OA12288A - Protease inhibitors. - Google Patents

Protease inhibitors. Download PDF

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OA12288A
OA12288A OA1200200377A OA1200200377A OA12288A OA 12288 A OA12288 A OA 12288A OA 1200200377 A OA1200200377 A OA 1200200377A OA 1200200377 A OA1200200377 A OA 1200200377A OA 12288 A OA12288 A OA 12288A
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OAPI
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methyl
oxo
azepan
butyl
amide
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OA1200200377A
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Maxwell D Cummings
Marquis Robert W Jr
Yu Ru
Scott K Thompson
Daniel F Veber
Dennis Yamashita
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Smithkline Beecham Corp
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Abstract

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

Description

012288
PROTEASE INHIBITORS f
y FEELDOF THE INVENTION
This invention relates in general to 4-amino-azepan-3-one protease inhibitors, 5 particuiarly such inhibitors of cysteine and serine proteases, more particularly compoundswhich inhibit cysteine proteases, even more particularly compounds which inhibit cysteineproteases of the papain superfamily, yet more particularly compounds which inhibitcysteine proteases of the cathepsin farnily, most particularly compounds which inhibitcathepsin K. Such compounds are particularly useful for treating diseases in which 10 cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss,e.g., osteoporosis, periodontitis, and arfhritis. BACKGROUND OF THE INVENTIONCathepsins are a family of enzymes which are part of the papain superfamily of 15 cysteine proteases. Cathepsins B, H, L, N and S hâve been described in the literature.Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide weredisclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has beenrecently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem.271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271,12511-12516; Bromme, 20 D., et al., (1996) J. Biol. Chem. 271,2126-2132.
Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature. The désignation cathepsin K is considered to be the more appropriate one.
Cathepsins function in the normal physiological process of protein dégradation in animais, including humans, e.g., in the dégradation of connective tissue. However, elevated 25 levels of these enzymes in the body can resuit in pathological conditions leading to disease.Thus, cathepsins hâve been implicated as causative agents in various disease States,including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi,trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria,tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the 30 like. See International Publication Number WO 94/04172, published on March 3,1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called 1 012288 gingipains, hâve been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2,445-458.
Cathepsin K is believed to play a causative rôle in diseases of excessive bone orcartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shapedcrystals of hydroxyapatite are incorporated. Type I collagen represents the major structuralprotein of bone comprising approximately 90% of the protein matrix. The remaining 10%of matrix is composed of anumber of non-collagenous proteins, inclnding osteocalcin,proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bonesialoprotein. Skeletal bone undergoes remodelling at discrète foci throughout life. Thesefoci, or remodelling units, undergo a cycle consisting of a bone résorption phase followedby a phase of bone replacement.
Bone résorption is carried out by osteoclasts, which are multinuclear cells ofhematopoietic lineage. The osteoclasts adhéré to the bone surface and form a tight sealingzone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
This créâtes an enclosed extracellular compartment on the bone surface that is acidified byproton pumps in the ruffled membrane, and into which the osteoclast sécrétés proteolyticenzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bonesurface, while the proteolytic enzymes digest the protein matrix. In this way, a résorptionlacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a newprotein matrix that is subsequently mineralized. In several disease States, such asosteoporosis and Paget’s disease, the normal balance between bone résorption andformation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leadsto weakening of the bone and may resuit in increased fracture risk with minimal trauma.
Several published studies hâve demonstrated that inhibitors of cysteine proteasesare effective at inhibiting osteoclast-mediated bone résorption, and indicate an essentialrôle for a cysteine proteases in bone résorption. For example, Délaissé, et al., Biochem. J.,1980,192, 365, disclose a sériés of protease inhibitors in a mouse bone organ cultureSystem and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN2)prevent bone résorption, while serine protease inhibitors were ineffective. Délaissé, et al.,Biochem. Biophys. Res. Commun., 1984,125, 441, disclose that E-64 and leupeptin are alsoeffective at preventing bone résorption in vivo, as measured by acute changes in sérumcalcium in rats on calcium déficient diets. Lemer, et al., J. Bone Min. Res., 1992, 7,433,disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated F· 2 012288 bone résorption in mouse calvariae. Other studies, such as by Délaissé, et al., Bone, 1987, S, 305, Hill, et al., J. Cell. Biochem., 1994,56,118, and Everts, et al., J. Cell. Physiol., 1992,150,221, also report a corrélation between inhibition of cysteine protease activity and bone résorption. Tezuka, et al., J. Biol. Chem., 1994, 269,1106, Inaoka, et al., 5 Biochem. Biophys. Res. Commun., 1995,206, 89 and Shi, et al., FEBS Lett., 1995, 357,129disclose that under normal conditions cathepsin K, a cysteine protease, is abnndantlyexpressed in osteoclasts and may be the major cysteine protease présent in these cells.
The abundant sélective expression of cathepsin K in osteoclasts strongly suggeststhat this enzyme is essential for bone résorption. Thns, sélective inhibition of cathepsin K 10 may provide an effective treatment for diseases of excessive bone loss, including, but notlimited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget’sdisease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levelshâve also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.Thus, sélective inhibition of cathepsin K may also be usefulfor treating diseases of 15 excessive cartilage or matrix dégradation, including, but not limited to, osteoarthritis andrheumatoid arthritis. Metastatic neoplastic cells also typically express high levels ofproteolytic enzymes that dégradé the surrounding matrix. Thus, sélective inhibition ofcathepsin K may also be useful for treating certain neoplastic diseases.
Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 20 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldéhydes,nitriles, α-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones,(acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds hâvealso been reported to inhibit cysteine proteases. See Palmer, id, and references cited 25 therein. U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irréversibleinhibitors of cysteine protease. Published International Patent Application No. WO94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, andEP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the 30 cysteine proteases cathepsins B, H and L. International Patent Application No. PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describealkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-lpconvertase. Alkoxymethyl and mercaptomethyl ketones hâve also been described as 3 012288 inhibitors of the serine protease kinmogenase (International Patent Application No.PCT/GB91/01479).
Azapeptides winch are designed to deliver the araarnino acid to the active site ofserine proteases, and which possess a good leaving group, are disclosed by Elmore et al.,Biochem. J., 1968,107,103, Garker et al., Biochem. J., 1974,139,555, Gray étal.,Tetrahedron, 1977,33, 837, Gupton et al., J. Biol. Chem., 1984,259, 42Ί9, Powers et al., J.Biol. Chem., 1984,259,4288, and are known to inhibit serine proteases. In addition, J.
Med. Chem., 1992,35,4279, discloses certain azapeptide esters as cysteine proteaseinhibitors.
Antipain and leupeptin are described as réversible inhibitors of cysteine protease inMcConnell et al., J. Med. Chem., 33, 86; and also hâve been disclosed as inhibitors ofserine protease in Umezawa et al., 45 Meih. Enzymol. 678. E64 and its synthetic analogsare also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201,189, andGrinde, Biochem. Biophys. Acta,, 701, 328). 1,3-diamido-propanones hâve been described as analgésie agents in U.S. PatentNos.4,749,792 and 4,638,010.
Thus, a structurally diverse variety of protease inhibitors hâve been identified. :However, these known inhibitors are not considered suitable for use as therapeutic agents inanimais, especially humans, because they suffer from varions shortcomings. Theseshortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapidplasma clearance. A need therefore exists for methods of treating diseases caused bypathological levels of proteases, particularly cysteine proteases, more particularlycathepsins, most particularly cathepsin K, and for novel inhibitor compounds useful in suchmethods.
We hâve now discovered a novel class of 4-amino-azepan-3-one compounds whichare protease inhibitors, most particularly of cathepsin K.
SUMMARY OF THE INVENTION
An object of the présent invention is to provide 4-amino-azepan-3-one carbonylprotease inhibitors, particularly such inhibitors of cysteine and serine proteases, moreparticularly such compounds which inhibit cysteine proteases, even more particularly suchcompounds which inhibit cysteine proteases of the papain superfamily, yet moreparticularly such compounds which inhibit cysteine proteases of the cathepsin family, most 4 012288 particularly such compounds winch inhibit cathepsin K, and which are useful for treatingdiseases which may be therapeutically modified by altering the activity of such proteases.
Accordingly, in the first aspect, this invention provides a compound according toFormula I. 5 In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent orexcipient.
Ih yet another aspect, this invention provides intermediates useful in thepréparation of the compounds of Formula I. 10 In still another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases,particularly cysteine and serine proteases, more particularly cysteine proteases, even moreparticularly cysteine proteases of the papain superfamily, yet more particularly cysteineproteases of the cathepsin family, most particularly cathepsin K. 15 In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases,such as gingivitis and periodontitis, or by excessive cartilage or matrix dégradation, such asosteoarthritis and rheumatoid arthritis.
20 DETAILED DESCRIPTION OF THE INVENTION
The présent invention provides compounds of Formula I:
25 wherein:
Rl is selected from the group consisting of: 5 01 22 8 a
* *· 5 R2 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-CQ.galkyl, Ar-C^alkyl, Het-Co_6alkyl, R9C(O)-, R9C(S)-, R9SO2-, R9OC(O>, N. ,C{0) /N. CH, r9r11nC(O)-, R9RnNC(S)-, R9(R11)NSO2-
, andR9SO2R11NC(O)-; 10 15 20 r3 is selected from the group consisting of: H, Ci-galkyl, C3-6cycloalkyl-Co-galkyl, C2_6alkenyl, C2_6alkynyl, HetCo-galkyl and ArCo-galkyl; R^ and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring; R^ is selected from the group consisting of: H, C^galkyl, C3_6cycloalkyl-C0-6alkyl, Ar-C().6alkyl, Het-Co-Ô^ R5C(O)-, R5C(S>-, R5SO2-, R5OC(O)-,r5r12NC(O)-, and R5R12NC(S)-; R5 is selected from the group consisting of: H, Cj.galkyl, C2-6alkenyl,C2-6alkynyl, C3_gcycloalkyl-Co-6alkyl, Ar-C^alkyl and Het-Co_galkyl; R6 is selected from the group consisting of: H, Ci^alkyl, Ar-Co-6alkyl, and Het-Co-6alkyl; R2 is selected from the group consisting of: H, C^galkyl, C3_gcycloalkyl-Co-6alkyl, Ar-Co^alkyl, Het-C0_6alkyl, R10C(O)-, R10C(S>, R10SO2-, RlOoC(O)-,r10r13NC(O)-, and R10R13NC(S)-; R8 is selected from the group consisting of: H, Ci-galkyl,· C2-6alkenyl, 6 012288 C2-6alkynyl, HetCQ.galkyl and ArCQ_galkyl·, K.9 îs selected from the group consisting of: Cpgalkyl, C3.gcycloalkyl-CQ.ga]kyl,
Ar-Co_6a3kyl and Het-CQ_galkyl; R.10 is selected from the group consisting of: C pgalkyl, C3_gcycloaIkyl-CQ.6alkyl,Ar-Co_galkyl and Het-CQ.galkyl; RH is selected from the group consisting of: H, Cpgalkyl, Ar-Co-6alkyl, and Het-CQ-galkyl; R12 is selected from the group consisting of: H, Cpgalkyl, Ar-Co-6alkyl, and Het-Co-ôalkyl;
Rl3 js selected from the group consisting of: H, Cpgalkyl, Ar-Co-6alkyl, and Het-
CoW R’ is selected from the group consisting of: H, Cpgalkyl, Ar-Co-ôalkyk and Het-Co-ôallcyl; R”is selected from the group consisting of: H, Cpgalkyl, Ar-Co.6alkyl, or Het-C0-6alkyl; : R’” is selected from the group consisting of: H, Cp^alkyl, Cpgcvcloalkyl-Co-6alkyl, Ar-Co„galkyl, and Het-C^alkyl; R””is selected from the group consisting of: Cpgalkyl, Cj.gcycloalkyl-CQ.galkylC2-6alkenyl, Co.galkynyl, HetCo_galkyî and ArC(pgaîkyl·, X is selected from the group consisting of: 0¾. S, and O; Z is selected from the group consisting of: C(O) and CH/?;n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvatés thereof.
In compounds of Formula I, when R^ is R r3 is selected from the group consisting of: H, Cpgalkyl, C3-6cycloalkyl-Co-6aîkyl,C2-6alkenyl5 C2-6aIkynyl, Het-CQ.galkyl and Ar-CQ.galkyl; R^ is preferably selected from the group consisting of: H, C3_6cycloalkyl-Co-6a1kyl} C2-6a&enyl, Ar-CQ„galkyl, and Cpgalkyl; R.3 îs mOre preferably selected from the group consisting of: 7 012288 H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl,cyclopropylmefhyl, cyclohexylmethyl, 2-methanesulfmyl-ethyl, 1-hydroxyethyl, toluyl,naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl. r3 is even more preferabïy selected from the group consisting of: toluyl, isobutyland cyclohexylmethyl. R.3 is most preferabïy isobutyl. R4 is selected from the group consisting of: H, Cp^alkyl, Cj.gcycloalkyl-Co_6alkyl, Ar-C0_6alkyl, Het-Co_6alkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-,r5r13NC(O)-, and r5r!3nC(S)-. R4 is preferabïy selected from the group consisting of: R^OCCO)-, r5c(O)- andR5SO2-. R4 is most preferabïy R^C(O)-.
In some embodiments, R4 is preferabïy methanesulfonyl. R5 is selected from the group consisting of: H, Cj.galkyl, C2_galkenyl,C2_6alkynyl, C3_6cycloalkyl-CQ.6alkyl, Ar-Co_galkyl or Het-Co_galkyl.
Preferabïy R^ is selected from the group consisting of: Cpgalkyl, Ar-CQ.galkyland Het-CQ-galkyl.
More preferabïy, and especially when R4 is R^C(O)-, R^ is selected from the groupconsisting of: methyl, especially halogenated methyl, more especially trifluoromethyl, especiallyCi_galkoxy substituted methyl, more especially phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-l-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4-, methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fIuorophenyl, especially phenyl substituted with one or morearyloxy or Ci_galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- 8 012288 methoxy-phenyl, especially phenyl substituted with one or more C^alkyl sulfonyl groups,more especially 4-methanesulfonyî-phenyl; benzyl; naphthalenyl, especially naphthylen-2-yl;benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-nitro-furan-2-yl, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyï)-iuran-2-yl,more especiallyhalogen substituted furanyl, even more especially 5-bromo-furan-2-yl, more especially arylsubstituted furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl, more especiallyCj.galkyl substituted furanyl, even more especially 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; tetrahydrofuranyl, tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, moreespecially 5-(2-piperazin-4-carboxylic acid iert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- l-yl-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially Cj.galkoxy substituted benzofuranyl,more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especially Cj.galkyl substitutedbenzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl,and 3-ethyl-benzofuran-2-yl; also 5-fluoro-3-methyl-benzofuran-2-yl, 6-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofüran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; naphtho[2,l-b]-furanyl, especially naphtho[2,l-b]-furan-2-yl, alkyl substitutednaphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[b]thiophenyl, especially benzo[è]thiophen-2-yl; especially Cpgalkoxysubstituted benzo[b]thiophenyl, more especially 5,6-dimethoxy- benzo[b]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, andquinolin-S-yl; quinoxalinyl, especially quinoxalin-2-yl; 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially Cj.galkyl substituted indolyl, more especially N-methyl-indol-2-yl; 9 012288 pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially Cpgalkylsubstituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especiallyl-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; furo[3,2-b]-pyridinyl, especially ftiro[3,2-b]-pyridin-2-yl, Cj.galkyl substitutedfuro[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, especially C^galkylsubstituted thiophenyl, more especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3-yl,especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; thieno[3,2-Z?3thiophene, especially thieno[3,2-è]thiophene-2-yl, more especiallyCj.galkyl substituted thieno[3,2-&]thiophene-2-yl, more especially 5-ierr-butyl-3-methyl-thieno[3,2-h]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl,more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl, 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl.
When R4 is R5SO2, R5 is preferably pyridin-2-yl or l-oxo-pyridin-2-yl. R’is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyI, and Het-Co-galkyl.
Preferably R’ is selected from the group consisting of: H and naphthalen-2-yl- methyl.
Most preferably R’ is H. R” is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, and Het-Co-ô^1·
Most preferably R” is H.
R” is selected from the group consisting of: H, Cj-galkyl, Cj-écycloalkyl-Co-6alkyl, and Het-Cg^alkyL R”5 is preferably selected from the group consisting of: H and C^galkyl. 10 012288
Rw is more preferably selected from the group consisting of: H, methyl and 6,6-dimethyl. R”5 is still more preferably selected from the group consisting of: H and 6,6-dimethyl.
Most preferably R”’ is H.
R’ O
In compounds of Formula I, when R^· is : R3 is selected from the group consisting of: Ci-galkyl, C3_6cycloalkyl-Co-6alkyî,Co-ôaikenyl, C2-6alkynyh Het-CQ^alkyl and Ar-C^galkyl. R3 is preferably Ci-ôalkyl· R3 is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclohexylmethyl, and toluyl. R’” is selected from the group consisting of: Ci-galkyl, C3_6cycloalkyî-
Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl and ArC()_galkyl; R’”’ is preferably Cj-ôalkyl; R’”’ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl. R”” is most preferably methyl.
In such compounds, R’, R”, R”’, R^, and R3 are as described above wherein R' R'
R’ O
In compounds of Formula I, when R^ is 11 012288 n is preferably an integer of from 1 to 5; andR, R , R , R4, and R^ are as described above wherein
O
R
Rl is R n is most preferably 3.
The ring may be unsubstituted or substituted with one or more of Ci-galkyl,Cj.gcycloalkyl-CQ^alkyl, C^alkenyl, C2-6alkynyl, HetCç^galkyl, ArCQ_gaîkyl; or halogen.
The ring is preferably unsubstituted.
In compounds of Formula I, R^ is selected ffom the group consisting of: H, Ci.galkyl, C3_6cycloalkyl-C0.6alkyl, Ar-Co_6alkyl, Het-Co-Ô^1’ R9C(O>-, R9C(S)-, R9SO2-, R9OC(O)-, R^llNCCOX R9RnNC(S)-, R9RHnSO2-,
More preferably R^ is selected from the group consisting of: Ar-Co-6aIkyl>
R9C(O)-,R9SO2, R^ilNCiO)-, and R
Even more preferably, R^ is selected from the group consisting of: Ar-Co-galkyl,R9C(O)-, and R9SO2.
Most preferably R- is R9SO2.
In such embodiments: 12 012288 RÔ Îs selected from the group consisting of: H, C^galkyl, Ar-C0-6alkyl, or Het-Cg.galkyl, preferably H. R7 is selected from the group consisting of: H, Cj.galkyl, Cj.gcycloalkyl-C^galkyl, Ar-C0.6alkyl, Het-C0.6alkyl, R10C(O)-, R10C(S)-, R10SO2-, R10OC(O)-,r10r14NC(O)-, rIOrWnC(S)-, R7 is preferably Rl°OC(O). r8 is selected from the group consisting of: H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl and ArCQ.galkyl; preferably Cj.galkyl, more preferablyisobutyl. R^ is selected from the group consisting of: Q.galkyl, C3_gcycloalkyl-Co_galkyl,Ar-Co_6alkyl, and Het-CQ_galkyl. R^ is preferably selected from the group consisting of: Cj.galkyl, Ar-CQ.galkyl,and Het-Co.galkyl.
More preferably, R^ is selected from the group consisting of:methyl; ethyl, especially Cj.galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl;propyl; butyl, especially Cj.gbutyl, more especially 3-methylbutyl;n?rf-butyl, particularly when R- is R^OC(O);isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially Cj.galkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, moreespecially 2-cyanophenyl; especially C^.galkyl substituted phenyl, more especially 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially C|.galkyl sulfonyl substitutedphenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yl)toluyl;naphthylene, especially naphthyl-2-ene;benzoic acid, especially 2-benzoic acid;benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl;benzo[l,2,5]oxadiazolyl, especially benzo[l,2,5]oxadiazol-4-yl; 13 012288 pyridinyl, especially pyridin-2-yl, pyridin-3-yI, especially 1-oxy-pyridinyl, moreespecially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially Cj^galkylpyridinyl, moreespecially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; thiophenyl, especially thiophenyl-2-yl;thiazolyl, especially thiazol-2-yl; lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, more especiallyCj.galkyl substituted imidazolyl, even more especially l-methyl-lH-imidazol-2-yl, 1-methyl-lH-imidazol-4-yl, and l,2-dimethyl-lH-imidazol-4-yl; triazolyl, especially lH-[l,2,4]triazolyl, more especially lH-[l,2,4]triazol-3-yl,especially Cj.galkyl substituted lH-[l,2,4]triazolyl, more especially 5-methyl-lH-[l,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially C|_galkyl substituted isoxazolyl,more especially 3,5-dimethyl- isoxazol-4-yl.
When R2 is R9SCb, R9 is most preferably selected from the group consisting of:pyridin-2-yl and l-oxy-pyridin-2-yl.
When R2 is R^SCbRÜNCCO)-, R9 is preferably Ar-C()_galkyl, more preferablyAr, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chlorophenyl, and 4-fluoro phenyl.
When R2 is R9C(O)-, R9 is preferably selected from the group consisting ofCj.galkyl, C3.gcycloalkyl-CQ-galkyl, and Het-C^galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl. R11 is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, and Het-CQ-galkyl.
When R2 is R9SO2R11NC(O)-, R1* is preferably H.
When R2 is Ar-CQ_galkyl, R2 is preferably phenyl, especially substituted phenyl,more especially halogen substituted phenyl, even more especially 2-fluorobenzyl.
When R2 is C^galkyl, R2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl. 14 012288
When is Het-CQ_galkyl, Het-CQ_galkyl is preferably Het-methyl, and Het in
Het-methyl is preferably selected ffom the group consisting of: pyridinyl, especially pyridin-2-yl, especially C|.galkylpyriâinyl, more especially 6- methyl-pyridin-2-yl; thiophenyl, especially thiophene-2-yl, more especially thiophen-2-yl orbenzo[b]thiophen-2-yl; thiazolyl, especially thiazol-4-yl such as l-(2-morpholin-4-yl-thiazol-4-yl), and 1-(isothiazol-3-yl); lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especiallyCj.galkyl substituted imidazolyl, more especially l-methyl-lH-imidazol-2yl; triazolyl, especially 3H-[l,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl,especially Cj.galkyl substituted 3H-[l,2,3]triazolyl, more especially 3-phenyl-3H-[l,2,3]triazolyl -4-yl; quinolinyl, especially quinoîin-2-yl, quinolin-2-yl; furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-ethyl-furan- 2-yl; thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, especiallyCj.galkyl substituted thieno[3,2-b]thiophenyl, especially 3,4-dimethyl-thieno[3,2-b]thiophene-2-yl. R.2 is also preferably: H; toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl.
Compounds of Formula I where R” and R’” are both H are preferred.
More preferred are compounds of Formula I wherein:
Rl is 15 012288
is selected from the group consisting of: Ar-Co-ô^lkyL R?C(O)-, R^SO2,
r9r11nC(O)-, and r3 is selected from the group consisting of: H, Ci_6alkyl, C3_6cycloalkyl-5 Co-galkyl and Ar-CQ_galkyl; is selected from the group consisting of: R^OCCO)-, R^C(O)- and R^SC^-; R5is selected from the group consisting of: C^galkyl, Ar-Co-galkyl and Het- C0-6alkyl-, R6 is H; 10 R7 is R10OC(O); r8 is Ci-ôalkyl; R^ is selected from the group consisting of: Cj_galkyl, Ar-CQ_galkyl and Het- C0_6alkyl; RIO is selected from the group consisting of: C^galkyl, Ar-CQ.galkyl and Het-15 Co_galkyl; R’isH; R”isH; R’”isH;and Z is selected from the.group consisting of: C(O) and 0¾. 20
Even more preferred are such compounds of Formula I wherein R7· is selected fromthe group consisting of: Ar-Co-ôa&yh R^C(O)-, R^SOj-
Yet more preferred are compounds of Formula I wherein: 25 R1 is R- is selected from the group consisting of: Ar-Co-galkyl, R^C(O)- and R^SÛ2;
16 012288 R.3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl,n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfmyl-ethyl, 1- bydroxyethyl, toluyl, naphthalen-2-ylmetbyl, benzyloxymethyl, and hydroxymethyl; R4isR5C(O)-; R-5 is sslected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl, especiallyCi-galkoxy substituted methyl, more especially phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-l-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4-methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or morearyloxy or C^.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-methoxy-phenyl, especially phenyl substituted with one or more C j_galkyl sulfonyï groups,more especially 4-methanesulfonyl-phenyl; benzyl; naphthalenyl, especially naphthylen-2-yl;benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; . furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-nitro-furan- 2- yl, 5-(4-nitrophenyI)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-furan-2-yl,more especiallyhalogen substituted furanyl, even more especially 5-bromo-furan-2-yl, more especially arylsubstituted furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl, more especiallyCj.galkyl substituted furanyl, even more especially 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yi, and 2,4-dimethyl-furan-3-yl; tetrahydrofuranyl, especially tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, moreespecially 5-(2-piperazin-4-carboxyïic acid îeri-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- 17 012288 morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- l-yl-ethoxy)benzofuran~2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially C^.galkoxy substituted benzofuranyl,more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yI, 5,6-dimethoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, especially Cj.galkyl substitutedbenzofuranyl, most especially 3-metbyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl,and 3-ethyl-benzofuran-2-yl; also 5-fluoro-3-methyl-benzofnran-2-yl, 6-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; naphtho[2,l-b]-furanyl, especially naphtho[2,l-b3-furan-2-yl, alkyl substitutednaphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[è]thiophenyl, especially benzo[è]thiophen-2-yl; especially Cj.galkoxysubstituted benzo[è]thiophenyl, more especially 5,6-dimethoxy- benzo[fc]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, qninolin-3-yl, quinolin-4-yl, quinolin-6-yl, andquinolin-8-yl; quinoxalinyl, especially quinoxalin-2-yl; 1,8 naphthyridinyl, especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially Cj_galkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C}_galkylsubstituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especiallyl-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Cj.galkyl substitutedfuro[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl, especially thiophen-3-yl, also tbiophen-2-yl, especially Cj.galkyîsubstituted thiophenyl, more especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3-yl,especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; thieno[3,2-Z?]thiophene, especially thieno[3,2-b]thiophene-2-yl, more especially C 2_galkyl substituted thieno[3,2-h]thiophene-2-yl, more especially 5-terf-butyl-3-methyl- thieno[3,2-b]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially Cj .galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl·, 18 012288 oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl, 2- phenyl-5-trifluoromethyl-oxazol-4-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl. R.9 is selected from the group consisting of:methyl; ethyl, especially C^.galliyl-substituted ethyl, more especially 2-cyclohexyl-ethyl;propyl; butyl, especially Ci^butyl, more especially 3-methylbutyl;ieri-butyl, particularly when R“ is R^OC(O);isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyi, 2-chlorophenyî, 3-chlorophenyl, 4-chîorophenyl, especially Cj.galkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, moreespecially 2-cyanophenyl; especially C^galkyl substituted phenyl, more especially 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially C j.galkyl sulfonyl substitutedphenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yl)toluyl; naphthylene, especially naphthyl-2-ene; benzoic acid, especially 2-benzoic acid; benzo[l,3]dioxolyî, especially benzo[l,3]dioxol-5-yl; benzo[l,2,5]oxadiazolyl, especially benzo[l,2,5]oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yi; especially C|_galkylpyridinyl, moreespecially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; thiophenyl, especially thiophenyl-2-yl;thiazolyl, especially thiazol-2-yl; lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yi, more especiallyCj.galkyl substituted imidazolyl, even more especially l-methyl-lH-imidazol-2-yl, 1-methyl-lH-imidazol-4-yl, and l,2-dimethyl-lH-imidazol-4-yl; 19 012288 . triazolyl, especially lH-[l,2,4]ttiazolyl, more especially lH-[l,2,4]triazol-3^yl,especially Cj.galkyl substimted lH-[l,2,4]triazolyl, more especially 5-methyl-lH-[l,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially Cj^alkyl substituted isoxazolyl,more especially 3,5-dimethyl- isoxazol-4-yl. R’is H; R” is H; andR”’isH.
More preferred are compounds of Formula I wherein: R* is
R2isR9SO2; R2 is isobutyl; R4 is R5C(O); R^ is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2-&]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl, preferably 3-methyl-benzofuran-2-yl; R^ is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl,preferably l-oxy-pyridin-2-yl. R’ is H; and R’”isH;
Most preferred is such compound wherein: R^ is 3-methyl-benzofnran-2-yl; and R^ is l-oxy-pyridin-2-yl. 20 012288
An embodiment (IA) of the présent invention provides compounds of Formula IA:
5 wherein:
Ri is selected from the group consisting of:
10 R2 is selected from the group consisting of: C|_galkyl, Ar-Co_galkyl, Het- C0.6alkyl, R9C(O>-, R9SO2-, R9RnNC(O)-, and R9SO2RnNC(O)-; R3 is selected from the group consisting of: Ci_6aîkyl, Cg-écycloalkyl-Co-galkyl,C2_6alkenyl, C2_6alkynyl, Het-CQ.galkyl and Ar-C(y.galkyl, preferably Ci-6alkyl; 15 R2 and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring; R4 is R5C(O)-; r5 is selected from the group consisting of : Cj-galkyl and Het-CQ.galkyl,preferably Het-CQ_galkyl; R9 is selected from the group consisting of: Cj_galkyl, C3.gcycloalkyl-Co_galkyl,20 Ar-CQ_galkyl and Het-Co_galkyl·, RH is selected from the group consisting of: H, Ci-galkyl, Ar-Co-6alkyl and Het-CQ_galkyl, preferably H; R’isH; R”is H; 25 R’” is selected from the group consisting of: H and C|.galkyl, preferably H; 21 012288 R”” is selected from the group consisting of: Ci-6alkyl, C^gcycloalkyl-CQ^alkyl C2-6alkenyl, C2-6alkynyl, HetCQ_galkyl and ArCQ-galkyl; and n is an integer from 1 to 5, preferably n is 3; and pharmaceutically acceptable salts, hydrates and solvatés thereof. R'
In embodiment IA, when R^ is R3 r3 is preferably Ci-6alkyl; r3 is more preferably selected from the group consisting of: but-2-yl and isobutyl. R^ is most preferably isobutyl. R4 is RSC(O)-. R3 is selected from the group consisting of : Ci-6alkyl and Het-CQ_galkyl,preferably Het-C^galkyl;
More preferably, R^ is selected from the group consisting of: piperidin-ethyl, especially piperidin-l-yl-ethyl; benzo[l,3]dioxolyl, especially benzo[l,3]dioxol-5-yl; furanyl, especially furan-2-yl, especially aryl substituted furanyl, such as 5-(3- trifluoromethyl-phenyl)-furan-2-yl, more especially Cj.galkyl substituted furanyl, evenmore especially 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-3-yl; benzofuranyl, especially benzofuran-2-yl, especially Cj.galkoxy substitutedbenzofuranyl, more especially 5-methoxy-benzofuran-2-yl, especially halogen substitutedbenzofuranyl, more especially 5-fluoro-benzofuran-2-yl, especially Cj.galkyl substitutedbenzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl,and 3-ethyl-benzofuran-2-yl; also 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; naphtho[2,l-b3-furanyl, especially naphtho[2,l-b]-furan-2-yl, Cj.galkyl substitutednaphtho[2,l-b3-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[£]thiophenyl, especially benzo[h]thiophen-2-yl;quinolinyl, especially quinolin-2-yl; 22 012288 quinoxalinyl, especialîy quinoxalin-2-yl; pyridinyl, especialîy pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, and oxy-pyridinyl,especialîy l-oxy-pyridin-2-yl and l-oxy-pyridin-3-yl; furo[3,2-b]-pyridinyl, especialîy furo[3,2-b]-pyridin-2-yl, Cj.galkyl substitutedfuro[3,2-b]-pyridin-2-yl, especialîy 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl, especialîy thiophen-3-yl, and thiophen-2-yl, Cj.galkyl substitutedthiophenyl, especialîy 5-methyî-thiophen-2-yland 5-methyl-thiophen-3-yl; and thieno[3,2-b]thiophene, especialîy thieno[3,2-h]thiophene-2-yl; andΙΗ-benzoimidazolyl, especialîy lH-benzoimidazoI-5-yl. R0 is more preferably selected from the group consisting of:3-methyl-benzofuran-2-yl, thieno[3,2-è]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl.
R’ O R4' R3
In embodiment IA, when is R^ is selected from the group consisting of: Ci-6alkyl, Cs-gcycloalkyl-CQ-ôalkyl, C2-6alkenyl, Cp-ôalkynyl. Het-CQ.galkyl and Ar-CQ_galkyl. R3 is preferably Ci-ôalkyl, C3-6cycloalkyl-Co-6alkyl, and Ar-CQ.galkyl. R^ is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclohexylmethyl, and toluyl. R”” is selected from the group consisting of: Ci_6alkyl, C3_6cycloalkyl-
Co-ôalkyl, C2-6aüænyl, Cp-éalkynyl, HetCQ.galkyl and ArCQ_galkyl; R”” is preferably Ci-6alkyl; R”” is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl.
Most preferably R”” is methyl.
In such compounds, R’ and R^ are as described above wherein 23 012288 R' 4/ Ο
R
In embodiment IA, when is R‘ ,4/
n is an integer of from 1 to 5; preferably 3; andR’ and R^ are as described above wherein
The cyclic ring may be unsubstitnted or substituted with one or more of Ci-galkyl,C3.gcycloalkyl-CQ.galkyl, C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl, ArC^galkyl, orhalogen.
The cyclic ring is preferably unsnbstituted.
In embodiment IA, R2 is selected from the group consisting of: C^galkyl, Ar-C^galkyl, Het-Co_6alkyl, R9C(O)-, R9SC>2-, r9r1 WX andR9SO2R11NC(O)-.
More preferably R2 is selected from the group consisting of: Ar-Co-6alkyl,R9C(O)-, R9SO2, and R9Rl lNC(O)-.
Even more preferably, R2 is selected from the group consisting of: Ar-C()-6alkyl,R9C(O)~, and R9SO2.
Most preferably R2 is R9SO2- 24 012288
In such embodiment: R9 is selected from the group consisting of: C j.galkyl, C3.gcycloalkyl-Co_gaîkyl,Ar-CQ.galkyl, and Het-CQ_^alkyl. R9 is preferably selected from the group consisting of: Cpgalkyl, Ar-C^galkyl,and Het-Co-6alkyl.
More preferably, R9 is selected from the group consisting of: ethyl, especially Cj.galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl, especially prop-l-yl; isopentyl; butyl, especially but-l-yl; phenyl, especially halogen substituted phenyl, more especially 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyî; especially Cj.galkyl substituted phenyl, more especially 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cj.galkyl suîfonyl substitutedphenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyî phenyl; pyridinyl, especially pyridin-2-yl, 1-oxy-pyridinyl, more especially 1-oxy-pyridin- 2-yl; IH-imidazolyl, especially lH-imidazol-2-yl Cj^alkyl substituted imidazolyl,especially l-methyl-lH-imidazol-2-yl; and isoxazolyl, especially isoxazol-4-yl, Cj^alkyl substituted isoxazolyl, especially3,5-dimethyl- isoxazol-4-yl.
When R^ is R9SÛ2, R9 is most preferably selected from the group consisting of:pyridin-2-yl and l-oxy-pyridin-2-yl.
When R- is R9SO2R^NC(O)-, R9 is preferably Ar-CQ_galkyl, more preferablyAr, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chlorophenyl, 4-fluoro phenyl.
When R- is R9SO2R^NC(O)-, R^ is selected from the group consisting of:
When R^ is R9C(O)-, R9 is preferably selected from the group consisting of
Ci_galkyl, C3_gcycloalkyl-CQ_galkyl, and Het-Co.galkyl, more preferably l-oxy-pyridin-2- yl, 2-cyclohexyl ethyl, and isopentyl. 25 012288 H, Cj.galkyl, Ar-Cç^galkyl and Het-Co_galkyl. Preferably in such embodiment, RÜ is H. may suitably be selected from the group consisting of: C^galkyl, Ar-CQ.galkyl and Het-CQ.galkyl, preferably Ci_galkyl and Het-Co-galkyl,
When is Ar-Co_galkyl, R^ is preferably phenyl, especially substituted phenyl,more especially halogen substituted phenyl, even more especially 2-fluorobenzyl.
When R^ is C^galkyl, R.2 is preferably selected from 1-propyl, 1-butyl, and 1-pentyl.
When r2 is Het-Co_galkyl, Het-CQ.galkyl is preferably Het-methyl, and Het inHet-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, C]_galkylpyridinyl, especially 6-methyl-pyridin- 2-yl; thiophenyl, especially thiophene-2-yl;benzo[b]thiophen-2-yl ; thiazolyl, especially thiazoî-4-yl such as isothiazol-3-yl; lH-imidazolyl, especially lH-imidazol-2-yl, Cj.galkyl substituted imidazolyl, especially l-methyl-lH-imidazol-2yl; triazolyl, especially 3H-[l,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl,especially C^galkyl substituted 3H-[l,2,3]triazolyl, more especially 3-phenyl-3H-[l,2,3]triazolyl -4-yl; quinolinyl, especially quinolin-2-yl, quinolin-2-yl; furanyl, especially furan-2-yl, especially substituted furanyl, such as 5-ethyl-furan- 2-yl; thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, C^galkylsubstituted thieno[3,2-b3thiophene-2-yl, especially 3,4-dimethyl-thieno[3,2-b]thiophene-2-yl.
The compounds of embodiment IA hâve the same uses described throughout thisspécification for compounds of Formula I. The compounds of embodiment IA may beformulated into phaimaceutical compositions and used in methods of treatment asdescribed for compounds of Formula I throughout this spécification. 26 012288
Compounds of Formula I selected from the following group are particularlypreferred embodiments of the présent invention:
Example Chemical Name
No. 1 {(S)-1-[ 1 -((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl}carbamic acid benzyl ester; 2 Naphthylene-2-cafboxylic acid[(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoy l)-3-methyl-butyl] amide; 3 Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 4 Benzofuran-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 5 Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 6 Naphthylene-2-sulphonyl [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 7 Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 8 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-niethyl-butyl]ainide; 9 4- {(S)-Methyl-2-[(quinoline-2-carbonyl)-amino]pentanoylamino} -3-oxo-1 - [2-(3-pyridin-2-yl-phenyl)-acetyl]azepanium; 10 l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{ (S)-4-methyl-2-[(2-quinoiline-2-carbonyl)-amino]-pentanoylamino)-3-oxo-azepanium; 11 l-Benzoyl-4-((S)-2-(benzo[l,33dioxole-carbonylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium; 12 l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium; 13 3-Oxo-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino} -pentanoylamino)- l-(4-methyl-pentanoyl)-azepanium; 27
01??aQ 012288 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- (l-benzenesuIfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]amide; 4- ((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino }-pentanoylamiiio)-3-oxo-azepane- 1-carboxylicacid phenylamide; 5- (2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l - {3-oxo-l -[2-(3-pyridui-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl }-butyl)amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S>- l-(benzoyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyljamide; 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- (l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyî)-3-methyl- butyl]amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-y lcarbamoyl} -butyl)amide ;
Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide;lH_Indole-2-carboxyIic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide;lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyî-butyl]amide;Benzofuran-2-carboxylic acid [(S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl} -butyl)amide;5-(2-Moipholmo-4-yl-ethoxy)-benzofu.ran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-phenethyl-azepan-4-ylcarbamoyl]-butyl}amide; 28 012288 27 Naphthylene-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-phenethyl-azepan-4-ylcarbamoyl]-butyi} amide; 28 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 29 Naphthylene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-butyl}-amide; 30 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylie acid {(S)- 3- methyl- l-[3-oxo-1 -(pyridiue-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 31 4-((S)-4-Methyl-2-{ [(5-(2-morpholmo-4-yl-ethoxy)-benzofuran-2-carbonyl3-ammo}-pentanoylamino)-3-oxo-azepane-l-carboxylicacid tert-butyl ester; 32 4-((S)-4-Methyl-2-{ [(5-(2-morpholmo-4-yl-ethoxy)-benzofurari-2-carboxylic acid t(S)-3-methyl-l-(3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 33 4-Methyl-pentanoic acid {3-oxo-l-[2-(3-pyridin-2-yl-phenyl-acetylJ-azepan-4-yl} -amide ; 34 ((S)-3-Methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl}-butyl)-naphthylene-2-methyl-carbamicacid tert-butyl ester; 35 (S)-4-Methyl-2-[(naphthylen-2-ylmethyl)-amino3-pentenoic acid[3-oxo-l-[2-(3-pyridin-2-yl-phenyl>-acetyl]-azepan-4-yl}-amide; 36 4-[2-(2-{(S)-3-Methyl-l-[3-oxo-l-(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester; 37 5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylie acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-3butyl}-amide; 38 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 29 012288 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1- {3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide; 4- [2-(2-{(S)-3-Methyl-l-[3-oxo-l-(3-pyridm-2-yl-phenyl)-ethyl[azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzoforan-5-yloxy)-ethyl]-piperazine-l-carboxylic acid zm-butyl ester; 5- (2-piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl }-butyl)amide; (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoicacid [3-oxo- l-(pyridine-2-sulphonyl)-azepan-4-yl3-amide;(S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoicacid {3-oxo-l-[2-(3-pyridm-2-yl-phenyl)-acetyl]-azepan-4-yl }-amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acidmethyl ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)a.cetyl]-azepan-4-ylcarbamoyl}-butyl)amide;Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-oxo-l-(pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl} -butyl)-N-naphthylen-2-ylmethyl-acetamide; 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoylammo]-3-oxo-azepane-l-carboxylic acid benzylester;
Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcaibamoyl]-butyl} amide;QuinoIine-8-caiboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl]-butyl} amide ;Quinoline-6-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 30 012288 51 QumoIine-4-carboxyEc acid {(S)-3-metbyl-l-[3-oxo-l-(pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 52 Quinoline-3-carboxyîic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide ; 53 Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 54 Isoquinoline-l-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}amide; 55 Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-butyl} amide; 56 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 57 l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 58 lH-Indole-2-carboxylic acid {(S)-3-metbyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl} amide; 59 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 60 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 61 Furaiî-2-earboxylic acid {(S)-3-methyî-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 62 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide ; 63 5-(4-Nitro-pbenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}amide; 64 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 65 Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 66 (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 31 012288 (S)-2-[2-(4-Huoro-phenoxy)-acetylamino]-4-methyl-pentanoic « acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo~l-(pyridine- „ 2-carbonyl)-azepan-4-ylcarbamoyl)-3-butyl3-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 4- ((S)-2-teit-ButylcarbonyIamino-4-methyI-pentanoyIamino)-3- oxo-azepane-l-carboxylic acid benzyl ester; 5,6-Dimethoxy-benzoforaxi-2-caiboxylic acid {(S)-3-methyl-l-[3- oxo-l-(l-methyl-lH-imidazole-4-sulfonyl)-azepan-4- ylcarbamoyî]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[l,2^]triazoIe-3-sulfonyl)-3“OXO-azepan-4-ylcarbamoylJ-butyl} amide;
Benzofùran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbarnoyl]-butyl}amide;Benzofnran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-ixnidazole-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}ainide;Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole- 2- sulfonyl)-azepaii-4-ylcarbamoyl]-butyl}ainide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 5- (4-Oxy-morpholino-4-yI-ethoxy)-benzofuran-2-carboxylic acid{(S)-3-methyl-1- [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 3- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyI-l-[3-oxo-l-(l-oxy-pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide;Quinoline-3-carboxylic acid {(S)-l-(3,4-dichloro-benzene-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl)]-3-methy 1-butyl} -amide; 32 012288 81 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl3-butyljamide; 82 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-snlfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl}-amide; 83 2-(4-{(S)-2-{(Benzofnran-2-carbonyl)-amino }-4-methyl-pentanoylamino}-3-oxo-azepane-l-snlfonyl)-benzoic acid; 84 3-(4- { (S)-2- {(B enzofuran-2-carbonyï)-amino]-4~methyI-pentanoylamino}-3-oxo-azepane-l-sulfonyl)-benzoic acid; 85 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-butyI}amide; 86 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-butyl} amide; 87 5,6-Dimethoxy-benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonÿl)-azepan-4-ylcarbaxnoyl]-butyl}amide; 88 l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-butyl} amide ; 89 (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 90 (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 91 (S)-4-Methyl-2-(3-phenyl-uriedo)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 92 Benzofuran-2-carboxylic acid {(S)-l-[6,6-dimethyl-3-oxo- 1 (pyridine-sulphonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 93 5-Methoxy-benzofwran-2-carboxylic acid {(S)-3-methyî-1 - [3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide; 33 012288
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl3- butyl} amide;
Qumoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-butyl}amide;Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}amide;Thiophene-3-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-bTityl} amide;lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl3-biityl} amide;Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide;Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide;(S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-oxo-1 -( 1 -oxy-pyridine-2-sulfonyI)-azepan-4-yî]-amide;lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 4- Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]-butyl}-benzamide; 5- (2-Morpholm-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-1 -[3-oxo-( 1 -oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]- -buty}-amide;
Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyI)-azepan-4-yîcarbamoyI]-butyI} amide;3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 6- Methyî-N-{(S)-3-methyl- l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yicarbamoyl]-butyl}-nicotinamide;(S)-4-Methyl-2-(2-thiopben-yl-acetylamino)-pentaiioic acid-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-butyl}amide; 34 012288 109 lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-buÎyl}amide; 110 Benzo[l,3]dioxole-5-carboxylie acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}ainide; 111 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-msthyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl>-azepan-4-ylcarbamoyl] butyl}amide; 112 . 5-Methyl-thiophene-2-carboxylic acid {(S)-3-mÊthyl-l-[3-oxo-l- (l-oxy-ρyridine-2-sulfonyl)-azepaIl-4-ylcaΓbamoyl]-butyl}amide; 113 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridme-2-su]fonyl)-azepan-4-yicarbamoyl]' brnyl} amide; 114 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyi-l-[3-oxo-l-(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl) amide; 115 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[ 1 -(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; 116 5-(3-Trifluoromethyl-phenyl)-faran-2-carboxylic acid {(S)-3-methyl-1 - [3-oxo-1-( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl} amide; 117 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyljamide; 118 Benzofuran-2-carboxyEc acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbainoyl]-butyl}-amide; 119 Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesuîfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; 120 Benzofuran-2-carboxyIic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole- 4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyl}-amide; 121 Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 35 012288 3-Methyl-benzofuran-2-carboxylic acid {(S^^methyt-l-tS-oxo-l- * (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo~ > 1- (pyridine-2-snlfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 5-iezÎ-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxyIic acid {(S)-3-methyl-1 - [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoylj-butyl} amide ; 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 2- Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3- methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide;
Quinoline-2-carboxyIic acid [(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyI-butyl]-amide;l-Methyl-lH-indoIe-2-carboxylic acid [(S)-l-(l-methanesulfonyl- 3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
Furan-2-carboxylic acid {[(S)-l-(l-methanesuifonyI-3-oxo- azepaB-4-ylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-amide;5-Metboxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyî-butyl]-aroide;
Quinoxaline-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyI3-amide;5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;(S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoicacid ( 1 -methanesulfonyl-3-oxo-azepan-4-yl)-amide;
QuinoIinô-2-carboxylic acid {[(S)-l-[l-(2-cyano-benzenesuIfonyl)-3-oxo-azepan-4-yicarbamoyî3-3-methyl-butyi} -amide; 1-Methyl-lH-indole -2-carboxylic acid {[(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyl} -amide; 36 012288 136 Furan-2-carboxylic acid ({(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-amide; 137 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-meihyl-butyI} -amide; 138 Quinoxaline-2-carboxyiic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-meÎhyl-butyl}-amide; 139 (S)-2-[2-(4-Me±oxy-phenyl)-acetylamino)-4-methyl-pentanoicacid [l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; 140 QuinoIine-2-carboxylic acid {[(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-meÎhyl-butyl}-amide; 141 .l-Methyl-lH-indole-2-carboxylic acid {[(S)-l-[l-(4-methoxy-benzenesulfonyI)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 142 Furan-2-carboxylic acid ({(S)-l-[l-(4-methoxy-beDzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)amide; 143 5-Methoxy-benzofuran-2-carboxyiic acid {[(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 144 Quinoxaiine-2-carboxylic acid {[(S)-l-[l-(4~methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 145 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoicacid [l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide; 146 l-Methyl-lH-indole-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl} -amide; 37 012288
Furan-2-carboxylic acid ({(S)-l-[l-(4-fluoro-benzenesulfonyl)-3- * oxo-azepan-4-ylcarbamoyl]-3-meÎhyl-butylcarbamoyl} -methyl)-amide; 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-l-[l-(4-fiuoro- benzenesulfonyl)-3-oxo~azepaa-4-ylcarbamoyl]-3-methyl-butyl}- amide;
Quinoxalme-2-carboxyiic acid {[(S)-l-[l-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyi-pentanoic acid [l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide;
Benzofaran-2-carboxylic acid- {(S)-1-[ l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 5-Methoxy-benzofuran-2-carboxylic acid-{ (S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 7-MeÎhoxy-benzoforan-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoy I]-3-methÿl-butyl} -amide; 5,6-Dimethoxy-benzofuran-2-carboxylic ?.-:.,<j-{(3)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-Tnethyl-butyl}- amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-1 -[ 1 -(3-chloro- bsnzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyl}- amide; 1-Methyl- lH-indole-2-carboxylic acid- {(S)-1 -[ 1 -(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 38 012288 158 Quinoxaline-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 159 Benzofuran-2-carboxy]ic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 160 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 161 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyI)-3-oxo-azepan-4-ylcarbamoyI]-3-methyl-butyl}-amide; 162 5J6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyI]-3-methyl-butyl}·amide; 163 5-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fiuoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbarnoyl]-3-methyl-butyl}·amide; 164 Benzo[b3thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyI)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 165 l-Methyl-lH-indole-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 166 (S)-4-Methyl-2-(l-oxy-pyridine-2-sulfonylammo)-peDtanoic acid[3-oxo-l-(pyridine-2-sulfonyi)-azepaa-4-yl]-amide; 167 Quinoxaline-2-carboxyIic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 168 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 169 7-Methoxy-benzoforan-2-carboxylic acid-{(S)-3-methyI-l-[3-oxo·1 -(thiophene-2-sulfonyl)-azepan-4-ylcarbamoy l]-butyl} -amide; 39 012288 5.6- Dimethoxy-benzofnran-2-carboxylic acid-{(S)-3-methyl-l-[3- oxo-l-(thiophene-2-su]fonyl)-azepan-4-ylcarbamoyl]-butyl}- * amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyI)-azepan-4-ylcarbamoyl3-butyl}-amide;Benzo[b]thiophene-2-carboxylic acid- {(S)-3-methyl-1 -[3-oxo-1 -(tbiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide ;l-Methyl-l-H-indole-2-carboxylic acid-{(S)-3-methyl-1-[3-oxo-1-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;Quinoxaline-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amids;Benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyI]-3-methyl-butyi}- amide; 7-Methoxy-benzofuran-2-carboxylic acid-{ (S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 5.6- Dimethoxy-benzofuran-2-carboxylic acid- {(S)-1 - [ 1 -(4-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 3-Methyl-benzofiiran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chioro- benzenesulphonyï)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 1 -Methyl- lH-indoIe-2-carboxylic acid- {(S)-1 -[l-(4-chioro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyl}- amide; 40 012288 182 Quinoxaline-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulphonyl)-3-oxo-azepan-4-ylcaxbamoyl}-3-methyl-butyl} -amide; 183 Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-meihyl-butyl}-amide; 184 5-Meihoxy-benzofûran-2-cafboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 185 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 186 5,6-Dimethoxy-benzofüran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 187 3-Methyl-benzofaran-2-carboxylic acid-{(S)-l-[.l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}·amide; 188 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 189 l-Methyl-lH-indole-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl] -3-methyl-butyl}amide; 190 Quinoxaline-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 191 Benzofuran-2-carboxylic acid-{(S)-3-methyH-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyi]-butyl}-amide; 192 Benzofuran-2-carboxylic acid {(S)-3-methy!-l-[(2,2’,4-tridueterio)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl} amide; 41 0Î2288
Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yIcarbamoyl]-butyl}-amide;Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-propyl}-amide;Benzofuran-2-carboxyIic acid {(S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl} -amide;Benzofuran-2-carboxylic acid {(S)-3-methanesulfînyl-l-[3-oxo-l-(pyridine-2-sulfonyî)-azepan-4-ylcarbamoyl]-propyl}-amide;Benzofuran-2-carboxylic acid {[3-oxo-l-(pyridine-2-sulfonyl)-azepaa-4-ylcarbamoyl]-methyl}-amide;
Benzofiiran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl}-amide;Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-propyl }-amide ;Benzofuran-2-carboxylic acid {(S)-2-hydroxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl} -amide;Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide;l-(Benzofuran-2-carbonyl)-pyrrolidine-2-carboxylic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl3-amide; 3,4-Dimethoxy-N-{ (S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-benzamide;Benzo[b]thiophene-2-carboxylic acid-{(S)-l-( l-(4-imethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-fluoro- benzenesulfonyl)-3-oxo-azepaii-4-ylcarbamoyl]-3methyl-butyl}- amide; 42 012288 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide;Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-oxo-azepan-4-ylcarbamoyl]-3-msthyl-buiyl} -amide; (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;(S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-arnide;Benzofuran-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepaiï-4-yl carbamoyl]-3-meÜiyI-butyI}-amide; N-{(S)-l-[l-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-3.4-dimethoxy-benzainide·,Cyclohexanecarboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-amide;(S)-2-(2-Benzyloxy-aceiylamino)-4-methyl-pentanoic acid[l-(methanesulfonyI)-3-oxo-azepan-4-yi]-amide;Benzo[b]thiophene-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;Benzo[l,3]dioxole-5-carboxylic acid-{(S)-l-(l-methanesulfonyl-3oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;Benzofuran-2-carboxylie acid- {(S)-1 -( 1 -methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;N-[(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methy 1-buty 1} -3,4-dimethoxy-benzamide ; (S)-2-(2-Benzyloxy-acetylainiiio)-4-methyl-pentanoic acid[ l-(2-cyano-benzensulfonyl)-3-oxo-azepan-4-yl]-amide;N-{(S)-l-[l-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-4-methanesulfonyl-l-bsnzamide; 43 012288
Benzo [b]thiophene-2-carboxylic acid- {(S)-l-[ l-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]- amide;
Benzo[l,3]dioxole-5-carboxylic acid-{ (S)-l-[l-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide; (S)-4-Metbyl-2-[4-oxo-4-((4-phenoxy-pbenyl)-butyrylamino}-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;N- {(S)-l -[( 1 -(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-metbyl-butyl}-3,4-dimethoxy-benzamide;Cyclohexanecarboxylic acid {(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-yIcafbamoyl }-3-methyl-butyl }-amide; 4-Methansuïfonyl-N- {(S)-1 - [4-metboxy-benzenesuifonyl)-3-oxo-azepan-4-carbamoyl]-3-methyl-butyl-benzamide; 4- Methansulfonyl-N-{(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3-methyl-butyl-benzamide;({(S)-3-Methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylcarbamoyl}-carbamic acid benzyl ester;(S)-2-[5-(4-Methoxy-phenyl)-pentanoylanmio]-4-methyl-pentanoicacid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;(S)-2-[2-(3-Benzyloxy-4-metboxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-metbyl-l-[l-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide;(S)-4-Methyl-2-(5-oxo-hexanoylaniino)-pentanoic acid [3-oxo-1-(pyridine-2-sulfonyI)-azepan-4-yî]-amide;
Benzofuran-2-cafboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyI} amide; 5- Methoxy~benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-suIfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 44 012288 237 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridme-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 238 7-Methoxy-benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 239 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyI]-butyl}amide; 240 (R)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl-1 - {3-oxo-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide; 241 (S)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl- l-{3-oxo-(pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 242 Benzofuran-2-carboxylic acid {(S)-2-cyclopropyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI)-ethyl]-amide; 243 Benzofuran-2-carboxylic acid {(S)-3-methylsulfanyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-propyl] -amide ; 244 Bsnzofuran-2-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; 245 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 246 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 247 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 248 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-1 - [ 1 -(3-methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide; 45 012288 5.6- Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-2-cyclohexyl-l-{3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide; 5-(4-Chloro-phenyl)-furan-2-carboxylic acid{ (S)-2-cyclohexyl-l-{3-oxo- l-(pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-ethyl }-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-siilphonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;5-(4-Chloro-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l~(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyI-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl} -amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 5.6- Dimethoxy-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl} -amide; 5,5-Bis-(4-methoxy-phenyl)-pent-4-enoic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]}-butyl}-amide;
Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;Naphthylene-l-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepaû-4-ylcarbamoyl]-2-phenyl-ethyl}-aniide;Naphthyridine-2-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 46 012288 262 Naphthylene-l-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide; 263 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(cyclohexyl-proprionyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 264 3-Methylbenzofiiran-2-cafboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(4-methyl-pentanoyl)-azepan-4-ylcarbamoyl]-butyl} -amide; 265 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl- l-[3-oxo-1-(l-oxy-pyridine-2-carbonyl)-azepan-4-ylcarbamoyl3-butyl}-ainide; 266 (S)-Acetylamino-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 267 Quinoline-2-carboxylic acid {1 - [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl }-amide; 268 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(cyclohexyl-proprionyl)-azepan-4-ylcarbamoyl]-buîyl}-amide; 269 Benzofiiran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(4-methyl-pentanoyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 270 Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide; 271 Benzofuran-2-carboxylic acid{(S)-2-benzyloxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl3-ethyî}-amide; 272 Benzofuran-2-carboxylic acid{(S)-2-hydroxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-aniide; 273 5-Metboxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(thiazole-2-sulfonyl)-azepan-4-y lcarbamoyl]-butyl} amide; 274 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 275 3-Methylbenzofnran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl} amide; 276 Benzo[b3thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyî3-butyl}amide; 277 l-Methyl-lH-indole-2-carboxylie acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 47 012288 278 Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole- 2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 279 Quinoline-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfonyl)- 3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
The following compounds are also particularly preferredembodiments of the présent invention: 280 Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensuîfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide; 281 , (S)-4-methyl-2-(3-piperidin-1 -yl-propanoylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 282 Benzofuran-2-carboxylic acid {(S)-l-[-(4-ethyl-benzensulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide; 283 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-1 - {3-oxo-1-(1-(1 -oxy-pyridin-2-yl)-methanoy]]-azepan-4-ylcarbamoyl}-butyl)-amide; 284 Benzo[l,3]-dioxole-5-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-oxy-pyridin-2-yl)-methanoyl3-azepan-4-ylcarbamoyl}-butyl)-amide; 285 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(3-cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 286 Benzo[l,3]-dioxole-5-carboxylic acid {(S)-l-[l-(3-cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 287 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxyIic acid {(S)-l-[l-(4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 288 Benzo[l,3]-dioxole-5-carboxylic acid {(S)-l-[l-(4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide ; 289 Benzofuran-2-carboxylic acid {(S)l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide 290 Benzofuran-2-carboxylic acid [(S)-l-[3-oxo-l-(ethanesulfonyl-azepan-4-ylcaibamoyl>3-methyl-l-butyl]- amide; 48 ΟΊ 228 8 291 5-Fliioro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 292 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 293 6-Huoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butylj-amide; 294 3-MethyI-benzofuran-2-carboxylic acid {(R)-3-methyl-l-[3-oxo-l·(l-oxy-pyridine-2-sulfonyl)-azepan-4-yIcarbamoyl3-butyl}-amide; 295 3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-roethyl-l-[-3-0X0-1 -( 1 -oxy-pyridine-2-sulfony l)-azepan-4-ylcarbamoyl]-butyl}-amide; 296 5-Msthoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; 297 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- ainide; 298 Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan~4-ylcarbamoyl]-3-niethyl-butyl} -amide; 299 3-methyl-furan-2-carboxyiic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 300 Quinoline-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 301 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; 302 Quinoxaline-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcafbamoyl]-3-methyl-butyl}-amide; 49 012288
Thiophene-2-carboxylic acid {(S)-î-[l-(3-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-inethyl-buÎyl} -amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl- 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl3-amide;3-Methyl-benzofiiran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-me±yl-butyl]-amide;Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyI-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl3-amide;3-Methyl-faran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;Quinoline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-metbyî-butyî]-amide;Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-inethyl-butyl]-amide;
Quinoxaline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;Thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-buiyl]-amide;5-Methyl-thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-niethyl-l-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane- l-sulfonyl)-azepan-4-ylcarbamoyl3-3-methyî-l-butyl}-amide;Beuzo[b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-me±yI-l-butyl}-ainide;3-Methyl-foran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcafbamoyl3-3-methyl-1 -butyl }-amide ; 50 012288 318 2,5-Dimethyl-foran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 319 . Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 320 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane- 1-sulfony l)-azepan-4-ylcarbamoyl]-3-methyl-1 -butyl} -amide; 321 Quinoxaline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- 1-butyl} -amide ; 322 Thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propàne-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 323 5-Methyl-thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyI]-3-m£thyl-l-butyl}-amide; 324 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}-amide; 325 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 326 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 327 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4~ylcarbamoyl]-butyl}-amide; 328 l-methyl-naphtho[2,l-b]-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}-amide; 329 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-butyl}-amide; 330 3-Methyl-benzofuran-2-carboxylic acid {l,3-dimethyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 51 012288
Benzofùran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin- 2- ylmethyl-azepan-4-ylcarbamoyl]-butyl}-arQide; 3- Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-qninolin-2-ylmethyl-azepan-4-yicarbamoyl]-butyl}-amide;Benzo[b3thiophene-2-carboxylic acid [(S)-3-m.ethyl-l-[3-oxo-l-quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide;Benzofuran-2-carboxylic acid ((S>-3-methyl-l-{3-oxo-l-[l-toluene-2-sulfonylamino)-meihanoyl]-azepan-4-ylcarbainoyl} -butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyI-l-{3-oxo-l-[ 1 -toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyI }-butyl)-amide;
Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-2-suIfonylamino)-niethanoyl]-azepan-4-ylcarbainoyI}- butyl)-amide;
Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro-benzenesulfonylammo)-methanoyl]-azepan-4-ylcarbamoyl} -buty l)-amide ;
Benzo[b]thiophene-2-carboxylic acid ((S)-3-rnethyl-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl]-azepaii-4-ylcarbamoyl} -butyl)-amide;
Benzofuran-2-carboxylic acid ((S)-3-metbyl-l-{3-oxo-l-[4-fluoro- benzenesulfonylamino)-methanoyI]-azepan-4-ylcarbamoyl}-butyl)- amide; 3-Methyl-benzofuran-2-carboxyiic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro-benzenesulfonyIamino)-methanoyl3-azepan-4-ylcarbamoyl} -butyl)-amide ;
Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro-benzenesulfonylainino)-methaiioyl3-azepan-4-ylcarbamoyl }-butyl)-amide; 52 012288 343 Benzoforan-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-4-sulfonylammo)-methanoyl]-azepan-4-ylcarbamoyl} -butyl)-ainide; 344 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-1- {3-oxo- Ι-Ε 1 -toluene-4-sulfonylamino)-methaiîoy l]-azepan-4-yicarbamoyl} -butyl)-amide; 345 Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[ltoluene-4-suIfonylanuno)-methanoyl]-azepan-4-ylcarbamoyi} -butyl)-amide; 346 Benzoforan-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-ylmethyl)-3-oxo-azspan-4-ylcarbamoyl]-butyl}-amide; 347 3-Metbyl-benzofuran-2-carboxylic acid {(S)-3~methyl-l-[l-(6-meihyl-pyridin-2-ylniethyl)-3-oxo-azepati-4-ylcafbamoyl]-butyl}-amide; 348 Benzo[b]thiophene-2-carboxyiic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-ylniethyl)-3-oxo-azepan-4-ylcarbainoyl]-butyl}-amide; 349 Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyï}·amide; 350 3-Metbyl-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}·amide; 351 2,4-Dimethylfuran-3-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 352 QumoxaIine-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyi]-3-methyl-butyl}amide; 353 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}amide; 53 012288
Quinoline-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenyicarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 4- Methyl-thiophene-2-carboxyIic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyi]-3-methyl-butyl}-aœide; 5- Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 4-Methyl-furan-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; (
Benzofuran-2-carboxylic acid [(S)-l-(l-butyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
Benzofarau-2-carboxylic acid [(S)-l-(l-propyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
Benzofüran-2-carboxylic acid {(S)-l-[l-(2-fluoro-benzyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide;Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-morpholin-4-yl-thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(5-ethyI-furan-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;Benzofttran-2-carboxylic acid {(S)-l-[l-(3,4-dimethyl-thieno[3,2-b]thiophene-2-ylmeihyl)-3-oxo-azepan-4-ylcarbainoyl3-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-3-rnethyl-l-[3-oxo-l-(3-phenyl- 3H-[l,2,3]triazol-4-ylmetbyl)-azepan-4-ylcarbamoyl]-butyl}- amide;
Benzofuran-2-carboxylic acid [(S)-l-[l-(isothiazol-3-ylmethyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl}-ainide;Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-thiophen-2-ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide; 54 012288 367 Benzofuran-2-carboxylic acid [(S)-l-(l-benzo[b]thiophen-2-ylmethyl- 3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl]-ainidé; 368 Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-pentyl-azepan-4-ylcarbamoyl)-butyl]-amide; 369 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazol-2-ylme±yl)-3-oxo-azepan-4-ylcarbamoyl]-buty}-amide; 370 l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl}-amide; 371 2-Oxy-pyridine-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl}-amide; 372 lH-Benzoimidazole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-aniide; 373 4- {(S)-2-[(l-Benzofaran-2-yl-methanoyl)-amino]-4-methyl-pentanoylamino}- l-methyl-3-oxo- 1-pentyl-azepanium; 374 Benzofuran-2- carboxylic acid {(S)-l-[l-(l,2-dimethyl-l H -ûnidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyI-butylj-amide; 375 Benzofuran-2- carboxylic acid {(S)-l-[l-(l-methyl-l H-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 376 Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methanesulfonyl-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 377 Benzofuran-2-carboxylic acid {(S)-l-[l-(2-methanesulfonyl-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 378 Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-isoxazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoy l]-3-methyl-butyl}-amide; 379 3-Methyl-benzofuran-2-cafboxylic acid {(lS,2R)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyî)-azepan-4-ylcarbamoyl]-butyl}-amide; 380 3-Methyl-benzofuran-2-carboxylic acid {l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclopentyl }-amide; and 55 381 012288
Furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-l-[-3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide.
Particularly preferred compounds of embodiment IA are Example Nos. 280 to 381in the list herein above.
Spécifie représentative compounds of the présent invention are set forth inExamples 1-381.
Compared to the corresponding 5 and 6 membered ring compounds, the 7membered ring compounds of the présent invention are configurationally more stable at thecarbon center alpha to the ketone.
The présent invention includes deuterated analogs of the inventive compounds. Areprésentative example of such a deuterated compound is set forth in Example 192. Areprésentative synthetic route for the deuterated compounds of the présent invention is setforth in Scheme 4, below. The deuterated compounds of the présent invention exhibitsuperior chiral stability compared to the protonated isomer.
Where possible the présent invention includes quatemary salts of the inventivecompounds. A représentative example of such a quatemary sait is set forth in Example373. A représentative synthetic route for the quatemary salts of the présent invention is setforth in Scheme 6, below. Définitions
The présent invention includes ail hydrates, solvatés, complexes and prodrugs ofthe compounds of this invention. Prodrugs are any covalently bonded compounds whichrelease the active parent drug according to Formula I in vivo. If a chiral center or anotherform of an isomeric center is présent in a compound of the présent invention, ail fonns ofsuch isomer or isomers, including enantiomers and diastereomers, are intended to becovered herein. Inventive compounds containing a chiral center may be used as a racemicmixture, an enantiomerically enriched mixture, or the racemic mixture may be separatedusing well-known techniques and an individual enantiomer may be used alone. In cases inwhich compounds hâve unsaturated carbon-carbon double bonds, both the cis (Z) and trans(E) isomers are within the scope of this invention. In cases wherein compounds may existin tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as 56 012288 being included within this invention whether existing in equilibrium or predominantly inone form.
The meaning of any substituent at any one occurrence in Formula I or anysubformula thereof is independent of its meaning, or any other substituent’s meaning, at anyother occurrence, unless specified otherwise.
Abbreviations and symbols commonly used in the peptide and Chemical arts areused herein to describe the compounds of the présent invention. In general, the amino acidabbreviations follow the ÏÏJPAC-IUB Joint Commission on Biochemical Nomenclature asdescribed in Eur. J. Biochem., 158,9 (1984). "Proteases" are enzymes that catalyze the cleavage of amide bonds of peptides andproteins by nucleophilic substitution at the amide bond, nltimately resulting in hydrolysis.Such proteases include: cysteine proteases, serine proteases, aspartic proteases, andmétalloprotéases. The compounds of the présent invention are capable of binding morestrongly to the enzyme than the substrate and in general are not subject to cleavage afterenzyme catalyzed attack by the nucleophile. They therefore competitively preventproteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors.
The terni "amino acid" as used herein refers to the D- or L- isomers of alanine,arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine,isoleucine, leucine, lysine, méthionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine. "Ci-galkyl" as applied herein is meant to include substituted and unsubstitutedmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl,neopentyl and hexyl and the simple aliphatic isomers thereof. Cj-galkyl may be optionallysubstituted by a moiety selected from the group consisting of: OR14, C(O)R14, SR·^4,S(O)R14, NR142, R14NC(O)OR5, CO2R14, CO2NR142, N(C=NH)NH2, Het, C3.gcycloalkyl, and Ar; where R^ is selected from the group consisting of: H, Cj^alkyl,C2-6alkenyl, C2_6alkynyl, Cj-gcycloalkyl-CQ^alkyl, Ar-CQ_galkyl and Het-CQ-galkyl;and Ri4 is selected from the group consisting of: H, Cp^alkyl, Ar-Co-6alkyl, and Het-Co.6alkyl; "C3-6cycloalkyl" as applied herein is meant to include substituted andunsubstituted cyclopropane, cyclobutane, cyclopentane and cyciohexane. "C2_6 alkenyl” as applied herein means an alkyl group of 2 to 6 carbons wherein acarbon-carbon single bond is replaced by a carbon-carbon double bond. C2_6alkenyl 57 012288 includes efhylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the severalisomeric pentenes and hexenes. Both cis and trans isomers are included. "C2-6a1kynyl" nieans an alkyl group of 2 to 6 carbons wherein one carbon-carbonsingle bond is replaced by a carbon-carbon triple bond. C2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne andhexyne. "Halogen" means F, Cl, Br, and I. "Ar" or "aryî" means phenyl or naphthyl, optionally substituted by one or more ofPh-CQ.galkyl; Het-CQ-galkyl; Cj.galkoxy; Ph-Co_galkoxy; Het-Co_galkoxy; OH, (CH^j,6NR15R^6; O(CH2)i-6NR15R16; Ci-6alkyl, OR17, N(R17)2, SR17, CF3, NO2, CN,CO2R17, CON(R17), F, Cl, Br or I; where R15 and R16 are H, Q.galkyl, Ph-C0_6alkyl,naphthyl-CQ-galkyl or Het-C^galkyl; and R^7 is phenyl, naphthyl, or Cpgalkyl.
As used herein "Het" or "heterocyclic" represents a stable 5- to 7-memberedmonocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclicheterocyclic ring which is either saturated or unsaturated, and which consists of carbonatoms and from one to three heteroatoms selected from the group consisting of N, O and S,and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quatemized, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom which results in thecréation of a stable structure, and may optionally be substituted with one or two moietiesselected from C0.6Ar, Ci_6alkyl, OR17, N(R17)2, SRi7, CF3, NO2, CN, CO2R17,CON(Rl7), F, Cl, Br and I, where R^7 is phenyl, naphthyl, or Cpgalkyl. Examples of suchheterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyirolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl,oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl,indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo[b]thiophenyl, thieno[3,2-£]thiophenyl, benzo[l,3]dioxolyl, 1,8 naphthyridinyl, pyranyl, tetrahydrofuranyl,tetrahydropyranyl, thienyl, benzoxazolyl, thiamoipholinyl sulfoxide, thiamorpholinylsulfone, and oxadiazolyl, as well as triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl,imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are available by routine 58 012288
Chemical synthesis and are stable. The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur.
Here and throughout this application the term Cq dénotés the absence of thesubstituent group immediately following; for instance, in the moiety ArCQ.galkyl, when Cis 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCQ.galkyl isidentified as a spécifie aromatic group, e.g., phenyl, it is understood that the value of C is 0.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butylradical. Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to thefluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to thebenzvloxycarbonyl radical.
Certain reagents are abbreviated herein. m-CPBA refers to 3-chloroperoxybenzoicacid. EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide, DMF refers todimethyl formamide, DMSO refers to dimethyl sulfoxide, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran.
Methods of Préparation
Compounds of the general formula I may be prepared in a fashion analogous to thatoutlined in Schemes 1. 2 and 3. Alkylation of ieri-butyl N-allylcarbamate (1) with a basesuch as sodium hydride and 5-bromo-l-pentene provides the diene 2. Treatment of 2 witheither 2,6-diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) orbis(tricyclohexylphosphine)benzylidine ruthénium (IV) dichloride olefin metathesiscatalysts developed by Grubbs provides the azepine 3. Epoxidation of 3 with standardoxidizing agents common to the art such as m-CPBA provide the epoxide 4. Nucleophilicepoxide ring opening may be effected with a reagent such as sodium azide to provide theazido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditionscommon to the art such as 1,3-propanedithiol and triethylamine in methanol or withhydrogen gas in the presence of a catalyst such as palladium on carbon. Acylation of 5with an acid such as Cbz-leucine in the presence of a coupling agent such as EDC followedby removal of the BOC protecting group under acidic conditions provides the amine sait 6.Coupling of 6 with Cbz-leucine may be effected with a coupling agent such as EDC toprovide the intermediate alcohol (not shown) which was oxidized with an oxidant such aspyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7. 59 012288
Scheme 1
α- 6 7
Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 2,6-diisopropylphenylimido 5 neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthénium(TV) dichloride catalyst, toluene c.) zn-CPBA, CHjCL,; d.) NaN3, CHjOH, Η,Ο, NH4C1; e.) 10%Pd/C, Hj, f.) Cbz-leucine, EDC, ΟΗ,Οζ; g.) HCl, EtOAc; h.) Cbz-leucine, EDC, CftCl^; i.)pyridine sulfur trioxide complex, DMSO, TEA. 10 Compounds of the general formula I wherein R1 and R2 are amides may be prepared in the general fashion outlined in Scheme 2. Alkylation of Ν-Cbz aüyl amine (8) with a basesuch as sodium hydride and 5-bromo-l-pentene provides the diene 9. Treatment of 9 withbis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride olefin metathesis catalystdeveloped by Grubbs provides the azepine 10. Epoxidation of 10 with standard oxidizing 15 agents conmon to the art such as m-CPBA provide the epoxide 11. Nucleophilic epoxidering opening may be effected with a reagent such as sodium azide to provide the azidoalcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agentsuch as propanedithiol in the presence of triethylamine. Acylation of 12 with N-Boc- 60 012288 leucine and a coupling agent such as EDC followed by removàl oFtfte Cbz protecting groupunder hydrogenolysis conditions provides the amine 13. Coupling of 13 with a carboxylicacid was effected with a coupling agent such as EDC followed by removal of the acid labileN-Boc protecting group with an acid such as HCl or TFA provides intermediate 14. 5 Acylation of 14 may be effected with a carboxylic acid in the présence of a coupling agentcommon to the art such as EDC to give the intermediate alcohoî (not shown) which isoxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO andtriethylamine to provide the ketone 15. 10
Scheme 2
o 11
OH
12
OH Η-Ό 0 h, î
OH &amp; j, k 'R2 13 14 15 (
Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthénium (TV) dichloride cataiyst, CHCb; c.) zn-CPBA, 15 CRC1,; d.) NaN,, ΟΗ,ΟΗ, Η,Ο, NH,C1; e.) propanedithiol, CH.OH, TEA; f.) Boc-leucine, EDC, CHClj; g.) 10% Pd/C, H2; h.) I^COJÏ, EDC, CHCL, or R.COCl, CEUCl,; i.) HCl/ EtOAc; j.) R_CO,H, EDC, CHjCLj; k.) pyridine sulfur trioxide complex, DMSO, ΊΈΑ. 61 012288
Compounds of the general formula I wherein R2 is an alkyl, urea or sulphonamide group and R1 is an amide may be prepared in the general fashion ouüined in Scheme 3.
Reductive amination of 13 may be effected by treatment with an aldéhyde followed by a reducing agent such as sodium triacetoxyborohydride. Subséquent deprotection of the N- 5 B oc group under acidic conditions provides the amine sait 16. Coupling of 16 with an acidchloride or with a carboxylic acid in the presence of a coupling agent common to the artsuch as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidantsuch as pyridine sulfur trioxide complex provides the ketone 17. Altematively, treatmentof amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the 10 amine sait 18. Acylation and oxidation provides the ketone 19. Further derivatization ofamine 13 may be effected by treatment with a sulphonÿl chloride followed by deprotectionof the N-Boc group to provide the amine sait 20. Acylation and oxidation provides theketone 21. 15
Scheme 3
OH
OH a, b Υ^ΝΗ,+α- ° c, d 13 16 17 f, b e.b ?” H Γ —* h
Rl'YvJ °
O 18 c, ci
"'Y
O 19
OH c, d R'"
Reagents and conditions: a.) R,CHO, NaBH(OAc)3; b.) HCl; c.) RCOJÎ, EDC, CH,C1,; d.)pyridine sulfur trioxide complex, DMSO, TEA; e.) R.NCO, base; f.) R,SC>2C1, TEA, ŒL.CL,. 62 012288
The deuterated compound of the Example 192 may be conveniently preparedaccording to Scheme 4. The skilled artisan will understand from Example 192 and Scheme4 how to make any of the the deuterated compounds of the présent invention.
The individual diastereomers of benzofuran-2-carboxylic acid {(S)-3-methyl-l-5 [(2,2’,4-trideuterio)-3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide 31 and 32 may be prepared as outlined in Scheme 4. Alkylation of allyl-carbamic acid benzylester 22 with 5-bromo-l-pentene in the presence of a base such as sodium hydride providesthe diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)benzylidineruthénium (TV) dichloride developed by Grubbs provides the 2,3,4,7-tetrahydro-azepine-l- 10 carboxylic acid benzyl ester 24. Epoxidation of azepine 24 may be effected with standardoxidizing agents common to the art such as «z-CPBA to provide epoxide 25. Nucleophilicepoxide ring opening of 25 may be effected with a reagent such as sodium azide to providethe azido alcohol (not shown). 63 » 012288
Scheme 4
31 32
Reagents and Conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 5 bis(tricyclohexylphosphine)benzylidine ruthénium (IV) dichloride, CHjC^; c.) îk-CPBA, CRCL,; d.)
NaN3, CHjOH, HjO, NH4C1; e.) 1,3-propanedithiol, TEA, methanol; f.) N-Boc-leucine, EDC,CHjCIj; g.) 10% Pd/C, Hj; h.) 2-pyridinesulphonyl chloride, TEA, CH^Ch; i.) 4 N HCl/dioxane,methanol; j.) benzofuran-2-cafboxylic acid, EDC, CHjCL,; k.) pyridine sulfur trioxide complex,DMSO,TEA;1.) CD3OD;D2O (10:1), TEA; m.) HPLC séparation. 64 012288
The intermediate azido alcohol may be reduced to the amino alcohol 26 under conditionscommon to the art such as 1,3-propanedithiol and triethylamine in methanol or withtriphenylphosphine in tetrahydrofuran and water. Acylation of 26 may be effected with anacid such as N-Boc-leucine in the presence of a coupling agent such as EDC. Removal ofthe benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/Cprovides the amine 27. Treatment of the amine 27 with 2-pyridinesulphonyl chloride in thepresence of triethylamine or saturated sodium bicarbonate and CH,C1, followed by removalof the rert-butoxycarbonyl protecting group under acidic conditions provides 28. Couplingof 28 with benzofuran-2-carboxylic acid may be effected with a coupling agent such asEDC to provide intermediate alcohol 29. Alcohol 29 may be oxidized with an oxidant suchas sulfur trioxide pyridine complex in DMSO and triethylamine to provide the ketone 30 asa mixture of diastereomers. Treatment of ketone 30 with triethylamine in CD.OD:D2O atreflux provides the deuterated analog as a mixture of diastereomers which are separated byHPLC to provide the deuterated compounds 31 and 32.
Compounds of the general formula I may also be prepared as outîined in Scheme 5.
The amine of compound 12 may be protected with with di-rert-butyldicarbonate to providethe N-Boc dérivative 33 (Scheme 2). Removal of the benzyloxycarbonyl protecting groupmay be effected by treatment of 33 with hydrogen gas in the presence of a catalyst such as10% Pd/C to provide the amine 34. Treatment of amine 34 with a sulfonyl chloride such as2-pyridinesulfonyl chloride in the presence of a base such as N-methylmorpholine ortriethylamine provides the sulfonamide dérivative 35. Removal of the rert-butoxycarbonylprotecting group may be effected with an acid such as hydrochloric acid to provideintermediate 36. Coupling of 36 with an acid such as N-Boc-cyclohexylalanine in thepresence of a coupling agent common to the art such as HBTU or polymer supported EDCprovides the alcohol intermediate 37. Removal of the rert-butoxycarbonyl protecting groupunder acidic conditions provides amine 38. Coupling of 38 with an acid such asbenzofuran-2-carboxylic acid in the presence of a coupling agent such as HBTU or polymersupported EDC provides alcohol 39. Alcohol 39 may be oxidized with an oxidant commonto the art such as pyridine sulfur trioxide complex in DMSO and triethylamine or the Dess-Martin periodinane to provide the ketone 40. 65 012288
Scheme 5
5 Reagents and Conditions: (a) Di-zeri-butyldicarbonate, THF; (b) Hj, 10% Pd/C, EtOAc; (c) 2-pyridylsulfonyl chloride, TEA ; (d) HCl, EtOAc; (e) N-Boc-cylohexylalanine, P-EDC, (f) HCl, CH,Cb; (g) benzofuran-2-carboxylic acid, P-EDC, CH,CL,; (h) Dess-Martin periodinane,methylene chloride. 10 The quateroized, 4-amino-azepan-3-one compounds of the présent invention may be conveniently prepared according to Scheme 6. The skilled artisan will nnderstand fromScheme 6 how to make any of the quatemized, 4-amino-azepan-3-one compounds of theprésent invention. Reductive amination of 13 may be effected by treatment with analdéhyde followed by a reducing agent such as sodium triacetoxyborohydride. Subséquent 15 deprotection of the N-Boc group under acidic conditions provides the amine sait 16.Treatment of 16 with an acid chloride or with a carboxylic acid in the presence of acoupling agent coimnon to the art such as EDC followed by oxidation of the intermediate 66 012288 alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Quatemization of the amine of 17 may be effected by treatment with an alkylating agent such as iodomethane to provide the qnatemary amine sait 41.
Scheme 6 oh H fo , ΓΛΎΝΥΛΝΛο'
HN O H R1
XJ 13 16
Reagents and conditions; a.) R,CHO, NaBH(OAc)3; b.)pyridine sulfur trioxide complex, DMSO, TEA; e.) iodometha HCl; c.) R,CO2H, EDC, CHLCk; d.)ne
The starting materials used herein are commercially available amino acids or areprepared by routine methods well known to those of ordinary skill in the art and can befound in standard reference books, such as the COMPENDIUM OF ORGANICSYNTHETIC METHODS, Vol. I-VT (published by Wiley-Interscience).
Coupling methods to form amide bonds herein are generally well known to the art.The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICEOF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J. Meienhofer,ΊΉΕ PEPTIDES, Vol. 1,1-284 (1979); and JM. Stewart and J.D. Young, SOLID PHASEPEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. axe generallyillustrative of the technique and are incorporated herein by reference.
Synthetic methods to préparé the compounds of this invention frequently employprotective groups to mask a reactive functionality or minimize unwanted side reactions.Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS INORGANIC SYNTHESIS, John Wiley &amp; Sons, New York (1981). The tenu "aminoprotecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and 67 012288 dérivatives thereof as known to the art. Methods for protection and deprotection, andreplacement of an amino protecting group with another moiety are well known.
Acid addition salts of the compounds of Formula I are prepared in a standardmanner in a suitable solvent from the parent compound and an excess of an acid, such ashydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic,maleic, succinic or methanesulfonic. Certain of the compounds form inner salts orzwitterions which may be acceptable. Cationic salts are prepared by treating the parentcompound with an excess of an alkaline reagent, such as a hydroxide, carbonate oralkoxide, containing the appropriate cation; or with an appropriate organic amine. Cationssuch as Li+, Na+, K+, Ca4"4", Mg4^ and NH44· are spécifie examples of cations présent inpharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetateand trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of unionsprésent in pharmaceutically acceptable salts. Quatemary ammonium salts are prepared bytreating a parent amine compound with an excess of alkyl halide, such as methyl iodide.
This invention also provides a pharmaceutical composition which comprises acompound according to Formula I and a pharmaceutically acceptable carrier, diluent orexcipient. Accordingly, the compounds of Formula I may be used in the manufacture of amédicament. Pharmaceutical compositions of the compounds of Formula I prepared ashereinbefore described may be formulated as solutions or lyophilized powders forparentéral administration. Powders may be reconstituted by addition of a suitable diluentor other pharmaceutically acceptable carrier prior to use. The liquid formulation may be abuffered, isotonie, aqueous solution. Examples of suitable diluents are normal isotoniesaline solution, standard 5% dextrose in water or buffered sodium or ammonium acetatesolution. Such formulation is especially suitable for parentéral administration, but may alsobe used for oral administration or contained in a metered dose inhaler or nebulizer forinsufflation. It may be désirable to add excipients such as polyvinylpyrrolidone, gelatin,hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodiumcitrate.
Altemately, these compounds may be encapsulated, tableted or prepared in anémulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquidcarriers may be added to enhance or stabilize the composition, or to facilitate préparation ofthe composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba,magnésium stéarate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers 68 012288 include syrup, peanut oil, olive oil, saline and water. The carrier may also include asustained release material such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. The amount of solid carrier varies but, preferably, will be between about 20mg to about 1 g per dosage unit. The pharmaceutical préparations are made following theconventional techniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms; or milling, mixing and filling for hardgelatin capsule forms. When a liquid carrier is used, the préparation will be in the form ofa syrup, élixir, émulsion or an aqueous or non-aqueous suspension. Such a liquidformulation may be administered directly p.o. or filled into a soft gelatin capsule.
For rectal administration, the compounds of this invention may also be combinedwith excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and moldedinto a suppository.
Noveï Intermédiares
Referring to the methods of preparing the compounds of Formula I set forth inSchemes 1-4 above, the skilled artisan will appreciate that the présent invention includes ailnovel intermediates required to make the compounds of Formula I. In particular, theprésent invention provides the compounds of Formula Π:
wherein:
Rl is selected from the group consisting of:
69 012288 R’ Ο R4'
R3 and R’ Ο N. R2 is selected from the group consisting of: H, C^galkyl, Cj.gcycloalkyl-Co^alkyl, Ar-Co-gaBcyl, Het-C0_6alkyl, R9C(O)-, R9C(S)-, R9SO2-, R9OC(O)-, r9r11nC(O)-, R9R11NC(S)-, R9(Rn)NSO2-
andR^SO^UNCCO)- ; R3 is selected from the group consisting of: H, Ci-éalkyl, C3_6cycloalkyl-Co-6alkyl, C2-6alkenyl, C2_6alkynyl, HetCo-ôa&amp;yl .and ArCo-galkyl; r3 and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring;is selected from the group consisting of: H, C^.galkyl, C3_gcycloalkyl- C0.galkyl, Ar-C0.6alkyl, Het-Co.galkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-,r5r12NC(O)-, and R5R12NC(S)-; r5 is selected from the group consisting of: H, Cj.galkyl, C2_6alkenyl,C2_6alkynyl, C3_gcycloalkyl-Co_galkyl, Ar-C^alkyl and Het-Co_galkyl; R^ is selected from the group consisting of: H, C^galkyl, Ar-Co_galkyl, or Het-Co.6alkyl; R2 is selected from the group consisting of: H, C]_galkyl, C3_gcycloalkyl-CQ_6alkyl, Ar-C0_6alkyl, Het-Co.6alkyl, Rl°C(O)-, R10C(S)-, R10SO2-, RIOOC(O)-,r1°r13nc(O)-, and R10R13NC(S)-; r8 is selected from the group consisting of: H, Ci_6alkyl, C2_6aîkenyl,C2-6alkynyl, HetCo-6alkyl and ArCo-galkyl; R9 is selected from the group consisting of: C^galkyl, C3_gcycloalkyl-CQ.galkyl,Ar-CQ.galkyl and Het-CQ,gaIkyl; R-æ is independently selected from the group consisting of: Cj.galkyl, 70 012288 C3_6cycl°alkyl-Co.6alkyl, Ar-CQ-galkyl and Het-CQ_galkyl; is selected from the group consisting of: H, C^alkyl, Ar-Co-6alkyl, and Het- C0_6alkyl; R.12 îs seiected from the group consisting of: H, Ci_galkyl, Ar-Co-6alkyl, and Het-c0-6aikyi;
Rl3 is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6aikyl, and Het-Co-6alkyi; R’ is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6aîkyl, and Het-Co-6aikyi; R” is selected from the group consisting of: H,.Cj_galkyl, Ar-CQ-galkyl, or Het-Co-ô311^1; R*” is selected from the group consisting of: H, C|.galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Co-galkyl, and Het-Co-galkyl; R””is selected from the group consisting of: Ci-galkyl, C3_6cycloalkyl-CQ_5alkylC2-6a&amp;enyl, C2-6alkynyl. HetCo.galkyl and ArCQ.galkyl; n is an integer of from 1 to 5;and salts, hydrates and solvatés thereof.
With reference to embodiment IA, the présent invention includes the novelintermédiares of Formula HA:
wherein: R1 is selected from the group consisting of:
71 012288 R.2 is selected from the group consisting of: C j.gaîkyl, Ar-CQ.galkyl, Het-Co_galkyl, R9C(O)-, R9SO2-, R9R2 ^0(0)-, and R9SO2R11NC(O)-; R^ is selected from the group consisting of: Ci-ôalkyl, C3-6cycloaîkyl-Co-6alkyl, C2-6alkenyl, C2-6alkynyl, Het-CQ.galkyl and Ar-CQ_galkyl, preferably Ci-galkyl; R3 and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring;R4isR5C(O)-; R^ is selected from the group consisting of : Ci_galkyl and Het-Co_galkyl,
Ar-C0_galkyl and Het-C()_galkyl; RÜ is selected from the group consisting of: H, Ci-6alkyl, Ar-Co_galkyl and Het-CQ_galkyl, preferably H; R’isH; : R”isH; R”5 is selected from the group consisting of: H and Cj.galkyl, preferably H; R”” is selected from the group consisting of: Ci_6alkyl, C3_gcycIoalkyl-CQ_galkyl, C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl and ArCQ_galkyl, preferably Ci-galkyl; andn is an integer from 1 to 5, preferably n is 3; and pharmaceutically acceptable salts, hydrates and solvatés thereof.
The following compounds are prefeired novel intermediates:[(S)-l(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester; (S)-2-Amino-4-methyl-pentanoic acid (l-benzyl-3-hydroxy-azepan-4-yl)-amide;(S)-2-Amino-4-methyl-pentanoic acid{ 3-hydroxy- l-[2-(3-pyridin-2-yl-phenyl)- aeetyl]-azepan-4-yl}-amide; {(S)-l-[4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepan-l- ylmethyl]-3-methyl-butyl}-caibamic acid benzyl ester; (S)-2-Amino-4-methyl-pentanoic acid-(l-benzoyl-3-hydroxy-azepan-4-yl)-amide; 72 012288 (S)-2-Amino-4~methyl-pentanoic acid [3-hydroxy-l-(4-meüiyl-pentanoyl)-azepan- 4-yl]-amide; (S)-2-Amino-4-methyl-pentanoic acid (l-benzsnesulfonyl-3-hydroxy-azepan-4-yl)- 1 amide; 5 thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine- 10 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide; 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyI} amide; quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; and 15 quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide.
Process for Synthesis of Inventive CompoundsReferring to Schemes 1-6 herein above, die présent invention provides a process for 20 the synthesis of compounds of Formula (I) comprising the step of oxidizing the appropriatecompound of Formula (Π) with an oxidant to provide the compound of Formula (I) as amixture of diastereomers. Preferably the oxidant is sulfur trioxide pyridine complex inDMSO and triethylamine.
Referring to Scheme 4, the présent invention also provides a process for the 25 synthesis of deuterated compounds of Formula (I). Specifically, when a deuterated isomeris desired, an additional step, following the oxidarion step, of deuterating the protonatedisomer with a deuterating agent to pro vide the deuterated compound of Formula (I) as amixture of diastereomers is added to the synthesis. Preferably, the deuterating agent isCD3OD:D2O (10:1) in triethylamine. 30 The process further comprises the step of separating the diasteromers of Formula (I) by separating means, preferably by high piesssure liquid chromatography (HPLC).
Referring to Scheme 6, the présent invention also provides a process for thesynthesis of quatemary salts of the 4-aroino-azepan-3-one compounds of Formula (I). 73 012288
Utility of the Présent Invention
The compounds of Formula I are useful as protease inhibitors, particularly asinhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteineproteases, even moTe particularly as inhibitors of cysteine proteases of the papainsuperfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsinfamily, most particularly as inhibitors of cathepsin K. The présent invention also providesuseful compositions and formulations of said compounds, including pharmaceuticalcompositions and formulations of said compounds.
The présent compounds are useful for treating diseases in which cysteine proteasesare implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanomabrucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis,metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases inwhich cathepsin K is implicated, most particularly diseases of excessive bone or cartilageloss, including osteoporosis, gingival disease including gingivitis and periodontitis,arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget’s disease;hypercalcemia of malignancy, and metabolic bone disease.
Metastatic neoplastic cells also typically express high levels of proteolytic enzymesthat dégradé the surrounding matrix, and certain tumors and metastatic neoplasias may beeffectively treated with the compounds of this invention.
The présent invention also provides methods of treatment of diseases caused bypathological levels of proteases, particularly cysteine and serine proteases, moreparticularly cysteine proteases, even more particularly cysteine proteases of the papainsuperfamily, yet more particularly cysteine proteases of the cathepsin family, whichmethods comprise administering to an animal, particularly a mammal, most particularly ahuman in need thereof a compound of the présent invention. The présent inventionespecially provides methods of treatment of diseases caused by pathological levels ofcathepsin K, which methods comprise administering to an animal, particularly a mammal,most particularly a human in need thereof an inhibitor of cathepsin K, including acompound of the présent invention. The présent invention particularly provides methodsfor treating diseases in which cysteine proteases are implicated, including infections bypneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; aswell as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, 74 012288 muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated,most particularly diseases of excessive bone or cartilage loss, including osteoporosis,gingival disease including gingivitis and periodontitis, arthritis, more specifically,osteoarthritis and rheumatoid arthritis, Paget’s disease, hypercalcemia of malignancy, andmetabolic bone disease.
This invention further provides a method for treating osteoporosis or inhibitingbone loss which comprises internai administration to a patient of an effective amount of acompound of Formula I, alone or in combination with other inhibitors of bone résorption,such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens,or calcitonin. In addition, treatment with a compound of this invention and an anabolicagent, such as bone morphogenic protein, iproflavone, may beused to preventbone loss orto increase bone mass.
For acute therapy, parentéral administration of a compound of Formulai ispreferred. An intravenous infusion of the compound in 5% dextrose in water or normalsaline, or a similar formulation with suitable excipients, is most effective, although anintramuscular bolus injection is also useful. Typically, the parentéral dose will be about0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain theconcentration of drug in the plasma at a concentration effective to inhibit cathepsin K. Thecompounds are administered one to four rimes daily at a level to achieve a total daily doseof about 0.4 to about 400 mg/kg/day. The précisé amount of an inventive compound whichis therapeutically effective, and the route by which such compound is best administered, isreadily determined by one of ordinary skill in the art by comparing the blood level of theagent to the concentration required to hâve a therapeutic effect.
The compounds of this invention may also be administered orally to the patient, ina manner such that the concentration of drug is sufficient to inhibit bone résorption or toachieve any other therapeutic indication as disclosed herein. Typically, a pharmaceuticalcomposition containing the compound is administered at an oral dose of between about 0.1to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably theoral dose would be about 0.5 to about 20 mg/kg.
No unacceptable toxicological effects are expected when compounds of the présentinvention are administered in accordance with the présent invention. 75 012288
Biological Assays
The compounds of this invention may be tested in one of several biological assays ” * to detennine the concentration of compound which is required to hâve a given pharmacological effect. Détermination of cathepsin K proteolytic catalytic activity AU assays for cathepsin K were carried out with human recombinant enzyme.
Standard assay conditions for the détermination of kinetic constants used a fluorogenicpeptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Naacetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutionswere prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrateconcentration in the assays. AU assays contained 10% DMSO. Independent experimentsfound that this level of DMSO had no effect on enzyme activity or kinetic constants. AUassays were conducted at ambient température. Product fluorescence (excitation at 360nM; émission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor Hfluorescent plate reader. Product progress curves were generated over 20 to 30 minutesfollowing formation of AMC product.
Inhibition studies
Potential inhibitors were evaluated using the progress curve method. Assays werecarried out in the presence of variable concentrations of test compound. Reactions wereinitiated by addition of enzyme to buffered solutions of inhibitor and substrate. Dataanalysis was conducted according to one of two procedures depending on the appearance ofthe progress curves in the presence of inhibitors. For those compounds whose progresscurves were linear, apparent inhibition constants (Κϊ,αρρ) were calculated according toéquation 1 (Brandt et al., Biochemitsry, 1989,28, 140): v — VmA / [Ka(l + I/Kît app) +AJ (1) where v is the velocity of the reaction with maximal velocity Vm, A is the concentration ofsubstrate with Michaelis constant of Ka and I is the concentration of inhibitor. 76 012288
For those compounds whose progress carves showed downward curvaturevf* characteristic of time-dependent inhibition, the data from individuel sets was analyzed to give kobs according to équation 2; *» 5' [AMC] = vsst + (vo - vss) [1 - exp (-kobst)J/kobs (2) where [AMC] is the concentration of product formed over time i, vq is the initial reactionvelocity and vss is the final steady State rate. Values for kobs were then analyzed as alinear function of inhibitor concentration to generate an apparent second order rate 10 constant (kobs ! inhibitor concentration or kobs ! Kl) describing the time-dependentinhibition. A complété discussion of this kinetic treatment has been fulïy described(Monison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201).
Human Osteoclast Résorption Assay 15 Aliquots of osteoclastoma-derived celî suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium bycentrifugation (1000 rpm, 5 min at 4°C). The medium was aspirated and replaced withmurine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30min on ice The cell suspension was mixed frequently. , 20 The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4°C) and then transferred to a stérile 15 mL centrifuge tube. The number ofmononuclear cells were enumerated in an improved Neubauer counting chamber.
Sufficient magnetic beads'(5 / mononuclear cell), coated with goat anti-mouse IgG,were removed from their stock bottle and placed into 5 mL of fresh medium (this washes 25 away the toxic azide preservative). The medium was removed by immobilizing the beadson a magnet and is replaced with fresh medium.
The beads were mixed with the cells and the suspension was incubated for 30 minon ice. The suspension was mixed frequently. The bead-coated cells were immobiîized ona magnet and the remaining cells (osteoclast-rich fraction) were decanted into a stérile 50 30 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge anytrapped osteoclasts. This wash process was repeated xlO. The bead-coated cells werediscarded. 77 012288
The osteoclasts were enumerated in a counting chamber, using a large-boredisposable plastic pasteur pipette to charge the chamber with the sample. The cells werepelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl0^/mL in EMEMmedium, supplemented with 10% fêtai calf sérum and 1.7g/litre of sodium bicarbonate. 3mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifugetubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriatetreatment was added (diluted to 50 uM in the EMEM medium). Also included wereappropriate vehicle Controls, a positive control (87MEM1 diluted to 100 ug/mL) and anisotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37°C for 30 min. 0.5 mL aliquots of the cells were seeded onto stérile dentine slices in a 48-wellplate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. Theslices were washed in six changes of warm PBS (10 mL l well in a 6-well plate) and thenplaced into fresh treatment or control and incubated at 37°C for 48 h. The slices were thenwashed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodiumcacodylate) for 5 min., following which they were washed in water and incubated in bufferfor 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetatebuffer / fast red gamet for 5 min at 4°C. Excess buffer was aspirated, and the slices wereair dried following a wash in water.
The TRAP positive osteoclasts were enumerated by bright-field microscopy andwere then removed from the surface of the dentine by sonication. Pit volumes weredetermined using the Nikon/Lasertec ILM21W confocal microscope.
General
Nuclear magnetic résonance spectra were recorded at either 250 or 400 MHz using,respectively, a Broker AM 250 or Broker AC 400 spectrometer. CDCI3 isdeuteriochloroform, DMSO-dg is hexadeuteriodimethylsulfoxide, and CD3OD istetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield fromthe internai standard tetramethylsilane. Abbreviations for NMR data are as follows: s =singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt =doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constantmeasured in Hertz. Continuons wave infrared (IR) spectra were recorded on aPerkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FI'iR) spectra wererecorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTÏR spectra were 78 012288 recorded in transmission mode, and band positions are reported in inverse wavenumbers(cm'l). Mass spectra were taken on either VG 70 FE, PE Syx API HI, or VG ZAB HFinstruments, using fast atom bombardment (FAB) or electrospray (ES) ionizatinntechniques. Elemental analyses were obtained using aPerkin-Elmer 240C elemental 5 analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and areuncorrected. Ail températures are reported in degrees Celsius.
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates wereused for thin layer chromatography. Both flash and gravity chromatography were carriedout on E. Merck Kieselgel 60 (230-400 mesh) silica gel. 10 Where indicated, certain of the materials were purchased from the Aldrich
Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, NewJersey, and Advanced Chemtech, Louisville, Kentucky.
Examples 15 In the following-synthetic examples, température is in degrees Centigrade (°C).
Unless otherwise indicated, ail of the starting materials were obtained from commercialsources. Without further élaboration, it is believed that one skilled in the art can, using thepreceding description, utilize the présent invention to its fullest extent. These Examples aregiven to illustrate the invention, not to limit its scope. Référencé is made to the daims for 20 what is reserved to the inventors hereunder. 79 012288
Example 1 -v
Préparation of 1 fS)-l-ri-((S)-2-Ben2ryloxvcarbonvlamino-4-methvl-pentanovI)-3-oxo- azepan-4-ylcaibamovl)cafbamic acid benzvl ester a. ) AUyl-pent-4-enyl-carbamic acid iert-butyl ester
To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed withhexanes) in DMF (30 wL) was added iert-butyl N-allylcarbamate (6.0 g, 38.2 mmol) in adropwise fashion. The mixture was stirred at room température for approximately 10minutes whereupon 5-bromo-l-pentene (6.78 mL, 57.24 mmol) was added in a dropwisefashion. The reaction was heated to 40°C for approximately 2 hours whereupon thereaction was partitioned between ethyl acetate and water. The organic layer was washedwith water (2 x’s), brine, dried (MgSOJ, filtered and concentrated to give 10 grams of thetitle compound as an oil: MS(EI) 226 (M+IT). b. ) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid ierî-butyl ester
To a solution of compound of Example la (4.5 g) in benzene was added the 2,6-diisopropylphenylimidoneophylidene molybdenum bis(i-butoxide) (600 mg). The reactionwas heated to reflux for 1.5 hours whereupon the reaction was concentrated in vacuo.
Chromatography (50% CHjChihexanes) of the residue gave 3.92 g of the product: c. ) 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid rert-butyl ester
To a solution of the compound of Example lb (3.0 g, 15.2 mmol) in CH2CI2 wasadded m-CPBA (7.8 g, 45.6 mmol). The mixture was stirred ovemight at room températurewhereupon it was partitioned between CHjCL, and staurated KjCO3. The organic layer waswashed with sat. NaHCO3, water, brine, dried (MgSOJ, filtered and concentrated to give3.11 g of the title compound as an oil: MS(EI) 214 (M+H+). d. ) 4-Azido-3-hydroxy-azepane-l-carboxylic acid îeri-butyl ester
To a solution of the epoxide from Example le ( 3.92 g, 20 mmol) inmethanol: water (180 mL of an 8:1 solution) was added NH4CI (3.18 g, 60 mmol) andsodium azide (3.9 g, 60 mmol). The reaction was heated to 40°C until complétéconsumption of the starting epoxide was observed by TLC analysis. The majority of the 80 012288 solvent was removed in vacuo and the remaining solution was diluted with ethyl acetateand washed with water, brine dried (Na2SÛ4), fïltered and concentrated. Columnchromatography (40% ethyl acetate:hexanes) of thé residue provided 3.43 g of the titlecompound. e. ) 4-Amino-3-hydroxy-azepane-l-carboxylic acid terf-butyl ester
To a solution of the azido alcohol of Example ld (3.4 g) and 10% Pd/C (catalytic)in ethyl acetatermethanol (2:1 solution) was affixed a balloon of hydrogen. The reactionwas stirred until complété consumption of the starting material was observed by TLCanalysis. The reaction was fïltered to remove the catalyst and the filtrate was concentratedin vacuo. Coluron chromatography of the residue (25% methanohdichloromethane)provided 2.57 g of the title compound: MS(EI) 231 (M+H+). f. ) 4-((S)-2-benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid tert butyl ester
To a solution of the amino alcohol of Example le (160 mg, 0.70 mmol) in CH2CI2was added EDC (134 mg), HOBt (94 mg) and Cbz-leucine (185 mg). The reaction wasmaintained at room température until complété consumption of the starting material wasobserved by TLC analysis. The reaction was diluted with ethyl acetate and washed withIN HCl, sat. K2CO3, water, brine, dried (MgSOzp, fïltered and concentrated. Columnchromatography of the residue (3% methanokdichloromethane) gave 200 mg of the titlecompound: MS(EI) 478 (M+H+), 500 (M+Na+). g. ) [(S)- l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-cafbamic acid benzyl ester A solution of the compound of Example lf (200 mg, 0.42 mmol) in methanol (5mL) was added 4M HCl in dioxane (5 mL). The reaction was stirred at room températurefor approximately 2 hours whereupon the solvent was removed in vacuo to provide 168 mgof the title compound: MS(EI) 378 (M+H+). 81 012288 b·) {(S)-1 -[4-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy- »
azepane-l-carbonyl]-3-methyl-butyl}carbamic acid benzyl ester *Y
To a solution of the amine sait of Example 1g (168 mg, 0.42 mmol) in CH2CI2was added EDC (81 mg), HOBt (57 mg), triethylamine (0.09 mL) and Cbz-leucine (111 5 mg). The reaction was stirred until complété by TLC analaysis. Workup foîlowed bycolumn chromatography (5% CH3OH:CH2Cl2) provided 159 mg of the title compound: MS(EI) 625 (M+H+). i.) {(S)-l-[4-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-oxo- 10 azepane-l-carbonyl]-3-methyl-butyl}carbamic acid benzyl ester
To a solution of the alcohol of Example lh (130 mg, 0.21 mmol) in DMSO was added TEA (0.17 mL) and pyridine sulfur trioxide complex (97 mg, 0.62 mmol). Thereaction was stirred at room température for approximately 2 hours whereupon it waspartitioned between ethyl acetate and water. The organic layer was washed with brine, 15 dried (MgSOzj), fîltered and concentrated. Column chromatography of the residue (5% CH3OH:CH2Cl2) provided 100 mg of the title compound as a mixture of diastereoniers: JHNMR (CDCy: δ 1.0 ( m, 12H), 1.5-2.1 ( m, 8H), 2.2 ( m, 4H), 3.0 (m, 1H), 3.5 (d, LH). 3.6(d, 1H), 4.01 (m, 1H), 4.5 ( m, 2H), 4.7 (m, 1H), 5.0 ( m, 5H), 7.3 (m, 10H): MS (El) 623(M+H+), 645 (M+Na+). Séparation of the diastereomers by HPLC provided 20 diastereomer 1:MS (El) 623 (M+H+), 645 (M+Na+) and diastereomer 2: MS (ES) 623(M+H+), 645 (M+Na+). 82 012288
Example 2
Préparation of Naphthvlene-2-carboxvlic acidr(S>-l-fl-benzvl-3-oxo-azepan-4- vlcarbamovl)-3-methvl-butvllamide a. ) AUyl-pent-4-enyl-carbamic acid benzyl ester
To a suspension of NaH (1.S3 g, 76.33 mmol of 90% NaH) in DMF was addedbenzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. Themixture was stirred at room température for approximately 10 minutes whereupon 5-bromo-l-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reactionwas heated to 40°C for approximately 4 hours whereupon the reaction was partitionedbetween dichloromethane and water. The organic layer was washed with water (2x’s),brine, dried (MgSC>4), filtered and concentrated. Column chromatography of the residue(10% ethyl acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(EI) ' 260 (M+H+). b. ) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid benzyl ester
To a solution of compound of Example 2a (50 g) in dichloromethane was addedbis(tricyclohexylphosphine)benzylidine ruthénium (IV) dichloride (5.0 g). The reactionwas heated to reflux until complété as determined by TLC analysis. The reaction wasconcentrated in vacuo. Column chromatography of the residue (50% dichloromethane:hexanes) gave 35 g of the title compound: MS(EI) 232 (M+H+). c. ) 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester
Following the general procedure of Example le except substituting the compoundof Example 2b the title compound was prepared: MS(EI) 248 (M+H+), 270 (M+Na+). d. ) 4-azido-3-hydroxy-azepane-l-carboxylic acid benzyl ester
To a solution of the epoxide ffom Example 2c (2.0 g, 8.1 mmol) in methanohwater(8:1 solution) was added NH4C1 (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30mmol). The reaction was heated to 40°C until complété consumption of the startingepoxide was observed by TLC analysis. The majority of the solvent was removed in vacuoand the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The 83 012288 organic layer was washed with sat. NaHCO3, water, brine dried (MgSOJ, filtered andconcentrated. Column chromatography (20% ethyl acetate:hexanes) of the residueprovided 1.3 g of the title compound: MS(EI) 291 (M+H+) plus 0.14 g of trans-4-hydroxy-3-azido-hexahydro- lH-azepine e. ) 4-amino-3-hydroxy-azepane-l-carboxylic acid benzyl ester
To a solution of the azido alcohol of Example 2d (1.1 g, 3.79 mmol) in methanolwas added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 mL).The reaction was stirred until complété consumption of the starting material was observedby TLC analysis whereupon the reaction was concentrated in vacuo. Columnchromatography of the residue (20% methanol:dichloromethane) provided 0.72 g of thetitle compound: MS(EI) 265 (M+H+). f. ) 4-((S)-2-iert-Butoxycarbonylarnino-4-methyl-pentanoylamino)-3-hydroxy-azepan- 1-carboxylic acid benzyl ester
To a solution of the amino alcohol of Example 2e (720 mg, 2.72 mmol) in CH2CI2was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction wasmaintained at room température until complété consumption of the starting material wasobserved by TLC analysis. The reaction was diluted with ethyl acetate and washed withIN HCl, sat. K2CO3, water, brine, dried (MgSO^j.), filtered and concentrated. Columnchromatography of the residue (3% methanokdichloromethane) gave 1.0 g of the titlecompound: MS(EI) 478 (M+H+). g·) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyll-carbamic acid tertbutyl ester
To a solution of the compound of Example 2f (1.0 g) and 10% Pd/C (catalytic) inethyl acetate:methanol (2:1 solution) was affixed a balloon of hydrogen. The reaction wasstirred until complété consumption of the starting material was observed by TLC analysis.The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuoto provide 0.82 g of the title compound: MS(EI) 344 (M+H+). 84 012288 b·) [(S)-l-(l-Benzyl-3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acidtert butyl ester
To a solution of the compound of Example 2g (0.69 g, 2.01 mmol) in CH2CI2 wasadded benzaldehyde (0.32 mL, 3.01 mmol) followed by sodium triacetoxyborohydride(0.85 g, 4.02 mmol). The reaction was stirred until complété as determined by TLCanalysis whereupon several drops of water were added to the reaction to destroy the excesssodium triacetoxyborohydride. The mixture was diluted with ethyl acetate washed with sat.NaHCC>3, water, brine, dried (Na2SÛ4), filtered and concentrated. Columnchromatography of the residue (5% methanobdichloromethane) gave 800 mg of the titlecompound: MSÇES) 434 (M+H+). i. ) (S)-2-Amino-4-methyl-pentanoic acid (l-benzyl-3-hydroxy-azepan-4-yl)-amide
To a solution of the compound of Example 2h (800 mg) in methanol (15 mL) wasadded 4M HCl in dioxane (15 mL). The reaction was stirred at room température ovemightwhereupon it was concentrated in vacuo to give 800 mg of tbe ride compound: MS(ES) 334 (M+H+). j. ) Naphthylene-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide
To a solution of the amine sait of Example 2i (200 mg, 0.49 mmol) in CH2CI2 wasadded triethylamine (0.17 mL, 1.22 mmol), EDC (103.5 mg, 0.54 mmol), HOBt (73 mg,0.54 mmol) and 2-naphthoic acid (93 mg, 0.54 mmol). The reaction was stirred untilcomplété by TLC analysis. The reaction was diluted with ethyl acetate and washed withsat. NaHCC>3, water, brine, dried (Na2SC>4), filtered and concentrated. Columnchromatography of the residue (5% methanobdichloromethane) gave 0.14 g of the titlecompound: MS(EI) 488 (M+H+). k. ) Naphthylene-2-carboxylic acid[(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyI)-3- methyl-butyl]-amide
Following the general procedure of Example li except substituting the compoundof Example 2j for the compound of Example li the title compound was prepared: lH NMR(CDC1,): δ 1.0 ( m, 6H)> 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H). 3.4 (m,1H), 3.7 (m, 2H), 4.7 ( m, 1H), 5.2 ( m, 1H), 7.2-8.4 (m, 12H); MS(EI): 486 85 012288 (M+H\100%). Séparation of the diastereomers by HPLC provided diastereomer 1: MS(El) 486.3 (M+H+), and diastereomer 2: MS (ES) 486.3 (M+H+).
Example 3 5
Préparation of Benzol 1.31dioxole-5-carboxvlic acid F(S)-l-(l-benzyl-3-oxo-azepap-4- vlcarbamovli-S-methyl-butvIlanride a. ) Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4- 10 ylcarbamoyl)-3-methyl-butyI]amide
Following the general procedure of Example 2j except substituting piperonylic acidfor 2-naphthoic acid the title compound was prepared: MS(ES) 482 (M+H+). b. ) Benzo[l,33dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4- 15 ylcarbamoyl)-3-methyl-butyl]amide
Following the general procedure of Example li except substituting the compoundof Example 3a the title compound was prepared: 'H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H),.2.9 (m, 1H), 3.0 ( m, 1H). 3.2 (d, 1H), 3.5 (q, 1H), 3.7 (m, 2H), 4.7 (m, 1H), 5.2 ( m, 1H), 6.0 (s, 2H), 6.8 (m, 2H).7.2 (m, 6H); MS(EI): 480 (M+H\100%). 20 The diastereomers were separated by préparative scale HPLC. lyophilisation of the eluentsprovided diastereomer 1: MS (El) 480.3 (M+H+), 959.6 2M+H+) and diastereomer 2: MS(El) 480.3 (M+H+), 959.6 2M+H+). 86 012288
Example 4
Préparation of Benzofuran-2-carboxyIic acid r(S)-l-(l-benzvI-3-oxo-azepan-4- vlcarbamovD-3-metfavl-butvnamide a. ) Benzofuran-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)- 3-methyl-butyl]amide
Following the general procedure of Example 2j except substituting benzofuran-2-carboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 478(M+H+). b. ) Benzofuran-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide
Following the general procedure of Example li except substituting the compoundof Example 4a the title compound was prepared: 476 MS(EI): 492 (M+H\100%). Thediastereomers were separated by préparative scaleHPLC. Lyophilisation of the ehientsprovided diastereomer 1: MS (El) 476.4 (M+H+), 951.6 (M+H+) and diastereomer 2: ·MS (El) 476.4 (M+H+), 951.6 2M+H+).
Example 5
Préparation of Benzoiblthiophene-2-carboxvlic acid i(S)-l-(l-benzvl-3-oxo-azepan-4- vlcarbamovl)-3-methyl-butvnamide a.) Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl)amide
Following the general procedure of Example 2j except substitutingbenzothiophene-2-carboxylic acid for 2-naphthoic acid the title compound was prepared:MS (ES) 494 (M+H+). 87 λ" 012288 b.) Benzo[b]thiophene-2-carboxyîic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyrjamide
Following tbe general procedure of Example li excepî substituting the compoundof Example 5a the title compound was prepared: ‘H NMR (CDCy: δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H). 3.4 (m, 1H), 3.7 (m, 2H), 4.7 (m, 1H), 5.2 (m, 1H),7.2-8.4 (m, 10H): MS(EI): 492 (M+lT,100%)
The diastereomers were separated by préparative scale HPLC. Lyophilisation ofthe eluents provided diastereomer 1: MS (El) 492.4 (M+H+), 983.7 2M+H+) anddiastereomer 2: MS (El) 492.4 (M+H+), 983.7 2M+H+).
Example 6
Préparation of Naphthvlene-2-sulphonvl rfS)-l-(l-benzvl-3-oxo-azepan-4-vlcarbamovD-3- methyl-butyll-amide a. ) Naphthylene-2-sulphonyl [(S)-1 -( 1 -benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methyl-butyl]-amide
To a solution of the amine sait of Example 2i (200 mg, 0.49 mmol) in CH2CI2 wasadded triethylamine (0.24 mL, 1.72 mmol) and 2-naphthalenesulphonyl chloride (122 mg,0.54 mmol). The reaction was stirred at room température until complété as determined byTLC analysis. The reaction was worked-up, dried (Na2SO4), filtered and concentrated.Column chromatography of the residue (10% methanol:dichloromethane) provided 52 mgof the title compound: MS(EI) 524 (M+H+). b. ) Naphthylene-2-suIphonyl [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyI)-3-methyl- butyl]-amide
Following tbe general procedure of Example li except substituting the compoundof Example 6a the title compound was prepared: : 'H NMR (CDC1,): δ 1.0 ( m, 6H), 1.5-2.1( m, 5H), 2.2 ( m, 2H), 2.7 (m, 1H), 3.0 (dd, 1H). 3.3 (m, 1H), 3.6 (m, 2H), 3.7 ( m, 1H),4.7 (m, 1H), 5.3 ( m, 1H), 7.2-8.4 (m, 12H): MS(EI): 522 (M+H*,100%) 88 012288
Example 7
Préparation of Quinoline-2-carboxvlic acid i(S')-l-(l-b&amp;nzvl-3-oxo-az&amp;pap-4-vlcarbamovb- 3-methvl-butvIlamide a. ) Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide
Following the general procedure of Example 2j except substituting 2-quinolinecarboxylic acid for 2-naphthoic acid the title compound was prepared: MS(ES)489 (M+H+). b. ) Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyfjamide
Following the general procedure of Example li except substituting the compoundof Example 7a the title compound was prepared: ’H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H). 3.4 (m, 1H), 3.7 (m, 2H), 4.7 < m, 1H), 5.2 ( m, 1H), 7.2-8.4 (m, 11H); MS(EI): 487 (M+IT,100%). The diastereomers wereseparated by préparative scale HPLC. Lyophilisation of the eluents provided diastereomer1: MS (El) 492.4 (M+H+), 983.7 2M+H+) and diastereomer 2: MS (El) 492.4 (M+H+),983.7 2M+H+).
Example 8
Préparation of 3,4-dichlorobenzoic acid i(S)-l-(l-benzvl-3-oxo-azepan-4-vlcarbarooyl)-3- methyl-butyllamide a.) 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyljamide
Following the general procedure of Example 2j except substituting 3,4-dichlorbenzoic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 506(M+H+). 89 012288 b.) 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl-3-oxo-azepan~4-ylcarbamoyl)-3-methyl- butyl]amide
Following the general procedure of Exemple li except substituting the compoundof Example 8a the title compound was prepared: ’H NMR (CDC10: δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H). 3.4 (m, 1H), 3.7 (m, 2H), 4.7 ( m, 2H), 5.2( m, 1H), 7.2-8.4 (m, 8H); MS(EI): 504 (M\100%).
Example 9
Préparation of 4-{(S)-Methvl-2-i(qumoline-2-carbopyl)-amino1pentanovlamino)-3-oxo-l- r2-f3-pyridin-2-vl-phenvl)-acetvriazepanium a. ) 4-((S)-2-?e7?-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepanium
To a solution of the compound of Example 2g (0.5g, 1.46 mmol) in CH2CI2 wasadded EDC (307 mg, 1.60 mmol), HOBt (216 mg, 1.60 mmol) and 3-(2-pyridyl)phenylacetic acid (341 mg, 1.60 mmol). The reaction was stirred at room température untilcomplété as determined by TLC analysis. Workup and column chromatography (2%methanolzdichloromethane) provided the title compound: MS(ES) 539 (M+H+). b. ) 4-((S)-Amino-4-methyl-pentanoylamino)-3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)- acetylj-azepanium
To a solution of the compound of Example 9a (1.3 g) dissolved in methanol (20 mLwas added 4M HCl in dixoane (20 mL). The reaction was stirred until complété by TLCanalysis whereupon it was concentrated in vacuo to give 1.1 g of the title compound: MS(EI) 439 (M+H+). c. ) 4- {(S)-Methyl-2-[(quinoline-2-carbonyl)-amino]pentanoylamino }-3-hydroxy-1-[2- (3-pyridin-2-yl-phenyl)-acetyl)azepanium
Following the procedure of Example 7a except substituting the compound ofExample 9b the title compound was prepared: MS(EI) 594 (M+H+). 90 012288 d.) 4-{(S)-Methyl-2-[(quinoline-2-carbonyl)-aminoJpentanoylamino}-3-oxo-l-[2-(3- pyridin-2-yl-phenyl)-acetyl]azepanium
Following the procedure of Ex ample li except substituting the compound ofExample 9c the title compound was prepared: lH NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.9 (m, 1H), 3.4 (dd, 1H). 3.8 (m, 3H), 4.1 (m, 2H), 4.7 ( m, 3H), 5.4 ( m, 1H), 7.2-8.4 (m, 14H); MS(EI): 592 (M+H\100%).
Example 10
Préparation of l-ffS)-2-Benzvloxvcarbonylamino-4-methyI-pentvI)-4-(fS)-4-m&amp;thvl-2-if2- quinoiline-2-carbonvl>>-aminol-pentaiiovlammo')-3-oxo-azepanium a. ) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-((S)-2-terr- butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepanïum
Following the procedure of Example 2h except substituting Cbz-leucinal forbenzaldehyde the title compound was prepared: MS(EI) 577 (M+H+). b. ) 4-((S)-2-Amino-4-methy-pentanoylamino)- l-((S)-2-iert-benzylxycarbonylamino-4-methyl-pentyl)-3-hydroxy-azepanium
Following the procedure of Example 2i except substituting the compound ofExample 10a the title compound was prepared: MS(EI) 477 (M+H+). c. ) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{ (S)-4-methyl-2-[(2- quinoiline-2-carbonyl)-amino]-pentanoylamino)-3-hydroxy-azepanium
Following the procedure of Example 7a except substituting the compound ofExample 10b the title compound was prepared: MS(EI) 632 (M+H+). d. ) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-{ (S)-4-methyl-2-[(2- quinoiline-2-carbonyl)-amino]-pentanoylamino)-3-oxo-azepanium
Following the procedure of Example li except substituting the compound ofExample 10c the title compound was prepared: ’H NMR (CDC10: δ 1.0 ( m, 12H), 15-2.1(m, 10H), 91 2.2 ( m, 4H), 2.9 (m, 1H), 3.4 ( Μ, 2H). 3.7 (m, 1H), 4.7 ( m, 2H), 5.2 ( m, 3H), 7.2 (m, 4H), 7.5 (m, 1H), 7.6 (m, 1H), 7.7 (m, 1H), 8.1 (m, 1H), 8.2 (m, 2H), 8.5 (m, 1H); MS(EI): 630 (M+H\100%) . 012288
Example 11
Préparation of 1 -B enzovl-4-f (S)-2-(benzoi 1.31dioxole-carbonyIaTnino)-4-methvl- pentanovlamino)-3-oxo-azepanium a. ) l-Benzoyl-4-((S)-2-iert-butoxycaibonylamino-4-methyl-pentanoylamino)-3- hydroxy-azepanium
Following the procedure of Example 9a except substituting benzoic acid for 3-(2-pyridyl)phenyl acetic acid the title compound was prepared: MS(ET) 448(M+H+). b. ) 4-((S)-2-Amino-4-methyl-pentanoylamino)-l-benzoyl-3-hydroxy-azepanium
Following the procedure of Example 2i except substituting the compound ofExample lia the title compound was prepared: MS(EI) 348 (M+H+). c. ) l-Benzoyl-4-((S)-2-(benzo[l,3]dioxole-carbonylamino)-4-methyl-pentanoylamino)- 3-hydroxy-azepanium
Following the procedure of Example 2j except substituting the compound ofExample 11b for the compound of Example 2j and piperonylic acid for 2-naphthoic acid thetitle compound was prepared: MS(EI) 496 (M+H+). d. ) l-Benzoyl-4-((S)-2-(benzo[l,3]dioxole-carbonylamino)-4-methyl-pentanoylamino)-3-oxo-azepanium
Following the procedure of Example li except substituting the compound ofExample 11c the title compound was prepared: 'H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.9 (m, 1H), 3.2 (dd, 1H). 3.4 (m, 1H), 3.7 (m, 2H), 4.7 ( m, 1H), 5.2 ( m, 1H), 6.0 (s, 2H), 7.2-8.4 (m, 8H); MS(EI): 494 (Μ+ΒΓ, 70%). 92 012288
Example 12
Préparation of l-Benzovl-4-f(S)-2-(4-fluoro-benzovlamino)-4-methvl-pentanovlaminoV3- oxo-azepanium a. ) l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-hydroxy- azepanium
Following the procedure of Example 11c except substitutmg 4-fluorobenzoic acidfor piperonylic acid the title compound was prepared: MS(EI) 470 (M+H+). b. ) l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-oxo- azepanium
Following the procedure of Example li except substituting the compound ofExample 12a the title compound was prepared: 'H NMR (CDCQ: δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (dd, 1H). 3.6 (m, 1H), 4.0 (m, 2H), 4.7 ( m, 1H), 5.2 (m, 1H), 7.2-8.4 (m, 9H); MS(EI): 468 (Μ+Ηζ 10%).
Example 13
Préparation of 3-Oxo-4-((S)-4-methvl-2-( i5-(2-morpholino-4-vl-ethoxv)-benzofuran-2- carbonvllamino)-pentanovlamino)-l-(4-methvl-pentanovl)-azepanium a. ) 4-((S)-2-rert-butoxycarbonylamino-4-methyI-pentanoylamino)-3-hydroxy-l-(4- methyl-pentanoyl)-azepanium
Following the procedure of Example 9a except substituting iso-caproic acid for 3-(2-pyridyl)phenyl acetic acid the title compound was prepared: MS(EI) 442 (M4-H+). b. ) 4-((S)-2-Amino-4-methyl-pentanoylammo)-3-hydroxy-l-(4-methyl-pentanoyl)- azepanium
Following the procedure of Example 2i except substitutmg the compound ofExample 13a the title compound was prepared: MS(EI) 342 (M+H+). 93 012288 c. ) 3-Hydroxy-4-((S)-4-methyl-2- {[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]amino}-pentanoylamino)-l-(4-methyl-pentanoyl)-azepanium
To a solution of the compound of Example 13b (200 mg, 0.53 mmol) indichloromethane was added EDC (111 mg, 0.58 mmol), HOBt (78 mg, 0.58 mmol), TEA(0.11 mL, 0.79 mmol) and 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid.
The reaction was stirred at room température until complété as indicated by TLC analysis.Workup and column chromatography (5% methanohdichloromethane) provided 160 mg ofthe title compound: MS (El) 615 (M+H+). d. ) 3-Oxo-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]aroino}-pentanoylamino)-l-(4-methyl-pentanpyl)-azepanium
Following the procedure of Example li except substituting the compound ofExample 13d the title compound was prepared: ’H NMR (CDC13): δ 1.0 ( m, 12H), 1.5-2.1(m, 8H), 2.2 (m, 2H), 2.3 (m, 1H), 2.4-2.5 (m, 2H), 2.6 (m 5H), 2.7 (m, 2H), 2.9 (m, 1H), 3.4 (m, 1H), 3.7 (m, 4H), 4.1 (m, 2H), 4.5-4.6 (m, 2H), 5.2 ( m, 1H), 7.2-8.4 (m, 4H):MS(EI): 613 (M+H\100%). The diastereomers were separated by préparative scale HPLC.Lyophilisation of the eluents provided diastereomer 1 and diastereomer 2.
Example 14
Préparation of 3-Oxo-4-ffS)-4-methvl-2-{i5-(2-morpholino-4-vl-ethoxv)-benzofuran-2- carbonvllaminol-pentanovlamino)-l-benzenesnlphonyl-azepanium a.) l-Benzenesulphonyl-4-((S)-2-îgri-butoxycarbonylamino-methyl-pentanoylamino)- 3-hydroxy-azepanium
To a solution of the amine of Example 2g (0.5 g, 1.46 mmol) in dichloromethanewas added triethylamine (0.4 mL, 2.92 mmol) followed by benzenesulphonyl chloride (0.28mL, 2.18 mmol). The reaction was stirred at room température until complété asdetermined by TLC analysis. Workup and column chromatography (10% methanokdichloromethane) provided 450 mg of the title compound: MS(EI) 484 (M+H+). 94 012288 b. ) 4-((S)-2-Amino-methyl-pentanoylamino) l-benzenesulphonyl-3-hydroxy- * azepanium
Folïowing the procedure of Example 2i except substituting the compound of • _
Example 14a the title compound was prepared: MS(EÏ) 384 (M+H+). 5 c. ) 3-Hydroxy-4-((S)-4-methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]amino}-pentanoylamino)-l-benzenesulphonyl-azepanium
Folïowing the procedure of Example 13c except substituting the compound ofExample 14b the title compound was prepared: MS(EI) 657 (M+H+). 10 d. ) 3-Oxo-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]anuno}-pentanoylamino)-l-benzenesulphonyî-azepanium
Folïowing the procedure of Example li except substituting the compound ofExample 14c the title compound was prepared: ’H NMR (CDC10: δ 1.0 ( m, 6H), 1.5-2.1 15 (m,- 5H), 2.2 (m, 2H), 2.4 (m, 1H), 2.7 (m, 4H), 2.8 (m, 2H), 3.5 (m, 1H), 3.8 (m, 4H), 4.0 (m, 1H), 4.1 (m, 2H), 4.4 (m, 1H), 4.5 (m, 1H), 4.7 (m, 1H), 5.1 ( m, 1H), 7.0 (m,3H), 7.3 (m, 2H), 7.5 (m, 3H), 7.7 (m, 2H): MS(EI): 655 (M+H\100%) .
Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 45:55 20 CH3CN:20 mm KHPO4 (pH 7 buffer) 60 min. gradient 1 mL/min.; inertsil ODS-3 column l 4.6 x 250 mm; UV détection at 215 nM) showed two peaks (R{ = 44.6 mins. and 45.9mins). The diastereomers were separated by préparative scale HPLC (40:60 to 50:50CH3CN: mm KHPO4 (pH 7 buffer)gradient, 12 mL/min., 60 mins; inertsil ODS-3 column250 x 20 mm; UV détection at 215 nM). Lyophilisation of the eluents provided 25 diastereomer 1 (anal. Rf = 44.6 mins.) and diastereomer 2 (anal. Rt = 45.9 mins). 95 012288
Example 15
Préparation of 4-((S)-4-Methyl-2-{ r5-f2-morphoIino-4-vl-ethoxv)-benzofuran-2- carbonvllamino )-pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenvlamide a. ) [(S)-l-(3-Hydroxy-l-phenylcarbamoyI-azepan-4-ylcarbamoyl)-3-methyl-butyî]- carbamic acid ïert-butyl ester
To a solution of the amine of Example 2g (0.5 g, 1.46 mmol) in dichloromethane(20 mL) was added phenyl isocyanate (0.24 mL, 2.18 mmol). The reaction was stirred atroom température until complété as determined by ILC analysis. Workup and columnchromatography (5% methanohdichloromethane) provided 578 mg of the title compound:MSÇEI) 463 (M+H+). b. ) 4-((S)-2-Amino-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylicacid phenyl amide
Following the procedure of Example 2i except substituting the compound ofExample 15a the title compound was prepared: MSÇEI) 363 (M+H+). c. ) 3-Hydroxy-4-((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]amino}-pentanoyIamino)-azepane-l-carboxyEc acid phenylamide
Following the procedure of Example 13c except substituting the compound ofExample 15b the title compound was prepared: MS(EI) 636 (M+H+). d. ) 4-((S)-4-Methyl-2-{ [5-(2-morphoIino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino }- pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide
Following the procedure of Example li except substituting the compound ofExample 15c the title compound was prepared: 'H NMR (CDC13): ): δ 1.0 ( m, 6H), 1.5-2.1( m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 3.0 (m, 2H), 3.1 (m, 1H), 3.8 (m, 1H), 3.9 (m, 4H), 4.2 (m, 1H), 4.3 (m, 2H), 4.9 (m, 2H), 5.2 ( m, 1H), 7.2-8.4 (m, 9H): MSÇEI): 634(M+H\100%)
Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH3CN:20 mMKHPO4 (pH 7 buffer) isocratic, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV 96 012288 détection at 215 nM) showed two peaks (Rt = 27.3 nains, and 30.1 mins). Thediastereomers were separated by préparative scale HPLC (40:60 to 50:50 CH3CN: 20 mMKHPO4 (pH 7 buffer) gradient, 12 mL/nain., 60 mins; inertsil ODS-3 column 250 x 20 mm;UV détection at 215 nM). Lyophilisation and desalting of the eluents by NaHCOgzethylacetate extraction provided diastereomer 1 (anal. Rt = 27.3 mins.) and diastereomer 2(anal. Rt = 30.1 mins).
Example 16
Préparation of 5-(2-Morpholino-4-yI-ethoxv)-benzofitran-2-carboxvlic acid ((S)-3-methvl-l- {3-oxo-l-r2-(3-pvridin-2-v1-phenyDacetvl1-azepan-4-vlc3rbamovl)~butvl)amide a. ) 5-(2-Morpholino-4-yl-ethoxy)-benzoforan-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyI)amide
Following the procedure of Example 13c except substituting the compound ofExample 9b the title compound was prepared: MS(EI) 712 (M+H+). b. ) 5-(2-Morpbolino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3- oxo-1 -[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl }-butyl)anaide
Following the procedure of Example li except substituting the compound ofExample 16c the title compound was prepared: ’H NMR (CDClj): ): δ 1.0 ( m, 6H), 1.5-2.1( m, 5H), 2.2 ( m, 2H), 2.7 (m, 4H), 2.8 (m, 2H), 2.9 (m, 1H), 3.5 (m, 1H), 3.7 (m, 4H),3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 ( m, 1H), 7.2-8.0 (m, 13H), 8.5 (m, 1H);MS(EI): 710 (Μ+Η*,100%) MS(EI).
Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH3CN:20 mMKHPO4 (pH 7 buffer) isocratic, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UVdétection at 215 nM) showed two peaks (Rt = 33.9 mins. and 37.9 mins). Thediastereomers were separated by préparative scale HPLC (40:60 to 45:55 CH3CN: 20 mMKHPO4 (pH 7 buffer) gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm;UV détection at 215 nM). Lyophilisation and desalting of the eluents by NaHCO3:ethylacetate extraction provided diastereomer 1: MS(EI) 710.3 (M+H+) (anal. Rt = 33.9 mins.)and diastereomer 2: MS(EI) 710.3 (M+H+) (anal. Rt = 37.9 mins). 97 012288
Example 17
Préparation of 5-(2-Morpholino-4-yl-ethoxv)-benzofuran-2-carboxvIic acid i(S)-l-(benzoyl- 3-oxo-azepan-4-ylcarbamoyl)-3-methvl-bntyl1amide a. ) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3- hydroxy-azepan-4-ylcarbamoyl)-3-methyI-butyl]amide
Following the procedure of Example 13c except substituting the compound ofExample 11b the title compound was prepared: MS(E0 621 (M+H+). b. ) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example li except substituting the compound ofExample 17a the title compound was prepared: ’H NMR (CDClj): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 2.9 (m, 2H), 3.0 (m, 1H), 3.7 (m, 5H), 4.0 (m, 1H), 4.1(m, 2H), 4.7 (m, 2H), 5.4 ( m, 1H), 7.2-8.4 (m, 11H): MS(EI): 619 (M+H\100%)
Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 55:45CH3CN:20 mM KHPO4 (pH 7 buffer) 30 min. gradient, 1 mL/min.; inertsil ODS-3 column4.6 x 250 mm; UV détection at 215 nM) showed two peaks (Rt = mins. 13.5 and 17.6mins). The diastereomers were separated by préparative scale HPLC (40:60 to 45:55CH3CN: mM KHPO4 (pH 7 buffer) 60 min. gradient, 15 mL/min., 60 mins; inertsil ODS-3column 250 x 20 mm; UV détection at 215 nM). Lyophilisation and desalting of theeluents by NaHCO3:ethyl acetate extraction provided diastereomer 1 (anal. Rt = 13.5mins.) and diastereomer 2 (anal. Rt = 17.6 mins). 98 012288
Example 18
Préparation of 5-f2-Pvrrohdin-l-yl-ethoxy)-benzofuran-2-carboxylic acid fYSM-fl- benzenesulfonvl-3-oxo-azepap-4-vlcarbamovl)-3-methyl-butyflaniide a. ) 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example 14c except substitating 5-(2-pyrrolidin-l-yl-ethyloxy)-benzofuran-2-carboxylic acid for 5-(2-morphoIin-4-yl-ethyIoxy)benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 641 (M+H+). b. ) 5-Ç2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example li except substitating the compound ofExample 18a the title compound was prepared: 'H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1(m, 9H), 2.2 ( m, 2H), 2.5 (m, 1H), 2.7 (m, 4H), 3.0 (m, 2H), 3.4 (m, 1H), 4.0 (m, 1H),4.1 (m, 2H), 4.5 (m, 1H), 4.6 (m, 1H), 5.0 ( m, 1H), 7.2-8.4 (m, 11H): MSÇEI): 639(M+H\100%).
Example 19
Préparation of 5-(2-Piperidin-l-vl-ethoxv)-benzofuran-2-carboxylic acid lYSH-Çl- benzenesulfopyl-3-oxo-azepan-4-ylcarbamovl)-3-methvl-butvl1amide a.) 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl3amide
Following the procedure of Example 14c except substitating 5-(2-piperidin-l-yl-ethyloxy)-benzofuran-2-carboxylic acid for 5-(2-moipholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid the title compound was prepared: MSÇEI) 655 (M+H+). 99 012288 b.) 5-(2-Piperidin-l-yl-ethoxy)-benzoiuran-2-carboxylic acid [(S)-l-(l-benzenesu]fonyl-3- hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example li except substituting the compound ofExample 18a the title compound was prepared: ’H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1(m, 11H), 2.2 (m, 2H), 2.5 (m, 5H), 2.7 (m, 2H), 3.5 (m, 1H), 4.0 (m, 1H), 4.1 (m, 2H), 4.5 (m, 1H), 4.6 (m, 1H), 5.0 (m, 1H), 7.2-8.4 (m,llH): MS(ED: 653 (M+H\100%) .
Example 20
Préparation of 5-(2-MorphoIino-4-yI-ethoxy)-benzofuran-2-carboxvlic acid ((S)-3-methvl- 1 - ( 3-oxo-l-i2-f3-pvridin-2-vl-phenyî)ethyn-azepan-4-vlcarbamovll-butvl')amide a. ) 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid methoxy methyl arnide
To a solution of 3-(2-pyridyl)phenyl acetic acid (lg) in dichloromethane was addedN, O-dimethylhydroxylamine hydrochloride (0.92 g), triethylamine (1.3 mL), HOBt (0.96g) and EDC (1.1 g). The reaction was stirred until complété. Workup and columnchromatography (40% .ethyl acetate-.hexanes provided 1.1 g of the title compound: MS(EI)257 (M+H+). b. ) 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde
To a solution of 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acidmethoxy methyl arnide (0.2 g) of Example 20a in THF was added LAH (2.0 mL of a 1 Msolution in THF). The reaction was stirred until complété consumption of the startingmaterial. Workup gave 160 mg of the title compound. c. ) ((S)-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-ethyl]-azepan-4-ylcarbamoyl}-3-methyl-butyl)-carbamic acid tert butyl ester
Following the general procedure of Example 2g except substituting 5-(2- morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde for benzaldehyde the title compound was prepared: MS(EI) 525 (M+H+). 100 012288 d. ) (S)-2-Amino-4-methyl-pentanoic acid-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-efhyl]-azepan-4-yl}-amide
Following the procedure of Example 2i except substituting the compound ofExample 20c the title compound was prepared. e. ) 5-(2-Morpholino-4-yl-ethoxy)-benzoiuran-2-carboxyîic acid ((S)-3-methyl-l-{3hydroxy—l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example 13c except substituting the compound ofExample 20d the title compound was prepared. f. ) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1- {3-oxy-l-[2-<3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example li except substituting the compound ofExample 20e the title compound was prepared: ‘H NMR (CDCy: δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 2.8 (m, 6H), 3.1 (m, 1H), 3.3 (m, 1H), 3.5 (m, 1H), 3.7 (m, 4H), 4.2 (m, 3H), 4.6 (m, 1H), 5.2 ( m, 1H), 7.2-8.4 (m, 13H), 8.6 (m, 1H);MS(EI): 696 (M+H\ 80%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 696 (M+H\ 100%), and the slower eluting diastereomer; MS(EI):696 (M+H\ 100%).
Example 21
Préparation of Naphthlene-2-carboxylic acid (fS)-3-methyl-l-{3-oxo-l-F2-(3-pvridip-2-yI- phenvl)ethvn-azepan-4-vlcarbamovl)-butvl)amide a.) Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyiidin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example 20f except substituting 2-naphthoic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-cafboxylic acid the title compound was prepared:MS(ET) 579 (M+H+). 101 012288 b.) Naphthlene-2-carboxylic acid ((S)-3-methyI-1- {3-oxo- l-[2-(3-pyridin-2-yl- phenyl)ethyl]-azepan-4-ylcarbamoyl} -butyl)amide
Following the procedure of Example li except substituting the compound ofExample 21b the title compound was prepared: ’H NMR (CDClj): δ 1.0 ( m, 6H), 1.5-2.1 5 (m, 6H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, 1H), 3.4 (d, 1H). 3.5 (m, 1H), 4.7 ( m, 1H), 5.0 ( m, 1H), 6.8-7.2 (m, 6H), 7.3 (m, 1H), 7.5 (m, 2H), 7.9 ( m, 6H), 8.2 (Μ, 1H), 8.7(m, 1H): MS(EI):577 (M+H\100%).
Example 22 10
Préparation of lH-Indole-2-carboxviic acid ffS)-3-methvl-l-{3-oxo-l-F2-(3-pyridin-2-yI- phenyDethyll-azepan-4-vlcarbamoyll-butvl)amide a.) ((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- 15 ylcarbamoyl}-butyl)amide
Following the procedure of Example 20f except substituting lH-indole-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid the titlecompound was prepared: MS(EI) 568 (M+H+). 20 b.) ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- ylcarbamoyl }-butyI)amide
Following the procedure of Example li except substituting the compound ofExample 22b the title compound was prepared: : !H NMR (CDClj): ): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m,' 1H), 3.4 (d, 1H). 3.5 (m, 1H), 4.7 ( m, 25 1H), 5.0 ( m, 1H), 6.8-7.2 (m, 6H), 7.0-7.9 (m, 12H), 8.7 (m, 1H), 9.5 (m, 1H): MS(EI): 566 (M+H\100%) 102 012288
Example 23
Préparation of lH-Indole-2-cafboxylic acid rfS)-l-(l-benzenesulfonvl-3-oxo-azepan-4- vlcarbamovl)-3-methvl-butvllamide a. ) lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example 2j except substituting the compound ofExample 14b and substituting lH-indole-2-carboxylic acid for naphthoic acid the titlecompound was prepared: MS(EI) 527 (M+H+). b. ) lH-Indole-2-carboxyIic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyljamide
Following the procedure of Example li except substituting the compound ofExample 23b the title compound was prepared: ‘H NMR (CDC15): δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (dd, 1H). 3.9 (m, 1H), 4.5 (dd, 2H), 4.7 (m, 1H),5.0 ( m, 1H), 7.2 -7.6 (m, 10H). 9.5 (b, 1H); MS(EI): 525 (M+H\ 10%).
Example 24
Préparation of Benzofuran-2-carboxylic acid ifS)-l-fl-benzenesulfonvl-3-oxo-azepan-4- vIcarbamovl)-3-methvl-butyllamide a. ) Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example 23a except substituting benzofuran-2-carboxylic acid for lH-indole 2-carboxylic acid the title compound was prepared: MS(EI)528 (M+H+). b. ) Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl>3-methyl-butyl]amide
Following the procedure of Example li except substituting the compound ofExample 24b the title compound was prepared: *H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 103 012288 (m, 5H), 2.2 (m, 2H), 2.6 (m, 1H), 3.5 (d, 1H). 4.1 (m, 1H), 4.7 ( m, 2H), 5.0 ( m, 1H), 7.2-7.2 (m, 10H).
Example 25
Préparation of Benzofuran-2-carboxvlic acid rfS)-3-methvl-l-i3-oxo-l-r2-('3-pvridin-2-vl- ρΗβην1)βΰινΠ-Ηζβρ3η-4-ν1θ3Γ83ΐηον1}-6ΰΐν1')ΗΓηΐά6 a.) Benzofuran-2-carboxylic acid [(S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example 20e except substituting benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic the titlecompound was prepared: MS(EI) 569 (M+H+). b.) Benzofuran-2-carboxylic acid [(S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example li except substituting the compound ofExample 25b the title compound was prepared: Ή NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 5H), 3.0 (m, 1H). 3.3 (m, 1H), 3.5 (m, 1H), 4.7 (m, 1H), 5.2(m, 1H), 7.2-7.7 (m, 14H), 8.7 (m, 1H); MS(EI): 567 (M+H\100%)
The diastereomeric mixture was separatedby HPLC to provide the faster elutingdiastereoemer; MS(EI): 656 (M+H\100%), and the slower eluting diastereomer; MS(EI):656 (M+H*,100%).
Example 26
Préparation of 5-(2-Morpholino-4-vl-ethoxv)-benzofuran-2-carboxvlic acid [YS)-3-methvI-l- (3-oxo-l-phenethvl-a2epap-4-ylcarbamovll-butvllamide
Following the procedures of Examples 20c-f except substitutingphenylacetaldehyde for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde ofExample 20c the title compound was prepared: ’H NMR (CDCy: δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 ( m, 2H), 2.4 (m, 1H), 2.6 (m,4H), 2.7 (m, 6H), 3.0 (m, 1H), 3.3 (dd, 1H), 3.5 104 012288 (q, 1H), 3.7 ( m, 4H). 4.2 (m, 2H), 4.7 (χη,ΙΗ), 5.0 ( m, 1H),7.2-7.2 (m, 11H); MS(EI):619 (M+H*, 80%)
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(ET): 619 (M+H\100%), and the slower eluting diastereomer; MS(EI):619 (M+H\100%).
Example 27
Préparation of Naphthvlene-2-carboxvlic acid r(S)-3-methvl-l-(3-oxo-l-phenethvl-azepan- 4-vlcarbamoyll-butvl 1 amide
Following the procedures of Examples 2h-k except substituting phenylacetaldehydefor benzaldehyde of Example 2h the title compound was prepared: ’H NMR (CDCl·): δ 1.0( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.4 (m, 1H), 2.7 (m, 4H), 3.0 (m, 1H), 3.7 (d, 1H), 3.5 (q, 1H), 4.7 ( m, 1H), 5.1 ( m, 1H), 6.9 -7.2 (m, 7H), 7.5 (m, 2H), 7.9 ( m, 4H) 8.4(m, 1H); MS(EI): 500 (M+H\100%) .
Example 28
Préparation of Benzofuran-2-carboxvlic acid KS)-3-methvl-l-r3-oxo-l-fpyridine-2- sulfonvl)-azepan-4-yIcarbamovll-butvllamide a. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Examples 14a-b except substituting 2-pyridinesulfonylchloride forbenzenesulfonyl chloride of Example 14a the title compound was prepared:MS(EI)385 (M+H+). b. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.15 g) in dichloromethane was added TEA(0.11 mL), HOBt (49 mg), EDC (69 mg) and benzofuran-2-carboxylic acid (58 mg). The 105 012288 reaction was stirred until complété. Workup and column chromatography (5%methanohethyl acetate) provided the title compound: MS(EI) 529 (M+H+). c.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyljamide
Following the procedure of Example li except substituting the compound ofExample 28b the title compound was prepared: ‘H NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (dd, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H); MS(EI): 527(M+H\ 40%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; ’HNMR: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (d, 1H); 4.0 (d, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0(m, 2H), 8.7 (m, 1H); MS(EI): 527 (M+H\ 100%), and the slower eluting diastereomer;’HNMR: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (d, 1H); 4.0 (d, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m,1H); MS(EI): 527 (M+H*, 100%).
Example 29
Préparation of Naphthvlene-2-carboxvlic acid KS)-3-methvl-l-f3-oxo-l-fpvridrne-2- sulfonvl)-azepan-4-ylcarbamovll-butvl ) amide a. ) Naphthylene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 2-naphthoic acid forbenzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 539 (M+H+). b. ) Naphthylene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-siilfonyl)- azepan-4-ylcarbamoyl]-butyl }amide
Following the procedure of Example li except substituting the compound ofExample 29a the title compound was prepared: ‘H NMR (CDClj): δ 1.0 ( m, 6H), 1.5-2.1(m, 5H), 2.2 ( m, 2H), 2.7 (m, 1H), 3.7 (dd, 1H). 4.0 (m, 1H), 4.7 ( m, 2H), 5.0 ( m, 1H), 106 012288 7.2-73 (m, 2H), 7.5 (m, 3H), 7.9 (m, 6H), 8.3 (m, 1H), 8.4 (m, 1H); MS(EI): 537(M+H\ 50%).
The diastereomeric mixture was séparated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 537 (M+H*, 100%), and the slower eluting diastereomer; MS(EI):537 (M+H*, 100%).
Example 30
Préparation of 5-(2-Morpholino-4-vl-ethoxv)-bePZofuran-2-carboxvlic acid ( (S)-3-methyl- l-r3-oxo-l-fpyridine-2-sulfonvl)-azepan-4-vlcarbamovH-butvl)amide a. ) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI)-butyl}amide
Following the procedure of Example 13c except substituting the compound ofExample 28a the title compound was prepared: MS(E0 658 (M+H+). b. ) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcaibamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 29a the title compound was prepared: ’H NMR (CDCl,): δ 1.0 (m, 6H), 1.5-2.1 m,5H), 2.2 (m, 2H), 2.7 (m, 1H), 33 ( m, 4H). 3.7 (m, 6H), 4.1 (m, 1H), 4.5 (m, 2H), 4.7 (m,2H), 5.0 (m, 1H), 7.2-73 (m, 4H), 7.4 (m, 2H), 8.0 (m, 2H), 8.7 (m, 1H), 8.7 (m, 1H);MS(EI): 656 (M+H*,100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 656 (M+H*, 100%), and the slower eluting diastereomer, MS(EI):656 (M+H*, 100%). 107 012288
Example 31
Préparation of 4-((S)-4-Methvl-2-{ i(5-(2-morphoIino-4-yl-ethoxv)-benzofuran-2-carbonyll- aminol-pentanovlarnino)-3-oxo-azepane-l-carboxvlic acid rgrr-butvl ester a. ) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid ierr-butyl ester
To a solution of the compound of Exemple lf (0.89 g) in ethyl acetate:methanol (30mL of a 2:1 mixture ) was added 10 % Pd/C and a balloon of hydrogen gas was attacbed.The reaction was stiired until complété by 1LC analysis wbereupon it was filtered andconcentrated to provide the title compound (0.57 g). b. ) 4-((S)-4-Methyl-2-{[(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-caibonyl]- amino}-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid rerr-butyl ester
Following the procedure of Example 13c except substituting the compound ofExample 31a the title compound was prepared. c. ) 4-((S)-4-Methyl-2-{ [(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]- amino}-péntanoylamino)-3-oxo-azepane-l-carboxylic acid ierr-butyl ester
Following the procedure of Example li except substituting the compound ofExample 31b the title compound was prepared: 'H NMR (CDClj): δ 1.0 (m, 6H), 1.5 (m,9H), 1.7 (m, 5H), 2.2 (m, 2H), 2.5 (m, 5H), 2.7 (m, 2H), 3.5 (m, 1H). 3.8 (m, 4H), 4.1 (m,3H), 4.2 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 5H); MS(EI): 615 (M+H\100%) .
Example 32
Préparation of 4-(YS)-4-Methyl-2-{ r(5-(2-morpholino-4-yl-ethoxv)-benzofuran-2-cafboxvlic acid F(S)-3-methvl-l-(3-oxo-azepan-4-ylcarbamoyll-butyllamide
To a solution of the compound of Example 31c in THF (5 mL) was added IM HClin ether (5 mL). Th reaction was stiired ovemight whereupon it was concentrated toprovide the title compound: ’H NMR (CDC1J: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 108 012288 2.7 (m, 4H), 3.2 (dd, 3H). 3.7 (m, 6H), 4.0 (m, 3H), 4.5 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m,* 6H); MS(EI): 515 (M+H\100%).
R &amp;
Example 33 5
Préparation of 4-Methyl-pentanoic acid {3-oxo-l-r2-(3-pyridin-2-yl-phenvl-aeetyri-azepan- 4-vl)-amide a. ) 3-Hydroxy-4-(4-methyl-pentanoylamino)-azepane-l-carboxylic acid ierr-butyl ester 10 Following the procedure of Example lf except substituting 4-methylpentanoic acid for Cbz-leucine the title compound was prepared: MS(ET) 329 (M+H+). b. ) 4-Methyl pentanoic acid (3-hydroxy-azepan-4-yl)-amide
To a solution of the compound of Example 33a (200 mg) in methanol (5 mL) was 15 added 4M HCl dioxane (5 mL). The reaction was stirred until complété whereupon it wasconcentrated to provide the title compound (132 mg): MS(EI) 229 (M+H+). c. ) 4-Methyl-pentanoic acid {3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl-acetyI3-azepan-4-yl}amide 20 Following the procedure of Example 9a except substituting the compound of
Example 33b the title compound was prepared: MS(EI) 424 (M+H+). d. ) 4-Methyl-pentanoic acid {3-oxo-l-[2-(3-pyridin-2-yl-phenyl-acetyl]-azepan-4-yl}-amide 25 Following the procedure of Example li except substituting the compound of
Example 33c the title compound was prepared: lH NMR (CDC1, ) δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 4.1 (m, 3H), 4.6 (m, 1H), 5.3 (m, 1H), 7.2-8.0 (m, 7H), 8.7 (m, 1H); MS(EI): 422 (Μ+Η\100%). 109 012288
Example 34
Préparation of ((S)-3-Methyl-l-{ 3-oxo-l-r2-(3-pvridin-2-vl-phenvl)-acetvn-azepan-4- vlcarbamovll-butyl)-naphthvlene-2-methvl-carbamîc acid terr-butyl ester a. ) (S)-4-Methyl-2-[naphthalene-2-ylmethyl)-amino]-pentanoic acid methyl ester
To a solution of leucine methyl ester hydrochloride (0.5 g) in dichlormethane wasadded triethylamine (0.9 mL), 2-naphthaldehyde (0.43 g) and sodium triacetoxyborohydride(0.87 g). The mixture was stiired until complété. Workup and column chromatography(5% ethyl acetate:dichloromethane) provided 0.4 g of the title compound: MS(EI) 286(M+H+). b. ) (S)-2-(ieri-Butoxycarbonyl-naphthlen-2-ylmethyl-amino)-4-metyhyl pentanoic acidmethyl ester
To a solution of the compound of Example 34a (0.35 g) in dichloromethane wasadded di-ferr-butyldicarbonate (0.29 g). After 2 hours at room température triethylaminewas added and the reaction heated to reflux. Upon completion, the reaction wasconcentrated and the residue was purified by column chromatography (50%hexane:dichloromethane) to provide 0.17 g of the title compound: MS(ET) 386 (M+H+). c. ) (S)-2-(i€rr-Butoxycarbonyl-naphthlen-2-ylmethyl-amino)-4-methyl pentanoic acid
To a solution of the compound of Example 34b (0.17 g) in THF:methanol (15 mLof a 2:1 solution) was added LiOH (0.019 g). The reaction was stirred ovemightwhereupon it was concentrated to provide the title compound . d. ) 4-[(S)-fert-butoxycarbonyl-naphthylen-2-ylmethyl-amino)-4-methyl- pentanoylamino3-3-hydroxy-azepane-l-caiboxylic acid benzyl ester
To a sloution of the compound of Example 2e (0.11 g) in dichloromethane wasadded EDC (0.08 g), HOBt (0.06 g) and the acid of Example 34c. Upon completion thereaction was worked up and chromatographed (5% methanol:dichloromethane) to providethe title compound (0.18 g): MS(EI) 618 (M+H+). 110 012288 V e.) [(S)-l-(3-Hydroxy-a2epan-4-ylcarbamoyl)-3-methyl-butyl]-naphthylen-2-ylmethylcarbamic acid reri-butyl ester ·* 5 To a solution of the compound of Example 34d (0.17 g) in ethyl acetate:methanol(20:10 mL) was added 10% Pd/C. A balloon of hydrogen was attached and the reactionwas stirred until complété consumption of the starting material. The reaction was fïlteredand concentrated to provide the title compound (0.10g): MSÇEI) 484 (M+H+). 10 f.) ((S)-3-Methyl-l-{3-hydroxy-l-[2-(3-pyridm-2-yl-phenyl)-acetyl]-azepan-4~ylcarbamoyl}-butyl)-naphthylene-2-methyl-carbamic acid ierr-butyl ester Following the procedure of Example 9a except substituting the compound ofExample 34e the title compound was prepared: MS(EI).679 (M+H+). 15 g.) ((S)-3-Methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-a2epan-4- - ylcarbamoyl}-butyl)-naphthylene-2-methyl-carbamic acid ieri-butyl ester Following the procedure of Example li except substituting the compound ofExample 34f the title compound was prepared: : ’H NMR (CDCf,): δ 1.0 (m, 6H), 1.5-22(m, 16H), 2.7 (m, 1H), 3.2 (m, 1H). 3.7 (m, 3H), 4.0 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.2-7.3 (m, 16H), 8.6 (m, 1H); MSÇEI): 677 (M+H*,100%) . 20 l Examnle 35 Préparation of (S)-4-Methvl-2-r(naphthvlen-2-vlmethvl)-aminol-pentenoic acid Γ3-οχο-1-Γ2- (3-pvridin-2-vl-phenvI)-acetvn-azepan-4-vIl-amide 25 To a solution of the compound of Example 34g (20 mg) in THF was added IM HClin ether. The reaction was stirred until complété consumption of the starting material 30 whereupon it was concentrated to provide the title compound: ’H NMR (CDCy: δ 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (m, 5H), 4.0 (m, 1H), 4.7 (m, 2H), 4.4(m, 1H), 7.2-8.0 (m, 16H), 8.7 (m, 1H); MS(ET): 577 (Μ+Ηζ100%). 111 012288
Example 36
Préparation of 4-Γ2-(2-{ (S)-3-Methvl-l-r3-oxo-l-(pyidine-2-sulfonvl)-azepan-4- vIcarbamovn-butvlcarbamoyl}-benzofttrap-5-yloxv)-ethvn-pipera2ine-l-carboxvIic acid terr-butyl ester a. ) 4-[2-(2-{(S)-3-Methyl-l-[3-hydroxy-l-(pyidine-2-sulfonyl)-azepan.-4-ylcarbamoyl]- butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-cafboxylic acid ieri-butyl ester
To a solution of the compound of Example 28a (0.15 g) in dichloromethane wasadded EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and4-[2-(2-carboxy-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid reri-butyl ester. The reaction wasstirred until complété. Work up and column chromatography (10 % methanol: ethylacetate) provided the title compound (0.10 g): MS(EI) 757 (M+H+). b. ) 4-[2-(2-{(S)-3-Methvl-l-[3-oxo-l-(pyidine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyIcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid ieri-butyl ester
Following the procedure of Example li except substituting the compound ofExample 36a the title compound was prepared: 'H NMR (CDCf,): Ô 1.0 (m, 6H), 1.5-2.1(m, 14H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (m, 2H), 3.5 (m, 4H). 3.7 (m, 6H), 4.1 (m, 1H), 4.5(m, 2H), 4.7 (m, 2H), 5.0 (m, 1H), 7.0-7.6 (m, 6H), 8.0 (m, 2H), 8.7 (m, 1H); MS(EI): 755 (Μ+Ηζ100%).
Example 37
Préparation of 5-(2-Piperizin-l-vI-ethoxv)-benzofüran-2-carboxvlic acid f (S)-3-methvl-l- r3-oxo-l-fpvridine-2-sulfonvl')-azepan-4-vlcarbamovD-3-butvn-araide
The compound of Example 36b (0.02 g) was dissolved in 4M HCl in dioxane. The reaction was stirred until complété whereupon it was concentrated to provide the title compound: 5H NMR (CDCy: δ 1.0 (m, 6H), 1.5-1.7 (m, 7H), 2.7 (m, 2H), 3.3 (Μ, 2H), 3.5 (m, 1H). 3.8 (m, 5H), 4.1 (m, 3H), 4.7 (m, 4H), 5.0 (m, 1H), 7.0-7.3 (m, 2H), 7.4 (m, 6H), 8.0 (m, 2H), 8.7 (m, 1H): MS(EI): 655 (M+H\100%) . 112 012288
Example 38
V " Préparation of 5-(2-CvciohexvI-ethoxv)-benzofuran-2-carboxvlic acid {(S)-3-methyl-l-F3- oxo-l-(-pvridipe-2-suIfonvlVaz&amp;pan-4-vlcarbamovll-butvl)amide 5 a. ) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
To a solution of the compound of Example 28a (0.15 g) in dichloromethane wasadded EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 5-(2-cyclohexyl-ethoxy)- 10 benzofuran carboxylic acid (0.01 g). The reaction was stirred until complété by TLCanalysis. Workup and column chromatography (100% ethyl acetate) provided the titlecompound (0.15 g): MS(EI) 655 (M+H+). b. ) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- 15 (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 38a the title compound was prepared: MS(ET) 653 (M+H+).
Example 39 20 /
Préparation of 5-(2-Cvclohexvl-ethoxy)-benzofuran-2-carboxvlic acid (TS)-3-methvl-l-{3- oxo-l-r2-(3-pyridin-2-vl-phenyl)ethvll-azepan-4-vlcarbamovl}-butyl)amide a.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3- 25 hydroxy-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
To a solution of the compound.of Example 20d (0.15 g) in dichloromethane was added EDC (0.06 g), HOBt (0.04 g), triethylamine (0.14 mL) and 5-(2-cyclohexyl-ethoxy)benzofuran carboxylic acid (0.09 g). The reaction was stirred until complété by TLCanalysis. Workup and column chromatography (100% ethyl acetate) provided the title 30 compound (0.10 g): MS (El) 695 (M+H+). 113 012288 b.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example li except substituting the compound ofExample 39a the title compound was prepared: ’H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 5 (m, 18H), 2.2 (m, 2H), 2.7 (m, 3H), 3.2 (m, 1H), 3.5 (m, 1H). 3.9 (m, 4H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 13H), 8.7 (m, 1H): MS(EI): 693 (M+H\100%)
Example 40 10 Préparation of 4-(2-(2-((S)-3-Methvl-l-r3-oxo-l-(3-pvridin-2-vI-phenyl)-ethyl iazepan-4- vlcarbamovll-butylcarbamoyll-benzofuran-5-vloxy)-ethvll-piperazine-l-cafboxvlic acid fgrf-butyl ester a. ) 4-[2-(2-{(S)-3-Methyl-l-[3-hydroxy-l-(3-pyridin-2-yl-phenyI)-ethyl [azepan-4- 15 ylcarbamoyl3-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid icrr-butyl ester
To a solution of the compound of Example 20d (0.15 g) in dichloromethane wasadded EDC (0.06 g), HOBt (0.04 g), triethylamine (0.14 mL) and 4-[2-(2-carboxy-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxy]ic acid ieri-butyl ester (0.12 g). The 20 reaction was stirred until complété by TLC analysis. Workup and column chromatography(10% methanolrethyl acetate) provided the title compound (0.09 g): MS(EI) 797 (M+H+). b. ) 4-[2-(2-{ (S)-3-Methyl-l-[3-oxo-l-(3-pyridin-2-yl-phenyl)-ethyl [azepan-4-ylcarbamoyl]-butylcarbamoyl} -benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid 25 ieri-butyl ester
Following the procedure of Example li except substituting the compound ofExample 40a the title compound was prepared: MS(EI) 795.9 (M+H+). 114 012288
Example 41
A
Préparation of 5-(2-piperizm-l-vl-ethoxv'>-benzofuran-2-carboxvlic acid f(S)-3-methvl-l- f3-oxo-l-r2-(3-pvridin-2-vl-phenvl)ethvl1-azepan-4-vlcarbamovlÎ-butvr)aimde 5
Following the procedure of Example 37 except substituting the compound ofExample 40b the title compound was prepared: 'H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 3.4-3.6 (m, 19H), 4.5 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2 (m,1H), 7.4 (m, 1H), 7.5 (m, 2H), 7.7 (m, 2H), 7.8 (m, 1H), 8.1 (m, 2H), 8.4 (m, 1H), 8.7 (m, 10 1H); MS(EI): 695 (Μ+Ηζ 70%).
Example 42
Préparation of (S)-4-Methvl-2-fmethyl-naphthalen-2-vlmethvl-amino)pentanoic acid Γ3- 15 oxo-l-fpvridine-2-sulphonvl~)-azepan-4-vn-amide a. ) 4-[(S)-2-(rer/-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-3- hydroxy-azepane-l-carboxylic acid benzyl ester
To a solution of the compound of Example 2e (0.35 g)in dichloromethane was20 added N-methyl-N-Boc-leucine (0.36 g), HOBt (0.2 g) and EDC (0.28 g). The reaction was l stirred until complété. Workup and column chromatography (5%methanobdichloromethane) provided 0.6 g of the title compound: MS(EI) 492 (M+H+). b. ) [(S)-l-(3-Hydroxy-azepan-4-yIcarbamoyl)-3-methyl-butyl]-methyl-carbamic acid 25 ieri-butyl ester
To a solution of the compound of Example 42a (0.6 g) in methanohethyl acetate(10:20 mL) was added 10% Pd/C and a balloon of hydrogen was attached. The reactionwas stirred ovemight whereupon it was filtered and concentrated to provide 0.50 g of thetitle: MS(EI) 358 (M+H+). 30 c. ) {(S)-l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcafbamoyI]-3-methyl-butyl} methyl-carbamic acid iert-butyl ester
To a solution of the compound of Example 42b (0.2 g) in dichloromethane wasadded triethylamine (0.16 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was 115 01 2288 stirred until complété. Workup and column chromatography (5% methanohethyl acetate) provided the title cowpound (0.23 g): MS(EI) 499 (M+H+). d. ) (S)-4-Methyl-2-methylamino-pentanoic acid [3-hydroxy-l-(2-pyridine-2-sulfonyl)- azepan-4-yl]-amide
To a solution of the compound of Example 42c (0.23 g) in methanol (3.0 mL) wasadded 4M HCl in dioxane (3.0 mL), The reaction was stirred until complété.
Concentration provided the title compound: MS(ET) 399 (M+H+). e. ) (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-ammo)pentanoic acid [3-hydroxy-l- (pyridine-2-sulphonyl)-azepan-4-yl]-amide
To a solution of the compound of Example 42d (0.05 g) in dichloromethane wasadded triethylamine (0.07 mL), 2-naphthaldehyde (0.05 g) and sodiumtriacetoxyborohydride (0.11 g). The reaction was stirred until complété. Workup andcolumn chromatography (5% methanol ethyl acetate) provided the title compound (0.03 g):MS(EI) 539 (M+H+). f. ) (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-oxo-l- (pyridine-2-sulphonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substituting the compound ofExample 42e the title compound was prepared: 'H NMR (CDC10: δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 5H), 2.6 (m, 1H), 3.3 (m, 1H), 3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 1H), 5.2(m, 1H), 7.2-8.0 (m, 10H), 8.7 (m, 1H); MS(EI): 537 (M+H\100%).
Example 43
Préparation of (S)-4-Methvl-2-(methyl-naphthalen-2-vlmethvl-amino)pentanoic acid (3- oxo-l-r2-(3-pyridin-2-vl-phenvl)-acetvn-azepan-4-vIÎ-amide a.) ((S)-l-{ 3-Hydroxy-l-[2-(3-pyridin-2~yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl }-3- methyl-butyl)-methyl-carbamic acid iert-butyl ester
To a solution of the compound of Example 42b (0.25 g) was added 3-(2-pyridyl)phenyl acetic acid (0.16 g), HOBt (0.12 g) and EDC (0.15 g). The reaction was 116 012288
stiired until complété. Workup and column chromatography (5% methanohethyl acetate)provided the title compound (0.24 g): MS(EE) 553 (M+H+X b. ) (S)-4-Methyl-2-methylamino-pentanoic acid {3-hydroxy-l-[2-(3-pyridin-2-yl- 5 phenyl)-acetyl]-azepan-4-yl}-amide
Following the procedure of Example 42d except substituting the compound ofExample 43a the title compound was produced: MS(EI) 453 (M+H+). c. ) (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid {3-oxo-l-[2- 10 (3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-yl}-amide
Following the procedures of Examples 42e-f except substituting the compound ofExample 43b the title compound was produced: 'H NMR (CDCy: 6 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 5H), 3.0 (m, 1H), 3.5 (m, 1H), 3.7 (m, 4H), 4.1 (m, 1H), 4.7 (m, 2H), 5.2(m, 1H), 7.2-8.0 (m, 15H), 8.7 (m, 1H); MS(EI): 591 (M+H*,100%) . 15
Example 44
Préparation of 5-(2-Morpholino-4-vl-ethoxy)-benzofuran-2-carboxvlic acidmethyl ((S)-3- methvl-l-(3-oxo-l-f2-(3-pvridin-2-yl-phenvl)acetyn-azepap-4-vlcarbamovl)-butvllamide 20 a. ) 5-(2-Moipholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl- 1- {3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl} -butyl)amide
To a solution of the compound of Example 43b (0.1 g) in dichloromethane wasadded 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid (0.06 g), HOBt (0.026 25 g), TEA (0.07 mL) and EDC (0.04 g). The reaction was stirred until complété. Workup and chromatography (20% methanohethyl acetate) provided the title compound (0.07 g):MS(ET> 726 (M+H+). b. ) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl- 30 l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide
Following the procedure of Example li except substituting the compound ofExample 44a the title compound was prepared: 'H NMR (CDCl,): ): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 5H), 2.7 (m, 4H), 2.8 (m, 2H), 2.9 (m, 1H), 3.5 (m, 1H), 3.7 (m, 4K), 117 01 2288 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 (m, 1H), 7.2-8.0 (m, 12H), 8.5 (m, 1H);MS(EI): 724 (M+H\100%).
Example 45
Préparation of Benzofuran-2-carboxvlic acid methyl {fS)-3-methvl-l-f3-oxo-l-fpvridin&amp;-2- suIfonyI)-azepan-4-vlcarbamovl)-3-methyl-buM1-amide a. ) Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide
To a solution of the compound of Example 42d (0.1 g) in dichloromethane wasadded benzofuran-2-carboxylic acid (0.04 g), TEA (excess), HOBt (0.03 g), and EDC (0.04g). The reaction was stirred until complété. Workup and column chromatography (5%methanolzdicbloromethane) provided the title compound (0.04 g): MS(EI) 542.9 (M+H+). b. ) Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide
Following the procedure of Example li except substituting the compound ofExample 45a the title compound was prepared: ’H NMR (CDC^): δ 1.0 (m, 6H), 1.5-2.1(m, 8H), 2.2 (m, 2H), 2.7 (m, 1H), 3.0 (m, 1H), 3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 1H), 5.2(m, 1H), 72-8.0 (m, 8H), 8.7 (m, 1H); MS(EI): 541 (Μ+Ηζ 10%).
Example 46
Préparation of 222-Trifluoro-N-((S)-3-methvl-l-(3-oxo-l-r2-f3-pvridin-2-vl-phenyl)- acetvn-azepan-4-vlcarbamovlÎ-butvl)-N-naphthylep-2-vImethvl-acetamide a.) (S)-4-Methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoicacid methyl ester
To a solution of the compound of Example 34a (0.5 g) in dichloromethane wasadded potassium carbonate (catalytic amount), and trifluoroacetic acid (0.44 g). Thereaction was stirred at room température for 1 hour whereupon it was concentrated andchromatographed (20% ethyl acetate:hexane) to provide the title compound. 118 012288 b. ) (S)-4-Methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-aceÎyl)-amino]-pentanoic * K acid lithium sait
To a solution of the compound of Example 46a (0.49 g) in THFrwater (3 mL of a * 2:1 solution) wasadded lithium hydroxide monohydrate (0.06 g). The reaction was stiired5 ovemight whereupon it was concentrated to provide the title compound (0.46 g): MS(ET) 366 (M+H+). c. ) 3-Hydroxy-4-{(S)-4-methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-acetyl)- amino]-pentanoylamino}-azepane-l-carboxylic acid benzyl ester 10 To a solution of the compound of Example 2e (0.29 g) in dichloromethane was added EDC (0.24 g), HOBt (0.16 g) and the compound qf Example 46b (0.46 g). Thereaction was stirred until complété. Workup and column chromatography (5%methanol.-ethyl acetate) provided the title compound (0.25 g): MS(EÎ) 614 (M+H+). 15 d.) 2,2,2-Trifluoro-N-[(S)-l-(3-hydroxy-azepan-ylcarbamoyl)-3-methyl-butyl]-N- naphthlen-2-ylmethyl-acetamide
Following the procedure of Example 42b except substituting the compound ofExample 46c the title compound was produced: MS(EI) 4S0 (M+H+). 20 e.) 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]- l azepan-4-ylcarbamoyl }-butyl)-N-naphthylen-2-ylmethyl-acetamide
Following the procedure of Example 43a except substituting the compound of
Example 46d the title compound was produced: MS(EI) 675 (M+H+). 25 f.) 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]- azepan-4-yicarbamoyl}-butyl)-N-naphthylen-2-ylmethyl-acetaniide
Following the procedure of Example li except substituting the compound ofExample 46e the title compound was prepared: ’H NMR (CDCy: δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.7 (m, 3H), 4.1 (m, 1H), 4.5 (m, 2H), 4.7 30 (m, 2H), 5.2 (m, 1H), 7.2-8.0 (m, 14H), 8.7 (m, 1H): MS(EI): 673 (Μ+ΚΓ,100%). 119 012288
Example 47 z-
Préparation of 4-rfSVfMethanesulphonvl-naphthvlen-2-vlmethvl-amino)-4-methvl- pentanovIamiuol-3-oxo-azepane-l-carboxviic acid benzvl ester a. ) (S)-2-(Methanesulfonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoic acid methylester
To a solution of the compound of Example 34a (0.5 g) in dichloromethane wasadded triethylamine (0.36 mL) and methansulfonyl chloride (0.16 mL). The reaction wasstirred at room température until complété. Workup and chromatography (20% ethylacetate:hexanes) provided the title compound (0.24 g). b. ) (S)-2-(MethanesuIfonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoic acid lithium sait
Following the procedure of Example 46b except substituting the compound ofExample 47a the title compound was prepared: MS(EI) 348 (M+H+). c. ) 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl- pentanoylamino]-3-hydroxy-azepane-l-carboxylic acid benzyl ester
Following the procedure of Example 46c except substituting the compound ofExample 47b the title compound was prepared: MS(EÎ) 596 (M+H+). d. ) 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl- pentanoylamino]-3-oxo-azepane-l-carboxylic acid benzyl ester
Following the procedure of Example li except substituting the compound ofExample 47c the title compound was prepared: “H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 5H), 3.0 (m, 1H), 3.5 (m, 1H), 4.1 (m, 1H), 4.5 (m, 3H), 4.7 (m, 1H), 5.2(m, 3H), 7.2-8.0 (m, 13H); MS(EI): 596 (M+3H\100%). 120 012288
Example 48 y br
Préparation of QuinoIine-2-carboxylic acid {fS)-3-methvl-l-i3-oxo-l-fpvridine-2-suIfonvl>· azenan-4-vlcarbamovll-butvl ) amide 5 a. ) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide
Foïlowing the procedure of Example 28b except substituting quinoline-2-carboxylicacid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 10 CM+H+). b. ) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl3-butyl} amide
Foïlowing the procedure of Example li except substituting the compound of 15 Example 48a the title compound was prepared: 'H NMR (CDCQ: δ 1.0 (m, 6H), 1.5-2.1(ra, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.1 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H),7.0-7.2 (m, 1H), 7.3 (m, 1H). 7.5 (m, 1H), 7.7 (m, 1H), 7.8 (m, 3H), 8.1 (m, 1H), 8.3 (m,2H), 8.7 (m, 2H); MS(EI): 538 (M+lT,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting 20 diastereoemer; MSÇEI): 538 (M+H\100%), and the slower eluting diastereomer; MS(EI): / 538 (M+H\100%).
Example 49 25 Préparation of Ouinoline-8-carboxvlic acid ((S)-3-methvl-l-r3-oxo-l-(pyridine-2-suIfonvr)- azepan-4-vlcarbamovn-butvl ) amide a.) QuinoIine-8-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide 30 Foïlowing the procedure of Example 28b except substituting quinoline-8-carboxyIic acid for benzofuran-2-carboxylic acid the title compound was prepared: MSÇEI) 540 (M+H+). 121 012288 b.) Quinoline-8-carboxylic acid {(S)-3-methyl7l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl} amide
Following the procedure of Example li except substituting the compound of
Example 49a the title compound was prepared: lH NMR (CDClj): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H),.3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.5(m, 4H), 7.6 (m, 1H), 7.7 (m, 3H), 8.2 (m, 1H), 8.6 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H);MS(EI): 538 <M+HT,100%).
Example 50
Préparation of Ouinoline-6-carboxvlic acid ifS)-3-methyI-l-r3-oxo-l-fpvridine-2-sulfonyI)- azepan-4-vlcarbamovn-butyI ) amide a.) Quinoline-6-carboxylic acid {(S)-3-methyI-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- a2epan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting quinoline-6-carboxylicacid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540(M+H+). b.) Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ) amide
Following the procedure of Example li except substituting the compound ofExample 50a the title compound was prepared: ‘H NMR (CDClj): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.0(m, 2H), 7.5 (m, 2H), 7.9 (m, 2H), 8.0 (m, 3H), 82 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H); MS(EI): 538 (M+H\100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 538 (M+H\l00%), and the slower eluting diastereomer; MS(EI):538 (M+H*,100%). 122 012288
Si-f»
Example 51
Préparation of Ouinolme-4-carboxvlic acid f(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-vlcarbamovn-butvl 1 aroide a.) Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting quinoline-4-carboxylicacid for benzofurau-2-carboxylic acid the title compound was prepared: MS (El) 540 10 (M+H+). b.) Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-su]fonyl)-azepan-4-ylcarbamoyl]-butyl) amide
Following the procedure of Example li except substituting the compound of15 Example 51a the title compound was prepared: ‘H NMR (CDCjQ: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.5- 7.2 (m, 2H), 7.4 (m, 2H), 7.5 (m, 1H), 7.7 (m, 1H), 7.9 (m, 2H), 8.0 (m, 1H), 8.2 (m, 1H), 8.7 (m, 1H), 8.9 (m, 1H); MS(EI): 538 (Μ+Ηζ100%)
The diastereomeric mixture was separated by HPLC to provide the faster eluting20 diastereoemer; MS(EI): 538 (M+H\100%), and the slower eluting diastereomer; MS(EI): 538 (M+H\100%).
Example 52 25 Préparation of Ouinoline-3-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(pyridine-2-sulfonvl)- azepan-4-vlcafbamovn-butvl) amide a.) Quinoline-3-cafboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide 30 Following the procedure of Example 28b except substituting quinoline-3-cafboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540(M+H+). 123 012288 b.) Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substituting the compound of 'Example 52a the title compound was prepared: ’H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 5 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2 (m 2H), 7.5 (m, 1H), 7.6 (m, 1H), 7.7-7.9 (m, 4H), 8.1 (m, 1H), 8.5 (m, 1H), 8.6 (m, 1H), 9.3 (m, 1H); MS(EI): 538 (M+H\100%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 538 (M+H\100%), and the slower eluting diastereomer; MS(EI): 10 538 (M+H*,100%).
Example 53
Préparation of Isoquinoline-3-car-oxvlic acid ÎfS)-3-methvl-l-r3-oxo-l-fpvridine-2- 15 suif on vr)-azepan-4-vlcarbamovll-butvl 1 amide a. ) Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting isoquinoline-3- 20 carboxylic acid for benzofuran-2-carboxyIic acid the title compound was prepared: MS(EI)540 (M+H+). b. ) Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide 25 Following the procedure of Example li except substituting the compound of
Example 53a the title compound was prepared: 'H NMR (CDClj): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.0(m, 1H). 7.5 (m, 1H), 7.7 (m, 2H), 7.9 (m, 4H), 8.7 (m, 3H), 9.2 (m, 1H); MS(EI): 538(M+H\100%). 30 124
012288
Example 54
Préparation of Isoquinoline-l-carboxvlic acid ifS'>-3-methvl-l-r3-oxo-l-('pvridme-2- suIfonvI)-azepan-4-vlcarbamovll-butvl} amide5 a.) Isoquinoline-l-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)·azepan-4-ylcarbamoyl] -buty 1} amide
Following the procedure of Example 28b except substituting isoquinoline-l-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 10 540 (M+H+). b.) Isoquinoline-l-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-butyl} amide
Following the procedure of Example li except substituting the compound of15 Example 54a the title compound .was prepared: ‘H NMR (CDC10: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.3(m, 1H), 7.5 (m, 1H), 7.7-8.0 (m, 6H), 8.7 (m, 3H), 9.5 (m, 1H); MS(EI): 538(M+H*,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting20 diastereoemer; MS(ET): 537 (M*,100%), and the slower eluting diastereomer; MS(EI): 537 (M*,100%).
Example 55 25 Préparation of Ouinoxâline-2-carboxvlic acid f(S)-3-methvl-l-r3-oxo-l-(pvridine-2- sulfonvl~)-azepan-4-vlcarbamovll-butvI ) amide a.) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl]-butyl} amide 30 Following the procedure of Example 28b except substituting quinoxaline-2- caiboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI)541 (M+H+). 125 012288 b.) Quinoxaline-2-carboxylic acid {(S)-3-meÜïyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 55a the title compound was prepared: !H NMR (CDCy: δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7..0- 7.2 (m, 2H), 7.5 (m, 1H), 7.7 (m, 3H), 8.2 (m, 2H), 8.3 (m, 1H), 8.7 (m, 1H), 9.5 (m,1H); MS(EI): 539 (M+H\ 30%).
Example 56
Préparation of Benzoiblthiophene-2-carboxvlic acid i(S)-3-methvl-l-i3-oxo-l-('pvridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butvl I amide a. ) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except subst/ :îing benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI)545 (M+H+). b. ) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 56a the title compound was prepared: ‘H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.8- 7.2 (m, 1H), 7.5 (m, 3H), 8.0 (m, 6H), 8.7 (m, 1H); MS(EI): 543 (M+H\ 60%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; ’HNMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.8 (m,lH),4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H), 8.7 (m, 1H); MS(EI): 543(M+H*,100%), and the slower eluting diastereomer; 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m,1H), 3.8 (m,lH), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m, 8H), 8.7 (m, 1H);MS(EI): 543 (M+H\100%). 126 012288
Example 57
Préparation of 1.8-Naphthvndine-2-cafboxvlic acid {(Sy3-methvl-l-i3-oxo-l-fpvridlne-2- sulfonvn-azepan-4-vlcarbamovll-butvl 1 amide 5 a. ) l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl] -butyl} amide
Following the procedure of Example 28b except substituting l,8-naphthyridine-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 10 541 (M+H+). b. ) l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substituting the compound of15 Example 57a the title compound was prepared: ’H NMR (CDCQ: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2(m, 1H), 7.6 (m, 2H), 7.9 (m, 2H), 8.3 (m, 1H), 8.4 (m, 2H), 8.5 (m, 2H), 9.2 (m, 1H);MS(ER: 539 (M+H\100%) 20 Example 58 1
Préparation of lH-3hdole-2-earboxylic acid KSl-3-methvl-l-r3-oxo-l-(pvridine-2-sulfonvl~)- azepan-4-vlcarbamovn-butyl I amide 25 a.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting lH-indole-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI)528 (M+H+). 30 b.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcaibamoyl3-butyl}amide
Following the procedure of Example li except substituting the compound ofExample 58a the title compound was prepared: ‘H NMR (CDC1,): δ 1.0 (m, 6H), 1.5-2.1 127 01228b (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.8(m, 1H), 7.1 (m, 1H), 7.3 (m, 3H), 7.4 (m, 1H), 7.5 (m, 1H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H), 9.4 (b, 1H); MS(EI): 526 (M+H\ 80%).
4 .
Example 59
Préparation of 5-Methoxvbenzofuran-2-carboxylic acid ((S)-3-methvl-l-r3-oxo-l-(pvridine- 2-sulfon vl)-azepan-4-vlcarbamovn-butvl 1 amide a. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyTidme-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS (ED 559 (M+H+). b. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 59a the title compound was prepared: ‘H NMR (CDC13): 8 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 4H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.0(m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (m, 1H); MS(ED: 557 (Μ+ΙΓ, 70%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; lHNMR (CDOQ: 8 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.7 (m, 4H). 4.0 (d, 1H), 4.7 (m, 2H), 5.0 (d, 1H), 7.0 (m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (d, 1H); MS(ED: 557 (M+H\100%), and the slower eluting diastereomer; MS (ED: 557(M+H*,100%). 128 012288
Example 60
Préparation of 5-Bromo-furan-2-carboxvlic acid ifS)-3-methvl-l-i3--oxo-l-(pvridine-2- sulfonvB-azepan-4-vlcarbamovH-butyl} amide 5 a. ) 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide .·
Following the procedure of Example 28b except substituting 5-bromo-2-furoic acidfor benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 558 (M+H+). 10 b. ) 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 60a the title compound was prepared: lH NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 15 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1Η),·6.5 (m, 1H), 6.7 (m, 1H), 7.1 (m, 2H), 7.5 (m, ÎH), 8.0 (m, 2H), 8.7 (m, 1H); MS<EI): 555(Μ+Ηζ 60%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 555 (M+FF,100%), and the slower eluting diastereomer; MS(EI): 20 555 (M+H\100%).
Example 61
Préparation of Furan-2-carboxvlic acid {fS)-3-methvl-l-r3-oxo-l-(pyridipe-2-sulfonvl)- 25 azepan-4-vlcarbamnvll-butvl ) amide a.) Furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 2-furoic acid for 30 benzofuran-2-carboxyîic acid the title compound was prepared: MS(EI) 479 (M+H+). 129 012288 b.) Furan-2-cafboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following tbe procedure of Example li except substituting the compound ofExample 61a the title compound was prepared: ’H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.5(m, 1H), 7.2 (m, 3H)? 7.5 (m, 2H), 8.0 (m, 2H), 8.7 (m, 1H); MS(EI): 477 (M+H\ 50%)
Example 62
Préparation of 5-Nitro-furan-2-carboxylic acid f (S)-3-methvl-l-i3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-yIcarbamoyll-butvl 1 amide a. ) 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 5-nitro-2-furoic acidfor benzofuran-2-carboxylic acid the title compound was prepared: MS (El) 524 (M+H+). b. ) 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 62a the title compound was prepared: ’H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2(m, 1H), 7.3 (m, 1H), 7.5 (m, 1H), 7.9 (m, 2H), 8.7 (m, 1H); MS(EI): 522 (M+fT,80%). 130 012288
Example 63
Préparation of 5-(4-Nitro-phenvl)-furan-2-carboxylic acid ( (S)-3-methvl-l-i3-oxo-l- (pvridine-2-suIfonviy azepart-4-vlcarbamovl'i-butvl 1 amide 5 a. ) 5-(4-Nitro-phenyl)-furan-2-caiboxylic acid {(S)-3-methyl-l-[3-hydroxy-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 5-(4-nitrophenyl)-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS (El) 600 10 (M+H+). b. ) 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substituting the compound of15. Example 63a the title compound was prepared: lH NMR (CDClj): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.9(m, 1H), 7.2 (m, 1H), 7.5 (m, 2H), 7.9-8.0 (m, 4H), 8.5 (m, 1H), 8.6 (m, 1H); MS(EI):598 (M+H\ 80%). 20 Example 64
Préparation of 5-(3-Trifluoromethvl-phenvl)-fttran-2-carboxvlic acid KS)-3-methvî-l-r3- oxo-l-fpvridine-2-suifonvl)-azepan-4-vlcarbamovl1-butvl 1 amide 25 a.) 5-(3-Trifhioromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy- l-(pyridine-2-sulfonyl)-azepan-4-ylcafbamoyl]-butyl}amide
Following the procedure of Example 28b except substituting 5-[3-(trifluoromethyl)phenyl]-2-furoic acid for benzofuran-2-carboxylic acid the title compoundwàs prepared: MS(H) 623 (M+H+). 30 b.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substituting the compound ofExample 64a the tiüe compound was prepared: ’H NMR (CDCy : δ 1.0 (m, 6H), 1.5-2.1 131 012288 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.1(m, 1H), 7.5 (m, 3H), 8.0 (m, 4H) 8.7 (m, 1H); MS(EI): 621 (M+H\ 80%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 621 (M+H\100%), and the slower eluting diastereomer; MS(EI):621 (M+H\100%).
Example 65
Préparation of Tetrahydro-furan-2-carboxylic acid HS)-3-methvl-l-i3-oxo-l-fpyridine-2- sulfonyI)-azepan-4-vlcarbamovll-butvl 1 amide a. ) Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting tetrahydrofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS (El)483 (M+H+). b. ) Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound ofExample 65a the title compound was prepared: Ή NMR (CDClj): 8 1.0 (m, 6H), 1.5-2.2(m, 12H), 2.7 (m, 1H), 3.8 (m, 3H). 4.0 (m, 1H), 4.5 (m, 2H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0(m, 1H), 7.5 (m, 1H), 7.9 (m, 2H), 8.7 (m, 1H). MS(EI): 481 (M+iT, 80%).
Example 66
Préparation of (S)-4-Methvl-2-(2-phenoxy-acetvlamino)-pentanoic acid F3-oxo-(pyridine-2- suîfonvl)-azepan-4-vll-amide a.) (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-hydroxy-(pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 28b except substituting phenoxyacetic acid forbenzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 519 (M+H+). 132 012288 b.) (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substituting the compound ofExample 66a the title compound was prepared: 'H NMR (CDC1J: δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.5 (m, 3H), 4.7 (m, 1H), 5.1(m, 1H), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS(EI): 517(M+H\ 60%).
Example 67
Préparation of fS)-2-r2-f4-Fluoro-phenoxy)-acetylamino1-4-methyl-pentanoic acid Γ3-οχο- <'pyridine-2-sulfonvl)-azepan-4-vll-amide a. ) (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino3-4-methyl-pentanoic acid [3-hydroxy- (pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 28b except substituting4-fluorophenoxyaceticacid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 537(M+H+). b. ) (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo- (pyridine-2-sulfonyl)-azepan-4-yl)-amide
Following the procedure of Example li except substituting the compound ofExample 67a the title compound was prepared: ‘H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.6 (d, 1H). 4.0 (m, 1H), 4.5 (, 3H), 4.8 (m, 1H), 5.1(m, 1H), 7.0 (m, 4H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS(EI): 535 (Μ+Ηζ 50%). 133 012288 ~ f»
Example 68
Préparation of Benzofuran-2-carboxvlic acid ((S)-3-msthyl-l-r3-oxo-l-(pvridme-2- carbonvl)-azepan-4-vlcarbamovl)-3- butyll-amide a. ) {(S)-l-[3-Hydroxy-l-(pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl} -carbamic acid fert-butyl ester
To a solution of the compound of Example 2g (0.25 g) in dichloromethane wasadded picolinic acid (0.09g), EDC (0.14 g) and HOBt (0.10 g). The reaction was stiireduntil complété. Workup and column chromatography (5% methanobethyl acetate) providedthe title compound (0.35 g). b. ) (S)-2-Amino-4-methylpentanoic acid [3-hydroxy-l-(pyridine-2-carbonyl)-azepan-4- yl]-amide
To a solution of the compound of Example 68a (0.34 g) in methanol (6 mL) wasadded 4M HCl in dioxane (6 mL). The reaction was stiired until complété whereupon itwas concentrated to provide the title compound (0.34 g): MS(EI) 349 (M+H+). c. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-carbonyl)- azepan-4-ylcarbamoyl)-3- butyl]-amide
Following the procedure of Example 28b except substituting the compound ofExample 68b the title compound was prepared: MS(EI) 493 (M+H+). d. ) Benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-carbonyl)- azepan-4-ylcarbamoyl)-3- butyl]-amide
Following the procedure of Example li except substituting the compound ofExample 68c the title compound was prepared: ‘H NMR (CDCL,): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.7 (m, 1H), 4.7 (m, 4H), 5.0 (m, 1H), 7.0-7.5 (m, 8H), 8.2 (m, 1H); MS(EI): 491 (M7,100%). 134 012288
Example 69
Préparation of Ben.zofaran-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(l-oxy-pvridine-2- carbonyl)-azepan-4-ylcarbamovll-butyl)amide 5
Following the procedures of Examples 68a-d except substituting picolinic acid N-oxide for picolinic acid of Example 68c the title compound was prepared: 'H NMR(CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H). 4.0 (τα, 1H), 4.7 (m, 3H), 5.5 (m, 1H), 7.0 (m, 2H), 7.2-7.5 (m, 7H), 8.1 (m, 2H); MS(EI): 507 (M*, 10 20%).
Example 70
Préparation of 4-((S)-2-re7?-Butylcarbonylamino-4-inethyl-pentapovlamino)-3-oxo-azepane- 15 l-carboxvlic acid benzyl ester
Following the procedure of Example 92j, except substituting 4-((S)-2-iert-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acidbenzyl ester for benzofuran-2-carboxylic acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-(pyridine- 20 2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+):476.2; iH-NMR (400 MHz, CDC13): · 7.40-6.95(m, 7H), 5.25-4.60(m, 4H), 4.40-4.06(m,2H), 3.70-3.58(t, 1H), 2.70-2.50(m, 1H), 2.25-1.30(m, 1 6H); and the second elutingdiastereomer:, 1.00-0.85(d, 6H); and the second eluting diastereomer: MS (M+H+) 476.2. 25
Example 71
Préparation of 5,6-Dimethoxvben2ofuran-2-carboxylic acid 1 (S)-3-methyl-l-F3-oxo-l-(l- fflethvI-lH-imidazoIe-4-sulfonvl)-azepan-4-ylcarbamoyl)-butvI}amide 30 a.) {(S)-l-[3-Hydroxy-l-(l-methyl-lH-imidazole-2-sulfonyl)-azepan-4-ylcarbamoyl}- 3-methyl-butyl}-carbamic acid tert-butyl ester
To a solution of the amine of Example 2g in methylene chloride (5ml) was addedpyridine (92pL, 1.14mmol) followed by l-methylimidazole-4-sulfonylchloride (0.112g, 135 012288 0.623mmol). The reaction was allowed to stir for I6h at room température. The solutionwas then washed with saturated aqueous NaHCO3, water and brine. The product waspurified by column chromatography (silica gel: methanol/ methylenechloride) to yield thetitle compound as a white solid (0.172g, 68%): lHNMR (400MHz, CDCIj) δ 7.6 (d, 1H), 7.5 (d, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H); MS(ESI): 488.2 (M+H)+ b. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(l-methyl-lH-imidazole-2- sulfonyl)-azepan-4-yl3-amide
To a solution of the compound of Example 71a (0.172g, 0.353mmol) in minimalMeOH was added 4M HCl in dioxane (lOmL) and stirred for 4h at room température. Thereaction mixture was concentrated and azeotroped with toulene (2x’s) to yield the titlecompound as an off white solid: MS(ESI): 388.2 (M+H)+ c. ) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l- methyl-lH-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
To a stiiring solution of the compound of Example 71b (0.137g, 0.353 mmol), 5,6-dimethoxybenzofuran-2-carboxylic acid (0.86g, 0.388mmol), triethylamine (246 mL, 1.77mmol) and 1-hydroxybenzotriazole (0.01g, 0.070mmol) in DMF (5mL) was added l-(3-dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.074g, 0.388mmol). Afterstirring at room température for 16h, the solution was diluted with EtOAc and washedsuccessively with saturated aqueous sodium bicarbonate, water (2x’s), and saturated brine.The organic layer was dried over Na,SO4, filtered and concentrated. The product waspurified by column chromatography ( silica gel; methanol/dichloromethane) to yield thetitle compound as a white solid (0.088g, 42%): MS(ESI): 592.1 (M+H)+ d. ) 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-methyl- lH-unidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Oxalyl chloride (52pL, 0.596mmol) chloride was cooled to -78°. To this was addeddimethyl sulfoxide (106pL, 1.49mmol) in methylene chloride dropwise. After stirring for15min at -78°, the alcohol in methylene chloride was added slowly and allowed to stir forIh when Et3N (416pL,2.98mmol) was added. The solution was then brought to roomtempérature and quenched with water and extracted into methylene chloride. The organiclayer was separated and washed with brine, dried overMgSO4, filtered and concentrated.The product was purified by column chromatography (silica gel: methanol/methylene 136 012288 chloride) to yield the titie compound as white soîid (0.068g, 78%): ’H NMR (400MHz,CDC10 δ 6.8-7.6 (m, 14H), 4 (d, 12H), 1 (d, 12H); MS(ESI): 590.1 (M+H)+
Example 72
Préparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-il-(5-methyI-lH- Γ1.2.41triazole-3-sulfonyl~>-3-oxo-azepan-4-ylcarbamoyn-butvl 1 amide a. ) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-1 -carboxylic acid benzyl ester
To a stirring solution of the compound of Example 2f (3.5 g, 7.33 mmol) in EtOAc(0.5 mL) was added 4M HCl in dioxane (12.8 mL). The mixture was stirred for lh at roomtempérature. The reaction mixture was then concentrated and azeotroped with tûluene(2x20 mL) to yield the titie compound as a pale yellow oil (3.13g, 100%): MS(ESI) 378.4(M+H)+ b. ) 4-{(S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-l-carboxyîic acid benzyl ester
To a stirring solution of the compound of Example 72a (3.13g, 7.57mmol),benzofuran-2-carboxylic acid (1.35g, 8.32mmol), triethylamine (1.17ml, 8.25mmol) and 1-hydroxybenzotriazole (0.2g, 1.48mmol) in DMF (30mL) was added l-(3- dimethylaminopropyl)3-ethylcarbodimide hydrochloride (1.6g, 8.33mmol). After stirring atroom température for 16h, the solution was diluted with EtOAc and washed successivelywith saturated aqueous sodium bicarbonate, water (2X), and brine. The organic layer wasdried over Na^O.,, filtered and concentrated. The product was purifîed by columnchromatography (silica gel; ethylacetate/dichloromethane) to yield the titie compound(3.7g, 93%). ‘HNMR (400MHz, CDCy δ 6.8-7.7 (m, 12H), 5.35 (s, 2H), 1.0 (d, 6H):MS(ESI): 522 (M+H)+ c. ) Benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl- butylj-amide
To a solution the compound of Example 72b (2.6 g, 4.9 mmol) in EtOAc (150 mL)was added 10% palladium on carbon (1.3 g) and stirred at room température for 64 h under 137 01 2288 a hydrogen atmosphère. The mixture was then filtered through celite and the filtrateconcentrated to yield the title compound as a white solid (1.92 g, 100%): ’H NMR(400MHz, CDCL) δ 6.8-7.7(m, 7H), 1.02 (d, 6H); MSÇESI) 388 (M+H)+ d. ) Benzofuran-2-carboxylic acid {(S)-3-naethyl-l-[l-(5-methyl-lH-[l,2,4]triazole-3- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
To a stining solution of the compound of Example 72c (0.100g, 0.25mmol) andtriethylamine (35pL, 0.25mmol) in methylene chloride (2mL) was added 5-metbyl-lH-1,2,4-triazolesulfonylchloride (0.043g, 0.25mmol). The reaction was allowed to stir for 10min and washed with saturated aqueous NaHCO3, water and saturated brine. The organiclayer was dried over Na,SO4, filtered and concentrated. The compound was purified bycolumn chromatography (silica gel; ethylacetate/ hexane) to yield the title compound as apale yellow oil (0.111, 84%); MSÇESI) 532.73 (M+H)+ e. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[l,2,4]triazole-3- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
To a stirring solution of the compound of Example 72d (0.108g,, 0.206mmol) indimethylsulfoxide (2mL) was added triethylamine (172pL, 1.23mmol) followed by sulfurtrioxide pyridine (0.116g, 0.718mmol) and stirred for 16h at room température. Thereaction mixture was diluted with EtOAc and washed with water (X2). The organic layerwas dried over Na^SO^ filtered and conentrated. The crade product was purified by columnchromatography (silica gel; methanol/methylenechloride) to yield the title compound as awhite solid (0.08g, '81%): ’HNMR (400MHz, CDC13) δ 7.1-7.7 (m, 7H), 2.65 (s, 3H), 1.0 (d,6H); MS(ESI): 552.71 (M+Na)+ 138 012288
Example 73
Préparation of Benzofuran-2-carboxvlic acid {(S~)-3-methvl-l-ri-(l-methvl-lH-imidazole-3- sulfonyl)-3-oxo-azepan-4-vlcarbamoyri-butvl)amide a. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
To a stirring solution of the compound of Example 72c (0.100g, 0.25mmol) andtriethylamine (35pL, 0.25mmol) was added 1-methylimidazole sulfonyl chloride (0.046g,0.255mmol). The reaction was allowed to stir for 10min and washed with satorated aqueousNaHCO3, water and satorated brine. The organic layer was dried over Na,SO4, filtered andconcentrated. The compound was purified by column chromatography (silica gel;ethylacetate Zhexane) to yield the title compound as a pale yellow oil (0.113g, 82%):‘HNMR (400 MHz, CDCL,) 5 6.9-7.7 (m, 9H), 3.9 (2s, 3H), 1.0 (d, 6H); MS(ESI): 531.8(M+H)+ b. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
To a stirring solution of the compound of Example 73a (0.085g, 0.159mmol) indimethylsulfoxide was added triethylamine (133pL, 0.95mmol) followed by sulfurtrioxidepyridine (0.08g, 0.5mmol) and stirred for 16h at room température. The reaction mixturewas diluted with EtOAc and washed with water (X2). The organic layer was dried overNa,SO4, filtered and conentrated. The crade product was purified by columnchromatography (silica gel; methanol/methylenechloride) to yield the title compound as awhite solid (0.072g, 83%). MS(ESI): 529.76 (M+H)+ 139
Example 74 012288
Préparation of Benzofuran-2-carboxvlic acid ((S)-3-methvl-l-ri-(lH-imidazole-2-sulfonvl)- 3-oxo-azepan-4-vlcarbamoyl)-butyl 1 amide a. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl} amide
To a stirring solution of the compound of Example 72c (0.100g, 0.25mmol) and triethylamine (35gL, 0.25mmol) was added 2-imidazolesulfonyl chloride (0.046g, 0.255mmol). The reaction was allowed to stir for 10min and washed with saturated aqueous
NaHCO3, water and saturated brine. The organic layer was dried over Na2SO4, filtered and concentrated. The compound was purified by column chromatography (silica gel; ethylacetate/hexane) to yield the title compound as a pale yellow oil (0.113g, 82%): ’HNMR (400MHz, CDC1}) δ 7.1-7.7 (m, 9H), 4.8 (s, 1H), d, 6H); MS(ESI): 517.76 (M+H)+* b. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo- azep an-4-ylcarbamoyl]-butyl} amide
To a stirring solution of the compound of Example 74a (0.107g, 0.206mmol) indimethylsulfoxide (2mL) was added triethylamine (172pL, 1.23mmol) followed bysulfurtrioxide pyridine (0.115g, 0.718mmol) and stirred for 16h at room température. Thereaction mixture was diluted with EtOAc and washed with water (X2). The organic layerwas dried over Na^O,,, filtered and conentrated. The crude product was purified by columnchromatography (silica gel; methanol/methylenechloride) to yield the title compound as awhite solid (0.09g, 85%); MS(ESI): 515.84 (M+H)+ 140 012288
Example 75
Préparation of Benzofuran-2-carboxyIic acid KS)-3-methvl-î-r3-oxo-l-fthiazole-2- sulfon vl)-azepan-4-vlcarbamoyn -butvl 1 amide a. ) {(S)-1- [3-Hydroxy- l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl} -3-methyl- butyl}-carbamic acid tert-butyl ester
To a solution of the compound of Example 2g (2.50g, 7.29mmol) in DCE (100 mL)was added P-NMM (4.0 g) and thioazole-2-sulphonyl chloride (1.6 g, 8.75 mmol). Aftershaking at room température ovemight, the solution was filtered. The filtrate wasconcentrated to yield the title compound as white solid (2.50 g, 5.10 mmol, 70%); MS:490.91 (M+Hf. b. ) Benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[3-hyroxy-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }-amide
To a solution of the compound of Example 75b (0.15 g, 0.45 mmol) in CE^Clj (20mL) was added benzofuran-2-carboxylic acid (0.109 g, 0.172 mmol), 1-hydroxybenzotriazole (0.106 g, 0.762mmol), and P-EDC (0.85g, Immol/g) in CH2C12 (10mL) . After shaking at room température ovemight, the solution was treated with tisamine(0.589g, 3.75mmol/g). After shaking for another 2hr, the solution was filtered andconcentrated to yield the title compound as a white solid (166.7 mg, 70%); MS (ESI):535.3 (M+H)+. c. ) Benzofuran-2-carboxylic acid[S }-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-yIcarbamoyl]-butyI }-amide
To a stirring solution of the compound of Example 75c (166.7 mg, 0.313 mmol) indichloromethane (4 mL) was added Dess-Martin reagent (265.5 mg, 0.626 mmol). Afterstirring at room température for 2 h, solutions of sodium thiosulfate (2 mL of 10% inwater) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to thesolution. The aqueous was extracted with dichloromethane (2x). The organic phases werecombined, washed with saturated brine, dried (MgSOJ, filtered and concentrated. Theresidue was purified by HPLC (50:50 éthanol: hexane, 20mL/min, 25min, WhelkO-l(R,R)21x250mm column, UV détection at 280 nm and 305 nm) to yield the first elution as a 141 012288 white solid (84.8mg, 50.8 %). MS (ESI): 533.2 (M+H)+ and the second elution as a whitesolid (50.1mg, 30.0%) MS: 533.2 (Μ+ΙΓ).
Example 76
Préparation ofBenzofuran-2-carboxvlic acid {(S)-3-methvl-l-fî-(l-methvi-lH-imidazole-4- sulfonyI)-3-oxo-azepan-4-vIcarbamovï')-butyi)amide a·) {(S)-1 -[3-Hydroxy-l-( 1-methyl- lH-imidazole-2-sulfonyl)-azepan-4-ylcarbamoyl }- 3-methyl-butyl}-carbamic acid ieri-butyl ester
To a solution of the amine of Example 2g in methylenechloride (5ml) was addedpyridine (92pL, 1.14mmol) followed by l-methylixnidazole-4-sulfonylchlori.de (0.112g,0.623mmol). The reaction was allowed to stir for 16h at room température. The solutionwas then washed with saturated aqueous NaHCO3, water and brine. The product waspurifîed by column chromatography (silica gel: methanol/ methylenechloride) to yield thetitle compound as a white solid (0.172g, 68%): 'HNMR (400MHz, CDC13) δ 7.6 (d, 1H), 7.5 (d, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 1.5 (s, 9H), 1 (d, 6H);MS(ESI): 488.2 (M+H)+ b. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(l-methyl-lH-imidazole-2- sulfonyl)-azepan-4-yl]-amide
To a solution of the compound of Example 76a (0.172g, 0.353mmol) in minimalMeOH was added 4M HCl in dioxane (lOmL) and stiired for 4h at room température. Thereaction mixture was concentrated and azeotroped with toulene (2x’s) to yield the titlecompound as an off white solid. MS(ESI): 388.2 (M+H)* c. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
To a stirring solution of the compound of Exampîe 72c (0.2g, 0.47 Immol),benzofuran-2-carboxylic acid (0.084 g, 0.388 mmol), triethylamine (72pL, 0.517mmol) and1-hydroxybenzotriazole (0.012 g, 0.088 mmol) in DMF (5 mL) was added l-(3-dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.099g, 0.515mmol). Afterstirring at room température for 16h, the solution was diluted with EtOAc and washedsuccessively with saturated aqueous sodium bicarbonate, water (2x’s), and saturated brine.The organic layer was dried over NajSO4, filtered and concentrated. The product was 142 012288 purified by column chromatography (silica gel; methanol/dichloromethane) to yield the title compound as a white solid (0.226g, 90%): ’HNMR (400MHz, CDCy δ 6.9-8.1 (m, 18H), 3.75 (2s, 6H), 1 (d, 12H); MS(ESI): 531.80(M+H)*· d.) Benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
To a stining solution of the compound of Example 76a (0.226 g, 0.426mmol) indimethylsulfoxide (2mL) was added triethylamine (355pL, 2.55mmol) followed by sulfurtrioxide pyridine (0.238g, 1.48mmol) and stiired for 16h at room température. The reactionmixture was diluted with EtOAc and washed with water (X2). The organic layer was driedover NajSO4, fîltered and conentrated. The crude product was purified by columnchromatography (silica gel; methanol/methylenechloride) to yield the title compound as awhite solid (0.168g, 76%): ’HNMR (400MHz, CDC1,) δ 7.1-7.7 9m, 18H), 3.7 (2s, 6H), 0.9(d, 12H); MSÇESI): 529.80 (M+H)+
Example 77
Préparation of 5-(4-Oxv-morpholino-4-vI-ethoxy)-benzofuran-2-carboxvIic acid lfSl-3- methvl-r-r3-oxo-l -(nvridine-2-sulfonvl)-azepan-4-ylcarbamovn-butyl lamide
To a solution of the compound of Example 30b (0.01 g) in dichloromethane (2 mL)was added m-CPBA (0.008 g). The reaction was stirred ovemight. Workup and columnchromatography (30% methanobdichloromethane) provided the title compound: ’H NMR(CDCl^: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 4H), 2.7 (m, 1H), 2.8 (m 2H), 3.7 (m, 4H), 3.8 (q, 1H). 4.0 (m, 3H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0 (m, 3H),7.4 (m, 2H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS(EI): 671 (M*, 100%) . 143 012288
Example 78
Préparation of Benzofaran-2-carboxvIic acid ïfS)43-methyl-l-i3-oxo-l-(pvridine-3- sulfonvl)-azepan-4-vlcarbamovll-butyl 1 amide a. ) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid benzylester
To a solution of 4-((S)-2-iert-butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan-l-carboxylic acid benzyl ester of Example 2f (4.0 g) in methanol (20 mL)was added 4M HCl in dioxane (20 mL). The reaction was stirred at room température for 2hours whereupon it was concentrated to provide the title compound (3.8 g): MS (El) 378(M+H+). b. ) 4-{(S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy- azepane-l-carboxylic acid benzyl ester
To a solution of 4-((S)-2-amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid benzyl ester of Example 78a (3.2 g) in dichloromethane (200 mL) wasadded EDC (1.48 g), HOBt (1.05 g), TEA (1.29 mL) and benzofuran-2-carboxylic acid.
The reaction was stirred until complété. Workup and column chromatography (2%methanol-.dichloromethane) provided the title compound (3.78 g): MS(EI) 521 (M+H+). c. ) Benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl- butyl]-amide
To a solution of 4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-l-carboxylic acid benzyl ester of Example 78b (1.6 g)in methanohethyl acetate (50 mL:100 mL) was added 10% Pd/C. The reaction was stirredunder aballoon of hydrogen for 2 hours whereupon it was fîltered and concentrated toprovide the title compound (1.16 g): MS(E1) 387 (M+H+). d. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-3-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }amide
To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl3-amide of Example 78c (0.3 g) in dichloromethane was addedtriethylamine (0.17 mL) followed by 3-pyridinesulfonyl chloride (0.25 g). The reaction was 144 012288 stirred at room température until complété as determined by TLC analysis. Workup andcolumn chromatography (5% methanoLethyl acetate) provided 0.32 g of the titlecompound: MS(ET) 528 (M+H+). e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting benzofuran-2-carboxylicacid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 78d the title compound was prepared: NMR (CDCI3): δ 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H). 4.0 (m, 1H), 4.7 (m, 1H), 4.8(m, 1H), 5.0 (m, 1H), 7.0 (m, 2H), 7.2-7.5 (m, 6H), 8.1 (m, 1H), 8.9-9.0 (m, 2H); MS(EI):526 (M+,100%).
Example 79
Préparation of Benzofuran-2-carboxvlic acid {(SM-metfavl-l-O-oxo-l-il-oxy-pvridine-S- sulfonvB-azepan-4-vlcarbamovII-butyl 1 amide a. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-3- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
To a solution of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 78d (0.05g) indichloromethane was added m-CPBA (0.05 g). The reacrton was stirred ovemight.
Workup and column chromatography (10% methanohdichloromethane) provided the titlecompound (0.03 g): MSÇEI) 544 (M+H+). b. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-3- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting benzofuran-2-carboxylicacid {(S>3-methyl-l-[3-hydroxy-l-(l-oxy-pyridme-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyljamide of Example 79a the title compound was prepared: :H NMR (CDC13): δ 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 1H), 3.5 (d, 1H). 4.0 (m, 1H), 4.5 (m, 1H), 4.7(m, 1H), 5.0 (m, 1H), 7.2-7.5 (m, 7H), 8.1-8.2 (m, 2H). MS(EI): 542 (M7,50%). 145 012288
Example 80
Préparation of Ouinoline-3-carboxvIic acid {(S)-l-(3.4-dichloro-benzene-sulfonvl)-3-oxo- azepan-4-ylcarbamovl)l-3-methvl-butvl}-amide
Following the procedures of Example 75a-d except substituting 3,4-dichlorosulfonyl chloride for thioazole-2-sulphonyl chloride of Example 75a and quinoline-3-carboxylic acid for benzofura-2-carboxylic acid the title compound was prepared: ’HNMR(CDC13, 400 MHz) Ô 9.34 (s, 1H), 8.61 (s, 1H), 8.14 (m, 1H), 7.81 (m, 3H), 7.60 (m,3H), 7.19 m, 2H), 5.09 (m, 1H), 4.88 (m, 1H), 4.50 (m, 1H), 3.92 (m, 1H), 3.51 (m, 1H),2.57 (m, 1H), 2.23 (m, 2H), 1.60 (m, 5H), 1.01 (m, 6H).
Example 81
Prepeparation of 5-Hvdroxv-benzofuran-2-carboxylic acid {(S)-3-methvl-l-ri-(l-methyl- lH-imidazole-4-sulfonvl)-3-oxo-azepan-4-vlcarbamoyll-butvl)amide a.) 5-Hydroxy-benzofuran-2-carboxyIic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl3-butyl}amide
To a stiiring solution of the compound of Example 76b (0.1 g, 0.235 mmol), 5-hydroxybenzofuran-2-carboxyIic acid(0.046g, 0.256mmol), triethylamine (36 pL, 0.258mmol) and 1-hydroxybenzotriazole (0.006g, 0.044mmol) in DMF (5mL) was added l-(3-dimethylanainopropyl)3-ethylcarbodimide hydrochloride (0.05g, 0.26mmol). After stiningat room température for 16h, the solution was diluted with EtOAc and washed successivelywith saturated aqueous sodium bicarbonate, water (2X), and saturated brine. The organiclayer was dried over NajSO4, fîltered and concentrated. The product was purified by columnchromatography ( silica gel; methanol/dichloromethane) to yield the title compound as awhite solid (0.129g, 100%). ’HNMR (400MHz, CDC13) δ 6.8-8 (m, 16H), 3.6 (2s, 6H), 0.85(d, 12H). MS(ESI): 547.88(M+H)+· 146 012288 b.) 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyî-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
Oxalyl chloride (13 pL, 0.149 mmol) chloride was taken to -78°. To this was addeddimethyl sulfoxide (28 pL, 0.394mmol) in methylene chloride dropwise. After stirring for15min at-78 the alcohol of Example 8la in methylene chloride was added slowly andallowed to stir for Ih when Et,N (7 pL, 0.05 mmol) was added. The solution was thenbrought to room température and quenched with water and extracted into methylenechloride. The organic layer was separated and washed with brine, dried over MgSO4,filtered and concentrated. The product was purified by column chromatography (silica gel:methanol/methylene chloride) to yield the title compound as white solid (0.021g, 78%):MS(ESI) 545.9(M+H)+'
Example 82
Préparation of Benzofuran-2-carboxvlic acid {(S)-3-mëthyl-l-f3-oxo-l-(l-oxv-pyridine-2- sulfon vl )-azepan-4-vlcarbamovl)l-3-methyl-butvl 1-amidë a.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl}-amide
To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-àzepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.10 g) in dichloromethane wasadded triethylamine (0.07 mL) followed by 2-pyidinesulphonylchloride N-oxide. Thereaction was stirred at room température ovemight. Workup and chromatography (10%methanobdichloromethane) provided the title compound (0.01 g): MS(EI) 544 (M+H+). 147 012288 b.) {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-a2epan-4-ylcafbamoyl)]-3-methyl-butyl} -amide
Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-suîfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl}-amide of Example 82a the title compound was prepared: ’H NMR (CDC10: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0(m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0 -7.5 (m, 9H), 8.1-8.2 (m, 2H). MS(EI):542 (M*, 20%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; 'HNMR (CDC10: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.8 (d, 1H). 4.0 (d, 1H), 4.7 (m, 1H), 4.8 (d, 1H), 5.0 (m, 1H), 7.0-7.5 (m, 9H), 8.1-8.2 (m,2H); MSÇEI): 542 (M\100%), and the slower eluting diastereomer; MSÇEI): 542 (M+H*,100%).
Example 83
Préparation of 2-(4-( (S)-2-( fBenzofuran-2-carbonyD-amino}-4-methyl-pentanoyIamino)-3- oxo-azepane- l-sulfonvl)-benzoic acid a. ) 2-(4- {(S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino }-3- hydroxy-azepane-l-sulfonyl)-benzoic acid methyl ester
Following the procedure of Example 75a-c, except substituting 2-carboxymethylsulphonyl chloride for 2-thiazolesulfonyl chloride, the title compound wasprepared: MS (M+H* ) = 585.56, M+Na* = 607.76,2M+H* = 1170.48. b. ) 2-(4-{ (S)-2-[(Benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino }-3- hydroxy-azepane- l-sulfonyl)-benzoic acid 2-(4- {(S)-2-[(benzofuran-2-carbonyl)-aminoJ-4-methyl-pentanoylamino }-3-hydroxy-azepane-l-sulfonyl)-benzoic acid methyl ester (compound 83a, 180 mg, 0.309mmol) was dissolved in 5:1 MeOHZwater (6 ml) LiOH (14 mg, 0.34 mmol) was added andthe reaction mixture was stirred and refluxed for 6 h. The reaction mixture was thenquenched with water and 6 N HCl (adjusted to pH=2), extracted with EtOAc (3x10 ml),dried with MgSO4, filtered, concentrated, and chromatographed (silica gel, 1% acetic acid/ 148 012288 4% MeOH/ CHjClj) to yield the title compound as a white solid (48 mg, 27%): M+H" =572.2 c.) 2-(4-{(S)-2-[(Benzofuran-2-carbonyl)-amino3-4-methyl-pentanoylamino}-3-oxo-azepane-l-sulfonyl)-benzoic acid
Following the procedure of Example 75d, except substituting 2-(4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-l-sulfonyl)-benzoic acid for benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide, the tille compound was prepared:MS (M+H+): 570.2 (M+H+). *H NMR(400Hz,CDCl3-CD3OD): δ 8.05-7.95 (m, 1H), 7.70-7.15 (m, 8H), 5.15-5.00 (m,lH), 4.95-4.75 (m, 2H), 4.15-4.00 (m, 1H), 3.65 (d, 1H), 2.85-2.70 (m, 1H), 2.25-2.05 (m, 2H), 1.90-1.70 (m, 4H), 1.60-1.45 (m, 1H), 0.95 (d, 6H).
Example 84
Préparation of 3-(4-( (S)-2-{fBenzofuran-2-carbonvn-ammol-4-methvl-pentanovlaminol-3- oxo-azepane-l-sulfonvD-benzoic acid
Following the procedure of Example 83, except substituting 3-carboxymethylbenzenesulphonyl chloride for 2-carboxymethylbenzenesulfonyl chloride,the title compound was prepared: MS 570.2 (M+H+); NMR (400Hz,CDCl3-CD3OD): δ 8.46 (d,lH), 8.31-8.25 (m,lH), 8.00-7.97 (m,lH), 7.70-7.62 (m, 2H), 7.55-7.46(m, 1H), 7.45-7.35 (m,lH), 7.30-7.25 (m, 1H), 5.10-5.05 (m,lH), 4.95-4.78 (m,lH), 4.75-4.55 (q,lH), 4.00 (d,lH), 3.5 (d, 1H), 2.60-2.40 (m, 2H), 2.25-2.15 (m,lH), 1.95-1.70 (m,4H), 1.55-1.40 (m,lH), 0.98 (t, 6H). 149 012288
Example 85
Préparation of Benzorblthiophene-2-carboxvIic acid ï(S)-3-methyl-l-r3-oxo-l-{T-oxy- nvridine-Z2-sulfonvl)-azepan-4-ylcarbamoyri-butvl ) aroide a. ) {(S)- l-[3-Hydroxy-1 -( 1 -oxy-pyridine-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- butyl-carbamic acid iert-butyl ester
To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester of Example 2g (2.5 g) in dichloromethane (100 mL) andsaturated sodium bicarbonate was added freshly prepared 2-pyidinesulphonyî chloride N-oxide (prepared by bubbling chlorine gas through a solution of 2-mercaptopyridine-N-oxidein 9M HCl for approximately 90 minutes. Removal of excess chlorine under vacuumprovided the 2-pyridinesulfony] chloride-N-oxide). The reaction was stirred at roomtempérature for 1 hour. Workup and column chromatography (10% methanol .-dichloromethane) provided the title compound (2.0 g): MSÇEI) 500 (Μ+ΡΓ). b. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(l-oxy-pyyridine-sulfonyl)- azepart^t-yl]-amide
To a solution of {(S)-l-[3-hydroxy-l-(l-oxy-pyridine-suIfonyî)-azepan-4-ylcarbamoyl]-3-methyl-butyl-carbamic acid reri-butyl ester of Example 85a (2.0 g) inmethanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred atroom température for 1.5 hours whereupon it was concentrated to provide the titlecompound (1.8 g): MSÇEI) 400 (M+H+). c. ) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid (3-hydroxy-l-(l-oxy-pyyridine-sulfonyI)-azepan-4-yl]-amide of Example 85b (0.25 g) in dichloromethane (12mL) was added triethylamine (0.12 mL), EDC (0.11 g), HOBt (0.077 g) andbenzo(b]thiophene-2-carboxylic acid. The reaction was stiired until complété. Workup andcolumn chromatography (10% methanol: dichloromethane) provided the title compound(0.26 g): MSÇEI) 560 (M+H+). 150 01 2288 d.) Ben2Xt[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} anaide
Following the procedure of Example li except substituting benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 85c the title compound was prepared: ’H NMR(CDClj): Ô 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.5 (m, 4H), 7.8 (m, 3H), 8.1-8.2 (m, 2H). MS(EI):558 (NT,100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 558 (^,100%), and the slower eluting diastereomer; MS(EI): 558(M*,100%).
Example 86
Préparation of 5-Bromo-furan-2-carboxvlic acid ifS)-3-methvl-l-f3-oxo-l-('l-oxv-pvridine- 2-su]fonyb-azepan-4-vlcarbamoyll-butyl)armde a. 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting 5-bromo-2-furoic acidfor benzo[b3thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 574(M+H+). b. ) 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-«4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 5-bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 86a the title compound was prepared: Ή NMR(CDCJJ: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0 (m, 2H), 7.4 (m, 2H), 8.1-8.2 (m, 2H); MS(EI):570 (M*,100%). 151 01 2288
The diastereomeric mbtture was separated bÿ'HPLC to provide the faster elutingdiastereoemer; MS (El): 572 (M+H+,100%), and the slower eluting diastereomer; MS(EI):572(M+H\100%).
Example 87
Préparation of 5.6-Dimethoxybenzofüran-2-carboxylic acid KS)-3-methvl-l-r3-oxo-l-(l- oxv-pvridine-2-sulfonyl)-azepan-4-vïcarbamovIl-butvI ) amide a. ) 5,6-Dimethoxybenzofuran-2-carboxyüc acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting 5,6-dimethoxybenzofuran-2-carboxylic acid for benzo[b3thiophene-2-carboxylic acid the titlecompound was prepared: MSÇEI) 604 (M+H+). b. ) 5,6-Dimethoxybenzofuran-2-carboxyEc acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ) amide
Following the procedure of Example li except substituting 5,6-dimethoxybenzoftxran-2-carboxylic acid {(S)-3-methyî-l-[3-hydroxy-l-(l-oxy~pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 87a the title compound wasprepared: 'H NMR (CDCI,): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8(m, 7H). 4.0 (m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.0-7.5 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 602 (M\100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 602 (M*,100%), and the slower eluting diastereomer; MS(EI): 602(M*,100%). 152 012288
Exanrole 88 ·
Préparation of l-Oxy-pyridine-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-(pvridine-2- suIfonvl)-azepan-4-vlcarbamovri-butvl 1 amide a. ) l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting picolinic acid N-oxidefor benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 505 (M+H+). b. ) l-Oxy-pyridine-2-cafboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl j-butyl} amide
Following the procedure of Example li except substituting l-oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoylj-butyl} amide of Example 88a the tiüe compound was prepared: 'H NMR(CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.1 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.5 (m, 3H), 7.9 (m 2H), 8.3-8.4 (m, 2H), 8.6 (m, 1H); MSÇEI):503 (NT,100%).
Example 89
Préparation of (S~)-4-Methyl-2-(pvridine-2-sulfonvlamino)-pentanoic acid Γ3-οχο-1- (pyridine-2-sulfonvl)-azepan-4-vH-amide a.) (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl)-amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl3-amide of Example 28a (0.25 g) in dichloromethane was addedtriethylamine (0.27 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirreduntil complété. Workup and colunm chromatography (5% methanokdichloromethane)provided the title compound (0.09 g): MS(EI) 525 (M+H+). 153 012288 b.) (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine- 2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substitutmg (S)-4-methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 89a the title compound was prepared: 'H NMR (CDC13): δ 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), 4.7 (m, 1H), 5.0(m, 1H), 5.5 (m, 1H), 7.0 (m 1H), 7.5 (m, 2H), 7.9 (m 3H), 8.6 (m, 2H). MS(EI): 523(M\100%) .
Example 90
Préparation of (S)-2-(3-Benzyl-ureido)-4-methvl-pentauoic acid i3-oxo-l-(pyridme-2- sulfonvl)-azepan-4-yl1-amide a. ) (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-yl]-amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyyridine-sulfonyl)-azepan-4-yI]-amide of Example 28a (0.25 g) in dichloromethane was addedtriethylamiue (0.17 mL) and benzyl isocyanate (0.088g). The reaction was stirred untilcomplété. Workup and column chromatography (5% methanolrdichloromethane) providedthe title compound (0.12 g). b. ) (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-yl]-amide
Following the procedure of Example li except substituting (S)-2-(3-benzyl-ureido)- 4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide ofExample 89a the title compound was prepared: 'H NMR (CDClj): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 3H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m,1H), 7.2 (, 5H), 7.5 (m, 1H), 7.9 (m, 2H), 8.6 (m, 1H); MS(EI): 515 (M*, 60%).
The diastereomeric mixture was separated by HPLC to provide the faster elutrngdiastereoemer; MS(EI): 516 (M+H\100%), and the slower eluting diastereomer; MS(EI):516 (M+H*,100%). 154 012288
Example 91
Préparation of (S)-2-(3-Phenvl-uriedo)-4-methvl pentanoic acid r3-oxo-l-(pvridine-2- suIfonvD-azepap-4-vll-amide a. ) (S)-2-(3-Phenyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 90a except substituting phenyl isocyante forbenzyl isocyanate the titiLe compound was prepared: : MS(EI) 503 (M+H+). b. ) (S)-2-(3-Phenyl-ureido)-4-methyI-pentanoic acid [3-oxo-î-(pyridine-2-suîfonyl)- azepan-4-yl]-amide
Following the procedure of Example li except substituting (S)-2-(3-phenyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide ofExample 91a the title compound was prepared: ‘H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2;1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.S (q, 1H). 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m,1H), 7.0-7.9 (m, 8H), 8.6 (m, 1H). MS(EI): 501 (M\ 60%).
Example 92
Préparation of Benzofuran-2-carboxvlic acid {fSVl-i6.6-dimethvl-3-oxo-l(pyridine- sulphonvb-azepan-4-vlcarbamovIl-3-methvl-butvl ) -amide a.) Allyl-(2,2-dimethyl-pent-4-enylidene)-amme 2,2-Dimethyl-4-pentenal (2.8 g, 25 mmol) was dissolved in 15 mL benzene. To thissolution aîlylamine (2.85 g, 50 mmol) was added. A few molecular sieves were used toabsorb water generated during the reaction. The mixture was stirred at room températureovemight Removal of the solvent and excess amount of aîlylamine on rotavapor provided3.76 g of the title compound as clear liquid (yield 100%). ^H-NMR (400 MHz, CDCI3): ·7.52(s, 1H), 5.99-5.90(m, 1H), 5.80-5.70(m, 1H), 5.15-4.99(m, 4H), 4.01-3.99(m, 2H),2.17(d, 2H), 1.06(s, 6H). 155 012288 b. ) Allyl-(2,2-dimethyl-pent-4-enyl)-amine
Allyl-(2,2-dimethyl-pent-4-enylidene)-amine of Example 92a (3.76g, 25mmol) wasdiluted in 5ml MeOH. To the solution NaBH4 (0.95g, 25mmol) was added at 0°C. Afteraddition the mixture was stirred at r.t. for 5h. Methanol was removed on rotavapor and theresidue was partitioned between EtOAc/ 20% NaOH. The organic layer was dried overNa^SCb fitered and evaperated to give 2.26 g of the title compound: MS (M+H+): 154.0;H-NMR (400 MHz, CDC13): 5.93-5.76(m, 2H), 5.29-4.99(m, 4H), 3.22(d, 2H), 2.34(s, 2H), 2.01(d, 2H), 0.94(s, 6H). c. ) Pyridine-2-sulfonic acid allyl-(2,2-dimethyl-pent-4-enyl)-amide
Allyl-(2,2-dimethyl-pent-4-enyl)-amine (0.43 g, 2.8 mmol) and NMM (0.57g,5.6mmol) were mixed in 30 mL CH2CI2.2-pryridinesulphonyl chloride was added slowlyto the solution while it was cooled in an ice-water bath. After addition, the reaction mixturewas stirred at r.t. ovemight. Washed by 10% NaHCO3 and the brine. Purified by coîumnchromatography gave 0.6 g colorless oil in 73% yield. MS (M+H+): 295.2; ^H-NMR (400MHz, CDCI3): · 8.71-8.70(d, 1H), 7.98-7.86(m, 2H), 7.48-7.46(m, 1H), 5.88-5.77(m, 1H),5.55-5.45(m, 1H), 5.13-5.00(m, 4H), 4.05-4.04(d, 2H), 3.24(s, 2H), 2.07-2.05(d, 2H), 0.96(s, 6H) d. ) .3,3-Dimethyl-l-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro-lH-azepine
Pyridine-2-sulfonic acid allyl-(2,2-dimethyl-pent-4-enyl)-amide (0.6g, 2mmol) wasdiluted in CH2CI2 (50ml) After carefully degass by Ar, Grubbs catalyst (0.17g, 0.2mmol)was added under Ar protection. The mixture was then refluxed for 2h before the solventwas removed on rotavapor. The crude product was purified by coîumn chromatography(5%-20% E/H) to give 0.47g of the title compound in 87% yield. MS (M+H+): 267.0; ^H-NMR (400 MHz, CDCI3): · 8.70-8.69(d, 1H), 7.96-7.S8(m, 2H), 7.49-7.46(m, 1H), 5.81-5.70(m, 2H), 3.93-3.92(d, 2H), 3.26(s, 2H), 2.13-2.12(d, 2H), 1.00(s, 6H) e. ) 5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane
To the solution of the compound of Example 92d (1.2 g, 4.5 mmol) in 50 mLCH2CÎ2 was added NaHCO3 (2.4 g, 13.5 mmol) and then MCPBA (1.2 g, 13.5 mmol) inportions. The reaction was stirred at r.t for 4h before it was worked up by washing with15% NaOH, saturated K2CO3, brine and dried (Na2SO4)to give 1.0g crude product in 79 156 012288 % yield ( good enough for next reaction without further purification.) MS (M+H+): 283.0; iH-NMR (400 MHz, CDC13): · 8.68-8.67(d, 1H), 8.03-7.87(m, 2H), 7.49-7.40(m, 1H), 4.44~3.89(q, 1H), 3.62-3.59(d, 1H), 3.50(m, 1H), 3.00(m, 1H), 2.78-2.62(m, 2H), 2.12- 2.06(m, 1H), 1.52-1.46(q, 1H), 1.20(s, 3H), 0.89(s, 3H). f. ) 4-Azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol 5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane ffomExample 92e (1.2 g, 4.3 rnmol) was dissolved in the mixture of 7 ml MeOH and 1 ml H2O.NaN3 (0.83 g, 13 mmol) and NH4CI (0.7 g, 13 rnmol) were added to the solution. Theresulting mixture was refluxed ovemight. After the removal of MeOH, the residue wasdiluted in EtOAc and washed with 10% NaHCÛ3 and brine. Purified on colunmchromatography gave 0.4g 4-azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol (yield29%); MS (M+H+): 326.2; iH-NMR (400 MHz, CDCI3): · 8.68-8.67(m, 1H), 8.05-7.90(m,2H), 7.53-7.50(m, 1H), 3.75-3.60(m, 3H), 3.49-3.30(m, 3H), 1.73-1.66(m, 1H), 1.56-1.52(d, 1H), 1.07(s, 3H), 0.99(s, 3H) g. ) 4-Amino-6,6-dimethyl- l-(pyridine-2-sulfonyl)-azepan-3-ol 4-Azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol ffom Example 92f (0.4 g, 1.23 mmol) was dissolved in THF (50 ml) and H2O (0.2 ml). PPI13 (0.48 g, 1.85 mmol)was added to this solution. The reaction mixture was stirred at 45°C over night. TLCshowed no starting material left. THF was evaporated, azeotroped with toluene (2x’s). Theresulting thick oil was dissolved in MeOH, treated with HCl in ether to adjust pH to acidic.More ether was added and the solution tumed cloudy. 0.22 g white precipitate of the titlecompound was collected. (45% yield); iH-NMR (400 MHz, CD3OD): · 8.68(m, 1H), 8.10-7.93(m, 2H), 7.62(m, 1H), 3.90(m, 1H), 3.68(m,lH), 3.40-2.90(m, 4H), l.S2(m, 1H), 1.53(d, 1H), 1.05(s, 6H) h. ) {(S)-1 -[3-Hy droxy-6,6-dimethyl- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-3- methyl-butyl}-carbamic acid ieri-butyl ester 4-Amino-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol HCl saltfrom Example92g (0.22 g, 0.6 mmol) was dissolved in 5ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.9 mmol)and HBTU (0.34 g, 0.9 mmol) and then NMM (0.24 g, 2.4 mmol).The mixture was stirred at r.t. ovemight. DMF was removed under high vacuum. The 157 012288 residue was diluted with EtOAc and washed with H2O,10% NaHCC>3 and brine.Purification by column chromatography gave 0.22 g of tbe title compound (72% yield); MS (M+H+): 512.9; *H-NMR (400 MHz, CDCI3): · 8.68-8.67(d, 1H), 7.97-7.88(m, 2H),7.69-7.64(m, 1H), 6.62-6.53(m, 1H), 5.06-5.00(m, 1H), 4.03-3.18(m, 7H), 1.80-1.42(m,15H), 1.04-0.92(m, 12H). i. ) Benzofuran-2-carboxylic acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
To {(S)-l-[3-Hydroxy-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid ieri-butyl ester of Example 92h (0.22g,0.43mmol) was added HCl/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t.for 2h before solvents and excess amount of HCl was removed on rotavapor. The resultingwhite solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylicacid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). Themixture was stirred at r.t. ovemight. DMF was then removed and the residue was re-dissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml x 2) and brine (50 ml).Evaporation of the solvent gave crude product 0.26 g. Purification by columnchromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8;^H-NMR (400 MHz, CDCI3): · 8.66-8.63(m, 1H), 7.94-7.1 l(m, 10H), 4.72(m, 1H), 4.01-2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H). j. ) Benzofuran-2-carboxyIic acid {(S)-l-[3-oxo-6,6-dimethyl-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
To a solution of benzofuran-2-carboxylic acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl}-3-metbyl-butyl}-amide from Example 92i(100 mg, 0.18mmol) in 2 ml CH,CL,, was added Dess-Martin reagent (76 mg, 0.18 mmol) atr.t.. The solution was stirred for 2h when 20 ml CHjCL, was added and then washed withNaHCO3 and brine. Purification by column chromatograghy (50% ethyl acetate in hexane)gave 70 mg of the title compound in 70% yield. MS (M+H+): 555.4; 1H-NMR (400 MHz,CDCQ: · 8.68-8.67(d, 1H), 7.97-7.93(m, 2H), 7.69-7.28(m, 6H), 7.32-6.92(m, 2H), 5.24(m,1H), 4.79-4.69(m, 2H), 3.80-3.71(m, 2H), 2.54-2.50(d, 1H), 1.92-1.76(m, 4H), 1.45-1.40(m, 4H), 1.01-0.91(m, 9H). 158 01 2288
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS (M+H+): 555.2, and the slower eluting diastereomer, MS (M+H+):555.2.
Example 93
Préparation of 5-Methoxvbenzofuran-2-carboxvlic acid {fS)-3-rnethvl-l-i3-oxo-l-n-oxv- pvridine-2-sulfonvî)-azepan-4-vlcarbamovll-butyl)amide a. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl} amide
Following the procedure of Example 85c except substituting 5-methoxybenzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound wasprepared: MS(EI) 574 (M+H+). b. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 93 a the title compound was prepared: ’H NMR(CDCl,): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 ( m, 4H). 4.0 (m,1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 8H) 8.0-8.2 (m, 2H); MS(EI): 572(M", 30%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer, ’HNMR (CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H),3.7 (s, 3H), 3.8 (d, 1H). 4.0 (d, 1H), 4,7 (m, 1H), 4.8 (d, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 8H)8.0-8.2 (m, 2H); MS(EI): 573 (M+H*,100%) and the slower eluting diastereomer, MS(EI):573 (M+H*,100%). 159 01 2288
Example 94 *
Préparation of Thienor3,2-blthiophene-2-carboxvlic acid f(S)-3-methyl-l-r3-oxo-l-(l-oxy- * pvridine-2-sulfonvl)-azepan-4-vlcarbamovI'l-butvl} araide a. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxyIic acid the title compoundwas prepared: MS(ET) 566 (M+H+). b. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-1 - [3-hydroxy-1 -( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 94a the title compound was prepared: ‘H NMR(CDCy: δ 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), · 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-7.5 (m, 6H), 7.7 (d, 1H), 8.0-8.2 (m, 2H). MS(EI): 564 (Μζ100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; ’HNMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, 1H), 3.8 (d, 1H). 4.0 (d, 1H), 4,5 (m, 1H),4.7 (d, 1H), 5.0 (m, 1H), 7.4-7.5 (m, 6H), 7.7 (d, 1H), 8.0-8.2 (m, 2H); MS(EI): 565 (M+H",100%) and the slower eluting diastereomer; MS (El): 565 (M+H\100%). 160 012288
Example 95
Préparation of Oumoxaline-2-carboxvlic acid {('S')-3-methvl-l-r3-oxo-l-(T-oxv-pvridine-2- sulfonvl)-azepan-4-vlcarbamovil-butvl | amide a. ) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- snlfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example S5c except substituting quinoxaline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MSÇEI) 556 (M+H+). b. ) Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substuting quinoxaline-2-cafboxylicacid {(S)-3-methyI-1 -[3-hydroxy- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 95a the title compound was prepared: 'H NMR (CDClj): 5 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m,1H), 7.4-7.5 (m, 2H), 7.9 (m, 1H), 8.0-8.4 (m, 4H, 9.6 (d, 1H); MS(EI): 554 (M\100%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 555 (M+H\100%) and the slower eluting diastereomer; MSÇEI):555 (M+H\100%).
Example 96
Préparation of Quinoline-2-carboxvlic acid {(S)-3-methvl-l-r3-oxo-l-fl-oxy-pvridine-2- sulfonvI)-azepan-4-ylcarbamoyri-butvl 1 amide a.) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 85c except substituting quinoline-2-carboxylicacid forbenzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS (El) 555 (M+H+). 161 012288 b.) Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridme-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substuting quinoline-2-carboxylicacid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 96a the title compound was prepared: ’H NMR (CDC13): δ 1.0(m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), 4,5 (t, 1H), 4.7(m, 1H), 5.0 (m, 1H), 7.4-8.6 (m, 10H); MS(EI): 553 (NT,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 554 (Μ+ΐΤ,100%) and the slower eluting diastereomer; MS(EI):554 (M+H*,100%).
Example 97
Préparation of Thiophene-3-carboxvIic acid ffS)-3-methyl-l-r3-oxo-l-fl-oxy-pvridine-2- sulf onvl)-azepan-4-ylcarbaroovI'|-butvl ) amide a. ) Thiophene-3-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting thiophene-3-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MS(EI) 510(M+H+). b. ) Thiophene-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfcnyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting thiophene-3-carboxylicacid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-butyl} amide of Example 97a the title compound was prepared: ‘H NMR (CDCl,): δ 1.0 (m,6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H). 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m,1H), 5.0 (m, 1H), 7.4-8.0 (m, 4H), 7.8 (m, 1H), 8.1-8.2 (m, 2H); MSÇEI): 508 (M*, 80%). 162 012288
Example 98
Préparation of lH-lhdole-5-carboxylic acid ((S)-3-methvl-l-r3-oxo-l-(l-oxv-pvridme-2- sulfonvl)-azepan-4-vlcarbamovll-butvl 1 amide a. ) lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following tbe procedure of Example 85c except substituting lH-indole-5-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MS(EI) 543 (M+). b. ) lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of'Example li except substating of lH-indole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 98a the title compound was prepared: ’H NMR(CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H) , 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H),4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 8.6 (b, 1H); MS(EI):541 (M\100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MS(EI): 542 (M+H*,80%) and the slower eluting diastereomer; MS(ET): 542(M+H\80%).
Example 99
Préparation of Benzon,31dioxole-5-carboxvlic acid f(S)-3-methvl-l-F3-oxo-l-fl-oxy- pvridine-2-sulfonvI)-azepan-4-ylcarbamoyll-butvl 1 amide a.) Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 85c except substituting Benzo[l,3]dioxole-5-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MS(EI) 548 (M+). 163 012288 b.) Benzo[l,3]dioxole-5-caxboxylic acid {(S)-3-methyÂ-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting benzo[l,3]dioxole-5-carboxy lie acid {(S)-3-methyl-1 -[3-hydroxy-1 -( 1 -oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 99a the title compound was prepared: 'H NMR(CDCy : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4.5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 6.0 (s, 2H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H);MS(EI): 546 <M\100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer; MSÇEI): 547 (Μ+ίΓ,100%) and the slower elutmg diastereomer; MSÇEI):547 (M+H\100%).
Example 100
Préparation of Furan-2-carboxvlic acid ((,S)-3-methvl-l-i3-oxo-l-fl-oxy-pvridine-2- sulfonyl)-azepan-4-ylcarbamôyll-butyl ) amide a. ) Furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting furoic acid forbenzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 494 (M+). b. ) Furan-2-cafboxylic acid [(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoy!3-butyl} amide
Following the procedure of Example li except substuting furan-2-cafboxylic acid{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 100a the title compound was prepared: JH NMR (CDC13): δ 1.0(m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7(m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MSÇEI): 492 (M\l00%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutmgdiastereoemer MSÇEI): 493 ÇM+H\100%) and the slower eluting diastereomer; MS(EI):493 (M+H-,100%). 164 012288
Example 101
Préparation of ('S)-4-MethvI-2-('2-thiophen-2-vl-acetvIamipo)-pentanoic acid Γ3-οχο-1-Π- oxv-pvridine-2-sulfonvlVazepan-4~vll-arriide a. ) (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 85c except substituting thiophene-2-aceticacid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. b. ) (S)-4-Metbyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substuting (S)-4-methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yi]-amide of
Example 101a the title compound was prepared: ’H NMR (CDC^): δ 1.0 (m, 6H), 1.5-2.1(m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (m, 3H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0(m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 522 (M*, 20%).
Example 102
Préparation of lH-Indole-2-carboxviic acid KS)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonvl)-azepan-4-vlcarbamovll-butyl ) amide a. ) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting lH-indole-2-carboxylic acid for benzo[b3thiophene-2-carboxyIic acid the title compound was prepared:MS(ET) 543 (M+). b. ) lH-ïndole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl) azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substuting lH-indole-2-carboxylicacid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-su3fonyl)-azepan-4-ylcarbamoyl]- 165 01 2288 butyl}amîde of Example 102a the titie compound was prepared: ’H NMR (CDCy: δ 1.0(m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7(m, 1H), 5.0 (m, 1H),7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 9.4 (b, 1H); MS(EJ): 541(M+,100%) . 5 The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 542 (M+HT,100%) and the slower eluting diastereomer; MSÇEI): 542 (M+H\100%).
Example 103 10
Préparation of 4-Fluoro-{ÇS)-3-methyl-l-r3-oxo-l-f l-oxv-pvridine-2-sulphonyl)-azepan-4- carbamovll-bntylï-benzamide a.) 4-Fluoro-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4- 15 carbamoyl]-butyl}-benzamide
Following the procedure of Example 85c except substituting 4-fluorobenzoic acidfor benzo[b]thiophene-2-carboxylic acid the titie compound was prepared: MSÇEI) 522(M+). 20 b.) 4-Fluoro-{ (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4- carbamoylj-butyl }-benzamide
Following the procedure of Example li except substuting 4-fluoro-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4-carbamoyl]-butyl}-benzamide ofExample 103a the titie compound was prepared: ’H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 25 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, ----lH);7Æ87OTXFHT87l-872(mT2IÎ)r3ÎS^T52OW7l00%)^
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereomer: MSÇEI): 521 ÇM+H\100%) and the slower eluting diastereomer MSÇEI):521 (Μ+Η\100%). 30 166 012288
Example 104
Préparation of 5-(2-MowhoHn-4-vI-ethoxv~)-benzofaraD-2-carboxvIic acid f(S)-3-methvl-l- r3-oxo-fl-oxv-pvridine2-sulphopvl)-azepan-4-vlcarbamovn-buty)-amide a. ) 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- hydroxy-(l-oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]-buty} -amide
Following the procedure of Example 85c except substituting 5-(2-morpholin-4-yI-ethyloxy)benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxyIic acid the titlecompound was prepared: MS(EI) 673 (M+). b. ) 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- (l-oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]-buty}-amide
Following the procedure of Example li except substuting 5-(2-moipholin-4-yl-ethoxy)-benzofijran-2-caiboxylic acid {(S)-3-methyl-l-[3-hydroxy-(l-oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyl]-buty}-amide of Example 104a the tiüe compound wasprepared: Ή NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 4H), 2.7(m, 3H), 3.7 (m, 4H); 3.9 (m, 1H), 4,5 (m, 3H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H),8.1-8.2 (m, 2H); MS(EI): 671 (Μ\100%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereomer. MS(EI): 672 (M+H*, 100%) and the slower eluting diastereomer MSÇEI):672 (Μ+Η*,100%).
Example 105
Préparation of Thiophene-2-carboxvlic acid f(S)-3-methvl-l-r3-oxo-l-il-oxy-pvridine-2- sulfonvI)-azepap-4-ylcarbamovll-butvl 1 amide a.) Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-stdfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MSÇEI) 510 (M+). 167 012288 b.) Thiophene-2-carboxyüc acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substuting thiophene-2-carboxylicacid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-butyl}amide of Example 105a the title compound was prepared: ’H NMR (CDClj): δ 1.0(m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7(m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 508 (M*,100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereomer: MS(EI): 509 (M+H*,100%) and the slower eluting diastereomer MS(EI):509 (M+IT,100%).
Example 106
Préparation of 3-Methylbenzofuran-2-carboxvlic acid ffS>-3-methyl-l-[3-oxo-l-n-oxy- pyridine-2-sulfonvl)-azepan-4-ylcarbamovn-butyl 1 amide a. ) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 85c except substituting 3-methylbenzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MS(EI) 558 (M+). b. ) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl3-butyl} amide
Following the procedure of Example li except substuting 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 106a the title compound was prepared: ‘H NMR(CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H);4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS(EI): 556 <M*,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: ‘H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (t, 1H), 3.8 (d, 1H); 4.1 (d, 1H), 4,7 (m, 1H), 4.7 (d, 1H), 5.0 (m, 1H), 7.0 (m, 2H), 7.3 168 012288 (m, 2H), 7.4 (m, 4H), 8.1 (d, 1H), 8.2 (d, 1H); MSÇEI): 557 (M+H\10Û%) and the slower eluting diastereomer MS(EI): 557 (M+H*,100%).
Example 107
Préparation of 6-Methyl-N-{fS)-3-methvI-l-r3-oxo-l-f l-oxy-pyridine-2-sulfonvl)-azepan-4- ylcarbamovH-butyl l-nicotinamide a. ) 6-Methyl-N-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-nicotinamide
Following the procedure of Example 85c except substituting 6-methylnicotinic acidfor benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MSÇEI) 519(M+). b. ) 6-Methyl-N-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-nicotinamide
Following the procedure of Example li except substuting of 6-methyl-N-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridme-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-nicotinamide Example 107a the title compound was prepared: : ‘H NMR (CDCLj): δ 1.0(m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0 (m, 1H), 4,5(t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 3H), 9.0 (m, 1H); MSÇEI): 517 (M\100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MSÇEI): 518 (M+H\10Û%) and the slower eluting diastereomer MSÇEŒ): 518 (M+H*,100%). 169 υ ι 2288
Example 108
Préparation of fS)-4-Methvl-2-f2-thiophen-vl-acetvlamino')-peptapoic acid-i3-oxo-l- fpyridine-2-sulfonvI)-azepan-4-vl1-butvl 1 amide a. ) (S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-hydroxy-1 -(pyridine- 2-sulfonyI)-azepan-4-yl]-butyI}amide
Following the procedure of Example 28b except substituting thiophene-2-aceticacid for benzofuran-2-carboxyîic acid the titie compound was prepared: MS(ESI) 508.8(M+H+). b. ) (S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-yl]-butyl} amide
Following the procedure of Example li except substuting (S)-4-methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-butyl}amide of Example 108a the titie compound was prepared: MS(ESI) 506.8 (M+H+).
Example 109
Préparation of lH-Indole-6-carboxvlic acid KS)-3-methvl-l-r3-oxo-l-(pyridme-2-sulfonvr)- azepan-4-ylcarbamovn-butvl 1 amide a. ) lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting lH-indole-6-carboxylic acid for benzofuran-2-carboxylic acid the titie compound was prepared: MS(EI)527 (M+H+). b. ) lH-ïndole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substuting lH-indole-6-carboxylicacid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 109a the titie compound was prepared: MS(EI) 525 (M+H+). 170 012288
Example 110
Préparation of BenzoF1.31dioxole-5-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pvridine-2- sulfon vl)-azepan-4-ylcarbamovll-butyl ) amide a.) Benzo[1.3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 28b except substituting piperonylic acid forbenzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 532.7 (M+H+). b.) Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfony l)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyI-1 -[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 110a the title compound was prepared: MS(EI) 530.8 (M+H+).
Example 111
Préparation of 3.4-Dihvdro-2H-benzoibiri.41dioxepine-7-carboxvlic acid {CSl-S-methyl-l- F 3-oxo-l -( 1 -oxy-pvridine-2-sulf onvl)-a2epan-4-vlcarbamoyl1-butvl ) amide a. ) 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3- hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 85c except substituting 3,4-dihydro-2H-l,5-benzodioxepine-7-cafboxylic acid for benzo[b]thiophene-2-carboxyIic acid the titlecompound was prepared: MS(EI) 576 (M+). b. ) 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-oxo- 1 -( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting 3,4-dihydro-2H-benzo[b][l,43dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 111a the title compound wasprepared: 'HNMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 4H), 2.5 (d, 3H), 2.7 171 012288 (m, 1H), 3.S (q, 1H); 4.0 (m, 1H), 4.2 (m, 4H), 4^*(t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 575 (M+ïT,100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(EI): 575 (M+H*,100%) and the slower eluting diastereomer MS(EI):575 (M+H*,100%).
Example 112
Préparation of 5-Methyl-thiophene-2-cafboxvlic acid {(S)-3-methvl-l-r3-oxo-l-fl-oxv- PVridine-2-sulfonvl)-azepan-4-ylcarbamovll-butyllamide a. ) 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting 5-methyl thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared:MS(EI) 524 (M+). b. ) 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting 5-methyl-thiophene-2-carboxylic acid {(S)-3-methyl- l-[3-hydroxy-1-( l-oxy-pyridine-2-sulfonyI)-azepan-4-ylcarbamoyl]-butyl} amide of Example 112a the title compound was prepared: *H NMR(CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (xn, 2H), 2.5 (d, 3H), 2.7 (m, 1H), 3.8 (q, 1H);4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 4H), 8.1-8.2 (m, 2H);MS(EI): 523 (M+H,100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(EI): 523 (M+H\100%) and the slower eluting diastereomer MS(EI):523 (M+H,100%). 172 012288
Example 113
Préparation of 4,5-Dibromo-thiophene-2-carboxvIic acid ifS)-3-methvl-l-r3-oxo-l-(l-oxv- pvridme-2-sulfonvD-azepan-4-ylcarbamoyn-bûtvl 1 amide a. ) 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting 4,5-dibromo-thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compoundwas prepared: MS(EI) 668 (M+). b. ) 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide **Following the procedure of Example li except substuting 4,5-dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 113a the title compound was prepared: ‘HNMR (CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (q, 1H); 4.0(m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 2H); MS(EI):665 (M+H\100%).
Example 114
Préparation of 3,5-Dimethyl-isoxazole-4-carboxvlic acid fÎS)-3-TOethvl-l-r3-oxo-l-fl-oxv- pyridine-2-sulfonvI')-azepan-4-vlcarbamovn-butvI} amide a.) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting 3,5-dimethyl-isoxazole-4-carboxylic acid for benzo[b]thiophene-2-carboxyIic acid the title compoundwas prepared: MS(EI) 524 (M+H+). 173 012288 b.) 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting 3,5-dimethyl-isoxazole-4-carboxylic acid { (S)-3-methyl- l-[3-hydroxy-1-( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 114a the title compound was prepared: ’HNMR(CDC1,): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, 3H), 2.6 (m, 3H), 2.7 (m, 1H),3.S (q. 1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 5H), 8.1-8.2 (m,2H); MS(EI): 521 (M\100%).
Example 115
Préparation of (S)-2-(2-Benz\doxv-acetvlamino)-4-methvl-pentanoic acidri-(4-methoxv- benzenesulfonvl)-3-oxo-azepan-4-yll-amide a. ) {(S)- l-[3-Hydroxy-1 -(4-methoxy-benzenesulfonyl)-azepan-4-ylcarbamoyl]-3- methyl-butyl}-carbamic acid-zen-butyl ester [(S)-1 -(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid-rert-butyl ester (compound 2g, 0.8 g, 2.33 mmoî) was dissolved in 1,2-dichloroethane (DCE, 20ml). Then, morpholinemethyl polystyrène resin beads (1.26 g, 3.7 mmol/g, Nova) wereadded and the solution was shaken for 5 minutes. Then, p-methoxybenzenesulfonylchloride (0.48 g, 2.33 mmol) was dissolved in DCE (10 ml), and this solution was added tothe reaction mixture. The reaction was shaken ovemight, fîltered, washed with DCE (2 x10 ml), then CHjClj (10 ml). The combined organics were concentrated in vacuo, and usedin the next reaction without further purification: M+£F = 514.2. b. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(4-methoxy-benzenesulfonyl)- azepan-4-yl]-amide-HCl sait {(S)-l-[3-Hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid-ierr-butyl ester (compound 207a, 0.59 g, 1.15 mmol) wasdissolved in CHjClj (8 ml), then a solution of 4 M HCl in dioxane (8 ml) was added and thereaction was stirred at RT for 4h. The reaction mixture was concentrated in vacuo,azeotroped from toluene twice (10 ml) in vacuo, and was used in the next reaction withoutfurther purification: M+H* = 413.8. 174 012288 c. ) (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy-l-(4- methoxy-benzenesulfonyl)-azepan-4-yl]-amide (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-yl]-amide-HCl sait (crade product from reaction mixture of 115b) was dissolvedin MeOH (10 ml) and was treated with carbonate-polystyrene resin beads (1.75 g, 2.63mmolZg, 4.6 mmol) and was shaken for 2h, filtered, washed with MeOH (10 ml) and thecombined organics were concentrated in vacuo. The product was then dissolved in DCE (2ml) and morpholinemethyl polystyrène resin beads (0.25 g, 3.77 mmol/g, 0.91 mmol,
Nova) were added and the reaction was shaken for 5 minutes. Then, benzylacetyl chloride(0.0S1 g, 0.44 mmol) was added and the reaction mixture was shaken ovemight. Then,trisamine polystyrène beads (0.1g, 3.66 mmol/g, 0.366 mmol) was added and the reactionmixture was shaken for 1.5 h. The reaction mixture was then filtered, washed with DCE(2x10 ml) and CH,CL, (10 ml), and the combined organics were concentrated in vacuo. Thecrade product was used in the next reaction without further purification: M+H* = 562.2. d. ) (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [l-(4-methoxy- benzenesulfonyl)-3-oxo-azepan- 4-yl]-amide (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-yî3-amide (compound 207c, 0.24 g, 0.44 mmol) wasdissolved in CHLC^ (5 ml), then Dess-Martin periodinane (0.3 g, 0.7 mmol) was added andthe reaction was stirred for 30 min. The reaction was diluted with CKLCL, (20 ml), then wasextracted with aqueous 10% Na^O^ (10 ml), then aqueous 10% NaHCO3 (10 ml), water(10 ml), brine (10 ml). The combined organics were concentrated in vacuo. The residuewas purifiedby HPLC (50:50 Ethanol: hexanes, 20mL/min, 25min, WhelkO-l(R,R)21x250mm column, UV détection at 280nm and 305nm) to yield the first elution as a whitesolid (47 mg, 43 %): MS 560.4 (Μ+Η+^Η NMR (400Hz,CDCl3): 5 7.73 (d, 2H), 7.40-7.30 (m, 5H), 7.05 (d, 2H), 3.99 (s, 2H), 3.88 (s, 3H), 2.28-2.10 (m, 2H), 0.95 (t, 6H) andsecond eluting diastereomer: MS 560.2 (M+H+). 175
Example 116 012288
Préparation of 5-Ç3-Trifluoromethyl-phenvl)-furan-2-carboxvlic acid {ÇS)-3-methvl-l-r3- oxo-1-Ç l-oxv-pyridme-2-sulfonvl)-azepan-4-vlcarbamovri-butyl ) aroide ? a. ) 5-Ç3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 85c except substituting 5-Ç3-trifluoromethyl-phenyl)-furan-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the titlecompound was prepared: MSÇEI) 638 (M+). b. ) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {ÇS)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}amide
Following the procedure of Example li except substuting 5-Ç3-trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-Çl-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 116a the title compound wasprepared: Ή NMR (CDC1,): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 Çm, 2H), 2.6 (d, 3H), 2.7(m, 1H), 3.8 (q, 1H); 4.1 (m, 1H), 4,7 (t, 1H), 4.8 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 9H),8.1-8.2 (m, 2H); MSÇEI): 637 (M+îT,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(EI): 637 ÇM+H\ 100%) and the slower eluting diastereomer MSÇEI)·.637 (Μ+Η\ 100%) .
Example 117
Préparation of 5-Methvl-2-phenvl-oxazole-4-carboxylic acid US)-3-methyl-l-F3-oxo-l-Çl- oxy-pyridine-2-sulfonyl)-azepan-4-vlcarbamovï)-butvl ) amide a.) 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l- oxy-pyridine-2-sulfonyï)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c except substituting 5-methyl-2-phenyl- oxazole-4-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MSÇEI) 585 (M+). 176 012288 b.) 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substuting 5-methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 117a the title compound was prepared:NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, 1H), 3.8 (q,1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0 (m, 1H), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H);MS(EI): 584 (Μ+Ηζ 100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(EI): 584 (Μ+ΕΓ, 100%) and the slower eluting diastereomer MS(EI):584 (Μ+ΕΓ, 100%).
Example 118
Préparation of Benzofuran-2-cafboxvlic acid ((S)-l~r l-(3.4-dimethoxy-benzenesulfonvl)-3- oxo-azepan-4-ylcarbamovîl-butvl 1-amide a. ) Benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dünethoxy-benzenesulfonyl)-3- hydroxy-azepan-4-ylcarbamoyl]-butyl} -amide
To a solution of benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide of Example 78c (0.175 g) indichloromethane was added triethylamine (0.1 mL) and 3,4-dimethoxybenzenesulfonylchloride (0.12 g). The reaction was stirred until complété. Workup and columnchromatography (5% methanohdicloromethane) provided the title compound (0.21 g):MS(EI) 587 (M+). b. ) Benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcafbamoyl]-butyl }-amide
Following the procedure of Example li except substuting benzofuran-2-carboxylicacid {(S)-1-[ l-(3,4-dimethoxy-benzenesu]fonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl }-amide of Example 118a the title compound was prepared: : NMR (CDCI3): δ 1.0 (m,6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.5 (d, 1H); 3.7 (t, 6H), 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m,1H), 5.0 (m, 1H), 7.4-8.0 (m, 8H); MSÇEI): 586 (M+H\ 100%). 177 012288
Example 119
Préparation of Benzofuran-2-carboxylic acid {fS)-l-il-f4-bromo-benzenesalfonvl)-3-oxo- azepan-4-vlcarbamoyH-3-methvl-bntvR-amide a. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-hydroxy- azepan-4-ylcarbamoyl]-3-metihyl-butyl}-amide
Following the procedure of Example 1 ISa except substituting 4-bromobenzenesulfonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the titlecompound was prepared: MS(EI) 606 (M+). b. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example li except substituting benzofuran-2-carboxyIicacid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide of Example 119a the title compound was prepared: *H NMR (CDCI3): δ 1.0(m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.5 (d, 1H); 4.0 (m, 1H), 4,5 (t, 1H), 4.7 (m, 1H), 5.0(m, 1H), 7.4-8.0 (m, 9H); MS(EI): 604 (M*, 100%).
Example 120
Préparation of Benzofnran-2-carboxvlic acid {(S)-l-fl-fbenzoil.2.51oxadiazole-4-sulfonvl)- 3-oxo-azepan-4-ylcarbamovll-3-metbyl-butyI ) -amide a. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5)oxadiazole-4-sulfonyl)-3- hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example 118a except substituting benzofurazan-4-sulfonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the title compound wasprepared: MS(EI) 569 <M+). b. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole-4-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example li except substituting Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole-4-sulfonyl)-3-hydroxy-azepan-4- 178 012288 ylcarbamoyl]-3-methyl-butyl}-amide of Example 120a the title compound was prepared: 'H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, 1H), 3.7 (m, 1H); 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); MS(EI): 568 (Μ+Ηζ 100%).
Example 121
Préparation of Benzofuran-2-carboxvIic acid ifS)-l-ri-f3.5-dimethyI-oxazole-4 -suIfonvD- 3- oxo-azepan-4-vlcarbamovll-3-methvl-butyl)-amide a. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3- hy droxy-azepan-4-ylcarbamoyl]-3-methyl-butyî} -amide
Following the procedure of Example 118a except substitating 3,5-dimethyloxazole- 4- sulphonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the'title compound wasprepared: MS(EI) 546 (M+). b. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyI}-amide of Example 121a the title compound was prepared:'H NMR (CDCy: δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.4 (d, 3H), 2.7 (t, 3H), 3.6(d, 1H), 4.1 (m, 1H), 4.4 (t, 1H), 4.7 (m, 1H), 5.2 (m, 1H), 7.4-8.0 (m, 5H); MS(EI): 544(M*, 100%).
Example 122
Préparation of 3-Methvlbenzofuran-2-carboxylic acid f (S)-3-methvl-l-i3-oxo-l-(pvridine- 2-sulfonvl)-azepan-4-vlcarbamoyll-butyl ) amide a.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 28b except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared:MS(EI) 542 (M+). 179 012288 b.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 122a the title compound was prepared: 'H NMR(CDCy: 5 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, 1H), 3.8 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 7H); 8.7 (m, 1H); MS(EI): 540(M*, 100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: Ή NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, 1H), 3.8 (d, 1H); 4.1 (d, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 7H); 8.7 (m, 1H) ; MS (El): 541 (M+H\100%) and the slower eluting diastereomer MS(EI): 541 (Μ+Ηζ100%).
Example 123
Préparation of Thienor3,2-blthiophene-2-carboxvlic acid i(S)-3-methvl-l-r3-oxo-l- (pvridine-2-sulfonvl)-azepan-4-ylcarbamoyll-butvl 1 amide a. ) Thieno[3,2-b3thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting thieno[3,2-bJthiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound wasprepared: MS(EI) 550 (M+). b. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-suîfonyl)-azepan-4-ylcaihamoyl]-butyl} amide of Example 123a the title compound was prepared: 'H NMR(CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8 (m, 1H); 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (m, 1H); MS(EI): 548 (M*, 100%). 180 01 2288
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: 'HNMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.7 ( t, 1H), 3.8 (d, 1H); 4.1 (d, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (d, 1H); MSÇEI):549 (M+H\100%) and the slower eluting diastereomer MSÇEI): 549 (M+H\ 100%) .
Example 124
Préparation of 5-fe7t-Butvl-3-methvl-thienor3.2-b1thiophene-2-carboxvlic acid KS)-3- methvl-l-r3-oxo-l-fpyridine-2-sulfonvI)-azepan-4-vlcarbamovH-butyl)an3ide a. ) 5-re?r-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxyIic acid {(S)-3-methyl-l-[3 hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 28b except substituting 5-reri-butyl-3-methyl·thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the titlecompound was prepared: MSÇEI) 620 (M+). b. ) 5-rert-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3 oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 5-teri-butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylie acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 124a the title compound wasprepared: ‘H NMR (CDC13): δ 1.0 (m, 6H), 1.45 (s, 9H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.4(d, 3H), 2.7 (m, 1H), 3.8 (m, 1H); 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 4H); 8.7 (m, 1H); MS(EI): 618 (Μζ 100%). 181 012288
Example 125
Préparation of 5-Methvl-2-phenyl-oxazole-4-carboxvlic acid {(S)-3-methvl-l-i3-oxo-l- (pvridine-2-sulfonvl)-azepan-4-vlcarbamovll -butvl 1 amide a. ) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 5-methyl-2-phenyl-oxazole-4-cafboxylic acid for benzofuran-2-cafboxylic acid the title compound wasprepared: MS(EI) 569 (M+). b. ) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 5-methyl-2-phenyl-oxazole-4-cafboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide of Example 125a the title compound was prepared: ‘H NMR(CDCl,): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, 1H), 2.6 (m, 3H), 3.8 (m, 1H);4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (m, 1H); MS(EI): 567 (NT,100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(EI): 568 (M+H+,100%) and the slower eluting diastereomer MS(EI): 568 (M+H*,100%)
Example 126
Préparation of 2-Phenvl-5-trifluoromethvI-oxazole-4-carboxvlic acid i(5)-3-methvl-l-r3- oxo-1 -(pvridine-2-sulfonvl)-azepan-4-ylcarbamovll-butvl ) amide a.) 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydrox-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid for benzofuran-2-carboxylic acid the titlecompound was prepared: MS(EI) 623 (M+). 182 012288 b.) 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-butyl}amide
Following the procedure of Example li except substituting 2-phenyl-5-trifluoromethyl-oxazole-4-cafboxylic acid {(S)-3-methyl-l-[3-hydrox-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl3-butyl}axnide of Example 126a the title compound wasprepared: 'H NMR (CDC13): 5 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, 1H), 3.8(m, 1H); 4.1 (m, 1H), 4.7 (m, 2H), 5.2 (m, 1H), 7.4-8.0 (m, 8H); 8.7 (m, 1H); MS(EI): 621(M*, 100%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(EI): 622 (M+H+,100%) and the slower eluting diastereomer: MS(EI):622 (M+H\100%).
Example 127
Préparation of Quinoline-2-carboxylic acid FfS)-l-(l-methanesulfonvl-3-oxo-azepan-4- vlcarbamovI)-3-methvl-butvll-amide
Following the procedure of Example 75, except substituting methanesulfonylchloride for thiazole-2-sulfonyl chloride and 2-quinoline carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. Firsteluting diastereomer; MS (M+H+): 475.2; iH-NMR (400 MHz, CDC13): · 8.65(d, 1H),8.35-8.28(q, 2H), 8.20-8.18(d, 1H), 7.91-7.89(d, 1H), 7.80-7.78(t, 1H), 7.67-7.65(t, 1H),7.10(d, 1H), 5.08(m, 1H), 4.73 (m, 1H), 4.56-4.51(d, 1H), 4.00(m, 1H), 3.67-3.62(d, 1H),2.91(s, 3H), 2.70(m, 1H), 2.32-2.10(m, 2H), 1.95-1.40(m, 5H), 1.02-1.00(m, 6H); and thesecond eluting diastereomer: MS (M+H+): 475.2
Example 128
Préparation of l-Methyl-lH-indole-2-carboxvlic acid iïS)-l-fl-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butvn-amide
Following the procedure of Example 75, except substituting methanesulfonylchloride for thiazole-2-sulfonyl chloride and N-methylindole-2-carboxylic acid for 183 012288 benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS (M+H+): 477.2; 1-H-NMR (400 MHz, CDCI3): ·7.65-7.63(d, 1H), 7.39-7.33(m, 2H), 7.17-7.14(t, 1H), 6.98-6.95(m, 2H), 6.65(d, 1H),5.08(m, 1H), 4.68 (m, 1H) 4.56-4.52(d, 1H), 4.03(m, 4H), 3.67-3.63(d, 1H), 2.92(s, 3H),2.71(m, 1H), 2.32-2.10(m, 2H), 1.95-1.40(m, 5H), 1.02-1.00(d, 6H); and the second elutingdiastereomer: MS (M+H+): 477.2
Example 129
Préparation of Furan-2-carboxylic acid ir(S)-l-(l-methanesulfonvl-3-oxo-azepan-4- ylcarbamovD-3-me±vl-butylcarbamovn-methvl)-amide
Following the procedure of Example 75, except substituting methanesuîfonylchloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine forbenzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC.First eluting diastereomer; MS (M+H+): 471.2; ÎH-NMR (400 MHz, CDCI3): · 7.50(m,1H), 7.15(m, 1H), 7.05(m, 1H), 6.90(d, 1H), 6.55(m, 2H), 5.08(m, 1H), 4.55 (m, 2H),4.12(m, 2H), 4.05(m, 1H), 3.70(d, 1H), 2.92(s, 3H), 2.75(m, 1H), 2.20-1.40(m, 7H), 0.95(m, 6H); and the second eluting diastereomer: MS (M+H+): 471.4.
Example 130
Préparation of 5-Methoxvbenzofaran-2-carboxylic acid iïSl-l-f l-methanesulfonyI-3-oxo- azepan-4-vlcarbamovll-3-methyl-butvll-amide
Following the procedure of Example 75, except substituting methanesuîfonylchloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2-carboxylic acid forbenzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS (M+H+): 494.2; ^H-NMR (400 MHz, CDCI3): ·7.42-7.40(d, 2H), 7.08-6.94(m, 4H), 5.10(m, 1H), 4.71(m, 1H), 4.56-4.52(d, 1H), 4.02(m,1H), 3.86(s, 3H), 3.68-3.63(d, 1H), 2.92(s, 3H), 2.72(m, 1H), 2.30-1.15(m, 2H), 1.95-1.40(m, 5H), 0.99 (d, 6H); and the second eluting diastereomer: MS (M+H+): 494.2. 184 012288
Example 131
Préparation of Quinoxalme-2-carboxvlic acid r(S)-l-(l-methanesulfonvl-3-oxo-azepan-4- vlcarbamovD-3-methvI-butyll-amide
Following the procedure of Example 75, except substituting methanesulfonylchloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifîed by HPLC.First eluting diastereomer; MS (M+H+): 476.2; ^H-NMR (400 MHz, CDCI3): · 9.66(s,1H), 8.38(d, 1H), 8.20-8.18(m, 2H), 7.88(m, 2H), 7.01(d, 1H), 5.10(m, 1H), 4.77(m, 1H),4.57-4.52(d, 1H), 4.08-4.00(m, 1H), 3.69-3.64(d, 1H), 2-92(s, 3H), 2.71(m, 1H), 2.42-2.15(m, 2H), 1.95-1.42(m, 5H), 1.02-1.01(d, 6H); and the second eluting diastereomer: MS (M+H+): 476.2.
Example 132
Préparation of 5-(4-Chloro-phenvl)-furan-2-carboxylic acid {(S)-3-methvl-l-r3-oxo-l- (pyridine-2-sulfonvl)-azepan-4-ylcarbamoyI]-butyl 1 amide a. ) 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 5-(4-cblorophenyl)-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 590(M+H+). b. ) 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 5-(4-chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl) amide of Example 132a the title compound was prepared: ‘H NMR(CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H), 4.0 (m, 1H),4.7 (m, 2H), 5.0 (m, 1H), 6.7 (m, 1H), 7.2 (m, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.7 (m, 2H),8.0 (m, 2H), 8.7 (m, 1H); MS(EI): 587 (M*, 80%) 185
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 587 (M+H\100%) and the slower eluting diastereomer: MS(EI): 587 (M+H*,100%). 012288
Example 133
Préparation of (S)-2-i2-(4-Methoxv-phenvl)-acetvlamino')-4-methvl-pentanoic acid (1- methanesulfonyl-3-oxo-azepan-4-vD-aroide
Following the procedure of Example 75, except substituting 4- methanesulfonylchloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic acid forbenzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS (M+H+): 468.2; ^H-NMR (400 MHz, CDCI3): ·7.19-7.17(d, 2H), 6.90-6.8S(d, 3H), 5.83-5.81(d, 1H), 5.00(m, 1H), 4.53-4.40(m, 2H), 4.03-3.99(m. 1H), 3.81(s, 3H), 3.66-3.61(d, 1H), 3.53(s, 2H), 2.91(s, 3H), 2.73(t, 1H), 2.22-2.10(m, 2H), 1.99( m, 1H). 1.62-1.35(m, 4H), 0.90-0.88(d, 6H); and the second elutingdiastereomer: MS (M+H+): 468.2.
Example 134
Préparation of Ouinoïine-2-carboxvlic acid f [YS)-l-!~l-f2-cvano-benzenesulfonvl)-3-oxo- a2epan-4-ylcarbamoyri-3-meth yl-butvl 1 -amide
Following the procedure of Example 75, except substituting 2-cyanobenzenestüfonyl chloride for thiazole-2-sulfonyl chloride and quinoline-2-carboxylicacid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer; MS (M+H+): 562.2; ^H-NMR (400 MHz,CDCI3): · 8.65(d, 1H), 8.48-8.40(q, 2H), 8.25-S.10(q, 2H), 7.91-7.65(m, 6H); and thesecond eluting diastereomer:, 7.12(d, 1H), 5.10(m, 1H), 4.73 (m, 1H) 4,61-4.56(d,lH),4.20(m, lH),3.73-3.68(d, 1H), 2.80(m, 1H), 2.27(m, 2H), 1.91-1.40(m, 5H), 1.03-1.01(m, 6H); and the second eluting diastereomer. MS (M+H+): 562.2. 186 012288
Example 135
Préparation of 1-Methvl-lH-indole -2-carboxvlic acid {|TS)-l-ri-(2-cvano- benzenesulfonvl)-3-oxo-azepan-4-ylcafbamovll-3-methyl-butvlï-amide
Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purifîed by HPLC. First eluting diastereomer; MS (M+H+): 564.2; ^H-NMR(400 MHz, CDC13): · 8.13(d, 1H), 7.89(d, 1H), 7.77-7.67(m, 3H), 7.38-7.16(m, 4H), 6.97(s,1H), 6.70(d, 1H), 5.05(m, 1H), 4.70-4.60 (m, 1H), 4.55-4.50(d, 1H), 4.07(m, 1H), 4.05(s,3H), 3.76-3.71(d, 1H), 2.75(m, 1H), 2.30(m, 2H), 2.00-1.45(m, 5H), 1.00(d, 6H); and thesecond eluting diastereomer: MS (M+H+) 564.2.
Example 136
Préparation of Furan-2-carboxylic acid ff(S)-l-ri-(2-cvano-benzenesuIfonyD-3-oxo-azepan- 4-vlcarbamoyll-3-methvl-butvlcarbamovll-methvI)-amide
Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residuewas purifîed by HPLC. First eluting diastereomer; MS (M+H+): 558.2; ^H-NMR (400MHz, CDCI3): · 8.14-8.12(d, 1H), 7.91-7.90(d, 1H), 7.80-7.72(m, 2H), 7.48(s, 1H), 7.14(d,2H), 6.98(d, 1H), 6.80(d, 1H), 6.52-6.51(t, 1H), 5.03(m, 1H), 4.60-4.53 (m, 2H), 4.17-4.14(m, 3H), 3.74-3.69(d, 1H), 2.80(m, 1H), 2.25(m, 2H), 2.00-1.40(m, 5H), 1.03-1.01(m,6H); and the second eluting diastereomer: MS (M+H+) 558.2. 187 012288
Example 137
Préparation of 5-Methoxvbenzofnran-2-carboxvlic acid f(S)-l-ri-(2-cyano- benzepesulfonyl)-3-oxo-azepap-4-vlcarbamovll-3-methvl-butvl)-amide 5
Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 581.4; ^H-NMR 10 (400 MHz, CDCI3): · 8.15-8.13(d, 1H), 7.92-7.90(d, 1H), 7.81-7.74(m, 2H), 7.42-7.40(m, 2H), 7.08-7.03(m, 3H), 6.96(d, 1H), 5.10(m, 1H), 4.72-4.60 (m, 2H), 4.17 (d, 1H), 3.85(s,3H), 3.75-3.70(d, 1H), 2.83-2.76(t, 1H), 2.27(m, 2H), 1.92-1.51(m, 5H), 1.02-1.01(m, 6H);and the second eluting diastereomer: MS (M+H+) 581.2. 15 Example 138
Préparation of Ouinoxaline-2-carboxvlic acid {(S)-l-ri-(2-cyano-benzenesuIfonvD-3-oxo- azepan-4-ylcarbamovll -3-methvl-butvl} -amide 20 Following the procedure of Example 75, except substituting 2- cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxyIicacid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer; MS (M+H+): 563.2; ^H-NMR (400 MHz,CDCI3): · 9.65(s, 1H), 8.40(m, 1H), 8.22-8.10(m, 3H), 7.90-7.22(m, 5H), 7.00(d, 1H), 25 5.10(m, 1H), 4.75(m, 1H), 4.65-4.60(d, 1H), 4.20-4.10(m, 1H), 3.72-3.70(d, 1H), 2.70(m, 1H), 2.38(m, 2H), 1.95-1.40(m, 5H), 1.02(d, 6H); and the second eluting diastereomer: MS (M+H+) 563.2. 188 012288
Example 139
Préparation of ('Sl-2-r2-(4-Methoxv-phenvll-acetvlaminol-4-methvl-pentanoic acid Fl-f2- cvano-benzenesulfonvD-3-oxo-azepan-4-yll-amide 10 15 • Following the procedure of Example 7 5, except substituting 2-cyanophenylsulf onyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic acid forbenzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS (M+H+): 555.2; ^H-NMR (400 MHz, CDC13): ·8.14-8.12(d, 1H), 7.91-7.89(d, 1H), 7.79-7,73(m, 2H), 7.19-7.17(d, 2H), 6.90-6.88(d, 3H),5.8O(d, 1H), 5.02(m, 1H), 4.59-4.55(d, 1H), 4.45-4.42(m, 1H), 4.18-4.15(m, 1H), 3.82(s,3H), 3.72-3.67(d, 1H), 3.53(s, 2H), 2.82-2.79(t, 1H), 2.22(m, 2H), 1.92( m, 1H), 1.60-1.30(m, 4H), 0.91-0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 555.2.
Example 140
Préparation of Ouinoline-2-carboxylic acid {iïS)-l-ri-(4-methoxv-benzenesulfonvB-3-oxo- azepan-4-vlcarbamovI~i-3-methvl-butvl)-anude 20 Following the procedure of Example 75, except substituting 4- methoxybenzenesulfonyl chloride for thiazole-2-sulfonyl chloride and 2-quinolinecarboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 567.2; ^H-NMR(400 MHz, CDCI3): · 8.72-8.61(d, 1H), 8.35-8.28(q, 2H) 8.21-8.18(d, 1H), 7.91-7.60(m, 25 5H), 7.10-6.99(m, 3H), 5.05(m, 1H), 4.73 (m, 1H) 4,59-4.52(d, lH),4.00(m, 1H), 3.88(s, 3H), 3.45-338(d, 1H), 2.42(m, 1H), 2.30-1.35 (m, 7H), 1.03-1.01(m, 6H); and the secondeluting diastereomer: MS(M+H+) 567.2. 189 012288
Example 141
Préparation of l-Methvl-lH-indole-2-carboxvlic acid irfS)-l-ri-(4-rnethoxv- benzenesnIfonvl)-3-oxo-azepap-4-ylcarbamovH-3-methvI-butyn-amide
Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methyl-indole-2-carboxyEc acid for benzofuran-2-cafboxylic acid, the title compound was prepared. Theresidue was purifiedby HPLC. First eluting diastereomer; MS (M+H+): 569.2; 1H-NMR(400 MHz, CDCI3): · 7.78-7.72(d, 2H), 7.70-7.65(d, 1H), 7.42-7.30(m, 2H), 7.17-7.14(t,1H), 7.05-6.95(m, 4H), 6.65(d, 1H), 5.05(m, 1H), 4.70-4.50 (m, 2H), 4.03(s, 3H), 3.88(s,3H), 3.45-3.40(d, 1H), 2.45(m, 1H), 2.30-2.10(m, 2H), 1.90-1.35(m, 6H); and the secondeluting diastereomer:, 1.00(d, 6H); and the second eluting diastereomer: MS (M+H+)569.2.
Example 142
Préparation of Furan-2-carboxylic acid (ffS)-l-ri-f4-methoxy-benzenesulfonvl)-3-oxo- azepan^-vlcarbamovU-S-methvl-butylcarbamovB-methyD-amide
Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine for benzofuran-2-carboxyIic acid, the title compound was prepared. The residuewas purified by HPLC. First eluting diastereomer; MS (M+H+): 563.2; ^-H-NMR (400MHz, CDCI3): · 7.74-7.72(d, 2H), 7.47 (s, 1H), 7.15-6.99(m, 4H), 6.91(d, 1H), 6.70(d, 1H),6.52-6.51(m, 1H), 5.01(m, 1H), 4.53-4.49 (m, 2H), 4.17-4.14(m, 2H), 4.00-3.90(m, 1H),3.88(s, 3H), 3.45-3.41(d, 1H), 2.47(m, 1H), 2.17(m, 2H), 1.85-1.40(m, 5H), 0.95(m, 6H);and the second eluting diastereomer: MS (M+H+) 563.2. 190 012288
Example 143
Préparation of 5-Methoxvbenzofuran-2-carboxvIic acid {f.(S)-l-ri-(4-methoxv- benzenesuIfonyl)-3-oxo-azepan-4-vIcarbamoyl1-3-methvl-butvll-amide
Following the procedure of Example 75, except substituting 4-methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compoundwasprepared. The residue was purified by HPLC. First eluting diastereomer; MS(M+H+): 586.2; ÎH-NMR (400 MHz, CDC13): · 7.75-7.73(d, 2H), 7.42-7.40(m, 2H), 7.08-6.99(m, 5H), 6.9 l(d, 1H), 5.05(m, 1H), 4.70-4.55(m, 2H), 4.05-4.00(m, 1H), 3.89(s, 3H),3.86(s, 3H), 3.45-3.40(d, 1H), 2.50-2.40(m, 1H), 2.30-2.10(m, 2H), 1.90-1.35(m, 5H),1.01(m, 6H); and the second eluting diastereomer. MS(M+H+) 586.2.
Example 144
Préparation of Ouipoxaline-2-carboxvlic acid {FfS>-l-ri-i4-methoxv-benzenesulfonvD-3- oxo-azepan-4-ylcarbamoyll-3-methvl-butyIÏ-aniide
Following the procedure of Example 75, except substituting 4-methoxyphenylsnlfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 568.2; ^H-NMR(400 MHz, CDCI3): · 9.66(s, 1H), 8.40-8.35(m, 1H), 8.19(m, 2H), 7.88(m, 2H), 7.75-7.73(d, 2H), 7.02-6.90(m, 3H), 5.10-5.05(m, 1H), 4.75(m, 1H), 4.60-4.55(d, 1H), 4.05-3.95(m, 1H), 3.89(s, 3H), 3.45-3.41(d, 1H), 2.45(m, 1H), 2.30-2.10(m, 2H), 1.95-1.40(m,5H), 1.04-1.02(d, 6H); and the second eluting diastereomer: MS (M+H+) 568.2. 191 012288
Example 145 if '
Préparation of (S)-2-i2-(4-Methoxv-phenvl')-acetylamino)-4-methvi-Î>entanoic acid !T-f4- * methoxv-benzenesulfonvl)-3-oxo-azepan-4-vll-amide
Following the procedure of Example 75, except substituting 4~methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 560.4; ^H-NMR(400 MHz, CDC13): · 7.74-7,71(d, 2H), 7.19-7.17(d, 2H), 7.01-6.99(d, 2H), 6.90-6.88(d, 2H), 6.85(d, 1H), 5.8l(d, 1H), 4.99(iû, 1H), 4.55-4.44(m, 2H), 3.97(m, 1H), 3.88(s, 3H), 3.81(s, 3H), 3.53(s, 2H), 3.43-3.38(d, 1H), 2.43(t, lH),2.14(m, 2H), 1.85-1.35(m, 5H), 0.90-0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 560.2.
Example 146
Préparation of lrMethvl-lH-indoIe-2-carboxvlic acid KfSl-l-ri-^fluoro- benzenesulfonvD-3-oxo-azepan-4-vlcarbamovll-3-methyl-butyI | -amide
Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methyl-indole-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 557.2; ^H-NMR(400 MHz, CDCI3): · 7.84-7,80(m, 2H), 7.66-7.65(d, 1H), 7.40-7.14(m, 5H), 6.95(m, 2H), 6.65-6.63(d, 1H), 5.07(m, 1H), 4.68-4.55 (m, 2H), 4.04(s, 3H), 3.48-3.43(d, 1H), 2.49(m, 1H), 2.25(m, 2H), 1.89-1.38(m, 6H); and the second eluting diastereomer:, 1.01(d, 6H);and the second eluting diastereomer: MS (M+H+) 557.4. 192 012288 *1 > -Â
Example 147 ·»
Preparationof Furan-2-carboxvIic acid f i('S~)-l-ri-f4-fluoro-benzenesulfonvl')-3-oxo- azepan-4-ylcarbamovll-3-methyl-butylcarbamoyl)-methyD-amide
Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residuewas purified by HPLC. First eluting diastereomer; MS (M+H+): 551.4; ^H-NMR (400 10 MHz, CDC13): 7.81(m, 2H), 7.48(s, 1H), 7.27-7.16(m, 3H), 7.05(m, 1H), 6.90(d, 1H),6.52(m, 2H), 5.00(m, 1H), 4.60-4.48 (m, 2H), 4.14(m, 2H), 4.00-3.90(d, 1H), 3.48-3.44(d,1H), 2.50(m, 1H), 2.20(m, 2H), 1.90-1.40(m, 5H), 0.95(m, 6H); and the second elutingdiastereomer: MS(M+H+) 551.2. 15 Example 148
Préparation of 5-Methoxvbenzofuran-2-carboxvlic acid f[fS)-l-Fl-(4-fluoro- benzenesulfonyI~)-3-oxo-azepan-4-vlcarbamovll-3-methyl-butyl 1 -amide 20 Following the procedure of Example 75, except substituting 4- fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-methoxybenzoforan-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 574.2; ^H-NMR(400 MHz, CDCI3): · 7.84-7.81(m, 2H), 7.42-7.40(m, 2H), 7.27-7.22(m, 2H), 7.08-7.04(m, 25 3H), 6.93(d, 1H), 5.10-5.02(m, 1H), 4.69-4.55(m, 2H), 4.05-4.00(m, 1H), 3.86(s, 3H), 3.47· 3.43(d, 1H), 2.49(m, 1H), 2.24(m, 2H), 1.90-1.40(m, 5H), 1.01(m, 6H); and the secondeluting diastereomer: MS (M+H+): 574.2 193 012288
Example 149
Préparation of Ouinoxaline-2-carboxvlic acid f r(S)-l-fl-(4-fluoro-benzenesulfonvl)-3-oxo- azepan-4-vlcarbamovll-3-methvl-butyl1 -amide
Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid, the titie compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 556.2; ^H-NMR(400 MHz, CDC13): · 9.66(s, 1H), 8.40-8.35(d, 1H), 8.21-8.18(m, 2H), 7.90-7.81(m, 4H),7.27-7.22(m, 2H), 6.97(d, 1H), 5.10-5.02(m, 1H), 4.75(m, 1H), 4.59-4.55(d, 1H), 4.05-4.39(m, 1H), 3.48-3.44(d, 1H), 2.49(m, 1H), 2.32-2.10(m, 2H), 1.90-1.40(m, 5H), 1.03-1.02(d, 6H); and the second eluting diastereomer: MS (M+H+) 556.2.
Example 150
Préparation of fS)-2-i2-(4-Methoxv-phenvl)-acetvlamino)-4-methvl-pentanoic acid Γ1-Γ4- fluoro-benzenesulfonvl)-3-oxo-azepan-4-vn-amide
Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)~acetic acid for benzofuran-2-carboxylic acid, the titie compound was prepared. Theresidue was purified by HPLC. First eluting diastereomer; MS (M+H+): 548.2; ^H-NMR(400 MHz, CDCI3): · 7.83-7.80(m, 2H), 7.27-7,17(m, 4H), 6.90-6.88(d, 3H), 5.85(d, 1H),4.98(m, 1H), 4.55-4.43(m, 2H), 4.00-3.97(m, 1H), 3.81(s, 3H), 3.53(s, 2H), 3.45-3.41(d,1H), 2.48(t, 1H), 2.17-2.14(m, 2H), 1.90-1.30(m, 5H), 0.90-0.88(d, 6H); and the secondeluting diastereomer: MS (M+H+): 548.4. 194 012288
Example 151
Préparation of Benzoforan-2-carboxylic acid-ï (S)-l-ri-(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-vlcarbamoyll-3-methy]-butyi)-arnide 5 « a. ) {(S)-l -[ 1 -(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl- butyl}-carbamic acid ieri-butyl ester
To a solution of the compound of Example 2g (2.50g, 7.29mmol) in DCE (100ml)was added P-NMM (4.0g) and 3-chlorobenzenesulphonyl chloride (1.85g, 8.75mmol). 10 After shaking at room température ovemight, the solution was filtered. The fîltrate wasconcentrated to yield the title compound as white solid (3.13g, 83.3%). MS: 539.78 ' (M+Na)+. b. ) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-chloro-benzenesulfonyl)-3-hydroxy- 15 azepan-4-yl]-amide
To a stirring solution of the compound of Example 151a (1.0g, 1.93mmol) inmethnol (10 ml) was added HCl (4M in Dioxane) (10 ml). After stirring at roomtempérature for 3 hr the solution was concentrated to provide a white solid. To a solutionof the white solid (0.68 g, 1.50 mmol, 78%) in methnol (37 ml) was added P-CO3 (2.85g, 20 2.63mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.59 g, 1.42 mmol, 95%). MS: 417.86 (M+H)+. c. ) Benzofuran-2-cafboxylic acid-{ (S)-l-[l-(3-chloro-benzenesulphonyl)-3-hydroxy- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide 25 To a solution of the compound of Example 15 lb (0.14 g, 0.33 mmol) in CHjCL, (20 mL) was added benzofuran-2-carboxylic acid (0.81,0.50 mmol), 1-hydroxybenzotriazole(0.77 g, 0.57 mmol), and P-EDC (0.67g, 1 mmol/g) in CHjClj (10 mL) . After shaking atroom température ovemight, the solution was treated with tisamine (0.45 g, 3.75 mmol/g).After shaking for another 2 hr, the solution was filtered and concentrated to yield the title 30 compound as a white solid (122 mg, 65%). MS (ESI): 562.2 (M+H)+. 195 012288 d.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulphonyl)-3-oxo-- azepan-4-ylcarbamoyI]-3-methyl-butyl}-amide
To a stirring solution of the compound of Example 151c (122 mg, 0.22 mmol) in » dichloromethane (4 mL) was added Dess-Martin reagent (185 mg, 0.44 mmol). Afterstirring at room température for 2 h, solutions of sodium thiosulfate (2 mL of 10% inwater) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to thesolution. The aqueous layer was extracted with dichloromethane (2x). The organic phaseswere combined, washed with saturated brine, dried (MgSOJ, filtered and concentrated. Theresidue was purified by HPLC to yield the first elutihg diastereomer as a white solid (62.7mg, 51.6 %), MS (ESI): 560.2 (M+H)+ and the second eluting diastereomer as a whitesolid (40.2 mg, 33.1 %). MS (ESI): 560.2 (M+H)+
Example 152
Préparation of 5-Methoxvbenzofuran-2-carboxylic acid-i(S)-l-ri-f3-chIoro- benzenesulphonvD-3-oxo-azepan-4-vlcarbamoyri-3-methvl-butvl}-amide
Following the procedure of Example 151c-d, except substituting 5-methoxÿbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (64.4 mg, 50.3%): MS (ESI): 590.2 (M+H)+ and the secondeluting distereomer as a white solid (44.4 mg, 34.7%): MS (ESI): 590.2 (M+H)+
Example 153
Préparation of 7-Methoxybenzofuran-2-carboxylic acid-f(S)-l-ri-f3-chloro- benzenesulphonvI)-3-oxo-azepan-4-ylcarbamovn-3-methvI-butvI)-amide
Following the procedure of Example 151c-d except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-cafboxylic acid of Example 151cprovided the title compound which was separated by HPLC to give first elutingdiastereomer as a white solid (51.1mg, 39.9%), MS (ESI): 590.2 (M+H)+ and the secondeluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 590.2 (M+H)+ 196 012288
Example 154
Préparation of 5,6-Dimethoxvbenzofuran-2-carboxyIic acid-f(S)-l-ri-(3-chloro- ben2enesulphoDvl)-3-oxo-azepan-4-vlcarbamovn-3-metbvI-butyI)-amide 5 Following the procedure of Example 151c-d except substituting 5,6- dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151cprovided the title compound which was separated by HPLC to give first elutingdiastereomer as a white solid (51.1mg, 39.9%), MS (ESI): 622.2 (M+H)+ and the secondeluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 622.2 (M+H)+ 10 Example 155
Préparation of 3-Methvlbenzofuran-2-carboxvlic acid-ίfS)-l-ri-f3-chIoro- ben2enesulphonvI)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butyl)-amide 15 Following the procedure of Example 15 lc-d except substituting 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 151cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (78.6mg, 63.1%), MS (ESI): 574.2 (M+H)+ and the secondeluting diastereomer as a white solid (40.7mg, 32.6%). MS (ESI): 574.2 (M+H)+ 20 Example 156
Préparation of Benzorblthiophene-2-carboxvlic acid-KS)-l-ri-(3-chloro- ben2enesulphonvI)-3-oxo-azepan-4-ylcarbamovll-3-methvl-butvl ï -amide 25 Following the procedure of Example 15 lc-d except substituting benzo[b)thiophene- 2-carboxylic acid forbenzofuran-2-carboxylic acid in step 151c provided the titlecompound which was separated by HPLC to give the first eluting diastereomer as a whitesolid (41.0 mg, 32.8%), MS (ESI): 576.2 (M+H)+ and the second eluting diastereomer as awhite solid (31.0 mg, 24.8%). MS (ESI): 576.4 (M+H)+ 30 197 012288
Example 157
Préparation of l-Methvl-lH-indole-2-carboxvlic acid-f fSl-l-fl-G-chloro- \ benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovl1-3-methvl-butvl)-amide
Following the procedure of Example 151c-d except substituting l-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 151c provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (28.5mg, 22.9%), MS (ESI): 573.2 (M+H)+ and the second eluting diastereomer as a whitesolid (28.5mg, 22.9%). MS (ESI): 573.2 (M+H)+
Example 158
Préparation of Ouinoxaline-2-carboxylic acid-f fS)-l-ri-(3-chloro-bepzenesulphonyl)-3- oxo-azepan-4-ylcarbamovn-3-methyl-butvl}-amide
Following the procedure of Example 151c-d except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step 151c provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (63.1mg, 50.8%), MS (ESI): 572.2 (M+H)+ and the second eluting distereomer as a white solid(43.2 mg, 34.8%), MS (ESI): 572.2 (M+H)+
Example 159
Préparation of Benzofuran-2-carboxylic acid-f(S)-l-fl-(2-fluoro-benzenesulphonvl)-3-oxo- azepan-4-vlcarbamoyll-3-methvl-butyll-amide a.) {(S)-l-[l-(2-Fïuoro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyI3-3-methyI-butylj-carbamic acid iert-butyl ester
To a solution of the compound of Example 2g (1.03 g, 3.00 mmol) in DCE (20 ml)was added P-NMM (1.65 g, 3.64 mmol/g) and 2-fluorobenzenesulphony Ichloride (0.70 g, 3.60 mmol). After shaking at room température ovemight, the solution was filtered. The 198 012288 fîltrate was concentrated to yield the title compound as white solid (1.13 g, 75.1%): MS: $· 523.88 (M+Na)*. » * b.) (S)-2-Amino-4-methyl-pentanoic acid (l-(2-fluoro-benzenesulfonyl)-3-hydroxy- 5 azepan-4-yl]-amide
To a stirring solution of the compound of Example 159a (1.13 g, 2.25 mmol) inmethnol (15 ml) was added HCl (4M in dioxane) (15 ml). After stirring at roomtempérature for 3 br, the solution was concentrated to get white solid. To a solution of thewhite solid (1.11 g, 2.60 mmol, 75%) in methnol (50 ml) was added P-CO3 (5.70 g, 2.63 10 mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the titlecompound as white solid (0.868g, 2.l6mmol, 96%): MS: 401.96 (M+H)+. c. ) Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-hydroxy- azepan-4-ylcarbamoyl]-3-methyI-butyl} -amide 15 To a solution of the compound of Example 159b (0.11 g, 0.26 mmol) in CH,C1, (10 mL) was added benzofuran-2-carboxylic acid (64.7 mg, 0.39 mmol), 1-hydroxybenzotriazole (61.1g, 0.45 mmol), and P-EDC (0.53 g, 1 mmol/g) in CHLCL, (10mL). After shaking at room température ovemight, the solution was treated with tisamine(0.35 g, 3.75 mmol/g). After shaking for another 2 hr, the solution was filtered and 20 concentrated to yield the title compound as a white solid (103.5 mg, 70%): MS (ESI) t 546.2 (M+H)+. d. ) Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide 25 To a stirring solution of the compound of Example 159c (103.5 mg, 0.19 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (164.7 mg, 0.39 mmol). Afterstirring at room température for 2 h, solutions of sodium thiosulfate (2 mL of 10% inwater) and saîurated aqueous sodium bicarbonate (2 mL) were added simultaneously to thesolution. The aqueous was extracted with dichloromethane (2x). The organic phases were 30 combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. Theresidue was purified by HPLC to yield the first eluting diastereomer as a white solid (76.2mg, 73.6 %): MS (ESI) 544.2 (M+H)+ and the second eluting diastereomer as a whitesolid (20.7mg, 20.0%) MS (ESI) 544.4 (M+H)+ 199 012288
Example 160
Préparation of 5-Methoxvbenzofuran-2-carboxylic acid-ifS)-l-ri-f2-fluoro- benzenesuIphonyl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvI)-amide
Following the procedure of Example 159c-d, except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (48.3 mg, 59.2%) MS (ESI): 574.2 (M+H)+ and the secondeluting diastereomer as a white solid (24.2mg, 29.6%) MS (ESI): 574.2 (M+H)+
Example 161
Préparation of 7-Methoxvbenzofuran-2-carboxvIic acid-f (S)-l-ri-(2-fluoro- benzenesulphonyI)-3-oxo-azepan-4-vlcarbamovll-3-methvI-butvll-amide
Following the procedure of Example 159c-d except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159cprovided the title compound which was separated by HPLC to give the first eluting- diastereomer as a white solid (47.7 mg, 58.5%): MS (ESI) 574.2 (M+H)+ and the secondeluting diastereomer as a white solid (27.7 mg, 33.9%).
Example 162
Préparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acid-f (S)-l-ri-(2-fluoro- benzenesulphonvI)-3-oxo-azepan-4-ylcarbamovl1-3-methvl-butvl 1 -amide
Following the procedure of Example 159c-d except substituting 5,6- dimethoxybenzofiiran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MS (ESI) 606.4 (M+H)+ and the second eluting diastereomer as a white solid MS(ESI) 606.4 (M+H). 200 012288
Example 163 * « Préparation of 3-MetbvIbenzofuran-2-carboxvlic acid-KS')-l-ri-(2-fluoro- benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butyI}-amide 5
Following the procedure of Example 159c-d except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 160cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (50.5 mg, 63.7%): MS (ESI) 558.2 and the second elutinfg 10 diastereoemer as a white solid (20.6 mg); MS 558.2 (M+H)+.
Example 164
Préparation of Benzorblthiophene-2-carboxvlic acid-{fS)-l-ri-(2-fluoro- 15 benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butyIl-amide
Following the procedure of Example 159c-d except substituting benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the titlecompound which was separated by HPLC to give the first eluting diastereomer as a white 20 solid (52.5 mg, 65.9%): MS (ESI) 560.2 (M+H)+ and the second eluting diastereomer as awhite solid (20.7mg, 26.0%); MS(ESI) 560.2 (M+H)*.
Example 165 25 Préparation of l-Methvl-lH-indole-2-carboxylic acid-( (S)-l~ri-(2-fluoro- benzenesulphopyl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butvl)-amide
Following the procedure of Example 159c-d except substituting l-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compound 30 which was separated by HPLC to give the first eluting diastereomer as a white solid (51.4mg, 64.9%): MS (ESI) 557.2 (M+H)+ and the seond eluting diastereoemer as a white solid(21.0 mg, 26.5%); MS 557.2 (M+H)*. 201 012288
Example 166
Préparation of (S)-4-Methvl-2-(l-oxy-pvridine-2-suIfonvlamino)-pentanoic acid i3-oxo-l- (pyridine-2-sulfonyI)-azepan-4-yl'|-amide a. ) (S)-4-MethyI-2-(l-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l- (pyridine-2-sulfonyl)-azepan-4-yl]-amide
To a solution of the compound of Example 28a (0.1 g) in dichlorormethane (10mL) and saturated NaHCO3 was added 2-pryridinesulfonyl chloride N-oxide (0.9 mL) in adropwise fashion over 3 minutes. The reaction was stirred at room température for 30minutes. Workup and columnn chromatography provided 9.2 mg of the title compound:MS (ESI) 541 (Μ+ΚΓ). b. ) (S)-4-Methyl-2-(l-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substituting the compound ofExample 166a the title compound was prepared: MS (ESI) 539 (Μ+ΕΓ).
Example 167
Préparation of Ouinoxaline-2-carboxylic acid-{ (S>l-ri-f2-fluoro-benzenesulphonvl)-3-oxo- azepan-4-yIcarbamoyH-3-methyl-butvl ) -amide
Following the procedure of Example 159c-d except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step 159c provided the title compoundwhich was purified by HPLC to give the first eluting diastereomer as a white solid (49.7mg, 62.9%): MS (ESI) 556.2 (M+H)+ and the second eluting diastereomer as a white solid(19.9 mg, 25.1%): MS 556.4 (M+H)+.
Example 168
Préparation of 5-Methoxvbepzofuran-2-carboxvIic acid-l(S)-3-methvl-l-i3-oxo-l- ( thiophene-2-suIfon vB-azepan-4-vlcarbamovIl-butvn-amide
Following the procedure of Example 75a-d except substituting 2-thiophensulfonyl chloride for 2-thiazolesupfonyl chloride of Example 75a and 5-methoxybenzofuran-2- 202 012288
tP çarboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compoundwhich was purified by HPLC to give the first eluting diastereomer as a white solid (71 mg,65%); MS (ESI) 562.2 (M+H)+ and the second eluting diastereomer as a white solid (21.6mg, 20.0%) MS (ESI): 562.2 (M+H)+. 5
Example 169
Préparation of 7-Methoxybenzofurap-2-carboxylic acid-ίfS)-3-methvl-l-r3-oxo-l- (thiophene-2-snlfonyl)-azepan-4-ylcarbamovll-butvl)-amide 10 Following the procedure of Example 168 except substituting 7- methoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acidprovided the title compound winch ws purified by HPLC to give the first elutingdiastereomer as a white solid (88 mg, 80%); MS (ESI) 562.2 (M+H)+ and the secondeluting diastereomer as a white solid (18 mg, 16%) MS (ESI): 562.2 (M+H)+. 15 '
Example 170
Préparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acid-{(S)-3-methvl-l-F3-oxo-l- (thiophene-2-sulfonvI)-azet>an-4-vIcarbamoyn-butvl)-amide 20 Following the procedure of Example 168 except substituting 5,6- dimethoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acidprovided the title compound which was purified by HPLC to give the first elutingdiastereomer MS (ESI) 594.2 (M+H)+ and the second eluting diastereomer. 25 Example 171
Préparation of 3-Methvlbenzofaran-2-carboxylic acid-{ (S)-3-methyl-l-i3-oxo-l-(thiophene- 2-sulfonyl)-azepan-4-vlcarbamoyH-butvl)-amide
Following the procedure of Example 168 except substituting 3-methybenzofuran-2- 30 carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compoundwhich was purified by HPLC to give the first eluting diastereomer as a white solid (88 mg,83%): MS (ESI) 546.2 (M+H)+ and the second eluting diastereomer as a white solid (16mg, 15%): MS (ESI) 546.2 (M+H)+. 203 012288
Example 172
Préparation of Benzoiblthiophene-2-carboxvlic acid-f fS)-3-methyl-l-f3-oxo-l-fthiophehê> 2-sulfonyI)-azepan-4-vlcarbamovH-butvl)-amide
Following the procedure of Example 168 except substituting benzo[b]thiophene-2-carboxylic acid 5-methoxybenzofuran-2-carboxylic acid provided the title compound whichwas purified by HPLC to give the first eluting diastereomer as a white solid (43.4 mg, 41%): MS (ESI) 548.4 (M+H)+ and the second eluting diastereomer as a white solid (33.4mg, 31.5%): MS (ESI) 548.2 (M+H)+.
Example 173
Préparation of l-Methvl-lH-indole-2-carboxylic acid-f (S)-3-methyl-l-f3-oxo-l-(thiophene- 2-sulfonvl)-azepan-4-vlcarbamovl]-butvl}-amide
Following the procedure of Example 168 except substituting l-methylindole-2-carboxylic acid fo: 5-methoxybenzofuran-2-carboxylic acid provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (35.8mg, 34.0%): MS (ESI) 545.2 (M+H)+ and the second eluting diastereomer as a white solid(45.8 mg, 43%): MS (ESI) 545.2 (M+H)+.
Example 174
Préparation of Quinoxaline-2-carboxvlic acid-f fS)-3-methvl-l-r3-oxo-l-(thiophene-2- sulfonyl)-azepan-4-vlcarbamovn-butvl)-amide
Following the procedure of Example 168 except substituting quinoxaline-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (60mg, 56%): MS (ESI) 544.4 (M+H)+ and the second eluting diastereomer as a white solid(38.7 mg, 37%): MS (ESI) 544.4 (M+H)+. 204 012288
Example 175
Préparation of Benzofuran-2-carboxvlic acid-{ (S)-l-Fl-(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamovll-3-methvl-butvl 1 -amide 5 a. ) {(S)-l-[l-(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl- butylj-carbamic acid ieri-butyl ester
To a solution of the compound of Example 2g (2.50 g, 7.29mmol) in DCE (100 ml)was added P-NMM (4.0g) and 4-chlorobenzenesulphonyl chloride (1.85g, 8.75mmol). 10 After shaking at room température for over night, the solution was filtered. The filtrate wasconcentrated to yield the title compound as white solid (3.13g, 83.3%). MS: 539.78(M+Na)*. b. ) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-chloro-benzenesulfonyl)-3-hydroxy- 15 azepan-4-yl]-amide
To a stirring solution of the compound of example 175a (1.0 g, 1.93mmol) inmethnol (10 ml) was added HCl (4M in dioxane) (10 ml). After stirring at roomtempérature for 3 hr, the solution was concentrated to provide a white solid. To a solutionof the white solid (0.68 g, 150 mmol, 78%) in methnol (37 ml) was added P-CO3 (2.85 g, 20 2.63 mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.59 g, 1.42 mmol, 95%): MS: 417.86 (M+H)+. c. ) Benzofuran-2-carboxylic acid-{ (S)-l-[l-(4-chloro-benzenesulphonyl)-3-hydroxy- azepan-4-ylcarbamoyll-3-methyl-butyl} -amide 25 To a solution of the compound of Example 175b (0.14 g, 0.335 mmol) in CHjClj (20 mL) was added benzofuran-2-carboxylic acid (0.81,0.50 mmol), 1-hydroxybenzotriazole (0.77g, 0.569mmol), and P-EDC (0.67g, lmmol/g) in CRjCLj (10mL). After shaking at room température ovemight, the solution was treated with tisa-mine(0.446 g, 3.75 mmol/g). After shaking for another 2 hr, the solution was filtered and 30 concentrated to yield the title compound as a white solid (122.2 mg, 65%). MS (ESI): 562.2 (M+H)+. 205 012288 d.) Benzofuran-2-carboxylic acid-{ (S)-l-[l-(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methy 1-butyl} -amide
To a stirring solution of the compound of Example 175c (122.2mg, 0.217mmol) indichloromethane (4 mL) was added Dess-Martin reagent (184.8mg, 0.436mmol). After 5 stixring at room température for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simuîtaneously to thesolution. The aqueous was extracted with dichloromethane (2x). The organic phases werecombined, washed with saturated brine, dried (MgSOJ, filtered and concentrated. Theresidue was purified by HPLC to yield the fïrst eluting diastereomer as a white solid 10 (62.7mg, 51.6 %): MS (ESI) 560.2 (M+H)+ and the second elution as a white solid (32.7mg, 26.9 %): MS (ESI) 560.2 (M+H)+.
Example 176 15 · Préparation of 5-Methoxvbenzofnran-2-carboxylic acid-ί (S)-l-H-(4-chloro- benzenesulphonvI)-3-oxo-azepan-4-vlcarbamoyn-3-methvI-butyl)-amide
Following the procedure of Example 175c-d except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175 c 20 provided the title compound which was separated by HPLC to give the fïrst eluting diastereomer as a white solid (64.4 mg, 50%): MS (ESI) 590.2 (M+H)+ and the secondeluting diastereoemer as a white solid (32.2 mg, 25.2%): MS (ESI) 590.0 (M+H)+.
Example 177 25
Préparation of 7-Methoxvbenzofuran-2-carboxvlic acid-((S)-l-IT-(4-chloro- benzenesuIphonvî')-3-oxo-azepan-4-vlcarbamovI'i-3-meÎhvl-butvl)-amide
Following the procedure of Example 175c-d except substituting 7- 30 methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175cprovided the title compound which was separated by HPLC to give the fïrst elutingdiastereomer as a white solid (51.1 mg, 40%): MS (ESI) 590.2 (M+H)+ and the secondeluting diastereoemer as a white solid (41 mg, 32%) : MS (ESI) 590.2 (M+H)+. 206 012288
Example 178
Préparation of 5.6-Dimethoxvbenzofuran-2-carboxvlic acid-((S)-l-ri-(4-chIoro- benzenesulphonvl)-3-oxo-azepan-4~ylcarbamovn-3-methvl-butvl)-amide
Following the procedure of Example 175c-d except substituting 5,6-dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer: MS (ESI) 622.2 (M+H)+ and the second eluting diastereoemer: MS (ESI) 622.2 (M+H)+.
Example 179
Préparation of 3-Methvlbenzofuran-2-carboxylic acid-i(S)-l-ri-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-vlcarbamovri-3-methyI-butyl}-amide
Following the procedure of Example 175c-d except substituting 3-methylbenzofuran-2-carboxylic acid forbenzofuran-2-carboxylic acid in step 175cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (78.6 mg, 63%): MS (ESI) 574.2 (M+H)+ and the secondeluting diastereoemer as a white solid (27.6 mg, 22%): MS (ESI) 574.2 (M+H)+.
Example 180
Préparation of Benzorblthiophene-2-cari)oxvlic acid-((S)-l-il-f4-chloro- bepzenesulphonvD-3-oxo-azepap-4-vlcarbamovll-3-methyl-butvl)-amide
Following the procedure of Example 175c-d except substituting benzo[b]thiophene2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the titlecompound which was separated by HPLC to give the first eluting diastereomer as a whitesolid (41 mg, 33%): MS (ESI) 5762 (M+H)+ and the second eluting diastereoemer as awhite solid (32.6 mg, 26%); MS (ESI) 576.2 (M+H)+. 207 012288
Example 181
Préparation of l-MethvI-lH-indole-2-carboxvlic acid-f(S)-l-il-f4-chloro- benzenesulphonvlV3-oxo-azepan-4-vlcarbamovll-3-methyl-butvli-araide
Following the procedure of Example 175c-d except substituting l-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (2S.5mg, 23%): MS (ESI) 573.2 (M+H)+and the second eluting diastereoemer as a white solid(38.5 mg, 31%): MS (ESI) 573.2 (M+H)+.
Example 182
Préparation of Quinoxaline-2-carboxvlic acid-{(S)-l-ri-(4-chloro-benzenesulphonvl)-3- oxo-azepan-4-vlcarbamovl)-3-methvl-butyl)-amide
Following the procedure of Example 175c-d except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (63mg, 51%): MS (ESI) 572.2 (M+H)+ and the second eluting diastereoemer as a white solid(44.5 mg, 36%): MS (ESI) 572.2 (M+H)+.
Example 183
Préparation of Benzofuran-2-carboxvlic acid-{(S)-l-ri-(3-methoxv-benzenesulphonvl)-3- oxo-azepan-4-vIcafbamovll-3-methvI-butyI ) -amide a.) {(S)-l-[l-(3-Methoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butylj-carbamic acid rm-butyl ester
To a solution of the compound of Example 2g (1.60g, 4.66mmoî) in DCE (50ml)was added P-NMM (2.56g, 3.64mmol/g ) and 3-methoxy-benzenesulphonyl chloride(1.15g, 5.59mmol). After shaking at room température for over night, the solution was 208 012283 filtered. The filtrats was concentrated to yield the title compound as white solid (1.70g,71.1%): MS 535.8 (M+Na)+. b. ) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-methoxy-benzenesulfonyl)-3-hydroxy- azepan-4-yl]-amide
To a stirring solution of the compound of example 183a (1.70 g, 3.3Immol) inmethnol (22 ml) was added HCl (4M in dioxane) (22 ml). After stirring at roomtempérature for 3 hr, the solution was concentrated to get white solid. To a solution of thewhite solid (1.19 g, 2.64 mmol, 80%) in methnol (50 ml) was added P-CO3 (5.02 g, 2.63mmol/g). After shaking for 2 hr the solution was filtered and concentrated to yield the titlecompound as white solid (1.03 g, 2.49 mmol, 96%): MS 413.90 (M+H)+. c. ) Benzofuran-2-carboxylic acid-{ (S)-l-[l-(3-methoxy-benzenesulphonyl)-3- hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
To a solution of tbe compound of Example 183b (0.11 g, 0.26 mmol) in 01,0, (10mL) was added benzofuran-2-carboxylic acid (64.69mg, 0.399 mmol), 1-hydroxybenzotriazole (61.1g, 0.452mmol), and P-EDC (0.532g, Immol/g) in CE^Clj (10mL) . After shaking at room température for over night, the solution was treated withtisamine (0.355g, 3.75mmol/g). After shaking for another 2hr, the solution was filtered andconcentrated to yield the title compound as a white solid (103.5 mg, 70%): MS (ESI) 558.2(M+H)+. d. ) Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
To a stirring solution of the compound of Example 183c (103 mg, 0.19 mmol) indichloromethane (4 mL) was added Dess-Martin reagent (157 mg, 0.37 mmol). Afterstirring at room température for 2 h, solutions of sodium thiosulfate (2 mL of 10% inwater) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to thesolution. The aqueous was extracted with dichloromethane (2x). The organic phases werecombined, washed with saturated brine, dried (MgSOJ, filtered and concentrated. Theresidue was purified by HPLC to yield the first eluting diastereomer as a white solid (76.2mg, 73.6 %): MS (ESI: 556.2 (M+H)+ and the second eluting diastereomer as a whitesolid (24.1 mg, 23.3 %): MS (ESI) 556.2 (M+H)+ 209 012288
Example 184
Préparation of 5-Methoxybenzofuran-2-carboxylic acid-{(S)-l-ri-(3-methoxv- benzenesulphonvl)-3-oxo-azepan-4-ylcarbamoyn-3-methvl-butvï}-amide
Following the procedure of Example 183c-d except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (33 mg, 31%): MS (ESI) 586.2 (M+H)+ and the secondeluting diastereoemer as a white solid (35.2 mg, 32%): MS (ESI) 586.2 (M+H)+.
Example 185
Préparation of 7-Methoxybenzofuran-2-carboxvlic acid-((S)-l-il-(3-methoxv- bepzepesulphonvl)-3-oxo-azepap-4-ylcarbamovll-3-methvl-butvl)-amide
Following the procedure of Example 183c-d except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (41 mg, 38%): MS (ESI) 586.4 (M+H)+ and the secondeluting diastereoemer as a white solid (39.5 mg, 36%): MS (ESI) 586.2 (M+H)+.
Example 186
Préparation of 4.5-Dimethoxybenzofuran-2-carboxylic acid-j fS)-l-ri-(3-methoxv- benzenesulphonvl)-3-oxo-azepan-4-vlcarbamovll-3-meth vl-butvl ) -amide
Following the procedure of Example 183c-d except substituting 5,6-dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer: MS (ESI) 618.4 (M+H)+ and the second eluting diastereoemer. . 210 012288
Example 187
Préparation of 3-Methvlbenzofuran-2-cafboxylic acid-ί (S)-l-il-(3-metfaoxv- benzenesulphonvl)-3-oxo-azepan-4-vlcarbamoyl]-3-methvl-butylï-amide 5
Following the procedure of Example 183c-d except substituting 3-methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183cprovided the title compound which was separated by HPLC to give the first elutingdiastereomer as a white solid (76 mg, 72%): MS (ESI) 570.2 (M+H)+ and the second 10 eluting diastereoemer as a white solid (23.2 mg, 22%): MS (ESI) 570.2 (M+H)+.
Example 188
Préparation of BenzoFblthiophene-2-carboxvlic acid-{(S)-î-fl-(3-methoxy- 15 benzeoesulphonyl)-3-oxo-azepan-4-vlcarbamovIl-3-methvl-butyll-amide
Following the procedure of Example 183c-d except substituting benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the titlecompound which was separated by HPLC to give the first eluting diastereomer as a white 20 solid (37 mg, 35%): MS (ESI) 572.2 (M+H)+and the second eluting diastereoemer as awhite solid (31 mg, 29%); MS (ESI) 572.2 (M+H)+.
Example 189 25 Préparation of l-Methvl-lH-indole-2-cafboxylic acid-KSl-l-ri-fë-methoxv- benzepesulphonvl)-3-oxo-azepap-4-vlcafbamovI]-3-methvl-butvl)-amide
Following the procedure of Example 183c-d except substituting l-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound 30 which was separated by HPLC to give the first eluting diastereomer as a white solid (34mg, 32%): MS (ESI) 569.2 (M+H)+ and the second eluting diastereoemer as a white solid(38 mg, 38%): MS (ESI) 569.4 (M+H)+. 211 012288
Example 190
Préparation of Ouinoxaline-1(S)-l-Fl-(3-methoxv-benzenesulphonvl)-3-oxo-azepan-4- ylcarbamovlI-3-methvl-butvl ) -amide
Following the procedure of Example 183c-d except substituting quinoxaIine-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compoundwhich was separated by HPLC to give the first eluting diastereomer as a white solid (71mg, 67%): MS (ESI) 568.2 (M+H)+ and the second eluting diastereoemer as a white solid(27 mg, 24%); MS (ESI) 568.2 (M+H)+. '
Example 191
Préparation of Benzofuran-2-carboxvlic acid-{(S)-3-methyl-l-r3-oxo-l-(thiophene-2- sulfonvD-azepan-4-vlcarbamov'P-butvI ) -amide
Following the procedure of Example 168 except substituting benzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compoundwhich ws purified by HPLC to give the first eluting diastereomer as a white solid (76 mg,73%): MS (ESI) 532.2 (M+H)+ and the second eluting diastereomer as a white solid (25mg, 23%) MS (ESI): 532.2 (M+H)+
Example 192
Préparation of Benzofuran-2-carboxylic acid {(S>-3-methvl-l-i(2.2’.4-trideuterio)-3-oxo-l- (pvridine-2-sulfonyl)-azepan-4-vlcarbamovll-butyl ) amide
To a solution of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcaibamoyl]-butyl} amide of Example 28c (0.03 g) in DjO:CD3OD(0.4:4 mL) was added triethylamine (0.04 mL). The reaction was heated to reflux for 2hours whereupon it was concentrated and dried under vacuum. The residue was theredissolved in the same mixture and heated to reflux ovemight. The reaction wasconcentrated and the residue purified by column chromatography (5% methanobdichloromethane) to provide the title compound (0.02 g): ‘HNMR: δ 1.0 (m, 6H), 212 012288 1.5-2.2 (m, 6H), 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 7.4-8.0 (m, 8H), 8.7 (m, 1H);MS(ET): 529 (M*, 45%).
The diastereomeric mixture was separated by HPLC to provide the faster elutingdiastereoemer: MS(E3): 530 (M+lT,100%) and the slower eluting diastereomer: MS(ET):530 (M+H*,100%).
Example 193
Préparation of Benzofuran-2-carboxvIic acid ((S)-2-methvl-l-r3-oxo-l-(pvridine-2- suIfonyI)-azepan-4-vlcarbamoyil-butyl)-amide a. ) 4-tezi~Butoxycarbonylamino-3-hydroxy-azepane- 1-carboxylicacïd benzyl ester
To a stirring solution of compound of Example 2e (1.04 g, 3.92mmol) in THF wasadded di-ierr-butyldicarbonate (0.864 g). After stining at room température for 30 minutes,the reaction mixture was diluted with diethylether and extracted with saturated NaHCO.The organic layer was dried over anhydrous Na2SO4, fîltered, concentrated, and purifîed bysilica gel column to give the title compound as a yellow oil (0.963 g, 2.64 mmol, 67%). MS(ESI): 365.03 (M+H)+. b. ) (3-Hydroxy-azepan-4-yl)-carbamic acid terî-butyl ester
To a solution of compound of Example 193a (0.963g, 2.64mmol) in ethyl acetate(16 ml) was added 10% palladium on carbon (500 mg). After stirring the solution at roomtempérature for 48 hours, the mixture was filtered through celite. The fîlterate wasconcentrated to yield the title compound ( 0.529 g, 2.29mmol, 87%): MS(ESI): 231.92(M+H)+. c. ) [3-Hydroxy-l-(pyridine-2-sulfonyI)-azepan-4-yl]-carbamic acid rcrr-butyl ester
To a solution of the compound of Example 193b (0.53,2.29 mmol) indichloromethane (20 ml) was added triethylamine (232 mg) and pyridine-2-sulfonylchloride (410 mg, 2.32 mmol). After stirring at room température for 30 minutes, themixture was washed with saturated NaHCO3 The. organic layer was dried, fîltered,concentrated and purifîed on a silica gel column to give the title compound as a solid (0.58g, 1.57 mmol, 68%): MSQ2ST): 372.95 (M+H)+. 213 012288 d. ) 4-Amino-1 -(pryidine-2-sulfonyl)-azepan-3-ol
To a stirring solution of the compound of Example 193c (0.583 g, 1.57mmol) inethyl acetate (0.5 ml) was added HCl (4M in dioxane, 3.9 ml). After stiiring the reactionmixture for 30 minutes at room température, the mixture was concentrated to yield a whitesolid. The solid was treated with NaOH and then extracted with ethylacetate. The organiclayer was dried, filtered, and concentrated to yield a yellow solid (0.35 g, 1.28 mmol, 81%):MS (ESI) 272.93 (M+H)+. e. ) {(S)-1 -[3-Hydroxy-l-(pryidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-meth-butyl}- carbamic acid ieri-butyl ester
To a solution of the compound of example 193d (19 mg, 0.070 mmol) in CH,C12was added N-Boc-isoleucine (24.5 mg, 0.10 mmol), 1-hydroxybenzotriazole (16.1 mg, 0.12mmol), and P-EDC (140 mg, 0.14 mmol ) in CH^Clj . After shaking at room températureovemight, the mixture was treated with PS-Trisamine. After shaking for another 2 hours,the mixture was filtered and concentrated to yield the title compound as a solid. MS (ESI)484.97 (M+H)+. f. ) (S)-2-Amino-3-methyl-penatanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan- 4-y]]-amide
To a stirring solution of the compound of example 193e (34 mg, 0.07 mmol) inCH.CL, (0.50 ml) was added HCl (4M in dioxane) (0.165 ml). After stirring at roomtempérature for 30 minutes, the mixture was concentrated, giving a white solid. The whitesolid was azeotroped with toluene then treated with MP-carbonate (0.35 mmol) inmethanol. After four hours of shaking, the mixture was filtered and concentrated to give thetitle compound as a solid.: MS(ESI) 384.9 (M+H)+. g. ) Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
To a solution of the compound of example 193f (27 mg, 0.070 mmol) in CH, CL,was added 2-benzofurancarboxyEc acid (17.0 mg, 0.106mmol), 1-hydroxybenzotriazole(16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in CHjClj . After shaking atroom température ovemight, the mixture was treated with PS-Trisamine. After shaking for 214 012288 another 2 hours, the mixture was filtered and concentrated to yield the title compound as a solid: MS (ESI) 52S.9 (M+H)+. h.) Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-butyl }-amide
To a stining solution of the compound of example 193g (37 mg, 0.07 mmol) inCHjClj (0.5 ml) was added Dess-Martin reagent (45 mg, 0.105 mmol). After stirring for 30minutes, solutions of sodium thiosulfate (10% in water, 0.50 ml) and satiirated aqueoussodium bicarbonate (0.50 ml) were added simultaneously to the reaction. The mixture wasthen extracted with dichloromethane (2 times). The organic layer was dried, filtered, andconcentrated. The residue was purified by HPLC to yield the two diastereomers of the titlecompound as solids (first eluting: 7mg, second eluting: 5.5 mg): MS (ESI) 526.91(M+H)+.
Example 194
Préparation of Benzofuran-2-carboxvlic acid l(S)-l-i3-oxo-l-(pyridine-2-suïfonv])-azepan- 4-vlcarbamoyn-propvl ) -amide
Following the procedure of Example 193e-h, except substituting N-Boc-alpha-aminobutyric acid in step 193e the title compound was purified to yield two diastereomersas solids (first eluting: 5 mg, second eluting: 5 mg) MS(ESI) 543.S (M+H)+.
Example 195
Préparation of Benzofuran-2-carboxvlic acid {(S)-2-cyclohexyl-l-r3-oxo-l-(pyridine-2- sulfonvl)-azepan-4-vlcarbamoyll-ethvl)-amide
Following the procedure of Example 193e-h, except substituting N-Boc-cyclohexylalanine in step 193e, the title compound was purified to yield two diastereomersas solids (first eluting: 4.5 mg second eluting: 4.5 mg): MS(ESI): 566.S7 (M+H)+. 215 012288
Example 196
Préparation of Benzofuran-2-carboxylic acid {(S)-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamoyn-etbvl l-amide
Following the procedure of Example 193e-h, except substituting N-Boc-alanine forstep 193e, the title compound was purified to yield two diastereomers as solids (firsteluting: 5.5 mg, second eluting: 5 mg).
Example 197
Préparation of Benzofuran-2-carboxvlic acid {(S)-3-methanesulfinvl-l-r3-oxo-l-(pyridipe- 2-sulfonvl)-a2epan-4-ylcarbamoyll-propvl ) -amide
Following the procedure of Example 193e-h, except substituting N-Boc-L-methionine for step l(f), the title compound was purified to yield two diastereomers assolids (first eluting: 3 mg, second eluting: 3 mg). MS(ESI): 560.7 (M+H)*.
Example 198
Préparation of Benzofuran-2-carboxylic acid {r3-oxo-l-(pyridine-2-sulfonvl)-azepan-4- vlcarbamoyll-methvD-amide
Following the procedure of Example 193e-h, except substituting N-Boc-glycinefor step 193e, the title compound was purified to yield two diastereomers as solids (firsteluting: 3mg,second eluting: 3 mg). MS(ESI): 470.81 (M+H)*. 216 012288
Example 199
Préparation of Benzofuran-2-carboxvlic acid ((S)-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepan- 4-vlcarbamovïl-pentvl ) -amide
Following the procedure of Example 193e-h, except substituting N-Boc-norleucinefor step 193e, the title compound was purified to yield two diastereomers as solids (firsteluting: 4 mg, second eluting: 5 mg). MSÇESI): 526.85 (M+H)+.
Example 200
Préparation of Benzofuran-2-carboxvIic acid {(S)-l-r3-oxo-l-(pvridine-2-sulfonvl)-azepap- 4-vlcarbamovn-butyl l-amide
Following the procedure of Example 193e-h, except substituting N-Boc-norvalinefor step 193e, the title compound was purified to yield two diastereomers as solids (firsteluting: 7.5 mg, second eluting: 3.5 mg). MSÇESI): 512.8 (M+H)+.
Example 201
Préparation of Benzofuran-2-carboxvlic acid {(Sl-2-methvl-l-i3-oxo-l-(pvridine-2- sulfonvl)-azepan-4-vIcarbamovll-propvl)-amide
Following the procedure of Example 193e-h, except substituting N-Boc-valine forstep 193e, the title compound was purified to yield two diastereomers as solids (firsteluting: 6 mg, second eluting: 45 mg). MSÇESI): 512.8 (M+H)*. 217 012288
Example 202
Préparation of Benzofuran-2-carboxvlic acid {(Sl-2-hvdroxy-î-i3-oxo-l-(pvridine-2- sulfonyiyazepan-4-vlcarbamoyIl-propvl ) -aroide
Following the procedure of Example 193e-h, except substituting N-Boc-L-threonine for step 193e, the title compound was purified to yield two diastereomers assolids (first elutmg: 3 mg, second eluting: 3 mg).
Example 203
Préparation of Benzofuran-2-carboxvlic acid ((S)-l-r3-oxo-l-(pvridine-2-sulfonyl)-azepan- 4-ylcarbamovn-2-phenvI-ethvl ) -amide
Following the procedure of Example 193e-h, except substituting N-Boc-phenylalanine for step 193e, the title compound was purified to yield two diastereomers assolids (first eluting:5mg, second eluting: 5mg). MS(ESI): 560.8 (M+H)+.
Example 204
Préparation of lfBenzofuran-2-carbonvD-pyrrolidme-2-carboxvlic acid r3-oxo-l-fpvridine- 2-sulfonyl)-azepan-4-yn-amide
Following the procedure of Example 193e-h, except substituting N-Boc-L-prolinefor step 193e, the title compound was purified to yield two diastereomers as solids (firsteluting: 4 mg, second eluting: 5mg). MSÇESI): (M+H)+.
Example 205
Préparation of 3,4-Dimethoxv-N- ((S)-l-( l-(4-imethoxy-benzenesulfonyl)-3-oxo-azepan-4- vIcarbamoyn-3-methyl-butvl }-benzamide
Following the procedure of Example 115, except substituting 3,4- dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. 218 012288
The residue was purified by HPLC. First eluting diastereomer: MS 576.4(M+H+)Jh NMR (500 MHz,CDCl3): δ 7.68 (d, 2H),7.00 (d,lH), 6.89 (s, 2H),3.84 (s, 3H),3.77 (s, 6H), 2.38 (t,lH), 0.94 (d, 6H): MS 576.4 (M+H+). 5 Example 206
Préparation of Benzorblthiophene-2-carboxvlic acid-{(S)-l-i l-(4-imethoxv- benzenesulfonyl)-3-oxo-azepan^4-vlcarbamoyn-3-methvl-butyI}-armde 10 Following the procedure of Example 115, except substituting 2-thiophene-carbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer: MS 572.2 (M+H+VHNMR (500MHz,CDC13): δ 7.80-7.68 (m, 5H), 7.38-7.34 (m, 2H), 7.01-6.93 (m, 4H), 3.83 (s, 3H), 2.38 (t, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 572.2 (M+H+). 15
Example 207
Préparation of Benzori.31dioxole-5-carboxylic acid {(S)-l-ri-(4-fluoro-benzenesulfonvI'>-3- oxo-azepap-4-ylcarbamovn-3methvl-butvl}-amide 20
Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4-methylenedioxybenzoyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purified by HPLC. First eluting diastereomer; MS 548.2 25 (M+H+); XH NMR (400Hz,CDCl3): δ 7.85-7.78 (m, 2H), 7.38-7.20 (m, 4H), 7.05 (d, 1H), 2.52-2.40 (m,lH), 1.0 (d, 6H). Second eluting diastereomer: MS 548.2 (M+H+). 219 θ’2288
Example 208
Préparation of (S)-2-(2-Benzvloxy-acetylamino)-4-methyi-pentanoic acidri-(4-fluoro- benzenesulfonvl)-3-oxo-azepan-4-vn-amide
Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the titlecompound was prepared. The residue was purifîed by HPLC. First eluting diastereomer:MS 548.2 (M+H+)JH NMR (400Hz,CDC13-CD3OD) δ 7.88-7.80 (m, 2H), 7.45-7.30 (m,5H), 7.30-7.20 (m, 2H), 4.00 (s, 2H), 2.60-2.48 (m,lH), 0.96 (t, 6H): MS 548.2 (M+H+).
Example 209
Préparation of Benzoiblthiophene-2-carboxylic acid-l(S)-l-F l-(4-fluoro-ben2enesulfonyl)- 3-oxo-azepan-4-yI carbamovll-3-methvl-butyl 1 -aroide
Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride andbenzo[b]tbiophenecarbonyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purifîed by HPLC. First eluting diastereomer: MS 560.2(Μ+Η+)ΛΗ NMR (500 MHz,CDC13): δ 7.80-7.72 (m, 5H).7.37-7.34 (m, 2H), 7.33-7.15(m, 4H), 2.43 (t, 1H), 0.96 (d, 6H). Second eluting diastereomer: MS 560.2 (M+H+).
Ex ample 210
Préparation of Benzofuran-2-carboxvlic acid {('S)-l-ri-benzoyl-3-oxo-azepan-4- vIcarbamoylI-3-methyl-butvI }-amide a.) Benzofuran-2-carboxyîic acid {(S)-l-[l-benzoyl-3-bydroxy-azepan-4-ylcarbamoyl]- 3-methyl—butyl}-amide
To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.2 g) in dichloromethane was addedbenzoic acid (0.12 g), HOBt (0.07 g) and EDC (0.99 g). The reaction was stirred until 220 012288 complété. Workup and column chromatography (5% methanol:dichloromethane) provided the titie compound (02 g): lH NMR (CDC^): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.8 (m,lH), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.0-7.7 (m, 10H), 8.7 (m, 1H); MS(EI): 492 (M+H\ 100%). b.) Benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide
Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-hydroxy-azepan-4-ylcaibamoyl]-3-methyl-butyl}-amide of Example 210a the titie compound was prepared: ’H NMR (CDC13): δ 1.0 (m, 6H),1 -5-2.2 (m, 6H), 2.7 (m, 1H), 3.7 (m,lH), 4.0 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.4-8.0 (m,8H); MS(EI): 490 (M+FT, 100%).
Example 211
Préparation of fSV-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid f3-oxo-l- (pyriàine-2-sulfonyl)-azepan-4-vp-amide a. ) (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-hydroxy-l- (pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 89a except substituting 8-quinolinesulfonylchloride for 2-pyridinesulfonyl chloride the titie compound was prepared: MS(EI) 576(M+H+). b. ) (S)-4-Methyl-2-(quinolihe-8-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substituting (S)-4-methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3-hydroxy- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 211a the titie compound was prepared: 'H NMR (CDC13): δ 0.5-0.8(m, 6H), 1.4-1.8 (m, 7H), 2.5 (m, 1H), 3.5-3.9 (m, 3H), 4.4 (m, 1H), 4.6 (m, 1H), 5.5 (m,1H), 6.7 -7.0 (m, 2H), 7.5 (m, 3H), 8.0 (m, 2H), 8.3 (m, 2H), 8.6 (m, 1H), 9.0 (m, 1H);MS(EI): 674 (M+H\ 100%). 221
ο)22SS
Example 212
Préparation of (S)-4-Methvl-2-(naphthylene-2-sulfonvlamino)-pentanoic acid (3-oxo-l- fpvridine-2-sulfonvl)-azepan-4-yll-amide a. ) (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-hydroxy-l- (pyridine-2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 89a except substituting 2-naphthylenesulfonylchloride for 2-pyridinesulfonyl chloride the title compound was prepared: MS(EI) 575(M+H+). b. ) (S)-4-Methyl-2-(naphthylene-2-sulfonylammo)-pentanoic acid [3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example li except substituting (S)-4-methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan- 4-yl]-amide of Example 212a the title compound was prepared: ’H NMR (CDC13): δ 0.5-0.8 (m, 6H). 1.4-1.8 (m, 7H), 2.5 (m, 1H), 3.5-3.9 (m, 3H), 4.5 (m, 1H), 4.6 (m, 1H), 5.5(m, 1H), 6.7 (m, 1H), 7.5-8.0 (m, 9H), 8.5-8.6 (m, 2H); MS(EI): 673 (M+H\ 100%).
Example 213
Préparation of Benzofuran-2-carboxvlic acid-{fS)-l-r l-(4-fluoro-benzenesulfonyD-3-oxo- azepan-4-yl carbamovn-3-methvl-butvl }-amide
Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 2-benzofurancarbonyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purified by HPLC. First eluting diastereomer: MS544.2.(M+H+).1HNMR (500MHz,CDC13): δ 7.79-7.77 (m, 2H), 7.61 (d, 1H), 7.46-7.38(m, 3H), 7.25-7.06 (m, 5H), 2.43 (t, 1H), 0.95 (d, 6H). Second eluting diastereomer: MS544.4 (M+H+). 222
Example 214
Préparation of N~f (SV l-il-(4-Fhioro-benzenesulfonyr)-3-oxo-azepan-4-ylcarbamovl)-3- roethyl-butyl }-3.4-dimethoxv-benzamide
Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4-dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared.The residue was purified by HPLC. First eluting diastereomer: MS 564.2.(M+H+). NMR (500 MHz,CDC13): δ 7.80-7.76 (m, 2H),7.19 (t, 2H),7.05 (d, 1H), 6.88 (s, 2H), 6.78(d, 1H), 6.53 (s, 1H), 3.77 (s, 6H), 2.43 (t, 1H), 0.94 (d, 6H). Second eluting diastereomer:MS 546.2 (M+H+).
Example 215
Préparation of Cyclohexanecarboxylic acid {fS')-l-ri-(4-fiuoro-benzenesulfonvD-3-oxo- azepan-4-vlcarbamoyI ΐ -3-methvl-butyl 1-amide
Following the procedure of Example 115, except substituting 4-fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride andcyclohexylcarbonyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purified by HPLC. First eluting diastereomer: MS510.4.(M+H+).lH NMR (400Hz,CDC13): δ 7.83-7.80 (m, 2H), 7.27-7.20 (m, 2H), 6.92 (d,1H), 6.95 (d, 1H). 2.50 (t, 1H), 1.90-1.20 (m, 15H), 0.94 (t, 6H). Second elutingdiastereomer: MS 510.2 (M+H+).
Example 216
Préparation of (S)-2-(2-Benzyloxy-acetvlaminoV4-methyl-pentanoic acidri- (methanesulfonyl)-3-oxo-azepan-4-vn-amide
Following the procedure of Example 115, except substituting methanesulphonylchloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The 223 012288
residue was purifîed by HPLC. First eluting diastereomer: MS 468.2 (M+H+)JH NMR (500 MHz,CDC13): δ 7.37-7.24 (m, 4H), 6.93-6.91 (m, 2H), 5.02-5.00 (m, 1H), 2.88 (s, 3H), 2.70 (t, 1H), 0.92 (t, 6H). Second eluting diastereomer: MS 468.2 (M+H+). *
Example 217
Préparation of Benzorblthiophene-2-carboxvlic acid-ί(S)-l-(l-methanesulfonvl-3-oxo- azepan-4-vl carbamovl)-3-methvl-butyl1-amide
Following the procedure of Example 115, except substituting methanesulphonylchloride for 4-methoxybenzenesulfonyl chloride and benzo[b]thiophenecarbonyl chloridefor benzyloxyacetyl chloride, the title compound was prepared. The residue was purifîedbyHPLC. First eluting diastereomer: MS 480.2 (M+H+^HNMR (500 MHz,CDC13):δ 7.83-7.78 (m, 3H),7.42-7.37 (m, 2H),6.94 (d, 1H), 6.75 (d, 1H), 2.89 (s, 3H), Ï68 (t, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 480.2 (M+H+).
Example 218
Préparation of Benzori.31dioxole-5-carboxylic acid-{(S)-l-fl-methanesulfonvl-3-oxo- azepan-4-yl carbamovl)-3-methvl-butvl1-amide
Following the procedure of Example 115, except substituting methanesulphonylchloride for 4-methoxybenzenesulfonyl chloride and piperonylcarbonyl chloride forbenzyloxyacetyl chloride, the title compound was prepared. The residue was purifîed byHPLC. First eluting diastereomer: MS 468.2 (M+H+)JHNMR (500 MHz,CDC13): δ7.31-7.24 (m, 2H), 6.91 (d, 1H), 6.00 (s, 2H), 2.89 (s, 3H), 2.67 (t, 1H), 0.95 (d,'6H).
Second eluting diastereomer: MS 468.2 (M+H+). 224 012288
Example 219
Préparation of Benzofuran-2-carboxylic acid-{(SVl-(l-methanesuifonyl-3-oxo-azepap-4-yl carbamovl~)-3-methvl-butvll-amide
Foïlowing the procedure of Example 115, except substituting methanesulphonylchloride for 4-methoxybenzenesulfonyl chloride and 2-benzofurancarbonyl chloride forbenzyloxyacetyl chloride, the title compound was prepared. The residue was purified byHPLC. First eluting diastereomer: MS 464.2 (M+H+).^H NMR (500 MHz,CDCl3): δ7.64 (d, 1H), 7.51-7.37 (m, 3H), 7.29-7.2S (m, 1H), 2.89 (s, 3H), 2.67 (t, 1H), 0.97 (d, 6H).Second eluting diastereomer: MS 464.2 (M+H+).
Example 220
Préparation ofN-i(S)-l-(l-Methanesulfonvl)-3-oxo-azepan-4-ylcarbamoylï-3-methyl- butyl 1-3.4-dimethoxy-benzamide
Foïlowing the procedure of Example 115, except substituting methanesulphonylchloride for 4-methoxybenzenesulfonyl chloride and 3,4-dimethoxybenzoyl chloride forbenzyloxyacetyl chloride, the title compound was prepared. The residue was purified byHPLC. First eluting diastereomer: MS 484.2 (Μ+Η+)ΛΗ NMR (500 MHz,CDC13): δ6.94-6.88 (m, 3H), 6.58-655 (m, 2H), 3.80 (s, 6H), 2.89 (s, 3H), 0.95 (d, 6H). Secondeluting diastereomer: MS 484.2 (M+H+).
Example 221
Préparation of (S)-2-(2-Benzyloxv-acetvlamino)-4-methyI-pentanoic acidri-(2-cvano- benzensulfonvl)-3-oxo-azepan-4-vll-amide
Foïlowing the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compoundwas prepared. The residue was purified by HPLC. First eluting diastereomer: MS 555.2(Μ+Η+)Λη NMR (500 MHz,CDC13): δ 8.10 (d, 1H), 7.86 (d, 1H), 7.76-7.70 (m, 2H), 225 012288 Ί.35-Ί.31 (m, 5H), 6.93 (d, 2H), 4.61-4.47 (m, 4H), 2.77 (t, 1H), 0.92 (t, 6H). Secondeluting diastereomer: MS 555.2 (M+H+).
Example 222
Préparation of N-{ (S)-l-F l-(2-Cyano-benzenesulfonyl~)-3-oxo-azepan-4-ylcarbamoyl'i-3- methyl-butyl 1-4-methanesulfonyl-1 -benzamide
Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 4-methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purified by HPLC. First eluting diastereomer: MS 589.2(M+H+).lH NMR (500 MHz,CDC13): δ 8.10 (d,lH), 7.96 (s, 4H), 7.88 (d, 1H), 7.78-7.71(m, 2H), 3.05 (s, 3H), 2.79 (t, 1H), 0.97 (t, 6H). Second eluting diastereomer: MS 589.2(M+H+).
Example 223
Préparation of Benzorblthiophene-2-carboxylic acid-l(S)-l-il-(2-cvano-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamovl)-3-methvl-butvll-amide
Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride andbenzo[b]thiophene-2-carbonyl chloride for benzyloxyacetyl chloride, the title compoundwas prepared. The residue was purified by HPLC. First eluting diastereomer: MS 567.2(M+H+).lH NMR (500 MHz,CDCl3): δ 8.10 (d, 1H), 7.86-7.70 (m, 6H), 7.37-7.30 (m,2H), 2.76 (t, 1H), 0.98 (d; 6H). Second eluting diastereomer: MS 567.2 (M+H+). 226 012288
Example 224
Préparation of Benzon.31dioxole-5-carboxvlic acid-{ (S)-l-ri-f2-cvano-benzenesulfonvr)-3- oxo-azepan-4-vlcarbamovl')-3-methvl-buÎvl1-amide
Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and piperonyloylchloride for benzyloxyacetyl chloride, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer MS 555.2 (M+H+)JH NMR (500MHz,CDC13): Ô 8.11 (d, 1H), 7.87 (d, 1H), 7.76-7.71 (m, 2H), 7.31-7.24 (m, 2H), 6.00 (s,2H), 2.77 (t, 1H), 0.97 (d, 6H). Second eluting diastereomer: MS 555.4 (M+H+).
Example 225
Préparation of (S>-4-Methyl-2-r4-oxo-4-((4-phenoxv-phenyl')-butvrvlaminol-t>entanoic acid [3-oxo-l-(pyridine-2-sulfopvl)-azepap-4-vîl-amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonylchloride for thiaxole-2-sulfonyl chloride and 4-phenoxyphenyl-carboxylic acid forbenzofuran-2-carboxyIic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS (M+H+) 635.4; ^H-NMR (400 MHz, CDCI3): ·8.69(d, 1H), 7.99-7.94(m, 4H), 7.53-7.39(m, 3H), 7.23-6.95(m, 7H), 6.20(d, 1H), 5.07(m,1H), 4.77-4.72(d, 1H), 4.46(m, 1H), 4.13-4.09(m, 1H), 3.85-3.80(d, 1H), 3.33(m, 2H), 2.70-2.64(m, 3H), 2.20-1.40(m, 6H); and the second eluting diastereomer:, 0.96-0.92(m, 6H);and the second eluting diastereomer: MS (M+H+) 635.4.
Example 226
Préparation of N-{ (S~)-l-r(l-(2-cyano-benzenesuIfonvl)-3-oxo-azepan-4-vlcarbamoyl 1-3- methvl-butvl 1-3.4-dimethoxv-benzamide
Following the procedure of Example 115, except substituting 2-cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 3,4- 227 012288 dimethoxybenzoyl chloride forbenzyloxyacetyl chloride, the title compound was prepared.
The residue was purified by HPLC. First eluting diastereomer: MS 571.4 (Μ+Η+Ι^Η NMR (500 MHz,CDC13): δ 8.10 (d, 1H), 7.87 (d, 1H), 7.76-7.70 (m, 2H), 6.98 (s, 2H), 6.89 \ (s, 2H), 3.79 (s, 6H), 2.76 (t, 1H), 0.96 (d, 6H). Second eluting diastereomer: MS 571.4 (M+H+).
Example 227
Préparation of Cyclohexanecarboxvlic acid {(S)-l-il-(4-methoxy-benzenesulfonvn-3-oxo- azepan-4-ylcarbamovl }-3-methvl-butyI }-amide
Following the procedure of Example 115, except substituting cyclohexylcarbonylchloride for benzyloxyacetyl chloride, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer: MS 522.4 (M+H+).^H NMR (500MHz,CDC13): δ 7.70 (d, 2H), 6.97 (d, 2H), 2.40 (t, 1H), 1.90-1.20 (m, 16H), 0.92 (d, 6H).Second eluting diastereomer: MS 522.4 (M+H+).
Example 228
Préparation of 4-Methansulfonvl-N-f fS)-l-r4-methoxv-benzenesulfonyl)-3-oxo-azepan-4- carbamovll-3-methyl-butvl-benzamide
Following the procedure of Example 115, except substituting 4-methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purified by HPLC. First eluting diastereomer: MS 594.2(Μ+Η^ΛΗ NMR (500 MHz,CDC13): δ 7.96 (s, 4H), 7.69 (d, 2H), 7.25 (d,lH), 6.98(d,3H), 3.85 (s, 3H), 3.04 (d, 3H), 2.42 (t, 1H), 0.95 (d, 6H). Second eluting diastereomer:MS 594.2 (M+H+). 228 012288
Example 229
Préparation of 4-Methansulfonvl-N-i fS')-l-r4-fluoro-benzepesulfonvl)-3-oxo-azepan-4- carbamovll-3-methvl-butvl-benzamide 5
Following the procedure of Example 115, except substituting 4-fluorophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and substituting 4-methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound wasprepared. The residue was purified by HPLC. First eluting diastereomer: MS 582.2 10 (M+H+).!h NMR (500 MHz,CDCl3): δ 7.94 (s, 4H), 7.80-7.77 (m, 2H), 7.25-7.19 (m, 3H), 7.00 (d, 1H), 3.04 (s, 3H), 0.96 (d, 6H). Second eluting diastereomer: MS 582.2(M+H+).
Example 230 15
Préparation of ({(S)-3-Methvl-l-r3-oxo-l-(pvridine-2-sulfopyr>-azepan-4-vlcarbamoyri- butylcarbamoyn-carbamic acid benzvl ester
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl 20 chloride for benzenesulfonyl chloride and N-carbobenzyloxycarbonyl-glycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer; MS (M+H+): 574.2; ^H-NMR (400 MHz, CDCI3): ·8.60(d, 1H), 7.97-7.90(m, 2H), 7.50(m, 1H), 7.42-7.25(m, 5H), 6.90(m, 1H), 6.42(m, 1H),5.38(m, 1H), 5.18-5.10(m, 4H), 4.78-4.72(d, 1H), 4.50(m, 1H), 4.12-4.05(m, 1H), 3.95- 25 3.85(m, 2H), 2.72(m, 1H), 2.25-2.10(m, 2H), 1.90-1.40(m, 5H), 0.92(m, 6H); and the second eluting diastereomer: MS(M+H+) 574.2. 229 012288
Bxample 231
Préparation of fS)-2-r5-f4-Methoxv-phenvD-pentanovlamniol-4-methvl-pentanoic acid Γ3- oxo-l-(pvridine-2-sulfonyl)-azepan-4-vll-amide 5
Following the procedure of Example 75, except substituting 2-pyridylsulfonylchlori.de for benzenesulfonyl chloride and 5-(4-methoxyphenyl)-pentanoic acid forbenzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifîedby HPLC. First eluting diastereomer; MS (M+H+): 573.4; ^H-NMR (400 MHz, CDCI3): · 10 8.59(d, 1H), 7.97-7.94(m, 2H), 7.53(m, 1H), 7.09-7.07(d, 2H), 6.89-6.81(m, 3H), 5.90(m, 1H), 5.12(m, 1H), 4.79-4.74(d, 1H), 4.48(m, 1H), 4.12(m, 1H), 3.86-3.81(d, 1H), 3.79(s,3H), 2.69(m, 1H), 2.59-2.57(m, 2H), 2.23-2.10(m, 3H), 1.75-1.45(m, 10H), 0.96-0.95(m, “6H); and the second eluting diastereomer. MS (M+H+) 573.4. 15 Example 232
Préparation of (S')-2-F2-f3-Benzyloxy-4-methoxv-phenyl)-acetvlamniol-4-methvlpentanoic acid r3-oxo-l-(pvridine-2-sulfonvl>-azepan-4-vll-amide 20 Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and (3-benzyloxy-4-methoxy-phenyI)-acetic acid forbenzofuran-2-carboxylic acid, the title compound was prepared. The residue was purifîedby HPLC. First eluting diastereomer; MS (M+H+): 637.4; ^H-NMR (400 MHz, CDCI3): ·8.69(d, 1H), 7.98-7.91(m, 2H), 7.53-7,30(m, 6H); and the second eluting diastereomer:, 25 6.89-6.82(m, 4H), 5.82(m, 1H), 5.14-5.07(m, 3H), 4.78-4.73(d, 1H), 4.43(m, 1H), 4.09(m, 1H), 3.89(s, 3H), 3.82(d, 1H), 3.49(s, 2H), 2.69(m, 1H), 2.14(m, 2H), 1.82-1.40(m, 5H),0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 637.4. 230 012288
Example 233
Préparation of 5,6-Difluoro-ben2ofuran-2-carboxvIic acid fCSl-S-methvl-l-il-fpyridine^- sulfonvfi-3-oxo-azepan-4-vlcarbamovn-butvl ) amide a. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2- su]fonyl)-3-hydroxy-azepan-4-ylcaibamoyl]-butyl}amide
Following the procedure of Example 28b except substituting 5,6-difluorobenzofuran-2-carboxylic acid for bemzofuran-2-carboxylic acid provided the titlecompound: MS (M+H+): 564 b. ) 5,6-Diïluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compoundof Example 233a provided the title compound. The residue was purified by HPLC. Firsteluting diastereomer, MS (M+H+): 562; and the second eluting diastereomer MS (M+H+)562.
Example 234
Préparation of fS)-4-Methvl-2-f5-oxo-hexanovlamino')-pentanoic acid i3-oxo-l-(pvridine-2- sulfopvl)-azepap-4-vll-amide
Following the procedure of Example 115, except substituting 2-pyridinesulphonylchloride for 4-methoxybenzenesulfonyl chloride and substituting 5-oxo-hexanoyl chlorideforbenzyloxyacetyl chloride, the title compound was prepared. The residue was purifiedby HPLC. First eluting diastereomer: MS 495.4 (M+H+); Second eluting diastereomerMS 495.4 (M+H+). 231 012288
Example 235
Préparation of Benzofuran-2-cafboxylic acid {(S)-3-methvl-l-ri-(6-methvl-pvridine-2- ♦ suIfonvl)-3-oxo-azenan-4-vlcarbamovl]-butvl} amide a. ) 6-methyl-pyridine-2-sulphonyl chloride
The title compound was prepared in a similar fashion as that described in Example85a for the préparation of 2-pyridinesulfonyl chloride-N-oxide. b. ) {(S)-l-[3-Hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-3- methyl-butyl}-carbamic acid ferf-butylester
To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbaxnic acid icrr-butyl ester of Example 2g (1.0 g) in dichloromethane (20 mL) was addedsaturated sodium bicarbonate (50 mL). To this solution was added 6-methyl-pyridine-2-sulphonyl chloride (6.44 mL of a 0.13 g/mL solution in 9M HCl). The reaction was stirreduntil complété. Workup and column chromatography (5% methanohdichloromethane)provided the title compound (1.2 g). c. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2- sulfonyl)-azepan-4-ylj-amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-sulfonyI)-azepan-4-yI]-amide of Example 235a (1.2 g) in methanol (20 mL)was added 4M HCl in diopxane (20 mL). The reaction was stirred until complétéwhereupon it was concentrated to provide the title compound (1 g). d. ) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3- hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide ofExample 235c the title compound was prepared: MS(EI) 542 (M+). 232 012288 e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting benzofuran-2- carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- 5 ylcarbamoyl]-butyl}amide of Example 235d the title compound was prepared: ‘H NMR(CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H),5.3 (m, 1H), 7.4-8.0 (m, 8H); MS(EI); 540 (M\ 100%).
Example 236 10
Préparation of 5-Methoxybenzofuran-2-carboxvlic acid KSl-S-methyl-l-il-fô-methyl- p vri dine-2-sulfonyl)-3-oxo-azepan-4-vlcarbamoyn-butyl 1 anaide a. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- 15 sulfonyI)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 28b except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and (S)-2-amino-4-methyl-pentanoicacid [3-hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-yl3-amide of Example 235c for(S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]- 20 amide of Example 28b the title compound was prepared: MS(EI) 572 (M+). b. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcaibamoyl]-butyl}amide
Following the procedure of Example li except substituting 5-methoxybenzofuran-25 2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- ylcarbamoyl]-butyl} amide of Example 236a the title compound was prepared: ’H NMR(CDClj): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, 1H), 3.8 (s, 3H); 4.1 (m, 1H), 4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0, (m, 7H); MS(EI): 570 (M*, 100%). 233 012288
Example 237
Préparation of 3-Methylbenzofuran-2-carboxvlic acid f(S)-3-methyl-l-il-f6-methvl-
Pvridine-2-sulfonyl)-3-oxo-azepaa-4-vlcarbamovl]-butyl)amide a. ) 3-Methylbenzoftiran-2-cai’boxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 236a except substituting 3-methylbenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid the title compound wasprepared: MS(EI) 556 (M+). b. ) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-y lcarbamoyl]-butyl} amide î
Following the procedure of Example li except substituting 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- ylcarbamoyl]-butyl)amide of Example 237a the title compound was prepared: 'H NMR(CDC13): Ô 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, 1H), 3.8 (s, 1H); 4.1 (m, 1H), 4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H); MS(EI): 564 (M+, 100%).
Example 238
Préparation of 7-Methoxybenzofuran-2-carboxylic acid (fS~)-3-methyl-l-il-fpyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butvl ) amide a. ) 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compoundwas prepared: MS(EI) 559 (M+H+). b. ) 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan~4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substituting 7-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- 234 ylcarbamoyl]-butyl} amide of Example 238a the title compound was prepared: MS(EI) 557 (M+H+). 012288
Example 2395
Préparation of 5.6-Dimethoxy-benzorblthiophene-2-carboxylic acid KS)-3-rnethyl-l-R- fpvridine-2-sulfonvl)-3-oxo-azepan-4-ylcarbamovl1-butvl ) amide а. ) 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl- 10 pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 28b except substituting 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compoundwas prepared: MS(EI) 604 (M+). 15 b.) 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide of Example 239a the title compound was 20 prepared: MS(EI) 602.9 (M+H+).
Example 240
Préparation of (R)-l-Benzvl-5-oxo-pvrrolidine-2-carboxvlic acid {(S)-3-methyl-l-{3-oxo- 25 (pvridine-2-sulfonvll-azepan-4-ylcarbamovIl-butvl)aniide
Following the procedure of Example 75, except substituting 2-pyridylsulfonylchloride for thiazole-2-sulfonyl chloride and (R)-l-benzyl-5-oxo-pyrrolidine-2-carboxylicacid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was 30 purified by HPLC. First eluting diastereomer; MS (M+H+): 584.4; iH-NMR (400 MHz,CDC13): · 8.69(d, 1H), 7.99-7,92(m, 2H), 7.52(m, 1H), 7.32-7.22(m, 5H), 6.92(d, 1H), б. 38(d, 1H), 5.15-5.08(m, 2H), 4.80-4.75(d, 1H), 4.47-4.44(m, 1H), 4.14-4.10(m, 1H),3.89-3.80(m, 3H), 2.75-2.63(m, 2H), 2.46-1.44(m, 10H), 0.95(d, 6H); and the secondeluting diastereomer: MS (M+H+) 584.4. 235 07 228 8
Example 241
Préparation of (S)-l-Benzyl-5-oxo-pyn-olidine-2-carboxylic acid f(S)-3-methyl-î-{3-oxo- ( p vridine-2-sulfonvI)-azepan-4-vlcarbamoyll-butyl ) amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonylchloride for benzenesulfonyl chloride and (S)-l-benzyl-5-oxo-pyrrolidine-2-carboxylicacid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer; MS (M+H+): 584.4; ^H-NMR (400 MHz,CDC13): · 8.69(d, 1H), 7.98-7.92(m, 2H), 7.52(m, 1H), 7.32-7.22(m, 5H), 6.92(d, 1H),6.38('d. 1H), 5.22-5.18(d, 1H), 5.10(m, 1H), 4.80-4.75(d, 1H), 4.51(m, 1H), 4.12-4.08 (m,1H). 3.91-3.79(m, 3H), 2.71-1.38(m, 12H), 0.97(d, 6H); and the second elutingdiastereomer: MS (M+H+): 584.4.
Example 242
Préparation of Benzofuran-2-carboxvlic acid {(S)-2-cyclopropvl-l-r3-oxo-l-(pyridine-2- suIfonvI)-azepan-4-ylcarbarooyl'>-ethvl'|-aroide
Following the procedure of Example 193e-h except substituting N-Boc-cyclopropylalanine for step 193e, the title compound was purified to yield twodiastereomers as solids (first eluting: 8 mg, second eluting: 8 mg): MS(ESI): 525 (M+H)+.
Example 243
Préparation of Benzofuran-2-carboxvlic acid {(S)-3-methvlsulfanvl-l-i3-oxo-l-(pvridipe-2- sulfonvl)-azepan-4-vlcarbamoyl)-propvll-amide
Following the procedures of Examples 193e-g except substituted N-Boc-L-methionine in step 193e. The oxidation of Example 193g was performed by adding sulfurtrioxide-pyridine complex (34mg, 0.211 mmol ) and triethylamine ( 0.077 ml) to thealcohol intermediate in DMSO solvent (0.200 ml). After stirring at room température fortwo hours, the mixture was diluted with water and extracted with ethyl acetate. The organic 236 012288 layer was dried, filtered, concentrated, and purified by HPLC to yield two diastereomers of the title compound as solids (first eluting: 8mg, second eluting: 5 mg). MS(ESI): 545 (M+H)+.
Example 244
Préparation of Benzofuran-2-carboxylic acid KS)-2-naphthvlen-2-yl-l-f3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyll-amide
Following the procedure of Example 193e-h except substituting except substitutingN-(t-butoxycarbonyl)-3-(2-naphthyl)-L-alanine, the title compound was purified to yieldtwo diastereomers as solids (first eluting: 5.3 mg, second eluting: 3.3 mg): MS(ESI): 610.8(M+H)+-
Example 245
Préparation of Thienoi3.2-blthiophene-2-carboxylic acid f(S)-3-methyl-l-[l-(6-methvl- pyridine-2-sulfonyl)-3-oxo-azepan-4-vlcarbamoyn-butvl}amide a. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 236a except substituting thieno[3,2-b]thiophene-2-carboxyïic acid for 5-methoxybenzofuran-2-carboxylic acid the titlecompound was prepared: MS(EI) 564 (M+). b. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide of Example 245a the title compound was prepared: ’HNMR(CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 2.7 (m, 1H), 3.8 (s, 1H); 4-1 (m, 1H), 4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H); MS(EI): 562 (M*, 100%). 237 012288
Example 246 <r»
Préparation of Thienoi3.2-blthiophene-2-carboxylic acid i(S)-3-methvl-l-ri-f3-methvl- r pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamovI1-butyl)amide ’ a. ) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(3-methyl-pyridine-2- sulfonyl)-azepan-4-yl]-amide
Following the procedure of Examples 235b-c except substituting 3-methyl-pyridine-2-sulfonyl chloride for 6-methyl-pyridine-2-sulfonyl chloride the title compoundwas prepared: MS(EI) 399 (M+). b. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- suIfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(3-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 246a (0.25 g) in dichloromethane wasadded thieno[3,2-b]thiophene (0.10 g), triethylamine (0.12 mL), HOBt (0.085 g) and EDC(0.12 g). The reaction was stirred until complété. Workup and column chromatography(5% methanol: dichloromethane) provided the title compound (0.18 g): MS(EI) 564 (M+). c. ) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substituting thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide of Example 245a the title compound was prepared: ‘H NMR(CDCy: δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 3.0 (m, 1H), 3.8 (s, 3H); 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 5H), 8.4 (m, 1H); MS(EI): 562 (M*, 100%). 238 012288
Exemple 247
Préparation of 3-Methylbenzofuran-2-carboxylic acid ffS)-3-methvl-l-fl-(3-methvl- pyridine-2-suIfonvD-3-oxo-azepan-4-vlcarbamoyn-butvl ) amide a. ) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Ex ample 246c except substituting 3-methylbenzofuran-2-carboxylic acid for thieno[3,2-bjthiophene the title compound was prepared: MS(EI) 556(M+). b. ) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting 3-methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-Il-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide of Example 247a the title compound was prepared: ’H NMR(CDClj): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 2.6 (m, 3H), 3.0 (m, 1H), 4.1 (m,2H), 4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H), 8.4 (m, 1H); MS(EI): 554 (M\ 100%).
Example 248
Préparation of 5-Methoxvbenzofuran-2-carboxyIic acid {('Sl-S-methyl-l-fl-fS-methvl- pyridine-2-sulfonvl)-3-oxo-azepan-4-ylcarbamovll-butyl) amide a. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 246c except substituting 5-methoxybenzofuran-2-carboxylic acid for thieno[3,2-b]thiophene the title compound wasprepared: MS(EI) 572 (M+). b. ) 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl ) amide
Following the procedure of Example li except substituting 5-methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- 239 0’2288 ylcarbamoyl]-butyl} amide of Example 247a the title compound was prepared: ’H NMR(CDCQ: δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 3.0 (m, 1H), 3.8 (s, 3H); 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, 1H), 7.4-8.0 (m, 6H), 8.4 (m, 1H); MS(EI): 570 (M*, 100%).
Example 249
Préparation of 5,6-Difluoro-benzofuraii-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy- pvridine-2-sulfonvD-azepan-4-vlcarbamovll-butyl'Î amide a. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example 85c exept substituting 5,6-difluorobenzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound wasprepared: MS(ESI) 580.9 (M+KF). b. ) 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide
Following the procedure of Example li exept substituting the compound ofExample 249a the title compound was prepared: MSÇESI) 578.87 (M+KF).
Example 250
Préparation of S-O-Trifluoromethyl-phenvD-furan-Z-carboxvlic acid{(S)-2-cyclohexvl-l- {3-oxo-l-(pvridine-2-sulfonvl)-azepan-4-vlcarbamoyn-ethyl 1-amide a.) 4-((S)-2-tert-Butoxycarbonylamino-3-cyclohexyl-proprionylamino)-3-hydroxy-azepane-l-carboxylic acid benzyl ester
To a solution of the compound of Example 2e (3.2 g, 12.2 namol) in DMF (35 mL) was added N-Boc-cyclohexylalanine (3.3 g), HOBt (1.8 g) and EDC (2.56 g). The reaction was stirred until complété. Workup and column chromatography of the residue (65% hexanes:ethyl acetate) provided 5.5 g of the title compound. 240
I 01228b b. ) ï(S)-Cyclohexyl-l-(3-hydroxy-a2epan-4-ylcarbamoyl)-ethyl]-carbamic acid tert- butyl ester
To a solution of the compound of Example 250a (5.5 g) in etyhl acetate:methanol(185 mL:40 mL) was added 10% PdZC. This mixture was stirred under an atmosphère of 5 hydrogen until complété consumption of the starting material was observed. The reactionwas filtered and concentrated to provide 3.75 g of the title compound. c. ) {(S)-2-Cyclohexyl-1 -[3-hydroxy-1 -(pyridine-2-sulfonyî)-azepan-4-ylcarbamoyl]- ethylj-carbamic acid feri-butyl ester 10 To a solution of the compound of Example 250 b (1.0 g, 1.91 romol) in dichloromethane (5 mL) was added water (10 mL) and sodium bicarbonate (1 g). To thismixture was added 2-pryidinesulfonyl chloride (0.55 g in 5 mL dichloromethane) dropwise.The mixture was stirred for 20 minutes whereupon the organic layer was separated andwashed with water, brine, dried filtered and concentrated. Column chromatography (2% 15 methanol:dichloromethane) of the residue provided 1.0 g of the title compound: MS (ESI)525 (M+H*). d. ) (S)-2-Amino-3-cyclohexyl-N-[3-hydroxy-(pyridine-2-sulfonyl)-azepan-4-yl]- proprionamide 20 To a solution of the compound of Example 250c (1.0 g) in methanol (10 mL) was added HCl (10 mL of 4M HCl in dioxane). The reaction was stirred until complétéconsumption of the starting material whereupon it was concentrated. The residue wasazeotroped with toluene then washed with ether to provide 0.95 g of the title compound. 25 e.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-{3- hydroxy-l-(pyridine-2-sulfonyI)-azepan-4-ylcarbamoyI3-ethyl}-amide
To a solution of the compound of Example 250d (0.20 g, 0.4 mmol) in DMF (0.5mL) was added diisopropylethylamine (0.16 mL), HOBt (0.06 g), EDC (0.084 g) and 5-[3-(trifluoromethyl)phenyl]-2-furoic acid (0.11 g). ). The reaction was stirred until complété 30 consumption of the starting material. Workup and column chromatography 4%methanohdichloromethane) provided 0.23 g of the title compound. 241 012288 f.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-2-cyclohexyl-1- {3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide «
Following the procedure of Example 75d except substituting the compound of *
Example 250e the title compound was prepared. Séparation of the diastereomers by HPLCprovided the first eluting disatereomer (52 mg): MS (ESI) 661.4 and the second elutingdiastereomer (45.8 mg): MS (ESI) 661.6.
Example 251 .
Préparation of 5-(4-Chloro-phenyl)-furan-2-carboxvlic acid{(S)-2-cyclohexyl-l-{3-oxo-l- (pyridine-2-sulfon yl)-azepan-4-ylcarbamovn-eth vl ) -amide
Following the procedures of Example 250e-f except substituting 5-(4-chlorophenyl)-2-furoic acid for 5-[3-(trifluoromethyl)phenyl]-2-furoic acid of Example252e the title compound was prepared. Séparation of the diastereomers by HPLC providedthe first eluting diastereomer (57 mg): MS (ESI) 627.4 and the second eluting diastereomer(53 mg): MS (ESI) 627.4.
Example 252
Préparation of Benzofuran-2-carboxvlic acid I (S)-3-methvl-l-r6-methyl-3-oxo-l-(pyridine- sulphonvD-azepan-4-vlcarbamoyH-butvl I -amide
Following the procedure of Example 92, except substituting, 2-methyl-4-pentenalfor 2,2-dimethyl-4-pentenal the title compound was prepared. The residue was purified byHPLC. First eluting diastereomer; MS (M+H+): 541.2; iH-NMR (400 MHz, CDCI3): ·8.71-8.66(m, 1H), 7.98-7.93(m, 2H), 7.91(d, 1H), 7.67-7.29(m, 5H), 7.15-6.92(m, 2H),5.28-5.20(m, 1H), 4.82-4.47(m, 2H), 3.97-3.78(m, 1H), 3.65-2.98(m, 1H), 2.37-2.34(m,1H), 2.20-1.55(m, 3H), 1.22-1.19(m, 3H), 1.00-0.86(m, 9H). 242 012288
Example 253
Préparation of 5-f4-Chloro-phenvl)-ftiran-2-carboxylic acidl(S)-2-cvclohexyl-l-i3-oxo-l- ( 1 -oxv-p yridine-2-sulfonyI)-azepan>4-vlcarbamovll-ethvl 1 -amide 5
Following the procedures of Example 250c-f except substituting 2-pyridinesulfonylchloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c and substituting 5-(4-chlorophenyl)-2-furoic acid for 5-[3-(trifiuoromethyl)phenyl]-2-furoic acid of Example252e the title compound was prepared. Séparation of the diastereomers by HPLC provided 10 the fîrst eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS(ESI) 643.2.
Example 254 15 Préparation of 5-(3-Trifluoromethvl-phenvl)-furan-2-carboxvlic acid{(S)-2-cvçlohexyl-l-i3- oxo-l-(l-oxv-pyridine-2-sulfonyl)-azepan-4-vlcarbamoyl1-ethyll-amide
Following the procedures of Example 250c-f except substituting 2-pyridinesulfonylchloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c the title compound was 20 prepared. Séparation of the diastereomers by HPLC provided the fîrst eluting diastereomer:MS (ESI) 677.2 and the second eluting diastereomer: MS (ESI) 677.4.
Example 255 25 Préparation of 5-Fluoro-benzofnran-2-cafboxylic acid {(S)-3-methvl-l-r3-oxo-l-(pyridine- 2-sulfopyl)-azepan-4-vlcarbamovlI-butyIl-amide a.) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-suIfonyl)-azepan-4-yIcarbamoyl]-butyl} -amide 30 Following the procedure of Example 28b except substituting 5-fluorobenzofuran-2- carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ESI) 547 (M+H*). 243 012288 b.) 5-Ruoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide
Following the procedure of Example li except substituting the compound ofExample 255a the title compound was prepared: MSÇESI) 544.9 (M+FF).
Example 256
Préparation of 5.6-Dimethoxybenzofuran-2-carboxylic acid{(S)-2-cyclohexvl-l-i3-oxo-l- ( l-oxv-pyridine-2-sulfonyl)-azepan-4-ylcarbamovll-ethvl l-amide
Following the procedures of Example 250c-f except substituting 2-pyridinesulfonylchloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c and substituting 5,6-dimethoxybenzofuran-2-carboxylic acid for 5-[3-(trifluoromethyl)phenyl]-2-furoic acid ofExample 252e the title compound was prepared. Séparation of the diastereomers by HPLCprovided the first eluting diastereomer: MS (ESI) 643.4 and the second elutingdiastereomer: MS (ESI) 643.2.
Example 257
Préparation of 5,5-Bis-(4-methoxv-phenvl)-pent-4-enoic acid f(S)-3-methyl-l-F3-oxo-l- ( pyridine-2-sulfonyl)-azepan-4-ylcarbamovll 1-butyl )-amide
Following the procedure of Example 75 except substituting 2-pyridylsulfonylchloride for thiazole-2-sulfonyl chloride and 5,5-bis-(4-methoxy-phenyl)-pent-4-enoic acidfor benzofuran-2-carboxylic acid, the title compound was prepared. The residue waspurified by HPLC. First eluting diastereomer; MS (M+H+) 677.4; ^H-NMR (400 MHz,CDC13): · 8.69(d, 1H), 7.98-7.92(m, 2H), 7.53-7.50(m, 1H), 7.27-6.77(m, 10H), 6.00-5.87(m, 2H), 5.08(m, 1H), 4.76-4.72(d, 1H), 4.48(m, 1H), 4.08(m, 1H), 3.83(s, 3H), 3.78(s,3H), 2.70-1.35(m, 12H), 0.91(d, 6H); and the second eluting diastereomer: MS (M+H+)677.4. 244 012288
Examole 258
Préparation of Quinoline-8-carboxvlic acid {(S)-2-naphthvlen-2-vl-l-r3-oxo-l-fpvridine-2- sulfonvl)-azepan-4-vlcarbamovB-&amp;tbvll-amid&amp; a. ) 4-Amino-l-(pyridine-2-sulfonyl)-azepan-3-ol
To a solution of the compound of Example 193c (1.5 g) in methanol (10 mL) wasadded HCl (10 mL of 4M HCl in dioxane). The reaction was stirred until complété by TLCanalysis whereupon it was concentrated to provide 1.2 g of the title compound as a whitesolid. I ,!Î : ' ΐ ; I !j! b. ) . {(S)-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yIcarbamoyl3-2-napthylene-2-yl-ethyl}-carbamic acid rert-butyl ester
To a solution of the compound of Example 258a (225 mg) in dichloromethane wasadded TEA (0.15 mL), HOBt (99 mg), EDC (140 mg) and N-Boc-L-2-naphthylalanine (230mg). The reaction was stirred until complété. Workup and column chromatography of theresidue (3% methanohdichloromethane) provided 0.35g.ofJhe title compound: MS(ESI)569 (M+H*). c. ) (S)-2-Amino-N-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-3-naphthylen-2-yl- proprionamide
To a solution of the compound of Example 258b (0.35 g) in methanol (5 mL) wasadded HCl (5 mL of 4M HCl in dioxane). The reaction was stirred until complété by TLCanalysis whereupon it was concentrated to provide 0.31 g of the title compound as a whitesolid. d. ) Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-yIcarbamoyl)-ethyl]-amide
To a solution of the compound of Example 258c (131 mg) in dichloromethane was added TEA, HOBt (39 mg), EDC (55 mg) and quinoline-8-carboxylic acid (51 mg). The reaction was stirred until complété. Workup and column chromatography of the residue (5% methanokdichloromethane) provided 0.35g of the title compound: MS(ESI) 574 (Μ+ΙΓ). 245 012288 e.) Quinoline-8-carboxylic acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide
Following the procedure of Example li except substituting the compound ofExample 258d the title compound was prepared.
Example 259
Préparation of Naphthylene-l-carboxvîic acid (fS')-2-naphthylen-2-vl-l-i3-oxo-l-fpyridine- 2-sulfoPVÏ)-azepan-4-ylcarbamovï)-ethvn-amide
Following the procedures of Examples 258d-e except substituting 1-naphthoic acidfor quinoline-8-carboxylic acid the title compound was prepared.
Example 260
Préparation of Ouinoline-8-carboxylic acid {(S)-l-r3-oxo-l-Îpyridine-2-sulfonyl)-azepan-4- ylcarbamovll-2-phenyl-ethyl }-amide
Following the procedures of Examples 258a-e except substituting N-Boc-phenylalanine for N-Boc-L-2-naphthylalanine the title compound was prepared.
Example 261
Préparation of Naphthvridine-2-carboxylic acid {(S)-3-methvl-l-f3-oxo-l-(pyridine-2- suifonvl~)-azepan-4-vlcarbamoyll-butvl)-amide
Following the procedure of Example 28b-c exept subsituting l,6-naphthyridine-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared. 246 012288
Example 262
Préparation of Naphthylene-l-carboxvlic acid ((S)-l-r3-oxo-l-fpyridine-2-sulfonvi)- azepan-4-vlcarbamovll-2-phenyI-ethvlI-amide
Following the procedure of Example 260 except substituting 1-naphthoic acid forquinoline-8-carboxylic acid the title compound was prepared.
Example 263
Préparation of 3-Methylben2ofuran-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l- ( cvclohexvI-proprionyl)-azepan-4-vlcarbamovll-butyl ) -amide a. ) 4-{(S)-2-[(3-Methylbenzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3- hydroxy-azepane-l-carboxylic acid benzyl ester
To a solution of the compound of Example 72a (1.2 g, 2.67 mmol) was added EDC(0.56 g), HOBt (0.36 g), TEA (0.67 g) and 3-methylbenzofuran-2-carboxylic acid (0.47 g).The reaction was stirred until complété consumption of the starting materiel was observed.Workup and colum chromatography (4:1 hexanes:ethyl acetate) provided 1.05 g of the titlecompound: MS (ESI) 536 (M+H> b. ) 3-Methylbenzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan~4-ylcarbamoyl)-3 methyl-butyl]-amide
Following the procedure of Example 2g except substituting the compound ofExample 263a the title compound was prepared: MS (ESI) 402 (M+H4). c. ) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(cyclohexyl- proprionyl)-azepan-4-ylcarbamoyl]-butyl} -amide
Following the procedure of Example 263a except substituting the compound ofExample 263b and 3-cyclohexylpropionic acid for 3-methylbenzofuran-2-carboxylic acidthe title compound was prepared: MS (ESI) 540 (M+H4). 247 012288 d.) 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(cyclohexyl- proprionyl)-azepan-4-yIcarbamoyI]-butyl }-amide
Following the procedure of Example li except substituting the compound of «
Example 263c the title compound was prepared: MS (EST) 538 (M+EE).
Example 264
Préparation of 3-Methvlbenzofuran-2-carboxylic acid I (S)-3-methvl-l-i3-oxo-l-(4-methyl- pentanovI)-azepan-4-vlcarbamovn-butvl}-amide
Following the procedures of Example 263c-d except substituting 4-methylpentanoicacid for 3-cyclohexylpropionic acid the title compound was prepared; MS (ESI) 498(Μ+1-Γ).
Example 265
Préparation of 3-Methvlbenzofuran-2-carboxvlic acid ifS)-3-methyl-l-i3-oxo-l-(l-oxv- pvridine-2-carbonvl~)-azepan-4-vlcarbamoyn-butvll-amide
Following the procedures of Example 263c-d except substituting picolinic acid N-oxide for 3-cyclohexylpropionic acid the title compound was prepared: MS (ESI) 498(Μ+ΙΓ).
Example 266
Préparation of (S)-Acetylamino-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonvD- azepan-4-yll-amide
Following the procedure of Example 75c-d except substituting acetic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by HPLC to give the first eluting diastereoemer: MS (M+H+) 425.2; ^H-NMR (400Hz, CDCI3): · 8.69(d, 1H), 7.96-7,94(m, 2H), 7.53-7.52(m, 1H), 7.05(m, 1H), 5.92(m, 1H), 5.08(m, 1H), 4.69-4.53(m, 2H), 4.05-3.90(m, 2H), 2.80(m, 1H), 2.25-2.12(m, 2H), 1.64(s, 248 012288 3Η), 1.90-1.40(m, 5Η), 0.95(m, 6H); and the second eluting distereomer: MS (M+H+): 425.2
Example 267 5
Préparation of Quinoline-2-carboxvlic acid {(S)-l-i3-oxo-l-(pyridine-2-sulfonvl)-azepan-4- ylcarbamovll-pentyl }-amide a.) 4-((S)-2-ieri-Butoxycarbonylamino-hexanoylanaino)-3-hydroxy-azepane-1- 10 carboxylic acid benzyl ester
To a stirring solution of compound of the amino alcohol of Example 2e (200 mg,0.74mmol) in DMF (4 ml) was added N-Boc-norleucine (175 mg, 0.76mmol), EDC-HC1(145 mg, 0.76mmol), and 1-hydroxybenzotriazole (21 mg, O.lômmol). Reaction allowed toproceed ovemight at room température. The following moming the mixture was diluted 15 with ethyl acétate, washed with sat. NaHCO3, Η,Ο, and brine. Dried on MgSO4, fîltered andpurified by column chromatography to give 300 mg of the title compound: MS(ESI)478.11 (M+H)+. b·) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-pentyl]-carbamic acid ierf-butyl ester 20 To a solution of compound of Example 267a (300 mg, 0.6 3mmol) in ethyl acetate (5 ml) was added 10% palladium on carbon (160 mg) and Hj from a filled balloon. Afterstirring the solution at room température for 48 hours, the mixture was fîltered throughcelite. The filterate was concentrated to yield the title compound (crude, 161mg,0.47mmol): MS(ESI): 344.19 (M+H)+. 25 c.) {(S)-l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl}- carbamic acid iert-butyl ester
To a solution of the compound of Example 267b (161 mg,0.47 mmol) indichloromethane (6 ml) was added triethylamine (0.065 ml, 0.47mmol) and pyridine-2- 30 sulfonyl chloride (83mg, 0.47 mmol). After stirring at room température for 1 hr themixture was washed with saturated NaHCO3 The organic layer was dried, fîltered,concentrated and purified on a silica gel column to give the title compound (142mg,0.29mmol): MS(ESI): 485.10 (M+H)+. 249 012288 d. ) (S)-2-Amino-hexanoic acid {3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]- amide *
To a stirring solution of the compound of Example 267c (142mg, 0.29mmol) inethyl acetate was added HCl (4M in dioxane) (0.760 ml, 3.0 mmol). After stirring thereaction mixture for 1 hr at room température, the mixture was concentrated to yield awhite solid. The solid was azeotroped with toluene twice on rotavap and then treated with aresin bound carbonate (1.47 mmol) in methanol and placed on a shaker. After 4 hr thesuspension was filtered and concentrated to yield 104 mg crude product: MS (ESI) 385.08(M+H)+. e. ) Quinoline-2-carboxylic acid {(S)-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoylj-pentyl }-amide
To a solution of the compound of Example 267d (104 mg, 0.27mmol) in CH2CL,was added quinaldic acid (47mg, 0.27 mmol), 1-hydroxybenzotriazole (7.4, .055 mmol), EDC-HCL (52 mg, 0.27 mmol) in DMF (2 ml). After stirring at room températureovemight, the mixture was diluted with ethylacetate, washed with sat. NaHCO3, H^O, driedon MgSO4, and filtered to obtain 172mg crude product: MS(ESI) 539.90 (M+H)+. f. ) Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-pentyl}-amide
To a stirring solution of the compound of Example 267e (172mg crude, 0.32mmol)in 1 ml DMSO was added sulfur trioxide-pyridine complex ( 260mg, 1.6 mmol) ) andtriethylamine (0.88 ml, 3.2mmol). After stirring at room température for two hours, themixture was diluted with water and extracted with ethyl acetate. The organic layer wasdried, filtered, concentrated, and purified by HPLC to yield two diastereomers of the titlecompound as solids (first: 40 mg: second:43mg): MS(ESI) 537.86 (M+H)+. 250 ί 012288
Example 268
Préparation of Benzofuran-2-carboxvlic acid ffS)-3-methyl-l-i3-oxo-l-fcvclohexvl- proprionvl)-azepan-4-vlcarbamovl1-butyl)-amide
Following the procedures of Example 263a-d except substituting benzofuran-2-carboxylic acid for 3-methylbenzofuran-2-carboxylic acid of Example 263a the titlecompound was prepared: MS(ESI) 524 (M+H*).
Example 269
Préparation of Benzofuran-2-carboxylic acid {('Sl-3-methvl-l-r3-oxo-l-(4-methvl- pentano vD-azepan-4-vlcarbamoyll -butvl 1 -amide
Following the procedures of Example 263a-d except substituting benzofuran-2-carboxylic acid for 3-methylbenzofuran-2-carboxylic acid of Example 263a and 5-methylpentanoic aicd for cyclohexyl propionic acid the title compound was prepared: MS (ESI)484 (M+H4)-
Example 270
Préparation of Quinoline-2-carboxylic acid {(S)-l-r3-oxo4-(pvridine-2-sulfonvr)-azepan-4- vlcarbamoyll-2-phenyl-ethvl 1 -amide
Following the procedure of Example 267a-f except substituting N-Boc-phenylalanine for N-Boc-norleucine in step 267a the title compound was prepared.Séparation of the mixture by HPLC provided two diastereomers as solids (fîrst eluting: 20.5mg; second eluting: 27 mg ): MS(ESI) 571.95 (M+Hf. 251 012288
Example 271
Préparation of Benzofuran-2-carboxvlic acidf (S)-2-benzyloxv-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepane-4-vlcarbamoyH-ethyl)-amide
Following the procedure of Example 193e-h, except substituting N-Boc-O-benzyl-L-serine in step 193e the title compound was prepared as a mixture of distereoemers. To asolution of benzofuran-2-carboxylic acid {(S)-2-benzyloxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-amide (90 mg) in ethyl acetate (2 mL) was added10% Pd/C (50 mg). Upon hydrogenolysis of approximately 50% of the starting benzylether the reaction was filtered and concentrated. Purification of this 4 component mixtureby HPLC provided the first eluting diastereomer of the title compound (1 mg) and thesecond eluting diastereomer of the title compound (0.3 mg): MS(ESI): 590.94(M+H)+.Additionally the two individual diastereoemers of benzofuran-2-carboxylic acid{(S)-2-hydroxy-1 -[3-oxo-l -(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl} -amide were alsoisolated as described below in Example 272.
Example 272
Préparation of Benzofuran-2-carboxvlic acid {(S)-2-hvdroxy-l-r3-oxo-l-(pvridine-2- sulfonyl)-azepane-4-ylcarbamovn-ethvl 1 -amide
The title compound was obtained as discussed above in Example 271.
Purification of the mixture by HPLC provided the two diastereomers in solid form (firsteluting: 1.6 mg; second eluting 2.1 mg): MS(ESI): 500.9 (M+H)+.
Example 273
Préparation of 5-Methoxybenzofuran-2-carboxvlic acid (fS)-3-methyl-l-r3-oxo-l-(thiazole- 2-sulfonvl)-azepan-4-ylcarbamovll-butyl 1 amide • Following the procedure of Example 75c-d except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75cprovided the title compound which was separated by HPLC to give the first eluting 252 f 012288 diastereoemer as a white solid (144.3 mg, 85.1%): MS (ESI) 563.2 (M+H)+and thesecond eluting diastereomer as a white solid (16.9mg, 10.0%) MS (ESI): 563.0 (M+H)+
Example 274
Préparation of 7-Methoxybenzofuran-2-carboxvlic acid i(S)-3-methvl-l-r3-oxo-l-(thiazole- 2-sulfonvl)-azepan-4-ylcarbamovll-butyl 1 amide
Following the procedure of Example 75c-d except substituting 7-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75cprovided the title compound which was separated by HPLC to give the first elutingdiastereoemer as a white solid (75 mg, 47%): MS (ESI) 563.2 (M+H)+ and the secondeluting diastereomer as a white solid (57 mg, 35%): MS (ESI) 563.0 (M+H)+
Example 275
Préparation of 3-Methvlbenzofuran-2-cafboxvlic acid ( (S)-3-methvl-l-i3-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
Following the procedure of Example 75c-d except substituting 3-methylbenzofuran-2-carboxyIic acid for benzofuran-2-carboxylic acid in step 75c providedthe title compound which was separated by HPLC to give the first eluting diastereoemer asa white solid (69.5 mg, 42%): MS (ESI) 547.2 (M+H)+ and the second elutingdiastereomer as a white solid (65 mg, 40%); MS (ESI) 547.2 (M+H)+
Example 276
Préparation of Benzoiblthiophene-2-carboxylic acid |(S)-3-methyl-l-i3-oxo-l-ithiazole-2- sulfonvl)-azepan-4-vlcarbamovn-butvl 1 amide
Following the procedure of Example 75c-d except substituting benzo[b]thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was separated by HPLC to give the first eluting diastereoemer as a white solid (79.5 253 012288 mg, 48%): MS (ESI) 549.3 (M+H)+ and the second eluting diastereomer as a white solid (50.5 mg, 31%); MS (ESI) 549.2 (M+H)+
Example 277
Préparation of l-Methvl-lH-indole-2-carboxvlic acid {(S)-3-methyl-l-F3-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl} aroide
Following the procedure of Example 75c-d except substituting l-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided tlie title compoundwhich was separated by HPLC to give the first eluting diastereoemer as a white solid (75mg, 47%): MS (ESI) 563.2 (M+H)+and the second eluting diastereomer as a white solid(57 mg, 35%): MS (ESI) 563.0 (M+H)+
Example 278
Préparation of Ouinoxaline-2-carboxvlic acid {(S)-3-methyl-l-F3-oxo-l-(thiazole-2- sulfonvl~)-azepan-4-ylcarbamovll-butvl ) amide
Following the procedure of Example 75c-d except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compoundwhich was separated by HPLC to give the first eluting diastereoemer as a white solid (126mg, 77%): MS (ESI) 545.2 (M+H)+ and the second eluting diastereomer as a white solid(25 mg, 15%): MS (ESI) 545.2 (M+H)+ 254 012288
Example 279
Préparation of Quinoline-2-carboxvlic acid f rfS)-l-fl-(4-fluoro-benzenesulfonvl)-3-oxo- azepan-4-vlcarbaroovn-3-methvl-butvll-amide 5
Following the procedure of Example 75, except substituting 4-fluorophenylsulfonylchloride for benzenesulfonyl chloride and 2-quinoline carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC.
First eluting diastereomer; MS (M+H+): 555.2; ^H-NMR (400Hz, CDCI3): · 8.62(d, 1H), 10 8.34-8.23(q, 2H) 8.19-8.17(d, 1H), 7.90-7.88(d, 1H), 7.88-7.80(m, 3H), 7.66-7.64(1,1H), 7.25-7.07(m, 3H), 5.08(m, 1H), 4.72 (m, 1H), 4.58-4.53(d, lH),4.00(m, 1H), 3.46-3.42(d,1H), 2.47(m, 1H), 2.27-2.12(m, 2H), 1.90-1.40(m, 5H), 1.03-1.01(m, 6H); and the secondeluting diastereomer: MS (M+H+): 555.4. 15 Example 280
Préparation of Benzofuran-2-carboxylic acid i<Sl-l-i-(3-fluoro-benzensulfonvl)-3-oxo- azepan-4-ylcarbamoyll-3-methvl-l-butvll- amide 20 a.) Allyl-pent-4-enyl-carbamic acid benzyl ester
To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added
allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. The mixture wasstirred at room température for approximately 10 minutes whereupon 5-bromo-l-pentene(6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40°C 25 for approximately 4 hours whereupon the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2x’s), brine, dried(MgSOJ, filtered and concentrated. Column chromatography of the residue (10% ethylacetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(ES) 260(M+H+). 30 255 012288 b. ) 2,3,4,7 -Tetrahydro-azepine- 1-carboxylic acid benzyl ester
To a solution of compound of Example 280a (50 g) in dichloromethane was addedbis(tricyclohexylphosphine)benzylidine ruthénium (TV) dichloride (5.0 g). The reactionwas heated to reflux until complété as determined by TLC analysis. The reaction wasconcentrated in vacuo. Column chromatography of the residue (50% dichloromethane:hexanes) gave 35 g of the title compound: MS(ES) 232 (M+H+). c. ) 8-Oxa-3-aza-bicyclo[5.1.0]octane-3~carboxylic acid benzyl ester
To a solution of the compound of Example 280b (35 g, 1.5 mol) in CH2C^ wasadded /n-CPBA (78 g, 0.45 mol). The mixture was stirred ovemight at room températurewhereupon it was filtered to remove the solids. The filtrate was washed with saturatedwater and saturated NaHCO3 (several times). The organic layer was dried (MgSO4), filteredand concentrated to give 35 g of the title compound which was of sufficient purity to carryon to the next step: MS(ES) 248 (M+H+), 270 (M+Na+). d. ) 4-Azido-3-hydroxy-azepane-l-carboxylic acid benzyl ester
To a solution of the epoxide from Example 280c (2.0 g, 8.1 mmol) inmethanol:water (8:1 solution) was added NH4C1 (1.29 g, 24.3 mmol) and sodium azide(1.58 g, 24.30 mmol). The reaction was heated to 40°C until complété consumption of thestarting epoxide was observed by TLC analysis. The majority of the solvent was removedin vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer.The organic layer was washed with sat. NaHCO3, water, brine dried (MgSO,,), filtered andconcentrated. Column chromatography (20% ethyl acetate:hexanes) of the residueprovided 1.3 g of the title compound: MS(ES) 291 (M+H+) plus 0.14 g of trans-4-hy droxy-3-azido-hexahydro-1 H-azepine e. ) 4-Amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
To a solution of the azido alcohol of Example 280d (1.1 g, 3.79 mmol) in methanolwas added triethyamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37mmoL). The reaction was stirred until complété consumption of the starting material wasobserved by TLC analysis whereupon the reaction was concentrated in vacuo. Columnchromatography of the residue (20% methanol:dichloromethane) provided 0.72 g of thetitle compound: MS(ES) 265 (M+H+). 256 012288 f. ) 4-((S)-2-ieri-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan“l- carboxyïic acid benzyl ester
To a solution of the amino alcohol of Example 280e (720 mg, 2.72 wmol) inCH2C12 was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). Thereaction was maintained at room température until complété consumption of the startingmaterial was observed by TLC analysis. The reaction was diluted with ethyl acetate andwashed with IN HCl, sat. K,CO3, water, brine, dried (MgSOJ, filtered and concentrated.Column chromatography of the residue (3% methanohdichloromethane) gave 1.0 g of thetitle componnd: MS(ES) 478 (M+H+). g. ) [(S)- l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyI-butyl]-carbamic acid tert butyl ester
To a solution of the compound of Example 280f (1.0 g) and 10% Pd/C (catalytic) inethyl acetate:methanol (2:1 solution) was affîxed a balloon of hydrogen. The reaction wasstirred until complété consumption of the starting material was observed by TLC analysis.The reaction was filtered to remove the catalyst and thefîltrate was concentrated to provide0.82 g of the title compound: MS(ES) 344 (M+H+). h. ) (S)-2-Amino-4-methyl-pentanoic acid [l-(3-fluoro-benzenesulfonyl)-3-hydroxy- azepan-4-yl]-amide
To a solution of the compound of Example 280g (0.2 g) in dichloroethane (20 mL)was added p-NMM (0.32 g) and 3-fluorobenzenesulfonyl chloride (0.11 g). The reactionwas stirred until complété as determined by MS analysis whereupon it was filtered,concentrated. The residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10mL) was added. The reaction was maintained at room température until complétéconsumption of the starting material whereupon it was concentrated. The residue wasdissolved in methanol whereupon p-carbonate resin was added. The mixture was shaken atroom température for 4 hours then filtered and concentrated to provide 0.64 g of the titlecompound. 257 01 2288 i. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesuIfonyl)-3-hydroxy- azepan-4-y lcarbamoyl]3-methyl-buty 1} -amide
To a solution of the compound of Example 280h (0.15 g) in ŒLC^ was addedbenzofuran-2-carboxylic acid (0.56 mmol), HOBt (0.09 mg), and p-EDC (0.75 mg). Thereaction was stirred ovemight whereupon trisamine (0.50 g) was added and stirred anadditional 1.5 hours. The reaction was filtered and concentrated to provide the titlecompound. j. ) Benzofuran-2-carboxylic acid {(S)-l-[l-(3-fîuoro-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]3-methyl-butyl} -amide
To a solution of the compound of Example 280i (0.3 mmol) in CH2C12 was addedDess-Martin periodinane (0.25 g). The réaction was stirred until complété as determinedby MS analysis. Workup and HPLC chromatography provided diastereomer 1: MS(ES)543.2 (M+H)+ and diastereomer 2: MS(ES) 543.2 (M+H)+.
Example 281
Préparation of (S)-4-Methyl-2-(3-piperidin-l-vI-propanoylamino)-pentanoic acid Γ3-ΟΧΟ-1- (pvridine-2-sulfonyl)-azepan-4-yll-amide
Following the general procedures of Examples 280h-j except substituting 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride and 1-piperidinepropionoicacid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 521.9(M+H)+.
Example 282
Préparation of Benzofuran-2-carboxylic acid {(S)-l-[-(4-ethvl-benzensulfonyl)-3-oxo- azepan-4-vlcarbamoyn-3-methyl-1 -butyl 1 - amide
Following the general procedures of Examples 280h-j except substituting 4-ethylnezenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride the title compound was 258 012288 prepared: Séparation of the diastereomers provided diastereomer 1 MS(ES) 554.4 (M+H)+ and distereomer 2 MS (ES) 554.4 (M+H)+.
Example 283
Préparation of 5-(3-Trifhioromethyl-phenvl)-furan--2-carboxylic acid (fS)-3-methvl-l-{3- oxo-1 - ί 1 -(1 -oxv-pyridin-2-yl)-methanovn-azepan-4-vlcarbamovl )-butyD-amide a. ) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid benzvl ester
To a solution of the compound of Example 280f (7.32 g) in methanol was added4M HCl in dioxane (38 mL). The reaction was stirred until complété wherenpon it wasconcentrated to give 6.9 g of the title compound as a white solid. b. ) 3-Hydroxy-4-[(S)-4-methyl-2-({l-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]- methanoyl}-amino)-pentanoylamino]azepane-1-carboxylic acid benzyl ester
To a solution of the compound of Example 283a (1.2 g) in dichloromethane wasadded TEA (0.93 mL), EDC (0.56 g), HOBt (0.36 g) and 5-[3-(trifluoromethyl) phenyl]-2-furoic acid (0.68 g). The reaction was stirred at room température until complété asdetermined by TLC analysis. Workup and column chromatography provided 1.35 g of thetitle compound: MS (ES) 616 (M+H)+. c. ) 5-[3-(Trifluoromethyl)phenyl]-furan-2-carboxylic acid [(S)-l-(3-hydroxy-azepan- 4-ylcarbamoyl)-3-methyl-butyl]-amide
To a solution of the compound of Example 283b (1.3 g) in ethyl acetatermethanol(20 mL of an 8:1 mixture) was added 10% Pd\C. The mixture was stirred under a balloon ofhydrogen gas until complété consumption of the starting material was observed by TLCanalysis. The reaction was filtered and concentrated to provide 0.96 g of the titlecompound which was used directly in the following reaction with no further purification. 259 012288 d. ) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy- l-[l-(l-oxy-pyridin-2-yl)-methanoyl]-azepan-4-yIcarbamoyl}-butyl)-amide
To a solution of the compound of Exemple 283c (0.3 g) in dichloromethane wasadded TEA (0.22 mL), EDC (0.13 g), HOBt (0.8 g) and picolinic acid N-oxide (0.09 g).
The reaction was stirred at room température until complété as determined by TLCanalysis. Workup and coluinn chromatography provided 0.16 g of the title compound: MS(ES) 603 (M+H)+. e. ) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l- [l-(l-oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide
To a solution of the compound of Example 283d (0.15 g) in DMSO (1.5 mL) wasadded TEA (0.37 mL) and pyridine sulfur trioxide complex (0.21 g). The reaction wasstirred until complété as determined by LCMS. Workup and column chromatography (10%methanol.'dichloromethane) provided 0.12 g of the title compound: MS (ES) 601 (M+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 anddiastereomer 2.
Example 284
Préparation of Benzol-1.31-dioxole-5-carboxvlic acid ((S)-3-methvl-l-f3-oxo-l-|T-oxv-
Pvridin-2-vl)-methanovll-azepan-4-vlcarbamoyl)-butvl)-amide
Following the general procedures of Examples 283b-e except substitutingpiperonylic acid for 5-[3-(trifluoromethyl) phenyl]-2-furoic acid the title compound wasprepared: MS(ES) 511 (M+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 anddiastereomer 2. 260 012288
Example 285
Préparation of 5-('3-Trifluoromethvl-phenyI)-furan-2-carboxylic acid {(S)-l-ri-(3- cyclohexyl-propanovl)-3-oxo-azepan-4-vlcarbamovl1-3-methyl-butvB-amide
Following the general procedures of Examples 283b-e except substituting 3-cyclohexylpropionic acid for picolinic acid N-oxide the title compound was prepared:MS(ES) 618 (M+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 anddiastereomer 2.
Example 286
Préparation of Benzoll,31-dioxoie-5-carboxyIïc acid {(S)-l-ii-(3-cyclohexyl-propanoyI)-3- oxo-a2epan-4-ylcarbamovl1-3-methyl-butyl}-amide
Following the general procedures of Examples 283b-e except substituting 3-cyclohexylpropionic acid for picolinic acid N-oxide and piperonylic acid for 5-[3-(trifluoromethyl) phenylj-2-furoic acid the title compound was prepared: MS(ES) 528(M+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 anddiastereomer 2.·
Example 287
Préparation of 5-<3-TrifluoromethyI-phenvl')-furan-2-carboxyIic acid KSI-l-il-M-methyl- pentapovb-3-oxo-azepan-4-vlcarbamovll-3-methyl-butvB-amide
Following the general procedures of Examples 283b-e except substituting 4- methyl-pentanoic acid for picolinic acid N-oxide the title compound was prepared: MSÇES) 578 (M+H)+. 261 012288
The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2. 1
Example 288
Préparation of BenzoiL31-dioxole-5-carboxvlic acid {('S)-l-il-f4-methyl-pentanovI')-3- oxo-azepan-4-ylcarbamovll-3-methyl-butyll-amide
Following the general procedures of Exemples 2S3b-e except substituting 4-methyl-pentanoic acid for picolinic acid N-oxide and piperonylic acid for 5-[3-(trifluoromethyl) phenyl]-2-furoic acid the title compound was prepared: MS(ES) 488(M+HÏ.
The diastereomers were separated by HPLC to provide diastereomer 1 anddiastereomer 2.
Example 289
Préparation of Benzofuran-2-carboxvlic acid {fSll-i3-oxo-l-fpropane-l-sulfonyl)-azepan- 4-ylcarbamovll-3-methvl-l-butyl 1- amide
Following the general procedures of Examples 280h-j except substitutingpropanesulfonyl chloride for 3-fluorosulfonyl chloride the title compound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 491.2(M+H)+ and diastereomer 2: MS(ES) 491.2 (M+H)+.
Example 290
Préparation of Benzofuran-2-carboxvlic acid IYS)-l-i3-oxo-l-(ethanesulfonyl-azepan-4- vlcarbamoyl)-3-methyI-l-butyn- amide
Following the general procedures of Examples 280h-j except substitutingethanesulfonyl chloride for 3-fluorobenzenesulfonyl chloride the title compound wasprepared. 262 012288 Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 477.4(M+H)+ and diastereomer 2: MSÇES) 477.4 (M+H)+. i» 5 Example 291
Préparation of 5-Fluoro-benzofuran-2-carboxyIic acid KS)-3-methvl-l-i3-oxo-l-(l-oxv- pyridine-2-sulfonvr)-azepan-4-vlcarbamovn-butyl ) -amide 10 a.) {(S)-l-[3-Hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3- methyl-butylj-carbamic acid ieri-butyl ester Génération of 2-pyridinesulfonylchloride-N-oxide: To a 0°C solution of 2-mercaptopyridine-N-oxide (2.23 g, 17.55 mmol) in 9M HCl (33 mL) was bubbled chlorinegas for approximately 90 minutes. The dissolved chlorine was removed under vacuum at 15 0°C.
To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid terî butyl ester of Example 280g (2.5 g, 7.28 mmol) in CHjClj (100 mL) andsat. NaHCO3 (400 mL) was added the solution of 2-pyridinesulfonylchloride-N-oxide (27mL, 102 mg/mL) dropwise in portions. As the addition proceeds additional sat. NaHCO3 is 20 added in order to maintain the pH at approximately 8-9. Upon complété addition of thesulfonylchloride the reaction is stirred for an additional hour whereupon the organic layerwas removed and washed with brine. The organic layer was evaporated and the residuechromatographed (5% methanobdichloromethane) to provide 2.5 g of the titïe compound:MS (ES) 500 (M+H*). 25 b.) (S)-2-Amino-4-methyl-pentanoic acid-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amîde
To a solution of {(S)-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- 30 ylcarbamoyl)-3-methyl-butyl}-carbamic acid rert-butyl ester of Example 29 la (2.0 g) in methanol (20 mL) was added 4 M HCl in dioxane (20 mL). The reaction was stirred at room température for 1.5 hours whereupon it was concentrated to provide 1.8 g of the title compound: MS (ES) 400 (M+H*). 263 012288 c. ) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy- · pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide «
To a solution of the compound of Example 291b (0.30 g) in CH2CL, was added 5-fluoro-benzofuran-2-carboxyîic acid (0.11 g), EDC (0.13 g), HOBt (0.086 g), and ΊΈΑ(0.22 inL). The reaction was stirred until complété as determined by LCMS whereupon itwas diluted with ethyl acetate and washed with water, sat. K^COj, IN HCl, brine, dried(MgSOJ, filtered and concentrated. Column chromatography (10% methanol:dichloromethane) of the residue provided 0.27 g of the title compound: MS(ES) 563(M+H)+. d. ) 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
To a solution of the compound of Example 291c (0.19 g) in DMSO (1.5 mL) wasadded sulfur trioxide pyridine complex (0.26 g). The reaction was stirred until complété asdetermined by LCMS whereupon it was diluted with ethyl acetate and washed with sat.
NaHCO3, brine dried, filtered and concentrated. Column chromatography of the residueprovided 0.15 g of the title compound as a mixture of diastereomers: MS(ES) 561 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2.
Example 292
Préparation of 5-Fluoro-3-methyl-benzofnran-2-carboxylic acid {(S)-3-methvl-l-F3-oxo-l- ( 1 -oxy-pvridine-2-sulfonvl)-azepan-4-vlcarbamovn-butvl ) -amide
Following the general procedure of Examples 291c-d except substituting 5-fluoro- 3-methyl benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid providedthe title compound as a mixture of diastereomers: MS(ES) 575 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2. 264 012288
Example 293
Préparation of 6-Fluoro-3-methvl-benzofuran-2-carboxvlic acid 1fSl-3-methyl-l-i3-oxo-l- fl-oxy-pyridine-2-suIfonvl)-azepan-4-ylcarbamoyll-butvlÎ-amide 5
FoIIowing the general procedure of Examples 291c-d except substituting 6-fluoro-3-methyl benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid providedthe title compound as a mixture of diastereomers: MSÇES) 575 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1 and10 diastereomer 2,
Exampie 294
Préparation of 3-Methvl-benzofuran-2-carboxyIic acid (ÇR)-3-methvl-l-f3---oxo-l-Çl-oxy- 15 pyridine-2-sulfonyD-azepan-4-vlcarbamoyri-butvll-amide
FoIIowing tbe general procedures of Examples 280f-i except substituting N-Boc-Dleucine for N-Boc-L-leucine, 2-pyridinesulfonylchloride N-oxide for 3-fluorobenzenesulfonyl chloride and 3-methyl-benzofuran-2-carboxylic acid for benzofuran 20 2-carboxylic acid the title compound was prepared: MSÇES) 556 ÇM+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2. 265
Example 295 012288
Préparation of 3-Methvl-furoi3.2-bl-pyridine-2-carboxylic acid KS)-3-methvl-l-f-3-oxo-l- ( l-oxv-pvridine-2-snlfonvl~)-a2epan-4-vlcarbamoyil-butvl l-amide
Following the general procedure of Examples 291c-d except substituting 3-methyl~furo[3,2-b]-pyridine-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid providedthe title compound as a mixture of diastereomers: MS(ES) 558 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2.
Example 296
Préparation of 5-Methoxy-benzofuran-2-carboxylic acid l(S)-l-il-(3-fluoro- bepzenesulfonvl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butyll-amide
Following the general procedure of Examples 280h-j except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid provided the titlecompound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 574.5(M+H)+ and diastereomer 2 574.5 (M+H)+.
Example 297
Préparation of 3-Methvl-benzofuran-2-carboxvlic acid {fS)-l-ri-(3-fluoro- benzenesulfonyD-3-oxo-azepan-4-yIcarbamovî1-3-methyI-butyl 1 -amide
Following the general procedure of Examples 280h-j except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compoundas a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 557.4(M+H)+ and diastereomer 2 557.4 (M+H)+. 266 012288
Example 298
Préparation of Benzoiblthiophene-2-carboxvlic acid {(S)-l-il-(3-fluoro-benzenesulfonvll- 5 3-oxo-azepan-4-ylcarbamoyll-3-methyI-butyl}-amide
Following the general procedure of Examples 280h-j except substitutingbenzo[b]thiophene-2-carboxylic acid_for benzofuran-2-carboxylic acid provided the titlecompound as a mixture of diastereomers. 10 Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 559.4 (M+H)+ and diastereomer 2 559.4 (M+H)+.
Example 299 15 Préparation of 3-Methvl-furan-2-carboxvlic acid {(S)-l-il-(3dduoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamovll-3-methyl-butvl}-amide
Following the general procedure of Examples 280h-j except substituting 3-methyl-furan-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a 20 mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.2(M+H)+ and diastereomer 2 507.4 (M+H)+. 267 01 2288
Example 300
Préparation of Quinoline-2-carboxylic acid ((S'Î-l-il-O-fluoro-benzenesulfonvn-S-oxo- azepan-4-ylcarbamoyll-3-methyl-butvl}-amide
Following the general procedure of Examples 280h-j except substituting quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as amixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 554.2(M+H)+ and diastereomer 2 MS(ES) 545.2 (M+H)+.
Example 301
Préparation of Thienor3.2-blthiophene-2-carboxvlic acid {(S)-l-ri-f3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methvl-butvl ) -amide
Following the general procedure of Examples 280h-j except substitutingthieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid provided thetitle compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 565.2(M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)+.
Example 302
Préparation of Ouinoxaline-2-carboxvlic acid {('S)-l-ri-f3-fluoro-benzenesulfonvl'>-3-oxo- azepan-4-ylcarbamovll-3-methyl-butyl)-amide
Following the general procedure of Examples 280h-j except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 555.4 (M+H)+ and diastereomer 2 MS(ES) 555.4 (M+H)+. 268 012288
Example 303
Préparation of Thiophene-2-carboxylic acid {fS)-l-ri-('3-fluoro-benzeûesulfonvl')-3-oxo- azepan-4-ylcarbaraovH-3-methvl-butvl 1 -amide
Following the general procedure of Examples 280h-j except substituting thiophene 2- carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as amixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 509.4(M+H)+ and diastereomer 2 MS(ES) 509.2 (M+H)+.
Example 304
Préparation of 5-Methvl-thiophene-2-carboxvlic acid KS')-l-fl-f3-fluoro-benzenesulfonvB 3- oxo-azepan-4-vlcarbamoyll-3-methvl-butyl}-amide
Following the general procedure of Examples 280h-j except substituting 5-methyI-thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compoundas a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS0BS) 523.2(M+H)+ and diastereomer 2 MS(ES) 523.4 (M+H)+. 269 ΰ ! 22 8 8
Example 305
Préparation of 5-Methoxv-benzofuran-2-carboxylic acid i(S)-l-(l-ethanesulfonvl-3-oxo- azepan-4-ylcarbaniovl~)-3-methvl-butvll-amide
Following the general procedure of Examples 280h-j except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid andethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound asa mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS (ES) 507.4(M+H)+ and diastereomer 2 MS(ES) 507.4 (M+H)+.
Example 306
Préparation of 3-Methvl-benzofuran-2-carboxylic acid r(S)-l-(l-ethanesulfonvl-3-oxo- azepan-4-vlcarbamoyl)-3-methvl-butvn-amide
Following the general procedure of Examples 280h-j except substituting 3-methyl-benzofuràn-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloridefor 3-flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 491.2(M+H)+ and diastereomer 2 MS(ES) 491.2 (M+H)+.
Example 307
Préparation of Benzolblthiophene-2-carboxvlic acid IYS)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamovl)-3-methvl-butvl]-amide
Following the general procedure of Examples 280h-j except substituting benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. 270 012288 Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 493.4(M+H)+ and diastereomer 2 MS (ES) 493.4 (M+Hf.
Example 308
Préparation of 3-Methyl-furan-2-carboxylic acid FfS)-l-(l-etbanesulfonyl-3-oxo-azepan-4- y 1 carbamovl)-3-methvI-butvn-amide
Following the general procedure of Examples 280h-j except substituting 3-methyl-furan-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 441.2(M+H)* and diastereomer 2 MS(ES) 441.2 (M+H)+.
Example 309
Préparation of Ouinoline-2-carboxyiic acid ÎYS)-l-(l-ethanesulfonyl-3-oxo-azepan-4- ylcarbamovl)-3-methyI-butvn~amide
Folio wing the general procedure of Examples 280h-j except substituting quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 488.2(M+H)+ and diastereomer 2 MS(ES) 488.2 (M+H)+.
Example 310
Préparation of Thienor3.2-blthiophene-2-carboxylic acid r(S)-l-(l-ethanesulfonvl-3-oxo- azepan-4-vlcarbamoyl)-3-methvl-butvll-amide
Following the general procedure of Examples 280h-j except substitutingthieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-cafboxylic acid and 271 01228ο ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 499.4 (M+H)+ and diastereomer 2 MS(ES) 499.4 (M+H)+.
Example 311
Préparation of Ouinoxaline-2-carboxvlic acid f(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4- vlcarbamoyl)-3-methyI-butvl1-amide
Following the general procedure of Examples 280h-j except substitutingquinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonylchloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 489.2(M+H)+ and diastereomer 2 MS(ES) 489.2 (M+H)+.
Example 312
Préparation of Thiophene-2-carboxylic acid r(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyll-3-methyl-butyll-amide
Following the general procedure of Examples 280h-j except substituting thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 443.4(M+H)* and diastereomer 2 MS (ES) 443.2 (M+H)*. 272 ( 012288
Example 313
Préparation of 5-Methyl-thiophene-2-carboxylic acid f(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-vlcarbamovl)-3-methvI-butvn-amide
Following the general procedure of Examples 280h-j except substituting 5-methyl-thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloridefor 3-flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 457.2(M+H)+ and diastereomer 2 MS(ES) 457.4 (M+H)+.
Example 314
Préparation of 5-Methoxy-benzofuran-2-carboxylic acid ((S)-l-r3-oxo-l-(propane-l- sulfonvl)-azepan-4-ylcarbamovH-3-methyl-l-butyl 1- amide
Following the general procedure of Examples 280h-j except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compoundas a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 521.4(M+H)+ and diastereomer 2 MSÇES) 521.2 (M+H)+. 273 012288
Example 315
Préparation of 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1 -butyl} - amide 5
Foliowing the general procedure of Examples 2S0h-j except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonylchloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. 10 Séparation of the diastereomers by HPLC provided diastereomer 1 : MS(ES) 505.4 (M+H)+ and diastereomer 2 MS(ES) 505.2 (M+H)+.
Example 316 15 Préparation of Benzorblthiophene-2-carboxylic acid {(S)-l-i3-oxo-l-(propane-l-sulfonyl)- azepan-4-ylcarbamoyn-3-methvl-l-butvl)- amide
Following the general procedure of Examples 280h-j except substitutingbenzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and 1- 20 propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compoundas a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.4(M+H)+ and diastereomer 2 MS(ES) 507.4 (M+H)+- 274 f 012288
Example 317
Préparation of 3-Methvl-furan-2-carboxylic acid {fS)-l-F3-oxo-l-fpropane-l-sulfonvb- azepan-4-ylcarbamovl1-3-methvl-l-butyll- amide 5
Following the general procedure of Examples 280h-j except substituting 3-methyl-furan-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloridefor 3-flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. 10 Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 455.2 (M+H)+ and diastereomer 2 MS(ES) 455.4 (M+H)+.
Example 318 15 Préparation of 2.5-Dimethyl-benzofuran-2-carboxvIic acid {(S)-l-f3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyll-3-methvl-l-butvl|- amide i
Following the general procedure of Examples 280h-j except substituting 2,5-dimethyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and Ι- ΣΟ propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compoundas a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 469.4(M+H)+ and diastereomer 2 MS(ES) 469.2 (M+H)+. 275 012288
Example 319
Préparation of Ouinoline-2-carboxylic acid {(S)-l-r3-oxo-l-(propane-l-sulfonyl)-azepan-4- vlcarbamovll-3-methyl-l-butvl}- amide5
Following the general procedure of Examples 280h-j except substituting quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 565.210 (M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)+.
Example 320
Préparation of ThienoF3,2-b1thiophene-2-carboxylic acid {(S)-l-r3-oxo-l-(propane-l- 15 sulfonyl)-azepan-4-vlcarbamoyH-3-methvl- 1-butvl 1- amide
Following the general procedure of Examples 280h-j except substitutingthieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound 20 as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 513.2(M+H)+ and diastereomer 2 MS (ES) 513.2 (M+H)+. 276 { 012288
Example 321
Préparation of Quinoxaline-2-carboxylic acid ifS)-l-i3-oxo-l-fpropane-l-sulfopyD- azepan-4-ylcarbamovI1-3-methvl-l-butyl}- amide
Following the general procedure of Examples 280h-j except substitutingquinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonylchloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 503.4·(M+H)+ and diastereomer 2 MS(ES) 503.4 (M+H)+.
Example 322
Préparation of Thiophene-2-carboxylic acid Î(S)-l-f3-oxo-l-(propane-l-sulfonvD-azepan- 4-vlcarbamovll-3-methyl-l-butvIl- amide
Following the general procedure of Examples 280h-j except substituting thiophene2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 457.4(M+H)+ and diastereomer 2 MS(ES) 457.4 (M+Hf. 277 01 2288
Example 323
Préparation of 5-Methyl-thiophene-2-carboxvlic acid KS)-l-i3-oxo-l-(propane-l- sulfonyD-azepan-4-vlcarbamovll-3-methyl-l-butvl)- amide
Following the general procedure of Examples 280h-j except substituting 5-methyl-thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid and 1-propanesulfonylchloride for 3~flurobenzenesulfonyl chloride provided the title compound as a mixture ofdiastereomers. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 471.4(M+H)+ and diastereomer 2 MS(ES) 471.4 (M+H)+.
Example 324
Préparation of 5-Methoxv-3-methvl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-i3-oxo- 1 -( l-oxv-pyridine-2-sulfonyl)-azepap-4-vlcarbamoyll-butyl }-amide
Following the general procedure of Examples 291c-d except substituting 5-methoxy-3-methyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acidprovided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 565.2(M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)+.
Example 325
Préparation of 3.5-Dimethvl-benzofuran-2-carboxvlic acid {(S)-3-meihyl-l-l'3-oxo-î-('l- oxv-Pvridine-2-sulfonvi)-azepan-4-ylcarbamoyll-butyl)-amide
Following the general procedure of Examples 291c-d except substituting 3,5- dimethyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 571 ÇM+H)*. Séparation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. 278 i 012288
Example 326
Préparation of 3-Ethyl-benzofuran-2-carboxvlic acid KS~)-3-methvl-l-f3-oxo-l-(l-oxv- pyridine-2-sulfonyP)-azepan-4-vlcarbamovll-butyl 1 -amide
Following the general procedure of Examples 291c-d except substituting 3-ethyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the titlecompound as a mixture of diastereomers: MS(ES) 571 (M+H)\ Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2.
Example 327
Préparation of 4-Methoxv-3-methyl-benzofuran-2-carboxylic acid {fS~)-3-methvl-l-F3-oxo- l-fl-oxY-pyridine-2-sulfonyr)-azepan-4-vlcarbamovri-butyl)-amide
Following the general procedure of Examples 291c-d except substituting 4-methoxy-3-methyl-benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-caiboxylic acidprovided the title compound as a mixture of diastereomers: MSÇES) 587 (M+H)\ Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2.
Example 328
Préparation of l-Methvl-naphthof2,l-bl-furan-2-carboxylic acid KS)-3-methyl-l-f3-oxo-l- £1^ —
Following the general procedure of Examples 291c-d except substituting 1-methyl- naphtho[2,l-b]-furan-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 607 (M+H)*. Séparation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. 279 012288
Bxample 329
Préparation of 6-Methoxy-3-methvl-benzofuran-2-carboxvlic acid {(S)-3-methyl-l-r3-oxo- l-( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcafbamovl]-butyl )-amide
Following the general procedure of Examples 291c-d except substituting 6-methoxy-3-methyl-benzofuran-2-carboxyliç acid for 5-fluoro-benzofuran-2-carboxylic acidprovided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1 anddiastereomer 2.
Example 330
Préparation of 3-Methyl-benzofüran-2-carboxylic acid {l,3-dimethvl-l-i3-oxo-l-(T-oxv- pvridine-2-sulfonvl)-azepan-4-ylcarbamovll-butvll-amide a. ) 4-(2-ieri-Butoxycarbonylamino-2,4-dimethyl-pentanoylamino)-3-hydroxy- azepane-l-carboxylic acid benzyl ester
To a solution of N-[(l,l-dimethylethoxy)carbonyl]-2-methyl-(d,l)-leucine (3.0g) inmethlene chloride was added EDC (2.34g), HOBt (1.65g), ΕίβΝ (1.7 ml) and the compoundof Example 280e (3.23 g). After stirring at room température over night the mixture waswashed with 0.1N HCl, Sat. ΝβΗΟΟβ, H2O, Brine. The organic layer was concentrated andresidue was purified by flash column chromatography eluting with CH2CI2 : CH3OH(95:5) to give the title compound as a white solid (4.0g, 66.6%). MS: 492.4 (M+H)+ b. ) [l-(3-Hydroxy-azepan~4-ylcarbamoyl)-l,3-dimethyl-butyl]~carbamic acid tert-butyl ester
To a solution of the compound of Example 330(a) (3.04 g, 8.00 mmol) in ethylacetate (50 mL) was added 10% palladium on carbon (1.5 g). After stirring at roomtempérature under a hydrogen atmosphère for 16 h, the mixture was filtered through celite.The filtrate was concentrated to yield the title compound as a yellow oil (1.97 g, 100%). MS (ESI): 358.4 (M+H)+. 280 { 01228b c. ) {1 - [3-Hy droxy-1 -( 1 -hy droxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-1,3-dimethyl-butyl}-carbamic acid ieri-butyl ester 2-Mercaptane N-oxide (1.25g) was disolved in concentrated HCl (5.5ml). After· 5 cooled to 0°C water (3ml) was added. CI2 gas was bubbled through this solution for 1.5h.Water solution was extacted with cold CH2CI2 then the combined organic layer waswashed with Sat.NaHCC>3, brine. To a solution of the compound of Example 330b (1.20 g)and Et3N (1.3 ml) in DCE (10 ml) was added the sulfonyl chloride which was freshlyprepared above at 0°C. Stirring was kept for lh then the reaction mixture was washed with 10 brine, dried over Na2SC»4, concentrated and purifîed through flash column chromatograpghy eluting with CH2CI2: CH3OH (95:5). The filtrate was concentrated toyield the title compound as white solid (1.2 g, 70%). MS: 515.4 (M+H)+. d. ) 2-Amino-2,4-dimethyl-pentanoic acid [3-hy droxy-l-(hydroxy-pyridine-2-sulfonyl)- azepan-4-yl]-amide 15 To a stirring solution of the compound of Example 330c (1.0g, 2.04 mmol) in methanol (10ml) was added HCl (4M in Dioxane) (10 ml). After stirring at roomtempérature for 3hr, the solution was concentrated to get white solide. To a solution of thewhite solid (0.81g, 1.53mmol, 75%) in methnol (30ml) was added P-CO3 (2.9g,2.63mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the 20 title compound as white solid (0.57g, 1.45mmol, 95%). MS: 415.4 (M+H)+. e. ) 3-Methyl-benzofuran-2-carboxylic acid [l,3-dimethyl-l-[3-hydroxy-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
To a solution of the compound of Example 330d (0.150 g, 0.448 mmol) in CH/Zl, 25 (20 mL) was added 3-methvl henznfuran-?-narboyyHc acidffl ÎOQ g); ΐ------ hydroxybenzotriazole (0.106g, 0.762mmol), and P-EDC (0.85g, lwmol/g) in CHjClj (10mL). After shaking at room température for over night, the solution was treated withtisamine (0.589g, 3.75mmol/g). After shaking for another 2hr, the solution was filtered andconcentrated to yield the title compound as a white solid (166.7mg, 70%). MS (ESI): 30 573.2(M+H)+. 281 υ ί 2288 f.) 3-Methyl-benzofuran-2-carboxylic acid{ l,3-dimethyl-l-[3-oxo-l-(oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
To a stirring solution of the compound of Example 330e (140.7mg, 0.245mmol) inDMSO (2mL) was added Py-SO3 (155.7mg, 0.98mniol) and Et3N (0.27ml, 1.96mmol). 5 After stirring at room température for 2 h. Sat. NaHCO3 and ethyl acetate was added toquench the reaction. Organic layer was washed with brine, dried over Na SO4 andconcentrated.The residue was purified through flash column chromatograghy eluting withCH2CI2 :CH3OH (95:5) to yield the title compound as a white solid (69.9mg, 50.8 %). MS (ESI): 571.2(M+H)+. 10
Example 331
Préparation of Benzofuran-2-carboxylic acid r(S)-3-methyl-l-r3-oxo-l-quinolin-2- vlmethvl-azepan-4-ylcarbamoyn-butyll-amide 15 a. ) [(S)-l-(3-Hydroxy-l-quinoline-2-ylmethyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid rerr-butyl ester
To a solution of the compound of Example 280g (1.0 g) in CHjC^ was added a-quinoline carbaldehyde (0.68 g) and NaBH(OAc)3 (1.2 g). Workup and column 20 chromatography (6% methanol: dichloromethane) provided 1.4 g of the title compound:MS(ES) 485 (M+H)+. b. ) (S)-2-Amino-4-methyl-pentanoic acid (3-hydroxy-l-quinolin-2-methyl-azepan-4-yl)-amide 25 To a solution of the compound of Example 331a (1.4 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred until complété whereupon thereaction was concentrated to provide 1.3 g of the title compound: MS(ES) 385 (M+H)+. 282 ! 01 2288 c. ) Benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-hydroxy-l-quinolin-2-ylmethyl-azepan-4-ylcarbamoyï]-butyl }-amide
Following the general procedure of Example 291c except substituting thecompound of Example 331b and benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 545 (M+H)+. d. ) Benzofuran-2-carboxyIic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyI- azepan -4-y Icarbamoy l]-buty 1}-amide
Following the general procedure of Example 291d except substituting thecompound of Example 331c the title compound was prepared: MS(ES) 543 (M+H)+.
Example 332
Préparation of 3-Methvl-benzofuran-2-carboxvlic acid f(S)-3-methyl-l-r3-oxo-l-quinolin- 2-vlmethyl-azepan-4~yicarbamovl]-butyl)-amide
Following the procedure of Example 331c-d except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxyIic acid the title compound wasprepared: MS(ES) 541 (M+H)\
Example 333
Préparation of Benzorblthiophene-2-carboxvlic acid ffS)-3-methyl-l-r3-oxo-l-quinolin-2- y lmethyl-azepan-4-ylcarbamoyll-butvl 1 -amide
Following the procedure of Example 331c-d except substituting benzo[b]thiophene-2-çarbûxylicacidforbenzofuran-2-carboxylic acidthe title compoündwasprepared:MS(ES) 541 (M+H)+. 283 01 2288
Example 334
Préparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-ri-toluene-2- sulfonylamino~)-methanoyIl-azepan-4-vIcarbamovl 1 -butyl)-amide a. ) ((S)-1 - {3-Hydroxy-l - [ l-(toluene-2-sulfony lamino)-methanoyl]-azepan-4- ylcarbamoyl}-3-methyl-butyl)-carbamic acid iert-butyl ester
To a solution of the compound of Example 280g (1.0 g) in CH3C12 was added o-toluenesulfonyl isocyanate (0.68 g). The reaction was stirred until complété consumptionof the starting material was observed. Workup and column chromatography (6%methanohdichloromethane) provided 1.28 g of the title compound: MS(ES) 541 (M+H)+. b. ) (S)-2-Amino-4-methyl-pentanoic acid {3-hydroxy-l-[l-(toluene-2-sulfonylamino)- methanoyl]-azepan-4-yl }-amide
Following the procedure of Example 283a except substituting the compound ofExample 334a the title compound was prepared: MS(ES)441 (M+H)+. c. ) Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-hydroxy-l-[l-toluene-2- sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedure of Example 280i except substituting the compound ofExample 334b the title compound was prepared: MS(ES) 585 (M+H)+. d. ) Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-2- sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedure of Example 291d except substituting the compound ofExample 334c the title compound was prepared: MS(ES) 583 (M+H)+. 284 01 2288
Example 335
Préparation of 3-Methvl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-Î3-oxo-l-ri- .tolüene-2-SQtfonvlamino)-methanoyll-azepan-4-ylcarbamovn-butyI)-amide
Following the procedures of Example 334c-d except substituting 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound wasprepared: MS(ES) 597 (M+H)+.
Example 336
Préparation of Benzoiblthiophene-2-carboxvlic acid (fS)-3-methyl-l-{3-oxo-l-ri-toIuene- 2-sulfonylamino)-methanovn-azepan-4-vlcarbamovl)-butvl')-amide
Following the procedures of Example 334c-d except substitutingBenzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compoundwas prepared: MS(ES) 599 (M+H)+.
Example 337
Préparation of Benzofuran-2-carboxvlic acid (fS)-3-inethvl-l-{3-oxo-l-f2-chloro- benzenesulfonylamino)-methanoyll-azepan-4-vlcarbamoyl}-butvr)-amide
Following the procedures of Example 334a-d except substituting 2-chlorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound wasprepared: MS(ES) 603 (M+H)+. 285 012288
Example 338
Préparation of 3-Methyl-benzofuran-2-carboxvlic acid (fS)-3-methvl-l-<3-oxo-l-r2-chloro- » benzenesulfonvlamino)-methanoyIl-azepan-4-ylcarbamovl}-butvl)-amide 5
Following the procedures of Example 334a-d except substituting 2-chlorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound wasprepared: MS(ES) 617 (M+H)+- 10
Example 339
Préparation of BenzoMthiophene-2-carboxvlic acid ((S)-3-methvl-l-{3-oxo-l-i2-chloro- benzenesulfonyIamino)-methanovn-azepan-4-vlcarbamoyl)-butvD-amide 15
Following the procedures of Example 334a-d except substituting 2-chlorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylicacid for benzofuran-2-carboxylic acid the title compound was prepared: MSÇES) 619(M+H)\ 20
Example 340
Préparation of Benzofuran-2-carboxvlic acid ((S)-3-methvl-l-i3-oxo-l-i4-fluoro- benzenesulfonvlamino)-methanoyll-azepan-4-vlcarbamovn-butyl)-amide 25
Following the procedures of Example 334a-d except substituting 4-fluorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 587 (M+H)+. 286 ί 012288
Example 341
Préparation of 3-Methvl-bepzofuran-2-carboxvlic acid ((S)-3-methyl-l-{3-oxo-l-r4-fluoro- benzenesulfonvlamino)-methanovl1-azepan-4-vlcarbamovll-butvl)-amide
Following the procedures of Example 334-d except substituting 4-fluorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylicacid for benzofuran-2-carboxylic acid the title compound was prepared: MS (ES) 601(M+H)+-
Example 342
Préparation of Benzorblthiophene-2-carboxylic acid ((S)-3-methvl-l-{3-oxo-l-[4-fluoro- bepzenesulfonylamino)-methanovll-azepan-4-ylcarbamoyl)-butyD-amide
Following the procedures of Example 334a-d except substituting 4-fluorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylicacid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 603(M+H)+.
Example 343
Préparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-ri-toluene-4- sulfonylamino)-methanovll-azepan-4-vlcarbamoyll-butvl)-amide
Following the procedures of Example 334a-d except substituting p-toluenesulfonylisocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS (ES) 583(M+H)+. 287
Example 344 012288
Préparation of 3-Methvl-benzofuran-2-carboxvlic acid ((S)-3-methvl-l-{3-οχο-Ι-ΓΙ- * tohiene-4-sulfonvlamino)-methanovll-azepan-4-vlcarbamovl)-butvr)-amide "
Following the procedures of Example 334a-d except substituting p-toluenesulfonylisocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid_forbenzofuran-2-carboxylic acid the title coxnpound was prepared: MS (ES) 597 (M+H)+.
Example 345
Préparation of Benzorblthiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-fl-toluene- 4-sulfonvlamino)-methanovll-azepan-4-vlcarbamovl)-butyl)-amide
Following the procedures of Example 334a-d except substituting p-toluenesulfonylisocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid forbenzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+.
Example 346
Préparation of Benzofuran-2-carboxylic acid {(S)-3-methvI-l-ri-(6-methyl-pyridin-2- vlmethyl)-3-oxo-azepan-4-ylcarbamovll-butvl)-amide
Following the general procedures of Example 331a-d except substituting 6-methylpyridine-2-aldehyde for α-quinoline carbaldehyde the title compound was prepared: MS(ES)491 (M+H)+.
The diastereomers were separated by HPLC to provide diastereoemr 1 anddiastereomer 2. 288 012288
Example 347
Préparation of 3-Methyl-benzofuran-2-carboxvlic acid ï(S)-3-methvl-l-iT-(6-methyl- pvridin-2-vlmethvl)-3-oxo-azepan-4-ylcarbamovn-butvll-amide 5
Following the general procedures of Example 331a-d except substituting 6-methylpyridine-2-aldehyde for α-quinoline carbaldehyde and 3-methyl-benzofuran-2-carboxylic acid for benzofuran carboxylic acid the title compound was prepared: MS(ES)505 (M+H)+. 10 The diastereomers were separated by HPLC to provide diastereoemr 1 and diastereomer 2.
Example 348 15 Préparation of Benzoiblthiophene-2-carboxylic acid {(S)-3-metbvl-l-fl-f6-methvl-pvridin- 2- ylmethvl)-3-oxo-azepan-4-vlcarbamovll-bntyn-amide
Following the general procedures of Example 331a-d except substituting 6-methylpyridine-2-aldehyde for α-quinoline carbaldehyde and benzo[b]thiophene-2- 20 carboxylic acid for benzofuran carboxylic acid the title compound was prepared: MS(ES)507 (M+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 anddiastereomer 2. 25 Example 349
Préparation of Benzorblthiophene-2-carboxvlic acid KS'>-l-[l-f2-fluoro-phenvlcarbamovl)- 3- oxo-azepan-4-ylcarbamoyll-3-methvl-butyl)-amide 30 a.) {(S)-l-[l-(2-fluorophenylcarbamoyl)-3-hydroxy-azepan~4-ylcarbamoyl]-3~methyl- butylj-carbamic acid tert-butyl ester
To a solution of the compound of Example 280g (0.1 gm, 0.29mmol) dissolved inTHF was added 2-flurophenyl isocyanate (32 ml, 0.29 mmol) and stirred for lhr. THF was 289 012288 removed in vaccuo and the compound was direcüy used in the next step: MS(ES):481.02(M+H)+. b. ) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid 5 (2-fluoro-phenyl)-amide
To a solution of the compound of Example 349a (1.96 g, 4.1 inmol) dissolved inMeOH was added 4M HCl/ dioxane (5ml, 20.3 mmoi) and allowed to stir at RT for 2hr.
Excess reagent was removed in vaccuo and azeotroped with toluene to yield 1.84gm of theproduct. 10 c. ) Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3- hydroxy-azepan-4-yIcarbamoylj-3-methyl-butyl} -amide
To a solution of the compound of Example 349b (0.11 g, 0.28 mmol) dissolved indichloromethane were added P-EDC (0.35 g , 1.8 mmol/g), HOBT ( 0.06 g, 0.49 mmol) and 15 2-benzothiophene carboxylic acid (0.077 gm, 0.432 mmol). The reaction mixture wasshaken for 16 hr. The reaction was continued for one more hour by the addition oftrisamine(0.38 gm, 3.7 mmol/g), followed by the filtration of the product. The product waspurified on a silica gel column to yield 112.5 mg of the product: MS(ES): 541.2(M+H)\ 20 d.) Benzo[b)thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-yIcarbamoyl]-3-methyI-butyl}-amide
To a solution of the compound of example 349c (0.112 g, 0.2 mmol) was dissolvedin dichloromethane followed by the addition of Dess-Martin periodinane (0.175 g, 0.41mmol). The reaction was stirred for lhr followed whereupon it was washed with NajS2O3, 25 NaHCO, and brine. The compound was purified on a silica gel column to yield 78 mg ofthe product as a mixture of diastereomers. Séparation of the diastereomers by HPLCprovided diastereomer 1: MS (ES) 539 (M+H)+ and diastereomer 2: 539 MS(ES) (M+H)+. 290 !
Example 350
Préparation of 3-Methvl~benzofuran-2-carboxylic acid {(S)-l-il-(2-fluoro- phenvicarbamovl)-3-oxo-azepan-4-vlcarbamovn-3-methvl-butylÎ-amide
Following the general procedures of example 349c-d except substituting 3-methyl-benzoforan-2-carboxylic acid for benzo[bJthiophene-2-carboxylic acid the title compoundwas prepared.
Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 537(M+H)* and diastereomer 2: MS(ES) 537 (M+H)L
Example 351
Préparation of 2,4-Dimethvlfuran-3-carboxvlic acid {fS)-l-[l-(2-fluoro-phenvlcarbamoyl)- 3-oxo-azepan-4-vlcarbamovn-3“methvl-butyl ) -amide
Following the general procedures of example 349c-d except substituting 2,4-dimethylfuran-3-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the titlecompound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 501(M+H)+ and diastereomer 2: MS(ES) 501 (M+H)\
Example 352
Préparation of Ouinoxaline-2-carboxylic acid {(S)-l-ri-(2-fluoro-phenylcarbamovl')-3-oxo- azepan-4-ylcarbamoyll-3-methvl-butvl I -amide
Following the general procedures of example 349c-d except substitutingquinoxaline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compoundwas prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 535(M+H)+ and diastereomer 2: MS(ES) 535 (M+H)*. 291 Ο12288
Example 353 r
Préparation of Thienoi3.2-blthiophene-2-carboxylic acid {(S)-l-fl-(2-fiuoro- w phenvlcarbamovl)-3-oxo-azepan-4-vlcarbamoyl1-3-methvl-butvll-aiaide
Following the general procedures of example 349c-d except substitutingthieno[3,2-b]thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxyIic acid the titlecompound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS (ES) 545(M+H)+ and diastereomer 2: MS(ES) 545 (M+H)+.
Example 354
Préparation of Quinoline-2-carboxylic acid {(S)-l-il-(2-fluoro-phenylcarbamovl)-3-oxo- azepan-4-ylcarbamoyll-3-methvl-butyl 1 -amide
Following the general procedures of example 349c-d except substituting quinoline-2-carboxylic acid_for benzo[b]thiophene-2-carboxylic acid the title compound wasprepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 534(M+H)+ and diastereomer 2: MS(ES) 534 (M+Hf.
Example 355
Préparation of 4-MethvI-thiophene-2-carboxvlic acid {fS)-l-il-(2~fluoro- phepvlcarbamovl)-3-oxo-azepan-4-vlcarbamoyll-3-methyl-butyl 1 -amide
Following the general procedures of example 349c-d except substituting 4-methyl-(hiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compoundwas prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS (ES) 503(M+H)+ and diastereomer 2: M5(ES) 503 (M+H)+. 292 01 2288
Example 356
Préparation of 5-Methoxy-benzofuran-2-carboxvlic acid KSl-1-ί l-(2-fluoro- phenvlcarbamovl)-3-oxo-azepan-4-vIcarbamovn-3-methvl-butvn-amide
Following the general procedures of example 349c-d except substituting 5-methoxy-benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the titlecompound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 553(M+H)+ and diastereomer 2: MS(ES) 553 (M+H)+.
Example 357
Préparation of 4-Methyl-furan-2-carboxvlic acid KS)-l-Fl-(2-fluoro-phenvlcarbamoyl)-3- oxo-azepan-4-ylcarbamovll-3-methyl-butvl ) -amide
Following the general procedures of example 349c-d except substituting 4-methyl-furan-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound wasprepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 487(M+H)+ and diastereomer 2: MS (ES) 487 (M+H)+.
Example 358
Préparation of Benzofuran-2-carboxvlic acid r(S)-l-(l-butvl-3-oxo-azepan-4-ylcarbamovl) 3-methvI-butvll-amide
Following the general procedure of Examples 331a-d except substitutingbutyraldéhyde for α-quinoline carbaldehyde the title compound was prepared. Séparationof the diastereomers by HPLC provided diastereomer 1: MS(ES) 441.9 (M+H)+ anddiastereomer 2: MS(ES) 441.9 (M+H)+. 293 01 2288
Example 359 r>-
Préparation of Benzofuran-2-carboxvlic acid rÇS)-l-Çl-propvl-3-oxo-azepan-4- „ vlcarbamovl)-3-methvl-butyll-amide
Following the general procedure of Examples 331a-d except substitutingpropionaldéhyde for α-quinoline carbaldehyde the title compound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 428 ÇM+H)+and diastereomer 2: MS(ES) 428 (M+H)+.
Example 360
Préparation of Benzofuran-2-carboxylic acid {(S)-l-[l-( 494.2)-3-oxo-azepan-4- y lcarbamoyl]-3-methyl-butyl} -amide
Following the general procedure of Examples 331a-d except substituting 2-fluorobenzaldeyde for α-quinoline carbaldehyde the title compound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) (M+H)+ anddiastereomer 2: MSÇES) 494.2 ÇM+H)+.
Example 361
Préparation of Benzofuran-2-carboxylic acid {ÇS)-3-methvl-l-ri-Ç2-morpholin-4-yl-thiazol- 4-ylmethyl)-3-oxo-a2epan-4-ylcarbamovll-butyl)-amide
Following the general procedure of Examples 331a-d except substituting 2-morpholin-4-yl-thiazole-4-carbaldehyde for α-quinoline carbaldehyde the title compoundwas prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 568.2 ÇM+H)+ and diastereomer 2: MSÇES) 568.4 ÇM+H)+· 294 01 228»
Example 362
Préparation of Benzofuran-2-carboxylic acid l(S~)-l-ri-(,5-ethyl-furan-2-ylmethvD-3-oxo- azepan-4-vlcarbamoyll-3-methyl-butvll-amide 5
Following the general procedure of Examples 331a-d except substituting 5-ethyl-2-furaldehyde for α-quinoline carbaldehyde the title compound was prepared. Séparation ofthe diastereomers by HPLC provided diastereomer 1: MS(ES) 549.4 (M+H)+ anddiastereomer 2: MS(ES) 549.4 (M+H)+. 10
Example 363
Préparation of Benzofüran-2-carboxylic acid {(S)-l-ri-(3,4-dimethvl-thienor3,2- bHhiophene-2-vlmethvB-3-oxo-azepan-4-vlcarbamovll-3-rnethvl-butvl)-amide 15
Following the general procedure of Examples 331a-d except substituting 3,4-diemethylthieno[b]thiophene-2-carboxaldehyde for α-quinoline carbaldehyde the titlecompound was prepared. Séparation of the diastereomers by HPLC provided diastereomer1: MS(ES) 566.2 (M+H)+ and diastereomer 2: MS(ES) 566.2 (M+H)+. 20
Example 364
Préparation of Benzofuran-2-carboxvlic acid f(S)-3-methvl-l-f3-oxol-f3-phenvl-3H- Γ1,2,31triazol-4-vlroethyl)-azepan-4-ylcarbamoyll-butyl 1 -arnide 25
Following the general procedure of Examples 331a-d except substituting 2-phenyl-2H-pyrazole-3-carbaldehyde for α-quinoline carbaldehyde the title compound wasprepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES)543.2 (M+H)* and diastereomer 2: MS(ES) 543.4 (M+H)*. 30 295 01 2288
Example 365 r
Préparation of Benzofuran-2-carboxvlic acid r(S)-141-(isothiazol-3-ylmethvl-3-oxo- azepan-4-vlcafbamovl~)-3-methvl-butvll-amide
Following the general procedure of Examples 331a-d except substitutingisothiazole-3-carbaldehyde for α-quinoline carbaldebyde the title compound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 483.1 (M+H)+and diastereomer 2: MS(ES) 483.1 (M+H)+.
Example 366
Préparation of Benzofuran-2-earboxylic acid IYS~)-3-methyl-l-(3-oxo-l-thiophen-2- vlmethvl-a2epan-4-vlcarbamoyr)-bütvil-amide
Following the general procedure of Examples 331a-d except substitutingthiophene-2-carbaldehyde for α-quinoline carbaldehyde the title compound was prepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 582 (M+H)+and diastereomer 2: MS(ES) 582 (M+H)+.
Example 367
Préparation of Benzofuran-2-carboxvlic acid rfS~)-3-methvl-l-(3-oxo-l-thiophen-2- vlmethyl-azepan-4-vlcarbamovl')-butyl1-amide
Following the general procedure of Examples 331a-d except substitutingbenzo[b]thiophene-2-carbaldehyde for ce-quinoline carbaldebyde the title compound wasprepared. Séparation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 546(M+H)+ and diastereomer 2: MS(ES) 546 (M+H)+. 296 ί 012283
Exampie 368
Préparation of Benzofuran-2-carboxviic acid r(S)-3-methyl-l-(3-oxo-l-pentyl-azepan-4- ylcarbamovD-butvll-amide
Following the general procedure of Examples 331a-d except substituting pentanalfor α-quinoline carbaldehyde the title compound was prepared. Séparation of thediastereomers by HPLC provided diastereomer 1: MS (ES) 556 (M+H)* and diastereomer 2:MS(ES) 556 (M+H)*.
Example 369
Préparation of Benzofuran-2-carboxylic acid {(S)-3-methvl-l-fl-(l-methvl-lH-imidazol-2- vlmethvl)-3-oxo-azepan-4-ylcarbamovn-butyl-anude
Following the general procedure of Exampîes 331a-d except Substituting 3-methyl-3H-imidazole-4-carbaldehyde for α-quinoline carbaldehyde the title compound wasprepared: MS(ES) 480.4 (M+H)*.
Example 370
Préparation of l-Oxy-pvridine-2-carboxylic acid {(SV3-methvl-l-F3-oxo-l-Î'pvridine-2- sulfonyl)-azepan-4-vlcarbamoyl 1-butvl )-amide
Following the procedure of Example 280h-j except substituting l-oxy-pyridine-2-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Séparation of thediastereomers by HPLC gave diastereomer 1 (ESMS: M+H* = 504.2) and diastereomer 2(ESMS: M+H* = 504.2). 297 288 •w
Example 371
Préparation of 2-Oxy-pyridine-3-carboxylic acid i(S)-3-methyl-l-i3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-vlcarbamoyl 1-butyl l-am *
Following the procedure of Example 280h-j except substituting 2-oxy-pyridine-3-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Séparation of thediastereomers by HPLC gave diastereomer 1 (ESMS: M+ϊΓ = 504.2) and diastereomer 2(ESMS: M+îT = 504.2).
Example 372
Préparation of lH-Benzoimidazole-5-carboxylic acid {(S)-3-methyl-l-i3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-vlcarbamoyl1-butvll-amide
Following the procedure of Example 280h-j except substituting 1H-benzoimidazole-5-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the titlecompound. Séparation of the diastereomers by HPLC gave diastereomer 1 (ESMS: Μ+ΕΓ= 504.2) and diastereomer 2 (ESMS: M+H" = 504.2).
Example 373
Préparation of 4-( (S)-2-i(l-Benzofran-2-yl-methanovl)-aminol-4-methvl- pentanoylammo1 - l-methvl-3-oxo- 1-pentyl-azepanium A solution of the compound of Example 368 in neat methyl iodide was heated atreflux for 48 hours whereupon the mixture was concentrated to provide the title compound:MS(ES) 471.6 (M+H)+- 298 01228«
Example 374
Préparation of Benzofuran-2- carboxvlic acid i(S)-l-il-(l,2-dimethyl-l H -imidazole-4- sulfonyb-3-oxo-azepan-4-vlcarbamovll-3-methyl-butyl)-amide
Following tbe procedure of Example 280h-j except substituting 1,2-dimethyl-l H -imidazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the titlecompound: MS(ES) 544.4 (M+H)+.
Example 375
Préparation of Benzofuran-2- carboxvlic acid {(S)-l-ri-(f-raethyl-l H -imidazole-4- sulfonyB-3-oxo-azepan-4-vIcarbamoyll-3-methvl-butvn-amide
Following the procedure of Example 280h-j except substituting 1-methyl-l H -imidazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the titlecompound: MSÇES) 530.2 (M+H)\
Example 376
Préparation of Benzofuran-2- carboxvlic acid {(Sl-l-il-d-methvl-l H -imidazole-4- sulfonyl)-3-oxo-azepan-4-vlcarbamovll-3-methvl-butvH-amide
Following the procedure of Example 280h-j except substituting 4-methanesulfonyl-benzenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the titlecompound. Séparation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 604.2(M+H)+ and diastereomer 2: MSÇES) 604.2 (M+H)+. 299 01 2288
Example 377
Préparation of Benzofuran-2-carboxylic acid {fS)-l-il-(2-metbanesulfopyl- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamovl1-3-methvl-butyl ) -amids
Following the procedure of Example 280h-j except substituting 2-methanesulfonyl-benzenesulfonyl chloride for 3-fIuorobenzenesulfonyl chloride provided the titlecompound. Séparation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 604.2(M+H)+ and diastereomer 2: MS(ES) 604.2 (M+H)+·
Example 378
Préparation of Benzofuran-2-carboxylic acid KS~)-l-il-f3,5-dimethvl-isoxazole-4- sulfonvO-S-oxo-azepan-^-ylcarbamov 11-3-methyI-butyl l-amide
Following the procedure of Example 280h-j except substituting 3,5-dimethyl-isoxazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the titlecompound. Séparation of the diastereomers by HPLC gave diastereomer 1: MSÇES) 545.2(M+H)+ and diastereomer 2: MS(ES) 545.2 (M+H)+.
Example 379
Préparation of 3-Methvl-benzofuran-2-carboxvlic acid f(lS.2R)-2-methvl-l-i3-oxo-l- (pvridine-2-suIfonvD-azepap-4-ylcarbamoyll-butyl)-amide a.) 3-MethyI-benzofuran-2-carboxylic acid {(lS,2R)-2-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide
Following the general proceures of Example 280f-i except substituting N-Boc-allo- isoleucine for N-Boc-leucine and 2-pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared. 300 012288 b.) 3-Methyl-benzofuran-2-carboxylic acid {(lS,2R)-2-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoylJ-butyl}-amide * Following the general procedure of Example 29 ld except substituting the compound of Example 105b the title compound was prepared. Séparation of the 5 diastereomers by HPLC provided diastereomer 1: MS (ES) 541 (M+H)+ and diastereomer 2: MSÇES) 541 10 Example 380 Préparation of 3-Methvl-benzofuran-2-carboxvlic acid T 143-oxo-l-(pvridme-2-sulfonvl)- azepan-4-vlcarbamovll-cvclopentvll-amide 15 Following the general procedures of Examples 379a-b except substituting N-Boc- cycloleucine for N-Boc-allo-leucine the title compound was prepared: MSÇES) 539 (M+H)+. Example 381 20 l Préparation of Furor3,2-bl-pvridine-2-carboxvlic acid f(S)-3-methvl-l-F-3-oxo-l-fl-oxv- ovridine-2-sulfonvl)-azepan-4-Ylcarbamovn-butvll-ainide 25 Following the general procedure of Examples 291c-d except substituting furo [3,2-b]-pyridine-2-carboxylic acid for 5-fluoro-benzofhran-2-carboxylic acid provided the titlecompound as a mixture of diastereomers: MSÇES) 587 (M+H)+. Séparation of the diastereomers by HPLC provided diastereomer 1: MSÇES) 544.2(M+H)+ and diastereomer 2: MSÇES) 544.2 (M+H)+. 30 The above spécification and Examples fully disclose how to make and use thecompounds of the présent invention. However, the présent invention is not limited to theparticular embodiments described hereinabove, but includes ail modifications thereof within the scope of the following daims. The various references to joumals, patents and other publications which are cited herein comprise the State of the art and are incorporated herein by référencé as though fully set forth. 301

Claims (33)

  1. 01 2288 r We daim:
    1. A compound of Formula IA:
    IA wherein: RJ is selected from the group consisting of:
    R- is selected from the group consisting of: Cj.galkyl, Ar-CQ-galkyl, Het-CQ-galkyl, R9C(O)-, R9SO2-, R9r! ^0(0)-, and R9SO2RUNC(O)-; R^ is Cj-galkyl; R4 is R5C(O)-, R^ is Het-CQ.galkyl; R9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-CQ_6alkyl,Ar-CQ-galkyl and Het-CQ_galkyl; R11 is selected from the group consisting of: H, Cpgalkyl, Ar-Co-galkyl, and Het-C()_6alkyl; R’ is H; R” is H; R’” is H; R”” is selected from the group consisting of: Ci-6alkyl, Cj.gcycloalkyl-CQ^alkylC2-6alkenyl, C2-6alkynyl, HetCQ-galkyl and ArCQ_galkyl; 302 012288 n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvatés thereof.
  2. 2. A compound according to Claim 1 wherein R^ is R' 4/
  3. 3. A compound according to Claim 1 wherein R^ is selected from the groupconsisting of: isobutyl and but-2-yl. 10 15 20 25
  4. 4. A compound according to Claim 3 wherein R^ is isobutyl.
  5. 5. A compound according to Claim 1 wherein R^ is selected from the groupconsisting of: piperidinyl-ethyl;benzo[ 1,3]dioxolyl; furanyl, aryl substituted furanyl, Cj.gallcyl substituted furanyl;benzofuranyl, Cj.galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, Cj.galkyl substituted benzofuranyl; napththo[2,l-b]-furanyl, C^galkyl substituted napththo[2,l-b]-furanyl;benzo[b]thiophenyl; quinolinyl; quinoxalinyl; 1-oxy-pyridinyl; furo[3,2-b]-pyridinyl, Cj.galkyl substituted furo[3,2-b]-pyridinyl;thiophenyl, Cj.galkyl substituted thiophenyl;thieno[3,2-h]thiophenyl; and lH-benzoïmidazol-S-yl.
  6. 6. A compound according to Claim X wherein is selected from the groupconsisting of: 30 piperidin-l-yl-ethyl; benzo [ 1,3]dioxol-5-yl, 303 012288 furan-2-yl; benzofuran-2-yl; napththo[2, l-b]-furan-2-yl benzo[&amp;]thiophen-2-yl; quinolin-2-yl; quinoxalin-2-yl; l-oxy-pyridin-2~yl, l-oxy-pyridin-3-yl; furo[3,2-b]-pyridin-2-yl; thiophene-2-yl; thieno[3,2-£]thiophene-2-yl; andlH-benzoimidazol-5-yl.
  7. 7. A compound according to Claim 1 wherein R-5 is selected from the groupconsisting of: 5-(3-trifluoromethyl-phenyl)-furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2.5- dimethyl-furan-2-yl, 2,4-dimethyl-furan-2-yl; 5-methoxy-benzofura-2-yl, 5-iluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3.5- dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl,5-methoxy-3-methyl~benzofuran-2~yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2~yl; 1 -inethy l-naphtho[2,1 -b]-furan-2-yl; 5-methyl-thiophen-2-yl, and3-methyl-furo [3,2b]pyridin-2-yl.
  8. 8. A compound according to Claim 1 wherein RP is selected from the groupconsisting of: 3-methyI-benzofuran-2-yl, thieno[3,2-bJthiophen-2-yl, 5-methoxybenzofuran-2~yl, quinoxalin-2-yl, and quinolin-2-yl.
  9. 9. A compound according to Claim 1 wherein R^ is
  10. 10. A compound according to Claim 9 wherein R’”’ is Ci_6alkyl. 304 10 10 15 '11. 15 20 20 25 25 012288 A compound according to Claim 10 wherein Ci-galkyl is methyl. R’ O
  11. 12. A compound according to Claim 1 wherein is ~ n
  12. 13. A compound according to Claim 12 wherein n is 3.
  13. 14. A compound according to Claim 1 wherein R^ is selected from the groupconsisting of: ethyl, and Cg.gcycloalkyl-substituted ethyl·, propyl; butyl; isopentyl; phenyl, especially halogen substituted phenyl, Cj.galkyl substituted phenyl,Cj.galkylsulfonyl substituted phenyl;pyridinyl, Cj.galkyl substituted pyridinyl; 1-oxy-pyridinyl; and isoxazolyl, C^galkyl substituted isoxazolyl.
  14. 15. A compound according to Claim 1 wherein R^ js selected from the groupconsisting of: cyclohexyl-ethyl; prop-l-yl but-l-yl; 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl,4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; pyridin-2-yl, l-oxy-pyridin-2-yl; l,2-dimethyl-lH-imidazoî-2-yl, l-methyl-lH-imidazol-2-yl, and3,5-dimethyl-isoxazol-4-yl.
  15. 16. A compound according to Claim 1 wherein is selected from the groupconsisting of: Cj_galkyl, Ar-Co-galltyl and Het-CQ_gallcyl. 305 01228®
  16. 17. A compound according to Claim 16 wherein is selected frein the group * consisting of: C j.galkyl and Het-CQ.galkyl. #
  17. 18. A compound according to Claim 17 wherein Cj.galkyl and Het-CQ_gaikyl are selected from the group consisting of: Het-substituted methyl and pentyl.
  18. 19. A compound according to Claim 18 wherein Het-substituted methyl is selected from the group consisting of: quinolin-2-ylmethyl; 6-methyl~pyridin-2-ylmethyl; 2- morpholin-4-yl-thiazol~4-ylmethyl; 5-ethyl-furan-2-ylmethyl; 3,4dimethyl-tliieno[3,2-b]thiophene-2-ylmelhyl; 3- phenyl-3H- [ 1,2,3]triazol-4-ylmethyl;isothiazol-3-ylmethy 1 ;thiophen-2-ylrnethyl ;benzo[b]thiophen-2-ylmethyl; and 1 -methyl- lH-imidazol-2-yhnethyl.
  19. 20. A compound according to Claim 1 wherein R- is selected from the groupconsisting of: Ai-Co-ô^yl R9C(O)-, R9SO2, and r9ruNC(O)-.
  20. 21. A compound according to Claim 20 wherein is selected from the groupconsisting of: Ar-Co-galkyl, R9C(O)-, and R9SQ2.
  21. 22. A compound according to Claim 21 wherein R^ is r9sO2.
  22. 23. A compound according to Claim 22 wherein R9 is selected from the groupconsisting of: C^galkyl, Ar-CQ_galkyl and Het-CQ.gaîkyl.
  23. 24. A compound according to Claim 1 wherein: 306 012288
    R2isR9SO2; and R2 is isobutyl; R9 is selected from the group consisîing of: C-^galkyl, Ar-CQ.galkyl and Het- Co_galkyl.
  24. 25. A compound according to Claim 24 wherein: R5 is selected from the group consisting of: 10 piperidinyl-ethyl; benzo [ 1,3]dioxolyl; furanyl., aryl substituted furanyl, C|_galkyl substituted furanyl;benzofuranyl, Cq.galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, Cq.galkyl substituted benzofuranyl; 15 napththo[2,l-b]-furanyl, Cj.galkyl substituted napththo[2,l-b]-furanyl; benzo[è]thiophenyl;quinolinyl;quinoxalinyl; 1-oxy-pyridinyl; 20 furo[3,2-b]-pyridinyl, Cj _galkyl substituted furo[3,2-b]-pyridinyl; thiophenyl, C^galkyl substituted thiophenyl;thieno [3,2-b] thiophenyl; and lH-benzoimidazol-5-yl; andR9 is selected from the group consisting of: 25 ethyl, Cg^cycloalkyl-substituted ethyl; propyl;butyl;isopentyl; halogen substituted phenyl, C^galkyl substituted phenyl, C^galkylsulfonyl 30 substituted phenyl; pyridinyl, Cpgaîkyl substituted pyridinyl; 307 012288 1-oxy-pyridinyl; and isoxazolyl, C^galkyl substituted isoxazolyl.
  25. 26. A compound according to Claim 24 wherein: is selected from the groupconsisting of: piperidin-1 -y 1-ethy 1;benzo [ 1,3]dioxol-5-y] ;furan-2-yl;benzofuran-2-yl;napththo[2, l-b]-furan-2-ylbenzo[&amp;]thiophen-2-yl;quinoliu-2-yl;quinoxalin-2-yl; l-oxy-pyridin~2-yl, l-oxy-pyridin-3-yl;furo [3,2-b] -pyridin-2-yl;thiophene-2-yl; thieno[3,2-Z>]thiophene-2-yl; andlH-benzoimidazol-5-yl.
  26. 27. A compound according to Claim 24 wherein js selected from the groupconsisting of: 5-(3-triflouromethyl-phenyl)-furan~2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2.5- dimethyl-furan-2-yl, 2,4-dimethyl-furan-2-yl; 5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3.5- dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl~benzofuran-2-yl,5-methoxy-3-methyl-benzofuran-2-yl, 4-meÜioxy-3-methyî-benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; 1 -methyl~naphtho[2, l-b]~furan-2-yl; 5-metliyl-thiophen-2-yl, and3~methyl-furo[3,2b3pyridin-2-yl.
  27. 28. A compound according to Claim 24 wherein R^ is selected from the groupconsisting of: 308 01 2288 cyclohexyl-ethyl; prop-l-yl but-l-yl; 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl,5 4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; pyridin-2-yl, l-oxy-pyridin-2-yl; l,2-dimethyl-lH-imidazol-2-yl, l-methyl-lH-imidazol-2-yl, and 3,5-dimethyI-isoxazol-4-yl. 10 29. A compound according to Claim 24 wherein: R5 is selected from the group consisting of: 3-methyl-benzofaran-2-yl,thieno[3,2-b]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, or quinolin-2-yl;and 15 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
  28. 30. A compound according to Claim 29 wberein is 3-methyl-benzofuran-2-yl.
  29. 31. A compound according to Claim 30 wberein R^ is l-oxy-pyridin-2-yl. 20
  30. 32. A compound according to Claim 1 selected from the group consisting of:Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-l -butyl} -amide; (S)-4-methyl-2-(3-piperidin-l-yl-propanoylamino)-pentaooic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yI]-amide; Benzofuran-2-caxboxylic acid {(S)-l-[-(4-ethyl-benzensulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-1 -[1 -( l-oxy-pyridin-2-yl)-methanoyl]~azepan-4-ylcarbamoyl} -butyl)-arnide; Benzo[l,3]-dioxole-5-carboxylic acid((S)-3-methyl-l-{3-oxo-l-[l-oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; 309 01 2288 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(3- cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyrj-3-methyl-butyl}- amide; Benzo[l ,3]-dioxole-5~carboxylic acid {(S)- l-[l-(3-cyclohexyl-propanoyl)- 3-oxo-azepan-4-ylcarbamoyl3-3-metbyl-butyl}-amide;5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(4-methyl-pentanoyl)-3-oxo-azepau-4-ylcarbamoyl]-3-methyl~butyl }-amide;Benzo[l,3]-dioxole-5-carboxyIic acid {(S)-l-[l-(4-methyl-pentauoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4~ylcarbamoyl]-3-niethyl-l-butyl}- amide; Beuzofuran-2-carboxylic acid [(S)~l-[3-oxo-l-(ethanesulfonyl-azepan-4-y!carbamoyl)-3-methyl-l-butyl]- amide;
    5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyï-ï-[3-oxo-1-( 1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
    5- Fluoro-3-methyl-benzofurao-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-1 -( 1 -oxy-pyridme-2-sulfony l)-azepan-4-y lcarbamoyl]-butyl} -amide ;
    6- Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
    3-Metiiyl-benzofuran-2-carboxylic acid {(R)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;3-Methyl-furo[3.2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-l-[-3-oxo-l-(lOxy-pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-bntyl}-aniide;5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfoxiyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;3-Methyl-benzofuran-2~carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-meihyl-butyl}-amide;Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;3-methyl-furan-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3~oxo-azepan-4-ylcarbamoyl]-3-methyl~butyl}-anride; QuinoIine-2-carboxyiic acid {(S)~l-[l-(3-fluoro-benzenesulfonyl)-3-oxo- -azepan-4~ylcarbamoyl] -3-methyl-butyl }-amide ; 310 012288 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fiuoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-anâde;Quinoxaline-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Thiopheue-2-carboxyIic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl3-3-methyl-butyl} -amide;
    5-Methyl~Üûophene-2-carboxylic acid {(S)-l-[l-(3~fluoro-benzenesulfonyl)-3-oxo-azepau-4-ylcarbamoyl]-3-methyl-butyl}-amide;5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
    3-Methyl-benzofuran-2-carboxyIic acid [(S)-l-(l-ethanesnlfonyl-3-oxo-azepan-4-yicarbamoyI)-3-methyl-butyl]-aniide; Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4~yIcarbamoyl)-3-methyl“butyI]-ainide;
    3- Methyl-furan-2-carboxylic acid [(S)-l-(l-ethanesuifonyl-3-oxo-azepan- 4- ylcarbamoyl)-3-metbyl-butyl]-amide; Quinoline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyi)-3-methyl-butyl]-ainide; / Quiaoxaline-2-carboxyiic acid [(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butylj-amide; Thiophene-2-carboxylic acid [(S)-l-(l“ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
    5- Metbyi-thiophene-2-carboxylic acid [(S)-l-(l-Êthanesulfûnyl-3-oxo-azepan~4-ylcarbamoyl)-3-methyl-butyl]-amide;5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyI]-3-methyl-l-butyl}-amide;3-Methyl-beazofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide;Benzo[b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- 1-butyl}-amide; 311 012288
    3- Methyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbainoyl]-3-methyl-l-butyl}-amide; 2,5-Dimethyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan~4-y lcarbamoyl]-3-methyl-1 -butyl}-amide ; Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan- 4- ylcarbamoyl]-3-methyl-1 -butyl}-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepau-4-ylcarbamoyl3-3-inethyl- 1-butyl }-amide; Quinoxaline-2-carboxylic acid {(S)- l-[3-oxo- l-(propane-1 -sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-1 -butyl} -amide; Thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)~ azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
    5- Methyl-thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-niethyl-l-butyl}-amide;
    5- Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepau-4-ylcarbamoyl]-butyl}-amide; 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yIcarbamoyï]-butyl}-amide;
    3- Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoyl] -butyl} -amide ;
    4- Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridiue-2-sulfouyl)-azepan-4-ylcarbamoyl]-butyl}-amide;l-methyl-naphtho[2,l-b]-furan-2-carboxylic acid {(S)-3-metbyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]~butyl}-amide;
    6- Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-metbyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;3-Methyl-benzofuran-2-carboxylic acid {l,3-dimethyl-l-[3-oxo-l-(l-oxy-pyi'idine-2-sulfonyl)-azepan-4-ylcarbamoyI]-butyl}-atnide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-f3-oxo-l-quinoliii-2-ylmetliyl-azepan-4-ylcarbamoyl]-butyl}-amide;
    3-Methyl-benzofuran-2-carboxylic acid [(S)-3-metbyl-l-[3-oxo-l-quinolm-2-ylmetbyl-azepan-4-ylcarbamoyl3-butyl}-amide; 312 012288 Benzo[b]thiophene-2-carboxylic acid [(S)-3-metbyl-l-[3-oxo-l-quinolin-2-T, ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-2-sulfonylaxnino)-metbaiioyl]-azepan-4-ylcarbaDioyl} -butyl)-amide;3-Methyl~bsnzofuran-2-carboxylic acid ((S)-3-meihyl-l-{3-oxo-l-[l-toluene-2“Sulfonylarnino)-meihanoyl]-azepan-4-ylcarbamoyl}-butyl)~amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-2-sulfonylamino)-rnethanoyl]-azepan-4-ylcarbamoyl}~butyl)·- amide; Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-methaiîoyl3-azepan-4-ylcaibamoyl}-bntyl)-amide;3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro-benzenesulfonylamino)-xnethanoyl]-azepan-4-ylcarbamoyl} -butyl)-amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-1-{ 3-oxo-l-[2-chloro-benzenesulfonylamino)-methanoyl3-azepaii-4-ylcarbamoyl} -butyl)-amide;Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyi}-butyl)-amide;3-Methyl-benzofuran-2-carboxyIic acid ((S)-3-methyl-l-{3~oxo-l-[4- t fluoro-benzenesuIfonylamixio)~methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl~l-{3-oxo-l-[4-fluoro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbanioyl }-butyI)-amide;Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-4-sulfonylamino)-methanoyl]-azepan-4-yicarbanioyl}-butyl)-amide;3-Methyl-beuzofuran-2-carboxylic acid «S)-3-methyl-l-{3-oxo-l-[l-toluene-4-sulfonylamino)-methai)oyl]~azepan-4-ylcarbamoyl}-butyi)-amide; Benzo[b]thiophene-2-carboxyiic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-4-sulfonylamino)~methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide; 313 012288 Benzofuran-2-carboxylic acid {(S)~3-methyl-l-[l-(6-methyl-pyridin-2-ylmethyl)-3~oxo-azepan'4--ylcaxbamoyl]-butyl}-amide;3-MetIiyl-benzoiiiran~2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin~2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amxde;Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridin-2-yImelhyl)-3-oxo-azepan-4’ylcarbamoyl]-butyl}-amids;Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyi)-3-oxo-azepan~4-ylcarbamoyl]-3-methyl-butyl}-ainide;
    3- Methyl-benzofuran-2'carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3~oxo-azepan-4-ylcarbamoyl]-3-methyl“butyl}-amide;2,4~Dimethylfuran-3-carboxylic acid {(S)-l-[l-(2-fluoro-pIienylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyî-butyl}-amide;Quinoxaline-2-carboxylic acid {(S)-1 -[ 1 -(2-fluoro-phenylcarbamoyl)-3-oxo-azepaii~4--ylcarbamoyl]-3-methyl-butyl}-aniide;Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcaibamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;Quinoline-2-carboxylic acid {(S)-l~[l-(2-.fluoro-phenylcarbamoyl)-3~oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
    4- Metbyl-thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-yIcarbamoyI]-3-methyI-butyl}-amide;
    5- Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenyîcarbainoyl)-3-oxo-azepan-4-ylcarbamoylj -3-methyl-butyl} -amide;4-Methyl-furan-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid [(S)-l-(l-butyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid [(S)-l-(l-propyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]~axaide; Benzofuran-2-carboxyiic acid {(S)-l-[l-(2-fluoro-benzyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-morpholin-4-yl-thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}~amide; 314 û i 2288 Benzofuran-2-carboxylic acid {(S)-l-[l-(5-ethyl-furan-2-ylinethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(3,4-dimethyl-thieno[3,2-Z?]thiophene-2-y Imethy l)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide; Benzofuran-2-carboxylic acid {(5)-3-methyl-l-[3-oxo-l-(3-phenyl~3H- [l,2,3]triazol-4-ylmethyl)-azepan-4~ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid [(S)-l-[l-(isothiazol-3-ylrnethyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl~butyl}-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-thiophen-2- ylmethyl-azepan-4-ylcarbaaioyl)-butyl]-ainide; Benzofuran-2-carboxylic acid [(S)-l-(l-benzo[b]thiophen-2-ylmethyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid [(S>3-methyl-l-(3-oxo-l-pentyl-azepan-4-ylcarbamoyl)-butyl]-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazol-2-y Imethy l)-3-oxo-azepan-4-ylcarbamoyl]-buty} -amide;
    1- Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl ]-butyl}-amide;
    2- Oxy-pyridine-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl J-butyl} -araide;lH-Benzoinùdazole-5-cafboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-arnide; 4- {(S)-2~[( l-Benzofuran-2-yl-methanoyl)-araino]-4-methyl-pentanoylamino}-l-methyl-3-oxo-l-pentyl-azepaniura; Benzofuran-2- carboxylic acid {(S)-l-[l-(l,2-dimethyl-l H-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcafbamoyl]-3-methyI-butyl}-amide; Benzofuran-2- carboxylic acid {(S)-l-[l-(l-methyl-l H -imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methanesulfonyl-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl} -amide ;Benzofuran-2-carboxyîic acid {(S)-l-[l-(2-methanesulfonyl-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 315 01 2288 „ Benzofuran-2-carboxylic acid {(S)-i-[l'(3,5-dnnethyl-isoxazole-4- suîfonyl)-3-oxo-azepan-4-ylcarbamoy l]-3-methyl-butyl}-amide;
    3-Methyl-benzofuran-2-carboxylic acid {(lS,2R)~2-methyl-1-[3-oxo- 1- (pyridine-2-sulfonyl)-azspaii-4-ylcarbamoyl]-butyl}-amide;
    3-Methyl-benzofuran-2-carboxylic acid {l-[3-oxo-l-(pyridine-2-sulfonyl)- . θ azepan-4-ylcaîbamoyl]-cyclopeatyl }-amide; and Furo [3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyi- l-[-3-oxo-1-( 1 -oxy-pyridine-2-sulfonyl)-azepan~4-ylcaibamoyl]-butyl} -anaide.
  31. 33. A pfaarmaceutical composition comprising a compound according to any one ofClaims 1 to 32 and a phannaceutically acceptable carrier, diluent or excipient.
  32. 34 . A compound of Formula HA: 20
    wherein: Rl is selected froro the group consisting of:
    25 is selected frora the group consisting of: Cp.galkyl, Ar-CQ.gaIkyl, Het-Cp.6alkyl, R9C(O)-, R9SÜ2-, R9RnNC(O)~, and R9SO2RnNC(O)~;
    3 U
    R.3 is Ci_6alkyl; R3 4 is R5C(O)~, R5 is Het-C0.6alkyl; R^ is selected fromthe group consisting of: Cpgalkyl, C^.gcycloalkyl-CQ.galkyl,Ar-CQ-galkyl and Het-C^galkyl; RÜ is selected from the group consisting of: H, Cj.galkyl, Ar-Co-6alkyl, and Het-C0-6alkyl; R’is H; R”is H; R”’is H; R””is selected from the group consisting of: Ci-^alkyl, Cy.gcycloalkyl-CQ.galkylC2-6alkenyl, HetCQ.galkyî and ArCQ.galkyl; and n is an integer from l'to 5; and salts, hydrates and solvatés thereof. A process for the synthesis of a compound according to Claim 1 comprising thestep of oxidizing a corresponding compound of Claim 3*r with an oxidant to provide thecompound of Formula (IA) as a mixture of diastereomers. . The process of Claim 3ί wherein the oxidant is sulfur trioxide pyridine complex inDMSO and triethylamine. 3 γ· The process of Claim 2» further comprising the step of separating the diasteromers by separating means. 35 The process of Claim 57 wherein said separating means is high presssure liquidchromatography (HPLC). 3e! The process of Claim 35 further comprising the step of deuterating said diastereomers with a deuterating agent. 012288 4û The process of Claim 3^ wherein said deuterating agent is CD3OD: D2O (10:1) in triethylamine. Ç{ Use of a compound according to any one of Claims 1 to 32 in the manufacture of amédicament for use in inhibiting a protease selected from the group consisting of a cysteineprotease and a serine protease. Ç2. A use according to Claim 4? wherein said protease is a cysteine protease. A use according to Claim 42 wherein said cysteine protease is cathepsin K. 4¼ Use of a compound according to any one of Claims 1 to 32 in the manufacture of amédicament for use in treating a disease characterized by bone loss. L'-j. A use according to Claim 4¼ wherein said disease is osteoporosis. A use according to Claim wherein said disease is periodontitis. ÇdL A use according to Claim 4.4 wherein said disease is gingivitis. Use of a compound according to any one of Claims 1 to 32 in the manufacture of amédicament for use in treating a disease characterized by excessive cartilage or matrixdégradation. A use according to Claim 4% wherein said disease is osteoarthritis.
  33. 50- A use according to Claim 4 S wherein said disease is rheumatoid arthritis. 5 L Use of a compound according to any one of Claims 1 to 32 in the manufacture of a médicament for use in. treating a parasitic disease. 31g
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JP2003513926A (en) * 1999-11-10 2003-04-15 スミスクライン・ビーチャム・コーポレイション Protease inhibitor
HUP0301964A3 (en) * 2000-11-22 2007-09-28 Smithkline Beecham Corp Protease inhibitors
US7709510B2 (en) 2001-02-20 2010-05-04 Chugai Seiyaku Kabushiki Kaisha Azoles as malonyl-CoA decarboxylase inhibitors useful as metabolic modulators
PT1370260E (en) 2001-02-20 2011-02-01 Chugai Pharmaceutical Co Ltd Azoles as malonyl-coa decarboxylase inhibitors useful as metabolic modulators
EP1401453A4 (en) * 2001-05-17 2005-04-06 Smithkline Beecham Corp Protease inhibitors
EP1658071B1 (en) 2003-08-01 2008-09-10 Chugai Seiyaku Kabushiki Kaisha Cyanoguanidine-based azole compounds useful as malonyl-coa decarboxylase inhibitors
EP1653944B1 (en) 2003-08-01 2010-11-10 Chugai Seiyaku Kabushiki Kaisha Heterocyclic compounds useful as malonyl-coa decarboxylase inhibitors
CA2533749C (en) 2003-08-01 2012-07-10 Chugai Seiyaku Kabushiki Kaisha Piperidine compounds useful as malonyl-coa decarboxylase inhibitors
EP2240491B1 (en) 2008-01-09 2015-07-15 Amura Therapeutics Limited TETRAHYDROFURO(2,3-b)PYRROL-3-ONE DERIVATIVES AS INHIBITORS OF CYSTEINE PROTEINASES
CN103275070A (en) * 2013-05-10 2013-09-04 郑彪 Tetracyclic compound for adjusting proliferation of mononuclear cells and application of tetracyclic compound
US9427441B2 (en) 2014-02-19 2016-08-30 Indiana University Research And Technology Corporation Targeting primary cilia to treat glaucoma

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DZ2285A1 (en) * 1996-08-08 2002-12-25 Smithkline Beecham Corp Cysteine protease inhibitors.
HUP0104768A3 (en) * 1998-12-23 2002-05-28 Smithkline Beecham Corp 4-amino-3-oxo-azepanes as protease inhibitors and pharmaceutical compositions containing the same
EP1235577A4 (en) * 1999-11-10 2003-04-09 Smithkline Beecham Corp Protease inhibitors
JP2003513926A (en) * 1999-11-10 2003-04-15 スミスクライン・ビーチャム・コーポレイション Protease inhibitor
EP1320370A4 (en) * 2000-09-01 2008-10-22 Smithkline Beecham Corp Method of treatment
HUP0301964A3 (en) * 2000-11-22 2007-09-28 Smithkline Beecham Corp Protease inhibitors
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AR032622A1 (en) 2003-11-19
HUP0301231A2 (en) 2003-08-28
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CZ20024086A3 (en) 2003-05-14

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