Protease Inhibitors

专利摘要:
The present invention provides C 1-6 alkyl-4-amino-azpan-3-one protease inhibitors that inhibit proteases, including cathepsin K and their pharmaceutically acceptable salts, hydrates and solvates, pharmaceuticals of such compounds Bone loss or excessive cartilage or matrix degradation, including osteoporosis, comprising inhibiting bone loss or excessive cartilage or matrix degradation by administering a composition, a new intermediate of such a compound, and a compound of the present invention to a patient in need thereof ; Gum diseases including gingivitis, periodontitis; Arthritis, more specifically osteoarthritis and rheumatoid arthritis; Paget's disease; Hypercalcemia in pregnancy; Metabolic bone disease; And a method of treating parasitic diseases comprising maleia.
公开号:KR20020082896A
申请号:KR1020027012366
申请日:2001-03-07
公开日:2002-10-31
发明作者:맥스웰 디. 큐밍스；로버트 더블유 쥬니어 마르키스；유 류；스코트 케이. 톰슨；다니엘 에프. 베버；데니스 에스. 야마시타
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; Darke, 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, cathepsins include infections with schistosomiasis, malaria, cancer metastasis, familial encephalopathy, muscular dystrophy, muscular dystrophy and the like, as well as pneumocystis carinii, cruise tripanosoma bruce tripanosoma and cryiddia fuzicurata It has been implicated as a trigger in various diseases (but not limited to). 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. Two bacterial cysteine proteases from P. gingivallis called gingipains 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, osteolectin, 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 carried out 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 top (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 formation 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 pointed out the 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 serineprotease inhibitors have no effect while cysteine protease inhibitors (eg, leupetin, Z-Phe-Ala-). CHN ₂ ) has shown to prevent 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 uptake. Thus, selective inhibition of cathepsin K may lead to excessive bone loss diseases, including but not limited to gum disease, such as osteoporosis, gingivitis and periodontitis, Paget's disease, malignant hypercalcemia and metabolic bone disease. It will provide an effective treatment. 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 but not limited to osteoarthritis and rheumatoid arthritis. 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 are alkoxymethyl ketones and mercaptomethyl ketones that inhibit cysteine protease cathepsin B, H and L Describe. 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] It has been pointed out that azaamino acids carry to the active sites of serine proteases and azapeptides with 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 its synthetic analogs 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, structurally diverse protease inhibitors have been identified. 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 new class of C _1-6 alkyl-4-amino-azpan-3-one compounds that are protease inhibitors, most particularly cathepsin K inhibitors.
[1] The present invention generally relates to C _1-6 alkyl-4-amino-azpan-3-one protease inhibitors, in particular cysteine and serine protease inhibitors, more particularly compounds that inhibit cysteine protease, more particularly papain phase; (superfamily) compounds that inhibit cysteine protease, very more particularly compounds that inhibit the cathepsin family cysteine protease, most particularly compounds that inhibit cathepsin K. Such compounds are particularly useful for the treatment of diseases involving cysteine proteases, in particular diseases of excess bone or cartilage, such as osteoporosis, periodontitis and arthritis, and diseases caused by certain parasites, such as malaria.
[16] Summary of the Invention
[17] It is an object of the present invention to provide C _1-6 alkyl-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 compounds that inhibit and cysteine proteases, very more particularly cathepsin and compounds that inhibit cysteine protease, most particularly cathepsin K, which inhibitors alter the activity of the protease It is useful for the treatment of diseases that can be alleviated.
[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 diseases characterized by bone loss such as osteoporosis and gum diseases such as gingivitis and periodontitis or by excessive degradation of cartilage or stroma such as osteoarthritis and rheumatoid arthritis. .
[23] Detailed description of the invention
[24] The present invention provides compounds of formula (I) and their pharmaceutically acceptable salts, hydrates or solvates thereof.
[25]
[26] (here,
[27] R ¹ is , , , And Is selected from the group consisting of
[28] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-6 alkyl, R ⁹ C (O)-, R ⁹ C (S)-, R ⁹ SO _2- , R ⁹ 0C (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ (R ¹¹ ) NSO _2- , , And Is selected from the group consisting of
[29] R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, C _{6 O-alkyl, O-ArC 6} alkyl It is selected from _{O-C 6} heteroaryl group consisting of alkyl, -, _{Ar-O ArC-6} alkyl, hetero-Ar- C _O-6 alkyl, heteroaryl, -ArC _O-6-alkyl, and heteroaryl
[30] R ³ and R ′ may be linked to form a pyrrolidine, piperidine or morpholine ring,
[31] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-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)-,
[32] R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl _- C _O-6 alkyl, C _2-6 alkanoyl, Ar-C _{O -6} is selected from alkyl, and _heteroaryl-O -C ₆ group consisting of alkyl,
[33] R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and heteroC _O-6 alkyl,
[34] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, heteroaryl, -C _0-6 ^{alkyl, R 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)-,
[35] R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroC _O-6 alkyl and ArC _0-6 alkyl,
[36] R ⁹ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl,
[37] R ¹⁰ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl,
[38] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
[39] R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
[40] R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
[41] R 'is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ alkyl,
[42] R "is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and a heteroaromatic group consisting of -C _0-6 alkyl,
[43] R "'is C _1-6 alkyl,
[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 from 1 to 5)
[47] In compounds of formula (I), R ¹ is When is
[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, hetero-C _0-6 alkyl, Ar-C ₀ heteroaryl is selected from the group consisting of C _{0-6 alkyl--6} alkyl, Ar-ArC _0-6 alkyl, Ar- C _0-6 alkyl, heteroaryl, heteroaryl -ArC _0-6 alkyl, and heteroaryl. R ³ is preferably Ar-C _0-6 alkyl, more preferably 3-isobutyl biphenyl.
[49] In compounds of formula (I), R ¹ is When, n is 4 is preferable and a 1-amino-1- acyl cyclohexane compound is provided. This cycloalkyl ring may comprise one or more C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroC _0-6 alkyl, ArC _{0 It} may or may not be substituted by _-6 alkyl, or halogen.
[50] More preferably, the cycloalkyl ring is unsubstituted.
[51] In compounds of formula (I), R ¹ is R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero-C _0-6 alkyl, Ar heteroaryl is selected from the group consisting of C _0-6 alkyl, - -C _0-6 alkyl, Ar-ArC _0-6 alkyl, Ar- C _0-6 alkyl, heteroaryl, heteroaryl -ArC _0-6 alkyl, and heteroaryl
[52] R ³ is preferably selected from the group consisting of H, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, and C _1-6 alkyl,
[53] 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,
[54] R ³ is more preferably selected from the group consisting of toluyl, isobutyl and cyclohexylmethyl,
[55] R ³ is most preferably isobutyl.
[56] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-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)-.
[57] R ⁴ is preferably selected from the group consisting of R ⁵ OC (O) —, R ⁵ C (O) — and R ⁵ SO ₂ —.
[58] R ⁴ is most preferably R ⁵ C (O)-.
[59] In some embodiments R ⁴ is preferably methanesulfonyl.
[60] R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl _- C _O-6 alkyl, C _2-6 alkanoyl, Ar-C _{O -6} is selected from the group consisting of alkyl or heteroaromatic -C _{6 O-alkyl.}
[61] Preferably R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkanoyl, Ar-C _O-6 alkyl and hetero- C _0-6 alkyl.
[62] More preferably R ⁵ , in particular when R ⁴ is R ⁵ C (O)-,
[63] Methyl, in particular halogenated methyl, more particularly trifluoromethyl, in particular C _1-6 alkoxy and aryloxy substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxy-methyl, in particular heterocycle Substituted methyl, more particularly 2-thiophenyl-methyl;
[64] Butyl, especially aryl substituted butyl, more particularly 4- (4-methoxy) phenyl-butyl;
[65] Isopentyl;
[66] Cyclohexyl;
[67] Pentanyl, especially 4-pentanyl;
[68] Butenyl, especially aryl substituted butenyl, more particularly 4,4-bis (4-methoxyphenyl) -but-3-enyl;
[69] 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 C _1-6 alkoxy or aryloxy groups, more particularly 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, in particular phenyl substituted with one or more sulfonyl groups, especially 4-methanesulfonyl-phenyl;
[70] benzyl;
[71] Naphthalenyl, especially naphthylene-2-yl;
[72] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[73] Furanyl, especially furan-2-yl, in particular 5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5- (3-trifluoromethyl-phenyl) -furan Substituted furanyl such as -2-yl, more particularly halogen substituted furanyl, very more particularly 5-bromo-furan-2-yl, more particularly aryl substituted furanyl, very even more particularly 5- ( 4-chloro-phenyl) -furan-2-yl;
[74] Tetrahydrofuranyl, in particular tetrahydrofuran-2-yl;
[75] Benzofuranyl, in particular benzofuran-2-yl and especially C _1-6 alkoxy 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; 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more particularly 5 -Fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, in particular C 1-6 alkyl substituted benzofuranyl, most particularly 3-methyl-benzofuran-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-5-yl, in particular 1-oxy-pyridin-2-yl, in particular C _1-6 alkyl substituted pyridinyl, more particularly 2-methyl-pyridin-5-yl ;
[82] Furo [3,2-b] pyridinyl, in particular furo [3,2-b] pyridin-2-yl, and C _1-6 alkyl substituted furo [3,2-b] pyridinyl, especially 3-methyl- Furo [3,2-b] pyridin-2-yl;
[83] Thiophenyl, in particular thiophen-3-yl, in particular C _1-6 alkyl substituted thiophenyl, more particularly 5-methyl-thiophen-2-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-methyl-thieno [3,2-b] thiophen-2-yl;
[85] Isoxazolyl, in particular 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 Is selected.
[87] When R ⁴ is R ⁵ SO ₂ , R ⁵ is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.
[88] R 'is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ group consisting of alkyl.
[89] Preferably R 'is selected from the group consisting of H and naphthalen-2-yl-methyl,
[90] Most preferably R 'is H.
[91] R "is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl, and -C heteroaryl group consisting of _0-6 alkyl.
[92] Most preferably R ″ is H.
[93] R ″ ′ is C _1-6 alkyl, especially selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, more particularly methyl;
[94] Preferably 5-, 6- or 7-C _1-6 alkyl, in particular selected from the group consisting of 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl , More particularly 5-, 6- or 7-methyl;
[95] More preferably 6- or 7-C _1-6 alkyl, in particular selected from the group consisting of 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl, more particularly 6 Or 7-methyl;
[96] More preferably cis-7-C _1-6 alkyl as shown in formula (Ia),
[97]
[98] Wherein R ″ 'is C _1-6 alkyl, in particular selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl
[99] Most preferably cis-7-methyl as shown in formula (la) above, in which case R ″ 'is methyl.
[100] In the compounds of formula (I), R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl, heteroaryl, -C _0-6 alkyl, R ⁹ C (O)-, R ⁹ C (S)-, R ⁹ SO ₂ , R ⁹ 0C (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ R ¹¹ NSO _2- , , And Is selected from the group consisting of
[101] Preferably R ² is Ar—C _O-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ , R ⁹ R ¹¹ NC (O) — and Is selected from the group consisting of
[102] More preferably R ² is selected from the group consisting of Ar—C _O-6 alkyl, R ⁹ C (O) — and R ⁹ SO ₂ ,
[103] Most preferably R ² is R ⁹ SO ₂ .
[104] In such embodiments:
[105] R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl or hetero-C _O-6 alkyl, preferably H.
[106] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-6 alkyl, R ¹⁰ C (O)-, R ¹⁰ C (S)-, R ¹⁰ SO _2- , R ¹⁰ OC (O)-, R ¹⁰ R ¹³ NC (O)-, R ¹⁰ R ¹³ NC (S)-, and R ⁷ is Preferably R ¹⁰ OC (O).
[107] R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroC _O-6 alkyl and Ar-C _0-6 alkyl, preferably C _1-6 alkyl, more preferably isobutyl.
[108] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl and _heteroaryl-O -C ₆ group consisting of alkyl.
[109] More preferably, R ⁹ is
[110] methyl;
[111] Ethyl, especially C _1-6 alkyl substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[112] Butyl, in particular C _1-6 butyl, more particularly 3-methylbutyl;
[113] Tert-butyl, especially when R ² is R ⁹ OC (O);
[114] Isopentyl;
[115] Phenyl, in particular halogen substituted phenyl, more particularly 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 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;
[116] Toluyl, in particular hetero substituted toluyl, more particularly 3- (pyridin-2-yl) toluyl;
[117] Naphthylenyl, in particular naphthylene-2-yl;
[118] Benzoyl, especially 2-benzoyl;
[119] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[120] Benzo [1,2,5] oxadiazolyl, in particular benzo [1,2,5] oxadiazol-4-yl;
[121] 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;
[122] Thiophene, especially thiophen-2-yl;
[123] Thiazolyl, in particular thiazol-2-yl;
[124] 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, more particularly C _1-6 alkyl substituted imidazolyl, more particularly 1-methyl-1H-imide Dazol-2-yl, 1-methyl-1H-imidazol-4-yl;
[125] 1H- [1,2,4] triazolyl, in particular 1H- [1,2,4] triazol-3-yl, more particularly C _1-6 alkyl substituted 1H- [1,2,4] triazolyl , More particularly 5-methyl-1H- [1,2,4] triazol-3-yl; And
[126] It is selected from the group consisting of quinolinyl.
[127] 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.
[128] R ¹⁰ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl;
[129] Preferably from C _1-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl.
[130] Z is selected from the group consisting of C (O) and CH ₂ .
[131] R ₂ is also preferably
[132] H;
[133] Toluyl;
[134] Aryl substituted ethyl, especially 2-phenylethyl, 2- [3- (pyridin-2-yl) phenyl] ethyl.
[135] Preferred are compounds of formula (I), wherein R "is H and R" 'is methyl.
[136] R ¹ is ego,
[137] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl -C _{6 O-alkyl, Ar-C O-6} alkyl, heteroaryl, -C _0-6 ^{alkyl, R 9 C (O) -} , R 9 C (S)-, R ⁹ SO ₂ , R ⁹ 0C (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ R ¹¹ NSO _2- , , And Is selected from the group consisting of
[138] R ³ is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and Ar-C _O-6 alkyl,
[139] R ⁴ is selected from the group consisting of R ⁵ OC (O) —, R ⁵ SO ₂ , and R ⁵ OC (O) —,
[140] R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkanoyl, Ar-C _O-6 alkyl and hetero-C _{0- 6} is selected from the group consisting of alkyl,
[141] R ⁶ is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl, and heteroaryl group consisting of -C _0-6 alkyl,
[142] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S)-, R ¹⁰ SO2-, R ¹⁰ OC (O)-, R ¹⁰ R ¹³ NC (O)-, and R ¹⁰ R ¹³ NC (S)-,
[143] R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero-C _0-6 alkyl and ArC _0-6 alkyl,
[144] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
[145] R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
[146] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl, C _3-6 cycloalkylC _0-6 alkyl, and hetero-C _0-6 alkyl,
[147] R ¹² is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl, and heteroaryl group consisting of -C _0-6 alkyl,
[148] R ¹³ is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl, and heteroaryl group consisting of -C _0-6 alkyl,
[149] R 'is H,
[150] R "is H,
[151] R "'is
[152] C _1-6 alkyl, especially those selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, more particularly methyl;
[153] Preferably selected from the group consisting of 5-, 6- or 7-C _1-6 alkyl, in particular 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl , More particularly 5-, 6- or 7-methyl;
[154] More preferably 6- or 7-C _1-6 alkyl, in particular 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl, more particularly 6 Or 7-methyl;
[155] More preferably cis-7-C _1-6 alkyl as shown in formula (Ia)
[156] Is selected from the group consisting of
[157] Formula Ia
[158]
[159] Wherein R ″ 'is C _1-6 alkyl, in particular selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl
[160] Most preferably cis-7-methyl as shown in formula (Ia), in which case R ″ 'is methyl,
[161] More preferred are compounds of formula (I), wherein Z is selected from the group consisting of C (O) and CH ₂ .
[162] Particular preference is given to compounds wherein R ³ is isobutyl.
[163] R ¹ is ego,
[164] R ² is Ar—C _O-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ , R ⁹ R ¹¹ NC (O) —, and Is selected from the group consisting of
[165] R ³ is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and Ar-C _0-6 alkyl,
[166] R ⁴ is selected from the group consisting of R ⁵ OC (O) —, R ⁵ C (O) — and R ⁵ SO ₂ —,
[167] R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkanoyl, Ar-C _0-6 alkyl and hetero-C _{0- 6} is selected from the group consisting of alkyl,
[168] R ⁶ is H,
[169] R ⁷ is R ¹⁰ OC (O),
[170] R ⁸ is C _1-6 alkyl,
[171] R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
[172] R ¹⁰ is selected from the group consisting of C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
[173] R ¹¹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
[174] R 'is H,
[175] R "is H,
[176] R "'is methyl, preferably 5-, 6- or 7-methyl, more preferably 6- or 7-methyl, most preferably cis-7-methyl (R" as shown in formula (Ia) 'Is methyl),
[177] Formula Ia
[178]
[179] More preferred are compounds of formula (I), wherein Z is selected from the group consisting of C (O) and CH ₂ .
[180] R ² is Ar-C _0-6 ^{alkyl, R 9 C (O) -} , R ⁹ SO is that the compound is selected from the group consisting of ₂ is particularly more preferred.
[181] R ¹ is ego,
[182] R ² is selected from the group consisting of Ar—C _O-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ ,
[183] 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,
[184] R ⁴ is R ⁵ C (O)-,
[185] R ⁵ is methyl, in particular halogenated methyl, more particularly trifluoromethyl, in particular C _1-6 alkoxy and aryloxy substituted methyl, more particularly phenoxy-methyl, 4-fluoro-phenoxy-methyl, in particular Hetero cycle substituted methyl, more particularly 2-thiophenyl-methyl;
[186] Butyl, especially aryl substituted butyl, more particularly 4- (4-methoxy) phenyl-butyl;
[187] Isopentyl;
[188] Cyclohexyl;
[189] Pentanyl, especially 4-pentanyl;
[190] Butenyl, especially aryl substituted butenyl, more particularly 4,4-bis (4-methoxyphenyl) -but-3-enyl;
[191] 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 C _1-6 alkoxy groups or aryloxy groups, more particularly Is 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, in particular phenyl substituted with one or more sulfonyl groups, more particularly 4-methanesulfonyl-phenyl;
[192] benzyl;
[193] Naphthylene-2-yl;
[194] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[195] Furanyl, especially furan-2-yl, in particular 5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5- (3-trifluoromethyl-phenyl) -furan Substituted furanyl such as -2-yl, more particularly halogen substituted furanyl, more particularly 5-bromo-furan-2-yl, more particularly aryl substituted furanyl, more particularly 5- ( 4-chloro-phenyl) -furan-2-yl;
[196] Tetrahydrofuran-2-yl;
[197] Benzofuranyl, in particular benzofuran-2-yl, in particular C _1-6 alkoxy 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; 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxybenzofuran-2-yl, especially halogen substituted benzofuranyl, more particularly 5- Fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, in particular C _1-6 alkyl substituted benzofuranyl, most particularly 3-methyl-benzofuran-2-yl ;
[198] 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;
[199] Quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl and quinolin-8-yl;
[200] Quinoxalinyl, especially quinoxalin-2-yl;
[201] 1,8-naphthyridinyl, especially 1,8-naphthyridin-2-yl;
[202] 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;
[203] Pyridinyl, in particular pyridin-2-yl, pyridin-5-yl, in particular 1-oxy-pyridin-2-yl, in particular C _1-6 alkyl substituted pyridinyl, more particularly 2-methyl-pyridin-5-yl ;
[204] Furo [3,2-b] pyridinyl, in particular furo [3,2-b] pyridin-2-yl, and C _1-6 alkyl substituted furo [3,2-b] pyridinyl, especially 3-methyl- Furo [3,2-b] pyridin-2-yl;
[205] Thiophenyl, in particular thiophen-3-yl, in particular C _1-6 alkyl substituted thiophenyl, more particularly 5-methyl-thiophen-2-yl, in particular halogen substituted thiophenyl, more particularly 4,5- Dibromo-thiophen-2-yl;
[206] 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;
[207] Isoxazolyl, in particular isoxazol-4-yl, in particular C _1-6 alkyl substituted isoxazolyl, more particularly 3,5-dimethyl-isoxazol-4-yl; And
[208] Oxazolyl, in particular oxazol-4-yl, more particularly 5-methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl and ,
[209] R ⁹ is
[210] methyl;
[211] Ethyl, especially C _1-6 alkyl substituted ethyl, more particularly 2-cyclohexyl-ethyl;
[212] Butyl, in particular C _1-6 butyl, more particularly 3-methylbutyl;
[213] Tert-butyl, especially when R ² is R ⁹ OC (O);
[214] Isopentyl;
[215] Phenyl, in particular halogen substituted phenyl, more particularly 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 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;
[216] Toluyl, in particular hetero substituted toluyl, more particularly 3- (pyridin-2-yl) toluyl;
[217] Naphthylene, in particular naphthyl-2-ene;
[218] Benzoyl, especially 2-benzoyl;
[219] Benzo [1,3] dioxolyl, in particular benzo [1,3] dioxol-5-yl;
[220] Benzo [1,2,5] oxadiazolyl, in particular benzo [1,2,5] oxadiazol-4-yl;
[221] 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;
[222] Thiophenyl, especially thiophen-2-yl;
[223] Thiazolyl, in particular thiazol-2-yl;
[224] 1H-imidazolyl, especially 1H-imidazol-2-yl (74), 1H-imidazol-4-yl, more particularly C _1-6 alkyl substituted imidazolyl, more particularly 1-methyl- 1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;
[225] 1H- [1,2,4] triazolyl, in particular 1H- [1,2,4] triazol-3-yl, more particularly C _1-6 alkyl substituted 1H- [1,2,4] triazolyl , More particularly 5-methyl-1H- [1,2,4] triazol-3-yl; And
[226] Selected from the group consisting of quinolinyl,
[227] R 'is H,
[228] R "is H,
[229] R ″ 'is methyl, preferably 5-, 6- or 7-methyl, more preferably 6- or 7-methyl, most preferably cis-7-methyl as shown in formula (la) Very more preferred are compounds of formula (I), wherein R ″ 'is methyl.
[230] Formula Ia
[231]
[232] R ¹ is ego,
[233] R ² is R ⁹ SO ₂ ,
[234] R ³ is C _1-6 alkyl,
[235] R ⁴ is R ⁵ C (O),
[236] R ⁵ is hetero-C _0-6 alkyl,
[237] R ⁹ is hetero-C _0-6 alkyl,
[238] R 'is H,
[239] R "is H,
[240] R ″ 'is selected from the group consisting of 5-, 6- or 7-methyl, preferably 6- or 7-methyl, most preferably cis-7-methyl as shown in formula (Ia) Very particular preference is given to the compounds of (I).
[241] Formula Ia
[242]
[243] Wherein R ″ 'is methyl
[244] R ¹ is ego,
[245] R ² is R ⁹ SO ₂ ,
[246] R ³ is isobutyl,
[247] R ⁴ is R ⁵ C (O),
[248] R ⁵ is 5-methoxybenzofuran-2-yl, benzo [b] thiophen-2-yl, 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2- 1, benzofuran-2-yl, furo [3,2-b] pyridin-2-yl, 3-methyl-furo [3,2-b] pyridin-2-yl; Preferably benzofuran-2-yl, furo [3,2-b] pyridin-2-yl, 3-methyl-furo [3,2-b] pyridin-2-yl; Most preferably selected from the group consisting of benzofuran-2-yl,
[249] R ⁹ is selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-yl, preferably pyridin-2-yl,
[250] R 'is H,
[251] R "is H,
[252] R ″ 'is selected from the group consisting of 5-, 6- or 7-methyl, preferably 6- or 7-methyl, most preferably cis-7-methyl as shown in formula (Ia) The compounds of (I) are very particularly very more preferred.
[253] Formula Ia
[254]
[255] Wherein R ″ 'is methyl
[256] Compounds of formula (I) selected from the following groups are particularly preferred embodiments of the invention.
[257] 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide:
[258]
[259] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide:
[260]
[261] Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -3-methyl-butyl} -amide:
[262]
[263] Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide:
[264]
[265] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide:
[266]
[267] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide:
[268]
[269] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide:
[270]
[271] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide:
[272]
[273] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide:
[274]
[275] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 7S) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide:
[276]
[277] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7S) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide:
[278]
[279] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} -amide:
[280]
[281] Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide:
[282]
[283] 2,2,4-tridutro-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo -1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide:
[284]
[285] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[286]
[287] 2,2,4-tridutro-3-methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl -3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide:
[288]
[289] Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide:
[290]
[291] Quinoline-3-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide:
[292]
[293] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide:
[294]
[295] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide:
[296]
[297] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[298]
[299] Quinoxaline-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide:
[300]
[301] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy- Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[302]
[303] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Ponyl) -Azepan-4-ylcarbamoyl] -butyl} -amide:
[304]
[305] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide:
[306]
[307] Quinoline-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide:
[308]
[309] 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine -2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[310]
[311] 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy- Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[312]
[313] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[314]
[315] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1- Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[316]
[317] Cyclohexanecarboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide:
[318]
[319] (S) -2- (cyclohexyl-ethanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -Azpan-4-yl] -amides:
[320]
[321] (S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2- Sulfonyl) -azpan-4-yl] -amides:
[322]
[323] (S) -2- (4-cyclohexyl-butanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Ponyl) -Azepan-4-yl] -amides:
[324]
[325] (S) -2- (5-cyclohexyl-pentanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Ponyl) -Azepan-4-yl] -amides:
[326]
[327] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoromethylpyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -butyl} -amide:
[328]
[329] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoromethyl-pyridine -2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[330]
[331] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoro Rommethyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[332]
[333] Benzofuran-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -cyclohexyl }-amides:
[334]
[335] Thiophene-3-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} -amide:
[336]
[337] Furan-2-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide:
[338]
[339] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[340]
[341] Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -ethyl} -amide:
[342]
[343] Furan-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -ethyl} -amide:
[344]
[345] Thiophene-3-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -ethyl} -amide:
[346]
[347] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- ( Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide:
[348]
[349] (2R, 4aR, 8aR) -octahydro-benzo [1,4] dioxine-2-carboxylic acid [(S) -1-((4S, 7R) -1-methanesulfonyl-7-methyl-3 -Oxo-azepane-4-ylcarbamoyl) -3-methyl-butyl] -amide:
[350]
[351] Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl) -ethyl ]-amides:
[352]
[353] Thiophene-3-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl)- Ethyl] -amide:
[354]
[355] Benzofuran-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azpan-4-ylcarbamoyl)- Ethyl] -amide:
[356]
[357] 1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid ((4S, 7R) -1-cyclohexylmethyl-7-methyl-3-oxo-azpan-4-yl) -amide:
[358]
[359] Benzofuran-2-carboxylic acid [1-((4S, 7R) -1-cyclohexylmethyl-7-methyl-3-oxo-azepane-4-ylcarbamoyl) -cyclohexyl] -amide:
[360]
[361] Benzofuran-2-carboxylic acid [(S) -3-methyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azpan-4-ylcarbamoyl) -butyl ]-amides:
[362]
[363] (2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl-6-oxo-azepane-1-carboxylic acid benzyl ester :
[364]
[365] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3-oxo- Azepan-4-ylcarbamoyl] -butyl} -amide:
[366]
[367] (S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3-oxo-azpan-4-yl] -amides:
[368]
[369] (2R, 5S) -5-{(S) -2-[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -2-methyl-6-oxo- Azepan-1-carboxylic acid (tetrahydro-pyran-4-yl) -amide:
[370]
[371] (S) -2-{[1-((2R, 5S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoyl Amino} -2-methyl-6-oxo-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester:
[372]
[373] (S) -2-{[1-((2R, 5S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoyl Amino} -2-methyl-6-oxo-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid:
[374]
[375] (S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester:
[376]
[377] (S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid:
[378]
[379] (S) -4-methyl-2-{[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-methanoyl ) -Amino] -pentanoylamino} -6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid methyl ester:
[380]
[381] (S) -4-methyl-2-{[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-methanoyl ) -Amino] pentanoylamino} -6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid:
[382]
[383] (R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester:
[384]
[385] (R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid:
[386]
[387] 4,5 (R, S) -Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} amide:
[388]
[389] 4S, 5S-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcar Barmoyl] -butyl} amide:
[390]
[391] 4S, 5R-Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcar Barmoyl] -butyl} amide:
[392]
[393] 4R, 5R-Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcar Barmoyl] -butyl} amide:
[394]
[395] 4R, 5S-benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcar Barmoyl] -butyl} amide:
[396]
[397] (R) -2-biphenyl-3-yl-4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepan-4- General] -amides:
[398]
[399] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -cyclohexyl} -amide:
[400]
[401] 1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid [(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- General] -amides:
[402]
[403] The most particularly preferred embodiment of the present invention is benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide:
[404]
[405] Representative compounds of the invention are shown in Examples 1-64.
[406] Compared to the corresponding 5- and 6-membered ring compounds, the 7-membered ring compounds of the invention are more atomically stable at the carbon center, which is in the alpha position in the ketone.
[407] The present invention includes deuterated analogs of the compounds of the present invention. Representative examples of such deuterated compounds are shown in Examples 7, 9, and 11. Representative synthetic methods for the deuterated compounds of the invention are shown in Scheme 4 below. The deuterated compounds of the invention exhibit superior chiral stability compared to the protonated isomers.
[408] Justice
[409] The present invention includes all hydrates, solvates, complexes and prodrugs of the present invention. Prodrugs are any covalently bound compounds that release the active pattern drug of formula (I) in vivo. If chiral centers or other forms of isomeric centers are present in the compounds of the present invention, all such forms of isomers, including enantiomers and diastereomers, are intended to be included in the present invention. The compounds of the present 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 in a well known manner. Where the compound has a saturated 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. .
[410] The meaning of any substituent of one compound of formula (I) or a formula thereof is independent of the meaning of another compound of formula (I), ie the meaning of substituents, unless specifically defined otherwise.
[411] Abbreviations and symbols commonly used in the art of peptides and chemistry are used herein to describe the compounds of the present invention. In general, amino acid abbreviations are described in Eur. J. Biochem., 158, 9 (1984), follow the IUPAC-IUB Joint Committee on Biochemical Nomenclature.
[412] A "protease" is an enzyme that catalyzes the segmentation of amino bonds of peptides and proteins by nucleophilic substitution in 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 fragmented after enzymatic catalyzed attack by nucleophiles. Thus, the compounds of the present invention competitively prevent the protease from recognizing and hydrolyzing the natural substrate and thereby act as inhibitors.
[413] The term "amino acid" as used herein refers to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine It means the D- or L- isomer.
[414] "Hydrogen" or "H" includes all possible isotopes, including "deuterium" or "D" or "2H" and "tritium" or "T" or "3H".
[415] As used herein, "C _1-6 alkyl" refers to substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neo Pentyl and 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 , hetero, C _3-6 cycloalkyl and aryl 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, -C _0-6 alkyl, Ar-C _0-6 alkyl and is selected from the group consisting of heteroaryl -C _0-6 alkyl, R ¹⁴ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and _heteroaryl-O -C ₆ alkyl).
[416] As used herein, "C _3-6 cycloalkyl" is substituted and unsubstituted cyclopropane, cyclobutane. It is intended to include cyclopentane and cyclohexane.
[417] As used herein, "C _2-6 alkenyl" refers to an alkyl group having from 2 to 6 carbons in which a carbon-carbon single bond is replaced with a carbon-carbon double bond. C _2-6 alkenyl includes ethylene, 1-propylene, 2-propene, 1-butene, 2-butene, isobutene and several isomers pentene and hexene. It also includes both cis and trans isomers.
[418] As used herein, "C _2-6 alkanoyl" is intended to include substituted and unsubstituted acetyl, propanonyl, butanonyl, pentanyl, and hexanonyl.
[419] "C _2-6 alkynyl" refers to an alkyl group having from 2 to 6 carbons, with the carbon-carbon single bond replaced by 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.
[420] "Halogen" means F, Cl, Br and I.
[421] "Ar" or "aryl" is phenyl or naphthyl, optionally one or more phenyl-C _0-6 alkyl; Heteroaryl -C _{6 O-alkyl;} C _1-6 alkoxy; _{Ph-C O-6} alkoxy; _Heteroaryl-O -C ₆ alkoxy; OH, (CH ₂ ) _1-6 NR ¹⁵ R ¹⁶ ; O (CH ₂ ) _1-6 NR ¹⁵ R ¹⁶ ; C _1-6 alkyl, OR ¹⁷ , N (R ¹⁷ ) ₂ , SR ¹⁷ , CF ₃ , N0 ₂ , CN, CO ₂ R ¹⁷ , CON (R ¹⁷ ), F, Cl, Br or I (where R ¹⁵ And R ¹⁶ is H, C _1-6 alkyl, phenyl-C _O-6 alkyl, naphthyl _- C _O-6 alkyl or hetero-C _O-6 alkyl, R ¹⁷ is phenyl, naphthyl or C _1-6 Alkyl).
[422] "Ar-Ar" means aryl covalently bonded to the second aryl. Examples of "Ar-Ar" include biphenyl or naphthyl-phenyl or phenyl-naphthyl.
[423] As used herein, "hetero" or "heterocyclic" consists of 1 to 3 heteroatoms selected from the group consisting of carbon atoms and N, 0 and S, wherein nitrogen and sulfur heteroatoms are optionally Can be oxidized, and nitrogen heteroatoms may optionally be quadrupled), a saturated or unsaturated 5-7 membered stable monocyclic heterocyclic ring, 7-10 membered stable bicyclic heterocyclic ring, or 11 to 18 membered stable tricyclic heterocyclic rings, wherein any one of these heterocyclic rings comprises 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 include, but are not limited to, triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl, which are obtainable by typical chemical synthesis and Ridinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrroly Diyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thia Zolinyl, thiazolyl, quinuclidinyl, 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, py Carbonyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzoxazolyl, thiazol-morpholinyl sulfoxide include side, thiazol-morpholinyl sulfone, and oxadiazolyl. As used herein, the term hetero atom means oxygen, nitrogen and sulfur.
[424] "Ar-hetero" means an aryl group covalently bonded to a heterocycle. Examples of "Ar-hetero" include phenyl-piperidine, phenyl-piperazine, phenyl-2-oxopiperazine, naphthyl-piperidine, naphthyl-piperazine, and naphthyl-2-oxopiperazine. Include.
[425] "Hetero-Ar" refers to a heterocycle covalently bonded to an aryl group. Examples of "hetero-Ar" include piperidinyl-phenyl, piperazinyl-phenyl, 2-oxopiperazinyl-phenyl, piperidinyl-naphthyl, piperazinyl-naphthyl, 2-oxopiperazinyl- Contains naphthyl.
[426] "Hetero-hetero" means a heterocycle covalently bonded to a second heterocycle. Examples of “hetero-hetero” include baapiridine, pyridinyl-piperidine, pyridinyl-piperazine, pyridinyl-2-oxopiperazine, thiophenyl-piperidine, thiophenyl-piperazine, and thiophenyl- 2-oxopiperazine.
[427] Throughout this specification the term C ₀ means that there is no substituent immediately following. For example, when C is zero at ArC _O-6 alkyl moiety is the substituent is Ar, e.g., phenyl. If a station, _{ArC-6 O-alkyl,} for the specific aromatic group, e.g., defined by phenyl, C values are to be understood to zero.
[428] Some radical groups are abbreviated herein. t-Bu stands for tert-butyl radical, Boc stands for t-butyloxycarbonyl radical, Fmoc stands for fluorenylmethoxycarbonyl radical, Ph stands for phenyl radical, Cbz stands for benzyloxycarbonyl radical.
[429] Certain reactants are herein abbreviated. m-CPBA is 3-chloroperoxybenzoic acid, EDC is N-ethyl-N '(dimethylaminopropyl) -carbodiimide, DMF is dimethyl formamide, DMSO is dimethyl sulfoxide, TEA is triethylamide TFA means trifluoroacetic acid and THF means tetrahydrofuran.
[430] Manufacturing method
[431] Compounds of formula (I) may be prepared by methods analogous to those summarized in Schemes 1-8.
[432]
[433] 2-methyl-pent-4-enoic acid ethyl ester is aldehyde reduced, reductive amination with allylamine is carried out, sulfonylation with 2-pyridyl sulfonyl chloride, Grubbs Olefin metathesis using a catalyst is converted to N-2-pyridinesulfonylazapine. Epoxidation with mCPBA gives an epoxide mixture that can be separated by column chromatography. This syn epoxide is ring-opened with sodium azide and then converted to amino alcohol by reduction with triphenylphosphine. This free amine is acylated with Boc-leucine and a coupling agent (e.g. HBTU or EDC), followed by the removal of the Boc protecting group using HCl and various aromatic carboxylic acids and coupling agents (e.g. HBTU or EDC) Acylation to obtain intermediate alcohols. Final oxidation with Dess-Martin periodinane and HPLC is carried out to give the desired ketone.
[434]
[435] Reductive amination of 5-hexen-2-one with allylamine was carried out, protected with carbobenzyloxychloride, and olefin metathesis using Grubbs catalyst to N-carbobenzyloxy Switch to azapine. Epoxidation with mCPBA gives an epoxide mixture that can be separated by column chromatography. Each epoxide is ring-opened with sodium azide and then converted to amino alcohol by reduction with triphenylphosphine. This free amine is acylated using Boc-leucine and a coupling agent (e.g., HBTU or EDC), and then hydrolyzed to remove the Cbz protecting group to obtain a secondary amine. This secondary amine is again sulfonylated with 2-pyridine sulfonylchloride. The Boc protecting group is removed using HCl and acylated with various aromatic carboxylic acids and coupling agents (eg HBTU or EDC) to obtain intermediate alcohols. Final oxidation with Dess-Martin periodinane and HPLC is carried out to give the desired ketone.
[436]
[437] Carbobenzyloxy-D-alanineol (Cbz-D-alanineol) is first converted to iodide and then reacted with allyl Grignard and copper (I) catalysts, or similar allyl organometallic materials. This amine is then alkylated with allyl iodide. Subsequently, closed ring metathesis is performed using a Grubbs catalyst to form an azapine ring. This alkene is epoxidized, the diastereoisomers are separated, and the intermediate azido alcohol is obtained by ring opening of the minor component epoxide using a sonic azide. This azide is reduced and acylated with an amine using a protected amino acid (eg Boc-leucine), followed by the removal of the Cbz protecting group to give an intermediate secondary amine. This secondary amine is sulfonylated with sulfonyl chloride (eg pyridine sulfonylchloride). The Boc protecting group is removed and then acylated with an acylating agent (e.g. quinoline-6-carboxylic acid, HBTU, NMM) and the secondary alcohol is oxidized (e.g. sulfur trioxide-pyridine or des-martin periodinan). Final oxidation using to convert to ketone to give the desired product.
[438]
[439] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Parental inhibitors such as ylcarbamoyl] -butyl} -amide are treated with a base (e.g. triethyl amine) and deuterated by stirring for several days in a deuterated proton solvent (e.g. CD ₃ 0D: D ₂ O). Inhibitors can be prepared.
[440]
[441] Intermediate (S) -3-cyclohexyl-N-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-yl) -2-methyl-propionamide (described in Scheme 3) Reduction of amination is carried out using aldehydes or ketones (eg propionaldehyde) with Boc-L-leucine in place of aldehydes or ketones (eg propionaldehyde) and treated with a reducing agent (eg sodium borohydride). The Boc protecting group is removed and then acylated with an acylating agent (eg 2-furan carboxylic acid, HBTU, NMM) and the final alcohol is finally oxidized with an oxidizing agent (eg sulfur trioxide-pyridine) to ketone. Conversion to obtain the desired product.
[442]
[443] Intermediate described in Scheme 3 [(S) -1-((S) -3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (S Acylation is carried out using an isocyanate such as)-(-)-2-isocyanato-4-methylvalleic acid methyl ester. The Boc protecting group is removed and then acylated with an acylating agent (e.g. benzofuran-2-carboxylic acid, HBTU, NMM) and the secondary alcohol is oxidized (e.g. des-martin periodinan or sulfur trioxide-pyridine Final oxidation using) to convert to ketone to give the desired product.
[444]
[445] C-5 methyl azepineone, 4,5 (R, S) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine- A scheme of the synthesis of 2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} amide (Example 61) is shown in Scheme 7 above. Nitromethane is added to ethyl crotonate (7-1) followed by Michael reduction using an reducing agent (e.g., diisobutyl aluminum hydride (Dibal-H)) to obtain aldehyde (7-2). Reductive amination of aldehyde (7-2) is carried out using N-benzyl ethanolamine in the presence of a reducing agent (e.g. sodium triacetoxybrohydride) to give nitro-alcohol (7-3). Nitro-alcohol (7-3) is oxidized using oxidizing agents (e.g., DMSO and oxalyl chloride) conventional in the art, and then the crude intermediate aldehyde is treated with a base (e.g. triethylamine) to give a nitro-aldol reaction. To obtain azepanol (7-4). After reducing the nitro group to zinc in the presence of hydrochloric acid, the resulting amine is coupled with N-Boc-leucine in the presence of a coupling agent (e.g., EDC) customary in the art to obtain intermediate (7-5). Reduction of the N-benzyl moiety with hydrogen gas in the presence of a catalyst (e.g. 10% Pd on carbon) followed by sulfonyl chloride in the presence of a base (e.g. N-methylmorpholine or triethyl amine) Sulfonylation is carried out to obtain sulfonamide intermediate (7-6). The N-Boc protecting group is removed under acidic conditions, the resulting amine salt is coupled with benzofuran-2-carboxylic acid, and the alcohol is oxidizing agent conventional in the art (e.g. pyridine sulfur trioxide complex or des-martin periodinan) It is oxidized to give ketone (7). Each diastereomer (7-7) can be separated by HPLC to obtain diastereomers (7-8, 7-9, 7-10, 7-11).
[446]
[447] Intermediate (2R, 5R, 6R) -5-amino-6-hydroxy-2-methyl-azepan-1-carboxylic acid benzyl ester (derived from the main epoxide of Scheme 3) is protected with Boc anhydride. Next, the Cbz group is removed by hydrogenolysis. Sulfonylation is then carried out using 2-pyridine sulfonyl chloride and the Boc group is removed with hydrochloric acid in dioxane. Primary amines were coupled with 2-biphenyl-3-yl-4-methyl-pentanoic acid (J. Am. Chem. Soc. 1997, 120, 9114) and then oxidizing agents (e.g., Dess-Martin periodi Egg or sulfur trioxide-pyridine) is used to convert the secondary alcohol to a ketone. The azepanone is then epimerized with triethylamine in MeOH to give the diastereomeric mixture. The diastereoisomers are separated using chiral HPLC to afford the desired compounds.
[448] Starting materials for use in the present invention may be obtained commercially or may be prepared by conventional methods well known to those skilled in the art, and may be standard books (e.g. COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI, published by Wiley-Interscience). Can be found at
[449] Coupling methods for forming amide bonds in the present invention are generally well known in the art. Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979) and J.M. Stewart and JDYoung, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, III., 1984] Peptide synthesis methods generally presented are generally representative examples of this technique and are incorporated herein by reference. do.
[450] Synthetic methods for preparing compounds of the present invention often introduce protecting groups to mask reactive functional groups or to 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, as known in the art. Protection and deprotection methods and the replacement of amino protecting groups with other residues are well known.
[451] Acid addition salts of formula (I) are prepared by standard methods from the parent compound and from excess acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid. It may be prepared in a suitable solvent. Some of these compounds form an acceptable internal salt or zwitterion. Cationic salts are prepared by treating the parent compound with an excess of alkaline reagents, such as hydroxides, carbonates or alkoxides containing suitable cations or with a suitable organic amine. Cations such as Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺⁺ , Mg ⁺⁺ and NH ₄ ⁺ are special examples of cations present in pharmaceutically acceptable salts. Halides, sulfates, phosphates, alkanoates (such as acetates and trifluoroacetates), benzoates and sulfonates (such as mesylates) are examples of anions present in pharmaceutically acceptable salts.
[452] The present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. Thus, the compound of formula (I) can be used for the manufacture of a medicament. Pharmaceutical compositions of formula (I) prepared by the above methods may be formulated in solution or lyophilized powder for parenteral administration. The powder may be reconstitution by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered isotonic aqueous solution. Examples of suitable diluents are prescribed isotonic saline, standard 5% dextrose in water, or sodium acetate or ammonium acetate buffer. Such formulations are particularly suitable for parenteral administration, but can also be used for oral administration or in a metered dose inhaler or nebulizer for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
[453] Alternatively, such compounds may be encapsulated, tableted or prepared in emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may comprise a sustained release agent, such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax. The amount of solid carrier varies but is preferably about 20 mg to about 1 g per dosage unit. Pharmaceutical formulations include milling, mixing, granulating and (if necessary) pressing for tablets; Or according to conventional pharmaceutical techniques including milling, mixing, and filling for hard gelatin capsule forms. When using liquid carriers, the preparations may be in the form of syrups, elixirs, emulsions or aqueous or non-aqueous suspensions. Such liquid formulations may be administered orally directly or filled into soft gelatin capsules.
[454] For rectal administration, the compounds of the invention can also be molded into suppositories by mixing with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol.
[455] New intermediates
[456] With reference to the methods for preparing compounds of formula (I) shown in Schemes 1-8 above, one skilled in the art 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) and pharmaceutically acceptable salts, hydrates and solvates thereof.
[457]
[458] (here,
[459] R ¹ is , , , And Is selected from the group consisting of
[460] R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-6 alkyl, R ⁹ C (O)-, R ⁹ C (S)-, R ⁹ SO _2- , R ⁹ 0C (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ (R ¹¹ ) NSO _2- , , And Is selected from the group consisting of
[461] R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl C _0-6 alkyl, ArC _0-6 alkyl, , Ar-ArC _0-6 alkyl, Ar- C _0-6 alkyl, heteroaryl, heteroaryl -ArC _0-6 alkyl, and heteroaryl-heteroaryl is selected from the group consisting of C _0-6 alkyl,
[462] R ³ and R ′ may be joined to form a pyrrolidine, piperidine or morpholine ring,
[463] R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-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),
[464] R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _{O -6} alkyl, and
[465] R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl and heteroC _O-6 alkyl,
[466] R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-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)-,
[467] R ⁸ is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, C _{6 O-alkyl} and _O-6 ArC the group consisting of alkyl,
[468] R ⁹ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl,
[469] R ^1O is independently selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl,
[470] R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
[471] R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and heteroC _O-6 alkyl,
[472] R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and heteroC _O-6 alkyl,
[473] R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
[474] R 'is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl and heteroaryl C _O-6 alkyl,
[475] R ″ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, or hetero-C _O-6 alkyl,
[476] R ″ 'is selected from the group consisting of C _1-6 alkyl, in particular methyl, ethyl, propyl, butyl, pentyl and hexyl, more particularly methyl;
[477] Preferably selected from the group consisting of 5-, 6- or 7-C _1-6 alkyl, in particular 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl , More particularly 5-, 6- or 7-methyl;
[478] More preferably 6- or 7-C _1-6 alkyl, in particular 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl, more particularly 6 Or 7-methyl;
[479] More preferably cis-7-C _1-6 alkyl as shown in formula (Ia);
[480] Formula Ia
[481]
[482] Wherein R ″ 'is selected from the group consisting of C _1-6 alkyl, in particular methyl, ethyl, propyl, butyl, pentyl and hexyl
[483] Most preferably selected from the group consisting of cis-7-methyl (when R ″ ′ is methyl) as shown in formula (Ia) above;
[484] X is selected from the group consisting of CH ₂ , S and 0,
[485] Z is selected from the group consisting of C (O) and CH ₂ ,
[486] n is an integer from 1 to 5)
[487] The following compounds are preferred novel intermediates:
[488] 3-methyl-1- (pyridine-2-sulfonyl) -2,3,4,7-tetrahydro-1H-azepine;
[489] 5-methyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane;
[490] 4-azido-5-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol;
[491] 4-amino-6-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol;
[492] {(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert- Butyl esters;
[493] 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -3-methyl-butyl} -amide;
[494] Allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester;
[495] 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;
[496] 4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester;
[497] 5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
[498] 5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
[499] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[500] (2S, 5R, 6R) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[501] [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[502] [(S) -1-((3R, 4R, 7S) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[503] [(S) -1-((3S, 4S, 7R) -1-benzenesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
[504] [(S) -1-((3R, 4R, 7S) -1-benzenesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
[505] (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
[506] (S) -2-Amino-4-methyl-pentanoic acid ((3R, 4R, 7S) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
[507] Benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide;
[508] Benzofuran-2-carboxylic acid {(S) -1-[(3R, 4R, 7S) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide;
[509] ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester;
[510] Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester;
[511] 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;
[512] (1S, 4R, 7R) -4-Methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester;
[513] (2R, 5S, 6S) -5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
[514] (2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
[515] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[516] [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[517] [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
[518] (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
[519] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3R, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[520] Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(3S, 4S, 6S) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
[521] Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(3R, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
[522] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 6S) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
[523] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(3R, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
[524] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(3S, 4S, 6S) -6-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[525] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(3S, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[526] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
[527] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7S) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
[528] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3R, 4R, 7S) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
[529] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3R, 4R, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
[530] ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester;
[531] ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester;
[532] Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester;
[533] 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;
[534] (1S, 4R, 7R) -4-Methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester;
[535] (2R, 5S, 6S) -5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
[536] (2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
[537] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[538] [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[539] [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
[540] (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
[541] Furo [3,2-b] pyridine-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[542] Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
[543] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2 -Sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
[544] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[545] Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;
[546] Quinoline-3-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;
[547] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[548] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
[549] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine -2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[550] Quinoxaline-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
[551] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1 -Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[552] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[553] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
[554] Quinoline-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -butyl} -amide;
[555] 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1- Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl-amide;
[556] 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1 -Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[557] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine -2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[558] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[559] Cyclohexanecarboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide;
[560] (S) -2- (2-cyclohexyl-ethanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-yl] -amide;
[561] (S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine -2-sulfonyl) -azpan-4-yl] -amide;
[562] (S) -2- (4-cyclohexyl-butanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-yl] -amide;
[563] (S) -2- (5-cyclohexyl-pentanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-yl] -amide;
[564] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (5 trifluoromethyl-pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[565] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (5-trifluoro Methyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[566] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (5 -Trifluoromethyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[567] Benzofuran-2-carboxylic acid {1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -Cyclohexyl} -amide;
[568] Thiophene-3-carboxylic acid {(S) -3,3-dimethyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
[569] Furan-2-carboxylic acid {(S) -3,3-dimethyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide;
[570] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3,3-dimethyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
[571] Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -ethyl} -amide;
[572] Furan-2-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -ethyl} -amide;
[573] Thiophene-3-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -ethyl} -amide;
[574] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy- 1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
[575] (2R, 4aR, 8aR) -octahydro-benzo [1,4] dioxine-2-carboxylic acid [(S) -1-((3S, 4S, 7R) -1-methanesulfonyl-7-methyl -3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
[576] Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propylazane-4-ylcarbamoyl) -Ethyl] -amide;
[577] Thiophene-3-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propyl-azpan-4-ylcarba Moyl) -ethyl] -amide;
[578] Benzofuran-2-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propyl-azpan-4-ylcarba Moyl) -ethyl] -amide;
[579] 1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid ((3S, 4S, 7R) -1-cyclohexylmethyl-7-methyl-3-hydroxy-azpan-4-yl) -amides;
[580] Benzofuran-2-carboxylic acid [1-((3S, 4S, 7R) -1-cyclohexylmethyl-7-methyl-3-hydroxy-azpan-4-ylcarbamoyl) -cyclohexyl]- amides;
[581] Benzofuran-2-carboxylic acid [(S) -3-methyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propyl-azpan-4-ylcarbamoyl ) -Butyl] -amide;
[582] (2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl-6-hydroxy-azepane-1-carboxylic acid benzyl ester;
[583] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3- Hydroxy-azpan-4-ylcarbamoyl] -butyl} -amide;
[584] (S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-1- (1-morpholin-4-yl-meta Noyl) -3-hydroxy-azpan-4-yl] -amide;
[585] (2R, 5S, 6S) -5-{(S) -2-[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -2-methyl-6- Hydroxy-azane-1-carboxylic acid (tetrahydro-pyran-4-yl) -amide;
[586] (S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl- Pentanoylamino} -2-methyl-6-hydroxy-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
[587] (S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-hydrate Oxy-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
[588] (S) -4-methyl-2-{[1-((2R, 5S, 6S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl- Metanoyl) -amino] -pentanoylamino} -6-hydroxy-azpan-1-yl) -methanoyl] -amino} -pentanoic acid methyl ester;
[589] (R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-hydrate Oxy-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
[590] 2-biphenyl-3-yl-4-methyl-pentanoic acid [(3R, 4R, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl ]-amides;
[591] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -cyclohexyl} -amide; And
[592] 1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid [(4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4 -Yl] -amide.
[593] Methods for Synthesizing Compounds of the Invention
[594] Referring to Schemes 1-8 above, the present invention involves the oxidation of a suitable compound of formula (II) with an oxidizing agent to obtain a compound of formula (I) as diastereoisomers. To provide. Preferably the oxidant is a sulfur trioxide-pyridine complex.
[595] Referring to Scheme 4, the present invention also provides a process for the synthesis of deuterated compounds of formula (I). In particular, if deuterated isomers are required, an additional step is added to the synthesis process after the oxidation step, in which the protonated isomers are deuterated with deuteration agents to obtain deuterated compounds of formula (I) as diastereomeric mixtures. Preferably, the deuteration agent is CD ₃ OD: D ₂ O (1O: 1) in triethylamine.
[596] The method further comprises the step of separating the diastereomers of formula (I) by separation means, preferably by high pressure liquid chromatography (HPLC).
[597] Utility of the present invention
[598] 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 Useful as cathepsin K inhibitors. The present invention also provides useful compositions and formulations of such compounds, including pharmaceutical compositions and formulations of the compounds.
[599] The compounds include infections with schistosomiasis, malaria, cancer metastasis, familial encephalopathy, muscular dystrophy, muscular dystrophy, and the like, as well as pneumocystis carinii, cruise tripanosoma Bruce tripanosoma, and cryiddia fujikurata. 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 hypercalcium It is useful for treating excessive bone or cartilage loss diseases, including hyperemia and metabolic bone disease.
[600] Parasites known to use cysteine proteases in their life cycles (and diseases caused by these parasites) are Tripanosoma Cruz, Tripanosoma Bruce [Tripanosomiasis (African Sleep Disease, Chagas Disease)], Laishmania Mexicana, Laishmania FIFANOI, Laishmania Major (Lacemaniasis), Sistosaoma Mansoni (Shistosomiasis), Oncoserca Volbulus [Oncoserciasis (river name)] Brugia Pahanji, Entamoeva Heath Tortica, Giardia Rambia, Haemonchus Contortus and Pasiola Hepatica worms, Spiromella, Trikinella, Necator and Ascartis worms, and Cryptosporidium, Emeria, Toxoplasma and Naegle This includes Leria protozoa. The compounds of the present invention are suitable for the treatment of diseases caused by such parasites that can modulate therapeutically by modulating the activity of cysteine proteases. In particular, the compounds of the present invention are useful for treating maleia by inhibiting falcipain.
[601] 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.
[602] 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 invention also includes infections with schistosomiasis, malaria, cancer metastasis, familial encephalopathy, muscular dystrophy, muscular dystrophy, etc., as well as pneumocystis carinii, cruise tripanosoma Bruce tripanosoma, and cryiddia fuzicurata , Diseases associated with cysteine protease and especially diseases involving cathepsin K, most particularly gum diseases including osteoporosis, gingivitis and periodontitis, arthritis, more particularly osteoarthritis and rheumatoid arthritis, Paget's disease, malignant hypercalcium Provided are methods for treating, but not limited to, excess bone or cartilage loss, including hyperemia and metabolic bone disease.
[603] The method of the invention inhibits papain phase and cysteine protease by administering at least one of the compounds described above to a patient, especially an animal, more particularly a mammal, most particularly a human, in need thereof, thereby inhibiting the papain phase and cysteine protease, [Trifanosomiasis (African Sleeping Disease, Chagas Disease)], Laishmania Mexicana, Laishmania Pifanoi, Laishmania Major (Lacemaniasis), Sistosaoma Mansonia (Shistosomiasis), Oncocerca Volbulus [Oncocerciasis (river name)] Brugia Pahanji, Entamoeva Histolica, Giardia Rambia, Haemonchus Contortus and Pasiola Hepatica worms, spirometra, tree Infected by Kinella, Necator and Ascartis worms, and Cryptosporidium, Emeria, Toxoplasma and Naeglea protozoa It provides a way to treat the disease.
[604] In particular, the present invention is directed to a patient in need of treatment, in particular an animal, more particularly a mammal, most particularly a human, by administering at least one of the compounds described above to inhibit falcipine, It provides a way to treat malaria.
[605] The methods of the present invention can be carried out by administering the compounds described above alone or in combination with each other, or in combination with other pharmaceutically effective compounds.
[606] 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. It provides a method for treating osteoporosis or suppressing bone loss. It is also possible to treat compounds of the invention and anabolic agents such as bone forming proteins, iproflavones to prevent bone loss or to increase bone mass.
[607] For acute treatment, parenteral administration of the compound of formula (I) is preferred. Although intramuscular bolus infusion 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 the drug in 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.
[608] 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.
[609] Administration of a compound of the present invention in accordance with the present invention does not expect any unacceptable toxin effect.
[610] Biological analysis
[611] The compounds of the present invention can be tested by one of a variety of biological assays to determine the concentrations of compounds needed to have the pharmacological effects indicated.
[612] Determination of Catalytic K's Proteolytic Catalytic Activity
[613] All assays for cathepsin K are performed with human recombinant enzyme. Standard assay conditions for determining rate constants were determined using a fluorescence generating 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 stock 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 analytes contained 10% DMSO. Independent experiments showed that this level of DMSO had no effect on enzyme activity or rate constants. All analyzes were performed at room temperature. Product fluorescence (excitation at 360 nM, emission at 460 nM) was detected with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20-30 minutes after AMC product formation.
[614] Inhibition studies
[615] Potential inhibitors were assessed using the course 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 course 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).
[616] v = V _m A / [K _a (1 + I / K _{i, app} ) + A]
[617] 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)
[618] For compounds with elapsed curves with downward curves with time-dependent inhibitory properties, the data from each set were analyzed to yield k _obs according to equation (2).
[619] [AMC] = v _5S t + ( v ₀ - v _5S ) [1-exp ( -k _obs t)] / k _obs
[620] (Where [AMC] is the concentration of product produced during time t, v ₀ is the initial reaction rate, v _5S is the final steady state rate)
[621] 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 kinetics is fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol. , 1988 , 61, 201).
[622] Human Keel Cell Uptake Assay
[623] An aliquot of the cell suspension derived from the keel cell tumor was taken from the liquid nitrogen vessel, 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 off and replaced with murine anti-HLA-DR antibody, diluted 1: 3 in RPMI-1640 medium and incubated for 30 minutes on ice. Cell suspensions were mixed frequently.
[624] 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 monocytes was counted in an improved Neubauer counter.
[625] Sufficient magnetic beads (5 / mononuclear cells) coated with goat anti-mouse IgG were removed from the storage vessel and placed in 5 mL fresh medium (this washes out toxic azide preservatives). Beads were fixed to magnets to remove the medium and replaced with fresh medium.
[626] 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 in magnets and the remaining cells (fractions enriched with 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.
[627] Using a large diameter disposable plastic Pasteur pipette, the counting chamber was filled with a sample and the keel cells were counted. Cells were pelleted by centrifugation and 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 drug) was transferred to a 15 mL centrifuge tube. These cells were pelleted by centrifugation. 3 mL of each tube sieve appropriate drug was added (diluted to 50 uM in EMEM medium). Also included were the appropriate vehicle control, positive control (87MEM1 diluted to 100 ug / mL) and isotopic control (IgG2a diluted to 100 ug / mL). The tube was incubated at 37 ° C. for 30 minutes.
[628] 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 drug was screened four times. Slices were washed 6 times with warm PBS (10 mL / well, 6-well plates) and placed in new drug or control and incubated for 48 hours at 37 ° C. Slices were washed in phosphate buffer saline and fixed in 2% glutaraldehyde (in 0.2 M sodium cacodylate), then washed with water and incubated at 37 ° C. for 5 minutes 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 washed with water and dried.
[629] TRAP-positive keel cells were counted with a bright-field microscope and removed from the dentin surface by sonication. Membrane pore volume was measured with a Nikon / Laserec ILM21W confocal microscope.
[630] Normal
[631] 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-d6 is hexadutriodimethylsulfoxide and CD ₃ OD is tetradutrimethanol. Chemical shifts are reported in parts per million from the internal standard tetramethylsilane in the downfield direction. NMR data abbreviations 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 Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode and band position was reported for wave number (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 apparatus. All temperatures are reported in ° C.
[632] Analtech Silica Gel GF and E. Merck Silica Gel (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 Kieselgel 60 (230-400 mesh) silica gel.
[633] When indicated, certain materials are described in Alsrich Chemical Co., Wiscons1N, Milwaukee. And Chemical Dynamics Corp., New Jersey South Pla1Nfield. And Advanced Chemtech, Kentucky, Louisville.
[634] In the following synthetic examples, the temperature is ° C. Unless stated otherwise, all starting materials were obtained from commercial products. Without further explanation, those skilled in the art will be able to fully utilize the present invention with reference to the foregoing description. These examples are intended to illustrate the invention, but not to limit the scope thereof.
[635] Example 1
[636] 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide
[637] , And
[638] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide
[639]
[640] a. Allyl- (2-methyl-pent-4-enyl) -amine
[641] A solution of DIBAL (1.0 M in hexane, 75 ml) was added dropwise to a solution of 2-methyl-pent-4-enoic acid ethyl ester (7.1 g, 50 mmol) at −78 ° C. for 1.0 h. After the dropwise addition, the reaction mixture was stirred at -78 ° C for 1 hour. The reaction was quenched with saturated NH ₄ C1 (10 ml) and 4% HCl, then extracted with EtOAc (3 × 100 ml). The combined organic extracts were dried using MgSO ₄ , filtered and concentrated by rotary evaporation to give the crude reaction product for next reaction without further purification. 2-methyl-4-pentenal (3.3 g, 33.7 mmol) was dissolved in CH ₂ Cl ₂ (100 ml). To this solution allylamine (2.9 g, 50.5 mmol) was added. Molecular sieves (5 g) were used to absorb the water produced during the reaction. The reaction was stirred at rt overnight. The reaction mixture was concentrated by rotary evaporation and the crude product was used for the next reaction without further purification. Allyl- (2-methyl-pent-4-enylidene) -amine (3.2 g, 23.4 mmol) was diluted in 50 ml MeOH. To this solution was added NaBH ₄ (1.0 g, 26.3 mmol) at 0 ° C. After addition, the reaction was stirred at rt for 5 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc / 20% NaOH aqueous solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation to give allyl- (2-methyl-pent-4-enyl) -amine (1.5 g 48% yield).
[642]
[643] b. Pyridine-2-sulfonic acid allyl- (2-methyl-pent-4-enyl) -amide
[644] Allyl- (2-methyl-pent-4-enyl) -amine (1.0 g, 7.2 mmol) and NMM (1.7 g, 17.2 mmol) were mixed in 30 ml of CH ₂ C1 ₂ . 2-pyridinesulfonyl chloride (1.53 g, 8.6 mmol) was added slowly while cooling the solution in an ice water bath. After addition, the reaction mixture was stirred at rt overnight. The reaction mixture was washed with 10% NaHCO ₃ and brine and then purified by column chromatography to give the title compound as a colorless oil (1.2 g, 60% yield). MS (M + H < + >)281.2;
[645]
[646] c. 3-methyl-1- (pyridine-2-sulfonyl) -2,3,4,7-tetrahydro-1H-azepine
[647] Pyridine-2-sulfonic acid allyl- (2-methyl-pent-4-enyl) -amide (1.2 g, 4.3 mmol) was diluted in CH ₂ Cl ₂ (100 ml). After carefully degassing with Ar, Grubbs catalyst (0.35 g, 0.43 mmol) was added under Ar protection. This mixture was then refluxed for 2 hours and then the reaction mixture was concentrated by rotary evaporation. The product was purified by column chromatography (5% -20% EtOAc / hexanes) to give the title compound (0.9 g, 83% yield).
[648]
[649] d. 5-Methyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane
[650] NaHCO ₃ (1.3 g, 15.5 mmol) followed by mCPBA (2.67 g, 15.5 mmol) was added 3-methyl-1- (pyridine-2-sulfonyl) -2,3,4, in CH ₂ C1 ₂ (50 ml). To the solution of 7-tetrahydro-1H-azepine (1.3 g, 5.16 mmol) was added portionwise. After stirring for 4 hours at room temperature, the solution was worked up by washing with 15% NaOH, saturated K ₂ CO ₃ and brine. Dry over Na ₂ SO ₄ . The reaction mixture was concentrated by rotary evaporation and the two isomers separated by column chromatography (30% -40% EtoAc / hexanes). The first eluate (trans-isomer, 230 mg) was used for the next step and the second eluate (cis-isomer, 200 mg) was stored.
[651]
[652] e. 4-azido-5-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol
[653] 5-Methyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane (230 mg, 0.86 mmol) was mixed with 8 ml of MeOH and 2 ml of H ₂ O. Dissolved in. To this solution was added NaN ₃ (170 mg, 2.6 mmol) and NH ₄ C1 (140 mg, 2.6 mmol). The resulting mixture was refluxed overnight. After removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO ₃ and brine. Purification by column chromatography gave the title compound (170 mg, yield 64%).
[654]
[655] f. 4-amino-6-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol
[656] 4-azido-6-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol (0.33 g, 1.06 mmol) was dissolved in THF (50 ml) and H ₂ 0 (0.2 ml). To this solution was added PPh 3 (0.42 g, 1.59 mmol). The reaction mixture was stirred at 45 ° C. overnight. TLC showed no starting material present. THF was evaporated and azeotropic with toluene (2 × 100 ml). The resulting thick oil was dissolved in MeOH and treated with HCl in ether to adjust the pH to acidic. More ether was added and the solution was cloudy and the title compound was obtained as a white precipitate (0.21 g, 71% yield).
[657]
[658] g. {(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[659] 4-amino-6-methyl-1- (pyridine-2-sulfonyl) -azpan-3-ol HCl salt (0.21 g, 0.59 mmol) was dissolved in 5 ml of DMF. To this solution was added Boc-Leu-OH (0.22 g, 0.88 mmol) and HBTU (0.34 g, 0.90 mmol), followed by NMM (0.24 g, 2.4 mmol). The reaction was stirred at rt overnight. DMF was removed under high vacuum. The residue was diluted in EtOAc and washed with H ₂ O, 10% NaHCO ₃ and brine. Purification by column chromatography gave the title compound (0.2 g, 68% yield).
[660]
[661] h. 5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -3-methyl-butyl} -amide
[662] HCl / dioxane (4M, 2.8 ml, 11.2 mmol) was added {(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azepane-4-ylcarba Moyl] -3-methyl-butyl} -carbamic acid tert-butyl ester (0.13 g, 0.28 mmol). After the mixture was stirred at room temperature for 2 hours, the solvent and excess HCl were removed by rotavapor. The resulting white solid was dissolved in 5 ml of DMF. To this solution was added 5-methoxy-benzofuran-2-carboxylic acid (63.4 mg, 0.33 mmol), HBTU (125 g, 0.33 mmol) and NMM (0.14 g, 1.34 mmol). The reaction was stirred at rt overnight. The DMF was then removed and the residue was redissolved in EtOAc (50 ml) and then washed with 10% NaHCO ₃ (50 ml × 2) and brine (50 ml). The combined organics were concentrated by rotary evaporation. Purification by column chromatography gave the title compound (110 mg, 2 steps) in 69% yield.
[663]
[664] i. 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide and 5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 6R) -6-methyl -3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide
[665] Dess-Martin reactant (122 mg, 0.29 mmol) at room temperature was added 5-methoxy-benzofuran-2-carboxylic acid in 5 ml CH ₂ Cl ₂ {(S) -1- [3-hydroxy-6-methyl- To a solution of 1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide (110 mg, 0.19 mmol). The solution was stirred for 2 hours, 50 ml of CH ₂ Cl ₂ was added and then washed with 10% NaHCO ₃ and brine. Purification by column chromatography (50% ethyl acetate in hexanes) gave the title compound (90 mg, 82% yield).
[666]
[667] Example 2
[668] Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -3-methyl-butyl} -amide
[669] , And
[670] Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide
[671]
[672] The title compound was prepared according to the method of Example 1 (ai) except for replacing "5-methoxy-benzofuran-2-carboxylic acid" with "benzo [b] thiophene-2-carboxylic acid" Got:
[673]
[674] Example 3
[675] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide
[676] , And
[677] 3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide
[678]
[679] The title compound was prepared according to the method of Example 1 (ai) except for replacing "5-methoxy-benzofuran-2-carboxylic acid" with "3-methyl-benzofuran-2-carboxylic acid" Got:
[680]
[681] Example 4
[682] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[683] , And
[684] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[685]
[686] The method of Example 1 (ai) except that "5-methoxy-benzofuran-2-carboxylic acid" was replaced with "thieno [3,2-b] thiophene-2-carboxylic acid" Thus obtaining the title compound:
[687]
[688] Example 5
[689] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide
[690] , And
[691] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 7S) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide
[692]
[693] a. Allyl- (1-methyl-pent-4-enylidene) -amine allyl- (1-methyl-pent-4-enyl) -amine
[694] Hex-5-ene in a stirred solution of allylamine (8.55 mmol, 11.25 ml, 150 mmol), 4 'molecular sieves (52 g), and p-toluene sulfonic acid (10 mg) in CH ₂ C1 ₂ (200 ml) 2-one (9.8 g, 11.6 ml, 100 mmol) was added and stirred overnight. The reaction mixture was concentrated by rotary evaporation in vacuo and used for the next reaction without further purification (13 g, 95%).
[695]
[696] b. Racemate allyl- (1-methyl-pent-4-enyl) -amine
[697] To a stirred solution of allyl- (1-methyl-pent-4-enylidene) -amine (6.5 g, 47 mmol) in MeOH (100 ml) at 0 ° C. was added sodium borohydride (2.7 g, 71 mmol). A little bit was added. The reaction mixture was stirred for 30 minutes and then warmed up to room temperature. About 90 ml of MeOH was removed from the reaction mixture by rotary evaporation and the reaction mixture was diluted with ether (200 ml) and then extracted with water and then brine. The combined organics were dried over MgSO ₄ , filtered and concentrated by rotary evaporation in vacuo to give a pale yellow liquid (5.2 g, 80%). This was used for the next reaction without further purification.
[698] c. Racemate allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester
[699] Stirring of allyl- (1-methyl-pent-4-enyl) -amine (7 g, 50 mmol) and triethylamine (5.5 g, 8.0 ml, 57.5 mmol) in CH ₂ Cl ₂ (100 ml) at 0 ° C. Carbobenzyloxy chloride (9.56 g, 8 ml) was added dropwise to one solution. The reaction mixture was allowed to warm up to room temperature and then stirred for 2 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (100 ml) and then extracted with water then brine. The combined organics were dried over MgSO ₄ , filtered, concentrated by rotary evaporation in vacuo, and then chromatographed (silica gel, 4% EtOAc / hexanes) to afford the title compound (8.9 g, 65% yield):
[700]
[701] d. Racemate 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester
[702] Allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester (1.036 g, 3.8 mmol) is dissolved in CH ₂ C1 ₂ (10 ml) and the argon gas stream is bubbled into the reaction mixture for 10 minutes. I was. Bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (Strem Chemicals, Grubbs' catalyst, 22 mg, 0.027 mmol) was then added and the reaction mixture was refluxed for 2 hours. Further bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (11 mg, 0.014 mmol) was added and the reaction mixture was further refluxed for 1.5 hours. The reaction was cooled to rt overnight under argon, concentrated by rotary evaporation in vacuo and then chromatographed (silica gel, 5% EtOAc / hexanes) to afford the title compound (0.83 g, 89%):
[703]
[704] e. Racemate (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester
[705] To a solution of 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.83 g, 3.34 mmol) in CH ₂ Cl ₂ at 0 ° C. 1.05 g, 57-86% pure). The reaction mixture was stirred for half an hour and then warmed up to room temperature. Further m-chloro-benzoic peroxide (0.3 g, 57-86% purity) was added and the reaction stirred for 2 hours. The reaction mixture was concentrated by rotary evaporation in vacuo, 80 ml of 9: 1 hexanes / EtOAc was added and then the reaction mixture was filtered. The filtrate was concentrated by rotary evaporation in vacuo and then chromatographed (silica gel, 20% EtOAc: hexane) to give racemate (1S, 4R, 7S) -4-methyl-8-oxa-3-aza-bicyclo [ 5.1.0] -octane-3-carboxylic acid benzyl ester (0.44 g, 50%) and the title compound were obtained as a racemate mixture of the title compound (0.15 g, 17% yield):
[706]
[707] f. Racemate (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[708] Racemate (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carbone in MeOH (5 ml) and H ₂ 0 (0.5 ml) To a solution of the acid benzyl ester (0.75 g, 2.87 mmol) and ammonium chloride (0.46 g, 8.62 mmol) was added sodium azide (0.56 g, 8.62 mmol) and then refluxed for 6 hours. The reaction mixture was dried by rotary evaporation in vacuo, diluted with water (5 ml) and then extracted with EtOAc (10 ml). The organic layer was then extracted with water and brine, dried over MgSO ₄ , filtered, concentrated by rotary evaporation in vacuo, and then chromatographed (silica gel, 20% EtOAc / hexanes) to afford the title compound (0.7 g, 80%):
[709]
[710] g. Racemate (2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[711] Triphenylphosphine (1.94 g, 7.4 mmol) was added to racemate (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl in THF (185 ml) and H ₂ 0 (0.7 ml). Add to a solution of azepan-1-carboxylic acid benzyl ester (1.5 g, 4.93 mmol) and heat to 45 ° C. overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and azeotropic twice with rotary evaporation in vacuo. The resulting oil was dissolved in HCl and MeOH in Et ₂₀ and the resulting salts were collected and filtered to use for the next reaction without further purification (1.4 g, 90%).
[712] h. (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1- Carboxylic acid benzyl esters and (2S, 5R, 6R) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-ase PAN-1-carboxylic acid benzyl ester
[713] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.33 g, 1.73 mmol) was added Boc-leucine-hydrate (0.43 g, 1.7 mmol), diisopropylethylamine (0.22) in DMF (10 ml). g, 0.3 ml, 1.7 mmol), hydroxybenztriazole (0.25 g, 1.85 mmol), and racemate (2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane- To a solution of 1-carboxylic acid benzyl ester (0.5 g, 1.6 mmol). The reaction was stirred at rt overnight, then diluted with EtOAc (100 ml), washed with H ₂ 0 (3 × 50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and rotary evaporated in vacuo. Concentrated with chromatography and chromatographed (silica gel, 50% EtOAc / hexanes) to give the title compound (0.78 g, 100%):
[714]
[715] i. [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester and [(S) -1-((3R, 4R, 7S) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[716] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl ester and (2S, 5R, 6R) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane- 1-carboxylic acid benzyl ester (0.77 g, 1.57 mmol) was dissolved in EtOAc (27.5 ml) and MeOH (5.5 ml). Next, 10% Pd / C (0.39 g) was added and stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through celite, concentrated through rotary evaporation in vacuo and then used for the next reaction without further purification (0.56 g):
[717]
[718] j. [(S) -1-((3S, 4S, 7R) -1-benzenesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester and [(S) -1-((3R, 4R, 7S) -1-benzenesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3- Methyl-butyl] -carbamic acid tert-butyl ester
[719] 2-pyridine sulfonyl chloride (0.6 g, 3.4 mmol) was added [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azane in CH ₂ Cl ₂ (35 ml). 4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester and [(S) -1-((3R, 4R, 7S) -3-hydroxy-7-methyl-azane 4-ylcarbamoyl) -3-methyl butyl] -carbamic acid tert-butyl ester (1.0, g, 2.8 mmol), added to a solution of N-methyl morphine (0.45 ml, 4.1 mmol) and overnight at room temperature Stirred. The reaction mixture is diluted with EtOAc (100 ml), washed with H ₂ 0 and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 2.5% MeOH / CH ₂ C1 ₂ ) to give the title compound (0.9 g, 64%):
[720]
[721] k. (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azepane-4- Yl) -amide and (S) -2-amino-4-methyl-pentanoic acid ((3R, 4R, 7S) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azane -4-yl) -amide
[722] HCl in dioxane (4.0 M, 15 ml) was added [(S) -1-((3S, 4S, 7R) -1-benzenesulfonyl-3-hydroxy-7-methyl-ase in MeOH (15 ml). Pan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester and [(S) -1-((3R, 4R, 7S) -1-benzenesulfonyl-3-hydroxy -7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.9 g, 1.8 mmol) was added to the stirred solution. The reaction mixture was stirred at rt for 2 h, concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (0.85 g).
[723] l. Benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide and benzofuran-2-carboxylic acid {(S) -1-[(3R, 4R, 7S) -3-hydroxy-7-methyl-1- ( Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide
[724] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.35 g, 1.85 mmol) was added 2-benzofuran-carboxylic acid (0.3 g, 1.85 mmol), (S)-in DMF (10 ml). 2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amide and ( S) -2-Amino-4-methyl-pentanoic acid ((3R, 4R, 7S) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl)- To a solution of amide (0.85 g, 1.8 mmol), diisopropylethylamine (0.48 g, 0.65 ml, 3.7 mmol), hydroxybenztriazole (0.25 g, 1.85 mmol) was added and stirred at rt overnight. The reaction mixture was then warmed up to room temperature and then stirred overnight. The reaction mixture is diluted with EtOAc (100 ml), washed with H ₂ 0 and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 2.5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.8 g, 82%):
[725]
[726] m. Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide and benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 7S) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[727] Dess-Martin periodinan (1.0 g, 2.36 mmol) was added benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydrate in CH ₂ Cl ₂ (20 ml). Roxy-7-methyl-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl] -3-methyl-butyl} -amide and benzofuran-2-carboxylic acid {(S)- 1-[(3R, 4R, 7S) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide (0.8 g, 1.48 mmol) was added to the solution and stirred at room temperature for 45 minutes. This solution was washed with 10% NaHCO ₃ and brine. Purification by column chromatography (60% ethyl acetate / hexanes) gave the title compound as a mixture of diastereomers (0.75 g, 94%):
[728]
[729] Example 6
[730] Preparation of single diastereomers:
[731] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide
[732]
[733] a. ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester
[734] Triphenylphosphine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH ₂ C1 ₂ (231 ml) and then cooled to 0 ° C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then pale brown. After 5 minutes ((R) -2-hydroxy-1-methyl-ethyl) -carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Then H ₂ 0 (7 ml) was added and the reaction mixture was partitioned between CH ₂ Cl ₂ (300 ml) and H ₂ 0 (600 ml). The aqueous layer was extracted again with CH ₂ Cl ₂ (200 ml). The combined organic layers were washed with a solution of 1: 9 saturated Na ₂ S ₂ 0 ₃ aqueous solution: H ₂ 0 (140 ml) followed by brine (400 ml). The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo, filtered through a plug of silica gel and washed with 15% EtOAc / hexanes (1.5 liters). The solution was concentrated in vacuo, the solid was washed with hexanes and the resulting white solid was used for the next reaction without further purification (1 lg, 75%).
[735] b. ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester
[736] Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml) and then cooled to -78 ° C. Allyl magnesium chloride solution (9.4 ml, 2M in THF, Aldrich) was added dropwise and then the solution was stirred for 30 minutes. ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled THF (3 ml) was added dropwise and the reaction was allowed to warm to -40 ° C and then 2.5 Stir for hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (4 ml) at −40 ° C. and warmed to room temperature, then the gray reaction mixture turned light blue. THF was removed in vacuo. Et ₂ O was then added and the reaction mixture was filtered to remove precipitated solids. This solid was washed with additional Et ₂ O. The combined organics were washed with 10% NH ₄ 0H (3 ×), then brine. The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo, filtered through a plug of silica gel and washed with 20% EtOAc / hexanes (100 ml). The solution was concentrated in vacuo and the resulting Colorless oil was used for the next reaction without further purification (0.8 g, 73%).
[737] c. Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester
[738] ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and then cooled to 0 ° C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol) is added and the reaction mixture is stirred at 0 ° C. for 3 hours. H ₂ 0 (10 ml) was added and the pH was adjusted to 1 by dropwise addition of 2N HCl. The reaction mixture was extracted with Et ₂ 0 (2 × 50 ml). The combined organics were washed sequentially with 2N aqueous HCl solution, aqueous NaHCO ₃ solution, and brine. The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo and chromatographed on silica gel (5% EtOAc / hexanes) to afford the title compound as a colorless oil (883 mg, 95%).
[739] d. 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester
[740] Allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester (0.872 g, 3.19 mmol) is dissolved in CH ₂ Cl ₂ (10 ml) and the argon gas stream is bubbled into the reaction mixture for 10 minutes. I was. Bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was then added and the reaction mixture was refluxed for 2 hours. Further bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (mg, 0.0108 mmol) was added and the reaction mixture was further refluxed for 1.5 h. The reaction was cooled to room temperature under argon overnight, concentrated via rotary evaporation in vacuo and then chromatographed (silica gel, 5% EtOAc / hexanes) to afford the title compound (0.72 g, 92%):
[741]
[742] e. (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester
[743] m-chloro-benzoic peroxide (1.10 g, 57-86% purity) was 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester in CH ₂ Cl ₂ at 0 ° C. (0.72 g, 2.94 mmol) was added to the solution. The reaction mixture was stirred for 30 minutes and then warmed up to room temperature. Further m-chloro-benzoic peroxide (0.660 g, 57-86% purity) was added and the reaction stirred for 2 hours. The reaction mixture was concentrated via rotary evaporation in vacuo, 80 ml of 9: 1 hexanes / EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated via rotary evaporation in vacuo and then chromatographed (silica gel, 20% EtOAc: hexanes) to give (1S, 4R, 7S) -4-methyl-8-oxa-3-aza-bicyclo [5.1. 0] -octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield) were obtained:
[744]
[745] f. (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[746] Sodium azide (0.139 g, 2.14 mmol) was dissolved in MeOH (1.5 ml) and H ₂ O (0.15 ml) (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1. To a solution of 0] -octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) was added and refluxed for 6 hours. The reaction mixture was concentrated via rotary evaporation in vacuo, diluted with water (5 ml) and then extracted with EtOAc (10 ml). The organic layer was then extracted with water and brine, dried over MgSO ₄ , filtered, concentrated via rotary evaporation in vacuo, and then chromatographed (silica gel, 20% EtOAc / hexanes) to afford the title compound (0.192 g , 89%):
[747] 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m, 2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d);
[748]
[749] g. (2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[750] Triphenylphosphine (0.25 g, 0.952 mmol) was added (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azane in THF (10 ml) and H ₂ 0 (0.04 ml). To a solution of -1-carboxylic acid benzyl ester (0.193 g, 0.635 mmol) was heated to 45 ° C. overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and azeotropic twice by rotary evaporation in vacuo. The resulting oil was dissolved in HCl and MeOH in Et ₂ O, the resulting salts were collected, filtered and used for the next reaction without further purification (0.27 g, 90%).
[751] h. (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1- Carboxylic acid benzyl ester
[752] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.164 g, 0.22 mmol) was dissolved in DMF (3.2 ml) Boc-leucine-hydrate (0.190 g, 0.76 mmol), diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole (0.114 g, 0.83 mmol), and racemate (2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane- To a solution of 1-carboxylic acid benzyl ester (0.27 g, 0.57 mmol). The reaction was stirred at rt overnight, diluted with EtOAc (100 ml), washed with H ₂ O (3 × 50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and rotary evaporation in vacuo. After concentration through, chromatography (silica gel, 50% EtOAc / hexanes) gave the title compound (0.218 g, 72%):
[753]
[754] i. [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] carbamic acid tert-butyl ester
[755] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl ester (0.169 g, 0.344 mmol) was dissolved in EtOAc (3 ml) and MeOH (1 ml). 10% Pd / C (0.183 g, 0.172 mmol) was then added and stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through celite, concentrated through rotary evaporation in vacuo and used for the next reaction without further purification (0.126 g):
[756]
[757] j. [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester
[758] 2-pyridine sulfonyl chloride (0.71 g, 0.4 mmol) was dissolved in [(S) -1-((3S, 4S, 7R) -3-hydrate in CH ₂ Cl ₂ (3 ml) and H ₂ O (2 ml). Roxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.126 g, 0.344 mmol), sodium barcarbonate (0.87 g, 1.03 mmol) Solution was added and stirred at room temperature for 30 minutes. The reaction mixture is diluted with EtOAc (100 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 3% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.180 g, 70%):
[759]
[760] k. (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides
[761] HCl in dioxane (4.0 M, 1.5 ml) was added [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-ase in MeOH (1.5 ml). To a stirred solution of pan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.090 g, 0.18 mmol). The reaction mixture was stirred at rt for 2 h, concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (0.072 g).
[762] l. Benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide
[763] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.046 g, 0.36 mmol) was added 2-benzofuran-carboxylic acid (0.032 g, 0.198 mmol), (S)-in DMF (2 ml). 2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amide (0.072 g, 0.18 mmol), diisopropylethylamine (0.046 g, 0.06 ml, 0.36 mmol), and a solution of hydroxybenztriazole (0.029 g, 0.36 mmol) were added and stirred at rt overnight. The reaction mixture is diluted with EtOAc (10 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 2.5% MeOH / CH ₂ C1 ₂ ) to give the title compound (0.092 g, 94%):
[764]
[765] m. Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide
[766] Dess-Martin periodinan (0.077 g, 0.182 mmol) was added benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydride in CH ₂ Cl ₂ (10 ml). To a solution of oxy-7-methyl-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl] -3-methyl-butyl} -amide (0.058 g, 0.107 mmol) and added to room temperature Stirred for 1 h. The solution was in turn washed with 10% Na ₂ S ₂ O ₃ aqueous solution, saturated NaHCO ₃ aqueous solution, and brine. Purification by column chromatography (50% to 80% ethyl acetate / hexanes) gave the title compound (0.056 g, 97%):
[767]
[768] Example 7
[769] 2,2,4-tridutro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2 -Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[770] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ilcarbamoyl] -butyl} -amide was dissolved in d4-methanol (CD ₃ 0D) and D ₂ 0 (10: 1), then triethyl amine was added and the reaction mixture was stirred for 3 days. Concentration in vacuo to azeotrope with toluene to afford the title compound.
[771] Example 8
[772] Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide
[773]
[774] a. ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester
[775] Triphenylphosphine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH ₂ Cl ₂ (231 ml) and then cooled to 0 ° C. To this suspension iodine (23.3 g, 91.8 mmol) was added. The reaction mixture turned yellow, then pale brown. After 5 minutes, ((R) -2-hydroxy-1-methyl-ethyl) -carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. . Then H ₂ 0 (7 ml) was added and the reaction mixture was partitioned between CH ₂ Cl ₂ (300 ml) and H ₂ O (600 ml). The aqueous layer was extracted again with CH ₂ Cl ₂ (200 ml). The combined organic layers were washed again with a 1: 9 saturated Na ₂ S ₂ 0 ₃ aqueous solution: H ₂ 0 (140 ml) solution followed by brine (400 ml). The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo, filtered through a silica gel plug and washed with 15% EtOAc / hexanes (1.5 liters). The solution was concentrated in vacuo, the solid was washed with hexane and the resulting white solid was used for the next reaction without further purification (11 g, 75%).
[776] b. ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester
[777] Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml) and then cooled to -78 ° C. Allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added dropwise and then the solution was stirred for 30 minutes. ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled THF (3 ml) was added dropwise and the reaction was allowed to warm to -40 ° C and then 2.5 Stir for hours. The reaction mixture was quenched with saturated aqueous NH ₄ C1 solution (4 ml) at −40 ° C. and warmed to room temperature. The gray reaction mixture turned light blue. THF was removed in vacuo. Et ₂ O was then added and the reaction mixture was filtered to remove precipitated solids. This solid was washed with additional Et ₂ O. The combined organics were extracted with 10% NH ₄ 0H (3 ×), and then brine. The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo, filtered through a plug of silica gel and washed with 20% EtOAc / hexanes (100 ml). After the solution was concentrated in vacuo, the resulting colorless oil was used for the next reaction without further purification (0.8 g, 73%).
[778] c. Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester
[779] ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and cooled to 0 ° C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol) was added and the reaction mixture was stirred at 0 ° C. for 3 hours. H ₂ O (10 ml) was added, followed by dropwise addition of 2N HC1 to adjust the pH to 1. The reaction mixture was extracted with Et ₂ 0 (2 × 50 ml). The combined organics were washed sequentially with 2N aqueous HCl solution, aqueous NaHCO ₃ solution, and brine. The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo and chromatographed on silica gel (5% EtOAc / hexanes) to give the title compound as a colorless oil (883 mg, 95%).
[780] d. 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester
[781] Allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester (0.872 g, 3.19 mmol) is dissolved in CH ₂ C1 ₂ (10 ml) and the argon gas stream is bubbled into the reaction mixture for 10 minutes. I was. Bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was then added and the reaction mixture was refluxed for 2 hours. Further bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (mg, 0.0108 mmol) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to rt overnight under argon, concentrated via rotary evaporation in vacuo and then chromatographed (silica gel, 5% EtOAc / hexanes) to afford the title compound (0.72 g, 92%):
[782]
[783] e. (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester
[784] m-chloro-benzoic peroxide (1.10 g, 57-86% purity) was 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester in CH ₂ Cl ₂ at 0 ° C. (0.72 g, 2.94 mmol) was added to the solution. The reaction mixture was stirred for 30 minutes and then warmed up to room temperature. Further m-chloro-benzoic peroxide (0.660 g, 57-86% purity) was added and the reaction stirred for 2 hours. The reaction mixture was concentrated via rotary evaporation in vacuo, 80 ml of 9: 1 hexanes / EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated via rotary evaporation in vacuo and chromatographed (silica gel, 20% EtOAc: hexanes) to (1S, 4R, 7S) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0 ] -Octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield) were obtained:
[785]
[786] f. (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[787] Sodium azide (0.139 g, 2.14 mmol) was dissolved in MeOH (1.5 ml) and H ₂ O (0.15 ml) (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1. It was added to a solution of 0] -octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) and then refluxed for 6 hours. The reaction mixture was concentrated via rotary evaporation in vacuo, diluted with water (5 ml) and then extracted with EtOAc (10 ml). The organic layer was extracted with water and brine, dried over MgSO ₄ , filtered, concentrated via rotary evaporation in vacuo, and then chromatographed (silica gel, 20% EtOAc / hexanes) to afford the title compound (0.192 g, 89 %):
[788]
[789] g. (2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[790] Triphenylphosphine (0.25 g, 0.952 mmol) was added (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azane in THF (10 ml) and H ₂ 0 (0.04 ml). After addition to a solution of -1-carboxylic acid benzyl ester (0.193 g, 0.635 mmol), it was heated to 45 ° C. overnight. The reaction mixture was diluted with toluene (100 ml x 2) and azeotropic twice by rotary evaporation in vacuo. The resulting oil was dissolved in HCl and MeOH in Et ₂ O, the resulting salts were combined, filtered and used for the next reaction without further purification (0.27 g, 90%).
[791] h. (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1- Carboxylic acid benzyl ester
[792] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.164 g, 0.22 mmol) was dissolved in DMF (3.2 ml) Boc-leucine-hydrate (0.190 g, 0.76 mmol), diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole (0.114 g, 0.83 mmol), and racemate (2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane- To a solution of 1-carboxylic acid benzyl ester (0.27 g, 0.57 mmol). The reaction was stirred at rt overnight, diluted with EtOAc (100 ml), washed with H ₂ 0 (3 × 50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and via rotary evaporation in vacuo. After concentration, chromatography (silica gel, 50% EtOAc / hexanes) afforded the title compound (0.218 g, 72%):
[793]
[794] i. [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[795] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl ester (0.169 g, 0.344 mmol) was dissolved in EtOAc (3 ml) and MeOH (1 ml). 10% Pd / C (0.183 g, 0.172 mmol) was then added and stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through celite, concentrated through rotary evaporation in vacuo and used for the next reaction without further purification (0.126 g):
[796]
[797] j. [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester
[798] 2-pyridine sulfonyl chloride (0.71 g, 0.4 mmol) was added [(S) -1-((3S, 4S, 7R) -3-hydride in CH ₂ C1 ₂ (3 ml) and H ₂ O (2 ml). Roxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.126 g, 0.344 mmol) and sodium bacarbonate (0.87 g, 1.03 mmol) Solution was added and stirred at room temperature for 30 minutes. The reaction mixture is diluted with EtOAc (100 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 3% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.180 g, 70%):
[799]
[800] k. (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides
[801] HCl in dioxane (4.0 M, 1.5 ml) was added [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-ase in MeOH (1.5 ml). To a stirred solution of pan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.090 g, 0.18 mmol). The reaction mixture was stirred at rt for 2 h, concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (0.072 g).
[802] l. Furo [3,2-b] pyridine-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -Azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide
[803] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.035 g, 0.185 mmol) was diluted to furo [3,2-b] pyridine-2-carboxylic acid (0.034 g, 0.2 in DMF (1.5 ml). mmol, described in Shiotani, Shunsaku; Morita, Hiroyuki J. Heteroerocycl. Chem. 1991, 28 (6), 1469-1480)), (S) -2-amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amide (0.077 g, 0.16 mmol), diisopropylethyl To a solution of amine (0.05 g, 0.07 ml, 0.4 mmol), and hydroxybenztriazole (0.025 g, 0.185 mmol) was added and stirred at rt overnight. The reaction mixture was then warmed up to room temperature and stirred overnight. The reaction mixture is diluted with EtOAc (20 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 2.5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.056 g, 64%):
[804]
[805] m. Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide
[806] Sulfur trioxide-pyridine complex (0.050 g, 0.31 mmol) was diluted to furo [3,2-b] pyridine-2-carboxylic acid in DMSO (1.0 ml) and triethylamine (0.085 ml, 0.6 mmol) {(S) -1 -[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide ( 0.056 g, 0.103 mmol) was added and stirred at room temperature for 1 hour. The reaction was not complete so additional triethyl amine (0.04 ml, 0.3 mmol) and sulfur pyridine trioxide complex (0.0025 g, 0.15 mmol) were added and the reaction stirred for 1 hour more. The reaction mixture was diluted with water and extracted with EtOAc. Next, the organic layer was extracted with brine. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (50% to 80% ethyl acetate / hexanes) to give the title compound (12.5 mg, 22%):
[807]
[808] Example 9
[809] 2,2,4-tridutro-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo Preparation of -1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[810]
[811] Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide is dissolved in d4-methanol (CD ₃ 0D) and D ₂ 0 (10: 1), triethyl amine is added, and then the reaction mixture is Stir for 3 days. Concentration in vacuo to azeotropic toluene gave the title compound.
[812] Example 10
[813] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- Preparation of 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[814]
[815] "Furo [3,2-b] pyridine-2-carboxylic acid" to "3-methyl-furo [3,2-b] pyridine-2-carboxylic acid (Shiotani, Shunsaku; Morita, Hiroyuki J. Heteroerocycl Chem. 1991, 28 (6), 1469-1480), except for the substitution of the title compound for the procedure of Example 8 (am):
[816]
[817] Example 11
[818] 2,2,4-tridutro-3-methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl Preparation of 3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide
[819]
[820] "Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sul Ponyyl) -azepane-4-ylcarbamoyl] -butyl} -amide "is referred to as" 3-methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1 Except as substituted with "-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide" The title compound was obtained following the method of Example 9.
[821] Example 12
[822] Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Preparation of Carbamoyl] -Butyl} -amide
[823]
[824] a. ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester
[825] Triphenylphosphine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH ₂ C1 ₂ (231 ml) and cooled to 0 ° C. To this suspension iodine (23.3 g, 91.8 mmol) was added. The reaction mixture turned yellow, then pale brown. After 5 minutes, ((R) -2-hydroxy-1-methyl-ethyl) -carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. . Then H ₂ 0 (7 ml) was added and the reaction mixture was partitioned between CH ₂ Cl ₂ (300 ml) and H ₂ O (600 ml). The aqueous layer was extracted again with CH ₂ Cl ₂ (200 ml). The combined organic layers were washed again with a 1: 9 saturated Na ₂ S ₂ 0 ₃ aqueous solution: H ₂ 0 (140 ml) solution followed by brine (400 ml). The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo, filtered through a silica gel plug and washed with 15% EtOAc / hexanes (1.5 liters). The solution was concentrated in vacuo, the solid was washed with hexane and the resulting white solid was used for the next reaction without further purification (11 g, 75%).
[826] b. ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester
[827] Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml) and then cooled to -78 ° C. Allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added dropwise and then the solution was stirred for 30 minutes. ((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled THF (3 ml) was added dropwise and the reaction was allowed to warm to -40 ° C and then 2.5 Stir for hours. The reaction mixture was quenched with saturated aqueous NH ₄ C1 solution (4 ml) at −40 ° C. and warmed to room temperature. The gray reaction mixture turned light blue. THF was removed in vacuo. Et ₂ O was then added and the reaction mixture was filtered to remove precipitated solids. This solid was washed with additional Et ₂ O. The combined organics were extracted with 10% NH ₄ 0H (3 ×), and then brine. The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo, filtered through a plug of silica gel and washed with 20% EtOAc / hexanes (100 ml). After the solution was concentrated in vacuo, the resulting colorless oil was used for the next reaction without further purification (0.8 g, 73%).
[828] c. Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester
[829] ((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and cooled to 0 ° C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol) is added and the reaction mixture is stirred at 0 ° C. for 3 hours. H ₂ O (10 ml) was added, followed by dropwise addition of 2N HC1 to adjust the pH to 1. The reaction mixture was extracted with Et ₂ 0 (2 × 50 ml). The combined organics were washed sequentially with 2N aqueous HCl solution, aqueous NaHCO ₃ solution, and brine. The combined organics were dried over MgSO ₄ , filtered, concentrated in vacuo and chromatographed on silica gel (5% EtOAc / hexanes) to give the title compound as a colorless oil (883 mg, 95%).
[830] d. 2-Methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester
[831] Allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester (0.872 g, 3.19 mmol) is dissolved in CH ₂ C1 ₂ (10 ml) and the argon gas stream is bubbled into the reaction mixture for 10 minutes. I was. Bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was then added and the reaction mixture was refluxed for 2 hours. Further bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (mg, 0.0108 mmol) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to rt overnight under argon, concentrated via rotary evaporation in vacuo and then chromatographed (silica gel, 5% EtOAc / hexanes) to afford the title compound (0.72 g, 92%):
[832]
[833] e. (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester
[834] m-chloro-benzoic peroxide (1.10 g, 57-86% purity) was 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester in CH ₂ Cl ₂ at 0 ° C. (0.72 g, 2.94 mmol) was added to the solution. The reaction mixture was stirred for 30 minutes and then warmed up to room temperature. Further m-chloro-benzoic peroxide (0.660 g, 57-86% purity) was added and the reaction stirred for 2 hours. The reaction mixture was concentrated via rotary evaporation in vacuo, 80 ml of 9: 1 hexanes / EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated via rotary evaporation in vacuo and chromatographed (silica gel, 20% EtOAc: hexanes) to (1S, 4R, 7S) -4-methyl-8-oxa-3-aza-bicyclo [5.1.0 ] -Octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield) were obtained:
[835]
[836] f. (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[837] Sodium azide (0.139 g, 2.14 mmol) was dissolved in MeOH (1.5 ml) and H ₂ 0 (0.15 ml) (1S, 4R, 7R) -4-methyl-8-oxa-3-aza-bicyclo [5.1. It was added to a solution of 0] -octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) and then refluxed for 6 hours. The reaction mixture was concentrated via rotary evaporation in vacuo, diluted with water (5 ml) and then extracted with EtOAc (10 ml). The organic layer was extracted with water and brine, dried over MgSO ₄ , filtered, concentrated via rotary evaporation in vacuo, and then chromatographed (silica gel, 20% EtOAc / hexanes) to afford the title compound (0.192 g, 89 %):
[838]
[839] g. (2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[840] Triphenylphosphine (0.25 g, 0.952 mmol) was added (2R, 5S, 6S) -5-azido-6-hydroxy-2-methyl-azane in THF (10 ml) and H ₂ 0 (0.04 ml). After addition to a solution of -1-carboxylic acid benzyl ester (0.193 g, 0.635 mmol), it was heated to 45 ° C. overnight. The reaction mixture was diluted with toluene (100 ml x 2) and azeotropic twice by rotary evaporation in vacuo. The resulting oil was dissolved in HCl and MeOH in Et ₂ O, the resulting salts were combined, filtered and used for the next reaction without further purification (0.27 g, 90%).
[841] h. (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1- Carboxylic acid benzyl ester
[842] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.164 g, 0.22 mmol) was converted to Boc-leucine-hydrate (0.190 g, 0.76 mmol), diisopropylethylamine (0.164) in DMF (3.2 ml). g, 0.22 ml, 1.27 mmol), hydroxybenztriazole (0.114 g, 0.83 mmol), and racemate (2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane- To a solution of 1-carboxylic acid benzyl ester (0.27 g, 0.57 mmol). The reaction was stirred at rt overnight, diluted with EtOAc (100 ml), washed with H ₂ 0 (3 × 50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and via rotary evaporation in vacuo. After concentration, chromatography (silica gel, 50% EtOAc / hexanes) afforded the title compound (0.218 g, 72%):
[843]
[844] i. [(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[845] (2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl ester (0.169 g, 0.344 mmol) was dissolved in EtOAc (3 ml) and MeOH (1 ml). 10% Pd / C (0.183 g, 0.172 mmol) was then added and stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through celite, concentrated through rotary evaporation in vacuo and then used for the next reaction without further purification (0.126 g):
[846]
[847] j. [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester
[848] Pyridine-2-sulfonyl chloride (0.71 g, 0.4 mmol) was added [(S) -1-((3S, 4S, 7R) -3- in CH ₂ C1 ₂ (3 ml) and H ₂ O (2 ml). Hydroxy-7-methyl-azepane-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.126 g, 0.344 mmol) and sodium barcarbonate (0.87 g, 1.03 mmol) ), And stirred at room temperature for 30 minutes. The reaction mixture is diluted with EtOAc (100 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 3% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.180 g, 70%):
[849] k. (S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides
[850] HCl in dioxane (4.0 M, 1.5 ml) was added [(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-ase in MeOH (1.5 ml). To a stirred solution of pan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester (0.090 g, 0.18 mmol). The reaction mixture was stirred at rt for 2 h, concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (0.072 g).
[851] l.Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} -amide
[852] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (76 mg, 0.4 mmol) was diluted with quinoline-6-carboxylic acid (64 mg, 0.37 mmol) in DMF (3 ml), (S) -2 -Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amide (160 mg , 0.37 mmol), diisopropylethylamine (56 mg, 0.075 ml, 0.43 mmol), and hydroxybenztriazole (50 mg, 0.37 mmol) were added and stirred overnight at room temperature. The reaction mixture was then warmed up to room temperature and stirred overnight. The reaction mixture is diluted with EtOAc (20 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 4.5% MeOH / CH ₂ Cl ₂ ) to give the title compound (138 mg, 69%):
[853]
[854] m. Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide
[855] Sulfur trioxide-pyridine complex (11 mg, 0.7 mmol) was converted to quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S) in DMSO (2.0 ml) and triethylamine (0.2 ml, 1.4 mmol). , 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide (130 mg, 0.235 mmol) And stirred at room temperature for 1 hour. The reaction was not complete so additional triethyl amine (0.2 ml, 1.4 mmol) and sulfur pyridine trioxide complex (11 mg, 0.7 mmol) were added and the reaction stirred for 1 hour more. The reaction mixture was diluted with water and extracted with EtOAc. Next, the organic layer was extracted with brine. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (3% MeOH / CH ₂ Cl ₂ ) to give the title compound (100 mg, 77%):
[856]
[857] Example 13
[858] Quinoline-3-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Preparation of Carbamoyl] -Butyl} -amide
[859]
[860] The title compound was obtained following the method of Example 12 (a-m) except that "Quinoline-6-carboxylic acid" was replaced with "Quinoline-3-carboxylic acid":
[861]
[862] Example 14
[863] 5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Preparation of Azepan-4-ylcarbamoyl] -butyl} -amide
[864]
[865] The title compound was obtained following the method of Example 12 (a-m) except that "Quinoline-6-carboxylic acid" was substituted with "5-methoxy-benzofuran-2-carboxylic acid":
[866]
[867] Example 15
[868] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -ase Preparation of Pan-4-ylcarbamoyl] -butyl} -amide
[869]
[870] The title compound was obtained following the method of Example 12 (a-m) except that "Quinoline-6-carboxylic acid" was substituted with "3-methyl-benzofuran-2-carboxylic acid":
[871]
[872] Example 16
[873] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2- Preparation of Sulfonyl) -Azepan-4-ylcarbamoyl] -butyl} -amide
[874]
[875] The title compound was obtained following the method of Example 12 (am) except that "Quinoline-6-carboxylic acid" was substituted with "thieno [3,2-b] thiophene-2-carboxylic acid" :
[876]
[877] Example 17
[878] Quinoxaline-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Preparation of Ilcarbamoyl] -Butyl} -amide
[879]
[880] The title compound was obtained following the method of Example 12 (a-m) except that "Quinoline-6-carboxylic acid" was substituted with "quinoxaline-2-carboxylic acid":
[881]
[882] Example 18
[883] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy- Preparation of Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[884]
[885] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are referred to as "1-oxy-pyridine-2-sulfonyl chloride" and "thieno [3,2-b] thiophene-2-carbide The title compound was obtained following the method of Example 12 (am) except that it was substituted with " acid "
[886]
[887] Example 19
[888] 3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Preparation of Ponyl) -Azepan-4-ylcarbamoyl] -butyl} -amide
[889]
[890] Substitute "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "1-oxy-pyridine-2-sulfonyl chloride" and "3-methyl-benzofuran-2-carboxylic acid" The title compound was obtained following the procedure of Example 12 (am) except that:
[891]
[892] Example 20
[893] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -ase Preparation of Pan-4-ylcarbamoyl] -butyl} -amide
[894]
[895] Except for replacing "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "1-oxy-pyridine-2-sulfonyl chloride" and "benzofuran-2-carboxylic acid" The title compound was obtained following the method of Example 12 (am):
[896]
[897] Example 21
[898] Quinoline-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane Preparation of 4-ylcarbamoyl] -butyl} -amide
[899]
[900] Except for replacing "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "1-oxy-pyridine-2-sulfonyl chloride" and "quinoline-2-carboxylic acid" Example 12 (am) was followed to yield the title compound:
[901]
[902] Example 22
[903] 5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine Preparation of -2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide
[904]
[905] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are referred to as "1-oxy-pyridine-2-sulfonyl chloride" and "5,6-difluoro-benzofuran-2-carboxyl The title compound was obtained following the method of Example 12 (am) except that it was substituted with “acid”:
[906]
[907] Example 23
[908] 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy- Preparation of Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[909]
[910] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are referred to as "1-oxy-pyridine-2-sulfonyl chloride" and "5-fluoro-3-methyl-benzofuran-2-car The title compound was obtained following the method of Example 12 (am) except that it was substituted with " acid "
[911]
[912] Example 24
[913] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2- Preparation of Sulfonyl) -Azepan-4-ylcarbamoyl] -butyl} -amide
[914]
[915] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" to "1-oxy-pyridine-2-sulfonyl chloride" and "5-fluoro-benzofuran-2-carboxylic acid" Except for the substitution, the title compound was obtained following the method of Example 12 (am):
[916]
[917] Example 25
[918] 3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1- Preparation of Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[919]
[920] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" to "1-oxy-pyridine-2-sulfonyl chloride" and "3-methyl-furo [3,2-b]] pyridine- The title compound was obtained following the method of Example 12 (am) except that it was substituted with "2-carboxylic acid":
[921]
[922] Example 26
[923] Cyclohexanecarboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide
[924]
[925] Example except for replacing "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "1-oxy-pyridine-2-sulfonyl chloride" and "cyclohexanecarboxylic acid" The title compound was obtained following the method of 12 (am):
[926]
[927] Example 27
[928] (S) -2- (2-cyclohexyl-ethanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Preparation of Ponyl) -Azepan-4-yl] -amide
[929]
[930] Example 12 except for replacing "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "1-oxy-pyridine-2-sulfonyl chloride" and "cyclohexyl-acetic acid" The title compound was obtained following the method in (am):
[931]
[932] Example 28
[933] (S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2- Preparation of Sulfonyl) -Azepan-4-yl] -amide
[934]
[935] Except that "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are substituted with "1-oxy-pyridine-2-sulfonyl chloride" and "3-cyclohexyl-propionic acid" The title compound was obtained following the method in Example 12 (am):
[936]
[937] Example 29
[938] (S) -2- (4-cyclohexyl-butanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Preparation of Ponyl) -Azepan-4-yl] -amide
[939]
[940] Except that "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are substituted with "1-oxy-pyridine-2-sulfonyl chloride" and "4-cyclohexyl-butyric acid" The title compound was obtained following the method in Example 12 (am):
[941]
[942] Example 30
[943] (S) -2- (5-cyclohexyl-pentanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Preparation of Ponyl) -Azepan-4-yl] -amide
[944]
[945] Except for replacing "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "1-oxy-pyridine-2-sulfonyl chloride" and "5-cyclohexyl-pentanoic acid" Example 12 (am) was followed to yield the title compound:
[946]
[947] Example 31
[948] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoromethyl-pyridine-2-sulfonyl ) -Azepan-4-ylcarbamoyl] -butyl} -amide
[949]
[950] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" substituted with "5-trifluoromethyl-pyridine-2-sulfonyl chloride" and "benzofuran-2-carboxylic acid" Except for the following, the title compound was obtained following the method of Example 12 (am):
[951]
[952] Example 32
[953] 5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoromethyl-pyridine Preparation of -2-sulfonyl) -azepane-4-ylcarbamoyl] -butyl} -amide
[954]
[955] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are referred to as "5-trifluoromethyl-pyridine-2-sulfonyl chloride" and "5-fluoro-benzofuran-2-carboxyl The title compound was obtained following the method of Example 12 (am) except that it was substituted with “acid”:
[956]
[957] Example 33
[958] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoro Preparation of Rhomethyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[959]
[960] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are referred to as "5-trifluoromethyl-pyridine-2-sulfonyl chloride" and "thieno [3,2-b] thiophene- The title compound was obtained following the method of Example 12 (am) except that it was substituted with "2-carboxylic acid":
[961]
[962] Example 34
[963] Benzofuran-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -cyclohexyl } Preparation of Amide
[964]
[965] Except that "Boc-L-leucine" and "quinoline-6-carboxylic acid" are substituted with "N-Boc-amino-cyclohexane carboxylic acid" and "benzofuran-2-carboxylic acid" The title compound was obtained following the method in Example 12 (am):
[966]
[967] Example 35
[968] Thiophene-3-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane- Preparation of 4-ylcarbamoyl] -butyl} -amide
[969]
[970] Example 12 (except for replacing "Boc-L-Leucine" and "Quinoline-6-carboxylic acid" with "N-Boc-tert-butylalanine" and "thiophene-3-carboxylic acid" The method of am) gave the title compound:
[971]
[972] Example 36
[973] Furan-2-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide
[974]
[975] Example 12 (am, except that “Boc-L-Leucine” and “Quinoline-6-carboxylic acid” were replaced with “N-Boc-tert-butylalanine” and “furan-2-carboxylic acid” Following the method of) the title compound was obtained:
[976]
[977] Example 37
[978] Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- Preparation of 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide
[979]
[980] Substitution of "Boc-L-leucine" and "quinoline-6-carboxylic acid" with "N-Boc-tert-butylalanine" and "thieno [3,2-b] thiophene-2-carboxylic acid" The title compound was obtained following the procedure of Example 12 (am) except that:
[981]
[982] Example 38
[983] Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 Preparation of -ylcarbamoyl] -ethyl} -amide
[984]
[985] Example 12 except for replacing "Boc-L-Leucine" and "Quinoline-6-carboxylic acid" with "N-Boc-L-cyclohexylalanine" and "benzofuran-2-carboxylic acid" The title compound was obtained following the method in (am):
[986]
[987] Example 39
[988] Furan-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Preparation of Ilcarbamoyl] -ethyl} -amide
[989]
[990] Example 12 (except for replacing "Boc-L-leucine" and "quinoline-6-carboxylic acid" with "N-Boc-L-cyclohexylalanine" and "furan-2-carboxylic acid" The method of am) gave the title compound:
[991]
[992] Example 40
[993] Thiophene-3-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 Preparation of -ylcarbamoyl] -ethyl} -amide
[994]
[995] Example 12 except for replacing "Boc-L-Leucine" and "Quinoline-6-carboxylic acid" with "N-Boc-L-cyclohexylalanine" and "thiophene-3-carboxylic acid" The title compound was obtained following the method in (am):
[996]
[997] Example 41
[998] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- ( Preparation of Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide
[999]
[1000] "Boc-L-Leucine" and "Quinoline-6-carboxylic acid" are referred to as "N-Boc-L-cyclohexylalanine" and "3-methyl-furo [3,2-b] -pyridine-2-carboxyl The title compound was obtained following the method of Example 12 (am) except that it was substituted with “acid”:
[1001]
[1002] Example 42
[1003] (2R, 4aR, 8aR) -octahydro-benzo [1,4] dioxine-2-carboxylic acid [(S) -1-((4S, 7R) -1-methanesulfonyl-7-methyl-3 Preparation of Oxo-Azepan-4-ylcarbamoyl) -3-methyl-butyl] -amide
[1004]
[1005] "Pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" are referred to as "methyl sulfonylchloride" and (2R, 4aR, 8aR) -octahydro-benzo [1,4] dioxine-2-car The title compound was obtained following the method of Example 12 (am) except that it was substituted with " acid "
[1006]
[1007] Example 43
[1008] Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl) -ethyl ] -Made of Amide
[1009]
[1010] a. [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -3-hydroxy-7-methyl-1-propyl-azpan-4-ylcarbamoyl) -ethyl] -carbamic acid tert-butyl ester
[1011] [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -ethyl] -carbamic acid-tert-butyl The method of Example 12 ae, 1.5 g, 3.78 mmol) was dissolved in CH ₂ Cl ₂ (30 mL) except that the ester (“Boc-L-leucine” was replaced with “Boc-L-cyclohexylalanine”) Afterwards, propionaldehyde (0.41 mL, 5.67 mmol) was added. Then sodium borohydride (1.6 g, 7. 56 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated via rotary evaporation in vacuo, filtered and the filtrate was chromatographed (silica gel, 1-4% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (84%, 1.4 g). :
[1012]
[1013] b. (S) -2-Amino-3-cyclohexyl-N-((3S, 4S, 7R) -3-hydroxy-7-methyl-1-propyl-azpan-4-yl) -propionamide
[1014] HCl in dioxane (4.0 M, 15 ml) was added [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -3-hydroxy-7-methyl-1- in MeOH (5 ml). Propyl-azepane-4-ylcarbamoyl) -ethyl] -carbamic acid tert-butyl ester (1.4 g, 3.0 mmol) was added to the stirred solution. The reaction mixture was stirred at rt for 2 h, concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (1.4 g).
[1015] c. Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -3-hydroxy-7-methyl-1-propyl-azpan-4-ylcarbamoyl ) -Ethyl] -amide
[1016] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.10 g, 0.53 mmol) was added furan-2-carboxylic acid (0.059 g, 0.53 mmol) in DMF (2.0 ml), (S) -2 -Amino-3-cyclohexyl-N-((3S, 4S, 7R) -3-hydroxy-7-methyl-1-propyl-azpan-4-yl) -propionamide (0.15 g, 0.36 mmol), To a solution of 4-methylmorphine (0.14 g, 0.16 ml, 1.44 mmol), hydroxybenztriazole (0.071 g, 0.53 mmol) was added and stirred at rt overnight. The reaction mixture was allowed to warm up to room temperature and then stirred overnight. The reaction mixture is diluted with EtOAc (30 ml), washed with H ₂ 0 and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 2.5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.12 g, 76%):
[1017]
[1018] d. Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl) -ethyl ]-amides
[1019] Sulfur trioxide-pyridine complex (0.035 g, 2.2 mmol) was added to furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -3-hydroxy in DMSO (4.0 ml). To a solution of -7-methyl-1-propyl-azepane-4-ylcarbamoyl) -ethyl] -amide (0.19 g, 0.44 mmol) and triethylamine (0.61 ml, 4.4 mmol) at room temperature Stir for 1 hour. The reaction mixture was diluted with water and then extracted with EtOAc. Next, the organic layer was extracted with brine. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (3% methanol / methylene chloride) to give the title compound (0.15 mg, 79%):
[1020]
[1021] Example 44
[1022] Thiophene-3-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl)- Preparation of Ethyl] -amide
[1023]
[1024] The title compound was obtained following the method of Example 43 (a-d) except that “furan-2-carboxylic acid” was replaced with “thiophene-3-carboxylic acid”:
[1025]
[1026] Example 45
[1027] Benzofuran-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azpan-4-ylcarbamoyl)- Preparation of Ethyl] -amide
[1028]
[1029] The title compound was obtained following the method of Example 43 (a-d) except for replacing "furan-2-carboxylic acid" with "benzofuran-2-carboxylic acid":
[1030]
[1031] Example 46
[1032] Of 1- (3-cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid ((4S, 7R) -1-cyclohexylmethyl-7-methyl-3-oxo-azpan-4-yl) -amide Produce
[1033]
[1034] "Boc-L-cyclohexylalanine", "propionaldehyde" and "furan-2-carboxylic acid" are referred to as "N-Boc-amino-cyclohexane carboxylic acid", "cyclohexanecarbaldehyde" and "furan- The title compound was obtained following the method of Example 43 (ad) except that it was substituted with "2-carboxylic acid":
[1035]
[1036] Example 47
[1037] Preparation of benzofuran-2-carboxylic acid [1-((4S, 7R) -1-cyclohexylmethyl-7-methyl-3-oxo-azpan-4-ylcarbamoyl) -cyclohexyl] -amide
[1038]
[1039] "Boc-L-cyclohexylalanine", "propionaldehyde" and "furan-2-carboxylic acid" are referred to as "N-Boc-amino-cyclohexane carboxylic acid", "cyclohexanecarbaldehyde" and "benzofuran The title compound was obtained following the method of Example 43 (ad) except that it was substituted with "-2-carboxylic acid":
[1040]
[1041] Example 48
[1042] Benzofuran-2-carboxylic acid [(S) -3-methyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl) -butyl ] -Made of Amide
[1043]
[1044] Example 43 except for replacing "Boc-L-cyclohexylalanine" and "furan-2-carboxylic acid" with "N-Boc-L-leucine" and "benzofuran-2-carboxylic acid" The title compound was obtained following the method of (ad):
[1045]
[1046] Example 49
[1047] (2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl-6-oxo-azepane-1-carboxylic acid benzyl ester Manufacture
[1048]
[1049] "Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide "to" (2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl- The title compound was obtained following the method of Example 12 (m) except that it was substituted with "6-hydroxy-azepane-1-carboxylic acid benzyl ester".
[1050]
[1051] Example 50
[1052] Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3-oxo- Preparation of Azepan-4-ylcarbamoyl] -butyl} -amide
[1053]
[1054] Example 12 except that “pyridine-2-sulfonyl chloride” and “quinoline-6-carboxylic acid” were replaced with “morphine-4-carbonyl chloride” and “benzofuran-2-carboxylic acid” The title compound was obtained following the method in (am):
[1055]
[1056] Example 51
[1057] (S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) Preparation of 3-Oxo-Azepan-4-yl] -amide
[1058]
[1059] Example 12 (am, except that “pyridine-2-sulfonyl chloride” and “quinoline-6-carboxylic acid” were replaced with “morphine-4-carbonyl chloride” and “cyclohexyl-3-propionic acid” Following the method of) the title compound was obtained:
[1060]
[1061] Example 52
[1062] (2R, 5S) -5-{(S) -2-[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -2-methyl-6-oxo- Preparation of Azepan-1-carboxylic acid (tetrahydro-pyran-4-yl) -amide
[1063]
[1064] Except for replacing "pyridine-2-sulfonyl chloride" and "quinoline-6-carboxylic acid" with "tetrahydro-pyran-4-amino-carbonyl chloride" and "benzofuran-2-carboxylic acid" And following the method of Example 12 (am) to afford the title compound:
[1065]
[1066] Example 53
[1067] (S) -2-{[1-((2R, 5S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoyl Preparation of Amino} -2-methyl-6-oxo-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester
[1068]
[1069] a. (S) -2-({1-[(2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl-6-hydrate Roxy-Azepan-1-yl] -Methanoyl} -amino) -4-methyl-pentanoic acid methyl ester
[1070] [(S) -3-Methyl-1-((4S, 7R) -7-methyl-3-hydroxy-azpan-4-ylcarbamoyl) -butyl] -carbamic acid tert-butyl ester (Example 12a-i, 500 mg, 1.4 mmol) was dissolved in THF (7 ml), and (S)-(-)-2-isocyanato-4-methylvaleric acid methyl ester (180 mg, 1.05 mmol) After addition, the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated via rotary evaporation in vacuo and then chromatographed (silica gel, 1% to 2% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (91%, 506 mg):
[1071]
[1072] b. (S) -2-({1-[(2R, 5S) -5-((S) -2-amino-4-methyl-pentanoylamino) -2-methyl-6-hydroxy-azepane-1 -Yl] -methanoyl} -amino) -4-methyl-pentanoic acid methyl ester
[1073] HCl (8 ml) in 4.0 M dioxane was dissolved in (S) -2-({1-[(2R, 5S) -5-((S) -2-tert-butoxycarbonylamino in MeOH (8 ml)). Of 4-methyl-pentanoylamino) -2-methyl-6-hydroxy-azpan-1-yl] -methanoyl} -amino) -4-methyl-pentanoic acid methyl ester (490 mg, 0.93 mmol) It was added to the stirred solution. The reaction mixture was stirred at rt for 2.5 h, concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (430 mg).
[1074] c. (S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl- Pentanoylamino} -6-hydroxy-2-methyl-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester
[1075] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (214 g, 1.12 mmol) was added benzofuran-2-carboxylic acid (166 g, 1.02 mmol), (S)-in DMF (5 ml). 2-({1-[(2R, 5S) -5-((S) -2-Amino-4-methyl-pentanoylamino) -2-methyl-6-hydroxy-azpan-1-yl]- Metanoyl} -amino) -4-methyl-pentanoic acid methyl ester (430 mg, 0.93 mmol), diisopropylethylamine (240 mg, 0.32 ml, 1.86 mmol), and hydroxybenztriazole (151 mg, 1.12 mmol) and stirred overnight at room temperature. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 ml) and washed with cold 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution, and brine, dried over magnesium sulfate, filtered and via rotary evaporation in vacuo. After concentration, chromatography (silica gel, 2% to 3% MeOH / CH ₂ Cl ₂ ) gave the title compound (478 mg, two steps 84%):
[1076]
[1077] d. (S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl- Pentanoylamino} -6-oxo-2-methyl-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester
[1078] Dess-Martin periodinan (500 mg, 1.18 mmol) was added (S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2 in CH ₂ Cl ₂ (16 ml). -[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -6-hydroxy-2-methyl-azpan-1-yl) -methanoyl] -amino } -4-methyl-pentanoic acid methyl ester (450 mg, 0.79 mmol) was added to and stirred at room temperature for 3 hours. The solution was washed with 10% Na ₂ S ₂ O ₃ aqueous solution, saturated NaHCO ₃ aqueous solution, and brine. Purification by column chromatography (silica gel, 1% to 2% MeOH / CH ₂ Cl ₂ ) gave the title compound (405 mg, 90%):
[1079]
[1080] Example 54
[1081] (S) -2-{[1-((2R, 5S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoyl Preparation of Amino} -2-methyl-6-oxo-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid
[1082]
[1083] a. (S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl- Pentanoylamino} -6-oxo-2-methyl-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester (58 mg, 0.1 mmol) was dissolved in MeOH (1.0 ml) and Dissolve in H ₂ 0 (0.5 ml), potassium carbonate (28 mg, 0.2 mmol) was added and the reaction mixture was stirred at rt for 20 h. The reaction mixture was acidified with cold 1N HCl aqueous solution, extracted with CH ₂ C1 ₂ , washed with brine and dried over magnesium sulfate. Filtered, and concentrated by rotary evaporation and purified by column chromatography (silica _{gel, 2% MeOH / CH 2 Cl} 2 to _{5% MeOH / CH 2 Cl 2} ) to give the title compound as a white solid (28 mg, 50 %):
[1084]
[1085] Example 55
[1086] (S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo Preparation of Azepan-1-yl) -Methanoyl] -amino} -4-methyl-pentanoic acid methyl ester
[1087]
[1088] "(2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester" is referred to as "(3S, 4S) -4-amino-3-hydroxy- The title compound was obtained following the method of Example 53 (ad) except that it was substituted with azepan-1-carboxylic acid benzyl ester (Marquis, RJ Med. Chem., 2001):
[1089]
[1090] Example 56
[1091] (S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo Preparation of Azepan-1-yl) -Methanoyl] -amino} -4-methyl-pentanoic acid
[1092]
[1093] (S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl- Pentanoylamino} -6-oxo-2-methyl-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester "is referred to as" (S) -2-{[1- ( 4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo-azpan-1-yl) -methanoyl ] -Amino} -4-methyl-pentanoic acid methyl ester "was obtained following the method of Example 54 (a) to afford the title compound:
[1094]
[1095] Example 57
[1096] "(S) -4-methyl-2-{[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-meta Noyl) -Amino] -pentanoylamino} -6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid methyl ester
[1097]
[1098] The title compound was obtained following the method of Example 53 (a-d) except that "benzofuran-2-carboxylic acid" was substituted with "quinoline-8-carboxylic acid":
[1099]
[1100] Example 58
[1101] (S) -4-methyl-2-{[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-methanoyl ) -Amino] -pentanoylamino} -6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid
[1102]
[1103] "(S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl -Pentanoylamino} -6-oxo-2-methyl-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester "is referred to as" (S) -4-methyl-2- {[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-methanoyl) -amino] -pentanoylamino}- 6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid methyl ester ", followed by the procedure of Example 54 (a) to afford the title compound:
[1104]
[1105] Example 59
[1106] (R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo Preparation of Azepan-1-yl) -Methanoyl] -amino} -4-methyl-pentanoic acid methyl ester
[1107]
[1108] "(2R, 5S, 6S) -5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester" and "(S)-(-)-2-isocyanato- 4-methylvaleric acid methyl ester "is referred to as" (3S, 4S) -4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester "and (R)-(+)-2-isocyane The title compound was obtained following the method of Example 53 (ad) except that it was substituted with "ITO-4-methylvaleric acid methyl ester":
[1109]
[1110] Example 60
[1111] (R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo Preparation of Azepan-1-yl) -Methanoyl] -amino} -4-methyl-pentanoic acid
[1112]
[1113] "(S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl -Pentanoylamino} -6-oxo-2-methyl-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester "is referred to as" (R) -2-{[1- (4-{(S) -2-[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo-azpan-1-yl) -meta No title] -amino} -4-methyl-pentanoic acid methyl ester "was followed to obtain the title compound following the method of Example 54 (a):
[1114]
[1115] Example 61
[1116] 4,5 (R, S) -Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane Preparation of -4-ylcarbamoyl] -butyl} amide
[1117]
[1118] a. 3-methyl-4-nitro-butyric acid ethyl ester
[1119] Ethyl 2-crotonate (10 g, 87 mmol) was dissolved in nitromethane (23 mL, 438 mmol) and 1,1,3,3, -tetramethylguanidine (2 g, 17 mmol) was added. The solution was stirred at rt for 24 h. Ether was added (500 mL) and the organic phase was washed with 1N HC1 (100 mL) and then dried over sodium sulphate. The solution was filtered, concentrated and the product was purified on silica gel column to give 14 g of the title compound:
[1120]
[1121] b. 3-methyl-4-nitro-butyaldehyde
[1122] DIBAL-H (1.5 M solution) in a solution of 3-methyl-4-nitro-butyric acid ethyl ester (1.0 g, 5.71 mmol) of Example 61a in dry toluene at −78 ° C. to maintain internal temperature below −65 ° C. 4 mL) cold solution was added slowly. The reaction was stirred for 2 more hours. Next, cold MeOH (-78 ° C) was added slowly to quench the reaction and again maintain the internal temperature below -65 ° C. The resulting white emulsion was poured slowly over 15 min into 1N HC1 cooled with ice with stirring and the mixed aqueous solution was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated to afford the crude product. It was purified again on a silica gel column to give the pure product as a pale yellow oil. (0.73 g):
[1123]
[1124] c. 2- [benzyl- (3-methyl-4-nitro-butyl) -amino] -ethanol
[1125] Sodium triacetoxyborohydride (1.57 g, 7.4 mmol) and N-benzyl ethanol in a solution of 3-methyl-4-nitro-butyaldehyde (0.73 g, 5.57 mmol) of Example 61b in methylene chloride (6.0 ml) Amine (0.55 g, 3.67 mmol) was added. The reaction was stirred for 16 h, ketched with water, diluted with EtOAc and washed with NaHCO ₃ and brine. The organic layer was dried over sodium sulphate, concentrated and immediately used for the next reaction:
[1126]
[1127] d. 3,4,5- (R, S) -1-benzyl-5-methyl-4-nitro-azpan-3-ol
[1128] DMSO (1.25 mL, 17.6 mmol) was slowly added to a solution of oxalyl chloride (2M in CH ₂ Cl ₂ ) (3.38 mL) in methylene chloride at −78 ° C. After 15 minutes, this alcohol (0.60 g, 2.25 mmol) dissolved in methylene chloride was added slowly. The reaction was continued for 1 hour at -78 ° C. Triethylamine (4.7 mL, 33.8 mmol) was added and the reaction mixture was brought to room temperature, then quenched with water and the product extracted into methylene chloride. The organic layer was dried over sodium sulphate, filtered and concentrated. Triethyl amine was added to the crude product in THF and the mixture was stirred for 16 hours to afford the title compound. The crude product was purified on silica gel column:
[1129]
[1130] e. 3,4,5- (R, S) -4-Amino-1-benzyl-5-methyl-azepan-3-ol
[1131] Zn powder (0.43 g, 6.47 mmol) was slowly added to a 10: 1 solution of methanol (56 mL) and 12N HCl (5.60 mL). The compound of Example 61d (171 mg, 0.65 mmol) was added and the reaction heated to reflux for 18 hours and concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate and water and basified with solid KOH. The mixture was washed with brine, dried over sodium sulphate, filtered and concentrated to give 120 mg of the title compound:
[1132]
[1133] f. [(S) -1- (1-Benzyl-3-hydroxy-5-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[1134] To a solution of the compound of Example 61e (1.12 g, 4.76 mmol) in methylene chloride was added Boc-leucine (1.3 g, 4.76 mmol), EDC (1 g, 4.76 mmol) and HOBt (0.13 g, 0.96 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate, washed with aqueous sodium barcarbonate solution, and the organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified on silica gel column to give the title compound:
[1135]
[1136] g. [(S) -1- (3-hydroxy-5-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester
[1137] To a solution of the compound of Example 61f in methanol: EtOAc 1: 3 was added 10% Pd / C. This mixture was shaken for 16 hours using a Parr Hydrogenation apparatus of 45 psi of hydrogen gas. The reaction mixture was filtered through a pad of celite and concentrated to afford the title compound:
[1138]
[1139] h. {(S) -1- [3-hydroxy-5-methyl-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert-butyl ester
[1140] To a solution of Example 61g (6 g, 16.8 mmol) in methylene chloride was added 2-pyridinesulfonyl chloride (3 g, 16.9 mmol) and triethylamine (3 mL, 22.5 mmol). The reaction was stirred at rt for 16 h and then washed with NaHC0 ₃ . The organic layer was dried over sodium sulphate, filtered, concentrated and purified on a silica gel column to give 5.36 g of the title compound:
[1141]
[1142] i. (S) -2-Amino-4-methyl-pentanoic acid [3-hydroxy-5-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide
[1143] To a solution of Example 61h compound (5.36 g, 11.57 mmol) in MeOH (2 mL) was added 4M HCl / dioxane (25 mL) and stirred for 2 h. Excess HC1 was removed in vacuo and the residue was dried over toluene (2 ×) to give 5.37 g of the title compound as hydrochloride.
[1144]
[1145] j. 3,4,5 (R, S) -benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -butyl} amide
[1146] To a solution of the compound of Example 61i (0.66 g, 1.26 mmoL) in methylene chloride, 2-benzofuran carboxylic acid (0.24 g, 1.51 mmol), EDC (0.29 g, 1.51 mmol), HOBt (0.04 g, 0.29 mmol) , And Et ₃ N (1 mL) were added. The reaction was stirred at room temperature for 3 hours and then washed with aqueous sodium barcarbonate solution. The organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified on silica gel column to give the title compound:
[1147]
[1148] k. 4,5 (R, S) benzofuran-2-carboxylic acid {(S) -3-methyl-1- [5-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} amide
[1149] To a solution of the compound of Example 61j (0.15 g, 0.27 mmol) in methylene chloride was added des-martin reactant (0.17 g, 0.41 mmol). The reaction was stirred at rt for 1 h, diluted with methylene chloride, washed with sodium thiosulfate, followed by sodium barcarbonate and brine. The organic layer was dried over sodium sulphate, filtered and purified on a silica gel column to give the title compound as a mixture of four diastereomers (0.1 g):
[1150]
[1151] This mixture was purified by HPLC to give four respective diastereomers as white powders.
[1152]
[1153]
[1154]
[1155]
[1156] Example 62
[1157] (R) -2-biphenyl-3-yl-4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Preparation of Il] -amides
[1158]
[1159] a. (2R, 5R, 6R) -5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[1160] Sodium azide (1.8 g, 27.7 mmol) was dissolved in MeOH (16 ml) and H ₂ O (1.6 ml) (1R, 4R, 7S) -4-methyl-8-oxa-3-aza-bicyclo [5.1. To a solution of 0] -octane-3-carboxylic acid benzyl ester (2.4 g, 9.2 mmol, Example le) and ammonium chloride (1.48 g, 27.7 mmol) was added and refluxed overnight. The reaction mixture was concentrated via rotary evaporation in vacuo, diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was washed with water and brine, dried over MgSO ₄ , filtered, concentrated via rotary evaporation in vacuo, and then chromatographed (silica gel, 25% EtOAc / hexanes) to give the title compound (1.76 g, 63 %);
[1161]
[1162] b. (2R, 5R, 6R) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[1163] Triphenylphosphine (2.13 g, 8.14 mmol) was added (2R, 5R, 6R) -5-azido-6-hydroxy-2-methyl-azane in THF (200 ml) and H ₂ O (0.8 ml). Was added to a solution of -1-carboxylic acid benzyl ester (1.65 g, 5.43 mmol) and heated to 45 ° C. overnight. The reaction mixture was diluted with toluene (100 ml × 2) and azeotropic twice by rotary evaporation in vacuo. The resulting oil was dissolved in HC1 and MeOH in Et ₂ O, the resulting salts were collected, filtered and used for the next reaction without further purification (1.7 g, quantitative).
[1164] c. (2R, 5R, 6R) -5-tert-butoxycarbonylamino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester
[1165] Boc anhydride (0.9 g, 4. 13 mmol) was added (2R, 5R, 6R) -5-amino-6-hydroxy-2-methyl-azepane- in THF (5 ml) and H ₂ O (5 ml). To a solution of 1-carboxylic acid benzyl ester (1.0 g, 3.18 mmol) and triethylamine (0.38 g, 0.53 ml, 3.82 mmol) was added and stirred at room temperature for 1 hour. THF and excess triethylamine are removed in vacuo, the reaction mixture is diluted with H ₂ 0 (10 ml), extracted with EtOAc (3 × 20 ml), and the combined organics are H ₂ O (30 ml) and brine. (30 ml), dried over MgSO ₄ , filtered through silica gel, concentrated and used for the next reaction without further purification (1.0 g, 83%):
[1166]
[1167] d. ((3R, 4R, 7R) -3-hydroxy-7-methyl-azpan-4-yl) -carbamic acid tert-butyl ester
[1168] (2R, 5R, 6R) -5-tert-butoxycarbonylamino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.9 g, 2.4 mmol) in EtOAc (40 ml) Dissolved in, 10% Pd / C (0.45 g) was added, and argon was bubbled for 5 minutes to remove gas from the reaction mixture. The reaction was then stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through celite, concentrated via rotary evaporation in vacuo, azeotropic with toluene (20 ml) and then used for the next reaction without further purification (0.58 g, quantitative):
[1169]
[1170] e. [(3R, 4R, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl] -carbamic acid tert-butyl ester
[1171] Pyridine-2-sulfonyl chloride (0.55 g, 3.1 mmol) was added ((3R, 4R, 7R) -3-hydroxy-7-methyl- in CH ₂ Cl ₂ (10 ml) and H ₂ 0 (3 ml). To a solution of azepan-4-yl) -carbamic acid tert-butyl ester (0.58 g, 0.24 mmol) and sodium barcarbonate (0.84 g, 10 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture is diluted with EtOAc (100 ml), washed with H ₂ O and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 45:55 EtOAC). / Hexane) to give the title compound (0.6 g, 65%):
[1172]
[1173] f. (3R, 4R, 7R) -4-Amino-7-methyl-1- (pyridine-2-sulfonyl) -azpan-3-ol
[1174] HC1 (4.0 M, 10 ml) in dioxane was removed from [(3R, 4R, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azepane- in MeOH (10 ml). 4-yl] -carbamic acid tert-butyl ester (0.6 g, 1.55 mmol) was added to the stirred solution. The reaction mixture was stirred at rt for 1 h, diluted with toluene (20 ml), concentrated via rotary evaporation in vacuo and then used for the next reaction without further purification (0.5 g, quantitative):
[1175]
[1176] g. 2-biphenyl-3-yl-4-methyl-pentanoic acid [(3R, 4R, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl ]-amides
[1177] 2-biphenyl-3-yl-4-methyl-pentanoic acid in DMF (5 ml) (270 mg, 1.0 mmol, prepared as described in J. Am. Chem. Soc. 1997, 120, 9114). , (3R, 4R, 7R) -4-amino-7-methyl-1- (pyridine-2-sulfonyl) -azpan-3-ol (320 mg, 1.0 Mmol, Example 1k), EDCI (190 mg , 1.0 Mmol), HOBT (135 mg, 1.0 mmol) and diisopropylethylamine (1.7 g, 0.23 ml, 1.3 mmol) were stirred at rt for 4 h. The reaction mixture is diluted with EtOAc (20 ml), washed with H ₂ 0 and brine, dried over magnesium sulfate, filtered and concentrated via rotary evaporation in vacuo, followed by chromatography (silica gel, 40% EtOAc / Hexane) to give the title compound (330 mg, 62%):
[1178]
[1179] h. (R) -2-Biphenyl-3-yl-4-methyl-pentanoic acid [(4S, 7R) -7-Methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane- 4-yl] -amide
[1180] Dess-Martin periodinan (400 mg, 0.93 mmol) was added 2-biphenyl-3-yl-4-methyl-pentanoic acid [(3R, 4R, 7R) -7-methyl in CH ₂ C1 ₂ (15 ml). To a solution of -3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide (330 mg, 0.62 mmol) was added and stirred at room temperature for 4 hours. The solution was washed with 10% Na ₂ S ₂ O ₃ aqueous solution, saturated NaHC ₀₃ aqueous solution, and brine, concentrated in vacuo and chromatographed (silica gel, 50% EtOAc / hexanes) to give a mixture of diastereomers. (260 mg, 60%). It was dissolved in MeOH (12 ml) and triethylamine (0.44 g, 0.6 ml, 4.4 mmol) and stirred at rt for 3 days. The reaction mixture was concentrated in vacuo and then chromatographed to yield the main components (R)-and (S) -2-biphenyl-3-yl-4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3- A mixture of oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl] -amide was obtained (200 mg, 77%). This diastereomer is separated using HPLC (R, R-Whelk-O preparative column, 40% EtOH / hexanes):
[1181]
[1182] Example 63
[1183] 3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -ase Preparation of Pan-4-ylcarbamoyl] -cyclohexyl} -amide
[1184]
[1185] "Boc-L-Leucine" and "Quinoline-6-carboxylic acid" are referred to as "N-Boc-amino-cyclohexane carboxylic acid" and "3-methyl-furo [3,2-b] -pyridine-2- Carboxylic acid "was followed to obtain the title compound following the method of Example 12 (am):
[1186]
[1187] Example 64
[1188] 1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid [(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Preparation of Il] -amides
[1189]
[1190] Example except for replacing "Boc-L-Leucine" and "Quinoline-6-carboxylic acid" with "N-Boc-amino-cyclohexane carboxylic acid" and "3-cyclohexyl-propanoic acid" The title compound was obtained following the method of 12 (am):
[1191]
[1192] The above specification and examples fully describe the preparation and use of the compounds of the invention. However, the invention is not limited to the particular 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 the state of the art and are incorporated herein by reference in their entirety.

权利要求:
Claims (104)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[Formula I]
(here,
R ¹ is , , , And Is selected from the group consisting of
R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-6 alkyl, R ⁹ C (O)-, R ⁹ C (S)-, R ⁹ SO _2- , R ⁹ 0C (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ (R ¹¹ ) NSO _2- , , And Is selected from the group consisting of
R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl, C _{6 O-alkyl, O-ArC 6} alkyl It is selected from _{O-C 6} heteroaryl group consisting of alkyl, -, _{Ar-O ArC-6} alkyl, hetero-Ar- C _O-6 alkyl, heteroaryl, -ArC _O-6-alkyl, and heteroaryl
R ³ and R ′ may be linked to form a pyrrolidine, piperidine or morpholine ring,
R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _O-6 alkyl, hetero-C _O-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)-,
R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl _- C _O-6 alkyl, C _2-6 alkanoyl, Ar-C _{O -6} is selected from alkyl, and _heteroaryl-O -C ₆ group consisting of alkyl,
R ⁶ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and heteroC _O-6 alkyl,
R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, _{Ar-C O-6} alkyl, heteroaryl, -C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S)-, R ¹⁰ SO _2- , R ¹⁰ OC (O)-, R ¹⁰ R ¹³ NC (O)-and R ¹⁰ R ¹³ NC (S)-,
R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroC _O-6 alkyl and ArC _0-6 alkyl,
R ⁹ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl,
R ¹⁰ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl and hetero-C _O-6 alkyl,
R ¹¹ is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl _- C _O-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
R ¹³ is selected from the group consisting of H, C _1-6 alkyl, Ar-C _O-6 alkyl, and hetero-C _O-6 alkyl,
R 'is selected from the group consisting of H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and _heteroaryl-O -C ₆ alkyl,
R "is selected from H, C _1-6 alkyl, _{Ar-O-C 6} alkyl, and a heteroaromatic group consisting of -C _0-6 alkyl,
R "'is C _1-6 alkyl,
X is selected from the group consisting of CH ₂ , S and O,
Z is selected from the group consisting of C (O) and CH ₂ ,
n is an integer from 1 to 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 C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, and ArC _0-6 alkyl.
[4" claim-type="Currently amended] The compound of claim 3, wherein R ³ is H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methane A compound selected from the group consisting of sulfinyl-ethyl, 1-hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl and hydroxymethyl.
[5" claim-type="Currently amended] The compound of claim 4, wherein R ³ is selected from the group consisting of toluyl, isobutyl and cyclohexylmethyl.
[6" claim-type="Currently amended] The compound of claim 5, wherein R ³ is isobutyl.
[7" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is selected from the group consisting of R ⁵ OC (O) —, R ⁵ C (O) —, and R ⁵ SO ₂ —.
[8" claim-type="Currently amended] 8. A compound according to claim 7, wherein R ⁴ is R ⁵ C (O)-.
[9" claim-type="Currently amended] The compound of claim 8, wherein R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkanoyl, Ar-C _0-6 alkyl And hetero-C _0-6 alkyl.
[10" claim-type="Currently amended] The compound of claim 9, wherein R ⁵ is
Methyl, halogenated methyl, C _1-6 alkoxy and aryloxy substituted methyl, heterocycle substituted methyl;
Butyl, aryl substituted butyl;
Isopentyl;
Cyclohexyl;
Butenyl, aryl substituted butenyl;
Fentanonyl;
Phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more C _1-6 alkoxy groups, phenyl substituted with one or more sulfonyl groups;
benzyl;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Furanyl, halogen substituted furanyl, aryl substituted furanyl;
Tetrahydrofuranyl;
Benzofuranyl, C _1-6 alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C _1-6 alkyl substituted benzofuranyl;
Benzo [b] thiophenyl, C _1-6 alkoxy substituted benzo [b] thiophenyl;
Quinolinyl;
Quinoxalinyl;
1,8-naphthyridinyl;
Indolyl, C _1-6 alkyl substituted indolyl;
Pyridinyl, C _1-6 alkyl substituted pyridinyl, 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, halogen substituted thiophenyl;
Thieno [3,2-b] thiophenyl;
Isoxazolyl, C _1-6 alkyl substituted isoxazolyl; And
Oxazolyl
Compound selected from the group consisting of.
[11" claim-type="Currently amended] The compound of claim 9, wherein R ⁵ is
4-pentanyl;
Naphthylene-2-yl;
Benzo [1,3] dioxol-5-yl;
Tetrahydrofuran-2-yl;
Furan-2-yl
Benzofuran-2-yl;
Benzo [b] thiophen-2-yl;
Quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl;
Quinoxalin-2-yl;
1,8-naphthyridin-2-yl;
Indol-3-yl, indol-5-yl;
Pyridin-2-yl, pyridin-5-yl;
Furo [3,2-b] pyridin-2-yl;
Thiophen-3-yl;
Thieno [3,2-b] thiophen-2-yl;
Isoxazol-4-yl; And
Oxazol-4-yl
Compound selected from the group consisting of.
[12" claim-type="Currently amended] The compound of claim 9, wherein R ⁵ is
Trifluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl, 2-thiophenyl-methyl;
4- (4-methoxy) phenyl-butyl;
4,4-bis (4-methoxyphenyl) -but-3-enyl;
3,4-dichlorophenyl, 4-fluorophenyl, 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, 4-methanesulfonyl-phenyl;
5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5- (3-trifluoromethyl-phenyl) -furan-2-yl, 5-bromo-furan -2-yl, 5- (4-chloro-phenyl) -furan-2-yl;
5- (2-piperazin-4-carboxylic acid tert -butyl ester-ethoxy) benzofuran-2-yl, 5- (2-morpholino-4-yl-ethoxy) -benzofuran-2- 1, 5- (2-piperazin-1-yl-ethoxy) -benzofuran-2-yl, 5- (2-cyclohexyl-ethoxy) -benzofuran-2-yl, 7-methoxy-benzo Furan-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 5,6-difluoro R-benzofuran-2-yl, 3-methyl-benzofuran-2-yl;
5,6-dimethoxy-benzo [b] thiophen-2-yl;
N-methyl-indol-2-yl;
1-oxy-pyridin-2-yl, 2-methyl-pyridin-5-yl;
3-methyl-furo [3,2-b] pyridin-2-yl;
5-methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-yl;
5-tert-butyl-3-methyl thieno [3,2-b] thiophen-2-yl;
3,5-dimethyl-isoxazol-4-yl; And
5-methyl-2-phenyl oxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-4-yl
Compound selected from the group consisting of.
[13" claim-type="Currently amended] 10. The compound of claim 9, wherein R ⁵ is 5-methoxybenzofuran-2-yl, benzo [b] thiophen-2-yl, 3-methyl-benzofuran-2-yl, thieno [3,2-b ] Thiophen-2-yl, benzofuran-2-yl, furo [3,2-b] pyridin-2-yl, and 3-methyl-furo [3,2-b] pyridin-2-yl And selected from the group of compounds.
[14" claim-type="Currently amended] The compound of claim 1, wherein R ′ is selected from the group consisting of H and naphthalen-2-yl-methyl.
[15" claim-type="Currently amended] The compound of claim 13, wherein R ′ is H. 15.
[16" claim-type="Currently amended] The compound of claim 1, wherein R ″ is H. 7.
[17" claim-type="Currently amended] The compound of claim 1, wherein R ″ ′ is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.
[18" claim-type="Currently amended] 18. The compound of claim 17, wherein R "'is methyl.
[19" claim-type="Currently amended] The compound of claim 1, wherein R ″ is H and R ″ ′ is methyl.
[20" claim-type="Currently amended] The compound of claim 1, wherein R ″ ′ is selected from the group consisting of 5-, 6-, and 7-C _1-6 alkyl.
[21" claim-type="Currently amended] The compound of claim 20, wherein 5-, 6- and 7-C _1-6 alkyl is from the group consisting of 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl, and -hexyl The compound selected.
[22" claim-type="Currently amended] The compound of claim 21, wherein 5-, 6- and 7-C _1-6 alkyl is selected from the group consisting of 5-, 6- and 7-methyl.
[23" claim-type="Currently amended] The compound of claim 20, wherein R ″ ′ is selected from the group consisting of 6- and 7-C _1-6 alkyl.
[24" claim-type="Currently amended] The compound of claim 23, wherein 6- and 7-C _1-6 alkyl is selected from the group consisting of 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl, and -hexyl.
[25" claim-type="Currently amended] The compound of claim 24, wherein 6- and 7-C _1-6 alkyl is selected from the group consisting of 6- and 7-methyl.
[26" claim-type="Currently amended] The compound of claim 23, wherein R ″ ′ is 7-C _1-6 alkyl.
[27" claim-type="Currently amended] 27. The compound of claim 26, wherein 7-C _1-6 alkyl is selected from the group consisting of 7-methyl, -ethyl, -propyl, -butyl, -pentyl, and -hexyl.
[28" claim-type="Currently amended] The compound of claim 27, wherein 7-C _1-6 alkyl is 7-methyl.
[29" claim-type="Currently amended] 27. A compound of formula (Ia) according to claim 26.
Formula Ia

Wherein R ″ ′ is cis-7-C _1-6 alkyl
[30" claim-type="Currently amended] The compound of claim 29, wherein R ″ ′ is cis-7-methyl.
[31" claim-type="Currently amended] The compound of claim 1, wherein R ² is Ar—C _0-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ , R ⁹ R ¹¹ NC (O) —, and Compound selected from the group consisting of.
[32" claim-type="Currently amended] The compound of claim 31, wherein R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) —, and R ⁹ SO ₂ .
[33" claim-type="Currently amended] The compound of claim 32, wherein R ² is R ⁹ SO ₂ .
[34" claim-type="Currently amended] 32. The compound of claim 31, wherein R ⁶ is H.
[35" claim-type="Currently amended] 32. The compound of claim 31, wherein R ⁷ is R ¹⁰ OC (O).
[36" claim-type="Currently amended] _{32. The} compound of claim 31, wherein R ⁸ is C _1-6 alkyl.
[37" claim-type="Currently amended] The compound of claim 36, wherein R ⁸ is isobutyl.
[38" claim-type="Currently amended] The method of claim 33, wherein R ⁹ being a C _1-6 alkyl, Ar-C _0-6 alkyl and -C _0-6 heteroatoms selected from the group consisting of alkyl.
[39" claim-type="Currently amended] The compound of claim 38, wherein R ⁹ is
methyl;
Ethyl, and C _1-6 alkyl substituted ethyl;
Butyl, C _1-6 alkyl substituted butyl;
tert -butyl;
Isopentyl;
Phenyl, halogen substituted phenyl, C _1-6 alkoxy phenyl, cyanophenyl;
Toluyl, heterosubstituted toluyl;
Benzoyl;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Benzo [1,2,5] oxadiazolyl;
Pyridinyl, 1-oxy-pyridinyl, C _1-6 alkyl pyridinyl;
Furo [3,2-b] pyridinyl, C _1-6 alkyl substituted furo [3,2-b] pyridinyl;
Thiophenyl;
Thiazolyl;
1H-imidazolyl, C _1-6 alkyl substituted imidazolyl;
1H- [1,2,4] triazolyl, C _1-6 alkyl substituted 1H- [1,2,4] triazolyl; And
Quinolinyl
Compound selected from the group consisting of.
[40" claim-type="Currently amended] The compound of claim 39, wherein R ⁹ is
2-cyclohexyl-ethyl;
3-methylbutyl;
3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4 Dimethoxyphenyl, 2-cyanophenyl;
2-benzoyl;
Naphthylene-2-yl;
Benzo [1,3] dioxol-5-yl;
Benzo [1,2,5] oxadiazol-4-yl;
Pyridin-2-yl, pyridin-3-yl, 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl, 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2- Work;
Furo [3,2-b] pyridin-2-yl, 3-methyl-furo [3,2-b] pyridin-2-yl;
Thiophen-2-yl;
Thiazol-2-yl;
1H-imidazol-2-yl, 1H-imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;
1H- [1,2,4] triazol-3-yl, 5-methyl-1H- [1,2,4] triazol-3-yl; And
Quinolin-2-yl
Compound selected from the group consisting of.
[41" claim-type="Currently amended] The method of claim 1,
R ¹ is ego,
R ² is Ar—C _0-6 alkyl, R ⁹ C (O) —, R ⁹ SO ₂ , R ⁹ R ¹¹ NC (O) — and Is selected from the group consisting of
R ³ is selected from the group consisting of H, C _1-6 alkyl and ArC _0-6 alkyl,
R ⁴ is selected from the group consisting of R ⁵ OC (O) —, R ⁵ C (O) — and R ⁵ SO ₂ —,
R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkanoyl, Ar-C _0-6 alkyl and hetero-C _{0- 6} is selected from the group consisting of alkyl,
R ⁶ is H,
R ⁷ is R ¹⁰ OC (O),
R ⁸ is C _1-6 alkyl,
R 'is H,
R ″ is H.
[42" claim-type="Currently amended] The method of claim 41, wherein
R ² is selected from the group consisting of Ar—C _0-6 alkyl, R ⁹ C (O) — and R ⁹ SO ₂ ,
R ³ is H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1 -Hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl,
R ⁴ is R ⁵ C (O)-,
R ⁵ is
Methyl, halogenated methyl, C _1-6 alkoxy substituted methyl, heterocycle substituted methyl;
Butyl, aryl substituted butyl;
Isopentyl;
Fentanonyl;
Cyclohexyl;
Butenyl, aryl substituted butenyl;
Phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more C _1-6 alkoxy groups or aryloxy groups, phenyl substituted with one or more sulfonyl groups;
benzyl;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Furanyl, halogen substituted furanyl, aryl substituted furanyl;
Tetrahydrofuran-2-yl;
Benzofuranyl, C _1-6 alkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C _1-6 alkyl substituted benzofuranyl;
Benzo [ b ] thiophenyl, C _1-6 alkoxy substituted benzo [ b ] thiophenyl;
Quinolinyl;
Quinoxalinyl;
1,8-naphthyridinyl;
Indolyl, C _1-6 alkyl substituted indolyl;
Pyridinyl, C _1-6 alkyl substituted pyridinyl, 1-oxy-pyridinyl;
Furo [3,2-b] pyridinyl, C _1-6 alkyl substituted furo [3,2-b] pyridin-2-yl;
Thiophenyl, C _1-6 alkyl substituted thiophenyl, halogen substituted thiophenyl;
Thieno [3,2- b ] thiophenyl, C _1-6 alkyl thieno [3,2- b ] thiophenyl;
Isoxazolyl, C _1-6 alkyl substituted isoxazolyl; And
Oxazolyl
Is selected from the group consisting of
R ⁹ is
methyl;
Ethyl, C _1-6 alkyl substituted ethyl;
Butyl, C _1-6 alkyl substituted butyl;
tert -butyl;
Isopentyl;
Phenyl, halogen substituted phenyl, C _1-6 alkoxy phenyl, cyanophenyl;
Toluyl, heterosubstituted toluyl;
Benzoyl;
Naphthylenyl;
Benzo [1,3] dioxolyl;
Benzo [1,2,5] oxadiazolyl;
Pyridinyl, 1-oxy-pyridinyl, C _1-6 alkyl pyridinyl;
Thiophenyl;
Thiazolyl;
1H-imidazolyl, C _1-6 alkyl substituted imidazolyl;
1H- [1,2,4] triazolyl, C _1-6 alkyl substituted 1H- [1,2,4] triazolyl; And
A compound selected from the group consisting of quinolinyl.
[43" claim-type="Currently amended] The compound of claim 41, wherein R ⁵ is
4-pentanyl;
Naphthylene-2-yl;
Benzo [1,3] dioxol-5-yl;
Furan-2-yl;
Benzofuran-2-yl;
Benzo [ b ] thiophen-2-yl;
Quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl;
Quinoxalin-2-yl;
1,8-naphthyridin-2-yl;
Indol-3-yl, indol-5-yl;
Pyridin-2-yl, pyridin-5-yl;
Furo [3,2-b] pyridin-2-yl;
Thiophen-3-yl;
Thieno [3,2- b ] thiophen-2-yl;
Isoxazol-4-yl; And
Oxazol-4-yl
Compound selected from the group consisting of.
[44" claim-type="Currently amended] The compound of claim 41, wherein R ⁵ is
Trifluoromethyl, phenoxy-methyl, 4-fluoro-phenoxy-methyl, 2-thiophenyl-methyl;
4- (4-methoxy) phenyl-butyl;
4,4-bis (4-methoxyphenyl) -but-3-enyl;
3,4-dichlorophenyl, 4-fluorophenyl, 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, 4-methanesulfonyl-phenyl;
5-nitro-furan-2-yl, 5- (4-nitrophenyl) -furan-2-yl, 5- (3-trifluoromethyl-phenyl) -furan-2-yl, 5-bromo-furan -2-yl, 5- (4-chloro-phenyl) -furan-2-yl;
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, 7-methoxy-benzofuran- 2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 5,6-difluoro- Benzofuran-2-yl, 3-methyl-benzofuran-2-yl;
5,6-dimethoxy-benzo [ b ] thiophen-2-yl;
N-methyl-indol-2-yl;
1-oxy-pyridin-2-yl, 2-methyl-pyridin-5-yl;
3-methyl-furo [3,2-b] pyridin-2-yl;
5-methyl-thiophen-2-yl, 4,5-dibromo-thiophen-2-yl;
5- tert -butyl-3-methyl thieno [3,2- b ] thiophen-2-yl;
3,5-dimethyl-isoxazol-4-yl;
5-methyl-2-phenyl oxazol-4-yl, and 2-phenyl-5-trifluoromethyl-oxazol-4-yl
Compound selected from the group consisting of.
[45" claim-type="Currently amended] The compound of claim 41, wherein R ⁹ is
2-cyclohexyl-ethyl;
3-methylbutyl;
3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4 Dimethoxyphenyl, 2-cyanophenyl;
2-benzoyl;
Naphthylene-2-yl;
Benzo [1,3] dioxol-5-yl;
Benzo [1,2,5] oxadiazol-4-yl;
Pyridin-2-yl, pyridin-3-yl, 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl, 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2- Work;
Thiophen-2-yl;
Thiazol-2-yl;
1H-imidazol-2-yl, 1H-imidazol-4-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl;
1H- [1,2,4] triazol-3-yl, 5-methyl-1H- [1,2,4] triazol-3-yl; And
Quinolin-2-yl
Compound selected from the group consisting of.
[46" claim-type="Currently amended] The method of claim 41, wherein
R ² is R ⁹ SO ₂ ,
R ³ is C _1-6 alkyl,
R ⁴ is R ⁵ C (O),
R ⁹ is hetero-C _0-6 alkyl,
R "'is 7-C _1-6 alkyl
compound.
[47" claim-type="Currently amended] 47. The method of claim 46 wherein
R ³ is isobutyl,
R ⁵ is 5-methoxybenzofuran-2-yl, benzo [b] thiophen-2-yl, 3-methyl-benzofuran-2-yl, thieno [3,2-b] thiophen-2- 1, benzofuran-2-yl, furo [3,2-b] pyridin-2-yl, and 3-methyl-furo [3,2-b] pyridin-2-yl,
R ⁹ is selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-yl,
R "'is 7-C _1-6 alkyl
compound.
[48" claim-type="Currently amended] 48. A compound of formula (Ia) according to claim 47.
Formula Ia

Wherein R ″ ′ is cis-7-C _1-6 alkyl
[49" claim-type="Currently amended] 49. The compound of claim 48, wherein R "'is cis-7-methyl.
[50" claim-type="Currently amended] The compound of claim 49, wherein R ⁵ is benzofuran-2-yl.
[51" claim-type="Currently amended] 51. The compound of claim 50, wherein R ⁹ is pyridin-2-yl.
[52" claim-type="Currently amended] The compound of claim 1 selected from the group below.
5-methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -3-methyl-butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -3-methyl-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(4S, 6S) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(4R, 6R) -6-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 7S) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7S) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4R, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- Ylcarbamoyl] -butyl} -amide;
Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
2,2,4-tridutro-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo -1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
2,2,4-tridutro-3-methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl -3-oxo-1- (pyridine-2-sulfonyl) -azane-4-ylcarbamoyl] -butyl} -amide;
Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide;
Quinoline-3-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -butyl} -amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Quinoxaline-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy- Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide;
Quinoline-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-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-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy- Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-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-[(4S, 7R) -7-methyl-3-oxo-1- (1- Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Cyclohexanecarboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
(S) -2- (cyclohexyl-ethanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sulfonyl) -Azepan-4-yl] -amide;
(S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2- Sulfonyl) -azpan-4-yl] -amide;
(S) -2- (4-cyclohexyl-butanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Phonyl) -azpan-4-yl] -amide;
(S) -2- (5-cyclohexyl-pentanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (1-oxy-pyridine-2-sul Phonyl) -azpan-4-yl] -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoromethylpyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -butyl} -amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoromethyl-pyridine -2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (5-trifluoro Rhomethyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -cyclohexyl }-amides;
Thiophene-3-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane- 4-ylcarbamoyl] -butyl} -amide;
Furan-2-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3,3-dimethyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -ethyl} -amide;
Furan-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azane-4- Ylcarbamoyl] -ethyl} -amide;
Thiophene-3-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4 -Ylcarbamoyl] -ethyl} -amide;
3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -2-cyclohexyl-1-[(4S, 7R) -7-methyl-3-oxo-1- ( Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
(2R, 4aR, 8aR) -octahydro-benzo [1,4] dioxine-2-carboxylic acid [(S) -1-((4S, 7R) -1-methanesulfonyl-7-methyl-3 -Oxo-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl) -ethyl ]-amides;
Thiophene-3-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azepane-4-ylcarbamoyl)- Ethyl] -amide;
Benzofuran-2-carboxylic acid [(S) -2-cyclohexyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azpan-4-ylcarbamoyl)- Ethyl] -amide;
1- (3-cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid ((4S, 7R) -1-cyclohexylmethyl-7-methyl-3-oxo-azpan-4-yl) -amide;
Benzofuran-2-carboxylic acid [1-((4S, 7R) -1-cyclohexylmethyl-7-methyl-3-oxo-azepane-4-ylcarbamoyl) -cyclohexyl] -amide;
Benzofuran-2-carboxylic acid [(S) -3-methyl-1-((4S, 7R) -7-methyl-3-oxo-1-propyl-azpan-4-ylcarbamoyl) -butyl ]-amides;
(2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl-6-oxo-azepane-1-carboxylic acid benzyl ester ;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3-oxo- Azepan-4-ylcarbamoyl] -butyl} -amide;
(S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3-oxo-azpan-4-yl] -amide;
(2R, 5S) -5-{(S) -2-[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -2-methyl-6-oxo- Azepan-1-carboxylic acid (tetrahydro-pyran-4-yl) -amide;
(S) -2-{[1-((2R, 5S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoyl Amino} -2-methyl-6-oxo-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
(S) -2-{[1-((2R, 5S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoyl Amino} -2-methyl-6-oxo-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid;
(S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
(S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid;
(S) -4-methyl-2-{[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-methanoyl ) -Amino] -pentanoylamino} -6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid methyl ester;
(S) -4-methyl-2-{[1-((2R, 5S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl-methanoyl ) -Amino] -pentanoylamino} -6-oxo-azpan-1-yl) -methanoyl] -amino} -pentanoic acid;
(R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
(R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-oxo -Azepan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid;
(R) -2-biphenyl-3-yl-4-methyl-pentanoic acid [(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepan-4- General] -amide;
3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -cyclohexyl} -amide; And
1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid [(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) -azepane-4- General] -amide.
[53" claim-type="Currently amended] 53. The compound of claim 52, wherein the benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl) Azepan-4-ylcarbamoyl] -butyl} -amide.
[54" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
[55" claim-type="Currently amended] A method of inhibiting protease, comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof.
[56" claim-type="Currently amended] The method of claim 55, wherein said protease is selected from the group consisting of cysteine proteases and serine proteases.
[57" claim-type="Currently amended] The method of claim 56, wherein the protease is cysteine protease.
[58" claim-type="Currently amended] 58. The method of claim 57, wherein said cysteine protease is cathepsin K.
[59" claim-type="Currently amended] 58. The method of claim 57, wherein said cysteine protease is falcipain.
[60" claim-type="Currently amended] 54. A method for treating a disease characterized by bone loss, comprising inhibiting bone loss by administering an effective amount of the compound of claims 1-53 to a patient in need thereof.
[61" claim-type="Currently amended] 61. The method of claim 60, wherein the disease is osteoporosis.
[62" claim-type="Currently amended] 61. The method of claim 60, wherein the disease is periodontitis.
[63" claim-type="Currently amended] 61. The method of claim 60, wherein the disease is gingivitis.
[64" claim-type="Currently amended] A disease characterized by excessive cartilage or matrix degradation, comprising inhibiting excessive cartilage or matrix degradation by administering an effective amount of a compound according to claim 1 to a patient in need of inhibition of excessive cartilage or matrix degradation. Method of treatment.
[65" claim-type="Currently amended] 65. The method of claim 64, wherein the disease is osteoarthritis.
[66" claim-type="Currently amended] The method of claim 64, wherein the disease is rheumatoid arthritis.
[67" claim-type="Currently amended] An effective amount of a compound according to claims 1-53 is Plasmodium Palmiparum, Tripanosoma Cruise, Tripanosoma Bruce, Laishmania Mexicana, Laishmania Pifanoi, Laishmania Major, Shestosoma Mansoni, Oncoser Carbolbulus, Brugia Pahanji, Entamoeba histolytica, Giardia lambvia, Haemonchus contortus and Pasciola hepatica worms, spiromera, trikinella, necator and ascartis And by administering to a patient in need of inhibition of the expression of cysteine protease causing disease characterized by infection by a parasite selected from the group consisting of Cryptosporidium, Emeria, Toxoplasma and Naeglea protozoa. The level of the disease, including inhibiting expression of the cysteine protease causing the disease Ryo method.
[68" claim-type="Currently amended] 67. The method of claim 67, wherein the disease consists of malaria, tripanosomiasis (African sleeping sickness, chagas disease), lacymaniasis, schistosomiasis, oncoserciasis (river blindness), and giardiasis. The method of treatment is selected from the group.
[69" claim-type="Currently amended] The method of claim 68, wherein the disease is malaria.
[70" claim-type="Currently amended] A compound of formula II: or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
[Formula II]
Wherein R ¹ is , , , And Is selected from the group consisting of
R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 9 C (O) -} , R 9 C (S)-, R ⁹ SO _2- , R ⁹ OC (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-, R ⁹ (R ¹¹ ) NSO _2- , , And Is selected from the group consisting of
R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroaryl C _0-6 alkyl, ArC _0-6 alkyl, , Ar-ArC _0-6 alkyl, Ar- C _0-6 alkyl, heteroaryl, heteroaryl -ArC _0-6 alkyl, and heteroaryl-heteroaryl is selected from the group consisting of C _0-6 alkyl,
R ³ and R ′ may be joined to form a pyrrolidine, piperidine or morpholine ring,
R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S)-, R ⁵ SO _2- , R ⁵ OC (O)-, R ⁵ R ¹² NC (O)-and R ⁵ R ¹² NC (S)-,
R ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkanoyl, Ar-C _{0 -6} alkyl and hetero-C _0-6 alkyl;
R ⁶ is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, heteroaryl, -C _0-6 ^{alkyl, R 10 C (O) -} , R 10 C (S)-, R ¹⁰ SO _2- , R ¹⁰ OC (O)-, R ¹⁰ R ¹³ NC (O)-and R ¹⁰ R ¹³ NC (S)-,
R ⁸ is selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero-C _0-6 alkyl and Ar-C _0-6 alkyl,
R ⁹ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R ¹⁰ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R ¹¹ is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R ¹² is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R ¹³ is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R 'is selected from the group consisting of H, C _1-6 alkyl, Ar-C _0-6 alkyl and heteroaryl -C _0-6 alkyl,
R "is selected from H, C _1-6 alkyl, Ar-C _0-6 alkyl and -C heterocyclic group consisting of _0-6 alkyl,
R "'is C _1-6 alkyl,
X is selected from the group consisting of CH ₂ , S and O,
Z is selected from the group consisting of C (O) and CH ₂ ,
n is an integer from 1 to 5)
[71" claim-type="Currently amended] The compound of claim 70, wherein R ″ ′ is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.
[72" claim-type="Currently amended] The compound of claim 71, wherein R ″ ′ is methyl.
[73" claim-type="Currently amended] The compound of claim 70, wherein R ″ ′ is selected from the group consisting of 5-, 6-, and 7-C _1-6 alkyl.
[74" claim-type="Currently amended] 75. The compound of claim 73, wherein 5-, 6- and 7-C _1-6 alkyl is from the group consisting of 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl, and -hexyl The compound selected.
[75" claim-type="Currently amended] 75. The compound of claim 74, wherein 5-, 6- and 7-C _1-6 alkyl is selected from the group consisting of 5-, 6- and 7-methyl.
[76" claim-type="Currently amended] The compound of claim 73, wherein R ″ ′ is selected from the group consisting of 6- and 7-C _1-6 alkyl.
[77" claim-type="Currently amended] 77. The compound of claim 76, wherein 6- and 7-C _1-6 alkyl is selected from the group consisting of 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl, and -hexyl.
[78" claim-type="Currently amended] 78. The compound of claim 77, wherein 6- and 7-C _1-6 alkyl is selected from the group consisting of 6- and 7-methyl.
[79" claim-type="Currently amended] 77. The compound of claim 76, wherein R "'is 7-C _1-6 alkyl.
[80" claim-type="Currently amended] 80. The compound of claim 79, wherein 7-C _1-6 alkyl is selected from the group consisting of 7-methyl, -ethyl, -propyl, -butyl, -pentyl, and -hexyl.
[81" claim-type="Currently amended] _{81. The} compound of claim 80, wherein 7-C _1-6 alkyl is 7-methyl.
[82" claim-type="Currently amended] 80. The compound of formula 79, wherein formula (la).
Formula Ia

Wherein R ″ ′ is cis-7-C _1-6 alkyl
[83" claim-type="Currently amended] 83. The compound of claim 82, wherein cis-7-C _1-6 alkyl is cis-7-methyl.
[84" claim-type="Currently amended] The compound of claim 70, selected from the group below.
3-methyl-1- (pyridine-2-sulfonyl) -2,3,4,7-tetrahydro-1H-azepine;
5-methyl-3- (pyridine-2-sulfonyl) -8-oxa-3-aza-bicyclo [5.1.0] octane;
4-azido-5-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol;
4-amino-6-methyl-1- (pyridin-2-sulfonyl) -azpan-3-ol;
{(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid tert- Butyl esters;
5-methoxy-benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-6-methyl-1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl ] -3-methyl-butyl} -amide;
Allyl- (1-methyl-pent-4-enyl) -carbamic acid benzyl ester;
2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;
4-methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester;
5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
5-amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
(2S, 5R, 6R) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[(S) -1-((3R, 4R, 7S) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[(S) -1-((3S, 4S, 7R) -1-benzenesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
[(S) -1-((3R, 4R, 7S) -1-benzenesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
(S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
(S) -2-Amino-4-methyl-pentanoic acid ((3R, 4R, 7S) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
Benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -1-[(3R, 4R, 7S) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -azpan-4-yl Carbamoyl] -3-methyl-butyl} -amide;
((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester;
Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester;
2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;
(1S, 4R, 7R) -4-Methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
(S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3R, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(3S, 4S, 6S) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
Benzo [b] thiophene-2-carboxylic acid {(S) -1-[(3R, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(3S, 4S, 6S) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -1-[(3R, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -3-methyl-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(3S, 4S, 6S) -6-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -1-[(3S, 4R, 6R) -6-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azepane-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7S) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3R, 4R, 7S) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3R, 4R, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
((R) -2-iodo-1-methyl-ethyl) -carbamic acid benzyl ester;
((R) -1-Methyl-pent-4-enyl) -carbamic acid benzyl ester;
Allyl-((R) -1-methyl-pent-4-enyl) -carbamic acid benzyl ester;
2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester;
(1S, 4R, 7R) -4-Methyl-8-oxa-3-aza-bicyclo [5.1.0] -octane-3-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester;
(2R, 5S, 6S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -6-hydroxy-2-methyl-azepane-1-carboxyl Acid benzyl esters;
[(S) -1-((3S, 4S, 7R) -3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert-butyl ester;
[(S) -1-((3S, 4S, 7R) -2-pyridinesulfonyl-3-hydroxy-7-methyl-azpan-4-ylcarbamoyl) -3-methyl-butyl] -carr Chest acid tert-butyl ester;
(S) -2-Amino-4-methyl-pentanoic acid ((3S, 4S, 7R) -1- (2-pyridine) -sulfonyl-3-hydroxy-7-methyl-azpan-4-yl) -amides;
Furo [3,2-b] pyridine-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
Furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -1-[(3S, 4S, 7R) -3-hydroxy-7-methyl-1- (pyridine-2 -Sulfonyl) -azpan-4-ylcarbamoyl] -3-methyl-butyl} -amide;
3-Methyl-furo [3,2-b] pyridine-2-carboxylic acid {(S) -3-methyl-1-[(4S, 7R) -7-methyl-3-oxo-1- (pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Quinoline-6-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;
Quinoline-3-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane- 4-ylcarbamoyl] -butyl} -amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sul Phonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine -2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Quinoxaline-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1 -Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
3-Methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl ) -Azepane-4-ylcarbamoyl] -butyl} -amide;
Quinoline-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -Azpan-4-ylcarbamoyl] -butyl} -amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1- Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl-amide;
5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1 -Oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-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-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Cyclohexanecarboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide;
(S) -2- (2-cyclohexyl-ethanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-yl] -amide;
(S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine -2-sulfonyl) -azpan-4-yl] -amide;
(S) -2- (4-cyclohexyl-butanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-yl] -amide;
(S) -2- (5-cyclohexyl-pentanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (1-oxy-pyridine- 2-sulfonyl) -azpan-4-yl] -amide;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (5 trifluoromethyl-pyridine-2- Sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (5-trifluoro Methyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (5 -Trifluoromethyl-pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepane-4-ylcarbamoyl] -Cyclohexyl} -amide;
Thiophene-3-carboxylic acid {(S) -3,3-dimethyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -butyl} -amide;
Furan-2-carboxylic acid {(S) -3,3-dimethyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -butyl} -amide;
Thieno [3,2-b] thiophene-2-carboxylic acid {(S) -3,3-dimethyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (Pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -butyl} -amide;
Benzofuran-2-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -ethyl} -amide;
Furan-2-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azane -4-ylcarbamoyl] -ethyl} -amide;
Thiophene-3-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -ase Pan-4-ylcarbamoyl] -ethyl} -amide;
3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {(S) -2-cyclohexyl-1-[(3S, 4S, 7R) -7-methyl-3-hydroxy- 1- (pyridine-2-sulfonyl) -azpan-4-ylcarbamoyl] -ethyl} -amide;
(2R, 4aR, 8aR) -octahydro-benzo [1,4] dioxine-2-carboxylic acid [(S) -1-((3S, 4S, 7R) -1-methanesulfonyl-7-methyl -3-hydroxy-azpan-4-ylcarbamoyl) -3-methyl-butyl] -amide;
Furan-2-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propylazane-4-ylcarbamoyl) -Ethyl] -amide;
Thiophene-3-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propyl-azpan-4-ylcarba Moyl) -ethyl] -amide;
Benzofuran-2-carboxylic acid [(S) -2-cyclohexyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propyl-azpan-4-ylcarba Moyl) -ethyl] -amide;
1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid ((3S, 4S, 7R) -1-cyclohexylmethyl-7-methyl-3-hydroxy-azpan-4-yl) -amides;
Benzofuran-2-carboxylic acid [1-((3S, 4S, 7R) -1-cyclohexylmethyl-7-methyl-3-hydroxy-azpan-4-ylcarbamoyl) -cyclohexyl]- amides;
Benzofuran-2-carboxylic acid [(S) -3-methyl-1-((3S, 4S, 7R) -7-methyl-3-hydroxy-1-propyl-azpan-4-ylcarbamoyl ) -Butyl] -amide;
(2R, 5S) -5-((S) -2-tert-butoxycarbonylamino-4-methyl-pentanoylamino) -2-methyl-6-hydroxy-azepane-1-carboxylic acid benzyl ester;
Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(3S, 4S, 7R) -7-methyl-1- (1-morpholin-4-yl-methanoyl) -3- Hydroxy-azpan-4-ylcarbamoyl] -butyl} -amide;
(S) -2- (3-cyclohexyl-propanoylamino) -4-methyl-pentanoic acid [(3S, 4S, 7R) -7-methyl-1- (1-morpholin-4-yl-meta Noyl) -3-hydroxy-azpan-4-yl] -amide;
(2R, 5S, 6S) -5-{(S) -2-[(1-Benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -2-methyl-6- Hydroxy-azane-1-carboxylic acid (tetrahydro-pyran-4-yl) -amide;
(S) -2-{[1-((2R, 5S, 6S) -5-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl- Pentanoylamino} -2-methyl-6-hydroxy-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
(S) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-hydrate Oxy-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
(S) -4-methyl-2-{[1-((2R, 5S, 6S) -2-methyl-5-{(S) -4-methyl-2-[(1-quinolin-8-yl- Metanoyl) -amino] -pentanoylamino} -6-hydroxy-azpan-1-yl) -methanoyl] -amino} -pentanoic acid methyl ester;
(R) -2-{[1- (4-{(S) -2-[(1-benzofuran-2-yl-methanoyl) -amino] -4-methyl-pentanoylamino} -3-hydrate Oxy-azpan-1-yl) -methanoyl] -amino} -4-methyl-pentanoic acid methyl ester;
2-biphenyl-3-yl-4-methyl-pentanoic acid [(3R, 4R, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azpan-4-yl ]-amides;
3-Methyl-furo [3,2-b] -pyridine-2-carboxylic acid {1-[(4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl)- Azepan-4-ylcarbamoyl] -cyclohexyl} -amide; And
1- (3-Cyclohexyl-propanoylamino) -cyclohexanecarboxylic acid [(4S, 7R) -7-methyl-3-hydroxy-1- (pyridine-2-sulfonyl) -azepan-4 -Yl] -amide.
[85" claim-type="Currently amended] 72. A process for the preparation of a compound according to claim 1 comprising oxidizing the corresponding compound of claim 70 with an oxidizing agent to obtain a compound of formula (I) as a mixture of diastereomers.
[86" claim-type="Currently amended] 86. The process of claim 85, wherein the oxidant is a sulfur dioxide-pyridine complex.
[87" claim-type="Currently amended] 86. The method of claim 85, further comprising the step of separating the diastereomers by separation means.
[88" claim-type="Currently amended] 88. The method of claim 87, wherein said separation means is high pressure liquid chromatography (HPLC).
[89" claim-type="Currently amended] 86. The process of claim 85, further comprising deuteration of said diastereomer with a deuteration agent.
[90" claim-type="Currently amended] 90. The process of claim 89, wherein said deuteration agent is CD ₃ OD: D ₂ O (10: 1) in triethylamine.
[91" claim-type="Currently amended] Use of the compound according to any one of claims 1 to 53 for the manufacture of a medicament for use in inhibiting a protease selected from the group consisting of cysteine proteases and serine proteases.
[92" claim-type="Currently amended] 92. The use of claim 91, wherein said protease is a cysteine protease.
[93" claim-type="Currently amended] 93. The use of claim 92, wherein the cysteine protease is cathepsin K.
[94" claim-type="Currently amended] 93. The use of claim 92, wherein said cysteine protease is falcipine.
[95" claim-type="Currently amended] 54. A pharmaceutical use of a compound according to any one of claims 1 to 53 for use in the treatment of a disease characterized by bone loss.
[96" claim-type="Currently amended] 95. The use of claim 95, wherein said disease is osteoporosis.
[97" claim-type="Currently amended] 97. The use of claim 95, wherein the disease is periodontitis.
[98" claim-type="Currently amended] 97. The use of claim 95, wherein the disease is gingivitis.
[99" claim-type="Currently amended] Use of the compound according to any one of claims 1 to 53 for the manufacture of a medicament for use in the treatment of a disease characterized by excessive cartilage or matrix degradation.
[100" claim-type="Currently amended] The use of claim 99, wherein said disease is osteoarthritis.
[101" claim-type="Currently amended] The use of claim 99, wherein said disease is rheumatoid arthritis.
[102" claim-type="Currently amended] Plasmodium Palmiparum, Tripanosoma Cruise, Tripanosoma Bruce, Laishmania Mexicana, Laishmania Pifanoi, Laishmania Major, Shestosoma Mansoni, Oncoserca Volbulus, Brugia Pahanji, Entamoeva Heath Tortica, Giardia Rambia, Haemonchus Contortus and Pasiola Hepatica worms, Spiromella, Trikinella, Necator and Ascartis worms, and Cryptosporidium, Emeria, Toxoplasma and Naegle Use of the compound according to any one of claims 1 to 53 for the manufacture of a medicament for use in the treatment of a disease caused by an infection of a parasite selected from the group consisting of L. protozoa.
[103" claim-type="Currently amended] 107. The disease according to claim 102, wherein the disease consists of malaria, tripanosomiasis (African sleeping sickness, chagas disease), lacymaniasis, schistosomiasis, oncoserciasis (river blindness), and giardiasis. Use selected from the group.
[104" claim-type="Currently amended] 109. The use of claim 103, wherein the disease is malaria.

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同族专利:

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公开号 | 公开日

---

AP200202593A0|2002-09-30|

---

EP1307203A4|2005-08-17|

---

WO2001070232A1|2001-09-27|

---

EA005893B1|2005-06-30|

---

EP1307203A1|2003-05-07|

---

US20060194787A1|2006-08-31|

---

AR032877A1|2003-12-03|

---

AP1540A|2006-01-11|

---

IL150964D0|2003-02-12|

---

EA200201001A1|2003-02-27|

---

NO20024528L|2002-11-19|

---

AU4344101A|2001-10-03|

---

US7563784B2|2009-07-21|

---

NZ520588A|2004-06-25|

---

CN1416346A|2003-05-07|

---

HU0300068A2|2003-05-28|

---

US7071184B2|2006-07-04|

---

US20040044201A1|2004-03-04|

---

MXPA02009305A|2003-03-12|

---

MY141596A|2010-05-31|

---

SK13632002A3|2003-02-04|

---

OA12323A|2006-05-15|

---

UY26625A1|2001-09-28|

---

PE20011233A1|2002-02-07|

---

AU2001243441B2|2004-11-25|

---

CA2404206A1|2001-09-27|

---

PL357727A1|2004-07-26|

---

NO20024528D0|2002-09-20|

---

JP2003527429A|2003-09-16|

---

BG106962A|2003-03-31|

---

DZ3318A1|2001-09-27|

---

CZ20023168A3|2003-02-12|

---

BR0109356A|2003-06-03|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2000-03-21|Priority to US19100000P

---

2000-03-21|Priority to US60/191,000

---

2000-05-23|Priority to US20634100P

---

2000-05-23|Priority to US60/206,341

---

2000-06-14|Priority to US60/211,759

---

2000-06-14|Priority to US21175900P

---

2000-07-10|Priority to US21744500P

---

2000-07-10|Priority to US60/217,445

---

2001-03-07|Application filed by 스미스클라인 비참 코포레이션

---

2001-03-07|Priority to PCT/US2001/007094

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2002-10-31|Publication of KR20020082896A

优先权:

---

申请号 | 申请日 | 专利标题

---

US19100000P| true| 2000-03-21|2000-03-21|

---

US60/191,000|2000-03-21|

---

US20634100P| true| 2000-05-23|2000-05-23|

---

US60/206,341|2000-05-23|

---

US21175900P| true| 2000-06-14|2000-06-14|

---

US60/211,759|2000-06-14|

---

US21744500P| true| 2000-07-10|2000-07-10|

---

US60/217,445|2000-07-10|

---

PCT/US2001/007094|WO2001070232A1|2000-03-21|2001-03-07|Protease inhibitors|