EP1307204A1 - Protease inhibitors - Google Patents

Protease inhibitors

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Publication number
EP1307204A1
EP1307204A1 EP01946344A EP01946344A EP1307204A1 EP 1307204 A1 EP1307204 A1 EP 1307204A1 EP 01946344 A EP01946344 A EP 01946344A EP 01946344 A EP01946344 A EP 01946344A EP 1307204 A1 EP1307204 A1 EP 1307204A1
Authority
EP
European Patent Office
Prior art keywords
methyl
azepan
oxo
amide
butyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01946344A
Other languages
German (de)
French (fr)
Other versions
EP1307204A4 (en
Inventor
Robert W. Marquis, Jr.
Yu Ru
Daniel F. Veber
Maxwell D. Cummings
Scott K. Thompson
Dennis Yamashita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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Publication date
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Publication of EP1307204A1 publication Critical patent/EP1307204A1/en
Publication of EP1307204A4 publication Critical patent/EP1307204A4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates in general to 4-amino-azepan-3-one protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteme proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K.
  • Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
  • Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Client. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
  • Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature.
  • the designation cathepsin K is considered to be the more appropriate one.
  • Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have 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 like.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
  • Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • disease states such as osteoporosis and Paget's disease
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al, Biochem.
  • cystatin an endogenous cysteine protease inhibitor
  • cystatin an endogenous cysteine protease inhibitor
  • Other studies such as by Delaisse, et al, Bone, 1987, 8, 305, Hill, et al, J. Cell. Biochem., 1994, 56, 118, and Everts, et al, J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1106, Inaoka, et al, Biochem. Biophys. Res.
  • cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix.
  • selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
  • cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, O2 and cruzain. Other classes of compounds, such as aldehydes, nitriles, -ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, id, and references cited therein.
  • U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease.
  • Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.
  • Azapeptides which are designed to deliver the azaamino acid to the active site of serine 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 et al,
  • An object of the present invention is to provide 4-amino-azepan-3-one carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • this invention provides intermediates useful in the preparation of the compounds of Formula I.
  • 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 more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
  • 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 degradation, such as osteoarthritis and rheumatoid arthritis.
  • the present invention provides compounds of Formula I:
  • Rl is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, C ⁇ galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 _6alkyl, Het-C 0 _ 6 alkyl, R 9 C(O)-, R 9 C(S)-, R 9 SO 2 -, R 9 OC(O)-,
  • R 3 is selected from the group consisting of: H, C ⁇ _6alkyl, C3_6cycloalkyl- Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCo_6alkyl and ArCo_6 lkyl;
  • R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • 4 is selected from the group consisting of: H, C galkyl, C ⁇ .gcycloalkyl- C 0 . 6 alkyl, Ar-C 0 _6alkyl, Het-C 0 -6alkyl, R 5 C(O)-, R 5 C(S)-, R 5 SO 2 -, R 5 OC(0)-, R 5 R 12 NC(O)-, and R 5 R 12 NC(S)-;
  • 5 is selected from the group consisting of: H, C ⁇ .galkyl, C 2 -6alkenyl, C 2 _6alkynyl, C3_gcycloalkyl-Co-6alkyl, Ar-Co_6alkyl and Het-Co_6 a lkyl;
  • R" is selected from the group consisting of: H, C ⁇ .galkyl, Ar-C()-6alkyl, and Het- C 0 . 6 alkyl;
  • R' is selected from the group consisting of: H, Cj.galkyl, C ⁇ .gcycloalkyl- C 0 _6alkyl, Ar-C 0 . 6 alkyl, Het-C 0 _6alkyl, R 10 C(O)-, Rl°C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 13NC(S)-;
  • R ⁇ is selected from the group consisting of: H, Cl_6alkyl, C 2 _6alkenyl, C 2 -6alkynyl, HetC ⁇ -6- ⁇ lkyl ⁇ ArCo_6alkyl;
  • R 9 is selected from the group consisting of: C ⁇ .galkyl, C3_gcycloalkyl-Co_6alkyl, Ar-Co_6alkyl and Het-Co_6 a lkyl;
  • RIO is selected from the group consisting of: C ⁇ galkyl, C3_6cycloalkyl-C()-6alkyl, Ar-Co-6alkyl and Het-Co- ⁇ alkyl;
  • RU is selected from the group consisting of: H, C j .galkyl, Ar-C()-6alkyl, and Het- CQ_6al yl;
  • R ⁇ 2 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6 a -kyl, and Het- C 0 -6alkyl
  • R!3 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6 a lkyl, and Het-
  • R' is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6alkyl, and Het- C 0 _6alkyl;
  • R" is selected from the group consisting of: H, C ⁇ .galkyl, Ar-C ⁇ -6 a lkyl, or Het- C 0 _ 6 alkyl; :
  • R' is selected from the group consisting of: H, C ⁇ .galkyl, C3_gcycloalkyl- Co_6 a l yl, Ar-CQ-galkyl, and Het-Co_6 a lkyl;
  • R" is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Co_6 lkyl C 2 -6alkenyl, C 2 _6alkynyl, HetCQ.6alkyl and ArCo- ⁇ al yl;
  • X is selected from the group consisting of: CH 2 , S, and O;
  • Z is selected from the group consisting of: C(O) and CH 2 ; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R is selected from the group consisting of: H, Ci-galkyl, C3_6cycloalkyl- C ⁇ -6alkyl,C 2 -6alkenyl, C 2 _6alkynyl, Het-Co_galkyl and Ar-CQ-galkyl;
  • R 3 is preferably selected from the group consisting of: H, C3-6cycloalkyl- Co-6alkyl, C _6alkenyl, Ar-Co_galkyl, and Ci-galkyl;
  • R 3 is more preferably selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfiny 1-ethyl, 1 -hydroxy ethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl.
  • R3 is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.
  • R 3 is most preferably isobutyl.
  • R4 is selected from the group consisting of: H, C ⁇ .galkyl, C3.gcycl0-.lkyl- C 0 -6alkyl, Ar-C 0 . 6 alkyl, Het-C 0 -6alkyl, R 5 C(O)-, R 5 C(S)-, R 5 SO 2 -, R 5 OC(O)-, R 5 R 13 NC(O)-, and R 5 R 13 NC(S)-.
  • R ⁇ is preferably selected from the group consisting of: R5oC(O)-, R ⁇ C(O)- and
  • R ⁇ is most preferably R C(O)-.
  • R ⁇ is preferably methanesulfonyl.
  • R ⁇ is selected from the group consisting of: H, C j .galkyl, C 2 _galkenyl, C 2 _galkynyl, C3_gcycloalkyl-C()-6alkyl, Ar-C .galkyl or Het-Co-g lkyl.
  • R ⁇ is selected from the group consisting of: Cj.galkyl, Ar-CQ.galkyl and Het-C () -6alkyl.
  • R? is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially
  • 1,8 naphthyridinyl especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially C ⁇ .
  • galkyl substituted indolyl more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially Cj.galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Cj.galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, especially Cj.galkyl substituted thiophenyl, more especially 5-methyl-thiophen-2-yland 5-methyl
  • R? is preferably pyridin-2-yl or l-oxo-pyridin-2-yl.
  • R' is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -galkyl, and Het-
  • R' is selected from the group consisting of: H and naphthalen-2-yl- methyl.
  • R' is H.
  • R" is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6 a -kyl, and Het- C 0 .galkyl.
  • R" is H.
  • R' is selected from the group consisting of: H, C ⁇ galkyl, C3_gcycloalkyl-
  • R'" is preferably selected from the group consisting of: H and C j .galkyl.
  • R'" is more preferably selected from the group consisting of: H, methyl and 6,6- dimethyl.
  • R'" is still more preferably selected from the group consisting of: H and 6,6- dimethyl. Most preferably R'" is H.
  • R 3 is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-C ⁇ -6alkyl,
  • R 3 is preferably Ci-galkyl.
  • R 3 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: C ⁇ _galkyl, C3_gcycloalkyl-
  • Co-galkyl C 2 .galkenyl, C 2 .galkynyl, HetCQ.galkyl and ArCg-galkyl;
  • R"" is preferably Ci-galkyl
  • 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.
  • R , R , R ⁇ , and R ⁇ are as described above wherein
  • n is preferably an integer of from 1 to 5;
  • R', R ', R ", R4, and R are as described above wherein
  • n is most preferably 3.
  • the ring may be unsubstituted or substituted with one or more of Ci-galkyl, C3_gcycloalkyl-Co-.galkyl, C _galkenyl, C 2 .galkynyl, HetCg-galkyl, ArCo_galkyl, or halogen.
  • the ring is preferably unsubstituted.
  • R 2 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: Ar-C ⁇ -6alkyl,
  • R 2 is selected from the group consisting of: Ar-C ⁇ -6alkyl,
  • R 2 is R 9 SO 2 .
  • R" is selected from the group consisting of: H, C ⁇ _galkyl, Ar-C ⁇ -6alkyl, or Het- Co_galkyl, preferably H.
  • R' is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl- C 0 .galkyl, Ar-C 0 _galkyl, Het-C 0 . alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 14 NC (O)-, R10R14 NC (S)-, R7 i s preferably R 10 OC(O).
  • R° > is selected from the group consisting of: H, Cl-galkyl, C 2 _galkenyl, C 2 -galkynyl, HetC ⁇ _galkyl and ArCo-galkyl; preferably Co.galkyl, more preferably isobutyl.
  • R 9 is selected from the group consisting of: C ⁇ .galkyl, C3_gcycloalkyl-Co_galkyl,
  • R 9 is preferably selected from the group consisting of: C ⁇ galkyl, Ar-Co_galkyl, and Het-Co-galkyl.
  • R 9 is selected from the group consisting of: methyl; ethyl, especially Cj.galkyl-substituted ethyl, more especially 2-cyclohexy 1-ethyl; propyl; butyl, especially C _gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 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 C j .galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially Co
  • R 9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
  • R 9 is preferably Ar-C 0 .galkyl, more preferably Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl.
  • R 9 is preferably selected from the group consisting of C j .galkyl, C3_gcycloalkyl-Co_galkyl, and Het-C Q .galkyl, more preferably l-oxy-pyridin-2- yl, cyclohexyl ethyl, and 3-methyl butyl.
  • RI 1 is selected from the group consisting of: H, Ci.galkyl, Ar-C()-6 a lkyl, and Het-
  • R 2 is R 9 SO 2 R u NC(O)-
  • RU is preferably H.
  • R 2 is Ar-C Q -galkyl
  • R 2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl.
  • R 2 is Ci.galkyl
  • R 2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl.
  • R 2 is Het-Cg-galkyl
  • Het-Cg-galkyl is preferably Het-methyl
  • Het in Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially Ci-galkylpyridinyl, more especially 6- methyl-pyridin-2-yl; thiophenyl, especially thiophene-2-yl, more especially thiophen-2-yl or benzo[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
  • R 2 is also preferably: H; toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl.
  • R 2 is selected from the group consisting of: Ar-C()-6 a lkyl, R 9 C(O)-, R 9 SO 2 , R ⁇ R- Z - R 9 R n NC(O)-, and R ;
  • R 3 is selected from the group consisting of: H, Ci -galkyl, C3_gcycloalkyl- C ⁇ -6alkyl and Ar-Co_galkyl;
  • R 4 is selected from the group consisting of: R 5 OC(O)-, R 5 C(O)- and R 5 SO 2 -;
  • R ⁇ is selected from the group consisting of: C .galkyl, Ar-C ⁇ _galkyl and Het- C 0 .galkyl;
  • R 6 is H; R7 is R 10 OC(O);
  • R 8 is Ci.galkyl
  • R 9 is selected from the group consisting of: Ci.galkyl, Ar-Cg-galkyl and Het- C 0 -galkyl;
  • R*" is selected from the group consisting of: C ⁇ .galkyl, Ar-Co_galkyl and Het- C 0 .galkyl;
  • Z is selected from the. group consisting of: C(O) and CH 2 .
  • R 2 is selected from the group consisting of: Ar-C ⁇ -6 a lkyl, R 9 C(O)-, R 9 SO 2 .
  • R 2 is selected from the group consisting of: Ar-C()-6alkyl, R 9 C(O)- and R SO 2 ;
  • 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-methanesulfinyl-ethyl, 1 -hydroxy ethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;
  • R 4 is R 5 C(O)-;
  • R5 is selected from the group consisting of: methyl, especially halogenated methyl, more especially tfifluoromethyl , especially C ⁇ _galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy- methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-y 1-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-d
  • R 9 is selected from the group consisting of: methyl; ethyl, especially C ⁇ _galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially Ci.gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(O); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromopheny ⁇ , 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, especially Ci.galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially Cigalkyl substituted
  • R' is H
  • R" is H
  • R'" is H.
  • R 2 is R 9 SO 2 ;
  • R 3 is isobutyl
  • R 4 is R 5 C(O);
  • R ⁇ is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2- b]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl, preferably 3-methyl-benzofuran-2-yl;
  • R 9 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
  • R'" is H
  • RI is selected from the group consisting of:
  • R 2 is selected from the group consisting of: Ci-galkyl, Ar-Cg-galkyl, Het-
  • R 3 is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-C ⁇ -galkyl, C 2 .galkenyl, C 2 _galkynyl, Het-Cg-galkyl and Ar-Cg-galkyl, preferably Ci-galkyl; R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R 4 is R 5 C(O)-
  • R ⁇ is selected from the group consisting of : Cl-galkyl and Het-Co-galkyl, preferably Het-Co-galkyl;
  • R 9 is selected from the group consisting of: Cigalkyl, C3_gcycloalkyl-C()-galkyl, Ar-Co-galkyl and Het-C Q _galkyl;
  • RU is selected from the group consisting of: H, Ci-galkyl, Ar-C()-6alkyl and Het- C Q -galkyl, preferably H;
  • R' is H;
  • R" is H;
  • R' is selected from the group consisting of: H and C galkyl, preferably H;
  • R"" is selected from the group consisting of: Ci .galkyl, C3_gcycloalkyl-Co_galkyl C 2 .galkenyl, C 2 .galkynyl, HetCo_galkyl and ArCo-galkyl; and
  • n is an integer from 1 to 5, preferably n is 3; and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R 3 is preferably Ci-galkyl
  • R 3 is more preferably selected from the group consisting of: but-2-yl and isobutyl. R 3 is most preferably isobutyl.
  • R 4 is R 5 C(O)-.
  • R5 is selected from the group consisting of : Cl_galkyl and Het-Cg-galkyl, preferably Het-Cj .galkyl;
  • R-> is selected from the group consisting of: piperidin-ethyl, especially piperidin- 1 -y 1-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 Ci.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; benzofuranyl, especially benzofuran-2-yl, especially Ci.galkoxy substituted benzofuranyl, more especially 5-methoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2
  • R 3 is selected from the group consisting of: Ci .galkyl, C3_gcycloalkyl-C()-galkyl, C 2 _galkenyl, C 2 -6 a lkynyl, Het-Co_galkyl and Ar-Co-galkyl.
  • R 3 is preferably Ci-galkyl, C3-gcycloalkyl-C ⁇ -6 a lkyl, and Ar-C ⁇ _galkyl.
  • R 3 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_gcycloalkyl- C ⁇ -6alkyl, C 2 _galkenyl, C 2 .galkynyl, HetCQ.galkyl and ArCg-galkyl;
  • R"" is preferably Ci-galkyl
  • R" is more preferably selected from the group consisting of methyl, ethyl, n- propyl, n-butyl, isobutyl and t-butyl.
  • R"" is methyl
  • R' and R 4 are as described above wherein
  • n is an integer of from l to 5; preferably 3;
  • the cyclic ring may be unsubstituted or substituted with one or more of C ⁇ _galkyl, C3_gcycloalkyl-Co-galkyl, C 2 _galkenyl, C 2 .galkynyl, HetC Q -galkyl, ArCo_galkyl, or halogen.
  • the cyclic ring is preferably unsubstituted.
  • R 2 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: Ar-C ⁇ -galkyl, R 9 C(O)-, R 9 SO 2 , and R 9 R* !NC(0)-.
  • R 2 is selected from the group consisting of: Ar-C()-6alkyl, R 9 C(O)-, and R 9 SO 2 .
  • R 2 is R 9 SO 2 .
  • R 9 SO 2 is R 9 SO 2 .
  • R 9 is selected from the group consisting of: Ci.galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Co-galkyl, and Het-Co_galkyl.
  • R 9 is preferably selected from the group consisting of: Ci.galkyl, Ar-Co-galkyl, and Het-Co-galkyl.
  • R 9 is selected from the group consisting of: ethyl, especially Ci.galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl, especially prop-1-yl; isopentyl; butyl, especially but-l-yl; phenyl, especially halogen substituted phenyl, more especially 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl; especially Cigalkyl substituted phenyl, more especially 4- ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Ci.galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; pyridinyl, especially pyridin-2-yl, 1 -oxy-pyridinyl, more especially 1-oxy-pyridin-
  • R 9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
  • R 9 is preferably Ar-C 0 .galkyl, more preferably
  • Ar most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, 4-fluoro phenyl.
  • R 9 is preferably selected from the group consisting of Ci.galkyl, C3_gcycloalkyl-Co_galkyl, and Het-Co-galkyl, more preferably l-oxy-pyridin-2- yl, 2-cyclohexyl ethyl, and isopentyl.
  • R 11 is selected from the group consisting of: H, Ci.galkyl, Ar-CQ-galkyl and Het-Co-galkyl.
  • RU is H.
  • R 2 may suitably be selected from the group consisting of: Cj. galkyl, Ar-Co_6alkyl and Het-C ⁇ -galkyl, preferably O ⁇ .galkyl and Het- Co_6alkyl,
  • R 2 is Ar-CQ-galkyl
  • R 2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl.
  • R 2 is Cigalkyl
  • R 2 is preferably selected from 1-propyl, 1-butyl, and 1-pentyl.
  • Het-CQ.galkyl is preferably Het-methyl, and Het in Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, Ci.galkylpyridinyl, especially 6-methyl-pyridin- 2-yl; thiophenyl, especially thiophene-2-yl; benzo [b] thiophen-2-y 1 ; thiazolyl, especially thiazol-4-yl such as isothiazol-3-yl; lH-imidazolyl, especially lH-imidazol-2-yl, Cigalkyl substituted imidazolyl, especially 1-methyl- lH-imidazol-2yl; triazolyl, especially 3H-fl,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl, especially Ci.galkyl substituted 3H-[l,
  • the compounds of embodiment IA have the same uses described throughout this specification for compounds of Formula I.
  • the compounds of embodiment IA may be formulated into pharmaceutical compositions and used in methods of treatment as described for compounds of Formula I throughout this specification.
  • Compounds of Formula I selected from the following group are particularly preferred embodiments of the present invention:
  • 162 5 ,6-Dimethoxy-benzofuran-2-carboxy lie acid- ⁇ (S)- 1 - [ 1 -(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl ⁇ - amide;
  • 181 1 -Methyl- lH-indole-2-carboxylic acid- ⁇ (S)-l-[l-(4-chIoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl ⁇ - amide; 182 Quinoxaline-2-carboxylic acid- ⁇ (S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl ⁇ - amide;
  • Naphthylene-1 -carboxy lie acid ⁇ (S)-2-naphthylen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
  • 342 Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l- ⁇ 3-oxo-l-[4- fluoro-benzenesulfonylamino)-methanoyl]-azepan-4- ylcarbamoyl ⁇ -butyl)-amide ; 343 Benzofuran-2-carboxylic acid ((S)-3-methyl-l- ⁇ 3-oxo-l-[l- toluene-4-sulfonylamino)-methanoyl]-azepan-4-y lcarbamoyl ⁇ - butyl)-amide;
  • Particularly preferred compounds of embodiment IA are Example Nos. 280 to 381 in the list herein above.
  • the 7 membered ring compounds of the present invention are configurationally more stable at the carbon center alpha to the ketone.
  • the present invention includes deuterated analogs of the inventive compounds. A representative example of such a deuterated compound is set forth in Example 192. A representative synthetic route for the deuterated compounds of the present invention is set forth in Scheme 4, below. The deuterated compounds of the present invention exhibit superior chiral stability compared to the protonated isomer. Where possible the present invention includes quaternary salts of the inventive compounds. A representative example of such a quaternary salt is set forth in Example
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases.
  • the compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors.
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • Ci-galkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • R ⁇ is selected from the group consisting of: H, Ci-galkyl, Ar-C ⁇ -galkyl, and Het-
  • C 0 _galkyl; "C3_gcycloalkyl” as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • C 2 _g alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C 2 _galkenyl includes ethylene, 1-propene, 2-propene, 1 -butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C 2 .galkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C _g alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen means F, CI, Br, and I.
  • Ar or “aryl” means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-C Q -galkyl; Ci-galkoxy; Ph-C Q -galkoxy; Het-C 0 -galkoxy; OH, (CH 2 ) ⁇ _ gNR 15 R 16 ; O(CH 2 ) ⁇ -gNR 15 R 16 ; Ci-galkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF 3 , NO 2 , CN, CO 2 R 17 , CON(R 17 ), F, CI, Br or I; where R 15 and R 16 are H, Cigalkyl, Ph-C 0 -galkyl, naphthyl-C ⁇ -galkyl or Het-Co-galkyl; and R 7 is phenyl, naphthyl, or Ci-galkyl.
  • Het represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms 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 the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C 0 _gAr, Ci-galkyl, OR 17 , N(R 17 ) , SR 17 , CF 3 , NO 2 , CN, CO 2 R 17 , CON(Rl 7 ), F, CI, Br and I, where R* 7 is phenyl, naphthyl, or C ⁇ _galkyl.
  • heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 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, benzoimid
  • CQ denotes the absence of the substituent group immediately following; for instance, in the moiety ArCg-galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo-galkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical.
  • m-CPBA refers to 3-chloroperoxybenzoic acid
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide
  • DMF refers to dimethyl formamide
  • DMSO refers to dimethyl sulfoxide
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Epoxidation of 3 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 4.
  • Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon.
  • Acylation of 5 with an acid such as Cbz-leucine in the presence of a coupling agent such as EDC followed by removal of the BOC protecting group under acidic conditions provides the amine salt 6.
  • Coupling of 6 with Cbz-leucine may be effected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.
  • a coupling agent such as EDC
  • an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine
  • Reagents and conditions a.) NaH, 5-bromo-l-pentene, DMF; b.) 2,6-diisopropylphenylimido neophylidene molybenum bis (tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, toluene c.) m-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H 2 0, ⁇ H 4 C1; e.) 10% Pd/C, H 2 , f.) Cbz-leucine, EDC, CH.C1.; g.) HC1, EtOAc; h.) Cbz-leucine, EDC, CH 2 C1 2 ; i.) pyridine sulfur trioxide complex, DMSO, TEA.
  • Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine.
  • a reducing agent such as propanedithiol in the presence of triethylamine.
  • Acylation of 12 with N-Boc- leucine and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13.
  • Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HC1 or TFA provides intermediate 14.
  • Acylation of 14 may be effected with a carboxylic acid in the presence of a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15.
  • a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15.
  • Reagents and conditions a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CH 2 C1 2 ; c.) m-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H 2 0, NH 4 C1; e.) propanedithiol, CH 3 OH, TEA; f.) Boc-leucine, EDC, CH 2 C1 2 ; g.) 10% Pd/C, H 2 ; h.) R,C0 2 H, EDC, CH 2 C1 2 or R.COC1, CH 2 C1 2 ; i.) HC1/ EtOAc; j.) R.CCgH, EDC, CH 2 C1 2 ; k.) pyridine sulfur trioxide complex, DMSO, TEA.
  • amine 13 treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18.
  • Acylation and oxidation provides the ketone 19.
  • Further derivatization of amine 13 may be effected by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20.
  • Acylation and oxidation provides the ketone 21.
  • Reagents and conditions a.) R,CHO, NaBH(OAc) 3 ; b.) HCl; c.) R j CO.H, EDC, CH 2 C1 2 ; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R,S0 2 C1, TEA, CH 2 C1 2 .
  • the deuterated compound of the Example 192 may be conveniently prepared according to Scheme 4. The skilled artisan will understand from Example 192 and Scheme 4 how to make any of the the deuterated compounds of the present invention.
  • Reagents and Conditions a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH 2 C1 2 ; c.) m-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H 2 0, NH 4 C1; e.) 1,3-propanedithiol, TEA, methanol; f.) N-Boc-leucine, EDC, CH 2 C1 2 ; g.) 10% Pd/C, H 2 ; h.) 2-pyridinesulphonyl chloride, TEA, CH 2 C1 2 ; i.) 4 N HCl/dioxane, methanol; j.) benzofuran-2-carboxylic acid, EDC, CH 2 C1 2 ; k.) pyridine sulfur trioxide complex,
  • the intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water.
  • Acylation of 26 may be effected with an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC.
  • EDC a coupling agent
  • Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 27.
  • Alcohol 29 may be oxidized with an oxidant such as sulfur trioxide pyridine complex in DMSO and triethylamine to provide the ketone 30 as a mixture of diastereomers.
  • an oxidant such as sulfur trioxide pyridine complex in DMSO and triethylamine
  • Treatment of ketone 30 with triethylamine in CD 3 OD:D 2 O at reflux provides the deuterated analog as a mixture of diastereomers which are separated by HPLC to provide the deuterated compounds 31 and 32.
  • Removal of the tert-butoxycarbonyl protecting group may be effected with an acid such as hydrochloric acid to provide intermediate 36.
  • Coupling of 36 with an acid such as N-Boc-cyclohexylalanine in the presence of a coupling agent common to the art such as HBTU or polymer supported EDC provides the alcohol intermediate 37.
  • Removal of the tert-butoxycarbonyl protecting group under acidic conditions provides amine 38.
  • Coupling of 38 with an acid such as benzofuran-2-carboxylic acid in the presence of a coupling agent such as HBTU or polymer supported EDC provides alcohol 39.
  • Alcohol 39 may be oxidized with an oxidant common to the art such as pyridine sulfur trioxide complex in DMSO and triethylamine or the Dess- Martin periodinane to provide the ketone 40.
  • Reagents and Conditions (a) Di-terf-butyldicarbonate, THF; (b) H., 10% Pd/C, EtOAc; (c) 2- pyridylsulfonyl chloride, TEA ; (d) HCl, EtOAc; (e) N-Boc-cylohexylalanine, P-EDC, CH 2 C1 2 ; (f) HCl, CH 2 C1 2 ; (g) benzofuran-2-carboxylic acid, P-EDC, CH 2 C1 2 ; (h) Dess-Martin periodinane, methylene chloride.
  • the quaternized, 4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 6.
  • the skilled artisan will understand from Scheme 6 how to make any of the quaternized, 4-amino-azepan-3-one compounds of the present invention.
  • Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N-Boc group under acidic conditions provides the amine salt 16.
  • Reagents and conditions a.) R,CHO, NaBH(OAc) 3 ; b.) HCl; c.) P ⁇ CO-H, EDC, CH 2 C1 2 ; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) iodomethane
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
  • Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH-J+ are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
  • Quaternary ammonium salts are prepared by treating a parent amine compound with an excess of alkyl halide, such as methyl iodide.
  • This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of Formula I may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • RI is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl-Co_galkyl, Ar- C 0 - 6 alkyl, Het-C 0 -6alkyl, R 9 C(O)-, R C(S)-, R 9 SO 2 -, R 9 OC(O)-,
  • R 3 is selected from the group consisting of: H, Ci-galkyl, C3-gcycloalkyl- C ⁇ -6alkyl, C2-6alkenyl, C2-6alkynyl, HetC ⁇ -6alkyl and ArC ⁇ -6alkyl;
  • R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R4 is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl- Co-galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 5 C(O)-, R 5 C(S)-, R 5 SO 2 -, R 5 OC(O)-, R 5 R 12 NC(O)-, and R 5 R 12 NC(S)-;
  • R ⁇ is selected from the group consisting of: H, C -galkyl, C 2 -galkenyl,
  • R° is selected from the group consisting of: H, C -galkyl, Ar-C ⁇ -6 a -kyl, or Het- C 0 . 6 alkyl;
  • R 1 is selected from the group consisting of: H, Ci.galkyl, C3-gcycloalkyl- C 0 .galkyl, Ar-C 0 -galkyl, Het-C 0 _galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 Rl NC(S)-;
  • R° is selected from the group consisting of: H, Ci-galkyl, C 2 -galkenyl, C 2 -galkynyl, HetC ⁇ -6alkyl and ArC ⁇ -6alkyl;
  • R 9 is selected from the group consisting of: Ci.galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Co-galkyl and Het-Co-galkyl;
  • R i O is independently selected from the group consisting of: C ⁇ -galkyl, C3-gcycloalkyl-Co-galkyl, Ar-Co-galkyl and Het-Co-galkyl;
  • RU is selected from the group consisting of: H, C ⁇ -galkyl, Ar-C ⁇ -6 a -kyl, and Het- Co-galkyl;
  • R 2 is selected from the group consisting of: H, C j -galkyl, Ar- )-6alkyl, and Het- Co-galkyl;
  • Rl3 is selected from the group consisting of: H, C j -galkyl, Ar-C ⁇ -6alkyl, and Het- Co-galkyl;
  • R' is selected from the group consisting of: H, C j -galkyl, Ar- )-6alkyl, and Het- C 0 -galkyl;
  • R" is selected from the group consisting of: H, C j -galkyl, Ar-C ⁇ -6alkyl, or Het-
  • R' is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl- Co-galkyl, Ar-Co-galkyl, and Het-Co-galkyl;
  • R" is selected from the group consisting of: Ci-galkyl, C3-gcycloalkyl-Co_galkyl C 2 -6alkenyl, C 2 .galkynyl, HetCQ-galkyl and ArCo-galkyl; n is an integer of from 1 to 5; and salts, hydrates and solvates thereof.
  • the present invention includes the novel intermediates of Formula IIA:
  • RI is selected from the group consisting of:
  • R 2 is selected from the group consisting of: C galkyl, Ar-Co_galkyl, Het- Co-galkyl, R 9 C(O , R 9 SO 2 -, R 9 R ⁇ NC(O)-, and R SO 2 R ⁇ NC(O)-;
  • R3 is selected from the group consisting of: Ci -galkyl, C3-gcycloalkyl-C ⁇ -6alkyl,
  • R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R 4 is R 5 C(O)-;
  • R ⁇ is selected from the group consisting of : Ci .galkyl and Het-CQ.galkyl, preferably Het-Co-galkyl;
  • R 9 is selected from the group consisting of: C ⁇ -galkyl, C3_gcycloalkyl-Co-galkyl, Ar-C Q -galkyl and Het-CQ-galkyl;
  • RU is selected from the group consisting of: H, Ci-galkyl, Ar-C ⁇ -galkyl and Het- C Q -galkyl, preferably H; R' is H; !
  • R" is H
  • R'" is selected from the group consisting of: H and C ⁇ -galkyl, preferably H;
  • R"" is selected from the group consisting of: Ci-galkyl, C3-gcycloalkyl-CQ.galkyl, C 2 _galkenyl, C 2 -galkynyl, HetCo-galkyl and ArCQ-galkyl, preferably Ci-galkyl; and
  • n is an integer from 1 to 5, preferably n is 3; and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the present invention provides a process for the synthesis of compounds of Formula (I) comprising the step of oxidizing the appropriate compound of Formula (II) with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers.
  • the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine.
  • the present invention also provides a process for the synthesis of deuterated compounds of Formula (I). Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound of Formula (I) as a mixture of diastereomers is added to the synthesis.
  • the deuterating agent is CD 3 OD:D 2 O (10:1) in triethylamine.
  • the process further comprises the step of separating the diasteromers of Formula
  • the present invention also provides a process for the synthesis of quaternary salts of the 4-amino-azepan-3-one compounds of Formula (I).
  • the compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K.
  • the present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
  • the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amy trophy; 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, and metabolic bone disease.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
  • the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention.
  • the present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof an inhibitor of cathepsin K, including a compound of the present invention.
  • the present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, 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, and metabolic bone disease.
  • diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of Formula I alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • parenteral administration of a compound of Formula I is preferred.
  • the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K.
  • the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
  • the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 20 mg/kg. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • Biological Assays The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • 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 away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
  • the beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded. The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
  • the cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl ⁇ 4/mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype 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 sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
  • the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.
  • Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-dg is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.
  • diastereomer 1 MS (El) 623 (M+H+), 645 (M+Na+) and diastereomer 2: MS (ES) 623 (M+H+), 645 (M+Na+).
  • Example 4a Following the general procedure of Example li except substituting the compound of Example 4a the title compound was prepared: 476 MS(EI): 492 (M+H + ,100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided 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+).
  • diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MS (El) 492.4 (M+H+), 983 J 2M+H+) and diastereomer 2: MS (El) 492.4 (M+H+), 983.7 2M+H+).
  • Example 6a Following the general procedure of Example li except substituting the compound of Example 6a the title compound was prepared: : ⁇ NMR (CDC1 3 ): ⁇ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.7 (m, IH), 3.0 (dd, IH). 3.3 (m, IH), 3.6 (m, 2H), 3.7 ( m, IH),
  • Example 7a Following the general procedure of Example li except substituting the compound of Example 7a the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 11H); MS(EI): 487 (M+H ⁇ 100%). The diastereomers were separated by preparative scale HPLC.
  • Example 8a Following the general procedure of Example li except substituting the compound of Example 8a the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, 2H), 5.2 ( m, IH), 7.2-8.4 (m, 8H); MS(EI): 504 (M + ,100%) .
  • Example 9b the title compound was prepared: MS(EI) 594 (M+H + ).
  • MS(EI) 594 (M+H + ).
  • Example 10a the title compound was prepared: MS(EI) 477 (M+H+).
  • Example 10b the title compound was prepared: MS(EI) 632 (M+H+).
  • Example 10c the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 1.0 ( m, 12H), 1.5-2.1 (m, 10H), 2.2 ( m, 4H), 2.9 (m, IH), 3.4 ( M, 2H). 3.7 (m, IH), 4.7 ( m, 2H), 5.2 ( m, 3H), 7.2 (m, 4H), 7.5 (m, IH), 7.6 (m, IH), 7.7 (m, IH), 8.1 (m, IH), 8.2 (m, 2H), 8.5 (m, IH); MS(EI): 630 (M+H + ,100%) .
  • Example 2j Following the procedure of Example 2j except substituting the compound of Example 1 lb for the compound of Example 2j and piperonylic acid for 2-naphthoic acid the title compound was prepared: MS(EI) 496 (M+H+).
  • Example 12a Following the procedure of Example li except substituting the compound of Example 12a the title compound was prepared: ⁇ NMR (CDCL): ⁇ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (dd, IH). 3.6 (m, IH), 4.0 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 9H); MS(EI): 468 (M+H + , 10%).
  • Example 13a the title compound was prepared: MS(EI) 342 (M+H+). c.) 3-Hydroxy-4-((S)-4-methyl-2- ⁇ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl] amino ⁇ -pentanoylamino)- 1 -(4-methyl-pentanoyl)-azepanium
  • Example 14c Following the procedure of Example li except substituting the compound of Example 14c the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, IH), 2.7 (m, 4H), 2.8 (m, 2H), 3.5 (m, IH), 3.8 (m, 4H), 4.0 (m, IH), 4.1 (m, 2H), 4.4 (m, IH), 4.5 (m, IH), 4.7 (m, IH), 5.1 ( m, IH), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, 3H), 7.7 (m, 2H): MS(EI): 655 (M+H ⁇ 100%) .
  • Example 9b the title compound was prepared: MS(EI) 712 (M+H + ).
  • Example 16c the title compound was prepared: ⁇ NMR (CDC1 3 ): ): ⁇ 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, IH), 3.5 (m, IH), 3.7 (m, 4H), 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 ( m, IH), 7.2-8.0 (m, 13H), 8.5 (m, IH); MS(EI): 710 (M+H ⁇ 100%) MS(EI).
  • Example 18a Following the procedure of Example li except substituting the compound of Example 18a the title compound was prepared: ⁇ NMR (CDCl.): ⁇ 1.0 ( m, 6H), 1.5-2.1 (m, 9H), 2.2 ( m, 2H), 2.5 (m, IH), 2.7 (m, 4H), 3.0 (m, 2H), 3.4 (m, IH), 4.0 (m, IH), 4.1 (m, 2H), 4.5 (m, IH), 4.6 (m, IH), 5.0 ( m, IH), 7.2-8.4 (m, 11H): MS(EI): 639 (M+H + ,100%) .
  • Example 18a Following the procedure of Example li except substituting the compound of Example 18a the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 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, IH), 4.0 (m, IH), 4.1 (m, 2H), 4.5 (m, IH), 4.6 (m, IH), 5.0 (m, IH), 7.2-8.4 (m, 11H): MS(EI): 653 (M+H + ,100%) .
  • Example 20a To a solution of 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid methoxy methyl amide (0.2 g) of Example 20a in THF was added LAH (2.0 mL of a 1 M solution in THF). The reaction was stirred until complete consumption of the starting material. Workup gave 160 mg of the title compound.
  • the diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 696 (M+H ⁇ 100%), and the slower eluting diastereomer; MS(EI): 696 (M+H + , 100%).
  • Example 21b Following the procedure of Example li except substituting the compound of Example 21b the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 1.0 ( m, 6H), 1.5-2.1 (m, 6H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, IH), 3.4 (d, IH). 3.5 (m, IH), 4.7 ( m, IH), 5.0 ( m, IH), 6.8-7.2 (m, 6H), 7.3 (m, IH), 7.5 (m, 2H), 7.9 ( m, 6H), 8.2 (M, IH), 8.7 (m, IH): MS(EI):577 (M+H + ,100%) .
  • Example 22b the title compound was prepared: : ⁇ NMR (CDC1 3 ): ): ⁇ 1.0 ( m, 6H), 1.5-
  • Example 24b Following the procedure of Example li except substituting the compound of Example 24b the title compound was prepared: ⁇ NMR (CDCL): ⁇ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (m, IH), 3.5 (d, IH). 4.1 (m, IH), 4.7 ( m, 2H), 5.0 ( m, IH), 7.2-7.2 (m, 10H).
  • the diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 656 (M+H + ,100%), and the slower eluting diastereomer; MS(EI): 656 (M+IT,100%).
  • the diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 619 (M+H + ,100%), and the slower eluting diastereomer; MS(EI): 619 (M+H ⁇ 100%).
  • Example 29a Following the procedure of Example li except substituting the compound of Example 29a the title compound was prepared: ⁇ NMR (CDCL): ⁇ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.7 (m, IH), 3.7 (dd, IH). 4.0 (m, IH), 4.7 ( m, 2H), 5.0 ( m, IH), 7.2-7.3 (m, 2H), 7.5 (m, 3H), 7.9 (m, 6H), 8.3 ( m, IH), 8.4 (m, IH); MS(EI): 537 (M+H ⁇ 50%).
  • the diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 537 (M+H ⁇ 100%), and the slower eluting diastereomer; MS(EI): 537 (M+IT, 100%).
  • Example 31a the title compound was prepared.
  • Example 31b the title compound was prepared: ⁇ NMR (CDCL): ⁇ 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 , IH). 3.8 (m, 4H), 4.1 (m, 3H), 4.2 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 5H); MS(EI): 615 (M+H ⁇ 100%) .
  • Example 33b the title compound was prepared: MS(EI) 424 (M+H + ).
  • Example 33c the title compound was prepared: ⁇ NMR (CDC1 3 ) ⁇ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 2.9 (m, IH), 3.5 (m, IH), 3.7 (m, 2H), 4.1 (m, 3H), 4.6 (m, IH), 5.3 (m, IH), 7.2-8.0 (m, 7H), 8.7 (m, IH); MS(EI): 422 (M+H ⁇ 100%) .
  • Example 34 Example 34
  • Example 34e the title compound was prepared: MS(EI) 679 (M+H+).
  • Example 34f the title compound was prepared: : ⁇ NMR (CDC1 3 ): ⁇ 1.0 (m, 6H), 1.5-2.2 (m, 16H), 2.7 (m, IH), 3.2 (m, IH). 3.1 (m, 3H), 4.0 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.2-7.3 (m, 16H), 8.6 (m, IH); MS(EI): 677 (M+H + ,100%) .

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

PROTEASE INHIBITORS
FIELD OF THE INVENTION
This invention relates in general to 4-amino-azepan-3-one protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteme proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
BACKGROUND OF THE INVENTION
Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Client. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature. The designation cathepsin K is considered to be the more appropriate one.
Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have 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 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 gingipains, have 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 role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface. This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma. Several published studies have demonstrated that inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al, Biochem. J., 1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN2) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al, Biochem. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium deficient diets. Lerner, et al, J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al, Bone, 1987, 8, 305, Hill, et al, J. Cell. Biochem., 1994, 56, 118, and Everts, et al, J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1106, Inaoka, et al, Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al, FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.
The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, O2 and cruzain. Other classes of compounds, such as aldehydes, nitriles, -ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, id, and references cited therein.
U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the 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 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- lβconvertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No.
PCT/GB91/01479).
Azapeptides which are designed to deliver the azaamino acid to the active site of serine 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 et al,
Tetrahedron, 1977, 33, 837, Gupton et al, J. Biol. Chem., 1984, 259, 4279, 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 protease inhibitors. Antipain and leupeptin are described as reversible inhibitors of cysteine protease in
McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and
Grinde, Biochem. Biophys. Acta, , 701, 328). 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent
Nos.4,749,792 and 4,638,010.
Thus, a structurally diverse variety of protease inhibitors have been identified.
However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance. A need therefore exists for methods of treating diseases caused by pathological levels of proteases, particularly cysteine proteases, more particularly cathepsins, most particularly cathepsin K, and for novel inhibitor compounds useful in such methods. We have now discovered a novel class of 4-amino-azepan-3-one compounds which are protease inhibitors, most particularly of cathepsin K.
SUMMARY OF THE INVENTION
An object of the present invention is to provide 4-amino-azepan-3-one carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to
Formula I. In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula I. 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 more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K. 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 degradation, such as osteoarthritis and rheumatoid arthritis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula I:
wherein:
Rl is selected from the group consisting of:
R2 is selected from the group consisting of: H, C^galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C0_6alkyl, Het-C0_6alkyl, R9C(O)-, R9C(S)-, R9SO2-, R9OC(O)-,
R9RπNC(O)-, R RπNC(S)-, R9(R )NSO2-
R3 is selected from the group consisting of: H, Cι_6alkyl, C3_6cycloalkyl- Co-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCo_6alkyl and ArCo_6 lkyl;
R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring; 4 is selected from the group consisting of: H, C galkyl, Cβ.gcycloalkyl- C0.6alkyl, Ar-C0_6alkyl, Het-C0-6alkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(0)-, R5R12NC(O)-, and R5R12NC(S)-; 5 is selected from the group consisting of: H, C^.galkyl, C2-6alkenyl, C2_6alkynyl, C3_gcycloalkyl-Co-6alkyl, Ar-Co_6alkyl and Het-Co_6alkyl;
R" is selected from the group consisting of: H, C^.galkyl, Ar-C()-6alkyl, and Het- C0.6alkyl;
R' is selected from the group consisting of: H, Cj.galkyl, Cβ.gcycloalkyl- C0_6alkyl, Ar-C0.6alkyl, Het-C0_6alkyl, R10C(O)-, Rl°C(S)-, R10SO2-, R10OC(O)-, R10R13NC(O)-, and R10 13NC(S)-;
R^ is selected from the group consisting of: H, Cl_6alkyl, C2_6alkenyl, C2-6alkynyl, HetCθ-6-ιlkyl ^ ArCo_6alkyl;
R9 is selected from the group consisting of: C^.galkyl, C3_gcycloalkyl-Co_6alkyl, Ar-Co_6alkyl and Het-Co_6alkyl;
RIO is selected from the group consisting of: C^galkyl, C3_6cycloalkyl-C()-6alkyl, Ar-Co-6alkyl and Het-Co-βalkyl;
RU is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het- CQ_6al yl;
R^2 is selected from the group consisting of: H, C j.galkyl, Ar-Cθ-6a-kyl, and Het- C0-6alkyl; R!3 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het-
C0_6alkyl;
R' is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, and Het- C0_6alkyl;
R" is selected from the group consisting of: H, C^.galkyl, Ar-Cθ-6alkyl, or Het- C0_6alkyl; :
R'" is selected from the group consisting of: H, C^.galkyl, C3_gcycloalkyl- Co_6al yl, Ar-CQ-galkyl, and Het-Co_6alkyl;
R"" is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Co_6 lkyl C2-6alkenyl, C2_6alkynyl, HetCQ.6alkyl and ArCo-βal yl; X is selected from the group consisting of: CH2, S, and O;
Z is selected from the group consisting of: C(O) and CH2; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
In compounds of Formula I, when R* is
R is selected from the group consisting of: H, Ci-galkyl, C3_6cycloalkyl- Cθ-6alkyl,C2-6alkenyl, C2_6alkynyl, Het-Co_galkyl and Ar-CQ-galkyl;
R3 is preferably selected from the group consisting of: H, C3-6cycloalkyl- Co-6alkyl, C _6alkenyl, Ar-Co_galkyl, and Ci-galkyl;
R3 is more preferably selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfiny 1-ethyl, 1 -hydroxy ethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl.
R3 is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.
R3 is most preferably isobutyl.
R4 is selected from the group consisting of: H, C^.galkyl, C3.gcycl0-.lkyl- C0-6alkyl, Ar-C0.6alkyl, Het-C0-6alkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R13NC(O)-, and R5R13NC(S)-. R^ is preferably selected from the group consisting of: R5oC(O)-, R^C(O)- and
R5SO2-.
R^ is most preferably R C(O)-.
In some embodiments, R^ is preferably methanesulfonyl.
R^ is selected from the group consisting of: H, Cj.galkyl, C2_galkenyl, C2_galkynyl, C3_gcycloalkyl-C()-6alkyl, Ar-C .galkyl or Het-Co-g lkyl.
Preferably R^ is selected from the group consisting of: Cj.galkyl, Ar-CQ.galkyl and Het-C()-6alkyl.
More preferably, and especially when R^ is R5C(O)-, R? is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially
Cj.galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy- methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-y 1-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-fluorophenyl, especially phenyl substituted with one or more aryloxy or Ci_6-Uko y groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more Cχ_galkyl sulfonyl 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-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-furan-2-yl,more especially halogen substituted furanyl, even more especially 5-bromo-furan-2-yl, more especially aryl substituted furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl, more especially Cj.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, more especially 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-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 substituted benzofuranyl, 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-benzofuran-2-yl, 4-fnethoxy-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 substituted naphtho[2,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[b]thiophenyl, especially benzo[&]thiophen-2-yl; especially Cχ_galkoxy substituted benzo[έ»]thiophenyl, more especially 5,6-dimethoxy- benzo[Z?]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-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 C\. galkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially Cj.galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Cj.galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, especially Cj.galkyl substituted 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-Z?]thiophene-2-yl, more especially Cj.galkyl substituted thieno[3,2-b]thiophene-2-yl, more especially 5-tert-butyl-3-methyl- thieno [3 ,2-b] thiophene-2-y 1 ; 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 R^SO2, R? is preferably pyridin-2-yl or l-oxo-pyridin-2-yl.
R' is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-galkyl, and Het-
C0.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-Cθ-6a-kyl, and Het- C0.galkyl.
Most preferably R" is H.
R'" is selected from the group consisting of: H, C^galkyl, C3_gcycloalkyl-
Co-6alkyl, and Het-CQ.galkyl.
R'" is preferably selected from the group consisting of: H and Cj.galkyl. R'" is more preferably selected from the group consisting of: H, methyl and 6,6- dimethyl.
R'" is still more preferably selected from the group consisting of: H and 6,6- dimethyl. Most preferably R'" is H.
In compounds of Formula I, when R is
R3 is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Cθ-6alkyl,
C2_galkenyl, C2.galkynyl, Het-CQ.galkyl and Ar-Co-galkyl.
R3 is preferably Ci-galkyl.
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: Cι_galkyl, C3_gcycloalkyl-
Co-galkyl, C2.galkenyl, C2.galkynyl, HetCQ.galkyl and ArCg-galkyl;
R"" is preferably Ci-galkyl;
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 R^ are as described above wherein
In compounds of Formula I, when R is n is preferably an integer of from 1 to 5; and
R', R ', R ", R4, and R are as described above wherein
n is most preferably 3.
The ring may be unsubstituted or substituted with one or more of Ci-galkyl, C3_gcycloalkyl-Co-.galkyl, C _galkenyl, C2.galkynyl, HetCg-galkyl, ArCo_galkyl, or halogen.
The ring is preferably unsubstituted.
In compounds of Formula I, R2 is selected from the group consisting of:
H, C galkyl, C3_gcycloalkyl-C0_galkyl, Ar-C0_galkyl, Het-C0.galkyl, R9C(0)-, R9C(S)-,
R9SO2-, R9OC(O)-, R9RπNC(O)-, R9R NC(S)-, R9RπNSO2-,
More preferably R2 is selected from the group consisting of: Ar-Cθ-6alkyl,
R9C(O)-, R9SO2, R9RπNC(O)-, and
Even more preferably, R2, is selected from the group consisting of: Ar-Cθ-6alkyl,
R9C(O)-, and R9SO2.
Most preferably R2 is R9SO2.
In such embodiments: R" is selected from the group consisting of: H, Cι_galkyl, Ar-Cθ-6alkyl, or Het- Co_galkyl, preferably H.
R' is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl- C0.galkyl, Ar-C0_galkyl, Het-C0. alkyl, R10C(O)-, R10C(S)-, R10SO2-, R10OC(O)-, R10R14NC(O)-, R10R14NC(S)-, R7 is preferably R10OC(O).
R°> is selected from the group consisting of: H, Cl-galkyl, C2_galkenyl, C2-galkynyl, HetCø_galkyl and ArCo-galkyl; preferably Co.galkyl, more preferably isobutyl. R9 is selected from the group consisting of: C^ .galkyl, C3_gcycloalkyl-Co_galkyl,
Ar-Co-galkyl, and Het-Co-galkyl.
R9 is preferably selected from the group consisting of: C^galkyl, Ar-Co_galkyl, and Het-Co-galkyl.
More preferably, R9 is selected from the group consisting of: methyl; ethyl, especially Cj.galkyl-substituted ethyl, more especially 2-cyclohexy 1-ethyl; propyl; butyl, especially C _gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R2 is R9OC(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, more especially 2-cyanophenyl; especially Co.galkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cj, alkyl sulfonyl substituted phenyl, 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; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1 -oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially Cι_galkylpyridinyl, more especially 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 especially Ci.galkyl substituted imidazolyl, even more especially 1-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 R9SO2, R9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
When R2 is R9SO2R! 1NC(O)-, R9 is preferably Ar-C0.galkyl, more preferably Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl.
When R2 is R9C(O)-, R9 is preferably selected from the group consisting of Cj.galkyl, C3_gcycloalkyl-Co_galkyl, and Het-CQ.galkyl, more preferably l-oxy-pyridin-2- yl, cyclohexyl ethyl, and 3-methyl butyl.
RI 1 is selected from the group consisting of: H, Ci.galkyl, Ar-C()-6alkyl, and Het-
C0.galkyl.
When R2 is R9SO2RuNC(O)-, RU 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 Ci.galkyl, R2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl. When R2 is Het-Cg-galkyl, Het-Cg-galkyl is preferably Het-methyl, and Het in Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially Ci-galkylpyridinyl, more especially 6- methyl-pyridin-2-yl; thiophenyl, especially thiophene-2-yl, more especially thiophen-2-yl or benzo[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, especially
Ci.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 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, especially Ci.galkyl substituted thieno[3,2-b]thiophenyl, especially 3,4-dimethyl-thieno[3,2- b]thiophene-2-yl.
R2 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:
R! is
R2 is selected from the group consisting of: Ar-C()-6alkyl, R9C(O)-, R9SO2, Rβ R- Z - R9RnNC(O)-, and R ;
R3 is selected from the group consisting of: H, Ci -galkyl, C3_gcycloalkyl- Cθ-6alkyl and Ar-Co_galkyl;
R4 is selected from the group consisting of: R5OC(O)-, R5C(O)- and R5SO2-; R^is selected from the group consisting of: C .galkyl, Ar-Cø_galkyl and Het- C0.galkyl;
R6 is H; R7 is R10OC(O);
R8 is Ci.galkyl;
R9 is selected from the group consisting of: Ci.galkyl, Ar-Cg-galkyl and Het- C0-galkyl;
R*" is selected from the group consisting of: C\ .galkyl, Ar-Co_galkyl and Het- C0.galkyl;
R' is H; R" is H; R'" is H; and
Z is selected from the. group consisting of: C(O) and CH2.
Even more preferred are such compounds of Formula I wherein R2 is selected from the group consisting of: Ar-Cθ-6alkyl, R9C(O)-, R9SO2.
Yet more preferred are compounds of Formula I wherein: R1 is
R2 is selected from the group consisting of: Ar-C()-6alkyl, R9C(O)- and R SO2; R3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1 -hydroxy ethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;
R4 is R5C(O)-; R5 is selected from the group consisting of: methyl, especially halogenated methyl, more especially tfifluoromethyl , especially Cι_galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy- methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-y 1-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-fluorophenyl, especially phenyl substituted with one or more aryloxy or Cj.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more Ci.galkyl sulfonyl 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-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)-furan-2-yl,more especially halogen substituted furanyl, even more especially 5-bromo-furan-2-yl, more especially aryl substituted furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl, more especially Ci.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, especially tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin- l-yl-ethoxy)benzofuran-2-yl, 5- (2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially Cι_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 Ci.galkyl substituted benzofuranyl, 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-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-b]-furan-2-yl, alkyl substituted naphtho [2, 1 -b]-furanyl, especially 1 -methy 1-naphtho [2, 1 -b] -furan-2-yl; benzo [έ]thiophenyl, especially benzo[έ]thiophen-2-yl; especially Cι_galkoxy substituted 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, and quinolin-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 C\_ galkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C .galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl;; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C^galkyl substituted furo [3 ,2-b] -pyridinyl, especially 3-methyl-furo [3 ,2-b] -pyridin-2-y 1 ; thiophenyl, especially thiophen-3-yl, also thiophen-2-yl, especially C^galkyl substituted 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-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, more especially Ci.galkyl substituted thieno[3,2-b]thiophene-2-yl, more especially 5-tert-butyl-3-methyl- thieno[3,2-&]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially Ci.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.
R9 is selected from the group consisting of: methyl; ethyl, especially Cι_galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially Ci.gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R2 is R9OC(O); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyϊ, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, especially Ci.galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially Cigalkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Ci.galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Hex-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; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially l-oxy-pyridin-2-yl, l-oxy-pyridin-3-yl; especially Ci.galkylpyridinyl, more especially 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 especially Cigalkyl substituted imidazolyl, even more especially 1-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 Ci.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 Cigalkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl.
R' is H;
R" is H; and
R'" is H.
More preferred are compounds of Formula I wherein:
R! is
R2 is R9SO2;
R3 is isobutyl;
R4 is R5C(O);
R^ is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2- b]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl, preferably 3-methyl-benzofuran-2-yl;
R9 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'" is H;
Most preferred is such compound wherein: R-> is 3-methyl-benzofuran-2-yl; and R9 is l-oxy-pyridin-2-yl. An embodiment (IA) of the present invention provides compounds of Formula IA:
IA wherein:
RI is selected from the group consisting of:
R2 is selected from the group consisting of: Ci-galkyl, Ar-Cg-galkyl, Het-
C0.galkyl, R9C(O)-, R SO2-, R9RπNC(O)-, and R9SO2R NC(O)-;
R3 is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Cθ-galkyl, C2.galkenyl, C2_galkynyl, Het-Cg-galkyl and Ar-Cg-galkyl, preferably Ci-galkyl; R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
R4 is R5C(O)-;
R^ is selected from the group consisting of : Cl-galkyl and Het-Co-galkyl, preferably Het-Co-galkyl;
R9 is selected from the group consisting of: Cigalkyl, C3_gcycloalkyl-C()-galkyl, Ar-Co-galkyl and Het-CQ_galkyl;
RU is selected from the group consisting of: H, Ci-galkyl, Ar-C()-6alkyl and Het- CQ-galkyl, preferably H; R' is H; R" is H; R'" is selected from the group consisting of: H and C galkyl, preferably H; R"" is selected from the group consisting of: Ci .galkyl, C3_gcycloalkyl-Co_galkyl C2.galkenyl, C2.galkynyl, HetCo_galkyl and ArCo-galkyl; and n is an integer from 1 to 5, preferably n is 3; and pharmaceutically acceptable salts, hydrates and solvates thereof.
In embodiment IA, when
R3 is preferably Ci-galkyl;
R3 is more preferably selected from the group consisting of: but-2-yl and isobutyl. R3 is most preferably isobutyl.
R4 is R5C(O)-.
R5 is selected from the group consisting of : Cl_galkyl and Het-Cg-galkyl, preferably Het-Cj .galkyl;
More preferably, R-> is selected from the group consisting of: piperidin-ethyl, especially piperidin- 1 -y 1-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 Ci.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; benzofuranyl, especially benzofuran-2-yl, especially Ci.galkoxy substituted benzofuranyl, more especially 5-methoxy-benzofuran-2-yl, especially halogen substituted benzofuranyl, more especially 5-fluoro-benzofuran-2-yl, especially Ci.galkyl substituted benzofuranyl, 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- benzofαran-2-yl; naphtho[2,l-b]-furanyl, especially naphtho[2,l-b]-furan-2-yl, Cμgalkyl substituted naphtho[2, 1-bj-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; quinolinyl, especially quinolin-2-yl; quinoxalinyl, especially quinoxalin-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yl and l-oxy-pyridin-3-yl; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Ci.galkyl substituted furo[3,2-b]-pyridin-2-yl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl, especially thiophen-3-yl, and thiophen-2-yl, Cigalkyl substituted thiophenyl, especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3-yl; and thieno[3,2-b]thiophene, especially thieno[3,2-Z?]thiophene-2-yl; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl. R5 is more preferably selected from the group consisting of:
3-methyl-benzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl.
In embodiment IA, when R is
R3 is selected from the group consisting of: Ci .galkyl, C3_gcycloalkyl-C()-galkyl, C2_galkenyl, C2-6alkynyl, Het-Co_galkyl and Ar-Co-galkyl.
R3 is preferably Ci-galkyl, C3-gcycloalkyl-Cθ-6alkyl, and Ar-Cø_galkyl.
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_gcycloalkyl- Cθ-6alkyl, C2_galkenyl, C2.galkynyl, HetCQ.galkyl and ArCg-galkyl;
R"" is preferably Ci-galkyl;
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 R4 are as described above wherein
In embodiment IA, when R* is
n is an integer of from l to 5; preferably 3; and
R and R4 are as described above wherein
The cyclic ring may be unsubstituted or substituted with one or more of Cι_galkyl, C3_gcycloalkyl-Co-galkyl, C2_galkenyl, C2.galkynyl, HetCQ-galkyl, ArCo_galkyl, or halogen.
The cyclic ring is preferably unsubstituted.
In embodiment IA, R2 is selected from the group consisting of:
Cigalkyl, Ar-C0_galkyl, Het-C0.galkyl, R9C(O)-, R9SO2-, R9R! 1NC(O)-, and R9SO2RnNC(O)-.
More preferably R2 is selected from the group consisting of: Ar-Cθ-galkyl, R9C(O)-, R9SO2, and R9R* !NC(0)-.
Even more preferably, R2 is selected from the group consisting of: Ar-C()-6alkyl, R9C(O)-, and R9SO2.
Most preferably R2 is R9SO2. In such embodiment:
R9 is selected from the group consisting of: Ci.galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Co-galkyl, and Het-Co_galkyl.
R9 is preferably selected from the group consisting of: Ci.galkyl, Ar-Co-galkyl, and Het-Co-galkyl.
More preferably, R9 is selected from the group consisting of: ethyl, especially Ci.galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl, especially prop-1-yl; isopentyl; butyl, especially but-l-yl; phenyl, especially halogen substituted phenyl, more especially 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl; especially Cigalkyl substituted phenyl, more especially 4- ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Ci.galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; pyridinyl, especially pyridin-2-yl, 1 -oxy-pyridinyl, more especially 1-oxy-pyridin-
2-yl; lH-imidazolyl, especially lH-imidazol-2-yl Ci.galkyl substituted imidazolyl, especially 1-methyl- lH-imidazol-2-yl; and isoxazolyl, especially isoxazol-4-yl, Ci.galkyl substituted isoxazolyl, especially 3,5-dimethyl- isoxazol-4-yl.
When R2 is R9SO2, R9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
When R2 is R9SO2R! !NC(O)-, R9 is preferably Ar-C0.galkyl, more preferably
Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, 4-fluoro phenyl.
When R2 is R9C(O)-, R9 is preferably selected from the group consisting of Ci.galkyl, C3_gcycloalkyl-Co_galkyl, and Het-Co-galkyl, more preferably l-oxy-pyridin-2- yl, 2-cyclohexyl ethyl, and isopentyl.
When R2 is R9SO2RHNC(O)-, R11 is selected from the group consisting of: H, Ci.galkyl, Ar-CQ-galkyl and Het-Co-galkyl. Preferably in such embodiment, RU is H.
R2 may suitably be selected from the group consisting of: Cj. galkyl, Ar-Co_6alkyl and Het-Cø-galkyl, preferably Oχ .galkyl and Het- Co_6alkyl,
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 Cigalkyl, R2 is preferably selected from 1-propyl, 1-butyl, and 1-pentyl.
When R2 is Het-CQ-galkyl, Het-CQ.galkyl is preferably Het-methyl, and Het in Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, Ci.galkylpyridinyl, especially 6-methyl-pyridin- 2-yl; thiophenyl, especially thiophene-2-yl; benzo [b] thiophen-2-y 1 ; thiazolyl, especially thiazol-4-yl such as isothiazol-3-yl; lH-imidazolyl, especially lH-imidazol-2-yl, Cigalkyl substituted imidazolyl, especially 1-methyl- lH-imidazol-2yl; triazolyl, especially 3H-fl,2,3]triazolyl, more especially 3H-[l,2,3]triazol-4-yl, especially Ci.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, Ci-galkyl substituted thieno[3,2-b]thiophene-2-yl, especially 3,4-dimethyl-thieno[3,2-b]thiophene-2-yl.
The compounds of embodiment IA have the same uses described throughout this specification for compounds of Formula I. The compounds of embodiment IA may be formulated into pharmaceutical compositions and used in methods of treatment as described for compounds of Formula I throughout this specification. Compounds of Formula I selected from the following group are particularly preferred embodiments of the present invention:
Example Chemical Name
No.
1 {(S)-l-[l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3- oxo-azepan-4-ylcarbamoyl}carbamic acid benzyl ester;
2 Naphthylene-2-carboxylic acid[(S)-l-(l-benzyl-3-oxo-azepan-4- ylcarbamoyl)-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-carboxy lie 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-methyl-butyl]amide;
9 4-{(S)-Methyl-2-[(quinoline-2-carbonyl)-amino]pentanoylamino}- 3-oxo-l-[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,3]dioxole-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; 14 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- (l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]amide;
15 4-((S)-4-Methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]amino}-pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide;
16 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)- 3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4- ylcarbamoyl } -butyl)amide ;
17 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- l-(benzoyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
18 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- (l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl] amide;
19 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l- (l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl] amide;
20 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- ylcarbamoyl } -butyl)amide;
21 Naphthlene-2-carboxylic acid ((S)-3-rnethyl-l-{3-oxo-l-[2-(3- pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide;
22 lH_Indole-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3- pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide;
23 lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
24 Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
25 Benzofuran-2-carboxylic acid [(S)-3-methyl-l-{3-oxo-l-[2-(3- pyridin-2-yl-phenyl)ethyl]-azepan-4-ylcarbamoyl}-butyl)amide;
26 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- 3-methyl- l-(3-oxo- l-phenethyl-azepan-4-ylcarbamoyl]- butyl} amide; 27 Naphthylene-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l- phenethyl-azepan-4-ylcarbamoyl]-butyl}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-ylcarbamoyl]-butyl}-amide;
30 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)- 3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} -amide;
31 4-((S)-4-Methyl-2- { [(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]-amino}-pentanoylamino)-3-oxo-azepane-l-carboxylic acid tert-butyl ester;
32 4-((S)-4-Methyl-2- { [(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carboxylic acid [(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- acetyl]-azepan-4-yl } -amide;
34 ((S)-3-Methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]- azepan-4-y lcarbamoyl } -butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester;
35 (S)-4-Methyl-2- [(naphthylen-2-ylmethyl)-amino]-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-1 -carboxylic acid tert-butyl ester;
37 5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3- methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3- butylj-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; 39 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;
40 4-[2-(2-{(S)-3-Methyl-l-[3-oxo-l-(3-pyridin-2-yl-phenyl)-ethyl [azepan-4-ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)- ethylj-piperazine-l-carboxylic acid tert-butyl ester;
41 5-(2-piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3- methyl- 1- { 3-oxo- 1 -[2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- ylcarbamoyl }-butyl)amide;
42 (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid [3-oxo- l-(pyridine-2-sulphonyl)-azepan-4-yl]-amide;
43 (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid {3-oxo-l-[2-(3-pyridin-2-yl-phenyι)-acetyl]-azepan-4-yl}- amide;
44 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl- phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide;
45 Benzofuran-2-carboxylic acid methyl {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide;
46 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;
47 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4- methyl-pentanoylamino]-3-oxo-azepane-l-carboxylic acid benzyl ester;
48 Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
49 Quinoline-8-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
50 Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; 51 Quinoline-4-carboxylic acid {(S)-3-rnethyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
52 Quinoline-3-carboxylic 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- 1 -carboxylic acid { (S)-3-methyl-l -[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
55 Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
56 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-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-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-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- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
61 Furan-2-carboxylic acid {(S)-3-methyl-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-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
64 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3- methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butylj 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; 67 (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
68 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-carbonyl)-azepan-4-ylcarbamoyl)-3- butyl]-amide;
69 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-carbonyl)-azepan-4-y lcarbamoyl] -butyl } amide ;
70 4-((S)~2-tert-Butylcarbonylamino-4-methyl-pentanoylamino)-3- oxo-azepane-1-carboxylic acid benzyl ester;
71 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- oxo-l-(l-methyl-lH-imidazole-4-sulfonyl)-azepan-4- ylcarbamoyl] -butyl }amide;
72 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH- [ 1 ,2,4]triazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl} amide;
73 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH- imidazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
74 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole- 2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide;
75 Benzofuran-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- l-(thiazole- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
76 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH- imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
77 5-(4-Oxy-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]~butyl}amide;
78 Benzofuran-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- 1 -(pyridine- 3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
79 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
80 Quinoline-3-carboxylic acid {(S)-l-(3,4-dichloro-benzene- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl)]-3-methyl-butyl } -amide; 81 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-mefhyl-l-[l-(l- methyl-lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl} amide;
82 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-3-methyl-butyl}- amide;
83 2-(4-{ (S)-2-{ (Benzofuran-2-carbonyl)-amino }-4-methyl- pentanoylamino}-3-oxo-azepane-l-sulfonyl)-benzoic acid;
84 3-(4- { (S)-2- { (Benzofuran-2-carbonyl)-amino]-4-methyl- 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-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
86 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
87 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- oxo-l-(l-oxy-pyridine~2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide;
88 l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-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~benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide; 94 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;
95 Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-suIfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
96 Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
97 Thiophene-3-carboxylic acid { (S)-3-methyl-l- [3-oxo- l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
98 lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
99 Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
100 Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
101 (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid [3- oxo- 1 -( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-yl]-amide ;
102 lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
103 4-Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulphonyι)- azepan-4-carbamoyl]-butyl}-benzamide;
104 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3- methyl- 1 - [3-oxo-( l-oxy-pyridine2-sulphonyl)-azepan-4- ylcarbamoyl]- -butyj-amide;
105 Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-suIfonyl)-azepan-4-ylcarbamoyI]-butyl}amide;
106 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
107 6-Me thyl-N- { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-nicotinamide;
108 (S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-butyl}amide; 109 lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
110 Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
111 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3- methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2-sulf onyl)-azepan-4- ylcarbamoyl] butyl }amide;
112 . 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
113 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide;
114 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide;
115 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[l-(4- methoxy-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide;
116 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3- methyl- 1 - [3-oxo- 1 -( l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
117 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid { (S)-3-methyl- 1-[3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide;
118 Benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;
119 Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
120 Benzofuran-2-carboxylic acid {(S)-l-[l-(benzo[l,2,5]oxadiazole- 4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-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; 122 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
123 Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
124 5-tert-Butyl-3-methyl-thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoyl]-butyl } amide ;
125 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3- oxo- 1 -(pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide ;
126 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3- methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4-ylcarbamoyl]- butyl} amide;
127 Quinoline-2-carboxylic acid [(S)-l-(l-mefhanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
128 l-Methyl-lH-indole-2-carboxylic acid [(S)-l-(l-methanesulfonyl- 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
129 Furan-2-carboxylic acid {[(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-ylcarbamoy l)-3-methyl-buty lcarbamoyl] -methyl } -amide ;
130 5-Mefhoxy-benzofuran-2-carboxylic acid [(S)-l-(l- methanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide;
131 Quinoxaline-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
132 5-(4-Chloro-ρhenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
133 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid ( 1 -methanesulfonyl-3-oxo-azepan-4-yl)-amide;
134 Quinoline-2-carboxylic acid { [(S)- 1 - [ 1 -(2-cy ano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide;
135 1-Methyl-lH-indole -2-carboxylic acid { [(S)-l-[l-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 136 Furan-2-carboxylic acid ({(S)-l-[l-(2-cyano-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyι)- amide;
137 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano- benzenesulf onyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide;
138 Quinoxaline-2-carboxylic acid { (S)- 1 - [ 1 -(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
139 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide;
140 Quinoline-2-carboxylic acid {[(S)-l-[l-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
141 l-Methyl-lH-indole-2-carboxylic acid {[(S)-l-[l-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
142 Furan-2-carboxylic acid ({(S)-l-[l-(4-methoxy-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)- amide;
143 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-l-[l-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
144 Quinoxaline-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-pentanoic acid [ 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-methyl-butyl } - amide; 147 Furan-2-carboxylic acid ({(S)-l-[l-(4-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)- amide;
148 5-Methoxy-benzofuran-2-carboxylic acid {[(S)-l-[l-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
149 Quinoxaline-2-carboxylic acid { [(S)-l-[l-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
150 (S)-2-[2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid [l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide;
151 Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
152 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
153 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
154 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{ (S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
155 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
156 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide;
157 l-Methyl-lH-indole-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 158 Quinoxaline-2-carboxylic acid-{(S)-l-[l-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
159 Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide;
160 5-Methoxy-benzofuran-2-carboxylic acid-{JS)-l-[l-(2-fmoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
161 7-Methoxy-benzofuran-2-carboxy lie acid- {(S)-l-[l -(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
162 5 ,6-Dimethoxy-benzofuran-2-carboxy lie acid- { (S)- 1 - [ 1 -(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
163 5-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
164 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro- benzenesulphonyl)-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-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
167 Quinoxaline-2-carboxylic 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- 1 - [3-oxo- 1 -(fhiophene-2-sulf onyl)-azepan-4-y lcarbamoyl] -butyl } -amide ;
169 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo- l-(thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 170 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{ (S)-3-methyl-l-[3- oxo-l-(thiophene-2-sulfonyl)-azeρan-4-ylcarbamoyl]-butyl}- amide;
171 3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide;
172 Benzo[b]thiophene-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
173 l-Methyl-l-H-indole-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
174 Quinoxaline-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
175 Benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
176 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyI)-3-oxo-azepan-4-ylcarbamoyI]-3-methyl-butyl}- amide;
177 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
178 5,6-Dimethoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
179 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
180 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
181 1 -Methyl- lH-indole-2-carboxylic acid-{(S)-l-[l-(4-chIoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; 182 Quinoxaline-2-carboxylic acid-{(S)-l-[l-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
183 Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
184 5-Methoxy-benzofuran-2-carboxylic 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-benzofuran-2-carboxylic acid-{(S)-l-[l-(3- methoxy-benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3- methyl-butyl } -amide ;
187 3-Methyl-benzofuran-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- benzenesulphony l)-3-oxo-azepan-4-y lcarbamoyl] -3-methyl-butyl } - amide;
191 Benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
192 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(2,2',4- tridueterio)-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide; 193 Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
194 Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide;
195 Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
196 Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
197 Benzofuran-2-carboxylic acid {(S)-3-methanesulfinyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide;
198 Benzofuran-2-carboxylic acid { [3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-methyl}-amide;
199 Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-pentyl}-amide;
200 Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2- sulf ony l)-azepan-4-y lcarbamoyl] -butyl } -amide ;
201 Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide;
202 Benzofuran-2-carboxylic acid {(S)-2-hydroxy-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-propyl}-amide;
203 Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(ρyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide;
204 l-(Benzofuran-2-carbonyl)-pyrrolidine-2-carboxylic acid [3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-yl]-amide;
205 3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl } -benzamide;
206 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-imethoxy- benzenesulf onyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } - amide;
207 Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3methyl-butyl}- amide; 208 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[l-(4- fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl]-amide;
209 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl] -3-methyl-butyl }- amide;
210 Benzofuran-2-carboxylic acid {(S)-l-[l-benzoyl-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
211 (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid [3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
212 (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
213 Benzofuran-2-carboxylic acid-{(S)-l-[ l-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}- amide;
214 N-{(S)-l-[l-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl } -3-methyl-butyl } -3 ,4-dimethoxy-benzamide ;
215 Cyclohexanecarboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-amide;
216 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[l- (methanesulfonyl)-3-oxo-azepan-4-yl]-amide;
217 Benzo[b]thiophene-2-carboxylic acid-{ (S)-l-(l-methanesulfonyl- 3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;
218 Benzo[l ,3]dioxole-5-carboxylic acid- { (S)- 1-( l-methanesulfonyl-3- oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;
219 Benzofuran-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;
220 N-[(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-yIcarbamoyl}-3- methy 1-buty 1 } -3 ,4-dimethoxy-benzamide ;
221 (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid[l-(2- cyano-benzensulfonyl)-3-oxo-azepan-4-yl]-amide;
222 N-{(S)-l-[l-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4- y lcarbamoyl } -3-methyl-butyl } -4-methanesulf ony 1- 1 -benzamide ; 223 Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]- amide;
224 Benzo[l,3]dioxole-5-carboxylic acid-{(S)-l-[l-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide;
225 (S)-4-Methyl-2-[4-oxo-4-((4-phenoxy-phenyl)-butyrylamino}- pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
226 N-{ (S)-l-[(l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoy 1 } -3-methyl-butyl } -3 ,4-dimethoxy-benzamide;
227 Cyclohexanecarboxylic acid {(S)-l-[l-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}- amide;
228 4-Methansulfonyl-N-{(S)-l-[4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-carbamoyl]-3-methyl-butyl-benzamide;
229 4-Methansulfonyl-N-{(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-carbamoyl]-3-methyl-butyl-benzamide;
230 ( { (S)-3-Methyl- l-[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butylcarbamoyl}-carbamic acid benzyl ester;
231 (S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
232 (S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4- methy Ipentanoic acid [3-oxo- l-(pyridine-2-sulf onyl)-azepan-4-yl]- amide;
233 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l- (pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
234 (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid [3-oxo- 1- (pyridine-2-sulfonyI)-azepan-4-yl]-amide;
235 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide;
236 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6- methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl} amide; 237 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6- methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl} amide;
238 7-Methoxy-benzofuran-2-carboxylic 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-ylcarbamoyl]- 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-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide;
242 Benzofuran-2-carboxylic acid { (S)-2-cyclopropy 1-1 -[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
243 Benzofuran-2-carboxylic acid {(S)-3-methylsulfanyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-propyl]-amide;
244 Benzofuran-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-l-[l-(3- methyl-pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]- butyl} amide; 249 5,6-Dif uoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide;
250 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2- cyclohexyl-l-{3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl}-amide;
251 5-(4-Chloro-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l- { 3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }- amide;
252 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l- (pyridine-sulphonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
253 5-(4-Chloro-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l- [3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- ethyl}-amide;
254 5-(3-Trit uoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2- cyclohexyl-I-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-ethyl } -amide;
255 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
256 5,6-Dimethoxy-benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-l- [3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- ethyl} -amide;
257 5,5-Bis-(4-methoxy-phenyl)-pent-4-enoic acid {(S)-3-methyl-l- [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-y lcarbamoyl] }-butyl }- amide;
258 Quinoline- 8-carboxy lie acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
259 Naphthylene-1 -carboxy lie acid {(S)-2-naphthylen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
260 Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2 -sulfonyl)-azepan-4-ylcarbamoyl]-2-phenyl-ethyl}-amide;
261 Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 262 Naphthylene-1-carboxy lie 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-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l- [3-oxo-l-(4~methyl-pentanoyι)-azepan-4-ylcarbamoyl]-butyl}- amide;
265 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (l-oxy-pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
266 (S)-Acetylamino-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-yl]-amide;
267 Quinoline-2-carboxylic acid { l-[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]-butyl}-amide;
269 Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(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-ylcarbamoyl]-ethyl}-amide;
272 Benzofuran-2-carboxylic acid{(S)-2-hydroxy-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-amide;
273 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo- l-(thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-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-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
276 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
277 l-Methyl-lH-indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (thiazole-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 278 Quinoxaline-2-carboxylic acid {(S)-3-methy 1-1 -[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 preferred embodiments of the present invention:
280 Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl- 1-butyl }- amide;
281 (S)-4-methyl-2-(3-piperidin-l-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- l-{3-oxo-l-[l-(l -oxy-pyridin-2-yl)-methanoyl]-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)-methanoyl]-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-carboxylic 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-ylcarbamoyl)-3-methyl- 1-butyl]- amide; 291 5-Fluoro-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- 1 -( 1 -oxy-pyridine-2-sulf onyl)-azepan-4-y lcarbamoyl] - butyl} -amide;
293 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;
294 3-Methyl-benzofuran-2-carboxylic acid {(R)-3-methyl-l-[3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
295 3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-l- [-3-oxo-l-(l-oxy-ρyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} -amide;
296 5-Methoxy-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}- amide;
298 Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
299 3-methyl-furan-2-carboxylic 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-ylcarbamoyl]-3-methyl-butyl}- amide; 303 Thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
304 5-Methyl-thiophene-2-carboxylic acid {(S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
305 5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl- 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
306 3-Methyl-benzofuran-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
307 Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
308 3-Methyl-furan-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
309 Quinoline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
310 Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-l-(l- ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]- amide;
311 Quinoxaline-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
312 Thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
313 5-Methyl-thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
314 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l- (propane- 1 -sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- 1 -butyl } - amide;
315 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(propane- 1 -sulf onyl)-azepan-4-ylcarbamoyl] -3-methyl- 1 -butyl } -amide;
316 Benzo[b]thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
317 3-Methyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 318 2,5-Dimethyl-furan-2-carboxylic acid { (S)- 1 - [3-oxo- 1 -(propane- 1 - sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
319 Quinoline-2-caxboxylic 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-l-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide;
321 Quinoxaline-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
322 Thiophene-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
323 5-Methyl-thiophene-2-carboxylic acid { (S)-l- [3-oxo- 1 -(propane- 1- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-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-ylcarbamoyl]- butyl}-amide;
325 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}- amide;
326 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
( 1 -oxy-pyridine-2-sulf onyl)-azepan-4-y lcarbamoyl] -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-ylcarbamoyl]- butyl} -amide;
329 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl- l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-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; 331 Benzofuran-2-carboxylic acid [(S)-3-methyl- 1- [3-oxo- 1-quinolin- 2-ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide;
332 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l- quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl } -amide;
333 Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l- quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide;
334 Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-2-sulfonylamino)-methanoyl]-azepan-4-y lcarbamoyl } - butyl)-amide;
335 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l- [ 1 -toluene-2-sulf onylamino)-methanoyl] -azepan-4-ylcarbamoy 1 } - butyl)-amide;
336 Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}- butyl)-amide;
337 Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyι)- amide;
338 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl- 1- { 3-oxo- 1- [2-chloro-benzenesulfonylamino)-methanoyl]-azepan-4- ylcarbamoyl } -butyl)-amide ;
339 Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2- chloro-benzenesulfonylamino)-methanoyl]-azepan-4- ylcarbamoyl } -butyl)-amide ;
340 Benzofuran-2-carboxylic acid ((S)-3-methyl- 1 - { 3-oxo- 1 - [4-fluoro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarban oyl}-butyl)- a ide;
341 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l- [4-fluoro-benzenesulfonylamino)-methanoyl]-azepan-4- ylcarbamoyl } -buty l)-amide ;
342 Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4- fluoro-benzenesulfonylamino)-methanoyl]-azepan-4- ylcarbamoyl } -butyl)-amide ; 343 Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-4-sulfonylamino)-methanoyl]-azepan-4-y lcarbamoyl } - butyl)-amide;
344 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l- [l-toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}- butyl)-amide;
345 Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}- butyl)-amide;
346 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl- pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;
347 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6- methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4~ylcarbamoyl]-butyl}- amide;
348 Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6- methyl-pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}- amide;
349 Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
350 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl } - amide;
351 2,4-Dimethylfuran-3-carboxylic acid { (S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl } - amide;
352 Quinoxaline-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-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-methy 1-butyl } - amide; 354 Quinoline-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
355 4-Methyl-thiophene-2-carboxylic acid { (S)- 1-[ l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
356 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
357 4-Methyl-furan-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide; ι
358 Benzofuran-2-carboxylic acid [(S)-l-(l-butyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide;
359 Benzofuran-2-carboxylic acid [(S)-l-(l-propyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide;
360 Benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-benzyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide;
361 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-moφholin-4- yl-thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}- amide;
362 Benzofuran-2-carboxylic acid {(S)-l-[l-(5-ethyl-furan-2- ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
363 Benzofuran-2-carboxylic acid {(S)-l-[l-(3,4-dimethyl-thieno[3,2- b]thiophene-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl- butyl} -amide;
364 Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(3-phenyl- 3H-[l,2,3]triazol-4-ylmethyl)-azepan-4-ylcarbamoyl]-butyl}- amide;
365 Benzofuran-2-carboxylic acid [(S)-l-[l-(isothiazol-3-ylmethyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl}-amide;
366 Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-thiophen- 2-ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide; 367 Benzofuran-2-carboxylic acid [(S)-l-(l-benzo[b]thiophen-2- ylmethyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl]-amide;
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-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-buty}-amide;
370 l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulf onyl)-azepan-4-y lcarbamoyl ]-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}-amide;
373 4-{(S)-2-[(l-Benzofuran-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 - imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl- butyl}-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-methy 1-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-carboxylic acid {(lS,2R)-2-methyl-l-[3- oxo-l-(pyridine-2-sulfonyl)-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 381 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 381 in the list herein above.
Specific representative compounds of the present invention are set forth in
Examples 1-381.
Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds of the present invention are configurationally more stable at the carbon center alpha to the ketone. The present invention includes deuterated analogs of the inventive compounds. A representative example of such a deuterated compound is set forth in Example 192. A representative synthetic route for the deuterated compounds of the present invention is set forth in Scheme 4, below. The deuterated compounds of the present invention exhibit superior chiral stability compared to the protonated isomer. Where possible the present invention includes quaternary salts of the inventive compounds. A representative example of such a quaternary salt is set forth in Example
373. A representative synthetic route for the quaternary salts of the present invention is set forth in Scheme 6, below.
Definitions
The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have 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 exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
The meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). "Proteases" are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis.
Such proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. The compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors. The term "amino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
"Ci-galkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Ci -galkyl may be optionally substituted by a moiety selected from the group consisting of: OR 4, C(O)Rl4, SR*4, S(O)R14, NR14 2, R14NC(O)OR5, CO2R14 CO2NR14 2, N(C=NH)NH2, Het, C3. gcycloalkyl, and Ar; where R^ is selected from the group consisting of: H, Ci-galkyl,
C2-galkenyl, C2-galkynyl, C3-gcycloalkyl-Co-galkyl, Ar-CQ-galkyl and Het-CQ.galkyl; and R^ is selected from the group consisting of: H, Ci-galkyl, Ar-Cθ-galkyl, and Het-
C0_galkyl; "C3_gcycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.
"C2_g alkenyl" as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2_galkenyl includes ethylene, 1-propene, 2-propene, 1 -butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
"C2.galkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C _g alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
"Halogen" means F, CI, Br, and I.
"Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-CQ-galkyl; Ci-galkoxy; Ph-CQ-galkoxy; Het-C0-galkoxy; OH, (CH2)ι_ gNR15R16; O(CH2)ι-gNR15R16; Ci-galkyl, OR17, N(R17)2, SR17, CF3, NO2, CN, CO2R17, CON(R17), F, CI, Br or I; where R15 and R16 are H, Cigalkyl, Ph-C0-galkyl, naphthyl-Cø-galkyl or Het-Co-galkyl; and R 7 is phenyl, naphthyl, or Ci-galkyl.
As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms 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 the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C0_gAr, Ci-galkyl, OR17, N(R17) , SR17, CF3, NO2, CN, CO2R17, CON(Rl7), F, CI, Br and I, where R*7 is phenyl, naphthyl, or Cι_galkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 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 [bjthiophenyl, thieno [3,2- b]thiophenyl, benzo[l,3]dioxolyl, 1,8 naphthyridinyl, pyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are available by routine 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 denotes the absence of the substituent group immediately following; for instance, in the moiety ArCg-galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo-galkyl is identified as a specific 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 butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. m-CPBA refers to 3-chloroperoxybenzoic acid, EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide, DMF refers to dimethyl formamide, DMSO refers to dimethyl sulfoxide, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, and THF refers to tetrahydrofuran.
Methods of Preparation Compounds of the general formula I may be prepared in a fashion analogous to that outlined in Schemes 1, 2 and 3. Alkylation of tert-butyl N-allylcarbamate (1) with a base such as sodium hydride and 5-bromo-l-pentene provides the diene 2. Treatment of 2 with either 2,6-diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride olefin metathesis catalysts developed by Grubbs provides the azepine 3. Epoxidation of 3 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 4. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon. Acylation of 5 with an acid such as Cbz-leucine in the presence of a coupling agent such as EDC followed by removal of the BOC protecting group under acidic conditions provides the amine salt 6. Coupling of 6 with Cbz-leucine may be effected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7. Scheme 1
6
Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 2,6-diisopropylphenylimido neophylidene molybenum bis (tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, toluene c.) m-CPBA, CH2C12; d.) NaN3, CH3OH, H20, ΝH4C1; e.) 10% Pd/C, H2, f.) Cbz-leucine, EDC, CH.C1.; g.) HC1, EtOAc; h.) Cbz-leucine, EDC, CH2C12; i.) pyridine sulfur trioxide complex, DMSO, TEA.
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 N-Cbz allyl amine (8) with a base such as sodium hydride and 5-bromo-l-pentene provides the diene 9. Treatment of 9 with bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride olefin metathesis catalyst developed by Grubbs provides the azepine 10. Epoxidation of 10 with standard oxidizing agents common to the art such as m- P A provide the epoxide 11. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine. Acylation of 12 with N-Boc- leucine and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13. Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HC1 or TFA provides intermediate 14. Acylation of 14 may be effected with a carboxylic acid in the presence of a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15.
Scheme 2
10
11 12
13 14 15
Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CH2C12; c.) m-CPBA, CH2C12; d.) NaN3, CH3OH, H20, NH4C1; e.) propanedithiol, CH3OH, TEA; f.) Boc-leucine, EDC, CH2C12; g.) 10% Pd/C, H2; h.) R,C02H, EDC, CH2C12 or R.COC1, CH2C12; i.) HC1/ EtOAc; j.) R.CCgH, EDC, CH2C12; k.) pyridine sulfur trioxide complex, DMSO, TEA. 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 outlined in Scheme 3. Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N- Boc group under acidic conditions provides the amine salt 16. Coupling of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Alternatively, treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18. Acylation and oxidation provides the ketone 19. Further derivatization of amine 13 may be effected by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20. Acylation and oxidation provides the ketone 21.
Scheme 3
13 16 17
20 21
Reagents and conditions: a.) R,CHO, NaBH(OAc)3; b.) HCl; c.) RjCO.H, EDC, CH2C12; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R,S02C1, TEA, CH2C12. The deuterated compound of the Example 192 may be conveniently prepared according to Scheme 4. The skilled artisan will understand from Example 192 and Scheme 4 how to make any of the the deuterated compounds of the present invention.
The individual diastereomers of benzofuran-2-carboxylic acid {(S)-3-methyl-l- [(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 benzyl ester 22 with 5-bromo-l-pentene in the presence of a base such as sodium hydride provides the diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride developed by Grubbs provides the 2,3,4,7-tetrahydro-azepine-l- carboxylic acid benzyl ester 24. Epoxidation of azepine 24 may be effected with standard oxidizing agents common to the art such as m-CPBA to provide epoxide 25. Nucleophilic epoxide ring opening of 25 may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown).
Scheme 4
22 23 24
25 26
27 28
29 30
31 32
Reagents and Conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH2C12; c.) m-CPBA, CH2C12; d.) NaN3, CH3OH, H20, NH4C1; e.) 1,3-propanedithiol, TEA, methanol; f.) N-Boc-leucine, EDC, CH2C12; g.) 10% Pd/C, H2; h.) 2-pyridinesulphonyl chloride, TEA, CH2C12; i.) 4 N HCl/dioxane, methanol; j.) benzofuran-2-carboxylic acid, EDC, CH2C12; k.) pyridine sulfur trioxide complex, DMSO, TEA; 1.) CD3OD;D20 (10:1), TEA; m.) HPLC separation. The intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water. Acylation of 26 may be effected with an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC. Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 27. Treatment of the amine 27 with 2-pyridinesulphonyl chloride in the presence of triethylamine or saturated sodium bicarbonate and CH2C12 followed by removal of the tert-butoxycarbonyl protecting group under acidic conditions provides 28. Coupling of 28 with benzofuran-2-carboxylic acid may be effected with a coupling agent such as
EDC to provide intermediate alcohol 29. Alcohol 29 may be oxidized with an oxidant such as sulfur trioxide pyridine complex in DMSO and triethylamine to provide the ketone 30 as a mixture of diastereomers. Treatment of ketone 30 with triethylamine in CD3OD:D2O at reflux provides the deuterated analog as a mixture of diastereomers which are separated by HPLC to provide the deuterated compounds 31 and 32.
Compounds of the general formula I may also be prepared as outlined in Scheme 5. The amine of compound 12 may be protected with with di-tert-butyldicarbonate to provide the N-Boc derivative 33 (Scheme 2). Removal of the benzyloxycarbonyl protecting group may be effected by treatment of 33 with hydrogen gas in the presence of a catalyst such as 10% Pd/C to provide the amine 34. Treatment of amine 34 with a sulfonyl chloride such as 2-pyridinesulfonyl chloride in the presence of a base such as N-methylmorpholine or triethylamine provides the sulfonamide derivative 35. Removal of the tert-butoxycarbonyl protecting group may be effected with an acid such as hydrochloric acid to provide intermediate 36. Coupling of 36 with an acid such as N-Boc-cyclohexylalanine in the presence of a coupling agent common to the art such as HBTU or polymer supported EDC provides the alcohol intermediate 37. Removal of the tert-butoxycarbonyl protecting group under acidic conditions provides amine 38. Coupling of 38 with an acid such as benzofuran-2-carboxylic acid in the presence of a coupling agent such as HBTU or polymer supported EDC provides alcohol 39. Alcohol 39 may be oxidized with an oxidant common to the art such as pyridine sulfur trioxide complex in DMSO and triethylamine or the Dess- Martin periodinane to provide the ketone 40. Scheme 5
12 33 34
35 36
37 38
39 40
Reagents and Conditions: (a) Di-terf-butyldicarbonate, THF; (b) H., 10% Pd/C, EtOAc; (c) 2- pyridylsulfonyl chloride, TEA ; (d) HCl, EtOAc; (e) N-Boc-cylohexylalanine, P-EDC, CH2C12; (f) HCl, CH2C12; (g) benzofuran-2-carboxylic acid, P-EDC, CH2C12; (h) Dess-Martin periodinane, methylene chloride.
The quaternized, 4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 6. The skilled artisan will understand from Scheme 6 how to make any of the quaternized, 4-amino-azepan-3-one compounds of the present invention. Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N-Boc group under acidic conditions provides the amine salt 16. Treatment of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Quaternization of the amine of 17 may be effected by treatment with an alkylating agent such as iodomethane to provide the quaternary amine salt 41.
Scheme 6
41
Reagents and conditions: a.) R,CHO, NaBH(OAc)3; b.) HCl; c.) P^CO-H, EDC, CH2C12; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) iodomethane
The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I- VI (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 PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and I.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incorporated herein by reference.
Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions. Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li+, Na+, K+, Ca++, Mg++ and NH-J+ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts. Quaternary ammonium salts are prepared by treating a parent amine compound with an excess of alkyl halide, such as methyl iodide. This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
Novel Intermediates Referring to the methods of preparing the compounds of Formula I set forth in
Schemes 1-4 above, the skilled artisan will appreciate that the present invention includes all novel intermediates required to make the compounds of Formula I. In particular, the present invention provides the compounds of Formula II:
II
wherein:
RI is selected from the group consisting of:
R2 is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl-Co_galkyl, Ar- C0-6alkyl, Het-C0-6alkyl, R9C(O)-, R C(S)-, R9SO2-, R9OC(O)-,
R9R11NC(O)-, R9RπNC(S)-, R9(R1 1)NSO2-
R3 is selected from the group consisting of: H, Ci-galkyl, C3-gcycloalkyl- Cθ-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCθ-6alkyl and ArCθ-6alkyl;
R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring; R4 is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl- Co-galkyl, Ar-C0.galkyl, Het-C0.galkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R12NC(O)-, and R5R12NC(S)-; R^ is selected from the group consisting of: H, C -galkyl, C2-galkenyl,
C2_galkynyl, C3-gcycloalkyl-Co_galkyl, Ar-CQ-galkyl and Het-Co-galkyl;
R° is selected from the group consisting of: H, C -galkyl, Ar-Cθ-6a-kyl, or Het- C0.6alkyl;
R1 is selected from the group consisting of: H, Ci.galkyl, C3-gcycloalkyl- C0.galkyl, Ar-C0-galkyl, Het-C0_galkyl, R10C(O)-, R10C(S)-, R10SO2-, R10OC(O)-, R10R13NC(O)-, and R10Rl NC(S)-;
R° is selected from the group consisting of: H, Ci-galkyl, C2-galkenyl, C2-galkynyl, HetCø-6alkyl and ArCθ-6alkyl;
R9 is selected from the group consisting of: Ci.galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Co-galkyl and Het-Co-galkyl;
RiO is independently selected from the group consisting of: C\ -galkyl, C3-gcycloalkyl-Co-galkyl, Ar-Co-galkyl and Het-Co-galkyl;
RU is selected from the group consisting of: H, C\ -galkyl, Ar-Cθ-6a-kyl, and Het- Co-galkyl;
R 2 is selected from the group consisting of: H, Cj-galkyl, Ar- )-6alkyl, and Het- Co-galkyl;
Rl3 is selected from the group consisting of: H, Cj-galkyl, Ar-Cθ-6alkyl, and Het- Co-galkyl;
R' is selected from the group consisting of: H, Cj -galkyl, Ar- )-6alkyl, and Het- C0-galkyl; R" is selected from the group consisting of: H, Cj -galkyl, Ar-Cθ-6alkyl, or Het-
Co-galkyl;
R'" is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl- Co-galkyl, Ar-Co-galkyl, and Het-Co-galkyl;
R"" is selected from the group consisting of: Ci-galkyl, C3-gcycloalkyl-Co_galkyl C2-6alkenyl, C2.galkynyl, HetCQ-galkyl and ArCo-galkyl; n is an integer of from 1 to 5; and salts, hydrates and solvates thereof.
With reference to embodiment IA, the present invention includes the novel intermediates of Formula IIA:
IIA
wherein: RI is selected from the group consisting of:
R2 is selected from the group consisting of: C galkyl, Ar-Co_galkyl, Het- Co-galkyl, R9C(O , R9SO2-, R9RπNC(O)-, and R SO2RπNC(O)-;
R3 is selected from the group consisting of: Ci -galkyl, C3-gcycloalkyl-Cθ-6alkyl,
C2.galkenyl, C2-galkynyl, Het-Co-galkyl and Ar-CQ-galkyl, preferably Cι_galkyl;
R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring; R4 is R5C(O)-;
R^ is selected from the group consisting of : Ci .galkyl and Het-CQ.galkyl, preferably Het-Co-galkyl;
R9 is selected from the group consisting of: C\ -galkyl, C3_gcycloalkyl-Co-galkyl, Ar-CQ-galkyl and Het-CQ-galkyl;
RU is selected from the group consisting of: H, Ci-galkyl, Ar-Cθ-galkyl and Het- CQ-galkyl, preferably H; R' is H; !
R" is H;
R'" is selected from the group consisting of: H and C\ -galkyl, preferably H; R"" is selected from the group consisting of: Ci-galkyl, C3-gcycloalkyl-CQ.galkyl, C2_galkenyl, C2-galkynyl, HetCo-galkyl and ArCQ-galkyl, preferably Ci-galkyl; and n is an integer from 1 to 5, preferably n is 3; and pharmaceutically acceptable salts, hydrates and solvates thereof.
The following compounds are preferred 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)- acetyl]-azepan-4-y 1 } -amide ; {(S)-l-[4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepan-l- ylmethyl]-3-methyl-butyl}-carbamic acid benzyl ester;
(S)-2-Amino-4-methyl-pentanoic acid-(l-benzoyl-3-hydroxy-azepan-4-yl)-amide; (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- 1 -(4-methyl-pentanoyl)-azepan- 4-yl]-amide;
(S)-2-Amino-4-methyl-pentanoic acid (l-benzenesulfonyl-3-hydroxy-azepan-4-yl)- amide; thieno[3,2-b]thioρhene-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- 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]-butyl } amide; quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; and 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 Compounds
Referring to Schemes 1-6 herein above, the present invention provides a process for the synthesis of compounds of Formula (I) comprising the step of oxidizing the appropriate compound of Formula (II) with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers. Preferably the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine.
Referring to Scheme 4, the present invention also provides a process for the synthesis of deuterated compounds of Formula (I). Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound of Formula (I) as a mixture of diastereomers is added to the synthesis. Preferably, the deuterating agent is CD3OD:D2O (10:1) in triethylamine. The process further comprises the step of separating the diasteromers of Formula
(I) by separating means, preferably by high presssure liquid chromatography (HPLC).
Referring to Scheme 6, the present invention also provides a process for the synthesis of quaternary salts of the 4-amino-azepan-3-one compounds of Formula (I). Utility of the Present Invention
The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds. The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amy trophy; 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, and metabolic bone disease.
Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
The present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention. The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof an inhibitor of cathepsin K, including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, 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, and metabolic bone disease.
This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
For acute therapy, parenteral administration of a compound of Formula I is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K. The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention. Biological Assays The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
Determination of cathepsin K proteolytic catalytic activity
All assays for cathepsin K were carried out with human recombinant enzyme. Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
Inhibition studies Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound. Reactions were initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progress curves were linear, apparent inhibition constants (Ki>app were calculated according to equation 1 (Brandt et al, Biochemitsry, 1989, 28, 140):
v = VmA /[Ka(l + UKi, app) +A] (1)
where v is the velocity of the reaction with maximal velocity Vm , A is the concentration of substrate with Michaelis constant of Ka, and / is the concentration of inhibitor. For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give k0bs according to equation 2:
[AMC] = vss t + (vo - vss) [1 - exp (-k0bst)] / kODS (2)
where [AMC] is the concentration of product formed over time t, vo is the initial reaction velocity and vss is the final steady state rate. Values for k0bs ere tnen analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k0bs / inhibitor concentration or k0bs / [I]) describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al, Adv. Enzymol. Relat. Areas Mol. Biol, 1988, 61, 201).
Human Osteoclast Resorption Assay Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, wanned rapidly at 37 °C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4°C). The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice The cell suspension was mixed frequently. The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear 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 away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
The beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded. The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xlθ4/mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype 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 sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.
General
Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-dg is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal 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 constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin- Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm-1). Mass spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Where indicated, certain of the materials were purchased from the Aldrich
Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey, and Advanced Chemtech, Louisville, Kentucky.
Examples In the following synthetic examples, temperature is in degrees Centigrade (°C).
Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These Examples are given to illustrate the invention, not to limit its scope. Reference is made to the claims for what is reserved to the inventors hereunder.
Example 1
Preparation of { (S)-l-ri-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoyl)-3-oxo- azepan-4-ylcarbamoyllcarbamic acid benzyl ester
a.) Allyl-pent-4-enyl-carbamic acid tert-butyl ester
To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed with hexanes) in DMF (30 mL) was added tert-butyl N-allylcarbamate (6.0 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature 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 for approximately 2 hours whereupon the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water (2 x's), brine, dried (MgSO4), filtered and concentrated to give 10 grams of the title compound as an oil: MS(EI) 226 (M+H+).
b.) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid tert-butyl ester
To a solution of compound of Example la (4.5 g) in benzene was added the 2,6- diisopropylphenylimidoneophylidene molybdenum bis(t-butoxide) (600 mg). The reaction was heated to reflux for 1.5 hours whereupon the reaction was concentrated in vacuo. Chromatography (50% CH2Cl2:hexanes) of the residue gave 3.92 g of the product:
c.) 8-Oxa-3-aza-bicyclo[5.LO]octane-3-carboxylic acid tert-butyl ester
To a solution of the compound of Example lb (3.0 g, 15.2 mmol) in CH2C12 was added m-CPBA (7.8 g, 45.6 mmol). The mixture was stirred overnight at room temperature whereupon it was partitioned between CH2Cl2and staurated K^COj. The organic layer was washed with sat. NaHCO3, water, brine, dried (MgSO4), filtered and concentrated to give 3.11 g of the title compound as an oil: MS(EI) 214 (M+H+).
d.) 4-Azido-3-hydroxy-azepane-l-carboxylic acid tert-butyl ester To a solution of the epoxide from Example lc ( 3.92 g, 20 mmol) in methanol:water (180 mL of an 8:1 solution) was added NH4CI (3.18 g, 60 mmol) and sodium azide (3.9 g, 60 mmol). The reaction was heated to 40°C until complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was diluted with ethyl acetate and washed with water, brine dried (Na2SO4), filtered and concentrated. Column chromatography (40% ethyl acetate:hexanes) of the residue provided 3.43 g of the title compound.
e.) 4-Amino-3-hydroxy-azepane-l-carboxylic acid tert-butyl ester
To a solution of the azido alcohol of Example Id (3.4 g) and 10% Pd/C (catalytic) in ethyl acetate:methanol (2: 1 solution) was affixed a balloon of hydrogen. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo. Column chromatography of the residue (25% methano dichloromethane) 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-carboxy lie acid tert butyl ester
To a solution of the amino alcohol of Example le (160 mg, 0.70 mmol) in CH2C12 was added EDC (134 mg), HOBt (94 mg) and Cbz-leucine (185 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with IN HCl, sat. K2CO3, water, brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3% mefhanokdichloromethane) gave 200 mg of the title compound: MS(EI) 478 (M+H+), 500 (M+Na+).
g-) [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester
A solution of the compound of Example If (200 mg, 0.42 mmol) in methanol (5 mL) was added 4M HCl in dioxane (5 mL). The reaction was stirred at room temperature for approximately 2 hours whereupon the solvent was removed in vacuo to provide 168 mg of the title compound: MS(EI) 378 (M+H+). h.) { (S)- 1 - [4-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy- azepane-l-carbonyl]-3-methyl-butyl}carbamic acid benzyl ester
To a solution of the amine salt of Example lg (168 mg, 0.42 mmol) in CH2C12 was added EDC (81 mg), HOBt (57 mg), triethylamine (0.09 mL) and Cbz-leucine (111 mg). The reaction was stirred until complete by TLC analay sis. Workup followed by column 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- 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). The reaction was stirred at room temperature for approximately 2 hours whereupon it was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (5%
CH3OH:CH Cl2) provided 100 mg of the title compound as a mixture of diastereomers: *H NMR (CDC13): δ 1.0 ( m, 12H), 1.5-2.1 ( m, 8H), 2.2 ( m, 4H), 3.0 (m, IH), 3.5 (d, IH). 3.6 (d, IH), 4.01 (m, IH), 4.5 ( m, 2H), 4.7 (m, IH), 5.0 ( m, 5H), 7.3 (m, 10H): MS (El) 623(M+H+), 645 (M+Na+). Separation of the diastereomers by HPLC provided diastereomer 1 :MS (El) 623 (M+H+), 645 (M+Na+) and diastereomer 2: MS (ES) 623 (M+H+), 645 (M+Na+).
Example 2
Preparation of Naphthylene-2-carboxylic acidr(S)-l-(l-benzyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl1amide
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 benzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon 5- bromo- 1-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40°C for approximately 4 hours whereupon the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2x's), brine, dried (MgSO4), 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 added bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (5.0 g). The reaction was heated to reflux until complete as determined by TLC analysis. The reaction was concentrated 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 lc except substituting the compound of 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 from Example 2c (2.0 g, 8.1 mmol) in methanol: 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 complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic layer was washed with sat. NaHCO3, water, brine dried (MgSO4), filtered and concentrated. Column chromatography (20% ethyl acetate :hexanes) of the residue provided 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 methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 mL). The reaction was stirred until complete consumption of the starting material was observed by TLC analysis whereupon the reaction was concentrated in vacuo. Column chromatography of the residue (20% methano dichloromethane) provided 0J2 g of the title compound: MS(EI) 265 (M+H+).
f.) 4-((S)-2-tert-Butoxycarbonylamino-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 CH2C1 was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with IN HCl, sat. K2CO3, water, brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3% methanol: dichloromethane) gave 1.0 g of the title compound: MS(EI) 478 (M+H+).
g-) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester
To a solution of the compound of Example 2f (1.0 g) and 10% Pd/C (catalytic) in ethyl acetate:methanol (2: 1 solution) was affixed a balloon of hydrogen. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis.
The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo to provide 0.82 g of the title compound: MS(EI) 344 (M+H+). h.) [(S)-l-(l-Benzyl-3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester
To a solution of the compound of Example 2g (0.69 g, 2.01 mmol) in CH2C1 was added benzaldehyde (0.32 mL, 3.01 mmol) followed by sodium triacetoxyborohydride (0.85 g, 4.02 mmol). The reaction was stirred until complete as determined by TLC analysis whereupon several drops of water were added to the reaction to destroy the excess sodium triacetoxyborohydride. The mixture was diluted with ethyl acetate washed with sat. N--HCO3, water, brine, dried (Na2SO4), filtered and concentrated. Column chromatography of the residue (5% methanokdichloromethane) gave 800 mg of the title compound: MS(ES) 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) was added 4M HCl in dioxane (15 mL). The reaction was stirred at room temperature overnight whereupon it was concentrated in vacuo to give 800 mg of the title 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 salt of Example 2i (200 mg, 0.49 mmol) in CH2C12 was added 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 until complete by TLC analysis. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. Column chromatography of the residue (5% methanokdichloromethane) gave 0.14 g of the title compound: MS(EI) 488 (M+H+).
k.) Naphthylene-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 compound of Example 2j for the compound of Example li the title compound was prepared: Η NMR (CDCI3): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 12H); MS(EI): 486 (M+H+,100%). Separation 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
Preparation of Benzori,31dioxole-5-carboxylic acid f(S)-l-(l-benzyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyllamide
a.) Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4~ ylcarbamoyl)-3-methyl-butyl]amide
Following the general procedure of Example 2j except substituting piperonylic acid for 2-naphthoic acid the title compound was prepared: MS(ES) 482 (M+H+).
b.) Benzo[l,3]dioxole-5-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 compound of Example 3a the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H),,2.9 (m, IH), 3.0 ( m, IH). 3.2 (d, IH), 3.5 (q, IH), 3.7 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 6.0 (s, 2H), 6.8 (m, 2H).7.2 (m, 6H); MS(EI): 480 (M+H\100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided 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+).
Example 4
Preparation of Benzofuran-2-carboxylic acid f(S)-l-(l-benzyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butvnamide
a.) Benzofuran-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)- 3-methy 1-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- methy 1-butyl] amide
Following the general procedure of Example li except substituting the compound of Example 4a the title compound was prepared: 476 MS(EI): 492 (M+H+,100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided 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
Preparation of Benzo rblthiophene-2-carboxylic acid r(S)-l-(l-benzyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butynamide
a.) Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4- ylcarbamoyl)-3-methy 1-butyl] amide
Following the general procedure of Example 2j except substituting benzothiophene-2-carboxylic acid for 2-naphthoic acid the title compound was prepared:
MS(ES) 494 (M+H+). b.) Benzo [b]thiophene-2-carboxy lie acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3- methy 1-butyl] amide
Following the general procedure of Example li except substituting the compound of Example 5a the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 (m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 10H): MS(EI): 492 (M+H+J 00%)
The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MS (El) 492.4 (M+H+), 983 J 2M+H+) and diastereomer 2: MS (El) 492.4 (M+H+), 983.7 2M+H+).
Example 6
Preparation of Naphthylene-2-sulphonyl r(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyll-amide
a.) Naphthylene-2-sulphonyl [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methyl-butyl]-amide
To a solution of the amine salt of Example 2i (200 mg, 0.49 mmol) in CH2C12 was added triethylamine (0.24 mL, 1.72 mmol) and 2-naphthalenesulphonyl chloride (122 mg,
0.54 mmol). The reaction was stirred at room temperature until complete as determined by
TLC analysis. The reaction was worked-up, dried (Na2SO4), filtered and concentrated.
Column chromatography of the residue (10% methanohdichloromethane) provided 52 mg of the title compound: MS(EI) 524 (M+H+).
b.) Naphthylene-2-sulphonyl [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]-amide
Following the general procedure of Example li except substituting the compound of Example 6a the title compound was prepared: : Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.7 (m, IH), 3.0 (dd, IH). 3.3 (m, IH), 3.6 (m, 2H), 3.7 ( m, IH),
4.7 (m, IH), 5.3 ( m, IH), 7.2-8.4 (m, 12H): MS(EI): 522 (M+H*,100%) Example 7
Preparation of Quinoline-2-carboxylic acid r(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)- 3-methyl-butvnamide
a.) Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methy 1-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- butyl] amide
Following the general procedure of Example li except substituting the compound of Example 7a the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 11H); MS(EI): 487 (M+H\100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1: MS (El) 492.4 (M+H+), 983 J 2M+H+) and diastereomer 2: MS (El) 492.4 (M+H+), 983.7 2M+H+).
Example 8
Preparation of 3.4-dichlorobenzoic acid r(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyll amide
a.) 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methy 1-butyl] amide
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+). b.) 3,4-dichlorobenzoic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]amide
Following the general procedure of Example li except substituting the compound of Example 8a the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, 2H), 5.2 ( m, IH), 7.2-8.4 (m, 8H); MS(EI): 504 (M+,100%) .
Example 9
Preparation of 4-{ (S)-Methyl-2-r(quinoline-2-carbonyl)-amino1pentanoylamino l-3-oxo-l- r2-(3-pyridin-2-yl-phenyl)-acetyl1azepanium
a.) 4-((S)-2-tert-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 CH2C12 was added EDC (307 mg, 1.60 mmol), HOBt (216 mg, 1.60 mmol) and 3-(2-pyridyl)phenyl acetic acid (341 mg, 1.60 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (2% methanol:dichloromethane) 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)- acetyl]-azepanium
To a solution of the compound of Example 9a (1.3 g) dissolved in methanol (20 mL was added 4M HCl in dixoane (20 mL). The reaction was stirred until complete by TLC analysis 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]azepaniurn Following the procedure of Example 7a except substituting the compound of
Example 9b the title compound was prepared: MS(EI) 594 (M+H+). d.) 4-{(S)-Methyl-2-[(quinolme-2-carbonyl)-amino]pentanoylamino}-3-oxo-l-[2-(3- pyridin-2-yl-phenyl)-acetyl]azepanium
Following the procedure of Example li except substituting the compound of Example 9c the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.9 (m, IH), 3.4 (dd, IH). 3.8 (m, 3H), 4.1 (m, 2H), 4.7 ( m, 3H), 5.4 ( m, IH), 7.2-8.4 (m, 14H); MS(EI): 592 (M+H\100%) .
Example 10
Preparation of 1 -(( S )-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4- { (S )-4-methyl-2- f(2- quinoiline-2-carbonyl)-amino1-pentanoylamino)-3-oxo-azepanium
a.) l-((S)-2-Benzyloxycarbonylamino-4-methyl-pentyl)-4-((S)-2-tert- butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepanium Following the procedure of Example 2h except substituting Cbz-leucinal for benzaldehyde the title compound was prepared: MS(EI) 577 (M+H+).
b.) 4-((S)-2-Amino-4-methy-pentanoylamino)-l-((S)-2-tert-benzylxycarbonylamino-4- methyl-pentyl)-3-hydroxy-azepanium Following the procedure of Example 2i except substituting the compound of
Example 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 of
Example 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 of
Example 10c the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 12H), 1.5-2.1 (m, 10H), 2.2 ( m, 4H), 2.9 (m, IH), 3.4 ( M, 2H). 3.7 (m, IH), 4.7 ( m, 2H), 5.2 ( m, 3H), 7.2 (m, 4H), 7.5 (m, IH), 7.6 (m, IH), 7.7 (m, IH), 8.1 (m, IH), 8.2 (m, 2H), 8.5 (m, IH); MS(EI): 630 (M+H+,100%) .
Example 11
Preparation of l-Benzoyl-4-((S)-2-(benzori.31dioxole-carbonylamino)-4-methyl- pentanoylamino)-3-oxo-azepanium
a.) l-Benzoyl-4-((S)-2-tert-butoxycarbonylamino-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(EI) 448(M+H+).
b .) 4-((S)-2-Amino-4-methyl-pentanoylamino)- 1 -benzoyl-3-hydroxy-azepanium Following the procedure of Example 2i except substituting the compound of Example 1 la 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 of Example 1 lb for the compound of Example 2j and piperonylic acid for 2-naphthoic acid the title 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 of Example lie the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.9 (m, IH), 3.2 (dd, IH). 3.4 (m, IH), 3.7 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 6.0 (s, 2H), 7.2-8.4 (m, 8H); MS(EI): 494 (M+H+, 70%). Example 12
Preparation of l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3- oxo-azepanium
a.) l-Benzoyl-4-((S)-2-(4-fluoro-benzoylamino)-4-methyl-pentanoylamino)-3-hydroxy- azepanium
Following the procedure of Example lie except substituting 4-fluorobenzoic acid for 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 of Example 12a the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (dd, IH). 3.6 (m, IH), 4.0 (m, 2H), 4.7 ( m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 9H); MS(EI): 468 (M+H+, 10%).
Example 13
Preparation of 3-Oxo-4-((S)-4-methyl-2-{ r5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonynamino}-pentanoylamino)-l-(4-methyl-pentanoyl)-azepanium
a.) 4-((S)-2-tert-butoxycarbonylamino-4-methyl-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 (M+H+).
b.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-l-(4-methyl-pentanoyl)- azepanium Following the procedure of Example 2i except substituting the compound of
Example 13a the title compound was prepared: MS(EI) 342 (M+H+). c.) 3-Hydroxy-4-((S)-4-methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl] amino } -pentanoylamino)- 1 -(4-methyl-pentanoyl)-azepanium
To a solution of the compound of Example 13b (200 mg, 0.53 mmol) in dichloromethane was added EDC (111 mg, 0.58 mmol), HOBt (78 mg, 0.58 mmol), TEA (0.11 mL, 0.79 mmol) and 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid. The reaction was stirred at room temperature until complete as indicated by TLC analysis. Workup and column chromatography (5% methanoLdichloromethane) provided 160 mg of the title compound: MS(EI) 615 (M+H+).
d.) 3-Oxo-4-((S)-4-methyl-2-{ [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl] amino } -pentanoylamino)- 1 -(4-methyl-pentanoyl)-azepanium
Following the procedure of Example li except substituting the compound of Example 13d the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 12H), 1.5-2.1 (m, 8H), 2.2 (m, 2H), 2.3 (m, IH), 2.4-2.5 (m, 2H), 2.6 (m 5H), 2.7 (m, 2H), 2.9 (m, IH), 3.4 (m, IH), 3.7 (m, 4H), 4.1 (m, 2H), 4.5-4.6 (m, 2H), 5.2 ( m, IH), 7.2-8.4 (m, 4H):
MS(EI): 613 (M+H\100%). The diastereomers were separated by preparative scale HPLC. Lyophilisation of the eluents provided diastereomer 1 and diastereomer 2.
Example 14
Preparation of 3-Oxo-4-((S)-4-methyl-2- j r5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyll amino } -pentanoylamino)- 1 -benzenesulphonyl-azepanium
a.) l-Benzenesulphonyl-4-((S)-2-tert-butoxycarbonylamino-methyl-pentanoylamino)- 3-hydroxy-azepanium
To a solution of the amine of Example 2g (0.5 g, 1.46 mmol) in dichloromethane was added triethylamine (0.4 mL, 2.92 mmol) followed by benzenesulphonyl chloride (0.28 mL, 2.18 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (10% methanokdichloromethane) provided 450 mg of the title compound: MS(EI) 484 (M+H+). b.) 4-((S)-2-Amino-methyl-pentanoylamino) l-benzenesulphonyl-3-hydroxy- azepanium
Following the procedure of Example 2i except substituting the compound of Example 14a the title compound was prepared: MS(EI) 384 (M+H+).
c.) 3-Hydroxy-4-((S)-4-methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl] amino } -pentanoylamino)- 1 -benzenesulphonyl-azepanium
Following the procedure of Example 13c except substituting the compound of Example 14b the title compound was prepared: MS(EI) 657 (M+H+).
d.) 3-Oxo-4-((S)-4-methyl-2- { [5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]amino}-pentanoylamino)-l-benzenesulphonyl-azepanium
Following the procedure of Example li except substituting the compound of Example 14c the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.4 (m, IH), 2.7 (m, 4H), 2.8 (m, 2H), 3.5 (m, IH), 3.8 (m, 4H), 4.0 (m, IH), 4.1 (m, 2H), 4.4 (m, IH), 4.5 (m, IH), 4.7 (m, IH), 5.1 ( m, IH), 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 CH3CN:20 mm KHPO4 (pH 7 buffer) 60 min. gradient 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (R{ = 44.6 mins. and 45.9 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 50:50 CH3CN: mm KHPO4 (pH 7 buffer)gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation of the eluents provided diastereomer 1 (anal. R( = 44.6 mins.) and diastereomer 2 (anal. Rt = 45.9 mins).
Example 15
Preparation of 4-((S)-4-Methyl-2-{ r5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonynaminol-pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide
a.) [(S)-l-(3-Hydroxy-l-phenylcarbamoyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert-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 at room temperature until complete as determined by TLC analysis. Workup and column chromatography (5% methanohdichloromethane) provided 578 mg of the title compound: MS(EI) 463 (M+H+).
b.) 4-((S)-2-Amino-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid phenyl amide
Following the procedure of Example 2i except substituting the compound of Example 15a the title compound was prepared: MS(EI) 363 (M+H+).
c.) 3-Hydroxy-4-((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyl]amino}-pentanoylamino)-azepane- 1-carboxylic acid phenylamide
Following the procedure of Example 13c except substituting the compound of Example 15b the title compound was prepared: MS(EI) 636 (M+H+).
d.) 4-((S)-4-Methyl-2-{[5-(2-morpholino-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 of Example 15c the title compound was prepared: Η NMR (CDCL): ): 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, IH), 3.8 (m, IH), 3.9 (m, 4H), 4.2 (m, IH), 4.3 (m, 2H), 4.9 (m, 2H), 5.2 ( m, IH), 7.2-8.4 (m, 9H): MS(EI): 634 (M+H+,100%)
Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH3CN:20 mM KHPO4 (pH 7 buffer) isocratic, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (Rt = 27.3 mins. and 30.1 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 50:50 CH3CN: 20 mM KHPO4 (pH 7 buffer) gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHCO3:ethyl acetate extraction provided diastereomer 1 (anal. Rt = 27.3 mins.) and diastereomer 2 (anal. Rt = 30.1 mins).
Example 16
Preparation of 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-mefhyl-l- 13-oxo- 1 - r2-(3-pyridin-2-yl-phenyl)acetyl1 -azepan-4-y lcarbamoyl I -butvDamide
a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3- hydroxy-l-[2-(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide Following the procedure of Example 13c except substituting the compound of
Example 9b the title compound was prepared: MS(EI) 712 (M+H+).
b.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-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 of
Example 16c the title compound was prepared: Η NMR (CDC13): ): 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, IH), 3.5 (m, IH), 3.7 (m, 4H), 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 ( m, IH), 7.2-8.0 (m, 13H), 8.5 (m, IH); MS(EI): 710 (M+H\100%) MS(EI).
Analysis of the diastereomeric mixture by analytical HPLC (40:60 CH3CN:20 mM KHPO4 (pH 7 buffer) isocratic, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (Rt = 33.9 mins. and 37.9 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 45:55 CH3CN: 20 mM KHPO4 (pH 7 buffer) gradient, 12 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHCO3:ethyl acetate 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). Example 17
Preparation of 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid r(S)-l-(benzoyl- 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl1amide
a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(benzoyl-3- hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example 13c except substituting the compound of Example 1 lb the title compound was prepared: MS(EI) 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 ϋ except substituting the compound of Example 17a the title compound was prepared; Η NMR (CDCL): 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, IH), 3.7 (m, 5H), 4.0 (m, IH), 4.1 (m, 2H), 4.7 (m, 2H), 5.4 ( m, IH), 7.2-8.4 (m, 11H): MS(EI): 619 (M+H+,100%)
Analysis of the diastereomeric mixture by analytical HPLC (40:60 to 55:45 CH3CN:20 mM KHPO4 (pH 7 buffer) 30 min. gradient, 1 mL/min.; inertsil ODS-3 column 4.6 x 250 mm; UV detection at 215 nM) showed two peaks (Rt = mins. 13.5 and 17.6 mins). The diastereomers were separated by preparative scale HPLC (40:60 to 45:55 CH3CN: mM KHPO4 (pH 7 buffer) 60 min. gradient, 15 mL/min., 60 mins; inertsil ODS-3 column 250 x 20 mm; UV detection at 215 nM). Lyophilisation and desalting of the eluents by NaHCO3:ethyl acetate extraction provided diastereomer 1 (anal. Rj = 13.5 mins.) and diastereomer 2 (anal. Rt = 17.6 mins).
Example 18
Preparation of 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid 1(S)-1-(1- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butvnamide
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 substituting 5-(2-pyrrolidin-l-yl- ethyloxy)-benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2- carboxylic acid the title compound was prepared: MS(EI) 641 (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 of Example 18a the title compound was prepared: Η NMR (CDCl.): δ 1.0 ( m, 6H), 1.5-2.1 (m, 9H), 2.2 ( m, 2H), 2.5 (m, IH), 2.7 (m, 4H), 3.0 (m, 2H), 3.4 (m, IH), 4.0 (m, IH), 4.1 (m, 2H), 4.5 (m, IH), 4.6 (m, IH), 5.0 ( m, IH), 7.2-8.4 (m, 11H): MS(EI): 639 (M+H+,100%) .
Example 19
Preparation of 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid KS)-1-(1- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl1amide
a.) 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example 14c except substituting 5-(2-piperidin-l-yl- ethyloxy)-benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2- carboxylic acid the title compound was prepared: MS(EI) 655 (M+H+). b.) 5-(2-Piρeridin-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 li except substituting the compound of Example 18a the title compound was prepared: Η 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, IH), 4.0 (m, IH), 4.1 (m, 2H), 4.5 (m, IH), 4.6 (m, IH), 5.0 (m, IH), 7.2-8.4 (m, 11H): MS(EI): 653 (M+H+,100%) .
Example 20
Preparation of 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl- l-{3-oxo-l-r2-(3-pyridin-2-yl-phenyl)ethyl1-azepan-4-ylcarbamoyl|-butyl)amide
a.) 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid methoxy methyl amide
To a solution of 3-(2-pyridyl)phenyl acetic acid (lg) in dichloromethane was added N, O-dimethylhydroxylamine hydrochloride (0.92 g), triethylamine (1.3 mL), HOBt (0.96 g) and EDC (1.1 g). The reaction was stirred until complete. Workup and column chromatography (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 acid methoxy methyl amide (0.2 g) of Example 20a in THF was added LAH (2.0 mL of a 1 M solution in THF). The reaction was stirred until complete consumption of the starting material. 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+). d.) (S)-2-Amino-4-methyl-pentanoic acid-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-ethyl]- azepan-4-yl } -amide
Following the procedure of Example 2i except substituting the compound of Example 20c the title compound was prepared.
e.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic 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 of Example 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 of Example 20e the title compound was prepared: Η NMR (CDC13): 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, IH), 3.3 (m, IH), 3.5 (m, IH), 3.7 (m, 4H), 4.2 (m, 3H), 4.6 (m, IH), 5.2 ( m, IH), 7.2-8.4 (m, 13H), 8.6 (m, IH); MS(EI): 696 (M+H+, 80%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 696 (M+H\ 100%), and the slower eluting diastereomer; MS(EI): 696 (M+H+, 100%).
Example 21
Preparation of Naphthlene-2-carboxylic acid ((S)-3-methyl-l-13-oxo-l-r2-(3-pyridin-2-yl- phenyl)ethvn-azepan-4-ylcarbamoyll-butyl)amide
a.) Naphthlene-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 20f except substituting 2-naphthoic acid for 5- (2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 579 (M+H+). b.) Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl- phenyl)ethyl]-azepan-4-y lcarbamoyl } -butyl)amide
Following the procedure of Example li except substituting the compound of Example 21b the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 6H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m, IH), 3.4 (d, IH). 3.5 (m, IH), 4.7 ( m, IH), 5.0 ( m, IH), 6.8-7.2 (m, 6H), 7.3 (m, IH), 7.5 (m, 2H), 7.9 ( m, 6H), 8.2 (M, IH), 8.7 (m, IH): MS(EI):577 (M+H+,100%) .
Example 22
Preparation of lH-Indole-2-carboxylic acid ((S)-3-mefhyl-l-l3-oxo-l-f2-(3-pyridin-2-yl- phenyl)ethyll-azepan-4-ylcarbamoyll-butyl)amide
a.) ((S)-3-methyl- 1 - { 3-hydroxy- 1 - [2-(3-pyridin-2-yl-phenyl)ethyl]-azepan-4- 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 title compound was prepared: MS(EI) 568 (M+H+).
b.) ((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 of
Example 22b the title compound was prepared: : Η NMR (CDC13): ): δ 1.0 ( m, 6H), 1.5-
2.1 ( m, 5H), 2.2 (m, 2H), 2.9 (m, 4H), 3.0 (m," IH), 3.4 (d, IH). 3.5 (m, IH), 4.7 ( m, IH), 5.0 ( m, IH), 6.8-7.2 (m, 6H), 7.0-7.9 (m, 12H), 8.7 (m, IH), 9.5 (m, IH): MS(EI):
566 (M+H+J00%)
Example 23
Preparation of lH-Indole-2-carboxylic acid r(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl1amide
a.) lH-lndole-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 of Example 14b and substituting lH-indole-2-carboxylic acid for naphthoic acid the title compound was prepared: MS(EI) 527 (M+H+).
b.) lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyljamide
Following the procedure of Example li except substituting the compound of Example 23b the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (dd, IH). 3.9 (m, IH), 4.5 (dd, 2H), 4.7 (m, IH), 5.0 ( m, IH), 7.2 -7.6 (m, 10H). 9.5 (b, IH); MS(EI): 525 (M+H+, 10%).
Example 24
Preparation of Benzofuran-2-carboxylic acid r(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl1amide
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 IH-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 of Example 24b the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (m, IH), 3.5 (d, IH). 4.1 (m, IH), 4.7 ( m, 2H), 5.0 ( m, IH), 7.2-7.2 (m, 10H).
Example 25
Preparation of Benzofuran-2-carboxylic acid r(S)-3-methyl-l-|3-oxo-l-r2-(3-pyridin-2-yl- phenyl)ethyH-azepan-4-ylearbamoyll-butyl)amide
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-morphoIin-4-yl-ethyloxy)benzofuran-2-carboxylic the title compound 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 of Example 25b the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 5H), 3.0 (m, IH). 3.3 (m, IH), 3.5 (m, IH), 4.7 (m, IH), 5.2 (m, IH), 7.2-7.7 (m, 14H), 8.7 (m, IH); MS(EI): 567 (M+H+,100%)
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 656 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 656 (M+IT,100%).
Example 26
Preparation of 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid [YS)-3-mexhyl-l- (3-oxo- 1 -phenethyl-azepan-4-ylcarbamoyll -butyl I amide
Following the procedures of Examples 20c-f except substituting phenylacetaldehyde for 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carbaldehyde of Example 20c the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.4 (m, IH), 2.6 (m,4H), 2.7 (m, 6H), 3.0 (m, IH), 3.3 (dd, IH), 3.5 (q, IH), 3.7 ( m, 4H). 4.2 (m, 2H), 4.7 (m,lH), 5.0 ( m, IH), 7.2-7.2 (m, 11H); MS(EI): 619 (M+H+, 80%)
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 619 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 619 (M+H\100%).
Example 27
Preparation of Naphthylene-2-carboxylic acid r(S)-3-methyl-l-(3-oxo-l-phenethyl-azepan- 4-ylcarbamovπ-butyl I amide
Following the procedures of Examples 2h-k except substituting phenylacetaldehyde for benzaldehyde of Example 2h the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 ( m, 5H), 2.2 ( m, 2H), 2.4 (m, IH), 2.7 (m, 4H), 3.0 (m, IH), 3.7 (d, IH), 3.5 (q, IH), 4.7 ( m, IH), 5.1 ( m, IH), 6.9 -7.2 (m, 7H), 7.5 (m, 2H), 7.9 ( m, 4H) 8.4 (m, IH); MS(EI): 500 (M+HU00%) .
Example 28
Preparation of Benzofuran-2-carboxylic acid j(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyll -butyl I amide
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-pyridinesulfonyl chloride for benzenesulfonyl 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 reaction was stirred until complete. Workup and column chromatography (5% methanolrethyl 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- ylcarbamoyl]-butyl} amide
Following the procedure of Example li except substituting the compound of Example 28b the title compound was prepared: Η NMR (CDC13): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (dd, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, IH), 8.0 ( m, 2H), 8.7 (m, IH); MS(EI): 527 (M+KT, 40%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.7 (d, IH); 4.0 (d, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, IH), 8.0 (m, 2H), 8.7 (m, IH); 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, IH), 3.7 (d, IH); 4.0 (d, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, IH), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 527 (M+H\ 100%).
Example 29
Preparation of Naphthylene-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoylTbutyl|amide
a.) Naphthylene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example 28b except substituting 2-naphthoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS (El) 539 (M+H+).
b.) Naphthylene-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 of Example 29a the title compound was prepared: Η NMR (CDCL): δ 1.0 ( m, 6H), 1.5-2.1 (m, 5H), 2.2 ( m, 2H), 2.7 (m, IH), 3.7 (dd, IH). 4.0 (m, IH), 4.7 ( m, 2H), 5.0 ( m, IH), 7.2-7.3 (m, 2H), 7.5 (m, 3H), 7.9 (m, 6H), 8.3 ( m, IH), 8.4 (m, IH); MS(EI): 537 (M+H\ 50%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 537 (M+H\ 100%), and the slower eluting diastereomer; MS(EI): 537 (M+IT, 100%).
Example 30
Preparation of 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- l-r3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyllamide
a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 13c except substituting the compound of Example 28a the title compound was prepared: MS(EI) 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-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substituting the compound of Example 29a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 m,
5H), 2.2 (m, 2H), 2.7 (m, IH), 3.5 ( m, 4H). 3.7 (m, 6H), 4.1 (m, IH), 4.5 (m, 2H), 4.7 (m,
2H), 5.0 (m, IH), 7.2-7.3 (m, 4H), 7.4 (m, 2H), 8.0 (m, 2H), 8.7 (m, IH), 8.7 (m, IH);
MS(EI): 656 (M+H+,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS (El): 656 (M+H+, 100%), and the slower eluting diastereomer; MS (El):
656 (M+H\ 100%).
Example 31
Preparation of 4-((S)-4-Methyl-2-{ r(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyn- amino}-ρentanoylamino)-3-oxo-azepane-l-carboxylic acid tert-butyl ester
a.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-carboxylic acid tert-butyl ester
To a solution of the compound of Example If (0.89 g) in ethyl acetate:methanol (30 mL of a 2: 1 mixture ) was added 10 % Pd/C and a balloon of hydrogen gas was attached. The reaction was stirred until complete by TLC analysis whereupon it was filtered and concentrated to provide the title compound (0.57 g).
b.) 4-((S)-4-Methyl-2-{ [(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]- amino}-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid tert-butyl ester Following the procedure of Example 13c except substituting the compound of
Example 31a the title compound was prepared.
c.) 4-((S)-4-Methyl-2-{ [(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]- amino}-pentanoylamino)-3-oxo-azepane- 1-carboxylic acid tert-butyl ester Following the procedure of Example li except substituting the compound of
Example 31b the title compound was prepared: Η NMR (CDCL): 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 , IH). 3.8 (m, 4H), 4.1 (m, 3H), 4.2 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 5H); MS(EI): 615 (M+H\100%) .
Example 32
Preparation of 4-((S)-4-Methyl-2- j r(5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid F(S)-3-methyl-l-(3-oxo-azepan-4-ylcarbamoyl1-butyl)amide
To a solution of the compound of Example 31c in THF (5 mL) was added 1M HCl in ether (5 mL). Th reaction was stirred overnight whereupon it was concentrated to provide the title compound: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 4H), 3.2 (dd, 3H). 3.7 (m, 6H), 4.0 (m, 3H), 4.5 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 6H); MS(EI): 515 (M+H+,100%) .
Example 33
Preparation of 4-Methyl-pentanoic acid {3-oxo-l-r2-(3-pyridin-2-yl-phenyl-acetyl1-azepan- 4-yll -amide
a.) 3-Hydroxy-4-(4-methyl-pentanoylamino)-azepane-l-carboxylic acid tert-butyl ester Following the procedure of Example If except substituting 4-methylpentanoic acid for Cbz-leucine the title compound was prepared: MS(EI) 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 added 4M HCl dioxane (5 mL). The reaction was stirred until complete whereupon it was concentrated 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-acetyl]-azepan-4-yl} amide 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 Following the procedure of Example li except substituting the compound of
Example 33c the title compound was prepared: Η NMR (CDC13 ) δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 2.9 (m, IH), 3.5 (m, IH), 3.7 (m, 2H), 4.1 (m, 3H), 4.6 (m, IH), 5.3 (m, IH), 7.2-8.0 (m, 7H), 8.7 (m, IH); MS(EI): 422 (M+H\100%) . Example 34
Preparation of ((S)-3-Methyl-l-f3-oxo-l-r2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4- ylcarbamoyl|-butyl)-naphthylene-2-methyl-carbamic acid tert-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 dichlormefhane was added triethylamine (0.9 mL), 2-naphthaldehyde (0.43 g) and sodium triacetoxyborohydride (0.87 g). The mixture was stirred until complete. Workup and column chromatography (5% ethyl acetate:dichloromethane) provided 0.4 g of the title compound: MS(EI) 286 (M+H+).
b.) (S)-2-(tert-Butoxycarbonyl-naphthlen-2-ylmethyl-amino)-4-metyhyl pentanoic acid methyl ester To a solution of the compound of Example 34a (0.35 g) in dichloromethane was added di-tert-butyldicarbonate (0.29 g). After 2 hours at room temperature triethylamine was added and the reaction heated to reflux. Upon completion, the reaction was concentrated and the residue was purified by column chromatography (50% hexane:dichloromethane) to provide 0.17 g of the title compound: MS(EI) 386 (M+H+).
c.) (S)-2-(tert-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 mL of a 2:1 solution) was added LiOH (0.019 g). The reaction was stirred overnight whereupon it was concentrated to provide the title compound .
d.) 4-[(S)-tert-butoxycarbonyl-naphthylen-2-ylmethyl-amino)-4-methyl- pentanoylamino]-3-hydroxy-azepane-l -carboxylic acid benzyl ester
To a sloution of the compound of Example 2e (0.11 g) in dichloromethane was added EDC (0.08 g), HOBt (0.06 g) and the acid of Example 34c. Upon completion the reaction was worked up and chromatographed (5% methanohdichloromethane) to provide the title compound (0.18 g): MS(EI) 618 (M+H+). e-) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-naphthylen-2-ylmethyl carbamic acid tert-butyl ester
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 reaction was stirred until complete consumption of the starting material. The reaction was filtered and concentrated to provide the title compound (0.10g): MS(EI) 484 (M+H+).
f.) ((S)-3-Mefhyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4- ylcarbamoyl}-butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester Following the procedure of Example 9a except substituting the compound of
Example 34e the title compound was prepared: MS(EI) 679 (M+H+).
g.) ((S)-3-Methyl-l-{ 3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4- yIcarbamoyl}-butyl)-naphthylene-2-methyl-carbamic acid tert-butyl ester Following the procedure of Example li except substituting the compound of
Example 34f the title compound was prepared: : Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 16H), 2.7 (m, IH), 3.2 (m, IH). 3.1 (m, 3H), 4.0 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.2-7.3 (m, 16H), 8.6 (m, IH); MS(EI): 677 (M+H+,100%) .
Example 35
Preparation of (S)-4-Methyl-2-r(naphthylen-2-ylmethyl)-amino]-pentenoic acid r3-oxo-l-r2- (3-pyridin-2-yl-phenyl)-acetyl1-azepan-4-yl}-amide
To a solution of the compound of Example 34g (20 mg) in THF was added 1M HCl in ether. The reaction was stirred until complete consumption of the starting material whereupon it was concentrated to provide the title compound: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (m, 5H), 4.0 (m, IH), 4.7 (m, 2H), 4.4 (m, IH), 7.2-8.0 (m, 16H), 8.7 (m, IH); MS(EI): 577 (M+H+,100%) . Example 36
Preparation of 4-r2-(2-l(S)-3-Methyl-l-r3-oxo-l-(pyidine-2-sulfonyl)-azepan-4- ylcarbamoyll -butylcarbamoyl I -benzofuran-5-yloxy)-ethyl1-piperazine- 1 -carboxylic acid tert-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-carboxylic acid tert-butyl ester To a solution of the compound of Example 28a (0.15 g) in dichloromethane was added EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 4-[2-(2-carboxy- benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester. The reaction was stirred until complete. Work up and column chromatography (10 % methanol: ethyl acetate) provided the title compound (0.10 g): MS (El) 757 (M+H+).
b.) 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
Following the procedure of Example li except substituting the compound of Example 36a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 14H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (m, 2H), 3.5 (m, 4H). 3.7 (m, 6H), 4.1 (m, IH), 4.5 (m, 2H), 4.7 (m, 2H), 5.0 (m, IH), 7.0-7.6 (m, 6H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 755 (M+H+J00%) .
Example 37
Preparation of 5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid |(S)-3-methyl-l- r3-oxo- 1 -(pyridme-2-sulf onyl)-azepan-4-ylcarbamoyl)-3-butyl1 -amide
The compound of Example 36b (0.02 g) was dissolved in 4M HCl in dioxane. The reaction was stirred until complete whereupon it was concentrated to provide the title compound: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5- 1.7 (m, 7H), 2.7 (m, 2H), 3.3 (M, 2H), 3.5 (m , IH). 3.8 (m, 5H), 4.1 (m, 3H), 4.7 (m, 4H), 5.0 (m, IH), 7.0-7.3 (m, 2H), 7.4 (m, 6H), 8.0 (m, 2H), 8.7 (m, IH): MS(EI): 655 (M+H+,100%) . Example 38
Preparation of 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-butyl|amide
a.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3- hydroxy- 1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide
To a solution of the compound of Example 28a (0.15 g) in dichloromethane was added EDC (0.07 g), HOBt (0.05 g), triethylamine (0.11 mL) and 5-(2-cyclohexyl-ethoxy)- benzofuran carboxylic acid (0.01 g). The reaction was stirred until complete by TLC analysis. Workup and column chromatography (100% ethyl acetate) provided the title compound (0.15 g): MS(EI) 655 (M+H+).
b.) 5-(2-Cyclohexyl-ethoxy)-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 of Example 38a the title compound was prepared: MS(EI) 653 (M+H+).
Example 39
Preparation of 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-l3- oxo-l-r2-(3-pyridin-2-yl-phenyl)ethyl1-azepan-4-ylcarbamoyl|-butyl)amide
a.) 5-(2-Cyclohexyl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3- hydroxy- 1 -[2-(3-pyridin-2-yl-phenyl)ethyl] -azepan-4-y lcarbamoyl } -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 complete by TLC analysis. Workup and column chromatography (100% ethyl acetate) provided the title compound (0.10 g): MS(EI) 695 (M+H+). 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 of Example 39a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 18H), 2.2 (m, 2H), 2.7 (m, 3H), 3.2 (m, IH), 3.5 (m, IH). 3.9 (m, 4H), 4.7 (m, 2H), 5.0 (m, IH), 7.2-7.3 (m, 13H), 8.7 (m, IH): MS(EI): 693 (M+H+,100%)
Example 40
Preparation of 4-[2-(2-{(S)-3-Methyl-l-r3-oxo-l-(3-pyridin-2-yl-phenyl)-ethvi razepan-4- ylcarbamoyl1-butylcarbamoyl)-benzofuran-5-yloxy)-ethvn-piperazine-l-carboxylic acid tert-butyl ester
a.) 4-[2-(2-{(S)-3-Methyl-l-[3-hydroxy-l-(3-pyridin-2-yl-phenyl)-ethyl [azepan-4- ylcarbamoyl]-butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester
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 4-[2-(2-carboxy- benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester (0.12 g). The reaction was stirred until complete by TLC analysis. Workup and column chromatography
(10% methanohethyl 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 tert-butyl ester
Following the procedure of Example li except substituting the compound of Example 40a the title compound was prepared: MS(EI) 795.9 (M+H+).
Example 41
Preparation of 5-(2-piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l- l3-oxo-l-r2-(3-pyridin-2-yl-phenyl)ethvn-azepan-4-ylcarbamoyl)-butyl)amide
Following the procedure of Example 37 except substituting the compound of Example 40b the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 3.4-3.6 (m, 19H), 4.5 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m, IH), 7.4 (m, IH), 7.5 (m, 2H), 1.7 (m, 2H), 7.8 (m, IH), 8.1 (m, 2H), 8.4 (m, IH), 8.7 (m, IH); MS(EI): 695 (M+IT, 70%).
Example 42
Preparation of (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid 3- oxo-1 -(pyridine-2-sulphonyl)-azepan-4-vn -amide
a.) 4-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-3- hydroxy-azepane- 1-carboxylic acid benzyl ester
To a solution of the compound of Example 2e (0.35 g)in dichloromethane was added N-methyl-N-Boc-leucine (0.36 g), HOBt (0.2 g) and EDC (0.28 g). The reaction was stirred until complete. Workup and column chromatography (5% methanoLdichloromethane) provided 0.6 g of the title compound: MS(EI) 492 (M+H+).
b.) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-methyl-carbamic acid tert-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 reaction was stirred overnight whereupon it was filtered and concentrated to provide 0.50 g of the title: MS(EI) 358 (M+H+).
c.) {(S)-l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}- methyl-carbamic acid tert-butyl ester
To a solution of the compound of Example 42b (0.2 g) in dichloromethane was added triethylamine (0.16 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirred until complete. Workup and column chromatography (5% methanohefhyl acetate) provided the title compound (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) was added 4M HCl in dioxane (3.0 mL). The reaction was stirred until complete. Concentration provided the title compound: MS(EI) 399 (M+H+).
e.) (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)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 was added triethylamine (0.07 mL), 2-naphthaldehyde (0.05 g) and sodium triacetoxyborohydride (0.11 g). The reaction was stirred until complete. Workup and column 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 of
Example 42e the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 2.6 (m, IH), 3.3 (m, IH), 3.7 (m, 2H), 4.1 (m, IH), 4.7 (m, IH), 5.2 (m, IH), 7.2-8.0 (m, 10H), 8.7 (m, IH); MS(EI): 537 (M+H\100%) .
Example 43
Preparation of (S)-4-Methyl-2-(methyl-naphthalen-2-ylmethyl-amino)pentanoic acid { 3- oxo-l-r2-(3-pyridin-2-yl-phenyl)-acetyl1-azepan-4-yll-amide
a.) ((S)-l-{3-Hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-ylcarbamoyl}-3- methyl-butyl)-methyl-carbamic acid tert-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 stirred until complete. Workup and column chromatography (5% methanohethyl acetate) provided the title compound (0.24 g): MS(EI) 553 (M+H+).
b.) (S)-4-Methyl-2-methylamino-pentanoic acid {3-hydroxy-l-[2-(3-pyridin-2-yl- pheny l)-acetyl]-azepan-4-yl }-amide
Following the procedure of Example 42d except substituting the compound of Example 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- (3-pyridin-2-yl-phenyl)-acetyl]-azepan-4-yl} -amide
Following the procedures of Examples 42e-f except substituting the compound of Example 43b the title compound was produced: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 3.0 (m, IH), 3.5 (m, IH), 3.7 (m, 4H), 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.2-8.0 (m, 15H), 8.7 (m, IH); MS(EI): 591 (M+H\100%) .
Example 44
Preparation of 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylie acid methyl ((S)-3- methyl- l-{3-oxo-l- r2-(3-pyridin-2-yl-phenyl)acetyll -azepan-4-ylcarbamoyl I -butyl) amide
a.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl- 1 - { 3-hydroxy- 1 - [2-(3-pyridin-2-yl-phenyl) acetyl] -azepan-4-y lcarbamoyl } -butyl)amide To a solution of the compound of Example 43b (0.1 g) in dichloromethane was added 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid (0.06 g), HOBt (0.026 g), TEA (0.07 mL) and EDC (0.04 g). The reaction was stirred until complete. Workup and chromatography (20% methanohethyl acetate) provided the title compound (0.07 g): MS(EI) 726 (M+H+).
b.) 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid methyl ((S)-3-methyl- 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 of Example 44a the title compound was prepared: Η 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, IH), 3.5 (m, IH), 3.7 (m, 4H), 3.9 (m, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.4 (m, IH), 7.2-8.0 (m, 12H), 8.5 ( , IH); MS(EI): 724 (M+H\100%) .
Example 45
Preparation of Benzofuran-2-carboxylic acid methyl ((S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-3-methyl-butvn-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 was added benzofuran-2-carboxylic acid (0.04 g), TEA (excess), HOBt (0.03 g), and EDC (0.04 g). The reaction was stirred until complete. Workup and column chromatography (5% methanohdichloromethane) 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 of
Example 45a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 8H), 2.2 (m, 2H), 2.7 (m, IH), 3.0 (m, IH), 3.7 (m, 2H), 4.1 (m, IH), 4.7 (m, IH), 5.2
(m, IH), 7.2-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 541 (M+H\ 10%).
Example 46
Preparation of 2.2.2-Trifluoro-N-frS)-3-methyl-l-{3-oxo-l-r2-(3-pyridin-2-yl-phenyl)- acetyll -azepan-4-y lcarbamoyl I -butyl)-N-naphthylen-2-ylmethyl-acetamide
a.) (S)-4-Methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoic acid methyl ester To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added potassium carbonate (catalytic amount), and trifluoroacetic acid (0.44 g). The reaction was stirred at room temperature for 1 hour whereupon it was concentrated and chromatographed (20% ethyl acetate:hexane) to provide the title compound. b.) (S)-4-Methyl-2-[naphthylen-2-ylmethyl-(2,2,2-trifluoro-acetyl)-amino]-pentanoic acid lithium salt
To a solution of the compound of Example 46a (0.49 g) in THF:water (3 mL of a 2:1 solution) was added lithium hydroxide monohydrate (0.06 g). The reaction was stirred overnight whereupon it was concentrated to provide the title compound (0.46 g): MS(EI) 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 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 of Example 46b (0.46 g). The reaction was stirred until complete. Workup and column chromatography (5% mefhanokethyl acetate) provided the title compound (0.25 g): MS(EI) 614 (M+H+).
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 of Example 46c the title compound was produced: MS(EI) 480 (M+H+).
e.) 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]- 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+).
f.) 2,2,2-Trifluoro-N-((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)-acetyl]- azepan-4-y lcarbamoyl } -butyl)-N-naphthylen-2-ylmethyl-acetaπiide
Following the procedure of Example li except substituting the compound of Example 46e the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.2 (m, IH), 3.7 (m, 3H), 4.1 (m, IH), 4.5 (m, 2H), 4.7 (m, 2H), 5.2 (m, IH), 7.2-8.0 (m, 14H), 8.7 (m, IH): MS(EI): 673 (M+H\100%) . Example 47
Preparation of 4-r(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl- pentanoylamino1-3-oxo-azepane-l-carboxylic acid benzyl ester
a.) (S)-2-(Methanesulfonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoic acid methyl ester
To a solution of the compound of Example 34a (0.5 g) in dichloromethane was added triethylamine (0.36 mL) and methansulfonyl chloride (0.16 mL). The reaction was stirred at room temperature until complete. Workup and chromatography (20% ethyl acetate:hexanes) provided the title compound (0.24 g).
b.) (S)-2-(Methanesulfonyl-naphthylen-2-ylmethyl-amino)-4-methyl-pentanoic acid lithium salt Following the procedure of Example 46b except substituting the compound of
Example 47a the title compound was prepared: MS (El) 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 of
Example 47b the title compound was prepared: MS(EI) 596 (M+H+).
d.) 4-[(S)-(Methanesulphonyl-naphthylen-2-ylmethyl-amino)-4-methyl- pentanoylamino]-3-oxo-azepane- 1-carboxylic acid benzyl ester Following the procedure of Example li except substituting the compound of
Example 47c the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 5H), 3.0 (m, IH), 3.5 (m, IH), 4.1 (m, IH), 4.5 (m, 3H), 4.7 (m, IH), 5.2 (m, 3H), 7.2-8.0 (m, 13H); MS(EI): 596 (M+3H+,100%) . Example 48
Preparation of Ouinoline-2-carboxylic acid f(S)-3-methyl-lT3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll -butyl ) amide
a.) Quinoline-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 quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+).
b.) Quinoline-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 of Example 48a the title compound was prepared: Η NMR (CDCl.): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.1 (m, IH), 4.7 (m, 2H), 5.0 (m, IH),
7.0-7.2 (m, IH), 7.3 (m, IH), 7.5 (m, IH), 7.7 (m, IH), 7.8 (m, 3H), 8.1 (m, IH), 8.3 (m,
2H), 8.7 (m, 2H); MS(EI): 538 (M+H\100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H+,100%), and the slower eluting diastereomer; MS(EI):
538 (M+H+,100%).
Example 49
Preparation of Quinoline-8-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll -butyl I amide
a.) Quinoline-8-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-8-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+). b.) Quinoline-8-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 49a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H),.3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.5 (m, 4H), 7.6 (m, IH), 7.7 (m, 3H), 8.2 (m, IH), 8.6 (m, IH), 8.7 (m, IH), 8.9 (m, IH); MS(EI): 538 (M+H+,100%) .
Example 50
Preparation of Ouinoline-6-carboxylic acid f (S)-3-mefhyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl 1 amide
a.) Quinoline-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 quinoline-6-carboxylic acid 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 of
Example 50a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0 (m, 2H), 7.5 (m, 2H), 7.9 (m, 2H), 8.0 (m, 3H), 8.2 (m, IH), 8.7 (m, IH), 8.9 (m, IH);
MS(EI): 538 (M+H+,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H\100%), and the slower eluting diastereomer; MS(EI):
538 (M+H\100%). Example 51
Preparation of Ouinoline-4-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide
a.) Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridme-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example 28b except substituting quinoline-4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+).
b.) Quinoline-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 the compound of Example 51a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.5-
7.2 (m, 2H), 7.4 (m, 2H), 7.5 (m, IH), 7.7 (m, IH), 7.9 (m, 2H), 8.0 (m, IH), 8.2 (m, IH),
8.7 (m, IH), 8.9 (m, IH); MS(EI): 538 (M+H+,100%)
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H+,100%), and the slower eluting diastereomer; MS(EI):
538 (M+H\100%).
Example 52
Preparation of Ouinoline-3-carboxylic acid |(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll -butyl } amide
a.) Quinoline-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 quinoline-3-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+). 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: Η NMR (CDC13) : δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m 2H), 7.5 (m, IH), 7.6 (m, IH), 7.7-7.9 (m, 4H), 8.1 (m, IH), 8.5 (m, IH), 8.6 (m, IH), 9.3 (m, IH); MS(EI): 538 (M+H\100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 538 (M+H+,100%).
Example 53
Preparation of Isoquinoline-3-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll -butyl 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- carboxylic acid for benzofuran-2-carboxylic 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 Following the procedure of Example li except substituting the compound of
Example 53a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0 (m, IH). 7.5 (m, IH), 1.1 (m, 2H), 7.9 (m, 4H), 8.7 (m, 3H), 9.2 (m, IH); MS(EI): 538 (M+H\100%) . Example 54
Preparation of Isoquinoline- 1-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl1 -butyl I amide
a.) Isoquinoline- 1-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- 1- carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 540 (M+H+).
b.) Isoquinoline- 1-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 54a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.3
(m, IH), 7.5 (m, IH), 7.7-8.0 (m, 6H), 8.7 (m, 3H), 9.5 (m, IH); MS(EI): 538
(M+H\100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 537 (M+,100%), and the slower eluting diastereomer; MS(EI): 537
(M\100%).
Example 55
Preparation of Ouinoxaline-2-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl|amide
a.) Quinoxaline-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 quinoxaline-2- carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 541 (M+H+). b.) Quinoxaline-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 of Example 55a the title compound was prepared: Η NMR (CDCl.): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.1 (m, 2H), 5.0 (m, IH), 7..0- 7.2 (m, 2H), 7.5 (m, IH), 1.1 (m, 3H), 8.2 (m, 2H), 8.3 (m, IH), 8.7 (m, IH), 9.5 (m, IH); MS(EI): 539 (M+H\ 30%).
Example 56
Preparation of Benzorblthiophene-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyn-butyl I amide
a.) Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulf onyl)-azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example 28b except substituting benzo[b]fhiophene-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- sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substituting the compound of Example 56a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.8- 7.2 (m, IH), 7.5 (m, 3H), 8.0 (m, 6H), 8.7 (m, IH); MS(EI): 543 (M+H+, 60%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; "HNMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 3.8 (m,lH), 4.1 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.4-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 543 (M+H+,100%), and the slower eluting diastereomer; 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 3.8 (m,lH), 4.1 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.4-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 543 (M+H\100%). Example 57
Preparation of l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl I amide
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) 541 (M+H+).
b.) l,8-Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example li except substituting the compound of Example 57a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m, IH), 7.6 (m, 2H), 7.9 (m, 2H), 8.3 (m, IH), 8.4 (m, 2H), 8.5 (m, 2H), 9.2 (m, IH); MS(EI): 539 (M+H+,100%)
Example 58
Preparation of lH-Indole-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamovH-butyl I amide
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+).
b.) lH-Indole-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 of Example 58a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.1 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.8 (m, IH), 7.1 (m, IH), 7.3 (m, 3H), 7.4 (m, IH), 7.5 (m, IH), 7.6 (m, IH), 8.0 (m, 2H), 8.7 (m, IH), 9.4 (b, IH); MS(EI): 526 (M+H\ 80%).
Example 59
Preparation of 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine- 2-sulf onyl)-azepan-4-ylcarbamoyl1 -butyl 1 amide
a.) 5-Methoxybenzofuran-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-methoxybenzofuran-
2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared:
MS(EI) 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 of
Example 59a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, 4H). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.0
(m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 557 (M+H+, 70%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH),
3.7 (m, 4H). 4.0 (d, IH), 4.7 (m, 2H), 5.0 (d, IH), 7.0 (m, 4H), 7.6 (m, 3H), 8.0 (m, 2H), 8.7 (d, IH); MS(EI): 557 (M+H\100%), and the slower eluting diastereomer; MS(EI): 557
(M+H\100%).
Example 60
Preparation of 5-Bromo-furan-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl 1 amide
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 acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 558 (M+H+).
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 of Example 60a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.5 (m, IH), 6.1 (m, IH), 7.1 (m, 2H), 7.5 (m, IH), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 555 (M+H+, 60%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 555 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 555 (M+H+,100%).
Example 61
Preparation of Furan-2-carboxylic acid l(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll -butyl ) 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 benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 479 (M+H+). b.) 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 of Example 61a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.1 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.5 (m, IH), 7.2 (m, 3H), 7.5 (m, 2H), 8.0 (m, 2H), 8.7 (m, IH); MS(EI): 477 (M+H\ 50%).
Example 62
Preparation of 5-Nitro-furan-2-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl 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 acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 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 of
Example 62a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.2 (m, IH), 7.3 (m, IH), 7.5 (m, IH), 7.9 (m, 2H), 8.7 (m, IH); MS(EI): 522 (M+lT, 80%).
Example 63
Preparation of 5-(4-Nitro-phenyl)-furan-2-carboxylic acid |(S)-3-mefhyl-l-r3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-butyl } amide
a.) 5-(4-Nitro-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-nitrophenyl)-2- furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 600 (M+H+).
b.) 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substituting the compound of Example 63a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.1 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 6.9 (m, IH), 7.2 (m, IH), 7.5 (m, 2H), 7.9-8.0 (m, 4H), 8.5 (m, IH), 8.6 (m, IH); MS(EI): 598 (M+H+, 80%).
Example 64
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid KS)-3-methyl-l-r3- oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-butyl ) amide
a.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy- 1 -(pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl] -butyl } amide
Following the procedure of Example 28b except substituting 5-[3- (trifluoromethyl)phenyl]-2-furoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 623 (M+H+).
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 of Example 64a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.1 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.7 (m, 2H), 5.0 (m, IH), 7.1 (m, IH), 7.5 (m, 3H), 8.0 (m, 4H) 8.7 (m, IH); MS(EI): 621 (M+H+, 80%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 621 (M+ET,100%), and the slower eluting diastereomer; MS(EI): 621 (M+H+,100%).
Example 65
Preparation of Tetrahydro-furan-2-carboxylic acid j(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamovn-butyl 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(EI) 483 (M+H+).
b.) Tetrahydro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl } amide Following the procedure of Example li except substituting the compound of
Example 65a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 12H), 2.7 (m, IH), 3.8 (m, 3H). 4.0 (m, IH), 4.5 (m, 2H), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, IH), 7.5 (m, IH), 7.9 (m, 2H), 8.7 (m, IH). MS(EI): 481 (M+H+, 80%).
Example 66
Preparation of (S)-4~Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid r3-oxo-(pyridine-2- sulfonyl)-azepan-4-vn-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 for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 519 (M+H+). b.) (S)-4-Methyl-2-(2-phenoxy-acetylamino)-pentanoic acid [3-oxo-(pyridine-2- sulf onyl)-azepan-4-yl] -amide
Following the procedure of Example li except substituting the compound of Example 66a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH). 4.0 (m, IH), 4.5 (m, 3H), 4.7 (m, IH), 5.1 (m, IH), 7.0 (m, 3H), 7.3 (m, 2H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 517 (M+H\ 60%).
Example 67
Preparation of (S)-2-r2-(4-Fluoro-phenoxy)-acetylamino1-4-methyl-pentanoic acid r3-oxo- (pyridine-2"SuIfonyl)-azepan-4-yll-amide
a.) (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-hydroxy- (pyridine-2-sulfonyl)-azepan-4-yl] -amide
Following the procedure of Example 28b except substituting 4-fluorophenoxyacetic acid 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 of Example 67a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.6 (d, IH). 4.0 (m, IH), 4.5 (, 3H), 4.8 (m, IH), 5.1 (m, IH), 7.0 (m, 4H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 535 (M+H+, 50%).
Example 68
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2- carbonyl)-azepan-4-ylcarbamoyl)-3- butyl1-amide
a.) {(S)-l-[3-Hydroxy-l-(pyridine-2-carbonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}- carbamic acid tert-butyl ester
To a solution of the compound of Example 2g (0.25 g) in dichloromethane was added picolinic acid (0.09g), EDC (0.14 g) and HOBt (0.10 g). The reaction was stirred until complete. Workup and column chromatography (5% methanoLethyl acetate) provided the 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) was added 4M HCl in dioxane (6 mL). The reaction was stirred until complete whereupon it was 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 of Example 68b the title compound was prepared: MS(EI) 493 (M+H+).
d.) Benzofuran-2-carboxylic 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 of
Example 68c the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.7 (m, IH), 4.7 (m, 4H), 5.0 (m, IH), 7.0-7.5 (m,
8H), 8.2 (m, IH); MS(EI): 491 (M+,100%). Example 69
Preparation of Benzofuran-2-carboxylic acid l(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- carbonyl)-azepan-4-ylcarbamovn-butyl I amide
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 (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (d, IH). 4.0 (m, IH), 4.7 (m, 3H), 5.5 (m, IH), 7.0 (m, 2H), 7.2-7.5 (m, 7H), 8.1 (m, 2H); MS(EI): 507 (M+, 20%).
Example 70
Preparation of 4-((S)-2-tert-Butylcarbonylamino-4-methyl-pentanoylamino)-3-oxo-azepane- 1-carboxylic acid benzyl ester
Following the procedure of Example 92j, except substituting 4-((S)-2-tert- Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1 -carboxylic acid benzyl ester for benzofuran-2-carboxylic acid {(S)-l-[3-hydroxy-6,6-dimethyl-l-(pyridine- 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; * H-NMR (400 MHz, CDC13): • 7.40-6.95(m, 7H), 5.25-4.60(m, 4H), 4.40-4.06(m, 2H), 3J0-3.58(t, IH), 2J0-2.50(m, IH), 2.25-1.30(m, 1 6H); and the second eluting diastereomer:, 1.00-0.85(d, 6H); and the second eluting diastereomer: MS (M+H+) 476.2.
Example 71
Preparation of 5,6-Dimefhoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l- methyl- 1 H-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyn-butyl I amide
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 added pyridine (92μL, 1.14mmol) followed by l-methylimidazole-4-sulfonylchloride (0.112g, 0.623mmol). The reaction was allowed to stir for 16h at room temperature. The solution was then washed with saturated aqueous NaHCO3, water and brine. The product was purified by column chromatography (silica gel: methanol/ methylenechloride) to yield the title compound as a white solid (0.172g, 68%): 'HNMR (400MHz, CDCL) δ 7.6 (d, IH), 7.5 (d, IH), 6.6 (d, IH), 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 71a (0.172g, 0.353mmol) in minimal MeOH was added 4M HCl in dioxane (lOmL) and stirred for 4h at room temperature. The reaction mixture was concentrated and azeotroped with toulene (2x's) to yield the title compound 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 stirring 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, 1.77 mmol) and 1-hydroxybenzotriazole (O.Olg, 0.070mmol) in DMF (5mL) was added l-(3- dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.074g, O.388mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2x's), and saturated brine. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography ( silica gel; mefhanol/dichloromethane) to yield the title 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-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide
Oxalyl chloride (52μL, 0.596mmol) chloride was cooled to -78°. To this was added dimethyl sulfoxide (106μL, 1.49mmol) in methylene chloride dropwise. After stirring for 15min at -78°, the alcohol in methylene chloride was added slowly and allowed to stir for lh when Et3N (416μL,2.98mmol) was added. The solution was then brought to room temperature and quenched with water and extracted into methylene chloride. 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 (0.068g, 78%): Η NMR (400MHz, CDC13) δ 6.8-7.6 (m, 14H), 4 (d, 12H), 1 (d, 12H); MS(ESI): 590.1 (M+H)+
Example 72
Preparation of Benzofuran-2-carboxylic acid {(S)-3-mefhyl-l-|TJ5-methyl-lH- T 1 ,2,41triazole-3-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl 1 amide
a.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-l-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 room temperature. The reaction mixture was then concentrated and azeotroped with toluene (2x20 mL) to yield the title 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- 1-carboxylic 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 at room temperature for 16h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2X), and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (silica gel; ethylacetate/dichloromethane) to yield the title compound (3.7g, 93%). 'HNMR (400MHz, CDC ) 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 temperature for 64 h under a hydrogen atmosphere. The mixture was then filtered through celite and the filtrate concentrated to yield the title compound as a white solid (1.92 g, 100%): Η NMR (400MHz, CDC13) δ 6.8-7.7(m, 7H), 1.02 (d, 6H); MS(ESI) 388 (M+H)+
d.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[l,2,4]triazole-3- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl } amide
To a stirring solution of the compound of Example 72c (O.lOOg, 0.25mmol) and triethylamine (35μL, 0.25mmol) in methylene chloride (2mL) was added 5-methyl-lH- 1,2,4-triazolesulfonylchloride (0.043g, 0.25mmol). The reaction was allowed to stir for 10 min 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 (0.111, 84%): MS(ESI) 532.73 (M+H)+
e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(5-methyl-lH-[l,2,4]triazole-3- sulf onyl)-3-oxo-azepan-4-y lcarbamoyl] -butyl } amide
To a stirring solution of the compound of Example 72d (0.108g, , 0.206mmol) in dimethy lsulf oxide (2mL) was added triethylamine (172μL, 1.23mmol) followed by sulfur trioxide pyridine (0.116g, 0.718mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na2SO4, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.08g, '81%): 'HNMR (400MHz, CDCL) δ 7.1-7.7 (m, 7H), 2.65 (s, 3H), 1.0 (d, 6H); MS(ESI): 552.71 (M+Na)+
Example 73
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-ri-(l-methyl-lH-imidazole-3- sulf onyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl I 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 (O.lOOg, 0.25mmol) and triethylamine (35μL, 0.25mmol) was added 1-methylimidazole sulfonyl chloride (0.046g, 0.255mmol). The reaction was allowed to stir for lOmin 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 (400 MHz, CDCL) δ 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- sulf onyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide
To a stirring solution of the compound of Example 73a (0.085g, 0.159mmol) in dimethylsulfoxide was added triethylamine (133μL, 0.95mmol) followed by sulfurtrioxide pyridine (0.08g, 0.5mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na2SO4, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.072g, 83%). MS(ESI): 529.76 (M+H)+
Example 74
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-ri-(lH-imidazole-2-sulfonyl')-
3-oxo-azepan-4-ylcarbamoyn-butyl } 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 (0.1 OOg, 0.25mmol) and triethylamine (35μL, 0.25mmol) was added 2-imidazolesulfonyl chloride (0.046g, 0.255mmol). The reaction was allowed to stir for lOmin and washed with saturated aqueous
NaHCOj, 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, CDC13) δ 7.1-7.7 (m, 9H), 4.8 (s, IH), d, 6H); MS(ESI): 517.76 (M+H)+
b.) 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 74a (0.107g, 0.206mmol) in dimethylsulfoxide (2mL) was added triethylamine (172μL, 1.23mmol) followed by sulfurtrioxide pyridine (0.115g, 0J18mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na2SO4, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.09g, 85%); MS(ESI): 515.84 (M+H)+
Example 75
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(thiazole-2- sulf onyl)-azepan-4-ylcarbamoyl1 -butyl } amide
a.) {(S)-l-[3-Hydroxy-l-(thiazole-2-sulfonyl)-azepan~4-ylcarbamoyl}-3-methyl- butylj-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, 8J5 mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (2.50 g, 5.10 mmol, 70%); MS: 490.91 (M+H)+.
b.) Benzofuran-2-carboxylic 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 CH2C12 (20 mL) was added benzofuran-2-carboxylic acid (0.109 g, 0.172 mmol), 1- hydroxybenzotriazole (0.106 g, 0J62mmol), and P-EDC (0.85g, lmmol/g) in CH2C12 (10 mL) . After shaking at room temperature overnight, the solution was treated with tisamine (0.589g, 3J5mmol/g). After shaking for another 2hr, the solution was filtered and concentrated 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-ylcarbamoyI]-butyl}-amide To a stirring solution of the compound of Example 75c (166.7 mg, 0.313 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (265.5 mg, 0.626 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by HPLC (50:50 ethanol: hexane, 20mL/min, 25min, WhelkO-l(R,R) 21x250mm column, UV detection at 280 nm and 305 nm) to yield the first elution as a white solid (84.8mg, 50.8 %). MS (ESI): 533.2 (M+H)+ and the second elution as a white solid (50.1mg, 30.0%) MS: 533.2 (M+IT).
Example 76
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-ri-(l-methyl-lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl}amide
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 methylenechloride (5ml) was added pyridine (92μL, 1.14mmol) followed by l-methylimidazole-4-sulfonylchloride (0.112g, 0.623mmol). The reaction was allowed to stir for 16h at room temperature. The solution was then washed with saturated aqueous NaHCO3, water and brine. The product was purified by column chromatography (silica gel: methanol/ methylenechloride) to yield the title compound as a white solid (0.172g, 68%): 'HNMR (400MHz, CDCL) δ 7.6 (d, 1H),^ 7.5 (d, IH), 6.6 (d, IH), 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 minimal
MeOH was added 4M HCl in dioxane (lOmL) and stirred for 4h at room temperature. The reaction mixture was concentrated and azeotroped with toulene (2x's) to yield the title compound 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- sulf onyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl } amide
To a stirring solution of the compound of Example 72c (0.2g, 0.471mmol), benzofuran-2-carboxylic acid (0.084 g, 0.388 mmol), triethylamine (72μL, 0.517mmol) and 1-hydroxybenzotriazole (0.012 g, 0.088 mmol) in DMF (5 mL) was added l-(3- dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.099g, 0.515mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2x's), and saturated brine. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (silica gel; methanol/dichloromethane) to yield the title compound as a white solid (0.226g, 90%): 'HNMR (400MHz, CDC13) δ 6.9-8.1 (m, 18H), 3.75 (2s, 6H), 1 (d, 12H); MS(ESI): 531.80(M+H)+'
d.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide
To a stirring solution of the compound of Example 76a (0.226 g, 0.426mmol) in dimethylsulfoxide (2mL) was added triethylamine (355μL, 2.55mmol) followed by sulfur trioxide pyridine (0.238g, 1.48mmol) and stirred for 16h at room temperature. The reaction mixture was diluted with EtOAc and washed with water (X2). The organic layer was dried over Na2SO4, filtered and conentrated. The crude product was purified by column chromatography (silica gel; methanol/methylenechloride) to yield the title compound as a white solid (0.168g, 76%): 'HNMR (400MHz, CDCL δ 7.1-7.7 9m, 18H), 3.7 (2s, 6H), 0.9 (d, 12H); MS(ESI): 529.80 (M+H)+
Example 77
Preparation of 5-(4-Oxy-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3- methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}amide
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 overnight. Workup and column chromatography (30% methanol :dichloromethane) provided the title compound: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, 4H), 2.7 (m, IH), 2.8 (m 2H), 3.1 (m, 4H), 3.8 (q, IH). 4.0 (m, 3H), 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, 3H), 7.4 (m, 2H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 671 (M\100%) .
Example 78
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-3- sulfonyl)-azepan-4-ylcarbamoyl1-butyl|amide
a.) 4-((S)-2-Ajτ no-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid benzyl ester
To a solution of 4-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-3- hydroxy-azepan- 1-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 temperature for 2 hours 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- 1-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) was added EDC (1.48 g), HOBt (1.05 g), TEA (1.29 mL) and benzofuran-2-carboxylic acid.
The reaction was stirred until complete. Workup and column chromatography (2% methanoLdichloromethane) 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- 1 -carboxylic acid benzyl ester of Example 78b ( 1.6 g) in methanoLethyl acetate (50 mL:100 mL) was added 10% Pd/C. The reaction was stirred under a balloon of hydrogen for 2 hours whereupon it was filtered and concentrated to provide the title compound (1.16 g): MS(EI) 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-butyl]-amide of Example 78c (0.3 g) in dichloromethane was added triethylamine (0.17 mL) followed by 3-pyridinesulfonyl chloride (0.25 g). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (5% methanoLethyl acetate) provided 0.32 g of the title compound: MS(EI) 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-carboxylic acid { (S)-3-methyl- 1- [3-hydroxy- 1 -(pyridine-3-sulf onyl)-azepan-4-ylcarbamoyl]- butyllamide of Example 78d 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, IH), 3.5 (d, IH). 4.0 (m, IH), 4.7 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, 2H), 7.2-7.5 (m, 6H), 8.1 (m, IH), 8.9-9.0 (m, 2H); MS(EI): 526 (M+,100%) .
Example 79
Preparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-3- sulfonyl)-azepan-4-ylcarbamoyl1-butyl 1 amide
a.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-3- sulf onyl)-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) in dichloromethane was added m-CPBA (0.05 g). The reacrton was stirred overnight.
Workup and column chromatography (10% methanoLdichloromethane) provided the title compound (0.03 g): MS(EI) 544 (M+H+).
b.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-3- sulfonyl)-azeρan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substituting benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-3-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide of Example 79a the title compound was prepared: JH NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (m, IH), 3.5 (d, IH). 4.0 (m, IH), 4.5 (m, IH), 4.1 (m, IH), 5.0 (m, IH), 7.2-7.5 (m, 7H), 8.1-8.2 (m, 2H). MS(EI): 542 (M+, 50%). Example 80
Preparation of Ouinoline-3-carboxylic acid {(S)-l-(3.4-dichloro-benzene-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl)1-3-methyl-butyl}-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: Η NMR(CDCI3, 400 MHz) δ 9.34 (s, IH), 8.61 (s, IH), 8.14 (m, IH), 7.81 (m, 3H), 7.60 (m, 3H), 7.19 m, 2H), 5.09 (m, IH), 4.88 (m, IH), 4.50 (m, IH), 3.92 (m, IH), 3.51 (m, IH), 2.57 (m, IH), 2.23 (m, 2H), 1.60 (m, 5H), 1.01 (m, 6H).
Example 81
Prepeparation of 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-lTlJl-methyl- lH-imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl|amide
a.) 5-Hydroxy-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 Example 76b (0.1 g, 0.235 mmol), 5- hydroxybenzofuran-2-carboxylic acid(0.046g, 0.256mmol), triethylamine (36 μL, 0.258 mmol) and 1-hydroxybenzotriazole (0.006g, 0.044mmol) in DMF (5mL) was added l-(3- dimethylaminopropyl)3-ethylcarbodimide hydrochloride (0.05 g, 0.26mmol). After stirring at room temperature for 16h, the solution was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water (2X), and saturated brine. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography ( silica gel; methanol/dichloromethane) to yield the title compound as a white solid (0.129g, 100%). 'HNMR (400MHz, CDCL) δ 6.8-8 (m, 16H), 3.6 (2s, 6H), 0.85 (d, 12H). MS(ESI): 547.88(M+H)+' b.) 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH- imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide
Oxalyl chloride (13 μL, 0.149 mmol) chloride was taken to -78°. To this was added dimethyl sulfoxide (28 μL, 0.394mmol) in methylene chloride dropwise. After stirring for 15min at -78 °, the alcohol of Example 81a in methylene chloride was added slowly and allowed to stir for lh when Et3N (7 μL, 0.05 mmol) was added. The solution was then brought to room temperature and quenched with water and extracted into methylene chloride. 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
Preparation of Benzofuran-2-carboxylic acid j(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)1-3-methyl-butyl 1 -amide
a.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)]-3-methy 1-butyl } -amide To a solution of benzofuran-2-carboxylic acid [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.10 g) in dichloromethane was added triethylamine (0.07 mL) followed by 2-pyidinesulphonylchloride N-oxide. The reaction was stirred at room temperature overnight. Workup and chromatography (10% methanoLdichloromethane) provided the title compound (0.01 g): MS(EI) 544 (M+H+).
b.) {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)]-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-sulfonyl)-azepan-4- ylcarbamoyl)]-3-methyl-butyl}-amide of Example 82a 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, IH), 3.8 (q, IH). 4.0 (m, IH), 4.7 ( , IH), 4.8 (m, IH), 5.0 (m, IH), 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 eluting diastereoemer; 'HNMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.8 (d, IH). 4.0 (d, IH), 4.7 (m, IH), 4.8 (d, IH), 5.0 (m, IH), 7.0 -7.5 (m, 9H), 8.1-8.2 (m, 2H); MS(EI): 542 (M\100%), and the slower eluting diastereomer; MS(EI): 542 (M+H+,100%).
Example 83
Preparation of 2-(4-{(S)-2-{(Benzofuran-2-carbonyl)-amino|-4-methyl-pentanoylaminol-3- oxo-azepane- l-sulfonyl)-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 was prepared: 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)-amino]-4-methyl-pentanoylamino}-3- hydroxy-azepane-l-sulfonyl)-benzoic acid methyl ester (compound 83a, 180 mg, 0.309 mmol) was dissolved in 5:1 MeOH/water (6 ml) LiOH (14 mg, 0.34 mmol) was added and the reaction mixture was stirred and refluxed for 6 h. The reaction mixture was then quenched with water and 6 N HCl (adjusted to pH=2), extracted with EtOAc (3 x 10 ml), dried with MgSO4, filtered, concentrated, and chromatographed (silica gel, 1% acetic acid/ 4% MeOH/ CH2C12) to yield the title compound as a white solid (48 mg, 27%): M+H+ = 572.2
c.) 2-(4-{(S)-2-[(Benzofuran-2-carbonyl)-amino]-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 title compound was prepared: MS (M+H+): 570.2 (M+H+). H NMR(400Hz,CDCl3-CD OD): δ 8.05-7.95 (m, IH), 7.70- 7.15 (m, 8H), 5.15-5.00 (m,lH), 4.95-4.75 (m, 2H), 4.15-4.00 (m, IH), 3.65 (d, IH), 2.85- 2.70 (m, IH), 2.25-2.05 (m, 2H), 1.90-1.70 (m, 4H), 1.60-1.45 (m, IH), 0.95 (d, 6H).
Example 84
Preparation of 3-(4-{ (S)-2-i (Benzofuran-2-carbonyl)-amino1-4-methyl-pentanoylamino 1-3- oxo-azepane- 1-sulf onvD-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+); 1H NMR (400Hz,CDCl3- CD3OD): δ 8.46 (d,lH), 8.31-8.25 (m,lH), 8.00-7.97 (m,lH), 1.10-1.62 (m, 2H), 7.55-7.46 (m, IH), 7.45-7.35 (m,lH), 7.30-7.25 (m, IH), 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, IH), 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).
Example 85
Preparation of Benzorblthiophene-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl1 -butyl I amide
a.) {(S)-l-[3-Hydroxy-l-(l-oxy-pyridine-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- butyl-carbamic acid tert-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) and saturated sodium bicarbonate was added freshly prepared 2-pyidinesulphonyl 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 vacuum provided the 2-pyridinesulfonyl chloride-N-oxide). The reaction was stirred at room temperature for 1 hour. Workup and column chromatography (10% methanoLdichloromethane) provided the title compound (2.0 g): MS(EI) 500 (M+H+).
b.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy-l-(l-oxy-pyyridine-sulfonyl)- azepan-4-yl] -amide
To a solution of {(S)-l-[3-hydroxy-l-(l-oxy-pyridine-sulfonyl)-azepan-4- ylcarbamoyl]-3-methyl-butyl-carbamic acid tert-butyl ester of Example 85a (2.0 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 1.5 hours whereupon it was concentrated to provide the title compound (1.8 g): MS(EI) 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-sulfonyl)-azepan-4-yl]-amide of Example 85b (0.25 g) in dichloromethane (12 mL) was added triethylamine (0.12 mL), EDC (0.11 g), HOBt (0.077 g) and benzo[b]thiophene-2-carboxylic acid. The reaction was stirred until complete. Workup and column chromatography (10% methanol: dichloromethane) provided the title compound
(0.26 g): MS(EI) 560 (M+H+). d.) Benzo[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 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: Η NMR
(CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.1 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4.1 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.5 (m, 4H), 7.8 (m, 3H), 8.1-8.2 (m, 2H). MS(EI): 558 (MM 00%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 558 (M+,100%), and the slower eluting diastereomer; MS(EI): 558 (MM 00%).
Example 86
Preparation of 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyn-butyl}amide
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 acid for benzo[b]thiophene-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: Η NMR (CDC ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.1 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4.1 (m, IH), 4.8 (m, IH), 5.0 (m, IH), 7.0 (m, 2H), 7.4 (m, 2H), 8.1-8.2 (m, 2H); MS(EI): 570 (MM 00%) . The diastereomeric mixture iivas separated byΗPLC to provide the faster eluting diastereoemer; MS(EI): 572 (M+H+,100%), and the slower eluting diastereomer; MS (El): 572 (M+H+,100%).
Example 87
Preparation of 5,6-Dimethoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[~3-oxo-l-(l- oxy-pyridine-2-sulfonyI)-azepan-4-ylcarbamoyll-butyl } amide
a.) 5,6-Dimethoxybenzofuran-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 5,6- dimethoxybenzofuran-2-carboxylic acid for benzo[b]thiophene-2~carboxylic acid the title compound was prepared: MS (El) 604 (M+H+).
b.) 5,6-Dimethoxybenzofuran-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 5,6- dimethoxybenzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-hydroxy- l-(l-oxy-ρyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 87a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8
(m, 7H). 4.0 (m, IH), 4.7 (m, IH),
4.8 (m, IH), 5.0 (m, IH), 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 eluting diastereoemer; MS(EI): 602 (MM 00%), and the slower eluting diastereomer; MS(EI): 602
(MM 00%).
Example 88
Preparation of l-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl } 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-oxide for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 505 (M+H+).
b.) l-Oxy-ρyridine-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 l-oxy-pyridine-2- carboxylic acid { (S)-3-methyl- l-[3-hydroxy- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide of Example 88a the title compound was prepared: Η NMR
(CDCl.): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.1 (m, IH),
4.7 (m, 2H), 5.0 (m, IH), 7.5 (m, 3H), 7.9 (m 2H), 8.3-8.4 (m, 2H), 8.6 (m, IH); MS(EI):
503 (MM 00%) .
Example 89
Preparation of (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid F3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yll-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-yl]-amide of Example 28a (0.25 g) in dichloromethane was added triethylamine (0.27 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirred until complete. Workup and column chromatography (5% methanoLdichloromethane) provided the title compound (0.09 g): MS(EI) 525 (M+H+). b.) (S)-4-Methyl-2-(pyridine-2-sulfonylamino)-pentanoic acid [3-hydroxy-l-(pyridine- 2-sulfonyl)-azeρan-4-yl]-amide
Following the procedure of Example li except substituting (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: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4.1 (m, IH), 5.0 (m, IH), 5.5 (m, IH), 7.0 ( IH), 7.5 (m, 2H), 7.9 (m 3H), 8.6 (m, 2H). MS(EI): 523 (M+,100%) .
Example 90
Preparation of (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid F3-oxo-l-(pyridine-2- sulf onyl)-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-yl]-amide of Example 28a (0.25 g) in dichloromethane was added triethylamine (0.17 mL) and benzyl isocyanate (0.088g). The reaction was stirred until complete. Workup and column chromatography (5% methanoLdichloromethane) provided the 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 of Example 89a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, 3H), 4,5 (t, IH), 4.1 (m, IH), 5.0 (m, IH), 7.2 (, 5H), 7.5 (m, IH), 7.9 (m, 2H), 8.6 (m, IH); MS(EI): 515 (M+, 60%). The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 516 (M+H+,100%), and the slower eluting diastereomer; MS(EI): 516 (M+H+J00%). Example 91
Preparation of (S)-2-(3-Phenyl-uriedo)-4-methyl pentanoic acid r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-yl]-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 for benzyl isocyanate the title compound was prepared: : MS(EI) 503 (M+H+).
b.) (S)-2-(3-Phenyl-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-phenyl- ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 91a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m,
IH), 7.0-7.9 (m, 8H), 8.6 (m, IH). MS(EI): 501 (M+, 60%).
Example 92
Preparation of Benzofuran-2-carboxylic acid ((S)-l-F6,6-dimethyl-3-oxo-l(pyridine- sulphonyl)-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
a.) Allyl-(2,2-dimethyl-pent-4-enylidene)-amine 2,2-Dimethyl-4-pentenal (2.8 g, 25 mmol) was dissolved in 15 mL benzene. To this solution allylamine (2.85 g, 50 mmol) was added. A few molecular sieves were used to absorb water generated during the reaction. The mixture was stirred at room temperature overnight. Removal of the solvent and excess amount of allylamine on rotavapor provided 3.76 g of the title compound as clear liquid (yield 100%). !H-NMR (400 MHz, CDC13): • 7.52(s, IH), 5.99-5.90(m, IH), 5.80-5J0(m, IH), 5.15-4.99(m, 4H), 4.01-3.99(m, 2H), 2.17(d, 2H), 1.06(s, 6H). b.) Allyl-(2,2-dimethyl-pent-4-enyl)-amine
Allyl-(2,2-dimethyl-pent-4-enylidene)-amine of Example 92a (3J6g, 25mmol) was diluted in 5ml MeOH. To the solution NaBH4 (0.95g, 25mmol) was added at 0°C. After addition the mixture was stirred at r.t. for 5h. Methanol was removed on rotavapor and the residue was partitioned between EtOAc/ 20% NaOH. The organic layer was dried over Na SO , fitered and evaperated to give 2.26 g of the title compound: MS (M+H+): 154.0;
2 4
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 CH C12. 2-pryridinesulphonyl chloride was added slowly to the solution while it was cooled in an ice-water bath. After addition, the reaction mixture was stirred at r.t. overnight. Washed by 10% NaHCO3 and the brine. Purified by column chromatography gave 0.6 g colorless oil in 73% yield. MS (M+H+): 295.2; ΪH-NMR (400 MHz, CDCI3): • 8Jl-8J0(d, IH), 7.98-7.86(m, 2H), 7.48-7.46(m, IH), 5.88-5J7(m, IH), 5.55-5.45(m, IH), 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) was diluted in CH2C12 (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 solvent was removed on rotavapor. The crude product was purified by column chromatography (5%-20% E/H) to give 0.47g of the title compound in 87% yield. MS (M+H+): 267.0; 1H- NMR (400 MHz, CDCI3): • 8.70-8.69(d, IH), 7.96-7.88(m, 2H), 7.49-7.46(m, IH), 5.81- 5J0(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 mL
CH2C12 was added NaHCO3 (2.4 g, 13.5 mmol) and then MCPBA (1.2 g, 13.5 mmol) in • portions. The reaction was stirred at r.t. for 4h before it was worked up by washing with 15% NaOH, saturated K2CO3, brine and dried (Na2SO4) to give l.Og crude product in 79 % yield ( good enough for next reaction without further purification.) MS (M+H+): 283.0; 1H-NMR (400 MHz, CDC13): • 8.68-8.67(d, IH), 8.03-7.87(m, 2H), 7.49-7.40(m, IH), 4.44-3.89(q, IH), 3.62-3.59(d, IH), 3.50(m, IH), 3.00(m, IH), 2J8-2.62(m, 2H), 2.12- 2.06(m, IH), 1.52-1.46(q, IH), 1.20(s, 3H), 0.89(s, 3H).
f .) 4-Azido-6,6-dimethyl- 1 -(pyridine-2-sulfonyl)-azepan-3-ol
5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.Ojoctane from Example 92e (1.2 g, 4.3 mmol) was dissolved in the mixture of 7 ml MeOH and 1 ml H2O. NaN3 (0.83 g, 13 mmol) and NH4CI (0J g, 13 mmol) were added to the solution. The resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO3 and brine. Purified on column chromatography gave 0.4g 4-azido-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol (yield 29%); MS (M+H+): 326.2; 1H-NMR (400 MHz, CDCI3): • 8.68-8.67(m, IH), 8.05-7.90(m, 2H), 7.53-7.50(m, IH), 3J5-3.60(m, 3H), 3.49-3.30(m, 3H), 1J3-I.66(m, IH), 1.56- 1.52(d, IH), 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 from 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. TLC showed no stalling material left. THF was evaporated, azeotroped with toluene (2x's). The resulting thick oil was dissolved in MeOH, treated with HCl in ether to adjust pH to acidic.
More ether was added and the solution turned cloudy. 0.22 g white precipitate of the title compound was collected. (45% yield); * H-NMR (400 MHz, CD3OD): • 8.68(m, IH), 8.10- 7.93(m, 2H), 7.62(m, IH), 3.90(m, IH), 3.68(m,lH), 3.40-2.90(m, 4H), 1.82(m, IH),
1.53(d, IH), 1.05(s, 6H)
h.) {(S)-l-[3-Hydroxy-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3- methyl-butylj-carbamic acid tert-butyl ester 4-Amino-6,6-dimethyl-l-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt from Example
92g (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. overnight. DMF was removed under high vacuum. The residue was diluted with EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave 0.22 g of the title compound (72% yield); MS (M+H+): 512.9; 1H-NMR (400 MHz, CDC13): • 8.68-8.67(d, IH), 7.97-7.88(m, 2H), 7.69-7.64(m, IH), 6.62-6.53(m, IH), 5.06-5.00(m, IH), 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 tert-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 resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The mixture was stirred at r.t. overnight. 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 column chromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8; 1H-NMR (400 MHz, CDCI3): • 8.66-8.63(m, IH), 7.94-7.1 l(m, 10H), 4J2(m, IH), 4.01- 2.98(m, 7H), 1J8-I.39(m, 5H), 1.02-0.85(m, 12H).
j.) Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-6,6-dimethyl-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoyl] -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-methy 1-butyl } -amide from Example 92i
(100 mg, 0.18mmol) in 2 ml CH2C12, was added Dess-Martin reagent (76 mg, 0.18 mmol) at r.t.. The solution was stirred for 2h when 20 ml CH2C12 was added and then washed with NaHC03 and brine. Purification by column chromatograghy (50% ethyl acetate in hexane) gave 70 mg of he title compound in 70% yield. MS (M+H+): 555.4; 1H-NMR (400 MHz, CDCL): • 8.68-8.67(d, IH), 7.97-7.93(m, 2H), 7.69-7.28(m, 6H), 7.32-6.92(m, 2H), 5.24(m, IH), 4J9-4.69(m, 2H), 3.80-3Jl(m, 2H), 2.54-2.50(d, IH), 1.92-lJ6(m, 4H), 1.45- 1.40(m, 4H), 1.01-0.91(m, 9H). The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS (M+H+): 555.2, and the slower eluting diastereomer; MS (M+H+): 555.2.
Example 93
Preparation of 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-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 was prepared: 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-mefhoxybenzofuran-2- carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- y lcarbamoyl] -butyl} amide of Example 93a the title compound was prepared: Η NMR
(CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 ( m, 4H). 4.0 (m,
IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 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 eluting diastereoemer; 'HNMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH),
3.7 (s, 3H), 3.8 (d, IH). 4.0 (d, IH), 4,1 (m, IH), 4.8 (d, IH), 5.0 (m, IH), 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+HM00%). Example 94
Preparation of ThienoF3,2-b1thiophene-2-carboxylic acid l(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl1 -butyl ) amide
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-carboxylic acid the title compound was prepared: MS(EI) 566 (M+H+).
b.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substuting 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 of Example 94a 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, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-7.5 (m, 6H), 7.7 (d, IH), 8.0-8.2 (m, 2H). MS(EI):
564 (MM 00%) . The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; 'HNMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (t, IH), 3.8 (d, IH). 4.0 (d, IH), 4,5 (m, IH), 4.7 (d, IH), 5.0 (m, IH), 7.4-7.5 (m, 6H), 7.7 (d, IH), 8.0-8.2 (m, 2H); MS(EI): 565 (M+H+,100%) and the slower eluting diastereomer; MS(EI):
565 (M+H+,100%).
Example 95
Preparation of Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl I amide
a.) Quinoxaline-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 quinoxaline-2- carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 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-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyLJ- butyl} amide of Example 95a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m,
IH), 7.4-7.5 (m, 2H), 7.9 (m, IH), 8.0-8.4 (m, 4H, 9.6 (d, IH); MS(EI): 554 (M+,100%) . The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 555 (M+H+,100%) and the slower eluting diastereomer; MS(EI):
555 (M+H+,100%).
Example 96
Preparation of Quinoline-2-carboxylic acid |(S)-3-methyl-l-F3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl I amide
a.) Quinoline-2-carboxylic acid { (S)-3-methy 1-1 -[3-hydroxy- 1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 85c except substituting quinoline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 555 (M+H+). b.) Quinoline-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 quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl Jamide 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, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.6 (m, 10H); MS(EI): 553 (M+,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 554 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 554 (M+HM00%).
Example 97
Preparation of Thiophene-3-carboxylic acid l(S)-3-methyl-l-F3-oxo-l-(l-oxy-pyridine-2- sul onylV azepan-4-ylcarbamoyri-bu-yl } 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-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide Following the procedure of Example li except substuting thiophene-3-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyljamide of Example 97a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH). 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 4H), 7.8 (m, IH), 8.1-8.2 (m, 2H); MS(EI): 508 (M\ 80%). Example 98
Preparation of lH-Indole-5-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamovn-butyl I amide
a.) lH-Indole-5-carboxylic acid { (S)-3-methyl-l- [3-hydroxy- 1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide
Following the 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 substuting 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
(CDCI3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H) , 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH),
4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 8.6 (b, IH); MS(EI):
541 (MM 00%) . The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 542 (M+H+,80%) and the slower eluting diastereomer; MS(EI): 542
(M+H+,80%).
Example 99
Preparation of BenzoFL3]dioxole-5-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl 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+). b.) Benzo[l,3]dioxole-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 substuting benzo[l,3]dioxole-5- carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide of Example 99a the title compound was prepared: Η NMR
(CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4.5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 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 eluting diastereoemer; MS(EI): 547 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 547 (M+H+,100%).
Example 100
Preparation of Furan-2-carboxylic acid j(S)-3-methyl-l-F3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-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 for benzo [b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 494 (M+).
b.) 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 substuting furan-2-carboxylic 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: !H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 492 (M 00%) ■ The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer MS(EI): 493 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 493 (M+H+,100%). Example 101
Preparation of (S)-4-Methyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid F3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-yl1-amide
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-acetic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared.
b.) (S)-4-Methyl-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- 1 -( 1 -oxy-pyridine-2-sulf onyl)- azepan-4-yl]-amide of
Example 101a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1
(m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, 3H); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0
(m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 522 (M\ 20%).
Example 102
Preparation of lH-Indole-2-carboxylic acid |(S)-3-methyl-l-F3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl } amide
a.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulf onyl)-azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example 85c except substituting lH-indole-2- carboxylic acid for benzo [b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 543 (M+).
b.) lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example li except substuting lH-indole-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl} amide of Example 102a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, lH),7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H), 9.4 (b, IH); MS(EI): 541 (MM 00%) . The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 542 (M+H+,100%) and the slower eluting diastereomer; MS(EI): 542 (M+H+,100%).
Example 103
Preparation of 4-Fluoro-{ (S)-3-methyl-l-F3-oxo-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4- carbamoyl] -butyl } -benzamide
a.) 4-Fluoro-{(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulphonyl)-azepan-4- carbamoyl]-butyl}-benzamide
Following the procedure of Example 85c except substituting 4-fluorobenzoic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 522 (M+).
b.) 4-Fluoro-{ (S)-3-methy 1-1 -[3-oxo- 1-(1 -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 of
Example 103a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, lH),7.4-8.0 (m, 6H), 8.1-8.2 (m, 2H); MS(EI): 520 (MM 00%) •
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 521 (M+H+, 100%) and the slower eluting diastereomer MS(EI):
521 (M+H+,100%). Example 104
Preparation of 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid |(S)-3-methyl-l- r3-oxo-(l-oxy-pyridine2-sulphonyl)-azepan-4-ylcarbamoyn-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-yl- ethyloxy)benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound 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-morpholin-4-yl- ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-(l-oxy-pyridine2- sulphonyl)-azepan-4-ylcarbamoyl]-buty} -amide of Example 104a the title compound was prepared: Η 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, IH), 4,5 (m, 3H), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 6H),
8.1-8.2 (m, 2H); MS(EI): 671 (MM 00%) • The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 672 (M+H+,100%) and the slower eluting diastereomer MS(EI):
672 (M+H+,100%).
Example 105
Preparation of Thiophene-2-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamovn-butyl } amide
a.) 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 thiophene-2- carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 510 (M+). b.) Thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example li except substuting thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyljamide of Example 105a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 508 (MM 00%) •
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereomer: MS(EI): 509 (M+H+,100%) and the slower eluting diastereomer MS(EI): 509 (M+H+,100%).
Example 106
Preparation of 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1 -butyl } 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-ylcarbamoyl]-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: Η NMR (CDClj): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 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 eluting diastereoemer: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (t, IH), 3.8 (d, IH); 4.1 (d, IH), 4,1 (m, IH), 4.7 (d, IH), 5.0 (m, IH), 7.0 (m, 2H), 7.3 (m, 2H), 7.4 (m, 4H), 8.1 (d, IH), 8.2 (d, IH); MS(EI): 557 (M+H+,100%) and the slower eluting diastereomer MS(EI): 557 (M+H+,100%).
Example 107
Preparation of 6-Methyl-N- ( (S)-3-methyl- 1 -F3-oxo- 1 -( 1 -oxy-pyridine-2-sulf onyl)-azepan-4- ylcarbamoyll-butyl }-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 acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 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- 1 -[3-hydroxy- 1 -( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } - nicotinamide Example 107a the title compound was prepared: : Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5
(t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 3H), 9.0 (m, IH); MS(EI):
517 (MM00%) •
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 518 (M+H+,100%) and the slower eluting diastereomer MS (El): 518 (M+H+,100%).
Example 108
Preparation of (S)-4-Methyl-2J2-thiophen-yl-acetylamino)-pentanoic acid-F3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yll-butyl } amide
a.) (S)-4-Methyl-2-(2-thiophen-yl-acetylamino)-pentanoic acid-[3-hydroxy- 1 -(pyridine- 2-sulfonyl)-azepan-4-yl] -butyl } amide
Following the procedure of Example 28b except substituting thiophene-2-acetic acid for benzofuran-2-carboxylic acid the title 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- sulf onyl)-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 title compound was prepared: MS(ESI) 506.8 (M+H+).
Example 109
Preparation of lH-Indole-6-carboxylic acid l(S)-3-methyl-l-F3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyπ-butyl 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 title compound was prepared: MS(EI) 527 (M+H+).
b.) lH-Indole-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-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyljamide of Example 109a the title compound was prepared: MS(EI) 525 (M+H+). Example 110
Preparation of BenzoF1.31dioxole-5-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamovH-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 for benzofuran-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- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example li except substuting benzo[l,3]dioxole-5- carboxylic acid { (S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide of Example 110a the title compound was prepared: MS(EI) 530.8 ( +H+).
Example 111
Preparation of 3,4-Dihydro-2H-benzoFb1FL41dioxepine-7-carboxylic acid |(S)-3-methyl-l- F3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl)amide
a.) 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3- hydroxy- 1 -( 1 -oxy-pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide Following the procedure of Example 85c except substituting 3,4-dihydro-2H-l,5- benzodioxepine-7-carboxylic acid for benzo [b]thiophene-2-carboxy lie acid the title compound 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] [1,4] dioxepine-7-carboxylic acid { (S)-3-methyl- 1 -[3-hydroxy- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example I l ia the title compound was prepared: *H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 4H), 2.5 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4.2 (m, 4H), 4,5*(t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 575 (M+H+,100%) .
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 575 (M+H+,100%) and the slower eluting diastereomer MS(EI): 575 (M+HM00%).
Example 112
Preparation of 5-Methyl-thiophene-2-carboxylic acid |(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}amide
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-ρyridine-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-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide of Example 112a the title compound was prepared: Η NMR
(CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.5 (d, 3H), 2.7 (m, IH), 3.8 (q, IH);
4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 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 eluting diastereoemer: MS(EI): 523 (M+H+,100%) and the slower eluting diastereomer MS(EI):
523 (M+H+,100%). Example 113
Preparation of 4.5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1~butyl } 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 compound was 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: Η NMR (CDCy: δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 3H), 8.1-8.2 (m, 2H); MS(EI): 665 (M+H+,100%) .
Example 114
Preparation of 3,5-Dimethyl-isoxazole-4-carboxylic acid |(S)-3-methyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl } 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-carboxylic acid the title compound was prepared: MS(EI) 524 (M+H+) . 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-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide of Example 114a the title compound was prepared: Η NMR (CDCL): 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, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 5H), 8.1-8.2 (m, 2H); MS(EI): 521 (M+,100%) .
Example 115
Preparation of (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acidFl-(4-mefhoxy- benzenesulfonyl)-3-oxo-azepan-4-yl1-amide
a.) {(S)-l-[3-Hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-ylcarbamoyl]-3- methyl-butylj-carbamic acid-tert-butyl ester •
[(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid-tert- butyl ester (compound 2g, 0.8 g, 2.33 mmol) was dissolved in 1,2-dichloroethane (DCE, 20 ml). Then, morpholinemethyl polystyrene resin beads (1.26 g, 3.1 mmol/g, Nova) were added and the solution was shaken for 5 minutes. Then, p-methoxybenzenesulfonyl chloride (0.48 g, 2.33 mmol) was dissolved in DCE (10 ml), and this solution was added to the reaction mixture. The reaction was shaken overnight, filtered, washed with DCE (2 x 10 ml), then CH2C12 (10 ml). The combined organics were concentrated in vacuo, and used in the next reaction without further purification: M+H+ = 514.2.
b.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- l-(4-methoxy-benzenesulfonyl)- azepan-4-yl]-amide-HCl salt
{(S)-l-[3-Hydroxy-l-(4-methoxy-benzenesulfonyl)-azepan-4-ylcarbamoyl]-3- methyl-butylj-carbamic acid-tert-butyl ester (compound 207a, 0.59 g, 1.15 mmol) was dissolved in CH2C12 (8 ml), then a solution of 4 M HCl in dioxane (8 ml) was added and the reaction 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 without further purification: M+H+ = 413.8. c.) (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy- 1 -(4- methoxy-benzenesulfonyl)-azepan-4-yl]-amide
(S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- 1 -(4-methoxy-benzenesulfonyl)- azepan-4-yl]-amide-HCl salt (crude product from reaction mixture of 115b) was dissolved in MeOH (10 ml) and was treated with carbonate-polystyrene resin beads (1.75 g, 2.63 mmol/g, 4.6 mmol) and was shaken for 2h, filtered, washed with MeOH (10 ml) and the combined organics were concentrated in vacuo. The product was then dissolved in DCE (2 ml) and morpholinemethyl polystyrene resin beads (0.25 g, 3.77 mmol/g, 0.91 mmol, Nova) were added and the reaction was shaken for 5 minutes. Then, benzylacetyl chloride (0.081 g, 0.44 mmol) was added and the reaction mixture was shaken overnight. Then, trisamine polystyrene beads (O.lg, 3.66 mmol/g, 0.366 mmol) was added and the reaction mixture was shaken for 1.5 h. The reaction mixture was then filtered, washed with DCE (2x10 ml) and CH2C12 (10 ml), and the combined organics were concentrated in vacuo. The crude 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-mefhoxy- benzenesulfonyl)-3-oxo-azepan- 4-yl]-amide
(S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy- 1 -(4- methoxy-benzenesulfonyl)-azepan-4-yl]-amide (compound 207c, 0.24 g, 0.44 mmol) was dissolved in CH2C12 (5 ml), then Dess-Martin periodinane (0.3 g, 0J mmol) was added and the reaction was stirred for 30 min. The reaction was diluted with CH2C12 (20 ml), then was extracted with aqueous 10% Na2S2O. (10 ml), then aqueous 10% NaHCO3 (10 ml), water (10 ml), brine (10 ml). The combined organics were concentrated in vacuo. The residue was purified by HPLC (50:50 Ethanol: hexanes, 20mL/min, 25min, WhelkO-l(R,R)
21x250mm column, UV detection at 280nm and 305nm) to yield the first elution as a white solid (47 mg, 43 %): MS 560.4 (M+H+).1H NMR (400Hz,CDCl3): δ 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) and second eluting diastereomer: MS 560.2 (M+H+). Example 116
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid |(S)-3-methyl-l-F3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl|amide
a.) 5-(3-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-(3-trifluoromethyl- phenyl)-furan-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared: MS(EI) 638 (M+).
b.) 5-(3-Trifluoromethyl-phenyl)-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 substuting 5-(3-trifluoromethyl- phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 116a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7
(m, IH), 3.8 (q, IH); 4.1 (m, IH), 4,1 (t, IH), 4.8 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 9H),
8.1-8.2 (m, 2H); MS(EI): 637 (M+H+,100%) . The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 637 (M+H+, 100%) and the slower eluting diastereomer MS(EI):
637 (M+H+, 100%) .
Example 117
Preparation of 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid j(S)-3-methyl-l-F3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
a.) 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
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: MS(EI) 585 (M+). 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: !H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, IH), 3.8 (q, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 7H), 8.1-8.2 (m, 2H); MS(EI): 584 (M+H+, 100%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS (El): 584 (M+H\ 100%) and the slower eluting diastereomer MS(EI): 584 (M+H+, 100%) .
Example 118
Preparation of Benzofuran-2-carboxylic acid {(S)-l-F l-(3,4-dimethoxy-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyn-butyl}-amide
a.) Benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-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) in dichloromethane was added triethylamine (0.1 mL) and 3,4-dimethoxybenzenesulfonyl chloride (0.12 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol :dicloromethane) 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-ylcarbamoyl] -butyl } -amide
Following the procedure of Example li except substuting benzofuran-2-carboxylic acid {(S)-l-[ l-(3,4-dimethoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}- amide of Example 118a the title compound was prepared: : JH NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, IH), 3.5 (d, IH); 3.7 (t, 6H), 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 8H); MS(EI): 586 (M+H+, 100%). Example 119
Preparation of Benzofuran-2-carboxylic acid {(S)-lTlJ4-bromo-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamovn-3-methyl-butyl)-amide
a.) Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-hydroxy- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example 118a except substituting 4- bromobenzenesulfonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the title compound was prepared: MS(EI) 606 (M+).
b.) Benzofuran-2-carboxylic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-oxo-azepan- 4-y lcarbamoyl] -3-methyl-butyl } -amide
Following the procedure of Example li except substituting benzofuran-2-carboxyIic acid {(S)-l-[l-(4-bromo-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl- butylj-amide of Example 119a the title compound was prepared: !H NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, IH), 3.5 (d, IH); 4.0 (m, IH), 4,5 (t, IH), 4.7 (m, IH), 5.0 (m, IH), 7.4-8.0 (m, 9H); MS(EI): 604 (M+, 100%).
Example 120
Preparation of Benzofuran-2-carboxylic acid f (S)-l-Fl-(benzoF1.2.51oxadiazole-4-sulfonyl)- 3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl } -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 was prepared: 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- ylcarbamoyl]-3-methyl-butyl}-amide of Example 120a the title compound was prepared: 'H NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.1 (m, 6H), 2.6 (m, IH), 3.7 (m, IH); 4.1 (m, IH), 4.1 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); MS(EI): 568 (M+H+, 100%).
Example 121
Preparation of Benzofuran-2-carboxylic acid |(S)-l-Fl-(3,5-dimethyl-oxazole-4 -sulfonyl)- 3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
a.) Benzofuran-2-carboxylic acid {(S)-l-[l-(3,5-dimethyl-oxazole-4 -sulfonyl)-3- hydroxy-azepan-4-y lcarbamoyl] -3-methyl-butyl } -amide
Following the procedure of Example 118a except substituting 3,5-dimethyloxazole-
4-sulphonyl chloride for 3,4-dimethoxybenzenesulfonyl chloride the title compound was prepared: 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-butyl}-amide of Example 121a the title compound was prepared:
'H NMR (CDCL): 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, IH), 4.1 (m, IH), 4.4 (t, IH), 4.7 (m, IH), 5.2 (m, IH), 7.4-8.0 (m, 5H); MS(EI): 544
(M\ 100%).
Example 122
Preparation of 3-Methylbenzofuran-2-carboxylic acid i(S)-3-methyl-l-r3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-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+). 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: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (d, 3H), 2.7 (m, IH), 3.8 (m, IH), 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 7H); 8.7 (m, IH); MS(EI): 540 (M+, 100%). The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: Η NMR (CDCl.): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.6 (s, 3H), 2.7 (m, IH), 3.8 (d, IH); 4.1 (d, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 7H); 8.7 (m, IH); MS(EI): 541 (M+H+,100%) and the slower eluting diastereomer MS(EI): 541 (M+H+, 100%) .
Example 123
Preparation of ThienoF3,2-blthiophene-2-carboxylic acid |(S)-3-methyl-l-F3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyllamide
a.) Thieno[3,2-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 substituting thieno [3,2- b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: 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-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide of Example 123a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (m, IH); MS(EI): 548 (M+, 100%). The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: 'HNMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H) 2.7 ( t, IH), 3.8 (d, IH); 4.1 (d, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (d, IH); MS(EI): 549 (M+tT,100%) and the slower eluting diastereomer MS(EI): 549 (M+HT, 100%) .
Example 124
Preparation of 5-tert-Butyl-3-methyl-thienoF3,2-b]thiophene-2-carboxylic acid l(S)-3- methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}amide
a.) 5-tert-Butyl-3-methyl-thieno[3,2-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 substituting 5-tert-butyl-3-methyl- thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 620 (M+).
b.) 5-tert-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-tert-butyl-3-methyl- thieno [3, 2-b]thiophene-2-carboxy lie acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 124a the title compound was prepared: Η NMR (CDCL): 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, IH), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 4H); 8.7 (m, IH); MS(EI): 618 (M+, 100%).
Example 125
Preparation of 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-F3-oxo-l- (pyridine-2-sulf onyl)-azepan-4-y lcarbamoyl] -butyl } amide
a.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l- (pyridine-2-sulf onyl)-azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example 28b except substituting 5-methyl-2-phenyl- oxazole-4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 569 (M+).
b.) 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-
2-sulf onyl)-azepan-4-y lcarbamoyl] -butyl } amide
Following the procedure of Example li except substituting 5-methyl-2-phenyl- oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide of Example 125a the title compound was prepared: Η NMR
(CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, IH), 2.6 (m, 3H), 3.8 (m, IH);
4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (m, IH); MS(EI): 567 (M+,
100%). The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 568 (M+H+,100%) and the slower eluting diastereomer MS(EI):
568 (M+H+,100%)
Example 126
Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-F3- oxo- 1 -(pyridine-2-sulf onyl)-azepan-4-ylcarbamoyll -butyl } 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-oxazoler4-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 623 (M+). 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-carboxylic acid {(S)-3-methyl-l-[3-hydrox-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 126a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.2 (m, 2H), 2.7 (m, IH), 3.8 (m, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.2 (m, IH), 7.4-8.0 (m, 8H); 8.7 (m, IH); MS(EI): 621 (M+, 100%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 622 (M+H+,100%) and the slower eluting diastereomer: MS(EI): 622 (M+HM00%).
Example 127
Preparation of Quinoline-2-carboxylic acid F(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl1-amide
Following the procedure of Example 75, except substituting methanesulfonyl chloride 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. First eluting diastereomer; MS (M+H+): 475.2; 1H-NMR (400 MHz, CDC13): • 8.65(d, IH), 8.35-8.28(q, 2H), 8.20-8.18(d, IH), 7.91-7.89(d, IH), 7.80-7J8(t, IH), 7.67-7.65(t, IH), 7.10(d, IH), 5.08(m, IH), 4J3 (m, IH), 4.56-4.5 l(d, IH), 4.00(m, IH), 3.67-3.62(d, IH), 2.91(s, 3H), 2J0(m, IH), 2.32-2.10(m, 2H), 1.95-1.40(m, 5H), 1.02-1.00(m, 6H); and the second eluting diastereomer: MS (M+H+): 475.2
Example 128
Preparation of l-Methyl-lH-indole-2-carboxylic acid F(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyn-amide
Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and N-methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 477.2; 1H-NMR (400 MHz, CDC13): • 7.65-7.63(d, IH), 7.39-7.33(m, 2H), 7.17-7.14(t, IH), 6.98-6.95(m, 2H), 6.65(d, IH), 5.08(m, IH), 4.68 (m, IH) 4.56-4.52(d, IH), 4.03(m, 4H), 3.67-3.63(d, IH), 2.92(s, 3H), 2Jl(m, IH), 2.32-2.10(m, 2H), 1.95-1.40(m, 5H), 1.02-1.00(d, 6H); and the second eluting diastereomer: MS (M+H+): 477.2
Example 129
Preparation of Furan-2-carboxylic acid IF(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butylcarbamoyl1 -methyl } -amide
Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and N-(2-furan-carbonyl)-glycine for benzofuran- 2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 471.2; -NMR (400 MHz, CDCI3): • 7.50(m, IH), 7.15(m, IH), 7.05(m, IH), 6.90(d, IH), 6.55(m, 2H), 5.08(m, IH), 4.55 (m, 2H), 4.12(m, 2H), 4.05(m, IH), 3J0(d, IH), 2.92(s, 3H), 2J5(m, IH), 2.20-1.40(m, 7H), 0.95 (m, 6H); and the second eluting diastereomer: MS (M+H+): 471.4.
Example 130
Preparation of 5-Methoxybenzofuran-2-carboxylic acid F(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl1-amide
Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and 5-mefhoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 494.2; 1H-NMR (400 MHz, CDCI3): 7.42-7.40(d, 2H), 7.08-6.94(m, 4H), 5.10(m, IH), 4Jl(m, IH), 4.56-4.52(d, IH), 4.02(m, IH), 3.86(s, 3H), 3.68-3.63(d, IH), 2.92(s, 3H), 2.72(m, IH), 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. Example 131
Preparation of Quinoxaline-2-carboxylic acid r(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide
Following the procedure of Example 75, except substituting methanesulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran- 2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 476.2; 1H-NMR (400 MHz, CDC13): • 9.66(s, IH), 8.38(d, IH), 8.20-8.18(m, 2H), 7.88(m, 2H), 7.01(d, IH), 5.10(m, IH), 4J7(m, IH), 4.57-4.52(d, IH), 4.08-4.00(m, IH), 3.69-3.64(d, IH), 2.92(s, 3H), 2Jl(m, IH), 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
Preparation of 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-F3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl } 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-chlorophenyl)-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: Η NMR
(CDC13): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.7 (d, IH), 4.0 (m, IH),
4.7 (m, 2H), 5.0 (m, IH), 6.7 (m, IH), 7.2 (m, IH), 7.3 (m, 2H), 7.5 (m, IH), 7.7 (m, 2H),
8.0 (m, 2H), 8.7 (m, IH); MS(EI): 587 (M+, 80%) 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%).
Example 133
Preparation of (S)-2-r2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid (1- methanesulfonyl-3-oxo-azepan-4-yl)~amide
Following the procedure of Example 75, except substituting 4- methanesulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 468.2; ΪH-NMR (400 MHz, CDC13): • 7.19-7.17(d, 2H), 6.90-6.88(d, 3H), 5.83-5.81(d, IH), 5.00(m, IH), 4.53-4.40(m, 2H), 4.03- 3.99(m, IH), 3.81(s, 3H), 3.66-3.61(d, IH), 3.53(s, 2H), 2.91(s, 3H), 2.73(t, IH), 2.22- 2.10(m, 2H), 1.99( m, IH), 1.62-1.35(m, 4H), 0.90-0.88(d, 6H); and the second eluting diastereomer: MS (M+H+): 468.2.
Example 134
Preparation of Ouinoline-2-carboxylic acid I F(S)-l-Fl-(2-cyano-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl] -3-methyl-butyl ) -amide
Following the procedure of Example 75, except substituting 2- cyanobenzenesulfonyl chloride for thiazole-2-sulfonyl chloride and quinoline-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 562.2; ΪH-NMR (400 MHz, CDCI3): • 8.65(d, IH), 8.48-8.40(q, 2H), 8.25-8.10(q, 2H), 7.91-7.65(m, 6H); and the second eluting diastereomer:, 7.12(d, IH), 5.10(m, IH), 4.73 (m, IH) 4,61-4.56(d, lH),4.20(m, lH),3.73-3.68(d, IH), 2.80(m, IH), 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. Example 135
Preparation of 1-Methyl-lH-indole -2-carboxylic acid IF(S)-l-Fl-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyn-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 2- cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-mefhylindole-2- carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 564.2; 1H-NMR (400 MHz, CDC13): • 8.13(d, IH), 7.89(d, IH), 7.77-7.67(m, 3H), 7.38-7.16(m, 4H), 6.97(s, IH), 6.70(d, IH), 5.05(m, IH), 4.70-4.60 (m, IH), 4.55-4.50(d, IH), 4.07(m, IH), 4.05(s, 3H), 3.76-3.71(d, IH), 2.75(m, IH), 2.30(m, 2H), 2.00-1.45(m, 5H), 1.00(d, 6H); and the second eluting diastereomer: MS (M+H+) 564.2.
Example 136
Preparation of Furan-2-carboxylic acid ({(S)-l-Fl-(2-cyano-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl1-3-methyl-butylcarbamoyl}-methyl)-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 residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 558.2; H-NMR (400 MHz, CDCI3): • 8.14-8.12(d, IH), 7.91-7.90(d, IH), 7.80-7 J2(m, 2H), 7.48(s, IH), 7.14(d, 2H), 6.98(d, IH), 6.80(d, IH), 6.52-6.5 l(t, IH), 5.03(m, IH), 4.60-4.53 (m, 2H), 4.17-
4.14(m, 3H), 3J4-3.69(d, IH), 2.80(m, IH), 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.
Example 137
Preparation of 5-Methoxybenzofuran-2-carboxylic acid l(S)-l-Fl-(2-cyano- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 2- cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-mefhoxybenzofuran-2- carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 581.4; 1H-NMR (400 MHz, CDC13): • 8.15-8.13(d, IH), 7.92-7.90(d, IH), 7.81-7J4(m, 2H), 7.42-7.40(m, 2H), 7.08-7.03(m, 3H), 6.96(d, IH), 5.10(m, IH), 4J2-4.60 (m, 2H), 4.17 (d, IH), 3.85(s, 3H), 3J5-3J0(d, IH), 2.83-2J6(t, IH), 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.
Example 138
Preparation of Quinoxaline-2-carboxylic acid {(S)-l-ri-(2-cyano-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamovH-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 2- cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 563.2; ΪH-NMR (400 MHz, CDCI3): • 9.65(s, IH), 8.40(m, IH), 8.22-8.10(m, 3H), 7.90-7.22(m, 5H), 7.00(d, IH), 5.10(m, IH), 4J5(m, IH), 4.65-4.60(d, IH), 4.20-4.10(m, IH), 3J2-3J0(d, IH), 2J0(m, IH), 2.38(m, 2H), 1.95-1.40(m, 5H), 1.02(d, 6H); and the second eluting diastereomer: MS (M+H+) 563.2.
Example 139
Preparation of (S)-2-F2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid Fl-(2- cvano-benzenesulfonyl)-3-oxo-azepan-4-yll-amide
Following the procedure of Example 75, except substituting 2-cyanophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)-acetic 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; XH-NMR (400 MHz, CDC13): • 8.14-8.12(d, IH), 7.91-7.89(d, IH), 7J9-7J3(m, 2H), 7.19-7.17(d, 2H), 6.90-6.88(d, 3H), 5.80(d, IH), 5.02(m, IH), 4.59-4.55(d, IH), 4.45-4.42(m, IH), 4.18-4.15(m, IH), 3.82(s, 3H), 3J2-3.67(d, IH), 3.53(s, 2H), 2.82-2J9(t, IH), 2.22(m, 2H), 1.92( m, IH), 1.60- 1.30(m, 4H), 0.91-0.89(d, 6H); and the second eluting diastereomer. MS (M+H+) 555.2.
Example 140
Preparation of Quinoline-2-carboxylic acid { F(S)-l-Fl-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 4- methoxybenzenesulfonyl chloride 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. First eluting diastereomer; MS (M+H+): 567.2; H-NMR (400 MHz, CDCI3): • 8J2-8.61(d, IH), 8.35-8.28(q, 2H) 8.21-8.18(d, IH), 7.91-7.60(m, 5H), 7.10-6.99(m, 3H), 5.05(m, IH), 4J3 (m, IH) 4,59-4.52(d, lH),4.00(m, IH), 3.88(s, 3H), 3.45-3.38(d, IH), 2.42(m, IH), 2.30-1.35 (m, 7H), 1.03-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+) 567.2.
Example 141
Preparation of l-Methyl-lH-indole-2-carboxylic acid (F(S)-l-Fl-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 4- methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and N-methyl-indole-2- carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 569.2; 1H-NMR (400 MHz, CDC13): • 7.78-7.72(d, 2H), 7J0-7.65(d, IH), 7.42-7.30(m, 2H), 7.17-7.14(t, IH), 7.05-6.95(m, 4H), 6.65(d, IH), 5.05(m, IH), 4J0-4.50 (m, 2H), 4.03(s, 3H), 3.88(s, 3H), 3.45-3.40(d, IH), 2.45(m, IH), 2.30-2.10(m, 2H), 1.90-1.35(m, 6H); and the second eluting diastereomer:, 1.00(d, 6H); and the second eluting diastereomer: MS (M+H+) 569.2.
Example 142
Preparation of Furan-2-carboxylic acid (|(S)-l-Fl-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butylcarbamoyl } -methvD-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-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 563.2; ^-NMR (400 MHz, CDCI3): • 7.74-7.72(d, 2H), 7.47 (s, IH), 7.15-6.99(m, 4H), 6.91(d, IH), 6J0(d, IH), 6.52-6.51(m, IH), 5.01(m, IH), 4.53-4.49 (m, 2H), 4.17-4.14(m, 2H), 4.00-3.90(m, IH), 3.88(s, 3H), 3.45-3.41(d, IH), 2.47(m, IH), 2.17(m, 2H), 1.85-1.40(m, 5H), 0.95(m, 6H); and the second eluting diastereomer: MS (M+H+) 563.2. Example 143
Preparation of 5-Mexhoxybenzofuran-2-carboxylic acid f F(S)-l-Fl-(4-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-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 compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 586.2; 1H-NMR (400 MHz, CDCI3): • 7J5-7J3(d, 2H), 7.42-7.40(m, 2H), 7.08- 6.99(m, 5H), 6.91(d, IH), 5.05(m, IH), 4J0-4.55(m, 2H), 4.05-4.00(m, IH), 3.89(s, 3H), 3.86(s, 3H), 3.45-3.40(d, IH), 2.50-2.40(m, IH), 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
Preparation of Ouinoxaline-2-carboxylic acid F F(S)-l-Fl-(4-methoxy-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 4- methoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and quinoxaline-2- carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 568.2; 1H-NMR (400 MHz, CDCI3): • 9.66(s. IH), 8.40-8.35(m, IH), 8.19(m, 2H), 7.88(m, 2H), 7.75- 7.73(d, 2H), 7.02-6.90(m, 3H), 5.10-5.05(m, IH), 4J5(m, IH), 4.60-4.55(d, IH), 4.05- 3.95(m, IH), 3.89(s, 3H), 3.45-3.41(d, IH), 2.45(m, IH), 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.
Example 145
Preparation of (S)-2-F2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid Fl-(4- methoxy-benzenesulfonyl)-3-oxo-azepan-4-vn-amide
Following the procedure of Example 75, except substituting 4- mefhoxyphenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 2-(4-methoxyphenyl)- acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 560.4; 1H-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, IH), 5.8 l(d, IH), 4.99(m, IH), 4.55-4.44(m, 2H), 3.97(m, IH), 3.88(s, 3H), 3.81(s, 3H), 3.53(s, 2H), 3.43-3.38(d, IH), 2.43(t, IH), 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
Preparation of 1 -Methyl- lH-indole-2-carboχylic acid IF(S)-l-Fl-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl|-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. The residue 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, IH), 7.40-7.14(m, 5H), 6.95(m, 2H), 6.65-6.63(d, IH), 5.07(m, IH), 4.68-4.55 (m, 2H), 4.04(s, 3H), 3.48-3.43(d, IH), 2.49(m, IH), 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.
Example 147
Preparation of Furan-2-carboxylic acid ({(S)-l-Fl-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butylcarbamoyl}-methyl)-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 residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 551.4; XH-NMR (400 MHz, CDC13): 7.81(m, 2H), 7.48(s, IH), 7.27-7.16(m, 3H), 7.05(m, IH), 6.90(d, IH),
6.52(m, 2H), 5.00(m, IH), 4.60-4.48 (m, 2H), 4.14(m, 2H), 4.00-3.90(d, IH), 3.48-3.44(d, IH), 2.50(m, IH), 2.20(m, 2H), 1.90-1.40(m, 5H), 0.95(m, 6H); and the second eluting diastereomer: MS (M+H+) 551.2.
Example 148
Preparation of 5-Methoxybenzofuran-2-carboxylic acid IF(S)-l-Fl-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 4- fluorophenylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5-mefhoxybenzofuran-2- carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 574.2; 1 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, 3H), 6.93(d, IH), 5.10-5.02(m, IH), 4.69-4.55(m, 2H), 4.05-4.00(m, IH), 3.86(s, 3H), 3.47- 3.43(d, IH), 2.49(m, IH), 2.24(m, 2H), 1.90-1.40(m, 5H), 1.01(m, 6H); and the second eluting diastereomer: MS (M+H+): 574.2
Example 149
Preparation of Ouinoxaline-2-carboxylic acid IF(S)-l-Fl-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyll-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 title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 556.2; iH-NMR (400 MHz, CDC13): • 9.66(s, IH), 8.40-8.35(d, IH), 8.21-8.18(m, 2H), 7.90-7.81(m, 4H), 7.27-7.22(m, 2H), 6.97(d, IH), 5.10-5.02(m, IH), 4J5(m, IH), 4.59-4.55(d, IH), 4.05- 4.39(m, IH), 3.48-3.44(d, IH), 2.49(m, IH), 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
Preparation of (S)-2-F2-(4-Methoxy-phenyl)-acetylamino)-4-methyl-pentanoic acid Fl-(4- fluoro-benzenesulfonyl)-3-oxo-azepan-4-yll-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 title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 548.2; ΪH-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, IH), 4.98(m, IH), 4.55-4.43(m, 2H), 4.00-3.97(m, IH), 3.81(s, 3H), 3.53(s, 2H), 3.45-3.41(d, IH), 2.48(t, IH), 2.17-2.14(m, 2H), 1.90-1.30(m, 5H), 0.90-0.88(d, 6H); and the second eluting diastereomer: MS (M+H+): 548.4.
Example 151
Preparation of Benzofuran-2-carboxylic acid-f (S)-l-ri-(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyn-3-mefhyl-butyl|-amide
a.) {(S)-l-[l-(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl- butylj-carbamic acid tert-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, 8J5mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated 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- azepan-4-yl]-amide
To a stirring solution of the compound of Example 151a (l.Og, 1.93mmol) in methnol (10 ml) was added HCl (4M in Dioxane) (10 ml). After stirring at room temperature for 3 hr the solution was concentrated to provide a white solid. To a solution of the white solid (0.68 g, 1.50 mmol, 78%) in methnol (37 ml) was added P-CO3 (2.85g, 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-carboxylic acid-{ (S)-l-[l-(3-chloro-benzenesulphonyl)-3-hydroxy- azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide To a solution of the compound of Example 151b (0.14 g, 0.33 mmol) in CH2C12 (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 CH2C12 (10 mL) . After shaking at room temperature overnight, 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 compound as a white solid (122 mg, 65%). MS (ESI): 562.2 (M+H)+. d.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-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). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous layer was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (62.7 mg, 51.6 %), MS (ESI): 560.2 (M+H)+ and the second eluting diastereomer as a white solid (40.2 mg, 33.1 %). MS (ESI): 560.2 (M+H)+
Example 152
Preparation of 5-Methoxybenzofuran-2-carboxylic acid-l(S)-l-Fl-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 151c-d, except substituting 5- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (64.4 mg, 50.3%): MS (ESI): 590.2 (M+H)+ and the second eluting distereomer as a white solid (44.4 mg, 34.7%): MS (ESI): 590.2 (M+H)+
Example 153
Preparation of 7-Methoxybenzofuran-2-carboxylic acid-j(S)-l-Fl-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl)-amide
Following the procedure of Example 151c-d except substituting 7- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151c provided the title compound which was separated by HPLC to give first eluting diastereomer as a white solid (51.1mg, 39.9%), MS (ESI): 590.2 (M+H)+ and the second eluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 590.2 (M+H)+ Example 154
Preparation of 5,6-Dimethoxybenzofuran-2-carboxylic acid-{(S)-l-Fl-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
Following the procedure of Example 151c-d except substituting 5,6- dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid of Example 151c provided the title compound which was separated by HPLC to give first eluting diastereomer as a white solid (51.1mg, 39.9%), MS (ESI): 622.2 (M+H)+ and the second eluting diastereomer as a white solid (36.7 mg, 28.7%): MS (ESI): 622.2 (M+H)+
Example 155
Preparation of 3-Methylbenzofuran~2-carboxylic acid-((S)-l-Fl-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl}-amide
Following the procedure of Example 151c-d except substituting 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 151c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (78.6mg, 63.1%), MS (ESI): 574.2 (M+H)+ and the second eluting diastereomer as a white solid (40.7mg, 32.6%). MS (ESI): 574.2 (M+H)+
Example 156
Preparation of BenzoFblthiophene-2-carboxylic acid-|(S)-l-Fl-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 151c-d except substituting benzo[b]thiophene-
2-carboxylic acid for benzofuran-2-carboxylic acid in step 151c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (41.0 mg, 32.8%), MS (ESI): 576.2 (M+H)+ and the second eluting diastereomer as a white solid (31.0 mg, 24.8%). MS (ESI): 576.4 (M+H)+ Example 157
Preparation of l-Methyl-lH-indole-2-carboxylic acid-l(S)-l-Fl-(3-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-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 compound which was separated by HPLC to give the first eluting diastereomer as a white solid (28.5 mg, 22.9%), MS (ESI): 573.2 (M+H)+ and the second eluting diastereomer as a white solid (28.5mg, 22.9%). MS (ESI): 573.2 (M+H)+
Example 158
Preparation of Quinoxaline-2-carboxylic acid-{(S)-l-Fl-(3-chloro-benzenesulphonyl)-3- oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-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 compound which was separated by HPLC to give the first eluting diastereomer as a white solid (63.1 mg, 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
Preparation of Benzofuran-2-carboxylic acid-{(S)-l-Fl-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
a.) {(S)-l-[l-(2-Fluoro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyI]-3-methyl- butylj-carbamic acid tert-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 lchloride (0.70 g, 3.60 mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate 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- azepan-4-yl] -amide
To a stirring solution of the compound of Example 159a (1.13 g, 2.25 mmol) in methnol (15 ml) was added HCl (4M in dioxane) (15 ml). After stirring at room temperature for 3 hr, the solution was concentrated to get white solid. To a solution of the white solid (1.11 g, 2.60 mmol, 75%) in methnol (50 ml) was added P-CO3 (5J0 g, 2.63 mmol/g). After shaking for 2hr, the solution was filtered and concentrated to yield the title compound as white solid (0.868g, 2.16mmol, 96%): MS: 401.96 (M+H)+.
c .) B enzofuran-2-carboxylic acid- { (S)- 1 - [ 1 -(2-fluoro-benzenesulphonyl)-3-hy droxy- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide To a solution of the compound of Example 159b (0.11 g, 0.26 mmol) in CH2C12 (10 mL) was added benzofuran-2-carboxylic acid (64.7 mg, 0.39 mmol), 1- hydroxybenzotriazole (61. lg, 0.45 mmol), and P-EDC (0.53 g, 1 mmol/g) in CH2C12 (10 mL). After shaking at room temperature overnight, the solution was treated with tisamine (0.35 g, 3J5 mmol/g). After shaking for another 2 hr, the solution was filtered and concentrated to yield the title compound as a white solid (103.5 mg, 70%): MS (ESI) 546.2 (M+H)+.
d.) Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide 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 (164J mg, 0.39 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (76.2 mg, 73.6 %): MS (ESI) 544.2 (M+H)+ and the second eluting diastereomer as a white solid (20Jmg, 20.0%) MS (ESI) 544.4 (M+H)+ Example 160
Preparation of 5-Mefhoxybenzofuran-2-carboxylic acid-l(S)-l-Fl-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
Following the procedure of Example 159c-d, except substituting 5- methoxybenzofuran-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 as a white solid (48.3 mg, 59.2%) MS (ESI): 574.2 (M+H)+ and the second eluting diastereomer as a white solid (24.2mg, 29.6%) MS (ESI): 574.2 (M+H)+
Example 161
Preparation of 7-Mefhoxybenzofuran-2-carboxylic acid-f (S)-l-Fl-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
Following the procedure of Example 159c-d except substituting 7- methoxybenzofuran-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 as a white solid (47.7 mg, 58.5%): MS (ESI) 574.2 (M+H)+ and the second eluting diastereomer as a white solid (27.7 mg, 33.9%).
Example 162
Preparation of 5,6-Dimethoxybenzofuran-2-carboxylic acid-f (S)-l-Fl-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamovH -3-methyl-butyl } -amide
Following the procedure of Example 159c-d except substituting 5,6- dimethoxybenzofuran-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+). Example 163
Preparation of 3-Methylbenzofuran-2-carboxylic acid-f (SY l-riJ2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1 -3-methyl-butyl } -amide
Following the procedure of Example 159c-d except substituting 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 160c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (50.5 mg, 63J%): MS (ESI) 558.2 and the second elutinfg diastereoemer as a white solid (20.6 mg); MS 558.2 (M+H)+.
Example 164
Preparation of BenzoFblthiophene-2-carboxylic acid-f (S)-l-F l-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-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 title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (52.5 mg, 65.9%): MS (ESI) 560.2 (M+H)+ and the second eluting diastereomer as a white solid (20.7mg, 26.0%): MS(ESI) 560.2 (M+H)+.
Example 165
Preparation of l-Methyl-lH-indole-2-carboxylic acid-f (S)-l-ri-(2-fluoro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 159c-d except substituting 1 -methy lindole-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 as a white solid (51.4 mg, 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)+. Example 166 Preparation of (S)-4-Methyl-2-(l-oxy-pyridine-2-sulfonylamino)-pentanoic acid [3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yll-amide
a.) (S)-4-Methyl-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 (10 mL) and saturated NaHCO3 was added 2-pryridinesulfonyl chloride N-oxide (0.9 mL) in a dropwise fashion over 3 minutes. The reaction was stirred at room temperature for 30 minutes. Workup and columnn chromatography provided 9.2 mg of the title compound: MS (ESI) 541 (M+H*).
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 of Example 166a the title compound was prepared: MS (ESI) 539 (M+H+).
Example 167
Preparation of Quinoxaline-2-carboxylic acid-f fS)-l-Fl-(2-fluoro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyl}-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 compound which was purified by HPLC to give the first eluting diastereomer as a white solid (49.7 mg, 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 Preparation of 5-Mefhoxybenzofuran-2-carboxyric acid-f (S)-3-methyl-l-F3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl}-amide
Following the procedure of Example 75a-d except substituting 2-thiophensulfonyl chloride for 2-thiazolesupfonyl chloride of Example 75 a and 5-methoxybenzofuran-2- carboxylic acid for benzofuran-2-carboxylic acid in step 75c provided the title compound which was purified by HPLC to give the first eluting diastereomer as a white solid (71 mg, 65%): MS (ESI) 562.2 (M+H)+ and the second eluting diastereomer as a white solid (21.6 mg, 20.0%) MS (ESI): 562.2 (M+H)+.
Example 169 Preparation of 7-Methoxybenzofuran-2-carboxylic acid-f (S)-3-methyl-l-F3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl}-amide
Following the procedure of Example 168 except substituting 7- methoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which ws purified by HPLC to give the first eluting diastereomer as a white solid (88 mg, 80%): MS (ESI) 562.2 (M+H)+ and the second eluting diastereomer as a white solid (18 mg, 16%) MS (ESI): 562.2 (M+H)+.
Example 170 Preparation of 5,6-Dimethoxybenzofuran-2-carboxylic acid-f (S)-3-methyl-l-r3-oxo-l- (thiophene-2-sulfonyl)-azepan-4-ylcarbamovn-butyl}-amide
Following the procedure of Example 168 except substituting 5,6- dimethoxybenzofuran-2-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was purified by HPLC to give the first eluting diastereomer MS (ESI) 594.2 (M+H)+ and the second eluting diastereomer.
Example 171
Preparation of 3-Methylbenzofuran-2-carboxylic acid-f (S)-3-methyl-l-F3-oxo-l-(thiophene- 2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-amide
Following the procedure of Example 168 except substituting 3-methybenzofuran-2- carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which 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 (16 mg, 15%): MS (ESI) 546.2 (M+H)+. Example 172 Preparation of BenzoFb]thiophene-2-carboxylic acid-f fS)-3-methyl-l-F3-oxo-l-(thiophene- 2-sulfonyl)-azepan-4-ylcarbamovn-butyll-amide
Following the procedure of Example 168 except substituting benzo[b]thiophene-2- carboxylic acid 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was 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 (33.4 mg, 31.5%): MS (ESI) 548.2 (M+H)+
Example 173 Preparation of 1 -Methyl- lH-indole-2-carboxylic acid-f (S)-3-methyl-l-F3-oxo-l-(thiophene- 2-sulfonyl)-azepan-4-ylcarbamovn-butyll-amide
Following the procedure of Example 168 except substituting 1 -methy lindole-2- carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (35.8 mg, 34.0%): MS (ESI) 545.2 (M+H)+ and the second eluting diastereomer as a white solid (45.8 mg, 43%): MS (ESI) 545.2 (M+H)+.
Example 174 Preparation of Quinoxaline-2-carboxylic acid-f (S)-3-methyl-l-F3-oxo-l-(thiophene-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-amide
Following the procedure of Example 168 except substituting quinoxaline-2- carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (60 mg, 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)+. Example 175
Preparation of Benzofuran-2-carboxylic acid-f (S)-l-ri-(4-chloro-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoylT3-methyl-butyl 1 -amide
a.) f (S)-l-[l-(3-Chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl- butylj-carbamic acid tert-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, 8J5mmol). After shaking at room temperature for over night, the solution was filtered. The filtrate was concentrated 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- azepan-4-yl]-amide
To a stirring solution of the compound of example 175a (1.0 g, 1.93mmol) in methnol (10 ml) was added HCl (4M in dioxane) (10 ml). After stirring at room temperature for 3 hr, the solution was concentrated to provide a white solid. To a solution of the white solid (0.68 g, 1.50 mmol, 78%) in methnol (37 ml) was added P-CO3 (2.85 g, 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-ylcarbamoyl]-3-methyl-butyl}-amide To a solution of the compound of Example 175b (0.14 g, 0.335 mmol) in CH2C12
(20 mL) was added benzofuran-2-carboxylic acid (0.81, 0.50 mmol), 1- hydroxybenzotriazole (0J7g, 0.569mmol), and P-EDC (0.67g, lmmol/g) in CH2C12 (10 mL) . After shaking at room temperature overnight, the solution was treated with tisamine (0.446 g, 3.75 mmol/g). After shaking for another 2 hr, the solution was filtered and concentrated to yield the title compound as a white solid (122.2 mg, 65%). MS (ESI): 562.2 (M+H)+. d.) B enzofuran-2-carboxy lie acid- { (S)- 1 - [ 1 -(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) in dichloromethane (4 mL) was added Dess-Martin reagent (184.8mg, 0.436mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (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
Preparation of 5-Methoxybenzofuran-2-carboxylic acid-f (S)-l-FlJ4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 175c-d except substituting 5- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (64.4 mg, 50%): MS (ESI) 590.2 (M+H)+ and the second eluting diastereoemer as a white solid (32.2 mg, 25.2%): MS (ESI) 590.0 (M+H)+.
Example 177
Preparation of 7-Methoxybenzofuran-2-carboxylic acid-f (S)-l-Fl-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butvπ-amide
Following the procedure of Example 175c-d except substituting 1- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (51.1 mg, 40%): MS (ESI) 590.2 (M+H)+ and the second eluting diastereoemer as a white solid (41 mg, 32%): MS (ESI) 590.2 (M+H)+. Example 178
Preparation of 5.6-Dimethoxybenzofuran-2-carboxylic acid-f (S)-l-Fl-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyn-3-methyl-butyl}-amide
Following the procedure of Example 175c-d except substituting 5,6- dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MS (ESI) 622.2 (M+H)+ and the second eluting diastereoemer: MS (ESI) 622.2 (M+H)+.
Example 179
Preparation of 3-Methylbenzofuran-2-carboxylic acid-f (S)-l-Fl-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example 175c-d except substituting 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (78.6 mg, 63%): MS (ESI) 574.2 (M+H)+ and the second eluting diastereoemer as a white solid (27.6 mg, 22%): MS (ESI) 574.2 (M+H)+.
Example 180
Preparation of BenzoFblfhiophene-2-carboxylic acid-f (S)-l-Fl-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyll-amide
Following the procedure of Example 175c-d except substituting benzo[b]thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid in step 175c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (41 mg, 33%): MS (ESI) 576.2 (M+H)+ and the second eluting diastereoemer as a white solid (32.6 mg, 26%): MS (ESI) 576.2 (M+H)+. Example 181
Preparation of l-Methyl-lH-indole-2-carboxylic acid-f (S)-l-fl-(4-chloro- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
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 compound which was separated by HPLC to give the first eluting diastereomer as a white solid (28.5 mg, 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
Preparation of Quinoxaline-2-carboxylic acid-f (S)-l-f l-(4-chloro-benzenesurphonyl)-3- oxo-azepan-4-y lcarbamoyl] -3-methyl-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 compound which was separated by HPLC to give the first eluting diastereomer as a white solid (63 mg, 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
Preparation of Benzofuran-2-carboxylic acid-f (S)-l-ri-(3-methoxy-benzenesulphonyl)-3- oxo-azepan-4-ylcarbamovn-3-methyl-butyl } -amide
a.) f(S)-l-[l-(3-Methoxy-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3- methyl-butyl }-carbamic acid tert-butyl ester
To a solution of the compound of Example 2g (1.60g, 4.66mmol) 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 temperature for over night, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (lJOg, 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, 3.31mmol) in methnol (22 ml) was added HCl (4M in dioxane) (22 ml). After stirring at room temperature for 3 hr, the solution was concentrated to get white solid. To a solution of the white solid (1.19 g, 2.64 mmol, 80%) in methnol (50 ml) was added P-CO3 (5.02 g, 2.63 mmol/g). After shaking for 2 hr the solution was filtered and concentrated to yield the title compound as white solid (1.03 g, 2.49 mmol, 96%): MS 413.90 (M+H)+.
c.) Benzofuran-2-carboxylic acid-f (S)-l-[l-(3-methoxy-benzenesulphonyl)-3- hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide To a solution of the compound of Example 183b (0.11 g, 0.26 mmol) in CH2C12 (10 mL) was added benzofuran-2-carboxylic acid (64.69mg, 0.399 mmol), 1- hydroxybenzotriazole (61.1g, 0.452mmol), and P-EDC (0.532g, 1 mmol g) in CH2C12 (10 mL) . After shaking at room temperature for over night, the solution was treated with tisamine (0.355g, 3J5mmol/g). After shaking for another 2hr, the solution was filtered and concentrated to yield the title compound as a white solid (103.5 mg, 70%): MS (ESI) 558.2 (M+H)+.
d.) Benzofuran-2-carboxylic acid-f (S)-l-[l-(3-methoxy-benzenesulphonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide To a stirring solution of the compound of Example 183c (103 mg, 0.19 mmol) in dichloromethane (4 mL) was added Dess-Martin reagent (157 mg, 0.37 mmol). After stirring at room temperature for 2 h, solutions of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) were added simultaneously to the solution. The aqueous was extracted with dichloromethane (2x). The organic phases were combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by HPLC to yield the first eluting diastereomer as a white solid (76.2 mg, 73.6 %): MS (ESI: 556.2 (M+H)+ and the second eluting diastereomer as a white solid (24.1 mg, 23.3 %): MS (ESI) 556.2 (M+H)+ Example 184
Preparation of 5-Methoxybenzofuran-2-carboxylic acid-f (S)-l-ri-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl)-amide
Following the procedure of Example 183c-d except substituting 5- methoxybenzofur-m-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (33 mg, 31%): MS (ESI) 586.2 (M+H)+ and the second eluting diastereoemer as a white solid (35.2 mg, 32%): MS (ESI) 586.2 (M+H)+.
Example 185
Preparation of 7-Methoxybenzofuran-2-carboxylic acid-f (S)-l-Fl-(3-methoxy- benzenesulphonyD-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
Following the procedure of Example 183c-d except substituting 7- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (41 mg, 38%): MS (ESI) 586.4 (M+H)+ and the second eluting diastereoemer as a white solid (39.5 mg, 36%): MS (ESI) 586.2 (M+H)+.
Example 186
Preparation of 4,5-Dimefhoxybenzofuran-2-carboxylic acid-f (S)-l-F l-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-y lcarbamoyl] -3-methyl-butyl } -amide
Following the procedure of Example 183c-d except substituting 5,6- dimethoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer: MS (ESI) 618.4 (M+H)+ and the second eluting diastereoemer. Example 187
Preparation of 3-Methylbenzofuran-2-carboxylic acid-f (S)-l-Fl-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyn-3-methyl-butyl}-amide
Following the procedure of Example 183c-d except substituting 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (76 mg, 72%): MS (ESI) 570.2 (M+H)+ and the second eluting diastereoemer as a white solid (23.2 mg, 22%): MS (ESI) 570.2 (M+H)+.
Example 188
Preparation of Benzorblthiophene-2-carboxylic acid-f (S)-l-Fl-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4~ylcarbamoyl]-3-methyl-butyl}-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 title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (37 mg, 35%): MS (ESI) 572.2 (M+H)+ and the second eluting diastereoemer as a white solid (31 mg, 29%): MS (ESI) 572.2 (M+H)+.
Example 189
Preparation of l-Methyl-lH-indole-2-carboxylic acid-f (S)-l-Fl-(3-methoxy- benzenesulphonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyI}-amide
Following the procedure of Example 183c-d except substituting 1 -methy lindole-2- carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (34 mg, 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)+. Example 190
Preparation of Ouinoxaline-f (S)-l-f l-(3-methoxy-benzenesulphonyl)-3-oxo-azepan-4- ylcarbamovn-3-methyl-butyl}-amide
Following the procedure of Example 183c-d except substituting quinoxaline-2- carboxylic acid for benzofuran-2-carboxylic acid in step 183c provided the title compound which was separated by HPLC to give the first eluting diastereomer as a white solid (71 mg, 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
Preparation of Benzofuran-2-carboxylic acid-f (S)-3-methyl-l-F3-oxo-l-(thiophene-2- sulfonyl)-azepan-4-ylcarbamovn-butyl } -amide
Following the procedure of Example 168 except substituting benzofuran-2- carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid provided the title compound which 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 (25 mg, 23%) MS (ESI): 532.2 (M+H)+.
Example 192
Preparation of Benzofuran-2-carboxylic acid f(S)-3-methyl-l-F(2.2',4-trideuterio)-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-y lcarbamoyl! -butyl } amide
To a solution of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide of Example 28c (0.03 g) in D2O:CD3OD (0.4:4 mL) was added triethylamine (0.04 mL). The reaction was heated to reflux for 2 hours whereupon it was concentrated and dried under vacuum. The residue was the redissolved in the same mixture and heated to reflux overnight. The reaction was concentrated and the residue purified by column chromatography (5% methanoLdichloromethane) to provide the title compound (0.02 g): 'HNMR: δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 4.1 (m, IH), 4.7 (m, 2H), 7.4-8.0 (m, 8H), 8.7 (m, IH); MS(EI): 529 (M+, 45%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 530 (M+H+,100%) and the slower eluting diastereomer: MS(EI): 530 (M+H\100%).
Example 193
Preparation of Benzofuran-2-carboxylic acid f (S)-2-methyl-l-F3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyn -butyl I -amide
a.) 4-tert-Butoxycarbonylamino-3-hydroxy-azepane-l-carboxylicacid benzyl ester
To a stirring solution of compound of Example 2e (1.04 g, 3.92mmol) in THF was added di-tert-butyldicarbonate (0.864 g). After stirring at room temperature for 30 minutes, the reaction mixture was diluted with diethylether and extracted with saturated NaHCO. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column to give the title compound as a yellow oil (0.963 g, 2.64 mmol, 67%). MS (ESI): 365.03 (M+H)+.
b.) (3-Hydroxy-azepan-4-yl)-carbamic acid tert-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 room temperature for 48 hours, the mixture was filtered through celite. The filterate was concentrated to yield the title compound ( 0.529 g, 2.29mmol, 87%): MS(ESI): 231.92 (M+H)+.
c.) [3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-carbamic acid tert-butyl ester
To a solution of the compound of Example 193b (0.53, 2.29 mmol) in dichloromethane (20 ml) was added triethylamine (232 mg) and pyridine-2-sulfonyl chloride (410 mg, 2.32 mmol). After stirring at room temperature for 30 minutes, the mixture was washed with saturated NaHCO3 The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound as a solid ( 0.58 g, 1.57 mmol, 68%): MS(ESI): 372.95 (M+H)+. d.) 4- Amino- 1 -(pryidine-2-sulf onyl)-azepan-3-ol
To a stirring solution of the compound of Example 193c (0.583 g, 1.57mmol) in ethyl acetate (0.5 ml) was added HCl (4M in dioxane, 3.9 ml). After stirring the reaction mixture for 30 minutes at room temperature, the mixture was concentrated to yield a white solid. The solid was treated with NaOH and then extracted with ethylacetate. The organic layer 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)-l-[3-Hydroxy-l-(pryidine-2-sulfonyl)-azepan-4-ylcarbamoyl]-2-meth-butyl}- carbamic acid tert-butyl ester
To a solution of the compound of example 193d (19 mg, 0.070 mmol) in CH2C12 was added N-Boc-isoleucine (24.5 mg, 0.10 mmol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in CH2C12 . After shaking at room temperature overnight, 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-yl]-amide
To a stirring solution of the compound of example 193e (34 mg, 0.07 mmol) in CH2C12 (0.50 ml) was added HCl (4M in dioxane) (0.165 ml). After stirring at room temperature for 30 minutes, the mixture was concentrated, giving a white solid. The white solid was azeotroped with toluene then treated with MP-carbonate (0.35 mmol) in methanol. After four hours of shaking, the mixture was filtered and concentrated to give the title 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 CH2C12 was added 2-benzofurancarboxylic acid (17.0 mg, 0.106mmol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in CH2C12 . After shaking at room temperature overnight, 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) 528.9 (M+H)+.
h.) Benzofuran-2-carboxylic acid {(S)-2-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-butyl}-amide
To a stirring solution of the compound of example 193g (37 mg, 0.07 mmol) in CH2C12 (0.5 ml) was added Dess-Martin reagent (45 mg, 0.105 mmol). After stirring for 30 minutes, solutions of sodium thiosulfate (10% in water, 0.50 ml) and saturated aqueous sodium bicarbonate (0.50 ml) were added simultaneously to the reaction. The mixture was then extracted with dichloromethane (2 times). The organic layer was dried, filtered, and concentrated. The residue was purified by HPLC to yield the two diastereomers of the title compound as solids (first eluting: 7mg, second eluting: 5.5 mg): MS (ESI) 526.91 (M+H)+.
Example 194
Preparation of Benzofuran-2-carboxylic acid f(S)-l-F3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamovn-propyl } -amide
Following the procedure of Example 193e-h, except substituting N-Boc-alpha- arninobutyric acid in step 193e the title compound was purified to yield two diastereomers as solids (first eluting: 5 mg, second eluting: 5 mg) MS(ESI) 543.8 (M+H)\
Example 195
Preparation of Benzofuran-2-carboxylic acid f(S)-2-cyclohexyl-l-F3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-ethyl}-amide
Following the procedure of Example 193e-h, except substituting N-Boc- cyclohexylalanine in step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4.5 mg second eluting: 4.5 mg): MS(ESI): 566.87 (M+H)+. Example 196
Preparation of Benzofuran-2-carboxylic acid f (S)-l-F3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-ethyl )-amide
Following the procedure of Example 193e-h, except substituting N-Boc-alanine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 5.5 mg, second eluting: 5 mg).
Example 197
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methanesulfinyl-l-r3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyn-proρyl ) -amide
Following the procedure of Example 193e-h, except substituting N-Boc-L- methionine for step 1(f), the title compound was purified to yield two diastereomers as solids (first eluting: 3 mg, second eluting: 3 mg). MS(ESI): 560J (M+H)+ .
Example 198
Preparation of Benzofuran-2-carboxylic acid f F3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll-methyl }-amide
Following the procedure of Example 193e-h, except substituting N-Boc-glycine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 3mg ,second eluting: 3 mg). MS(ESI): 470.81 (M+H)+ .
Example 199
Preparation of Benzofuran-2-carboxylic acid f (S)-l-F3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamovn-pentyl } -amide
Following the procedure of Example 193e-h, except substituting N-Boc-norleucine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4 mg, second eluting: 5 mg). MS(ESI): 526.85 (M+H)+ .
Example 200
Preparation of Benzofuran-2-carboxylic acid f (S)-l-F3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl] -butyl } -amide
Following the procedure of Example 193e-h, except substituting N-Boc-norvaline for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 7.5 mg, second eluting: 3.5 mg). MS(ESI): 512.8 (M+H)+ .
Example 201
Preparation of Benzofuran-2-carboxylic acid f (S)-2-methyl-l-F3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyn-propyl } -amide
Following the procedure of Example 193e-h, except substituting N-Boc- valine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 6 mg, second eluting: 4.5 mg). MS(ESI): 512.8 (M+H)+.
Example 202
Preparation of Benzofuran-2-carboxylic acid f (S)-2-hydroxy-l-F3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyll -propyl } -amide
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 as solids (first eluting: 3 mg, second eluting: 3 mg).
Example 203
Preparation of Benzofuran-2-carboxylic acid f (S)-l-F3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-2-phenyl-ethyl}-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 as solids (first eluting:5mg, second eluting: 5mg). MS(ESI): 560.8 (M+H)+ .
Example 204
Preparation of l(Benzofuran-2-carbonyl)-pyrrolidine-2-carboxylic acid r3-oxo-l-(pyridine- 2-sulf onyl)-azepan-4-yll -amide
Following the procedure of Example 193e-h, except substituting N-Boc-L-proline for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 4 mg, second eluting: 5mg). MS(ESI): (M+H)+ .
Example 205
Preparation of 3.4-Dimethoxy-N- f (S)-l-F l-(4-imethoxy-benzenesulfonyl)-3-oxo-azepan-4- vIcarbamovn-3-methyl-butyl}-benzamide
Following the procedure of Example 115, except substituting 3,4- dimethoxybenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 576.4(M+H+).1H 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+).
Example 206
Preparation of BenzoFblthiophene-2-carboxylic acid-f (S)-l-F l-(4-imethoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 115, except substituting 2-thiophene-carbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 572.2 (M+H+).1H NMR (500 MHz,CDCl3): 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, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 572.2 (M+H+).
Example 207
Preparation of Benzori,3]dioxole-5-carboxylic acid f(S)-l-Fl-(4-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3methyl-butyl}-amide
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 was prepared. The residue was purified by HPLC. First eluting diastereomer; MS 548.2 (M+H+); 1H NMR (400Hz,CDCl3): δ 7.85-7.78 (m, 2H), 7.38-7.20 (m, 4H), 7.05 (d, IH), 2.52-2.40 (m,lH), 1.0 (d, 6H). Second eluting diastereomer: MS 548.2 (M+H+).
Example 208
Preparation of (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acidFl-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-yl1-amide
Following the procedure of Example 115, except substituting 4- fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 548.2 (M+H+).1H NMR (400Hz,CDCl3-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
Preparation of BenzoFblthiophene-2-carboxylic acid-f(S)-l-F l-(4-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamovn-3-methyl-butyl } -amide
Following the procedure of Example 115, except substituting 4- fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzo[b]thiophenecarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 560.2 (M+H+).!H NMR (500 MHz,CDCl3): δ 1.80-1.12 (m, 5H)J.37-7.34 (m, 2H), 7.33-7.15 (m, 4H), 2.43 (t, IH), 0.96 (d, 6H). Second eluting diastereomer: MS 560.2 (M+H+).
Example 210
Preparation of Benzofuran-2-carboxylic acid f (S)-l-Fl-benzoyl-3-oxo-azepan-4- ylcarbamoyU-3~methyl-butyl } -amide
a.) Benzofuran-2-carboxylic acid f(S)-l-[l-benzoyl-3-hydroxy-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 added benzoic acid (0.12 g), HOBt (0.07 g) and EDC (0.99 g). The reaction was stirred until complete. Workup and column chromatography (5% methanoLdichloromethane) provided the title compound (0.2 g): Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 3.8 (m,lH), 4.1 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.0-7.7 (m, 10H), 8.7 (m, IH); 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 f (S)-l-[l-benzoyl-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide of Example 210a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, IH), 3.7 (m,lH), 4.0 (m, IH), 4.7 (m, 2H), 5.1 (m, IH), 7.4-8.0 (m, 8H); MS(EI): 490 (M+H", 100%).
Example 211
Preparation of (S)-4-Methyl-2-(quinoline-8-sulfonylamino)-pentanoic acid r3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yn-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-quinolinesulfonyl chloride for 2-pyridinesulfonyl chloride the title 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 title compound was prepared: Η NMR (CDC13): δ 0.5-0.8 (m, 6H), 1.4-1.8 (m, 7H), 2.5 (m, IH), 3.5-3.9 (m, 3H), 4.4 (m, IH), 4.6 (m, IH), 5.5 (m,
IH), 6.7 -7.0 (m, 2H), 7.5 (m, 3H), 8.0 (m, 2H), 8.3 (m, 2H), 8.6 (m, IH), 9.0 (m, IH);
MS(EI): 674 (M+H+, 100%). Example 212
Preparation of (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid F3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yl1-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-naphthylenesulfonyl chloride for 2-pyridinesulfonyl chloride the title compound was prepared: MS(EI) 575 (M+H+).
b.) (S)-4-Methyl-2-(naphthylene-2-sulfonylamino)-pentanoic acid [3-oxo-l-(pyridine- 2-sulfonyl)-azeρan-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: Η NMR (CDC13): δ 0.5- 0.8 (m, 6H), 1.4-1.8 (m, 7H), 2.5 (m, IH), 3.5-3.9 (m, 3H), 4.5 (m, IH), 4.6 (m, IH), 5.5 (m, IH), 6.7 (m, IH), 7.5-8.0 (m, 9H), 8.5-8.6 (m, 2H); MS(EI): 673 (M+H\ 100%).
Example 213
Preparation of Benzofuran-2-carboxylic acid-f (S)-l-F l-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-yl carbamoyll-3-methyl-butyl }-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 was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 544.2.(M+H+).1H NMR (500 MHz,CDCl3): δ 1.19-1.11 (m, 2H), 7.61 (d, IH), 7.46-7.38 (m, 3H), 7.25-7.06 (m, 5H), 2.43 (t, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 544.4 (M+H+). Example 214
Preparation of N-f(S)-l-Fl-(4-Fluoro-benzenesulfonyl -3-oxo-azepan-4-ylcarbamoyll-3- methyl-butyl)-3,4-dimethoxy-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+). 1H NMR (500 MHz,CDCl3): δ 7.80-7.76 (m, 2H),7.19 (t, 2H),7.05 (d, IH), 6.88 (s, 2H), 6.78 (d, IH), 6.53 (s, IH), 3.77 (s, 6H), 2.43 (t, IH), 0.94 (d, 6H). Second eluting diastereomer: MS 546.2 (M+H+).
Example 215
Preparation of Cyclohexanecarboxylic acid f(S)-l-Fl-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl}-3-methyl-butyl}-amide
Following the procedure of Example 115, except substituting 4- fluorobenzenesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and cyclohexylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 510.4.(M+H+).1H NMR (400Hz,CDCl3): δ 7.83-7.80 (m, 2H), 7.27-7.20 (m, 2H), 6.92 (d, IH), 6.95 (d, IH). 2.50 (t, IH), 1.90-1.20 (m, 15H), 0.94 (t, 6H). Second eluting diastereomer: MS 510.2 (M+H+).
Example 216
Preparation of (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acidFl- (methanesulfonyl)-3-oxo-azepan-4-ylTamide
Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M+H+^H NMR (500 MHz,CDCl3): δ 7.37-7.24 (m, 4H), 6.93-6.91 (m, 2H), 5.02-5.00 (m, IH), 2.88 (s, 3H), 2.70 (t, IH), 0.92 (t, 6H). Second eluting diastereomer: MS 468.2 (M+H+).
Example 217
Preparation of Benzorblthiophene-2-carboxylic acid-f (S)-l-(l-methanesulfonyl-3-oxo- azepan-4-yl carbamoyl)-3-methyl-butyl]-amide
Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzo[b]thiophenecarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 480.2 (M+H+^H NMR (500 MHz,CDCl3): δ 7.83-7.78 (m, 3R), 1.42-1.31 (m, 2H),6.94 (d, IH), 6.75 (d, IH), 2.89 (s, 3H), 2.68 (t, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 480.2 (M+H+).
Example 218
Preparation of BenzoF1.31dioxole-5-carboxylic acid-f (S)-l-(l-methanesulfonyl-3-oxo- azepan-4-yl carbamoyl)-3-methy 1-butyl] -amide
Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and piperonylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 468.2 (M+H+). H NMR (500 MHz,CDCl3): δ 7.31-7.24 (m, 2H), 6.91 (d, IH), 6.00 (s, 2H), 2.89 (s, 3H), 2.67 (t, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 468.2 (M+H+).
Example 219
Preparation of Benzofuran-2-carboxylic acid-f (S)-l-d-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butvπ-amide
Following the procedure of Example 115, except substituting methanesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and 2-benzofurancarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 464.2 (M+H+^H NMR (500 MHz,CDCl3): δ 7.64 (d, IH), 7.51-7.37 (m, 3H), 7.29-7.28 (m, IH), 2.89 (s, 3H), 2.67 (t, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 464.2 (M+H+).
Example 220
Preparation of N-F(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl- butyl } -3 ,4-dimethoxy-benzamide
Following the procedure of Example 115, except substituting methanesulphonyl 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 484.2 (M+H+^H NMR (500 MHz,CDCl3): δ 6.94-6.88 (m, 3H), 6.58-6.55 (m, 2H), 3.80 (s, 6H), 2.89 (s, 3H), 0.95 (d, 6H). Second eluting diastereomer: MS 484.2 (M+H+).
Example 221
Preparation of (S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acidFl-(2-cyano- benzensulfonyl)-3-oxo-azepan-4-yn-amide
Following the procedure of Example 115, except substituting 2- cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M+H+).!H NMR (500 MHz,CDCl3): δ 8.10 (d, IH), 7.86 (d, IH), 7.76-7.70 (m, 2H), 7.35-7.31 (m, 5H), 6.93 (d, 2H), 4.61-4.47 (m, 4H), 2.77 (t, IH), 0.92 (t, 6H). Second eluting diastereomer: MS 555.2 (M+H+).
Example 222
Preparation of N-f (S)-l-Fl-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3- methyl-butyl } -4-methanesulf onyl- 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 was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 589.2 M+H H NMR (500 MHz,CDCl3): δ 8.10 (d,lH), 7.96 (s, 4H), 7.88 (d, IH), 7.78-7.71 (m, 2H), 3.05 (s, 3H), 2.79 (t, IH), 0.97 (t, 6H). Second eluting diastereomer: MS 589.2 (M+H+).
Example 223
Preparation of BenzoFblthiophene-2-carboxylic acid-f (S)-l-Fl-(2-cyano-benzenesulfonvD- 3-oxo-azepan-4-yl earbamoyl)-3-methyl-butyl1-amide
Following the procedure of Example 115, except substituting 2- cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and benzo[b]thiophene-2-carbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 567.2 (M+H- H NMR (500 MHz,CDCl3): δ 8.10 (d, IH), 1.86-1.10 (m, 6H), 7.37-7.30 (m, 2H), 2.76 (t, IH), 0.98 (d; 6H). Second eluting diastereomer: MS 567.2 (M+H+).
Example 224
Preparation of BenzoFL31dioxole-5-carboxylic acid-f (,S)-l-Fl-(2-cyano-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl -3-methyl-butyl1-amide
Following the procedure of Example 115, except substituting 2- cyanophenylsulphonyl chloride for 4-methoxybenzenesulfonyl chloride and piperonyloyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 555.2 (M+H+). tø NMR (500 MHz,CDCl3): δ 8.11 (d, IH), 7.87 (d, IH), 1.16-1.11 (m, 2H), 7.31-7.24 (m, 2H), 6.00 (s, 2H), 2.77 (t, IH), 0.97 (d, 6H). Second eluting diastereomer: MS 555.4 (M+H+).
Example 225
Preparation of (S)-4-Methyl-2-F4-oxo-4-((4-phenoxy-phenyl)-butyrylamino|-pentanoic acid r3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-vH-amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for thiaxole-2-sulfonyl chloride and 4-phenoxyphenyl-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+) 635.4; ΪH-NMR (400 MHz, CDCI3): • 8.69(d, IH), 7.99-7.94(m, 4H), 7.53-7.39(m, 3H), 7.23-6.95(m, 7H), 6.20(d, IH), 5.07(m, IH), 4.77-4.72(d, IH), 4.46(m, IH), 4.13-4.09(m, IH), 3.85-3.80(d, IH), 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
Preparation of N-f (S)-l-r(l-(2-cvano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3- methyl-butyl}-3,4-dimethoxy-benzamide
Following the procedure of Example 115, except substituting 2- cyanophenylsulphonyl 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 571.4 (M+H+).1H NMR (500 MHz,CDCl3): δ 8.10 (d, IH), 7.87 (d, IH), 7.76-7.70 (m, 2H), 6.98 (s, 2H), 6.89 (s, 2H), 3.79 (s, 6H), 2.76 (t, IH), 0.96 (d, 6H). Second eluting diastereomer: MS 571.4 (M+H+).
Example 227
Preparation of Cyclohexanecarboxylic acid f (S)-l-Fl-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl } -3-methyl-butyl } -amide
Following the procedure of Example 115, except substituting cyclohexylcarbonyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 522.4 (M+H+^H NMR (500 MHz,CDCl3): δ 7.70 (d, 2H), 6.97 (d, 2H), 2.40 (t, IH), 1.90-1.20 (m, 16H), 0.92 (d, 6H). Second eluting diastereomer: MS 522.4 (M+H+).
Example 228
Preparation of 4-Methansulfonyl-N-f (S)-l-F4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- carbamoyl]-3-methyl-butyl-benzamide
Following the procedure of Example 115, except substituting 4- methanesulfonylbenzoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 594.2 ( +H+).!H NMR (500 MHz,CDCl3): 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, IH), 0.95 (d, 6H). Second eluting diastereomer: MS 594.2 (M+H+). Example 229
Preparation of 4-Methansulfonyl-N-f (S)-l-F4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- carbamoyl]-3-methyl-butyl-benzamide
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 was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 582.2 (M+H+).1H NMR (500 MHz,CDCl3): δ 7.94 (s, 4H), 1.80-1.11 (m, 2H), 7.25-7.19 (m, 3H), 7.00 (d, IH), 3.04 (s, 3H), 0.96 (d, 6H). Second eluting diastereomer: MS 582.2 (M+H+).
Example 230
Preparation of (f (S)-3-Methyl-l-F3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1- butylcarbamoyll-carbamic acid benzyl ester
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and N-carbobenzyloxycarbonyl-glycine for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 574.2; -NMR (400 MHz, CDC13): 8.60(d, IH), 7.97-7.90(m, 2H), 7.50(m, IH), 7.42-7.25(m, 5H), 6.90(m, IH), 6.42(m, IH), 5.38(m, IH), 5.18-5.10(m, 4H), 4J8-4J2(d, IH), 4.50(m, IH), 4.12-4.05(m, IH), 3.95- 3.85(m, 2H), 2J2(m, IH), 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.
Example 231
Preparation of (S)-2-F5-(4-Methoxy-phenyl)-pentanoylamnio1-4-methyl-pentanoic acid F3- oxo- 1 -(pyridine-2-sulf onyD-azepan-4-yl] -amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and 5-(4-methoxyphenyl)-pentanoic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 573.4; 1H-NMR (400 MHz, CDC13): • 8.59(d, IH), 7.97-7.94(m, 2H), 7.53(m, IH), 7.09-7.07(d, 2H), 6.89-6.81(m, 3H), 5.90(m, IH), 5.12(m, IH), 4.79-4.74(d, IH), 4.48(m, IH), 4.12(m, IH), 3.86-3.8 l(d, IH), 3.79(s, 3H), 2.69(m, IH), 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.
Example 232
Preparation of (S)-2-F2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio1-4-methylpentanoic acid F3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl1-amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and (3-benzyIoxy-4-methoxy-phenyl)-acetic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 637.4; *H-NMR (400 MHz, CDCI3): • 8.69(d, IH), 7.98-7.91(m, 2H), 7.53-7.30(m, 6H); and the second eluting diastereomer:, 6.89-6.82(m, 4H), 5.82(m, IH), 5.14-5.07(m, 3H), 4.78-4.73(d, IH), 4.43(m, IH), 4.09(m, IH), 3.89(s, 3H), 3.82(d, IH), 3.49(s, 2H), 2.69(m, IH), 2.14(m, 2H), 1.82-1.40(m, 5H), 0.89(d, 6H); and the second eluting diastereomer: MS (M+H+) 637.4.
Example 233
Preparation of 5,6-Difluoro-benzofuran-2-carboxylic acid f (S)-3-methyl-l-fl-(pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl } amide
a.) 5,6-Difluoro-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[l-(pyridine-2- sulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-butyl}amide
Following the procedure of Example 28b except substituting 5,6- difluorobenzofuran-2-carboxylic acid for bernzofuran-2-carboxylic acid provided the title compound: MS (M+H+): 564
b.) 5,6-Difluoro-benzofuran-2-carboxylic acid f(S)-3-methyl-l-[l-(pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example li except substituting the compound of Example 233a provided the title compound. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 562; and the second eluting diastereomer: MS (M+H+) 562.
Example 234
Preparation of (S)-4-Methyl-2-(5-oxo-hexanoylamino)-pentanoic acid F3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-yl]-amide
Following the procedure of Example 115, except substituting 2-pyridinesulphonyl chloride for 4-methoxybenzenesulfonyl chloride and substituting 5-oxo-hexanoyl chloride for benzyloxyacetyl chloride, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer: MS 495.4 (M+H+); Second eluting diastereomer: MS 495.4 (M+H+). Example 235
Preparation of Benzofuran-2-carboxylic acid f(S)-3-methyl-l-fl-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl}amide
a.) 6-methyl-pyridine-2-sulphonyl chloride
The title compound was prepared in a similar fashion as that described in Example 85a for the preparation of 2-pyridinesulfonyl chloride-N-oxide.
b.) { (S)-l-[3-Hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3- methy 1-butyl} -carbamic acid tert-butylester
To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert-butyl ester of Example 2g (1.0 g) in dichloromethane (20 mL) was added saturated 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 stirred until complete. Workup and column chromatography (5% methanoLdichloromethane) provided the title compound (1.2 g).
c.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- l-(6-methyl-py ridine-2- sulfonyl)-azepan-4-yl]-amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl- pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 235a (1.2 g) in methanol (20 mL) was added 4M HCl in diopxane (20 mL). The reaction was stirred until complete whereupon it was concentrated to provide the title compound (1 g).
d.) Benzofuran-2-carboxylic acid f (S)-3-methyl-l-[l-(6-methyl-ρyridine-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-ρyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 235c the title compound was prepared: MS(EI) 542 (M+). e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3- oxo-azepan-4-y lcarbamoyl] -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- ylcarbamoyLJ-butyl} amide of Example 235d the title compound was prepared: Η NMR (CDCl.): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, IH), 4.1 (m, IH), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 8H); MS(EI); 540 (M+, 100%).
Example 236
Preparation of 5-Methoxybenzofuran-2-carboxylic acid f(S)-3-methyl-l-Fl-(6-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl } amide
a.) 5-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 5-methoxybenzofuran- 2-carboxylic acid for benzofuran-2-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(6-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 235c for (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]- 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- sulf onyl)-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-(6-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- ylcarbamoyl]-butyl} amide of Example 236a the title compound was prepared: 'H NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, IH), 3.8 (s, 3H); 4.1 (m, IH), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0, (m, 7H); MS(EI): 570 (M\ 100%). Example 237
Preparation of 3-Methylbenzofuran-2-carboxylic acid f(S)-3-methyl-l-Fl-(6-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamovn-butyl } amide
a.) 3-Methylbenzofuran-2-carboxylic acid f(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 was prepared: MS(EI) 556 (M+).
b.) 3-Methylbenzofuran-2-carboxylic acid f(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 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: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H), 2.7 (m, IH), 3.8 (s, IH); 4.1 (m, IH), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H); MS(EI): 564 (M\ 100%).
Example 238
Preparation of 7-Methoxybenzofuran-2-carboxylic acid f(S)-3-methyl-l-fl-fpyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyπ-butyl)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 compound was prepared: MS(EI) 559 (M+H+).
b.) 7-Methoxybenzofuran-2-carboxylic acid f (S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulf onyl)-3-oxo-azepan-4-y lcarbamoyl] -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- ylcarbamoyl]-butyl} amide of Example 238a the title compound was prepared: MS(EI) 557 (M+H+).
Example 239
Preparation of 5.6-Dimethoxy-benzoFb1thiophene-2-carboxylic acid f(S)-3-methyl-l-fl- (pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide
a.) 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid f(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 5,6-dimethoxy- benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(EI) 604 (M+).
b.) 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid f(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 prepared: MS(EI) 602.9 (M+H+).
Example 240
Preparation of (R)-l-Benzyl-5-oxo-pyrroridine-2-carboxylic acid f (S)-3-mefhyl-l-13-oxo- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for thiazole-2-sulfonyl chloride and (R)-l-benzyl-5-oxo-pyrrolidine-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 584.4; iH-NMR (400 MHz, CDC13): • 8.69(d, IH), 7.99-7.92(m, 2H), 7.52(m, IH), 7.32-7.22(m, 5H), 6.92(d, IH), 6.38(d, IH), 5.15-5.08(m, 2H), 4.80-4J5(d, IH), 4.47-4.44(m, IH), 4.14-4.10(m, IH), 3.89-3.80(m, 3H), 2J5-2.63(m, 2H), 2.46-1.44(m, 10H), 0.95(d, 6H); and the second eluting diastereomer: MS (M+H+) 584.4. Example 241
Preparation of (S)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid f(S)-3-mefhyl-l-f3-oxo- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
Following the procedure of Example 75, except substituting 2-pyridylsulfonyl chloride for benzenesulfonyl chloride and (S)-l-benzyl-5-oxo-pyrrolidine-2-carboxylic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 584.4; ΪH-NMR (400 MHz, CDC13): • 8.69(d, IH), 7.98-7.92(m, 2H), 7.52(m, IH), 7.32-7.22(m, 5H), 6.92(d, IH), 6.38(d, IH), 5.22-5.18(d, IH), 5.10(m, IH), 4.80-4J5(d, IH), 4.51(m, IH), 4.12-4.08 (m, IH), 3.91-3J9(m, 3H), 2Jl-1.38(m, 12H), 0.97(d, 6H); and the second eluting diastereomer: MS (M+H+): 584.4.
Example 242
Preparation of Benzofuran-2-carboxylic acid f (S)-2-cvclopropyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-ethyll-amide
Following the procedure of Example 193e-h except substituting N-Boc- cyclopropylalanine for step 193e, the title compound was purified to yield two diastereomers as solids (first eluting: 8 mg, second eluting: 8 mg): MS(ESI): 525 (M+H)+
Example 243
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methylsulfanyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-propyH-arnide
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 sulfur trioxide-pyridine complex (34mg, 0.211 mmol ) and triethylamine ( 0.077 ml) to the alcohol intermediate in DMSO solvent (0.200 ml). After stirring at room temperature for two hours, the mixture was diluted with water and extracted with ethyl acetate. The organic 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
Preparation of Benzofuran-2-carboxylic acid f (S)-2-naphthylen-2-yl-l-r3-oxo-l-(pyridine- 2-sulfonylVazepan-4-ylcarbamoyl)-ethyl1-amide
Following the procedure of Example 193e-h except substituting except substituting
N-(t-butoxycarbonyl)-3-(2-naphthyl)-L-alanine, the title compound was purified to yield two diastereomers as solids (first eluting: 5.3 mg, second eluting: 3.3 mg): MS(ESI): 610.8 (M+H)+ .
Example 245
Preparation of Thieno[3,2-b1thiophene-2-carboxylic acid f (S)-3-methyl-l-ri-(6-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamovH-butyl}amide
a.) Thieno [3, 2-b]thiophene-2-carboxy lie acid f(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-carboxylic acid for 5-methoxybenzofuran-2-carboxylic acid the title compound 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 fhieno[3,2-b]thiophene-
2-carboxylic acid f (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: Η NMR
(CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 2.7 (m, IH), 3.8 (s, IH); 4-1 (m, IH),
4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H); MS(EI): 562 (M+, 100%). Example 246
Preparation of Thieno[3,2-blthiophene-2-carboxylic acid f(S)-3-methyl-l-[l-(3-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyn-butyl)amide
a.) (S)-2-Amino-4-methyl-pentanoic acid [3-hydroxy- l-(3-methyl-pyridine-2- sulf onyl)-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 compound was prepared: MS(EI) 399 (M+).
b.) Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulf onyl)-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 was added thieno[3,2-b]thiophene (0.10 g), triethylamine (0.12 mL), HOBt (0.085 g) and EDC (0.12 g). The reaction was stirred until complete. 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 f (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: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (m, 3H) 3.0 (m, IH), 3.8 (s, 3H); 4.1 (m, 2H),
4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 5H), 8.4 (m, IH); MS(EI): 562 (M\ 100%).
Example 247
Preparation of 3-Methylbenzofuran-2-carboxylic acid f(S)-3-methyl-l-ri-(3-methyl- pyridine-2-sulf onyl)-3-oxo-azepan-4-ylcarbamoyl1 -butyl } amide
a.) 3-Methylbenzofuran-2-carboxyιic acid f(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 3-methylbenzofuran- 2-carboxylic acid for thieno[3,2-b]thiophene 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-[l-(3-methyl-pyridine-2-sulfonyl)-3-hydroxy-azepan-4- ylcarbamoyl]-butyl} amide of Example 247a the title compound was prepared: Η NMR (CDC13): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 2.6 (m, 3H), 3.0 (m, IH), 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H), 8.4 (m, IH); MS(EI): 554 (M\ 100%).
Example 248
Preparation of 5-Methoxybenzofuran-2-carboxylic acid f(S)-3-methyl-l-ITJ3-mefhyl- pyridine-2-sulf onyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide
a.) 5-Methoxybenzofuran-2-carboxylic acid f (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 was prepared: MS(EI) 572 (M+).
b.) 5-Methoxybenzofuran-2-carboxylic acid f(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- ylcarbamoyl]-butyl} amide of Example 247a the title compound was prepared: Η NMR (CDCL): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.6 (d, 3H), 3.0 (m, IH), 3.8 (s, 3H); 4.1 (m, 2H), 4.7 (m, 2H), 5.3 (m, IH), 7.4-8.0 (m, 6H), 8.4 (m, IH); MS(EI): 570 (M+, 100%).
Example 249
Preparation of 5,6-Difluoro-benzofuran-2-carboxylic acid f(S)-3-mefhyl-l-F3-oxo-l-(l-oxy- pyridine-2-sulf onyD-azepan-4-ylcarbamoyιl-butyl } amide
a.) 5,6-Difluoro-benzofuran-2-carboxylic acid f(S)-3-methyl-l-[3-hydroxy-l-(l-oxy~ pyridine-2-suϊfonyl)-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 was prepared: MS(ESI) 580.9 (M+H+).
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 of Example 249a the title compound was prepared: MS(ESI) 578.87 (M+H1").
Example 250
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acidf (S)-2-cyclohexyl-l- f3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-ethyl}-amide
a.) 4-((S)-2-tert-Butoxycarbonylamino-3-cyclohexyl-proprionylamino)-3-hydroxy- azepane- 1-carboxylic acid benzyl ester
To a solution of the compound of Example 2e (3.2 g, 12.2 mmol) in DMF (35 mL) was added N-Boc-cyclohexylalanine (3.3 g), HOBt (1.8 g) and EDC (2.56 g). The reaction was stirred until complete. Workup and column chromatography of the residue (65% hexanes:ethyl acetate) provided 5.5 g of the title compound. b.) [(S)-Cyclohexyl-l-(3-hydroxy-azepan-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% Pd/C. This mixture was stirred under an atmosphere of hydrogen until complete consumption of the starting material was observed. The reaction was filtered and concentrated to provide 3.75 g of the title compound.
c.) {(S)-2-Cyclohexyl-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]~ ethyl} -carbamic acid tert-butyl ester To a solution of the compound of Example 250 b (1.0 g, 1.91 mmol) in dichloromethane (5 mL) was added water (10 mL) and sodium bicarbonate (1 g). To this mixture 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 and washed with water, brine, dried filtered and concentrated. Column chromatography (2% methanoLdichloromethane) 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 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 complete consumption of the starting material whereupon it was concentrated. The residue was azeotroped with toluene then washed with ether to provide 0.95 g of the title compound.
e.) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-{3- hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyI]-ethyl}-amide
To a solution of the compound of Example 250d (0.20 g, 0.4 mmol) in DMF (0.5 mL) 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 complete consumption of the starting material. Workup and column chromatography 4% methanoLdichloromethane) provided 0.23 g of the title compound. 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. Separation of the diastereomers by HPLC provided the first eluting disatereomer (52 mg): MS (ESI) 661.4 and the second eluting diastereomer (45.8 mg): MS (ESI) 661.6.
Example 251 .
Preparation of 5-(4-Chloro-phenyl)-furan-2-carboxylic acidf (S)-2-cyclohexyl-l-f 3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-ethyl}-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 Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer (57 mg): MS (ESI) 627.4 and the second eluting diastereomer (53 mg): MS (ESI) 627.4.
Example 252
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine- sulphonyl)-azepan-4-ylcarbamoyn-butyl } -amide
Following the procedure of Example 92, except substituting, 2-methyl-4-pentenal for 2,2-dimethyl-4-pentenal the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+): 541.2; 1H-NMR (400 MHz, CDC13): • 8.71-8.66(m, IH), 7.98-7.93(m, 2H), 7.91(d, IH), 7.67-7.29(m, 5H), 7.15-6.92(m, 2H), 5.28-5.20(m, IH), 4.82-4.47(m, 2H), 3.97-3.78(m, IH), 3.65-2.98(m, IH), 2.37-2.34(m, IH), 2.20-1.55(m, 3H), 1.22-1.19(m, 3H), 1.00-0.86(m, 9H). Example 253
Preparation of 5-(4-Chloro-phenyl)-furan-2-carboxylic acidf (S)-2-cyclohexyl-l-[3-oxo-l- ( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-yIcarbamoyll-ethyl I -amide
Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride 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 Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2.
Example 254
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acidf (S)-2-cyclohexyl-l-r3- oxo- 1 -( 1 -oxy-pyridine-2-sulf onyl)-azepan-4-ylcarbamoyn -ethyl } -amide
Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride N-oxide for 2-pyridinesulfonyl chloride of Example 250c the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer: MS (ESI) 677.2 and the second eluting diastereomer: MS (ESI) 677.4.
Example 255
Preparation of 5-Fluoro-benzofuran-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamovn-butyl}-amide
a.) 5-Fluoro-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide 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+). b.) 5-Fluoro-benzofuran-2-carboxylic acid f(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 255a the title compound was prepared: MS(ESI) 544.9 (M+H+).
Example 256
Preparation of 5.6-Dimethoxybenzofuran-2-carboxylic acidf (S)-2-cyclohexyl-l-r3-oxo-l- ( 1 -oxy-pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl] -ethyl } -amide
Following the procedures of Example 250c-f except substituting 2-pyridinesulfonyl chloride 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 of Example 252e the title compound was prepared. Separation of the diastereomers by HPLC provided the first eluting diastereomer: MS (ESI) 643.4 and the second eluting diastereomer: MS (ESI) 643.2.
Example 257
Preparation of 5,5-Bis-(4-methoxy-phenyl)-pent-4-enoic acid f (S)-3-methyl-H3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1 }-butyl )-amide
Following the procedure of Example 75 except substituting 2-pyridylsulfonyl chloride for thiazole-2-sulfonyl chloride and 5,5-bis-(4-methoxy-phenyl)-pent-4-enoic acid for benzofuran-2-carboxylic acid, the title compound was prepared. The residue was purified by HPLC. First eluting diastereomer; MS (M+H+) 677.4; H-NMR (400 MHz, CDC13): • 8.69(d, IH), 7.98-7.92(m, 2H), 7.53-7.50(m, IH), 7.27-6J7(m, 10H), 6.00- 5.87(m, 2H), 5.08(m, IH), 4J6-4J2(d, IH), 4.48(m, IH), 4.08(m, IH), 3.83(s, 3H), 3J8(s, 3H), 2J0-1.35(m, 12H), 0.91(d, 6H); and the second eluting diastereomer: MS (M+H+) 677.4. Example 258
Preparation of Quinoline-8-carboxylic acid f (S)-2-naphthylen-2-yl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-ethyl1-amide
a.) 4-Amino- 1 -(pyridine-2-sulfonyl)-azepan-3-ol
To a solution of the compound of Example 193c (1.5 g) in methanol (10 mL) was added HCl (10 mL of 4M HCl in dioxane). The reaction was stirred until complete by TLC analysis whereupon it was concentrated to provide 1.2 g of the title compound as a white solid.
b.) {(S)-l-[3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yIcarbamoyl]-2-napthylene-2- yl-ethyl} -carbamic acid tert-butyl ester
To a solution of the compound of Example 258a (225 mg) in dichloromethane was added TEA (0.15 mL), HOBt (99 mg), EDC (140 mg) and N-Boc-L-2-naphthylalanine (230 mg). The reaction was stirred until complete. Workup and column chromatography of the residue (3% methanoLdichloromethane) provided 0.35g of the 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) was added HCl (5 mL of 4M HCl in dioxane). The reaction was stirred until complete by TLC analysis whereupon it was concentrated to provide 0.31 g of the title compound as a white solid.
d.) Quinoline-8-carboxylic acid f (S)-2-naphthylen-2-yl-l-[3-hydroxy-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl)-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 complete. Workup and column chromatography of the residue (5% methanoLdichloromethane) provided 0.35g of the title compound: MS(ESI) 574 (M+H+). e.) Quinoline-8-carboxylic acid f (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 of Example 258d the title compound was prepared.
Example 259
Preparation of Naphthylene-1 -carboxylic acid f(S)-2-naphthylen-2-yl-l-r3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl)-ethvn-amide
Following the procedures of Examples 258d-e except substituting 1-naphthoic acid for quinoline-8-carboxylic acid the title compound was prepared.
Example 260
Preparation of Quinoline-8-carboxylic acid f(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-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
Preparation of Naphthyridine-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl -azepan-4-ylcarbamoyl]-butyl}-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. Example 262
Preparation of Naphthylene-1 -carboxylic acid f (S)-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyn-2-phenyl-ethyl)-amide
Following the procedure of Example 260 except substituting 1-naphthoic acid for quinoline-8-carboxylic acid the title compound was prepared.
Example 263
Preparation of 3-Methylbenzofuran-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l- (cyclohexyl-proprionyl)-azepan-4-ylcarbamovn-butyl 1 -amide
a.) 4-{(S)-2-[(3-Methylbenzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3- hydroxy-azepane- 1-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 complete consumption of the starting material was observed.
Workup and colum chromatography (4:1 hexanes:ethyl acetate) provided 1.05 g of the title compound: 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 of Example 263a the title compound was prepared: MS (ESI) 402 (M+H1).
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 of Example 263b and 3-cyclohexylpropionic acid for 3-methylbenzofuran-2-carboxylic acid the title compound was prepared: MS (ESI) 540 (M+H+). d.) 3-Methylbenzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(cyclohexyl- proprionyl)-azepan-4-ylcarbamoyl]-butyl}-amide
Following the procedure of Example li except substituting the compound of Example 263c the title compound was prepared: MS (ESI) 538 (M+H+).
Example 264
Preparation of 3-Methylbenzofuran-2-carboxylic acid f(S)-3-methyl-l-[3-oxo-l-(4-methyl- pentanoyl)-azepan-4-y lcarbamoyl] -butyl } -amide
Following the procedures of Example 263c-d except substituting 4-methylpentanoic acid for 3-cyclohexylpropionic acid the title compound was prepared: MS (ESI) 498 (M+H+).
Example 265
Preparation of 3-Methylbenzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-carbonyl)-azepan-4-ylcarbamovH-butyl}-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 (M+H+).
Example 266
Preparation of (S)-Acetylamino-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2-sulf on yl)- 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; iH-NMR (400Hz, CDC13): • 8.69(d, IH), 7.96-7.94(m, 2H), 7.53-7.52(m, IH), 7.05(m, IH), 5.92(m, IH), 5.08(m, IH), 4.69-4.53(m, 2H), 4.05-3.90(m, 2H), 2.80(m, IH), 2.25-2.12(m, 2H), 1.64(s, 3H), 1.90-1.40(m, 5H), 0.95(m, 6H); and the second eluting distereomer: MS (M+H+):
425.2
Example 267
Preparation of Quinoline-2-carboxylic acid f (S)-l-r3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll-pentyl }-amide
a.) 4-((S)-2-tert-Butoxycarbonylamino-hexanoylamino)-3-hydroxy-azepane-l- carboxylic acid benzyl ester
To a stirring solution of compound of the amino alcohol of Example 2e (200 mg, 0J4mmol) in DMF (4 ml) was added N-Boc-norleucine (175 mg, 0J6mmol), EDC-HC1 (145 mg, 0J6mmol), and 1-hydroxybenzotriazole (21 mg, 0.16mmol). Reaction allowed to proceed overnight at room temperature. The following morning the mixture was diluted with ethyl acetate, washed with sat. NaHCO3, H2O, and brine. Dried on MgSO4, filtered and purified 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 tert-butyl ester 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 H2 from a filled balloon. After stirring the solution at room temperature for 48 hours, the mixture was filtered through celite. The filterate was concentrated to yield the title compound (crude, 161mg,
0.47mmol): MS(ESI): 344.19 (M+H)\
c.) { (S)-l-[3-Hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-pentyl }- carbamic acid tert-butyl ester
To a solution of the compound of Example 267b (161 mg,0.47 mmol) in dichloromethane (6 ml) was added triethylamine (0.065 ml, 0.47mmol) and pyridine-2- sulfonyl chloride (83mg, 0.47 mmol). After stirring at room temperature for 1 hr the mixture was washed with saturated NaHCO3 The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound (142mg,
0.29mmol): MS (ESI): 485.10 (M+H)+. 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) in ethyl acetate was added HCl (4M in dioxane) (0J60 ml, 3.0 mmol). After stirring the reaction mixture for 1 hr at room temperature, the mixture was concentrated to yield a white solid. The solid was azeotroped with toluene twice on rotavap and then treated with a resin bound carbonate (1.47 mmol) in methanol and placed on a shaker. After 4 hr the suspension 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- ylcarbamoyl] -pentyl }-amide
To a solution of the compound of Example 267d (104 mg, 0.27mmol) in CH2C12 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 temperature overnight, the mixture was diluted with ethylacetate, washed with sat. NaHCO3, H2O, dried on MgSO4, and filtered to obtain 172mg crude product: MS(ESI) 539.90 (M+H)\
f.) Quinoline-2-carboxylic acid f (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) ) and triethylamine (0.88 ml, 3.2mmol). After stirring at room temperature for two hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, concentrated, and purified by HPLC to yield two diastereomers of the title compound as solids (first: 40 mg: second:43mg): MS(ESI) 537.86 (M+H)+.
Example 268
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(cyclohexyl- proprionyl)-azepan-4-ylcarbamoyl1-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 title compound was prepared: MS(ESI) 524 (M+H+).
Example 269
Preparation of Benzofuran-2-carboxylic acid f(S)-3-methyl-l-f3-oxo-l-(4-methyl- pentanoyl)-azepan-4-y lcarbamoyl] -butyl } -amide
Following the procedures of Example 263 a-d except substituting benzofuran-2- carboxylic acid for 3-methylbenzofuran-2-carboxylic acid of Example 263a and 5-methyl pentanoic aicd for cyclohexyl propionic acid the title compound was prepared: MS (ESI) 484 (M+H+).
Example 270
Preparation of Quinoline-2-carboxylic acid f(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll-2-phenyl-ethyl}-amide
Following the procedure of Example 267 a-f except substituting N-Boc- phenylalanine for N-Boc-norleucine in step 267a the title compound was prepared.
Separation of the mixture by HPLC provided two diastereomers as solids (first eluting: 20.5 mg; second eluting: 27 mg ): MS(ESI) 571.95 (M+H)+ .
Example 271
Preparation of Benzofuran-2-carboxylic acidf (S)-2-benzyloxy-lT3-oxo-l-(pyridine-2- sulfonyl)-azepane-4-ylcarbamovn-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 a solution of benzofuran-2-carboxylic acid f(S)-2-benzyloxy-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepane-4-ylcarbamoyl]-ethyl} -amide (90 mg) in ethyl acetate (2 mL) was added 10% Pd/C (50 mg). Upon hydrogenolysis of approximately 50% of the starting benzyl ether the reaction was filtered and concentrated. Purification of this 4 component mixture by HPLC provided the first eluting diastereomer of the title compound (1 mg) and the second eluting diastereomer of the title compound (0.3 mg): MS(ESI): 590.94(M+H)+. Additionally the two individual diastereoemers of benzofuran-2-carboxylic acidf (S)-2- hydroxy-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepane-4-ylcarbamoyl]-ethyl}-amide were also isolated as described below in Example 272.
Example 272
Preparation of Benzofuran-2-carboxylic acid f (S)-2-hydroxy-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepane-4-ylcarbamovn-ethyl } -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 (first eluting: 1.6 mg; second eluting 2.1 mg): MS(ESI): 500.9 (M+H)+.
Example 273
Preparation of 5-Methoxybenzofuran-2-carboxylic acid f(S)-3-methyl-l-r3-oxo-l-(thiazole- 2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
• Following the procedure of Example 75c-d except substituting 5- methoxybenzofuran-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 (144.3 mg, 85.1%): MS (ESI) 563.2 (M+H)+ and the second eluting diastereomer as a white solid (16.9mg, 10.0%) MS (ESI): 563.0 (M+H)+
Example 274
Preparation of 7-Methoxybenzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(thiazole- 2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
Following the procedure of Example 75c-d except substituting 7- methoxybenzofuran-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 (75 mg, 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 275
Preparation of 3-Methylbenzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl ) amide
Following the procedure of Example 75c-d except substituting 3- methylbenzofuran-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 (69.5 mg, 42%): MS (ESI) 547.2 (M+H)+ and the second eluting diastereomer as a white solid (65 mg, 40%): MS (ESI) 547.2 (M+H)+
Example 276
Preparation of Benzorb]thiophene-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl } 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 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
Preparation of 1 -Methyl- lH-indole-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
Following the procedure of Example 75c-d except substituting 1 -methy lindole-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 (75 mg, 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
Preparation of Quinoxaline-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(thiazole-2- sulf onyl)-azepan-4-ylcarbamovn-butyl } 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 compound which was separated by HPLC to give the first eluting diastereoemer as a white solid (126 mg, 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)+
Example 279
Preparation of Quinoline-2-carboxylic acid f [(S)-l-ri-(4-fluoro-benzenesulfonyl -3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 75, except substituting 4-fluorophenylsulfonyl chloride 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; 1H-NMR (400Hz, CDC13): • 8.62(d, IH), 8.34-8.23(q, 2H) 8.19-8.17(d, IH), 7.90-7.88(d, IH), 7.88-7.80(m, 3H), 7.66-7.64(t, IH), 7.25-7.07(m, 3H), 5.08(m, IH), 4J2 (m, IH), 4.58-4.53(d, lH),4.00(m, IH), 3.46-3.42(d, IH), 2.47(m, IH), 2.27-2.12(m, 2H), 1.90-1.40(m, 5H), 1.03-1.01(m, 6H); and the second eluting diastereomer: MS (M+H+): 555.4.
.. Example 280
Preparation of Benzofuran-2-carboxylic acid f (S)-l-r-(3-fluoro-benzensulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide
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 was stirred at room temperature 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 for approximately 4 hours whereupon the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2x's), brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (10% ethyl acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(ES) 260 (M+H+). b.) 2,3,4,7-Tetrahydro-azepine-l-carboxylic acid benzyl ester
To a solution of compound of Example 280a (50 g) in dichloromethane was added bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (5.0 g). The reaction was heated to reflux until complete as determined by TLC analysis. The reaction was concentrated 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 CH2C12 was added m-CPBA (78 g, 0.45 mol). The mixture was stirred overnight at room temperature whereupon it was filtered to remove the solids. The filtrate was washed with saturated water and saturated NaHCO3 (several times). The organic layer was dried (MgSO4), filtered and concentrated to give 35 g of the title compound which was of sufficient purity to carry on 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) in methanol: 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 complete consumption of the starting epoxide was observed by TLC analysis. The majority of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic layer was washed with sat. NaHCO3, water, brine dried (MgSO), filtered and concentrated. Column chromatography (20% ethyl acetate:hexanes) of the residue provided 1.3 g of the title compound: MS(ES) 291 (M+H+) plus 0.14 g of trans-4- hydroxy-3-azido-hexahydro-lH-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, 3J9 mmol) in methanol was added triethyamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 mmoL). The reaction was stirred until complete consumption of the starting material was observed by TLC analysis whereupon the reaction was concentrated in vacuo. Column chromatography of the residue (20% methanoLdichloromethane) provided 0J2 g of the title compound: MS(ES) 265 (M+H+). f.) 4-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan-l- carboxylic acid benzyl ester
To a solution of the amino alcohol of Example 280e (720 mg, 2.72 mmol) in CH2C12 was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with IN HCl, sat. K Oj, water, brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3% methanoLdichloromethane) gave 1.0 g of the title compound: MS(ES) 478 (M+H+).
g.) [(S)-l-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester
To a solution of the compound of Example 280f (1.0 g) and 10% Pd/C (catalytic) in ethyl acetate:methanol (2: 1 solution) was affixed a balloon of hydrogen. The reaction was stirred until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated to provide 0.82 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 reaction was stirred until complete as determined by MS analysis whereupon it was filtered, concentrated. The residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL) was added. The reaction was maintained at room temperature until complete consumption of the starting material whereupon it was concentrated. The residue was dissolved in methanol whereupon p-carbonate resin was added. The mixture was shaken at room temperature for 4 hours then filtered and concentrated to provide 0.64 g of the title compound. i.) Benzofuran-2-carboxylic acid f(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-hydroxy- azeρan-4-y lcarbamoyl] 3-methyl-butyl } -amide
To a solution of the compound of Example 280h (0.15 g) in CH2C12 was added benzofuran-2-carboxylic acid (0.56 mmol), HOBt (0.09 mg), and p-EDC (0.75 mg). The reaction was stirred overnight whereupon trisamine (0.50 g) was added and stirred an additional 1.5 hours. The reaction was filtered and concentrated to provide the title compound.
j.) Benzofuran-2-carboxylic acid f(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]3-methyl-butyl }-amide
To a solution ofthe compound of Example 280i (0.3 mmol) in CH2C12 was added Dess-Martin periodinane (0.25 g). The reaction was stirred until complete as determined by 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
Preparation of (S)-4-Methyl-2-(3-piperidin-l-yl-propanoylamino)-pentanoic acid [3-oxo-l- (pyridme-2-sulfonyl)-azepan-4-yl1-amide
Following the general procedures of Examples 280h-j except substituting 2- pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride and 1-piperidinepropionoic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 521.9 (M+H)+.
Example 282
Preparation of Benzofuran-2-carboxylic acid f (S)-l-r-(4-ethyl-benzensulfonyl)-3-oxo- azepan-4-ylcarbamovn-3-methyl-l-butyl}- amide
Following the general procedures of Examples 280h-j except substituting 4- ethylnezenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride the title compound was prepared: Separation of the diastereomers provided diastereomer 1 MS(ES) 554.4 (M+H)+ and distereomer 2 MS(ES) 554.4 (M+H)+.
Example 283
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-f 3- oxo-l-[l-(l-oxy-pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide
a.) 4-((S)-2-Amino-4-methyl-pentanoylamino)-3-hydroxy-azepane- 1-carboxylic acid benzyl ester
To a solution of the compound of Example 280f (7.32 g) in methanol was added 4M HCl in dioxane (38 mL). The reaction was stirred until complete whereupon it was concentrated 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 was added 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 temperature until complete as determined by TLC analysis. Workup and column chromatography provided 1.35 g of the title 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 acetate:methanol
(20 mL of an 8:1 mixture) was added 10% Pd\C. The mixture was stirred under a balloon of hydrogen gas until complete consumption of the starting material was observed by TLC analysis. The reaction was filtered and concentrated to provide 0.96 g of the title compound which was used directly in the following reaction with no further purification. 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-ylcarbamoyl}-butyl)-amide
To a solution of the compound of Example 283c (0.3 g) in dichloromethane was added TEA (0.22 mL), EDC (0.13 g), HOBt (0.8 g) and picolinic acid N-oxide (0.09 g). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column 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- 1- [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) was added TEA (0.37 mL) and pyridine sulfur trioxide complex (0.21 g). The reaction was stirred until complete as determined by LCMS. Workup and column chromatography (10% mefhanohdichloromefhane) provided 0.12 g of the title compound: MS (ES) 601 (M+H)+. The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2.
Example 284
Preparation of Benzo[1.31-dioxole-5-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-ri-oxy- pyridin-2-yl)-methanovn-azepan-4-ylcarbamoyl}-butyl)-amide
Following the general procedures of Examples 283b-e except substituting piperonylic acid for 5-[3-(trifluoromethyl) phenyl] -2-furoic acid the title compound was prepared: MS(ES) 511 (M+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2.
Example 285
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid f (S)-l-ri-(3- cvclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-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 and diastereomer 2.
Example 286
Preparation of BenzofL31-dioxole-5-carboxylic acid f(S)-l~ri-(3-cyeιohexyl-propanoyl)-3- oxo-azepan-4-ylcarbamoyl1-3-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) phenyl]-2-furoic acid the title compound was prepared: MS(ES) 528 (M+H)\
The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2.
Example 287
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid f(S)-l-|"l-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-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: MS(ES) 578 (M+H)+. The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2.
Example 288
Preparation of BenzorL31-dioxole-5-carboxylic acid f (S)-l-ri-(4-methyl-pentanoyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide
Following the general procedures of Examples 283b-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+H)+.
The diastereomers were separated by HPLC to provide diastereomer 1 and diastereomer 2.
Example 289
Preparation of Benzofuran-2-carboxylic acid f (S)l-r3-oxo-l-(propane-l-sulfonyl)-azepan- 4-y lcarbamoyl] -3-methyl- 1 -butyl } - amide
Following the general procedures of Examples 280h-j except substituting propanesulfonyl chloride for 3-fluorosulfonyl chloride the title compound was prepared.
Separation 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
Preparation of Benzofuran-2-earboxylic acid r(S)-l-[3-oxo-l-(ethanesulfonyl-azepan-4- ylcarbarnoyl)-3-methyl- 1 -butyl]- amide
Following the general procedures of Examples 280h-j except substituting ethanesulfonyl chloride for 3-fluorobenzenesulfonyl chloride the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 477.4 (M+H)+ and diastereomer 2: MS(ES) 477.4 (M+H)+.
Example 291
Preparation of 5-Fluoro-benzofuran-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl}-amide
a.) f(S)-l-[3-Hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3- methy 1-butyl} -carbamic acid tert-butyl ester
Generation 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 chlorine gas for approximately 90 minutes. The dissolved chlorine was removed under vacuum at 0°C.
To a solution of [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester of Example 280g (2.5 g, 7.28 mmol) in CH2C12 (100 mL) and sat. NaHCO3 (400 mL) was added the solution of 2-pyridinesulfonylchloride-N-oxide (27 mL, 102 mg/mL) dropwise in portions. As the addition proceeds additional sat. NaHCO3 is added in order to maintain the pH at approximately 8-9. Upon complete addition of the sulfonylchloride the reaction is stirred for an additional hour whereupon the organic layer was removed and washed with brine. The organic layer was evaporated and the residue chromatographed (5% methanoLdichloromethane) to provide 2.5 g of the title compound: MS (ES) 500 (M+H*).
b.) (S)-2-Amino-4-methyl-pentanoic acid-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-yl] -amide
To a solution of f (S)-l-[3-hydroxy-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-3-methyl-butyl} -carbamic acid tert-butyl ester of Example 291a (2.0 g) in methanol (20 mL) was added 4 M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 1.5 hours whereupon it was concentrated to provide 1.8 g of the title compound: MS (ES) 400 (M+H+). c.) 5-Fluoro-benzofuran-2-carboxylic acid f (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 CH2C12 was added 5- fluoro-benzofuran-2-carboxylic acid (0.11 g), EDC (0.13 g), HOBt (0.086 g), and TEA (0.22 mL). The reaction was stirred until complete as determined by LCMS whereupon it was diluted with ethyl acetate and washed with water, sat. KjCO.,, IN HCl, brine, dried (MgSOψ), 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 f(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) was added sulfur trioxide pyridine complex (0.26 g). The reaction was stirred until complete as determined by LCMS whereupon it was diluted with ethyl acetate and washed with sat. NaHC03, brine dried, filtered and concentrated. Column chromatography of the residue provided 0.15 g of the title compound as a mixture of diastereomers: MS(ES) 561 (M+H)+. Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 292
Preparation of 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-r3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl}-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 provided the title compound as a mixture of diastereomers: MS(ES) 575 (M+H)+. Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. Example 293
Preparation of 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l- fl-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-aιrude
Following the general procedure of Examples 291c-d except substituting 6-fluoro- 3-methyl benzofuran-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 575 (M+H)+.
Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 294
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f(R -3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
Following the general procedures of Examples 280f-i except substituting N-Boc-D- leucine for N-Boc-L-leucine, 2-pyridinesulfonylchloride N-oxide for 3- fluorobenzenesulfonyl chloride and 3-methyl-benzofuran-2-carboxylic acid for benzofuran- 2-carboxylic acid the title compound was prepared: MS(ES) 556 (M+H)+.
Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 295
Preparation of 3-Methyl-furor3.2-b1-pyridine-2-carboxylic acid f (S)-3-methyl-l-r-3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-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 provided the title compound as a mixture of diastereomers: MS(ES) 558 (M+H)+.
Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 296
Preparation of 5-Mefhoxy-benzofuran-2-carboxylic acid f(S)-l-ri-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the general procedure of Examples 280h-j except substituting 5- methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 574.5
(M+H)+ and diastereomer 2 574.5 (M+H)+.
Example 297
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f (S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl}-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 compound as a mixture of diastereomers.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 557.4 (M+H)+ and diastereomer 2 557.4 (M+H)\ Example 298
Preparation of Benzo[b]thiophene-2-carboxylic acid f (S)-l-Fl-(3-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
Following the general procedure of Examples 280h-j except substituting benzo[b]thiophene-2-carboxylic acid_for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 559.4
(M+H)+ and diastereomer 2 559.4 (M+H)+.
Example 299
Preparation of 3-Methyl-furan-2-earboxylic acid f(S)-l-ri-(3-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-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 mixture of diastereomers.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.2 (M+H)+ and diastereomer 2 507.4 (M+H)\
Example 300
Preparation of Ouinoline-2-carboxylic acid f(S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl] -3-methyl-butyl } -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 a mixture of diastereomers.
Separation 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
Preparation of Thienor3.2-b]thiophene-2-carboxylic acid f (S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the general procedure of Examples 280h-j except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers. Separation 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
Preparation of Ouinoxaline-2-carboxylic acid f (S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-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.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 555.4 (M+H)+ and diastereomer 2 MS(ES) 555.4 (M+H)+. Example 303
Preparation of Thiophene-2-carboxylic acid f ('S)-l-ri-(3-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the general procedure of Examples 280h-j except substituting thiophene- 2-carboxylic acid for benzofuran-2-carboxyIic acid provided the title compound as a mixture of diastereomers.
Separation of the diastereomers by HPLC provided diastereomer T. MS(ES) 509.4 (M+H)+ and diastereomer 2 MS(ES) 509.2 (M+H)\
Example 304
Preparation of 5-Methyl-thiophene-2-carboxylic acid f(S)-l-ri-(3-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamovn-3-methyl-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 compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1 : MS(ES) 523.2
(M+H)+ and diastereomer 2 MS(ES) 523.4 (M+H)+.
Example 305
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid r(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyll-amide
Following the general procedure of Examples 280h-j except substituting 5- methoxy-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation 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
Preparation of 3-Methyl-benzofuran-2-carboxylic acid r(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-mefhyl-butyll-amide
Following the general procedure of Examples 280h-j except substituting 3-methyl- benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers.
Separation 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
Preparation of Benzorblthiophene-2-carboxylic acid [("S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyn-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. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 493.4 (M+H)+ and diastereomer 2 MS(ES) 493.4 (M+H)+.
Example 308
Preparation of 3-Methyl-furan-2-carboxylic acid r(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl1-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. Separation 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
Preparation of Ouinoline-2-carboxylic acid r(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyll-amide
Following the general procedure of Examples 280h-j except substituting quinolihe-
2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3- flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation 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
Preparation of Thienor3,2-b1thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl1-amide
Following the general procedure of Examples 280h-j except substituting thieno[3,2-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.
Separation 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
Preparation of Quinoxaline-2-carboxylic acid r(S)-l-(l-efhanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyll-amide
Following the general procedure of Examples 280h-j except substituting quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation 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
Preparation of Thiophene-2-carboxylic acid r(S)-l-(l-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl1-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.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 443.4 (M+H)+ and diastereomer 2 MS(ES) 443.2 (M+H)\
Example 313
Preparation of 5-Methyl-thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide
Following the general procedure of Examples 280h-j except substituting 5-methyl- 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. Separation of the diastereomers by HPLC provided diastereomer 1 : MS(ES) 457.2
(M+H)+ and diastereomer 2 MS(ES) 457.4 (M+H)+.
Example 314
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid f(S)-lT3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyll-3-methyl- 1-butyl }- 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 compound as a mixture of diastereomers.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 521.4 (M+H)+ and diastereomer 2 MS(ES) 521.2 (M+H)+.
Example 315
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f(S)-l-[3-oxo-l-(propane-l- sulf onyl)-azepan-4-y lcarbamoyl] -3-methyl- 1 -butyl } - amide
Following the general procedure of Examples 280h-j except substituting 3-methyl- benzofuran-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. Separation 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
Preparation of BenzoFblthiophene-2-carboxylic acid f (S)-l-F3-oxo-l-(propane-l-sulfonyl)- azepan-4-ylcarbamoyn-3-methyl-l-butyl)- amide
Following the general procedure of Examples 280h-j except substituting benzo[b]thiophene-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.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.4 (M+H)+ and diastereomer 2 MS(ES) 507.4 (M+H)+.
Example 317
Preparation of 3-Methyl-furan-2-carboxylic acid f(S)-l-F3-oxo-l-(propane-l-sulfonyl)- azeρan-4-ylcarbamoyl]-3-methyl- 1-butyl } - amide
Following the general procedure of Examples 280h-j except substituting 3-mefhyl- furan-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. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 455.2
(M+H)+ and diastereomer 2 MS(ES) 455.4 (M+H)+.
Example 318
Preparation of 2.5-Dimethyl-benzofuran- 2-carboxylic acid f (S)-l-F3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide
Following the general procedure of Examples 280h-j except substituting 2,5- dimethyl-benzofuran-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.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 469.4 (M+H)+ and diastereomer 2 MS(ES) 469.2 (M+H)+.
Example 319
Preparation of Ouinoline-2-carboxylic acid f(S)-l-F3-oxo-l-(ρropane-l-sulfonyl)-azepan-4- ylcarbamoyll-3-methyl-l-butyl}- amide
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. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 565.2 (M+H)+ and diastereomer 2 MS(ES) 565.2 (M+H)+.
Example 320
Preparation of ThienoF3,2-b]thiophene-2-carboxylic acid f (S)-l-F3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl1-3-methyl-l-butyl}- amide
Following the general procedure of Examples 280h-j except substituting thieno[3,2-b]thiophene-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.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 513.2 (M+H)+ and diastereomer 2 MS(ES) 513.2 (M+H)+.
Example 321
Preparation of Quinoxaline-2-carboxylic acid l(S)-l-f3-oxo-l-(propane-l-sulfonvD- azepan-4-ylcarbamoyn-3-methyl-l-butyl}- amide
Following the general procedure of Examples 280h-j except substituting quinoxaline-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. Separation 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
Preparation of Thiophene-2-carboxylic acid f (S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan- 4-ylcarbamoyl1-3-methyl- 1-butyl }- amide
Following the general procedure of Examples 280h-j except substituting thiophene- 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.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 457.4 (M+H)+ and diastereomer 2 MS(ES) 457.4 (M+H)+.
Example 323
Preparation of 5-Methyl-thiophene-2-carboxylic acid f (S)-l-r3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl1-3-methyl- 1-butyl }- amide
Following the general procedure of Examples 280h-j except substituting 5-methyl- thiophene-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. Separation 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
Preparation of 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-f3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-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 acid provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+.
Separation 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
Preparation of 3,5-Dimethyl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-r3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-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 (M+H)+.
Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. Example 326
Preparation of 3-Ethyl-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulf onyl)-azepan-4-ylcarbamoyll-butyl } -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 title compound as a mixture of diastereomers: MS(ES) 571 (M+H)+. Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 327
Preparation of 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-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-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 328
Preparation of l-Methyl-naphtho[2,l-b]-furan-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l- ( l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide
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)+.
Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2. Example 329
Preparation of 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid f (S)-3-methyl-l-f3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-amide
Following the general procedure of Examples 291c-d except substituting 6- methoxy-3-methyl-benzofuran-2-carboxyliG acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. Separation of the diastereomers by HPLC provided diastereomer 1 and diastereomer 2.
Example 330
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f L3-dimethyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl}-amide
a.) 4-(2-tert-Butoxycarbonylamino-2,4-dimethyl-pentanoylamino)-3-hydroxy- azepane- 1-carboxylic acid benzyl ester To a solution of N-[(l,l-dimethylethoxy)carbonyl]-2-methyl-(d,l)-leucine (3.0g) in methlene chloride was added EDC (2.34g), HOBt (1.65g), Et3N (1.7 ml) and the compound of Example 280e (3.23 g). After stirring at room temperature over night the mixture was washed with 0.1N HCl, Sat. NaHCO3, H O, Brine. The organic layer was concentrated and residue was purified by flash column chromatography eluting with CH2C12 : 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 ethyl acetate (50 mL) was added 10% palladium on carbon (1.5 g). After stirring at room temperature under a hydrogen atmosphere 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)+. c.) { l-[3-Hydroxy-l-(l-hydroxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-l,3- dimethy 1-butyl} -carbamic acid tert-butyl ester
2-Mercaρtane N-oxide (1.25g) was disolved in concentrated HCl (5.5ml). After cooled to 0°C water (3ml) was added. Cl2 gas was bubbled through this solution for 1.5h. Water solution was extacted with cold CH2C12 then the combined organic layer was washed with Sat.NaHCO3, 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 freshly prepared above at 0°C. Stirring was kept for lh then the reaction mixture was washed with brine, dried over Na2SO4, concentrated and purified through flash column chromatograpghy eluting with CH2C12: CH3OH (95:5). The filtrate was concentrated to yield the title compound as white solid (1.2 g, 70%). MS: 515.4 (M+H)+.
d.) 2-Amino-2,4-dimethyl-pentanoic acid [3-hydroxy-l-(hydroxy-pyridine-2-sulfonyl)- azepan-4-yl]-amide
To a stirring solution of the compound of Example 330c (l.Og, 2.04 mmol) in methanol (10ml) was added HCl (4M in Dioxane) (10 ml). After stirring at room temperature for 3hr, the solution was concentrated to get white solide. To a solution of the white 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 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 CH2C12 (20 mL) was added 3-methyl benzofuran-2-carboxylic acid (0.109 g), 1- hydroxybenzotriazole (0.106g, 0J62mmol), and P-EDC (0.85g, lmmol/g) in CH2C12 (10 mL) . After shaking at room temperature for over night, the solution was treated with tisamine (0.589g, 3J5mmol/g). After shaking for another 2hr, the solution was filtered and concentrated to yield the title compound as a white solid (166Jmg, 70%). MS (ESI): 573.2(M+H)+. f.) 3-Methyl-benzofuran-2-carboxylic acidf 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 (140Jmg, 0.245mmol) in DMSO (2mL) was added Py-SO3 (155.7mg, 0.98mmol) and Et N (0.27ml, 1.96mmol). After stirring at room temperature for 2 h. Sat. NaHCO3 and ethyl acetate was added to quench the reaction. Organic layer was washed with brine, dried over Na SO4 and concentrated.The residue was purified through flash column chromatograghy eluting with CH2C12 :CH3OH (95:5) to yield the title compound as a white solid (69.9mg, 50.8 %). MS (ESI): 571.2(M+H)+ .
Example 331
Preparation of Benzofuran-2-carboxylic acid r(S)-3-methyl-l-r3-oxo-l-quinolin-2- ylmethyl-azepan-4-ylcarbamoyll-butyll-amide
a.) [(S)-l-(3-Hydroxy-l-quinoline-2-ylmethyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid terr-butyl ester
To a solution of the compound of Example 280g (1.0 g) in CH2C12 was added α- quinoline carbaldehyde (0.68 g) and NaBH(OAc)3 (1.2 g). Workup and column 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 To a solution of the compound of Example 33 la (1.4 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred until complete whereupon the reaction was concentrated to provide 1.3 g of the title compound: MS(ES) 385 (M+H)+.
c. ) Benzofuran-2-carboxylic acid [(S)-3-methy 1-1 -[3-hydroxy- l-quinolin-2-y lmethyl- azepan-4-ylcarbamoyl]-butyl}-amide
Following the general procedure of Example 291c except substituting the compound 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-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyl- azepan-4-ylcarbamoyl]-butyl } -amide
Following the general procedure of Example 29 Id except substituting the compound of Example 331c the title compound was prepared: MS(ES) 543 (M+H)+.
Example 332
Preparation of 3-Methyl-benzofuran-2-carboxylic acid r(S)-3-methyl-l-r3-oxo-l-quinolin- 2-ylmethyl-azepan-4-ylcarbamoyl1-butyl}-amide
Following the procedure of Example 331c-d except substituting 3-methyl- benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 541 (M+H)+.
Example 333
Preparation of Benzo[blthiophene-2-carboxylic acid [(S)-3-methyl-l-r3-oxo-l-quinolin-2- ylmethyl-azepan-4-ylcarbamoy 1] -butyl } -amide
Following the procedure of Example 331c-d except substituting benzo[b]thiophene- 2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 541 (M+H)+. Example 334
Preparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-[l-toluene-2- sulfonylamino)-methanoyl1-azepan-4-ylcarbamoyl}-butyl)-amide
a.) ((S)-l-{3-Hydroxy-l-[l-(toluene-2-sulfonylamino)-methanoyl]-azepan-4- ylcarbamoyl}-3-methyl-butyl)-carbamic acid tert-butyl ester
To a solution of the compound of Example 280g (1.0 g) in CH2C12 was added o- toluenesulfonyl isocyanate (0.68 g). The reaction was stirred until complete consumption of the starting material was observed. Workup and column chromatography (6% methanoLdichloromethane) provided 1.28 g of the title compound: MS(ES) 541 (M+H)+.
b.) (S)-2-Amino-4-methyl-pentanoic acid f3-hydroxy-l-[l-(toluene-2-sulfonylamino)- methanoyl]-azepan-4-yl}-amide Following the procedure of Example 283a except substituting the compound of
Example 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 of
Example 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 29 Id except substituting the compound of
Example 334c the title compound was prepared: MS(ES) 583 (M+H)+.
Example 335
Preparation of 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-mefhyl-l-f 3-oxo-l-fl- toluene-2-sulfonylamino)-methanovn-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334c-d except substituting 3-methyl- benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+.
Example 336
Preparation of Benzo[b]thiophene-2-carboxylic acid ((S -3-methyl-l-f 3-oxo-l-ri-toluene- 2-sulfonylamino)-methanoyl1-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334c-d except substituting
Benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 599 (M+H)+.
Example 337
Preparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-f 3-oxo-l-r2-chloro- benzenesulfonylamino)-methanoyn-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting 2- chlorobenzenesulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 603 (M+H)+.
Example 338
Preparation of 3-Methyl-benzofuran-2-carboxylic acid ((S -3-methyl-l-f 3-oxo-l-f2-chloro- benzenesulfonylamino)-methanoyll-azepan-4-ylcarbamoyl}-butyl)-amide
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 was prepared: MS(ES) 617 (M+H)+.
Example 339
Preparation of Benzorblthiophene-2-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-[2-chloro- benzenesulfonylamino)-methanoyl1-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting 2-chlorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 619 (M+H)+.
Example 340
Preparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-f 3-oxo-l-[4-fluoro- benzenesulfonylamino)-methanoyll-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting 4-fluorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 587 (M+H)+. Example 341
Preparation of 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-r4-fluoro- benzenesulfonylamino)-methanoyl1-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334-d except substituting 4-fluorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 601 (M+H)+.
Example 342
Preparation of Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-f3-oxo-l-[4-fluoro- benzenesulfonylamino)-methanovn-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting 4-fluorobenzene sulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 603 (M+H)+. Example 343
Preparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-f 3-oxo-l-[l-toluene-4- sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting p-toluenesulfonyl isocyanate for o-toluenesulfonyl isocyanate the title compound was prepared: MS(ES) 583 (M+H)+.
Example 344
Preparation of 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-mefhyl-l-f3-oxo-l-ri- toluene-4-sulfonylamino)-methanoyl1-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting p-toluenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and 3-methyl-benzofuran-2-carboxylic acid_for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+.
Example 345
Preparation of Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-f 3-oxo-l-ri-toluene- 4-sulfonylamino)-methanoyll-azepan-4-ylcarbamoyl}-butyl)-amide
Following the procedures of Example 334a-d except substituting p-toluenesulfonyl isocyanate for o-toluenesulfonyl isocyanate and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid the title compound was prepared: MS(ES) 597 (M+H)+.
Example 346
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methyl-l-[l-(6-methyl-pyridin-2- ylmethyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl}-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 and diastereomer 2. Example 347
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f(S)-3-mefhyl-l-lT-(6-methyl- pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamovn-butyl}-amide
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)+. The diastereomers were separated by HPLC to provide diastereoemr 1 and diastereomer 2.
Example 348
Preparation of Benzo[blthiophene-2-carboxylic acid f (S)-3-methyl-l-[l-(6-methyl-pyridin- 2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } -amide
Following the general procedures of Example 331a-d except substituting 6- methylpyridine-2-aldehyde for α-quinoline carbaldehyde and benzo[b]thiophene-2- 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 and diastereomer 2.
Example 349
Preparation of Benzorblthiophene-2-carboxylic acid f (S)-l-fl-(2-fluoro-phenylcarbamoyl)- 3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl}-amide
a.) f (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 in THF was added 2-flurophenyl isocyanate (32 ml, 0.29 mmol) and stirred for lhr. THF was removed in vaccuo and the compound was directly 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 (2-fluoro-phenyl)-amide
To a solution of the compound of Example 349a (1.96 g, 4.1 mmol) dissolved in
MeOH was added 4M HCl/ dioxane (5ml, 20.3 mmol) and allowed to stir at RT for 2hr.
Excess reagent was removed in vaccuo and azeotroped with toluene to yield 1.84gm of the product.
c.) Benzo[b]thiophene-2-carboxylic acid f (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3- hydroxy-azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide
To a solution of the compound of Example 349b (0.11 g, 0.28 mmol) dissolved in dichloromethane were added P-EDC (0.35 g , 1.8 mmol/g), HOBT ( 0.06 g, 0.49 mmol) and 2-benzothiophene carboxylic acid (0.077 gm, 0.432 mmol). The reaction mixture was shaken for 16 hr. The reaction was continued for one more hour by the addition of trisamine(0.38 gm, 3.1 mmol/g), followed by the filtration of the product. The product was purified on a silica gel column to yield 112.5 mg of the product: MS(ES): 541.2(M+H)\
d.) Benzo[b]thiophene-2-carboxylic acid f (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
To a solution of the compound of example 349c (0.112 g, 0.2 mmol) was dissolved in dichloromethane followed by the addition of Dess-Martin periodinane (0.175 g, 0.41 mmol). The reaction was stirred for lhr followed whereupon it was washed with Na2S2O3, NaHCO3 and brine. The compound was purified on a silica gel column to yield 78 mg of the product as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS (ES) 539 (M+H)+ and diastereomer 2: 539 MS(ES) (M+H)+.
Example 350
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the general procedures of example 349c-d except substituting 3-methyl- benzofuran-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 537 (M+H)+ and diastereomer 2: MS(ES) 537 (M+H)+.
Example 351 Preparation of 2,4-Dimethylfuran-3-carboxylic acid f (S)-l-ri-(2-fluoro-phenylcarbamoyl)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-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 title compound was prepared.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 501 (M+H)+ and diastereomer 2: MS(ES) 501 (M+H)+.
Example 352
Preparation of Quinoxaline-2-carboxylic acid f (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the general procedures of example 349c-d except substituting quinoxaline-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 535
(M+H)+ and diastereomer 2: MS(ES) 535 (M+H)+. Example 353
Preparation of Thieno[3.2-blthiophene-2-carboxylic acid f (S)-l-ri-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the general procedures of example 349c-d except substituting thieno[3,2-b]thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 545 (M+H)+ and diastereomer 2: MS(ES) 545 (M+H)+.
Example 354
Preparation of Quinoline-2-carboxylic acid f(S)-l-fl-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyl}-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 was prepared. Separation of the diastereomers by HPLC provided diastereomer 1 : MS(ES) 534
(M+H)+ and diastereomer 2: MS(ES) 534 (M+H)+.
Example 355
Preparation of 4-Methyl-thiophene-2-carboxylic acid f(S)-l-ri-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyn-3-methyl-butyl}-amide
Following the general procedures of example 349c-d except substituting 4-methyl- thiophene-2-carboxylic acid for benzo[b]thiophene-2-carboxylic acid the title compound was prepared.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 503 (M+H)+ and diastereomer 2: MS(ES) 503 (M+H)\ Example 356
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid f (S)-l-ri-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-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 title compound was prepared.
Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 553 (M+H)+ and diastereomer 2: MS(ES) 553 (M+H)+.
Example 357
Preparation of 4-Methyl-furan-2-carboxylic acid f (S)-l-ri-(2-fluoro-phenylcarbamoyl)-3- oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl } -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 was prepared. Separation of the diastereomers by HPLC provided diastereomer 1 : MS(ES) 487
(M+H)+ and diastereomer 2: MS(ES) 487 (M+H)+.
Example 358
Preparation of Benzofuran-2-carboxylic acid [(S)-l-(l-butyl-3-oxo-azepan-4-ylcarbamoyl)- 3-methyl-butyll-amide
Following the general procedure of Examples 331a-d except substituting butyraldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1 : MS(ES) 441.9 (M+H)+ and diastereomer 2: MS(ES) 441.9 (M+H)+. Example 359
Preparation of Benzofuran-2-carboxylic acid r(S)-l-(l-propyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butvn-amide
Following the general procedure of Examples 331a-d except substituting propionaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 428 (M+H)+ and diastereomer 2: MS(ES) 428 (M+H)\
Example 360
Preparation of Benzofuran-2-carboxylic acid f(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. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) (M+H)+ and diastereomer 2: MS(ES) 494.2 (M+H)+.
Example 361
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methyl-l-[l-(2-moφholin-4-yl-thiazol- 4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl1-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 compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 568.2 (M+H)+ and diastereomer 2: MS(ES) 568.4 (M+H)+. Example 362
Preparation of Benzofuran-2-carboxylic acid f (S -l-[l-(5-ethyl-furan-2-ylmethyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyl|-amide
Following the general procedure of Examples 331a-d except substituting 5-ethyl-2- furaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 549.4 (M+H)+ and diastereomer 2: MS(ES) 549.4 (M+H)\
Example 363
Preparation of Benzofuran-2-carboxylic acid f (S)-l-[l-(3,4-dimethyl-thieno[3.2- b]thiophene-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the general procedure of Examples 331a-d except substituting 3,4- diemethylthieno[b]thiophene-2-carboxaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 566.2 (M+H)+ and diastereomer 2: MS(ES) 566.2 (M+H)\
Example 364
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(3-phenyl-3H- rL2,31triazol-4-ylmethyl)-azepan-4-ylcarbamoyl]-butyl}-amide
Following the general procedure of Examples 331a-d except substituting 2-phenyl- 2H-pyrazole-3-carbaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 543.2 (M+H)+ and diastereomer 2: MS(ES) 543.4 (M+H)\ Example 365
Preparation of Benzofuran-2-carboxylic acid f(S)-lTl-dsothiazol-3-ylmethyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl)-amide
Following the general procedure of Examples 331a-d except substituting isothiazole-3-carbaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation 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
Preparation of Benzofuran-2-carboxylic acid r(S)-3-methyl-l-(3-oxo-l-thiophen-2- ylmethyl-azepan-4-ylcarbamoyl)-butyl1-amide
Following the general procedure of Examples 331a-d except substituting thiophene-2-carbaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 582 (M+H)+ and diastereomer 2: MS(ES) 582 (M+H)+.
Example 367
Preparation of Benzofuran-2-carboxylic acid r(S)-3-methyl-l-(3-oxo-l-thiophen-2- ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide
Following the general procedure of Examples 331a-d except substituting benzo[b]thiophene-2-carbaldehyde for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 546 (M+H)+ and diastereomer 2: MS(ES) 546 (M+H)+. Example 368
Preparation of Benzofuran-2-carboxylie acid [YS)-3-mefhyl-l-(3-oxo-l-pentyl-azepan-4- ylcarbamovD-butyll-amide
Following the general procedure of Examples 331a-d except substituting pentanal for α-quinoline carbaldehyde the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 556 (M+H)+ and diastereomer 2: MS(ES) 556 (M+H)+.
Example 369
Preparation of Benzofuran-2-carboxylic acid f (S)-3-methyl-l-ri-(l-methyl-lH-imidazol-2- ylmethyl)-3-oxo-azepan-4-ylcarbamoyl1-buty}-amide
Following the general procedure of Examples 331a-d except 'substituting 3-methyl- 3H-imidazole-4-carbaldehyde for α-quinoline carbaldehyde the title compound was prepared: MS(ES) 480.4 (M+H)+ .
Example 370
Preparation of l-Oxy-pyridine-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-y lcarbamoyl 1 -butyl } -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. Separation of the diastereomers by HPLC gave diastereomer 1 (ESMS: M+H* = 504.2) and diastereomer 2 (ESMS: M+H+ = 504.2). Example 371
Preparation of 2-Oxy-pyridine-3-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl 1-butyl}-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. Separation of the diastereomers by HPLC gave diastereomer 1 (ESMS: M+FF = 504.2) and diastereomer 2 (ESMS: M+H+ = 504.2).
Example 372 Preparation of lH-Benzoimidazole-5-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
Following the procedure of Example 280h-j except substituting \H- benzoimidazole-5-carboxylic acid for 2-benzofuran-2-carboxylic acid and 2- pyridinesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1 (ESMS: M+ET = 504.2) and diastereomer 2 (ESMS : M+H+ = 504.2).
Example 373
Preparation of 4-f(S)-2-[(l-Benzofran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino}-l-methyl-3-oxo-l-pentyl-azepanium
A solution of the compound of Example 368 in neat methyl iodide was heated at reflux for 48 hours whereupon the mixture was concentrated to provide the title compound: MS(ES) 471.6 (M+H)+. Example 374
Preparation of Benzofuran-2- carboxylic acid f(S)-l-fl-(L2-dimethyl-l H -imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example 280h-j except substituting 1,2-dimethyl-l H - imidazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound: MS(ES) 544.4 (M+H)\
Example 375
Preparation of Benzofuran-2- carboxylic acid f (S)-l-ri-(l-methyl-l H -imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl}-amide
Following the procedure of Example 280h-j except substituting 1 -methyl- 1 H - imidazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound: MS(ES) 530.2 (M+H)*.
Example 376
Preparation of Benzofuran-2- carboxylic acid f(S)-l-ri-(l-methyl-l H -imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 280h-j except substituting 4-methanesulfonyl- benzenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 604.2 (M+H)+ and diastereomer 2: MS(ES) 604.2 (M+H)+.
Example 377
Preparation of Benzofuran-2-carboxylic acid f (S)-l-ri-(2-methanesulfonyl- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example 280h-j except substituting 2-methanesulfonyl- benzenesulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation 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
Preparation of Benzofuran-2-carboxylic acid f (S)-l-[l-(3,5-dimethyl-isoxazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoy n-3-methyl-butyl } -amide
Following the procedure of Example 280h-j except substituting 3,5-dimethyl- isoxazole-4-sulfonyl chloride for 3-fluorobenzenesulfonyl chloride provided the title compound. Separation of the diastereomers by HPLC gave diastereomer 1: MS(ES) 545.2 (M+H)+ and diastereomer 2: MS(ES) 545.2 (M+H)+.
Example 379
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f (lS,2R)-2-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-amide
a.) 3-Methyl-benzofuran-2-carboxylic acid f(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. b.) 3-Methyl-benzofuran-2-carboxylic acid f (lS,2R)-2-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide
Following the general procedure of Example 29 Id except substituting the compound of Example 105b the title compound was prepared. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 541 (M+H)+ and diastereomer 2: MS(ES) 541 (M+H)+.
Example 380
Preparation of 3-Methyl-benzofuran-2-carboxylic acid f l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl1-cyclopentyl}-amide
Following the general procedures of Examples 379a-b except substituting N-Boc- cycloleucine for N-Boc-allo-leucine the title compound was prepared: MS(ES) 539 (M+H)+.
Example 381
Preparation of Furor3,2-b1-pyridine-2-carboxylic acid f (S)-3-methyl-l-r-3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-amide
Following the general procedure of Examples 291c-d except substituting furo [3,2- b]-pyridine-2-carboxylic acid for 5-fluoro-benzofuran-2-carboxylic acid provided the title compound as a mixture of diastereomers: MS(ES) 587 (M+H)+. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 544.2
(M+H)+ and diastereomer 2: MS(ES) 544.2 (M+H)+.
The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims

We claim:
A compound of Formula IA:
IA wherein:
R s selected from the group consisting of:
R is selected from the group consisting of: C\ -galkyl, Ar-CQ-galkyl, Het- CQ-galkyl, R9C(O)-, R9SO2-, R9R1 1NC(O)-, and R9SO2RHNC(O)-;
R3 is Ci -galkyl;
R4 is R5C(O)-, R5 is Het-CQ-galkyl;
R9 is selected from the group consisting of: Ci -galkyl, C3-gcycloalkyl-Co-galkyl, Ar-CQ-galkyl and Het-CQ-galkyl; RI * is selected from the group consisting of: H, Cχ_galkyl, Ar-Cθ-galkyl, and Het-
Co-6alkyl;
R' is H; R" is H; R'" is H; R"" is selected from the group consisting of: Ci -galkyl, C3_gcycloalkyl-CQ_galkyl
C _6alkenyl, C2-6alkynyl, HetCQ-galkyl and ArCQ-galkyl; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
A compound according to Claim 1 wherein R1 is
3. A compound according to Claim 1 wherein P is selected from the group consisting of: isobutyl and but-2-yl.
4. A compound according to Claim 3 wherein P is isobutyl.
5. A compound according to Claim 1 wherein R-> is selected from the group consisting of: piperidiny 1-ethyl ; benzo[ 1 ,3]dioxolyl; furanyl, aryl substituted furanyl, Cj -galkyl substituted furanyl; benzofuranyl, C -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, C -galkyl substituted furo[3,2-b]-pyridinyl; thiophenyl, Cχ_galkyl substituted thiophenyl; thieno[3,2-b]thiophenyl; and lH-benzoimidazol-5-yl.
6. A compound according to Claim 1 wherein P is selected from the group consisting of: piperidin-1-y 1-ethyl; benzo[l,3]dioxol-5-yl, furan-2-yl; benzofuran-2-yl; napththo[2, l-b]-furan-2-yl benzo [b]thiophen-2-yl ; quinolin-2-yl; quinoxalin-2-yl; l-oxy-ρyridin-2-yl, l-oxy-pyridin-3-yl; furo[3,2-b]-pyridin-2-yl; thiophene-2-yl; thieno[3,2-b]thiophene-2-yl; and lH-benzoimidazol-5-yl.
7. A compound according to Claim 1 wherein R is selected from the group consisting 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-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6- methoxy-3-methyl-benzofuran-2-yl;
1 -methyl-naphtho[2, l-b]-furan-2-yl;
5-methyl-thiophen-2-yl, and
3-methyl-furo[3,2b]pyridin-2-yl.
8. A compound according to Claim 1 wherein R-> is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, 5- methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl.
9. A compound according to Claim 1 wherein RI is
10. A compound according to Claim 9 wherein R"" is Cι_galkyl.
11. A compound according to Claim 10 wherein Ci-galkyl is methyl.
12. A compound according to Claim 1 wherein is
13. A compound according to Claim 12 wherein n is 3.
14. A compound according to Claim 1 wherein R9 is selected from the group consisting of: ethyl, and C3-gcycloalkyl-substituted ethyl; propyl; butyl; isopentyl; phenyl, especially halogen substituted phenyl, C\ -galkyl substituted phenyl,
C -galkylsulfonyl substituted phenyl; pyridinyl, C\ -galkyl substituted pyridinyl;
1-oxy-pyridinyl; and isoxazolyl, Cχ_galkyl substituted isoxazolyl.
15. A compound according to Claim 1 wherein R9 is selected from the group consisting of: cyclohexy 1-ethyl; prop-1-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-imidazol-2-yl, 1-methyl- lH-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl.
16. A compound according to Claim 1 wherein R is selected from the group consisting of: Cχ_galkyl, Ar-CQ-galkyl and Het-CQ-galkyl.
17. A compound according to Claim 16 wherein R^ is selected from the group consisting of: C -galkyl and Het-Co_galkyl.
18. A compound according to Claim 17 wherein C\ -galkyl and Het-Co_galkyl are selected from the group consisting of: Het-substituted methyl and pentyl.
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-mo holin-4-yl-thiazol-4-ylmethyl;
5-ethyl-furan-2-ylmethyl;
3,4dimethyl-thieno[3,2-b]thiophene-2-ylmethyl; 3-phenyl-3H-[l,2,3]triazol-4-ylmethyl; isothiazol-3-ylmethyl; thiophen-2-ylmethyl ; benzo[b]thiophen-2-ylmethyl; and l-methyl-lH-imidazol-2-ylmethyl.
20. A compound according to Claim 1 wherein R2 is selected from the group consisting of: Ar-Cθ-6alkyl, R9C(O)-, R9SO2, and R9RπNC(O)-.
21. A compound according to Claim 20 wherein R is selected from the group consisting of: Ar-Cθ-6alkyl, R9C(O)-, and R9SO2.
22. A compound according to Claim 21 wherein R2 is R9SO2
23. A compound according to Claim 22 wherein R9 is selected from the group consisting of: Cχ_galkyl, Ar-CQ-galkyl and Het-CQ-galkyl.
24. A compound according to Claim 1 wherein:
R2 is R9SO2; and P is isobutyl; R9 is selected from the group consisting of: Cj-galkyl, Ar-Co-galkyl and Het-
CQ-galkyl.
25. A compound according to Claim 24 wherein: R^ is selected from the group consisting of: piperidinyl-ethyl; benzo [ 1 ,3]dioxoly 1 ; furanyl, aryl substituted furanyl, C _galkyl substituted furanyl; benzofuranyl, C _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, Cχ_galkyl substituted furo[3,2-b]-pyridinyl; thiophenyl, Cj -galkyl substituted thiophenyl; thieno[3,2-b]thiophenyl; and lH-benzoimidazol-5-yl; and R9 is selected from the group consisting of: ethyl, C3_gcycloalkyl-substituted ethyl; propyl; butyl; isopentyl; halogen substituted phenyl, Cj -galkyl substituted phenyl, Cχ-galkylsulfonyl substituted phenyl; pyridinyl, C -galkyl substituted pyridinyl; 1-oxy-pyridinyl; and isoxazolyl, Cj-galkyl substituted isoxazolyl.
26. A compound according to Claim 24 wherein: R^ is selected from the group consisting of: piperidin- 1 -y 1-ethyl ; benzo[l,3]dioxol-5-yl; furan-2-yl; benzofuran-2-yl; napththo[2,l-b]-furan-2-yl benzo [b] thiophen-2-y 1 ; quinolin-2-yl; quinoxalin-2-yl;
1 -oxy-ρyridin-2-yl, 1 -oxy-ρyridin-3-yl ; furo[3,2-b]-pyridin-2-yl; thiophene-2-yl; thieno[3,2-b]thiophene-2-yl; and lH-benzoimidazol-5-yl.
27. A compound according to Claim 24 wherein R^ is selected from the group consisting of:
5-(3-triflouromethyl-phenyl)-furan-2-yl, 3-mefhyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, 2,4-dimethyl-furan-2-yl;
5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6- methoxy-3-methyl-benzofuran-2-yl; l-methyl-naphtho[2,l-b]-furan-2-yl; 5-methyl-thiophen-2-yl, and 3-methyl-furo[3,2b]pyridin-2-yl.
28. A compound according to Claim 24 wherein R9 is selected from the group consisting of: cyclohexyl-ethyl; prop-1-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-imidazol-2-yl, l-methyl-lH-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl.
29. A compound according to Claim 24 wherein:
R-> is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2-Z?]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, or quinolin-2-yl; and R9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
30. A compound according to Claim 29 wherein R^ is 3-methyl-benzofuran-2-yl.
31. A compound according to Claim 30 wherein R9 is l-oxy-pyridin-2-yl.
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)-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
Benzofuran-2-carboxylic acid f (S)- l-[-(4-ethyl-benzensulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl- 1-butyl } -amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-{3- oxo- 1 - [ 1 -( 1 -oxy-pyridin-2-yl)-methanoyl]-azepan-4-y lcarbamoyl } -butyl)- amide;
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; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid f(S)-l-[l-(3- cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
Benzo[l,3]-dioxole-5-carboxylic acid f(S)-l-[l-(3-cyclohexyl-propanoyl)-
3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-l-[l-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[l,3]-dioxole-5-carboxylic acid f(S)-l-[l-(4-methyl-pentanoyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid { (S) l-[3-oxo- l-(propane- 1-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-l-butyl}- amide;
Benzofuran-2-carboxylic acid [(S)-l-[3-oxo-l-(ethanesulfonyl-azepan-4- ylcarbamoyl)-3-methyl- 1-butyl]- amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
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;
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-Methyl-benzofuran-2-carboxylic acid f (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-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(3-fluoro- benzenesulfonyl)-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-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid f (S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-methyl-furan-2-carboxylic acid f (S)-l-[l-(3-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoline-2-carboxylic acid {(S)-l-[l -(3-fluoro-benzenesulf onyI)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Thieno[3,2-b]thiophene-2-carboxylic acid f(S)-l-[l-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoxaline-2-carboxylic acid f (S)-l-[l-(3-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Thiophene-2-carboxylic acid { (S)-l-[l-(3-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methyl-thiophene-2-carboxylic acid f (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-butyl]-amide;
3-Methyl-benzofuran-2-carboxylic acid [(S)- 1-( l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
Benzo[b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
3-Methyl-furan-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-methyl-butyl]-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-l-(l-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-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-methy 1-butyl] -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 f(S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid f (S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid f (S)-l-[3-oxo-l-(propane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 3-Methyl-furan-2-carboxylic acid { (S)-l-[3-oxo-l-(propane-l-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 2,5-Dimethyl-furan-2-carboxylic acid {(S)-l-[3-oxo-l-(propane-l- sulf onyl)-azepan-4-ylcarbamoyl]-3-methyl- 1 -butyl } -amide ; Quinoline-2-carboxylic acid f(S)-l-[3-oxo-l-(propane-l-sulfonyl)-azepan- 4-y lcarbamoyl] -3-methyl- 1-butyl } -amide ;
Thieno[3,2-b]thiophene-2-carboxylic acid f (S)-l-[3-oxo-l-(ρropane-l- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl- 1-butyl }-amide; Quinoxaline-2-carboxylic acid { (S)- 1- [3-oxo- l-(propane- 1-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl- 1 -butyl } -amide; Thiophene-2-carboxylic acid { (S)- 1 - [3-oxo- 1 -(propane- 1 -sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl- 1-butyl } -amide; 5-Methyl-thiophene-2-carboxylic acid { (S)-l -[3-oxo- 1 -(propane- 1- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-l-butyl}-amide; 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-[3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3,5-Dimethyl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide; 3-Ethyl-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulf onyl)-azepan-4-y lcarbamoyl] -butyl } -amide ; 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; l-methyl-naphtho[2, l-b]-furan-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid f(S)-3-methyl-l-[3- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-yIcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid { l,3-dimethyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2- ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l- quinolin-2-ylmethyl-azepan-4-y lcarbamoyl] -butyl } -amide ; Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-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)-methanoyl]-azepan-4-ylcarbamoyl } -butyl)-amide;
3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide;
Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide;
B enzofuran-2-carboxylic acid ((S)-3-methy 1- 1 - { 3-oxo- 1 - [2-chloro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;
3-Methy l-benzofuran-2-carboxylic acid ((S)-3-methyl- 1 - { 3-oxo- 1 - [2- chloro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide;
Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-chloro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;
Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4-fluoro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;
3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[4- fluoro-benzenesulfonylamino)-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-ylcarbamoyl}-butyl)-amide;
Benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l-toluene-4- sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide;
3-Methy l-benzofuran-2-carboxy lie acid ((S)-3-methyl- 1 - { 3-oxo- 1 - [ 1 - toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide;
Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[l- toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide; Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 -[ 1 -(6-methyl-pyridin-2- ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;
3-Methy l-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [ 1 -(6-methyl- pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl-l-[l-(6-methyl- pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid f (S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid f (S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
2,4-Dimethylfuran-3-carboxylic acid f(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoxaline-2-carboxylic acid f(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide;
Thieno[3,2-b]thiophene-2-carboxylic acid f(S)-l-[l-(2-fluoro- phenylcarbamoyl)-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-methy 1-butyl } -amide;
4-Methyl-thiophene-2-carboxylic acid f(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid f(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
4-Methyl-furan-2-carboxylic acid f(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]-amide;
Benzofuran-2-carboxylic acid { (S)- 1 - [ 1 -(2-fluoro-benzyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methy 1-butyl } -amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [ l-(2-morpholin-4-yl- thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[l-(5-ethyl-furan-2-ylmethyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid f(S)-l-[l-(3,4-dimethyl-thieno[3,2-
Z?]thiophene-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}- amide;
Benzofuran-2-carboxylic acid f(S)-3-methyl-l-[3-oxo-l-(3-phenyl-3H-
[ 1 ,2,3]triazol-4-ylmethyl)-azepan-4-ylcarbamoyl]-butyl }-amide;
Benzofuran-2-carboxylic acid [(S)-l-[l-(isothiazol-3-ylmethyl-3-oxo- azepan-4-ylcarbamoyl)-3-methy 1-butyl } -amide ;
Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-thiophen-2- ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide;
Benzofuran-2-carboxylic acid [(S)- l-(l-benzo[b]thiophen-2-ylmethyl-3- oxo-azepan-4-y lcarbamoyl] -3-methyl-butyl] -amide ;
Benzofuran-2-carboxylic acid [(S)-3-methyl-l-(3-oxo-l-pentyl-azepan-4- y lcarbamoyl)-butyl] -amide ;
Benzofuran-2-carboxylic acid f(S)-3-methyl-l-[l-(l-methyl-lH-imidazol-
2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-buty}-amide; l-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 f (S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoyl ]-butyl } -amide; lH-Benzoimidazole-5-carboxylic acid f(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide;
4- { (S)-2- [( l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino}-l-methyl-3-oxo-l-pentyl-azepanium;
Benzofuran-2- carboxylic acid f (S)-l-[l-(l,2-dimethyl-l H -imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2- carboxylic acid f(S)-l-[l-( 1-methyl- 1 H -imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid f(S)-l-[l-(4-methanesulfonyl- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid f (S)-l-[l-(2-methanesulfonyl- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid f(S)-l-[l-(3,5-dimethyl-isoxazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoy l]-3-methyl-butyl}-amide; 3-Methy l-benzofuran-2-carboxylic acid {(IS ,2R)-2-methyl- 1- [3-oxo- 1 - (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid { 1 -[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclopentyl }-amide; and
Furo[3,2-b]-pyridine-2-carboxylic acid f(S)-3-methyl-l-[-3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide.
33. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 32 and a pharmaceutically acceptable carrier, diluent or excipient.
34. A method of inhibiting a protease, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Claims 1 to 32.
35. A method according to Claim 34 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease.
36. A method according to Claim 35 wherein said protease is a cysteine protease.
37. A method according to Claim 36 wherein said cysteine protease is cathepsin K.
38. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to any one of Claims 1 to 32.
39. A method according to Claim 38 wherein said disease is osteoporosis.
40. A method according to Claim 38 wherein said disease is periodontitis.
41. A method according to Claim 38 wherein said disease is gingivitis.
42. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to any one of Claims 1 to 32.
43. A method according to Claim 42 wherein said disease is osteoarthritis. .
44. A method according to Claim 42 wherein said disease is rheumatoid arthritis.
45. A method of treating a parasitic disease by administering to a patient in need thereof an effective amount of a compound according to any one of Claims 1 to 32.
46. A method according to Claim 45 wherein said disease is selected from the group consisting of: schistosomiasis, malaria, and infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata.
47. A compound of Formula IIA:
IIA wherein:
RI is selected from the group consisting of:
R2 is selected from the group consisting of: C\ -galkyl, Ar-Co_galkyl, Het-CQ- galkyl, R9C(O)-, R9SO2-, R9RHNC(O)-, and R9SO2RπNC(O)-; R3 is Ci-galkyl; R4 is R5C(O)-, R5 is Het-CQ-galkyl; R9 is selected from the group consisting of: Cj -galkyl, C3-gcycloalkyl-Co-galkyl,
Ar-Co-galkyl and Het-Co-galkyl;
RU is selected from the group consisting of: H, Cj-galkyl, Ar-Co-galkyl, and HetCo-galkyl;
R' is H; R" is H;
R'" is H;
R"" is selected from the group consisting of: Ci -galkyl, C3-gcycloalkyl-CQ.galkyl C -galkenyl, C2_galkynyl, HetCQ.galkyl and ArCo-galkyl; and n is an integer from l'to 5; and salts, hydrates and solvates thereof.
48. A process for the synthesis of a compound according to Claim 1 comprising the step of oxidizing a corresponding compound of Claim 47 with an oxidant to provide the compound of Formula (IA) as a mixture of diastereomers.
49. The process of Claim 48 wherein the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine.
50. The process of Claim 48 further comprising the step of separating the diasteromers by separating means.
51. The process of Claim 50 wherein said separating means is high presssure liquid chromatography (HPLC).
52. The process of Claim 48 further comprising the step of deuterating said diastereomers with a deuterating agent.
53. The process of Claim 52 wherein said deuterating agent is CD3OD: D2O (10:1) in triethylamine.
54. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in inhibiting a protease selected from the group consisting of a cysteine protease and a serine protease.
55. A use according to Claim 54 wherein said protease is a cysteine protease.
56. A use according to Claim 55 wherein said cysteine protease is cathepsin K.
57. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a disease characterized by bone loss.
58. A use according to Claim 57 wherein said disease is osteoporosis.
59. A use according to Claim 57 wherein said disease is periodontitis.
60. A use according to Claim 57 wherein said disease is gingivitis.
61. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation.
62. A use according to Claim 61 wherein said disease is osteoarthritis.
63. A use according to Claim 61 wherein said disease is rheumatoid arthritis.
64. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a parasitic disease.
65. A use according to Claim 64 wherein said disease is selected from the group consisting of: schistosomiasis, malaria, and infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata.
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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
JP2003513927A (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
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US7709510B2 (en) 2001-02-20 2010-05-04 Chugai Seiyaku Kabushiki Kaisha Azoles as malonyl-CoA decarboxylase inhibitors useful as metabolic modulators
EP1379243B1 (en) 2001-02-20 2009-09-09 Chugai Seiyaku Kabushiki Kaisha Methods for treating metabolic diseases using malonyl-coa decarboxylase inhibitors
US20040157828A1 (en) * 2001-05-17 2004-08-12 Ren Xie Protease inhibitors
EP2208495B1 (en) 2003-08-01 2011-12-14 Chugai Seiyaku Kabushiki Kaisha Cyanoguanidine-based azole compounds useful as malonyl-CoA decarboxylase inhibitors
JP4727578B2 (en) 2003-08-01 2011-07-20 中外製薬株式会社 Heterocyclic compounds useful as malonyl-CoA decarboxylase inhibitors
EP1653957B1 (en) 2003-08-01 2008-07-09 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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998005336A1 (en) * 1996-08-08 1998-02-12 Smithkline Beecham Corporation Inhibitors of cysteine protease
WO2001034158A1 (en) * 1999-11-10 2001-05-17 Smithkline Beecham Corporation Protease inhibitors
WO2001034565A2 (en) * 1999-11-10 2001-05-17 Smithkline Beecham Corporation Protease inhibitors
WO2002017924A1 (en) * 2000-09-01 2002-03-07 Smithkline Beecham Corporation Method of treatment
WO2002092563A2 (en) * 2001-05-17 2002-11-21 Smithkline Beecham Corporation Protease inhibitors
WO2003053331A2 (en) * 2000-11-22 2003-07-03 Smithkline Beecham Corporation Protease inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1158986A4 (en) * 1998-12-23 2002-03-27 Smithkline Beecham Corp Protease inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998005336A1 (en) * 1996-08-08 1998-02-12 Smithkline Beecham Corporation Inhibitors of cysteine protease
WO2001034158A1 (en) * 1999-11-10 2001-05-17 Smithkline Beecham Corporation Protease inhibitors
WO2001034565A2 (en) * 1999-11-10 2001-05-17 Smithkline Beecham Corporation Protease inhibitors
WO2002017924A1 (en) * 2000-09-01 2002-03-07 Smithkline Beecham Corporation Method of treatment
WO2003053331A2 (en) * 2000-11-22 2003-07-03 Smithkline Beecham Corporation Protease inhibitors
WO2002092563A2 (en) * 2001-05-17 2002-11-21 Smithkline Beecham Corporation Protease inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of WO0195911A1 *
VEBER, DANIEL F. ET AL: "The role of conformational constraint in improved oral bioavailability of cathepsin K inhibitors" PEPTIDES 2000, PROCEEDINGS OF THE EUROPEAN PEPTIDE SYMPOSIUM, 26TH, MONTPELLIER, FRANCE, SEPT. 10-15, 2000 ( 2001 ), MEETING DATE 2000, 113-114. EDITOR(S): MARTINEZ, JEAN;FEHRENTZ, JEAN-ALAIN. PUBLISHER: EDITIONS EDK, PARIS, FR. , XP009028910 *

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