ).
[1291] c) Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-
[1292] Pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1293] (S) -2-amino-4-methyl-pentanoic acid of Example 85b (0.12 g) in THF was added to a solution of 0.12 g of triethylamine, 0.11 g of EDC, 0.077 g of HOBt and benzo [b] thiophene- Was added to a solution of 0.25 g of [3-hydroxy-1- (1-oxy-pyridine-sulfonyl) -azepan-4-yl] -amide. Stir until the reaction was complete. Workup followed by column chromatography (10% methanol: dichloromethane) afforded 0.26 g of the title compound: MS (EI) 560 (M + H ⁺ ).
[1294] d) benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1295] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- 4-ylcarbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H) (M, 1H), 4.7 (m, 1H), 4.8 (m, 1H) , 5.0 (m, 1H), 7.5 (m, 4H), 7.8 (m, 3H), 8.1-8.2 (m, 2H). MS (EI): 558 (M ^&lt; ⁺ & gt ^; , 100%).
[1296] (EI): 558 (M ⁺ , 100%) and the slower eluting diastereomer (MS (EI): 558 (M ⁺ , 100%)).
[1297] Example 86
[1298] (5-bromo-furan-2-carboxylic acid {(S) -3-methyl- Gt; &lt; RTI ID = 0.0 &gt; [baramoyl] -butyl} -amide
[1299] a) 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy-
[1300] -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1301] Methyl-benzo [b] thiophene-2-carboxylic acid was replaced by 5-bromo-2-furoic acid to give the title compound: MS (EI) 574 (M + H ⁺ ).
[1302] b) 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [ Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1303] The title compound was prepared analogously to example 86a starting from 5-bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3- hydroxy- 1- (1-oxy- 4-ylcarbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5 1H), 4.7 (m, 1H), 4.8 (m, 2H), 2.7 (m, 5.0 (m, 1H), 7.0 (m, 2H), 7.4 (m, 2H), 8.1-8.2 (m, 2H); MS (EI): 570 (M ^&lt; ⁺ & gt ^; , 100%).
[1304] (MS (EI): 572 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 572 + H & lt ^; + & gt ^; , 100%)).
[1305] Example 87
[1306] 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- -Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1307] a) 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (l-oxy- pyridine- 2 -sulfonyl) Yl-carbamoyl] -butyl} -amide
[1308] Benzo [b] thiophene-2-carboxylic acid was replaced by 5,6-dimethoxybenzofuran-2-carboxylic acid, the title compound was obtained following the method of example 85c: MS (EI ) 604 (M + H ^& lt ^{; +} & gt ^; ).
[1309] b) 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ -4-ylcarbamoyl] -butyl} -amide
[1310] The title compound was prepared from 5,6-dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- -azepan-4-ylcarbamoyl] -butyl} - and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H 1H), 4.7 (m, 1H), 4.8 (m, 2H), 2.5 (m, 1H), 5.0 (m, 1H), 7.0-7.5 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 602 (M &lt; ⁺ & gt ^; , 100%).
[1311] (MS (EI): 572 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 572 + H & lt ^; + & gt ^; , 100%)).
[1312] Example 88
[1313] 2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] } -Amide &lt; / RTI &gt;
[1314] a) Preparation of 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide
[1315] 2-carboxylic acid was replaced with picolinic acid N-oxide, the title compound was obtained following the method of example 28b: MS (EI) 505 (M + H <^+> ).
[1316] b) 1-Oxy-pyridine-2-carboxylic acid {(S) -3-methyl- -Butyl} -amide
[1317] The title compound was prepared from 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine- carbamoyl] -butyl} - along in example 1i, but replacing method of the amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, (M, 2H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, ), 7.9 (m 2H), 8. 3-8.4 (m, 2H), 8.6 (m, 1H); MS (EI): 503 (M ^&lt; ⁺ & gt ^; , 100%).
[1318] Example 89
[1319] Preparation of (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid 3-oxo-1- (pyridine-2- sulfonyl) -azepan-
[1320] a) (S) -4-Methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-
[1321] 0.27 ml of triethylamine and 0.15 g of 2-pyridine sulphonyl chloride were added to a solution of (S) -2-amino-4-methyl-pentanoic acid 3-hydroxy-1- (pyridine- Azepan-4-yl] -amide in 20 ml of tetrahydrofuran. The mixture was stirred until the reaction was completed. After work-up, column chromatography (5% methanol: dichloromethane) gave the title compound. MS (EI) 525 (M + H ^& lt ^{; +} & gt ^; ).
[1322] b) (S) -4-Methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
[1323] (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine- - and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m , 2H), 2.7 (m, 1 H), 3.8 (q, 1 H). 7.0 (m, 1H), 7.5 (m, 2H), 7.9 (m, 3H), 8.6 (m, m, 2H). MS (EI): 523 (M ^&lt; ⁺ & gt ^; , 100%).
[1324] Example 90
[1325] Preparation of (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid 3-oxo-1- (pyridine-2- sulfonyl) -azepan-4-yl]
[1326] a) (S) -2- (3-Benzyl-ureido) -4-methyl- pentanoic acid [3-hydroxy- 1- (pyridine-
[1327] -Azepan-4-yl] -amide
[1328] 0.17 ml of triethylamine and 0.088 g of benzyl isocyanate are added to a solution of (S) -2-amino-4-methyl-pentanoic acid 3-hydroxy-1- (pyridine- 4-yl] -amide. The mixture was stirred until the reaction was completed. After work-up, column chromatography (5% methanol: dichloromethane) gave 0.12 g of the title compound
[1329] b) (S) -2- (3-Benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
[1330] (S) -2- (3-Benzyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine- 2- sulfonyl) and it is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 3H), 4.5 (t, ), 7.5 (m, 1 H), 7.9 (m, 2 H), 8.6 (m, 1 H); MS (EI): 515 (M ^&lt; ^{+ &gt;} , 60%).
[1331] (MS (EI): 516 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 516 + H & lt ^; + & gt ^; , 100%)).
[1332] Example 91
[1333] Preparation of (S) -2- (3-phenyl-ureido) -4-methyl-pentanoic acid 3-oxo-1- (pyridine-2- sulfonyl) -azepan-
[1334] a) (S) -2- (3-Phenyl-ureido) -4-methyl-pentanoic acid 3-hydroxy- 1- (pyridine-
[1335] -Azepan-4-yl] -amide
[1336] MS (EI) 503 (M + H ^& lt ^{; +} & gt ^; ), was prepared following the procedure of Example 90a, but replacing benzyl isocyanate with phenyl isocyanate.
[1337] b) (S) 2- (3-Phenyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
[1338] (S) -2- (3-phenyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine- 2- sulfonyl) and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m , 2H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 (m, 1H) (m, 8 H), 8.6 (m, 1 H). MS (EI): 501 (M ^&lt; ^{+ &gt;} , 60%).
[1339] Example 92
[1340] Benzofuran-2-carboxylic acid {(S) -1- [6,6-dimethyl-3-oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] Butyl} amide
[1341] a) Allyl- (2,2-dimethyl-pent-4-enylidene) -amine
[1342] 2.8 g (25 mmol) of 2,2-dimethyl-4-pentenal were dissolved in 15 ml of benzene. To this solution was added 2.85 g (50 mmol) of allylamine. Several molecular sieves were used to absorb the water produced during the reaction. The mixture was stirred at room temperature overnight. The solvent and excess allylamine were removed on a rotor vapor to give 3.76 g of the title compound as a clear liquid (yield 100%). ¹ H-NMR (400 MHz, CDCl ₃ ): 7.52 (s, IH), 5.99-5.90 (m, IH), 5.80-5.70 3.99 (m, 2H), 2.17 (d, 2H), 1.06 (s, 6H).
[1343] b) Allyl- (2,2-dimethyl-pent-4-enyl) -amine
[1344] 3.76 g (25 mmol) of allyl- (2,2-dimethyl-pent-4-enylidene) -amine of Example 92a were diluted in 5 ml of MeOH. To this solution was added 0.95 g (25 mmol) of NaBH ₄ at 0 ° C. The mixture was then stirred at room temperature for 5 hours. Methanol was removed on rotavapper and the residue was partitioned between EtOAc / 20% NaOH. The organic layer was dried over Na ₂ SO _4, filtered and evaporated to give 2.26 g of the title compound: MS (M + H ⁺ ): 154.0; _{^{1 HNMR (400 MHz, CDC1 3}} ): δ5.93-5.76 (m, 2H), 5.29-4.99 (m, 4H), 3.22 (d, 2H), 2.34 (s, 2H), 2.01 (d, 2H) , 0.94 (s, 6H).
[1345] c) Pyridine-2-sulfonic acid allyl- (2,2-dimethyl-pent-4-enyl)
[1346] 0.43 g (2.8 mmol) of allyl- (2,2-dimethyl-pent-4-enyl) -amine and 0.57 g (5.6 mmol) of NMM were mixed in 30 ml of CH ₂ Cl ₂ . The 2-pyridine sulfonyl chloride was slowly added while cooling the solution in an ice bath. After the addition was complete, the reaction mixture was stirred overnight at room temperature. 10% NaHC0 ₃ and washed with brine. The residue was purified by column chromatography to obtain 0.6 g of a colorless oil in a yield of 73%. MS (M + H & lt ^; + & gt ^; ): 295.2; ¹ H NMR (400 MHz, CDCl ₃ ): 8.71-8.70 (d, 1H), 7.98-7.86 (m, 2H), 7.48-7.46 (m, 1H), 5.88-5.77 2H), 2.07-2.05 (d, 2H), 0.96 (s, 6H), 2.02 (m, 1H), 5.13-5.00 (m, 4H), 4.05-4.04
[1347] d) 3,3-Dimethyl-1- (pyridine-2-sulfonyl) -2,3,4,7-tetrahydro-1H-
[1348] 0.6 g ( ₂ mmol) of pyridine-2-sulfonic acid allyl- (2,2-dimethyl-pent-4-enyl) -amide was diluted in 50 ml of CH ₂ Cl ₂ . After careful degassing with Ar, 0.17 g (0.2 mmol) of Grubbs catalyst under Ar protection was added. The mixture was refluxed for 2 hours before removing the solvent from the rotavap. The crude product was purified by column chromatography (5% -20% E / H) to give 0.47 g of the title compound in 87% yield. MS (M + H & lt ^; + & gt ^; ): 267.0; ^{1 H-NMR (400 MHz,} CDC1 3): δ8.70-8.69 (d, 1H), 7.96-7.88 (m, 2H), 7.49-7.46 (m, 1H), 5.81-5.70 (m, 2H), 2H), 2.13-2.12 (d, 2H), 1.00 (s, 6H)
[1349] e) 5,5-Dimethyl-3- (pyridine-2-sulfonyl) -8-oxa- 3- aza- bicyclo [
[1350] 2.4 g (13.5 mmol) of NaHCO ₃ were added to a solution of 1.2 g (4.5 mmol) of the compound from Example 92d in 50 ml of CH ₂ Cl ₂ followed by the addition of 1.2 g (13.5 mmol) of MCPBA in small portions. The reaction was stirred at room temperature for 4 h, then worked up by washing with 15% NaOH saturated K ₂ CO ₃ , and brine, and dried (Na ₂ SO ₄ ) to give 1.0 g of crude product in 79% yield Good enough that no further purification was needed for the &lt; / RTI &gt; MS (M + H & lt ^; + & gt ^; ): 283.0; ^{1 H-NMR (400 MHz,} CDC1 3): δ8.68-8.67 (d, 1H), 8.03-7.87 (m, 2H), 7.49-7.40 (m, 1H), 4.44-3.89 (q, 1H), 2H), 2.12-2.06 (m, IH), 1.52-1.46 (q, IH), 3.00 (m, 1.20 (s, 3H), 0.89 (s, 3H).
[1351] f) Preparation of 4-azido-6,6-dimethyl-1- (pyridine-2-sulfonyl)
[1352] 1.2 g (4.3 mmol) of 5,5-dimethyl-3- (pyridine-2-sulfonyl) -8-oxa- 3-aza- bicyclo [5.1.0] octane from Example 92e in 7 ml MeOH and 1 ml It was dissolved in a mixture of H ₂ 0. 0.83 g (13 mmol) of NaN ₃ and 0.7 g (13 mmol) of NH ₄ Cl were added to this solution. The resulting mixture was refluxed overnight. After removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHC0 ₃ and brine. The residue was purified by column chromatography to obtain 0.4 g of 4-azido-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol (yield: 29%); MS (M + H & lt ^; + & gt ^; ): 326.2; ^{1 H-NMR (400 MHz,} CDCl 3): δ8.68-8.67 (m, 1H), 8.05-7.90 (m, 2H), 7.53-7.50 (m, 1H), 3.75-3.60 (m, 3H), 3H), 1.73-1.66 (m, 1H), 1.56-1.52 (d, 1H), 1.07 (s, 3H), 0.99 (s, 3H).
[1353] g) 4-Amino-6,6-dimethyl-1- (pyridine-2-sulfonyl)
[1354] 0.4 g (1.23 mmol) of 4-azido-6,6-dimethyl-l- (pyridine-2-sulfonyl) -azepan-3-ol of Example 92f was dissolved in 50 ml of THF and 0.2 ml of H ₂ O . To this solution was added 0.48 g (1.85 mmol) of PPh ₃ . The reaction mixture was stirred overnight at 45 占 폚. There was no starting material left after TLC. THF was evaporated and azeotroped with toluene (twice). The resulting thick oil was dissolved in MeOH and treated with HCl in ether to adjust the pH to acidic. The solution was cloudy as more ether was added. 0.22 g of the title compound was obtained as a white precipitate (45% yield); ^{1 H-NMR (400 MHz,} CD 3 OD): δ8.68 (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, IH), 1.53 (d, IH), 1.05 (s, 6H).
[1355] h) {(S) -1- [3-Hydroxy-6,6-dimethyl- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Carbamic acid tert-butyl ester
[1356] 0.22 g (0.6 mmol) of 4-amino-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepan-3-ol HCl salt of Example 92g was dissolved in 5 ml of DMF. To this solution was added 0.22 g (0.9 mmol) of Boc-Leu-OH and 0.34 g (0. 9 mmol) of HBTU followed by 0.24 g (2.4 mmol) of NMM. The mixture was stirred at room temperature overnight. The DMF was removed in a high vacuum. The residue was diluted with EtOAc and washed with H ₂ O, 10% NaHCO ₃ and brine. Purification by column chromatography gave 0.22 g of the title compound (72% yield); MS (M + H ^& lt ^{; +} & gt ^; ): 512.9; 1 H-NMR (400 MHz, CDCl ₃ ): 8.68-8.67 (d, 1H), 7.97-7.88 (m, 2H), 7.69-7.64 -5.00 (m, 1H), 4.03-3.18 (m, 7H), 1.80-1.42 (m, 15H), 1.04-0.92 (m, 12H).
[1357] i) Benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6-dimethyl- 1 -pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - 3-methyl-butyl} -amide
[1358] 20 ml (4M, 80 mmol) of HCl / dioxane was added to a solution of {(S) -1- [3-hydroxy-6,6-dimethyl- 1- (pyridine- 2- sulfonyl) 4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester in 5 ml of dimethylformamide was added to a solution of 0.22 g (0.43 mmol) The mixture was stirred at room temperature for 2 hours, then the solvent and excess HCl were removed on a rotavapor. The resulting white solid was dissolved in 5 ml DMF. 84 mg (0.52 mmol) of 2-benzofuran carboxylic acid, 0.2 g (0.52 mmol) of HBTU and 0.2 g (2 mmol) of NMM were added to this solution. The mixture was stirred at room temperature overnight. The DMF was removed and the residue was redissolved in EtOAc (50 ml) and then washed with 50 ml of 10% NaHCO ₃ (x 2) and 50 ml of brine. The solvent was evaporated to give 0. 26 g of crude product. Purification by column chromatography gave 0.15 g of the title compound in a total yield of 63%; MS (M + H & lt ^; + & gt ^; ): 556.8; ¹ H-NMR (400 MHz, CDCl ₃ ): 8.66-8.63 (m, 1H), 7.94-7.11 (m, 10H), 4.72 1.39 (m, 5H), 1.02-0.85 (m, 12H).
[1359] j) Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-6,6-dimethyl- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - 3-methyl-butyl} -amide
[1360] CH ₂ Cl ₂ Example benzofuran-2-carboxylic acid {(S) in 2ml of 92i-1 at room temperature [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) - To a solution of 100 mg (0.18 mmol) of Des-Martin reagent 76 mg (0.18 mmol) was added to a solution of 3-methyl-azepan-4-ylcarbamoyll- 20 mL of CH ₂ Cl ₂ was added and the solution was stirred for 2 h, then washed with NaHCO ₃ and brine. Purification by column chromatography (50% ethyl acetate in hexane) gave 70 mg of the title compound in 70% yield. MS (M + H & lt ^; + & gt ^; ): 555.4; ^{1 H-NMR (400 MHz,} CDC1 3): δ8.68-8.67 (d, 1H), 7.97-7.93 (m, 2H), 7.69-7.28 (m, 6H), 7.32-6.92 (m, 2H), (M, 4H), 1.45-1.40 (m, 4H), 5.24 (m, 2H) ), 1.01-0.91 (m, 9H).
[1361] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer (MS (M + H ⁺ ): 555.2) and the slower eluting diastereomer (MS (M + H ⁺ ): 555.2).
[1362] Example 93
[1363] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (1-oxy- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1364] a) Preparation of 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) Ylcarbamoyl] -butyl} amide &lt; / RTI &gt;
[1365] Benzo [b] thiophene-2-carboxylic acid was replaced by 5-methoxybenzofuran-2-carboxylic acid, the title compound was obtained following the method of Example 85c: MS (EI) 574 (M + H & lt ^; + & gt ^; ).
[1366] b) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [
[1367] -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1368] A mixture of 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- 4-ylcarbamoyl] -butyl} amide, the title compound was obtained following the procedure of Example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5- 2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (m, 4H). 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 8H) 8.0-8.2 (m, 2H); MS (EI): 572 (M ^&lt; ^{+ &gt;} , 30%).
[1369] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereoisomer ( ¹ HNMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, (d, IH), 4.7 (m, IH), 4.8 (d, IH) MS (EI): 573 (M & lt ^{; +} &gt;), MS (EI): 573 (M + H ⁺ , 100%) and the slower eluting diastereomer + H & lt ^; + & gt ^; , 100%)).
[1370] Example 94
[1371] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- -4-ylcarbamoyl] -butyl} amide
[1372] a) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- - &lt; / RTI &gt; azepan-4-ylcarbamoyl] -butyl} amide
[1373] Benzo [b] thiophene-2-carboxylic acid was replaced with thieno [3,2b] thiophene-2-carboxylic acid following the procedure of Example 85c: MS EI) 566 (M + H ^& lt ^{; +} & gt ^; ).
[1374] b) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Azepan-4-ylcarbamoyl] -butyl} amide
[1375] The title compound was prepared in analogy to Example 94a except that thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- sulfonyl) azepan-4-ylcarbamoyl] - along in example 1i method, but replacing butyl} -amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). (M, 1H), 7.7 (d, 1H), 8.0-8.2 (m, 1H) m, 2H). MS (EI): 564 (M ^&lt; ⁺ & gt ^; , 100%).
[1376] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereoisomer ( ¹ HNMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, (m, 1H), 3.8 (d, 1H), 4.0 (d, 1H), 4.5 ) And 7.7 (d, 1H), 8.0-8.2 (m, 2H); MS (EI): 565 (M + H ⁺ , 100%) and a slower eluting diastereomer (MS M + H & lt ^; + & gt ^; , 100%)).
[1377] Example 95
[1378] Oxo-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] - (3-methyl- Butyl} amide
[1379] a) Preparation of quinoxaline-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- Yl] -butyl} amide
[1380] Following the procedure of Example 85c, except substituting quinoxaline-2-carboxylic acid for benzo [b] thiophene-2-carboxylic acid, the title compound was obtained: MS (EI) 556 (M + H ⁺ ).
[1381] b) quinoxaline-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} amide
[1382] (S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine- 2- sulfonyl) -azepan-4-yl Carbamoyl] -butyl} amide, the title compound was obtained following the procedure of Example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 2H), 7.9 (m, 1H), 8.0-8.4 (m, 1H), 4.0 (m, 4H) 9.6 (d, 1 H); MS (EI): 554 (M ^&lt; ⁺ & gt ^; , 100%).
[1383] (MS (EI): 555 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 555 + H & lt ^; + & gt ^; , 100%)).
[1384] Example 96
[1385] 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - &lt; / RTI & } Preparation of amide
[1386] a) Preparation of quinoline-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} amide
[1387] Methyl-benzo [b] thiophene-2-carboxylic acid was replaced by quinoline-2-carboxylic acid: MS (EI) 555 (M + H ⁺ ).
[1388] b) quinoline-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} amide
[1389] The title compound was prepared analogously to example 96a from quinoline-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- carbamoyl] -butyl} along in example 1i, but replacing method of the amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H ), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 10H); MS (EI): 553 (M ^&lt; ⁺ & gt ^; , 100%).
[1390] MS (EI): 554 (M + H ⁺ , 100%) and the slower eluting diastereoisomer (MS (EI): 554 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1391] Example 97
[1392] Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Butyl} amide
[1393] a) Preparation of thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- Yl] -butyl} amide
[1394] Carboxylic acid was replaced by thiophene-3-carboxylic acid, the title compound was obtained following the method of Example 85c: MS (EI) 510 (M + H ⁺ ).
[1395] b) Preparation of thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- ] -Butyl} amide
[1396] (S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine- 2- sulfonyl) carbamoyl] to give the title compound according to in example 1i method, but replacing the butyl} _{^{-amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). (M, 1H), 7.8 (m, 1H), 8.1-8.2 (m, m, 2H); MS (EI): 508 (M ^&lt; ^{+ &gt;} , 80%).
[1397] Example 98
[1398] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} amide &lt; / RTI &gt;
[1399] a) 1H-Indole-5-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- Gt; &lt; RTI ID = 0.0 &gt; [
[1400] The title compound was obtained following the procedure of Example 85c, except substituting 1H-indole-5-carboxylic acid for benzo [b] thiophene-2- carboxylic acid: MS (EI) 543 (M ⁺ ).
[1401] b) 1H-Indole-5-carboxylic acid {(S) -3-methyl-
[1402] - &lt; / RTI &gt; azepan-4-ylcarbamoyl] -butyl} amide
[1403] Indole-5-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- Yl) carbamoyl] -butyl} amide, the title compound was obtained following the procedure of example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 , 4.5 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 8.6 (b, 1H); MS (EI): 541 (M ^&lt; ⁺ & gt ^; , 100%).
[1404] (MS (EI): 542 (M + H ⁺ , 80%)) and the slower eluting diastereoisomer (MS (EI): 542 + H & lt ^; + & gt ^; , 80%)).
[1405] Example 99
[1406] Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [ Ylcarbamoyl] -butyl} amide &lt; / RTI &gt;
[1407] a) benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- -4-ylcarbamoyl] -butyl} amide
[1408] Carboxylic acid was replaced by benzo [l, 3] dioxole-5-carboxylic acid: MS (EI ) 548 (M ^&lt; ^{+ &} gt ^; ).
[1409] b) Preparation of benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} amide
[1410] Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- azepan-4-ylcarbamoyl] -butyl} amide, but replacing, and is, along with the method of example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1H), 4.5 (m, 2H), 2.7 (m, 1H), 3.8 (q, , 5.0 (m, 1H), 6.0 (s, 2H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 546 (M &lt; ⁺ & gt ^; , 100%).
[1411] (EI): 547 (M + H ⁺ , 100%) and the slower eluting diastereomer (MS (EI): 547 + H & lt ^; + & gt ^; , 100%)).
[1412] Example 100
[1413] Furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] } Preparation of amide
[1414] a) furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} amide
[1415] Benzo [b] thiophene-2-carboxylic acid was replaced by furoic acid, the title compound was obtained following the method of Example 85c: MS (EI) 494 (M <^+> ).
[1416] b) furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} amide
[1417] Carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- carbamoyl] -butyl} along in example 1i, but replacing method of the amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H (M, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 492 (M &lt; + &gt;, 100%).
[1418] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer (MS (EI): 493 (M + H ⁺ , 100%)) and the slower eluting diastereomer (MS (EI): 493 + H & lt ^; + & gt ^; , 100%)).
[1419] Example 101
[1420] (2-thiophen-2-yl-acetylamino) -pentanoic acid [3-oxo-l- -Yl] -amide &lt; / RTI &gt;
[1421] a) (S) -4-Methyl-2- (2-thiophen-2- yl-acetylamino) -pentanoic acid [3-hydroxy- Yl] -amide
[1422] Benzo [b] thiophene-2-carboxylic acid was replaced by thiophene-2-acetic acid. The title compound was prepared following the procedure of Example 85c.
[1423] b) Synthesis of (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [ -4-yl] -amide
[1424] (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [3-hydroxy- -azepan-4-yl] - and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 ( 1H), 4.7 (m, 1H), 5.0 (m, 2H), 2.2 (m, 2H) (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 522 (M ^&lt; ^{+ &gt;} , 20%).
[1425] Example 102
[1426] Indole-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (l-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} amide &lt; / RTI &gt;
[1427] a) 1 H-Indole-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (l-oxy- pyridine- 2- sulfonyl) Gt; &lt; RTI ID = 0.0 &gt; [
[1428] The title compound was obtained following the procedure of Example 85c, except substituting 1H-indole-2-carboxylic acid for benzo [b] thiophene-2-carboxylic acid: MS (EI) 543 (M ⁺ ).
[1429] b) 1H-Indole-2-carboxylic acid {(S) -3-methyl-
[1430] - &lt; / RTI &gt; azepan-4-ylcarbamoyl] -butyl} amide
[1431] Indole-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (l-oxy- Yl) carbamoyl] -butyl} amide, the title compound was obtained following the procedure of example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 , 4.5 (m, 2H), 2.7 (m, 1H), 3.8 (q, 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 9.4 (b, 1H); MS (EI): 541 (M ^&lt; ⁺ & gt ^; , 100%).
[1432] (MS (EI): 542 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 542 + H & lt ^; + & gt ^; , 100%)).
[1433] Example 103
[1434] - (S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-carbamoyl] -butyl} Preparation of amide
[1435] a) Preparation of 4-fluoro - {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-carbamoyl] } -Benzamide
[1436] Benzo [b] thiophene-2-carboxylic acid was replaced by 4-fluorobenzoic acid, the title compound was obtained following the method of Example 85c: MS (EI) 522 (M ⁺ ).
[1437] b) Preparation of 4-fluoro - {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) - benzamide
[1438] (S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine- 2- sulfonyl) -azepane-4- carbamoyl] - butyl} - and is, along with the method of example 1i the title compound was obtained, but replacing in _{^{-benzamide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H) , 4.5 (m, 1H), 2.2 (m, 2H), 2.7 (m, ), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS (EI): 520 (M &lt; ⁺ & gt ^; , 100%).
[1439] (MS (EI): 521 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 521 + H & lt ^; + & gt ^; , 100%)).
[1440] Example 104
[1441] Synthesis of 5- (2-morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- Trifluoromethyl-phenyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1442] a) 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- methyl- 1- [3- hydroxy- (1-oxy- 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1443] Benzo [b] thiophene-2-carboxylic acid was replaced by 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid The title compound was thus obtained: MS (EI) 673 (M &lt; ^{+ &} gt ^; ).
[1444] b) 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- -Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1445] (S) -3-methyl-1- [3-hydroxy- (1-oxy-benzyl) -carbamic acid tert- pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] - was obtained according to the method of example 1i the title compound, except for replacing butyl} _{^{-amide: 1 H NMR (CDCl 3)}} : 2H), 2.5 (m, 4H), 2.7 (m, 3H), 3.7 (m, 4H), 3.9 (m, 1H) ), 4.5 (m, 3H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS (EI): 671 (M ^&lt; ⁺ & gt ^; , 100%).
[1446] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereomer (MS (EI): 672 (M + H ⁺ , 100%)) and the slower eluting diastereomer (MS (EI): 672 + H & lt ^; + & gt ^; , 100%)).
[1447] Example 105
[1448] Thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} amide
[1449] a) Preparation of thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- Yl] -butyl} amide
[1450] Benzo [b] and, in accordance with the method of Example 85c to give the title compound, but replacing thiophene-2-carboxylic acid thiophene-2-carboxylic acid: MS (EI) 510 (M +) .
[1451] b) Preparation of thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} amide
[1452] The title compound was prepared from thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- Carbamoyl] -butyl} amide, the title compound was obtained following the procedure of Example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, (M, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 ), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 508 (M ^&lt; ⁺ & gt ^; , 100%).
[1453] (MS (EI): 509 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 509 + H & lt ^; + & gt ^; , 100%)).
[1454] Example 106
[1455] 2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Yl] -butyl} amide &lt; / RTI &gt;
[1456] a) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) Ylcarbamoyl] -butyl} amide
[1457] The title compound was obtained following the procedure of Example 85c, except substituting 3-methylbenzofuran-2-carboxylic acid for benzo [b] thiophene-2-carboxylic acid: MS (EI) 558 M ⁺ ).
[1458] b) Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Carbamoyl] -butyl} amide
[1459] Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- 4-ylcarbamoyl] -butyl} amide, the title compound was obtained following the procedure of Example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5- (M, 2H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS (EI): 556 (M ^&lt; ⁺ & gt ^; , 100%).
[1460] The diastereomeric mixture was separated by HPLC to give the faster eluting diastereoisomer ( ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, (d, IH), 4.7 (d, IH), 4.7 (d, IH), 5.0 m, 2H), 7.3 (m , 2H), 7.4 (m, 4H), 8.1 (d, 1H), 8.2 (d, 1H); MS (EI): 557 (M + H +, 100%)) and (MS (EI): 557 (M + H ^& lt ^{; +} & gt ^; , 100%)) as a slightly eluting diastereomer.
[1461] Example 107
[1462] (S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - Preparation of nicotinamide
[1463] a) 6-Methyl-N - {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy-
[1464] Ylcarbamoyl] -butyl} -nicotinamide &lt; / RTI &gt;
[1465] Benzo [b] thiophene-2-carboxylic acid was replaced by 6-methylnicotinic acid, the title compound was obtained following the method of Example 85c: MS (EI) 519 (M ⁺ ).
[1466] b) 6-Methyl-N - {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Butyl} -nicotinamide
[1467] Methyl-N - {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbazole phenylcarbamoyl] - butyl} - and is, along with the method of example 1i the title compound was obtained, but replacing by _{^{nicotinamide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, (M, 2H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 ), 5.0 (m, 1H), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 3H), 9.0 (m, 1H); MS (EI): 517 (M ^&lt; ⁺ & gt ^; , 100%).
[1468] (EI): 518 (M + H ⁺ , 100%) and the slower eluting diastereomer (MS (EI): 518 + H & lt ^; + & gt ^; , 100%)).
[1469] Example 108
[1470] (S) -4-methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [ Preparation of amide
[1471] a) (S) -4-Methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [3-hydroxy- -Butyl} amide
[1472] 2-carboxylic acid was replaced by thiophene-2-acetic acid, the title compound was obtained following the method of Example 28b: MS (ESI) 508.8 (M + H <^+> ).
[1473] b) (S) -4-Methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [ Butyl} amide
[1474] (S) -4-methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [3-hydroxy-1- (pyridine- (ESI): 506.8 (M + H ^& lt ^{; +} & gt ^; ), was obtained in comparable yields according to the procedure for example 1i.
[1475] Example 109
[1476] (S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide Manufacturing
[1477] a) 1H-indole-6-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} amide
[1478] Methyl-benzofuran-2-carboxylic acid was replaced by 1H-indole-6-carboxylic acid. MS (EI) 527 (M + H ⁺ ).
[1479] b) 1H-Indole-6-carboxylic acid {(S) -3-methyl-
[1480] -4-ylcarbamoyl] -butyl} amide
[1481] Indole-6-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} amide, the title compound was obtained following the procedure of example 1i: MS (EI): 525 (M + H ^& lt ^{; +} & gt ^; ).
[1482] Example 110
[1483] Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [ ] -Butyl} amide &lt; / RTI &gt;
[1484] a) benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) Carbamoyl] -butyl} amide
[1485] The title compound was obtained following the procedure of Example 28b, except replacing benzofuran-2-carboxylic acid with piperonylic acid. MS (EI) 532.7 (M + H <^+> ).
[1486] b) Preparation of benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- Gt; &lt; RTI ID = 0.0 &gt; [
[1487] Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan- -Ylcarbamoyl] -butyl} amide, the title compound was obtained following the procedure of Example 1i: MS (EI): 530.8 (M + H <^+> ).
[1488] Example 111
[1489] Benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- -2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide
[1490] benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1- Oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide
[1491] Benzo [b] thiophene-2-carboxylic acid was reacted with 3,4-dihydro-2H-1,5-benzodioxepine-7- carboxylic acid following the procedure of Example 85c The title compound was obtained: MS (EI) 576 (M &lt; ^{+ &} gt ^; ).
[1492] b) 3,4-Dihydro-2H- benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3- - pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} amide
[1493] Benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] butyl} along in example 1i, but replacing method of the amide to give the title compound: ¹ H NMR (CDCl _{3): δ 1.0 (m,} 6H), 1.5-2.1 (m, 5H), 2.2 (m, 4H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H), 4.0 ( 2H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H), 4.5 (m, ; MS (EI): 575 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1494] (MS (EI): 575 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 575 + H & lt ^; + & gt ^; , 100%)).
[1495] Example 112
[1496] Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [ &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1497] a) 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy-
[1498] -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1499] Methylthiophene-2-carboxylic acid was replaced by 5-methylthiophene-2-carboxylic acid, the title compound was obtained following the method of Example 85c: MS (EI) 524 M ⁺ ).
[1500] b) 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [ Ylcarbamoyl] -butyl} amide
[1501] Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- 4-ylcarbamoyl] -butyl} amide, the title compound was obtained following the procedure of Example 1i: ¹ H NMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5- (M, 2H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 4H), 8.1-8.2 (m, 2H); MS (EI): 523 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1502] (EI): 523 (M + H ⁺ , 100%) and the slower eluting diastereomer (MS (EI): 523 + H & lt ^; + & gt ^; , 100%)).
[1503] Example 113 Synthesis of
[1504] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 1 -sulfonyl) -azepan- 4-ylcarbamoyl] -butyl} amide
[1505] a) 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- Azepan-4-ylcarbamoyl] -butyl} amide
[1506] Benzo [b] thiophene-2-carboxylic acid was replaced with 4,5-dibromo-thiophene-2-carboxylic acid, the title compound was obtained following the method of Example 85c: MS (EI) 668 (M &lt; ^{+ &} gt ^; ).
[1507] b) Preparation of 4,5-dibromo-thiophene-2-carboxylic acid {(S) -3-methyl- Yl-carbamoyl] -butyl} amide
[1508] Example 113a 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- ) - azepan-4-ylcarbamoyl] - along in example 1i method, but replacing butyl} -amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H 1H), 4.5 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 2H); MS (EI): 665 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1509] Example 114
[1510] 4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan- Ylcarbamoyl] -butyl} amide &lt; / RTI &gt;
[1511] a) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- -4-ylcarbamoyl] -butyl} amide
[1512] The title compound was obtained following the procedure of Example 85c, except substituting 3,5-dimethyl-isoxazole-4-carboxylic acid for MS (EI ) 524 (M + H ^& lt ^{; +} & gt ^; ).
[1513] b) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} amide
[1514] (S) -3-methyl-l- [3-hydroxy-l- (l-oxy-pyridine- 2- sulfonyl) - azepan-4-ylcarbamoyl] -butyl} amide, but replacing, and is, along with the method of example 1i the title compound was _{^{obtained: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), (M, 2H), 2.4 (m, 3H), 2.6 (m, 3H), 2.7 , 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS (EI): 521 (M &lt; ⁺ & gt ^; , 100%).
[1515] Example 115
[1516] ( S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4- methoxy- benzenesulfonyl) -3-oxo-azepan- Produce
[1517] a) {(S) -1- [3-Hydroxy-1- (4-methoxy-benzenesulfonyl) -azepan-4-ylcarbamoyl] -3-methyl- butyl} - butyl ester
[1518] To a solution of [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert- butyl ester in DCE, Ester The compound of Example 2g (0.8 g, 2.33 mmol) was dissolved. 1.26 g (3.7 mmol / g, Nova) of morpholine methyl polystyrene resin beads was then added and the solution shaken for 5 minutes. 0.48 g (2.33 mmol) of p-methoxybenzenesulfonyl chloride was dissolved in DCE (10 ml) and this solution was added to the reaction mixture. The reaction was shaken overnight, filtered, washed with DCE (2 x 10 mL) and washed with 10 mL of CH ₂ Cl ₂ . The combined organic layers were concentrated in vacuo and used without further purification for subsequent reactions: M + H ⁺ = 514.2.
[1519] b) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl)
[1520] -4-yl]
[1521] CH ₂ Cl ₂ in 8ml {(S) -1- [3- hydroxy-l- (4-methoxy-benzene sulfonyl) azepan-4-ylcarbamoyl] -3-methyl-butyl} - Butyl ester 0.59 g (1.15 mmol) of the compound of Example 207a was dissolved, and then 8 mL of 4M HCl solution in dioxane was added, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and azeotroped twice with toluene (10 ml) in vacuo and used in the subsequent reaction without further purification: M + H ⁺ = 413.8
[1522] c) (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [3-hydroxy-
[1523] Methoxy-benzenesulfonyl) -azepan-4-yl] -amide
[1524] To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy- benzenesulfonyl) -azepan-4-yl] -amide- (2.63 mmol / g, 4.6 mmol) and then shaken for 2 hours, filtered, washed with 10 ml of MeOH and extracted with ethyl acetate , And the combined organic layers were concentrated in vacuo. The product was dissolved in 2 ml of DCE and 0.25 g (3.77 mmol / g, 0.91 mmol, Nova) of morpholine methyl polystyrene resin beads was added and the reaction was shaken for 5 minutes. Then, 0.081 g (0.44 mmol) of benzyl acetyl chloride was added and the reaction mixture was stirred overnight. 0.1 g (3.66 mmol / g, 0.366 mmol) of trisamine polystyrene beads was added and the reaction mixture was shaken for 1.5 hours. The reaction mixture was filtered, washed with ₂ x 10 ml of DCE and 10 ml of CH ₂ Cl ₂ , and the combined organic layers were concentrated in vacuo. The crude product was used in the subsequent reaction without further purification: M + H ⁺ = 562.2.
[1525] d) (S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4- methoxy-benzenesulfonyl) amides
[1526] In _{5 ml CH 2 Cl 2 (S} ) -2- (2- benzyloxy-acetylamino) -4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) - azepan -4-yl] -amide 0.24 g (0.44 mmol) of the compound of Example 207c was dissolved, and 0.3 g (0.7 mmol) of des-martin periostane was added thereto, followed by stirring for 30 minutes. The reaction was diluted with 20 ml of CH ₂ Cl ₂ , extracted with 10 ml of 10% Na ₂ S ₂ O ₅ aqueous solution, extracted with 10 ml of 10% NaHCO ₃ aqueous solution, 10 ml of water and 10 ml of brine. The combined organic layers were concentrated in vacuo. The residue was purified by HPLC (50:50 ethanol: hexane, 20 ml / min, 25 min, WhelkO-1 (R, R) 21 x 250 mm column, UV detection at 280 nm and 305 nm) to yield 47 mg % of a) a white solid ^{(MS 560.4 (m + H +} ) l H NMR (400Hz, CDC1 3):. δ 7.73 (d, 2H), 7.40-7.30 (m, 5H), 7.05 (d, 2H), (MS 560.2 (M + H ⁺ )) was obtained in a yield of 3.99 (s, 2H), 3.88 (s, 3H), 2.28-2.10 .
[1527] Example 116
[1528] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) - azepan-4-ylcarbamoyl] -butyl} amide
[1529] a) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1530] The title compound was obtained following the procedure of Example 85c, except substituting 5- (3-trifluoromethylphenyl) -furan-2-carboxylic acid for benzo [b] thiophene- : MS (EI) 638 (M &lt; ^{+ &} gt ^; ).
[1531] b) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- Trifluoromethyl-phenyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1532] The title compound was prepared from 5- (3-trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 2-sulfonyl) azepan-4-ylcarbamoyl] - along in example 1i method, but replacing butyl} -amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 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 (EI): 637 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1533] (MS (EI): 637 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 637 + H & lt ^; + & gt ^; , 100%)).
[1534] Example 117
[1535] Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} amide
[1536] a) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-
[1537] - pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide
[1538] The title compound was obtained following the procedure of Example 85c, except substituting 5-methyl-2-phenyl-oxazole-4-carboxylic acid for MS (EI) 585 (M &lt; ^{+ &} gt ^; ).
[1539] b) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- Yl-carbamoyl] -butyl} amide
[1540] Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- ) - azepan-4-ylcarbamoyl] - along in example 1i method, but replacing butyl} -amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H ), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H); MS (EI): 584 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1541] (MS (EI): 584 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 584 + H & lt ^; + & gt ^; , 100%)).
[1542] Example 118
[1543] Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide Produce
[1544] a) benzofuran-2-carboxylic acid {(S) -1- [1- (3,4- dimethoxybenzenesulfonyl) -3-hydroxy- azepan- 4- ylcarbamoyl] -butyl} -amides
[1545] 0.1 ml of triethylamine and 0.12 g of 3,4-dimethoxybenzenesulfonyl chloride are added to a solution of benzofuran-2-carboxylic acid {(S) -1- [1- (3,4- 3-oxo-azepan-4-ylcarbamoyl] -butyl} -amide in 20 ml of tetrahydrofuran. The mixture was stirred until the reaction was completed. After work-up, column chromatography (5% methanol: dichloromethane) gave 0.21 g of the title compound: MS (EI) 587 (M ⁺ ).
[1546] b) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4- dimethoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] amides
[1547] The title compound was prepared analogously to example 118a from benzofuran-2-carboxylic acid {(S) -1- [1- (3,4- dimethoxybenzenesulfonyl) -3- hydroxy- azepan- butyl} - and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.5 (d, 1H), 3.7 (t, 6H), 4.0 (m, 7.4-8.0 (m, 8H); MS (EI): 586 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1548] Example 119
[1549] 3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) - Preparation of amide
[1550] a) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-Bromo-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -Butyl} -amide
[1551] The title compound was obtained following the method of Example 118a, but replacing 3,4-dimethoxybenzenesulfonyl chloride with 4-bromobenzenesulfonyl chloride: MS (EI) 606 (M ⁺ ).
[1552] b) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Butyl} -amide
[1553] Benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3 -methyl-butyl} - and is, along with the method of example 1i the title compound was obtained, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.1 (m, 6H (M, 1H), 2.6 (m, 1H), 3.5 (d, 1H), 4.0 9H); MS (EI): 604 (M ^&lt; ⁺ & gt ^; , 100%).
[1554] Example 120
[1555] Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4- sulfonyl) -3-oxo-azepan- ] -3-methyl-butyl} -amide
[1556] a) Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole- 4- sulfonyl) -3-hydroxy-azepan- Carbamoyl] -3-methyl-butyl} -amide
[1557] The title compound was obtained following the method of Example 118a, except substituting 3,4-dimethoxybenzenesulfonyl chloride with benzofuran-4-sulfonyl chloride: MS (EI) 569 (M ⁺ ).
[1558] b) Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole- 4- sulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide &lt; / RTI &gt;
[1559] The title compound was prepared in analogy to example 120a from benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole- 4- sulfonyl) -3-hydroxy-azepan- -ylcarbamoyl] -3-methyl-butyl} - according to in example 1i, but replacing method of the amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H) (M, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 1H) , 8H); MS (EI): 568 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1560] Example 121
[1561] Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-oxazole-4- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} amide &lt; / RTI &gt;
[1562] a) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl- oxazole- 4- sulfonyl) -3-hydroxy-azepan- ] -3-methyl-butyl} amide
[1563] The title compound was obtained following the procedure of Example 118a, except substituting 3,5-dimethyloxazole-4-sulfonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride: MS (EI) 546 ( M ⁺ ).
[1564] b) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl- oxazole- 4- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} amide
[1565] The title compound was prepared analogously to example 121a from benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl- oxazole- 4- sulfonyl) -3-hydroxy-azepan- carbamoyl] -3-methyl-butyl} along in example 1i, but replacing method of the amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.2 (m, 2H), 2.4 (d, 3H), 2.7 (t, 3H), 3.6 (d, m, 1 H), 5.2 (m, 1 H), 7.4-8.0 (m, 5 H); MS (EI): 544 (M &lt; + &gt;, 100%).
[1566] Example 122
[1567] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} amide
[1568] a) Preparation of 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2 -sulfonyl) Yl] -butyl} amide
[1569] Carboxylic acid was replaced by 3-methylbenzofuran-2-carboxylic acid, the title compound was obtained following the method of Example 28b: MS (EI) 542 (M &lt; ^{+ &} gt ^; ).
[1570] b) Preparation of 3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} amide
[1571] Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-yl carbamoyl] to give the title compound according to in example 1i method, but replacing butyl} _{^{-amide: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5-2.2 (m, (M, 2H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 ), 7.4-8.0 (m, 7H), 8.7 (m, 1H); MS (EI): 540 (M ^&lt; ⁺ & gt ^; , 100%).
[1572] Portions faster eluting and separating the diastereomeric mixture by HPLC stereoisomers _{^{(1 H NMR (CDC1 3)}} : δ1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2H), 5.2 (m, 1H), 7.4-8.0 (m, 7H), 2.6 (d, , 8.7 (m, 1H) and a slower eluting diastereomer (MS (EI): 541 (M + H ⁺ , 100%)).
[1573] Example 123
[1574] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Carbamoyl] -butyl} amide &lt; / RTI &gt;
[1575] a) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 4-ylcarbamoyl] -butyl} amide
[1576] The title compound was obtained following the procedure of Example 28b, but replacing benzofuran-2-carboxylic acid with thieno [3,2-b] thiophene-2-carboxylic acid: MS (EI) 550 (M ^&lt; ^{+ &} gt ^; ).
[1577] b) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} amide &lt; / RTI &gt;
[1578] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (pyridine- plate 4-ylcarbamoyl] - along in example 1i method, but replacing butyl} -amide to give the title _{^{compound: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5 (M, 2H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 7.4-8.0 (m, 8 H), 8.7 (m, 1 H); MS (EI): 548 (M ^&lt; ⁺ & gt ^; , 100%).
[1579] Example 124
[1580] 5- tert3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) - azepan-4-ylcarbamoyl] -butyl} -amide
[1581] a) 5- tert -Butyl-3-methyl-thieno [3,2- b] thiophene-2-carboxylic acid {(S) -3- -2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1582] Carboxylic acid was replaced by 5- tert -butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid The title compound was prepared: MS (EI) 620 (M ⁺ ).
[1583] b) 5- tert -Butyl-3-methyl-thieno [3,2- b] thiophene-2-carboxylic acid { 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1584] Of Example 124a 5- tert-butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1 (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -butyl} - the title compound was prepared in accordance with, and is the method of example 1i, but replacing amide: ¹ H NMR (CDCl ₃ ): 隆 1.0 (m, 6H), 1.45 (s, 9H), 1.5-2.2 (m, 6H), 2.2 (m, 1 H); 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 4H); 8.7 (m, 1 H); MS (EI) 618 (M &lt; ⁺ & gt ^; , 100%).
[1585] Example 125
[1586] Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- Gt; &lt; RTI ID = 0.0 &gt; [baramoyl] -butyl} -amide
[1587] a) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1588] The title compound was prepared according to the method of example 28b, except substituting 5-methyl-2-phenyl-oxazole-4-carboxylic acid for MS (EI) 569 (M ^&lt; ^{+ &} gt ^; ).
[1589] b) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1590] Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- Yl) carbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 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 (EI): 567 (M ^&lt; ⁺ & gt ^; , 100%).
[1591] MS (EI): 568 (M + H ⁺ , 100%)) and the more slowly eluting diastereomer (MS (EI): 568 M + H & lt ^; + & gt ^; , 100%)).
[1592] Example 126
[1593] (S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-carboxylic acid -Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1594] a) 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl- 1- [3- hydroxy- 1- (pyridine- Yl-carbamoyl] -butyl} -amide
[1595] The title compound was prepared according to the method of example 28b, except substituting 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid for MS: MS (EI) 623 (M &lt; ^{+ &} gt ^; ).
[1596] b) 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl- -4-ylcarbamoyl] -butyl} -amide
[1597] (S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -piperazin- The title compound was prepared according to the method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, ¹ H) 1H), 4.1 (m, 2H), 5.2 (m, 2H), 2.2 (m, m, 1 H), 7.4-8.0 (m, 8 H), 8.7 (m, 1 H); MS (EI): 621 (M &lt; ⁺ & gt ^; , 100%).
[1598] (MS (EI): 622 (M + H ⁺ , 100%)) and the more slowly eluting diastereoisomers (MS (EI): 622 (M + H & lt ^; + & gt ^; , 100%)).
[1599] Example 127
[1600] Preparation of [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide
[1601] The title compound was prepared according to the method of Example 75, substituting thiazole-2-sulfonyl chloride with methanesulfonyl chloride and replacing benzofuran-2-carboxylic acid with 2-quinolinecarboxylic acid . The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 475.2; ¹ H NMR (400 MHz, CDCl ₃ ): 8.65 (d, 1H), 8.35-8.28 (q, 2H), 8.20-8.18 (d, 1H), 7.91-7.89 1H), 4.00 (m, 1H), 4.73 (m, 1H), 4.67 (d, 2H), 1.95-1.40 (m, 5H), 1.02-1.00 (m, 6H), 2.70 (s, 3H) ; And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 475.2.
[1602] Example 128
[1603] (S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide Manufacturing
[1604] The title compound was prepared according to the method of Example 75, replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with N-methylindole- Lt; / RTI &gt; The residue was purified by HPLC. First eluting diastereomer: MS (M + H &lt; ⁺ & gt ^; ): 477.2; _{^{1 H NMR (400MHz, CDCl 3}} ): δ7.65-7.63 (d, 1H), 7.39-7.33 (m, 2H), 7.17-7.14 (t, 1H), 6.98-6.95 (m, 2H), 6.65 ( (d, IH), 5.08 (m, IH), 4.68 (m, IH), 4.56-4.52 (d, IH), 4.03 (m, 4H), 3.67-3.63 , 2.71 (m, 1H), 2.32-2.10 (m, 2H), 1.95-1.40 (m, 5H), 1.02-1.00 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 477.2.
[1605] Example 129
[1606] Methyl-butylcarbamoyl] -methyl} - &lt; / RTI &gt; &lt; RTI ID = 0.0 & Preparation of amide
[1607] The title compound was prepared following the method of Example 75, substituting thiazole-2-sulfonyl chloride with methanesulfonyl chloride and replacing benzofuran-2-carboxylic acid with N- (2-furan-carbonyl) The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 471.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.50 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.90 (d, 1H), 6.55 (m, 2H), 5.08 ( 3H), 2.75 (m, IH), 2.20-1.40 (m, IH), 4.55 (m, 7 H), 0.95 (m, 6 H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 471.4.
[1608] Example 130
[1609] Preparation of 5-methoxybenzofuran-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3- oxo-azepan-4-ylcarbamoyl) -3-methyl- Produce
[1610] The title compound was prepared following the method of Example 75, but replacing the thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 494.2; ¹ H-NMR (400 MHz, CDCl ₃ ): 7.42-7.40 (d, 2H), 7.08-6.94 (m, 4H), 5.10 (M, 2H), 2.32 (s, 3H), 2.72 (m, 1.95-1.40 (m, 5H), 0.99 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 494.2.
[1611] Example 131
[1612] Preparation of quinoxaline-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl]
[1613] Following the procedure of Example 75, except substituting benzofuran-2-carboxylic acid for quinoxaline-2-carboxylic acid for the thiazole-2-sulfonyl chloride with methanesulfonyl chloride, the title compound was prepared . The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 476.2; ^{1 H-NMR (400MHz, CDCl} 3): δ9.66 (s, 1H), 8.38 (d, 1H), 8.20-8.18 (m, 2H), 7.88 (m, 2H), 7.01 (d, 1H), 3H), 2.71 (s, 3H), 2.71 (d, IH) m, 1H), 2.42-2.15 (m, 2H), 1.95-1.42 (m, 5H), 1.02-1.01 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 476.2.
[1614] Example 132
[1615] Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-yl Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1616] a) 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 4-ylcarbamoyl] -butyl} -amide
[1617] The title compound was prepared according to the procedure of example 28b, except substituting 5- (4-chlorophenyl) -2-furonic acid for benzofuran-2-carboxylic acid: MS (EI) 590 + H ⁺ ).
[1618] b) 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1619] The title compound was prepared from 5- (4-chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- Yl) carbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H ), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H); 1H), 7.7 (m, 2H), 5.0 (m, 1H), 6.7 (m, (m, 2 H), 8.0 (m, 2 H), 8.7 (m, 1 H); MS (EI): 587 (M ^&lt; ^{+ &gt;} , 80%).
[1620] (EI): 587 (M + H ⁺ , 100%) and the slower eluting diastereomer (MS (EI): 587 M + H & lt ^; + & gt ^; , 100%)).
[1621] Example 133
[1622] Preparation of (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid (1- methanesulfonyl-3- oxo-azepan-
[1623] The title compound was prepared following the method of Example 75, substituting 2- (4-methoxyphenyl) -acetic acid for benzofuran-2-carboxylic acid with 4-methanesulfonyl chloride for thiazole- , The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 468.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.19-7.17 (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, ), 2.22-2.10 (m, 2H), 1.99 (m, 1H), 1.62-1.35 (m, 4H), 0.90-0.88 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 468.2.
[1624] Example 134
[1625] Yl} -3-methyl-butyl} - (2-cyano-benzenesulfonyl) -3-oxo-azepan- Preparation of amide
[1626] Following the procedure of Example 75, replacing thiazole-2-sulfonyl chloride with 2-cyanobenzenesulfonyl chloride and replacing benzofuran-2-carboxylic acid with quinoline-2-carboxylic acid The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 562.2; ^{1 H-NMR (400MHz, CDCl} 3): δ8.65 (d, 1H), 8.48-8.40 (q, 2H), 8.25-8.10 (q, 2H), 7.91-7.65 (m, 6H); And the second eluting diastereomer: 7.12 (d, 1H), 5.10 (m, 1H), 4.73 (m, 1H), 4.61-4.56 , 2.80 (m, 1H), 2.27 (m, 2H), 1.91 - 1.40 (m, 5H), 1.03 - 1.01 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 562.2.
[1627] Example 135
[1628] Indole-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan- -Methyl-butyl} -amide &lt; / RTI &gt;
[1629] The title compound was prepared in analogy to Example 75, replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid with N-methylindole- The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 564.2; ¹ H-NMR (400 MHz, CDCl ₃ ): 8.13 (d, IH), 7.89 (d, IH), 7.77-7.67 (m, 3H), 7.38-7.16 ), 6.70 (d, IH), 5.05 (m, IH), 4.70-4.60 (m, IH), 4.55-4.50 3.71 (d, 1H), 2.75 (m, 1H), 2.30 (m, 2H), 2.00 - 1.45 (m, 5H), 1.00 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 564.2.
[1630] Example 136
[1631] ({(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- &Lt; / RTI &gt; amide &lt; RTI ID = 0.0 &gt;
[1632] 2-sulfonyl chloride was replaced with 2-cyanophenylsulfonyl chloride, and benzofuran-2-carboxylic acid was replaced with N- (2-furan-carbonyl) -glycine. The title compound was prepared according to the method of 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 558.2; ^{1 H-NMR (400MHz, CDCl} 3): δ8.14-8.12 (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, IH), 6.80 (d, IH), 6.52-6.51 (t, IH), 5.03 (m, IH), 4.60-4.53 ), 3.74-3.69 (d, 1H), 2.80 (m, 1H), 2.25 (m, 2H), 2.00-1.40 (m, 5H), 1.03-1.01 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 558.2.
[1633] Example 137
[1634] 5-Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (2-cyano- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1635] The title compound was prepared in analogy to example 1, except that thiazole-2-sulfonyl chloride was replaced by 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced by 5-methoxybenzofuran- The title compound was prepared according to the method of 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 581.4; ^{1 H-NMR (400MHz, CDCl} 3): δ8.15-8.13 (d, 1H), 7.92-7.90 (d, 1H), 7.81-7.74 (m, 2H), 7.42-7.40 (m, 2H), 7.08 (M, 3H), 6.96 (d, 1H), 5.10 (m, 1H), 4.72-4.60 (m, 2H), 4.17 , 1H), 2.83-2.76 (t, 1H), 2.27 (m, 2H), 1.92-1.51 (m, 5H), 1.02-1.01 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 581.2.
[1636] Example 138
[1637] 3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) - Preparation of amide
[1638] The title compound was prepared according to the method of Example 75, substituting thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 563.2; ¹ H-NMR (400MHz, CDCl ₃ ): 9.65 (s, IH), 8.40 (m, IH), 8.22-8.10 (m, 3H), 7.90-7.22 1H), 5.70 (d, IH), 5.60 (d, IH) 2.38 (m, 2H), 1.95-1.40 (m, 5H), 1.02 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 563.2.
[1639] Example 139
[1640] (S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -Yl] -amide &lt; / RTI &gt;
[1641] The title compound was prepared in analogy to example 75, except for using thiazole-2-sulfonyl chloride as 2-cyanophenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with 2- (4-methoxyphenyl) , The titled compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 555.2; ^{1 H-NMR (400MHz, CDCl} 3): δ8.14-8.12 (d, 1H), 7.91-7.89 (d, 1H), 7.79-7.73 (m, 2H), 7.19-7.17 (d, 2H), 6.90 (M, 1H), 3.82 (d, IH), 4.82 (d, IH) (s, 3H), 3.72-3.67 (d, IH), 3.53 (s, 2H), 2.82-2.79 (t, IH), 2.22 , 4H), 0.91-0.89 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 555.2.
[1642] Example 140
[1643] -2-carboxylic acid {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Preparation of amide
[1644] The title compound was prepared according to the method of Example 75, replacing thiazole-2-sulfonyl chloride with 4-methoxybenzenesulfonyl chloride and benzofuran-2-carboxylic acid with 2-quinolinecarboxylic acid. Lt; / RTI &gt; The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 567.2; ^{1 H-NMR (400MHz, CDCl} 3): δ8.72-8.61 (d, 1H), 8.35-8.28 (q, 2H), 8.21-8.18 (d, 1H), 7.91-7.60 (m, 5H), 7.10 3H), 3.45 (m, 1H), 4.73 (m, 1H), 4.59-4.52 , 2.42 (m, 1 H), 2.30 - 1.35 (m, 7H), 1.03 - 1.01 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 567.2.
[1645] Example 141
[1646] Indole-2-carboxylic acid {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[1647] The title compound was prepared in analogy to example 75, except for using thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with N-methyl-indole- , The titled compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 569.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.78-7.72 (d, 2H), 7.70-7.65 (d, 1H), 7.42-7.30 (m, 2H), 7.17-7.14 (t, 1H), 7.05 3H), 3.88 (s, 3H), 3.45-3. 40 (m, 2H) , 2.45 (m, 1H), 2.30-2.10 (m, 2H), 1.90 - 1.35 (m, 6H); Second eluting diastereomer: 1.00 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 569.2.
[1648] Example 142 [
[1649] ({(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- &Lt; / RTI &gt; amide &lt; RTI ID = 0.0 &gt;
[1650] 2-sulfonyl chloride was replaced with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with N- (2-furan-carbonyl) -glycine. The title compound was prepared according to the method of 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 563.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.74-7.72 (d, 2H), 7.47 (s, 1H), 7.15-6.99 (m, 4H), 6.91 (d, 1H), 6.70 (d, 1H 2H), 4.00-3.90 (m, IH), 3.88 (s, 3H) ), 3.45-3.41 (d, 1H), 2.47 (m, 1H), 2.17 (m, 2H), 1.85-1.40 (m, 5H), 0.95 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 563.2.
[1651] Example 143
[1652] Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1653] The title compound was prepared in analogy to the procedure of Example 1, except that thiazole-2-sulfonyl chloride was replaced by 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced by 5-methoxybenzofuran- The title compound was prepared according to the method of 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 586.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.75-7.73 (d, 2H), 7.42-7.40 (m, 2H), 7.08-6.99 (m, 5H), 6.91 (d, 1H), 5.05 (m 3H), 3.45-3.40 (d, IH), 2.50-2.40 (m, IH), 4.70-4.55 (m, , 1 H), 2.30-2.10 (m, 2 H), 1.90 - 1.35 (m, 5 H), 1.01 (m, 6 H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 586.2.
[1654] Example 144
[1655] 3-methyl-butyl} -3-oxo-azepan-4-ylcarbamoyl] -3-oxo-azepan-2-carboxylic acid {(S) - Preparation of amide
[1656] The title compound was prepared following the method of Example 75, substituting thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with quinoxaline-2- The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 568.2; ^{1 H-NMR (400MHz, CDCl} 3): δ9.66 (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, IH), 4.75 (m, IH), 4.60-4.55 (d, IH), 4.05-3.95 ), 3.45-3.41 (d, 1H), 2.45 (m, 1H), 2.30-2.10 (m, 2H), 1.95-1.40 (m, 5H), 1.04-1.02 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 568.2.
[1657] Example 145
[1658] (S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -Yl] -amide &lt; / RTI &gt;
[1659] The title compound was prepared in analogy to example 75, except for using thiazole-2-sulfonyl chloride as the 4-methoxyphenylsulfonyl chloride and replacing the benzofuran-2-carboxylic acid with 2- (4-methoxyphenyl) , The titled compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 560.4; ^{1 H-NMR (400MHz, CDCl} 3): δ7.74-7.71 (d, 2H), 7.19-7.17 (d, 2H), 7.01-6.99 (d, 2H), 6.90-6.88 (d, 2H), 6.85 (d, IH), 5.81 (d, IH), 4.99 (m, IH), 4.55-4. 44 (m, 2H), 3.97 2H), 3.43-3.38 (d, 1H), 2.43 (t, 1H), 2.14 (m, 2H), 1.85-1.35 (m, 5H), 0.90-0.89 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 560.2.
[1660] Example 146
[1661] Indole-2-carboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[1662] The title compound was prepared in analogy to example 75, except that thiazole-2-sulfonyl chloride was replaced by 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced by N-methyl-indole- , The titled compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 557.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.84-7.80 (m, 2H), 7.66-7.65 (d, 1H), 7.40-7.14 (m, 5H), 6.95 (m, 2H), 6.65-6.63 (d, IH), 5.07 (m, IH), 4.68-4.55 (m, 2H), 4.04 (s, 3H), 3.48-3.43 ), 1.89-1.38 (m, 6H); And the second eluting diastereomer: 1.01 (d, 6H); And second eluting moiety isomer: MS (M + H ^& lt ^{; +} & gt ^; ) 557.4.
[1663] Example 147
[1664] Furan-2-carboxylic acid ({(S) -l- [l- (4- fluoro-benzenesulfonyl) -3-oxo-azepan-4- ylcarbamoyl] &Lt; / RTI &gt; amide &lt; RTI ID = 0.0 &gt;
[1665] 2-sulfonyl chloride was replaced with 4-fluorophenylsulfonyl chloride and the benzofuran-2-carboxylic acid was replaced with N- (2-furan-carbonyl) -glycine. The title compound was prepared according to the method of 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 551.4; ^{1 H-NMR (400MHz, CDCl} 3): δ7.81 (m, 2H), 7.48 (s, 1H), 7.27-7.16 (m, 3H), 7.05 (m, 1H), 6.90 (d, 1H), 2H), 4.00-3.90 (d, 1H), 3.48-3.44 (d, 1H), 2.50 (m, m, 1 H), 2.20 (m, 2 H), 1.90 - 1.40 (m, 5 H), 0.95 (m, 6 H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 551.2.
[1666] Example 148
[1667] 5-Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1668] Thiazole-2-sulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid, The title compound was prepared according to the method of 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 574.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.84-7.81 (m, 2H), 7.42-7.40 (m, 2H), 7.27-7.22 (m, 2H), 7.08-7.04 (m, 3H), 6.93 (d, 1 H), 3.45-3.43 (d, 1H), 2.49 (m, 2H) (m, 1 H), 2.24 (m, 2 H), 1.90 - 1.40 (m, 5 H), 1.01 (m, 6 H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 574.2.
[1669] Example 149
[1670] 3-methyl-butyl} -3-oxo-azepan-4-ylcarbamoyl] - (4- - Preparation of amide
[1671] The title compound was prepared following the method of Example 75, substituting thiazole-2-sulfonyl chloride with 4-fluorophenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with quinoxaline-2- The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 556.2; ^{1 H-NMR (400MHz, CDCl} 3): δ9.66 (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, IH), 5.10-5.02 (m, IH), 4.75 (m, IH), 4.59-4.55 (d, 1H), 2.49 (m, 1H), 2.32-2.10 (m, 2H), 1.90-1.40 (m, 5H), 1.03-1.02 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 556.2.
[1672] Example 150
[1673] (S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl- pentanoic acid [l- (4- fluoro-benzenesulfonyl) -Yl] -amide &lt; / RTI &gt;
[1674] The title compound was prepared in analogy to example 75, except for using thiazole-2-sulfonyl chloride as the 4-fluorophenylsulfonyl chloride and replacing the benzofuran-2-carboxylic acid with 2- (4-methoxyphenyl) , The titled compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 548.2; ^{1 H-NMR (400MHz, CDCl} 3): δ7.83-7.80 (m, 2H), 7.27-7.17 (m, 4H), 6.90-6.88 (d, 3H), 5.85 (d, 1H), 4.98 (m 2H), 3.45-3.47 (m, 1H), 3.81 (s, 3H), 3.53 ), 2.17-2.14 (m, 2H), 1.90-1.30 (m, 5H), 0.90-0.88 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 548.4.
[1675] Example 151
[1676] 3-methyl-butyl} - (3-chloro-benzenesulfonyl) -3-oxo-azepan- Preparation of amide
[1677] 3-Methyl-butyl} -carbamic acid tert -butyl (3-chloro-benzenesulfonyl) -3-hydroxy- azepan- ester
[1678] 4.0 g of P-NMM and 1.85 g (8.75 mmol) of 3-chlorobenzenesulfonyl chloride were added to a solution of 2.50 g (7.29 mmol) of the compound of Example 2g in 100 ml of DCE. After shaking overnight at room temperature, the solution was filtered. The filtrate was concentrated to give the title compound as a white solid (3.13 g, 83.3%). MS: 539.78 (M + Na &lt; ⁺ &gt;).
[1679] b) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-chloro-benzenesulfonyl) -3-hydroxy-azepan-
[1680] 10 ml of HCl (4M in dioxane) was added to a stirred solution of 1.0 g (1.93 mmol) of the compound of Example 151a in 10 ml of methanol. After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. 2.85 g (2.63 mmol / g) of P-CO ₃ was added to a solution of 0.68 g (1.50 mmol, 78%) of a white solid in 37 ml of methanol. After shaking for 2 h, the solution was filtered and concentrated to give the title compound as a white solid, 0.59 g (1.42 mmol, 95%). MS: 417.86 (M + H) &lt; ⁺ & gt ^; .
[1681] c) Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-hydroxy- azepan-4-ylcarbamoyl] Butyl} -amide
[1682] 0.67 g (0.5 mmol) of 1-hydroxybenzotriazole and 0.67 g (1 mmol / g) of P-EDC in 10 ml of CH ₂ Cl _{2 were} dissolved in CH _{To a} solution of 0.14 g (0.33 mmol) of the compound of Example 151b in 20 ml of ₂ Cl ₂ was added. After shaking at room temperature overnight, the solution was treated with 0.45 g (3.75 mmol / g) of thiamine. After shaking again for 2 hours, the solution was filtered and concentrated to give 122 mg (65%) of the title compound as a white solid. MS (ESI): 562.2 (M + H) &lt; ⁺ & gt ^; .
[1683] d) Benzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[1684] 185 mg (0.44 mmol) of Dess-Martin reagent was added to a stirred solution of 122 mg (0.22 mmol) of the compound of Example 151c in 4 ml of dichloromethane. After stirring at room temperature for 2 hours, 2 ml of sodium thiosulfate solution (10% in water) and 2 ml of a saturated aqueous sodium bicarbonate solution were simultaneously added to the solution. The aqueous layer was extracted twice with dichloromethane. Collect the organic layer was washed with saturated brine, dried (MaSO _4), filtered, and concentrated. The residue was purified by HPLC to give a second eluting diastereomer (MS (ESI): 560.2 (M + H) ⁺ ) of 62.7 mg (51.6%) as a white solid and 40.2 mg Diastereoisomer (MS (ESI): 560.2 (M + H) &lt; ⁺ & gt ^; ).
[1685] Example 152
[1686] Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1687] The title compound was obtained according to the procedure of Example 151c-d but replacing the benzofuran-2-carboxylic acid of Example 151c with 5-methoxybenzofuran-2-carboxylic acid and was purified by HPLC (MS (ESI): 590.2 (M + H) <^+> ) and 44.4 mg (34.7%) of a white solid were obtained as white solids from 64.4 mg (50.3%) of the first eluting diastereomer ESI): 590.2 (M + H) <^+> ).
[1688] Example 153
[1689] Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1690] The title compound was obtained according to the procedure of Example 151c-d but replacing the benzofuran-2-carboxylic acid from Example 151c with 7-methoxybenzofuran-2-carboxylic acid and was purified by HPLC (MS (ESI): 590.2 (M + H) ⁺ ) of 51.1 mg (39.9%) of white solid and 36.7 mg (28.7% ESI): 590.2 (M + H) <^+> ).
[1691] Example 154
[1692] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[1693] The title compound was obtained according to the method of Example 151c-d but replacing the benzofuran-2-carboxylic acid from Example 151c with 5,6-dimethoxybenzofuran-2-carboxylic acid and purified by HPLC To give the second eluting diastereomer (51.1 mg, 39.9%) of the first eluting diastereomer (MS (ESI): 622.2 (M + H) ⁺ ) and 36.7 mg (28.7% MS (ESI): 622.2 (M + H) <^+> ).
[1694] Example 155
[1695] 3-methylbenzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Butyl} -amide &lt; / RTI &gt;
[1696] The title compound was obtained by following the procedure of Example 151c-d but replacing benzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid in step 151c and separating by HPLC (MS (ESI): 574.2 (M + H) &lt; ⁺ &gt;) of a white solid, 78.6 mg (63.1%) of the first eluting diastereomer (MS (ESI): 574.2 : 574.2 (M + H) &lt; ⁺ & gt ^; ).
[1697] Example 156
[1698] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1699] The title compound was obtained following the procedure of Example 151c-d but replacing benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid in step 151c and separated by HPLC (MS (ESI): 576.2 (M + H) &lt; ⁺ &gt;) of 41.0 mg (32.8%) of a white solid and 31.0 mg (24.8% ): 576.4 (M + H) &lt; ⁺ & gt ^; ).
[1700] Example 157
[1701] Indole-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1702] The title compound was obtained by following the procedure of Example 151c-d but replacing benzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid in step 151c and separated by HPLC to give white MS (ESI): 28.5 mg (22.9%) of the first eluting diastereomer (MS (ESI): 573.2 (M + H) ⁺ ) and 28.5 mg 573.2 (M + H) &lt; ⁺ & gt ^; ).
[1703] Example 158
[1704] Yl} -3-methyl-butyl} - (3-chloro-benzenesulfonyl) -3-oxo-azepan- Preparation of amide
[1705] The title compound was obtained by following the procedure of Example 151c-d but replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid in step 151c and separated by HPLC to give white solid 63.1 in mg (50.8%) the first eluting diastereomer (MS (ESI): 572.2 ( M + H) +) and the second elution portion of the white solid 43.2 mg (34.8%) diastereomers (MS (ESI): 572.2 ( M + H) &lt; ⁺ & gt ^; ).
[1706] Example 159
[1707] Benzofuran-2-carboxylic acid {(S) -1- [1- (2- fluoro-benzenesulfonyl) -3-oxo-azepan- - Preparation of amide
[1708] a) {(S) -1- [ 1- ( 2-fluoro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert- Butyl ester
[1709] 1.65 g (3.64 mmol / g) of P-NMM and 0.70 g (3.60 mmol) of 2-fluorobenzenesulfonyl chloride were added to a solution of 1.03 g (3.00 mmol) of the compound of Example 2g in 20 ml of DCE. After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to give 1.13 g (75.1%) of the title compound as a white solid: MS (ESI): 523.88 (M + Na) &lt; ⁺ & gt ^; .
[1710] b) (S) -2-Amino-4-methyl-pentanoic acid [l- (2- fluoro-benzenesulfonyl) -3-hydroxy-azepan-
[1711] 15 ml of HCl (4M in dioxane) was added to a stirred solution of 1.13 g (2.25 mmol) of the compound of Example 159a in 15 ml of methanol. After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. 5.70 g (2.63 mmol / g) of P-CO ₃ was added to a solution of 1.11 g (2.60 mmol, 75%) of a white solid in 50 ml of methanol. After shaking for 2 h, the solution was filtered and concentrated to give 0.868 g (2.16 mmol, 96%) of the title compound as a white solid: MS: 401.96 (M + H) &lt; ⁺ & gt ^; .
[1712] c) Benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -Butyl} -amide
[1713] (1 mmol / g) of P-EDC in 10 ml of CH ₂ Cl ₂ and 61.1 g (0.45 mmol) of 1-hydroxybenzotriazole were added Was added to a solution of 0.11 g (0.26 mmol) of the compound of Example 159b. After shaking at room temperature overnight, the solution was treated with 0.35 g (3.75 mmol / g) of thiamine. After shaking again for 2 hours, the solution was filtered and concentrated to afford 103.5 mg (70%) of the title compound as a white solid: MS (ESI): 546.2 (M + H) <^+> .
[1714] d) Benzofuran-2-carboxylic acid {(S) -1- [1- (2- fluoro- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Butyl} -amide
[1715] 164.7 mg (0.39 mmol) of Desmartin reagent was added to a stirred solution of 103.5 mg (0.19 mmol) of the compound of example 159c in 4 ml of dichloromethane. After stirring at room temperature for 2 hours, 2 ml of a sodium thiosulfate solution (10% in water) and 2 ml of a saturated aqueous sodium bicarbonate solution were simultaneously added to the solution. The aqueous layer was extracted twice with dichloromethane. Collect the organic layer was washed with saturated brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by HPLC to give a second eluting diastereomer (MS (ESI): 544.2 (M + H) ⁺ ) of 76.2 mg (73.6%) as a white solid and 20.7 mg Diastereoisomer (MS (ESI): 544.4 (M + H) &lt; ⁺ & gt ^; ).
[1716] Example 160
[1717] Carboxylic acid {(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1718] The title compound was obtained according to the procedure of Example 159c-d but replacing benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid in step 159c and separation by HPLC the first eluted portion of the white solid 48.3 mg (59.2%) diastereomers (MS (ESI): 574.2 ( M + H) +) and the second elution portion of the white solid 24.2 mg (29.6%) diastereomers (MS (ESI ): 574.2 (M + H) <^+> ).
[1719] Example 161
[1720] 2-carboxylic acid {(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1721] The title compound was obtained according to the method of Example 159c-d, except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c and separation by HPLC Gave the second eluting diastereomer of 47.7 mg (58.5%) of a white solid as the first eluting diastereomer (MS (ESI): 574.2 (M + H) ⁺ ) and 27.7 mg (33.9%) of a white solid.
[1722] Example 162
[1723] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (2- fluoro-benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide &lt; / RTI &gt;
[1724] The title compound was obtained according to the procedure of Example 159c-d but replacing benzofuran-2-carboxylic acid with 5,6-dimethoxybenzofuran-2-carboxylic acid in step 159c, (MS (ESI): 606.4 (M + H) <^+> ) and the second eluting diastereomer (MS (ESI): 606.4 (M + H) <^+> ).
[1725] Example 163
[1726] 3-Methylbenzofuran-2-carboxylic acid {(S) -1- [1- (2- fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1727] The title compound was obtained according to the method of Example 159c-d, except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 160c and separation by HPLC (MS: 558.2 (M + H) &lt; ⁺ &gt;) of the first eluting diastereomer (MS (ESI): 558.2) and 20.6 mg of a white solid (50.5 mg, 63.7%
[1728] Example 164
[1729] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [l- (2- fluoro-benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide &lt; / RTI &gt;
[1730] The title compound was obtained according to the procedure of Example 159c-d but replacing benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid in step 159c and separated by HPLC (MS (ESI): 560.2 (M + H) &lt; ⁺ &gt;) of a white solid, 52.5 mg (65.9%) of the first eluting diastereomer (MS ): 560.2 (M + H) &lt; ⁺ & gt ^; ).
[1731] Example 165
[1732] Indole-2-carboxylic acid {(S) -1- [1- (2-fluoro- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[1733] The title compound was obtained according to the method of Example 159c-d, except substituting 1-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c, (MS: 557.2 (M) <+>) of 51.4 mg (64.9%) of a first eluting diastereomer (MS (ESI): 557.2 (M + H) <^+> ) and 21.0 mg (26.5% + H) &lt; ⁺ & gt ^; ).
[1734] Example 166
[1735] (S) -4-methyl-2- (l-oxy-pyridine-2- sulfonylamino) -pentanoic acid [ Preparation of amide
[1736] a) (S) -4-Methyl-2- (1-oxy-pyridine- 2- sulfonylamino) -pentanoic acid [3-hydroxy- 1- (pyridine- Yl] -amide
[1737] 2-pyridine sulfonyl chloride in the N- oxide 0.9 ml was added dropwise over 3 minutes to a solution of dichloromethane and 10 ml saturated NaHCO ₃ in Example 28a 0.1 g of the compound of the. The reaction was stirred at room temperature for 30 minutes. Work-up and column chromatography gave 9.2 mg of the title compound: MS (ESI) 541 (M + H ^& lt ^{; +} & gt ^; ).
[1738] b) (S) -4-Methyl-2- (l-oxy-pyridine- 2- sulfonylamino) -pentanoic acid [3-oxo- l- (pyridine- 2- sulfonyl) ]-amides
[1739] The title compound was prepared according to the procedure of example 1i, but substituting the compound of example 166a: MS (ESI) 539 (M + H <^+> ).
[1740] Example 167
[1741] 3-methyl-butyl} -3-oxo-azepan-4-ylcarbamoyl] - (2- - Preparation of amide
[1742] The title compound was obtained by following the procedure of Example 159c-d but replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid in step 159c to give the title compound as a white solid, 49.7 (MS: 556.4 (M + H) &lt; ⁺ &gt;) of the second eluting diastereomer (MS (ESI): 556.2 ) ^& Lt; ⁺ & gt ^; ).
[1743] Example 168
[1744] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1745] Except substituting the 2-thiazo sulfonyl chloride of Example 75a with 2-thiophenesulfonyl chloride and the benzofuran-2-carboxylic acid of Example 75c with 5-methoxybenzofuran-2-carboxylic acid (MS (ESI): 562.2 (M + H) &lt; ⁺ &gt;) as a white solid, 71 mg (65% ) And a second eluting diastereomer (MS (ESI): 562.2 (M + H) &lt; ⁺ & gt ^; ) of 21.6 mg (20.0%
[1746] Example 169
[1747] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1748] The title compound was obtained according to the procedure of Example 168, replacing 5-methoxybenzofuran-2-carboxylic acid with 7-methoxybenzofuran-2-carboxylic acid, which was then purified by HPLC the first eluted portion of the white solid 88 mg (80%) diastereomers (MS (ESI): 562.2 ( M + H) +) and the second elution portion of the white solid 18 mg (16%) diastereomers (MS (ESI) : 562.2 (M + H) &lt; ⁺ & gt ^; ).
[1749] Example 170
[1750] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (thiophene-2-sulfonyl) Yl] -butyl} -amide &lt; / RTI &gt;
[1751] The title compound was obtained according to the procedure of Example 168, but replacing 5-methoxybenzofuran-2-carboxylic acid with 5,6-dimethoxybenzofuran-2-carboxylic acid, which was separated by HPLC To give the first eluting diastereomer (MS (ESI): 594.2 (M + H) &lt; ⁺ & gt ^; ) and the second eluting diastereomer.
[1752] Example 171
[1753] (S) -3-methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide &lt; / RTI &gt;
[1754] The title compound was obtained according to the method of Example 168, substituting 3-methylbenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid, which was purified by HPLC to give white MS (ESI): a first eluting diastereomer (MS (ESI): 546.2 (M + H) ⁺ ) of 88 mg (83%) of a solid and 16 mg 546.2 (M + H) &lt; ⁺ & gt ^; ).
[1755] Example 172
[1756] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiophene- 2- sulfonyl) -Butyl} -amide &lt; / RTI &gt;
[1757] The title compound was obtained according to the procedure of Example 168, replacing 5-methoxybenzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid, which was then purified by HPLC (MS (ESI): 548.4 (M + H) &lt; ⁺ & gt ^; ) of the title compound as a white solid, 43.4 mg (41%) of the first eluting diastereomer (MS (ESI): 548.4 : 548.2 (M + H) &lt; ⁺ & gt ^; ).
[1758] Example 173
[1759] Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiophene- 2- sulfonyl) -azepan- ] -Butyl} -amide &lt; / RTI &gt;
[1760] The title compound was obtained according to the procedure of Example 168, but replacing 5-methoxybenzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid, which was purified by HPLC to yield a white solid the first eluting diastereomer of 35.8 mg (34.0%) (MS (ESI): 545.2 (M + H) +) and the second eluting diastereomer as a white solid 45.8 mg (43%) (MS (ESI): 545.2 (M + H) &lt; ⁺ & gt ^; ).
[1761] Example 174
[1762] Oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -carbamic acid tert- Preparation of amide
[1763] The title compound was obtained by following the procedure in Example 168, except replacing 5-methoxybenzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid, which was separated by HPLC to give 60 mg (MS (ESI): 544.4 (M) of the first eluting diastereomer (MS (ESI): 544.4 (M + H) ⁺ ) of the title compound (56%) and 38.7 mg + H) &lt; ⁺ & gt ^; ).
[1764] Example 175
[1765] Methyl-butyl} - &lt; / RTI &gt; &lt; RTI ID = 0.0 & Preparation of amide
[1766] a) {(S) -1- [ 1- (3- chloro-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[1767] 4.0 g of P-NMM and 1.85 g (8.75 mmol) of 4-chlorobenzenesulfonyl chloride were added to a solution of 2.50 g (7.29 mmol) of the compound of Example 2g in 100 ml of DCE. After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to give 3.13 g (83.3%) of the title compound as a white solid: MS: 539.78 (M + Na) &lt; ⁺ & gt ^; .
[1768] b) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-chloro-benzenesulfonyl) -3-hydroxy-azepan-
[1769] 10 ml of HCl (4M in dioxane) was added to a stirred solution of 1.0 g (1.93 mmol) of the compound of Example 175a in 10 ml of methanol. After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. 2.85 g (2.63 mmol / g) of P-CO ₃ was added to a solution of 0.68 g (1.50 mmol, 78%) of a white solid in 37 ml of methanol. After shaking for 2 h, the solution was filtered and concentrated to give 0.59 g (1.42 mmol, 95%) of the title compound as a white solid: MS: 417.86 (M + H) <^+> .
[1770] c) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-hydroxy- azepan- 4- ylcarbamoyl] Butyl} -amide
[1771] 0.67 g (1 mmol / g) of P-EDC in 10 ml of CH ₂ Cl ₂ and 0.77 g (0.569 mmol) of 1-hydroxybenzotriazole were dissolved in CH _{To a} solution of 0.14 g (0.335 mmol) of the compound of Example 175b in 20 ml of ₂ Cl ₂ was added. After shaking at room temperature overnight, the solution was treated with 0.446 g (3.75 mmol / g) of thiamine. After shaking again for 2 hours, the solution was filtered and concentrated to give 122.2 mg (65%) of the title compound as a white solid: MS (ESI): 562.2 (M + H) <^+> .
[1772] d) Benzofuran-2-carboxylic acid {(S) -1- [l- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] }-amides
[1773] 184.8 mg (0.436 mmol) of Desmartin reagent was added to a stirred solution of 122.2 mg (0.217 mmol) of the compound of Example 175c in 4 ml of dichloromethane. After stirring at room temperature for 2 hours, 2 ml of sodium thiosulfate solution (10% in water) and 2 ml of a saturated aqueous sodium bicarbonate solution were simultaneously added to the solution. The aqueous layer was extracted twice with dichloromethane. Mixing the organic layer, washed with saturated brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by HPLC to afford a second eluting diastereomer (MS (ESI): 560.2 (M + H) ⁺ ) of 62.7 mg (51.6%) as a white solid and 32.7 mg Diastereoisomer (MS (ESI): 560.2 (M + H) &lt; ⁺ & gt ^; ).
[1774] Example 176
[1775] Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1776] The title compound was obtained following the procedure of Example 175c-d but replacing benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid in step 175c and separated by HPLC To give the second eluting diastereomer (MS (ESI): 590.2 (M + H) ⁺ ) of the white eluate 64.4 mg (50%) of the first eluting diastereomer (MS ): 590.0 (M + H) &lt; ⁺ & gt ^; ).
[1777] Example 177
[1778] 2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl -Butyl} -amide &lt; / RTI &gt;
[1779] The title compound was obtained following the procedure of Example 175c-d but replacing benzofuran-2-carboxylic acid with 7-methoxybenzofuran-2-carboxylic acid in step 175c and separated by HPLC To give the second eluting diastereomer (MS (ESI): 590.2 (M + H) ⁺ ) of 51.1 mg (40%) of a white solid as a first eluting diastereomer (MS ): 590.2 (M + H) &lt; ⁺ & gt ^; ).
[1780] Example 178
[1781] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[1782] The title compound was obtained according to the procedure of Example 175c-d but replacing benzofuran-2-carboxylic acid with 5,6-dimethoxybenzofuran-2-carboxylic acid in step 175c, (MS (ESI): 622.2 (M + H) &lt; ⁺ & gt ^; ) and the second eluting diastereomer (MS (ESI): 622.2 (M + H) &lt; ⁺ & gt ^; ).
[1783] Example 179
[1784] Methylbenzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Butyl} -amide &lt; / RTI &gt;
[1785] The title compound was obtained according to the procedure of Example 175c-d but replacing benzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid in step 175c and separated by HPLC the first eluted portion of the white solid 78.6 mg (63%) diastereomers (MS (ESI): 574.2 ( M + H) +) and the second elution portion of the white solid 27.6 mg (22%) diastereomers (MS (ESI) : 574.2 (M + H) &lt; ⁺ & gt ^; ).
[1786] Example 180
[1787] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1788] The title compound was obtained following the procedure of Example 175c-d but replacing benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid in step 175c and separated by HPLC the first eluted portion of the white solid 41 mg (33%) diastereomers (MS (ESI): 576.2 ( M + H) +) and the second elution portion of the white solid 32.6 mg (26%) diastereomers (MS (ESI ): 576.2 (M + H) &lt; ⁺ & gt ^; ).
[1789] Example 181
[1790] Indole-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1791] The title compound was obtained according to the method of Example 175c-d but replacing benzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid in step 175c and separated by HPLC to give white MS (ESI): a second eluting diastereomer (MS (ESI): 573.2 (M + H) ⁺ ) of 28.5 mg (23%) of a solid and 38.5 mg 573.2 (M + H) &lt; ⁺ & gt ^; ).
[1792] Example 182
[1793] Yl} -3-methyl-butyl} - (4-chloro-benzenesulfonyl) -3-oxo-azepan- Preparation of amide
[1794] The title compound was obtained by following the procedure of Example 175c-d but replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid in step 175c and separated by HPLC to give white solid 63 MS (ESI): 572.2 (M + H) &lt; ⁺ &gt;) of the first eluting diastereomer (MS (ESI): 572.2 M + H) &lt; ⁺ & gt ^; ).
[1795] Example 183
[1796] 3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) - Preparation of amide
[1797] a) {(S) -1- [ 1- (3- methoxy-benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert- Butyl ester
[1798] 2.56 g (3.64 mmol / g) of P-NMM and 1.15 g (5.59 mmol) of 3-methoxy-benzenesulfonyl chloride were added to a solution of 1.60 g (4.66 mmol) of the compound of Example 2g in 50 ml of DCE. After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to afford 1.70 g (71.1%) of the title compound as a white solid: MS: 535.8 (M + Na) &lt; ⁺ & gt ^; .
[1799] b) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-methoxy-benzenesulfonyl) -3- hydroxy-
[1800] 22 ml of HCl (4M in dioxane) was added to a stirred solution of 1.70 g (3.31 mmol) of the compound of Example 183a in 22 ml of methanol. After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. 5.02 g (2.63 mmol / g) of P-CO ₃ was added to a solution of 1.19 g (2.64 mmol, 80%) of a white solid in 50 ml of methanol. After shaking for 2 h, the solution was filtered and concentrated to give 1.03 g (2.49 mmol, 96%) of the title compound as a white solid: MS: 413.90 (M + H) <^+> .
[1801] c) Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-hydroxy-azepan-4-ylcarbamoyl] -Butyl} -amide
[1802] 0.532 g (1 mmol / g) of P-EDC in 10 ml of CH ₂ Cl ₂ and 61.1 g (0.452 mmol) of 1-hydroxybenzotriazole were dissolved in CH To a solution of 0.11 g (0.26 mmol) of the compound of Example 183b in 10 ml of ₂ Cl ₂ was added. After shaking at room temperature overnight, the solution was treated with 0.355 g (3.75 mmol / g) of thiamine. After shaking again for 2 hours, the solution was filtered and concentrated to give 103.5 mg (70%) of the title compound as a white solid: MS (ESI): 558.2 (M + H) <^+> .
[1803] d) Benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] Butyl} -amide
[1804] Desmartin reagent 157 mg (0.37 mmol) was added to a stirred solution of 103 mg (0.19 mmol) of the compound of Example 183c in 4 ml dichloromethane. After stirring at room temperature for 2 hours, 2 ml of sodium thiosulfate solution (10% in water) and 2 ml of a saturated aqueous sodium bicarbonate solution were simultaneously added to the solution. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by HPLC to afford a second eluting diastereomer (MS (ESI): 556.2 (M + H) ⁺ ) of 76.2 mg (73.6%) as a white solid and 24.1 mg Diastereoisomer (MS (ESI): 556.2 (M + H) &lt; ⁺ & gt ^; ).
[1805] Example 184
[1806] 5-Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1807] The title compound was obtained according to the procedure of Example 183c-d but replacing benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid in step 183c and separated by HPLC To give the second eluting diastereomer (MS (ESI): 586.2 (M + H) ⁺ ) of the title compound as a white solid, 33 mg (31%) of the first eluting diastereomer (MS ): 586.2 (M + H) &lt; ⁺ & gt ^; ).
[1808] Example 185
[1809] Methoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide &lt; / RTI &gt;
[1810] The title compound was obtained according to the procedure of Example 183c-d but replacing benzofuran-2-carboxylic acid with 7-methoxybenzofuran-2-carboxylic acid in step 183c and separated by HPLC (MS (ESI): 586.4 (M + H) &lt; ⁺ & gt ^; ) of the title compound as a white solid (41 mg, 38% ): 586.2 (M + H) &lt; ⁺ & gt ^; ).
[1811] Example 186
[1812] 4,5-Dimethoxybenzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide &lt; / RTI &gt;
[1813] The title compound was obtained according to the method of Example 183c-d but replacing benzofuran-2-carboxylic acid with 5,6-dimethoxybenzofuran-2-carboxylic acid in step 183c, To give the first eluting diastereomer (MS (ESI): 618.4 (M + H) <^+> ) and eluent two diastereomers.
[1814] Example 187
[1815] 3-methylbenzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[1816] The title compound was obtained according to the method of Example 183c-d, except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c and separated by HPLC (MS (ESI): 570.2 (M + H) &lt; ⁺ & gt ^; ) of the title compound as a white solid, 76 mg (72%) of the first eluting diastereomer (MS : 570.2 (M + H) &lt; ⁺ & gt ^; ).
[1817] Example 188
[1818] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide &lt; / RTI &gt;
[1819] The title compound was obtained according to the procedure of Example 183c-d but replacing benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid in step 183c and separated by HPLC To give the second eluting diastereomer (MS (ESI): 572.2 (M + H) ⁺ ) of the title compound as a white solid, 37 mg (35%) of the first eluting diastereomer (MS ): 572.2 (M + H) &lt; ⁺ & gt ^; ).
[1820] Example 189
[1821] Indole-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide &lt; / RTI &gt;
[1822] The title compound was obtained according to the method of Example 183c-d but replacing benzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid in step 183c and separated by HPLC to give white MS (ESI): a second eluting diastereomer of 34 mg (32%) of a first eluting diastereomer (MS (ESI): 569.2 (M + H) ⁺ ) and 38 mg 569.4 (M + H) &lt; ⁺ & gt ^; ).
[1823] Example 190
[1824] Preparation of quinoxaline- {(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4- ylcarbamoyl] -3-methyl- butyl} -amide
[1825] The title compound was obtained by following the procedure of Example 183c-d but replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid in step 183c and separated by HPLC to give white solid 71 MS (ESI): 568.2 (M + H) &lt; ⁺ &gt;) of the first eluting diastereomer (MS (ESI): 568.2 M + H) &lt; ⁺ & gt ^; ).
[1826] Example 191
[1827] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2- sulfonyl) -azepan-4-ylcarbamoyl] Preparation of amide
[1828] Carboxylic acid was replaced by benzofuran-2-carboxylic acid, the title compound was obtained according to the procedure of example 168 and was purified by HPLC to yield 76 mg of a white solid (73%) of the first eluting diastereomer (MS (ESI): 532.2 (M + H) ⁺⁾ and the second elution portion of the white solid 25 mg (23%) diastereomers (MS (ESI): 532.2 (M + H) &lt; ⁺ & gt ^; ).
[1829] Example 192
[1830] Benzofuran-2-carboxylic acid {(S) -3-methyl-1 - [(2,2 ', 4-tridecarterio) -3-oxo-1- (pyridine- Yl-carbamoyl] -butyl} -amide &lt; / RTI &gt;
[1831] D ₂ O: CD ₃ OD 0.4: To a solution of benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- - azepan-4-ylcarbamoyl] -butyl} -amide in 20 ml tetrahydrofuran was added 0.04 ml triethylamine. The reaction was heated to reflux temperature for 2 hours, then it was concentrated and dried under vacuum. The residue was redissolved in the same mixture and heated to reflux overnight. The reaction is concentrated and the residue was purified by column chromatography (5% methanol: dichloromethane) to yield the title compound 0.02 g by: ¹ H-NMR: δ1.0 (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 (EI): 529 (M ^&lt; ^{+ &gt;} , 45%).
[1832] (EI): 530 (M + H ⁺ , 100%)) and the slower eluting diastereoisomer (MS (EI): 530 (M + H & lt ^; + & gt ^; , 100%)).
[1833] Example 193
[1834] Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Manufacturing
[1835] a) 4- tert -Butoxycarbonylamino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[1836] To a stirred solution of 1.04 g (3.92 mmol) of the compound from example 2e in THF was added 0.864 g of di-tert-butyl dicarbonate. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with diethyl ether and extracted with saturated NaHCO _3. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel column to give 0.963 g (2.64 mmol, 67%) of the title compound as a yellow oil. MS (ESI): 365.03 (M + H) &lt; ⁺ & gt ^; .
[1837] b) (3-Hydroxy-azepan-4-yl) -carbamic acid tert -butyl ester
[1838] To a solution of 0.963 g (2.64 mmol) of the compound of Example 193a in 16 ml of ethyl acetate was added 500 mg of 10% palladium on carbon. After stirring at room temperature for 48 hours, the mixture was filtered through celite. The filtrate was concentrated to give 0.529 g (2.29 mmol, 87%) of the title compound. MS (ESI): 231.92 (M + H) &lt; ⁺ & gt ^; .
[1839] c) [3-Hydroxy-1- (pyridine-2-sulfonyl) -azepan -4-yl] -carbamic acid tert- butyl ester
[1840] 232 mg of triethylamine and 410 mg (2.32 mmol) of pyridine-2-sulfonyl chloride were added to a solution of 0.53 g (2.29 mmol) of the compound of Example 193b in 20 ml of dichloromethane. After stirring at room temperature for 30 minutes, the mixture was washed with saturated NaHCO _3. The organic layer was dried, filtered, concentrated and purified by silica gel column to give 0.58 g (1.57 mmol, 68%) of the title compound as a solid. MS (ESI): 372.95 (M + H) &lt; ⁺ & gt ^; .
[1841] d) 4-Amino-1- (pyridine-2-sulfonyl) -azepan-3-ol
[1842] To a stirred solution of 0.583 g (1.57 mmol) of the compound of Example 193c in 0.5 ml ethyl acetate was added 3.9 ml HCl (4M in dioxane). After the reaction mixture was stirred at room temperature for 30 minutes, the mixture was concentrated to give a white solid. The solid was treated with NaOH and then extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give 0.35 g (1.28 mmol, 81%) of a yellow solid: MS (ESI): 272.93 (M + H) &lt; ⁺ & gt ^; .
[1843] e) {(S) -1- [ 3- hydroxy-1 (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -2-methyl-butyl} -carbamic acid tert-butyl ester
[1844] To a solution of CH ₂ Cl ₂ Example Compound 193d 19 mg (0.070 mmol) of of N-Boc- isoleucine 24.5 mg (0.10 mmol), 1- hydroxybenzotriazole 16.1 mg (0.12 mmol), and CH ₂ Cl 140 mg (0.14 mmol) of P-EDC in ₂ was added. After shaking at room temperature overnight, the mixture was treated with PS-triisamine. After shaking again for 2 hours, the mixture was filtered and concentrated to give the title compound as a solid. MS (ESI): 484.97 (M + H) &lt; ⁺ & gt ^; .
[1845] f) (S) -2-Amino-3-methyl-pentanoic acid [3-hydroxy-1- (pyridine- 2- sulfonyl) -azepan-
[1846] To a stirred solution of 34 mg (0.07 mmol) of the compound of example 193e in 0.50 ml of CH ₂ Cl ₂ was added 0.165 ml of HCl (4M in dioxane). After stirring at room temperature for 30 minutes, the mixture was concentrated to give a white solid. The white solid was azeotroped with toluene and treated with 0.35 mmol of MP-carbonate in methanol. After shaking for 4 h, the mixture was filtered and concentrated to give the title compound as a solid: MS (ESI): 384.9 (M + H) <^+> .
[1847] g) Synthesis of benzofuran-2-carboxylic acid {(S) -2-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides
[1848] CH ₂ Cl ₂ Example Compound 193f of 27 mg solution of benzofuran 2-carboxylic acid 17.0 mg (0.106 mmol) of the (0.070 mmol), 16.1 mg ( 0.12 mmol) 1- hydroxybenzotriazole in, and CH ₂ 140 mg (0.14 mmol) of P-EDC in Cl ₂ was added. After shaking at room temperature overnight, the mixture was treated with PS-triisamine. After shaking again for 2 h, the mixture was filtered and concentrated to give the title compound as a solid: MS (ESI): 528.9 (M + H) &lt; ⁺ & gt ^; .
[1849] 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - &lt; / RTI &gt; -amides
[1850] 45 mg (0.105 mmol) of Desmartin reagent was added to a stirred solution of 370 mg (0.07 mmol) of the compound of Example 193g in 0.5 ml of CH ₂ Cl ₂ . After stirring for 30 minutes, 0.50 ml of sodium thiosulfate solution (10% in water) and 0.50 ml of saturated sodium bicarbonate solution were simultaneously added to the reaction. The mixture was then extracted twice with dichloromethane. The organic layer was dried, filtered and concentrated. The residue was purified by HPLC to give two diastereomers of the title compound as a solid (first elution: 7 mg, second elution: 5.5 mg): MS (ESI): 526.91 (M + H) &lt; ⁺ & gt ^; .
[1851] Example 194
[1852] Preparation of (S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -propyl} -amide
[1853] The title compound was obtained following the method of Example 193e-h, but replacing N-Boc-alpha-aminobutyric acid in step 193e and purification yielded two diastereomers as solids (first elution: 5 mg, the second elution: 5 mg): MS (ESI): 543.8 (M + H) <^+> .
[1854] Example 195
[1855] Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Preparation of amide
[1856] Following the procedure of Example 193e-h, except substituting N-Boc-cyclohexylalanine in step 193e, the title compound was obtained and purified to give two diastereomers as a solid (first eluent: 4.5 mg , Second eluting: 4.5 mg): MS (ESI): 566.87 (M + H) <^+> .
[1857] Example 196
[1858] Preparation of (S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amide
[1859] The title compound was obtained following the method of Example 193e-h, replacing N-Boc-alanine in step 193e and purification yielded two diastereomers as solids (first elution: 5.5 mg, 2 elution: 5 mg).
[1860] Example 197
[1861] 2-sulfonyl) -azepan-4-ylcarbamoyl] -propyl} - &lt; / RTI &gt; - Preparation of amide
[1862] The title compound was obtained following the method of Example 193e-h but replacing N-Boc-L-methionine in step 1 (f) and purification yielded two diastereomers as solids Elution: 3 mg, second elution: 3 mg). MS (ESI): 560.7 (M + H) &lt; ⁺ & gt ^; .
[1863] Example 198
[1864] Preparation of benzofuran-2-carboxylic acid {[3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -methyl}
[1865] The title compound was obtained following the method of Example 193e-h, substituting N-Boc-glycine in step 193e and purification yielded two diastereomers as solids (first elution: 3 mg, Second elution: 3 mg). MS (ESI): 470.81 (M + H) &lt; ⁺ & gt ^; .
[1866] Example 199
[1867] Preparation of (S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide
[1868] The title compound was obtained following the procedure of Example 193e-h, but replacing N-Boc-norleucine in step 193e and purification yielded two diastereomers as a solid (first eluent: 4 mg , Second elution: 5 mg). MS (ESI): 526.85 (M + H) &lt; ⁺ & gt ^; .
[1869] Example 200
[1870] Preparation of (S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide
[1871] The title compound was obtained following the procedure of Example 193e-h, but replacing in step 193e by N-Boc-norvaline and purified to give two diastereomers as a solid (first eluent: 7.5 mg , Second elution: 3.5 mg). MS (ESI): 512.8 (M + H) &lt; ⁺ & gt ^; .
[1872] Example 201
[1873] Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl} Manufacturing
[1874] The title compound was obtained following the procedure of Example 193e-h, but replacing in step 193e by N-Boc-valine and purified to give two diastereomers as a solid (first elution: 6 mg, Second elution: 4.5 mg). MS (ESI): 512.8 (M + H) &lt; ⁺ & gt ^; .
[1875] Example 202
[1876] Benzofuran-2-carboxylic acid {(S) -2-hydroxy- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl} - Preparation of amide
[1877] The title compound was obtained following the method of Example 193e-h, but replacing in step 193e with N-Boc-L-threonine and purified to give two diastereomers as a solid (first eluent: 3 mg, the second elution: 3 mg).
[1878] Example 203
[1879] 2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -2- phenyl- ethyl} Manufacturing
[1880] The title compound was obtained by following the procedure of Example 193e-h but replacing N-Boc-phenylalanine in step 193e and purification yielded two diastereomers as a solid (first elution: 5 mg, Second elution: 5 mg). MS (ESI): 560.8 (M + H) &lt; ⁺ & gt ^; .
[1881] Example 204
[1882] Preparation of 1- (benzofuran-2-carbonyl) -pyrrolidine-2-carboxylic acid [3-oxo- 1- (pyridine-2- sulfonyl) -azepan-4-yl] -amide
[1883] The title compound was obtained according to the procedure of Example 193e-h, but replacing in step 193e with N-Boc-L-proline and purified to give two diastereomers as a solid (first elution: 4 mg, second elution: 5 mg). MS (ESI): (M + H) &lt; ⁺ & gt ^; .
[1884] Example 205
[1885] (S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl } -Benzamide &lt; / RTI &gt;
[1886] The title compound was prepared according to the method of Example 115, but replacing benzyloxyacetyl chloride with 3,4-dimethoxybenzoyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 576.4 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ7.68 (d, 2H), 7.00 (d, 1H), 6.89 (s, 2H), 3.84 (s, 3H), 3.77 (s, 6H), 2.38 (t , &Lt; / RTI &gt; 1H), 0.94 (d, 6H); Second eluting diastereomer: MS 576.4 (M + H ^& lt ^{; +} & gt ^; ).
[1887] Example 206
[1888] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide &lt; / RTI &gt;
[1889] The title compound was prepared according to the method of Example 115, but replacing benzyloxyacetyl chloride with 2-thiophene-carbonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 572.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ7.80-7.68 (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 ^& lt ^{; +} & gt ^; ).
[1890] Example 207
[1891] Benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (4- fluoro-benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide &lt; / RTI &gt;
[1892] Following the procedure of Example 115, except substituting 4-fluorobenzenesulfonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4-methylenedioxybenzoyl chloride for benzyloxyacetyl chloride, the title compound . The residue was purified by HPLC. First eluting diastereomer: MS 548.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} ): δ7.85-7.78 (m, 2H), 7.38-7.20 (m, 4H), 7.05 (d, 1H), 2.52-2.40 (m, 1H), 1.0 (d, 6H). Second eluting diastereomer: MS 548.2 (M + H ^& lt ^{; +} & gt ^; ).
[1893] Example 208
[1894] (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [l- (4- fluoro-benzenesulfonyl) -3-oxo-azepan- Produce
[1895] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 548.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} -CD 3 OD): δ7.88-7.80 (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 eluting diastereomer: MS 548.2 (M + H ^& lt ^{; +} & gt ^; ).
[1896] Example 209
[1897] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [l- (4- fluoro-benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide &lt; / RTI &gt;
[1898] Following the procedure of Example 115, except substituting 4-methoxybenzenesulfonyl chloride for 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride for benzo [b] thiophenecarbonyl chloride, the title compound . The residue was purified by HPLC. First eluting diastereomer: MS 560.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ7.80-7.72 (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 ^& lt ^{; +} & gt ^; ).
[1899] Example 210
[1900] Preparation of (S) -1- [1-benzoyl-3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl} -amide
[1901] a) Benzofuran-2-carboxylic acid {(S) -1- [1 -benzoyl- 3-hydroxy-azepan-4- ylcarbamoyl] -3-methyl- butyl}
[1902] To a solution of benzofuran-2-carboxylic acid {(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl- butyl} -amide in dichloromethane was added 0.12 g of benzoic acid, 0.07 g of HOBt and 0.99 g of EDC were added. The reaction was stirred until the reaction was complete. 0.2 g of the title compound was obtained by work-up and column chromatography (5% methanol: dichloromethane): ¹ H NMR (CDCl ₃ ): 隆 1.0 (m, 6H), 1.5-2.2 (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 MS (EI): 492 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1903] b) Preparation of benzofuran-2-carboxylic acid {(S) -1- [1 -benzoyl-3- oxo-azepan-4-ylcarbamoyl]
[1904] Benzoyl-3-hydroxy-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide in accordance with the general method of example 210c substituting benzofuran-2-carboxylic acid { the title compound was prepared in accordance with those conducted in the method of example 1i except _{^{that: 1 H NMR (CDCl 3)}} : δ1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H ), 3.7 (m, 1H), 4.0 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H); MS (EI): 490 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1905] Example 211
[1906] Preparation of (S) -4-methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid 3-oxo-1- (pyridine-2- sulfonyl) -azepan-
[1907] a) (S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-
[1908] The title compound was prepared according to the method of Example 89a, except substituting 8-quinoline sulfonyl chloride for 2-pyridinesulfonyl chloride: MS (EI): 576 (M + H <^+> ).
[1909] b) (S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
[1910] (S) -4-methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-hydroxy- 1- (pyridine- 2- sulfonyl) the title compound was prepared according to the is procedure of example 1i, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 0.5-0.8 (m, 6H), 1.4-1.8 (m, 7H), (M, 2H), 7.5 (m, 1H), 3.5 (m, 1H), 3.5-3.9 3H), 8.0 (m, 2H), 8.3 (m, 2H), 8.6 (m, 1H), 9.0 (m, 1H); MS (EI): 674 (M + H ^& lt ^{; +} & gt ^; , 100%).
[1911] Example 212
[1912] Preparation of (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid 3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-yl]
[1913] a) (S) -4-Methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-hydroxy- amides
[1914] The title compound was prepared according to the method of Example 89a, but substituting 2-naphthylenesulfonyl chloride for 2-pyridinesulfonyl chloride: MS (EI): 575 (M + H <^+> ).
[1915] b) Synthesis of (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-
[1916] (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine- ] - the title compound was prepared in accordance with, and is the method of example 1i, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 0.5-0.8 (m, 6H), 1.4-1.8 (m, 7H) , 2.5 (m, IH), 3.5-3.9 (m, 3H), 4.5 (m, IH), 4.6 , 9H), 8.5-8.6 (m, 2H): MS (EI): 673 (M + H ⁺ , 100%).
[1917] Example 213
[1918] 3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) - Preparation of amide
[1919] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride with 2-benzofuranecarbonyl chloride. Respectively. The residue was purified by HPLC. First eluting diastereomer: MS 544.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 7.79-7.77 (m, 2H), 7.61 (d, 1H), 7.46-7.38 (m, 3H), 7.25-7.06 (m, 5H), 2.43 (t, 1H ), 0.95 (d, 6H). Second eluting diastereomer: MS 544.4 (M + H ^& lt ^{; +} & gt ^; ).
[1920] Example 214
[1921] N - {(S) -1- [1- (4-Fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Lt; RTI ID = 0.0 &gt;
[1922] Following the procedure of Example 115, except substituting 4-methoxybenzenesulfonyl chloride for 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride for 3,4-dimethoxybenzoyl chloride, the title compound was prepared from . The residue was purified by HPLC. First eluting diastereomer: MS 564.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 7.80-7.76 (m, 2H), 7.19 (t, 2H), 7.05 (d, 1H), 6.88 (s, 2H), 6.78 (d, 1H), 6.53 ( s), 3.77 (s, 6H), 2.43 (t, IH), 0.94 (d, 6H). Second eluting diastereomer: MS 546.2 (M + H ^& lt ^{; +} & gt ^; ).
[1923] Example 215
[1924] Preparation of cyclohexanecarboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} Produce
[1925] The title compound was prepared according to the method of Example 115, replacing 4-methoxybenzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride with cyclohexylcarbonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 510.4 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.83-7.80 (m, 2H), 7.27-7.20 (m, 2H), 6.92 (d, 1H), 6.95 (d, 1H), 2.50 (t, 1H), 1.90-1.20 (m, 15H), 0.94 (t, 6H). Second eluting diastereomer: MS 510.2 (M + H ^& lt ^{; +} & gt ^; ).
[1926] Example 216
[1927] Preparation of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (methanesulfonyl) -3-oxo-azepan-
[1928] The title compound was prepared according to the method of Example 115, but replacing the 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 7.37-7.24 (m, 4H), 6.93-6.91 (m, 2H), 5.02-5.00 (m, 1H), 2.88 (s, 3H), 2.70 (t, 1H ), 0.92 (t, 6H). Second eluting diastereomer: MS 468.2 (M + H ^& lt ^{; +} & gt ^; ).
[1929] Example 217
[1930] Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl- Produce
[1931] The title compound was prepared according to the method of Example 115, but replacing the 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with benzo [b] thiophenecarbonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 480.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ7.83-7.78 (m, 3H), 7.42-7.37 (m, 2H), 6.94 (d, 1H), 6.75 (d, 1H), 2.89 (s, 3H) , 2.68 (t, 1 H), 0.97 (d, 6 H). Second eluting diastereomer: MS 480.2 (M + H ^& lt ^{; +} & gt ^; ).
[1932] Example 218
[1933] Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) Preparation of amide
[1934] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with piperonylcarbonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 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 ^& lt ^{; +} & gt ^; ).
[1935] Example 219
[1936] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl- butyl] -amide
[1937] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with 2-benzofuranecarbonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 464.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 7.64 (d, 1H), 7.51-7.37 (m, 3H), 7.29-7.28 (m, 1H), 2.89 (s, 3H), 2.67 (t, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 464.2 (M + H ^& lt ^{; +} & gt ^; ).
[1938] Example 220
[1939] Preparation of N - [(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-butyl] -3,4-dimethoxy-benzamide
[1940] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with 3,4-dimethoxybenzoyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 484.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 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 ^& lt ^{; +} & gt ^; ).
[1941] Example 221
[1942] Preparation of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-
[1943] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 8.10 (d, 1H), 7.86 (d, 1H), 7.76-7.70 (m, 2H), 7.35-7.31 (m, 5H), 6.93 (d, 2H), 4.61-4.47 (m, 4H), 2.77 (t, 1H), 0.92 (t, 6H). Second eluting diastereomer: MS 555.2 (M + H ^& lt ^{; +} & gt ^; ).
[1944] Example 222
[1945] N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl} -4- methanesulfonyl -1-benzamide
[1946] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride with 4-methanesulfonylbenzoyl chloride. Respectively. The residue was purified by HPLC. First eluting diastereomer: MS 589.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 8.10 (d, 1H), 7.96 (s, 4H), 7.88 (d, 1H), 7.78-7.71 (m, 2H), 3.05 (s, 3H), 2.79 ( t, 1 H), 0.97 (t, 6 H). Second eluting diastereomer: MS 589.2 (M + H ^& lt ^{; +} & gt ^; ).
[1947] Example 223
[1948] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-cyano- benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide &lt; / RTI &gt;
[1949] The title compound was prepared following the method of Example 115 substituting 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride with benzo [b] thiophene-2-carbonyl chloride The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 567.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ8.10 (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 ^& lt ^{; +} & gt ^; ).
[1950] Example 224
[1951] Benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (2- cyano- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide &lt; / RTI &gt;
[1952] The title compound was prepared following the procedure of Example 115, replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride with piperonyloyl chloride. . The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ8.11 (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, 1 H), 0.97 (d, 6 H). Second eluting diastereomer: MS 555.4 (M + H ^& lt ^{; +} & gt ^; ).
[1953] Example 225
[1954] (S) -4-Methyl-2- [4-oxo-4- (4-phenoxy-phenyl) - butyrylamino] -pentanoic acid [3-oxo-1 - (pyridin-2-sulfonyl) azetidine Yl] -amide &lt; / RTI &gt;
[1955] The title compound was prepared according to the procedure of Example 75, substituting tyrosol-2-sulfonyl chloride with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid with 4-phenoxyphenyl-carboxylic acid The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 635.4 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} ): δ 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, IH), 4.77-4.72 (d, IH), 4.46 (m, IH), 4.13-4.09 (m, IH), 3.85-3.80 2.70 - 2.64 (m, 3H), 2.20 - 1.40 (m, 6H); And second eluting diastereomer: 0.96-0.92 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 635.4.
[1956] Example 226
[1957] N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Lt; RTI ID = 0.0 &gt;
[1958] Following the procedure of Example 115, except substituting 4-methoxybenzenesulfonyl chloride for 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride for 3,4-dimethoxybenzoyl chloride, the title compound was prepared . The residue was purified by HPLC. First eluting diastereomer: MS 571.4 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 8.10 (d, 1H), 7.87 (d, 1H), 7.76-7.70 (m, 2H), 6.98 (s, 2H), 6.89 (s, 2H), 3.79 ( s, 6H), 2.76 (t, IH), 0.96 (d, 6H). Second eluting diastereomer: MS 571.4 (M + H ^& lt ^{; +} & gt ^; ).
[1959] Example 227
[1960] Preparation of cyclohexanecarboxylic acid {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Produce
[1961] The title compound was prepared according to the method of Example 115, but replacing benzyloxyacetyl chloride with cyclohexylcarbonyl chloride. The residue was purified by HPLC. First eluting diastereomer: MS 522.4 (M + H ^& lt ^{; +} & gt ^; ). ¹ H NMR (500 MHz, CDCl ₃ ): 7.70 (d, 2H), 6.97 (d, 2H), 2.40 (t, 1H), 1.90-1.20 (m, 16H), 0.92 Second eluting diastereomer: MS 522.4 (M + H ^& lt ^{; +} & gt ^; ).
[1962] Example 228
[1963] Preparation of 4-methanesulfonyl-N - [(S) -1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Produce
[1964] The title compound was prepared according to the method of Example 115, but replacing benzyloxyacetyl chloride with 4-methanesulfonylbenzoyl chloride. The residue was purified by HPLC. First eluting diastereoisomer: MS 594.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 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, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 594.2 (M + H ^& lt ^{; +} & gt ^; ).
[1965] Example 229
[1966] Preparation of 4-methanesulfonyl-N - [(S) -1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Produce
[1967] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzyloxyacetyl chloride with 4-methanesulfonylbenzoyl chloride. Respectively. The residue was purified by HPLC. First eluting diastereomer: MS 582.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (500MHz, CDCl 3}} ): δ 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 ^& lt ^{; +} & gt ^; ).
[1968] Example 230
[1969] Preparation of {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl} -carbamic acid benzyl ester
[1970] The title compound was prepared according to the method of Example 75, substituting benzenesulfonyl chloride with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid with N-carbobenzyloxycarbonyl-glycine. . The residue was purified by HPLC. First eluting diastereomer: MS 574.2 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.60 (d, 1H), 7.97-7.90 (m, 2H), 7.50 (m, 1H), 7.42-7.25 (m, 5H), 6.90 (m, 1H), 1H), 4.42 (m, 1H), 5.38 (m, 1H), 5.18-5.10 (m, 4H), 4.78-4.72 3.85 (m, 2H), 2.72 (m, 1H), 2.25-2.10 (m, 2H), 1.90-1.40 (m, 5H), 0.92 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 574.2.
[1971] Example 231
[1972] (S) -2- [5- (4-Methoxy-phenyl) -pentanoylamino] -4-methyl-pentanoic acid [ Lt; RTI ID = 0.0 &gt;
[1973] Following the procedure of Example 75, except substituting benzofuran-2-carboxylic acid for 5- (4-methoxyphenyl) -pentanoic acid with 2-pyridylsulfonyl chloride for benzenesulfonyl chloride, the title Lt; / RTI &gt; The residue was purified by HPLC. First eluting diastereoisomer: MS 573.4 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.59 (d, 1H), 7.97-7.94 (m, 2H), 7.53 (m, 1H), 7.09-7.07 (d, 2H), 6.89-6.81 (m, 3H ), 5.90 (m, IH), 5.12 (m, IH), 4.79-4.74 (d, IH), 4.48 s, 3H), 2.69 (m, 1H), 2.59-2.57 (m, 2H), 2.23-2.10 (m, 3H), 1.75-1.45 (m, 10H), 0.96-0.95 (m, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 573.4.
[1974] Example 232
[1975] (S) -2- [2- (3-benzyloxy-4-methoxy-phenyl) -acetylamino] -4- methylpentanoic acid [ Yl] -amide &lt; / RTI &gt;
[1976] The title compound was prepared following the method of Example 75, substituting benzenesulfonyl chloride with 2-pyridylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with (3-benzyloxy-4-methoxy-phenyl) , The title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 637.4 (M + H ^& lt ^{; +} & gt ^; ). _{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.69 (d, 1H), 7.98-7.91 (m, 2H), 7.53-7.30 (m, 6H); And the second eluting diastereomer was 6.89-6.82 (m, 4H), 5.82 (m, 1H), 5.14-5.07 (m, 3H), 4.78-4.73 (m, 1H), 3.89 (s, 3H), 3.82 (d, IH), 3.49 (s, 2H), 2.69 0.89 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 637.4.
[1977] Example 233
[1978] 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1979] a) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-hydroxy- Ylcarbamoyl] -butyl} amide &lt; / RTI &gt;
[1980] The title compound was obtained according to the method of example 28b, except substituting 5,6-difluorobenzofuran-2-carboxylic acid for MS (M + H ^& lt ^{; +} & gt ^; ): 564.
[1981] b) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[1982] The title compound was obtained according to the procedure for example 1i, but substituting the compound of example 233a. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 562; And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 562.
[1983] Example 234
[1984] Preparation of (S) -4-methyl-2- (5-oxo-hexanoylamino) -pentanoic acid 3-oxo-1- (pyridine-2- sulfonyl) -azepan-4-yl]
[1985] The title compound was prepared according to the method of Example 115, but replacing 4-methoxybenzenesulfonyl chloride with 2-pyridine sulfonyl chloride and benzyloxyacetyl chloride with 5-oxo-hexanoyl chloride. The residue was purified by HPLC. A first eluting diastereomer; MS 495.4 (M + H &lt; ⁺ & gt ^; ); Second eluting diastereomer: MS 495.4 (M + H ^& lt ^{; +} & gt ^; ).
[1986] Example 235
[1987] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine- 2- sulfonyl) -3-oxo-azepan- Butyl} -amide &lt; / RTI &gt;
[1988] a) 6-Methyl-pyridine-2-sulfonyl chloride
[1989] The title compound was prepared in a manner analogous to that described in Example 85a for the preparation of 2-pyridine sulfonyl chloride-N-oxide.
[1990] b) {(S) -1- [3-Hydroxy-1- (6-methyl- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl- butyl} tert -butyl ester
[1991] [(S) -1- (3- hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] - of the embodiments in dichloromethane to 20 ml solution of Example 2g-butyl ester 1.0 g - carbamic acid tert Was added 50 ml of saturated sodium bicarbonate. To this solution was added 6.44 ml of 6-methyl-pyridine-2-sulfonyl chloride (0.13 g / ml solution in 9M HCl). The reaction was stirred until the reaction was complete. Work-up and column chromatography (5% methanol: dichloromethane) gave 1.2 g of the title compound.
[1992] c) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-
[1993] To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine- -Amide in 20 ml of tetrahydrofuran was added 20 ml of 4M HCl in dioxane. The reaction was stirred until the reaction was complete, which was then concentrated to give 1 g of the title compound.
[1994] d) Benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-hydroxy-azepan- Yl] -butyl} -amide
[1995] (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-l- (6-methyl- pyridine- 2- sulfonyl) -azepan-4-yl] The title compound was prepared according to the procedure of example 28b: MS (EI) 542 (M &lt; ^{+ &} gt ^; ).
[1996] e) Benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl ] -Butyl} -amide
[1997] Example 235d was prepared from benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-hydroxy-azepan- Carbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H), 1.5-2.2 1H, 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 (EI); 540 (M ^&lt; ⁺ & gt ^; , 100%).
[1998] Example 236
[1999] 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Gt; &lt; RTI ID = 0.0 &gt; [baramoyl] -butyl} -amide
[2000] a) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-hydroxy-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2001] Carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid was prepared in analogy to example 28b starting from (S) -2-amino-4-methyl-pentanoic acid 3-hydroxy- 2-sulfonyl) -azepan-4-yl] -amide was prepared in analogy to Example 235c from (S) -2-amino-4-methyl-pentanoic acid 3-hydroxy- -2-sulfonyl) -azepan-4-yl] -amide, the title compound was prepared according to the method of example 28b: MS (EI) 572 (M ⁺ ).
[2002] b) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2003] The title compound was prepared analogously to Example 236a from 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2 -sulfonyl) 4-ylcarbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H) 1H), 4.7 (m, 2H), 5.3 (m, 1H), 2.5 (m, 2H) , 7.4-8.0 (m, 7H); MS (EI): 570 (M ^&lt; ⁺ & gt ^; , 100%).
[2004] Example 237
[2005] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Yl] -butyl} -amide &lt; / RTI &gt;
[2006] a) Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-hydroxy- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2007] The title compound was prepared according to the method of Example 236a, but replacing 5-methoxybenzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid: MS (EI) 556 (M ⁺ ).
[2008] b) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[2009] The title compound was prepared analogously to example 237a from 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6-methyl- 4- ylcarbamoyl] -butyl} - according to those conducted in the method of example 1i, but replacing -amide the title compound was _{^{prepared: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5 1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.3 (m, 1H) 7.4-8.0 (m, 6H); MS (EI): 564 (M ^&lt; ⁺ & gt ^; , 100%).
[2010] Example 238
[2011] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] - Butyl} -amide &lt; / RTI &gt;
[2012] a) 7-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-hydroxy-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2013] The title compound was prepared according to the procedure of example 28b, except substituting 7-methoxybenzofuran-2-carboxylic acid for MS (EI) 559 (M ⁺ ).
[2014] b) 7-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2015] The title compound was prepared from 7-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6-methyl-pyridine- 2- -4-ylcarbamoyl] -butyl} -amide in accordance with the general method of example 1i: MS (EI) 557 (M + H <^+> ).
[2016] Example 239
[2017] 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan- -Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2018] a) 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- Hydroxy-azepan-4-ylcarbamoyl] -butyl} -amide
[2019] The title compound was prepared according to the procedure of example 28b, except substituting 5,6-dimethoxy-benzo [b] thiophene-2-carboxylic acid for MS: MS (EI) 604 (M &lt; ^{+ &} gt ^; ).
[2020] b) 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- Oxo-azepan-4-ylcarbamoyl] -butyl} -amide
[2021] Example 239a 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- The title compound, MS (EI) 602.9 (M + H), was prepared in accordance with the general method of example 1i, except substituting 3-hydroxy-azepan-4-ylcarbamoyll- ⁺ ).
[2022] Example 240
[2023] (R) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -3-methyl- -Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2024] Thiazole-2-sulfonyl chloride with 2-pyridylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with (R) -1-benzyl-5- oxo-pyrrolidine- &Lt; / RTI &gt; The title compound, The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 584.4; _{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.69 (d, 1H), 7.99-7.92 (m, 2H), 7.52 (m, 1H), 7.32-7.22 (m, 5H), 6.92 (d, 1H), 1H), 6.38 (d, 1H), 5.15-5.08 (m, 2H), 4.80-4.75 (d, 1H), 4.47-4.44 ), 2.75-2.63 (m, 2H), 2.46-1.44 (m, 10H), 0.95 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 584.4.
[2025] Example 241
[2026] (S) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2027] Benzenesulfonyl chloride with 2-pyridylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with (S) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid , The titled compound was prepared according to the method of Example 75. The residue was purified by HPLC. First eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ): 584.4; _{^{1 H NMR (400MHz, CDCl 3}} ): δ8.69 (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, IH), 5.22-5.18 (d, IH), 5.10 (m, IH), 4.80-4.75 (d, IH), 4.51 -3.79 (m, 3H), 2.71 - 1.38 (m, 12H), 0.97 (d, 6H); And second eluting diastereomer: MS (M + H ^& lt ^{; +} & gt ^; ) 584.4.
[2028] Example 242
[2029] Benzofuran-2-carboxylic acid {(S) -2-cyclopropyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Preparation of amide
[2030] The title compound was obtained following the procedure of Example 193e-h, but replacing N-Boc-cyclopropylalanine in step 193e and purification yielded two diastereomers as solids (first elution: 8 mg, second elution: 8 mg): MS (ESI): 525 (M + H ^& lt ^{; +} & gt ^; ).
[2031] Example 243
[2032] Benzofuran-2-carboxylic acid {(S) -3-methylsulfanyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl) - Preparation of amide
[2033] Following the procedure of Example 193e-g but substituting N-Boc-L-methionine in step 193e. Oxidation of 193 g of Example 19 was carried out by adding 34 mg (0.211 mmol) of sulfur trioxide-pyridine complex and 0.077 ml of triethylamine to the alcohol intermediate in 0.200 ml of DMSO solvent. After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, concentrated and purified by HPLC to give two diastereomers of the title compound as a solid (first elution: 8 mg, second elution: 5 mg): MS (ESI): 545 (M + H & lt ^; + & gt ^; ).
[2034] Example 244
[2035] Benzofuran-2-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Ethyl} -amide &lt; / RTI &gt;
[2036] The title compound was obtained following the procedure of Example 193e-h but replacing N- (t-butoxycarbonyl) -3- (2-naphthyl) -L-alanine in step 193e to give the title compound (ESI): 610.8 (M + H) &lt; ⁺ & gt ^; .
[2037] Example 245
[2038] Thieno [2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2039] a) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- - azepan-4-ylcarbamoyl] -butyl} -amide
[2040] The title compound was prepared according to the method of Example 236a, but replacing the 5-methoxybenzofuran-2-carboxylic acid with thieno [3,2-b] thiophene-2-carboxylic acid : MS (EI) 564 (M &lt; ^{+ &} gt ^; ).
[2041] b) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- Azepan-4-ylcarbamoyl] -butyl} -amide
[2042] The title compound was prepared in analogy to example 245a from thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- hydroxy-azepan-4-ylcarbamoyl] -butyl} - the title compound was prepared in accordance with those conducted in the method of example 1i, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 ( 1H), 4.7 (m, 2H), 5.3 (m, 2H), 2.5 (m, (m, 1 H), 7.4-8.0 (m, 6 H); MS (EI): 562 (M ^&lt; ⁺ & gt ^; , 100%).
[2043] Example 246
[2044] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2045] a) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-
[2046] The title compound was prepared following the procedure of Example 235b-c but replacing 6-methyl-pyridine-2-sulfonyl chloride with 3-methyl-pyridine-2-sulfonyl chloride: MS (EI) 399 (M ^&lt; ^{+ &} gt ^; ).
[2047] b) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- - azepan-4-ylcarbamoyl] -butyl} -amide
[2048] To a solution of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (3-methyl- Amide, 0.10 g of thieno [3,2-b] thiophene, 0.12 ml of triethylamine, 0.085 g of HOBt and 0.12 g of EDC were added. The reaction was stirred until the reaction was complete. Workup and column chromatography (5% methanol: dichloromethane) gave 0.18 g of the title compound: MS (EI): 564 (M ⁺ ).
[2049] c) Preparation of thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Azepan-4-ylcarbamoyl] -butyl} -amide
[2050] The title compound was prepared in analogy to example 245a from thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [ hydroxy-azepan-4-ylcarbamoyl] -butyl} - the title compound was prepared in accordance with those conducted in the method of example 1i, but replacing _{^{amide: 1 H NMR (CDCl 3)}} : δ 1.0 ( 3H), 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, 2H) (m, 1 H), 7.4-8.0 (m, 5 H), 8.4 (m, 1 H); MS (EI): 562 (M ^&lt; ⁺ & gt ^; , 100%).
[2051] Example 247
[2052] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Yl] -butyl} -amide &lt; / RTI &gt;
[2053] a) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-hydroxy- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2054] The title compound was prepared according to the method of Example 246c, except substituting 3-methylbenzofuran-2-carboxylic acid for thieno [3,2-b] thiophene: MS (EI) 556 M ⁺ ).
[2055] b) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide &lt; / RTI &gt;
[2056] Example 247a 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-hydroxy- 4- ylcarbamoyl] -butyl} - according to those conducted in the method of example 1i, but replacing -amide the title compound was _{^{prepared: 1 H NMR (CDCl 3)}} : δ 1.0 (m, 6H), 1.5 2H), 4.7 (m, 2H), 5.3 (m, 1H), 2.6 (m, 3H) 7.4-8.0 (m, 6H), 8.4 (m, 1H); MS (EI): 554 (M ^&lt; ⁺ & gt ^; , 100%).
[2057] Example 248
[2058] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Gt; &lt; RTI ID = 0.0 &gt; [baramoyl] -butyl} -amide
[2059] a) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-hydroxy-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2060] The title compound was prepared according to the method of example 246c, except substituting 5-methoxybenzofuran-2-carboxylic acid for MS (EI) 572 (M ⁺ ).
[2061] b) 5-Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2062] The title compound was prepared from 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-hydroxy- 4-ylcarbamoyl] -butyl} -amide in accordance with the general method of example 1i: ¹ H NMR (CDCl ₃ ): 1.0 (m, 6H) 2H), 4.7 (m, 2H), 5.3 (m, 1H), 3.5 (m, 2H) , 7.4-8.0 (m, 6H), 8.4 (m, 1 H); MS (EI): 570 (M ^&lt; ⁺ & gt ^; , 100%).
[2063] Example 249
[2064] 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- 4-ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2065] a) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (1-oxy- Azepan-4-ylcarbamoyl] -butyl} -amide
[2066] Benzo [b] thiophene-2-carboxylic acid was replaced by 5,6-difluorobenzofuran-2-carboxylic acid, the title compound was prepared according to the method of example 85c: MS (ESI) 580.9 (M + H ^& lt ^{; +} & gt ^; ).
[2067] b) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ Yl-carbamoyl] -butyl} -amide
[2068] The title compound was prepared according to the method of example 1i, except substituting the compound of example 249a: MS (ESI): 578.87 (M + H <^+> ).
[2069] Example 250
[2070] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [ Ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2071] a) 4 - ((S) -2- tert -Butoxycarbonylamino-3-cyclohexyl-propionylamino) -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[2072] 3.3 g of N-Boc-cyclohexylalanine, 1.8 g of HOBt and 2.56 g of EDC were added to a solution of 3.2 g (12.2 mmol) of the compound of Example 2e in 35 ml of DMF. The reaction was stirred until the reaction was complete. The residue was purified by work-up and column chromatography (65% hexane: ethyl acetate) to give 5.5 g of the title compound.
[2073] b) [(S) - cyclohexyl-1- (3-hydroxy-azepan-4-ylcarbamoyl) -ethyl] -carbamic acid tert-butyl ester
[2074] To a solution of 5.5 g of the compound of Example 250a in 40 ml of ethyl acetate: methanol 185 ml 10% Pd / C was added. The mixture was stirred under hydrogen atmosphere until complete consumption of the starting material was observed. The reaction was filtered and concentrated to give 3.75 g of the title compound.
[2075] c) {(S) -2-cyclohexyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -ethyl} -carbamic acid tert-butyl ester
[2076] To a solution of 1.0 g (1.91 mmol) of the compound from example 250b in 5 ml dichloromethane was added 10 ml water and 1 g sodium bicarbonate. To this mixture was added 2-pyridine sulfonyl chloride (0.55 g in 5 ml of dichloromethane) dropwise. After stirring the mixture for 20 minutes, the organic layer was separated, washed with water and brine, dried, filtered and concentrated. The residue was subjected to column chromatography (2% methanol: dichloromethane) to obtain 1.0 g of the title compound: MS (ESI): 525 (M + H ⁺ ).
[2077] d) (S) -2-Amino-3-cyclohexyl-N- [3-hydroxy- (pyridine- 2- sulfonyl) -azepan-4-yl] -propionamide
[2078] To a solution of 1.0 g of the compound of Example 250c in 10 ml of methanol was added 10 ml of HCl (4M HCl in dioxane). The reaction was stirred until the starting material was completely consumed and then it was concentrated. The residue was azeotroped with toluene and then washed with ether to give 0.95 g of the title compound.
[2079] e) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-hydroxy- - azepan-4-ylcarbamoyl] -ethyl} -amide
[2080] To a solution of 0.20 g (0.4 mmol) of the compound from Example 250d in 0.5 ml of DMF was added 0.16 ml of diisopropylethylamine, 0.06 g of HOBt, 0.084 g of EDC and 0.50 g of 5- [3- (trifluoromethyl) phenyl] -2- 0.10 g of furoic acid was added. The reaction was stirred until the starting material was completely consumed. Workup and column chromatography (4% methanol: dichloromethane) gave 0.23 g of the title compound.
[2081] f) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [ Azepan-4-ylcarbamoyl] -ethyl} -amide
[2082] The title compound was prepared according to the method of Example 75d but substituting the compound of Example 250e. The diastereomers were separated by HPLC to give 52 mg (MS (ESI) 661.4) of the first eluting diastereomer and 45.8 mg (MS (ESI) 661.6) of the second diastereomer.
[2083] Example 251
[2084] (S) -2-Cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan- Ylcarbamoyl] -ethyl} -amide &lt; / RTI &gt;
[2085] Example 250e-f was prepared in analogy to example 250e-f except for replacing 5- [3- (trifluoromethyl) phenyl] -2-furoic acid with 5- (4-chlorophenyl) The title compound was prepared. The diastereoisomers were separated by HPLC to give 57 mg (MS (ESI): 627.4) of the first eluting diastereomer and 53 mg (MS (ESI): 627.4) of the second eluting diastereomer.
[2086] Example 252
[2087] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [6-methyl-3-oxo-1- (pyridine- 2- sulfonyl) Butyl} -amide &lt; / RTI &gt;
[2088] The title compound was prepared following the procedure of Example 92, except replacing 2,2-dimethyl-4-pentenal with 2-methyl-4-pentenal. The residue was purified by HPLC. A first eluting diastereomer; MS (M + H & lt ^; + & gt ^; ): 541.2; _{^{1 H NMR (400MHz, CDCl 3}} ): δ 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, -1.55 (m, 3H), 1.22-1.19 (m, 3H), 1.00-0.86 (m, 9H).
[2089] Example 253
[2090] Furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy- Yl-carbamoyl] -ethyl} -amide &lt; / RTI &gt;
[2091] 5- (3- (trifluoromethyl) phenyl] -2-furoic acid from Example 252e was reacted with 5- (4-tert-butoxycarbonylamino) Chloro-phenyl) -2-furoic acid, the title compound was prepared according to the method of Example 250c-f. The diastereomers were separated by HPLC to give the first eluting diastereomer (MS (ESI) 643.4) and the second eluting diastereoisomer (MS (ESI) 643.2).
[2092] Example 254
[2093] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-oxo-1- (1-oxy- ) -Azepan-4-ylcarbamoyl] -ethyl} -amide
[2094] The title compound was prepared following the procedure of Example 250c-f, but replacing the 2-pyridine sulfonyl chloride of Example 250c with 2-pyridine sulfonyl chloride N-oxide. The diastereomers were separated by HPLC to give the first eluting diastereomer (MS (ESI) 677.2) and the second eluting diastereomer (MS (ESI) 677.4).
[2095] Example 255
[2096] Preparation of 5-fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -Butyl} -amide &lt; / RTI &gt;
[2097] a) 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
[2098] The title compound was prepared according to the method of example 28b, except substituting 5-fluorobenzofuran-2-carboxylic acid for 5-fluorobenzofuran-2-carboxylic acid: MS (ESI) 547 (M + H ⁺ ).
[2099] b) 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ Yl] -butyl} -amide
[2100] The title compound was prepared according to the method of example 1i, except substituting the compound of Example 255a: MS (ESI) 544.9 (M + H ^& lt ^{; +} & gt ^; ).
[2101] Example 256
[2102] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -Ylcarbamoyl] -ethyl} -amide &lt; / RTI &gt;
[2103] Pyridine Sulfonyl chloride of Example 250c was reacted with 2-pyridine sulfonyl chloride N-oxide and 5- [3- (trifluoromethyl) phenyl] -2-furo [ The title compound was prepared according to the method of Example 250c-f, except substituting dimethoxybenzofuran-2-carboxylic acid. The diastereomers were separated by HPLC to give the first eluting diastereomer (MS (ESI) 643.4) and the second eluting diastereoisomer (MS (ESI) 643.2).
[2104] Example 257
[2105] [(S) -3-methyl-l- [3-oxo-l- (pyridine- 2- sulfonyl) -azepan- 4-ylcarbamoyl] -butyl} -amide &lt; / RTI &gt;
[2106] The replacement of thiazole-2-sulfonyl chloride with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid with 5,5-bis- (4-methoxy-phenyl) -pent- The title compound was prepared according to the procedure of Example 75. The residue was purified by HPLC. A first eluting diastereomer; MS (M + H & lt ^; + & gt ^; ): 677.4; _{^{1 H NMR (400MHz, CDCl 3}} ): δ 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, IH), 4.76-4.72 (d, IH), 4.48 (m, IH), 4.08 1.35 (m, 12 H), 0.91 (d, 6 H); And a second eluting diastereomer; MS (M + H & lt ^; + & gt ^; ): 677.4.
[2107] Example 258
[2108] -Quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo-1- (pyridine- Ethyl} -amide &lt; / RTI &gt;
[2109] a) 4-Amino-1- (pyridine-2-sulfonyl) -azepan-3-ol
[2110] To a solution of 1.5 g of the compound of Example 193c in 10 ml of methanol was added 10 ml of HCl (4M HCl in dioxane). The reaction was stirred by TLC analysis until the reaction was complete and then concentrated to give 1.2 g of the title compound as a white solid.
[2111] b) Synthesis of {(S) -1- [3-hydroxy-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -2-naphthylen- Tert -butyl ester
[2112] 0.15 ml of TEA, 99 mg of HOBt, 140 mg of EDC and 230 mg of N-Boc-L-2-naphthylalanine were added to a solution of 225 mg of the compound of Example 258a in dichloromethane. The reaction was stirred until the reaction was complete. The residue was purified by work-up and column chromatography (3% methanol: dichloromethane) to give 0.35 g of the title compound: MS (ESI): 569 (M + H ⁺ ).
[2113] c) Preparation of (S) -2-amino-N- [3-hydroxy-1- (pyridine- 2- sulfonyl) -azepan-4-yl] -3-naphthylen-
[2114] To a solution of 0.35 g of the compound of example 258b in 5 ml of methanol was added 5 ml of HCl (4M HCl in dioxane). The reaction was stirred by TLC analysis until the reaction was complete and then concentrated to give 0.31 g of the title compound as a white solid.
[2115] d) quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl- 1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan- Yl] -ethyl} -amide
[2116] To 131 mg of the compound of Example 258c in dichloromethane was added 39 mg of TEA, HOBt, 55 mg of EDC and 51 mg of quinoline-8-carboxylic acid. The reaction was stirred until the reaction was complete. The residue was purified by work-up and column chromatography (5% methanol: dichloromethane) to give 0.35 g of the title compound: MS (ESI): 574 (M + H ⁺ ).
[2117] e) Quinoline-8-carboxylic acid {(S) -2-naphthylen-2-yl-l- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan- ] -Ethyl} -amide
[2118] The title compound was prepared according to the method of example 1i, except substituting the compound of example 258d.
[2119] Example 259
[2120] Naphthylene-1-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -Ethyl} -amide &lt; / RTI &gt;
[2121] The title compound was prepared according to the method of Example 258d-e but replacing the quinoline-8-carboxylic acid with 1-naphthoic acid.
[2122] Example 260
[2123] 2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide as a light brown solid; Produce
[2124] The title compound was prepared according to the method of Example 258a-e but replacing N-Boc-L-2-naphthylalanine with N-Boc-phenylalanine.
[2125] Example 261
[2126] Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Manufacturing
[2127] Carboxylic acid was replaced by 1,6-naphthyridine-2-carboxylic acid, the title compound was prepared according to the procedure of Example 28b-c.
[2128] Example 262
[2129] 1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl- ethyl} Manufacturing
[2130] The title compound was prepared according to the method of Example 260, but replacing the quinoline-8-carboxylic acid with 1-naphthoic acid.
[2131] Example 263
[2132] 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl -propionyl) -azepan - 4-ylcarbamoyl] } -Amide &lt; / RTI &gt;
[2133] a) Preparation of 4 - {(S) -2 - [(3-methylbenzofuran-2-carbonyl) -amino] -4-methyl- pentanoylamino} -3- hydroxy- azepane- Benzyl ester
[2134] To a solution of 1.2 g (2.67 mmol) of the compound of example 72a, 0.56 g of EDC, 0.36 g of HOBt, 0.67 g of TEA and 0.47 g of 3-methylbenzofuran-2-carboxylic acid were added. The reaction was stirred until complete consumption of the starting material was observed. Workup and column chromatography (4: 1 hexanes: ethyl acetate) gave 1.05 g of the title compound: MS (ESI): 536 (M + H ^& lt ^{; +} & gt ^; ).
[2135] b) 3-Methylbenzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azepan-4- ylcarbamoyl) -3-methyl-
[2136] The title compound was prepared according to the procedure of Example 2g, except substituting the compound of Example 263a: MS (ESI): 402 (M + H ^& lt ^{; +} & gt ^; ).
[2137] c) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (cyclohexyl- propionyl) -azepan-4- ylcarbamoyl] -Butyl} -amide
[2138] The title compound was prepared according to the method of Example 263a, but replacing 3-methylbenzofuran-2-carboxylic acid with the compound of Example 263b and 3-cyclopropionic acid: MS (ESI): 540 ( M + H & lt ^; + & gt ^; ).
[2139] d) Preparation of 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] Butyl} -amide
[2140] The title compound was prepared according to the method of example 1i, except substituting the compound of Example 263c: MS (ESI): 538 (M + H ^& lt ^{; +} & gt ^; ).
[2141] Example 264
[2142] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (4-methyl-pentanoyl) -azepan-4- ylcarbamoyl] } -Amide &lt; / RTI &gt;
[2143] The title compound was prepared following the method of Example 263c-d but replacing 3-cyclohexylpropionic acid with 4-methylpentanoic acid: MS (ESI): 498 (M + H <^+> ).
[2144] Example 265
[2145] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- carbonyl) -azepan- Yl] -butyl} -amide &lt; / RTI &gt;
[2146] The title compound was prepared according to the procedure of Example 263c-d but replacing 3-cyclohexylpropionic acid with picolinic acid N-oxide: MS (ESI): 498 (M + H <^+> ).
[2147] Example 266
[2148] (S) -acetylamino-4-methyl-pentanoic acid [3-oxo-1- (pyridine-2- sulfonyl) -azepan-4-yl]
[2149] The title compound was prepared following the procedure of Example 75c-d but replacing benzofuran-2-carboxylic acid with acetic acid in step 75c and separated by HPLC to give the first eluting diastereomer (MS ( ^{m + H +) 425.2; 1} H NMR (400Hz, CDCl 3): δ 8.69 (d, 1H), 7.96-7.94 (m, 2H), 7.53-7.52 (m, 1H), 7.05 (m, 1H), (M, 2H), 1.64 (m, 2H), 5.92 (m, s, 3H), 1.90-1.40 (m, 5H), 0.95 (m, 6H) and second eluting diastereomer (MS (M + H ⁺ ) 425.2).
[2150] Example 267
[2151] Preparation of (S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide
[2152] a) 4- ((S) -2- tert -Butoxycarbonylamino-hexanoylamino) -3-hydroxy-azepane-1 -carboxylic acid benzyl ester
[2153] 175 mg (0.76 mmol) of N-Boc-norleucine, 145 mg (0.76 mmol) of EDC-HCl, and 1-hydroxy-2-pyrrolidinone were added to a stirred solution of 200 mg (0.74 mmol) of the compound of amino alcohol of Example 2e in 4 ml of DMF Benzotriazole 21 mg (0.16 mmol). The reaction was allowed to proceed overnight at room temperature. The next morning, the mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ , H ₂ O, and brine. MgSO ₄ dried, filtered, and purified by column chromatography to obtain 300 mg title compound: MS (ESI): 478.11 ( M + H +).
[2154] b) [(S) -1- ( 3- hydroxy-azepan-4-ylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester
[2155] To a solution of 300 mg (0.63 mmol) of the compound of example 267a in 5 ml of ethyl acetate was added 160 mg of 10% palladium on carbon and H ₂ from the filled apparatus. After the solution was stirred at room temperature for 48 hours, the mixture was filtered through celite. The filtrate was concentrated to afford 161 mg (0.47 mmol) of the title compound: MS (ESI): 344.19 (M + H <^+> ).
[2156] c) {(S) -1- [ 3- hydroxy-1 (pyridine-2-sulfonyl) azepan-4-ylcarbamoyl] -pentyl} -carbamic acid tert-butyl ester
[2157] 0.065 ml (0.47 mmol) of triethylamine and 83 mg (0.47 mmol) of pyridine-2-sulfonyl chloride were added to a solution of 161 mg (0.47 mmol) of the compound of Example 267b in 6 ml of dichloromethane. After stirring at room temperature for 1 hour, the mixture was washed with saturated NaHCO _3. The organic layer was dried, filtered, concentrated and purified on a silica gel column to give 142 mg (0.29 mmol) of the title compound: MS (ESI): 485.10 (M + H) <^+> .
[2158] d) (S) -2-Amino-hexanoic acid [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-
[2159] To a stirred solution of 142 mg (0.29 mmol) of the compound of example 267c in ethyl acetate was added 0.760 ml (3.0 mmol) of HCl (4M in dioxane). After the reaction mixture was stirred at room temperature for 1 hour, the mixture was concentrated to obtain a white solid. The solid was azeotroped twice with toluene on a rotavap, then treated with 1.47 mmol of resin-bound carbonate in methanol and placed on a shaker. After 4 hours the suspension was filtered and concentrated to give 104 mg of crude product: MS (ESI): 385.08 (M + H) &lt; ⁺ & gt ^; .
[2160] e) Quinoline-2-carboxylic acid {(S) -1- [3-hydroxy- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -pentyl} -amide
[2161] To a solution of 104 mg (0.27 mmol) of the compound of example 267d in CH ₂ Cl ₂ were added quinolidic acid 47 mg (0.27 mmol), 1-hydroxybenzotriazole 7.4 mg (0.55 mmol) and EDC-HCl 52 mg (0.27 mmol). After overnight stirring at room temperature, the mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ , H ₂ O, dried over MgSO ₄ and filtered to give 172 mg of crude product: MS (ESI): 539.90 (M + H) ⁺ .
[2162] f) Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2- carbonyl) -azepan-4-ylcarbamoyl] -pentyl}
[2163] 260 mg (1.6 mmol) of sulfur trioxide-pyridine complex and 0.88 ml (3.2 mmol) of triethylamine were added to a stirred solution of the crude compound of Example 267e (172 mg, 0.32 mmol) in 1 ml DMSO. After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, concentrated and purified by HPLC to give the diastereomer of the title compound as a solid (first elution: 40 mg, second elution: 43 mg): MS (ESI): 537.86 + H) ⁺ .
[2164] Example 268
[2165] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] -butyl} Produce
[2166] The title compound was prepared according to the method of Example 263a-d but replacing the 3-methylbenzofuran-2-carboxylic acid of Example 263a with benzofuran-2-carboxylic acid: MS (ESI ): 524 (M + H ^& lt ^{; +} & gt ^; ).
[2167] Example 269
[2168] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (4-methyl-pentanoyl) -azepan-4-ylcarbamoyl] -butyl} Manufacturing
[2169] Example 263a-d, except substituting 3-methylbenzofuran-2-carboxylic acid for benzo furan-2-carboxylic acid for cyclohexylpropionic acid with 5-methylpentanoic acid for example 263a The title compound, MS (ESI): 484 (M + H ^& lt ^{; +} & gt ^; ).
[2170] Example 270
[2171] 2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2- sulfonyl) Produce
[2172] The title compound was prepared following the procedure of Example 267a-f but replacing N-Boc-norleucine with N-Boc-phenylalanine in step 267a. The mixture was separated by HPLC to give two diastereomers as a solid (first elution: 20.5 mg, second elution: 27 mg): MS (ESI): 571.95 (M + H) &lt; ⁺ & gt ^; .
[2173] Example 271
[2174] Benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Preparation of amide
[2175] The title compound was prepared as a mixture of diastereomers according to the method of Example 193e-h, but substituting N-Boc-O-benzyl-L-serine in step 193e. To a solution of benzofuran-2-carboxylic acid {(S) -2-benzyloxy- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Ethyl} -amide in 50 ml of tetrahydrofuran was added 50 mg of 10% Pd / C. Upon hydrolysis of about 50% of the starting benzyl ether, the reaction was filtered and concentrated. The four component mixture was purified by HPLC to afford 1 mg of the first eluting diastereomer of the title compound and 0.3 mg of the second eluting diastereomer of the title compound: MS (ESI): 590.94 (M + H) &lt; ⁺ & gt ^; . In addition, benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Ethyl} -amide was isolated as described in Example 272 below.
[2176] Example 272
[2177] Benzofuran-2-carboxylic acid {(S) -2-hydroxy- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} Preparation of amide
[2178] The title compound was obtained as described in example 271 supra. The mixture was purified by HPLC to give two diastereomers as a solid (first elution: 1.6 mg, second elution: 2.1 mg): MS (ESI): 500.9 (M + H) &lt; ⁺ & gt ^; .
[2179] Example 273
[2180] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[2181] The title compound was obtained according to the procedure of Example 75c-d but replacing benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid in step 75c and separated by HPLC (10.0%, MS (ESI)): 144.3 mg (85.1%, MS (ESI): 563.2 (M + H) ⁺ ) of the first eluting diastereomer of the white solid and 16.9 mg 563.0 (M + H) &lt; ⁺ & gt ^; ).
[2182] Example 274
[2183] Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide &lt; / RTI &gt;
[2184] The title compound was obtained according to the procedure of Example 75c-d but replacing benzofuran-2-carboxylic acid with 7-methoxybenzofuran-2-carboxylic acid in step 75c and separated by HPLC (35%, MS (ESI): 562.2 (M + H) <^+> ) and a second eluting diastereomer of a white solid (75 mg, 47% 563.0 (M + H) &lt; ⁺ & gt ^; ).
[2185] Example 275
[2186] 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) Butyl} -amide &lt; / RTI &gt;
[2187] The title compound was obtained according to the method of Example 75c-d, except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c and separated by HPLC MS (ESI): 547.2 (M + H) ⁺ ) and the second eluting diastereomer of the white solid, 65 mg (40% (M + H) &lt; ⁺ & gt ^; ).
[2188] Example 276
[2189] Thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -Butyl} -amide &lt; / RTI &gt;
[2190] The title compound was obtained according to the procedure of Example 75c-d but replacing benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid in step 75c and separated by HPLC (ESI): 79.5 mg (48%, MS (ESI): 549.3 (M + H) &lt; ⁺ & gt ^; ) of the first eluting diastereomer of the white solid and 50.5 mg 549.2 (M + H) &lt; ⁺ & gt ^; ).
[2191] Example 277
[2192] Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide &lt; / RTI &gt;
[2193] The title compound was obtained according to the procedure of Example 75c-d but replacing benzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid in step 75c and separated by HPLC to give white MS (ESI): 563.0 (M + H) ⁺ ) and a second eluting diastereomer of a white solid, 57 mg (35%, MS (ESI): 563.0 M + H) &lt; ⁺ & gt ^; ).
[2194] Example 278
[2195] Oxo-1- (thiazole-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -carbamic acid tert- Preparation of amide
[2196] The title compound was obtained by following the procedure of Example 75c-d but replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid in step 75c and separated by HPLC to yield the title compound as a white solid MS (ESI): 545.2 (M + H) &lt; ⁺ & gt ^; ) and the second eluting diastereomer of the white solid (25 mg, H) &lt; ⁺ & gt ^; ).
[2197] Example 279
[2198] Yl} -3-methyl-butyl} - &lt; / RTI &gt; Preparation of amide
[2199] The title compound was obtained according to the procedure of Example 75, substituting benzenesulfonyl chloride with 4-fluorophenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with 2-quinolinecarboxylic acid. The residue was purified by HPLC. A first eluting diastereomer; MS (M + H & lt ^; + & gt ^; ): 555.2; ¹ H NMR (400 Hz, CDCl ₃ ): 8.62 (d, IH), 8.34-8.23 (q, 2H), 8.19-8.17 (d, IH), 7.90-7.88 1H), 4.00 (m, 3H), 4.72 (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 ^& lt ^{; +} & gt ^; ): 555.4.
[2200] The above specification and examples fully describe the preparation and use of the compounds of the present invention. However, the present invention is not limited to the specific embodiments described in the foregoing specification, and includes all modifications thereof within the scope of the following claims. Various references in the magazines, patents, and other publications cited herein are incorporated by reference in their entirety, including the prior art.

权利要求:
Claims (68)
[1" claim-type="Currently amended] Compounds of formula (I), and pharmaceutically acceptable salts, hydrates and solvates thereof.
(I)

Wherein R &lt; ¹ &gt; is , And &Lt; / RTI &gt;
R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 9 C (O) -} , R 9 ^{C (S) -, R 9} SO 2 -, R 9 OC (O) -, R 9 R 11 NC (O) -, R 9 R 11 NC (S) -, R 9 (R 11) NSO 2 -, , And &Lt; / RTI &gt;
R ³ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl C _0-6 alkyl, ArC _0-6 group consisting of alkyl,
R ³ and R 'may be connected to form a pyrrolidine, piperidine or morpholine ring,
R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S) -, R ⁵ SO ₂ -, R ⁵ OC (O) -, R ⁵ R ¹³ NC (O) - and R ⁵ R ¹³ NC (S) -,
R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _{0 Gt;} is selected from the group consisting of &lt; RTI ID = 0.0 &
R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl or heteroaryl, -C _0-6 alkyl,
R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S) -, R ¹⁰ SO ₂ -, R ¹⁰ OC (O) -, R ¹⁰ R ¹⁴ NC (O) - and R ¹⁰ R ¹⁴ NC (S) -,
R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero-C _0-6 alkyl and Ar-C _0-6 alkyl,
R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ¹⁴ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R &apos; is selected from the group consisting of H, _C1-6 alkyl, Ar- _C0-6 alkyl and hetero- _C0-6 alkyl,
R &quot; is selected from the group consisting of H, Ci- ₆ alkyl, Ar- _C0-6alkyl or hetero- _C0-6alkyl ,
R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
X is selected from the group consisting of CH ₂ , S and O,
Z is selected from the group consisting of C (O) and CH ₂ .
[2" claim-type="Currently amended] 2. The compound of claim 1 wherein R &lt; ^{1 &gt;} is / RTI &gt;
[3" claim-type="Currently amended] The compound of claim 1, wherein R ³ is H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, Ethyl, 1-hydroxyethyl, tolyl, naphthalene-2-ylmethyl, benzyloxymethyl and hydroxymethyl.
[4" claim-type="Currently amended] 4. The compound of claim 3 wherein R &lt; ³ &gt; is selected from the group consisting of tolyl, isobutyl, and cyclohexylmethyl.
[5" claim-type="Currently amended] 5. The compound according to claim 4, wherein R &lt; ³ &gt; is isobutyl.
[6" claim-type="Currently amended] The compound according to claim 1, wherein R ⁴ is selected from the group consisting of R ⁵ OC (O) -, R ⁵ C (O) - or R ⁵ SO ₂ -.
[7" claim-type="Currently amended] 7. The compound according to claim 6, wherein R &lt; ⁴ &gt; is R &lt; ⁵ &gt; C (O) -.
[8" claim-type="Currently amended] The method of claim 7 wherein the compound R ⁵ is selected from C _1-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl.
[9" claim-type="Currently amended] 9. The compound of claim 8, wherein R &lt; ⁵ &gt; is
Methyl, halogenated methyl, methyl substituted with alkoxy, methyl substituted with heterocycle;
Butyl, aryl substituted butyl;
Isopentyl;
Cyclohexyl;
Butenyl, aryl substituted butenyl;
Acetyl;
Phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more alkoxy groups, phenyl substituted with one or more sulfonyl groups,
benzyl;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Furanyl, halogen substituted furanyl, aryl substituted furanyl;
Tetrahydrofuran-2-yl;
Benzofuranyl, benzofuranyl substituted with alkoxy, benzofuranyl substituted with halogen, benzofuranyl substituted with alkyl;
Benzo [b] thiophenyl, alkoxy is replaced benzo [b] thiophenyl;
Quinolinyl;
Quinoxalinyl;
1,8-naphthyridinyl;
Indolyl, alkyl substituted indolyl;
Pyridinyl, pyridinyl substituted with alkyl, 1-oxy-pyridinyl;
Thiophenyl, thiophenyl substituted with alkyl, thiophenyl substituted with halogen;
Thieno [3,2- b ] thiophenyl;
Isoxazolyl, isoxazolyl substituted with alkyl; And
Oxazolyl
&Lt; / RTI &gt;
[10" claim-type="Currently amended] 9. The compound of claim 8, wherein R &lt; ⁵ &gt; is
Pentanoyl;
Naphthylen-2-yl;
Benzo [l, 3] dioxol-5-yl;
Furan-2-yl;
Benzofuran-2-yl;
Benzo [ b ] thiophen-2-yl;
Quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;
Quinoxalin-2-yl;
1, 8-naphthyridin-2-yl;
Yl, indol-5-yl;
Pyridin-2-yl, pyridin-5-yl;
Thiophen-3-yl;
Thieno [3,2- b ] thiophen-2-yl;
Isoxazol-4-yl; And
Oxazol-4-yl
&Lt; / RTI &gt;
[11" claim-type="Currently amended] 9. The compound of claim 8, wherein R &lt; ⁵ &gt; is
Trifluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl, 2-thiophenyl-methyl;
4- (4-methoxy) phenyl-butyl;
4-pentanonyl;
4,4-bis (4-methoxyphenyl) -but-3-enyl;
3,4-dichlorophenyl, 4-fluorophenyl, 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, 4-methanesulfonyl-phenyl;
Yl, 5-bromo-furan-2-yl, 5- (4-fluorophenyl) Yl, 5- (4-chloro-phenyl) -furan-2-yl;
5- (2-Piperazine-4-carboxylic acid tert -butyl ester-ethoxy) benzofuran-2-yl, 5- (2-morpholino- Benzofuran-2-yl, 7-methoxy-benzoic acid, benzofuran-2-yl, 5- (2-piperazin-1-yl-ethoxy) Yl, 5-fluoro-benzofuran-2-yl, 5,6-difluoro-2-yl, 5,6-dimethoxy- 2-yl, 3-methyl-benzofuran-2-yl;
5,6-dimethoxy-benzo [ b ] thiophen-2-yl;
N-methyl-indol-2-yl;
1-oxy-pyridin-2-yl, 2-methyl-pyridin-5-yl;
5-methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-yl;
5-tert-butyl-3-methylthieno [3,2- b ] thiophen-2-yl;
3,5-dimethyl-isoxazol-4-yl; And
Methyl-2-phenyloxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-
&Lt; / RTI &gt;
[12" claim-type="Currently amended] 10. The method of claim 8 wherein, R ⁵ is 3-methyl-benzofuran-2-yl utilized, thieno [3,2- b] Theo pen-2-yl, 5-methoxy-benzofuran-2-yl, quinoxaline- 2-yl, and quinolin-2-yl.
[13" claim-type="Currently amended] The compound of claim 1, wherein R 'is selected from the group consisting of H and naphthalen-2-yl-methyl.
[14" claim-type="Currently amended] 14. The compound of claim 13, wherein R 'is H.
[15" claim-type="Currently amended] The compound according to claim 1, wherein R &quot; is H.
[16" claim-type="Currently amended] The compound according to claim 1, wherein R "'is selected from the group consisting of H and 6,6-dimethyl.
[17" claim-type="Currently amended] 17. The compound of claim 16, wherein R "'is H.
[18" claim-type="Currently amended] The compound of claim 1, wherein R &quot; and R &quot; 'are both H.
[19" claim-type="Currently amended] The method according to claim 1,
R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 9 C (O) -} , R 9 ^{C (S) -, R 9} SO 2 -, R 9 OC (O) -, R 9 R 11 NC (O) -, R 9 R 11 NC (S) -, R 9 R 11 NSO 2 -, , And &Lt; / RTI &gt;
R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 10 C (O) -} , R 10 is selected from the group consisting of, - C (S) -, R 10 SO 2 -, R 10 OC (O) -, R 10 R 14 NC (O) -, and R ¹⁰ R ¹⁴ NC (S)
R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero-C _0-6 alkyl and Ar-C _0-6 alkyl,
R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl or heterocyclic group consisting of -C _0-6 alkyl,
And Z is selected from the group consisting of C (O) and CH ₂ .
[20" claim-type="Currently amended] 20. The compound of claim 19, wherein R ² is selected from the group consisting of Ar-C _0-6 alkyl, R ⁹ C (O) -, R ⁹ SO ₂ -, R ⁹ R ¹¹ NC (O) &Lt; / RTI &gt;
[21" claim-type="Currently amended] 21. The method of claim 20 wherein, R ² is Ar-C _0-6 alkyl, R ⁹ C (O) - and R ⁹ SO ₂ - compound selected from the group consisting of.
[22" claim-type="Currently amended] 22. The method of claim 21 wherein, R ² is SO ₂ R ⁹ in the compound.
[23" claim-type="Currently amended] 20. The compound of claim 19, wherein R &lt; ⁶ &gt;
[24" claim-type="Currently amended] 20. The compound of claim 19, wherein R &lt; ⁷ &gt; is R &lt; ¹⁰ &gt; OC (O).
[25" claim-type="Currently amended] 20. The method of claim 19 wherein, R ⁸ is C _1-6 alkyl.
[26" claim-type="Currently amended] 26. The compound of claim 25, wherein R &lt; ⁸ &gt; is isobutyl.
[27" claim-type="Currently amended] 20. The compound of claim 19 wherein R &lt; ⁹ &gt; is selected from the group consisting of Ci- ₆ alkyl, Ar- _C0-6 alkyl and hetero- _C0-6 alkyl.
[28" claim-type="Currently amended] 28. The compound of claim 27, wherein R &lt; ⁹ &gt; is
methyl;
Ethyl, and ethyl substituted with C _1-6 alkyl;
Butyl, C _1-6 alkyl substituted butyl;
tert -butyl;
Isopentyl;
Phenyl, halogen substituted phenyl, C _1-6 alkoxyphenyl, cyanophenyl;
Tolyl, hetero-substituted tolyl;
Benzoic acid;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Benzo [1,2,5] oxadiazolyl;
Pyridinyl, 1-oxy-pyridinyl, C _1-6 alkylpyridinyl;
Thiophene;
Thiazolyl;
Imidazolyl, imidazolyl substituted with C _1-6 alkyl;
1H- [1,2,4] triazolyl, C _1-6 alkyl, the substituted 1H- [1,2,4] triazolyl; And
Quinolinyl
&Lt; / RTI &gt;
[29" claim-type="Currently amended] 28. The compound of claim 27, wherein R &lt; ⁹ &gt; is
2-cyclohexyl-ethyl;
3-methylbutyl;
Bromophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4 - dimethoxyphenyl, 2-cyanophenyl;
2-benzoic acid;
Naphthylen-2-yl;
Benzo [l, 3] dioxol-5-yl;
Benzo [1,2,5] oxadiazol-4-yl;
Pyridin-2-yl, 6-methyl-pyridin-2-yl, Work;
Thiophen-2-yl;
Thiazol-2-yl;
Imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;
1H- [1,2,4] triazol-3-yl, 5-methyl-1H- [1,2,4] triazol-3-yl; And
Quinolin-2-yl
&Lt; / RTI &gt;
[30" claim-type="Currently amended] The method according to claim 1,
R ¹ is ego,
R ² is Ar-C _0-6 alkyl, R ⁹ C (O) -, R ⁹ SO ₂ -, R ⁹ R ¹¹ NC (O) - and &Lt; / RTI &gt;
R ³ is selected from the group consisting of H, C _1-6 alkyl and ArC _0-6 alkyl,
R ⁴ is selected from the group consisting of R ⁵ OC (O) -, R ⁵ C (O) - or R ⁵ SO ₂ -
R ⁵ is selected from C _1-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R &lt; ⁶ &gt; is H,
R ⁷ is R ¹⁰ OC (O) -,
R &lt; ⁸ &gt; is _C1-6alkyl ,
R ⁹ is selected from C _1-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R ¹⁰ is selected from C _1-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R 'is H,
R &quot; is H,
R &quot; 'is H.
[31" claim-type="Currently amended] 31. The method of claim 30,
R ² is selected from the group consisting of Ar-C _0-6 alkyl, R ⁹ C (O) - and R ⁹ SO ₂ -
R ³ is selected from the group consisting of H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, -Hydroxyethyl, tolyl, naphthalene-2-ylmethyl, benzyloxymethyl, and hydroxymethyl,
R &lt; ⁴ &gt; is R &lt; ⁵ &gt; C (O)
R ⁵ is
Methyl, halogenated methyl, methyl substituted with alkoxy, methyl substituted with heterocycle;
Butyl, aryl substituted butyl;
Isopentyl;
Cyclohexyl;
Butenyl, aryl substituted butenyl;
Acetyl;
Phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more alkoxy groups, phenyl substituted with one or more sulfonyl groups,
benzyl;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Furanyl, halogen substituted furanyl, aryl substituted furanyl;
Tetrahydrofuran-2-yl;
Benzofuranyl, benzofuranyl substituted with alkoxy, benzofuranyl substituted with halogen, benzofuranyl substituted with alkyl;
Benzo [b] thiophenyl, alkoxy is replaced benzo [b] thiophenyl;
Quinolinyl;
Quinoxalinyl;
1,8-naphthyridinyl;
Indolyl (22), alkyl substituted indolyl;
Pyridinyl, pyridinyl substituted with alkyl, 1-oxy-pyridinyl;
Thiophenyl, thiophenyl substituted with alkyl, thiophenyl substituted with halogen;
Thieno [3,2- b ] thiophenyl;
Isoxazolyl, isoxazolyl substituted with alkyl; And
Oxazolyl
&Lt; / RTI &gt;
R ⁹ is
methyl;
Ethyl, ethyl substituted with C _1-6 alkyl;
Butyl, C _1-6 alkyl substituted butyl;
tert -butyl;
Isopentyl;
Phenyl, halogen substituted phenyl, C _1-6 alkoxyphenyl, cyanophenyl;
Tolyl, hetero-substituted tolyl;
Benzoic acid;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Benzo [1,2,5] oxadiazolyl;
Pyridinyl, 1-oxy-pyridinyl, C _1-6 alkylpyridinyl;
Thiophene;
Thiazolyl;
Imidazolyl, imidazolyl substituted with C _1-6 alkyl;
1H- [1,2,4] triazolyl, C _1-6 alkyl, the substituted 1H- [1,2,4] triazolyl; And
Quinolinyl, &lt; / RTI &gt;
[32" claim-type="Currently amended] 31. The compound of claim 30, wherein R &lt; ⁵ &gt; is
Pentanonyl;
Naphthylen-2-yl;
Benzo [l, 3] dioxol-5-yl;
Furan-2-yl;
Benzofuran-2-yl;
Benzo [ b ] thiophen-2-yl;
Quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;
Quinoxalin-2-yl;
1, 8-naphthyridin-2-yl;
Yl, indol-5-yl;
Pyridin-2-yl, pyridin-5-yl;
Thiophen-3-yl;
Thieno [3,2- b ] thiophen-2-yl;
Isoxazol-4-yl; And
Oxazol-4-yl
&Lt; / RTI &gt;
[33" claim-type="Currently amended] 31. The compound of claim 30, wherein R &lt; ⁵ &gt; is
Trifluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl, 2-thiophenyl-methyl;
4- (4-methoxy) phenyl-butyl;
4-pentanonyl;
4,4-bis (4-methoxyphenyl) -but-3-enyl;
3,4-dichlorophenyl, 4-fluorophenyl, 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, 4-methanesulfonyl-phenyl;
Yl, 5-bromo-furan-2-yl, 5- (4-fluorophenyl) Yl, 5- (4-chloro-phenyl) -furan-2-yl;
2-yl) -5- (2-piperazin-4-carboxylic acid tert -butyl ester-ethoxy) benzofuran- (44), 5- (2-piperazin-1-yl-ethoxy) benzofuran-2-yl, 5- 2-yl, 5-fluoro-benzofuran-2-yl, 5,6-dimethoxy-benzofuran- Fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl;
5,6-dimethoxy-benzo [ b ] thiophen-2-yl;
N-methyl-indol-2-yl;
1-oxy-pyridin-2-yl, 2-methyl-pyridin-5-yl;
5-methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-yl;
5- tert -Butyl-3-methylthieno [3,2- b ] thiophen-2-yl;
3,5-dimethyl-isoxazol-4-yl;
Methyl-2-phenyloxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-
&Lt; / RTI &gt;
[34" claim-type="Currently amended] 31. The compound of claim 30, wherein R &lt; ⁹ &gt; is
2-cyclohexyl-ethyl;
3-methylbutyl;
Bromophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4 - dimethoxyphenyl, 2-cyanophenyl;
2-benzoic acid;
Naphthylen-2-yl;
Benzo [l, 3] dioxol-5-yl;
Benzo [1,2,5] oxadiazol-4-yl;
Pyridin-2-yl, 6-methyl-pyridin-2-yl, Work;
Thiophen-2-yl;
Thiazol-2-yl;
Imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;
1H- [1,2,4] triazol-3-yl, 5-methyl-1H- [1,2,4] triazol-3-yl; And
Quinolin-2-yl
&Lt; / RTI &gt;
[35" claim-type="Currently amended] 31. The method of claim 30,
R ² is R ⁹ SO ₂ ,
R ³ is isobutyl,
R &lt; ⁴ &gt; is R &lt; ⁵ &gt; C (O)
R ⁵ is selected from the group consisting of 3-methyl-benzofuran-2-yl, thieno [3,2- b ] thiophen- 2-yl, &lt; / RTI &gt;
R ⁹ is selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-
compound.
[36" claim-type="Currently amended] 36. The compound of claim 35, wherein R &lt; ⁵ &gt; is 3-methyl-benzofuran-2-yl.
[37" claim-type="Currently amended] 36. The method of claim 35 wherein, R ⁹ is 1-oxy-pyridin-2-yl.
[38" claim-type="Currently amended] The method according to claim 1,
Benzoyl) carbamic acid benzyl ester, {(S) -1- [1 - ((S) -2-benzyloxycarbonylamino-4-methyl-pentanoyl)
Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl-
Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4- ylcarbamoyl)
(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide,
Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3- oxo-azepan-4- ylcarbamoyl)
2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azepan-4- ylcarbamoyl) -3-methyl-
(S) -1- (1-benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide,
(S) -1- (1-Benzyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl-
2- (3-pyridin-2-yl-phenyl) -acetyl (3-methoxyphenyl) ] - azepanium,
(S) -2-r (2-quinoline-2-carbonyl) -amino] - Pentanoylamino} -3-oxo-azepanium,
Benzoyl-4 - ((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl- pentanoylamino)
(S) -2- (4-Fluoro-benzoylamino) -4-methyl-pentanoylamino) -3-oxo-azepanium,
((S) -4-methyl-2 - {[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino ) -1- (4-methyl-pentanoyl) -azepan,
Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan- Yl) -3-methyl-butyl] -amide,
Carbonyl] amino} -pentanoylamino) - 3- (4-methyl-2 - {[ Oxo-azepane-1-carboxylic acid phenylamide,
(S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine Yl) -phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide,
(S) -1- (Benzoyl-3-oxo-azepan-4-ylcarbamoyl) - benzofuran-2-carboxylic acid 3-methyl-butyl] -amide,
-Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) 3-methyl-butyl] -amide, &lt; / RTI &gt;
-Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) 3-methyl-butyl] -amide, &lt; / RTI &gt;
(S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine Yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide,
Naphthylene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; amide,
Indole-2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- Carbamoyl} -butyl) -amide,
(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide,
(S) -1- (1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide,
2-carboxylic acid ((S) -3-methyl-1- {3-oxo- 1- [2- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; amide,
(S) -3-methyl-1- (3-oxo-1-phenethyl-azepan-4-ylmethoxy) -Ylcarbamoyl) -butyl] -amide, &lt; / RTI &gt;
Naphthylene-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-phenethyl-azepan-4- ylcarbamoyl) -butyl] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} ,
Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} ,
Synthesis of 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [ ) -Azepan-4-ylcarbamoyl] butyl} amide,
4 - ((S) -4-methyl-2 - {[(5- (2-morpholino-4-yl- ethoxy) -benzofuran- 2- carbonyl] -amino} -pentanoylamino) 3-oxo-azepane-1-carboxylic acid tert-butyl ester,
4-methyl-2 - {[(5- (2-morpholino-4-yl-ethoxy) 1- (3-oxo-azepan-4-ylcarbamoyl) butyl] -amide,
(3-oxo-l- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-
(S) -3-methyl-1- {3-oxo-1- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepan-4-ylcarbamoyl} Naphthylene-2-methyl-carbamic acid tert-butyl ester,
(3-oxo-l- [2- (3-pyridin-2-yl-phenyl) -acetyl] -pentanoic acid - &lt; / RTI &gt; azepan-4-yl} -amide,
4- [2- (2 - {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl } -Benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester,
Preparation of 5- (2-piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- Yl] carbamoyl] -3-butyl} -amide,
Preparation of 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} -amide,
Preparation of 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl- 1- 3- Phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide,
(3-pyridin-2-yl-phenyl) -ethyl [azepan-4-ylcarbamoyl] -Butylcarbamoyl} -benzofuran-5-yloxy) ethyl] -piperazine-1-carboxylic acid tert-butyl ester,
(S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin- 2-yl-phenyl) ethyl] -azepan-4-ylcarbamoyl} -butyl) -amide,
(3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-yl] -amide,
(3-oxo-l- [2- (3-pyridin-2-yl-phenyl) -acetyl] -acetic acid Yl} -amide,
Methyl (S) -3-methyl-1 {3-oxo-1- [2- (3-pyridine Yl) -phenyl) acetyl] -azepan-4-ylcarbamoyl} -butyl) -amide,
Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -3-methyl -Butyl} -amide,
(S) -3-methyl-1- {3-oxo-1- [2- (3- pyridin- 2- yl- phenyl) -acetyl] -azepane Ylcarbamoyl} -butyl) -N-naphthylen-2-ylmethyl-acetamide,
4-methyl-pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl ester,
2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - amide,
8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4- ylcarbamoyl] -butyl}
3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4- ylcarbamoyl] -butyl} -amide,
3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide ,
[(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide ,
2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide as a colorless solid. ,
Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (pyridine- 2- sulfonyl) Butyl} -amide,
Naphthyridine-2-carboxylic acid {(S) -3-methyl-1- (3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Butyl} -amide,
Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides,
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ -Butyl} -amide,
Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide,
Furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] 5-Nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides,
Furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan- Carbamoyl] -butyl} -amide,
(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] butyl} -amide,
2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - &lt; / RTI &gt; -amides,
(S) -4-methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo (pyridine- 2- sulfonyl)
(S) -2- [2- (4-fluoro-phenoxy) -acetylamino] -4-methyl- pentanoic acid [3-oxo- (pyridine- 2- sulfonyl) -amides,
3-methyl-1- [3-oxo-1- (pyridine-2-carbonyl) -azepan-4-ylcarbamoyl] -amides,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxypyridine- 2-carbonyl) -azepan-4-ylcarbamoyl] }-amides,
4 - ((S) -2-tert-Butylcarbonylamino-4-methyl-pentanoylamino) -3-oxo-azepane-1 -carboxylic acid benzyl ester,
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1 -methyl-1 H- imidazole- Yl-carbamoyl] -butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole- Yl-carbamoyl] -butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- 3 -sulfonyl) -3-oxo-azepan- Yl] -butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1H-imidazole- }-amides,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1 -methyl-1 H- imidazole- 4- sulfonyl) -3-oxo-azepan- Yl] -butyl} -amide,
Synthesis of 5- (4-oxy-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3- Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -3-methyl-l- [3-oxo-1- (pyridine-3- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} ,
Benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxypyridine- 3- sulfonyl) -azepan-4-ylcarbamoyl] }-amides,
4-ylcarbamoyl)] - 3-methyl-butyl} -amide (prepared as described in Example 1, ,
Preparation of 5-hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (1 -methyl-1 H- imidazole- 4-ylcarbamoyl] butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) 3-methyl-butyl} -amide,
Amino-4-methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid, 2- (4 - {(S) -2 - [(benzofuran-
Amino-4-methyl-pentanoylamino} -3-oxo-azepane-1 -sulfonyl) -benzoic acid, 3- (4 - {(S) -2 - [(benzofuran-
Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
(5-bromo-furan-2-carboxylic acid {(S) -3-methyl- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- Ylcarbamoyl] butyl} -amide, &lt; RTI ID = 0.0 &gt;
2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides,
(3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-yl] -amide,
(S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
(3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-yl] -amide,
Benzofuran-2-carboxylic acid {(S) -1- [6,6-dimethyl-3-oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] Butyl} -amide,
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) Carbamoyl] -butyl} -amide,
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- -4-ylcarbamoyl] -butyl} -amide,
Oxo-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] - (3-methyl- Butyl} -amide,
2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - &lt; / RTI & }-amides,
Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Butyl} -amide,
Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide,
Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [ Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
Furan-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] }-amides,
(2-thiophen-2-yl-acetylamino) -pentanoic acid [3-oxo-l- -Yl] -amide,
Indole-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (l-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide,
(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine- 2- sulfonyl) azepan- 4- carbamoyl] -butyl} -benzamide ,
Synthesis of 5- (2-morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl- Trifluoromethyl-phenyl) -azepan-4-ylcarbamoyl] -butyl} -amide,
Thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide,
3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - nicotinamide,
(S) -4-methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid [ -amides,
Methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - amides,
Benzo [1,3] dioxole-5-carboxylic acid {(S) -3-methyl-1- [ ] -Butyl} -amide,
Benzo [b] [1,4] dioxepine-7-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- -2-sulfonyl) -azepan-4-ylcarbamoyl] butyl} -amide,
Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [ &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 1 -sulfonyl) -azepan- 4-ylcarbamoyl] -butyl} -amide,
4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) -azepan- Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [l- (4- methoxy- benzenesulfonyl) -3-oxo-azepan-
Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- pyridine- 2- sulfonyl) - azepan-4-ylcarbamoyl] -butyl} -amide,
Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- 4-ylcarbamoyl] -butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxybenzenesulfonyl) -3-oxo-azepan-4- ylcarbamoyl) -butyl}
3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) -amides,
Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4- sulfonyl) -3-oxo-azepan- ] -3-methyl-butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-oxazole-4- sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] - Butyl} -amide,
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- Carbamoyl] -butyl} -amide,
3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) Sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amide,
Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-carboxylic acid Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
Methyl-butyl] -amide, (S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)
(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide ,
Methyl-butylcarbamoyl] -methyl} - &lt; / RTI &gt; &lt; RTI ID = 0.0 & amides,
(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide ,
(S) -1- (1 -methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] -amide,
Carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-yl Carbamoyl] -butyl} -amide,
(S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4- methyl-
Yl} -3-methyl-butyl} - (2-cyano-benzenesulfonyl) -3-oxo-azepan- amides,
Indole-2-carboxylic acid {(S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
({(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Gt; &lt; RTI ID = 0.0 &gt; amide, &lt; / RTI &
Benzofuran-2-carboxylic acid {(S) -1- [1- (2-cyanobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) -amides,
(S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -Yl] -amide,
-2-carboxylic acid {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] amides,
Indole-2-carboxylic acid {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
({(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Gt; &lt; RTI ID = 0.0 &gt; amide, &lt; / RTI &
Benzofuran-2-carboxylic acid {[(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] - 3-methyl-butyl} -amide,
3-methyl-butyl} -3-oxo-azepan-4-ylcarbamoyl] -3-oxo-azepan-2-carboxylic acid {(S) -amides,
(S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -Yl] -amide,
Indole-2-carboxylic acid {(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Furan-2-carboxylic acid ({(S) -l- [l- (4- fluoro-benzenesulfonyl) -3-oxo-azepan-4- ylcarbamoyl] Gt; &lt; RTI ID = 0.0 &gt; amide, &lt; / RTI &
Benzofuran-2-carboxylic acid {(S) -1- (1- [4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
(S) -1- [1- (4-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl} - amides,
(S) -2- [2- (4-methoxy-phenyl) -acetylamino] -4-methyl- pentanoic acid [l- (4- fluoro-benzenesulfonyl) -Yl] -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4- ylcarbamoyl] -3-methyl- butyl} ,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] - 3-methyl-butyl} -amide,
(S) -1- [1- (3-chlorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl-benzofuran- Butyl} -amide,
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide,
Indole-2-carboxylic acid {(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Yl} -3-methyl-butyl} - (3-chloro-benzenesulfonyl) -3-oxo-azepan- amides,
Benzofuran-2-carboxylic acid {(S) -1- [1- (2- fluoro-benzenesulfonyl) -3-oxo-azepan- -amides,
Benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -5,6-dimethoxy- -3-methyl-butyl} -amide,
Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide,
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [l- (2- fluoro-benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide,
Indole-2-carboxylic acid {(S) -1- [1- (2-fluorobenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
(S) -4-methyl-2- (l-oxy-pyridine-2- sulfonylamino) -pentanoic acid [ amides,
3-methyl-butyl} -3-oxo-azepan-4-ylcarbamoyl] - (2- -amides,
Preparation of 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiophene-2- sulfonyl) -azepan- ] -Butyl} -amide,
7-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiophene-2- sulfonyl) -azepan- ] -Butyl} -amide,
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiophene-2-sulfonyl) &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (thiophene-2- sulfonyl) -Butyl} -amide,
Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- (3-oxo- 1- (thiophene-2- sulfonyl) -Butyl} -amide,
Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
Oxo-1- (thiophene-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -carbamic acid tert- amides,
Methyl-butyl} - &lt; / RTI &gt; &lt; RTI ID = 0.0 & amides,
Benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide,
3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide,
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide,
Indole-2-carboxylic acid {(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Yl} -3-methyl-butyl} - (4-chloro-benzenesulfonyl) -3-oxo-azepan- amides,
3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) -amides,
Benzofuran-2-carboxylic acid {(S) -1 - [(3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan- -3-methyl-butyl} -amide,
(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3- Methyl-butyl} -amide,
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-methoxy- benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide,
Indole-2-carboxylic acid {(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide,
(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -methyl- butyl} -amide ,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiophene-2- sulfonyl) -azepan-4-ylcarbamoyl] amides,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1 - [(2,2 ', 4-tridecarterio) -3-oxo-1- (pyridine- Yl-carbamoyl] -butyl} -amide,
Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl} ,
Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl}
Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides,
Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -ethyl}
2-sulfonyl) -azepan-4-ylcarbamoyl] -propyl} - &lt; / RTI &gt; -amides,
Benzofuran-2-carboxylic acid {[3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -methyl}
Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -pentyl}
Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl} ,
Benzofuran-2-carboxylic acid {(S) -2-hydroxy- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl} - amides,
2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -2- phenyl- ethyl} ,
2-carboxylic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-yl] -amide,
(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl } -Benzamide,
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (4-methoxy- benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide,
Benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (4- fluoro-benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide,
(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [l- (4- fluoro-benzenesulfonyl)
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [l- (4- fluoro-benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide,
Benzoyl-3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide,
(S) -4-Methyl-2- (quinoline-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
(S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
3-methyl-butyl} -3-oxo-azepan-2-carboxylic acid {(S) -amides,
N - {(S) -1- [1- (4-Fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Ethoxy-benzamide,
(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl}
(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (methanesulfonyl) -3-oxo-azepan-
Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1 -methanesulfonyl-3- oxo-azepan-4- ylcarbamoyl) -3-methyl-
Benzo [1,3] dioxole-5-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl) amides,
(S) -1- (1-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3-methyl- butyl] Methyl-butyl} -3,4-dimethoxy-benzamide, N, N-diisopropylethylamine, N - [(S) -1-
(S) -2- (2-Benzyloxy-acetylamino) -4-methyl-pentanoic acid [l- (2- cyano-benzenesulfonyl)
N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl} -4- methanesulfonyl -1-benzamide,
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-cyano- benzenesulfonyl) -3-oxo-azepan- Methyl-butyl} -amide,
Benzo [1,3] dioxole-5-carboxylic acid {(S) -1- [1- (2-cyano- benzenesulfonyl) -3-oxo-azepan- 3-methyl-butyl} -amide,
(3-oxo-l- (pyridine-2-sulfonyl) - (4-methyl- Azepan-4-yl] -amide,
N - {(S) -1- [1- (2-Cyano-benzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- Ethoxy-benzamide,
(S) -1- [1- (4-methoxybenzenesulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -3-methyl- butyl}
Methyl-butyl-benzamide, 4-methanesulfonyl-N - [(S) -1- (4- methoxy-benzenesulfonyl)
Methyl-butyl-benzamide, 4-methanesulfonyl-N - [(S) -1- (4- fluoro-benzenesulfonyl)
{(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butylcarbamoyl} -carbamic acid benzyl ester,
(S) -2- [5- (4-Methoxy-phenyl) -pentanoylamino] -4-methyl-pentanoic acid [ Yl] -amide,
(S) -2- [2- (3-benzyloxy-4-methoxy-phenyl) -acetylamino] -4- methylpentanoic acid [ -4-yl] -amide,
5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
(3-oxo-l- (pyridine-2-sulfonyl) -azepan-4-yl] -amide,
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine- 2- sulfonyl) -3-oxo-azepan- Butyl} -amide,
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide,
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (6- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azepan-4-ylcarbamoyl] -Butyl} -amide,
5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [1- (pyridine- 2- sulfonyl) -3-oxo-azepan- Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
(R) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -3-methyl- Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
(S) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
Benzofuran-2-carboxylic acid {(S) -2-cyclopropyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides,
2-carboxylic acid {(S) -3-methylsulfanyl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -propyl} -amides,
Benzofuran-2-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Ethyl} -amide,
Thieno [2-b] thiophene-2-carboxylic acid {(S) -3-methyl- -4-ylcarbamoyl] -butyl} -amide,
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- -4-ylcarbamoyl] -butyl} -amide,
3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [ &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt;
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl- 1- [1- (3- methyl- pyridine- 2- sulfonyl) -3-oxo-azepan- Carbamoyl] -butyl} -amide,
5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- 4-ylcarbamoyl] -butyl} -amide,
5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [ -4-ylcarbamoyl] -ethyl} -amide,
(S) -2-Cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan- Ylcarbamoyl] -ethyl} -amide, &lt; / RTI &gt;
(S) -3-methyl-1- [6-methyl-3-oxo-1- (pyridine-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} -amides,
Furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy- Ylcarbamoyl] -ethyl} -amide, &lt; / RTI &gt;
5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-oxo-1- (1-oxy- ) -Azepan-4-ylcarbamoyl] -ethyl} -amide,
Preparation of 5-fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -Butyl} -amide,
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -2-cyclohexyl- 1- [3-oxo- 1- (1-oxy- 4-ylcarbamoyl] -ethyl} -amide,
[(S) -3-methyl-l- [3-oxo-l- (pyridine- 2- sulfonyl) -azepan- 4-ylcarbamoyl] -butyl} -amide,
Yl} -1- [3-oxo- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} -amides,
Naphthylene-1-carboxylic acid {(S) -2-naphthylen-2-yl-1- [3-oxo- 1- (pyridine- 2- sulfonyl) -Ethyl} -amide,
2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide,
2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} - amide ,
1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl- ethyl} ,
3-methyl-1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] -butyl} -amides,
3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (4-methyl-pentanoyl) -azepan-4- ylcarbamoyl] }-amides,
3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-oxo- 1- (1-oxy- pyridine- 2- carbonyl) -azepan- Yl] -butyl} -amide,
(S) -acetylamino-4-methyl-pentanoic acid [3-oxo-1- (pyridine- 2- sulfonyl)
Carboxylic acid {1- [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -pentyl}
2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-propionyl) -azepan-4-ylcarbamoyl] -butyl}
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (4-methyl-pentanoyl) -azepan-4-ylcarbamoyl] -butyl} ,
2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] Benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] amides,
Benzofuran-2-carboxylic acid {(S) -2-hydroxy- 1- [3-oxo- 1- (pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -ethyl} amides,
Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide,
Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide,
3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) Butyl} -amide,
Thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -Butyl} -amide,
Indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- 1- (thiazole- 2- sulfonyl) -azepan-4-ylcarbamoyl ] -Butyl} -amide,
Oxo-1- (thiazole-2-sulfonyl) -azetan-4-ylcarbamoyl] -butyl} -carbamic acid tert- amides,
-3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl} - &lt; / RTI &gt; -amides
&Lt; / RTI &gt;
[39" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 1 to 38 and a pharmaceutically acceptable carrier, diluent or excipient.
[40" claim-type="Currently amended] A method of inhibiting a protease comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 38.
[41" claim-type="Currently amended] 41. The method of claim 40, wherein said protease is selected from the group consisting of cysteine protease and serine protease.
[42" claim-type="Currently amended] 42. The method of claim 41, wherein the protease is cysteine protease.
[43" claim-type="Currently amended] 43. The method of claim 42, wherein the cysteine protease is cathepsin K.
[44" claim-type="Currently amended] 38. A method of treating a disease characterized by bone loss, comprising inhibiting bone loss by administering an effective amount of a compound according to any one of claims 1 to 38 to a patient in need thereof.
[45" claim-type="Currently amended] 45. The method of claim 44, wherein the disease is osteoporosis.
[46" claim-type="Currently amended] 45. The method of claim 44, wherein the disease is periodontitis.
[47" claim-type="Currently amended] 45. The method of claim 44, wherein the disease is gingivitis.
[48" claim-type="Currently amended] Comprising administering an effective amount of a compound according to any one of claims 1 to 38 to a patient in need of such inhibition of excessive cartilage or substrate degradation, thereby inhibiting excessive cartilage or matrix degradation, of a disease characterized by excessive cartilage or matrix degradation Treatment method.
[49" claim-type="Currently amended] 49. The method of claim 48, wherein the disease is osteoarthritis.
[50" claim-type="Currently amended] 49. The method of claim 48, wherein said disease is rheumatoid arthritis.
[51" claim-type="Currently amended] Compounds of formula (II) &lt; EMI ID = 25.1 &gt; and pharmaceutically acceptable salts, hydrates and solvates thereof.
[Formula II]
Wherein R &lt; ¹ &gt; is &Lt; / RTI &gt;
R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 9 C (O) -} , R 9 ^{C (S) -, R 9} SO 2 -, R 9 OC (O) -, R 9 R 11 NC (O) -, R 9 R 11 NC (S) -, R 9 (R 11) NSO 2 -, , And &Lt; / RTI &gt;
R ³ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl C _0-6 alkyl, ArC _0-6 group consisting of alkyl,
R ³ and R 'may be connected to form a pyrrolidine, piperidine or morpholine ring,
R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S) -, R ⁵ SO ₂ -, R ⁵ OC (O) -, R ⁵ R ¹³ NC (O) - and R ⁵ R ¹³ NC (S) -,
R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _{0 Gt;} is selected from the group consisting of &lt; RTI ID = 0.0 &
R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl or heteroaryl, -C _0-6 alkyl,
R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S) -, R ¹⁰ SO ₂ -, R ¹⁰ OC (O) -, R ¹⁰ R ¹⁴ NC (O) - and R ¹⁰ R ¹⁴ NC (S) -,
R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero-C _0-6 alkyl and Ar-C _0-6 alkyl,
R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R ¹⁴ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R &apos; is selected from the group consisting of H, _C1-6 alkyl, Ar- _C0-6 alkyl and hetero- _C0-6 alkyl,
R &quot; is selected from the group consisting of H, Ci- ₆ alkyl, Ar- _C0-6alkyl or hetero- _C0-6alkyl ,
R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heterocycloalkyl group consisting of alkyl,
X is selected from the group consisting of CH ₂ , S and O,
Z is selected from the group consisting of C (O) and CH ₂ .
[52" claim-type="Currently amended] 52. The method of claim 51,
[(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl- butyl] -carbamic acid benzyl ester,
(S) -2-Amino-4-methyl-pentanoic acid (l-benzyl-3-hydroxy-azepan-
(3-hydroxy-l- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepan-
[(S) -1- [4 - ((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepan- Benzyl ester,
(S) -2-Amino-4-methyl-pentanoic acid (1-benzoyl-3-hydroxy-azepan-
(S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4-methyl-pentanoyl)
(S) -2-Amino-4-methyl-pentanoic acid (1-benzenesulfonyl-3-hydroxy-azepan-
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- Yl-carbamoyl] -butyl} -amide,
Methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- 1- (1-oxy- pyridine- 2- sulfonyl) Carbamoyl] -butyl} -amide,
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy- 1- (pyridine- Ylcarbamoyl] -butyl} -amide, &lt; / RTI &gt;
3-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl- 1- [3-hydroxy-1- (1-oxy- pyridine- 2- sulfonyl) Carbamoyl] -butyl} -amide,
2-sulfonyl) -azepan-4-ylcarbamoyl] - (3-methyl- Butyl} amide, and
Carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy- pyridine- 2- sulfonyl) -azepan-4-ylcarbamoyl] -Butyl} -amide
&Lt; / RTI &gt;
[53" claim-type="Currently amended] 53. A process for the preparation of a compound according to claim 1 comprising the step of oxidising the corresponding compound of claim 51 with an oxidizing agent to obtain the compound of formula (I) as a mixture of diastereomers.
[54" claim-type="Currently amended] 55. The method of claim 53, wherein the oxidizing agent is DMSO and a sulfur trioxide pyridine complex in triethylamine.
[55" claim-type="Currently amended] 55. The method of claim 54, further comprising separating the diastereomer by a separation means.
[56" claim-type="Currently amended] 56. The method of claim 55, wherein said means for separating is high pressure liquid chromatography (HPLC).
[57" claim-type="Currently amended] 54. The method of claim 53, further comprising deuteration of said diastereomer with deuterated agent.
[58" claim-type="Currently amended] The method of claim 57, wherein in said agent is deuterium triethylamine _{CD 3 OD:: D 2 O} (1 10).
[59" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 38 for the manufacture of a medicament for use in inhibiting a protease selected from the group consisting of cysteine proteases and serine proteases.
[60" claim-type="Currently amended] 60. The use of claim 59, wherein said protease is a cysteine protease.
[61" claim-type="Currently amended] 61. The use of claim 60, wherein said cysteine protease is cathepsin K.
[62" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 38 for the manufacture of a medicament for use in the treatment of a disease characterized by bone loss.
[63" claim-type="Currently amended] 63. The use of claim 62, wherein said disease is osteoporosis.
[64" claim-type="Currently amended] 63. The use of claim 62, wherein said disease is periodontitis.
[65" claim-type="Currently amended] 63. The use of claim 62, wherein said disease is gingivitis.
[66" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 38 for the manufacture of a medicament for use in the treatment of a disease characterized by excessive cartilage or matrix degradation.
[67" claim-type="Currently amended] 67. The use of claim 66, wherein said disease is osteoarthritis.
[68" claim-type="Currently amended] 67. The use of claim 66, wherein said disease is rheumatoid arthritis.

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DZ2977A1|2004-03-15|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-12-23|Priority to US11363698P

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1998-12-23|Priority to US60/113,636

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1999-11-10|Priority to US16458199P

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1999-11-10|Priority to US60/164,581

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1999-12-21|Application filed by 스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스, 스미스클라인 비참 코포레이션

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2001-10-08|Publication of KR20010089677A

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2006-10-09|Application granted

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2006-10-09|Publication of KR100630986B1

优先权:

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申请号 | 申请日 | 专利标题

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US11363698P| true| 1998-12-23|1998-12-23|

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US60/113,636|1998-12-23|

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US16458199P| true| 1999-11-10|1999-11-10|

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US60/164,581|1999-11-10|