Protease Inhibitors

专利摘要:
The present invention provides 4-amino-azpan-3-one protease inhibitors that inhibit proteases, including cathepsin K and their pharmaceutically acceptable salts, hydrates and solvates, pharmaceutical compositions of these compounds, new Bone loss or excessive cartilage or matrix degradation, including osteoporosis, comprising inhibiting bone loss or excessive cartilage or matrix degradation by administering an intermediate and a compound of the invention to a patient in need thereof; Gum disease including gingivitis, periodontitis; Arthritis, more specifically osteoarthritis and rheumatoid arthritis; Paget's disease; Hypercalcemia in pregnancy; Metabolic bone disease; And it provides a method for the treatment of parasitic diseases comprising maleia.
公开号:KR20030008220A
申请号:KR1020027017045
申请日:2001-06-14
公开日:2003-01-24
发明作者:로버트 더블유. 쥬니어 마르퀴스；유 류；다니엘 에프. 베버；멕스웰 디. 커밍스；스코트 케이. 톰슨；데니스 야마시따
申请人:스미스클라인 비참 코포레이션；
IPC主号:

专利说明:

Protease Inhibitors
[2] Cathepsins are a group of enzymes that are part of the papain phase and cysteine protease. Cathepsin B, H, L, N and S are described in the literature. Recently, cathepsin K polypeptides and cDNAs encoding such polypeptides have been described in U.S. 5,501,969 (herein referred to as cathepsin O). Cathepsin K has recently been published, purified and characterized. Bossard, M. J. et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H. Et al. (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D et al., (1996) J. Biol. Chem. 271, 2126-2132.
[3] Cathepsin K has been shown variously in the literature as cathepsin O or cathepsin O2. The name cathepsin K is considered to be more suitable.
[4] Cathepsin acts on the normal physiological process of proteolysis, such as connective tissue degradation, in animals, including humans. However, high levels of these enzymes in the body can lead to pathological conditions that cause disease. Thus, cathepsin is not only schistosomiasis, malaria, cancer metastasis, familial encephalopathy, muscular dystrophy, muscular dystrophy, etc. but also pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei and trypsanoma brucei. It has been included as a etiology in a variety of diseases and the like, including infection by Thithidia fusiculata. See International Publication WO 94/04172, published March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 A1 and the literature cited therein. Blood called gingipains. Two bacterial cysteine proteases from P. gingivallis have been thought to be associated with the development of gingivitis (Potempa, J. et al., (1994) Perspectives in Drug Discovery and Design, 2, 445- 458).
[5] It is believed that cathepsin K acts as a cause of excessive loss of bone or cartilage. Bone is composed of protein substrates incorporating fusiform or plate crystals of hydroxyapatite. Type I collagen represents the major structural protein of bone, making up about 90% of the protein substrate. The remaining 10% of the substrate consists of many non-collagen proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin and bone sialoprotein. Skeletal bone is reshaped in individual foci throughout life. This lesion, ie, the reshaping unit, undergoes a cycle consisting of a bone resorption phase and a subsequent bone replacement phase.
[6] Bone resorption is performed by keel cells, which are multinuclear cells of the hematopoietic lineage. Keel cells adhere to the bone surface to form a tight sealing zone, followed by extensive membrane ruffling on its normal (ie, absorption) surface. This causes a closed extracellular compartment to be formed on the bone surface that is acidified by the proton pump in the ruffled membrane, and the keel cells secrete proteolytic enzymes there. The low pH of this compartment dissolves hydroxyapatite on the bone surface, while proteolytic enzymes digest this protein substrate. In this way, absorption lacuna, ie vesicles, is formed. At the end of this phase of the cycle, osteoblasts lay new protein substrates that are subsequently mineralized. In some disease states, such as osteoporosis and Paget's disease, the normal balance between bone absorption and bone production is broken, thus resulting in net loss of bone in each cycle. Ultimately, this weakens bones and creates an increased risk of fractures even with minor trauma.
[7] Several published papers have shown that cysteine protease inhibitors are effective at inhibiting keel cell mediated bone resorption and have shown an important role of cysteine protease in bone resorption. For example, Delaisse et al., Biochem. J., 1980, 192, 365] disclose a series of protease inhibitors in a rat bone organ culture system, while serine protease inhibitors have no effect while cysteine protease inhibitors (eg, leupeptin, Z-Phe-Ala-CHN ₂ ) Prevents bone absorption. Delaisse et al., Biochem. Biophys. Res. Commun., 1984, 125, 441 discloses that E-64 and leupetin are also effective in preventing bone resorption in vivo, which was measured by sharp changes in serum calcium in rats on 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 absorption in the rat cranial canal. Delaisse et al., Bone, 1987, 8, 305, Hill et al., J. Cell. Biochem., 1994, 56, 118 and Everts et al., J. Cell. Physiol., 1992, 150, 221 also report a correlation between inhibition of cysteine protease activity and bone uptake. Tezuka et al., J. Biol. Chem., 1994, 269, 11O6, Inaoka et al., Biochem. Biophys. Res. Commun., 1995, 206, 89, and Shi et al., FEBS Lett., 1995, 357, 129, show that cathepsin K (cysteine protease) is abundantly expressed in keel cells under the normal conditions and is the primary It is disclosed to be a cysteine protease.
[8] This abundant selective expression of cathepsin K in keel cells suggests that this enzyme is essential for bone absorption. Thus, selective inhibition of cathepsin K will provide an effective treatment for excessive bone loss diseases including gum disease such as osteoporosis, gingivitis and periodontitis, Paget's disease, malignant hypercalcemia and metabolic bone disease and the like. Cathepsin K levels have also been demonstrated to increase in the chondrocytes of osteoarthritis synovial membranes. Therefore, selective inhibition of cathepsin K will also be useful for treating excessive cartilage or stromal disorders, including osteoarthritis and rheumatoid arthritis and the like. Metastatic tumor cells also show high levels of proteolytic enzymes that degrade the surrounding substrate. Thus, selective inhibition of cathepsin K may also be useful for treating certain tumor diseases.
[9] Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones that irreversibly inhibit cysteine proteases such as cathepsin B, L, S, O 2 and crozain. Other classes of compounds such as aldehydes, nitriles, α-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy) methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds also inhibit cysteine proteases It was reported. See Palmer, id and references cited therein.
[10] U.S. Patent U.S. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine proteases. Published international applications WO 94/04172, European patent applications EP 0 525 420 A1, EP 0 603 873 A1 and EP 0 611 756 A2 inhibit cysteine protease cathepsin B, H and L. Alkoxymethyl ketones and mercaptomethyl ketones are described. International patent application PCT / US94 / 08868 and European patent application EP 0 623 592 A1 describe alkoxymethyl ketones and mercaptomethyl ketones that inhibit the cysteine protease IL-1βconvertase. Alkoxymethyl ketones and mercaptomethyl ketones have also been described as inhibitors of serine protease kininogenase (international patent application PCT / GB91 / 01479).
[11] Azapeptides designed to transport azaamino acids to the active sites of serine proteases and have good leaving groups are described in Elmore et al., Biochem. J., 1968, 107, 103, Garger et al., Biochem. J., 1974, 139, 555, Gray et al., Tetrahedron, 1977, 33, 837, Gupton et al., J. Bioi. Chem., 1984, 259, 4279 and Powers et al., J. Bioi. Chem., 1984, 259, 4288 and are known to inhibit serine proteases. See also, J. Med. Chem., 1992, 35, 4279 describe certain azapeptide esters as cysteine protease inhibitors.
[12] Antipine and leupetin are described in McConnell et al., J. Med. Chem., 33, 86, are described as reversible inhibitors of cysteine protease and also as inhibitors of serine proteases in Umezawa et al., 45 Meth. Enzymol. 678. E64 and synthetic analogs thereof are also well known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189 and Grind, Biochem. Biophys. Acta., 701, 328).
[13] 1,3-Diamido-propanone is described in US Pat. 4,749,792 and 4,638,01O are described as analgesics.
[14] Therefore, several protease inhibitors have been identified structurally. However, such known inhibitors are not considered suitable for use as therapeutic agents for animals, especially humans, because of the various disadvantages present. These disadvantages include lack of selectivity, cell disruption by cell toxins, low solubility and excessively fast plasma clearance. Therefore, there is a need for methods for treating diseases caused by pathological levels of proteases, in particular cysteine proteases, more particularly cathepsin, most particularly cathepsin K, and novel inhibitor compounds useful for such methods.
[15] The inventors of the present invention have now discovered a novel species of 4-amino-azepane-3-one compounds that are protease inhibitors, most particularly cathepsin K inhibitors.
[16] Summary of the Invention
[17] It is an object of the present invention to inhibit 4-amino-azpan-3-one carbonyl protease inhibitors, in particular cysteine and serine protease inhibitors, more particularly compounds that inhibit cysteine protease, more particularly papain phase and cysteine protease. Compounds, very more particularly compounds that inhibit cathepsin and cysteine proteases, most particularly compounds that inhibit cathepsin K, which inhibitors can be therapeutically alleviated by altering the activity of the protease Useful in the treatment of
[18] Thus, in one aspect, the present invention provides a compound 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 invention provides proteases, in particular cysteine and serine proteases, more particularly cysteine proteases, more particularly papain phase and cysteine proteases, very more particularly cathepsin and cysteine proteases, most particularly cathepsin K It provides a method of treating a disease that can be cured therapeutically by inhibiting the condition.
[22] In particular aspects, the compounds of the present invention are particularly useful for treating bone loss such as osteoporosis and gum disease such as gingivitis and periodontitis, or diseases characterized by excessive degradation of cartilage or stroma, such as osteoarthritis and rheumatoid arthritis.
[1] The invention generally relates to 4-amino-azpan-3-one protease inhibitors, in particular cysteine and serine protease inhibitors, more particularly compounds that inhibit cysteine proteases, more particularly papain superfamily cysteine proteases. Compounds that inhibit, very more particularly compounds that inhibit cathepsin and the family cysteine protease, most particularly compounds that inhibit cathepsin K. Such compounds are particularly useful for the treatment of diseases in which cysteine proteases are associated, especially bone or cartilage excess loss diseases such as osteoporosis, periodontitis and arthritis.
[23] The present invention provides compounds of formula I and their pharmaceutically acceptable salts, hydrates or solvates.
[24]
[25] Where
[26] R ¹ is Is selected from the group consisting of;
[27] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 9 C (O) -} , R 9 C (S)-, R ⁹ S0 _2- , R ⁹ 0C (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ (R ¹¹ ) NSO _2- , , , And R ⁹ S0 ₂ -R ¹¹ NC (O)-;
[28] R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group consisting of;
[29] R ³ and R ′ may be joined to form a pyrrolidine, piperidine or morpholine ring;
[30] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S)-, R ⁵ SO _2- , R ⁵ 0C (O)-, R ⁵ R ¹² NC (O)-, and R ⁵ R ¹² NC (S)-;
[31] 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, Het-C _{0 -6} alkyl;
[32] R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[33] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S)-, R ¹⁰ SO _2- , R ¹⁰ OC (O)-, R ¹⁰ R ¹³ NC (O)-, and R ¹⁰ R ¹³ NC (S)-;
[34] R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and ArC _0-6 alkyl;
[35] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 group consisting of alkyl;
[36] R ^1O is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 group consisting of alkyl;
[37] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _1-6 alkyl;
[38] R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[39] R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[40] R 'is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[41] R ″ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[42] R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 group consisting of alkyl;
[43] R ″ ″ is composed of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group;
[44] X is selected from the group consisting of CH ₂ , S, and O;
[45] Z is selected from the group consisting of C (O) and CH ₂ ;
[46] n is an integer of 1-5.
[47] In compounds of formula (I), R ¹ is If
[48] R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and Ar-C _{0 -6} alkyl;
[49] R ³ is preferably selected from the group consisting of H, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, and C _1-6 alkyl;
[50] R ³ is more preferably H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl -Ethyl, 1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl.
[51] R ³ is even more preferably selected from the group consisting of toluyl, isobutyl and cyclohexylmethyl.
[52] R ³ is most preferably isobutyl.
[53] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S)-, R ⁵ S0 _2- , R ⁵ OC (O)-, R ⁵ R ¹³ NC (O)-, and R ⁵ R ¹³ NC (S)-.
[54] R ⁴ is preferably selected from the group consisting of R ⁵ OC (O) —, R ⁵ C (O) — and R ⁵ SO ₂ —.
[55] R ⁴ is most preferably R ⁵ C (O)-.
[56] In some embodiments, R ⁴ is preferably methanesulfonyl.
[57] R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, or Het-C _{0 It} is selected from the group consisting of _-6 alkyl.
[58] Preferably R ⁵ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl.
[59] More preferably, especially when R ⁴ is R ⁵ C (O)-, R ⁵ is
[60] Methyl, in particular methyl halide, more particularly trifluoromethyl, in particular C _1-6 alkoxy substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxymethyl, in particular heterocycle substituted methyl, more particularly 2- Thiophenyl-methyl;
[61] Ethyl, especially piperidin-1-yl-ethyl;
[62] Butyl, especially aryl substituted butyl, more particularly 4- (4-methoxy) phenyl-butyl;
[63] Isopentyl;
[64] Cyclohexyl;
[65] Pentanyl, especially 4-pentanyl;
[66] Butenyl, especially aryl substituted butenyl, more particularly 4,4-bis (4-methoxyphenyl) -but-3-enyl;
[67] Acetyl;
[68] Phenyl, in particular phenyl substituted with one or more halogens, more particularly 3,4-dichlorophenyl and 4-fluorophenyl, in particular phenyl substituted with one or more aryloxy groups or C _1-6 alkoxy groups, more particularly 3,4-dime Oxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, in particular phenyl substituted with one or more C _1-6 alkyl sulfonyl groups, more particularly 4-methanesulfonyl-phenyl;
[69] benzyl;
[70] Naphthalenyl, especially naphthylene-2-yl;
[71] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[72] Furanyl, especially furan-2-yl, in particular substituted furanyl, for example 5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5- (3-tri Fluoromethyl-phenyl) -furan-2-yl, more particularly halogen substituted furanyl, even more particularly 5-bromo-furan-2-yl, more particularly aryl substituted furanyl, even more particularly 5- (4-chloro -Phenyl) -furan-2-yl, more particularly C _1-6 alkyl substituted furanyl, even more particularly 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl- Furan-2-yl, and 2,4-dimethyl-furan-3-yl;
[73] Tetrahydrofuranyl, tetrahydrofuran-2-yl;
[74] Benzofuranyl, in particular benzofuran-2-yl, and substituted benzofuranyl, more particularly 5- (2-piperazin-4-carboxylic acid tert-butyl ester-ethoxy) benzofuran-2-yl, 5- ( 2-morpholino-4-yl-ethoxy) -benzofuran-2-yl, 5- (2-piperazin-1-yl-ethoxy) benzofuran-2-yl, 5- (2-cyclohexyl -Ethoxy) -benzofuran-2-yl; Especially C _1-6 alkoxy substituted benzofuranyl, more particularly 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxybenzofuran-2-yl , In particular halogen substituted benzofuranyl, more particularly 5-fluorobenzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, in particular C _1-6 alkyl substituted benzofuranyl, most In particular 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; Also 5-fluoro-3-methyl-benzofuran-2-yl, 6-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4 -Methoxy-3-methyl-benzofuran-2-yl and 6-methoxy-3-methyl-benzofuran-2-yl;
[75] Naphtho [2,1-b] -furanyl, in particular naphtho [2,1-b] -furan-2-yl, alkyl substituted naphtho [2,1-b] -furanyl, in particular 1-methyl Naphtho [2,1-b] -furan-2-yl;
[76] Benzo [b] thiophenyl, in particular benzo [b] thiophen-2-yl; In particular C _1-6 alkoxy substituted benzo [b] thiophenyl, more particularly 5,6-dimethoxy-benzo [b] thiophen-2-yl;
[77] Quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl;
[78] Quinoxalinyl, especially quinoxalin-2-yl;
[79] 1,8-naphthyridinyl, especially 1,8-naphthyridin-2-yl;
[80] Indolyl, in particular indol-2-yl, in particular indol-6-yl, indol-5-yl, in particular C _1-6 alkyl substituted indolyl, more particularly N-methyl-indol-2-yl;
[81] Pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, in particular C _1-6 alkyl substituted pyridinyl, more particularly 2-methyl-pyridin-5-yl, and oxy-pyridinyl In particular 1-oxy-pyridin-2-yl and 1-oxy-pyridin-3-yl;
[82] Furo [3,2-b] pyridinyl, in particular furo [3,2-b] pyridin-2-yl, C _1-6 alkyl substituted furo [3,2-b] pyridinyl, especially 3- Methyl-furo [3,2-b] pyridin-2-yl;
[83] Thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, in particular C _1-6 alkyl substituted thiophenyl, more particularly 5-methyl-thiophen-2-yl and 5-methyl-thiophene- 3-yl, in particular halogen substituted thiophenyl, more particularly 4,5-dibromo-thiophen-2-yl;
[84] Thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl, more particularly C _1-6 alkyl substituted thieno [3,2-b] thiophene- 2-yl, more particularly 5-tert-butyl-3-methylthieno [3,2-b] thiophen-2-yl;
[85] Isoxazolyl, especially isoxazol-4-yl, in particular C _1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl;
[86] Oxazolyl, in particular oxazol-4-yl, more particularly 5-methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl; And
[87] 1H-benzoimidazolyl, in particular 1H-benzoimidazol-5-yl.
[88] When R ⁴ is R ⁵ S0 ₂ , R ⁵ is preferably selected from pyridin-2-yl or 1-oxo-pyridin-2-yl.
[89] R 'is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and HetC _0-6 alkyl.
[90] Preferably R 'is selected from the group consisting of H and naphthalen-2-ylmethyl.
[91] Most preferably R 'is H.
[92] R ″ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and HetC _0-6 alkyl.
[93] Most preferably R ″ is H.
[94] R ″ 'is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and Het-C _0-6 alkyl.
[95] R ″ 'is preferably selected from the group consisting of H and C _1-6 alkyl.
[96] R "'is more preferably selected from the group consisting of H, methyl and 6,6-dimethyl.
[97] R ″ 'is even more preferably selected from the group consisting of H and 6,6-dimethyl.
[98] Most preferably R ″ 'is H.
[99] In compounds of formula (I), R ¹ is If:
[100] R ³ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and Ar-C _0-6 Selected from the group consisting of alkyl.
[101] R ³ is preferably C _1-6 alkyl.
[102] R ³ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclohexylmethyl, and toluyl.
[103] R ″ ″ is a group consisting of C _1-6 alkyl, C _3-6 cycloalkylC _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Is selected from;
[104] R ″ ″ is preferably C _1-6 alkyl;
[105] R ″ ″ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl.
[106] R "" is most preferably methyl.
[107] In the compound, R ', R ", R"', R ⁴ , and R ⁵ are As described above.
[108] In compounds of formula I, of R ¹ If:
[109] n is preferably an integer from 1 to 5;
[110] R ′, R ″, R ″ ′, R ⁴ , and R ⁵ are such that R ¹ is As described in the above.
[111] n is most preferably 3.
[112] Ring is unsubstituted or substituted by one or more C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, C _2- 6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl, ArC _{0- 6} alkyl, or halogen.
[113] The ring is preferably unsubstituted.
[114] In the compounds of formula I, R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-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 R ⁹ SO ² R ¹¹ NC (O)-.
[115] More preferably R ² is Ar-C _0-6 alkyl, R ⁹ C (O)-, R ⁹ SO _2- , R ⁹ R ¹¹ NC (O)-and It is selected from the group consisting of.
[116] Even more preferably, R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) — and R ⁹ SO ₂ .
[117] Most preferably, R ² is R ⁹ SO ₂ .
[118] In this embodiment:
[119] R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, or HetC _0-6 alkyl, preferably H.
[120] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-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)-, R ¹⁰ R ¹⁴ NC (S)-, and R ⁷ is preferably Preferably R ¹⁰ OC (O).
[121] R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl, preferably C _1-6 Alkyl, more preferably isobutyl.
[122] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 and the group consisting of alkyl.
[123] R ⁹ is preferably selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl.
[124] More preferably, R ⁹ is
[125] methyl;
[126] Ethyl, especially C _1-6 alkyl-substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[127] profile;
[128] Butyl, in particular C _1-6 butyl, more particularly 3-methylbutyl;
[129] Tert-butyl, especially when R ² is R ⁹ 0C (O);
[130] Isopentyl;
[131] Phenyl, in particular halogen substituted phenyl, more particularly 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl , 4-chlorophenyl, in particular C _1-6 alkoxy phenyl, more particularly 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, in particular cyanophenyl, more particularly 2-cyanophenyl; Especially C _1-6 alkyl substituted phenyl, more particularly 4-ethylphenyl, 2-methyl phenyl, 4-methyl phenyl, especially C _1-6 alkyl sulfonyl substituted phenyl, more particularly 4-methanesulfonyl phenyl, and 2 Methanesulfonyl phenyl;
[132] Toluyl, in particular Het-substituted toluyl, more particularly 3- (pyridin-2-yl) toluyl;
[133] Naphthylene, in particular naphthyl-2-ene;
[134] Benzoic acid, especially 2-benzoic acid;
[135] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[136] Benzo [1,2,5] oxadiazolyl, in particular benzo [1,2,5] oxadiazol-4-yl;
[137] Pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, in particular 1-oxy-pyridinyl, more particularly 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-2-yl;
[138] Thiophenyl, in particular thiophenyl-2-yl;
[139] Thiazolyl, in particular thiazol-2-yl;
[140] 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, more particularly C _1-6 alkyl substituted imidazolyl, even more particularly 1-methyl-1H-imidazol-2 -Yl, 1-methyl-1H-imidazol-4-yl, and 1,2-dimethyl-1H-imidazol-4-yl;
[141] Triazolyl, in particular 1H- [1,2,4] triazolyl, more particularly 1H- [1,2,4] triazol-3-yl, in particular C _1-6 alkyl substituted 1H- [1,2,4 ] Triazolyl, more particularly 5-methyl-1H- [1,2,4] triazol-3-yl; And
[142] Isoxazolyl, in particular isoxazol-4-yl, in particular C _1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl
[143] It is selected from the group consisting of.
[144] 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.
[145] When R ² is R ⁹ SO ₂ R ¹¹ NC (O)-, R ⁹ is preferably Ar-C _0-6 alkyl, more preferably Ar, most preferably substituted phenyl, for example 2- Methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl.
[146] When R ² is R ⁹ C (O)-, R ⁹ is preferably C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and Het-C _0-6 alkyl, more preferably Is selected from the group consisting of 1-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl.
[147] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and HetC _0-6 alkyl.
[148] When R ² is R ⁹ SO ₂ R ¹¹ NC (O) —, R ¹¹ is preferably H.
[149] When R ² is Ar—C _0-6 alkyl, R ² is preferably selected from the group consisting of phenyl, especially substituted phenyl, more particularly halogen substituted phenyl, even more particularly 2-fluorobenzyl.
[150] When R ² is C _1-6 alkyl, R ² is preferably selected from the group consisting of 1-propyl, 1-butyl, and 1-pentyl.
[151] When R ² is Het-C _0-6 alkyl, Het-C _0-6 alkyl is preferably Het-methyl and in Het-methyl Het is preferably
[152] Pyridinyl, in particular pyridin-2-yl, in particular C _1-6 alkylpyridinyl, more particularly 6-methyl-pyridin-2-yl;
[153] Thiophenyl, in particular thiophen-2-yl, more particularly thiophen-2-yl or benzo [b] thiophen-2-yl;
[154] Thiazolyl, in particular thiazol-4-yl, for example 1- (2-morpholin-4-yl-thiazol-4-yl), and 1- (isothiazol-3-yl);
[155] 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, in particular C _1-6 alkyl substituted imidazolyl, more particularly 1-methyl-1H-imidazol-2- Work;
[156] Triazolyl, in particular 3H- [1,2,3] triazolyl, more particularly 3H- [1,2,3] triazol-4-yl, in particular C _1-6 alkyl substituted 3H- [1,2,3 ] Triazolyl, more particularly 3-phenyl-3H- [1,2,3] triazolyl-4-yl;
[157] Quinolinyl, in particular quinolin-2-yl, quinolin-2-yl;
[158] Furanyl, especially furan-2-yl, especially substituted furanyl, for example 5-ethyl-furan2-yl;
[159] Thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl, in particular C _1-6 alkyl substituted thieno [3,2-b] thiophenyl, in particular 3,4-dimethyl-thieno [3,2-b] thiophen-2-yl
[160] It is selected from the group consisting of.
[161] R ² is also preferably:
[162] H;
[163] Toluyl;
[164] Aryl substituted ethyl, especially 2-phenyl ethyl, 2- [3- (pyridin-2-yl) phenyl] ethyl.
[165] Preferred are compounds of formula I, wherein R " and R " 'are both H.
[166] More preferably,
[167] R ¹ is ego;
[168] R ² is Ar—C _0-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ , R ⁹ R ¹¹ NC (O) — and Is selected from the group consisting of;
[169] R ³ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, and Ar-C _0-6 group consisting of alkyl;
[170] R ⁴ is selected from the group consisting of R ⁵ OC (O) —, R ⁵ C (O) — and R ⁵ SO ₂ —;
[171] R ⁵ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and HetC _1-6 alkyl;
[172] R ⁶ is H;
[173] R ⁷ is R ¹⁰ OC (O);
[174] R ⁸ is C _1-6 alkyl;
[175] R ⁹ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and HetC _0-6 alkyl;
[176] R ¹⁰ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and HetC _0-6 alkyl;
[177] R 'is H;
[178] R ″ is H;
[179] R "'is H;
[180] Z is a compound of Formula I selected from the group consisting of C (O) and CH ₂ .
[181] More preferably, R ² is Ar-C _0-6 alkyl, R ⁹ C (O) - is a compound of formula I is selected from the group consisting of, R ⁹ SO _2.
[182] Also more preferred is
[183] R ¹ is ego;
[184] R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) — and R ⁹ SO ₂ ;
[185] R ³ is H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1 -Hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;
[186] R ⁴ is R ⁵ C (O) —;
[187] R ⁵ is methyl, in particular methyl halide, more particularly trifluoromethyl, in particular C _1-6 alkoxy substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxymethyl, especially heterocycle substituted methyl, more Especially 2-thiophenyl-methyl;
[188] Ethyl, especially piperidin-1-yl-ethyl;
[189] Butyl, especially aryl substituted butyl, more particularly 4- (4-methoxy) phenyl-butyl;
[190] Isopentyl;
[191] Cyclohexyl;
[192] Pentanyl, especially 4-pentanyl;
[193] Butenyl, especially aryl substituted butenyl, more particularly 4,4-bis (4-methoxyphenyl) -but-3-enyl;
[194] Acetyl;
[195] Phenyl, in particular phenyl substituted with one or more halogens, more particularly 3,4-dichlorophenyl and 4-fluorophenyl, in particular phenyl substituted with one or more aryloxy groups or C _1-6 alkoxy groups, more particularly 3,4-dime Oxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, in particular phenyl substituted with one or more C _1-6 alkyl sulfonyl groups, more particularly 4-methanesulfonyl-phenyl;
[196] benzyl;
[197] Naphthalenyl, especially naphthylene-2-yl;
[198] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[199] Furanyl, especially furan-2-yl, in particular substituted furanyl, for example 5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5- (3-tri Fluoromethyl-phenyl) -furan-2-yl, more particularly halogen substituted furanyl, even more particularly 5-bromo-furan-2-yl, more particularly aryl substituted furanyl, even more particularly 5- (4-chloro -Phenyl) -furan-2-yl, more particularly C _1-6 alkyl substituted furanyl, even more particularly 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl- Furan-2-yl, and 2,4-dimethyl-furan-3-yl;
[200] Tetrahydrofuranyl, in particular tetrahydrofuran-2-yl;
[201] Benzofuranyl, in particular benzofuran-2-yl, and substituted benzofuranyl, more particularly 5- (2-piperazin-4-carboxylic acid tert-butyl ester-ethoxy) benzofuran-2-yl, 5- ( 2-morpholino-4-yl-ethoxy) -benzofuran-2-yl, 5- (2-piperazin-1-yl-ethoxy) benzofuran-2-yl, 5- (2-cyclohexyl -Ethoxy) -benzofuran-2-yl; Especially C _1-6 alkoxy substituted benzofuranyl, more particularly 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxybenzofuran-2-yl , In particular halogen substituted benzofuranyl, more particularly 5-fluorobenzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, in particular C _1-6 alkyl substituted benzofuranyl, most In particular 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; Also 5-fluoro-3-methyl-benzofuran-2-yl, 6-fluoro-3-methylbenzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4- Methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl;
[202] Naphtho [2,1-b] -furanyl, in particular naphtho [2,1-b] -furan-2-yl, alkyl substituted naphtho [2,1-b] -furanyl, in particular 1-methyl Naphtho [2,1-b] -furan-2-yl;
[203] Benzo [b] thiophenyl, in particular benzo [b] thiophen-2-yl; In particular C _1-6 alkoxy substituted benzo [b] thiophenyl, more particularly 5,6-dimethoxy-benzo [b] thiophen-2-yl;
[204] Quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl;
[205] Quinoxalinyl, especially quinoxalin-2-yl;
[206] 1,8-naphthyridinyl, especially 1,8 naphthyridin-2-yl;
[207] Indolyl, in particular indol-2-yl, in particular indol-6-yl, indol-5-yl, in particular C _1-6 alkyl substituted indolyl, more particularly N-methyl-indol-2-yl;
[208] Pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, in particular C _1-6 alkyl substituted pyridinyl, more particularly 2-methyl-pyridin-5-yl, and oxy-pyridinyl In particular 1-oxy-pyridin-2-yl and 1-oxy-pyridin-3-yl;
[209] Furo [3,2-b] pyridinyl, in particular furo [3,2-b] pyridin-2-yl, C _1-6 alkyl substituted furo [3,2-b] pyridinyl, especially 3- Methyl-furo [3,2-b] pyridin-2-yl;
[210] Thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, in particular C _1-6 alkyl substituted thiophenyl, more particularly 5-methyl-thiophen-2-yl and 5-methyl-thiophene- 3-yl, in particular halogen substituted thiophenyl, more particularly 4,5-dibromo-thiophen-2-yl;
[211] Thieno [3,2-b] thiophene, in particular thieno [3,2-b] thiophen-2-yl, more particularly C _1-6 alkyl substituted thieno [3,2-b] thiophene- 2-yl, more particularly 5-tert-butyl-3-methyl-thieno [3,2-b] thiophen-2-yl;
[212] Isoxazolyl, especially isoxazol-4-yl, in particular C _1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl;
[213] Oxazolyl, in particular oxazol-4-yl, more particularly 5-methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl; And
[214] 1H-benzoimidazolyl, in particular 1H-benzoimidazol-5-yl.
[215] R ⁹ is
[216] methyl;
[217] Ethyl, especially C _1-6 alkyl-substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[218] profile;
[219] Butyl, in particular C _1-6 butyl, more particularly 3-methylbutyl;
[220] Tert-butyl, especially when R ² is R ⁹ 0C (O);
[221] Isopentyl;
[222] Phenyl, in particular halogen substituted phenyl, more particularly 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl , 4-chlorophenyl, in particular C _1-6 alkoxy phenyl, more particularly 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, in particular cyanophenyl, more particularly 2-cyanophenyl; Especially C _1-6 alkyl substituted phenyl, more particularly 4-ethylphenyl, 2-methyl phenyl, 4-methyl phenyl, especially C _1-6 alkyl sulfonyl substituted phenyl, more particularly 4-methanesulfonyl phenyl, and 2 Methanesulfonyl phenyl;
[223] Toluyl, in particular Het-substituted toluyl, more particularly 3- (pyridin-2-yl) toluyl;
[224] Naphthylene, in particular naphthyl-2-ene;
[225] Benzoic acid, especially 2-benzoic acid;
[226] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[227] Benzo [1,2,5] oxadiazolyl, in particular benzo [1,2,5] oxadiazol-4-yl;
[228] Pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, in particular 1-oxy-pyridinyl, more particularly 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-2-yl;
[229] Thiophenyl, in particular thiophenyl-2-yl;
[230] Thiazolyl, in particular thiazol-2-yl;
[231] 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, more particularly C _1-6 alkyl substituted imidazolyl, even more particularly 1-methyl-1H-imidazol-2 -Yl, 1-methyl-1H-imidazol-4-yl, and 1,2-dimethyl-1H-imidazol-4-yl;
[232] Triazolyl, in particular 1H- [1,2,4] triazolyl, more particularly 1H- [1,2,4] triazol-3-yl, in particular C _1-6 alkyl substituted 1H- [1,2,4 ] Triazolyl, more particularly 5-methyl-1H- [1,2,4] triazol-3-yl; And
[233] Isoxazolyl, in particular isoxazol-4-yl, in particular C _1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl.
[234] R 'is H;
[235] R "is H;
[236] R "'is H.
[237] More preferably,
[238] R ¹ is ego;
[239] R ² is R ⁹ S0 ₂ ;
[240] R ³ is isobutyl;
[241] R ⁴ is R ⁵ C (O);
[242] R ⁵ is 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinoline -2-yl, preferably 3-methyl-benzofuran-2-yl;
[243] R ⁹ is pyridin-2-yl and 1-oxy-pyridin-2-yl, preferably 1-oxy-pyridin-2-yl.
[244] R 'is H;
[245] R "'is H.
[246] Most preferably,
[247] R ⁵ is 3-methyl-benzofuran-2-yl;
[248] R ⁹ is a compound that is 1-oxy-pyridin-2-yl.
[249] Embodiment IA of the present invention provides compounds of Formula IA, and pharmaceutically acceptable salts, hydrates, and solvates thereof.
[250]
[251] Where
[252] R ¹ is Is selected from the group consisting of;
[253] R ² is C _1-6 alkyl, Ar-C _0-6 alkyl, HetC _0-6 alkyl, R ⁹ C (O)-, R ⁹ SO _2- , R ⁹ R ¹¹ NC (O)-and R ⁹ SO ₂ R ¹¹ NC (O) —;
[254] R ³ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and Ar-C _0-6 Selected from the group consisting of alkyl, preferably C _1-6 alkyl;
[255] R ³ and R ′ may be joined to form a pyrrolidine, piperidine or morpholine ring;
[256] R ⁴ is R ⁵ C (O) —;
[257] R ⁵ is selected from the group consisting of C _1-6 alkyl and Het-C _0-6 alkyl, preferably Het-C _0-6 alkyl;
[258] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 group consisting of alkyl;
[259] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and HetC _0-6 alkyl, preferably H;
[260] R 'is H;
[261] R "is H;
[262] R ″ ′ is selected from the group consisting of H and C _1-6 alkyl, preferably H;
[263] R ″ ″ is composed of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group;
[264] n is an integer of 1-5, Preferably n is 3.
[265] In embodiment IA, R ¹ is If
[266] R ³ is preferably C _1-6 alkyl;
[267] R ³ is more preferably selected from the group consisting of but-2-yl and isobutyl.
[268] R ³ is most preferably isobutyl.
[269] R ⁴ is R ⁵ C (O)-.
[270] R ⁵ is selected from the group consisting of C _1-6 alkyl and Het-C _0-6 alkyl, preferably Het-C _1-6 alkyl.
[271] More preferably, R ⁵ is
[272] Piperidin-ethyl, especially piperidin-1-yl-ethyl;
[273] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[274] Furanyl, especially furan-2-yl, in particular aryl substituted furanyl, for example 5- (3-trifluoromethyl-phenyl) -furan-2-yl, more particularly C _1-6 alkyl substituted furanyl , Even more particularly 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl;
[275] Benzofuranyl, in particular benzofuran-2-yl, in particular C _1-6 alkoxy substituted benzofuranyl, more particularly 5-methoxy-benzofuran-2-yl, in particular halogen substituted benzofuranyl, more particularly 5- Fluoro-benzofuran-2-yl, in particular C _1-6 alkyl substituted benzofuranyl, most particularly 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3 -Ethyl-benzofuran-2-yl; Also 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methylbenzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6 -Methoxy-3-methylbenzofuran-2-yl;
[276] Naphtho [2,1-b] -furanyl, in particular naphtho [2,1-b] -furan-2-yl, C _1-6 alkyl substituted naphtho [2,1-b] -furanyl, Especially 1-methyl-naphtho [2,1-b] -furan-2-yl;
[277] Benzo [b] thiophenyl, in particular benzo [b] thiophen-2-yl;
[278] Quinolinyl, in particular quinolin-2-yl;
[279] Quinoxalinyl, especially quinoxalin-2-yl;
[280] Pyridinyl, in particular pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, and oxy-pyridinyl, in particular 1-oxy-pyridin-2-yl and 1-oxy-pyridin-3-yl;
[281] Furo [3,2-b] pyridinyl, in particular furo [3,2-b] pyridin-2-yl, C _1-6 alkyl substituted furo [3,2-b] pyridin-2-yl, In particular 3-methyl-furo [3,2-b] pyridin-2-yl;
[282] Thiophenyl, in particular thiophen-3-yl, and thiophen-2-yl, C _1-6 alkyl substituted thiophenyl, especially 5-methyl-thiophen-2-yl and 5-methyl-thiophen-3- Work;
[283] Thieno [3,2-b] thiophene, especially thieno [3,2-b] thiophen-2-yl; And
[284] 1H-benzoimidazolyl, in particular 1H-benzoimidazol-5-yl.
[285] R ⁵ is more preferably 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxaline-2- One, and quinolin-2-yl.
[286] In embodiment IA, R ¹ is If:
[287] R ³ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and Ar-C _0-6 Selected from the group consisting of alkyl.
[288] R ³ is preferably selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and Ar-C _0-6 alkyl.
[289] R ³ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclohexylmethyl, and toluyl.
[290] R ″ ″ is composed of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group;
[291] R ″ ″ is preferably C _1-6 alkyl;
[292] R ″ ″ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl.
[293] Most preferably R ″ ″ is methyl.
[294] In these compounds, R 'and R ⁴ are As described for.
[295] In embodiment IA, R ¹ is If:
[296] n is an integer from 1 to 5; Preferably 3;
[297] R 'and R ⁴ are the above As described for.
[298] The cyclic ring is unsubstituted or at least one C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl, ArC _0-6 alkyl, or halogen.
[299] The cyclic ring is preferably unsubstituted.
[300] In embodiment IA, R ² is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁹ C (O)-, R ⁹ S0 _2- , R ⁹ R ¹¹ NC ( O)-, and R ⁹ SO ₂ R ¹¹ NC (O)-.
[301] More preferably R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ , and R ⁹ R ¹¹ NC (O) —.
[302] Even more preferably, R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) —, and R ⁹ SO ₂ .
[303] Most preferably R ² is R ⁹ S0 ₂ .
[304] In this embodiment, R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 and the group consisting of alkyl.
[305] R ⁹ is preferably selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl.
[306] More preferably, R ⁹ is
[307] Ethyl, especially C _1-6 alkyl-substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[308] Propyl, in particular prop-1-yl;
[309] Isopentyl;
[310] Butyl, in particular but-1-yl;
[311] Phenyl, in particular halogen substituted phenyl, more particularly 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl; Especially C _1-6 alkyl substituted phenyl, more particularly 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially C _1-6 alkyl sulfonyl substituted phenyl, more particularly 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl;
[312] Pyridinyl, in particular pyridin-2-yl, 1-oxy-pyridinyl, more particularly 1-oxy-pyridin-2-yl;
[313] 1H-imidazolyl, especially 1H-imidazol-2-yl C _1-6 alkyl substituted imidazolyl, especially 1-methyl-1H-imidazol-2-yl; And
[314] Isoxazolyl, in particular isoxazol-4-yl, C _1-6 alkyl substituted isoxazolyl, in particular '3,5-dimethyl-isoxazol-4-yl.
[315] 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.
[316] When R ² is R ⁹ SO ₂ R ¹¹ NC (O)-, R ⁹ is preferably Ar-C _0-6 alkyl, more preferably Ar, most preferably substituted phenyl, for example 2- Methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, 4-fluoro phenyl.
[317] When R ² is R ⁹ C (O)-, R ⁹ is preferably from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and Het-C _0-6 alkyl Selected, more preferably 1-oxy-pyridin-2-yl, 2-cyclohexyl ethyl, and isopentyl.
[318] When R ² is R ⁹ SO ₂ R ¹¹ NC (O) —, R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl. Preferably, in this embodiment R ¹¹ is H.
[319] R ² is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl, preferably C _1-6 alkyl and Het-C _0-6 alkyl.
[320] When R ² is Ar-C _0-6 alkyl, R ² is preferably phenyl, especially substituted phenyl, more particularly halogen substituted phenyl, even more particularly 2-fluorobenzyl.
[321] When R ² is C _1-6 alkyl, R ² is preferably selected from 1-propyl, 1-butyl, and 1-pentyl.
[322] When R ² is Het-C _0-6 alkyl, Het-C _0-6 alkyl is preferably Het-methyl and Het-methyl Het is preferably
[323] Pyridinyl, in particular pyridin-2-yl, C _1-6 alkylpyridinyl, in particular 6-methyl-pyridin2-yl;
[324] Thiophenyl, especially thiophen-2-yl;
[325] Benzo [b] thiophen-2-yl;
[326] Thiazolyl, in particular thiazol-4-yl, for example isothiazol-3-yl;
[327] 1H-imidazolyl, especially 1H-imidazol-2-yl, C _1-6 alkyl substituted imidazolyl, especially 1-methyl-1H-imidazol-2-yl;
[328] Triazolyl, in particular 3H- [1,2,3] triazolyl, more particularly 3H- [1,2,3] triazol-4-yl, in particular C _1-6 alkyl substituted 3H- [1,2,3 ] Triazolyl, more particularly 3-phenyl-3H [1,2,3] triazolyl-4-yl;
[329] Quinolinyl, in particular quinolin-2-yl, quinolin-2-yl;
[330] Furanyl, in particular furan-2-yl, especially substituted furanyl, for example 5-ethyl-furan-2-yl;
[331] Thieno [3,2-b] thiophene, especially thieno [3,2-b] thiophen-2-yl, C _1-6 alkyl substituted thieno [3,2-b] thiophen-2- One, in particular 3,4-dimethyl-thieno [3,2-b] thiophen-2-yl.
[332] Compounds of embodiment IA have the same uses as described throughout this specification for compounds of Formula (I). Compounds of embodiment IA may be formulated into pharmaceutical compositions and used in the methods of treatment as described above for the compounds of formula (I) throughout this specification.
[333] Compounds of formula (I) are selected from the following group which are particularly preferred embodiments of the invention:
[334] Example number Chemical name
[335] 1 {(S) -1- [1-((S) -2-benzyloxycarbonylamino-4-methyl-pentanoyl) -3-oxo-azpan-4-ylcarbamoyl} carbamic acid benzyl ester;
[336] 2 naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[337] 3 benzo [1,3] dioxol-5-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[338] 4 benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[339] 5 benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[340] 6 naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[341] 7 quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[342] 8 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[343] 9 4-{(S) -methyl-2-[(quinolin-2-carbonyl) -amino] pentanoylamino} -3-oxo-1- [2- (3-pyridin-2-yl-phenyl)- Acetyl] azpanium;
[344] 10 1-((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4-{(S) -4-methyl-2-[(2-quinoline-2-carbonyl) -amino] -Pentanoylamino) -3-oxo-azpanium;
[345] 11 1-benzoyl-4-((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl-pentanoylamino) -3-oxo-azpanium;
[346] 12 1-benzoyl-4-((S) -2- (4-fluoro-benzoylamino) -4-methyl-pentanoylamino) -3-oxo-azpanium;
[347] 13 3-oxo-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoyl Amino) -1- (4-methyl-pentanoyl) -azpanium;
[348] 14 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[349] 15 4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino) -3 Oxo-azepane-1-carboxylic acid phenylamide;
[350] 16 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-) 2-yl-phenyl) acetyl] -azpan-4-ylcarbamoyl} -butyl) amide;
[351] 17 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azepane-4-ylcarbamoyl) -3- Methyl-butyl] amide;
[352] 18 5- (2-Pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl ) -3-methyl-butyl] amide;
[353] 19 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl ) -3-methyl-butyl] amide;
[354] 20 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-) 2-yl-phenyl) ethyl] -azpan-4-ylcarbamoyl} -butyl) amide;
[355] 21 Naphthalene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -Butyl) amide;
[356] 22 1H-indole-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarba Moyl} -butyl) amide;
[357] 23 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[358] 24 benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[359] 25 Benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl } -Butyl) amide;
[360] 26 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azepane-4- Ylcarbamoyl] -butyl} amide;
[361] 27 naphthylene-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azpan-4-ylcarbamoyl] -butyl} amide;
[362] 28 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[363] 29 naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[364] 30 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -Azepan-4-ylcarbamoyl] -butyl} -amide;
[365] 31 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;
[366] 32 4-((S) -4-methyl-2-{[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3-methyl-1 -(3-oxo-azpan-4-ylcarbamoyl] -butyl} amide;
[367] 33 4-Methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl-acetyl] -azepan-4-yl} -amide;
[368] 34 ((S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane-4-ylcarbamoyl} -butyl)- Naphthylene-2-methyl-carbamic acid tert-butyl ester;
[369] 35 (S) -4-methyl-2-[(naphthylene-2-ylmethyl) -amino] -pentenoic acid [3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl ] -Azepan-4-yl} -amide;
[370] 36 4- [2- (2-{(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butylcarbamoyl} -Benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester;
[371] 37 5- (2-piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-butyl} -amide;
[372] 38 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide;
[373] 39 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl ) Ethyl] -azpan-4-ylcarbamoyl} -butyl) amide;
[374] 40 4- [2- (2-{(S) -3-methyl-1- [3-oxo-1- (3-pyridin-2-yl-phenyl) -ethyl [azepan-4-ylcarbamoyl] -Butylcarbamoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester;
[375] 41 5- (2-Piperizin-1-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-2) -Yl-phenyl) ethyl] -azpan-4-ylcarbamoyl} -butyl) amide;
[376] 42 (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide ;
[377] 43 (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl]- Azepan-4-yl} amide;
[378] 44 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine -2-yl-phenyl) acetyl] -azepane-4-ylcarbamoyl} -butyl) amide;
[379] 45 Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -3-methyl-butyl ]amides;
[380] 46 2,2,2-trifluoro-N-((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl phenyl) -acetyl] -azepane -4-ylcarbamoyl} -butyl) -N-naphthylene-2-ylmethyl-acetamide;
[381] 47 4-[(S)-(methanesulfonyl-naphthylene-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3-oxo-azane-1-carboxylic acid benzyl ester;
[382] 48 quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[383] 49 quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[384] 50 quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[385] 51 quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[386] 52 quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[387] 53 isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[388] 54 isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[389] 55 quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[390] 56 benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[391] 57 1,8-naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[392] 58 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[393] 59 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides;
[394] 60 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[395] 61 furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[396] 62 5-nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide ;
[397] 63 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarba Moyl] -butyl} amide;
[398] 64 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide;
[399] 65 tetrahydro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[400] 66 (S) -4-methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[401] 67 (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl ]-amides;
[402] 68 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-carbonyl) -azpan-4-ylcarbamoyl) -3-butyl] -amide ;
[403] 69 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-carbonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[404] 70 4-((S) -2-tert-butylcarbonylamino-4-methyl-pentanoylamino) -3-oxo-azepane-1-carboxylic acid benzyl ester;
[405] 71 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-methyl-1H-imidazole-4-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide;
[406] 72 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole-3-sulfonyl) -3-oxo-azane -4-ylcarbamoyl] butyl} amide;
[407] 73 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-3-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -Butyl} amide;
[408] 74 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1H-imidazol-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} amide ;
[409] 75 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[410] 76 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -Butyl} amide;
[411] 77 5- (4-oxy-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[412] 78 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[413] 79 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[414] 80 quinoline-3-carboxylic acid {(S) -1- (3,4-dichloro-benzene-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl)]-3-methyl-butyl} -amide;
[415] 81 5-hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-4 -Ylcarbamoyl] -butyl} amide;
[416] 82 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl)]-3 -Methyl-butyl} -amide;
[417] 83 2- (4-{(S) -2-{(benzofuran-2-carbonyl) -amino} -4-methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid ;
[418] 84 3- (4-{(S) -2-{(benzofuran-2-carbonyl) -amino] -4-methyl pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid;
[419] 85 Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide;
[420] 86 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide;
[421] 87 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] butyl} amide;
[422] 88 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide ;
[423] 89 (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[424] 90 (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[425] 91 (S) -4-Methyl-2- (3-phenyl-ureido) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[426] 92 benzofuran-2-carboxylic acid {(S) -1- [6,6-dimethyl-3-oxo-1- (pyridine-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides;
[427] 93 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-ylcarba Moyl] -butyl} amide;
[428] 94 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} amide;
[429] 95 Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[430] 96 Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide ;
[431] 97 thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[432] 98 1H-indole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides;
[433] 99 Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide;
[434] 100 Furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide ;
[435] 101 (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [3-oxo-1- (1-oxy-pyridine-2-sulfonyl)-azepan- 4-yl] -amide;
[436] 102 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides;
[437] 103 4-Fluoro-{(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-carbamoyl] -butyl} -benz amides;
[438] 104 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine2-sulfonyl) -Azepan-4-ylcarbamoyl] -butyl} -amide;
[439] 105 thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[440] 106 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide;
[441] 107 6-Methyl-N-{(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} Nicotinamide;
[442] 108 (S) -4-methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl]- Butyl} amide;
[443] 109 1H-indole-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[444] 110 Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl]- Butyl} amide;
[445] 111 3,4-Dihydro-2H-benzo [b] [1,4] dioxepin-7-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] butyl} amide;
[446] 112 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide;
[447] 113 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide;
[448] 114 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide;
[449] 115 (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-yl] -amide ;
[450] 116 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} amide;
[451] 117 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] butyl} amide;
[452] 118 benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} -amide;
[453] 119 Benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[454] 120 Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl]- 3-methyl-butyl} -amide;
[455] 121 Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-oxazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[456] 122 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[457] 123 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarba Moyl] -butyl} amide;
[458] 124 5-tert-Butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[459] 125 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide;
[460] 126 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} amide;
[461] 127 quinoline-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[462] 128 1-methyl-1H-indole-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azepane-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[463] 129 furan-2-carboxylic acid {[(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butylcarbamoyl] -methyl} -amide;
[464] 130 5-methoxy-benzofuran-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide;
[465] 131 quinoxaline-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[466] 132 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} amide;
[467] 133 (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid (1-methanesulfonyl-3-oxo-azpan-4-yl) -amide;
[468] 134 quinoline-2-carboxylic acid {[(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[469] 135 1-Methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[470] 136 furan-2-carboxylic acid ({(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butylcarbamoyl} -Methyl) -amide;
[471] 137 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[472] 138 quinoxaline-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[473] 139 (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -3-oxo-azepane- 4-yl] -amide;
[474] 140 Quinoline-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[475] 141 1-methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Methyl-butyl} amide;
[476] 142 Furan-2-carboxylic acid ({(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butylcarbamoyl} -Methyl) -amide;
[477] 143 5-methoxy-benzofuran-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[478] 144 quinoxaline-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl}- amides;
[479] 145 (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepane- 4-yl] -amide;
[480] 146 1-methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[481] 147 furan-2-carboxylic acid ({(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butylcarbamoyl} -Methyl) -amide;
[482] 148 5-methoxy-benzofuran-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[483] 149 quinoxaline-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl}- amides;
[484] 150 (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane- 4-yl] -amide;
[485] 151 Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[486] 152 5-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[487] 153 7-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[488] 154 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide;
[489] 155 3-Methyl-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[490] 156 Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[491] 157 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[492] 158 quinoxaline-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[493] 159 Benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} amide ;
[494] 160 5-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[495] 161 7-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[496] 162 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl]- 3-methyl-butyl} -amide;
[497] 163 5-Methyl-benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[498] 164 benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[499] 165 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[500] 166 (S) -4-methyl-2- (1-oxy-pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amides;
[501] 167 quinoxaline-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl}- amides;
[502] 168 5-methoxy-benzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide;
[503] 169 7-methoxy-benzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide;
[504] 170 5,6-dimethoxy-benzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azepane-4-ylcarba Moyl] -butyl} -amide;
[505] 171 3-Methyl-benzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} -amide;
[506] 172 Benzo [b] thiophene-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} -amide;
[507] 173 1-Methyl-1H-indole-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide;
[508] 174 quinoxaline-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide ;
[509] 175 Benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[510] 176 5-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[511] 177 7-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[512] 178 5,6-dimethoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide;
[513] 179 3-Methyl-benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[514] 180 benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[515] 181 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[516] 182 quinoxaline-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[517] 183 Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl}- amides;
[518] 184 5-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[519] 185 7-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[520] 186 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl]- 3-methyl-butyl} -amide;
[521] 187 3-Methyl-benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[522] 188 Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[523] 189 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} amide;
[524] 190 Quinoxaline-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} amide ;
[525] 191 Benzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide ;
[526] 192 Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(2,2 ', 4-triduterio) -3-oxo-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] butyl} amide;
[527] 193 benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[528] 194 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide;
[529] 195 benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
[530] 196 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
[531] 197 Benzofuran-2-carboxylic acid {(S) -3-methanesulfinyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide ;
[532] 198 benzofuran-2-carboxylic acid {[3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -methyl} -amide;
[533] 199 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} -amide;
[534] 200 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[535] 201 benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide;
[536] 202 benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide;
[537] 203 benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide;
[538] 204 1- (benzofuran-2-carbonyl) -pyrrolidine-2-carboxylic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[539] 205 3,4-dimethoxy-N-{(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } -Benzamide;
[540] 206 benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[541] 207 benzo [1,3] dioxol-5-carboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
[542] 208 (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-yl] -amide ;
[543] 209 benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-yl carbamoyl] -3-methyl -Butyl} -amide;
[544] 210 benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[545] 211 (S) -4-methyl-2- (quinolin-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[546] 212 (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[547] 213 Benzofuran-2-carboxylic acid-{(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-yl carbamoyl] -3-methyl-butyl}- amides;
[548] 214 N-{(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -3,4-dime Oxy-benzamide;
[549] 215 cyclohexanecarboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -amide;
[550] 216 (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (methanesulfonyl) -3-oxo-azpan-4-yl] -amide;
[551] 217 benzo [b] thiophene-2-carboxylic acid-{(S) -1- (1-methanesulfonyl) -3-oxo-azpan-4-yl carbamoyl) -3-methyl-butyl] -amide;
[552] 218 Benzo [1,3] dioxol-5-carboxylic acid-{(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-yl carbamoyl) -3-methyl-butyl] -amide ;
[553] 219 benzofuran-2-carboxylic acid-{(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-yl carbamoyl) -3-methyl-butyl] -amide;
[554] 220 N-[(S) -1- (1-Methanesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -3,4-dimethoxy-benzamide;
[555] 221 (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-yl] -amide ;
[556] 222 N-{(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -4-methanesulfonyl -1-benzamide;
[557] 223 Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-yl carbamoyl) -3-methyl -Butyl] amide;
[558] 224 Benzo [1,3] dioxol-5-carboxylic acid-{(S)-[1- (2-cyano-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl) -3-methyl -Butyl] amide;
[559] 225 (S) -4-methyl-2- [4-oxo-4-((4-phenoxy-phenyl) -butyrylamino} pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-yl] -amide;
[560] 226 N-{(S) -1-[(1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -3,4- Dimethoxy-benzamide;
[561] 227 cyclohexanecarboxylic acid {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -amide;
[562] 228 4-methanesulfonyl-N-{(S) -1- [4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl-benzamide;
[563] 229 4-methanesulfonyl-N-{(S) -1- [4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl-benzamide;
[564] 230 ({(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butylcarbamoyl} -carbamic acid benzyl ester;
[565] 231 (S) -2- [5- (4-methoxy-phenyl) -pentanoylamino] -4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Yl] -amide;
[566] 232 (S) -2- [2- (3-benzyloxy-4-methoxy-phenyl) -acetylamino] -4-methylpentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-yl] -amide;
[567] 233 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl ] -Butyl} amide;
[568] 234 (S) -4-methyl-2- (5-oxo-hexanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[569] 235 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} amides;
[570] 236 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarba Moyl] -butyl} amide;
[571] 237 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl ] Butyl} amide;
[572] 238 7-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl }amides;
[573] 239 5,6-dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azepane-4- Ylcarbamoyl] -butyl} amide;
[574] 240 (R) -1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -3-methyl-1-3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide;
[575] 241 (S) -1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -3-methyl-1- {3-oxo- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} amide;
[576] 242 benzofuran-2-carboxylic acid {(S) -2-cyclopropyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl] -amide;
[577] 243 Benzofuran-2-carboxylic acid {(S) -3-methylsulfanyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -propyl] -amide ;
[578] 244 Benzofuran-2-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl ]-amides;
[579] 245 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepane- 4-ylcarbamoyl] -butyl} amide;
[580] 246 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepane- 4-ylcarbamoyl] butyl} amide;
[581] 247 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl ] -Butyl} amide;
[582] 248 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepane-4-ylcarba Moyl] -butyl} amide;
[583] 249 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide;
[584] 250 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- {3-oxo-1- (pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -ethyl} -amide;
[585] 251 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- {3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -ethyl} -amide;
[586] 252 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [6-methyl-3-oxo-1- (pyridine-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide ;
[587] 253 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] ethyl} -amide;
[588] 254 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -ethyl} -amide;
[589] 255 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }-amides;
[590] 256 5,6-dimethoxy-benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] ethyl} -amide;
[591] 257 5,5-bis- (4-methoxy-phenyl) -pent-4-enoic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl]}-butyl} -amide;
[592] 258 Quinoline-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl] -amides;
[593] 259 naphthylene-1-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl ]-amides;
[594] 260 quinoline-8-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide;
[595] 261 naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[596] 262 naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide;
[597] 263 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-proprioyl) -azpan-4-ylcarbamoyl] -butyl}- amides;
[598] 264 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (4-methyl-pentanoyl) -azpan-4-ylcarbamoyl] -butyl} amide ;
[599] 265 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-carbonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide;
[600] 266 (S) -acetylamino-4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide;
[601] 267 quinoline-2-carboxylic acid {1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} -amide;
[602] 268 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-proprioyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[603] 269 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (4-methyl-pentanoyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[604] 270 quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide;
[605] 271 benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
[606] 272 benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
[607] 273 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides;
[608] 274 7-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides;
[609] 275 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazol-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides;
[610] 276 Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides;
[611] 277 1-methyl-1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepane-4-ylcarbamoyl]- Butyl} amide;
[612] 278 quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazol-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide;
[613] 279 quinoline-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide .
[614] The following compounds are also particularly preferred embodiments of the invention:
[615] 280 Benzofuran-2-carboxylic acid {(S) -1-[-(3-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-1-butyl}- amides;
[616] 281 (S) -4-Methyl-2- (3-piperidin-1-yl-propanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Yl] -amide;
[617] 282 Benzofuran-2-carboxylic acid {(S) -1-[-(4-ethyl-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide ;
[618] 283 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1- (1-oxy-pyridin-2-yl ) -Methanoyl] -azpan-4-ylcarbamoyl} -butyl) -amide;
[619] 284 Benzo [1,3] -dioxol-5-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-oxy-pyridin-2-yl) -methanoyl] -azepane -4-ylcarbamoyl} -butyl) -amide;
[620] 285 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide;
[621] 286 benzo [1,3] -dioxol-5-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azepane-4-ylcarbamoyl] -3 -Methyl-butyl} -amide;
[622] 287 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepane-4-ylcarbamoyl ] -3-methyl-butyl} -amide;
[623] 288 Benzo [1,3] -dioxol-5-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[624] 289 Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide ;
[625] 290 benzofuran-2-carboxylic acid [(S) -1- [3-oxo-1- (ethanesulfonyl-azpan-4-ylcarbamoyl) -3-methyl-1-butyl] -amide;
[626] 291 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} -amide;
[627] 292 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} -amide;
[628] 293 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;
[629] 294 3-Methyl-benzofuran-2-carboxylic acid {(R) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} -amide;
[630] 295 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -Azepan-4-ylcarbamoyl] -butyl} -amide;
[631] 296 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[632] 297 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[633] 298 benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[634] 299 3-Methyl-furan-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides;
[635] 300 quinoline-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[636] 301 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[637] 302 quinoxaline-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[638] 303 thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[639] 304 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[640] 305 5-methoxy-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[641] 306 3-Methyl-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[642] 307 benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[643] 308 3-Methyl-furan-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[644] 309 quinoline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[645] 310 Thieno [3,2-b] thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amides;
[646] 311 quinoxaline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[647] 312 thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[648] 313 5-Methyl-thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[649] 314 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1 -Butyl} -amide;
[650] 315 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Butyl} -amide;
[651] 316 benzo [b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Butyl} -amide;
[652] 317 3-Methyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-1-butyl }-amides;
[653] 318 2,5-dimethyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1 -Butyl} -amide;
[654] 319 quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide;
[655] 320 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3 -Methyl-1-butyl} -amide;
[656] 321 quinoxaline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide ;
[657] 322 Thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide ;
[658] 323 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Butyl} -amide;
[659] 324 5-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] butyl} -amide;
[660] 325 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide;
[661] 326 3-ethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} -amide;
[662] 327 4-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] butyl} -amide;
[663] 328 1-Methyl-naphtho [2,1-b] -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -Azepan-4-ylcarbamoyl] -butyl} -amide;
[664] 329 6-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] butyl} -amide;
[665] 330 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} -amide;
[666] 331 benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide;
[667] 332 3-Methyl-benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide ;
[668] 333 Benzo [b] thiophene-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide ;
[669] 334 Benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl} -Butyl) -amide;
[670] 335 3-Methyl-benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4- Ylcarbamoyl} -butyl) -amide;
[671] 336 Benzo [b] thiophene-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4- Ylcarbamoyl} -butyl) -amide;
[672] 337 Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Butyl) -amide;
[673] 338 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino)-methanoyl] -azepane-4-yl Carbamoyl} -butyl) -amide;
[674] 339 Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino)-methanoyl] -azepane-4-yl Carbamoyl} -butyl) -amide;
[675] 340 Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro benzenesulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Butyl) -amide;
[676] 341 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino) -methanoyl] -azepane-4- Ylcarbamoyl} -butyl) -amide;
[677] 342 Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino)-methanoyl] -azepane-4- Ylcarbamoyl} -butyl) -amide;
[678] 343 Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl} -Butyl) -amide;
[679] 344 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4- Ylcarbamoyl} butyl) -amide;
[680] 345 Benzo [b] thiophene-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4- Ylcarbamoyl} -butyl) -amide;
[681] 346 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} -amides;
[682] 347 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl ] -Butyl} -amide;
[683] 348 Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl ] -Butyl} -amide;
[684] 349 Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides;
[685] 350 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[686] 351 2,4-dimethylfuran-3-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[687] 352 Quinoxaline-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
[688] 353 thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[689] 354 quinoline-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[690] 355 4-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
[691] 356 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[692] 357 4-Methyl-furan-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides;
[693] 358 benzofuran-2-carboxylic acid [(S) -1- (1-butyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[694] 359 benzofuran-2-carboxylic acid [(S) -1- (1-propyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[695] 360 benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-benzyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[696] 361 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (2-morpholin-4-yl-thiazol-4-ylmethyl) -3-oxo-azpan-4-yl Carbamoyl] -butyl} -amide;
[697] 362 benzofuran-2-carboxylic acid {(S) -1- [1- (5-ethyl-furan-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amides;
[698] 363 benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethyl-thieno [3,2-b] thiophen-2-ylmethyl) -3-oxo-azepane-4 -Ylcarbamoyl] -3-methyl-butyl} -amide;
[699] 364 Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (3-phenyl-3H- [1,2,3] triazol-4-ylmethyl) -azane -4-ylcarbamoyl] -butyl} -amide;
[700] 365 benzofuran-2-carboxylic acid [(S) -1- [1- (isothiazol-3-ylmethyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl} -amide;
[701] 366 benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-thiophen-2-ylmethyl-azpan-4-ylcarbamoyl) -butyl] -amide;
[702] 367 Benzofuran-2-carboxylic acid [(S) -1- (1-benzo [b] thiophen-2-ylmethyl-3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl]- amides;
[703] 368 benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-pentyl-azpan-4-ylcarbamoyl) -butyl] -amide;
[704] 369 benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazol-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl] -Butyl} -amide;
[705] 370 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl}- amides;
[706] 371 2-oxy-pyridine-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl}- amides;
[707] 372 1H-benzoimidazole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl}- amides;
[708] 373 4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -1-methyl-3-oxo-1-pentyl-ase Panium;
[709] 374 Benzofuran-2-carboxylic acid {(S) -1- [1- (1,2-dimethyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3 -Methyl-butyl} -amide;
[710] 375 Benzofuran-2-carboxylic acid {(S) -1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[711] 376 benzofuran-2-carboxylic acid {(S) -1- [1- (4-methanesulfonyl-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl}- amides;
[712] 377 benzofuran-2-carboxylic acid {(S) -1- [1- (2-methanesulfonyl-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl}- amides;
[713] 378 Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-isoxazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl -Butyl} -amide;
[714] 379 3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} -amide;
[715] 380 3-Methyl-benzofuran-2-carboxylic acid {1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -cyclopentyl} -amide; And
[716] 381 furo [3,2-b] -pyridine-2-carboxylic acid {(S) -3-methyl-1-[-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} -amide.
[717] Particularly preferred compounds of embodiment IA are Examples numbers 280 to 381 in the list above.
[718] Specific representative compounds of the present invention are described in Examples 1-33.
[719] Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds of the present invention are more morphologically stable at carbon center alpha for ketones.
[720] The present invention includes deuterated analogs of the compounds of the present invention. Representative examples of such deuterated compounds are described in Example 192. Representative synthetic routes to the deuterated compounds of the present invention are described in Scheme 4 below. The deuterated compounds of the present invention exhibit superior chiral stability compared to protonated isomers.
[721] Where possible, the present invention includes quaternary salts of the compounds of the present invention. Representative examples of such quaternary salts are described in Example 373. Representative synthetic routes of the quaternary salts of the present invention are described in Scheme 6 below.
[722] <Definition>
[723] The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of the present invention. Prodrugs are any covalently bound compound that releases the active patent drug of Formula I in vivo. If there are chiral centers or other forms of isomeric centers in the compounds of the present invention, all such forms of the isomer (s), including enantiomers and diastereomers, are included in the present invention. The compounds of the invention comprising chiral centers may be used as racemic mixtures (mixtures rich in enantiomers) or may be used separately for each isomer by separating the racemic mixtures using well known techniques. If the compound has an unsaturated carbon-carbon double bond, both the cis (Z) and trans (E) isomers are included within the scope of the present invention. Where a compound exhibits tautomeric forms, such as keto-enol tautomers, each tautomeric form is considered to be within the scope of the present invention, whether the tautomers are in equilibrium or mainly in one form. .
[724] In no case is the meaning of any substituent in Formula (I) or any subformula thereof independent of one another in any case, unless specifically defined otherwise.
[725] Abbreviations and symbols commonly used in the art of peptides and chemistry are used herein to describe the compounds of the present invention. Generally, amino acid abbreviations are described in Eur. J. Biochem., 158, 9 (1984), follows the IUPAC-IUB Joint Commission on Biochemical Nomenclature.
[726] A "protease" is an enzyme that catalyzes the cleavage of amino bonds of peptides and proteins by nucleophilic substitution at the amide binding moiety and ultimately causes hydrolysis. Such proteases include cysteine proteases, serine proteases, aspartic acid proteases and metalloproteases. The compounds of the present invention can bind stronger to the enzyme than the substrate and are therefore generally not cleaved even after enzymatic catalyzed attack by nucleophiles. Thus, the compounds of the present invention act as inhibitors because they competitively prevent proteases from recognizing and hydrolyzing natural substrates.
[727] The term "amino acid" as used herein refers to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine Means D- or L- isomer.
[728] As used herein, "C _1-6 alkyl" includes substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and It is meant to include hexyl and their simple aliphatic isomers. C _1-6 alkyl is OR ¹⁴ , C (O) R ¹⁴ , SR ¹⁴ , S (O) R ¹⁴ , NR ¹⁴ ₂ , R ¹⁴ NC (O) OR ⁵ , CO ₂ R ¹⁴ , CO ₂ NR ¹⁴ ₂ , N (C═NH) NH ₂ , Het, C _3-6 cycloalkyl and Ar may be optionally substituted by a moiety selected from the group consisting of R ⁵ is H, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl is selected from -C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl, R ¹⁴ is H, is selected from C _1-6 alkyl, Ar-C _0-6 alkyl and _heteroaryl-O -C ₆ group consisting of alkyl.
[729] As used herein, "C _3-6 cycloalkyl" is substituted and unsubstituted cyclopropane, cyclobutane. It is meant to include cyclopentane and cyclohexane.
[730] As used herein, "C _2-6 alkenyl" refers to an alkyl group having 2 to 6 carbons, wherein the carbon-carbon single bond is replaced with a carbon-carbon double bond. C _2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and various isomers of pentene and hexene. It also includes both cis and trans isomers.
[731] "C _2-6 alkynyl" means an alkyl group having from 2 to 6 carbons, wherein the carbon-carbon single bond is replaced with a carbon-carbon triple bond. C _2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and simple isomers of fentin and hexine.
[732] "Halogen" means F, Cl, Br and I.
[733] "Ar" or "aryl" is optionally one or more Ph-C _0-6 alkyl; _{Het-C O-6} alkyl; C _1-6 alkoxy; _{Ph-C O-6} alkoxy; _{Het-C O-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 (where R ¹⁵ and R ¹⁶ is H, C _1-6 alkyl, Ph-C _O-6 alkyl, naphthyl _- C _O-6 alkyl or Het-C _O-6 alkyl, R ¹⁷ is phenyl, naphthyl or C _1-6 alkyl Phenyl or naphthyl).
[734] As used herein, "Het" or "heterocyclic" refers to a saturated or unsaturated 5-7 membered stable monocyclic heterocyclic ring, 7-10 membered stable bicyclic heterocyclic ring or 11-18 membered. And a stable tricyclic heterocyclic ring of which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, 0 and S, wherein nitrogen and sulfur heteroatoms may be optionally oxidized And nitrogen heteroatoms may optionally be quaternized), any one of these heterocyclic rings including any bicyclic group fused to a benzene ring. The heterocyclic ring may be bonded to any heteroatom or carbon atom to form a stable structure, and 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 May be optionally substituted by. Examples of such heterocycles are triazolyl, thiadiazolyl, oxdiazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl, as well as piperidinyl, piperazinyl, 2 Oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl , Imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclyl Dinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo [b] thiophenyl, thieno [3,2-b] thiophenyl, benzo [1,3] dioxolyl, 1,8-naphthyridinyl, pyranyl, tetrahydrofuranyl, tetrahydropyranyl, Thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl, which are available and stable by conventional chemical synthesis. As used herein, the term hetero atom means oxygen, nitrogen and sulfur.
[735] Throughout this application the term C ₀ means that there is no substituent immediately following. For example, if C is zero at ArC _O-6 alkyl moiety is a substituent such as phenyl Ar. Conversely, if ArC _O-6 alkyl is defined as a particular aromatic group, such as phenyl, then the C value should be understood as zero.
[736] Certain radical groups are denoted abbreviated herein. t-Bu means tert-butyl radical, Boc means t-butyloxycarbonyl radical, Fmoc means fluorenylmethoxycarbonyl radical, Ph means phenyl radical, Cbz means benzyloxy Mean carbonyl radical.
[737] Certain reactants are herein abbreviated. m-CPBA means 3-chloroperoxybenzoic acid, EDC means N-ethyl-N '(dimethylaminopropyl) -carbodiimide, DMF means dimethyl formamide, DMSO stands for dimethyl sulfoxide TEA means triethylamide, TFA means trifluoroacetic acid, and THF means tetrahydrofuran.
[738] <Manufacturing method>
[739] Compounds of formula (I) can be prepared in a similar manner as outlined in Schemes 1, 2 and 3. Diene 2 is obtained by alkylating tert-butyl N-allylcarbamate (1) with a base such as sodium hydride and 5-bromo-1-pentene. Bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride olefins developed by 2,6-diisopropylphenylimido neophilidene molybdenum bis (tert-butoxide) or Grubbs Treatment of 2 with a metathesis catalyst yields azepine 3. Epoxide 4 is obtained by epoxidizing 3 with standard oxidants common in the art such as m-CPBA. A nucleophilic epoxide ring opening reaction is carried out using a reagent such as sodium azide to obtain azido alcohol (not shown), which is conventional in the art, such as 1,3-propanedithiol and triethylamine in methanol. It can be reduced to amino alcohol 5 using hydrogen gas under phosphorus conditions or in the presence of a catalyst such as palladium on carbon. The amine salt 6 is obtained by acylating 5 with an acid such as Cbz-leucine in the presence of a coupling agent such as DEC and then removing the BOC protecting group under acidic conditions. Coupling 6 with Cbz-leucine using a coupling agent such as EDC to obtain an intermediate alcohol (not shown), which is oxidized using an oxidizing agent such as pyridine sulfur trioxide complex in DMSO and triethylamine to give ketone 7.
[740]
[741] Reagents and conditions: a.) NaH, 5-bromo-1-pentene, DMF; b.) 2,6-diisopropylphenylimido neophilidene molybdenum 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.
[742] Compounds of formula I, wherein R ¹ and R ² are amides, can be prepared by the general method outlined in Scheme 2. N-Cbz allyl amine (8) is alkylated with a base such as sodium hydride and 5-bromo-1-pentene to give diene 9. Azepine 10 is obtained by treating 9 with a bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride olefin metathesis catalyst developed by Grubbs. 10 is epoxidized with a standard oxidant such as m-CPBA, which is conventional in the art to obtain epoxide 11. Performing a nucleophilic epoxide ring opening reaction with a reagent such as sodium azide to obtain azido alcohol (not shown), which is reduced to amino alcohol 12 using a reducing agent such as propanedithiol in the presence of triethylamine You can. Coupling agents such as N-Boc leucine and EDC are acylated 12 and the Cbz protecting group is removed under hydrocracking conditions to give amine 13. Intermediate 14 is obtained by coupling 13 to carboxylic acid using a coupling agent such as EDC and then removing the acid labile N-Boc protecting group using an acid such as HCl or TFA. Acylating 14 with carboxylic acid in the presence of coupling agents conventional in the art such as EDC affords an intermediate alcohol (not shown) which is oxidized with pyridine sulfur trioxide complex in DMSO and triethylamine to give ketone 15.
[743]
[744] 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 C0 ₂ H, EDC, CH ₂ Cl ₂ ; k.) Pyridine sulfur trioxide complex, DMSO, TEA.
[745] 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. After treatment with aldehyde, reductive amination of 13 is carried out by a reducing agent such as sodium triacetoxyborohydride. The N-Boc group is then deprotected under acidic conditions to afford amine salt 16. Coupling acid chloride with carboxylic acid or 16 in the presence of a coupling agent such as EDC conventional in the art and oxidizing an intermediate alcohol (not shown) using an oxidizing agent such as pyridine sulfur trioxide complex gives ketone 17. Alternatively, amine 13 is treated with isocyanate followed by deprotection of the N-Boc group to give amine salt 18. Acylation and oxidation yields ketone 19. Treatment with sulfonyl chloride further derivatizes amine 13 followed by deprotection of the N-Boc group to give amine salt 20. Acylation and oxidation afford ketone 21.
[746]
[747] 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.) RNCO, base; f.) R ₁ S0 ₂ Cl, TEA, CH ₂ Cl ₂ .
[748] The deuterated compound of Example 192 can be conveniently prepared according to Example 4. Those skilled in the art will understand how to prepare any of the deuterated compounds of the present invention from Example 192 and Scheme 4.
[749] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(2,2 ', 4-triduterio) -3-oxo-1- (pyridine-2-sulfonyl) -azane- Individual diastereomers of 4-ylcarbamoyl] -butyl} amide 31 and 32 can be prepared as outlined in Scheme 4. 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 diene 23. Treatment of diene 23 with bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride developed by Grubbs yields 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester 24 . Epoxide 25 is obtained by epoxidizing azepine 24 with standard oxidants common in the art such as m-CPBA. Nucleophilic epoxidation ring opening 25 is carried out with a reagent such as sodium azide to obtain azido alcohol (not shown).
[750]
[751] 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.) 10% Pd / C, H ₂ ; h.) 2-pyridinesulfonyl chloride, TEA, CH ₂ Cl ₂ ; i.) 4N HCl / dioxane, methanol; j.) benzofuran-2-carboxylic acid, EDC, CH ₂ Cl ₂ ; k.) pyridine sulfur trioxide complex, DMSO, TEA; l.) CD ₃ 0D: D ₂ O (10: 1), TEA; m.) HPLC separation.
[752] The intermediate azido alcohol can be reduced to amino alcohol 26 under conditions common in the art such as 1,3-propanedithiol and triethylamine in methanol, or using triphenylphosphine in tetrahydrofuran and water. . Acylation of 26 can be performed using an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC. Amine 27 is obtained by removing the benzyloxycarbonyl protecting group using hydrogen gas in the presence of 10% Pd / C. Treatment of amine 27 with 2-pyridinesulfonyl chloride in the presence of triethylamine or saturated sodium bicarbonate and CH ₂ Cl ₂ followed by removal of the tert-butoxycarbonyl protecting group under acidic conditions gives 28. Intermediate alcohol 29 can be obtained by coupling 28 with benzofuran-2-carboxylic acid using a coupling agent such as EDC. Ketone 30 can be obtained as a mixture of diastereomers by oxidizing alcohol 29 using an oxidizing agent such as sulfur trioxide pyridine complex in DMSO and triethylamine. Treatment of ketone 30 with triethylamine in CD ₃ OD: D ₂ O under reflux yields the deuterated analog as a mixture of diastereomers, which is separated by HPLC to give deuterated compounds 31 and 32.
[753] Compounds of formula (I) can also be prepared as outlined in Scheme 5. The amine of compound 12 can be protected with di-tert-butyldicarbonate to afford N-Boc derivative 33 (Scheme 2). By treating 33 with hydrogen gas in the presence of a catalyst such as 10% Pd / C, the benzyloxycarbonyl protecting group can be removed to give amine 34. Treatment of amine 34 with sulfonyl chloride, such as 2-pyridinesulfonyl chloride, in the presence of a base such as N-methylmorpholine or triethylamine yields sulfonamide derivative 35. An intermediate 36 can be obtained by removing the tert-butoxycarbonyl protecting group with an acid such as hydrochloric acid. The alcohol intermediate 37 is obtained by coupling 36 with an acid such as N-Boc-cyclohexylalanine in the presence of a coupling agent such as HBTU or polymer supported EDC, which is conventional in the art. Under acidic conditions the tert-butoxycarbonyl protecting group is removed to give amine 38. In the presence of a coupling agent such as HBTU or polymer supported EDC, 38 is coupled with an acid such as benzofuran-2-carboxylic acid to obtain alcohol 39. Ketone 40 can be obtained by oxidizing alcohol 39 with an oxidizing agent such as pyridine sulfur trioxide complex in DMSO and triethylamine, or Dess-Martin periodinan, which are conventional in the art.
[754]
[755] Reagents and Conditions: (a) di-tert-butyldicarbonate, THF; (b) H ₂ , 10% Pd / C, EtOAc; (c) 2-pyridylsulfonyl chloride, TEA; (d) HCl, EtOAc; (e) N-Boc-cyclohexylalanine, P-EDC, CH ₂ Cl ₂ ; (f) HCl, CH ₂ Cl ₂ ; (g) benzofuran-2-carboxylic acid, P-EDC, CH ₂ Cl ₂ ; (h) Dess-Martin periodinan, methylene chloride.
[756] The quaternized 4-amino-azepane-3-one compounds of the present invention can be conveniently prepared according to Scheme 6. From Scheme 6 the skilled person will understand how to prepare the quaternized 4-amino-azepane-3-one compound of the present invention. Reductive amination can be achieved by treating aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. The N-Boc group is then deprotected under acidic conditions to afford amine salt 16. Treatment of 16 with acid chlorides or carboxylic acids in the presence of coupling agents such as EDCs conventional in the art, followed by oxidation of intermediate alcohols (not shown) with oxidants such as pyridine sulfur trioxide complexes yields ketone 17. By treating with an alkylating agent such as iodomethyl, the amine of 17 can be quaternized to yield quaternized amine salt 41.
[757]
[758] 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.) iodomethane.
[759] Starting materials used herein are commercially available amino acids, or prepared by conventional methods well known to those of ordinary skill in the art, and described in standard reference books, eg, COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience).
[760] Coupling methods for forming amide bonds herein are generally well known in the art. Peptide synthesis methods are generally described in 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 JM Stewart and JD Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. (These are generally examples of techniques and are hereby incorporated by reference). have.
[761] Synthetic methods for preparing compounds of the present invention often use protecting groups to mask reactive functional groups or minimize unwanted 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 the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof known in the art. Methods of protection and deprotection and substitution reactions of amino protecting groups with other residues are well known.
[762] Acid addition salts of compounds of formula (I) are prepared from the parent compound and 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 in a suitable solvent. It is prepared by standard methods. Certain compounds form acceptable internal salts or zwitter ions. The parent compound may be selected from an excess of alkaline reagents containing suitable cations such as hydroxides, carbonates or alkoxides; Or cationic salts by treatment with a suitable 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 (eg acetate and trifluoroacetate), benzoates and sulfonates (eg mesylate) are examples of anions present in pharmaceutically acceptable salts. Quaternary ammonium salts are prepared by treating the parent amine compound with excess alkyl halide, for example methyl iodide.
[763] The invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. Thus, the compounds of formula (I) can be used for the preparation of a medicament. Pharmaceutical compositions of the compounds of formula (I) prepared as described above may be formulated as solutions for parenteral administration or lyophilized powder. The powder may be reconstituted by adding a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation can be an aqueous solution that is buffered and isotonic. Examples of suitable diluents are normal isotonic saline, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are particularly suitable for parenteral administration, but can also be used for oral administration or can be contained in metered dose inhalers or spray nebulizers. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
[764] Alternatively, these compounds may be encapsulated, tableted, or prepared in emulsion or syrup for oral administration. Pharmaceutically acceptable solid or pharmaceutical carriers may be added to enhance or stabilize the composition or to facilitate the preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, white earth, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also comprise a sustained release material, for example glyceryl monostearate or glyceryl distearate, alone or in combination with wax. The amount of solid carrier may vary but will preferably be from about 20 mg to about 1 g per dosage unit. Pharmaceutical formulations include grinding, mixing, granulating and compacting (if necessary) for tablet form; Or in accordance with conventional techniques of pharmaceuticals, including grinding, mixing and filling, for hard gelatin capsule forms. If a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. The liquid formulations can be administered orally directly or by filling into soft gelatin capsules.
[765] For rectal administration, the compounds of the present invention may be formulated into suppositories in combination with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol.
[766] <New intermediate>
[767] With reference to the process for preparing compounds of formula (I) described in Schemes 1-4 above, the skilled artisan will understand that the present invention includes all novel intermediates necessary to prepare compounds of formula (I). In particular, the present invention provides compounds of formula II, salts, hydrates and solvates thereof:
[768]
[769] Where
[770] R ¹ is ; Is selected from the group consisting of;
[771] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, ArC _0-6 alkyl, Het-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 R ⁹ SO ₂ R ¹¹ NC (O) —;
[772] R ³ consists of H, C _1-6 alkyl, C _3-6 cycloalkylC _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl, and ArC _0-6 alkyl Selected from the group;
[773] R ³ and R ′ may be linked to form a pyrrolidine, piperidine or morpholine ring;
[774] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S)-, R ⁵ SO _2- , R ⁵ OC (O)-, R ⁵ R ¹² NC (O)-, and R ⁵ R ¹² NC (S)-;
[775] 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, Het-C _{0 -6} alkyl;
[776] R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;
[777] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S)-, R ¹⁰ SO _2- , R ¹⁰ (OC) (O)-, R ¹⁰ R ¹³ NC (O)-, and R ¹⁰ R ¹³ NC (S)-;
[778] R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl;
[779] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 group consisting of alkyl;
[780] R ¹⁰ is independently selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkylC _0-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl;
[781] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[782] R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[783] R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[784] R 'is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[785] R ″ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl;
[786] R "'is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 and the group consisting of alkyl;
[787] R ″ ″ is composed of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group;
[788] n is an integer of 1-5.
[789] With reference to embodiment IA, novel intermediates of formula IIA of the present invention, pharmaceutically acceptable salts, hydrates and solvates thereof are included:
[790]
[791] Where
[792] R ¹ is Is selected from the group consisting of;
[793] R ² is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ −, R ⁹ R ¹¹ NC (O) —, and R ⁹ SO ₂ R ¹¹ NC (O) — is selected from the group consisting of;
[794] R ³ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and Ar-C _0-6 Selected from the group consisting of alkyl, preferably C _1-6 alkyl;
[795] R ³ and R ′ may be joined to form a pyrrolidine, piperidine or morpholine ring;
[796] R ⁴ is R ⁵ C (O) —;
[797] R ⁵ is selected from the group consisting of C _1-6 alkyl and Het-C _0-6 alkyl, preferably Het-C _0-6 alkyl;
[798] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 group consisting of alkyl;
[799] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and HetC _0-6 alkyl, preferably H;
[800] R 'is H;
[801] R "is H;
[802] R ″ ′ is selected from the group consisting of H and C _1-6 alkyl, preferably H;
[803] R ″ ″ is composed of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group, preferably C _1-6 alkyl;
[804] n is an integer of 1-5, Preferably n is 3.
[805] The following compounds are preferred novel intermediates:
[806] [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid benzyl ester;
[807] (S) -2-Amino-4-methyl-pentanoic acid (1-benzyl-3-hydroxy-azpan-4-yl) -amide;
[808] (S) -2-Amino-4-methyl-pentanoic acid {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) acetyl] -azpan-4-yl} -amide;
[809] {(S) -1- [4-((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azpan-1-ylmethyl] -3-methyl-butyl} -carr Chest acid benzyl ester;
[810] (S) -2-Amino-4-methyl-pentanoic acid- (1-benzoyl-3-hydroxy-azpan-4-yl) -amide;
[811] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-l- (4-methyl-pentanoyl) -azpan-4-yl] -amide;
[812] (S) -2-Amino-4-methyl-pentanoic acid- (1-benzenesulfonyl-3-hydroxy-azpan-4-yl) -amide;
[813] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} amide;
[814] 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide;
[815] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} amide;
[816] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide;
[817] Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide ; And
[818] Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides.
[819] <Synthesis method of the compound of the present invention>
[820] With reference to Schemes 1-6, the present invention provides a process for synthesizing a compound of Formula I comprising oxidizing an appropriate compound of Formula II with an oxidant to provide a compound of Formula I as a mixture of diastereomers do. Preferably the oxidant is a sulfur trioxide pyridine complex in DMSO and triethylamine.
[821] With reference to Scheme 4, the present invention also provides a process for the synthesis of deuterated compounds of formula (I). Specifically, if deuterated isomers are desired, an additional step is added to the synthesis to deuterate the protonated isomers using deuteration agents after the oxidation step to provide the deuterated compounds of formula I as mixtures of diastereomers. Preferably, the plasticizer is CD ₃ OD: D ₂ 0 (10: 1) in triethylamine.
[822] The method also comprises the step of separating the diastereomers of formula (I) by separation means, preferably by high pressure liquid chromatography (HPLC).
[823] With reference to Scheme 6, the present invention also provides a process for the synthesis of quaternary salts of 4-amino-azpan-3-one compounds of formula (I).
[824] <Usefulness of the present invention>
[825] Compounds of formula I are protease inhibitors, in particular cysteine and serine protease inhibitors, more particularly cysteine protease inhibitors, more particularly papain phase and cysteine protease inhibitors, very more particularly cathepsin and cysteine protease inhibitors, most particularly cathepsin It is useful as a K inhibitor. The present invention also provides useful compositions and formulations of the compounds, including pharmaceutical compositions and formulations of the compounds.
[826] The compounds are cysteine, including infections with alveolar nephropathy, malaria, cancer metastasis, familial encephalopathy, muscular dystrophy, muscular dystrophy, etc., as well as alveolar worms, paleomorphs, tryp-sanoma bruisei, and Cretidia pushkulata Diseases involving proteases, and particularly diseases involving cathepsin K, most particularly gum diseases including osteoporosis, gingivitis and periodontitis, arthritis, more particularly osteoarthritis and rheumatoid arthritis, Paget's disease, malignant hypercalcemia and metabolic bone Useful for treating excessive bone or cartilage loss diseases, including diseases.
[827] 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.
[828] The invention also provides for the treatment of diseases caused by pathological levels of proteases, in particular cysteine and serine proteases, more particularly cysteine proteases, more particularly papain phase and cysteine proteases, and even more particularly cathepsin and cysteine proteases. Provided are methods, which comprise administering a compound of the invention to an animal, in particular a mammal, most particularly a human, in need thereof. The present invention particularly provides a method for treating a disease caused by a pathological level of cathepsin K, which method comprises a compound of the invention in an animal, in particular a mammal, most particularly a human in need thereof. Administering a cathepsin K inhibitor. The present invention also includes infections with alveolar nematodes, malaria, cancer metastasis, familial encephalopathy, muscular dystrophy, muscular dystrophy and the like, as well as alveolar worms, palatine worms, trypsinoma bruisei and Cretidia pukkulata, Diseases involving cysteine protease and especially diseases involving cathepsin K, most particularly gum disease including osteoporosis, gingivitis and periodontitis, arthritis, more particularly osteoarthritis and rheumatoid arthritis, Paget's disease, malignant hypercalcemia and metabolic bone Provided are methods for treating a disease, such as excessive bone or cartilage loss, including the disease.
[829] The invention also includes administering an effective amount of a compound of Formula (I) alone or in combination with another bone resorption inhibitor, such as bisphosphonate (ie, alendronate), hormone replacement therapy, anti-estrogen or calcitonin to the patient, A method of treating osteoporosis or suppressing bone loss is provided. In addition, compounds of the invention and anabolic agents such as bone forming proteins, iproflavones, may be treated to prevent bone loss or increase bone mass.
[830] For acute treatment, parenteral administration of the compound of formula (I) is preferred. While intramuscular bolus injection is also useful, intravenous infusion of the compound in 5% dextrose in water or saline, or intravenous injection of a similar formulation containing a suitable excipient, is most effective. Typically, the parenteral dosage is about 0.01 to about 100 mg / kg, preferably 0.1 to 20 mg / kg, to maintain the concentration of drug in the plasma at a concentration effective 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 therapeutically accurate amounts of the compounds of the present invention and the most preferred route of administration of these compounds can be readily determined by one skilled in the art by comparing the concentrations necessary to be therapeutically effective with blood levels.
[831] The compounds of the present invention may be administered orally to a patient so that the concentration of the drug is at a concentration sufficient to inhibit bone resorption or to obtain other therapeutic effects disclosed herein. Typically, pharmaceutical compositions comprising a compound of the invention are administered at oral dosages of about 0.1 to about 50 mg / kg, depending on the condition of the patient. Preferably the oral dosage is about 0.5 to about 20 mg / kg.
[832] No unacceptable toxin effect is expected when the compound of the present invention is administered in accordance with the present invention.
[833] Biological analysis
[834] The compounds of the present invention can be tested by one of a variety of biological assays to determine the concentration of compounds needed to have a desired pharmacological effect.
[835] Determination of Catalytic K's Proteolytic Catalytic Activity
[836] All assays for cathepsin K were performed with human recombinant enzyme. Standard assay conditions for determining rate constants were determined using a fluorogenic peptide substrate, in particular Cbz-Phe-Arg-AMC, at 100 mM Na acetate, pH 5.5, containing 20 mM cysteine and 5 mM EDTA. The raw substrate solution was prepared at a concentration of 10 or 20 mM in DMSO and the final substrate concentration in the assay was 20 μΜ. All assays included 10% DMSO. It was found in separate experiments that this level of DMSO had no effect on enzyme activity or rate constants. All analyzes were performed at ambient temperature. Fluorescent products (excitation at 360 nM; emission at 460 nM) were monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progression curves were generated over 20-30 minutes after AMC product formation.
[837] Inhibition studies
[838] Potential inhibitors were evaluated using the progress curve method. The assay was performed in the presence of various concentrations of test compound. The reaction was initiated by adding the enzyme to a buffer solution of inhibitor and substrate. Data analysis was performed according to one of two methods depending on the shape of the progress curve in the presence of the inhibitor. For compounds with straight curves, the apparent inhibition constant (K _{i, app} ) was calculated according to Equation 1 (Brandt et al., Biochemistry , 1989 , 28, 140).
[839]
[840] Where v is the rate of reaction with maximum velocity V _m , A is the concentration of substrate with Michaelis constant K _a , and I is the concentration of inhibitor)
[841] For compounds whose progression curve is a downward curve with time-dependent inhibition properties, the data from each set were analyzed to yield k _obs according to equation (2).
[842]
[843] (Where [AMC] is the concentration of product produced during time t, v ₀ is the initial reaction rate and v _SS is the final steady state rate)
[844] The k _obs value was analyzed as a linear function of the inhibitor concentration to yield an apparent second order rate constant ( k _obs / inhibitor concentration or k _obs / [ I ]) that accounts for time dependent inhibition. A full discussion of this kinetic treatment is fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol. , 1988 , 61, 201).
[845] Human keel cell uptake assay
[846] An aliquot of the cell suspension derived from the keeloma was taken from the liquid nitrogen vessel and warmed rapidly at 37 ° C. and washed once in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4 ° C.). The medium was aspirated and replaced with mouse anti-HLA-DR antibody, diluted 1: 3 in RPMI-1640 medium and incubated for 30 minutes on ice. Cell suspensions were mixed frequently.
[847] Cells were washed twice with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 ° C.) and transferred to sterile 15 mL centrifuge tubes. The number of mononuclear cells was counted in an improved Neubauer counter.
[848] Sufficient magnetic beads (5 / mononuclear cells) coated with goat's anti-mouse IgG were removed from the storage vessel and placed in 5 mL of fresh medium, which washes off toxic azide preservatives. Beads were fixed to magnets to remove the medium and replaced with fresh medium.
[849] After mixing the beads with the cells the suspension was incubated for 30 minutes on ice. The suspension was mixed frequently. Bead coated cells were fixed on magnets and the remaining cells (fractions rich in keel cells) were transferred to sterile 50 mL centrifuge tubes. Fresh medium was added to the bead coated cells to remove trapped keel cells. This washing procedure was repeated 10 times. Bead coated cells were discarded.
[850] Using a large-caliber disposable plastic Pasteur pipette, the counting chamber was filled with a sample and the keel cells were counted. Cells were pelleted by centrifugation, adjusted to a concentration of 1.5 × 10 ⁴ / mL of keel cells in EMEM medium and 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate were added. An aliquot of the cell suspension (per therapeutic agent) was transferred to a 15 mL centrifuge tube. These cells were pelleted by centrifugation. 3 mL of the appropriate therapeutic agent was added to each tube (diluted to 50 μM in EMEM medium). Also included were the appropriate vehicle control, positive control (87MEM1 diluted to 100 μg / mL) and isotypes (IgG2a diluted to 100 ug / mL). The tube was incubated at 37 ° C. for 30 minutes.
[851] 0.5 mL of cell aliquots were seeded into sterile dentin slices in 48-well plates and incubated at 37 ° C. for 2 hours. Each treatment was screened four times. Slices were washed 6 times with warm PBS (10 mL / well, 6-well plates) and placed in new treatments or controls and incubated at 37 ° C. for 48 hours. Slices were washed in phosphate buffered drinking water (fixed in 0.2 M sodium cacodylate) and fixed in 2% glutaraldehyde, then washed with water and incubated for 5 minutes at 37 ° C. in buffer. Slices were washed in cold water and incubated for 5 minutes at 4 ° C. in cold acetate buffer / fast red garent. Excess buffer was aspirated off and the slices were washed with water and dried.
[852] TRAP-positive keel cells were counted by brightfield microscopy and removed from the dentin surface by sonication. The pore volume was measured with a Nikon / Laserec ILM21W confocal microscope.
[853] Normal
[854] Nuclear magnetic resonance spectra were recorded using either a Bruker AM 250 or a Bruker AC 400 spectrometer at 250 MHz or 400 MHz, respectively. CDCl ₃ is deuterated chloroform, DMSO-d ₆ is hexaduteriodimethylsulfoxide, and CD ₃ OD is tetraduteriomethanol. Chemical shifts were reported in parts per million in the lower field direction from the internal standard tetramethylsilane. The abbreviations in the NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, app = apparent br = Broad. J represents the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded with a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded with a Nicolelet Impact 400 D infrared spectrometer. It was. IR and FTIR spectra were recorded in transmission mode, and band positions were reported for wave numbers (cm ⁻¹ ). Mass spectra were measured with a VG 70 FE, PE Syx API III or VG ZAB HF device using fast atom bombardment (FAB) or electrospray ionization techniques. Elemental analysis was obtained using a Perkin-Elmer-240C elemental analyzer. Melting points were measured and not calibrated with a Thomas-Hoover melting point device. All temperatures are reported in ° C.
[855] Analtech Silica Gel GF and E. E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were performed on E. Merck Kiesselgel 60 (230-400 mesh) silica gel.
[856] When indicated, certain materials are advanced from Aldrich Chemical Co., Milwaukee, WI, and Chemical Dynamics Corp., South Plains, NJ, and Lewisville, KY. Purchased from Advanced Chemtech.
[857] In the synthetic examples below, the temperature is degrees Celsius (° C.). All starting materials were obtained from commercial sources unless otherwise indicated. Without further explanation, it is believed that one skilled in the art can, using the foregoing description, utilize the present invention to its fullest extent. These examples are intended to illustrate the invention, but not to limit the scope thereof. For what is retained by the inventors, see the claims below.
[858] <Example 1>
[859] Preparation of {(S) -1- [1-((S) -2-benzyloxycarbonylamino-4-methyl-pentanoyl) -3-oxo-azpan-4-ylcarbamoyl} carbamic acid benzyl ester
[860] a.) allyl-pent-4-enyl-carbamic acid tert-butyl ester
[861] To a suspension of NaH (3.05 g 60% NaH in oil, 76.33 mmol; washed with hexane) in DMF (30 mL) was added dropwise tert-butyl N-allylcarbamate (6.0 g, 38.2 mmol). The mixture was stirred at rt for about 10 min and 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added dropwise thereto. The reaction was heated to 40 ° C. for about 2 hours and the reaction was partitioned between ethyl acetate and water. The organic phase was washed with water (2 ×), brine, dried (MgSO ₄ ), filtered and concentrated to give 10 g of the title compound as an oil: MS (EI) 226 (M + H ⁺ ).
[862] b.) 2,3,4,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester
[863] To a solution of the compound of Example 1a (4.5 g) in benzene was added 2,6-diisopropylphenylimidoneopylidene molybdenum bis (t-butoxide) (600 mg). The reaction was heated to reflux for 1.5 h and concentrated in vacuo. The residue was chromatographed (50% CH ₂ Cl ₂ : hexanes) to afford 3.92 g of product.
[864] c.) 8-oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid tert-butyl ester
[865] To a solution of the compound of Example 1b (3.0 g, 15.2 mmol) in CH ₂ Cl ₂ was added m-CPBA (7.8 g, 45.6 mmol). This mixture was stirred overnight at room temperature and partitioned between CH ₂ Cl ₂ and saturated K ₂ CO ₃ . The organic layer was washed with saturated NaHCO ₃ , water, brine, dried (MgSO ₄ ), filtered and concentrated to give 3.11 g of the title compound as an oil: MS (EI) 214 (M + H ⁺ ).
[866] d.) 4-azido-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester
[867] To a solution of the compound of Example 1c (3.92 g, 20 mmol) in methanol: water (180 mL of 8: 1 solution) was added NH ₄ Cl (3.18 g, 60 mmol) and sodium azide (3.9 g, 60 mmol). Added. The reaction was heated to 40 ° C. until TLC analysis showed that the starting epoxide was consumed completely. Most of the solvent was removed in vacuo and the remaining solution was diluted with ethyl acetate and washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was column chromatographed (40% ethyl acetate: hexane) to give 3.43 g of the title compound.
[868] e.) 4-amino-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester
[869] A hydrogen balloon was added to a solution of azido alcohol (3.4 g) and 10% Pd / C (catalyst amount) of Example 1d in ethyl acetate: methanol (2: 1 solution). The reaction was stirred until complete consumption of 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 column chromatographed (25% methanol: dichloromethane) to give 2.57 g of the title compound: MS (EI) 231 (M + H ⁺ ).
[870] f.) 4-((S) -2-benzyloxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azane-1-carboxylic acid tert butyl ester
[871] To a solution of the amino alcohol (160 mg, 0.70 mmol) of Example 1e in CH ₂ Cl ₂ was added EDC (134 mg), HOBt (94 mg) and Cbz-leucine (185 mg). The reaction was kept at room temperature until complete consumption of starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with 1N HCl, saturated K ₂ CO ₃ , water, brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (3% methanol: dichloromethane) to give 200 mg of the title compound: MS (EI) 478 (M + H ⁺ ), 500 (M + Na ⁺ ).
[872] g.) [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid benzyl ester
[873] To a solution of the compound of Example 1f (200 mg, 0.42 mmol) in methanol (5 mL) was added 4M HCl in dioxane (5 mL). The reaction was stirred at rt for about 2 h and the solvent was removed in vacuo to give 168 mg of the title compound: MS (EI) 378 (M + H ⁺ ).
[874] h.) {(S) -1- [4-((S) -2-benzyloxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carbonyl] -3 -Methyl-butyl} carbamic acid benzyl ester
[875] To a solution of Example 1g amine salt (168 mg, 0.42 mmol) in CH ₂ Cl ₂ was added EDC (81 mg), HOBt (57 mg), triethylamine (0.09 mL) and Cbz-leucine (111 mg). It was. The reaction was stirred until complete consumption of starting material was observed by TLC analysis. Finished and column chromatography (5% CH ₃ OH: CH ₂ Cl ₂ ) afforded 159 mg of the title compound: MS (EI) 625 (M + H ⁺ ).
[876] i.) {(S) -1- [4-((S) -2-benzyloxycarbonylamino-4-methyl-pentanoylamino) -3-oxo-azepane-1-carbonyl] -3- Methyl-butyl} carbamic acid benzyl ester
[877] To a solution of the alcohol of Example 1h (130 mg, 0.21 mmol) in DMSO was added TEA (0.17 mL) and pyridine sulfur trioxide complex (97 mg, 0.62 mmol). The reaction was stirred at rt for about 2 h and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (5% CH ₃ OH: CH ₂ Cl ₂ ) to give 100 mg of the title compound as a mixture of diastereomers:
[878]
[879] Diastereomers 1: MS (EI) 623 (M + H ⁺ ), 645 (M + Na ⁺ ) and Diastereomer 2: MS (ES) 623 (M + H ⁺ ) by separation of diastereomers by HPLC , 645 (M + Na ⁺ ) was obtained.
[880] <Example 2>
[881] Preparation of naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[882] a.) allyl-pent-4-enyl-carbamic acid benzyl ester
[883] To the suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added dropwise benzylallyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol). The mixture was stirred at rt for about 10 min and 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction was heated to 40 ° C. for about 4 hours and the reaction was partitioned between dichloromethane and water. The organic phase was washed with water (2 ×), brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (10% ethyl acetate: hexanes) to give 10.3 g of the title compound as an oil: MS (EI) 260 (M + H ⁺ ).
[884] b.) 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester
[885] To a solution of compound (50 g) of Example 2a in dichloromethane is added bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (5.0 g). The reaction was heated to reflux until complete consumption of starting material was observed by TLC analysis. The reaction was concentrated in vacuo. The residue was column chromatographed (50% dichloromethane: hexanes) to afford 35 g of the title compound: MS (EI) 232 (M + H ⁺ ).
[886] c.) 8-oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid benzyl ester
[887] Prepared according to the general procedure of Example 1c, with the exception of the title compound of Example 2b: MS (EI) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).
[888] d.) 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[889] To a solution of epoxide (2.0 g, 8.1 mmol) of Example 2c in methanol: water (8: 1 solution) was added NH ₄ Cl (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol) It was. The reaction was heated to 40 ° C until complete consumption of starting material 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, brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (20% ethyl acetate: hexanes) to give 1.3 g of the title compound (MS (EI) 291 (M + H ⁺ )) and 0.14 g of trans-4-hydroxy-3-azido-hexa Hydro-1H-azepine was obtained.
[890] e.) 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[891] To a solution of azido alcohol (1.1 g, 3.79 mmol) in Example 2d in methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 mL). The reaction was stirred until complete consumption of starting material was observed by TLC analysis and it was concentrated in vacuo. The residue was column chromatographed (20% methanol: dichloromethane) to give 0.72 g of the title compound: MS (EI) 265 (M + H ⁺ ).
[892] f.) 4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azane-1-carboxylic acid benzyl ester
[893] To a solution of the amino alcohol (720 mg, 2.72 mmol) of Example 2e in CH ₂ Cl ₂ was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was kept at room temperature until complete consumption of starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with 1N HCl, saturated K ₂ CO ₃ , water, brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (3% methanol: dichloromethane) to give 1.0 g of the title compound: MS (EI) 478 (M + H ⁺ ).
[894] g.) [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert butyl ester
[895] A hydrogen balloon was added to a solution of compound (1.0 g) and 10% Pd / C (catalyst amount) of Example 2f in ethyl acetate: methanol (2: 1 solution). The reaction was stirred until complete consumption of starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo to afford 0.82 g of the title compound: MS (EI) 344 (M + H ⁺ ).
[896] h.) [(S) -1- (1-Benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert butyl ester
[897] To a solution of Example 2 g of compound (0.69 g, 2.01 mmol) in CH ₂ Cl ₂ was added benzaldehyde (0.32 mL, 3.01 mmol) followed by sodium triacetoxyborohydride (0.85 g, 4.02 mmol). The reaction was stirred until complete consumption of starting material was observed by TLC analysis and a few drops of water were added to the reaction to remove excess sodium triacetoxyborohydride. The mixture was diluted with ethyl acetate, washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was column chromatographed (5% methanol: dichloromethane) to give 800 mg of the title compound: MS (ES) 434 (M + H ⁺ ).
[898] i.) (S) -2-Amino-4-methyl-pentanoic acid (1-benzyl-3-hydroxy-azpan-4-yl) -amide
[899] To a solution of Example 2h compound (800 mg) in methanol (15 mL) was added 4M HCl in dioxane. The reaction was stirred at room temperature until complete consumption of starting material was observed by TLC analysis, which was concentrated in vacuo to give 800 mg of the title compound: MS (ES) 334 (M + H ⁺ ).
[900] j.) Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[901] To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH ₂ Cl ₂ , triethylamine (0.17 mL, 1.22 mmol), EDC (103.5 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and 2-naphthoic acid (93 mg, 0.54 mmol) was added. Stir until the reaction is complete by TLC analysis. The reaction was diluted with ethyl acetate and washed with saturated NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was column chromatography (5% methanol: dichloromethane) to give 0.14 g of the title compound: MS (EI) 488 (M + H ⁺ ).
[902] k.) Naphthylene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[903] The title compound was prepared according to the general procedure of Example li, except that the compound of Example li was replaced with the compound of Example 2j:
[904]
[905] Diastereomers were separated by HPLC to give diastereomer 1: MS (EI) 486.3 (M + H ⁺ ), and diastereomer 2: MS (ES) 486.3 (M + H ⁺ ).
[906] <Example 3>
[907] Preparation of benzo [1,3] dioxol-5-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[908] a.) Benzo [1,3] dioxol-5-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[909] The title compound was prepared following the general procedure of Example 2j, except that 2-naphthoic acid was replaced by piperonylic acid (piperonylic acid): MS (ES) 482 (M + H ⁺ ).
[910] b.) Benzo [1,3] dioxol-5-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[911] Except for replacing with the compound of Example 3a, the title compound was prepared according to the general procedure of Example li:
[912]
[913] Diastereomers were separated by preparative scale HPLC. Lyophilization of the eluate to give 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 ⁺ ).
[914] <Example 4>
[915] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[916] a.) Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[917] The title compound was prepared following the general procedure of Example 2j, except for replacing 2-naphthoic acid with benzofuran-2-carboxylic acid: MS (ES) 478 (M + H ⁺ ).
[918] b.) Benzofuran-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[919] Except for the replacement with Example 4a, the title compound was prepared following the general procedure of Example li: 476 MS (EI): 492 (M + H ⁺ , 100%). Diastereomers were separated by preparative scale HPLC. Lyophilization of the eluate to give diastereomer 1: MS (EI) 476.4 (M + H ⁺ ), 951.6 (M + H ⁺ ) and diastereomer 2: MS (EI) 476.4 (M + H ⁺ ), 951.6 2M + H ⁺ ).
[920] Example 5
[921] Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[922] a.) Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[923] The title compound was prepared following the general procedure of Example 2j, except that 2-naphthoic acid was replaced with benzothiophene-2-carboxylic acid: MS (ES) 494 (M + H ⁺ ).
[924] b.) Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[925] Except for replacing with the compound of Example 5a, the title compound was prepared according to the general procedure of Example li:
[926]
[927] Diastereomers were separated by preparative scale HPLC. Lyophilization of the eluate to give 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 ⁺ )
[928] <Example 6>
[929] Preparation of naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[930] a.) Naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[931] To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH ₂ Cl ₂ was added triethylamine (0.24 mL, 1.72 mmol) and 2-naphthalenesulfonyl chloride (122 mg, 0.54 mmol). The reaction was stirred at rt until the reaction was complete by TLC analysis. The reaction was finished, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was column chromatography (10% methanol: dichloromethane) to give 52 mg of the title compound: MS (EI) 524 (M + H ⁺ ).
[932] b.) naphthylene-2-sulfonyl [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[933] Except for replacing with the compound of Example 6a, the title compound was prepared according to the general procedure of Example li:
[934]
[935] <Example 7>
[936] Preparation of Quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[937] a.) Quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[938] The title compound was prepared following the general procedure of Example 2j, except for replacing 2-naphthoic acid with 2-quinolinecarboxylic acid: MS (ES) 489 (M + H ⁺ ).
[939] b.) Quinoline-2-carboxylic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methylbutyl] amide
[940] Except for replacing with the compound of Example 7a, the title compound was prepared according to the general procedure of Example li:
[941] . Diastereomers were separated by preparative scale HPLC. Lyophilization of the eluate to give 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 ⁺ )
[942] <Example 8>
[943] Preparation of 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[944] a.) 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-hydroxy-azpan-4-ylcarbamoyl) -3methyl-butyl] amide
[945] The title compound was prepared following the general procedure of Example 2j, except for replacing 2-naphthoic acid with 3,4-dichlorobenzoic acid: MS (ES) 506 (M + H ⁺ ).
[946] b.) 3,4-dichlorobenzoic acid [(S) -1- (1-benzyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[947] Except for the replacement of the compound of Example 8a, the title compound was prepared according to the general procedure of Example li:
[948]
[949] Example 9
[950] 4-{(S) -Methyl-2-[(quinolin-2-carbonyl) -amino] pentanoylamino} -3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl ] Manufacture of Azepanium
[951] a.) 4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -Acetyl] -azpanium
[952] To a solution of Example 2 g of compound (0.5 g, 1.46 mmol) in CH ₂ Cl ₂ , EDC (307 mg, 1.60 mmol), HOBt (216 mg, 1.60 mmol) and 3- (2-pyridyl) phenyl acetic acid (341 mg, 1.60 mmol) was added. The reaction was stirred at rt until completion of the reaction by TLC analysis. Finished and column chromatography (2% methanol: dichloromethane) gave the title compound: MS (ES) 539 (M + H ⁺ ).
[953] b.) 4-((S) -Amino-4-methyl-pentanoylamino) -3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) acetyl] -azpanium
[954] To a solution of the compound of Example 9a (1.3 g) dissolved in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred until completion of the reaction by TLC analysis and concentrated in vacuo to give 1.1 g of the title compound: MS (EI) 439 (M + H ⁺ ).
[955] c.) 4-{(S) -methyl-2-[(quinolin-2-carbonyl) -amino] pentanoylamino} -3-hydroxy-1- [2- (3-pyridin-2-yl- Phenyl) -acetyl] azpanium
[956] Except for the replacement of the compound of Example 9b, the title compound was prepared according to the process of Example 7a: MS (EI) 594 (M + H ⁺ ).
[957] d.) 4-{(S) -methyl-2-[(quinolin-2-carbonyl) -amino] pentanoylamino} -3-oxo-1- [2- (3-pyridin-2-yl-phenyl ) -Acetyl] azpanium
[958] Except for replacing with the compound of Example 9c, the title compound was prepared according to the process of Example li:
[959]
[960] <Example 10>
[961] 1-((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4-{(S) -4-methyl-2-[(2-quinoline-2-carbonyl) -amino]- Preparation of Pentanoylamino) -3-oxo-azpanium
[962] a.) 1-((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) 3-hydroxy-azpanium
[963] The title compound was prepared according to the process of Example 2h except for replacing benzaldehyde with Cbz-leucinal: MS (EI) 577 (M + H ⁺ ).
[964] b.) 4-((S) -2-amino-4-methyl-pentanoylamino) -1-((S) -2-tert-benzyloxycarbonylamino-4-methyl-pentyl) -3-hydrate Roxy-Azepanium
[965] Except for the replacement of the compound of Example 10a, the title compound was prepared according to the process of Example 2i: MS (EI) 477 (M + H ⁺ ).
[966] c.) 1-((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4-{(S) -4-methyl-2-[(2-quinoline-2-carbonyl)- Amino] -pentanoylamino) -3-hydroxy-azpanium
[967] Except for the replacement of the compound of Example 10b, the title compound was prepared according to the process of Example 7a: MS (EI) 632 (M + H ⁺ ).
[968] d.) 1-((S) -2-benzyloxycarbonylamino-4-methyl-pentyl) -4-{(S) -4-methyl-2-[(2-quinoline-2-carbonyl)- Amino] -pentanoylamino) -3-oxo-azpanium
[969] Except for replacing with the compound of Example 10c, the title compound was prepared according to the process of Example 1i:
[970]
[971] <Example 11>
[972] Preparation of 1-benzoyl-4-((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl-pentanoylamino) -3-oxo-azpanium
[973] a.) 1-benzoyl-4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azpanium
[974] The title compound was prepared according to the process of Example 9a, except that 3- (2-pyridyl) phenyl acetic acid was replaced with benzoic acid: MS (EI) 448 (M + H ⁺ ).
[975] b.) 4-((S) -2-amino-4-methyl-pentanoylamino) -1-benzoyl-3-hydroxy-azpanium
[976] Except for the replacement of the compound of Example 11a, the title compound was prepared according to the process of Example 2i: MS (EI) 348 (M + H ⁺ ).
[977] c.) 1-benzoyl-4-((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl-pentanoylamino) 3-hydroxy-azpanium
[978] The title compound was prepared according to the process of Example 2j, except that the compound of Example 2j was replaced with the compound of Example 11b and 2-naphthoic acid was replaced by pyreronilic acid: MS (EI) 496 (M + H ⁺ ).
[979] d.) 1-benzoyl-4-((S) -2- (benzo [1,3] dioxol-carbonylamino) -4-methyl-pentanoylamino) -3-oxo-azpanium
[980] Except for replacing with the compound of Example 11c, the title compound was prepared according to the procedure of 1i:
[981]
[982] <Example 12>
[983] Preparation of 1-benzoyl-4-((S) -2- (4-fluoro-benzoylamino) -4-methyl-pentanoylamino) -3-oxo-azpanium
[984] a.) 1-benzoyl-4-((S) -2- (4-fluoro-benzoylamino) -4-methyl-pentanoylamino) -3-hydroxy-azpanium
[985] Except for replacing piperonylic acid with 4-fluorobenzoic acid, the title compound was prepared following the process of Example 11c: MS (EI) 470 (M + H ⁺ ).
[986] b.) 1-benzoyl-4-((S) -2- (4-fluoro-benzoylamino) -4-methyl-pentanoylamino) -3-oxo-azpanium
[987] The title compound was prepared according to the process of Example 1i, except that it was replaced with the compound of Example 12a:
[988]
[989] Example 13
[990] 3-oxo-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino ) -1- (4-Methyl-pentanoyl) -azpanium Preparation
[991] a.) 4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-1- (4-methyl-pentanoyl) -azpanium
[992] The title compound was prepared according to the process of Example 9a, except that 3- (2-pyridyl) phenyl acetic acid was replaced with iso-capronic acid: MS (EI) 442 (M + H ⁺ ).
[993] b.) 4-((S) -2-amino-4-methyl-pentanoylamino) -3-hydroxy-1- (4-methyl-pentanoyl) -azpanium
[994] Except for the replacement of the compound of Example 13a, the title compound was prepared according to the process of Example 2i: MS (EI) 342 (M + H ⁺ ).
[995] c.) 3-hydroxy-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -Pentanoylamino) -1- (4-methyl-pentanoyl) -azpanium
[996] To a solution of the compound of Example 13b (200 mg, 0.53 mmol) in dichloromethane was added EDC (111 mg, 0.58 mmol), HOBt (78 mg, 0.58 mmol), TEA (0.11 mL, 0.79 mmol) and 5- (2- Morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid was added. The reaction was stirred at room temperature until TLC analysis indicated the reaction was complete. Finished and column chromatography (5% methanol: dichloromethane) gave 160 mg of the title compound: MS (EI) 615 (M + H ⁺ ).
[997] d.) 3-oxo-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino}- Pentanoylamino) -1- (4-methyl-pentanoyl) -azpanium
[998] The title compound was prepared according to the process of Example 1i, except that the compound of Example 13d was replaced:
[999]
[1000] Diastereomers were separated by preparative scale HPLC. The eluate was lyophilized to give diastereomer 1 and diastereomer 2.
[1001] <Example 14>
[1002] 3-Oxo-4-((S) -4-methyl-2-{[5- (2-morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1 Preparation of -benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1003] a.) 1-Benzenesulfonyl-4-((S) -2-tert-butoxycarbonylamino-methyl-pentanoylamino) -3-hydroxy-azpanium
[1004] To a solution of Example 2 g (0.5 g, 1.46 mmol) of amine in dichloromethane was added triethylamine (0.4 mL, 2.92 mmol) followed by benzenesulfonyl chloride (0.28 mL, 2.18 mmol). The reaction was stirred at room temperature until indicated by TLC analysis. Finished and column chromatography (10% methanol: dichloromethane) gave 450 mg of the title compound: MS (EI) 484 (M + H ⁺ ).
[1005] b.) 4-((S) -2-amino-methyl-pentanoylamino) 1-benzenesulfonyl-3-hydroxy-azpanium
[1006] Except for the replacement of the compound of Example 14a, the title compound was prepared according to the process of Example 2i: MS (EI) 384 (M + H ⁺ ).
[1007] c.) 3-hydroxy-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -Pentanoylamino) -1-benzenesulfonyl-azpanium
[1008] Except for replacing with the compound of Example 14b, the title compound was prepared according to the process of Example 13c: MS (EI) 657 (M + H ⁺ ).
[1009] d.) 3-oxo-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino}- Pentanoylamino) -1-benzenesulfonyl-azpanium
[1010] The title compound was prepared according to the process of Example 1i, except that the compound of Example 14c was replaced:
[1011]
[1012] By analytical HPLC (40:60 to 45:55 CH ₃ CN: 20 mm KHPO ₄ (pH 7 buffer) 60 min gradient 1 mL / min; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) Analysis of the diastereomeric mixture showed two peaks (R _t = 44.6 minutes and 45.9 minutes). Preparation scale HPLC (40:60 to 50:50 CH ₃ CN: mm KHPO ₄ (pH 7 buffer) gradient, 12 mL / min., 60 min; inertsil ODS-3 column 250 × 20 mm; UV detection at 215 nM) The diastereomers were separated by The eluate was lyophilized to give diastereomer 1 (analytical R _t = 44.6 min) and diastereomer 2 (analytical R _t = 45.9 min).
[1013] <Example 15>
[1014] 4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino) -3- Preparation of oxo-azepane-1-carboxylic acid phenylamide
[1015] a.) [(S) -1- (3-hydroxy-1-phenylcarbamoyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[1016] To a solution of Example 2 g (0.5 g, 1.46 mmol) amine in dichloromethane (20 mL) was added phenyl isocyanate (0.24 mL, 2.18 mmol). The reaction was stirred at room temperature until indicated by TLC analysis to complete. Finished and column chromatography (5% methanol: dichloromethane) gave 578 mg of the title compound: MS (EI) 463 (M + H ⁺ ).
[1017] b.) 4-((S) -2-amino-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid phenylamide
[1018] Except for the replacement of the compound of Example 15a, the title compound was prepared according to the process of Example 2i: MS (EI) 363 (M + H ⁺ ).
[1019] c.) 3-hydroxy-4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -Pentanoylamino) -azepane-1-carboxylic acid phenylamide
[1020] Except for the replacement of the compound of Example 15b, the title compound was prepared according to the process of Example 13c: MS (EI) 636 (M + H ⁺ ).
[1021] d.) 4-((S) -4-methyl-2-{[5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} pentanoylamino)- 3-oxo-azepane-1-carboxylic acid phenylamide
[1022] Except for substituting the compound of Example 15c, the title compound was prepared according to the process of Example 1i:
[1023]
[1024] Diastereomer by Analytical HPLC (40:60 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) isocratic elution, 1 mL / min .; inertsil ODS-3 column 4.6 × 250 mm; UV detection at 215 nM) Analysis of the mixture showed two peaks (R _t = 27.3 min and 30.1 min). Preparation scale HPLC (40:60 to 50:50 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) gradient, 12 mL / min., 60 min; LTV detection at inertsil ODS-3 column 250 × 20 mm; 215 nM The diastereomers were separated by). The eluate was lyophilized and desalted by NaHC0 ₃ : ethyl acetate extraction to give diastereomer 1 (analysis R _t = 27.3 min) and diastereomer 2 (analysis R _t = 30.1 min).
[1025] <Example 16>
[1026] 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-2) Preparation of -yl-phenyl) acetyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1027] a.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3 -Pyridin-2-yl-phenyl) acetyl] -azpan-4-ylcarbamoyl} -butyl) amide
[1028] Except for the replacement of the compound of Example 9b, the title compound was prepared according to the process of Example 13c: MS (EI) 712 (M + H ⁺ ).
[1029] b.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3- Pyridin-2-yl-phenyl) acetyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1030] The title compound was prepared according to the process of Example 1i, except that the compound of Example 16c was replaced:
[1031]
[1032] Analysis of diastereomeric mixtures by analytical HPLC (40:60 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) 1 mL / min .; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) Two peaks (R _t = 33.9 min and 37.9 min) were shown. Preparation scale HPLC (40:60 to 45:55 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) gradient, 12 mL / min., 60 min; UV detection at inertsil ODS-3 column 250 x 20 mm; 215 nM The diastereomers were separated by). Lyophilized and desalted by NaHCO ₃ : ethyl acetate extraction to give diastereomer 1: MS (EI) 710. 3 (M + H ⁺ ) (analytical R _t = 33.9 min) and diastereomer 2: MS (EI) 710.3 (M + H ⁺ ) (analysis R _t = 37.9 min).
[1033] <Example 17>
[1034] 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl -Butyl] amide
[1035] a.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1036] Except for replacing with the compound of Example 11b, the title compound was prepared according to the process of Example 13c: MS (EI) 621 (M + H ⁺ ).
[1037] b.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azpan-4-ylcarbamoyl)- 3-methyl-butyl] amide
[1038] The title compound was prepared according to the process of Example 1i, except that the compound of Example 17a was replaced:
[1039]
[1040] In analytical HPLC (40:60 to 55:45 CH ₃ CN: 20 mM KHPO ₄ (pH 7 buffer) 30 min gradient, 1 mL / min .; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) Analysis of the diastereomeric mixture by showed two peaks (R _t = 13.5 min and 17.6 min). Preparation scale HPLC (40:60 to 45:55 CH ₃ CN: mM KHPO ₄ (pH 7 buffer) 60 min gradient, 15 mL / min., 60 min; 250 x 20 mm inertsil ODS-3 column; UV at 215 nM Detection) to separate diastereomers. Lyophilization and desalting by NaHCO ₃ : ethyl acetate extraction gave diastereomer 1 (analytical R _t = 13.5 min) and diastereomer 2 (analytical R _t = 17.6 min).
[1041] Example 18
[1042] 5- (2-Pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) Preparation of -3-methyl-butyl] amide
[1043] a.) 5- (2-Pyrrolidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azepane-4- Ylcarbamoyl) -3-methyl-butyl] amide
[1044] 5- (2-Morpholin-4-yl-ethyloxy) -benzofuran-2-carboxylic acid replaced with 5- (2-pyrrolidin-1-yl-ethyloxy) -benzofuran-2-carboxylic acid Except for the title compound, following the procedure in Example 14c: MS (EI) 641 (M + H ⁺ ).
[1045] b.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (benzoyl-3-oxo-azpan-4-ylcarbamoyl)- 3-methyl-butyl] amide
[1046] The title compound was prepared according to the process of Example 1i, except that the compound of Example 18a was replaced:
[1047]
[1048] Example 19
[1049] 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) Preparation of -3-methyl-butyl] amide
[1050] a.) 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-yl Carbamoyl) -3-methyl-butyl] amide
[1051] 5- (2-morpholin-4-yl-ethyloxy) -benzofuran-2-carboxylic acid with 5- (2-piperidin-1-yl-ethyloxy) -benzofuran-2-carboxylic acid Except for the title compound, following the procedure in Example 14c: MS (EI) 655 (M + H ⁺ ).
[1052] b.) 5- (2-Piperidin-1-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azepane-4- Ylcarbamoyl) -3-methyl-butyl] amide
[1053] Except for the replacement of the compound of Example 18a, the title compound was prepared according to the process of Example 1i:
[1054]
[1055] Example 20
[1056] 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-2) Preparation of -yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1057] a.) 5- (2-Morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid methoxy methyl amide
[1058] To a solution of 3- (2-pyridyl) phenyl acetic acid (1 g) in dichloromethane N, O-dimethylhydroxylamine hydrochloride (0.92 g), triethylamine (1.3 mL), HOBt (0.96 g) and EDC (1.1 g) was added. The reaction was stirred until complete. Finished and column chromatography (40% ethyl acetate: hexanes) gave 1.1 g of the title compound: MS (EI) 257 (M + H ⁺ ).
[1059] b.) 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carbaldehyde
[1060] To a solution of 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid methoxy methyl amide (0.2 g) of Example 20a in THF was added LAH (2.0 mL of 1 M solution in THF). Added. The reaction was stirred until the starting material was consumed completely. Finishing gave 160 mg of the title compound.
[1061] c.) ((S)-{3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -ethyl] -azepane-4-ylcarbamoyl} -3-methyl-butyl) -Carbamic acid tert butyl ester
[1062] The title compound was prepared according to the general procedure of Example 2g, except that benzaldehyde was replaced by 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carvaldehydro: MS (EI ) 525 (M + H ⁺ ).
[1063] d.) (S) -2-Amino-4-methyl-pentanoic acid- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -ethyl] -azpan-4-yl }-amides
[1064] The title compound was prepared according to the process of Example 2i, except that the compound of Example 20c was replaced.
[1065] e.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3 -Pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1066] The title compound was prepared according to the process of Example 13c, except that the compound of Example 20d was replaced.
[1067] f.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxy-1- [2- (3- Pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1068] The title compound was prepared according to the process of Example 1i, except that the compound of Example 20e was replaced:
[1069]
[1070] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 696 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 696 (M + H ⁺ , 100%) was obtained.
[1071] Example 21
[1072] Naphthalene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl}- Preparation of Butyl) amide
[1073] a.) Naphthalene-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azpan-4-yl Carbamoyl} -butyl) amide
[1074] The title compound was prepared according to the process of Example 20f, except that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid was replaced with 2-naphthoic acid: MS (EI ) 579 (M + H ⁺ ).
[1075] b.) Naphthalene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarba Moyl} -butyl) amide
[1076] The title compound was prepared according to the process of Example 1i, except that the compound of Example 21b was replaced:
[1077]
[1078] <Example 22>
[1079] 1H-indole-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl } -Butyl) amide
[1080] a.) ((S) -3-Methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl )amides
[1081] The title compound was prepared according to the process of Example 20f, except that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid was replaced with 1H-indole-2-carboxylic acid: MS (EI) 568 (M + H ⁺ ).
[1082] b.) ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amides
[1083] Except for substituting the compound of Example 22b, the title compound was prepared according to the process of Example 1i:
[1084]
[1085] <Example 23>
[1086] Preparation of 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1087] a.) 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1088] The title compound was prepared according to the process of Example 2j, except for replacing the compound of Example 14b and naphthoic acid with 1H-indole-2-carboxylic acid: MS (EI) 527 (M + H ⁺ ) .
[1089] b.) 1H-indole-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1090] The title compound was prepared according to the process of Example 1i, except that the compound of Example 23b was replaced:
[1091]
[1092] <Example 24>
[1093] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1094] a.) Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1095] The title compound was prepared according to the process of Example 23a, except that 1H-indole 2-carboxylic acid was replaced with benzofuran-2-carboxylic acid: MS (EI) 528 (M + H ⁺ ).
[1096] b.) Benzofuran-2-carboxylic acid [(S) -1- (1-benzenesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1097] The title compound was prepared according to the process of Example 1i, except that the compound of Example 24b was replaced:
[1098]
[1099] <Example 25>
[1100] Benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -Butyl) amide
[1101] a.) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azepane-4- Ylcarbamoyl} -butyl) amide
[1102] The title compound was prepared according to the process of Example 20e, except that 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid was replaced with benzofuran-2-carboxylic acid: MS (EI) 569 (M + H ⁺ ).
[1103] b.) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1- [2- (3-pyridin-2-yl-phenyl) ethyl] -azpan-4-yl Carbamoyl} -butyl) amide
[1104] Except for substituting the compound of Example 25b, the title compound was prepared according to the process of Example 1i:
[1105]
[1106] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 656 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 656 (M + H ⁺ , 100%) was obtained.
[1107] Example 26
[1108] 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azpan-4-yl Preparation of Carbamoyl] -Butyl} amide
[1109] The title compound, according to the procedure of Example 20c-f, except that the 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carbaldehyde of Example 20c was replaced by phenylacetaldehyde Was prepared:
[1110]
[1111] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 619 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 619 (M + H ⁺ , 100%) was obtained.
[1112] Example 27
[1113] Preparation of naphthylene-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-phenethyl-azpan-4-ylcarbamoyl] -butyl} amide
[1114] The title compound was prepared following the procedure of Example 2h-k, except that the benzaldehyde of Example 2h was replaced by phenylacetaldehyde:
[1115]
[1116] <Example 28>
[1117] Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[1118] a.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1119] The title compound was prepared following the procedure of Examples 14a-b except that the benzenesulfonyl chloride of Example 14a was replaced with 2-pyridinesulfonyl chloride: MS (EI) 385 (M + H ⁺ ).
[1120] b.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1121] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-l- (pyridine-2-sulfonyl) -azpan-4-yl] -amide of example 28a in dichloromethane (0.15 g) ) Was added TEA (0.11 mL), HOBt (49 mg), EDC (69 mg) and benzofuran-2-carboxylic acid (58 mg). The reaction was stirred until complete. Finished and column chromatography (5% methanol: ethyl acetate) gave the title compound: MS (EI) 529 (M + H ⁺ ).
[1122] c.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1123] Except for substituting the compound of Example 28b, the title compound was prepared according to the process of Example 1i:
[1124]
[1125] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC;
[1126] And diastereomers eluted later;
[1127]
[1128] <Example 29>
[1129] Preparation of naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[1130] a.) Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1131] The title compound was prepared following the procedure of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 2-naphthoic acid: MS (EI) 539 (M + H ⁺ ).
[1132] b.) Naphthylene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1133] Except for the replacement of the compound of Example 29a, the title compound was prepared according to the process of Example 1i:
[1134]
[1135] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 537 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 537 (M + H ⁺ , 100%) was obtained.
[1136] <Example 30>
[1137] 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl)- Preparation of Azepan-4-ylcarbamoyl] -butyl} -amide
[1138] a.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1139] Except for replacing with the compound of Example 28a, the title compound was prepared according to the process of Example 13c: MS (EI) 658 (M + H ⁺ ).
[1140] b.) 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sul Ponyl) -Azepan-4-ylcarbamoyl] -butyl} amide
[1141] Except for the replacement of the compound of Example 29a, the title compound was prepared according to the process of Example 1i:
[1142]
[1143] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 656 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 656 (M + H ⁺ , 100%).
[1144] <Example 31>
[1145] 4-((S) -4-methyl-2-{[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] -amino} -pentanoylamino)- Preparation of 3-oxo-azepane-1-carboxylic acid tert-butyl ester
[1146] a.) 4-((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid tert-butyl ester
[1147] A balloon of 10% Pd / C and hydrogen gas was attached to a solution of the compound of Example 1f (0.89 g) in ethyl acetate: methanol (30 mL of 2: 1 mixture). The reaction was stirred until complete by TLC analysis, filtered and concentrated to give the title compound (0.57 g).
[1148] b.) 4-((S) -4-methyl-2-{[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] amino} -pentanoylamino ) -3-hydroxy-azane-1-carboxylic acid tert-butyl ester
[1149] The title compound was prepared according to the process of Example 13c, except that the compound of Example 31a was replaced.
[1150] c.) 4-((S) -4-methyl-2-{[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carbonyl] -amino} -pentanoyl Amino) -3-oxo-azepane-1-carboxylic acid tert-butyl ester
[1151] The title compound was prepared according to the process of Example 1i, except that the compound of Example 31b was replaced:
[1152]
[1153] <Example 32>
[1154] 4-((S) -4-methyl-2-{[(5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid [(S) -3-methyl-1- Preparation of (3-oxo-azpan-4-ylcarbamoyl] -butyl} amide
[1155] To a solution of the compound of Example 31c in THF (5 mL) was added 1M HCl in ether (5 mL). The reaction was stirred overnight and concentrated to afford the title compound:
[1156]
[1157] <Example 33>
[1158] Preparation of 4-Methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl-acetyl] -azpan-4-yl} -amide
[1159] a.) 3-hydroxy-4- (4-methyl-pentanoylamino) -azane-1-carboxylic acid tert-butyl ester
[1160] The title compound was prepared following the procedure of Example 1f except for replacing Cbz-leucine with 4-methylpentanoic acid: MS (EI) 329 (M + H ⁺ ).
[1161] b.) 4-methyl pentanic acid (3-hydroxy-azpan-4-yl) -amide
[1162] To a solution of the compound of Example 33a (200 mg) in methanol (5 mL) was added 4M HCl dioxane (5 mL). The reaction was stirred until complete and concentrated to give the title compound (132 mg): MS (EI) 229 (M + H ⁺ ).
[1163] c.) 4-Methyl-pentanoic acid {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl-acetyl] -azpan-4-yl} amide
[1164] Except for replacing with the compound of Example 33b, the title compound was prepared according to the process of Example 9a: MS (EI) 424 (M + H ⁺ ).
[1165] d.) 4-Methyl-pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl-acetyl] -azpan-4-yl} amide
[1166] Except for the replacement of the compound of Example 33c, the title compound was prepared according to the process of Example 1i:
[1167]
[1168] <Example 34>
[1169] ((S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane-4-ylcarbamoyl} -butyl) -naph Preparation of Tylene-2-methyl-carbamic acid tert-butyl ester
[1170] a.) (S) -4-methyl-2- [naphthalen-2-ylmethyl) -amino] -pentanoic acid methyl ester
[1171] To a solution of leucine methyl ester hydrochloride (0.5 g) in dichloromethane was added triethylamine (0.9 mL), 2-naphthaldehyde (0.43 g) and sodium triacetoxyborohydride (0.87 g). The mixture was stirred until complete. Finished and column chromatography (5% ethyl acetate: dichloromethane) gave 0.4 g of the title compound: MS (EI) 286 (M + H ⁺ ).
[1172] b.) (S) -2- (tert-butoxycarbonyl-naphthalen-2-ylmethyl-amino) -4-methyl pentanic acid methyl ester
[1173] To a solution of the compound of Example 34a (0.35 g) in dichloromethane was added di-tert-butyldicarbonate (0.29 g). After 2 h at rt, triethylamine was added and the reaction heated to reflux. Upon completion, the reaction was concentrated and the residue was purified by column chromatography (50% hexanes: dichloromethane) to give 0.17 g of the title compound: MS (EI) 386 (M + H ⁺ ).
[1174] c.) (S) -2- (tert-butoxycarbonyl-naphthalen-2-ylmethyl-amino) -4-methyl pentanic acid
[1175] LiOH (0.019 g) was added to a solution of the compound of Example 34b (0.17 g) in THF: methanol (15 mL of 2: 1 solution). The reaction was stirred overnight and concentrated to afford the title compound.
[1176] d.) 4-[(S) -tert-butoxycarbonyl-naphthylene-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3-hydroxy-azane-1-carboxylic acid benzyl ester
[1177] To a solution of compound of Example 2e (0.11 g) in dichloromethane was added EDC (0.08 g), HOBt (0.06 g) and the acid of Example 34c. Upon completion the reaction was finished and chromatographed (5% methanol: dichloromethane) to give the title compound (0.18 g): MS (EI) 618 (M + H ⁺ ).
[1178] e.) [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -naphthylene-2-ylmethyl carbamic acid tert-butyl ester
[1179] To a solution of the compound of example 34d (0.17 g) in ethyl acetate: methanol (20:10 mL) was added 10% Pd / C. The hydrogen balloon was attached and the reaction stirred until complete consumption of the starting material. The reaction was filtered and concentrated to give the title compound (0.1O g): MS (EI) 484 (M + H ⁺ ).
[1180] f.) ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane-4-ylcarbamoyl}- Butyl) -naphthylene-2-methyl-carbamic acid tert-butyl ester
[1181] Except for the replacement of the compound of Example 34e, the title compound was prepared according to the process of Example 9a: MS (EI) 679 (M + H ⁺ ).
[1182] g.) ((S) -3-Methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane-4-ylcarbamoyl} -butyl ) -Naphthylene-2-methyl-carbamic acid tert-butyl ester
[1183] Except for the replacement of the compound of Example 34f, the title compound was prepared according to the process of Example 1i:
[1184]
[1185] <Example 35>
[1186] (S) -4-methyl-2-[(naphthylene-2-ylmethyl) -amino] -pentenoic acid [3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] Preparation of -Azepan-4-yl} -amide
[1187] To a solution of Example 34 g of compound (20 mg) in THF was added 1M HCl in ether. The reaction was stirred until the starting material was consumed completely and concentrated to give the title compound:
[1188]
[1189] <Example 36>
[1190] 4- [2- (2-{(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butylcarbamoyl}- Preparation of Benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[1191] a.) 4- [2- (2-{(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl Carbamoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[1192] To a solution of the compound of Example 28a (0.15 g) in dichloromethane EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 4- [2- (2-carboxybenzofuran-5-yljade C) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester was added. The reaction was stirred until complete. Finished and column chromatography (10% methanol: ethyl acetate) gave the title compound (0.10 g): MS (EI) 757 (M + H ⁺ ).
[1193] b.) 4- [2- (2-{(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butylcarba Moyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[1194] The title compound was prepared according to the process of Example 1i, except that the compound of Example 36a was replaced:
[1195]
[1196] <Example 37>
[1197] 5- (2-Piperizin-1-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -ase Preparation of Pan-4-ylcarbamoyl] -3-butyl} -amide
[1198] The compound of Example 36b (0.02 g) was dissolved in 4M HCl in dioxane. The reaction was stirred until complete and concentrated to give the title compound:
[1199]
[1200] <Example 38>
[1201] 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Preparation of Ilcarbamoyl] -Butyl} amide
[1202] a.) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} amide
[1203] To a solution of the compound of Example 28a (0.15 g) in dichloromethane was added EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 5- (2-cyclohexyl-ethoxy) benzofuran carboxylic acid ( 0.01 g) was added. The reaction was stirred until complete by TLC analysis. Finished and column chromatography (100% ethyl acetate) gave the title compound (0.15 g): MS (EI) 655 (M + H ⁺ ).
[1204] b.) 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[1205] Except for the replacement of the compound of Example 38a, the title compound was prepared according to the process of Example 1i: MS (EI) 653 (M + H ⁺ ).
[1206] <Example 39>
[1207] 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) Preparation of Ethyl] -Azepan-4-ylcarbamoyl} -butyl) amide
[1208] a.) 5- (2-Cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridine-2- Phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1209] To a solution of the compound of Example 20d (0.15 g) in dichloromethane was added EDC (0.06 g), HOBt (0.04 g), triethylamine (0.14 mL) and 5- (2-cyclohexyl-ethoxy) benzofuran carboxylic acid ( 0.09 g) was added. The reaction was stirred until complete by TLC analysis. Finished and column chromatography (100% ethyl acetate) gave the title compound (0.10 g): MS (EI) 695 (M + H ⁺ ).
[1210] b.) 5- (2-cyclohexyl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl -Phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1211] The title compound was prepared according to the process of Example 1i, except that the compound of Example 39a was replaced:
[1212]
[1213] <Example 40>
[1214] 4- [2- (2-{(S) -3-methyl-1- [3-oxo-1- (3-pyridin-2-yl-phenyl) -ethyl [azepan-4-ylcarbamoyl]- Butylcarbamoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[1215] a.) 4- [2- (2-{(S) -3-methyl-1- [3-hydroxy-1- (3-pyridin-2-yl-phenyl) -ethyl [azepan-4-yl Carbamoyl] -butylcarbamoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[1216] To a solution of the compound of Example 20d (0.15 g) in dichloromethane, EDC (0.06 g), HOBt (0.04 g), triethylamine (0.14 mL) and 4- [2- (2-carboxybenzofuran-5-yljade C) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester (0.12 g) was added. The reaction was stirred until complete by TLC analysis. Finished and column chromatography (10% methanol: ethyl acetate) gave the title compound (0.09 g): MS (EI) 797 (M + H ⁺ ).
[1217] b.) 4- [2- (2-{(S) -3-methyl-1- [3-oxo-1- (3-pyridin-2-yl-phenyl) -ethyl [azepane-4-ylcarba Moyl] -butylcarbamoyl} -benzofuran-5-yloxy) -ethyl] -piperazine-1-carboxylic acid tert-butyl ester
[1218] Except for the replacement of the compound of Example 40a, the title compound was prepared according to the process of Example 1i: MS (EI) 795.9 (M + H ⁺ ).
[1219] <Example 41>
[1220] 5- (2-Piperizin-1-yl-ethoxy) -benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-2- Preparation of yl-phenyl) ethyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1221] The title compound was prepared according to the process of Example 37, except that the compound of Example 40b was replaced:
[1222]
[1223] <Example 42>
[1224] Of (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide Produce
[1225] a.) 4-[(S) -2- (tert-butoxycarbonyl-methyl-amino) -4-methyl-pentanoylamino] -3-hydroxy-azane-1-carboxylic acid benzyl ester
[1226] To a solution of the compound of Example 2e (0.35 g) in dichloromethane was added N-methyl-N-Boc-leucine (0.36 g), HOBt (0.2 g) and EDC (0.28 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave 0.6 g of the title compound: MS (EI) 492 (M + H ⁺ ).
[1227] b.) [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -methyl-carbamic acid tert-butyl ester
[1228] To a solution of the compound of Example 42a (0.6 g) in methanol: ethyl acetate (10:20 mL) was added 10% Pd / C and a hydrogen balloon was attached. The reaction was stirred overnight, filtered and concentrated to give 0.50 g of the title compound: MS (EI) 358 (M + H ⁺ ).
[1229] c.) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} methyl-carbamic acid tert-butyl ester
[1230] To a solution of compound (0.2 g) of Example 42b in dichloromethane was added triethylamine (0.16 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: ethyl acetate) gave the title compound (0.23 g): MS (EI) 499 (M + H ⁺ ).
[1231] d.) (S) -4-methyl-2-methylamino-pentanoic acid [3-hydroxy-1- (2-pyridine-2-sulfonyl) azpan-4-yl] -amide
[1232] To a solution of compound of Example 42c (0.23 g) in methanol (3.0 mL) was added 4 M HCl in dioxane (3.0 mL). The reaction was stirred until complete. Concentration gave the title compound: MS (EI) 399 (M + H ⁺ ).
[1233] e.) (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl ]-amides
[1234] To a solution of the compound of Example 42d (0.05 g) in dichloromethane was added triethylamine (0.07 mL), 2-naphthaldehyde (0.05 g) and sodium triacetoxyborohydride (0.11 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol ethyl acetate) gave the title compound (0.03 g): MS (EI) 539 (M + H ⁺ ).
[1235] f.) (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amides
[1236] Except for substituting the compound of Example 42e, the title compound was prepared according to the process of Example 1i:
[1237]
[1238] <Example 43>
[1239] (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -ase Preparation of Pan-4-yl} amide
[1240] a.) ((S) -1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane-4-ylcarbamoyl} -3-methyl- Butyl) -methyl-carbamic acid tert-butyl ester
[1241] To the solution of compound (0.25 g) of Example 42b was added 3- (2-pyridyl) phenyl acetic acid (0.16 g), HOBt (0.12 g) and EDC (0.15 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: ethyl acetate) gave the title compound (0.24 g): MS (EI) 553 (M + H ⁺ ).
[1242] b.) (S) -4-methyl-2-methylamino-pentanoic acid {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azpan-4-yl }-amides
[1243] Except for the replacement of the compound of Example 43a, the title compound was obtained following the procedure of Example 42d: MS (EI) 453 (M + H ⁺ ).
[1244] c.) (S) -4-methyl-2- (methyl-naphthalen-2-ylmethyl-amino) pentanoic acid {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl ] -Azepan-4-yl} -amide
[1245] Except for replacing with the compound of Example 43b, the title compound was prepared according to the process of Examples 42e-f:
[1246]
[1247] <Example 44>
[1248] 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridine-) Preparation of 2-yl-phenyl) acetyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1249] a.) 5- (2-Morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-hydroxy-1- [2- ( 3-pyridin-2-yl-phenyl) acetyl] -azepane-4-ylcarbamoyl} -butyl) amide
[1250] To a solution of compound (0.1 g) of example 43b in dichloromethane, 5- (2-morpholin-4-yl-ethyloxy) benzofuran-2-carboxylic acid (0.06 g), HOBt (0.026 g), TEA (0.07 mL) and EDC (0.04 g) were added. The reaction was stirred until complete. Finished and chromatographed (20% methanol: ethyl acetate) gave the title compound (0.07 g): MS (EI) 726 (M + H ⁺ ).
[1251] b.) 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid methyl ((S) -3-methyl-1- {3-oxo-1- [2- (3 -Pyridin-2-yl-phenyl) acetyl] -azpan-4-ylcarbamoyl} -butyl) amide
[1252] The title compound was prepared according to the process of Example 1i, except that the compound of Example 44a was replaced:
[1253]
[1254] <Example 45>
[1255] Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -3-methyl-butyl] Preparation of Amides
[1256] a.) Benzofuran-2-carboxylic acid methyl {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -3- Methyl-butyl] -amide
[1257] To a solution of the compound of example 42d (0.1 g) in dichloromethane was added benzofuran-2-carboxylic acid (0.04 g), TEA (excess), HOBt (0.03 g), and EDC (0.04 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (0.04 g): MS (EI) 542.9 (M + H ⁺ ).
[1258] b.) Methyl benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -3-methyl -Butyl] -amide
[1259] The title compound was prepared according to the process of Example 1i, except that the compound of Example 45a was replaced:
[1260]
[1261] <Example 46>
[1262] 2,2,2-trifluoro-N-((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] -azepane Preparation of 4-ylcarbamoyl} -butyl) -N-naphthylene-2-ylmethyl-acetamide
[1263] a.) (S) -4-methyl-2- [naphthylene-2-ylmethyl- (2,2,2-trifluoro-acetyl) -amino] -pentanoic acid methyl ester
[1264] To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added potassium carbonate (catalyst amount), and trifluoroacetic acid (0.44 g). The reaction was stirred at rt for 1 h, concentrated and chromatographed (20% ethyl acetate: hexane) to afford the title compound.
[1265] b.) (S) -4-methyl-2- [naphthylene-2-ylmethyl- (2,2,2-trifluoro-acetyl) -amino]-lithium pentanate
[1266] To a solution of the compound of Example 46a (0.49 g) in THF: water (3 mL of 2: 1 solution) was added lithium hydroxide monohydrate (0.06 g). The reaction was stirred overnight and concentrated to give the title compound (0.46 g): MS (EI) 366 (M + H ⁺ ).
[1267] c.) 3-hydroxy-4-{(S) -4-methyl-2- [naphthylene-2-ylmethyl- (2,2,2-trifluoro-acetyl) amino] -pentanoylamino} Azepan-1-carboxylic acid benzyl ester
[1268] To a solution of the compound of Example 2e (0.29 g) in dichloromethane was added EDC (0.24 g), HOBt (0.16 g) and Compound of Example 46b (0.46 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: ethyl acetate) gave the title compound (0.25 g): MS (EI) 614 (M + H ⁺ ).
[1269] d.) 2,2,2-trifluoro-N-[(S) -1- (3-hydroxy-azpan-ylcarbamoyl) -3-methyl-butyl] -naphthalen-2-ylmethyl- Acetamide
[1270] Except for the replacement of the compound of Example 46c, the title compound was prepared according to the process of Example 42b: MS (EI) 480 (M + H ⁺ ).
[1271] e.) 2,2,2-trifluoro-N-((S) -3-methyl-1- {3-hydroxy-1- [2- (3-pyridin-2-yl-phenyl) -acetyl ] Azepan-4-ylcarbamoyl} -butyl) -N-naphthylene-2-ylmethyl-acetamide
[1272] Except for the replacement of the compound of Example 46d, the title compound was prepared according to the process of Example 43a: MS (EI) 675 (M + H ⁺ ).
[1273] f.) 2,2,2-trifluoro-N-((S) -3-methyl-1- {3-oxo-1- [2- (3-pyridin-2-yl-phenyl) -acetyl] Azepan-4-ylcarbamoyl} -butyl) -N-naphthylene-2-ylmethyl-acetamide
[1274] Except for substituting the compound of Example 46e, the title compound was prepared according to the process of Example 1i:
[1275]
[1276] <Example 47>
[1277] Preparation of 4-[(S)-(methanesulfonyl-naphthylene-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3-oxo-azane-1-carboxylic acid benzyl ester
[1278] a.) (S) -2- (methanesulfonyl-naphthylene-2-ylmethyl-amino) -4-methyl-pentanoic acid methyl ester
[1279] To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added triethylamine (0.36 mL) and methanesulfonyl chloride (0.16 mL). The reaction was stirred at rt until complete. Finished and chromatographed (20% ethyl acetate: hexane) to give the title compound (0.24 g).
[1280] b.) (S) -2- (methanesulfonyl-naphthylene-2-ylmethyl-amino) -4-methyl- lithium pentanate
[1281] Except for the replacement of the compound of Example 47a, the title compound was prepared following the procedure of Example 46b: MS (EI) 348 (M + H ⁺ ).
[1282] c.) 4-[(S)-(methanesulfonyl-naphthylene-2-ylmethyl-amino) -4-methyl-pentanoylamino] -3-hydroxy-azane-1-carboxylic acid benzyl ester
[1283] Except for the replacement of the compound of Example 47b, the title compound was prepared following the procedure of Example 46c: MS (EI) 596 (M + H ⁺ ).
[1284] d.) 4-[(S)-(methanesulfonyl-naphthylene-2-ylmethyl-amino) -4-methylpentanoylamino] -3-oxo-azane-1-carboxylic acid benzyl ester
[1285] The title compound was prepared according to the process of Example 1i, except that the compound of Example 47c was replaced:
[1286]
[1287] <Example 48>
[1288] Preparation of quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1289] a.) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1290] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with quinoline-2-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1291] b.) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1292] Except for the replacement of the compound of Example 48a, the title compound was prepared according to the process of Example 1i:
[1293]
[1294] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 538 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 538 (M + H ⁺ , 100%) was obtained.
[1295] <Example 49>
[1296] Preparation of quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1297] a.) Quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1298] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with quinoline-8-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1299] b.) Quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1300] Except for replacing with the compound of Example 49a, the title compound was prepared according to the process of Example 1i:
[1301]
[1302] <Example 50>
[1303] Preparation of quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1304] a.) Quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) azpan-4-ylcarbamoyl] -butyl} amide
[1305] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with quinoline-6-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1306] b.) Quinoline-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1307] Except for substituting the compound of Example 50a, the title compound was prepared according to the process of Example 1i:
[1308]
[1309] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 538 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 538 (M + H ⁺ , 100%) was obtained.
[1310] <Example 51>
[1311] Preparation of quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1312] a.) Quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1313] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with quinoline-4-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1314] b.) Quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1315] Except for the replacement of the compound of Example 51a, the title compound was prepared according to the process of Example 1i:
[1316]
[1317] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 538 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 538 (M + H ⁺ , 100%) was obtained.
[1318] <Example 52>
[1319] Preparation of quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1320] a.) Quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1321] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with quinoline-3-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1322] b.) Quinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1323] Except for substituting the compound of Example 52a, the title compound was prepared according to the process of Example 1i:
[1324]
[1325] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 538 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 538 (M + H ⁺ , 100%).
[1326] <Example 53>
[1327] Preparation of Isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1328] a.) Isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1329] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with isoquinoline-3carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1330] b.) Isoquinoline-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1331] The title compound was prepared according to the procedure of Example 1i, except that the compound of Example 53a was replaced:
[1332]
[1333] <Example 54>
[1334] Preparation of Isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1335] a.) Isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1336] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with isoquinoline-1-carboxylic acid: MS (EI) 540 (M + H ⁺ ).
[1337] b.) Isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1338] The title compound was prepared according to the process of Example 1i, except that the compound of Example 54a was replaced:
[1339]
[1340] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 537 (M ⁺ , 100%), and diastereomers eluting later; MS (EI): 537 (M ⁺ , 100%).
[1341] <Example 55>
[1342] Preparation of Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1343] a.) Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1344] The title compound was prepared according to the procedure of Example 28b except for the replacement of benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid: MS (EI) 541 (M + H ⁺ ).
[1345] b.) quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1346] Except for replacing with the compound of Example 55a, the title compound was prepared according to the process of Example 1i:
[1347]
[1348] <Example 56>
[1349] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1350] a.) Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1351] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid: MS (EI) 545 (M + H ⁺ ).
[1352] b.) Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1353] Except for substituting the compound of Example 56a, the title compound was prepared according to the process of Example 1i:
[1354]
[1355] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC;
[1356] And diastereomers eluted later;
[1357]
[1358] <Example 57>
[1359] 1,8-naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1360] a.) 1,8-naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1361] The title compound was prepared following the procedure of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 1,8-naphthyridine-2-carboxylic acid: MS (EI) 541 (M + H ⁺ ).
[1362] b.) 1,8-naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1363] Except for the replacement of the compound of Example 57a, the title compound was prepared according to the process of Example 1i:
[1364]
[1365] <Example 58>
[1366] Preparation of 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1367] a.) 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides
[1368] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 1H-indole-2-carboxylic acid: MS (EI) 528 (M + H ⁺ ).
[1369] b.) 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1370] Except for substituting the compound of Example 58a, the title compound was prepared according to the process of Example 1i:
[1371]
[1372] <Example 59>
[1373] 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1374] a.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1375] The title compound was prepared according to the procedure of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 5-methoxybenzofuran-2-carboxylic acid: MS (EI) 559 (M + H ⁺ ).
[1376] b.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1377] The title compound was prepared according to the process of Example 1i, except that the compound of Example 59a was replaced:
[1378]
[1379] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC;
[1380] And diastereomers eluted later; MS (EI): 557 (M + H ⁺ , 100%) was obtained.
[1381] <Example 60>
[1382] 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1383] a.) 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1384] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 5-bromo-2-furonic acid: MS (EI) 558 (M + H +).
[1385] b.) 5-bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl]- Butyl} amide
[1386] Except for replacing the compound of Example 60a, the title compound was prepared according to the process of Example 1i:
[1387]
[1388] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 555 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 555 (M + H ⁺ , 100%) was obtained.
[1389] <Example 61>
[1390] Preparation of furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1391] a.) Furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1392] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 2-furonic acid: MS (EI) 479 (M + H ⁺ ).
[1393] b.) furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1394] The title compound was prepared according to the process of Example 1i, except that the compound of Example 61a was replaced:
[1395]
[1396] <Example 62>
[1397] 5-nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Produce
[1398] a.) 5-nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1399] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 5-nitro-2-furonic acid: MS (EI) 524 (M + H ⁺ ).
[1400] b.) 5-nitro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides
[1401] Except for substituting the compound of Example 62a, the title compound was prepared according to the process of Example 1i:
[1402]
[1403] <Example 63>
[1404] 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide
[1405] a.) 5- (4-Nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1406] The title compound was prepared following the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 5- (4-nitrophenyl) -2-furonic acid: MS (EI) 600 (M + H ⁺ ).
[1407] b.) 5- (4-nitro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} amide
[1408] Except for replacing the compound of Example 63a, the title compound was prepared according to the process of Example 1i:
[1409]
[1410] <Example 64>
[1411] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Preparation of Ilcarbamoyl] -Butyl} amide
[1412] a.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} amide
[1413] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 5- [3- (trifluoromethyl) phenyl] -2-furonic acid: MS (EI) 623 (M + H ⁺ ).
[1414] b.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[1415] Except for the replacement of the compound of Example 64a, the title compound was prepared according to the process of Example 1i:
[1416]
[1417] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 621 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 621 (M + H ⁺ , 100%) was obtained.
[1418] <Example 65>
[1419] Preparation of tetrahydro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1420] a.) Tetrahydro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides
[1421] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced by tetrahydrofuran-2carboxylic acid: MS (EI) 483 (M + H ⁺ ).
[1422] b.) tetrahydro-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides
[1423] Except for the replacement of the compound of Example 65a, the title compound was prepared according to the process of Example 1i:
[1424]
[1425] Example 66
[1426] Preparation of (S) -4-methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1427] a.) (S) -4-methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-hydroxy- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1428] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with phenoxyacetic acid: MS (EI) 519 (M + H ⁺ ).
[1429] b.) (S) -4-methyl-2- (2-phenoxy-acetylamino) -pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1430] Except for the replacement of the compound of Example 66a, the title compound was prepared according to the process of Example 1i:
[1431]
[1432] <Example 67>
[1433] (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl] Preparation of -amides
[1434] a.) (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-hydroxy- (pyridine-2-sulfonyl) -azepane- 4-yl] -amide
[1435] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 4-fluorophenoxyacetic acid: MS (EI) 537 (M + H ⁺ ).
[1436] b.) (S) -2- [2- (4-Fluoro-phenoxy) -acetylamino] -4-methyl-pentanoic acid [3-oxo- (pyridine-2-sulfonyl) -azepane-4 -Yl] -amide
[1437] Except for replacing with the compound of Example 67a, the title compound was prepared according to the process of Example 1i:
[1438]
[1439] <Example 68>
[1440] Of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-carbonyl) -azpan-4-ylcarbamoyl) -3-butyl] -amide Produce
[1441] a.) {(S) -1- [3-hydroxy-1- (pyridine-2-carbonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[1442] To a solution of Example 2 g of compound (0.25 g) in dichloromethane was added picolinic acid (0.09 g), EDC (0.14 g) and HOBt (0.10 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: ethyl acetate) gave the title compound (0.35 g).
[1443] b.) (S) -2-Amino-4-methylpentanoic acid [3-hydroxy-1- (pyridine-2-carbonyl) -azpan-4-yl] -amide
[1444] To a solution of the compound of Example 68a (0.34 g) in methanol (6 mL) was added 4 M HCl in dioxane (6 mL). The reaction was stirred until complete and concentrated to give the title compound (0.34 g): MS (EI) 349 (M + H ⁺ ).
[1445] c.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-carbonyl) -azpan-4-ylcarbamoyl) -3-butyl ]-amides
[1446] Except for the replacement of the compound of Example 68b, the title compound was prepared following the procedure of Example 28b: MS (EI) 493 (M + H ⁺ ).
[1447] d.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-carbonyl) -azpan-4-ylcarbamoyl) -3-butyl] -amides
[1448] The title compound was prepared according to the process of Example 1i, except that the compound of Example 68c was replaced:
[1449]
[1450] <Example 69>
[1451] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-carbonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1452] The title compound was prepared following the procedure of Examples 68a-d, except that the picolinic acid of Example 68c was replaced with picolinic acid N-oxide:
[1453]
[1454] <Example 70>
[1455] Preparation of 4-((S) -2-tert-butylcarbonylamino-4-methyl-pentanoylamino) -3-oxo-azepane-1-carboxylic acid benzyl ester
[1456] Benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl- Except for replacing butyl} -amide with 4-((S) -2-tertbutoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azane-1-carboxylic acid benzyl ester The title compound was prepared following the procedure in Example 92j. The residue was washed by HPLC. Diastereomers eluted first;
[1457]
[1458] ; And diastereomers eluted next; 1.00-0.85 (d, 6 H); And then eluted diastereomer: MS (M + H ⁺ ) 476.2.
[1459] <Example 71>
[1460] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-methyl-1H-imidazole-4-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1461] a.) {(S) -1- [3-hydroxy-1- (1-methyl-1H-imidazole-2-sulfonyl) -azepane-4-ylcarbamoyl} -3-methyl-butyl} -Carbamic acid tert-butyl ester
[1462] To a solution of Example 2 g of amine in methylene chloride (5 ml) was added pyridine (92 μl, 1.14 mmol) followed by 1-methylimidazole-4-sulfonylchloride (0.112 g, 0.623 mmol). The reaction was stirred at rt for 16 h. The solution was then washed with saturated aqueous NaHCO ₃ , water and brine. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give the title compound as a white solid (0.172 g, 68%):
[1463]
[1464] b.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-methyl-1 H-imidazole-2-sulfonyl) -azpan-4-yl] -amide
[1465] To a solution of the compound of Example 71a (0.172 g, 0.353 mmol) in the minimum amount of MeOH was added 4M HCl in dioxane (10 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated and azeotropic with toluene (2x) to give the title compound as an off-white solid: MS (ESI): 388.2 (M + H) ⁺
[1466] c.) 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-methyl-1H-imidazole-4-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} amide
[1467] Compound of Example 71b (0.137 g, 0.353 mmol), 5,6-dimethoxybenzofuran-2-carboxylic acid (0.86 g, 0.388 mmol) in DMF (5 mL), triethylamine (246 mL, 1.77 mmol) and To a stirred solution of 1-hydroxybenzotriazole (0.1 g, 0.070 mmol) was added 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.074 g, 0.388 mmol). After stirring for 16 h at rt, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2 ×), and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.088 g, 42%): MS (ESI): 592.1 (M + H) ⁺
[1468] d.) 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-methyl-1H-imidazole-4-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} amide
[1469] Oxalyl chloride (52 μl, 0.596 mmol) was cooled to -78 ° C. To this was added dimethyl sulfoxide (106 μl, 1.49 mmol) in methylene chloride dropwise. After stirring at −78 ° C. for 15 minutes, alcohol in methylene chloride was slowly added and stirred for 1 hour while Et ₃ N (416 μl, 2.98 mmol) was added. The solution was then brought to room temperature, quenched with water and extracted with methylene chloride. 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 (0.068 g, 78%):
[1470]
[1471] <Example 72>
[1472] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole-3-sulfonyl) -3-oxo-azepane- Preparation of 4-ylcarbamoyl] butyl} amide
[1473] a.) 4-((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester
[1474] To a stirred solution of the compound of Example 2f (3.5 g, 7.33 mmol) in EtOAc (0.5 mL) was added 4M HCl in dioxane (12.8 mL). The mixture was stirred at rt for 1 h. The reaction mixture was concentrated and azeotropic with toluene (2 x 20 mL) to give the title compound as pale yellow oil (3.13 g, 100%): MS (ESI) 378.4 (M + H) ⁺
[1475] b.) 4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azane-1-carboxylic acid benzyl ester
[1476] Compound of Example 72a (3.13 g, 7.57 mmol), benzofuran-2-carboxylic acid (1.35 g, 8.32 mmol) in DMF (30 mL), triethylamine (1.17 ml, 8.25 mmol) and 1-hydroxybenzotria To a stirred solution of sol (0.2 g, 1.48 mmol) was added 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (1.6 g, 8.33 mmol). After stirring for 16 h at rt, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2 ×), and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; ethyl acetate / dichloromethane) to give the title compound (3.7 g, 93%).
[1477]
[1478] c.) Benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[1479] To a solution of the compound of Example 72b (2.6 g, 4.9 mmol) in EtOAc (150 mL) was added 10% palladium on carbon (1.3 g) and stirred for 64 h at room temperature under aqueous atmosphere. The mixture was then filtered through celite and the filtrate was concentrated to give the title compound as a white solid (1.92 g, 100%):
[1480]
[1481] d.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole-3-sulfonyl) -3-hydroxy -Azpan-4-ylcarbamoyl] -butyl} amide
[1482] To a stirred solution of the compound of Example 72c (0.100 g, 0.25 mmol) and triethylamine (35 μl, 0.25 mmol) in methylene chloride (2 mL) was 5-methyl-1H-1,2,4-triazolesulfonylchloride (0.043 g, 0.25 mmol) was added. The mixture was stirred for 10 minutes and washed with saturated aqueous NaHCO ₃ , water and labeled brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The compound was purified by column chromatography (silica gel; ethyl acetate / hexanes) to give the title compound as light yellow oil (0.111, 84%): MS (ESI) 532.73 (M + H) ⁺
[1483] e.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (5-methyl-1H- [1,2,4] triazole-3-sulfonyl) -3-oxo- Azepan-4-ylcarbamoyl] -butyl} amide
[1484] To a stirred solution of the compound of Example 72d (0.108 g, 0.206 mmol) in dimethylsulfoxide (2 mL) was added triethylamine (172 μl, 1.23 mmol) followed by sulfur trioxide pyridine (0.116 g, 0.718 mmol) and room temperature Stirred for 16 h. The reaction mixture was diluted with EtOAc and washed with water (× 2). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the title compound as a white solid (0.08 g, 81%):
[1485]
[1486] <Example 73>
[1487] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-3-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl]- Preparation of Butyl} amide
[1488] a.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazol-3-sulfonyl) -3-hydroxy-azpan-4-yl Carbamoyl] -butyl} amide
[1489] To a stirred solution of the compound of Example 72c (0.100 g, 0.25 mmol) and triethylamine (35 μl, 0.25 mmol) was added 1-methylimidazole sulfonyl chloride (0.046 g, 0.255 mmol). The reaction was stirred for 10 minutes and washed with saturated aqueous NaHCO ₃ , water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The compound was purified by column chromatography (silica gel; ethyl acetate / hexanes) to give the title compound as a pale yellow oil (0.113 g, 82%):
[1490]
[1491] b.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-3-sulfonyl) -3-oxo-azepane-4-ylcarba Moyl] -butyl} amide
[1492] To a stirred solution of the compound of Example 73a (0.085 g, 0.159 mmol) in dimethylsulfoxide was added triethylamine (133 μl, 0.95 mmol) followed by sulfur trioxide pyridine (0.08 g, 0.5 mmol) and for 16 hours at room temperature. Stirred. The reaction mixture was diluted with EtOAc and concentrated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the title compound as a white solid (0.072 g, 83%). MS (ESI): 529.76 (M + H) ⁺
[1493] <Example 74>
[1494] Of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1H-imidazol-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} amide Produce
[1495] a.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1H-imidazol-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl }amides
[1496] To a stirred solution of the compound of Example 72c (0.100 g, 0.25 mmol) and triethylamine (35 μl, 0.25 mmol) was added 2-imidazolesulfonyl chloride (0.046 g, 0.255 mmol). The reaction was stirred for 10 minutes and washed with saturated aqueous NaHCO ₃ , water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The compound was purified by column chromatography (silica gel; ethyl acetate / hexanes) to give the title compound as a pale yellow oil (0.113 g, 82%):
[1497]
[1498] b.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1H-imidazol-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl }amides
[1499] To a stirred solution of the compound of Example 74a (0.107 g, 0.206 mmol) in dimethylsulfoxide (2 mL) was added triethylamine (172 μl, 1.23 mmol) followed by sulfur trioxide pyridine (0.115 g, 0.718 mmol) and room temperature Stirred for 16 h. The reaction mixture was diluted with EtOAc and washed with water (× 2). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the title compound as a white solid (0.09 g, 85%); MS (ESI): 515.84 (M + H) ⁺
[1500] <Example 75>
[1501] Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1502] a.) {(S) -1- [3-hydroxy-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl} -3-methyl-butyl} -carbamic acid tert-butyl ester
[1503] To a solution of Example 2 g of compound (2.50 g, 7.29 mmol) in DCE (100 mL) was added P-NMM (4.0 g) and thiazole-2-sulfonyl chloride (1.6 g, 8.75 mmol). After stirring overnight at room temperature, 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) ⁺
[1504] b.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amides
[1505] Benzofuran-2-carboxylic acid (0.109 g, 0.172 mmol) in CH ₂ Cl ₂ (20 mL) of the compound in Example 75b (0.15 g, 0.45 mmol) CH 2 Cl 2 (10 mL) a solution of 1-hydroxy Roxybenzotriazole (0.106 g, 0.762 mmol), and P-EDC (0.85 g, 1 mmol / g) were added. After shaking overnight at room temperature, the solution was treated with tisamine (0.589 g, 3.75 mmol / g). After more shaking for 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) ⁺ .
[1506] c.) Benzofuran-2-carboxylic acid {S} -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[1507] To a stirred solution of the compound of Example 75c (166.7 mg, 0.313 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (265.5 mg, 0.626 mmol). After stirring for 2 hours at room temperature, a solution of sodium trisulfide (10% in 2 mL of water) and saturated aqueous sodium bicarbonate (2 mL) were added to the solution simultaneously. The aqueous phase was extracted with dichloromethane (2x). The organic phases 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) to give the first eluate white. Solid (84.8 mg, 50.8%, MS (ESI): 533.2 (M + H) ⁺ ) was obtained and a second eluate was obtained as a white solid (50.1 mg, 30.0%, MS: 533.2 (M + H ⁺ )).
[1508] <Example 76>
[1509] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl]- Preparation of Butyl} amide
[1510] a.) {(S) -1- [3-hydroxy-1- (1-methyl-1H-imidazole-2-sulfonyl) -azepane-4-ylcarbamoyl} -3-methyl-butyl} -Carbamic acid tert-butyl ester
[1511] To a solution of Example 2 g of amine in methylene chloride (5 ml) was added pyridine (92 μl, 1.14 mmol) followed by 1-methylimidazole-4-sulfonylchloride (0.112 g, 0.623 mmol). The reaction was stirred at rt for 16 h. The solution was then washed with saturated aqueous NaHCO ₃ , water and brine. The product was purified by column chromatography (silica gel: methanol / methylene chloride) to give the title compound as a white solid (0.172 g, 68%):
[1512]
[1513] b.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-methyl-1 H-imidazole-2-sulfonyl) -azpan-4-yl] -amide
[1514] To a solution of the compound of Example 76a (0.172 g, 0.353 mmol) in the minimum amount of MeOH was added 4M HCl in dioxane (10 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated and azeotropic with toluene (2 ×) to afford the title compound as an off white solid. MS (ESI): 388.2 (M + H) ⁺
[1515] c.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazol-4-sulfonyl) -3-hydroxy-azpan-4-yl Carbamoyl] -butyl} amide
[1516] Compound of Example 72c (0.2 g, 0.471 mmol), benzofuran-2-carboxylic acid (0.084 g, 0.388 mmol) in DMF (5 mL), triethylamine (72 μl, 0.517 mmol) and 1-hydroxybenzotria To a stirred solution of sol (0.012 g, 0.088 mmol) was added 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.099 g, 0.515 mmol). After stirring for 16 h at rt, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2 ×) and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.226 g, 90%):
[1517]
[1518] d.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-4-ylcarba Moyl] -butyl} amide
[1519] To a stirred solution of the compound of Example 76a (0.226 g, 0.426 mmol) in dimethylsulfoxide (2 mL) was added triethylamine (355 μl, 2.55 mmol) followed by sulfur trioxide pyridine (0.238 g, 1.48 mmol) and room temperature Stirred for 16 h. The reaction mixture was diluted with EtOAc and washed with water (× 2). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel; methanol / methylene chloride) to give the title compound as a white solid (0.168 g, 76%):
[1520]
[1521] <Example 77>
[1522] 5- (4-Oxy-morpholino-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl ) -Azepan-4-ylcarbamoyl] -butyl} amide
[1523] M-CPBA (0.008 g) was added to a solution of the compound of Example 30b (0.01 g) in dichloromethane (2 mL). The reaction was stirred overnight. Finished and column chromatography (30% methanol: dichloromethane) gave the title compound:
[1524]
[1525] <Example 78>
[1526] Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1527] a.) 4-((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester
[1528] 4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azane-1-carboxylic acid benzyl ester of Example 2f in methanol (20 mL) ( To 4.0 g) solution was added 4M HCl in dioxane (20 mL). The reaction was stirred at rt for 2 h and concentrated to give the title compound (3.8 g): MS (EI) 378 (M + H ⁺ ).
[1529] b.) 4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azane-1-carboxylic acid benzyl ester
[1530] Solution of 4-((S) -2-amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester (3.2 g) of Example 78a in dichloromethane (200 mL) To this was added EDC (1.48 g), HOBt (1.05 g), TEA (1.29 mL) and benzofuran-2-carboxylic acid. The reaction was stirred until complete. Finished and column chromatography (2% methanol: dichloromethane) gave the title compound (3.78 g): MS (EI) 521 (M + H ⁺ ).
[1531] c.) Benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[1532] 4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3- of Example 78b in methanol: ethyl acetate (50 mL: 100 mL) To a solution of hydroxy-azpan-1-carboxylic acid benzyl ester (1.6 g) was added 10% Pd / C. The reaction was stirred under hydrogen balloon for 2 h, filtered and concentrated to give the title compound (1.16 g): MS (EI) 387 (M + H ⁺ ).
[1533] d.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1534] Solution of benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide (0.3 g) in dichloromethane To triethylamine (0.17 mL) was added followed by 3-pyridinesulfonyl chloride (0.25 g). The reaction was stirred at rt until complete was confirmed by TLC analysis. Finished and column chromatography (5% methanol: ethyl acetate) gave 0.32 g of the title compound: MS (EI) 528 (M + H ⁺ ).
[1535] e.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1536] Benzofuran-2-carboxylic acid of Example 78d {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Except for the replacement with amides, the title compound was prepared following the procedure of Example 1i:
[1537]
[1538] <Example 79>
[1539] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1540] a.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1541] Benzofuran-2-carboxylic acid of Example 78d in dichloromethane {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl] M-CPBA (0.05 g) was added to a solution of -butyl} amide (0.05 g). The reaction was stirred overnight. Finished and column chromatography (10% methanol: dichloromethane) gave the title compound (0.03 g): MS (EI) 544 (M + H ⁺ ).
[1542] b.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-3-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1543] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-3-sulfonyl) -azane-4-ylcarbamoyl of Example 79a The title compound was prepared according to the process of Example 1i except for replacing with] -butyl} amide:
[1544]
[1545] <Example 80>
[1546] Preparation of quinoline-3-carboxylic acid {(S) -1- (3,4-dichloro-benzene-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl)]-3-methyl-butyl} -amide
[1547] Example 75a-d, except that the thioazole-2-sulfonyl chloride of Example 75a was replaced by 3,4-dichlorosulfonyl chloride and the benzofura-2-carboxylic acid was replaced by quinoline-3-carboxylic acid The title compound was prepared according to the process:
[1548]
[1549] <Example 81>
[1550] 5-hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azepane-4- Preparation of Ilcarbamoyl] -Butyl} amide
[1551] a.) 5-hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-hydroxy-ase Pan-4-ylcarbamoyl] -butyl} amide
[1552] Compound of Example 76b (0.1 g, 0.235 mmol), 5-hydroxybenzofuran-2-carboxylic acid (0.046 g, 0.256 mmol) in DMF (5 mL), triethylamine (36 μl, 0.258 mmol) and 1- To a stirred solution of hydroxybenzotriazole (0.006 g, 0.044 mmol) was added 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.05 g, 0.26 mmol). After stirring for 16 h at rt, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2 ×) 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%).
[1553]
[1554] MS (ESI): 547.88 (M + H) ⁺
[1555] b.) 5-hydroxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azane -4-ylcarbamoyl] -butyl} amide
[1556] Oxalyl chloride (13 μl, 0.149 mmol) was cooled to -78 ° C. To this was added dimethyl sulfoxide (28 μl, 0.394 mmol) in methylene chloride dropwise. After stirring at −78 ° C. for 15 minutes, the alcohol of Example 81a in methylene chloride was slowly added and stirred for 1 hour while Et ₃ N (7 μl, 0.05 mmol) was added. The solution was then brought to room temperature, quenched with water and extracted with methylene chloride. The organic phase 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) ⁺
[1557] <Example 82>
[1558] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl)]-3- Preparation of Methyl-Butyl} -amide
[1559] a.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) ] -3-methyl-butyl} -amide
[1560] Solution of benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide (0.10 g) in dichloromethane To triethylamine (0.07 mL) was added followed by 2-pyridinesulfonylchloride N-oxide. The reaction was stirred at rt overnight. Finished and chromatographed (10% methanol: dichloromethane) to give the title compound (0.01 g): MS (EI) 544 (M + H ⁺ ).
[1561] b.) {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl)]-3-methyl-butyl }-amides
[1562] Benzofuran-2carboxylic acid of Example 82a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-ylcarbamoyl) The title compound was prepared according to the process of Example 1i, except that it was replaced with] -3-methyl-butyl} -amide:
[1563]
[1564] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC;
[1565]
[1566] And diastereomers eluted later; MS (EI): 542 (M + H ⁺ , 100%) was obtained.
[1567] <Example 83>
[1568] 2- (4-{(S) -2-{(benzofuran-2-carbonyl) -amino} -4-methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid Produce
[1569] a.) 2- (4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1-sulfonyl ) -Benzoic acid methyl ester
[1570] The title compound was prepared following the procedure of Examples 75a-c except for replacing 2-thiazolesulfonyl chloride with 2-carboxymethylsulfonyl chloride: MS (M + H ⁺ ) = 585.56, M + Na ⁺ = 607.76, 2M + H ⁺ = 1170.48.
[1571] b.) 2- (4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1-sulfonyl ) -Benzoic acid
[1572] 2- (4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1-sulfonyl) -benzoic acid Methyl ester (Compound 83a, 180 mg, 0.309 mmol) was dissolved in 5: 1 MeOH / water (6 ml), LiOH (14 mg, 0.34 mmol) was added and the reaction mixture was stirred and refluxed for 6 hours. . The reaction mixture was quenched with water and 6N HCl (adjust pH = 2), extracted with EtOAc (3 × 10 ml), dried over MgSO ₄ , filtered and concentrated and chromatographed (silica gel, 1% acetic acid / 4% MeOH / CH ₂ Cl ₂ ) afforded the title compound as a white solid (48 mg, 27%): M + H ⁺ = 572.2
[1573] c.) 2- (4-{(S) -2-[(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -Benzoic acid
[1574] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide -(4-{(S) -2 [(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azepane-1-sulfonyl) -benzoic acid Except for one, the title compound was prepared following the procedure of Example 75d:
[1575]
[1576] <Example 84>
[1577] 3- (4-{(S) -2-{(benzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-oxo-azepane-1-sulfonyl) -benzoic acid Produce
[1578] The title compound was prepared according to the process of Example 83 except that 2-carboxymethylbenzenesulfonyl chloride was replaced with 3-carboxymethylbenzenesulfonyl chloride:
[1579]
[1580] <Example 85>
[1581] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[1582] a.) {(S) -1- [3-hydroxy-1- (1-oxy-pyridine-sulfonyl) -azpan-4-ylcarbamoyl] -3-methylbutyl-carbamic acid tert-butyl ester
[1583] [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert butyl ester of Example 2 g in dichloromethane (100 mL) and saturated sodium bicarbonate (2.5 g) solution of freshly prepared 2-pyridinesulfonyl chloride N-oxide (prepared by bubbling chlorine gas through a 2-mercaptopyridine-N-oxide solution in 9M HCl for about 90 minutes. Excess chlorine was removed under vacuum to give 2-pyridinesulfonyl chloride-N-oxide). The reaction was stirred at rt for 1 h. Finished and column chromatography (10% methanol: dichloromethane) gave the title compound (2.0 g): MS (EI) 500 (M + H ⁺ ).
[1584] b.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-sulfonyl) -azpan-4-yl] -amide
[1585] {(S) -1- [3-hydroxy-1- (1-oxy-pyridine-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl- of Example 85a in methanol (20 mL) To a solution of butyl-carbamic acid tert-butyl ester (2.0 g) was added 4M HCl in dioxane (20 mL). The reaction was stirred at rt for 1.5 h and concentrated to give the title compound (1.8 g): MS (EI) 400 (M + H ⁺ ).
[1586] c.) Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} amide
[1587] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-sulfonyl) -azpan-4-yl of Example 85b in dichloromethane (12 mL) To a solution of] -amide (0.25 g) was added triethylamine (0.12 mL), EDC (0.11 g), HOBt (0.077 g) and benzo [b] thiophene-2-carboxylic acid. The reaction was stirred until complete. Finished and column chromatography (10% methanol: dichloromethane) gave the title compound (0.26 g): MS (EI) 560 (M + H ⁺ ).
[1588] d.) Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide
[1589] Benzo [b] thiophene-2-carboxylic acid of Example 85c {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4 The title compound was prepared according to the process of Example 1i except for replacing with -ylcarbamoyl] -butyl} amide:
[1590]
[1591] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 558 (M ⁺ , 100%), and diastereomers eluting later; MS (EI): 558 (M ⁺ , 100%) was obtained.
[1592] <Example 86>
[1593] 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[1594] a.) 5-Bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} amide
[1595] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5-bromo-2-furonic acid: MS (EI) 574 (M + H ⁺ ).
[1596] b.) 5-bromo-furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide
[1597] 5-Bromo-furan-2-carboxylic acid of Example 86a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 The title compound was prepared according to the process of Example 1i except for replacing with -ylcarbamoyl] -butyl} amide:
[1598]
[1599] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 572 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 572 (M + H ⁺ , 100%) was obtained.
[1600] <Example 87>
[1601] 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] butyl} amide
[1602] a.) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxypyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1603] The title compound was prepared following the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5,6-dimethoxybenzofuran-2-carboxylic acid: MS (EI) 604 ( M + H ⁺ ).
[1604] b.) 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxypyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} amide
[1605] 5,6-Dimethoxybenzofuran-2-carboxylic acid of Example 87a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane The title compound was prepared according to the process of Example 1i except for replacing with 4-ylcarbamoyl] -butyl} amide:
[1606]
[1607] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 602 (M ⁺ , 100%), and diastereomers eluted later; MS (EI): 602 (M ⁺ , 100%).
[1608] <Example 88>
[1609] Of 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Produce
[1610] a.) 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1611] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with picolinic acid N-oxide: MS (EI) 505 (M + H ⁺ ).
[1612] b.) 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides
[1613] 1-oxy-pyridine-2-carboxylic acid of Example 88a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl-azpan-4-ylcarbamoyl]- Except for the replacement with butyl} amide, the title compound was prepared following the procedure of Example 1i:
[1614]
[1615] <Example 89>
[1616] Preparation of (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1617] a.) (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl]- amides
[1618] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide of Example 28a in dichloromethane (0.25 g To a solution of) triethylamine (0.27 mL) and 2-pyridinesulfonyl chloride (0.15 g) were added. The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (0.09 g): MS (EI) 525 (M + H ⁺ ).
[1619] b.) (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl]- amides
[1620] (S) -4-methyl-2- (pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] of example 89a] Except for the substitution with -amide, the title compound was prepared following the procedure of Example 1i:
[1621]
[1622] <Example 90>
[1623] Preparation of (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1624] a.) (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1625] Of (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-sulfonyl) -azpan-4-yl] -amide (0.25 g) of Example 28a in dichloromethane To the solution was added triethylamine (0.17 mL) and benzyl isocyanate (0.088 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (0.12 g).
[1626] b.) (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1627] (S) -2- (3-benzyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] of example 89a]- Except for the substitution with amides, the title compound was prepared following the procedure of Example 1i:
[1628]
[1629] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 516 (M + H ⁺ , 100%), and diastereomers eluting later; MS (EI): 516 (M + H ⁺ , 100%) was obtained.
[1630] <Example 91>
[1631] Preparation of (S) -2-methyl-2- (3-phenyl-ureido) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1632] a.) (S) -2- (3-phenyl-ureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2sulfonyl) -azpan-4-yl] -amide
[1633] The title compound was prepared according to the process of Example 90a, except that benzyl isocyanate was replaced with phenyl isocyanate: MS (EI) 503 (M + H ⁺ ).
[1634] b.) (S) -2- (3-phenyl-ureido) -4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1635] (S) -2- (3-phenylureido) -4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide of Example 91a Except for replacing with the title compound was prepared according to the process of Example 1i:
[1636]
[1637] <Example 92>
[1638] Benzofuran-2-carboxylic acid {(S) -1- [6,6-dimethyl-3-oxo-1- (pyridine-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl}- Preparation of Amides
[1639] a.) allyl- (2,2-dimethyl-pent-4-enylidene) -amine
[1640] 2,2-dimethyl-4-pentenal (2.8 g, 25 mmol) was dissolved in 15 mL of benzene. To this solution allylamine (2.85 g, 50 mmol) was added. Several molecular sieves were used to absorb the water generated during the reaction. The mixture was stirred at rt overnight. The solvent and excess allylamine were removed on a rotary evaporator to yield 3.76 g of the title compound as a clear liquid (yield 100%).
[1641]
[1642] b.) allyl- (2,2-dimethyl-pent-4-enyl) -amine
[1643] Allyl- (2,2-dimethyl-pent-4-enylidene) -amine (3.76 g, 25 mmol) of Example 92a was dissolved in 5 ml of MeOH. To this solution was added NaBH ₄ (0.95 g, 25 mmol) at 0 ° C. After addition, the mixture was stirred at rt for 5 h. Methanol was removed in a rotary evaporator 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:
[1644]
[1645] c.) Pyridine-2-sulfonic acid allyl- (2,2-dimethyl-pent-4-enyl) -amide
[1646] Allyl- (2,2-dimethyl-pent-4-enyl) -amine (0.43 g, 2.8 mmol) and NMM (0.57 g, 5.6 mmol) were mixed in 30 mL of CH ₂ Cl ₂ . 2-pyridinesulfonyl chloride was slowly added thereto while cooling the solution in an ice water bath. After addition, the reaction mixture was stirred at rt overnight. Washed with 10% NaHCO ₃ and brine. Purification by column chromatography gave 0.6 g of a colorless oil in 73% yield.
[1647]
[1648] d.) 3,3-dimethyl-1- (pyridine-2-sulfonyl) -2,3,4,7-tetrahydro-1H-azepine
[1649] Pyridine-2-sulfonic acid allyl- (2,2-dimethyl-pent-4-enyl) -amide (0.6 g, 2 mmol) was diluted in CH ₂ Cl ₂ (50 ml). After carefully degassing with Ar, Grubbs catalyst (0.17 g, 0.2 mmol) was added under Ar protection. The mixture was then horned for 2 hours, then the solvent was removed on a rotary evaporator. The crude product was purified by column chromatography (5% -20% E / H) to give 0.47 g of the title compound in 87% yield.
[1650]
[1651] e.) 5,5-dimethyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane
[1652] To a solution of the compound of Example 92d (1.2 g, 4.5 mmol) in 50 mL of CH ₂ Cl ₂ was added NaHC0 ₃ (2.4 g, 13.5 mmol) followed by MCPBA (1.2 g, 13.5 mmol) in several portions. The reaction was stirred at room temperature for 4 hours, then finished by washing with 15% NaOH, saturated K ₂ CO ₃ , brine and dried (Na ₂ SO ₄ ) to yield 1.O g of crude product in 79% yield (more purification). Good enough for the next reaction without.
[1653]
[1654] f.) 4-azido-6,6-dimethyl-1- (pyridin-2-sulfonyl) -azpan-3-ol
[1655] 5,5-dimethyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane (1.2 g, 4.3 mmol) from Example 92e was charged with 7 ml of MeOH. And 1 ml of H ₂ O in a mixture. NaN ₃ (0.83 g, 13 mmol) and NH ₄ Cl (0.7 g, 13 mmol) were added to the solution. The resulting mixture was stirred overnight. After removing MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO ₃ and brine. Purification by column chromatography gave 0.4 g of 4-azido-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azpan-3-ol (yield 29%);
[1656]
[1657] g.) 4-amino-6,6-dimethyl-1- (pyridin-2-sulfonyl) -azpan-3-ol
[1658] 4-azido-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azpan-3-ol (0.4 g, 1.23 mmol) from Example 92f was diluted with THF (50 ml) and H ₂ 0. (0.2 ml). PPh ₃ (0.48 g, 1.85 mmol) was added to this solution. The reaction mixture was stirred at 45 ° C overnight. TLC showed no starting material left. THF was evaporated and azeotropic with toluene (2 ×). The resulting thick oil was dissolved in MeOH and treated with HCl in ether to make the pH acidic. Additional ether was added and the solution turned cloudy. 0.22 g of a white precipitate of the title compound were collected (45% yield).
[1659]
[1660] h.) {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl] -3methyl-butyl} -carr Chest acid tert-butyl ester
[1661] 4-amino-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azpan-3-ol HCl salt (0.22 g, 0.6 mmol) from Example 92g was dissolved in 5 ml of DMF. To this solution, Boc-Leu-OH (0.22 g, 0.9 mmol) and HBTU (0.34 g, 0.9 mmol) were added followed by NMM (0.24 g, 2.4 mmol). The mixture was stirred at rt overnight. DMF was removed under high vacuum. Xyluru 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);
[1662]
[1663] i.) Benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide
[1664] {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl of Example 92h} To carbamic acid tert-butyl ester (0.22 g, 0.43 mmol) was added HCl / dioxane (4 M, 20 ml, 80 mmol). The mixture was stirred at rt for 2 h and the solvent and excess HCl were removed in a rotary evaporator. The white solid obtained was dissolved in 5 ml of DMF. To this solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The mixture was stirred at rt overnight. The DMF was then removed and the residue was redissolved in EtOAc (50 ml) and washed with 10% NaHCO ₃ (50 ml × 2) and brine (50 ml). 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%;
[1665]
[1666] j.) Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-6,6-dimethyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide
[1667] Benzofuran-2-carboxylic acid from Example 92i in 2 ml CH ₂ Cl ₂ {(S) -1- [3-hydroxy-6,6-dimethyl-1- (pyridine-2-sulfonyl) -ase To a solution of pan-4-ylcarbamoyl] -3-methyl-butyl} -amide (100 mg, 0.18 mmol) was added Dess-Martin reagent (76 mg, 0.18 mmol) at room temperature. The solution was stirred for 2 hours when 20 ml of CH ₂ Cl ₂ was added and washed with NaHCO ₃ and brine. Purification by column chromatography (50% ethyl acetate in hexanes) gave 70 mg of the title compound in 70% yield.
[1668]
[1669] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (M + H ⁺ ): 555.2, and diastereomers eluted later; MS (M + H ⁺ ): 555.2 was obtained.
[1670] <Example 93>
[1671] 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[1672] a.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} amide
[1673] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5-methoxybenzofuran-2-carboxylic acid: MS (EI) 574 (M + H ⁺ ).
[1674] b.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide
[1675] 5-methoxybenzofuran-2-carboxylic acid of Example 93a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane- The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1676]
[1677] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC;
[1678]
[1679] And diastereomers eluted later; MS (EI): 573 (M + H ⁺ , 100%) was obtained.
[1680] <Example 94>
[1681] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1682] a.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} amide
[1683] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with thieno [3,2b] thiophene-2-carboxylic acid: MS (EI) 566 (M + H ⁺ ).
[1684] b.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} amide
[1685] Thieno [3,2-b] thiophene-2-carboxylic acid of Example 94a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) The title compound was prepared according to the process of Example 1i, except that it was replaced with -azane-4-ylcarbamoyl] -butyl} amide:
[1686]
[1687] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC;
[1688]
[1689] And diastereomers eluted later; MS (EI): 565 (M + H ⁺ , 100%) was obtained.
[1690] <Example 95>
[1691] Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1692] a.) Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1693] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid: MS (EI) 556 (M + H ⁺ ).
[1694] b.) Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl]- Butyl} amide
[1695] Quinoxaline-2-carboxylic acid of Example 95a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-ylcarbamoyl The title compound was prepared according to the procedure of Example 1i, except that it was replaced with] butyl} amide:
[1696]
[1697] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 555 (M + H ⁺ , 100%) and later diastereomers; MS (EI): 555 (M + H ⁺ , 100%) was obtained.
[1698] <Example 96>
[1699] Of quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Produce
[1700] a.) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1701] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with quinoline-2-carboxylic acid: MS (EI) 555 (M + H ⁺ ).
[1702] b.) Quinoline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides
[1703] Quinoline-2-carboxylic acid of Example 96a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Except for the substitution with -butyl} amide, the title compound was prepared following the procedure of Example 1i:
[1704]
[1705] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 554 (M + H ⁺ , 100%) and later diastereomers; MS (EI): 554 (M + H ⁺ , 100%).
[1706] <Example 97>
[1707] Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1708] a.) Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1709] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with thiophene-3-carboxylic acid: MS (EI) 510 (M + H ⁺ ).
[1710] b.) Thiophene-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azpan-4-ylcarbamoyl] -butyl }amides
[1711] Thiophene-3-carboxylic acid of Example 97a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl The title compound was prepared according to the procedure of Example 1i, except that it was replaced with] butyl} amide:
[1712]
[1713] <Example 98>
[1714] 1H-indole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of Amides
[1715] a.) 1H-indole-5-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-ylcarbamoyl ] -Butyl} amide
[1716] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 1H-indole-5-carboxylic acid: MS (EI) 543 (M ⁺ ).
[1717] b.) 1H-indole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1718] 1H-indole-5-carboxylic acid of Example 98a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-ylcarba The title compound was prepared according to the process of Example 1i except for replacing with moyl] -butyl} amide:
[1719]
[1720] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 542 (M + H ⁺ , 80%) and later diastereomers; MS (EI): 542 (M + H ⁺ , 80%).
[1721] <Example 99>
[1722] Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-ylcarba Moyl] -butyl} amide
[1723] a.) Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} amide
[1724] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with benzo [1,3] dioxol-5carboxylic acid: MS (EI) 548 (M ⁺ ).
[1725] b.) Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1726] Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane of Example 99a The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1727]
[1728] Diastereomers which are eluted first by separating the diastereomeric mixture by HPLC; MS (EI): 547 (M + H ⁺ , 100%) and later diastereomers; MS (EI): 547 (M + H ⁺ , 100%) was obtained.
[1729] <Example 100>
[1730] Furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Produce
[1731] a.) furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1732] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with furonic acid: MS (EI) 494 (M ⁺ ).
[1733] b.) furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides
[1734] Furan-2-carboxylic acid of Example 100a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Except for the substitution with -butyl} amide, the title compound was prepared following the procedure of Example 1i:
[1735]
[1736] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereoisomers; MS (EI): 493 (M + H ⁺ , 100%) and later diastereomers; MS (EI): 493 (M + H ⁺ , 100%) was obtained.
[1737] <Example 101>
[1738] (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 Preparation of -yl] -amide
[1739] a.) (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl)- Azepan-4-yl] -amide
[1740] The title compound was prepared following the process of Example 85c, except that benzo [b] thiophene-2-carboxylic acid was replaced with thiophene-2-acetic acid.
[1741] b.) (S) -4-methyl-2- (2-thiophen-2-yl-acetylamino) -pentanoic acid [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-yl] -amide
[1742] (S) -4-methyl-2- (2thiophen-2-yl-acetylamino) -pentanoic acid [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) ase of Example 101a The title compound was prepared according to the process of Example 1i except for replacing with pan-4-yl] -amide:
[1743]
[1744] <Example 102>
[1745] 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of Amides
[1746] a.) 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide
[1747] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 1H-indole-2-carboxylic acid: MS (EI) 543 (M ⁺ ).
[1748] b.) 1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) azpan-4-ylcarbamoyl]- Butyl} amide
[1749] 1H-indole-2-carboxylic acid of Example 102a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-ylcarba The title compound was prepared according to the process of Example 1i except for replacing with moyl] -butyl} amide:
[1750]
[1751] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereomers: MS (EI): 542 (M + H ⁺ , 100%) and later diastereomers; MS (EI): 542 (M + H ⁺ , 100%) was obtained.
[1752] <Example 103>
[1753] 4-Fluoro-{(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-carbamoyl] -butyl} -benzamide Manufacture
[1754] a.) 4-Fluoro-{(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-carbamoyl] -butyl } -Benzamide
[1755] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 4-fluorobenzoic acid: MS (EI) 522 (M ⁺ ).
[1756] b.) 4-fluoro-{(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane-4-carbamoyl] -butyl} -Benzamide
[1757] 4-Fluoro-{(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-carbamoyl] of Example 103a]- The title compound was prepared according to the process of Example 1i, except that it was replaced with butyl} -benzamide:
[1758]
[1759] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereomers: MS (EI): 521 (M + H ⁺ , 100%) and later eluting body isomers (EI): 521 (M + H ⁺ , 100%).
[1760] <Example 104>
[1761] 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine-2-sulfonyl) Preparation of Azepan-4-ylcarbamoyl] -butyl} -amide
[1762] a.) 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy- (1-oxy-pyridine-2 -Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[1763] The title compound was prepared according to the procedure of Example 85c except for replacing benzo [b] thiophene-2-carboxylic acid with 5- (2-morpholin-4-ylethyloxy) -benzofuran-2-carboxylic acid. Prepared: MS (EI) 673 (M ⁺ ).
[1764] b.) 5- (2-Morpholin-4-yl-ethoxy) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo- (1-oxy-pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[1765] 5- (2-Morpholin-4-ylethoxy) -benzofuran-2-carboxylic acid of Example 104a {(S) -3-methyl-1- [3-hydroxy- (1-oxy-pyridine-2 The title compound was prepared according to the process of Example 1i except for replacing with -sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide:
[1766]
[1767] Separation of the diastereomeric mixture by HPLC, resulting in faster eluting diastereomers: MS (EI): 672 (M + H ⁺ , 100%) and later eluting diastereomers MS (EI): 672 (M + H ⁺ , 100%).
[1768] <Example 105>
[1769] Thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[1770] a.) Thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} amide
[1771] The title compound was prepared according to the procedure of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with thiophene-2-carboxylic acid: MS (EI) 510 (M ⁺ ).
[1772] b.) Thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1773] Thiophene-2-carboxylic acid of Example 105a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl The title compound was prepared according to the process of Example 1i except for replacing with] -butyl} amide:
[1774]
[1775] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereomers: MS (EI): 509 (M + H ⁺ , 100%) and later eluting body isomers (EI): 509 (M + H ⁺ , 100%).
[1776] <Example 106>
[1777] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Preparation of Butyl} amide
[1778] a.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide
[1779] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid: MS (EI) 558 (M ⁺ ) .
[1780] b.) 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} amide
[1781] 3-Methylbenzofuran-2-carboxylic acid of Example 106a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepan-4- The title compound was prepared according to the process of Example 1i, except that it was replaced with ilcarbamoyl] -butyl} amide:
[1782]
[1783] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereoisomers:
[1784]
[1785] And diastereomeric MS (EI) eluting later: 557 (M + H ⁺ , 100%).
[1786] <Example 107>
[1787] 6-Methyl-N-{(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl}- Preparation of Nicotinamide
[1788] a.) 6-Methyl-N-{(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -nicotinamide
[1789] The title compound was prepared according to the process of Example 85c, except that benzo [b] thiophene-2-carboxylic acid was replaced with 6-methylnicotinic acid: MS (EI) 519 (M ⁺ ).
[1790] b.) 6-Methyl-N-{(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} -nicotinamide
[1791] 6-Methyl-N-{(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl of Example 107a The title compound was prepared according to the process of Example 1i except for replacing with] -butyl} -nicotinamide:
[1792]
[1793] Separation of the diastereomeric mixture by HPLC, resulting in faster diastereomers: MS (EI): 518 (M + H ⁺ , 100%) and later eluting body isomers (EI): 518 (M + H ⁺ , 100%).
[1794] <Example 108>
[1795] (S) -4-Methyl-2- (2-thiophen-yl-acetylamino) -pentanoic acid- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -butyl } Production of Amide
[1796] a.) (S) -4-methyl-2- (2-thiophene-yl-acetylamino) -pentanoic acid- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4- General] -butyl} amide
[1797] The title compound was prepared following the procedure of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with thiophene-2-acetic acid: MS (ESI) 508.8 (M + H ⁺ ).
[1798] b.) (S) -4-methyl-2- (2-thiophene-yl-acetylamino) -pentanoic acid- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl ] -Butyl} amide
[1799] (S) -4-Methyl-2- (2-thiophene-yl-acetylamino) -pentanoic acid- [3-hydroxy-l- (pyridine-2-sulfonyl) -azepan-4 of Example 108a The title compound was prepared according to the process of Example 1i except for replacing with -yl] butyl} amide: MS (ESI) 506.8 (M + H ⁺ ).
[1800] <Example 109>
[1801] Preparation of 1H-indole-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1802] a.) 1H-indole-6-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amides
[1803] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 1H-indole-6-carboxylic acid: MS (EI) 527 (M + H ⁺ ).
[1804] b.) 1H-indole-6-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1805] 1H-indole-6-carboxylic acid of Example 109a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } The title compound was prepared following the procedure of Example 1i except for replacing with amide: MS (EI) 525 (M + H ⁺ ).
[1806] <Example 110>
[1807] Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } Production of Amide
[1808] a.) Benzo [1.3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl] -Butyl} amide
[1809] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with piperonylic acid: MS (EI) 532.7 (M + H ⁺ ).
[1810] b.) Benzo [1,3] dioxol-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl ] -Butyl} amide
[1811] Benzo [1,3] dioxol-5-carboxylic acid of Example 110a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl Except for the replacement with carbamoyl] -butyl} amide, the title compound was prepared following the procedure of Example 1i: MS (EI) 530.8 (M + H ⁺ ).
[1812] <Example 111>
[1813] 3,4-dihydro-2H-benzo [b] [1,4] dioxepin-7-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2 -Sulfonyl) -azpan-4-ylcarbamoyl] butyl} amide
[1814] a.) 3,4-dihydro-2H-benzo [b] [1,4] dioxepin-7-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy -Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1815] The title compound was prepared according to the procedure of Example 85c except that the benzo [b] thiophene-2-carboxylic acid was replaced with 3,4-dihydro-2H-1,5-benzodioxepin-7-carboxylic acid Was: MS (EI) 576 (M ⁺ ).
[1816] b.) 3,4-dihydro-2H-benzo [b] [1,4] dioxepin-7-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy- Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1817] 3,4-Dihydro-2H benzo [b] [1,4] dioxepin-7-carboxylic acid of Example 111a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy The title compound was prepared according to the process of Example 1i, except that it was replaced with -pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide:
[1818]
[1819] Separation of the diastereomer mixture by HPLC, which elutes faster: diastereomer: MS (EI): 575 (M + H ⁺ , 100%) and later diastereomer MS (EI): 575 (M + H ⁺ , 100%).
[1820] <Example 112>
[1821] 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[1822] a.) 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} amide
[1823] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5-methyl thiophene-2-carboxylic acid: MS (EI) 524 (M ⁺ ) .
[1824] b.) 5-Methyl-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide
[1825] 5-Methyl-thiophene-2carboxylic acid of Example 112a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- The title compound was prepared according to the process of Example 1i, except that it was replaced with ilcarbamoyl] -butyl} amide:
[1826]
[1827] Separation of the diastereomeric mixture by HPLC, resulting in faster diastereomers: MS (EI): 523 (M + H ⁺ , 100%) and later eluting body isomers (EI): 523 (M + H ⁺ , 100%).
[1828] <Example 113>
[1829] 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Preparation of Ilcarbamoyl] -Butyl} amide
[1830] a.) 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} amide
[1831] The title compound was prepared according to the procedure of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 4,5-dibromo-thiophene-2-carboxylic acid: MS (EI) 668 (M ⁺ ).
[1832] b.) 4,5-Dibromo-thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[1833] 4,5-Dibromothiophene-2-carboxylic acid of Example 113a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1834]
[1835] <Example 114>
[1836] 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4-ylcarba Moyl] -butyl} amide
[1837] a.) 3,5-dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} amide
[1838] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 3,5-dimethylisoxazole-4-carboxylic acid: MS (EI) 524 ( M + H ⁺ ).
[1839] b.) 3,5-dimethyl-isoxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1840] 3,5-Dimethyl-isoxazole-4-carboxylic acid of Example 114a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azane The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1841]
[1842] <Example 115>
[1843] Of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-yl] -amide Produce
[1844] a.) {(S) -1- [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid-tert -Butyl ester
[1845] [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid-tert-butyl ester (Compound 2 g, 0.8 g, 2.33 mmol) was added 1, Dissolved in 2-dichloroethane (DCE, 20 ml). Then morpholinemethyl polystyrene resin beads (1.26 g, 3.7 mmol / g, Nova) were added and the solution was shaken for 5 minutes. Then p-methoxybenzenesulfonyl chloride (0.48 g, 2.33 mmol) was dissolved in DCE (10 ml) and this solution was added to the reaction mixture. The reaction was shaken overnight, filtered and washed with DCE (2 × 10 ml) followed by CH ₂ Cl ₃ (10 ml). The combined organics were concentrated in vacuo and used for the next reaction without further purification: M + H ⁺ = 514.2.
[1846] b.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azpan-4-yl] -amide-HCl salt
[1847] {(S) -1- [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid-tert-butyl ester (Compound 207a, 0.59 g, 1.15 mmol) was dissolved in CH ₂ Cl ₂ (8 ml), then a solution of 4 M HCl in dioxane (8 ml) was added and the reaction stirred at rt for 4 h. The reaction mixture was concentrated in vacuo and azeotropically with toluene (10 ml) twice in vacuo and used for the next reaction without further purification: M + H ⁺ = 413.8.
[1848] c.) (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azpan-4-yl ]-amides
[1849] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azpan-4-yl] -amide-HCl salt (115b reaction mixture Crude product from) is dissolved in MeOH (10 ml), treated with carbonate-polystyrene resin beads (1.75 g, 2.63 mmol / g, 4.6 mmol), shaken for 2 hours, filtered, MeOH (10 ml), and the combined organics were concentrated in vacuo. The product was then dissolved in DCE (2 ml), morpholinemethyl polystyrene resin beads (0.25 g, 3.77 mmol / g, 0.91 mmol, Nova) were added and the reaction was shaken for 5 minutes. Benzylacetyl chloride (0.081 g, 0.44 mmol) was then added and the reaction mixture was shaken overnight. Trisamine polystyrene beads (0.1 g, 3.66 mmol / g, 0.366 mmol) were then added and the reaction mixture was shaken for 1.5 hours. The reaction mixture was filtered, washed with DCE (2 × 10 ml) and CH ₂ Cl ₂ (10 ml) and the combined organics were concentrated in vacuo. The crude product was used for the next reaction without further purification: M + H ⁺ = 562.2.
[1850] d.) (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-yl] -amides
[1851] (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [3-hydroxy-1- (4-methoxy-benzenesulfonyl) -azpan-4-yl] -amide (Compound 207c, 0.24 g, 0.44 mmol) to CH₂Cl₂After dissolving in (5 ml), Dess-Martin periodinane (0.3 g, 0.7 mmol) was added and the reaction stirred for 30 minutes. CH reactant₂Cl₂After dilution with (20 ml), aqueous 10% Na₂S₂0₅(10 ml) followed by aqueous 10 % NaHCO₃(10 ml), water (10 ml), brine (10 ml). The combined organics were concentrated in vacuo. The residue was purified by HPLC (50:50 ethanol: hexane, 20 mL / min, 25 minutes, WhelkO-l (R, R) 21 x 250 mm column, UV detection at 280 nm and 305 nm) to give the first eluate white. As a solid (47 mg, 43%):
[1852]
[1853] And second eluting diastereomer: MS 560.2 (M + H ⁺ ).
[1854] <Example 116>
[1855] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -ase Preparation of Pan-4-ylcarbamoyl] -butyl} amide
[1856] a.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sul Ponyl) -Azepan-4-ylcarbamoyl] -butyl} amide
[1857] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5- (3-trifluoromethylphenyl) -furan-2-carboxylic acid. EI) 638 (M ⁺ ).
[1858] b.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} amide
[1859] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid of Example 116a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2- The title compound was prepared according to the process of Example 1i, except that sulfonyl) -azepane-4-ylcarbamoyl] -butyl} amide was substituted:
[1860]
[1861] Separation of the diastereomeric mixture by HPLC, resulting in faster diastereomers: MS (EI): 637 (M + H ⁺ , 100%) and later eluting body isomers (EI): 637 (M + H ⁺ , 100%).
[1862] <Example 117>
[1863] 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Preparation of Ilcarbamoyl] butyl} amide
[1864] a.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} amide
[1865] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5-methyl-2-phenyloxazole-4-carboxylic acid: MS (EI) 585 (M ⁺ ).
[1866] b.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[1867] 5-Methyl-2-phenyloxazole-4-carboxylic acid of Example 117a {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) azepan The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1868]
[1869] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereomers: MS (EI): 584 (M + H ⁺ , 100%) and later eluting body isomers (EI): 584 (M + H ⁺ , 100%).
[1870] <Example 118>
[1871] Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} -amide
[1872] a.) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxy-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -butyl}- amides
[1873] Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxybenzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -butyl in dichloromethane To a solution of} -amide (0.175 g) was added triethylamine (0.1 mL) and 3,4-dimethoxybenzenesulfonyl chloride (0.12 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (0.21 g): MS (EI) 587 (M ⁺ ).
[1874] b.) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} -amide
[1875] Benzofuran-2-carboxylic acid of Example 118a {(S) -1- [1- (3,4-dimethoxy-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -butyl} Except for the substitution with -amide, the title compound was prepared following the procedure of Example 1i:
[1876]
[1877] <Example 119>
[1878] Of benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[1879] a.) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides
[1880] The title compound was prepared following the procedure of Example 118a, except that 3,4-dimethoxybenzenesulfonyl chloride was replaced with 4-bromobenzenesulfonyl chloride: MS (EI) 606 (M ⁺ ).
[1881] b.) Benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides
[1882] Benzofuran-2-carboxylic acid {(S) -1- [1- (4-bromo-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl- of Example 119a Except for the substitution with butyl} -amide, the title compound was prepared following the procedure of Example 1i:
[1883]
[1884] <Example 120>
[1885] Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3 Preparation of -methyl-butyl} -amide
[1886] a.) Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-hydroxy-azepane-4-ylcarba Moyl] -3-methyl-butyl} -amide
[1887] The title compound was prepared following the procedure of Example 118a, except that 3,4-dimethoxybenzenesulfonyl chloride was replaced with benzofurazane-4-sulfonyl chloride: MS (EI) 569 (M ⁺ ) .
[1888] b.) Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazole-4-sulfonyl) -3-oxo-azepane-4-ylcarbamoyl ] -3-methyl-butyl} -amide
[1889] Benzofuran-2-carboxylic acid {(S) -1- [1- (benzo [1,2,5] oxadiazol-4-sulfonyl) -3-hydroxy-azpan-4-yl of Example 120a The title compound was prepared according to the process of Example 1i, except that it was replaced with carbamoyl] -3-methyl-butyl} -amide:
[1890]
[1891] <Example 121>
[1892] Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-oxazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[1893] a.) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-oxazole-4-sulfonyl) -3-hydroxy-azepane-4-ylcarbamoyl]- 3-methyl-butyl} -amide
[1894] The title compound was prepared following the procedure of Example 118a, except that 3,4-dimethoxybenzenesulfonyl chloride was replaced with 3,5-dimethyloxazole-4-sulfonyl chloride: MS (EI) 546 (M ⁺ ).
[1895] b.) Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-oxazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide
[1896] Benzofuran-2-carboxylic acid of Example 121a {(S) -1- [1- (3,5-dimethyl-oxazole-4-sulfonyl) -3-hydroxy-azepane-4-ylcarbamoyl] The title compound was prepared according to the process of Example 1i except for replacing with 3-methyl-butyl} -amide:
[1897]
[1898] <Example 122>
[1899] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Produce
[1900] a.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} amide
[1901] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid: MS (EI) 542 (M ⁺ ).
[1902] b.) 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }amides
[1903] 3-Methylbenzofuran-2-carboxylic acid of Example 122a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Except for the substitution with -butyl} amide, the title compound was prepared following the procedure of Example 1i:
[1904]
[1905] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereoisomers:
[1906]
[1907] And Diastereomer MS (EI) eluted later: 541 (M + H ⁺ , 100%).
[1908] <Example 123>
[1909] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide
[1910] a.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1911] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with thieno [3,2b] thiophene-2-carboxylic acid: MS (EI) 550 (M ⁺ ) .
[1912] b.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} amide
[1913] Thieno [3,2-b] thiophene-2-carboxylic acid of Example 123a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1914]
[1915] Separation of diastereomeric mixtures by HPLC, resulting in faster diastereoisomers:
[1916]
[1917] And diastereomeric MS (EI) eluting later: 549 (M + H ⁺ , 100%).
[1918] <Example 124>
[1919] 5-tert-Butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl ) -Azepan-4-ylcarbamoyl] -butyl} amide
[1920] a.) 5-tert-Butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1921] The title compound was prepared according to the procedure of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 5-tert-butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid. Prepared: MS (EI) 620 (M ⁺ ).
[1922] b.) 5-tert-butyl-3-methyl-thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2 -Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide
[1923] 5-tert-Butyl-3-methylthieno [3,2-b] thiophene-2-carboxylic acid of Example 124a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-) The title compound was prepared according to the process of Example 1i, except that 2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide was substituted:
[1924]
[1925] <Example 125>
[1926] 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[1927] a.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} amide
[1928] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 5-methyl-2-phenyloxazole-4-carboxylic acid: MS (EI) 569 (M ⁺ ) .
[1929] b.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} amide
[1930] 5-Methyl-2-phenyloxazole-4-carboxylic acid of Example 125a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4- The title compound was prepared according to the process of Example 1i, except that it was replaced with ilcarbamoyl] -butyl} amide:
[1931]
[1932] Separation of the diastereomeric mixture by HPLC, resulting in faster diastereomers: MS (EI): 568 (M + H ⁺ , 100%) and later eluting body isomers (EI): 568 (M + H ⁺ , 100%).
[1933] <Example 126>
[1934] 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Preparation of Carbamoyl] -Butyl} amide
[1935] a.) 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[1936] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid: MS (EI) 623 (M ⁺ ).
[1937] b.) 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} amide
[1938] 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid of Example 126a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -ase The title compound was prepared according to the process of Example 1i except for the replacement with pan-4-ylcarbamoyl] -butyl} amide:
[1939]
[1940] Separation of diastereomeric mixtures by HPLC, which elutes faster: diastereomer: MS (EI): 622 (M + H ⁺ , 100%) and later diastereomer: MS (EI): 622 (M + H ⁺ , 100%).
[1941] <Example 127>
[1942] Preparation of quinoline-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[1943] The title compound was prepared according to the process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with methanesulfonyl chloride and benzofuran-2-carboxylic acid was replaced with 2-quinoline carboxylic acid. The residue was purified by HPLC. Firstly eluting diastereomers;
[1944]
[1945] And second eluting diastereomer: MS (M + H ⁺ ): 475.2.
[1946] <Example 128>
[1947] Preparation of 1-Methyl-1H-indole-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[1948] The title compound was prepared according to the process of Example 75 except for replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with N-methylindole-2-carboxylic acid. It was. The residue was purified by HPLC. Firstly eluting diastereomers;
[1949]
[1950] ; And secondly eluting diastereomer: MS (M + H &lt; + &gt;): 477.2.
[1951] <Example 129>
[1952] Preparation of furan-2-carboxylic acid {[(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butylcarbamoyl] -methyl} -amide
[1953] Except for replacing thiazole-2-sulfonyl chloride with methanesulfonyl chloride and benzofuran-2-carboxylic acid with N- (2-furan-carbonyl) -glycine, according to the process of Example 75 The title compound was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[1954]
[1955] ; And second eluting diastereomer: MS (M + H ⁺ ): 471.4.
[1956] <Example 130>
[1957] Preparation of 5-methoxybenzofuran-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide
[1958] The title compound, according to the process of Example 75, except that thiazole-2-sulfonyl chloride was replaced by methanesulfonyl chloride and benzofuran-2-carboxylic acid was replaced by 5-methoxybenzofuran-2-carboxylic acid Was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[1959]
[1960] ; And second eluting diastereomer: MS (M + H &lt; + &gt;): 494.2.
[1961] <Example 131>
[1962] Preparation of Quinoxaline-2-carboxylic acid [(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[1963] The title compound was prepared according to the process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with methanesulfonyl chloride and benzofuran 2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid. The residue was purified by HPLC.
[1964] Firstly eluting diastereomers;
[1965]
[1966] ; And second eluting diastereomer: MS (M + H ⁺ ): 476.2.
[1967] <Example 132>
[1968] 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} amide
[1969] a.) 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} amide
[1970] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 5- (4-chlorophenyl) -2-furonic acid: MS (EI) 590 (M + H ⁺ ).
[1971] b.) 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} amide
[1972] 5- (4-Chloro-phenyl) -furan-2-carboxylic acid of Example 132a {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azane- The title compound was prepared according to the process of Example 1i, except that 4-ylcarbamoyl] -butyl} amide was substituted:
[1973]
[1974] Separation of the diastereomeric mixture by HPLC, which elutes faster: diastereomer: MS (EI): 587 (M + H ⁺ , 100%) and later elutedomer: MS (EI): 587 (M + H ⁺ , 100%).
[1975] <Example 133>
[1976] Preparation of (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid (1-methanesulfonyl-3-oxo-azpan-4-yl) -amide
[1977] The process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-methanesulfonyl chloride and benzofuran-2-carboxylic acid was replaced by 2- (4-methoxyphenyl) -acetic acid. According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[1978]
[1979] And second eluting diastereomer: MS (M + H ⁺ ): 468.2.
[1980] <Example 134>
[1981] Of quinoline-2-carboxylic acid {[(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[1982] The title compound was prepared according to the process of Example 75 except that thiazole-2-sulfonyl chloride was replaced with 2-cyanobenzenesulfonyl chloride and benzofuran-2-carboxylic acid was replaced with quinoline-2-carboxylic acid. Prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[1983]
[1984] Secondly eluted diastereomer:
[1985]
[1986] And second eluting diastereomer: MS (M + H ⁺ ): 562.2.
[1987] <Example 135>
[1988] 1-Methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} -amide
[1989] Except for replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with N-methylindole-2-carboxylic acid, according to the process of Example 75 The title compound was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[1990]
[1991] And second eluting diastereomer: MS (M + H ⁺ ) 564.2.
[1992] <Example 136>
[1993] Furan-2-carboxylic acid ({(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butylcarbamoyl}- Preparation of Methyl) -amide
[1994] Example 75 except replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid with N- (2-furan-carbonyl) -glycine The title compound was prepared according to the procedure below. The residue was purified by HPLC. Firstly eluting diastereomers;
[1995]
[1996] And second eluting diastereomer: MS (M + H ⁺ ) 558.2.
[1997] <Example 137>
[1998] 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[1999] The process of Example 75, except replacing thiazole-2-sulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2000]
[2001] And second eluting diastereomer: MS (M + H ⁺ ) 581.2.
[2002] Example 138
[2003] Of quinoxaline-2-carboxylic acid {(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2004] The title compound, according to the process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid Was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[2005]
[2006] And second eluting diastereomer: MS (M + H ⁺ ) 563.2.
[2007] <Example 139>
[2008] (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -3-oxo-azepane-4 Preparation of -yl] -amide
[2009] Example 75, except that thiazole-2-sulfonyl chloride was replaced with 2-cyanophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with 2- (4-methoxyphenyl) -acetic acid. The title compound was prepared according to the process. The residue was purified by HPLC. Firstly eluting diastereomers;
[2010]
[2011] And second eluting diastereomer: MS (M + H ⁺ ) 555.2.
[2012] <Example 140>
[2013] Of quinoline-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2014] The title compound was prepared according to the process of Example 75 except for replacing thiazole-2-sulfonyl chloride with 4-methoxybenzenesulfonyl chloride and replacing benzofuran-2-carboxylic acid with 2-quinoline carboxylic acid. It was. The residue was purified by HPLC. Firstly eluting diastereomers;
[2015]
[2016] And second eluting diastereomer: MS (M + H ⁺ ) 567.2.
[2017] <Example 141>
[2018] 1-Methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} amide
[2019] The process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with N-methyl-indole-2-carboxylic acid. According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2020]
[2021] And second eluting diastereomer: MS (M + H ⁺ ) 569.2.
[2022] <Example 142>
[2023] Furan-2-carboxylic acid ({(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butylcarbamoyl}- Preparation of Methyl) -amide
[2024] Example 75, except that thiazole-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 process. The residue was purified by HPLC. Firstly eluting diastereomers;
[2025]
[2026] And second eluting diastereomer: MS (M + H ⁺ ) 563.2.
[2027] <Example 143>
[2028] 5-methoxybenzofuran-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2029] The process of Example 75, except replacing thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2030]
[2031] And second eluting diastereomer: MS (M + H ⁺ ) 586.2.
[2032] <Example 144>
[2033] Quinoxaline-2-carboxylic acid {[(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Manufacture
[2034] The title compound, according to the process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid Was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[2035]
[2036] And second eluting diastereomer: MS (M + H ⁺ ) 568.2.
[2037] <Example 145>
[2038] (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepane-4 Preparation of -yl] -amide
[2039] The process of Example 75, except replacing thiazole-2-sulfonyl chloride with 4-methoxyphenylsulfonyl chloride and benzofuran-2-carboxylic acid with 2- (4-methoxyphenyl) acetic acid According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2040]
[2041] And second eluting diastereomer: MS (M + H ⁺ ) 560.2.
[2042] <Example 146>
[2043] 1-Methyl-1H-indole-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} -amide
[2044] The process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with N-methyl-indole-2-carboxylic acid. According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2045]
[2046] And second eluting diastereomer: 1.01 (d, 6H); And second eluting diastereomer: MS (M + H ⁺ ) 557.4.
[2047] <Example 147>
[2048] Furan-2-carboxylic acid ({(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butylcarbamoyl}- Preparation of Methyl) -amide
[2049] Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with N- (2-furan-carbonyl) glycine. The title compound was prepared according to the process. The residue was purified by HPLC. Firstly eluting diastereomers;
[2050]
[2051] And second eluting diastereomer: MS (M + H ⁺ ) 551.2.
[2052] <Example 148>
[2053] 5-methoxybenzofuran-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2054] The process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with 5-methoxybenzofuran-2-carboxylic acid. According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2055]
[2056] And second eluting diastereomer: MS (M + H) ⁺ : 574.2.
[2057] <Example 149>
[2058] Quinoxaline-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Manufacture
[2059] The title compound, according to the process of Example 75, except that thiazole-2-sulfonyl chloride was replaced with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid Was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[2060]
[2061] And second eluting diastereomer: MS (M + H ⁺ ) 556.2.
[2062] <Example 150>
[2063] (S) -2- [2- (4-methoxy-phenyl) -acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane-4 Preparation of -yl] -amide
[2064] The process of Example 75, except replacing thiazole-2-sulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzofuran-2-carboxylic acid with 2- (4-methoxyphenyl) acetic acid According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2065]
[2066] And second eluting diastereomer: MS (M + H ⁺ ): 548.4.
[2067] <Example 151>
[2068] Of benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2069] a.) {(S) -1- [1- (3-Chloro-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[2070] To a solution of Example 2 g of compound (2.50 g, 7.29 mmol) in DCE (100 ml) was added P-NMM (4.0 g) and 3-chlorobenzenesulfonyl chloride (1.85 g, 8.75 mmol). 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) ⁺ .
[2071] b.) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-chloro-benzenesulfonyl) -3-hydroxy-azpan-4-yl] -amide
[2072] To a stirred solution of compound of Example 151a (1.O g, 1.93 mmol) in methanol (10 ml) was added HCl (4 M in dioxane) (10 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of a white solid (0.68 g, 1.50 mmol, 78%) in methanol (37 ml) was added P-CO ₃ (2.85 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.59 g, 1.42 mmol, 95%). MS: 417.86 (M + H) ⁺ .
[2073] c.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides
[2074] Benzofuran-2-carboxylic acid (0.81, 0.50 mmol) in CH ₂ Cl ₂ (20 mL) to a solution of the compound (0.14 g, 0.33 mmol) of Example _{151b CH 2 Cl 2 (10 mL} ), 1- hydroxy Benzotriazole (0.77 g, 0.57 mmol), and P-EDC (0.67 g, 1 mmol / g) were added. After shaking overnight at room temperature, the solution was treated with tisamine (0.45 g, 3.75 mmol / g). After 2 hours more shaking, the solution was filtered and concentrated to give the title compound as a white solid (122 mg, 65%). MS (ESI): 562.2 (M + H) ⁺ .
[2075] d.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides
[2076] To a stirred solution of the compound of Example 151c (122 mg, 0.22 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (185 mg, 0.44 mmol). After stirring at room temperature for 2 hours, a solution of sodium thiosulfate (10% 2 mL in water) and saturated aqueous sodium bicarbonate (2 mL) was added simultaneously to this solution. The aqueous layer was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluting diastereomer as a white solid (62.7 mg, 51.6%), MS (ESI): 560.2 (M + H) ⁺ ; A second eluting diastereomer was obtained as a white solid (40.2 mg, 33.1%). MS (ESI): 560.2 (M + H) ⁺
[2077] <Example 152>
[2078] 5-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2079] The title compound was prepared according to the procedure of Example 151c-d, except that the benzofuran-2-carboxylic acid of Example 151c was replaced with 5-methoxybenzofuran-2-carboxylic acid, and separated by HPLC First eluting diastereomer as white solid (64.4 mg, 50.3%): MS (ESI): 590.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (44.4 mg, 34.7%): MS (ESI): 590.2 (M + H) ⁺ .
[2080] <Example 153>
[2081] 7-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2082] The title compound was prepared according to the procedure of Example 151c-d, except that the benzofuran-2-carboxylic acid of Example 151c was replaced with 7-methoxybenzofuran-2-carboxylic acid, and purified by HPLC First eluting diastereomer as white solid (51.lmg, 39.9%), MS (ESI): 590.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 590.2 (M + H) ⁺ .
[2083] <Example 154>
[2084] 5,6-dimethoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} -amide
[2085] The title compound was prepared according to the procedure of Example 151c-d, except that the benzofuran-2-carboxylic acid of Example 151c was replaced with 5,6-dimethoxybenzofuran-2-carboxylic acid, and this was carried out by HPLC. Purification of the first eluting diastereomer as a white solid (51.1 mg, 39.9%), MS (ESI): 622.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 622.2 (M + H) ⁺ .
[2086] <Example 155>
[2087] 3-Methylbenzofuran-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} Preparation of -amides
[2088] Except for replacing the benzofuran-2-carboxylic acid of step 151c with 3-methylbenzofuran-2-carboxylic acid, the title compound was prepared according to the process of Example 151c-d and purified by HPLC first The eluting diastereomer as a white solid (78.6 mg, 63.1%), MS (ESI): 574.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (40.7 mg, 32.6%). MS (ESI): 574.2 (M + H) ⁺ .
[2089] <Example 156>
[2090] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2091] Except for replacing the benzofuran-2-carboxylic acid of step 151c with benzo [b] thiophene-2-carboxylic acid, the title compound was prepared according to the process of Example 151c-d and isolated by HPLC first The eluting diastereomer as white solid (41.0 mg, 32.8%), MS (ESI): 576.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (31.0 mg, 24.8%). MS (ESI): 576.4 (M + H) ⁺ .
[2092] <Example 157>
[2093] 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2094] Except for replacing the benzofuran-2-carboxylic acid of step 151c with 1-methylindole-2-carboxylic acid, the title compound was prepared according to the process of Example 151c-d, isolated by HPLC and eluted first. Diastereomer as white solid (28.5 mg, 22.9%), MS (ESI): 573.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (28.5 mg, 22.9%). MS (ESI): 573.2 (M + H) ⁺ .
[2095] <Example 158>
[2096] Of quinoxaline-2-carboxylic acid-{(S) -1- [1- (3-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2097] Except for replacing the benzofuran-2-carboxylic acid of step 151c with quinoxaline-2-carboxylic acid, the title compound was prepared according to the process of Example 151c-d, separated by HPLC and eluted first Isomer as a white solid (63.1 mg, 50.8%), MS (ESI): 572.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (43.2 mg, 34.8%), MS (ESI): 572.2 (M + H) ⁺ .
[2098] <Example 159>
[2099] Of benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} amide Produce
[2100] a.) {(S) -1- [1- (2-Fluoro-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methylbutyl} -carbamic acid tert-butyl ester
[2101] To a solution of Example 2 g of compound (1.03 g, 3.00 mmol) in DCE (20 ml) was added P-NMM (1.65 g, 3.64 mmol / g) and 2-fluorobenzenesulfonyl chloride (0.70 g, 3.60 mmol). Added. After shaking overnight at room temperature, the solution was filtered. The filtrate was concentrated to give the title compound as a white solid (1.13 g, 75.1%): MS: 523.88 (M + Na) ⁺ .
[2102] b.) (S) -2-Amino-4-methyl-pentanoic acid [1- (2-fluoro-benzenesulfonyl) -3-hydroxy-azpan-4-yl] -amide
[2103] To a stirred solution of the compound of Example 159a (1.13 g, 2.25 mmol) in methanol (15 ml) was added HCl (4M in dioxane) (15 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of a white solid (1.11 g, 2.60 mmol, 75%) in methanol (50 ml) was added P-CO ₃ (5.70 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.868 g, 2.16 mmol, 96%): MS: 401.96 (M + H) ⁺ .
[2104] c.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-hydroxyazepan-4-ylcarbamoyl] -3-methyl-butyl }-amides
[2105] Benzofuran-2-carboxylic acid (64.7 mg, 0.39 mmol) in CH ₂ Cl ₂ (10 mL) to a solution of the compound (0.11 g, 0.26 mmol) of Example _{159b CH 2 Cl 2 (10 mL} ), 1- hydroxy Roxybenzotriazole (61.1 g, 0.45 mmol), and P-EDC (0.53 g, 1 mmol / g) were added. After shaking overnight at room temperature, the solution was treated with tisamine (0.35 g, 3.75 mmol / g). After 2 hours more shaking citizens, the solution was filtered and concentrated to give the title compound as a white solid (103.5 mg, 70%): MS (ESI) 546.2 (M + H) ⁺ .
[2106] d.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides
[2107] To a stirred solution of the compound of Example 159c (103.5 mg, 0.19 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (164.7 mg, 0.39 mmol). After stirring at room temperature for 3 hours, a solution of sodium thiosulfate (10% 2 mL in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to this solution. The aqueous phase was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluting diastereomer as a white solid (76.2 mg, 73.6%): MS (ESI) 544.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (20.7 mg, 20.0%) MS (ESI) 544.4 (M + H) ⁺ .
[2108] <Example 160>
[2109] 5-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2110] The title compound was prepared according to the process of Example 159c-d, except that the benzofuran-2-carboxylic acid of step 159c was replaced with 5-methoxybenzofuran-2-carboxylic acid, and purified by HPLC to obtain the first compound. The diastereomer eluted with white solid (48.3 mg, 59.2%) MS (ESI): 574.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (24.2 mg, 29.6%) MS (ESI): 574.2 (M + H) ⁺ .
[2111] <Example 161>
[2112] 7-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2113] Except for replacing the benzofuran-2-carboxylic acid of step 159c with 7-methoxybenzofuran-2-carboxylic acid, the title compound was prepared according to the process of Example 159c-d and purified by HPLC to obtain the first compound. The diastereomer eluted with white solid (47.7 mg, 58.5%): MS (ESI) 574.2 (M + H) ⁺ ; And secondly eluting diastereomers as white solids (27.7 mg, 33.9%).
[2114] <Example 162>
[2115] 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3 Preparation of -methyl-butyl} -amide
[2116] The title compound was prepared according to the procedure of Example 159c-d, except that the benzofuran-2-carboxylic acid of step 159c was replaced with 5,6 dimethoxybenzofuran-2-carboxylic acid, and purified by HPLC. First eluting diastereomer: MS (ESI) 606.4 (M + H) ⁺ ; And secondly eluting diastereomers as white solids: MS (ESI) 606.4 (M + H ⁺ ).
[2117] <Example 163>
[2118] 3-Methylbenzofuran-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2119] Except for replacing the benzofuran-2-carboxylic acid of step 160c with 3-methylbenzofuran-2-carboxylic acid, the title compound was prepared according to the process of Example 159c-d and purified by HPLC for the first time Eluting diastereomer as white solid (50.5 mg, 63.7%): MS (ESI) 558.2; And a second eluting diastereomer as a white solid (20.6 mg); MS 558.2 (M + H) ⁺ .
[2120] <Example 164>
[2121] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2122] Except for replacing the benzofuran-2-carboxylic acid of step 159c with benzo [b] thiophene-2-carboxylic acid, the title compound was prepared according to the process of Example 159c-d and purified by HPLC to obtain the first compound. The diastereomer eluted with white solid (52.5 mg, 65.9%): MS (ESI) 560.2 (M + H) ⁺ ; And a second eluting diastereomer as white solid (20.7 mg, 26.0%): MS (ESI) 560.2 (M + H) ⁺ .
[2123] <Example 165>
[2124] 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} -amide
[2125] Except for replacing the benzofuran-2-carboxylic acid of step 159c with 1-methylindole-2-carboxylic acid, the title compound was prepared according to the process of Example 159c-d, which was purified by HPLC to elute first. The resulting diastereomer as a white solid (51.4 mg, 64.9%): MS (ESI) 557.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (21.0 mg, 26.5%): MS 557.2 (M + H) ⁺ .
[2126] <Example 166>
[2127] (S) -4-methyl-2- (1-oxy-pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl]- Preparation of Amides
[2128] a.) (S) -4-methyl-2- (1-oxy-pyridine-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4 -Yl] -amide
[2129] To the solution of Example 28a (0.1 g) and saturated NaHCO ₃ in dichloromethane (10 mL) was added 2-pyridinesulfonyl chloride N-oxide (0.9 mL) in a dropwise manner over 3 minutes. The reaction was stirred at rt for 30 min. Finished and column chromatography gave 9.2 mg of the title compound: MS (ESI) 541 (M + H ⁺ ).
[2130] b.) (S) -4-methyl-2- (1-oxy-pyridine-2-sulfonylamino) -pentanoic acid [3-oxo-1 (pyridine-2-sulfonyl) -azpan-4-yl ]-amides
[2131] Except for the replacement of the compound of Example 166a, the title compound was prepared according to the process of Example 1i: MS (ESI) 539 (M + H ⁺ ).
[2132] <Example 167>
[2133] Quinoxaline-2-carboxylic acid-{(S) -1- [1- (2-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide Manufacture
[2134] Except for replacing the benzofuran-2-carboxylic acid of step 159c with quinoxaline-2-carboxylic acid, the title compound was prepared according to the process of Example 159c-d and purified by HPLC to firstly elute Stereoisomer as a white solid (49.7 mg, 62.9%): MS (ESI) 556.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (19.9 mg, 25.1%): MS 556.4 (M + H) ⁺ .
[2135] <Example 168>
[2136] 5-methoxybenzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } Preparation of Amide
[2137] Except for replacing the 2-thiazolesulfonyl chloride of Example 75a with 2-thiophensulfonyl chloride and replacing the benzofuran-2-carboxylic acid of step 75c with 5-methoxybenzofuran-2-carboxylic acid, The title compound was prepared following the procedure of Examples 75a-d, which was purified by HPLC to give the first eluting diastereomer as a white solid (71 mg, 65%): MS (ESI) 562.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (21.6 mg, 20.0%) MS (ESI): 562.2 (M + H) ⁺ .
[2138] <Example 169>
[2139] 7-methoxybenzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } Preparation of Amide
[2140] The title compound was prepared according to the procedure of Example 168, except that 5-methoxybenzofuran-2-carboxylic acid was replaced with 7-methoxybenzofuran-2-carboxylic acid, which was first purified by HPLC. Eluting diastereomer as white solid (88 mg, 80%): MS (ESI) 562.2 (M + H) &lt; + &gt;; And a second eluting diastereomer as a white solid (18 mg, 16%) MS (ESI): 562.2 (M + H) ⁺ .
[2141] <Example 170>
[2142] 5,6-dimethoxybenzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} -amide
[2143] The title compound was prepared according to the procedure of Example 168 except for replacing 5-methoxybenzofuran-2-carboxylic acid with 5,6-dimethoxybenzofuran-2-carboxylic acid, which was purified by HPLC. First eluting diastereomer: MS (ESI) 594.2 (M + H) ⁺ ; And a second eluting diastereomer.
[2144] Example 171
[2145] 3-Methylbenzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of -amides
[2146] The title compound was prepared according to the procedure of Example 168, except for replacing 5-methoxybenzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid, which was purified by HPLC and eluted first. The resulting diastereomer as a white solid (88 mg, 83%): MS (ESI) 546.2 (M + H) ⁺ ; And a second eluting diastereomer as white solid (16 mg, 15%): MS (ESI) 546.2 (M + H) ⁺ .
[2147] <Example 172>
[2148] Benzo [b] thiophene-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophene-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } Preparation of Amide
[2149] The title compound was prepared according to the procedure of Example 168, except that 5-methoxybenzofuran-2-carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid, which was first purified by HPLC. Eluting diastereomer as white solid (43.4 mg, 41%): MS (ESI) 548.4 (M + H) ⁺ ; And second eluting diastereomer as white solid (33.4 mg, 31.5%): MS (ESI) 548.2 (M + H) ⁺ .
[2150] Example 173
[2151] 1-Methyl-1H-indole-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl]- Preparation of Butyl} -amide
[2152] The title compound was prepared according to the procedure of Example 168, except for replacing 5-methoxybenzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid, which was purified by HPLC and eluted first. Diastereomer as white solid (35.8 mg, 34.0%): MS (ESI) 545.2 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (45.8 mg, 43%): MS (ESI) 545.2 (M + H) ⁺ .
[2153] <Example 174>
[2154] Of quinoxaline-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide Produce
[2155] The title compound was prepared according to the procedure of Example 168, except that 5-methoxybenzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid, which was purified by HPLC to give the first eluted solid body. Isomer as a white solid (60 mg, 56%): MS (ESI) 544.4 (M + H) ⁺ ; And a second eluting diastereomer as a white solid (38.7 mg, 37%): MS (ESI) 544.4 (M + H) ⁺ .
[2156] <Example 175>
[2157] Of benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2158] a.) {(S) -1- [1- (3-Chloro-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methylbutyl} -carbamic acid tert-butyl ester
[2159] To a solution of Example 2 g of compound (2.50 g, 7.29 mmol) in DCE (100 ml) was added P-NMM (4.0 g) and 4-chlorobenzenesulfonyl chloride (1.85 g, 8.75 mmol). 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) ⁺ .
[2160] b.) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-chloro-benzenesulfonyl) -3-hydroxy-azpan-4-yl] -amide
[2161] To a stirred solution of the compound of Example 175a (1.0 g, 1.93 mmol) in methanol (10 ml) was added HCl (4M in dioxane) (10 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of a white solid (0.68 g, 1.50 mmol, 78%) in methanol (37 ml) was added P-C0 ₃ (2.85 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.59 g, 1.42 mmol, 95%): MS: 417.86 (M + H) ⁺ .
[2162] c.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-hydroxyazepan-4-ylcarbamoyl] -3-methyl-butyl} -amides
[2163] Benzofuran-2-carboxylic acid (0.81, 0.50 mmol) in CH ₂ Cl ₂ (20 mL) to a solution of the compound (0.14 g, 0.335 mmol) of Example _{175b CH 2 Cl 2 (10 mL} ), 1- hydroxy Benzotriazole (0.77 g, 0.569 mmol), and P-EDC (0.67 g, 1 mmol / g) were added. After shaking overnight at room temperature, the solution was treated with tisamine (0.446 g, 3.75 mmol / g). After further shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (122.2 mg, 65%). MS (ESI): 562.2 (M + H) ⁺ .
[2164] d.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides
[2165] To a stirred solution of the compound of Example 175c (122.2 mg, 0.217 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (184.8 mg, 0.436 mmol). After stirring for 2 hours at room temperature, to this solution a solution of sodium thiosulfate (10% in water, 2 mL) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously. The aqueous phase was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluted diastereomer as a white solid (62.7 mg, 51.6%): MS (ESI) 560.2 (M + H) ⁺ ; And a second eluate was obtained as a white solid (32.7 mg, 26.9%): MS (ESI) 560.2 (M + H) ⁺ .
[2166] <Example 176>
[2167] 5-methoxy-benzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2168] The title compound was prepared according to the procedure of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with 5-methoxybenzofuran-2-carboxylic acid, which was separated by HPLC to obtain first The diastereomer eluted with white solid (64.4 mg, 50%): MS (ESI) 590.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (32.2 mg, 25.2%): MS (ESI) 590.0 (M + H) ⁺ .
[2169] <Example 177>
[2170] 7-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2171] The title compound was prepared according to the process of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with 7-methoxybenzofuran-2-carboxylic acid, which was separated by HPLC to obtain first The diastereomer eluted with white solid (51.1 mg, 40%): MS (ESI) 590.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (41 mg, 32%): MS (ESI) 590.2 (M + H) ⁺ .
[2172] <Example 178>
[2173] 5,6-dimethoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} -amide
[2174] The title compound was prepared according to the process of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with 5,6-dimethoxybenzofuran-2-carboxylic acid, which was separated by HPLC. Diastereomer eluted first: MS (ESI) 622.2 (M + H) ⁺ ; And a second eluting diastereomer: MS (ESI) 622.2 (M + H) ⁺ .
[2175] Example 179
[2176] 3-Methylbenzofuran-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} Preparation of -amides
[2177] The title compound was prepared according to the process of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with 3-methylbenzofuran-2-carboxylic acid, which was first separated by HPLC. Eluting diastereomer as white solid (78.6 mg, 63%): MS (ESI) 574.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (27.6 mg, 22%): MS (ESI) 574.2 (M + H) ⁺ .
[2178] <Example 180>
[2179] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2180] The title compound was prepared according to the process of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with benzo [b] thiophene-2-carboxylic acid, which was separated by HPLC to obtain first The diastereomer eluted with white solid (41 mg, 33%): MS (ESI) 576.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (32.6 mg, 26%): MS (ESI) 576.2 (M + H) ⁺ .
[2181] <Example 181>
[2182] 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2183] The title compound was prepared according to the procedure of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with 1-methylindole-2-carboxylic acid, which was isolated by HPLC and eluted first. The resulting diastereomer as a white solid (28.5 mg, 23%): MS (ESI) 573.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (38.5 mg, 31%): MS (ESI) 573.2 (M + H) ⁺ .
[2184] <Example 182>
[2185] Of quinoxaline-2-carboxylic acid-{(S) -1- [1- (4-chloro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2186] The title compound was prepared according to the procedure of Example 175c-d, except that the benzofuran-2-carboxylic acid of step 175c was replaced with quinoxaline-2-carboxylic acid, which was separated by HPLC and the first eluted portion. Stereoisomer as a white solid (63 mg, 51%): MS (ESI) 572.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (44.5 mg, 36%): MS (ESI) 572.2 (M + H) ⁺ .
[2187] <Example 183>
[2188] Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Manufacture
[2189] a.) {(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert- Butyl ester
[2190] To a solution of Example 2 g of compound (1.60 g, 4.66 mmol) in DCE (50 ml) P-NMM (2.56 g, 3.64 mmol / g) and 3-methoxy-benzenesulfonyl chloride (1.15 g, 5.59 mmol) Was added. After shaking overnight at room temperature, the solution was filtered. The filtrate was concentrated to give the title compound as a white solid (1.70 g, 71.1%): MS 535.8 (M + Na) ⁺ .
[2191] b.) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-methoxy-benzenesulfonyl) -3-hydroxy-azpan-4-yl] -amide
[2192] To a stirred solution of the compound of Example 183a (1.70 g, 3.31 mmol) in methanol (22 ml) was added HCl (4M in dioxane) (22 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of a white solid (1.19 g, 2.64 mmol, 80%) in methanol (50 ml) was added P-CO ₃ (5.02 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (1.03 g, 2.49 mmol, 96%): MS 413.90 (M + H) ⁺ .
[2193] c.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide
[2194] Benzofuran-2-carboxylic acid (64.69 mg, 0.399 mmol) in CH ₂ Cl ₂ (10 mL) to a solution of the compound (0.11 g, 0.26 mmol) of Example _{183b CH 2 Cl 2 (10 mL} ), 1- hydroxy Roxybenzotriazole (61.1 g, 0.452 mmol), and P-EDC (0.532 g, 1 mmol / g) were added. After shaking overnight at room temperature, the solution was treated with tisamine (0.355 g, 3.75 mmol / g). After 2 more shaking, the solution was filtered and concentrated to give the title compound as a white solid (103.5 mg, 70%): MS (ESI) 558.2 (M + H) ⁺ .
[2195] d.) Benzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides
[2196] To a stirred solution of the compound of Example 183c (103 mg, 0.19 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (157 mg, 0.37 mmol). After stirring for 2 hours at room temperature, a solution of sodium thiosulfate (10% in water, 2 mL) and saturated aqueous sodium bicarbonate (2 mL) was added simultaneously to this solution. The aqueous phase was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by HPLC to give the first eluted diastereomer as a white solid (76.2 mg, 73.6%): MS (ESI): 556.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (24.1 mg, 23.3%): MS (ESI) 556.2 (M + H) ⁺ .
[2197] <Example 184>
[2198] 5-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2199] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with 5-methoxybenzofuran-2-carboxylic acid, and purified by HPLC to obtain the first compound. The diastereomer eluted with white solid (33 mg, 31%): MS (ESI) 586.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (35.2 mg, 32%): MS (ESI) 586.2 (M + H) ⁺ .
[2200] <Example 185>
[2201] 7-methoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2202] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with 7-methoxybenzofuran-2-carboxylic acid, and purified by HPLC to obtain the first compound. The diastereomer eluted with white solid (41 mg, 38%): MS (ESI) 586.4 (M + H) ⁺ ; And second eluting diastereomer as white solid (39.5 mg, 36%): MS (ESI) 586.2 (M + H) ⁺ .
[2203] <Example 186>
[2204] 4,5-dimethoxybenzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3 methyl Preparation of -Butyl} -amide
[2205] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with 5,6-dimethoxybenzofuran-2-carboxylic acid, which was purified by HPLC. Diastereomer eluted first: MS (ESI) 618.4 (M + H) ⁺ ; And secondly eluting diastereomers.
[2206] <Example 187>
[2207] 3-Methylbenzofuran-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2208] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with 3-methylbenzofuran-2-carboxylic acid, which was first purified by HPLC. Eluting diastereomer as white solid (76 mg, 72%): MS (ESI) 570.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (23.2 mg, 22%): MS (ESI) 570.2 (M + H) ⁺ .
[2209] Example 188
[2210] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2211] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with benzo [b] thiophene-2-carboxylic acid, and purified by HPLC to obtain the first compound. The diastereomer eluted with white solid (37 mg, 35%): MS (ESI) 572.2 (M + H) ⁺ ; And secondly eluting diastereomer as white solid (31 mg, 29%): MS (ESI) 572.2 (M + H) ⁺ .
[2212] Example 189
[2213] 1-Methyl-1H-indole-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} amide
[2214] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with 1-methylindole-2-carboxylic acid, which was purified by HPLC and eluted first. The resulting diastereomer as a white solid (34 mg, 32%): MS (ESI) 569.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (38 mg, 38%): MS (ESI) 569.4 (M + H) ⁺ .
[2215] Example 190
[2216] Of quinoxaline-2-carboxylic acid-{(S) -1- [1- (3-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} amide Produce
[2217] The title compound was prepared according to the procedure of Example 183c-d, except that the benzofuran-2-carboxylic acid of step 183c was replaced with quinoxaline-2-carboxylic acid, and purified by HPLC to obtain the first eluting portion. Stereoisomer as a white solid (71 mg, 67%): MS (ESI) 568.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (27 mg, 24%): MS (ESI) 568.2 (M + H) ⁺ .
[2218] Example 191
[2219] Of benzofuran-2-carboxylic acid-{(S) -3-methyl-1- [3-oxo-1- (thiophen-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide Produce
[2220] The title compound was prepared according to the procedure of Example 168, except that 5-methoxybenzofuran-2-carboxylic acid was replaced with benzofuran-2-carboxylic acid, which was purified by HPLC to give the first eluted solid body. Isomer as a white solid (76 mg, 73%): MS (ESI) 532.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (25 mg, 23%) MS (ESI): 532.2 (M + H) ⁺ .
[2221] <Example 192>
[2222] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(2,2 ', 4-triduterio) -3-oxo-1- (pyridine-2-sulfonyl) -azane- Preparation of 4-ylcarbamoyl] butyl} amide
[2223] Benzofuran-2-carboxylic acid of Example 28c in D ₂ O: CD ₃ OD (0.4: 4 mL) ((S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) To a solution of azepan-4-ylcarbamoyl] -butyl} amide (0.03 g) was added triethylamine (0.04 mL). The reaction was heated to reflux for 2 hours, which was concentrated in vacuo and dried. The residue was redissolved in the same mixture and heated to reflux overnight. The reaction was concentrated and the residue was column chromatography (5% methanol: dichloromethane) to give the title compound (0.02 g):
[2224]
[2225] Separation of the diastereomeric mixture by HPLC, which elutes more quickly isomer: MS (EI): 530 (M + H ⁺ , 100%) and later isomer isomer: MS (EI): 530 (M + H +, 100%).
[2226] Example 193
[2227] Preparation of benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[2228] a.) 4-tert-butoxycarbonylamino-3-hydroxy-azane-1-carboxylic acid benzyl ester
[2229] To a stirred solution of the compound of Example 2e (1.04 g, 3.92 mmol) in THF was added di-tert-butyldicarbonate (0.864 g). After stirring at room temperature for 30 minutes, the reaction mixture was diluted with diethyl ether and extracted with saturated NaHC0 ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel column to give the title compound as a yellow oil (0.963 g, 2.64 mmol, 67%). MS (ESI): 365.03 (M + H) ⁺ .
[2230] b.) (3-hydroxy-azpan-4-yl) -carbamic acid tert-butyl ester
[2231] To a solution of the compound of Example 193a (0.963 g, 2.64 mmol) in ethyl acetate (16 ml) was added 10% palladium on carbon (500 mg). After the solution was stirred at rt for 48 h, the mixture was filtered through celite. The filtrate was concentrated to give the title compound (0.529 g, 2.29 mmol, 87%): MS (ESI): 231.92 (M + H) ⁺ .
[2232] c.) [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -carbamic acid tert-butyl ester
[2233] To a solution of the compound of Example 193b (0.53, 2.29 mmol) in dichloromethane (20 ml) was added triethylamine (232 mg) and pyridine-2-sulfonyl chloride (410 mg, 2.32 mmol). After stirring for 30 minutes at room temperature, the mixture was washed with saturated NaHCO ₃ . The organic layer was dried, filtered, concentrated and purified on silica gel column to give the title compound as a solid (0.58 g, 1.57 mmol, 68%): MS (ESI): 372.95 (M + H) ⁺ .
[2234] d.) 4-amino-1- (pyridin-2-sulfonyl) -azpan-3-ol
[2235] To a stirred solution of the compound of Example 193c (0.583 g, 1.57 mmol) in ethyl acetate (0.5 ml) was added HCl (4M in dioxane, 3.9 ml). The reaction mixture was stirred at rt for 30 min, then the mixture was concentrated to give a white solid. The solid was treated with NaOH and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give a yellow solid (0.35 g, 1.28 mmol, 81%): MS (ESI) 272.93 (M + H) ⁺ .
[2236] e.) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-meth-butyl} carbamic acid tert-butyl ester
[2237] CH ₂ Cl ₂ mixture of the compound of Example 193d (19 mg, 0.070 mmol) in CH ₂ Cl ₂ solution of N-Boc- isoleucine (24.5 mg, 0.10 mmol), 1- hydroxybenzotriazole (16.1 mg, 0.12 of mmol), and P-EDC (140 mg, 0.14 mmol). After shaking overnight at room temperature, the mixture was treated with PS-trisamine. After further shaking for 2 hours, the mixture was filtered and concentrated to give the title compound as a solid. MS (ESI) 484.97 (M + H) ⁺ .
[2238] f.) (S) -2-Amino-3-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2239] To a solution of the compound of Example 193e (34 mg, 0.07 mmol) in CH ₂ Cl ₂ (0.50 ml) was added HCl (4M in dioxane) (0.165 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated to give a white solid. The white solid was azeotropic with toluene and then treated with MP-carbonate (0.35 mmol) in methanol. After shaking for 4 hours, the mixture was filtered and concentrated to give the title compound as a solid: MS (ESI) 384.9 (M + H) ⁺ .
[2240] g.) Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl}- amides
[2241] CH ₂ Cl ₂ mixture of the compound of Example 193f (27 mg, 0.070 mmol) in CH ₂ Cl ₂ solution of 2-benzofuran-carboxylic acid (17.0 mg, 0.106 mmol), 1- hydroxybenzotriazole (16.1 mg, 0.12 of mmol), and P-EDC (140 mg, 0.14 mmol). After shaking overnight at room temperature, the mixture was treated with PS-trisamine. After 2 h more shaking, the mixture was filtered and concentrated to give the title compound as a solid: MS (ESI) 528.9 (M + H) ⁺ .
[2242] h.) Benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[2243] To a stirred solution of Example 193 g of compound (37 mg, 0.07 mmol) in CH ₂ Cl ₂ (0.5 ml) was added Dess-Martin reagent (45 mg, 0.105 mmol). After stirring for 30 minutes, the reaction was added simultaneously with a solution of sodium thiosulfate (10% in water, 0.50 ml) and saturated aqueous sodium bicarbonate (0.50 ml). The mixture was then extracted with dichloromethane (twice). 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 eluent: 7 mg, second eluent: 5.5 mg): MS (ESI) 526.91 (M + H) ⁺ .
[2244] Example 194
[2245] Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide
[2246] Except for replacing N-Boc-alpha-aminobutyric acid in step 193e, the title compound was prepared according to the procedure of Example 193e-h, and purified to obtain two diastereomers as a solid (first Eluent: 5 mg, second eluent: 5 mg): MS (ESI) 543.8 (M + H) ⁺ .
[2247] <Example 195>
[2248] Preparation of benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide
[2249] The title compound was prepared following the procedure of Example 193e-h, except that N1Becyclohexylalanine was replaced in step 193e to obtain two diastereomers as a solid (first eluate). : 4.5 mg, 2nd eluent: 4.5 mg): MS (ESI): 566.87 (M + H) ⁺ .
[2250] Example 196
[2251] Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide
[2252] Except for replacing N-Boc-alanine in step 193e, the title compound was prepared according to the procedure of Example 193e-h, which was purified to give two diastereomers as a solid (first eluate: 5.5 mg, 2nd eluent: 5 mg).
[2253] <Example 197>
[2254] Of benzofuran-2-carboxylic acid {(S) -3-methanesulfinyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide Produce
[2255] The title compound was prepared according to the procedure of Example 193e-h, except that N-Boc-1-methionine was replaced in step 1 (f), and this was purified to give two diastereomers as solids ( First eluent: 3 mg, second eluent: 3 mg). MS (ESI): 560.7 (M + H) ⁺ .
[2256] Example 198
[2257] Preparation of benzofuran-2-carboxylic acid {[3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -methyl} -amide
[2258] Except for replacing N-Boc-glycine in step 193e, the title compound was prepared according to the procedure of Example 193e-h, which was purified to give two diastereomers as a solid (first eluate: 3 mg, 2nd eluent: 3 mg). MS (ESI): 470.81 (M + H) ⁺ .
[2259] <Example 199>
[2260] Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} -amide
[2261] Except for replacing N-Boc-norleucine in step 193e, the title compound was prepared according to the procedure of Example 193e-h, and purified to give two diastereomers as a solid (first eluate). : 4 mg, 2nd eluent: 5 mg). MS (ESI): 526.85 (M + H) ⁺ .
[2262] <Example 200>
[2263] Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[2264] Except for replacing N-Boc-norvaline in step 193e, the title compound was prepared according to the procedure of Example 193e-h, and purified to give two diastereomers as a solid (first eluate). : 7.5 mg, 2nd eluent: 3.5 mg). MS (ESI): 512.8 (M + H) ⁺ .
[2265] <Example 201>
[2266] Preparation of benzofuran-2-carboxylic acid {(S) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide
[2267] Except for replacing N-Boc-valine in step 193e, the title compound was prepared according to the procedure of Example 193e-h, which was purified to give two diastereomers as a solid (first eluate: 6 mg, 2nd eluent: 4.5 mg). MS (ESI): 512.8 (M + H) ⁺ .
[2268] <Example 202>
[2269] Preparation of benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -propyl} -amide
[2270] Except for replacing N-Boc-threonine in step 193e, the title compound was prepared according to the procedure of Example 193e-h, and purified to give two diastereomers as a solid (first eluate: 3 mg, 2nd eluent: 3 mg).
[2271] <Example 203>
[2272] Preparation of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide
[2273] Except for replacing N-Bocphenylalanine in step 193e, the title compound was prepared according to the procedure of Example 193e-h, and purified to give two diastereomers as a solid (first eluate: 5 mg, 2nd eluent: 5 mg). MS (ESI): 560.8 (M + H) ⁺ .
[2274] <Example 204>
[2275] Preparation of 1- (benzofuran-2-carbonyl) -pyrrolidine-2-carboxylic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2276] Except for replacing with N-Boc-1-proline in step 193e, the title compound was prepared according to the procedure of Example 193e-h, and purified to obtain two diastereomers as a solid (first eluting Water: 4 mg, second eluent: 5 mg). MS (ESI): (M + H) ⁺ .
[2277] <Example 205>
[2278] 3,4-dimethoxy-N-{(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} Preparation of Benzamide
[2279] The title compound was prepared according to the process of Example 115 except for replacing benzyloxyacetyl chloride with 3,4-dimethoxybenzoyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2280]
[2281] <Example 206>
[2282] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2283] The title compound was prepared, except that benzyloxyacetyl chloride was replaced with 2-thiophene-carbonyl chloride according to the process of Example 115. The residue was purified by HPLC. Firstly eluted diastereomers:
[2284]
[2285] Second eluting diastereomer: MS 572.2 (M + H ⁺ ).
[2286] <Example 207>
[2287] Benzo [1,3] dioxol-5-carboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl Preparation of -Butyl} -amide
[2288] Subject to the procedure of Example 115, except that 4-methoxybenzenesulfonyl chloride was replaced with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride was replaced by 3,4-methylenedioxybenzoyl chloride The compound was prepared. The residue was purified by HPLC. Firstly eluting diastereomers; MS 548.2 (M + H ⁺ );
[2289]
[2290] Second eluting diastereomer: MS 548.2 (M + H ⁺ ).
[2291] Example 208
[2292] Of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-yl] -amide Produce
[2293] The title compound was prepared according to the process of Example 115 except that 4-methoxybenzenesulfonyl chloride was replaced with 4-fluorobenzenesulfonyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2294]
[2295] <Example 209>
[2296] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-yl carbamoyl] -3-methyl- Preparation of Butyl} -amide
[2297] Subject to the procedure of Example 115, except that 4-methoxybenzenesulfonyl chloride was replaced with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride was replaced with benzo [b] thiophencarbonyl chloride The compound was prepared. The residue was purified by HPLC. Firstly eluted diastereomers:
[2298]
[2299] Second eluting diastereomer: MS 560.2 (M + H ⁺ ).
[2300] <Example 210>
[2301] Preparation of benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[2302] a.) Benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-hydroxy-azpan-4-ylcarbamoyl] 3-methyl-butyl} -amide
[2303] Solution of benzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide (0.2 g) in dichloromethane To benzoic acid (0.12 g), HOBt (0.07 g) and EDC (0.99 g) were added. The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (0.2 g):
[2304]
[2305] b.) Benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[2306] Except that it was replaced with the benzofuran-2-carboxylic acid {(S) -1- [1-benzoyl-3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide of Example 210a The title compound was prepared according to the procedure of Example 1i:
[2307]
[2308] Example 211
[2309] Preparation of (S) -4-methyl-2- (quinolin-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2310] a.) (S) -4-methyl-2- (quinolin-8-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl]- amides
[2311] The title compound was prepared according to the process of Example 89a, except that 2-pyridinesulfonyl chloride was replaced with 8-quinolinesulfonyl chloride: MS (EI) 576 (M + H ⁺ ).
[2312] b.) (S) -4-methyl-2- (quinolin-8-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2313] (S) -4-methyl-2- (quinolin-8-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] of example 211a Except for the substitution with -amide, the title compound was prepared following the procedure of Example 1i:
[2314]
[2315] Example 212
[2316] Preparation of (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2317] a.) (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amides
[2318] The title compound was prepared according to the process of Example 89a, except that 2-pyridinesulfonyl chloride was replaced with 2-naphthylenesulfonyl chloride: MS (EI) 575 (M + H ⁺ ).
[2319] b.) (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl]- amides
[2320] (S) -4-methyl-2- (naphthylene-2-sulfonylamino) -pentanoic acid [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan4-yl] of Example 212a Except for the substitution with -amide, the title compound was prepared following the procedure of Example 1i:
[2321]
[2322] <Example 213>
[2323] Benzofuran-2-carboxylic acid-{(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-yl carbamoyl] -3-methyl-butyl} -amide Manufacture
[2324] The title compound was prepared according to the procedure of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride with 2-benzofurancarbonyl chloride. Prepared. The residue was purified by HPLC. Firstly eluted diastereomers:
[2325]
[2326] Second eluting diastereomer: MS 544.4 (M + H ⁺ ).
[2327] <Example 214>
[2328] N-{(S) -1- [1- (4-Fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -3,4-dimethoxy Preparation of Benzamide
[2329] The title compound, according to the process of Example 115, except that 4-methoxybenzenesulfonyl chloride was replaced with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride was replaced with 3,4-dimethoxybenzoyl chloride Was prepared. The residue was purified by HPLC. Firstly eluted diastereomers:
[2330]
[2331] Second eluting diastereomer: MS 546.2 (M + H ⁺ ).
[2332] <Example 215>
[2333] Preparation of cyclohexanecarboxylic acid {(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl} -3-methyl-butyl} -amide
[2334] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride and benzyloxyacetyl chloride with cyclohexylcarbonyl chloride. . The residue was purified by HPLC. Firstly eluted diastereomers:
[2335]
[2336] Second eluting diastereomer: MS 510.2 (M + H ⁺ ).
[2337] <Example 216>
[2338] Preparation of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (methanesulfonyl) -3-oxo-azpan-4-yl] -amide
[2339] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2340]
[2341] Second eluting diastereomer: MS 468.2 (M + H ⁺ ).
[2342] <Example 217>
[2343] Preparation of benzo [b] thiophene-2-carboxylic acid-{(S) -1- (1-methanesulfonyl) -3-oxo-azpan-4-yl carbamoyl) -3-methyl-butyl] -amide
[2344] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with benzo [b] thiophencarbonyl chloride. . The residue was purified by HPLC. Firstly eluted diastereomers:
[2345]
[2346] Second eluting diastereomer: MS 480.2 (M + H ⁺ ).
[2347] Example 218
[2348] Of benzo [1,3] dioxol-5-carboxylic acid-{(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-yl carbamoyl) -3-methyl-butyl] -amide Produce
[2349] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with piperonylcarbonyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2350]
[2351] Second eluting diastereomer: MS 468.2 (M + H ⁺ ).
[2352] <Example 219>
[2353] Preparation of Benzofuran-2-carboxylic acid-{(S) -1- (1-methanesulfonyl-3-oxo-azpan-4-yl carbamoyl) -3-methyl-butyl] -amide
[2354] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with 2-benzofurancarbonyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2355]
[2356] Second eluting diastereomer: MS 464.2 (M + H ⁺ ).
[2357] <Example 220>
[2358] Preparation of N-[(S) -1- (1-methanesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -3,4-dimethoxy-benzamide
[2359] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with methanesulfonyl chloride and benzyloxyacetyl chloride with 3,4-dimethoxybenzoyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2360]
[2361] Second eluting diastereomer: MS 484.2 (M + H ⁺ ).
[2362] <Example 221>
[2363] Of (S) -2- (2-benzyloxy-acetylamino) -4-methyl-pentanoic acid [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-yl] -amide Produce
[2364] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2365]
[2366] Second eluting diastereomer: MS 555.2 (M + H ⁺ ).
[2367] <Example 222>
[2368] N-{(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -4-methanesulfonyl- Preparation of 1-benzamide
[2369] The title compound was prepared according to the procedure of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride with 4-methanesulfonylbenzoyl chloride. Prepared. The residue was purified by HPLC. Firstly eluted diastereomers:
[2370]
[2371] Second eluting diastereomer: MS 589.2 (M + H ⁺ ).
[2372] <Example 223>
[2373] Benzo [b] thiophene-2-carboxylic acid-{(S) -1- [1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-yl carbamoyl) -3-methyl- Preparation of Butyl] amide
[2374] The process of Example 115, except replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride with benzo [b] thiophene-2-carbonyl chloride According to the title compound. The residue was purified by HPLC. Firstly eluted diastereomers:
[2375]
[2376] Second eluting diastereomer: MS 567.2 (M + H ⁺ ).
[2377] <Example 224>
[2378] Benzo [1,3] dioxol-5-carboxylic acid-{(S)-[1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl) -3-methyl- Preparation of Butyl] amide
[2379] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride with piperonyloyl chloride It was. The residue was purified by HPLC. Firstly eluted diastereomers:
[2380]
[2381] Second eluting diastereomer: MS 555.4 (M + H ⁺ ).
[2382] <Example 225>
[2383] (S) -4-methyl-2- [4-oxo-4-((4-phenoxy-phenyl) -butyrylamino} pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -ase Preparation of Pan-4-yl] -amide
[2384] The title compound was prepared according to the procedure of Example 75 except for replacing thiazole-2-sulfonyl chloride with 2-pyridylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with 4-phenoxyphenyl-carboxylic acid. It was. The residue was purified by HPLC. Firstly eluting diastereomers;
[2385]
[2386] And second eluting diastereomer: 0.96-0.92 (m, 6H); And second eluting diastereomer: MS (M + H ⁺ ) 635.4.
[2387] <Example 226>
[2388] N-{(S) -1-[(1- (2-cyano-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl} -3-methyl-butyl} -3,4-dime Preparation of Toxy-Benzamide
[2389] The title compound, according to the process of Example 115, except that 4-methoxybenzenesulfonyl chloride was replaced with 2-cyanophenylsulfonyl chloride and benzyloxyacetyl chloride was replaced with 3,4-dimethoxybenzoyl chloride Was prepared. The residue was purified by HPLC. Firstly eluted diastereomers:
[2390]
[2391] Second eluting diastereomer: MS 571.4 (M + H ⁺ ).
[2392] <Example 227>
[2393] Preparation of cyclohexanecarboxylic acid {(S) -1- [1- (4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl} -3-methyl-butyl} -amide
[2394] The title compound was prepared according to the process of Example 115 except for replacing benzyloxyacetyl chloride with cyclohexylcarbonyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2395]
[2396] Second eluting diastereomer: MS 522.4 (M + H ⁺ ).
[2397] Example 228
[2398] Preparation of 4-methanesulfonyl-N-{(S) -1- [4-methoxy-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl-benzamide
[2399] The title compound was prepared according to the process of Example 115 except for replacing benzyloxyacetyl chloride with 4-methanesulfonylbenzoyl chloride. The residue was purified by HPLC. Firstly eluted diastereomers:
[2400]
[2401] Second eluting diastereomer: MS 594.2 (M + H ⁺ ).
[2402] <Example 229>
[2403] Preparation of 4-methanesulfonyl-N-{(S) -1- [4-fluoro-benzenesulfonyl) -3-oxo-azepane-4-carbamoyl] -3-methyl-butyl-benzamide
[2404] The title compound was prepared according to the procedure of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 4-fluorophenylsulfonyl chloride and benzyloxyacetyl chloride with 4-methanesulfonylbenzoyl chloride. Prepared. The residue was purified by HPLC. Firstly eluted diastereomers:
[2405]
[2406] Second eluting diastereomer: MS 582.2 (M + H ⁺ ).
[2407] <Example 230>
[2408] Preparation of ({(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butylcarbamoyl} -carbamic acid benzyl ester
[2409] The title compound was prepared according to the process of Example 75 except for replacing benzenesulfonyl chloride with 2-pyridylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with N-carbenzyloxycarbonyl-glycine It was. The residue was purified by HPLC. Firstly eluting diastereomers;
[2410]
[2411] And second eluting diastereomer: MS (M + H ⁺ ) 574.2.
[2412] <Example 231>
[2413] (S) -2- [5- (4-methoxy-phenyl) -pentanoylamino] -4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Preparation of Il] -amides
[2414] The title compound, according to the process of Example 75, except that benzenesulfonyl chloride was replaced with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with 5- (4-methoxyphenyl) -pentanoic acid Was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[2415]
[2416] And second eluting diastereomer: MS (M + H ⁺ ) 573.4.
[2417] Example 232
[2418] (S) -2- [2- (3-benzyloxy-4-methoxy-phenyl) -acetylamino] -4-methylpentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azane Preparation of 4-yl] -amide
[2419] The process of Example 75, except that benzenesulfonyl chloride was replaced with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced with (3-benzyloxy-4-methoxy-phenyl) -acetic acid. According to the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2420]
[2421] And second eluting diastereomers:
[2422]
[2423] And second eluting diastereomer: MS (M + H ⁺ ) 637.4.
[2424] <Example 233>
[2425] 5,6-difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[2426] a.) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-hydroxy-azepane-4- Ylcarbamoyl] -butyl} amide
[2427] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 5,6-difluorobenzofuran-2-carboxylic acid: MS (M + H ⁺ ): 564
[2428] b.) 5,6-difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridin-2-sulfonyl) -3-oxo-azpan-4-yl Carbamoyl] -butyl} amide
[2429] The title compound was prepared according to the process of Example 1i, except that the compound of Example 233a was replaced. The residue was purified by HPLC. Firstly eluting diastereomers; MS (M + H ⁺ ): 562; And second eluting diastereomer: MS (M + H ⁺ ) 562.
[2430] <Example 234>
[2431] Preparation of (S) -4-methyl-2- (5-oxo-hexanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2432] The title compound was prepared according to the process of Example 115 except for replacing 4-methoxybenzenesulfonyl chloride with 2-pyridinesulfonyl chloride and replacing benzyloxyacetyl chloride with 5-oxo-hexanoyl chloride. . The residue was purified by HPLC. First eluting diastereomer: MS 495.4 (M + H ⁺ ); Second eluting diastereomer: MS 495.4 (M + H ⁺ ).
[2433] <Example 235>
[2434] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[2435] a.) 6-methyl-pyridine-2-sulfonyl chloride
[2436] The title compound was prepared in a similar manner as described in Example 85a for the preparation of 2-pyridinesulfonyl chloride-N-oxide.
[2437] b.) {(S) -1- [3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[2438] [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester of 1.0 g in dichloromethane (20 mL) (1.0 g) To a solution of) saturated sodium bicarbonate (50 mL) was added. To this solution was added 6-methyl-pyridine-2-sulfonyl chloride (0.13 g / mL solution in 9M HCl, 6.44 mL). The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (1.2 g).
[2439] c.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2440] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azepane-4- of Example 235a in methanol (20 mL) To a solution of il] -amide (1.2 g) was added 4M HCl in dioxane (20 mL). The reaction was stirred until complete and concentrated to give the title compound (1 g).
[2441] d.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -Butyl} amide
[2442] Replaced with (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine-2-sulfonyl) -azpan-4-yl] -amide of Example 235c Except for one, the title compound was prepared following the process of Example 28b: MS (EI) 542 (M ⁺ ).
[2443] e.) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl]- Butyl} amide
[2444] Benzofuran-2-carboxylic acid of Example 235d {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl The title compound was prepared according to the process of Example 1i except for replacing with] -butyl} amide:
[2445]
[2446] <Example 236>
[2447] 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[2448] a.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane-4- Ylcarbamoyl] -butyl} amide
[2449] Replace benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid and replace (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (pyridine-2) of Example 28b. -Sulfonyl) -Azepan-4-yl] -amide was added to the (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-1- (6-methyl-pyridine-2-) of Example 235c. The title compound was prepared according to the process of Example 28b, except that sulfonyl) -azpan-4-yl] -amide was used: MS (EI) 572 (M ⁺ ).
[2450] b.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-sulfonyl) -3-oxo-azpan-4-yl Carbamoyl] -butyl} amide
[2451] 5-methoxybenzofuran-2-carboxylic acid of Example 236a {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane-4 The title compound was prepared according to the process of Example 1i except for replacing with -ylcarbamoyl] -butyl} amide:
[2452]
[2453] <Example 237>
[2454] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] butyl } Production of Amide
[2455] a.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-sulfonyl) -3-hydroxy-azpan-4-yl Carbamoyl] -butyl} amide
[2456] The title compound was prepared according to the process of Example 236a except that 5-methoxybenzofuran-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid: MS (EI) 556 (M ⁺ ) .
[2457] b.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarba Moyl] -butyl} amide
[2458] 3-Methylbenzofuran-2carboxylic acid of Example 237a {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-sulfonyl) -3-hydroxy-azpan-4-yl The title compound was prepared according to the process of Example 1i, except that it was replaced with carbamoyl] -butyl} amide:
[2459]
[2460] <Example 238>
[2461] 7-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[2462] a.) 7-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane-4- Ylcarbamoyl] -butyl} amide
[2463] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 7-methoxybenzofuran-2-carboxylic acid: MS (EI) 559 (M + H ⁺ ).
[2464] b.) 7-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-sulfonyl) -3-oxo-azpan-4-yl Carbamoyl] -butyl} amide
[2465] 7-methoxybenzofuran-2-carboxylic acid of Example 238a {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane-4 The title compound was prepared according to the process of Example 1i except for replacing with -ylcarbamoyl] -butyl} amide: MS (EI) 557 (M + H ⁺ ).
[2466] <Example 239>
[2467] 5,6-dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (pyridine-2-sulfonyl) -3-oxo-azpan-4-yl Preparation of Carbamoyl] -Butyl} amide
[2468] a.) 5,6-Dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methylpyridine-2-sulfonyl) -3-hydroxy -Azpan-4-ylcarbamoyl] -butyl} amide
[2469] The title compound was prepared according to the process of Example 28b, except that the benzofuran-2-carboxylic acid was replaced with 5,6-dimethoxybenzo [b] thiophene-2-carboxylic acid: MS (EI) 604 ( M ⁺ ).
[2470] b.) 5,6-dimethoxy-benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methylpyridine-2-sulfonyl) -3-oxo- Azepan-4-ylcarbamoyl] -butyl} amide
[2471] 5,6-Dimethoxybenzo [b] thiophene-2-carboxylic acid of Example 239a {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydrate The title compound was prepared according to the process of Example 1i except for the replacement with oxy-azpan-4-ylcarbamoyl] -butyl} amide: MS (EI) 602.9 (M + H ⁺ ).
[2472] <Example 240>
[2473] (R) -1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -3-methyl-1- {3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl Preparation of Carbamoyl] -Butyl} amide
[2474] Except for replacing thiazole-2-sulfonyl chloride with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid with (R) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid Was prepared according to the process of Example 75 to prepare the title compound. The residue was purified by HPLC. Firstly eluting diastereomers;
[2475]
[2476] And second eluting diastereomer: MS (M + H ⁺ ) 584.4.
[2477] <Example 241>
[2478] (S) -1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S) -3-methyl-1- {3-oxo- (pyridine-2-sulfonyl) -azpan-4-yl Preparation of Carbamoyl] -Butyl} amide
[2479] Example except that benzenesulfonyl chloride was replaced by 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid was replaced by (S) -1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid The title compound was prepared following the procedure for 75. The residue was purified by HPLC. Firstly eluting diastereomers;
[2480]
[2481] And second eluting diastereomer: MS (M + H ⁺ ): 584.4.
[2482] <Example 242>
[2483] Preparation of benzofuran-2-carboxylic acid {(S) -2-cyclopropyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl] -amide
[2484] Except for replacing N-Boc-cyclopropylalanine in step 193e, the title compound was purified according to the procedure of Example 193e-h to give two diastereomers as solids (first eluent: 8 mg, first 2 eluents: 8 mg) were obtained: MS (ESI): 525 (M + H) ⁺ .
[2485] <Example 243>
[2486] Of benzofuran-2-carboxylic acid {(S) -3-methylsulfanyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -propyl] -amide Produce
[2487] The process of Example 193e-g was followed, except that N1Boc-L-methionine was replaced in step 193e. Oxidation of Example 193 g was performed by adding sulfur trioxide-pyridine complex (34 mg, 0.211 mmol) and triethylamine (0.077 ml) to the alcohol intermediate in DMSO solvent (0.200 ml). After stirring for 2 hours at room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, concentrated and purified by HPLC to give two diastereomers of the title compound as a solid (first eluent: 8 mg, second eluent: 5 mg). MS (ESI): 545 (M + H) ⁺ .
[2488] <Example 244>
[2489] Benzofuran-2-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl] Preparation of -amides
[2490] Purification of the title compound was carried out according to the procedure of Example 193e-h, except that N- (t-butoxycarbonyl) -3- (2-naphthyl) -1-alanine was substituted for diastereomer 2 The species was obtained as a solid (first eluent: 5.3 mg, second eluent: 3.3 mg): MS (ESI): 610.8 (M + H) ⁺ .
[2491] <Example 245>
[2492] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-azepane-4 -Ylcarbamoyl] -butyl} amide
[2493] a.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy- Azepan-4-ylcarbamoyl] -butyl} amide
[2494] The title compound was prepared according to the process of Example 236a, except that 5-methoxybenzofuran-2-carboxylic acid was replaced with thieno [3,2-b] thiophene-2-carboxylic acid. ) 564 (M ⁺ ).
[2495] b.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-oxo-ase Pan-4-ylcarbamoyl] -butyl} amide
[2496] Thieno [3,2-b] thiophene2-carboxylic acid of Example 245a {(S) -3-methyl-1- [1- (6-methyl-pyridine-2-sulfonyl) -3-hydroxy- The title compound was prepared according to the process of Example 1i except for replacing with azepan-4-ylcarbamoyl] -butyl} amide:
[2497]
[2498] <Example 246>
[2499] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azepane-4 -Ylcarbamoyl] butyl} amide
[2500] a.) (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (3-methyl-pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2501] The title compound was prepared following the process of Example 235b-c, except that 6-methyl-pyridine-2-sulfonyl chloride was replaced with 3-methylpyridine-2-sulfonyl chloride: MS (EI) 399 (M ⁺ ).
[2502] b.) Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2sulfonyl) -3-hydroxy-ase Pan-4-ylcarbamoyl] -butyl} amide
[2503] (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-1- (3-methyl-pyridine-2-sulfonyl) -azpan-4-yl] of Example 246a in dichloromethane To a solution of amide (0.25 g) was added thieno [3,2-b] thiophene (0.10 g), triethylamine (0.12 mL), HOBt (0.085 g) and EDC (0.12 g). The reaction was stirred until complete. Finished and column chromatography (5% methanol: dichloromethane) gave the title compound (0.18 g): MS (EI) 564 (M ⁺ ).
[2504] c.) thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-ase Pan-4-ylcarbamoyl] -butyl} amide
[2505] Thieno [3,2-b] thiophene-2-carboxylic acid of Example 245a {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy The title compound was prepared according to the process of Example 1i, except that it was replaced with -azane-4-ylcarbamoyl] -butyl} amide:
[2506]
[2507] <Example 247>
[2508] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl]- Preparation of Butyl} amide
[2509] a.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridin-2-sulfonyl) -3-hydroxy-azpan-4-yl Carbamoyl] -butyl} amide
[2510] The title compound was prepared following the process of Example 246c, except that thieno [3,2-b] thiophene was replaced with 3-methylbenzofuran-2-carboxylic acid: MS (EI) 556 (M ⁺ ).
[2511] b.) 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarba Moyl] -butyl} amide
[2512] 3-Methylbenzofuran-2carboxylic acid of Example 247a {(S) -3-methyl-1- [1- (3-methyl-pyridin-2-sulfonyl) -3-hydroxy-azpan-4-yl The title compound was prepared according to the process of Example 1i, except that it was replaced with carbamoyl] -butyl} amide:
[2513]
[2514] <Example 248>
[2515] 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] Preparation of -Butyl} amide
[2516] a.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane-4- Ylcarbamoyl] -butyl} amide
[2517] The title compound was prepared following the process of Example 246c, except that thieno [3,2-b] thiophene was replaced with 5-methoxybenzofuran-2-carboxylic acid: MS (EI) 572 (M ⁺ ).
[2518] b.) 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (3-methyl-pyridin-2-sulfonyl) -3-oxo-azpan-4-yl Carbamoyl] -butyl} amide
[2519] 5-methoxybenzofuran 2-carboxylic acid of Example 247a {(S) -3-methyl-1- [1- (3-methyl-pyridine-2-sulfonyl) -3-hydroxy-azepane-4- The title compound was prepared according to the process of Example 1i, except that it was replaced with ilcarbamoyl] -butyl} amide:
[2520]
[2521] <Example 249>
[2522] 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Preparation of Ilcarbamoyl] -Butyl} amide
[2523] a.) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxypyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[2524] The title compound was prepared according to the process of Example 85c, except that the benzo [b] thiophene-2-carboxylic acid was replaced with 5,6-difluorobenzofuran-2-carboxylic acid: MS (ESI) 580.9 (M + H ⁺ ).
[2525] b.) 5,6-difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide
[2526] Except for the replacement of the compound of Example 249a, the title compound was prepared according to the process of Example 1i: MS (ESI) 578.87 (M + H ⁺ ).
[2527] <Example 250>
[2528] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- {3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 Preparation of -ylcarbamoyl] -ethyl} -amide
[2529] a.) 4-((S) -2-tert-butoxycarbonylamino-3-cyclohexyl-proprioylamino) -3-hydroxy-azane-1-carboxylic acid benzyl ester
[2530] To a solution of the compound of Example 2e (3.2 g, 12.2 mmol) in DMF (35 mL) was added N-Boc-cyclohexylalanine (3.3 g), HOBt (1.8 g) and EDC (2.56 g). The reaction was stirred until complete. Finished and the residue was column chromatography (65% hexanes: ethyl acetate) to give 5.5 g of the title compound.
[2531] b.) [(S) -cyclohexyl-1- (3-hydroxy-azpan-4-ylcarbamoyl) -ethyl] -carbamic acid tertbutyl ester
[2532] To a solution of compound of Example 250a (5.5 g) in ethyl acetate: methanol (185 mL: 40 mL) was added 10% Pd / C. The mixture was stirred under hydrogen atmosphere until it was observed that the starting material was consumed completely. The reaction was filtered and concentrated to give 3.75 g of the title compound.
[2533] c.) {(S) -2-cyclohexyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -carbamic acid tert-butyl ester
[2534] To a solution of compound of Example 250b (1.0 g, 1.91 mmol) in dichloromethane (5 mL) was added water (10 mL) and sodium bicarbonate (1 g). 2-pyridinesulfonyl chloride (0.55 g in 5 mL dichloromethane) was added dropwise to this mixture. The mixture was stirred for 20 minutes, the organic layer was separated, washed with water, brine, dried by filtration and concentrated. The residue was column chromatographed (2% methanol: dichloromethane) to give 1.0 g of the title compound: MS (ESI) 525 (M + H ⁺ ).
[2535] d.) (S) -2-amino-3-cyclohexyl-N- [3-hydroxy- (pyridine-2-sulfonyl) -azpan-4-yl] propionamide
[2536] To a solution of compound of Example 250c (1.0 g) in methanol (10 mL) was added HCl (4M HCl in dioxane, 10 mL). The mixture was stirred under hydrogen atmosphere and concentrated until it was observed that the starting material was consumed completely. The residue was azeotropic with toluene and washed with ether to give 0.95 g of the title compound.
[2537] e.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- {3-hydroxy-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -ethyl} -amide
[2538] To a solution of the compound of Example 250d (0.20 g, 0.4 mmol) in DMF (0.5 mL), diisopropylethylamine (0.16 mL), HOBt (0.06 g), EDC (0.084 g) and 5- [3- (tri Fluoromethyl) phenyl] -2-furonic acid (0.11 g) was added. The reaction was stirred until the starting material was consumed completely. Finished and column chromatography (4% methanol: dichloromethane) gave 0.23 g of the title compound.
[2539] f.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- {3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -ethyl} -amide
[2540] The title compound was prepared according to the process of Example 75d, except that the compound of Example 250e was replaced. Separation of diastereomers by HPLC and first eluting diastereomer (52 mg): MS (ESI) 661.4; And second eluting diastereomer (45.8 mg): MS (ESI) 661.6.
[2541] <Example 251>
[2542] 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- {3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -ethyl} -amide
[2543] Example 250e-f, except that 5- [3- (trifluoromethyl) phenyl] -2-furonic acid of Example 252e was replaced with 5- (4-chlorophenyl) -2-furonic acid. The title compound was prepared according to the process. Separation of the diastereomers by HPLC first eluting the diastereomer (57 mg): MS (ESI) 627.4; And second eluting diastereomer (53 mg): MS (ESI) 627.4.
[2544] <Example 252>
[2545] Of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [6-methyl-3-oxo-1- (pyridine-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide Produce
[2546] The title compound was prepared according to the process of Example 92, except that 2,2-dimethyl-4-pentenal was replaced with 2-methyl-4-pentenal. The residue was purified by HPLC. First eluting diastereomer;
[2547]
[2548] <Example 253>
[2549] 5- (4-Chloro-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane- Preparation of 4-ylcarbamoyl] ethyl} -amide
[2550] Replace 2-pyridinesulfonyl chloride of Example 250c with 2-pyridinesulfonyl chloride N-oxide and replace 5- [3- (trifluoromethyl) phenyl] -2-furonic acid of Example 252e with 5- (4 The title compound was prepared following the procedure of Example 250c-f, except that -chlorophenyl) -2-furonic acid was replaced. Separation of diastereomers by HPLC first eluting diastereomer: MS (ESI) 643.4; And second eluting diastereomer: MS (ESI) 643.2.
[2551] <Example 254>
[2552] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl)- Preparation of Azepan-4-ylcarbamoyl] -ethyl} -amide
[2553] The title compound was prepared according to the process of Example 250c-f, except that 2-pyridinesulfonyl chloride of Example 250c was replaced with 2-pyridinesulfonyl chloride N-oxide. Separation of diastereomers by HPLC first eluting diastereomer: MS (ESI) 677.2; And second eluting diastereomer: MS (ESI) 677.4.
[2554] <Example 255>
[2555] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of -amides
[2556] a.) 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} -amide
[2557] The title compound was prepared according to the process of Example 28b, except that benzofuran-2-carboxylic acid was replaced with 5-fluorobenzofuran-2-carboxylic acid: MS (ESI) 547 (M + H ⁺ ).
[2558] b.) 5-fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide
[2559] Except for the replacement of the compound of Example 255a, the title compound was prepared according to the process of Example 1i: MS (ESI) 544.9 (M + H ⁺ ).
[2560] <Example 256>
[2561] 5,6-dimethoxybenzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl Preparation of Carbamoyl] ethyl} -amide
[2562] Replace the 2-pyridinesulfonyl chloride of Example 250c with 2-pyridinesulfonyl chloride N-oxide and replace the 5- [3- (trifluoromethyl) phenyl] -2-furonic acid of Example 252e with 5,6- The title compound was prepared following the procedure of Example 250c-f, except that dimethoxybenzofuran-2-carboxylic acid was replaced. Diastereomers first eluted by separation of diastereomers by HPLC: MS (ESI) 643.4; And second eluting diastereomer: MS (ESI) 643.2.
[2563] <Example 257>
[2564] 5,5-bis- (4-methoxy-phenyl) -pent-4-enoic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane Preparation of -4-ylcarbamoyl]}-butyl} -amide
[2565] Replacing thiazole-2-sulfonyl chloride with 2-pyridylsulfonyl chloride and benzofuran-2-carboxylic acid with 5,5-bis- (4-methoxy-phenyl) -pent-4-enoic acid Except for the procedure of Example 75, the title compound was prepared. The residue was purified by HPLC. Firstly eluting diastereomers;
[2566]
[2567] And second eluting diastereomer: MS (M + H ⁺ ) 677.4.
[2568] <Example 258>
[2569] Quinoline-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl]- Preparation of Amides
[2570] a.) 4-amino-1- (pyridin-2-sulfonyl) -azpan-3-ol
[2571] To a solution of compound of Example 193c (1.5 g) in methanol (10 mL) was added HCl (4M HCl in dioxane, 10 mL). The reaction was stirred and concentrated to confirm completion by TLC analysis to give 1.2 g of the title compound as a white solid.
[2572] b.) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-naphthylene-2-yl-ethyl} -carr Chest acid tert-butyl ester
[2573] To a solution of the compound of Example 258a (225 mg) in dichloromethane was added TEA (0.15 mL), HOBt (99 mg), EDC (140 mg) and N-Boc-1-2-naphthylalanine (230 mg). It was. The reaction was stirred until complete. Finished and the residue was column chromatographed (3% methanol: dichloromethane) to give 0.35 g of the title compound: MS (ESI) 569 (M + H ⁺ ).
[2574] c.) (S) -2-amino-N- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -3-naphthylene-2-ylpropionamide
[2575] To a solution of compound of Example 258b (0.35 g) in methanol (5 mL) was added HCl (4M HCl in dioxane, 5 mL). The reaction was stirred and concentrated to confirm completion by TLC analysis to give 0.31 g of the title compound as a white solid.
[2576] d.) Quinoline-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -Ethyl] -amide
[2577] To a solution of the compound of Example 258c (131 mg) in dichloromethane was added TEA, HOBt (39 mg), EDC (55 mg) and quinoline-8-carboxylic acid (51 mg). The reaction was stirred until complete. Finished and the residue was column chromatography (5% methanol: dichloromethane) to give 0.35 g of the title compound: MS (ESI) 574 (M + H ⁺ ).
[2578] e.) Quinoline-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl)- Ethyl] -amide
[2579] The title compound was prepared according to the process of Example 1i, except that the compound of Example 258d was replaced.
[2580] <Example 259>
[2581] Naphthylene-1-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl) -ethyl] Preparation of -amides
[2582] The title compound was prepared following the process of Example 258d-e, except that quinoline-8-carboxylic acid was replaced with 1-naphthoic acid.
[2583] <Example 260>
[2584] Preparation of quinoline-8-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide
[2585] The title compound was prepared following the process of Example 258a-e, except that N-Boc-1-2-naphthylalanine was replaced with N-Boc-phenylalanine.
[2586] <Example 261>
[2587] Preparation of naphthyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[2588] The title compound was prepared following the procedure of Example 28b-c, except that benzofuran-2-carboxylic acid was replaced with 1,6-naphthyridine-2-carboxylic acid.
[2589] <Example 262>
[2590] Preparation of naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide
[2591] The title compound was prepared according to the process of Example 260 except for replacing quinoline-8-carboxylic acid with 1-naphthoic acid.
[2592] <Example 263>
[2593] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-propionyl) -azpan-4-ylcarbamoyl] -butyl} -amide Manufacture
[2594] a.) 4-{(S) -2-[(3-methylbenzofuran-2-carbonyl) -amino] -4-methyl-pentanoylamino} -3-hydroxy-azane-1-carboxylic acid benzyl ester
[2595] To a solution of the compound of Example 72a (1.2 g, 2.67 mmol) was added EDC (0.56 g), HOBt (0.36 g), TEA (0.67 g) and 3-methylbenzofuran-2-carboxylic acid (0.47 g). The reaction was stirred until it was observed that the starting material was consumed completely. Finished and column chromatography (4: 1 hexanes: ethyl acetate) gave 1.05 g of the title compound: MS (ESI) 536 (M + H ⁺ ).
[2596] b.) 3-Methylbenzofuran-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2597] Except for the replacement of the compound of Example 263a, the title compound was prepared according to the process of Example 2g: MS (ESI) 402 (M + H ⁺ ).
[2598] c.) 3-methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (cyclohexyl-proprioyl) -azpan-4-ylcarbamoyl]- Butyl} -amide
[2599] The title compound was prepared according to the process of Example 263a, except that the compound of Example 263b was replaced with 3-methylbenzofuran-2-carboxylic acid replaced with 3-cyclohexylpropionic acid: MS (ESI) 540 ( M + H ⁺ ).
[2600] d.) 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-proprioyl) -azpan-4-ylcarbamoyl] -butyl }-amides
[2601] Except for the replacement of the compound of Example 263c, the title compound was prepared according to the process of Example 1i: MS (ESI) 538 (M + H ⁺ ).
[2602] <Example 264>
[2603] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (4-methyl-pentanoyl) -azpan-4-ylcarbamoyl] -butyl} amide Produce
[2604] The title compound was prepared following the process of Example 263c-d, except that 3-cyclohexylpropionic acid was replaced with 4-methylpentanoic acid: MS (ESI) 498 (M + H ⁺ ).
[2605] <Example 265>
[2606] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-carbonyl) -azpan-4-ylcarbamoyl]- Preparation of Butyl} -amide
[2607] The title compound was prepared according to the process of Example 263c-d, except that 3-cyclohexylpropionic acid was replaced with picolinic acid N-oxide: MS (ESI) 498 (M + H ⁺ ).
[2608] Example 266
[2609] Preparation of (S) -acetylamino-4-methyl-pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2610] Except for replacing benzofuran-2-carboxylic acid with acetic acid in step 75c, the title compound was prepared according to the process of Example 75c-d, which was isolated by HPLC and eluted for the first time the diastereomer:
[2611]
[2612] And second eluting diastereomer: MS (M + H ⁺ ): 425.2.
[2613] <Example 267>
[2614] Preparation of quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} -amide
[2615] a.) 4-((S) -2-tert-butoxycarbonylamino-hexanoylamino) -3-hydroxy-azane-1-carboxylic acid benzyl ester
[2616] N-Boc-norleucine (175 mg, 0.76 mmol), EDC-HCl (145 mg, 0.76 mmol), in a stirred solution of compound (200 mg, 0.74 mmol) of the amino alcohol of Example 2e in DMF (4 ml), And 1-hydroxybenzotriazole (21 mg, 0.16 mmol) was added. The reaction was run 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. Dry over MgSO ₄ , filter and purify by column chromatography to give 300 mg of the title compound: MS (ESI) 478.11 (M + H) ⁺ .
[2617] b.) [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester
[2618] To a solution of the compound of Example 267a (300 mg, 0.63 mmol) in ethyl acetate (5 ml) was added 10% palladium on carbon (160 mg) and H ₂ from a filled balloon. After the solution was stirred at rt for 48 h, the mixture was filtered through celite. The filtrate was concentrated to give the title compound (crude, 161 mg, 0.47 mmol): MS (ESI): 344.19 (M + H) ⁺ .
[2619] c.) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} carbamic acid tert-butyl ester
[2620] To a solution of the compound of Example 267b (161 mg, 0.47 mmol) in dichloromethane (6 ml) was added triethylamine (0.065 ml, 0.47 mmol) and pyridine-2-sulfonyl chloride (83 mg, 0.47 mmol). . After stirring for 1 hour at room temperature, the mixture was washed with saturated NaHCO ₃ . The organic layer was dried, filtered, concentrated and purified on silica gel column to give the title compound (142 mg, 0.29 mmol): MS (ESI): 485.10 (M + H) ⁺ .
[2621] d.) (S) -2-Amino-hexanoic acid {3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2622] To a stirred solution of compound of Example 267c (142 mg, 0.29 mmol) in ethyl acetate was added HCl (4M in dioxane) (0.760 ml, 3.0 mmol). The reaction mixture was stirred at rt for 1 h, then the mixture was concentrated to give a white solid. The solid was azeotroduced on a rotary evaporator with toluene (twice) and treated with resin bound carbonate (1.47 mmol) 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) ⁺ .
[2623] e.) Quinoline-2-carboxylic acid {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} -amide
[2624] To a solution of the compound of Example 267d (104 mg, 0.27 mmol) in CH ₂ Cl ₂ , quinaldic acid (47 mg, 0.27 mmol), 1-hydroxybenzotriazole (7.4, 0.055 mmol) in DMF (2 ml), EDC-HCL (52 mg, 0.27 mmol) was added. After stirring at rt overnight, the mixture was diluted with ethyl acetate, 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) ⁺ .
[2625] f.) Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -pentyl} -amide
[2626] To a stirred solution of the compound of Example 267e (172 mg crude, 0.32 mmol) in 1 ml DMSO was added sulfur trioxide-pyridine complex (260 mg, 1.6 mmol) and triethylamine (0.88 ml, 3.2 mmol). After stirring for 2 hours at room temperature, 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: 40 mg: second: 43 mg): MS (ESI) 537.86 (M + H) ⁺ .
[2627] <Example 268>
[2628] Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (cyclohexyl-proprionyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[2629] The title compound was prepared according to the procedure of Examples 263a-d, except that the 3-methylbenzofuran-2-carboxylic acid of Example 263a was replaced with benzofuran-2-carboxylic acid: MS (ESI) 524 (M + H ⁺ ).
[2630] <Example 269>
[2631] Preparation of benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (4-methyl-pentanoyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[2632] Except for replacing the 3-methylbenzofuran-2-carboxylic acid of Example 263a with benzofuran-2-carboxylic acid and replacing the cyclohexyl propionic acid with 5-methyl pentanic acid, according to the process of Example 263a-d Compounds were prepared: MS (ESI) 484 (M + H ⁺ ).
[2633] <Example 270>
[2634] Preparation of quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide
[2635] The title compound was prepared following the procedure of Example 267a-f, except that N-Boc-norleucine was replaced with N-Bocphenylalanine in step 267a. The mixture was separated by HPLC to give two diastereomers as a solid (first eluent: 20.5 mg; second eluent: 27 mg): MS (ESI) 571.95 (M + H) ⁺ .
[2636] <Example 271>
[2637] Preparation of benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide
[2638] The title compound was prepared in a mixture of diastereomers according to the procedure of Example 193e-h, except that N1Boc-O-benzyl-L-serine was replaced in step 193e. Benzofuran-2-carboxylic acid in ethyl acetate (2 mL) {(S) -2-benzyloxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] To a solution of -ethyl} -amide (90 mg) was added 10% Pd / C (50 mg). The reaction was filtered and concentrated when about 50% of the starting material benzyl ether was hydrolyzed. The four-component mixture was purified by HPLC to give the first eluted diastereomer of the title compound (1 mg); And second eluting diastereomer of the title compound (0.3 mg): MS (ESI): 590.94 (M + H) ⁺ . Additionally benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl}- Two separate diastereomers of the amides were also isolated as described in Example 272 below.
[2639] Example 272
[2640] Preparation of benzofuran-2-carboxylic acid {(S) -2-hydroxy-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide
[2641] The title compound was obtained as discussed in Example 271 above. The mixture was purified by HPLC to give two diastereomers in solid form (first eluent: 1.6 mg; second eluent: 2.1 mg): MS (ESI): 500.9 (M + H) ⁺ .
[2642] <Example 273>
[2643] 5-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of Amides
[2644] Except for replacing benzofuran-2-carboxylic acid with 5-methoxybenzofuran-2-carboxylic acid in step 75c, the title compound was obtained following the procedure of Example 75c-d, which was separated by HPLC to give the first elution. The resulting diastereomer as a white solid (144.3 mg, 85.1%): MS (ESI) 563.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (16.9 mg, 10.0%) MS (ESI): 563.0 (M + H) ⁺ .
[2645] <Example 274>
[2646] 7-methoxybenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazol-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of Amides
[2647] Except for replacing benzofuran-2-carboxylic acid with 7-methoxybenzofuran-2-carboxylic acid in step 75c, the title compound was obtained according to the process of Example 75c-d, which was isolated by HPLC first. Eluting diastereomer as white solid (75 mg, 47%): MS (ESI) 563.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (57 mg, 35%): MS (ESI) 563.0 (M + H) ⁺ .
[2648] <Example 275>
[2649] 3-Methylbenzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} amide Manufacture
[2650] Except for replacing benzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid in step 75c, the title compound was obtained following the procedure of Example 75c-d, which was purified first by HPLC Eluting diastereomer as white solid (69.5 mg, 42%): MS (ESI) 547.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (65 mg, 40%): MS (ESI) 547.2 (M + H) ⁺ .
[2651] <Example 276>
[2652] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} Preparation of Amides
[2653] Except for replacing benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid in step 75c, the title compound was obtained following the procedure of Example 75c-d, which was purified first by HPLC. Eluting diastereomer as white solid (79.5 mg, 48%): MS (ESI) 549.3 (M + H) ⁺ ; And second eluting diastereomer as white solid (50.5 mg, 31%): MS (ESI) 549.2 (M + H) ⁺ .
[2654] <Example 277>
[2655] 1-Methyl-1H-indole-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } Production of Amide
[2656] Except for replacing benzofuran-2-carboxylic acid with 1-methylindole-2-carboxylic acid in step 75c, the title compound was obtained following the procedure of Example 75c-d, which was purified by HPLC to elute first. Diastereomer as white solid (75 mg, 47%): MS (ESI) 563.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (57 mg, 35%): MS (ESI) 563.0 (M + H) ⁺ .
[2657] <Example 278>
[2658] Preparation of Quinoxaline-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (thiazole-2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} amide
[2659] Except for replacing benzofuran-2-carboxylic acid with quinoxaline-2-carboxylic acid in step 75c, the title compound was obtained following the procedure of Example 75c-d, which was purified by HPLC to give the first eluted diastereomer. Isomer as a white solid (126 mg, 77%): MS (ESI) 545.2 (M + H) ⁺ ; And second eluting diastereomer as white solid (25 mg, 15%): MS (ESI) 545.2 (M + H) ⁺ .
[2660] <Example 279>
[2661] Of quinoline-2-carboxylic acid {[(S) -1- [1- (4-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2662] The title compound was prepared according to the process of Example 75 except for replacing benzenesulfonyl chloride with 4-fluorophenylsulfonyl chloride and replacing benzofuran-2-carboxylic acid with 2-quinoline carboxylic acid. The residue was purified by HPLC. Firstly eluting diastereomers;
[2663]
[2664] And second eluting diastereomer: MS (M + H ⁺ ): 555.4.
[2665] <Example 280>
[2666] Benzofuran-2-carboxylic acid {(S) -1-[-(3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide Manufacture
[2667] a.) allyl-pent-4-enyl-carbamic acid benzyl ester
[2668] To the suspension of NaH (1.83 g of 90% NaH, 76.33 mmol) in DMF was added dropwise allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol). The mixture was stirred at rt for about 10 min and 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction was heated to 40 ° C. for about 4 hours and the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2 ×), brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (10% ethyl acetate: hexanes) to give 10.3 g of the title compound as an oil: MS (ES) 260 (M + H ⁺ ).
[2669] b.) 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester
[2670] To a solution of compound (50 g) of Example 280a in dichloromethane is added bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (5.0 g). The reaction was heated to reflux until confirmed by TLC analysis to complete. The reaction was concentrated in vacuo. The residue was column chromatographed (50% dichloromethane: hexanes) to afford 35 g of the title compound: MS (ES) 232 (M + H ⁺ ).
[2671] c.) 8-oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid benzyl ester
[2672] To a solution of the compound of Example 280b (35 g, 1.5 mol) in CH ₂ Cl ₂ was added M-CPBA (78 g, 0.45 mol). The mixture was stirred overnight at room temperature, which was filtered to remove solids. The filtrate was washed with saturated water and saturated NaHCO ₃ (several times). The organic layer was dried (MgSO ₄ ), filtered and concentrated to afford 35 g of the title compound, which was pure enough to carry out the following steps: MS (ES) 248 (M + H ⁺ ), 270 (M + Na ⁺ ).
[2673] d.) 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[2674] To a solution of epoxide (2.0 g, 8.1 mmol) from Example 280c in methanol: water (8: 1 solution) was added NH ₄ Cl (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). Added. The reaction was heated to 40 ° C. until TLC analysis showed complete consumption of starting epoxide. Most 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, brine, dried (MgSO ₄ ) and filtered and concentrated. The residue was column chromatographed (20% ethyl acetate: hexanes) to give 1.3 g of the title compound: MS (ES) 291 (M + H ⁺ ); And 0.14 g of trans-4-hydroxy-3-azido-hexahydro-1H-azepine.
[2675] e.) 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[2676] To a solution of azido alcohol (1.1 g, 3.79 mmol) of Example 280d in methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 mmoL). The reaction was stirred until TLC analysis showed complete consumption of starting material and the reaction was concentrated in vacuo. The residue was column chromatographed (20% methanol: dichloromethane) to give 0.72 g of the title compound: MS (ES) 265 (M + H ⁺ ).
[2677] f.) 4-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -3-hydroxy-azane-1-carboxylic acid benzyl ester
[2678] To a solution of amino alcohol (720 mg, 2.72 mmol) of Example 280e in CH ₂ Cl ₂ was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was kept at room temperature until TLC analysis showed that starting material was consumed completely. The reaction was diluted with ethyl acetate, washed with 1N HCl, saturated CO ₃ , water, brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatographed (3% methanol: dichloromethane) to give 1.0 g of the title compound: MS (ES) 478 (M + H ⁺ ).
[2679] g.) [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert butyl ester
[2680] A hydrogen balloon was attached to a solution of compound (1.0 g) and 10% Pd / C (catalyst amount) of Example 280f in ethyl acetate: methanol (2: 1 solution). The reaction was stirred until TLC analysis showed that starting material was consumed completely. The reaction was filtered to remove the catalyst and the filtrate was concentrated to give 0.82 g of the title compound: MS (ES) 344 (M + H ⁺ ).
[2681] h.) (S) -2-Amino-4-methyl-pentanoic acid [1- (3-fluoro-benzenesulfonyl) -3-hydroxy-azpan-4-yl] -amide
[2682] To a solution of Example 280 g of compound (0.2 g) in dichloroethane (20 mL) was added p-NMM (0.32 g) and 3-fluorobenzenesulfonyl chloride (0.11 g). The reaction was stirred until MS analysis showed that the starting material was consumed completely. Xerulu was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL) was added. The reaction was kept at room temperature until the starting material was consumed completely and it was concentrated. The residue was dissolved in methanol and p-carbonate resin was added. The mixture was shaken at rt for 4 h, then filtered and concentrated to give 0.64 g of the title compound.
[2683] i.) Benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl }-amides
[2684] To a solution of compound of Example 280h (0.15 g) in CH ₂ Cl ₂ was added benzofuran-2-carboxylic acid (0.56 mmol), HOBt (0.09 mg), and p-EDC (0.75 mg). The reaction was stirred overnight, trisamine (0.50 g) was added and stirred for another 1.5 hours. The reaction was filtered and concentrated to give the title compound.
[2685] j.) Benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides
[2686] To a solution of the compound of Example 280i (0.3 mmol) in CH ₂ Cl ₂ was added des-martin periodinan (0.25 g). The reaction was stirred until complete by MS analysis. Finishing and HPLC chromatography to give diastereomer 1: MS (ES) 543.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 543.2 (M + H) ⁺ .
[2687] <Example 281>
[2688] (S) -4-Methyl-2- (3-piperidin-1-yl-propanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4- Preparation of Il] -amides
[2689] Except for replacing 3-fluorobenzenesulfonyl chloride with 2-pyridinesulfonyl chloride and benzofuran-2-carboxylic acid with 1-piperidinepropionoic acid, the general procedure of Example 280h-j The title compound was prepared according to the following: MS (ES) 521.9 (M + H) ⁺ .
[2690] <Example 282>
[2691] Of benzofuran-2-carboxylic acid {(S) -1-[-(4-ethyl-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide Produce
[2692] The title compound was prepared following the general procedure of Example 280h-j, except that 3-fluorobenzenesulfonyl chloride was replaced with 4-ethylbenzenesulfonyl chloride. Diastereoisomers to separate diastereomers 1: MS (ES) 554.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 554.4 (M + H) ⁺ .
[2693] <Example 283>
[2694] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1- (1-oxy-pyridin-2-yl) -Methanoyl] -Azepan-4-ylcarbamoyl} -butyl) -amide
[2695] a.) 4-((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid benzyl ester
[2696] To a solution of compound of Example 280f (7.32 g) in methanol was added 4M HCl in dioxane (38 mL). The reaction was stirred until complete and concentrated to give 6.9 g of the title compound as a white solid.
[2697] b.) 3-hydroxy-4-[(S) -4-methyl-2-({1- [5- (3-trifluoromethyl-phenyl) -furan-2-yl] -methanoyl}- Amino) -pentanoylamino] azepan-1-carboxylic acid benzyl ester
[2698] To a solution of compound of Example 283a (1.2 g) in dichloromethane, TEA (0.93 mL), EDC (0.56 g), HOBt (0.36 g) and 5- [3- (trifluoromethyl) phenyl] -2-fu Lonic acid (0.68 g) was added. The reaction was stirred at room temperature until confirmed by TLC analysis. Finished and column chromatography gave 1.35 g of the title compound: MS (ES) 616 (M + H) ⁺ .
[2699] c.) 5- [3- (trifluoromethyl) phenyl] -furan-2-carboxylic acid [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl ]-amides
[2700] To a solution of compound of Example 283b (1.3 g) in ethyl acetate: methanol (8: 1 mixture, 20 mL) was added 10% Pd / C. The mixture was stirred under a balloon of hydrogen gas until it was confirmed complete by TLC analysis. The reaction was filtered and concentrated to give 0.96 g of the title compound which was used directly in the next reaction without further purification.
[2701] d.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [1- (1-oxy-pyridine-) 2-yl) -methanoyl] -azepane-4-ylcarbamoyl} -butyl) -amide
[2702] To a solution of compound of Example 283c (0.3 g) in dichloromethane was added TEA (0.22 mL), EDC (0.13 g), HOBt (0.8 g) and picolinic acid N-oxide (0.09 g). The reaction was stirred at room temperature until confirmed by TLC analysis. Finished and column chromatography gave 0.16 g of the title compound: MS (ES) 603 (M + H) ⁺ .
[2703] e.) 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1- (1-oxy-pyridine-2) -Yl) -methanoyl] -azepane-4-ylcarbamoyl} -butyl) -amide
[2704] To a solution of the compound of Example 283d (0.15 g) in DMSO (1.5 mL) was added TEA (0.37 mL) and pyridine sulfur trioxide complex (0.21 g). The reaction was stirred until complete by LCMS. Finished and column chromatography (10% methanol: dichloromethane) gave 0.12 g of the title compound: MS (ES) 601 (M + H) ⁺ .
[2705] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2706] <Example 284>
[2707] Benzo [1,3] -dioxol-5-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-oxy-pyridin-2-yl) -methanoyl] -azepane- Preparation of 4-ylcarbamoyl} -butyl) -amide
[2708] The title compound was prepared following the general procedure of Example 283b-e, except that 5- [3- (trifluoromethyl) phenyl] -2-furonic acid was replaced by piperonylic acid: MS (ES) 511 (M + H) ⁺ .
[2709] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2710] <Example 285>
[2711] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azpan-4-ylcarba Moyl] -3-methyl-butyl} -amide
[2712] Prepared according to the general procedure of Example 283b-e, except the picolinic acid N-oxide title compound was replaced with 3-cyclohexylpropionic acid: MS (ES) 618 (M + H) ⁺ .
[2713] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2714] Example 286
[2715] Benzo [1,3] -dioxol-5-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Preparation of Methyl-Butyl} -amide
[2716] Example 283b-, except that picolinic acid N-oxide was replaced with 3-cyclohexylpropionic acid and 5- [3- (trifluoromethyl) phenyl] -2-furonic acid was replaced by piperonylic acid The title compound was prepared according to the general procedure of e: MS (ES) 528 (M + H) ⁺ .
[2717] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2718] <Example 287>
[2719] 5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepane-4-ylcarbamoyl] Preparation of 3-Methyl-butyl} -amide
[2720] The title compound was prepared following the general procedure of Example 283b-e, except the picolinic acid N-oxide was replaced with 4-methyl-pentanoic acid: MS (ES) 578 (M + H) ⁺ .
[2721] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2722] <Example 288>
[2723] Benzo [1,3] -dioxol-5-carboxylic acid {(S) -1- [1- (4-methyl pentanoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2724] Example 283b, except that picolinic acid N-oxide was replaced by 4-methyl-pentanoic acid and 5- [3- (trifluoromethyl) phenyl] -2-furonic acid was replaced by piperonylic acid The title compound was prepared following the general procedure of -e: MS (ES) 488 (M + H) ⁺ .
[2725] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2726] <Example 289>
[2727] Of benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide Produce
[2728] The title compound was prepared following the general procedure of Example 280h-j, except that 3-fluorosulfonyl chloride was replaced with propanesulfonyl chloride.
[2729] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 491.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 491.2 (M + H) ⁺ .
[2730] <Example 290>
[2731] Preparation of benzofuran-2-carboxylic acid [(S) -1- [3-oxo-1- (ethanesulfonyl-azpan-4-ylcarbamoyl) -3-methyl-1-butyl] -amide
[2732] The title compound was prepared following the general procedure of Example 280h-j, except that 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride.
[2733] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 477.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 477.4 (M + H) ⁺ .
[2734] <Example 291>
[2735] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} -amide
[2736] a.) {(S) -1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[2737] Preparation of 2-pyridinesulfonylchloride-N-oxide: Chlorine gas in a 0 ° C. solution of 2-mercaptopyridine-N-oxide (2.23 g, 17.55 mmol) in 9M HCl (33 mL) for about 90 minutes. Bubbling. Dissolved chlorine was removed at 0 ° C under vacuum.
[2738] Example 280 g of [(S) -1- (3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] in CH ₂ Cl ₂ (100 mL) and saturated NaHCO ₃ (400 mL)] To a solution of carbamic acid tert butyl ester (2.5 g, 7.28 mmol) was added dropwise a solution of 2-pyridinesulfonylchloride-N-oxide (27 mL, 102 mg / mL). Additional saturated NaHCO ₃ was added to maintain the pH at about 8-9. After the addition of sulfonyl chloride was complete, the reaction was stirred for an additional hour, the organic layer was removed and washed with brine. The organic layer was evaporated and the residue was chromatographed (5% methanol: dichloromethane) to give 2.5 g of the title compound: MS (ES) 500 (M + H ⁺ ).
[2739] b.) (S) -2-Amino-4-methyl-pentanoic acid- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-yl] -amide
[2740] {(S) -1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] of Example 291a in methanol (20 mL) -3- To a solution of methyl-butyl} -carbamic acid tert-butyl ester (2.0 g) was added 4 M HCl in dioxane (20 mL). The reaction was stirred at rt for 1.5 h and concentrated to give 1.8 g of the title compound: MS (ES) 400 (M + H ⁺ ).
[2741] c.) 5-fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide
[2742] To a solution of compound of Example 291b (0.30 g) in CH ₂ Cl ₂ , 5-fluoro-benzofuran-2-carboxylic acid (0.11 g), EDC (0.13 g), HOBt (0.086 g), and TEA (0.22 mL) ) Was added. The reaction was stirred until complete by LCMS, diluted with ethyl acetate, washed with water, saturated 1N HCl, brine, dried (MgSO ₄ ), filtered and concentrated. The residue was column chromatography (10% methanol: dichloromethane) to give 0.27 g of the title compound: MS (ES) 563 (M + H) ⁺ .
[2743] d.) 5-fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide
[2744] To a solution of the compound of Example 291c (0.19 g) in DMSO (1.5 mL) was added sulfur trioxide pyridine complex (0.26 g). The reaction was stirred until complete by LCMS, diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried, filtered and concentrated. The residue was column chromatographed to give 0.15 g of the title compound as a mixture of diastereomers: MS (ES) 561 (M + H) ⁺ .
[2745] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2746] <Example 292>
[2747] 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide
[2748] The title compound was diastereomer according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 5-fluoro-3-methyl benzofuran-2-carboxylic acid. Obtained as a mixture of: MS (ES) 575 (M + H) ⁺ .
[2749] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2750] <Example 293>
[2751] 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide
[2752] The title compound was diastereomer according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 6-fluoro-3-methyl benzofuran-2-carboxylic acid. Obtained as a mixture of: MS (ES) 575 (M + H) ⁺ .
[2753] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2754] <Example 294>
[2755] 3-Methyl-benzofuran-2-carboxylic acid {(R) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} -amide
[2756] N-Boc-1-leucine is replaced by N-Boc-D-leucine, 3-fluorobenzenesulfonyl chloride is substituted by 2-pyridinesulfonylchloride N-oxide, and benzofuran-2-carboxylic acid is 3-methyl- The title compound was prepared following the general procedure of Example 280f-i, except that it was replaced with benzofuran-2-carboxylic acid: MS (ES) 556 (M + H) ⁺ .
[2757] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2758] <Example 295>
[2759] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -3-methyl-1-[-3-oxo-1- (1-oxy-pyridine-2-sulfonyl)- Preparation of Azepan-4-ylcarbamoyl] -butyl} -amide
[2760] The title compound was prepared according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 3-methylfuro [3,2-b] pyridine-2-carboxylic acid. Obtained as a mixture of diastereomers: MS (ES) 558 (M + H) ⁺ .
[2761] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2762] <Example 296>
[2763] 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[2764] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 5-methoxy-benzofuran-2-carboxylic acid.
[2765] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 574.5 (M + H) ⁺ ; And diastereomer 2: 574.5 (M + H) ⁺ .
[2766] <Example 297>
[2767] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } -Preparation of Amide
[2768] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid.
[2769] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 557.4 (M + H) ⁺ ; And diastereomer 2: 557.4 (M + H) ⁺ .
[2770] <Example 298>
[2771] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2772] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid.
[2773] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 559.4 (M + H) ⁺ ; And diastereomer 2: 559.4 (M + H) ⁺ .
[2774] <Example 299>
[2775] 3-Methyl-furan-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} Preparation of -amides
[2776] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 3-methylfuran-2-carboxylic acid.
[2777] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 507.2 (M + H) ⁺ ; And diastereomer 2: 507.4 (M + H) ⁺ .
[2778] <Example 300>
[2779] Preparation of quinoline-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[2780] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with quinoline2-carboxylic acid.
[2781] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 554.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 545.2 (M + H) ⁺ .
[2782] <Example 301>
[2783] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl]- Preparation of 3-methyl-butyl} -amide
[2784] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with thieno [3,2-b] thiophene-2-carboxylic acid. .
[2785] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 565.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 565.2 (M + H) ⁺ .
[2786] Example 302
[2787] Of quinoxaline-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2788] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid.
[2789] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 555.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 555.4 (M + H) ⁺ .
[2790] <Example 303>
[2791] Of thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[2792] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with thiophene-2-carboxylic acid.
[2793] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 509.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 509.2 (M + H) ⁺ .
[2794] <Example 304>
[2795] 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl } -Preparation of Amide
[2796] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 5-methylthiophene-2-carboxylic acid.
[2797] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 523.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 523.4 (M + H) ⁺ .
[2798] <Example 305>
[2799] Preparation of 5-methoxy-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2800] General procedure of Example 280h-j, except for replacing benzofuran-2-carboxylic acid with 5-methoxy-benzofuran-2-carboxylic acid and replacing 3-fluorobenzenesulfonyl chloride with ethanesulfonyl chloride According to the title compound was obtained as a mixture of diastereomers.
[2801] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 507.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 507.4 (M + H) ⁺ .
[2802] Example 306
[2803] Preparation of 3-Methyl-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2804] Following the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. The title compound was obtained as a mixture of diastereomers.
[2805] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 491.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 4912 (M + H) ⁺ .
[2806] <Example 307>
[2807] Preparation of benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2808] The general procedure of Example 280h-j is followed, except that benzofuran-2-carboxylic acid is replaced with benzo [b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced with ethanesulfonyl chloride. The title compound was thus obtained as a mixture of diastereomers.
[2809] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 493.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 493.4 (M + H) ⁺ .
[2810] Example 308
[2811] Preparation of 3-methyl-furan-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2812] Subject to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 3-methylfuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. The compound was obtained as a mixture of diastereomers.
[2813] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 441.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 441.2 (M + H) ⁺ .
[2814] <Example 309>
[2815] Preparation of Quinoline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2816] The title compound was partially followed according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with quinoline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. Obtained as a mixture of stereoisomers.
[2817] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 488.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 488. 2 (M + H) ⁺ .
[2818] <Example 310>
[2819] Thieno [3,2-b] thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] amide Manufacture
[2820] Example 280h-, except that benzofuran-2-carboxylic acid was replaced with thieno [3,2-b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. The title compound was obtained as a mixture of diastereomers according to the general procedure of j.
[2821] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 499.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 499.4 (M + H) ⁺ .
[2822] Example 311
[2823] Preparation of Quinoxaline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2824] The title compound was prepared according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. Obtained as a mixture of diastereomers.
[2825] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 489.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 489.2 (M + H) ⁺ .
[2826] Example 312
[2827] Preparation of Thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2828] The title compound was prepared according to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. Obtained as a mixture of diastereomers.
[2829] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 443.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 443.2 (M + H) ⁺ .
[2830] <Example 313>
[2831] Preparation of 5-Methyl-thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[2832] Following the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 5-methylthiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with ethanesulfonyl chloride. The title compound was obtained as a mixture of diastereomers.
[2833] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 457.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 457.4 (M + H) ⁺ .
[2834] <Example 314>
[2835] 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Preparation of Butyl} -amide
[2836] Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 5-methoxy-benzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 1-propanesulfonyl chloride. According to the general procedure, the title compound was obtained as a mixture of diastereomers.
[2837] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 521.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 521.2 (M + H) ⁺ .
[2838] <Example 315>
[2839] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl } Preparation of Amide
[2840] General procedure of Example 280h-j, except for replacing benzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid and replacing 3-fluorobenzenesulfonyl chloride with 1-propanesulfonyl chloride According to the title compound was obtained as a mixture of diastereomers.
[2841] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 505.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 505.2 (M + H) ⁺ .
[2842] Example 316
[2843] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl } Preparation of Amide
[2844] General of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 1-propanesulfonyl chloride. The process gave the title compound as a mixture of diastereomers.
[2845] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 507.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 507.4 (M + H) ⁺ .
[2846] <Example 317>
[2847] 3-Methyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} Preparation of -amides
[2848] The general procedure of Example 280h-j is followed, except that benzofuran-2-carboxylic acid is replaced with 3-methylfuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride is replaced with 1-propanesulfonyl chloride. The title compound was thus obtained as a mixture of diastereomers.
[2849] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 455.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 455.4 (M + H) ⁺ .
[2850] <Example 318>
[2851] 2,5-dimethyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Preparation of Butyl} -amide
[2852] Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with 2,5-dimethyl-benzofuran-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 1-propanesulfonyl chloride. According to the general procedure of the title compound was obtained as a mixture of diastereomers.
[2853] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 469.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 469.2 (M + H) ⁺ .
[2854] <Example 319>
[2855] Preparation of quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide
[2856] The title compound was followed the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced by quinoline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced by 1-propanesulfonyl chloride Was obtained as a mixture of diastereomers.
[2857] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 565.2 (M + H) ⁺ ; And diastereomer 2MS (ES) 565.2 (M + H) ⁺ .
[2858] <Example 320>
[2859] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3- Preparation of Methyl-1-butyl} -amide
[2860] Example except that benzofuran-2-carboxylic acid was replaced with thieno [3,2-b] thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 1-propanesulfonyl chloride The title compound was obtained as a mixture of diastereomers according to the general procedure of 280h-j.
[2861] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 513.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 513.2 (M + H) ⁺ .
[2862] <Example 321>
[2863] Of quinoxaline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide Produce
[2864] Subject to the general process of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 1-propanesulfonyl chloride. The compound was obtained as a mixture of diastereomers.
[2865] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 503.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 503.4 (M + H) ⁺ .
[2866] <Example 322>
[2867] Of thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide Produce
[2868] Subject to the general procedure of Example 280h-j, except that benzofuran-2-carboxylic acid was replaced with thiophene-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 1-propanesulfonyl chloride. The compound was obtained as a mixture of diastereomers.
[2869] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 457.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 457.4 (M + H) ⁺ .
[2870] <Example 323>
[2871] 5-Methyl-thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl } -Preparation of Amide
[2872] General procedure of Example 280h-j, except for replacing benzofuran-2-carboxylic acid with 5-methylthiophene-2-carboxylic acid and replacing 3-fluorobenzenesulfonyl chloride with 1-propanesulfonyl chloride According to the title compound was obtained as a mixture of diastereomers.
[2873] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 471.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 471.4 (M + H) ⁺ .
[2874] <Example 324>
[2875] 5-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] butyl} -amide
[2876] The title compound was diastereous according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 5-methoxy-3-methyl-benzofuran-2-carboxylic acid. Obtained as a mixture of isomers: MS (ES) 587 (M + H) ⁺ .
[2877] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 565.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 565.2 (M + H) ⁺ .
[2878] <Example 325>
[2879] 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} -amide
[2880] A mixture of diastereomers of the title compound according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 3,5-dimethyl-benzofuran-2-carboxylic acid Obtained as: MS (ES) 571 (M + H) ⁺ .
[2881] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2882] <Example 326>
[2883] 3-Ethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] Preparation of -Butyl} -amide
[2884] The title compound was obtained in a mixture of diastereomers according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 3-ethylbenzofuran-2-carboxylic acid: MS (ES) 571 (M + H) ⁺ .
[2885] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2886] <Example 327>
[2887] 4-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] butyl} -amide
[2888] The diastereomer of the title compound was followed in the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 4-methoxy-3-methyl-benzofuran-2-carboxylic acid. Obtained as a mixture of isomers: MS (ES) 587 (M + H) ⁺ .
[2889] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2890] <Example 328>
[2891] 1-Methyl-naphtho [2,1-b] -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl)- Preparation of Azepan-4-ylcarbamoyl] -butyl} -amide
[2892] The title compound according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with 1-methylnaphtho [2,1-b] -furan-2-carboxylic acid Was obtained as a mixture of diastereomers: MS (ES) 607 (M + H) ⁺ .
[2893] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2894] Example 329
[2895] 6-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] butyl} -amide
[2896] The diastereomer of the title compound according to the general procedure of Example 291c-d, except for replacing 5-fluoro-benzofuran-2-carboxylic acid with 6-methoxy-3-methyl-benzofuran-2-carboxylic acid Obtained as a mixture of isomers: MS (ES) 587 (M + H) ⁺ .
[2897] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2898] <Example 330>
[2899] 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } -Preparation of Amide
[2900] a.) 4- (2-tert-butoxycarbonylamino-2,4-dimethyl-pentanoylamino) -3-hydroxyazane-1-carboxylic acid benzyl ester
[2901] In a solution of N-[(1,1-dimethylethoxy) carbonyl] -2-methyl- (d, l) -leucine (3.0 g) in methylene chloride, EDC (2.34 g), HOBt (1.65 g), Et ₃ N (1.7 ml) and compound of Example 280e (3.23 g) were added. After stirring at room temperature overnight, the mixture was washed with 0.1 N HCl, saturated NaHCO ₃ , H ₂ O, brine. The organic layer was concentrated and the residue was purified by flash column chromatography (eluted with CH ₂ Cl ₂ : CH ₃ OH (95: 5)) to afford the title compound as a white solid (4.0 g, 66.6%). MS: 492.4 (M + H) ⁺
[2902] b.) [1- (3-hydroxy-azpan-4-ylcarbamoyl) -1,3-dimethyl-butyl] -carbamic acid tert-butyl ester
[2903] To a solution of the compound of Example 330 (a) (3.04 g, 8.00 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (1.5 g). After stirring for 16 hours at room temperature under hydrogen atmosphere, the mixture was filtered through celite. The filtrate was concentrated to give the title compound as a yellow oil (1.97 g, 100%). MS (ESI): 358.4 (M + H) ⁺ .
[2904] c.) {1- [3-hydroxy-1- (1-hydroxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -1,3-dimethyl-butyl} -carbamic acid tert -Butyl ester
[2905] 2-mercaptan N-oxide (1.25 g) was dissolved in concentrated HCl (5.5 ml). After cooling to 0 ° C, water (3 ml) was added. Cl ₂ gas was bubbled through this solution for 1.5 hours. After the aqueous solution was extracted with cold CH ₂ Cl ₂ , the combined organic layers were washed with saturated NaHCO ₃ , brine. To a solution of formula (1.20 g) and Et ₃ N (1.3 ml) of Example 330b in DCE (10 ml) was added the sulfonyl chloride just prepared at 0 ° C. After stirring for 1 hour, the reaction mixture is washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography (eluted with CH ₂ Cl ₂ ). The filtrate was concentrated to give the title compound as a white solid (1.2 g, 70%). MS: 515.4 (M + H) ⁺ .
[2906] d.) 2-Amino-2, 4-dimethyl-pentanoic acid [3-hydroxy-l- (hydroxy-pyridine-2-sulfonyl) azepan-4-yl] -amide
[2907] To a stirred solution of compound of Example 330c (1.Og, 2.04 mmol) in methanol (10 ml) was added HCl (4M in dioxane) (10 ml). After stirring at room temperature for 3 hours, the solution was concentrated to give a white solid. To a solution of a white solid (0.81 g, 1.53 mmol, 75%) in methanol (30 ml) was added P-CO ₃ (2.9 g, 2.63 mmol / g). After shaking for 2 hours, the solution was filtered and concentrated to give the title compound as a white solid (0.57 g, 1.45 mmol, 95%). MS: 415.4 (M + H) ⁺ .
[2908] e.) 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} -amide
[2909] _{CH 2 Cl 2 (20 mL)} 3- methyl-benzofuran-2-carboxylic acid (0.109 g) of a solution of (0.150 g, 0.448 mmol) of Example _{330d CH 2 Cl 2 (10 mL} ), 1- hydroxy Roxybenzotriazole (0.106 g, 0.762 mmol), and P-EDC (0.85 g, 1 mmol / g) were added. After shaking overnight at room temperature, the solution was treated with tisamine (0.589 g, 3.75 mmol / g). After shaking for 2 more hours, the solution was filtered and concentrated to give the title compound as a white solid (166.7 mg, 70%). MS (ESI): 573.2 (M + H) ⁺ .
[2910] f.) 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-oxo-1- (oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl]- Butyl} -amide
[2911] To a stirred solution of compound of Example 330e (140.7 mg, 0.245 mmol) in DMSO (2 mL) was added Py-SO ₃ (155.7 mg, 0.98 mmol) and Et ₃ N (0.27 ml, 1.96 mmol). After stirring for 2 hours at room temperature, the reaction was quenched by addition of saturated NaHCO ₃ and ethyl acetate. The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash column chromatography (eluted with CH ₂ Cl ₂ : CH ₃ 0H (95: 5)) to afford the title compound as a white solid (69.9 mg, 50.8%). MS (ESI): 571.2 (M + H) ⁺ .
[2912] <Example 331>
[2913] Preparation of benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide
[2914] a.) [(S) -1- (3-hydroxy-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[2915] To a solution of Example 280 g of Compound (1.0 g) in CH ₂ Cl ₂ was added α-quinoline carbaldehyde (0.68 g) and NaBH (OAc) ₃ (1.2 g). Finished and column chromatography (6% methanol: dichloromethane) gave 1.4 g of the title compound: MS (ES) 485 (M + H) ⁺ .
[2916] b.) (S) -2-Amino-4-methyl-pentanoic acid (3-hydroxy-1-quinolin-2-methyl-azpan-4-yl) amide
[2917] To a solution of the compound of Example 331a (1.4 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred until complete and the reaction was concentrated to give 1.3 g of the title compound: MS (ES) 385 (M + H) ⁺ .
[2918] c.) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-hydroxy-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide
[2919] The title compound was prepared according to the general procedure of Example 291c, except that the compound of Example 331b was replaced with 5-fluoro-benzofuran-2-carboxylic acid replaced with benzofuran-2-carboxylic acid. ES) 545 (M + H) ⁺ .
[2920] d.) Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide
[2921] The title compound was prepared following the general procedure of Example 291d, except that the compound of Example 331c was replaced: MS (ES) 543 (M + H) ⁺ .
[2922] <Example 332>
[2923] 3-Methyl-benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide Produce
[2924] The title compound was prepared according to the procedure of Example 331c-d, except that benzofuran-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid: MS (ES) 541 (M + H) ⁺ .
[2925] <Example 333>
[2926] Of benzo [b] thiophene-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide Produce
[2927] The title compound was prepared following the procedure of Example 331c-d, except that the benzofuran-2-carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid: MS (ES) 541 (M + H) ⁺ .
[2928] <Example 334>
[2929] Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Preparation of Butyl) -amide
[2930] a.) ((S) -1- {3-hydroxy-1- [1- (toluene-2-sulfonylamino) -methanoyl] -azpan-4-ylcarbamoyl} -3-methyl-butyl ) -Carbamic acid tert-butyl ester
[2931] To a solution of Example 280 g (1.0 g) of the compound in CH ₂ Cl ₂ was added o-toluenesulfonyl isocyanate (0.68 g). The reaction was stirred until it was observed that the starting material was consumed completely. Finished and column chromatography (6% methanol: dichloromethane) gave 1.28 g of the title compound: MS (ES) 541 (M + H) ⁺ .
[2932] b.) (S) -2-Amino-4-methyl-pentanoic acid {3-hydroxy-1- [1- (toluene-2-sulfonylamino) -methanoyl] -azpan-4-yl}- amides
[2933] Except for the replacement of the compound of Example 334a, the title compound was prepared following the procedure of Example 283a: MS (ES) 441 (M + H) ⁺ .
[2934] c.) Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-hydroxy-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepan-4-yl Carbamoyl} -butyl) -amide
[2935] Except for the replacement of the compound of Example 334b, the title compound was prepared following the process of Example 280i: MS (ES) 585 (M + H) ⁺ .
[2936] d.) Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4-ylcarba Moyl} -butyl) -amide
[2937] Except for the replacement of the compound of Example 334c, the title compound was prepared following the process of Example 291d: MS (ES) 583 (M + H) ⁺ .
[2938] <Example 335>
[2939] 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azpan-4-yl Preparation of Carbamoyl} -Butyl) -amide
[2940] The title compound was prepared according to the process of Example 334c-d, except that benzofuran-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid: MS (ES) 597 (M + H) ⁺ .
[2941] <Example 336>
[2942] Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4-yl Preparation of Carbamoyl} -Butyl) -amide
[2943] The title compound was prepared following the procedure of Example 334c-d, except that the benzofuran-2-carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid: MS (ES) 599 (M + H) ⁺ .
[2944] <Example 337>
[2945] Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl} -butyl Preparation of Amide-amide
[2946] The title compound was prepared following the process of Examples 334a-d, except that o-toluenesulfonyl isocyanate was replaced with 2-chlorobenzenesulfonyl isocyanate: MS (ES) 603 (M + H) ⁺ .
[2947] <Example 338>
[2948] 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino)-methanoyl] -azepane-4-ylcarba Preparation of Moyl} -butyl) -amide
[2949] Except for replacing o-toluenesulfonyl isocyanate with 2-chlorobenzenesulfonyl isocyanate and benzofuran-2-carboxylic acid with 3-methylbenzofuran-2-carboxylic acid, according to the process of Examples 334a-d The title compound was prepared: MS (ES) 617 (M + H) ⁺ .
[2950] Example 339
[2951] Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino)-methanoyl] -azepane-4-ylcarba Preparation of Moyl} -butyl) -amide
[2952] Except for replacing o-toluenesulfonyl isocyanate with 2-chlorobenzene sulfonyl isocyanate and benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid, the process of Example 334a-d The title compound was prepared according to: MS (ES) 619 (M + H) ⁺ .
[2953] Example 340
[2954] Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Preparation of Butyl) -amide
[2955] The title compound was prepared according to the procedure of Examples 334a-d, except that o-toluenesulfonyl isocyanate was replaced with 4-fluorobenzene sulfonyl isocyanate: MS (ES) 587 (M + H) ⁺ .
[2956] Example 341
[2957] 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino)-methanoyl] -azpan-4-yl Preparation of Carbamoyl} -Butyl) -amide
[2958] Example 334-, except that benzofuran-2-carboxylic acid is replaced with 3-methyl-benzofuran-2-carboxylic acid, except that o-toluenesulfonyl isocyanate is replaced with 4-fluorobenzene sulfonyl isocyanate. The title compound was prepared according to the process of d: MS (ES) 601 (M + H) ⁺ .
[2959] <Example 342>
[2960] Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino)-methanoyl] -azepane-4-yl Preparation of Carbamoyl} -Butyl) -amide
[2961] The process of Examples 334a-d, except that o-toluenesulfonyl isocyanate is replaced with 4-fluorobenzene sulfonyl isocyanate and benzofuran-2-carboxylic acid is replaced with benzo [b] thiophene-2-carboxylic acid. The title compound was prepared according to: MS (ES) 603 (M + H) ⁺ .
[2962] Example 343
[2963] Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Preparation of Butyl) -amide
[2964] The title compound was prepared following the process of Examples 334a-d, except that o-toluenesulfonyl isocyanate was replaced with p-toluenesulfonyl isocyanate: MS (ES) 583 (M + H) ⁺ .
[2965] <Example 344>
[2966] 3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-yl Preparation of Carbamoyl} butyl) -amide
[2967] Except for replacing o-toluenesulfonyl isocyanate with p-toluenesulfonyl isocyanate and benzofuran-2-carboxylic acid with 3-methyl-benzofuran-2-carboxylic acid, according to the procedure of Example 334a-d The title compound was prepared: MS (ES) 597 (M + H) ⁺ .
[2968] <Example 345>
[2969] Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-yl Preparation of Carbamoyl} -Butyl) -amide
[2970] Except for replacing o-toluenesulfonyl isocyanate with p-toluenesulfonyl isocyanate and benzofuran-2-carboxylic acid with benzo [b] thiophene-2-carboxylic acid, according to the procedure of Example 334a-d The title compound was prepared: MS (ES) 597 (M + H) ⁺ .
[2971] <Example 346>
[2972] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl] -butyl}- Preparation of Amides
[2973] The title compound was prepared according to the general procedure of Examples 331a-d, except that 6-methylpyridine-2-aldehyde was substituted for α-quinoline carvalaldehyde: MS (ES) 491 (M + H) ⁺ .
[2974] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2975] <Example 347>
[2976] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl] Preparation of -Butyl} -amide
[2977] The title compound, according to the procedure of Example 331a-d, except that α-quinoline carbaldehyde was substituted for 6-methylpyridine-2-aldehyde and benzofuran carboxylic acid was replaced with 3-methyl-benzofuran-2carboxylic acid Was prepared: MS (ES) 505 (M + H) ⁺ .
[2978] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2979] <Example 348>
[2980] Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl] Preparation of -Butyl} -amide
[2981] Following the general procedure of Example 331a-d, except that α-quinoline carvalaldehyde was replaced with 6-methylpyridine-2-aldehyde and benzofuran carboxylic acid was replaced with benzo [b] thiophene-2-carboxylic acid. The title compound was prepared: MS (ES) 507 (M + H) ⁺ .
[2982] Diastereomers were separated by HPLC to give diastereomer 1 and diastereomer 2.
[2983] <Example 349>
[2984] Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl } Preparation of Amide
[2985] a.) {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[2986] To a solution of 280 g of compound (0.1 gm, 0.29 mmol) dissolved in THF was added 2-fluorophenyl isocyanate (32 ml, 0.29 mmol) and stirred for 1 hour. THF was removed in vacuo and the compound used directly in the next step: MS (ES): 481.02 (M + H) ⁺ .
[2987] b.) 4-((S) -2-Amino-4-methyl-pentanoylamino) -3-hydroxy-azepane-1-carboxylic acid (2-fluoro-phenyl) -amide
[2988] To a solution of the compound of Example 349a (1.96 g, 4.1 mmol) dissolved in MeOH was added 4M HCl / dioxane (5 ml, 20.3 mmol) and stirred at room temperature for 2 hours. Excess reagent was removed in vacuo and azeotropic with toluene to yield 1.84 mg of product.
[2989] c.) Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-hydroxy-azpan-4-ylcarbamoyl] -3 -Methyl-butyl} -amide
[2990] To a solution of the compound of Example 349b (0.11 g, 0.28 mmol) dissolved in dichloromethane, P-EDC (0.35 g, 1.8 mmol / g), HOBT (0.06 g, 0.49 mmol) and 2-benzothiophene carboxylic acid (0.077 gm, 0.432 mmol) was added. The reaction mixture was shaken for 16 hours. The reaction was continued for 1 hour by addition of trisamine (0.38 gm, 3.7 mmol / g) and the product was filtered off. The product was purified on silica gel column to give 112.5 mg of product: MS (ES): 541.2 (M + H) ⁺ .
[2991] d.) Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Methyl-butyl} -amide
[2992] To a solution of the compound of Example 349c (0.112 g, 0.2 mmol) dissolved in dichloromethane, des-martin periodinan (0.175 g, 0.41 mmol) was added. The reaction was stirred for 1 h and then washed with Na ₂ S ₂ 0 ₃ , NaHCO ₃ and brine. The compound was purified on a silica gel column and then 78 mg of product was obtained as a mixture of diastereomers. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 539 (M + H) ⁺ ; And diastereomer 2: 539 MS (ES) (M + H) ⁺ .
[2993] <Example 350>
[2994] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl } -Preparation of Amide
[2995] The title compound was prepared following the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with 3-methylbenzofuran-2-carboxylic acid. Diastereomers by HPLC Separation Diastereomer 1: MS (ES) 537 (M + H) ⁺ ; And diastereomer 2: MS (ES) 537 (M + H) ⁺ .
[2996] <Example 351>
[2997] 2,4-dimethylfuran-3-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl } -Preparation of Amide
[2998] The title compound was prepared according to the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with 2,4-dimethylfuran-3-carboxylic acid.
[2999] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 501 (M + H) ⁺ ; And diastereomer 2: MS (ES) 501 (M + H) ⁺ .
[3000] <Example 352>
[3001] Of quinoxaline-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Produce
[3002] The title compound was prepared according to the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with quinoxaline-2-carboxylic acid.
[3003] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 535 (M + H) ⁺ ; And diastereomer 2: MS (ES) 535 (M + H) ⁺ .
[3004] Example 353
[3005] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl]- Preparation of 3-methyl-butyl} -amide
[3006] The title compound was prepared according to the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with thieno [3,2-b] thiophene-2-carboxylic acid.
[3007] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 545 (M + H) ⁺ ; And diastereomer 2: MS (ES) 545 (M + H) ⁺ .
[3008] <Example 354>
[3009] Preparation of quinoline-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[3010] The title compound was prepared following the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with quinoline-2-carboxylic acid.
[3011] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 534 (M + H) ⁺ ; And diastereomer 2: MS (ES) 534 (M + H) ⁺ .
[3012] <Example 355>
[3013] 4-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl } -Preparation of Amide
[3014] The title compound was prepared following the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with 4-methylthiophene-2-carboxylic acid.
[3015] Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 503 (M + H) ⁺ ; And diastereomer 2: MS (ES) 503 (M + H) ⁺ .
[3016] <Example 356>
[3017] 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[3018] The title compound was prepared according to the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with 5-methoxy-benzofuran-2-carboxylic acid.
[3019] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 553 (M + H) ⁺ ; And diastereomer 2: MS (ES) 553 (M + H) ⁺ .
[3020] <Example 357>
[3021] 4-Methyl-furan-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} Preparation of -amides
[3022] The title compound was prepared following the general procedure of Example 349c-d, except that benzo [b] thiophene-2-carboxylic acid was replaced with 4-methylfuran-2-carboxylic acid.
[3023] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 487 (M + H) ⁺ ; And diastereomer 2: MS (ES) 487 (M + H) ⁺ .
[3024] <Example 358>
[3025] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-butyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[3026] The title compound was prepared following the general procedure of Examples 331a-d, except that α-quinoline carvalaldehyde was replaced with butyraldehyde. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 441.9 (M + H) ⁺ ; And diastereomer 2: MS (ES) 441.9 (M + H) ⁺ .
[3027] <Example 359>
[3028] Preparation of benzofuran-2-carboxylic acid [(S) -1- (1-propyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[3029] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carvalaldehyde was replaced with propionaldehyde. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 428 (M + H) ⁺ ; And diastereomer 2: MS (ES) 428 (M + H) ⁺ .
[3030] <Example 360>
[3031] Preparation of benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-benzyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide
[3032] The title compound was prepared according to the general procedure of Examples 331a-d, except that 2-fluorobenzaldehyde was substituted for α-quinoline carvalaldehyde. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) (M + H) ⁺ ; And diastereomer 2: MS (ES) 494.2 (M + H) ⁺ .
[3033] Example 361
[3034] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (2-morpholin-4-yl-thiazol-4-ylmethyl) -3-oxo-azpan-4-ylcarba Moyl] -butyl} -amide
[3035] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carbaldehyde was replaced with 2-morpholin-4-yl-thiazole-4-carbaldehyde. Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 568.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 568.4 (M + H) ⁺ .
[3036] Example 362
[3037] Benzofuran-2-carboxylic acid {(S) -1- [1- (5-ethyl-furan-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl}- Preparation of Amides
[3038] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carbalaldehyde was replaced with 5-ethyl-2-furaldehyde. Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 549.4 (M + H) ⁺ ; And diastereomer 2: MS (ES) 549.4 (M + H) ⁺ .
[3039] Example 363
[3040] Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethyl-thieno [3,2-b] thiophen-2-ylmethyl) -3-oxo-azepane-4- Preparation of Ilcarbamoyl] -3-methyl-butyl} -amide
[3041] The carbaldehyde title compound was prepared following the general procedure of Example 331a-d, except that α-quinoline was replaced with 3,4-dimethylthieno [b] thiophene-2-carboxaldehyde. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 566.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 566.2 (M + H) ⁺ .
[3042] Example 364
[3043] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (3-phenyl-3H- [1,2,3] triazol-4-ylmethyl) -azepane- Preparation of 4-ylcarbamoyl] -butyl} -amide
[3044] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carbaldehyde was replaced with 2-phenyl-2H-pyrazole-3-carbaldehyde. Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 543.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 543.4 (M + H) ⁺ .
[3045] <Example 365>
[3046] Preparation of benzofuran-2-carboxylic acid [(S) -1- [1- (isothiazol-3-ylmethyl-3-oxo-azepane-4-ylcarbamoyl) -3-methyl-butyl} -amide
[3047] The title compound was prepared following the general procedure of Examples 331a-d, except that α-quinoline carvalaldehyde was replaced with isothiazole-3-carvaldehydro. Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 483.1 (M + H) ⁺ ; And diastereomer 2: MS (ES) 483.1 (M + H) ⁺ .
[3048] Example 366
[3049] Preparation of benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-thiophen-2-ylmethyl-azpan-4-ylcarbamoyl) -butyl] -amide
[3050] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carbaldehyde was replaced with thiophene-2-carbaldehyde. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 582 (M + H) ⁺ ; And diastereomer 2: MS (ES) 582 (M + H) ⁺ .
[3051] Example 367
[3052] Preparation of benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-thiophen-2-ylmethyl-azpan-4-ylcarbamoyl) -butyl] -amide
[3053] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carbaldehyde was replaced with benzo [b] thiophene-2-carbaldehyde. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 546 (M + H) ⁺ ; And diastereomer 2: MS (ES) 546 (M + H) ⁺ .
[3054] Example 368
[3055] Preparation of benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-pentyl-azpan-4-ylcarbamoyl) -butyl] -amide
[3056] The title compound was prepared following the general procedure of Examples 331a-d, except that α-quinoline carvalaldehyde was replaced with fentanal. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 556 (M + H) ⁺ ; And diastereomer 2: MS (ES) 556 (M + H) ⁺ .
[3057] Example 369
[3058] Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazol-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl]- Preparation of Butyl} -amide
[3059] The title compound was prepared according to the general procedure of Examples 331a-d, except that α-quinoline carvalaldehyde was replaced with 3-methyl-3H-imidazole-4-carvaldehydro: MS (ES) 480.4 (M + H) ⁺ .
[3060] <Example 370>
[3061] 1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide Manufacture
[3062] Example 280h-j, except that 2-benzofuran-2-carboxylic acid was replaced with 1-oxy-pyridine-2-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 2-pyridinesulfonyl chloride. The title compound was prepared according to the process. Diastereomers were separated by HPLC to give diastereomer 1 (ESMS: M + H ⁺ = 504.2) and diastereomer 2 (ESMS: M + H ⁺ = 504.2).
[3063] <Example 371>
[3064] 2-oxy-pyridine-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide Manufacture
[3065] Example 280h-j, except that 2-benzofuran-2-carboxylic acid was replaced with 2-oxy-pyridine-3-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 2-pyridinesulfonyl chloride. The title compound was prepared according to the process. Diastereomers were separated by HPLC to give diastereomer 1 (ESMS: M + H ⁺ = 504.2) and diastereomer 2 (ESMS: M + H ⁺ = 504.2).
[3066] Example 372
[3067] 1H-benzoimidazole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide Manufacture
[3068] Example 280h-j, except that 2-benzofuran-2-carboxylic acid was replaced with 1H-benzoimidazole-5-carboxylic acid and 3-fluorobenzenesulfonyl chloride was replaced with 2-pyridinesulfonyl chloride. The title compound was prepared according to the process. Diastereomers were separated by HPLC to give diastereomer 1 (ESMS: M + H ⁺ = 504.2) and diastereomer 2 (ESMS: M + H ⁺ = 504.2).
[3069] Example 373
[3070] 4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -1-methyl-3-oxo-1-pentyl-azpanium Manufacture
[3071] The solution of the compound of Example 368 in pure methyl iodide was heated to reflux for 48 h, and the mixture was concentrated to give the title compound: MS (ES) 471.6 (M + H) ⁺ .
[3072] <Example 374>
[3073] Benzofuran-2-carboxylic acid {(S) -1- [1- (1,2-dimethyl-1H-imidazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Preparation of Methyl-Butyl} -amide
[3074] The title compound was obtained following the procedure of Example 280h-j, except that 3-fluorobenzenesulfonyl chloride was replaced with 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride: MS (ES ) 544.4 (M + H) ⁺ .
[3075] <Example 375>
[3076] Benzofuran-2-carboxylic acid {(S) -1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[3077] The title compound was obtained following the process of Example 280h-j, except that 3-fluorobenzenesulfonyl chloride was replaced with 1-methyl-1H-imidazole-4-sulfonyl chloride: MS (ES) 530.2 (M + H) ⁺ .
[3078] Example 376
[3079] Benzofuran-2-carboxylic acid {(S) -1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[3080] The title compound was obtained following the procedure of Example 280h-j except 3-fluorobenzenesulfonyl chloride was replaced with 4-methanesulfonylbenzenesulfonyl chloride. The diastereomers were separated by HPLC Stereoisomer 1: MS (ES) 604.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 604.2 (M + H) ⁺ .
[3081] Example 377
[3082] Benzofuran-2-carboxylic acid {(S) -1- [1- (2-methanesulfonyl-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide Manufacture
[3083] The title compound was provided according to the process of Example 280h-j, except that 3-fluorobenzenesulfonyl chloride was replaced with 2-methanesulfonylbenzenesulfonyl chloride. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 604.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 604.2 (M + H) ⁺ .
[3084] Example 378
[3085] Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-isoxazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Preparation of Butyl} -amide
[3086] The title compound was obtained following the process of Example 280h-j, except that 3-fluorobenzenesulfonyl chloride was replaced with 3,5-dimethylisoxazole-4-sulfonyl chloride. Diastereomers separated by HPLC to give diastereomer 1: MS (ES) 545.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 545.2 (M + H) ⁺ .
[3087] <Example 379>
[3088] 3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl } Preparation of Amide
[3089] a.) 3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-methyl-1- [3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} -amide
[3090] Replace N-Boc-leucine with N-Boc-allo-isoleucine, 3-fluorobenzenesulfonyl chloride with 2-pyridinesulfonyl chloride and benzofuran-2-carboxylic acid 3-methyl-benzofuran-2- The title compound was prepared following the general procedure of Example 280f-i, except for replacing with carboxylic acid.
[3091] b.) 3-methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl ] -Butyl} -amide
[3092] The title compound was prepared following the general procedure of Example 291d, except that the compound of Example 105b was replaced. Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 541 (M + H) ⁺ ; And diastereomer 2: MS (ES) 541 (M + H) ⁺ .
[3093] <Example 380>
[3094] Preparation of 3-methyl-benzofuran-2-carboxylic acid {1- [3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -cyclopentyl} -amide
[3095] The title compound was prepared following the general procedure of Examples 379a-b, except that N-Boc-allo-leucine was replaced with N-Boc-cycloleucine: MS (ES) 539 (M + H) ⁺ .
[3096] <Example 381>
[3097] Furo [3,2-b] -pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4- Preparation of Ilcarbamoyl] -Butyl} -amide
[3098] The title compound was diastereomer according to the general procedure of Example 291c-d, except that 5-fluoro-benzofuran-2-carboxylic acid was replaced with furo [3,2-b] -pyridine-2-carboxylic acid. Obtained as a mixture of: MS (ES) 587 (M + H) ⁺ .
[3099] Diastereomers were separated by HPLC to give diastereomer 1: MS (ES) 544.2 (M + H) ⁺ ; And diastereomer 2: MS (ES) 544.2 (M + H) ⁺ .
[3100] The above description and examples fully disclose methods for the preparation and use of the compounds of the invention. However, the invention is not limited to the specific embodiments described above, but includes all modifications thereof within the scope of the following claims. Various references to magazines, patents, and other publications cited herein include prior art status and are incorporated herein as if fully set forth by this name.

权利要求:
Claims (65)
[1" claim-type="Currently amended] Compounds of Formula (IA), and pharmaceutically acceptable salts, hydrates, and solvates thereof.
<Formula IA>

Where
R ¹ is Selected from the group consisting of;
R ² is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁹ C (O)-, R ⁹ SO _2- , R ⁹ R ¹¹ NC (O)-and R ⁹ SO ₂ R ¹¹ NC (O) —;
R ³ is C _1-6 alkyl;
R ⁴ is R ⁵ C (O)-;
R ⁵ is Het-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, Het-C _0-6 group consisting of alkyl;
R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl;
R 'is H;
R "is H;
R "'is H;
R ″ ″ is composed of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group;
n is an integer of 1-5.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is Phosphorus compounds.
[3" claim-type="Currently amended] The compound of claim 1, wherein R ³ is selected from the group consisting of isobutyl and but-2-yl.
[4" claim-type="Currently amended] The compound of claim 3, wherein R ³ is isobutyl.
[5" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is
Piperidinyl-ethyl;
Benzo [1,3] dioxolyl;
Furanyl, aryl substituted furanyl, C _1-6 alkyl substituted furanyl;
Benzofuranyl, C _1-6 alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C _1-6 alkyl substituted benzofuranyl;
Naphtho [2,1-b] -furanyl, C _1-6 alkyl substituted naphtho [2,1-b] -furanyl;
Benzo [b] thiophenyl;
Quinolinyl;
Quinoxalinyl;
1-oxy-pyridinyl;
Furo [3,2-b] pyridinyl, C _1-6 alkyl substituted furo [3,2-b] pyridinyl;
Thiophenyl, C _1-6 alkyl substituted thiophenyl;
Thieno [3,2-b] thiophenyl; And
1H-benzoimidazol-5-yl
Compound selected from the group consisting of.
[6" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is
Piperidin-1-yl-ethyl;
Benzo [1,3] dioxol-5-yl;
Furan-2-yl;
Benzofuran-2-yl;
Naphtho [2,1-b] -furan-2-yl;
Benzo [b] thiophen-2-yl;
Quinolin-2-yl;
Quinoxalin-2-yl;
1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl;
Furo [3,2-b] -pyridin-2-yl;
Thiophen-2-yl;
Thieno [3,2-b] thiophen-2-yl; And
1H-benzoimidazol-5-yl
Compound selected from the group consisting of.
[7" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is
5- (3-Trifluoromethyl-phenyl) -furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl , 2,4-dimethyl-furan-2-yl;
5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3- Ethyl-benzofuran-2-yl, 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl- Benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl;
1-methyl-naphtho [2,1-b] -furan-2-yl;
5-methyl-thiophen-2-yl, and
3-methyl-furo [3,2-b] pyridin-2-yl
Compound selected from the group consisting of.
[8" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxaline- 2-yl, and quinolin-2-yl.
[9" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is Phosphorus compounds.
[10" claim-type="Currently amended] The compound of claim 9, wherein R ″ ″ is C _1-6 alkyl.
[11" claim-type="Currently amended] The compound of claim 10, wherein C _1-6 alkyl is methyl.
[12" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is Phosphorus compounds.
[13" claim-type="Currently amended] 13. The compound of claim 12, wherein n is 3.
[14" claim-type="Currently amended] The compound of claim 1, wherein R ⁹ is
Ethyl, and C _3-6 cycloalkyl-substituted ethyl;
profile;
Butyl;
Isopentyl;
Phenyl, especially halogen substituted phenyl, C _1-6 alkyl substituted phenyl, C _1-6 alkylsulfonyl substituted phenyl;
Pyridinyl, C _1-6 alkyl substituted pyridinyl;
1-oxy-pyridinyl; And
Isoxazolyl, C _1-6 alkyl substituted isoxazolyl
Compound selected from the group consisting of.
[15" claim-type="Currently amended] The compound of claim 1, wherein R ⁹ is
Cyclohexyl-ethyl;
Prop-1-yl;
Boot-1-yl;
3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl;
Pyridin-2-yl, 1-oxy-pyridin-2-yl;
1,2-dimethyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, and
3,5-dimethyl-isoxazol-4-yl
Compound selected from the group consisting of.
[16" claim-type="Currently amended] The compound of claim 1, wherein R ² is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl.
[17" claim-type="Currently amended] The compound of claim 16, wherein R ² is selected from the group consisting of C _1-6 alkyl and Het-C _0-6 alkyl.
[18" claim-type="Currently amended] 18. The compound of claim 17, wherein C _1-6 alkyl and Het-C _0-6 alkyl are selected from the group consisting of Het-substituted methyl and pentyl.
[19" claim-type="Currently amended] The compound of claim 18, wherein the Het-substituted methyl is
Quinolin-2-ylmethyl;
6-methyl-pyridin-2-ylmethyl;
2-morpholin-4-yl-thiazol-4-ylmethyl;
5-ethyl-furan-2-ylmethyl;
3,4-dimethyl-thieno [3,2-b] thiophen-2-ylmethyl;
3-phenyl-3H- [1,2,3] triazol-4-ylmethyl;
Isothiazol-3-ylmethyl;
Thiophen-2-ylmethyl;
Benzo [b] thiophen-2-ylmethyl; And
1-methyl-1H-imidazol-2-ylmethyl
Compound selected from the group consisting of.
[20" claim-type="Currently amended] The compound of claim 1, wherein R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) —, R ⁹ SO _2, and R ⁹ R ¹¹ NC (O) —.
[21" claim-type="Currently amended] The compound of claim 20, wherein R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) — and R ⁹ SO ₂ .
[22" claim-type="Currently amended] The compound of claim 21, wherein R ² is R ⁹ SO ₂ .
[23" claim-type="Currently amended] The compound of claim 22, wherein R ⁹ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl, and Het-C _0-6 alkyl.
[24" claim-type="Currently amended] The method of claim 1,
R ¹ is ego;
R ² is R ⁹ S0 ₂ ;
R ³ is isobutyl;
R ⁹ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl.
[25" claim-type="Currently amended] The compound of claim 24, wherein R ⁵ is
Piperidinyl-ethyl;
Benzo [1,3] dioxolyl;
Furanyl, aryl substituted furanyl, C _1-6 alkyl substituted furanyl;
Benzofuranyl, C _1-6 alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C _1-6 alkyl substituted benzofuranyl;
Naphtho [2,1-b] -furanyl, C _1-6 alkyl substituted naphtho [2,1-b] -furanyl;
Benzo [b] thiophenyl;
Quinolinyl;
Quinoxalinyl;
1-oxy-pyridinyl;
Furo [3,2-b] pyridinyl, C _1-6 alkyl substituted furo [3,2-b] pyridinyl;
Thiophenyl, C _1-6 alkyl substituted thiophenyl;
Thieno [3,2-b] thiophenyl; And
1H-benzoimidazol-5-yl;
R ⁹
Ethyl, C _3-6 cycloalkyl-substituted ethyl;
profile;
Butyl;
Isopentyl;
Halogen substituted phenyl, C _1-6 alkyl substituted phenyl, C _1-6 alkylsulfonyl substituted phenyl;
Pyridinyl, C _1-6 alkyl substituted pyridinyl;
1-oxy-pyridinyl; And
Isoxazolyl, C _1-6 alkyl substituted isoxazolyl.
[26" claim-type="Currently amended] The method of claim 24,
R ⁵ is
Piperidin-1-yl-ethyl;
Benzo [1,3] dioxol-5-yl;
Furan-2-yl;
Benzofuran-2-yl;
Naphtho [2,1-b] -furan-2-yl;
Benzo [b] thiophen-2-yl;
Quinolin-2-yl;
Quinoxalin-2-yl;
1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl;
Furo [3,2-b] -pyridin-2-yl;
Thiophen-2-yl;
Thieno [3,2-b] thiophen-2-yl; And
1H-benzoimidazol-5-yl
Compound selected from the group consisting of.
[27" claim-type="Currently amended] The compound of claim 24, wherein R ⁵ is
5- (3-Trifluoromethyl-phenyl) -furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl , 2,4-dimethyl-furan-2-yl;
5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3- Ethyl-benzofuran-2-yl, 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl- Benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl;
1-methyl-naphtho [2,1-b] -furan-2-yl;
5-methyl-thiophen-2-yl, and
3-methyl-furo [3,2-b] pyridin-2-yl
Compound selected from the group consisting of.
[28" claim-type="Currently amended] The compound of claim 24, wherein R ⁹ is
Cyclohexyl-ethyl;
Prop-1-yl;
Boot-1-yl;
3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl;
Pyridin-2-yl, 1-oxy-pyridin-2-yl;
1,2-dimethyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, and
3,5-dimethyl-isoxazol-4-yl
Compound selected from the group consisting of.
[29" claim-type="Currently amended] The method of claim 24,
R ⁵ is 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, or quinoline 2--2-yl;
R ⁹ is selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-yl.
[30" claim-type="Currently amended] The compound of claim 29, wherein R ⁵ is 3-methyl-benzofuran-2-yl.
[31" claim-type="Currently amended] 32. The compound of claim 30, wherein R ⁹ is 1-oxy-pyridin-2-yl.
[32" claim-type="Currently amended] The method of claim 1,
Benzofuran-2-carboxylic acid {(S) -1-[-(3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-1-butyl} -amide ;
(S) -4-Methyl-2- (3-piperidin-1-yl-propanoylamino) -pentanoic acid [3-oxo-1- (pyridine-2-sulfonyl) -azepan-4- General] -amide;
Benzofuran-2-carboxylic acid {(S) -1-[-(4-ethyl-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide;
5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1- (1-oxy-pyridin-2-yl) -Methanoyl] -azepane-4-ylcarbamoyl} -butyl) -amide;
Benzo [1,3] -dioxol-5-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-oxy-pyridin-2-yl) -methanoyl] -azepane- 4-ylcarbamoyl} -butyl) -amide;
5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azpan-4-ylcarba Moyl] -3-methyl-butyl} amide;
Benzo [1,3] -dioxol-5-carboxylic acid {(S) -1- [1- (3-cyclohexyl-propanoyl) -3-oxo-azepane-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
5- (3-Trifluoromethyl-phenyl) -furan-2-carboxylic acid {(S) -1- [1- (4-methylpentanoyl) -3-oxo-azpan-4-ylcarbamoyl]- 3-methyl-butyl} -amide;
Benzo [1,3] -dioxol-5-carboxylic acid {(S) -1- [1- (4-methyl-pentanoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide;
Benzofuran-2-carboxylic acid [(S) -1- [3-oxo-1- (ethanesulfonyl-azpan-4-ylcarbamoyl) -3-methyl-1-butyl] -amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -Butyl} -amide;
5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(R) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide;
3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -3-methyl-1-[-3-oxo-1- (1-oxy-pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides;
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (3-fluorobenzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amides;
3-Methyl-furan-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides;
Quinoline-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl]- 3-methyl-butyl} -amide;
Quinoxaline-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
5-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (3-fluoro-benzenesulfonyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl }-amides;
5-methoxy-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azepane-4-ylcarbamoyl) -3-methyl-butyl] -amide;
3-Methyl-benzofuran-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Benzo [b] thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxoasepan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
3-Methyl-furan-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Quinoline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl]- amides;
Quinoxaline-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
5-Methyl-thiophene-2-carboxylic acid [(S) -1- (1-ethanesulfonyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl }-amides;
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl }-amides;
3-Methyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amides;
2,5-dimethyl-furan-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1- Butyl} -amide;
Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3- Methyl-1-butyl} -amide;
Quinoxaline-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide;
Thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl} -amide;
5-Methyl-thiophene-2-carboxylic acid {(S) -1- [3-oxo-1- (propane-1-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-1-butyl }-amides;
5-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarba Moyl] -butyl} -amide;
3-Ethyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -Butyl} -amide;
4-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
1-Methyl-naphtho [2,1-b] -furan-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
6-methoxy-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1- [3-oxo-1- (1-oxypyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amides;
Benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid [(S) -3-methyl-1- [3-oxo-1-quinolin-2-ylmethyl-azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Butyl) -amide;
3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azpan-4-yl Carbamoyl} -butyl) -amide;
Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-2-sulfonylamino) -methanoyl] -azepane-4-yl Carbamoyl} -butyl) -amide;
Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chlorobenzenesulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl} -butyl) -amides;
3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino)-methanoyl] -azepane-4-ylcarba Moyl} -butyl) -amide;
Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [2-chloro-benzenesulfonylamino)-methanoyl] -azepane-4-ylcarba Moyl} -butyl) -amide;
Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Butyl) -amide;
3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino)-methanoyl] -azpan-4-yl Carbamoyl} -butyl) -amide;
Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [4-fluoro-benzenesulfonylamino)-methanoyl] -azepane-4-yl Carbamoyl} -butyl) -amide;
Benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-ylcarbamoyl}- Butyl) -amide;
3-Methyl-benzofuran-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-yl Carbamoyl} -butyl) -amide;
Benzo [b] thiophene-2-carboxylic acid ((S) -3-methyl-1- {3-oxo-1- [1-toluene-4-sulfonylamino) -methanoyl] -azepane-4-yl Carbamoyl] -butyl) -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl] -butyl}- amides;
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl] -Butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid {(S) -3-methyl-1- [1- (6-methyl-pyridin-2-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl] -Butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluorophenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amides;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl }-amides;
2,4-dimethylfuran-3-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl }-amides;
Quinoxaline-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl]- 3-methyl-butyl} -amide;
Quinoline-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
4-Methyl-thiophene-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl }-amides;
5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
4-Methyl-furan-2-carboxylic acid {(S) -1- [1- (2-fluoro-phenylcarbamoyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl} -amides;
Benzofuran-2-carboxylic acid [(S) -1- (1-butyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Benzofuran-2-carboxylic acid [(S) -1- (1-propyl-3-oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Benzofuran-2-carboxylic acid {(S) -1- [1- (2-fluoro-benzyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (2-morpholin-4-ylthiazol-4-ylmethyl) -3-oxo-azpan-4-ylcarbamoyl ] -Butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -1- [1- (5-ethyl-furan-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl}- amides;
Benzofuran-2-carboxylic acid {(S) -1- [1- (3,4-dimethyl-thieno [3,2-b] thiophen-2-ylmethyl) -3-oxo-azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (3-phenyl-3H- [1,2,3] triazol-4-ylmethyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid [(S) -1- [1- (isothiazol-3-ylmethyl-3-oxo-azepane-4-ylcarbamoyl) -3-methyl-butyl} -amide;
Benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-thiophen-2-ylmethyl-azpan-4-ylcarbamoyl) -butyl] -amide;
Benzofuran-2-carboxylic acid [(S) -1- (1-benzo [b] thiophen-2-ylmethyl-3-oxo-azepane-4-ylcarbamoyl] -3-methyl-butyl] -amide ;
Benzofuran-2-carboxylic acid [(S) -3-methyl-1- (3-oxo-1-pentyl-azpan-4-ylcarbamoyl) -butyl] -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [1- (1-methyl-1H-imidazol-2-ylmethyl) -3-oxo-azepane-4-ylcarbamoyl]- Butyl} -amide;
1-oxy-pyridine-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide ;
2-oxy-pyridine-3-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide ;
1H-benzoimidazole-5-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide ;
4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -1-methyl-3-oxo-1-pentyl-azpanium ;
Benzofuran-2-carboxylic acid {(S) -1- [1- (1,2-dimethyl-1H-imidazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3- Methyl-butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -1- [1- (1-methyl-1H-imidazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -1- [1- (4-methanesulfonyl-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
Benzofuran-2-carboxylic acid {(S) -1- [1- (2-methanesulfonyl-benzenesulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ;
Benzofuran-2-carboxylic acid {(S) -1- [1- (3,5-dimethyl-isoxazole-4-sulfonyl) -3-oxo-azpan-4-ylcarbamoyl] -3-methyl- Butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(1S, 2R) -2-methyl-1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl }-amides;
3-Methyl-benzofuran-2-carboxylic acid {1- [3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -cyclopentyl} -amide; And
Furo [3,2-b] -pyridine-2-carboxylic acid {(S) -3-methyl-1-[-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide
Compound selected from the group consisting of.
[33" claim-type="Currently amended] 33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 and a pharmaceutically acceptable salt, diluent or excipient thereof.
[34" claim-type="Currently amended] 33. A method of inhibiting protease, comprising administering an effective amount of a compound according to any one of claims 1 to 32 to a patient in need of inhibition of the protease.
[35" claim-type="Currently amended] 35. The method of claim 34, wherein said protease is selected from the group consisting of cysteine proteases and serine proteases.
[36" claim-type="Currently amended] 36. The method of claim 35, wherein said protease is a cysteine protease.
[37" claim-type="Currently amended] 37. The method of claim 36, wherein said cysteine protease is cathepsin K.
[38" claim-type="Currently amended] 33. A method for treating a disease characterized by bone loss, comprising inhibiting bone loss by administering to the patient in need thereof an effective amount of the compound according to any one of claims 1 to 32.
[39" claim-type="Currently amended] The method of claim 38, wherein the disease is osteoporosis.
[40" claim-type="Currently amended] The method of claim 38, wherein the disease is periodontitis.
[41" claim-type="Currently amended] The method of claim 38, wherein the disease is gingivitis.
[42" claim-type="Currently amended] 33. Excessive cartilage or matrix degradation comprising inhibiting excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 32. A method for treating a disease characterized by
[43" claim-type="Currently amended] The method of claim 42, wherein the disease is osteoarthritis.
[44" claim-type="Currently amended] The method of claim 42, wherein the disease is rheumatoid arthritis.
[45" claim-type="Currently amended] 33. A method of treating parasitic diseases by administering an effective amount of a compound according to any one of claims 1 to 32 to a patient in need thereof.
[46" claim-type="Currently amended] 46. The disease according to claim 45, wherein the disease is associated with schistosomiasis, malaria, and pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Cristhidia fusiculata. And from the group consisting of infection by.
[47" claim-type="Currently amended] Compounds of formula (IA), and pharmaceutically acceptable salts, hydrates, and solvates thereof.
<Formula IIA>

Where
R ¹ is Selected from the group consisting of;
R ² is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁹ C (O)-, R ⁹ SO _2- , R ⁹ R ¹¹ NC (O)-and R ⁹ SO ₂ R ¹¹ NC (O) —;
R ³ is C _1-6 alkyl;
R ⁴ is R ⁵ C (O) —;
R ⁵ is Het-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, Het-C _0-6 group consisting of alkyl;
R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and HetC _0-6 alkyl;
R 'is H;
R ″ is H;
R "'is H;
R "" consists of C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and ArC _0-6 alkyl Selected from the group;
n is an integer from 1 to 5.
[48" claim-type="Currently amended] A method of synthesizing a compound according to claim 1 comprising oxidizing the corresponding compound of claim 47 using an oxidizing agent to obtain a compound of formula IA as a mixture of diastereomers.
[49" claim-type="Currently amended] 49. The method of claim 48, wherein the oxidant is a sulfur trioxide pyridine complex in DMSO and triethylamine.
[50" claim-type="Currently amended] 49. The method of claim 48, further comprising separating diastereomers by separation means.
[51" claim-type="Currently amended] 51. The method of claim 50, wherein said separation means is high pressure liquid chromatography (HPLC).
[52" claim-type="Currently amended] 49. The method of claim 48, further comprising deuteration of the diastereomers using a deuteration agent.
[53" claim-type="Currently amended] The method of claim 52, wherein the deuteration agent is CD ₃ 0D: D ₂ O (10: 1) in triethylamine.
[54" claim-type="Currently amended] 33. Use of a compound according to any one of claims 1 to 32 in the manufacture of a medicament for use in the inhibition of a protease selected from the group consisting of cysteine proteases and serine proteases.
[55" claim-type="Currently amended] 55. The use of claim 54, wherein said protease is a cysteine protease.
[56" claim-type="Currently amended] The use according to claim 55, wherein said cysteine protease is cathepsin K.
[57" claim-type="Currently amended] 33. Use of a compound according to any one of claims 1 to 32 in the manufacture of a medicament for use in the treatment of a disease characterized by bone loss.
[58" claim-type="Currently amended] 58. The use of claim 57, wherein the disease is osteoporosis.
[59" claim-type="Currently amended] 58. The use of claim 57, wherein said disease is periodontitis.
[60" claim-type="Currently amended] 58. The use of claim 57, wherein the disease is gingivitis.
[61" claim-type="Currently amended] 33. Use of a compound according to any one of claims 1 to 32 in the manufacture of a medicament for use in the treatment of a disease characterized by excessive cartilage or matrix degradation.
[62" claim-type="Currently amended] 62. The use of claim 61, wherein the disease is osteoarthritis.
[63" claim-type="Currently amended] 62. The use of claim 61, wherein the disease is rheumatoid arthritis.
[64" claim-type="Currently amended] 33. Use of a compound according to any one of claims 1 to 32 in the manufacture of a medicament for use in the treatment of parasitic diseases.
[65" claim-type="Currently amended] 65. The use according to claim 64, wherein said disease is selected from the group consisting of schistosomiasis, malaria, and infection with alveolar worms, wave flagella, trypsinoma brusei, and Critidial pukkulata.

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同族专利:

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公开号 | 公开日

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NZ522965A|2004-06-25|

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AR032622A1|2003-11-19|

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PL360508A1|2004-09-06|

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MXPA02012442A|2003-04-25|

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NO20025786D0|2002-12-02|

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PE20011374A1|2002-04-07|

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CN1444481A|2003-09-24|

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MA25758A1|2003-04-01|

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HU0301231A2|2003-08-28|

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BR0111693A|2004-04-06|

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CA2412353A1|2001-12-20|

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EP1307204A1|2003-05-07|

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AU6840701A|2001-12-24|

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BG107327A|2003-07-31|

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WO2001095911A1|2001-12-20|

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EP1307204A4|2004-06-02|

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ZA200209808B|2004-07-09|

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NO20025786L|2003-02-12|

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JP2004503502A|2004-02-05|

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OA12288A|2003-12-12|

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SK17592002A3|2003-05-02|

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EA200300018A1|2003-06-26|

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IL153421D0|2003-07-06|

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AP200202671A0|2002-12-31|

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ECSP024388A|2003-02-06|

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CZ20024086A3|2003-05-14|

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:
2000-06-14|Priority to US59384500A

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2000-06-14|Priority to US09/593,845

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2001-06-14|Application filed by 스미스클라인 비참 코포레이션

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2003-01-24|Publication of KR20030008220A

优先权:

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申请号 | 申请日 | 专利标题

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US59384500A| true| 2000-06-14|2000-06-14|

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US09/593,845|2000-06-14|