EP1320370A4 - Method of treatment - Google Patents

Method of treatment

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Publication number
EP1320370A4
EP1320370A4 EP01966474A EP01966474A EP1320370A4 EP 1320370 A4 EP1320370 A4 EP 1320370A4 EP 01966474 A EP01966474 A EP 01966474A EP 01966474 A EP01966474 A EP 01966474A EP 1320370 A4 EP1320370 A4 EP 1320370A4
Authority
EP
European Patent Office
Prior art keywords
methyl
carboxylic acid
azepan
oxo
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Withdrawn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
EP01966474A
Other languages
German (de)
French (fr)
Other versions
EP1320370A1 (en
Inventor
David G Tew
Scott K Thompson
Daniel F Veber
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US09/881,334 external-priority patent/US20030144175A1/en
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1320370A1 publication Critical patent/EP1320370A1/en
Publication of EP1320370A4 publication Critical patent/EP1320370A4/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Withdrawn legal-status Critical Current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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P33/06—Antimalarials
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

  • the present invention relates to methods for treating parasitic diseases using 4- amino-azepan-3-one protease inhibitors.
  • the present methods serve to inhibit cysteine proteases of the papain superfamily.
  • the present invention is useful for treating parasitic diseases which are mediated by the activity of such proteases.
  • the present invention relates to treating malaria by inhibiting falcipain.
  • Plasmodium falciparum Infection with Plasmodium falciparum, the most virulent human malaria pathogen, infects over 280 million people and is estimated to be responsible for over 1 million deaths annually (Gibbons, A. Science 1992, 256, 1135; Walsh, J. A. Arm. N. Y. Acad. Sci. 1989, 569, 1135).
  • the Plasmodium falciparum parasite has a 48 hour life cycle within host erythrocytes that is responsible for all of the clinical manifestations of falciparum malaria.
  • the erythrocyte is invaded by a merozoite, then the intracellular parasite develops from a ring stage into a more metabolically active trophozoite, divides asexually and becomes a schizont, and finally ruptures the host erythrocyte, releasing daughter merozoites that invade other erythrocytes to reinitiate the cycle.
  • the trophozoite stage hemoglobin from the host erythrocyte is degraded for use as the parasites principal source of amino acids.
  • Rosenthal and coworkers have identified a 28 kD trophozoite cysteine protease (TCP or falcipain) from malaria parasites that mediates host hemoglobin degradation (Rosenthal, P. J.; McKerrow, J. H.; Aikawa, M.; Nagasawa, H.; Leech, J. H. /. Clin. Invest. 1988, 82, 1560) and is expressed only at the trophozoite stage (Rosenthal, P. J.; Kim, J. H.; McKerrow, J. H.; Leech, J. H. J. Exp. Med. 1987, 166, 816).
  • a selective inhibitor of falcipain may be an effective anti-malarial therapy either in conjunction with or as a replacement for the quinoline-derived drugs.
  • cysteine proteases in their life cycle. These include Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi,
  • Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus [onchocerciasis (river blindness)]
  • Brugia pahangi Entamoeba histolytica, Giardia lambia, the helminths, Haemonchus contortus and Fasciola hepatica, as well as helminths of the genera Spirometra, Trichinella, Necator and Ascaris, and protozoa of the genera Cryptosporidium, Eimeria, Toxoplasma and Naegleria (McKerrow, J. H. (1995) in Perspect.
  • An object of the present invention is to provide methods of treatment which serve to inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily.
  • the present methods are useful for treating parasitic diseases which may be therapeutically modified by altering the activity of such proteases.
  • the present invention relates to treating malaria by inhibiting falcipain.
  • this invention provides a method of treating parasitic diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine proteases, using 4-amino-azepan-3-ones of Formula I.
  • proteases such as cysteine proteases
  • these compounds are used in the present method to treat parasitic diseases by inhibiting cysteine proteases of the papain superfamily.
  • the present invention provides a method of treating malaria by the inhibition of falcipain with such compounds.
  • the present invention provides a method for treating parasitic diseases which may be therapeutically modified by altering the activity of cysteine proteases by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more compounds of Formula I:
  • Rl is selected from the group consisting of:
  • R ⁇ is selected from the group consisting of: H, Cj.galkyl, C3_6cycloalkyl-Co_6 a lkyl, 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)-, R9R11NC(O)-, R9R11NC(S)-, R 9 (R 11 )NSO 2
  • R 3 is selected from the group consisting of: H, Cl-6alkyl, C3_6cycloalkyl-C ⁇ -6alkyl, C2-6alkenyl, C2-6alkynyl, HetC ⁇ - ⁇ alkyl and ArCo-6 lkyl;
  • R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R ⁇ is selected from the group consisting of: H, C ⁇ _6 lkyl, C ⁇ .gcycloalkyl-Co- ⁇ alkyl, Ar-C 0 -6alkyl, Het-C 0 -6alkyl, R 5 C(O)-, R 5 C(S)-, R 5 SO 2 -, R 5 OC(O)-, R 5 R 12 NC(0)-, and R5R12NC(S)-; R ⁇ is selected from the group consisting of: H, C galkyl, C 2 _6alkenyl, C 2 -6alkynyl,
  • R° is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het- C 0 .6 lkyl;
  • R ⁇ is selected from the group consisting of: H, C ⁇ galkyl, C3_gcycloalkyl-C()_galkyl, Ar-C 0 _6alkyl, Het-C 0 _6alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 13 NC(S)-;
  • R 0 " is selected from the group consisting of: H, Ci-6alkyl, C 2 -6alkenyl, C 2 _6alkynyl, HetC ⁇ -galkyl and ArCo- ⁇ alkyl;
  • R 9 is selected from the group consisting of: C j .galkyl, C3_ cycloalkyl-Co_6 l yl, Ar-Co_6alkyl and Het-Co-6 a lkyl;
  • RIO is selected from the group consisting of: C j .galkyl, C3_6cycloalkyl-C Q -6alkyl, Ar-Co- ⁇ alkyl and Het-Co_6 a lkyl;
  • RU is selected from the group consisting of: H, Cj. ⁇ alkyl, Ar-C()-6alkyl, and Het- C 0 _6alkyl
  • Rl2 is selected from the group consisting of: H, C _ ⁇ alkyl, Ar-Co ⁇ 6alkyl, and Het-
  • Rl3 is selected from the group consisting of: H, C ⁇ _galkyl, Ar-C ⁇ -6 a lkyl, and Het- C 0 . 6 alkyl;
  • R' is selected from the group consisting of: H, C galkyl, Ar-C ⁇ -6alkyl, and Het-C ⁇ . galkyl;
  • R" is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ _ galkyl; R'" is selected from the group consisting of: H, C j .galkyl, C3_gcycloalkyl-Co_galkyl,
  • R" is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Co_galkyl C 2 .galkenyl, C 2 _galkynyl, HetCQ-galkyl and ArCQ.galkyl;
  • 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 ; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R is preferably in compounds of Formula I.
  • R 3 is selected from the group consisting of: H, Cl -galkyl, C3_gcycloalkyl-C ⁇ - galkyl,C 2 .galkenyl, C 2 .galkynyl, Het-C ⁇ _galkyl and Ar-Co_galkyl;
  • R 3 is preferably selected from the group consisting of: H, C3-gcycloalkyl-C ⁇ -6alkyl, C .galkenyl, Ar-Co_galkyl, and Ci-galkyl;
  • R 3 is more preferably selected from the group consisting of:
  • R 3 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_gcycloalkyl- C 0 .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 13 NC(O)-, and R 5 R 13 NC(S)-.
  • R4 is preferably selected from the group consisting of: R ⁇ OC(O)-, R ⁇ C(O)- and R 5 SO 2 -. R 4 is most preferably R 5 C(O) ⁇ .
  • R 4 is preferably methanesulfonyl.
  • R-> is selected from the group consisting of: H, Cj.galkyl, C 2 .galkenyl, C 2 .galkynyl, C3_gcycloalkyl-Co_galkyl, Ar-CQ-galkyl or Het-Cg-galkyl.
  • R ⁇ is selected from the group consisting of: C ⁇ _ alkyl, Ar-CQ-galkyl and Het-C 0 .galkyl.
  • R-> is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially Ci.galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-d
  • R ⁇ is preferably pyridin-2-yl or l-oxo-pyridin-2-yl.
  • R' is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6alkyl, and Het-Cg. galkyl.
  • 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-C ⁇ -6alkyl, and Het-C ⁇ _ galkyl.
  • R" is H.
  • R'" is selected from the group consisting of: H, C j .galkyl, C3_gcycloalkyl- C ⁇ -6alkyl, and Het-Co_galkyl.
  • 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.
  • methyl is preferably selected from the group consisting of: 6- methyl and 7-methyl.
  • R'" is selected from the group consisting of: H, 6-methyl and 7-methyl, most preferably 7-methyl.
  • R 3 is selected from the group consisting of: Ci-galkyl, C3-gcycloalkyl-C ⁇ -6 a lkyl, C 2 _ galkenyl, C 2 .galkynyl, Het-CQ.galkyl and Ar-Co_galkyl.
  • 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- C ⁇ -6alkyl, C -6alkenyl, C 2 .galkynyl, HetCg-galkyl and ArC Q _galkyl; R"" is preferably C ⁇ _6alkyl;
  • 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 “, R 4 , and R ⁇ are as described above wherein
  • n is preferably an integer of from 1 to 5;
  • R , R , R"', R 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 2 -6alkenyl, C .galkynyl, HetCo-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 ⁇ -6 a lkyl, R C(O)-,
  • R 2 is selected from the group consisting of: Ar-C()-6alkyl
  • R 2 is R sO 2 .
  • R6 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6alkyl, or Het-CQ. galkyl, preferably H.
  • R' is selected from the group consisting of: H, C j .galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Co.galkyl, Het-C 0 -galkyl, RlOc(O)-, R!°C(S)-, R 10 SO 2 -, R 10 OC(O)-, R10R1 NC(O)-, R 10 Rl 4 NC(S)-, R 7 is preferably Rl°OC(O).
  • R° > is selected from the group consisting of: H, C galkyl, C 2 .galkenyl, C 2 _galkynyl, HetCo-galkyl and ArCo-galkyl; preferably Cj.galkyl, more preferably isobutyl.
  • R is selected from the group consisting of: C galkyl, C3_gcycloalkyl-Co-galkyl, Ar-CQ-galkyl, and Het-Co-galkyl.
  • R9 is preferably selected from the group consisting of: C j .galkyl, Ar-C Q -galkyl, and Het-Co.galkyl.
  • R 9 is selected from the group consisting of: methyl; ethyl, especially C j -galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially C j .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,
  • 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 ⁇ _ galkyl, C3_gcycloalkyl-Co-galkyl, and Het-Co_galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl.
  • Rl 1 is selected from the group consisting of: H, C _galkyl, Ar-C ⁇ -6alkyl, and Het- C 0 -galkyl.
  • R 11 is preferably H.
  • 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 Cj.galkyl
  • R 2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl.
  • Het-Co_galkyl is preferably Het-methyl
  • Het in Het- methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially C _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-y ⁇ ), and 1- (isothiazol-3-yl); lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especially C j .galkyl substituted imidazolyl, more especially l-methyl-lH-imidazol-2y
  • R 2 is also preferably: H; toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl.
  • R" and R'" are both H are preferred. Also preferred are such compounds wherein R'" is selected from the group consisting of: 6-methyl and 7- methyl, preferably 7-methyl.
  • R 2 is selected from the group consisting of: Ar-C ⁇ -6alkyl, R 9 C(O)-, R 9 SO 2 ,
  • R 3 is selected from the group consisting of: H, Ci-galkyl, C3_gcycloalkyl-C ⁇ -galkyl 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-CQ-galkyl and Het-CQ. galkyl;
  • R 6 is H
  • R 7 is R 10 OC(O); R 8 is C ⁇ _galkyl;
  • R 9 is selected from the group consisting of: C _galkyl, Ar-CQ.galkyl and Het-CQ. galkyl;
  • RIO is selected from the group consisting of: C j .galkyl, Ar-C Q .galkyl and Het-CQ. galkyl; R' is H;
  • R" is H
  • R'" is H
  • Z is selected from the group consisting of: C(O) and CH 2 .
  • R'" is selected from the group consisting of: 6-methyl and 7-methyl, preferably 7-methyl.
  • R 2 is selected from the group consisting of: Ar-Co-galkyl, R 9 C(O)-, R 9 SO 2 .
  • R 2 is selected from the group consisting of: Ar-C ⁇ -galkyl, R C(O)- and R 9 SO 2 ;
  • R 3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n- butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1- hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;
  • R 4 is R 5 C(O)-;
  • R-> is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , 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-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially
  • R 9 is selected from the group consisting of: methyl; ethyl, especially C j -galkyl-substituted ethyl, more especially 2-cyclohexyl-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-fluoro ⁇ henyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chloro ⁇ henyl, especially Cj.galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C
  • R' is H; R" is H; and
  • R'" is H.
  • R'" is selected from the group consisting of: 6-methyl and 7-methyl, preferably 7-methyl.
  • the following compounds are preferred for use in the present methods of treatment:
  • Naphthlene-2-carboxylic acid ((S)-3-methyl-l- ⁇ 3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl ⁇ -butyl)amide; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl] amide;
  • Naphthalene-2-carboxylic acid ⁇ (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ -amide; Quinoline-3-carboxylic acid ⁇ (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ amide;
  • Benzofuran-2-carboxylic acid ⁇ (S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ -amide; Benzofuran-2-carboxylic acid ⁇ (S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl ⁇ -amide;
  • Naphthalene- 1 -carboxylic acid ⁇ (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ -amide;
  • the present invention includes deuterated analogs of the inventive compounds.
  • a representative synthetic route for the deuterated compounds of the present invention is set forth in Scheme 7, below.
  • the deuterated compounds of the present invention exhibit superior chiral stability compared to the protonated isomer.
  • the compounds used in 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.
  • 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.
  • 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.
  • 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.
  • O ⁇ .galkyl may be optionally substituted by a moiety selected from the group consisting of: OR 4 ,
  • R is selected from the group consisting of: H, C ⁇ _ galkyl, C 2 .galkenyl, C 2 .galkynyl, C3_gcycloalkyl-CQ_galkyl, Ar-CQ.galkyl and Het-CQ. galkyl; and Rl 4 is selected from the group consisting of: H, C j .galkyl, Ar-Co_galkyl, and Het-C Q _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 _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 2 _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, Cl, Br, and I.
  • Ar or aryl means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-C 0 .galkyl; C j .galkoxy; Ph-C 0 .galkoxy; Het-C Q .galkoxy; OH, (CH 2 ) ⁇ .
  • R 15 and Rl 6 are H, C galkyl, Ph-C 0 .galkyl, naphthyl-CQ_galkyl or Het-CQ.galkyl; and R 7 is phenyl, naphthyl, or C ⁇ .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 Q .gAr, Cl .galkyl, ORI 7 , N(R 17 ) 2 , SR 17 , CF 3 , NO 2 , CN, CO 2 Rl 7 , CON(R 17 ), F, Cl, Br and I, where R 17 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 ArC Q .galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArC Q ,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.
  • m-CPBA 3-chloroperoxybenzoic acid
  • EDC N-ethyl-N'(dimethylaminopropyl)-carbodiimide
  • DMF dimethyl formamide
  • DMSO 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-propanedithioln 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 was effected with a coupling agent such as EDC provides 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 provides 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.
  • 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 HCl or TFA provides intermediate 14.
  • 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,COCl, CH 2 C1 2 ; i.) HCl/ EtOAc; j.) R.CO j H, 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.) I ⁇ CO.H, EDC, CH 2 C1 2 ; d.) pyridine sulfurtrioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R I S0 2 C1, TEA, CH 2 C1 2 .
  • Compounds of the general formula I may be prepared in a fashion analogous to that outlined in Schemes 4, 5, 6, and 7
  • 2-Methyl-pent-4-enoic acid ethyl ester is converted to a N-2-pyridinesulfonyl-azapine by reduction to the aldehyde, reductive amination with allylamine, sulfonylation with 2- pyridyl sulfonyl chloride, and olefin metathesis with Grubbs' catalyst.
  • Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography.
  • the syn epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine.
  • 5-Hexen-2-one is converted to a N-carbobenzyloxy-azapine by reductive amination with allylamine, protection with carbobenzyloxy chloride, and olefin metathesis with Grubbs' catalyst.
  • Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography. Each epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine.
  • Carbobenyzloxy-D-alaninol (Cbz-D-alaninol) is first converted to an iodide, then is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl organometallic reagent. The amine is then alkylated with allyl iodide. Grubbs' catalyst is then used to form the azapine ring by ring closing metathesis. Epoxidation of the alkene followed by separation of the diastereomers followed by opening of the epoxide of the minor component with sodium azide provides the intermediate azido alcohol.
  • Deuterated inhibitors can be prepared from the parent inhibitors such as benzofuran-2- carboxylic acid ⁇ (S)-3-methyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ -amide by treating with a base such as triethyl amine and stirring for several days in a deteurated protic solvent such as CD 3 OD: D 2 O.
  • a base such as triethyl amine
  • a deteurated protic solvent such as CD 3 OD: D 2 O.
  • the present invention provides a method of inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
  • the present invention also provides a method of treating a parasitic disease mediated by a cysteine protease by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
  • cysteine proteases Parasites known to utilize cysteine proteases in their life cycle include Plasmodium falciparum (malaria), Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi, Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus
  • the present method provides treatment of diseases caused by infection by these parasites by inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
  • the compounds of Formula I used in the inventive method are especially effective in inhibition of one or more of the following parasitic proteases: falcipain (P. falciparum), cruzain (T. cruzi), rhodazain (T. brucei rhodesiensi), leishmania L (Leishmania spp.), leishmania B (Leishmania spp.), and schistosoma B (S. manson ⁇ ).
  • the present invention provides a method of treating diseases selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
  • diseases selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
  • the present invention provides a method of treating malaria, caused by infection with Plasmodium falciparum, by the inhibition of falcipain by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the above-listed compounds.
  • the present method may be practiced by administering the above-listed compounds alone or in combination with other therapeutically effective compounds, including but not limited to quinoline-derived drugs.
  • 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.
  • the present invention includes all esters, hydrates, solvates, complexes and prodrugs of the above-listed compounds useful in the inventive method.
  • Prodrugs are any covalently bonded compounds which release the active parent drug 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.
  • compositions which comprise one or more of compounds of Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of Formula I may be used in the manufacture of a medicament useful in the practice oof the present methods of treatment.
  • Pharmaceutical compositions of 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.
  • 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 or filled into a soft gelatin capsule.
  • the compounds of Formula I may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • an effective amount of one or more compounds of Formula I is administered to inhibit the protease implicated with a particular condition or disease.
  • this dosage amount will further be modified according to the type of administration of the compound.
  • parenteral administration of an effective amount 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.
  • 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 the parasitic protease, e.g. falcipain in the case of treatment of malaria.
  • 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 compound may be administered in the form of a prodrug which, in general, is designed to enhance absorption and is cleaved in vivo to form the active component. Efficacious levels may also be achieved by administration of pharmaceutically active metabolites or bioisosteres of the compound.
  • Prodrugs of compounds of the present invention may be prepared by any suitable method.
  • the compounds used in this method may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit cysteine proteases, e.g. falcipain in the case of treatment of malaria, 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 0.1 to about 50 mg/kg given 1-2 times/day. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present method of treatment.
  • the compounds used in the present method may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
  • an assay for determining parasitic cysteine protease catalytic activity and an assay to determine the amount of cysteine protease inhibition by a compound of the inventive method are provided.
  • cysteine protease catalytic activity Standard assay conditions for the determination of kinetic constants used 10 uM fluorogenic peptide substrate, Cbz-Phe-Arg-AMC for the cysteine proteases from Leishmania spp and Schistosoma Mansoni, Cbz-Leu-Arg-AMC for the cysteine proteases from Plasmodium falciparum and Trypanosoma brucei rhodesiensi, and Ac-Lys-Glu-Lys- Leu-Arg-AMC (4 uM final substrate concentration) for the cysteine protease from Trypoanosoma cruzi, and were determined in 100 mM Na acetate at pH 5.5 containing 5 mM cysteine.
  • Stock substrate solutions were prepared at concentrations of 10 mM in DMSO with 10 uM (4 uM for Ac-Lys-Glu-Lys-Leu-Arg-AMC) final substrate concentration in the assays.
  • the final DMSO concentration was 2 % and the final volume was 100 uL. All assays were conducted at ambient temperature. Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
  • v V m A /[K a (l + VKi app) +A] (1)
  • v is the velocity of the reaction with maximal velocity V m
  • A is the concentration of substrate with Michaelis constant of K a
  • / is the concentration of inhibitor.
  • [AMC] v ss t + (VQ - v ss ) [1 - exp (-k 0 b s t)l / k 0 bs (2)
  • Table I provides exemplary data resulting from the testing of compounds of the present method for inhibition of one or more of the following parasitic disease cysteine proteases: falcipain, cruzain, rhodazin, leishmania L, leishmania B, schistosoma Bl, and schistosoma B2.
  • Plasmodium vinckei Rosenthal, P. J.; Le, G. K.; Smith, R. E. J. Clin. Invest. 1993, 91, 1052-
  • Example 18 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and naphthalne-2-carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 537 (M+H+). Example 18
  • Example 25 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2-carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+). Example 25
  • Example 28 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-3-carboxylic acid tert-butyl ester for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
  • Example 28 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-3-carboxylic acid tert-butyl ester for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
  • Example 60 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and indole-5-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 531 (M+H+). Example 60
  • Example 63 Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and thieno[3,2-b]thiophene-2- carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 565 (M+H+).
  • Example 63 Example 63
  • Example 73 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 2-Phenyl-5-trifluoromethyl- oxazole-4-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 622 (M+H + ). Example 73
  • Example 76 Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and furan-2-carboxylic acid for 5- (2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 493 (M+H+). Example 76
  • Example 84 Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2- carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H + ).
  • Example 84 Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2- carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H + ).
  • Example 84 Following the procedure of Example 6(a)-6(
  • Example 100 The title compound was isolated as the first eluting compound from the HPLC purification in Example 57. MS (ESI): 557 (M+H+). Example 100
  • Example 122 Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 4- methanesulfonylbenzoic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 582 (M+H+). Example 122
  • Example 168 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and benzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 541 (M+H+).
  • Example 168 Example 168
  • Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-cyclohexyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and 5,6- dimethoxybenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 643 (M+H+).
  • Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-(2-naphthyl)-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and naphthalene- 1- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 621 (M+H+).
  • Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoy ⁇ )- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and naphthalene- 1 -carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+).
  • Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and quinoline-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 572 (M+H+).
  • Hex-5-en-2-one (9.8 g, 11.6 ml, 100 mmol) was added to a stirred solution of allylamine (8.55 mmol, 11.25 ml, 150 mmol), 4 Angstrom molecular sieves (52 g), and p- toluene sulfonic acid (10 mg) in CH 2 C1 2 (200 ml) and was stirred overnight.
  • the reaction mixture was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (13 g, 95%).

Abstract

The present invention relates to methods of treating parasitic diseases which are mediated by cysteine proteases by administration of 4-amino-azepan-3-one protease inhibitors. In particular, the present invention relates to a method of treating malaria by inhibiting the cysteine protease falcipain.

Description

METHOD OF TREATMENT
FIELD OF THE INVENTION
The present invention relates to methods for treating parasitic diseases using 4- amino-azepan-3-one protease inhibitors. In particular, the present methods serve to inhibit cysteine proteases of the papain superfamily. Thus, the present invention is useful for treating parasitic diseases which are mediated by the activity of such proteases. In particular, the present invention relates to treating malaria by inhibiting falcipain.
BACKGROUND OF THE INVENTION
Infection with Plasmodium falciparum, the most virulent human malaria pathogen, infects over 280 million people and is estimated to be responsible for over 1 million deaths annually (Gibbons, A. Science 1992, 256, 1135; Walsh, J. A. Arm. N. Y. Acad. Sci. 1989, 569, 1135). The Plasmodium falciparum parasite has a 48 hour life cycle within host erythrocytes that is responsible for all of the clinical manifestations of falciparum malaria. During this cycle, the erythrocyte is invaded by a merozoite, then the intracellular parasite develops from a ring stage into a more metabolically active trophozoite, divides asexually and becomes a schizont, and finally ruptures the host erythrocyte, releasing daughter merozoites that invade other erythrocytes to reinitiate the cycle. During the trophozoite stage, hemoglobin from the host erythrocyte is degraded for use as the parasites principal source of amino acids.
Rosenthal and coworkers have identified a 28 kD trophozoite cysteine protease (TCP or falcipain) from malaria parasites that mediates host hemoglobin degradation (Rosenthal, P. J.; McKerrow, J. H.; Aikawa, M.; Nagasawa, H.; Leech, J. H. /. Clin. Invest. 1988, 82, 1560) and is expressed only at the trophozoite stage (Rosenthal, P. J.; Kim, J. H.; McKerrow, J. H.; Leech, J. H. J. Exp. Med. 1987, 166, 816). Inhibition of this enzyme results in a blocking of hemoglobin degradation and killing of cultured parasites (Rosenthal, P. J.; Wollish, W. S.; Palmer, J. T.; Rasnick, D. /. Clin. Invest. 1991, 88, 1467; Li, R.; Kenyon, G. L.; Cohen, F. E,; Chen, X.; Gong, B.; Dominguez, J. N.; Davidson, E.; Kurzban, G.; Miller, R. E.; Nuzum, E. O.; Rosenthal, P. J.; McKerrow, J. H. /. Med. Chem. 1995, 38, 5031). In a mouse model of infection with P. vinckei, the analogous murine malarial parasite, treatment with cysteine protease inhibitors resulted in a long-term curative effect (>75 days) in 80% of animals (Rosenthal, P. J.; Lee, G. K.; Smith R. E. J. Clin. Invest. 1993, 91, 1052). Thus, a selective inhibitor of falcipain may be an effective anti-malarial therapy either in conjunction with or as a replacement for the quinoline-derived drugs.
In addition to Plasmodium falciparum, other parasites utilize cysteine proteases in their life cycle. These include Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi,
Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus [onchocerciasis (river blindness)] Brugia pahangi, Entamoeba histolytica, Giardia lambia, the helminths, Haemonchus contortus and Fasciola hepatica, as well as helminths of the genera Spirometra, Trichinella, Necator and Ascaris, and protozoa of the genera Cryptosporidium, Eimeria, Toxoplasma and Naegleria (McKerrow, J. H. (1995) in Perspect.
Drug Dis. Des. 2, eds., Craik, C. S., Debouck, C, pp. 437-444; Robertson, C. D., Coombs, G.
H., North, M. J., Mottram, J. C. (1996) in Perspect. Drug Dis. Des. 6, eds., McKerrow, J. H. and James, M. N. G., pp. 99-118).
It has now been discovered that certain 4-amino-azepan-3-ones are protease inhibitors, most particularly inhibitors of falcipain, and that these compounds are useful for treating parasitic diseases, particularly malaria.
Summary of the Invention
An object of the present invention is to provide methods of treatment which serve to inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily. The present methods are useful for treating parasitic diseases which may be therapeutically modified by altering the activity of such proteases. In particular, the present invention relates to treating malaria by inhibiting falcipain.
Accordingly, in the first aspect, this invention provides a method of treating parasitic diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine proteases, using 4-amino-azepan-3-ones of Formula I.
In particular, these compounds are used in the present method to treat parasitic diseases by inhibiting cysteine proteases of the papain superfamily. Most particularly, the present invention provides a method of treating malaria by the inhibition of falcipain with such compounds. Detailed Description of the Invention
The present invention provides a method for treating parasitic diseases which may be therapeutically modified by altering the activity of cysteine proteases by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more compounds of Formula I:
wherein: Rl is selected from the group consisting of:
R^ is selected from the group consisting of: H, Cj.galkyl, C3_6cycloalkyl-Co_6alkyl, Ar-C0-6alkyl, Het-C0.6alkyl, R9C(O)-, R9C(S)-, R9SO2-, R9OC(O)-, R9R11NC(O)-, R9R11NC(S)-, R9(R11)NSO2
R3 is selected from the group consisting of: H, Cl-6alkyl, C3_6cycloalkyl-Cθ-6alkyl, C2-6alkenyl, C2-6alkynyl, HetCø-όalkyl and ArCo-6 lkyl;
R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
R^ is selected from the group consisting of: H, Cι_6 lkyl, Cβ.gcycloalkyl-Co-βalkyl, Ar-C0-6alkyl, Het-C0-6alkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R12NC(0)-, and R5R12NC(S)-; R^ is selected from the group consisting of: H, C galkyl, C2_6alkenyl, C2-6alkynyl,
C3_6cycloalkyl-CQ_galkyl, Ar-Co-βalkyl and Het-Co-6alkyl;
R° is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het- C0.6 lkyl;
R^ is selected from the group consisting of: H, C^galkyl, C3_gcycloalkyl-C()_galkyl, Ar-C0_6alkyl, Het-C0_6alkyl, R10C(O)-, R10C(S)-, R10SO2-, R10OC(O)-, R10R13NC(O)-, and R10R13NC(S)-;
R0" is selected from the group consisting of: H, Ci-6alkyl, C2-6alkenyl, C2_6alkynyl, HetCø-galkyl and ArCo-βalkyl;
R9 is selected from the group consisting of: Cj.galkyl, C3_ cycloalkyl-Co_6 l yl, Ar-Co_6alkyl and Het-Co-6alkyl;
RIO is selected from the group consisting of: Cj.galkyl, C3_6cycloalkyl-CQ-6alkyl, Ar-Co-βalkyl and Het-Co_6alkyl;
RU is selected from the group consisting of: H, Cj.βalkyl, Ar-C()-6alkyl, and Het- C0_6alkyl; Rl2 is selected from the group consisting of: H, C _βalkyl, Ar-Co~6alkyl, and Het-
C0_6alkyl;
Rl3 is selected from the group consisting of: H, Cι_galkyl, Ar-Cθ-6alkyl, and Het- C0.6alkyl; R' is selected from the group consisting of: H, C galkyl, Ar-Cθ-6alkyl, and Het-Cø. galkyl;
R" is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-6alkyl, or Het-Cø_ galkyl; R'" is selected from the group consisting of: H, Cj .galkyl, C3_gcycloalkyl-Co_galkyl,
Ar-Co-galkyl, and Het-Cg-galkyl;
R"" is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Co_galkyl C2.galkenyl, C2_galkynyl, HetCQ-galkyl and ArCQ.galkyl;
X is selected from the group consisting of: CH2, S, and O; Z is selected from the group consisting of: C(O) and CH ; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
R is preferably in compounds of Formula I. When Rl is
R3 is selected from the group consisting of: H, Cl -galkyl, C3_gcycloalkyl-Cθ- galkyl,C2.galkenyl, C2.galkynyl, Het-Cø_galkyl and Ar-Co_galkyl;
R3 is preferably selected from the group consisting of: H, C3-gcycloalkyl-Cθ-6alkyl, C .galkenyl, 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-methanesulfinyl-ethyl, 1-hydroxyethyl, 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, Cχ_galkyl, C3_gcycloalkyl- C0.galkyl, Ar-C0.galkyl, Het-C0.galkyl, R5C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R13NC(O)-, and R5R13NC(S)-.
R4 is preferably selected from the group consisting of: R^OC(O)-, R^C(O)- and R5SO2-. R4 is most preferably R5C(O)~.
In some embodiments, R4 is preferably methanesulfonyl.
R-> is selected from the group consisting of: H, Cj.galkyl, C2.galkenyl, C2.galkynyl, C3_gcycloalkyl-Co_galkyl, Ar-CQ-galkyl or Het-Cg-galkyl.
Preferably R^ is selected from the group consisting of: C\_ alkyl, Ar-CQ-galkyl and Het-C0.galkyl.
More preferably, and especially when R4 is R^C(O)-, R-> is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially Ci.galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or Ci.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more C^.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 C .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 Ci.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-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[£]thiophen-2-yl; especially Ci.galkoxy substituted benzo[&]thiophenyl, more especially 5,6-dimethoxy- benzo[£]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 Cj.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 1- oxy-pyridin-2-yland 1 -oxy-pyridin-3-yl ; ; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, Cι_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-£>]thiophene, especially thieno[3,2-έ>]thiophene-2-yl, more especially C galkyl substituted thieno[3,2-έ>]thiophene-2-yl, more especially 5-fert-butyl-3-methyl- thieno [3 ,2-b] thiophene-2-yl ; isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; 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-6alkyl, and Het-Cg. 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-6alkyl, and Het-Cø_ galkyl.
Most preferably R" is H.
R'" is selected from the group consisting of: H, Cj .galkyl, C3_gcycloalkyl- Cθ-6alkyl, and Het-Co_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.
When R'" is methyl, methyl is preferably selected from the group consisting of: 6- methyl and 7-methyl.
Even more preferably R'" is selected from the group consisting of: H, 6-methyl and 7-methyl, most preferably 7-methyl. In compounds of Formula I, when Rl 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: C galkyl, C3_gcycloalkyl- Cθ-6alkyl, C -6alkenyl, C2.galkynyl, HetCg-galkyl and ArCQ_galkyl; R"" is preferably Cι_6alkyl;
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 ", R4, 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"', R 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, C2-6alkenyl, C .galkynyl, HetCo-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-Co-galkyl, R9C(O)-, R9C(S)-,
R9SO2-, R9OC(O)-, R9R11NC(O)-, R9R1 iNC(S)-, R9R lNSO2-,
, ' , and R9SO2RllNC(O)-.
More preferably R2 is selected from the group consisting of: Ar-Cθ-6alkyl, R C(O)-,
Rβ
R9SO2, R9R11NC(O)-, and R
Even more preferably, R2 is selected from the group consisting of: Ar-C()-6alkyl,
R9C(O)-, and R9SO2.
Most preferably R2 is R sO2.
In such embodiments:
R6 is selected from the group consisting of: H, Cj .galkyl, Ar-Cθ-6alkyl, or Het-CQ. galkyl, preferably H.
R' is selected from the group consisting of: H, Cj .galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Co.galkyl, Het-C0-galkyl, RlOc(O)-, R!°C(S)-, R10SO2-, R10OC(O)-, R10R1 NC(O)-, R10Rl4NC(S)-, R7 is preferably Rl°OC(O).
R°> is selected from the group consisting of: H, C galkyl, C2.galkenyl, C2_galkynyl, HetCo-galkyl and ArCo-galkyl; preferably Cj.galkyl, more preferably isobutyl.
R is selected from the group consisting of: C galkyl, C3_gcycloalkyl-Co-galkyl, Ar-CQ-galkyl, and Het-Co-galkyl.
R9 is preferably selected from the group consisting of: Cj.galkyl, Ar-CQ-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-cyclohexyl-ethyl; propyl; butyl, especially Cj.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 Cj .galkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cχ_galkyl 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 C .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 Cχ_ 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 C _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 Ci.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 R9SO2Rl iNC(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 Cχ_ galkyl, C3_gcycloalkyl-Co-galkyl, and Het-Co_galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl.
Rl 1 is selected from the group consisting of: H, C _galkyl, Ar-Cθ-6alkyl, and Het- C0-galkyl.
When R2 is R9SO2RUNC(O)-, R11 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 Cj.galkyl, R2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl.
When R2 is Het-Co-galkyl, Het-Co_galkyl is preferably Het-methyl, and Het in Het- methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially C _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-yι), and 1- (isothiazol-3-yl); lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especially Cj.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 Cχ_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 Cj.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. Also preferred are such compounds wherein R'" is selected from the group consisting of: 6-methyl and 7- methyl, preferably 7-methyl.
More preferred are compounds of Formula I wherein:
Rl is
R2 is selected from the group consisting of: Ar-Cθ-6alkyl, R9C(O)-, R9SO2,
R3 is selected from the group consisting of: H, Ci-galkyl, C3_gcycloalkyl-Cθ-galkyl 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: Cχ.galkyl, Ar-CQ-galkyl and Het-CQ. galkyl;
R6 is H;
R7 is R10OC(O); R8 is Cι_galkyl;
R9 is selected from the group consisting of: C _galkyl, Ar-CQ.galkyl and Het-CQ. galkyl;
RIO is selected from the group consisting of: Cj .galkyl, Ar-CQ.galkyl and Het-CQ. galkyl; R' is H;
R" is H;
R'" is H; and
Z is selected from the group consisting of: C(O) and CH2.
Also preferred are such compounds wherein R'" is selected from the group consisting of: 6-methyl and 7-methyl, preferably 7-methyl.
Even more preferred are such compounds of Formula I wherein R2 is selected from the group consisting of: Ar-Co-galkyl, R9C(O)-, R9SO2.
Yet more preferred are compounds of Formula I wherein:
R! is
R2 is selected from the group consisting of: Ar-Cθ-galkyl, R C(O)- and R9SO2; 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- hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl; R4 is R5C(O)-;
R-> is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially Cχ_galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or Cχ.galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more Cj .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, 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 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 C _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,l-b]-furanyl, especially l-methyl-naphtho[2,l-b]-furan-2-yl; benzo[i»]thiophenyl, especially benzo[£>]thiophen-2-yl; especially Cj.galkoxy substituted benzo[έ»]thiophenyl, more especially 5,6-dimethoxy- benzo[6]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 1- 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-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- ?]thiophene, especially thieno[3,2-fo]thiophene-2-yl, more especially Cj_ galkyl substituted thieno[3,2-fo]thiophene-2-yl, more especially 5-tert-butyl-3-methyl- thieno[3,2-£]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, more especially 5-methyl-2-phenyl oxazol-4-yl, 2- phenyl-5-trifluoromethyl-oxazol-4-yl ; and lH-benzoimidazolyl, especially lH-benzoimidazol-5-yl.
R9 is selected from the group consisting of: methyl; ethyl, especially Cj-galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially Cχ_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-fluoroρhenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chloroρhenyl, especially Cj.galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C .galkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cj .galkyl 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 Cχ.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 Cχ_ 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 Cj.galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl;
R' is H; R" is H; and
R'" is H.
Also preferred are such compounds wherein R'" is selected from the group consisting of: 6-methyl and 7-methyl, preferably 7-methyl. The following compounds are preferred for use in the present methods of treatment:
Chemical Name
Benzo[ 1 ,3]dioxole-5-carboxylic acid [(S)- 1 -( l-benzyl-3-oxoazepan-4-ylcarbamoyl)-3- methyl-butyl] amide;
Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl] amide;
5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl- 1-{ 3-oxo- 1-[2-
(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-
(3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide;
4-((S)-4-Methyl-2-{[5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino}- pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide;
5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl}-butyl)amide; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl] amide;
Benzofuran-2-carboxylic acid [(S)- 1-( l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide;
5-(2-Pyrrolidin- l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- 1 -( 1 -benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 5-(2~Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-buyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } -amide ;
Naphthalene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide; 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl] -butyl } -amide ;
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;
5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl }-amide;
4-[2-(2- { (S)-3-Methyl- 1 -[3-oxo- l-(pyidine-2-sulfonyι)-azepan-4-ylcarbamoyl]- butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine-l-carboxylic acid tert-butyl ester; 5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyl}-amide;
Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-6-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide;
Quinoline-4-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoy l]-butyl } amide ;
Quinoline-3-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ; Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide ;
Isoquinoline- 1-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoxaline-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl} amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide; lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide ; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ;
5-(4-Nitro-phenyl)-furan-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2-sulf onyl)- azepan-4-ylcarbamoyrj-butyl } amide ;
(S)-2- [2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2- sulfonyl)-azepan-4-yl]-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-methyl-lH- imidazole-4-sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3- oxo-azepan-4-y lcarbamoyl] -butyl } amide ;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl } amide;
5-(4-Oxy-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)-azepan-
4-ylcarbamoyl)]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- 1-( l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)~3-methyl-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-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl)]-3-methyl-butyl}-amide; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)-azepan-
4-ylcarbamoy 1] -butyl } amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty }-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide; lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide;
Benzo[ 1 ,3]dioxole-5-carboxylic acid { (S)-3-methyl- 1 -[3-oxo- 1 -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide; 3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl}amide;
4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Thieno [3 ,2-b] thiophene-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-5-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl]-butyl } amide;
5-(4-Chloro-phenyl)-furan-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3methyl-butyl } -amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl}amide;
2-Pheny l-5-trifluoromethyl-oxazole-4-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide ;
Benzof 1 ,3]dioxole-5-carboxylic acid { (S)- l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
4-Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-carbamoyl]- butyl } -benzamide ;
3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl] amide;
5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- yl]-amide;
5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Furan-2-carboxylic acid ({(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-amide;
Quinoline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; l-Methyl-lH-indole-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl} -amide;
5-Methoxy-benzofuran-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoxaline-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfbnyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide ;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl } -amide; 5-Methoxy-benzofuran-2-carboxylic acid-{ (S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid- { (S)- 1-[ 1 -(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-methylbenzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; Quinoxaline-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo.-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1-( l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(2,2',4-tridueterio)-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- pentylj-amide;
Benzofuran-2-carboxylic acid { (S)- 1 -[3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
5-Methyl-2-phenyl-oxazole-4-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3- methyl-butyl } -benzamide ; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- yl carbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl } -amide;
N-{(S)-l-[l-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-3,4- dimethoxy-benzamide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid-{ (S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3- methyl-butyl]-amide;
N-[(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-3,4- dimethoxy-benzamide; N- { (S)- 1 -[ 1 -(2-Cy ano-benzenesulf onyl)-3-oxo-azepan-4-ylcarbamoyl } -3-methy 1-butyl } -4- methanesulfonyl-benzamide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide;
5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -butyj-amide;
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;
6-Methyl-N-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl } -nicotinamide; 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;
N- { (S)- 1 - [( 1 -(2-cy ano-benzenesulf onyl)-3-oxo-azepan-4-ylcarbamoyl } -3-methy 1-butyl } -3 ,4- dimethoxy-benzamide;
4-Methansulfonyl-N-{(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methyl-butyl-benzamide;
(S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo-l-(pyridine-
2-sulfonyl)-azepan-4-yl]-amide;
(S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
7-Methoxybenzofuran-2-carboxylic acid { (S)-3-methy 1- 1 - [3-oxo- 1 -(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
3-Methylbenzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl jamide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; 1 -Methyl- lH-indole-2-carboxy lie acid { (S)-3-methyl- 1 - [3-oxo- 1 -(thiazole-2-sulf onyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-chloro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyι)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methy 1-butyl } -amide; Benzo[b]thiophene-2-carboxylic acid-{ (S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide; l-Methyl-lH-indole-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide; 7-Methoxy-benzofuran~2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } -amide; Benzo[b]thiophene-2-carboxylic acid- { (S)-3-methyl- l-[3-oxo- l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } -amide;
Quinoxaline-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide;
1 -Methyl- l-H-indole-2-carboxy lie acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } -amide ;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl] -butyl } amide ;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl } amide; Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-6-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } amide ;
Quinoline-4-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Isoquinoline- 1-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Naphthalene-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide; Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
(R)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methyl-l-{3-oxo-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid { (S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-ethyl]-amide; 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;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-
3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [ l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl }amide;
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl- 1-[ l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl } amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Naphthalene- 1 -carboxylic acid {(S)-2-naphthalen-2-y 1-1 -[3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Quinoline-8-carboxylic acid { (S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide ;
Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide; Naphthalene- 1 -carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl}-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- l-[l-(2-methyl-furan-3-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoline-2-carboxylic acid { (S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- 2-phenyl-ethyl} -amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7S)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl}-amide;
Naphthalene- 1 -carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide;
Quinoline-5-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } -amide ;
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;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl } -amide; Naphthalene- 1 -carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl}-amide;
Quinoline-8-carboxylic acid {(S)-l-[3-oxo~l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl}-amide;
Naphthalene- 1-carboxylic acid { (S)- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl].-2-phenyl-ethyl}-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; 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- 1- [3-oxo- 1 -( 1 -oxy-pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
6-Fluoro-3-methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; .
3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
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; 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;
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;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(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- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 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;
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; l-methyl-naphtho[2,l-b]-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-
2-sulf onyl)-azepan-4-ylcarbamoyl]-butyl } -amide;
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;
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-ylcarbamoyl]-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl- 1 -[3-oxo- 1 -quinolin-2-ylmethyl-azepan-
4-y lcarbamoy l]-butyl } -amide; Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-
4-y lcarbamoy l]-3-methy 1-butyl } -amide;
Quinoxaline-2-carboxylic acid { (S)- 1 - [ 1 -(2-fluoro-pheny lcarbamoy l)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(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-methyl-butyl}-amide; 4-Methyl-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; and
4-Methyl-furan-2-carboxylic acid { (S)- 1-[ l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- y lcarbamoy 1] -3-methy 1-butyl } -amide. Specific representative compounds which are useful in the present methods are set forth in Examples 1-222.
The present invention includes deuterated analogs of the inventive compounds. A representative synthetic route for the deuterated compounds of the present invention is set forth in Scheme 7, below. The deuterated compounds of the present invention exhibit superior chiral stability compared to the protonated isomer.
Definitions
The compounds used in 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. 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. Oχ .galkyl may be optionally substituted by a moiety selected from the group consisting of: OR 4,
C(O)R14, SR14, S(0)R14, NRi4 2, R14NC(O)OR5, CO2Rl4, CO2NR14 2, N(C=NH)NH2, Het, C3_gcycloalkyl, and Ar; where R is selected from the group consisting of: H, Cχ_ galkyl, C2.galkenyl, C2.galkynyl, C3_gcycloalkyl-CQ_galkyl, Ar-CQ.galkyl and Het-CQ. galkyl; and Rl4 is selected from the group consisting of: H, Cj.galkyl, Ar-Co_galkyl, and Het-CQ_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.
"C _galkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2_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, Cl, Br, and I.
"Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-C0.galkyl; Cj.galkoxy; Ph-C0.galkoxy; Het-CQ.galkoxy; OH, (CH2)χ. gNR 5Rl6; O(CH2)I_6NR15R16; Ci-galkyl, ORI7, N(R17)2, SR17, CF3, NO2, CN, C 2R17, CON(Rl7), F, Cl, Br or I; where R15 and Rl6 are H, C galkyl, Ph-C0.galkyl, naphthyl-CQ_galkyl or Het-CQ.galkyl; and R 7 is phenyl, naphthyl, or Cχ.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 CQ.gAr, Cl .galkyl, ORI7, N(R17)2, SR17, CF3, NO2, CN, CO2Rl7, CON(R17), F, Cl, Br and I, where R17 is phenyl, naphthyl, or Cχ.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[b]thiophenyl, 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 ArCQ.galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCQ,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-propanedithioln 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 was effected with a coupling agent such as EDC provides 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
4
Cl-
7 Reagents and conditions: a.) NaH, 5-bromo-l-pentene, DMF; b.) 2,6-diisopropylphenylimido neophyhdene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, toluene c.) m-CPBA, CIL,C12; d.) NaN3, CH3OH, H20, NH4C1; e.) 10% Pd/C, H2, ; f.) Cbz-leucine, EDC, CH2C12; g.) HCl, EtOAc; h.) Cbz-leucine, EDC, CHjCl,; i.) pyridine sulfur trioxide complex, DMSO, TEA.
Compounds of the general formula I wherein Rl 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-CPBA 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 HCl 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,COCl, CH2C12; i.) HCl/ EtOAc; j.) R.COjH, 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 Rj 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 sulfurtrioxide 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
18 19
20 21
Reagents and conditions: a.) R,CHO, NaBH(OAc)3; b.) HCl; c.) I^CO.H, EDC, CH2C12; d.) pyridine sulfurtrioxide complex, DMSO, TEA; e.) R,NCO, base; f.) RIS02C1, TEA, CH2C12. Compounds of the general formula I may be prepared in a fashion analogous to that outlined in Schemes 4, 5, 6, and 7
Scheme 4
1) DIBAI
2-Methyl-pent-4-enoic acid ethyl ester is converted to a N-2-pyridinesulfonyl-azapine by reduction to the aldehyde, reductive amination with allylamine, sulfonylation with 2- pyridyl sulfonyl chloride, and olefin metathesis with Grubbs' catalyst. Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography. The syn epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine. Acylation of the free amine with Boc-leucine and a coupling reagent such as HBTU or EDC, followed by deprotection of the Boc group with HCl, and acylation with a variety of aromatic carboxylic acids and coupling reagents such as HBTU or EDC gives the intermediate alcohols. Final oxidation with Dess-Martin periodinane and HPLC affords the desired ketones.
Scheme 5
1) HCl, dioxane
2) 2-benzofuran carboxylic acid, HBTU
3) Dess-Martin periodinane 4) Chiral HPLC
5-Hexen-2-one is converted to a N-carbobenzyloxy-azapine by reductive amination with allylamine, protection with carbobenzyloxy chloride, and olefin metathesis with Grubbs' catalyst. Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography. Each epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine. Acylation of the free amine with Boc-leucine and a coupling reagent such as HBTU or EDC, followed by deprotection of the Cbz group by hydrogenolysis provides the secondary amines which are in turn sulfonylated with 2-pyridine sulfonylchloride. Deprotection of the Boc groups with HCl and acylation with a variety of aromatic carboxylic acids and coupling reagents such as HBTU or EDC gives the intermediate alcohols. Final oxidation with Dess-Martin periodinane and HPLC affords the desired ketones. CbzNH. . ,0H
complex
Carbobenyzloxy-D-alaninol (Cbz-D-alaninol)is first converted to an iodide, then is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl organometallic reagent. The amine is then alkylated with allyl iodide. Grubbs' catalyst is then used to form the azapine ring by ring closing metathesis. Epoxidation of the alkene followed by separation of the diastereomers followed by opening of the epoxide of the minor component with sodium azide provides the intermediate azido alcohol. Reduction of the azide followed by acylation of the amine with Boc-leucine followed by deprotection of the Cbz gives the intermediate secondary amine, which is then sulfonylated with an sulfonyl chloride. Deprotection of the Boc group followed by acylation and final oxidation of the secondary alcohol to the ketone provides the desired products. Scheme 7
Deuterated inhibitors can be prepared from the parent inhibitors such as benzofuran-2- carboxylic acid { (S)-3-methyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} -amide by treating with a base such as triethyl amine and stirring for several days in a deteurated protic solvent such as CD3OD: D2O.
Utility of the Invention
In general, the present invention provides a method of inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
The present invention also provides a method of treating a parasitic disease mediated by a cysteine protease by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
Parasites known to utilize cysteine proteases in their life cycle include Plasmodium falciparum (malaria), Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi, Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus
[onchocerciasis (river blindness)] Brugia pahangi, Entamoeba histolytica, Giardia lambia, the helminths, Haemonchus contortus and Fasciola hepatica, as well as helminths of the genera Spirometra, Tήchinella, Necator and Ascaris, and protozoa of the genera Cryptosporidium, Eimeria, Toxoplasma and Naegleria. The present method provides treatment of diseases caused by infection by these parasites by inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I. As demonstrated in Table 1 below, the compounds of Formula I used in the inventive method are especially effective in inhibition of one or more of the following parasitic proteases: falcipain (P. falciparum), cruzain (T. cruzi), rhodazain (T. brucei rhodesiensi), leishmania L (Leishmania spp.), leishmania B (Leishmania spp.), and schistosoma B (S. mansonϊ).
More particularly, the present invention provides a method of treating diseases selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
Most particularly, the present invention provides a method of treating malaria, caused by infection with Plasmodium falciparum, by the inhibition of falcipain by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the above-listed compounds.
The present method may be practiced by administering the above-listed compounds alone or in combination with other therapeutically effective compounds, including but not limited to quinoline-derived drugs.
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.
The present invention includes all esters, hydrates, solvates, complexes and prodrugs of the above-listed compounds useful in the inventive method. Prodrugs are any covalently bonded compounds which release the active parent drug 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 wherem 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 methods of treatment of this invention also use pharmaceutical compositions which comprise one or more of compounds of 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 useful in the practice oof the present methods of treatment. Pharmaceutical compositions of 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 or filled into a soft gelatin capsule. For rectal administration, the compounds of Formula I may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
In accordance with this invention, an effective amount of one or more compounds of Formula I is administered to inhibit the protease implicated with a particular condition or disease. Of course, this dosage amount will further be modified according to the type of administration of the compound. For example, for acute therapy, parenteral administration of an effective amount 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 the parasitic protease, e.g. falcipain in the case of treatment of malaria. 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 compound may be administered in the form of a prodrug which, in general, is designed to enhance absorption and is cleaved in vivo to form the active component. Efficacious levels may also be achieved by administration of pharmaceutically active metabolites or bioisosteres of the compound. Prodrugs of compounds of the present invention may be prepared by any suitable method.
The compounds used in this method may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit cysteine proteases, e.g. falcipain in the case of treatment of malaria, 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 0.1 to about 50 mg/kg given 1-2 times/day. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present method of treatment.
Biological Assays The compounds used in the present method may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect. For example, an assay for determining parasitic cysteine protease catalytic activity and an assay to determine the amount of cysteine protease inhibition by a compound of the inventive method are provided.
Determination of cysteine protease catalytic activity Standard assay conditions for the determination of kinetic constants used 10 uM fluorogenic peptide substrate, Cbz-Phe-Arg-AMC for the cysteine proteases from Leishmania spp and Schistosoma Mansoni, Cbz-Leu-Arg-AMC for the cysteine proteases from Plasmodium falciparum and Trypanosoma brucei rhodesiensi, and Ac-Lys-Glu-Lys- Leu-Arg-AMC (4 uM final substrate concentration) for the cysteine protease from Trypoanosoma cruzi, and were determined in 100 mM Na acetate at pH 5.5 containing 5 mM cysteine. Stock substrate solutions were prepared at concentrations of 10 mM in DMSO with 10 uM (4 uM for Ac-Lys-Glu-Lys-Leu-Arg-AMC) final substrate concentration in the assays. The final DMSO concentration was 2 % and the final volume was 100 uL. All assays were conducted at ambient temperature. 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 (K{>app) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140):
v = VmA /[Ka(l + VKi 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 kODS according to equation 2:
[AMC] = vss t + (VQ - vss) [1 - exp (-k0bst)l / k0bs (2)
where [AMC] is the concentration of product formed over time t, vβ is the initial reaction velocity and ^ is the final steady state rate. Values for k0bs were en analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (kQbs 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).
Table I provides exemplary data resulting from the testing of compounds of the present method for inhibition of one or more of the following parasitic disease cysteine proteases: falcipain, cruzain, rhodazin, leishmania L, leishmania B, schistosoma Bl, and schistosoma B2.
The in vivo and in vitro anti-parasitic efficacy of certain cysteine or serine protease inhibitors has been previously reported respecting the following parasites: Trypanosoma brucei: Morty, R. E.; Troeberg, L.; Powers, J. C; Ono, S.; Lonsdale-Eccles, J. D.; Coetzer, T. H. T. Biochem. Pharmacol. 2000, 60(10), 1497-1504;
Leishmania major. Selzer, P. M.; Pingel, S.; Hsieh, I.; Ugele, B.; Chan, V. J.; Engel, J. C; Bogyo, M.; Russell, D. G.; Sakanari, J. A.; McKerrow, J. H. Proc. Nat. Acad. Sci. U. S. A. 1999, 96(20), 11015-11022; Trypanosoma cruzi: Engel, J. C; Doyle, P. S.; Hsieh, I.; McKerrow, J. H. /. Exp. Med. 1998, 188(4), 725-734; and
Plasmodium vinckei: Rosenthal, P. J.; Le, G. K.; Smith, R. E. J. Clin. Invest. 1993, 91, 1052-
1056.
Engel and Rosenthal in particular show that administration of cysteine protease inhibitors can provide selective treatment of parasitic infection in animals. The data in Table I demonstrate that the compounds of the present invention are efficacious inhibitors of the cysteine protease of one or more of the parasites selected from the group consisting of: Leishmania spp, Schistosoma Mansoni, Plasmodium falciparum, Trypanosoma brucei rhodesiensi, and Trypoanosoma cruzi, and thus, if administered according to the present method, may be therapeutically effective in treating malaria and other parasitic diseases identified herein above in animals, particularly mammals, most particularly human beings. Alq < 1 μM is considered efficacious. Alq < 100 nM is preferred.
Examples In the following synthetic examples, 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. Flash column chromatography was performed using silica gel 60 (Merck Art 9385). lH NMR (300 MHz) spectra were measured in CDCI3 solutions and were determined on a Varian 300 instrument utilizing a Varian UNITY/?ZMJ300 operating software. Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane as the internal standard, and coupling constants are given in Hertz. The following abbreviations are used for spin multiplicity: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, cm = complex multiplet. Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series FTIR spectrometer and are reported in wave numbers (cm-1).
Example 1
Preparation of benzoli 1.31dioxole-5-carboxylic acid f(S)-l-(l-benzyl-3-oxoazepan-4- ylcarbamoyl)-3-methyl-butyllamide
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- 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 (ESI): 260 , (M+H+).
b) 2,3,4,7 -tetrahydro-azepine-1-carboxylic acid benzyl ester
To a solution of the compound of Example 1(a) (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 (ESI): 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 1(b) (3.0 g, 13.0 mmol) in CH2CI2 was added m-CPBA (6.7 g, 39.2 mmol). The mixture was stirred overnight at room temperature whereupon it was partitioned between CH2C12 and staurated K2CO3. The organic layer was washed with sat. NaHCO3, water, brine, dried (MgSO4), filtered and concentrated to give 3.08 g of the title compound as an oil. MS (ESI): 248 (M+H+), 270 (M+Na+).
d) 4-azido-3-hydroxy-azepane-l-carboxylic acid benzyl ester To a solution of the compound of Example 1(c) (2.0 g, 8.1 mmol) in methano water (8:1 solution) was added NH,C1 (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 (ESI): 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 1(d) (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 0.72 g of the title compound. MS (ESI): 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 1(e) (720 mg, 2.72 mmol) in CH2CI2 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% methanohdichloromethane) gave 1.0 g of the title compound. MS (ESI): 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 1(f) (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 (ESI): 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 1(g) (0.69 g, 2.01 mmol) in CH2CI2 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. NaHCO , water, brine, dried (Na2SO4), filtered and concentrated. Column chromatography of the residue (5% methanol:dichloromethane) gave 800 mg of the title compound. MS (ESI): 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 1(h) (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) benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methyl-butyl] -amide
To a solution of the amine salt of Example l(i) (200 mg, 0.49 mmol) in CH2CI2 was added triethylamine (0.17 mL, 1.22 mmol), EDC (103.5 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and benzo[l,3]dioxole-5-carboxylic acid (90 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 (ESI): 482 (M+H+).
k) benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxoazepan-4-ylcarbamoyl)-3- methyl-butyl]amide
To a solution of the alcohol of Example l(j) (130 mg, 0.21 mmol) in DMSO was added TEA (0.17 mL) and pyridine sulfur trioxide complex (96 mg, 0.61 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:CH2Cl2) provided 100 mg of the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC (Whelk-Ol; ethanol/hexanes) provided the title compound. MS (ESI): 480.3 (M+H+).
Example 2
Preparation of Ouinoline-2-carboxylic acid f(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)- 3-methyl-butyll amide
Following the procedure of Example l(a)-l(k), except substituting quinoline-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 492.4 (M+H+).
Example 3
Preparation of 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l- { 3-oxo- 1- r2-(3-pyridin-2-yl-phenyl)acetyll-azepan-4-ylcarbamoyl ) -butvDamide
a) methyl 3-(trifluoromethylsulfonyloxy)phenylacetate
To an oven-dried flask under argon atmosphere containing sodium hydride (2.54 g, 60% dispersion in mineral oil, 63.5 mmol) was added anhydrous pentane (20 mL). The slurry was allowed to stir for 5 min, allowed to settle, most of the pentane was removed, and anhydrous THF (40 mL) was added. To this suspension was added a solution of methyl 3- hydroxyphenylacetate (9.99 g, 60.1 mmol) in anhydrous THF (20 mL) and the reaction was allowed to stir at room temperature for 20 min. To this mixture was then added a solution of N-phenyltrifluoromethanesulfonimide (22.53 g, 63.1 mmol)) in anhydrous THF (40 mL) and the reaction was allowed to stir at room temperature until TLC analysis indicated the complete consumption of starting material (1.5 h). The reaction was quenched by the addition of H2O (10 mL), concentrated to one half original volume, then diluted with CHCI3 (200 mL) and washed with H2O. The aqueous layer was washed with fresh CHCI3 (50 mL), the combined organic layers were washed with 10% Na2CO3, water, and saturated brine, then dried (MgSO4), filtered and concentrated. Column chromatography of the residue (silica gel, 5:95 EtOAc: hexanes, then 10:90 EtOAc: hexanes) gave 17.47 g of the title compound. 1H NMR (400 MHz, CDC13) 7.42 (m, IH), 7.31-7.19 (m, 3H), 3.72 (s, 3H), 3.68 (s, 2H).
b) methyl 3-(2-pyridyl)phenylacetate
To a solution of the compound of Example 3(a) (6.86 g, 23.0 mmol) in anhydrous dioxane (100 mL) was added 2-pyridyltributylstannane (8.89 g, 24.1 mmol), LiCl (2.94 g, 69.3 mmol), 2,6-di-tert-butyl-4-methylphenol (a few crystals), and Pd(PPh3)4 (632.1 mg, 0.55 mmol). The reaction was protected from light with foil and heated at reflux overnight. The reaction was allowed to cool to room temperature and was concentrated. Column chromatography of the residue (silica gel, 1:3 EtOAc: hexanes, then 1:2 EtOAc: hexanes) gave 3.85 g of the title compound. MS (ESI): 228.1 (M+H)+
c) 3-(2-pyridyl)phenylacetic acid To a solution of the compound of Example 3(b) (3.8 g, 16.7 mmol) in THF (50 mL) was added a solution of LiOH»H2θ (780.2 mg, 18.6 mmol) in water (10 mL). The reaction was allowed to at room temperature until TLC analysis indicated the complete consumption of starting material (2 h). The reaction mixture was concentrated to remove THF, then neutralized to pH 7 by the addition of IN HCl, diluted with brine (50 mL), and washed with CHCI3 (100 mL) The aqueous layer was readjusted back to pH 7 by the addition on IN NaOH and washed with fresh CHCI3 (100 mL). After repeating this procedure once more, the organic layers were combined, dried (MgSO4), filtered and concentrated to give 3.79 g of the title compound.' MS (ESI): 214.3 (M+H)+.
d) ((S)-3-methyl-l {3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-ethanoyl]-azepan-4- ylcarbamoyl}-butyl)-carbamic acid te? -butyl ester
To a solution of the compound of Example 1(g) (0.5g, 1.46 mmol) in CH2CI2 was added EDC (307 mg, 1.60 mmol), HOBt (216 mg, 1.60 mmol) the compound of Example
3(c) (341 mg, 1.60 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (2% methano dichloromethane) provided the title compound. MS (ESI): 539 (M+H+).
e) ethyl 5-hydroxybenzofuran-2-carboxylate To a mixture of aluminum chloride (6.3 g, 47.7 mmol) and ethanethiol (4.5 g, 72.9 mmol) in dichloromethane (81 mL) at 0 °C was added ethyl 5-methoxybenzofuran-2- carboxylate (3.0 g, 13.6 mmol). After stirring for 16h at room temperature, the mixture was poured into water, acidified with 3N HCl and extracted with dichloromethane (2x). The organic layers were combined, washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (2.16 g, 77%). 1H NMR (400 MHz, CDC13) δ 7.45 (m, 2H), 7.08 (m, IH), 7.02 (m, IH), 5.35 (s b, IH), 4.44 (q, 2H), 1.42 (t, 3H).
f) ethyl 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylate
To a solution of the compound of Example 3(e) (0.200 g 0.971 mmol), 4-(2- hydroxyethyl)morpholine (0.165 g, 1.26 mmol), and triphenylphosphine (0.331 g, 1.26 mmol) in THF (4 mL) at 0 °C was added dropwise diisopropylazodicarboxylate (0.254 g, 1.26 mmol). After stirring at room temperature for 16h, the solution was concentrated and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.235 g, 76%). 1H NMR (400 MHz, CDCI3) δ 7.48 (m, 2H), 7.07 (m, 2H), 4.43 (q, 2H), 4.14 (m, 2H), 3.76 (m, 4H), 2.86 (m, 2H), 2.61 (m, 4H), 1.40 (t, 3H).
g) 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid
To a stirring solution of the compound of Example 3(f) (0.235 g, 0.74 mmol) in THF (4.0 mL) and water (4.0 mL) was added lithium hydroxide monohydrate (0.035 g, 0.81 mmol). After stirring at reflux for 16h, the solution was concentrated and the residue was dissolved in water and acidified with leq IN HCl. The mixture was frozen and placed on a lyophilizer for 16h to yield the title compound as an off-white solid (0.150 g, 70%). MS (ESI): 292.1 (M+H)+.
h) 5-(2-mo holino-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 l(i)-l(k), except substituting ((S)-3-methyl- l{3-hydroxy-l-[2-(3-pyridin-2-yl-phenyl)-ethanoyl]-azepan-4-ylcarbamoyl}-butyl)-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and 5-[2-(4-morpholino)ethoxy]benzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 710.3 (M+H+).
Example 4
Preparation of 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-l- { 3-oxo- l-r2-(3-pyridin-2-yl-phenyl)acetyn-azepan-4-ylcarbamoyl l-butyl)amide
The title compound was isolated as the second eluting compound from the HPLC purification in Example 3(h). MS (ESI): 710.3 (M+H+).
Example 5
Preparation of 4-((S)-4-Methyl-2-{ r5-(2-morpholino-4-yl-ethoxy)-benzofuran-2- carbonyllaminol-pentanoylaminoVS-oxo-azepane-l-carboxylic acid phenylamide
a) [(S)- l-(3-hydroxy- 1 -pheny lcarbamoy l-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester To a solution of the compound of Example 1(g) (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% methanol: dichloromethane) provided 578 mg of the title compound. MS (ESI): 463 (M+H+).
b) 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 l(i)-l(k), except substituting [(S)-l-(3- Hydroxy- l-phenylcarbamoyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert- butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (i) and 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 634 (M+H+). Example 6
Preparation of 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid ITSH-fl- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyllamide
a) [(S)-l-(3-hydroxy-l-phenylsulfonyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester
To a solution of the compound of Example 1(g) (0.5 g, 1.46 mmol) in dichloromethane was added triethylamine (0.4 mL, 2.92 mmol) followed by benzenesulfonyl chloride (0.28 mL, 2.18 mmol). The reaction was stirred at room temperature until complete as determined by TLC analysis. Workup and column chromatography (10% methanohdichloromethane) provided 450 mg of the title compound. MS (ESI): 484 (M+H+).
b) 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3- oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy- 1 -phenylsulf onyl-azeρan-4-y lcarbamoy l)-3-methy 1-butyl] -carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (i), and 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 655 (M+H+).
Example 7
Preparation of 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid f(S)-l-(l- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl1amide
The title compound was isolated as the second eluting compound from the HPLC purification in Example 6(b). MS (ESI): 655 (M+H+). Example 8
Preparation of 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid ITSM-d- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyllamide
Following the procedure of Example 6(a)-6(b), except substituting 5-(2- pyrrolidin- l-yl-ethoxy)benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 639 (M+H+).
Example 9
Preparation of 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid T(S)-1-(1- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl1amide
Following the procedure of Example 6(a)-6(b), except substituting 5-(2- piperidin-1- yl-ethoxy)benzofuran-2-carboxylic acid for 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 653 (M+H+).
Example 10
Preparation of Naphthlene-2-carboxylic acid ((S)-3-methyl-l-l3-oxo-l-r2-(3-pyridin-2-yl- phenyl)ethyll-azepan-4-ylcarbamoyli-butyl)amide
Following the procedure of Example l(a)-l(k), except substituting 5-(2- piperidin-1- yl-ethoxy)benzofuran-2-carboxylic acid for benzaldehyde in step (h), and naphthalene-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 557 (M+H+).
Example 11
Preparation of lH-Indole-2-carboxylic acid f~(S)-l-( -benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl>3-methyl-butyl1amide
Following the procedure of Example 6(a)-6(b), except substituting indole-2- carboxylic acid for 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 525 (M+H+).
Example 12
Preparation of Benzofuran-2-carboxylic acid r(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4- ylcarbamoyl>3-methyl-butyl1amide
Following the procedure of Example 6(a)-6(b), except substituting benzofuran-2- carboxylic acid for 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. JH NMR (CDC13): 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 13
Preparation of 5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid IYS)-1-(1- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl1amide
The title compound was isolated as the second eluting compound from the HPLC purification in Example 8. MS (ESI): 639 (M+H+).
Example 14
Preparation of 5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid |"(S)-1-(1- benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl")-3-methyl-butyl]amide The title compound was isolated as the first eluting compound from the HPLC purification in Example 9. MS (ESI): 653 (M+H+).
Example 15
Preparation of 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid j(S)-3-methyl-l- ri-(4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamovn-buyl}-amide
Following the procedure of Example 3(a)-3(h), except substituting isocaproic acid for 3-(2-Pyridyl)phenylacetic acid in step (d), the title compound was prepared. MS (ESI): 613 (M+H+).
Example 16
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyH-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 527 (M+H+).
Example 17
Preparation of Naphthalene-2-carboxylic acid j(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 -amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and naphthalne-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 537 (M+H+). Example 18
Preparation of 5-(2-Morpholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid l(S)-3-methyl-l- f3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 656 (M+H+).
Example 19
Preparation of 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l- T3-OXO- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 18. MS (ESI): 656 (M+H+).
Example 20
Preparation of 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid l(S)-3-methyl-l- r3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-butyl 1 -amide
The title compound was isolated as the second eluting compound from the HPLC purification in Example 18. MS (ESI): 656 (M+H+).
Example 21
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(ρyridine-2- sulf onyl)-azepan-4-ylcarbamoyll-butyl 1 -amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 16. MS (ESI): 527 (M+H+). Example 22
Preparation of 4-r2-(2-|(S)-3-Methyl-l-r3-oχo-l-('pyidine-2-sulfonyl)-azepan-4- ylcarbamoyll-butylcarbamoyll-benzofuran-5-yloxy)-ethvn-piperazine-l-carboxylic acid tert- butyl ester
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 4-[2-(2-carboxy-benzofuran-5- yloxy)-ethyl]-piperazine-l -carboxylic acid tert-butyl ester for 5-(2-moφholin-4-yl-ethoxy)- benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 757 (M+H+).
Example 23
Preparation of 5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3- oxo-l"(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-3-butyl}~amide
The compound of Example 22 (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. MS (ESI): 655 (M+H+).
Example 24
Preparation of Quinoline-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+). Example 25
Preparation of Quinoline-6-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(pyridine-2-surfonyl)- azepan-4-ylcarbamoyll-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-6-carboxylic acid tert-butyl ester for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
Example 26
Preparation of Ouinoline-4-carboxylic acid {(S)-3-methyl-l -r3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamovH -butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-4-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
Example 27
Preparation of Quinoline-3-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-3-carboxylic acid tert-butyl ester for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+). Example 28
Preparation of Isoquinoline-3-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-('pyridine-2- sulfonyl)-azepan-4-ylcarbamovn-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and isoquinoline-3-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
Example 29
Preparation of Isoquinoline-1 -carboxylic acid j(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamovπ-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and isoquinoline-1-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
Example 30
Preparation of Ouinoxaline-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoxaline-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 539 (M+H+). Example 31
Preparation of Benzorblthiophene-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamovH-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzo[b]thiophene-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 545 (M+H+).
Example 32
Preparation of lH-Indole-2-carboxylic acid f (S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and indole-2-carboxylic acid for 5- (2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 526 (M+H+).
Example 33
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyn-butyl|amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-methoxybenzofuran-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 557 (M+H+). Example 34
Preparation of 5-Bromo-furan-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-φyridine-2- sulfonvD-azepan-4-ylcarbamovπ-butyllamide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-bromofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H+).
Example 35
Preparation of 5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-nitrofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 522 (M+H+).
Example 36
Preparation of 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-(4-nitrophenyl)furan-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 598 (M+H+). Example 37
Preparation of (S)-2-r2-(4-Fluoro-phenoxy)-acetylamino1-4-methyl-pentanoic acid β-oxo- (pyridine-2-sulfonyl)-azepan-4-yll-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 2-(4-fluorophenoxy)acetic acid for 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 535 (M+H+).
Example 38
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(thiophene-2- sulfonyl)-azepan-4-ylcarbamoyll-butyll-amide
Following the procedure of Example 6(a)-6(b), except substituting thiophene-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 532 (M+H+).
Example 39
Preparation of 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l- methyl-lH-imidazole-4-sulfonyl)-azepan-4-ylcarbamoyll-butv amide
a) 2-hydroxy-4,5-dimethoxybenzaldehyde
To a stirring solution of 2-benzyloxy-4,5-dimethoxybenzaldehyde (1.0 g, 3.67 mmol) in ethyl acetate (25 mL) was added 10% palladium on carbon (0.50 g). The mixture was stirred under a hydrogen atmosphere for 4h, then filtered through Celite. The filtrate was concentrated to yield the title compound as a pale yellow solid (0.632 g, 95%). 1H NMR
(400 MHz, CDC13) δ 11.41 (s, IH), 9.72 (s, IH), 6.89 (s, IH), 6.48 (s, IH), 3.91 (s, 3H), 3.88
(s, 3H). b) 4,5-dimethoxy-2-ethoxycarbonylmethoxybenzaldehyde
To a stirring solution of the compound of Example 39(a) (0.628 g, 3.4 mmol), and ethyl bromoacetate (0.575 g, 3.4 mmol) in acetone (150 mL) was added K2CO3 (0.715 g, 5.2 mmol). After stirring at reflux for 4h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (0.758 g, 82%). 1H NMR (400 MHz, CDCI3) δ 10.39 (s, IH), 7.30 (s, IH), 6.41 (s, IH), 4.72 (s, 2H), 4.22 (q, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 1.26 (t, 3H).
c) ethyl 5,6-dimethoxybenzofuran-2-carboxylate
A mixture of the compound of Example 39(b) (0.758 g, 2.8 mmol) and potassium carbonate (0.975 g, 7.1 mmol) was stirred at 80 °C in DMF (20 mL) for 5h. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water and satruated brine then dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.405 g, 58%). 1H NMR (400 MHz, CDCI3) δ 7.45 (s, IH), 7.10 (s, IH), 7.04 (s, IH), 4.41 (q, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.41 (t, 3H).
d) 5,6-dimethoxybenzofuran-2-carboxylic acid
Following the procedure of Example 3(g), except substituting ethyl 5,6- dimethoxybenzofuran-2-carboxylate for ethyl 5-[2-(4-moφholino)ethoxy]benzofuran-2- carboxylate, the title compound was prepared as a white solid (0.263 g, 73%). 1H NMR (400
MHz, CDCI3) δ 7.40 (s, IH), 7.03 (s, IH), 7.01 (s, IH), 3.90 (s, 3H), 3.88 (s, 3H).
e) 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
Following the procedure of Example 6(a)-6(b), except substituting 1- methylimidazole-4-sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5,6- dimethoxybenzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 590 (M+H+).
Example 40 Preparation of Benzofuran-2-carboxylic acid j(S)-3-methyl-l-ri-(l-methyl-lH-imidazole-3- sulf onyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting 1- methylimidazole-2-sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran- 2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 530 (M+H+).
Example 41
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-ri-(lH-imidazole-2-sulfonyl)- 3-oxo-azepan-4-ylcarbamoyπ-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting imidazole-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 516 (M+H+).
Example 42
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-ri-d-methyl-lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting 1- methylimidazole-4-sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran- 2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 530 (M+H+).
Example 43
Preparation of 5-(4-Oxy-moφholino-4-yl-ethoxy')-benzofuran-2-carboxylic acid |(S~)-3- methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyI}amide To a solution of the compound of Example 18 (0.01 g) in dichloromethane (2 mL) was added m-CPBA (0.008 g). The reaction was stirred overnight. Workup and column chromatography (30% methano dichloromethane) provided the title compound. MS (ESI): 671 (M+H+).
Example 44
Preparation of 5-Hydroxy-benzofuran-2-carboxylic acid ((S)-3-methyl-l-ri-(l-methyl-lH- imidazole-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyllamide
Following the procedure of Example 6(a)-6(b), except substituting 1- methylimidazole-4-sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5- hydroxybenzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 546 (M+H+).
Example 45
Preparation of Benzofuran-2-carboxylic acid f (SV3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl ]-3-methyl-butyl } -amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 542 (M+H+).
Example 46
Preparation of Benzo[b1thiophene-2-carboxylic acid USV3-methyl-l-f3-oχo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzo[b]thiophene-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 558 (M+H+).
Example 47
Preparation of 5-Bromo-furan-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-bromofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 572 (M+H+).
Example 48
Preparation of 5.6-Dimethoxy-benzofuran-2-carboxylic acid {(SV3-methyl-l-r3-oxo-l-(l- oxy-pyridine-2-sulfonyl)~azepan-4-ylcarbamoyπ-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5,6-dimethoxybenzofuran-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 602 (M+H+).
Example 49
Preparation of Benzofuran-2-carboxylic acid US)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl")1-3-methyl-butyl 1 -amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 45. MS (ESI): 542 (M+H+). Example 50
Preparation of 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 47. MS (ESI): 572 (M+H+).
Example 51
Preparation of Benzorblthiophene-2-carboxylic acid l(S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamovH-butyl|amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 46. MS (ESI): 558 (M+H+).
Example 52
Preparation of 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 48. MS (ESI): 602 (M+H+).
Example 53
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid US)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-methoxybenzofuran-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 573 (M+H+). Example 54
Preparation of lH-Indole-5-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and indole-5-carboxylic acid for 5- (2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 542 (M+H+).
Example 55
Preparation of Benzol 1.31dioxole-5-carboxylic acid {(S -3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonylVazepan-4-ylcarbamoyll-butvU amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzo[l,3]dioxole-5-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 547 (M+H+).
Example 56
Preparation of 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid f (S -3-methyl-l- r3-oxo-(l-oxy-pyridine2-sulfonyl -azepan-4-ylcarbamoyl]- -buty|-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 672 (M+H+). Example 57
Preparation of 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 3-methylbenzofuran-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 557 (M+H+).
Example 58
Preparation of lH-Indole-6-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy 11-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and indole-6-carboxylic acid for 5- (2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 526 (M+H+).
Example 59
Preparation of Benzol 1.31dioxole-5-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyn-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and indole-5-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 531 (M+H+). Example 60
Preparation of 3.4-Dihvdro-2H-benzorbiri.4]dioxepine-7-carboxylic acid {(S)-3-methyl-l- r3-oxo-l-(l-oxy-pyridine-2-sulfonyl')-azepan-4-ylcarbamoyllbutyl)amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 3,4-dihydro-2H- benzo[b][l,4]dioxepine-7-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 575 (M+H+).
Example 61
Preparation of 4,5-Dibromo-thiophene-2-carboxylic acid j(SV3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 4,5-dibromothiophene-2- carboxylic acid for 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 665 (M+H+).
Example 62
Preparation of Thienor3.2-b1thiophene-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-d-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and thieno[3,2-b]thiophene-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 565 (M+H+). Example 63
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl ) amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 53. MS (ESI): 573 (M+H+).
Example 64
Preparation of lH-Indole-5-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonvD- azepan-4-ylcarbamoyD-butyl ) amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 54. MS (ESI): 542 (M+H+).
Example 65
Preparation of 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l- φyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-(4-chloro-phenyl)-furan-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 587 (M+H+).
Example 66
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(SV3-methyl-l-r3- oxo- 1 -ψyridine-2-sulfonyl)-azepan-4-ylcarbamoyπ-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-(3-trifluoromethyl-phenyl)- furan-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 621 (M+H+).
Example 67
Preparation of Benzor 31dioxole-5-carboxylic acid {(S)-l-ri-(4-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyll-3methyl-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 548 ( +H+).
Example 68
Preparation of 5-Bromo-furan-2-carboxylic acid ((S)-3-methyl- 143-0X0- l-φyridine-2- sulfonyl)-azepan-4-ylcarbamoyπ-butyl I amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 34. MS (ESI): 555 (M+H+).
Example 69
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid j(S)-3-methyl-l-r3-oxo-l-ψyridine- 2-sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 33. MS (ESI): 557 (M+H+).
Example 70
Preparation of 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(pyridine- 2-sulf onyl)-azepan-4-ylcarbamovn-butyl j amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 3-methylbenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 541 (M+H+).
Example 71
Preparation of Thienor3,2-b1thiophene-2-carboxylic acid |(S)-3-methyl-l-r3-oxo-l- φyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and thieno[3,2-b]thiophene-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 549 (M+H+).
Example 72
Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-earboxylic acid KS)-3-methyl-l-r3- oxo- 1 -(pyridine-2-sulf onylVazepan-4-ylcarbamoyll-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 2-Phenyl-5-trifluoromethyl- oxazole-4-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 622 (M+H+). Example 73
Preparation of Benzori,31dioxole-5-carboxylic acid l(S)-l-fl-(4-methoxy-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamovn-3-methyl-butyl}-amide
Following the procedure of Example 6(a)-6(b), except substituting 4- methoxybenzenesulfonyl chloride for benzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 560 (M+H+).
Example 74
Preparation of Benzofuran-2-carboxylic acid j(S)-l-ri-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methy 1-butyl ) -amide
Following the procedure of Example 6(a)-6(b), except substituting 4- methoxybenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 556 (M+H+).
Example 75
Preparation of Furan-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamovn-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and furan-2-carboxylic acid for 5- (2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 493 (M+H+). Example 76
Preparation of Benzoπ.31dioxole-5-carboxylic acid ((S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamovι"l-butyl } amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 55. MS (ESI): 547 (M+H+).
Example 77
Preparation of 4-Fluoro-{(S)-3-methyl-l-r3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- carbamoyll-butyl } -benzamide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 4-fluorobenzoic acid for 5-(2- moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 521 (M+H+).
Example 78
Preparation of 3.4-Dihydro-2H-benzo[biri.41dioxepine-7-carboxylic acid {(S)-3-methyl-l- r3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoynbutyl|amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 60. MS (ESI): 575 (M+H+).
Example 79
Preparation of 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-r3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyπ-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-methylthiophene-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 523 (M+H+).
Example 80
Preparation of (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid r3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-vH -amide
a) (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]- amide
Following the procedure of Example 6(a) except substituting 2-pyridinesulfonyl chloride for benzenesulfonyl chloride, the title compound was prepared. MS (ESI): 385 (M+H+).
b) (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)- azepan-4-yl]-amide
To a solution of the compound of Example 80(a) (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% methanol:dichloromethane) provided the title compound (0.12 g).
c) (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan- 4-yl]-amide
Following the procedure of Example l(k) except substituting (S)-2-(3-Benzyl- ureido)-4-methyl-pentanoic acid [3-hydroxy-l-(pyridine-2-sulfonyl)-azepan-4-yl]-amide for benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3- methyl-butyl]-amide, the title compound was prepared. MS (ESI): 516 (M+H+).
Example 81
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid r(S)-l-(l-methanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyll-amide
Following the procedure of Example 6(a)-6(b), except substituting methanesulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-methoxybnzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 494 (M+H+).
Example 82
Preparation of Furan-2-carboxylic acid fl(S -l-ri-(4-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butylcarbamoyl 1 -methvD-amide
Following the procedure of Example 6(a)-6(b), except substituting 4- methoxybenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and N-(2-furan- carbonyl)-glycine for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 563 (M+H+).
Example 83
Preparation of Ouinoline-2-carboxylic acid ir(S)-l-ri-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H+). Example 84
Preparation of l-Methyl-lH-indole-2-carboxylic acid {r(S)-l-ri-(4-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl 1 -amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 1-methylindole- 2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 557 (M+H+).
Example 85
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid (S)-l-ri-(4-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 5- methoxybenzofuran-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 574 (M+H+).
Example 86
Preparation of Ouinoxaline-2-carboxylic acid |f(S)-l-ri-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-quinolxaline-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 556 (M+H+). Example 87
Preparation of Benzorblthiophene-2-carboxylic acid I (S)-3-methyl- l-r3-oxo- l-(pyridine-2- sulf onyl)-azepan-4- ylcarbamoyll-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzo[b]thiophene-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 543 (M+H+).
Example 88
Preparation of Benzofuran-2-carboxylic acid-{(S)-l-IT-(3-chloro-benzenesulfonvι)-3-oxo- azepan-4-ylcarbamovH-3-methyl-butyl}-amide
a) {(S)-l-[l-(3-chloro-benzenesulfonyl)-3-hydroxy-azepan-4-ylcarbamoyl]-3-methyl-butyl}- carbamic acid tert-butyl ester
To a solution of the compound of Example 1(g) (2.50 g, 7.29 mmol) in dichloromethane (100ml) was added P-NMM (4.0 g) and 3-chlorobenzenesulfonyl chloride (1.85 g, 8.75 mmol). After shaking at room temperature overnight, the solution was filtered. The filtrate was concentrated to yield the title compound as white solid (3.13 g, 83.3%). MS (ESI): 539.8 (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 88(a) (1.0 g, 1.93 mmol) 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 (ESI): 417.9 (M+H)+. c) Benzofuran-2-carboxylic acid-{ (S)-l-[l-(3-chloro-benzenesulfonyl)-3-hydroxy-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide
To a solution of the compound of Example 88(b) (0.14 g, 0.33 mmol) in dichloromethane (20 mL) was added benzofuran-2-carboxylic acid (0.81 g, 0.50 mmol), 1- hydroxybenzotriazole (0.77 g, 0.57 mmol), and P-EDC (0.67 g, 1 mmol/g) in dichloromethane (10 mL). After shaking at room temperature overnight, the solution was treated with trisamine resin (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-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide
To a stirring solution of the compound of Example 88(c) (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 (Whelk-Ol; ethanol/hexanes) to yield the title compound as a white solid (62.7 mg, 52 %). MS (ESI): 560.2 (M+H)+.
Example 89
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid-((S)-l-ri-(3-chloro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 88(a)-88(d), except substituting 5- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 590 (M+H+). Example 90
Preparation of 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-ri-(3-chloro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl ) -amide
Following the procedure of Example 88(a)-88(d), except substituting 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 574 (M+H+).
Example 91
Preparation of Benzofuran-2-carboxylic acid-((S -l-ri-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl1-3-methyl-butyll-amide
Following the procedure of Example 88(a)-88(d), except substituting 2- fluorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 544 (M+H+).
Example 92
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-Hl-(2-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyn-3-methyl-butyl}-amide
Following the procedure of Example 88(a)-88(d), except substituting 2- fluorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 5- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 574 (M+H+).
Example 93
Preparation of 7-Methoxy-benzofuran-2-carboxylic acid- j(S)-l-ri-(2-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 2- fluorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 7- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 574 (M+H+).
Example 94
Preparation of 3-methylbenzofuran-2-carboxylic acid-KSV l-ri-(2-fluoro-benzenesulfonyD- 3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 2- fluorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 558 (M+H+).
Example 95
Preparation of Benzorblthiophene-2-carboxylic acid- j (S)-l-ri-("2-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl1-3-methyl-butylj-amide
Following the procedure of Example 88(a)-88(d), except substituting 2- fluorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 560 (M+H+). Example 96
Preparation of Quinoxaline-2-carboxylic acid-l(S -l-ri-(2-fluoro-benzenesulfonyl")-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyll-amide
Following the procedure of Example 88(a)-88(d), except substituting 2- fluorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and quinoxaline-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 556 (M+H+).
Example 97
Preparation of 3-Methyl-benzofuran-2-carboxylic acid l(S)-3-methyl-143-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyn-butyl}amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 70. MS (ESI): 541 (M+H+).
Example 98
Preparation of Thienor3.2-b1thiophene-2-carboxylic acid ((S)-3-methyl-143-oxo-l- (pyridine-2-sulfonyl")-azepan-4-y lcarbamoy 11-butyl } amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 71. MS (ESI): 549 (M+H+).
Example 99
Preparation of 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl I amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 57. MS (ESI): 557 (M+H+). Example 100
Preparation of Benzofuran-2-carboxylic acid ((S)-3-methyl-l-r(2.2,.4-tridueterio)-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl 1 amide
To a solution of the compound of Example 16 (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% methanokdichloromethane) to provide the title compound (0.02 g). Separation of the diastereomers by HPLC (Whelk-Ol; ethanol/hexanes) provided the title compound. MS (ESI): 530 (M+H+).
Example 101
Preparation of Quinoxaline-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2-sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoxaline-2-carboxylic acid for 5-(2- moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H+).
Example 102
Preparation of Benzofuran-2-carboxylic acid i(S)-2-cvclohexyl-143-oxo-l~(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl1 -ethyl 1 -amide
a) 4-tert-Butoxycarbonylamino-3-hydroxy-azepane-l-carboxylicacid benzyl ester
To a stirring solution of compound of Example 1(e) (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 NaHCO3 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): 365.0 (M+H)+.
b) (3-Hydroxy-azepan-4-yl)-carbamic acid tert-butyl ester To a solution of compound of Example 102(a) (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, 2.29 mmol, 87%). MS (ESI): 231.9 (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 102(b) (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): 373.0 (M+H)+.
d) 4-Amino-l-(pryidine-2-sulfonyl)-azepan-3-ol To a stirring solution of the compound of Example 102(c) (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): 272.9 (M+H) +.
e) { (S)- 1 -[3-Hydroxy- 1 -(pryidine-2-sulfonyl)-azepan-4-ylcarbamoyl] -2-meth-butyl } -carbamic acid tert-butyl ester
To a solution of the compound of example 102(d) (19 mg, 0.070 mmol) in CH2C12 was added N- tert-butoxycarbonyl-L-cyclohexylalanine (28.5 mg, 0.10 mmol), 1- hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in dichloromethane. 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): 525.0 (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 102(e) (37 mg, 0.07 mmol) in dicloromethane (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): 425.0 (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 102(f) (30 mg, 0.070 mmol) in ichloromethane was added benzofuran-2-carboxylic acid (17.0 mg, 0.106mmol), 1- hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in dichloromethane. 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): 569.0 (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 102(g) (40 mg, 0.07 mmol) in dichloromethane (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 (Whelk-Ol; ethanol/hexanes) to yield title compound as a white solid. MS (ESI): 567.0 (M+H)+.
Ill Example 103
Preparation of Benzofuran-2-carboxylic acid ((S)-l-[3-oxo-l-(pyridine-2-sulfonylVazepan- 4-ylcarbamoyll-pentyl ) -amide
Following the procedure of Example 102(a)-102(h), except substituting N-Boc- norleucine for N- tert-butoxycarbonyl-L-cyclohexylalanine in step (e), the title compound was prepared. MS (ESI): 527 (M+H+).
Example 104
Preparation of Benzofuran-2-carboxylic acid |(S)-143-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamovπ-2-phenyl-ethyl 1 -amide
Following the procedure of Example 102(a)- 102(h), except substituting N-tert- butoxycarbonyl-L-phenylalanine for N-Boc-cyclohexylalanine in step (e), the title compound was prepared. MS (ESI): 561 (M+H+).
Example 105
Preparation of 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-143- oxo-l-φyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 72. MS (ESI): 622 (M+H+).
Example 106
Preparation of 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-143-oxo-l- ψyridine-2-sulfonylVazepan-4-y lcarbamoy 11-butyl 1 amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-Methyl-2-phenyloxazole-4- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 568 (M+H+).
Example 107
Preparation of 3.4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl] -3-methyl-butyl 1 -benzamide
Following the procedure of Example 6(a)-6(b), except substituting 4- methoxybenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 3,4- dimethoxybenzoic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 576 (M+H+).
Example 108
Preparation of Benzorb]thiophene-2-carboxylic acid-{(S)-14 l-(4-fluoro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyll-3-methyl-butyl I -amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and benzo[b]thiophene-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid in step (b), the title compound was prepared. MS (ESI): 560 (M+H+).
Example 109
Preparation of Benzofuran-2-carboxylic acid-l (S 4 l-(4-fluoro-benzenesulfonyl')-3-oxo- azepan-4-yl carbamovn-3-methy 1-butyl I -amide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 544 (M+H+). Example 110
Preparation of N- 1 CSV 1 - r l-(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl ) -3- methy 1-butyl ) -3.4-dimethoxy-benzamide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 3,4- dimethoxybenzoic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 546 (M+H+).
Example 111
Preparation of Benzθι~b]thioρhene-2-carboxylic acid- j(S)-l-(l-methanesurfonyl-3-oxo- azepan-4-yl carbamoyl)-3-methyl-butyn-amide
Following the procedure of Example 6(a)-6(b), except substituting methanesulfonyl chloride for benzenesulfonyl chloride in step (a) and benzo[b]thioρhene-2-carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 480 (M+H+).
Example 112
Preparation of Benzofuran-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamovD-3-methyl-butyll-amide
Following the procedure of Example 6(a)-6(b), except substituting methanesulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for 5-(2- moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 464 (M+H+). Example 113
Preparation of N4fS)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl)-3,4-dimethoxy-benzamide
Following the procedure of Example 6(a)-6(b), except substituting methanesulfonyl chloride for benzenesulfonyl chloride in step (a) and 3,4-dimethoxybenzoic acid for 5-(2- moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 484 (M+H+).
Example 114
Preparation of N-i (S)-141-(2-Cvano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl)-3- methy 1-butyl I -4-methanesulf onyl-benzamide
Following the procedure of Example 6(a)-6(b), except substituting 2- cyanobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 4- methanesulfonylbenzoic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 589 (M+H+).
Example 115
Preparation of Benzofuran-2-carboxylic acid |(S)-l-[l-(2-cvano-benzenesulfonylV 3-oxo- azepan-4-yl carbamovπ-3-methyl-butyl l-amide
Following the procedure of Example 6(a)-6(b), except substituting 2- cyanobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2- carboxylic acid for 5-(2-moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 551 (M+H+). Example 116
Preparation of 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid KSl-S-methyl-l- r3-oxo-(l-oxy-pyridine2-sulfonvD-azepan-4-ylcarbamovπ- -butyl-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 56. MS (ESI): 672 (M+H+).
Example 117
Preparation of 5-Methyl-2 -phenyl-oxazole-4-carboxylic acid l(S)-3-methyl-143-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl ) amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-Methyl-2-phenyloxazole-4- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 584 (M+H+).
Example 118
Preparation of 6-Methyl-N-|(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll-butyll-nicotinamide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 6-methylnicotinic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 518 (M+H+).
Example 119
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid j(S)-3-methyl-143- oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl)amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-(3-trifluoromethyl-phenyl)- furan-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 637 (M+H+).
Example 120
Preparation of N- { (S)- 1 - [( l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl 1 -3- methyl-butyl ) -3.4-dimethoxy-benzamide
Following the procedure of Example 6(a)-6(b), except substituting 2- cyanobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 3,4- dimethoxybenzoic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+).
Example 121
Preparation of 4-Methansulfonyl-N~f (S)-144-fluoro-benzenesulfonyl)-3-oxo-azepan-4- carbamovn-3-methyl-butyl-benzamide
Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 4- methanesulfonylbenzoic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 582 (M+H+). Example 122
Preparation of fS)-2-[5-(4-Methoxy-phenyl)-pentanoylamniol-4-methyl-pentanoic acid \3- oxo-l-(pyridine-2-sulfonyl)-azepan-4-yl1-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-(4-methoxyphenyl)pentanoic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 573 (M+H+).
Example 123
Preparation of (S)-2- [2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamniol-4-methylpentanoic acid r3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-yl1-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 2-(3-Benzyloxy-4-methoxy- phenyl)acetic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 637 (M+H+).
Example 124
Preparation of 5-Methoxybenzofuran-2-carboxylic acid |(S)-3-methyl-l-[3-oxo-l-(thiazole- 2-sulfonyl)-azepan-4-ylcarbamoyll -butyl } amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 5-methoxybenzofuran- 2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 563 (M+H+). Example 125
Preparation of 7-Methoxybenzofuran-2-carboxylic acid l(S)-3-methyl-143-oxo-l-(thiazole- 2-sulfonyl)-azepan-4-ylcarbamovn-butyl I amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 7-mefhoxybenzofuran- 2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 563 (M+H+).
Example 126
Preparation of 3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl } amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 3-methylbenzofuran-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 547 (M+H+).
Example 127
Preparation of Benzorblthiophene-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(thiazole-2- sulf onylVazepan-4-ylcarbamoy 11 -butyl } amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and benzo[b]thiophene-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 549 (M+H+). Example 128
Preparation of 1 -Methyl- lH-indole-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyn-butyl 1 amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and l-methylindole-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 563 (M+H+).
Example 129
Preparation of Ouinoxaline-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(thiazole-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl 1 amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and quinoxaline-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 545 (M+H+).
Example 130
Preparation of Benzofuran-2-carboxylic acid l(SV3-methyl-143-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyH-butyl I amide
Following the procedure of Example 88(a)-88(d), except substituting thiazole-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 533 (M+H+). Example 131
Preparation of Benzofuran-2-carboxylic acid f (S)-141-f4-chloro-benzenesulfonyl)- 3-oxo- azepan-4-yl carbamoyll-3-methyl-butyl 1 -amide
Following the procedure of Example 88(a)-88(d), except substituting 4- chlorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 561 (M+H+).
Example 132
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid-l(S)-141-(4-chloro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 4- chlorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 5- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 590 (M+H+).
Example 133
Preparation of 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-141-(4-chloro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 88(a)-88(d), except substituting 4- chlorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 7- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 590 (M+H+). Example 134
Preparation of 3-Methyl-benzofuran-2-carboxylic acid-l(Syi41-(4-chloro-benzenesulfonyl)- 3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 4- chlorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 574 (M+H+).
Example 135
Preparation of Benzorblthiophene-2-carboxylic acid-{(S 41-(4-chloro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl1-3-methyl-butyll-amide
Following the procedure of Example 88(a)-88(d), except substituting 4- chlorobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 576 (M+H+).
Example 136
Preparation of Benzofuran-2-carboxylic acid- j(S)-141-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyll-amide
Following the procedure of Example 88(a)-88(d), except substituting 3- methoxybenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 536 (M+Na+). Example 137
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid-l(SV141-(3-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyn-3-methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 3-methoxy benzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 5- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 586 (M+H+).
Example 138
Preparation of 7-Methoxy-benzofuran-2-carboxylic acid-KSVl-ri-D-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyll-amide
Following the procedure of Example 88(a)-88(d), except substituting 3-methoxy benzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 7- methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 586 (M+H+).
Example 139
Preparation of 3-Methyl-benzofuran-2-carboxylic acid- KS 141 -(3-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamovH-3~methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 3-methoxy benzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 3- methylbenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 570 (M+H+). Example 140
Preparation of Benzorblthiophene-2-carboxylic acid-((S)-l-[l-(3-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamovπ-3-methyl-butyl)-amide
Following the procedure of Example 88(a)-88(d), except substituting 3-methoxy benzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and benzo[b]thiophene-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 572 (M+H+).
Example 141
Preparation of l-Methyl-lH-indole-2-carboxylic acid-{(S)-141-(3-methoxy- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyl}-amide
Following the procedure of Example 88(a)-88(d), except substituting 3-methoxy benzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 1- methylindole-2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 569 (M+H+).
Example 142
Preparation of Benzofuran-2-carboxylic acid-l (Sy3-methyl-143-oxo-l-(thiophene-2- sulfonyD-azepan-4-ylcarbamoyπ-butyl ) -amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 532 (M+H+). Example 143
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid-i(S)-3-methyl-143-oxo-l- Cthiophene-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl ) -amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 5-methoxybenzofuran- 2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 562 (M+H+).
Example 144
Preparation of 7-Methoxy-benzofuran-2-carboxylic acid- 1 (S)-3-methyl-l- [3-oxo- 1- (thiophene-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl|-amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 7-methoxybenzofuran- 2-carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 562 (M+H+).
Example 145
Preparation of 3-Methyl-benzofuran-2-carboxylic acid- 1 (S)-3-methy 1-1 -[3-oxo- l-(thiophene- 2-sulfonyl)-azepan-4-ylcarbamoyll-butyl I -amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and 3-methylbenzofuran-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 546 (M+H+). Example 146
Preparation of Benzorb1thiophene-2-carboxylic acid-{(S)-3-methyl-143-oxo-l-(thiophene-2- sulfonyl)-azepan-4-ylcarbamoyn-butylj-amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and benzo[b]thiophene-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 548 (M+H+).
Example 147
Preparation of Quinoxaline-2-carboxylic acid-((S)-3-methyl-l-[3-oxo-l-(thiophene-2- sulfonyl)-azepan-4-ylcarbamoyll-butyll-amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and quinoxaline-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 544 (M+H+).
Example 148
Preparation of 1 -Methyl- l-H-indole-2-carboxylic acid-{(S)-3-methyl-143-oxo-14thiophene- 2-sulfonyl)-azepan-4-ylcarbamoyll-butyl|-amide
Following the procedure of Example 88(a)-88(d), except substituting thiophene-2- sulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a) and l-methylindole-2- carboxylic acid for benzofuran-2-carboxylic acid in step (c), the title compound was prepared. MS (ESI): 545 (M+H+). Example 149
Preparation of 5.6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5,6-difluorobenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 562 (M+H+).
Example 150
Preparation of 5,6-Difluoro-benzofuran-2-carboxylic acid |(S)-3-methyl-141-φyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 149. MS (ESI): 562 (M+H+).
Example 151
Preparation of Quinoline-2-carboxylic acid |(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl1-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 24. MS (ESI): 538 (M+H+).
Example 152
Preparation of Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl ) amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 25. MS (ESI): 538 (M+H+). Example 153
Preparation of Quinoline-4-carboxylic acid f (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamovπ-butyl } amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 26. MS (ESI): 538 (M+H+).
Example 154
Preparation of Isoquinoline-1-carboxylic acid |(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 29. MS (ESI): 538 (M+H+).
Example 155
Preparation of Naphthalene-2-carboxylic acid |(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonylVazepan-4-ylcarbamoyl1-butyl)-amide
The title compound was isolated as the first eluting compound from the HPLC purification in.Example 17. MS (ESI): 537 (M+H+).
Example 156
Preparation of Ouinoline-3-carboxylic acid {(S)-3-methyl-l-f3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 27. MS (ESI): 538 (M+H+). Example 157
Preparation of 5.6-Dimethoxy-benzo[b1thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6- methyl-pyridine-2-sulfonyl)3-oxo-azepan-4-ylcarbamoyn-butyl)amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5,6- dimethoxybenzo[b]thiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 603 (M+H+).
Example 158
Preparation of (R)-l-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid {(S)-3-methvI-l-{3-oxo- (pyridine-2-sulfonyl -azepan-4-ylcarbamoyll-butyl|amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and (R)-l-benzyl-5-oxo- pyrrolidine-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 584 (M+H+).
Example 159
Preparation of Benzofuran-2-carboxylic acid |(S)-2-naphthalen-2-yl-143-oxo-l-(pyridine-2- sulfonylVazepan-4-ylcarbamoyl)-ethyll-amide
Following the procedure of Example 102(a)-102(h), except substituting N-tert- butoxycarbonyl-L-2-naphthylalanine for N-Boc-cyclohexylalanine in step (e), the title compound was prepared. MS (ESI): 611 (M+H+). Example 160
Preparation of Thienor3.2-b1thiophene-2-carboxylic acid {(S)-3-methyl-141-(3-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl)amide
Following the procedure of Example 6(a)-6(b), except substituting 3-methylpyridine- 2-sulfonyl chloride for benzenesulfonyl chloride in step (a) and thieno[3,2-b]thiophene-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 563 ( +H+).
Example 161
Preparation of 3-Methyl-benzofuran-2-carboxylic acid j(S)-3-methyl-l-[l-(3-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting 3-methylpyridine- 2-sulfonyl chloride for benzenesulfonyl chloride in step (a) and 3-methylbenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H+).
Example 162
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl- pyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamovπ-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting 3-methylpyridine- 2-sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-methoxybenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+). Example 163
Preparation of 5,6-Difluoro-benzofuran-2-carboxylic acid { (S)-3-methy 1-1- [3-oxo- l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl } amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5,6-difluorobenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 579 (M+H+).
Example 164
Preparation of 7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl- ρyridine-2-sulfonyl)-3-oxo-azepan-4-ylcarbamoyll-butyl I amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 7-methoxybenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 557 (M+H+).
Example 165
Preparation of 5,6-Dimethoxy-benzo[blthiophene-2-carboxylic acid |(S)-3-methyl-l-ri-(6- methyl-pyridine-2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl1-butyllamide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 157. MS (ESI): 603 (M+H+).
Example 166
Preparation of 5-Fluoro-benzofuran-2-carboxylic acid ((S)-3-methyl-143-oxo-l-φyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 -amide
)
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-fluorobenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 545 (M+H+).
Example 167
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-146-methyl-3-oxo-l-(pyridine- sulfonyl")-azepan-4-ylcarbamoyll-butyl 1 -amide
a) [(S)-l-(3-hydroxy-6-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester
Following the procedure of Example 1(a)- 1(g), except substituting 5-bromo-4- methyl-1-pentene for 5-bromo-l-pentene in step (a), the title compound was prepared. MS (ESI): 358 (M+H+).
b) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } -amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and benzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 541 (M+H+). Example 168
Preparation of 5-Fluoro-benzofuran-2-carboxylic acid [(SV3-methyl-l-[3-oxo-l-(pyridine-2- sulfonylVazepan-4-ylcarbamoyll-butyll-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 166. MS (ESI): 545 (M+H+).
Example 169
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid|(S)-2-cyclohexyl-143- oxo-l-(l-oxy-pyridine-2-sulfonyl>azepan-4-ylcarbamoyl1-ethyl|-amide
a) [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-carbamic acid tert butyl ester
Following the procedure of Example l(a)-l(g), except substituting N-tert- butoxycarbonyl-L-cyclohexylalanine for N-tert-butoxycarbonyl-L-leucine in step (f), the title compound was prepared. MS (ESI): 384 (M+H+).
b) 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-
2-cyclohexyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and 5-(3- trifluoromethyl-phenyl)-furan-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 677 (M+H+).
Example 170
Preparation of 5,6-Dimethoxy-benzofuran-2-carboxylic acid|(S)-2-cyclohexyl-l-[3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-ethyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-cyclohexyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and 5,6- dimethoxybenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 643 (M+H+).
Example 171
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid |(S)-3-methyl-l-[l-(3-methyl- pyridine-2-sulfonvD-3-oxo-azepan-4-ylcarbamovH-butyl 1 amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 162. MS (ESI): 571 (M+H+).
Example 172
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-141-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyllamide
Following the procedure of Example 6(a)-6(b), except substituting 3-methylpyridine- 2-sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 541 (M+H+). Example 173
Preparation of Benzofuran-2-carboxylic acid lfSy3-methyl-146-methyl-3-oxo-l-(pyridine- sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 -amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 167. MS (ESI): 541 (M+H+).
Example 174
Preparation of Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l- [3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethvn-amide
a) [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-2-(2-naphthyl)-ethyl]-carbamic acid tert butyl ester
Following the procedure of Example l(a)-l(g), except substituting N-terf- butoxycarbonyl-L-2-naphthylalanine for N-tert-butoxycarbonyl-L-leucine in step (f), the title compound was prepared. MS (ESI): 428 (M+H+).
b) Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-
2-(2-naphthyl)-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and quinoline-8- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 622 (M+H+).
Example 175 .
Preparation of Naphthalene- 1-carboxy lie acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethvn-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-(2-naphthyl)-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and naphthalene- 1- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 621 (M+H+).
Example 176
Preparation of Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyn-2-phenyl-ethyll-amide
a) [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert butyl ester
Following the procedure of Example 1(a)- 1(g), except substituting N-tert- butoxycarbonyl-L-phenylalanine for N-tert-butoxycarbonyl-L-leucine in step (f), the title compound was prepared. MS (ESI): 378 (M+H+).
b) Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyι)- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and quinoline-8-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 572 (M+H+). Example 177
Preparation of Naphthyridine-2-carboxylic acid l(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyll-butyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and naphthyridine-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 539 (M+H+).
Example 178
Preparation of Naphthalene- 1 -carboxylic acid l(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl~l-2-phenyl-ethyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyι)- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and naphthalene- 1 -carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+).
Example 179
Preparation of Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-methyl-furan-3- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl1-butyl 1 -amide
Following the procedure of Example 6(a)-6(b), except substituting 2-methylfuran-3- sulfonyl chloride for benzenesulfonyl chloride in step (a) and benzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 530 (M+H+). Example 180
Preparation of Ouinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll -2-phenyl-ethyl ) -amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and quinoline-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 572 (M+H+).
Example 181
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-[(4S.7S')-7-methyl-3-oxo-l- φyridine-2-sulfonyl)-azepan-4-ylcarbamovH-butyl)-amide
a) allyl-( l-methyl-pent-4-enylidene)-amine
Hex-5-en-2-one (9.8 g, 11.6 ml, 100 mmol) was added to a stirred solution of allylamine (8.55 mmol, 11.25 ml, 150 mmol), 4 Angstrom molecular sieves (52 g), and p- toluene sulfonic acid (10 mg) in CH2C12 (200 ml) and was stirred overnight. The reaction mixture was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (13 g, 95%). MS (ESI): 137.9 (M+H+).
b) allyl-(l-methyl-pent-4-enyl)-amine
Sodium borohydride (2.7 g, 71 mmol) was added portionwise to a stirred solution of the compound of Example 181(a) (6.5 g, 47 mmol) in MeOH (100 ml) at 0 C. The reaction mixture was stirred for 30 minutes, then warmed to RT. Approximately 90 ml of MeOH was removed from the reaction mixture by rotary evaporation, then the reaction mixture was diluted with ether (200 ml), then extracted with water then brine. The combined organics were dried with MgSO , filtered, concentrated in vacuo by rotary evaporation to give a pale yellow liquid that was used in the next reaction without further purification (5.2 g, 80%).
c) allyl-(l-methyl-pent-4-enyl)-carbamic acid benzyl ester Carbobenzyloxy chloride (9.56 g, 8 ml) was added dropwise to a stirred solution of the compound of Example 181(b) (7 g, 50 mmol), triethylamine (5.5 g, 8.0 ml, 57.5 mmol) in CH2C12 (100 ml) at 0 C. The reaction mixture was warmed to RT, then was stirred for 2 h. The reaction mixture was diluted with CH2C12 (100 ml), then was extracted with water, then brine. The combined organics were dried with MgSO , filtered, concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 4% EtOAc/ hexanes) to give the title compound (8.9 g, 65% yield). MS (ESI): 274.2 (M+H+).
d) 2-methyl-2,3,4,7-tetrahydro-azepine-l-carboxylic acid benzyl ester The compound of Example 181(c) (1.036 g, 3.8 mmol) was dissolved in CH2C12 (10 ml) and a stream of argon gas was bubbled into the reaction mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Strem Chemicals, Grubbs' catalyst, 22 mg, 0.027 mmol) was added and the reaction mixture was refluxed for 2 h. Additional bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (11 mg, 0.014 mmol) was added and the reaction mixtrue was refluxed for an additional 1.5 hours. The reaction was cooled to RT under argon overnight, then was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 5% EtOAc/ hexanes) to give the title compound (0.83 g, 89%). MS (ESI): 246.2 (M+H+).
e) (lS,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester m-Chloro-perbenzoic acid (1.05 g, 57-86% pure) was added to a solution of the compound of Example 181(d) (0.83 g, 3.34 mmol) in CH2C12 at 0 degrees C. The reaction mixture was stiπed for half an hour, then was warmed to RT. Additional m-chloro- perbenzoic acid (0.3 g, 57-86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc-.hexanes) to give racemic (lS,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3- carboxylic acid benzyl ester (0.44 g, 50%) and the title compound as a racemic mixture of the title compound (0.15 g, 17% yield). MS (ESI): 262.0 (M+ϊ ). f) (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester
Sodium azide (0.56 g, 8.62 mmol) was added to a solution of the compound of Example 181(e) (0.75 g, 2.87 mmol) and ammonium chloride (0.46 g, 8.62 mmol) in MeOH (5 ml) and H2O (0.5 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vαcwo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.7g, 80%). MS (ESI): 305.2 (M+H+).
g) (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester
Triphenylphosphine (1.94 g, 7.4 mmol) was added to a solution of the compound of Example 181(f) (1. 5 g, 4.93 mmol) in THF (185 ml) and H2O (0.7 ml), then was heated to 45 degrees C overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and was azeotroped in vacuo by rotary evaporation twice. The resxulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (1.4 g, 90%).
h) (2R,5S,6S)-5-((S)-2- tert -Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2- methyl-azepane-1 -carboxylic acid benzyl ester and (2S,5R,6R)-5-((S)-2- tert - Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane- 1 -carboxylic acid benzyl ester l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.33 g, 1.73 mmol) was added to a solution of Boc-leucine-hydrate (0.43 g, 1.7 mmol), diisopropylethylamine (0.22 g, 0.3 ml, 1.7 mmol), hydroxybenztriazole (0.25 g, 1.85 mmol), and the compound of Example 181(g) (0.5 g, 1.6 mmol) in DMF (10 ml). The reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml), washed with H2O (3x 50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexanes) to yield the title compound (0.78g, 100%). MS (ESI): 492.0 (M+H+). i) [(S)-l-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert -butyl ester and . [(S)-l-((3R,4R,7S)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3- methyl-butyl]-carbamic acid tert -butyl ester
The compound of Example 181(h) (0.77g, 1.57 mmol) was dissolved in EtOAc (27.5 ml), MeOH (5.5 ml). Then 10% Pd/C (0.39 g) was added and the reaction was stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.56 g). MS (ESI): 358.1 (M+H+).
j) [(S)-l-((3S,4S,7R)-l-Benzenesulfonyl-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3- methyl-butyl]-carbamic acid tert -butyl ester and [(S)-l-((3R,4R,7S)-l-Benzenesulfonyl-3- hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert -butyl ester
2-Pyridine sulfonyl chloride (0.6 g, 3.4 mmol) was added to a solution of the compound of Example 181(i) (1.0 g, 2.8 mmol), N-methyl moφholine (0.45 ml, 4.1 mmol) in CH2C12 (35 ml) and was stiπed at RT overnight. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2.5% MeOH/ CH2C12 ) to yield the title compound (0.9g, 64%). MS (ESI): 499.0 (M+H+).
k) (S)-2-Amino-4-methyl-pentanoic acid ((3S,4S,7R)-l-(2-pyridine)-sulfonyl-3-hydroxy-7- methyl-azepan-4-yl)-amide and (S)-2-Amino-4-methyl-pentanoic acid ((3R,4R,7S)-l-(2- pyridine)-sulfonyl-3-hydroxy-7-methyl-azepan-4-yl)-amide
HCl in dioxane (4.0 M, 15 ml) was added to a stirred solution of the compound of
Example 181(j) (0.9 g, 1.8 mmol) in MeOH (15 ml). The reaction mixture was stiπed for 2h at RT, then was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.85 g).
1) Benzofuran-2-carboxylic acid {(S)-l-[(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide and benzofuran-2-carboxylic acid {(S)-l-[(3R,4R,7S)-3-hydroxy-7-methyl-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3- methyl-butyl } -amide l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.35 g, 1.85 mmol) was added to a solution of 2-benzofuran-carboxylic acid (0.3 g, 1.85 mmol), the compound of Example 181(k) (0.85 g, 1.8 mmol), diisopropylethylamine (0.48 g, 0.65 ml, 3.7 mmol), hydroxybenztriazole (0.25 g, 1.85 mmol) in DMF (10 ml) and was stiπed at RT overnight. The reaction mixture was then warmed to RT and was stirred overnight. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2.5% MeOH/ CH2C12 ) to yield the title compound (0.8g, 82%). MS (ESI): 542.98 (M+H+).
m) Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7S)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide Dess-Martin periodinane (1.0 g, 2.36 mmol) was added to a solution of The compound of Example 181(1) (0.8 g, 1.48 mmol) in CH2C12 (20 ml) and was stiπed at RT for 45 minutes. The solution was washed with 10% NaHCO3 and brine. Purification by column chromatography (60% ethyl acetate/ hexanes) followed by HPLC (Whelk-Ol; ethanol hexanes) gave the title compound as a mixture of diasteromers (0.75 g, 94%). MS (ESI): 541 (M+H+).
Example 182
Preparation of Benzofuran-2-carboxylic acid |(S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l- φyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl}-amide
The title compound was isolated as the second eluting compound from the HPLC purification in Example 181. MS (ESI): 541 (M+H+).
Example 183
Preparation of Benzofuran-2-carboxylic acid |(S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl- 1-butyl I -amide
Following the procedure of Example 88(a)-88(d), except substituting 3- fluoobenzenesulfonyl chloride for 3-chlorobenzenesulfonyl chloride in step (a), the title compound was prepared. MS (ESI): 543 (M+H+). Example 184
Preparation of Naphthalene- 1 -carboxy lie acid {(S)-3-methyl-143-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl1-butyl 1 -amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and naphthalene- 1 -carboxy lie acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 537 (M+H+).
Example 185
Preparation of Ouinoline-5-carboxylic acid |(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyll-butylj-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-5-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
Example 186
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-l-|3- oxo-l-[l-d-oxy-pyridin-2-yl)-methanoyll-azepan-4-ylcarbamovU-butyl)-amide
Following the procedure of Example 3(d) and 3(h), except substituting 1- oxypicolinic acid for 3-(2-pyridyl)phenylacetic acid in step (d) and 5-(3-trifluoromethyl- phenyl)-furan-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 601 (M+H+). Example 187
Preparation of Ouinoline-8-carboxylic acid {(S)-2-naphthalen-2-y 1-1- [3-oxo- l-(pyridine-2- sulfonyl')-azepan-4-ylcarbamoyl1-ethyl)-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 174. MS (ESI): 622 (M+H+).
Example 188
Preparation of Naphthalene- 1 -carboxylic acid f(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamovn-ethyl}-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 175. MS (ESI): 621 (M+H+).
Example 189
Preparation of Quinoline-8-carboxylic acid |(S)-l-f3-oxo-l-("pyridine-2-sulfonyl)-azepan-4- ylcarbamoyll-2-phenyl-ethyll-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 176. MS (ESI): 572 (M+H+).
Example 190
Preparation of Naphthalene- 1 -carboxylic acid {(S)-143~oxo-l-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyll-2-phenyl-ethyl I -amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 178. MS (ESI): 571 (M+H+). Example 191
Preparation of 5-Fluoro-benzofuran-2-carboxylic acid {(Sy3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-fluorobenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 561 (M+H+).
Example 192
Preparation of 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid l(S>3-methyl-143-oxo-l- (l-oxy-pyridine-2-sulfonylVazepan-4-ylcarbamoyl1-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-fluoro-3-methylbenzofuran- 2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 575 (M+H+).
Example 193
Preparation of 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo~l- ( 1 -oxy-pyridine-2-sulf onylVazepan-4-ylcarbamoyll-butyl ) -amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 6-fluoro-3-methylbenzofuran- 2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 575 (M+H+). Example 194
Preparation of 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-d-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl|-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 191. MS (ESI): 561 (M+H+).
Example 195
Preparation of 5-Fluoro-3-methyl-benzofuran-2-carboxylic acid {(SV3-methyl-l-[3-oxo-l- ( 1 -oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamovn-butyl l-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 192. MS (ESI): 575 (M+H+).
Example 196
Preparation of 6-Fluoro-3-methyl-benzofuran-2-carboxylic acid f (S)-3-methyl-l-[3-oxo-l- d-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyli-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 193. MS (ESI): 575 (M+H+).
Example 197
Preparation of Benzo[blthiophene-2-carboxylic acid {(S)-3-methyl-146-methyl-3-oxo-l- φyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyll-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and benzo[b]thiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 557 (M+H+).
Example 198
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-146-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and 5- methoxybenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+).
Example 199
Preparation of 3-Methyl-benzofuran-2-carboxylic acid |(S)-3-methyl-l-[6-methyl-3-oxo-l- φyridine-2-sulfonyl)-azepan-4-ylcarbamovH-butyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and 3- methylbenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H+).
Example 200
Preparation of Thieno[3,2-b1thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo- l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl|-amide
Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and thieno[3,2- b]thiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 563 (M+H+).
Example 201
Preparation of 3.5-Dimethyl-benzofuran-2-carboxylic acid l(SV3-methyl-l-[3-oxo-l-d-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 -amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 3,5-dimethylbenzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+).
Example 202
Preparation of 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 3-ethylbenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+). Example 203
Preparation of 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid l(S)-3-methyl-l-[3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl)-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 4-methoxy-3- methylbenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 587 (M+H+).
Example 204
Preparation of 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid j(S)-3-methyl-l-[3-oxo-l- d-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl 1 -amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 6-methoxy-3- methylbenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 587 (M+H+).
Example 205
Preparation of 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid f(S)-3-methyl-143-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyll-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 5-methoxy-3- methylbenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 587 (M+H+). Example 206
Preparation of 3.5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo-l-(l-oxy- py ridine-2-sulf ony l)-azepan-4-y lcarbamoyll -butyl I -amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 201. MS (ESI): 571 (M+H+).
Example 207
Preparation of 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo-l-d-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl|-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 202. MS (ESI): 571 (M+H+).
Example 208
Preparation of 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid |(S)-3-methyl-l-[3-oxo-l- d-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-butyl|-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 203. MS (ESI): 587 (M+H+).
Example 209
Preparation of 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-buty -amide
The title compound was isolated as the second eluting compound from the HPLC purification in Example 203. MS (ESI): 587 (M+H+). Example 210
Preparation of l-methyl-naphthor2.1-bl-furan-2-carboχylic acid ((S>3-methyl-143-oxo-l- d-oxy-pyridine-2-sulfonyl)-azeρan-4-ylcarbamovn-butyl}-amide
Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and l-methyl-naphtho[2,l-b]-furan- 2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 607 (M+H+).
Example 211
Preparation of 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-143-oxo-l- d-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl1-butyl)-amide
The title compound was isolated as the first eluting compound from the HPLC purification in Example 204. MS (ESI): 587 (M+H+).
Example 212
Preparation of Benzofuran-2-carboxylic acid [("S)-3-methyl-l -[3-oxo- l-quinolin-2-ylmethyl- azepan-4-ylcarbamoyl]-butyl ) -amide
Following the procedure of Example l(a)-l(k), except substituting quinoline-2- carboxaldehyde for benzaldehyde in step (h) and benzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 527 (M+H+).
Example 213
Preparation of 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-143-oxo-l-quinolin-2- ylmethyl-azepan-4-ylcarbamovn-butyl ) -amide
Following the procedure of Example l(a)-l(k), except substituting quinoline-2- carboxaldehyde for benzaldehyde in step (h) and 3-methylbenzofura-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 541 (M+H+).
Example 214
Preparation of Benzo[blthiophene-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2- ylmethyl-azepan-4-ylcarbamoyll-butylj-amide
Following the procedure of Example l(a)-l(k), except substituting quinoline-2- carboxaldehyde for benzaldehyde in step (h) and benzo[b]thiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 543 (M+H+).
Example 215
Preparation of Benzo[b1thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)- 3-oxo-azepan-4-ylcarbamovH-3-methyl-butyl|-amide
a) [(S)-l-(3-hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert-butyl ester
Following the procedure of Example 5(a), except subsituting 2-fluorophenyl isocyanate for phenyl isocyanate, the title compound was prepared. MS (ESI): 482 (M+H+). b) Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-'4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and benzo[b]thiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 539 (M+H+).
Example 216
Preparation of 3-Methyl-benzofuran-2-carboxylic acid |(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and 3-methylbenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 537 (M+H+).
Example 217
Preparation of Quinoxaline-2-carboxylic acid l(S)-l-[l-("2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyl|-amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and quinoxaline-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 535 (M+H+). Example 218
Preparation of Thieno[3.2-b1thiophene-2-carboxylic acid {(S~)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl1-3-methyl-butyll-amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and thieno[3,2-b]thiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 545 (M+H+).
Example 219
Preparation of Ouinoline-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyll-amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and quinoline-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 534 (M+H+).
Example 220
Preparation of 4-Methyl-2-carboxylic acid l(S')-l-[l-(2-fluoro-phenylcarbamoyl')-3-oxo- azepan-4-ylcarbamoyll-3-methyl-butyl ) -amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tezt-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and 4-methylthiophene-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 503 (M+H+).
Example 221
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl|-amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluoroρhenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and 5-methoxybenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 553 (M+H+).
Example 222
Preparation of 4-Methyl-furan-2-carboxylic acid ((S)-l-[l-(2-fluoro-phenylcarbamoyl)-3- oxo-azepan-4-ylcarbamoyll-3-methyl-buty -amide
Following the procedure of Example l(i)-l(k), except substituting [(S)-l-(3- hydroxy-l-(2-fluorophenylcarbamoyl)-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester for [(S)-l-(l-benzyl-3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]- carbamic acid tert butyl ester in step (i) and 4-methylfuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (j), the title compound was prepared. MS (ESI): 487 (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 incoφorated herein by reference as though fully set forth.
We claim:
1. A method of treating a parasitic disease mediated by a cysteine protease by administering to a patient in need thereof one or more of the compounds of Formula I:
wherein:
Rl is selected from the group consisting of:
R^ is selected from the group consisting of: H, Ci-galkyl, C3.gcycloalkyl-Co_6alkyl,
Ar-C0.6alkyl, Het-C0_6alkyl, R9C(O)-, R9C(S)-, R9SO2-, R9OC(O)-,
R9Rl iNC(O)-, R9R! !NC(S)-, R9(R! !)NSO2-
R3 is selected from the group consisting of: H, Ci-galkyl, C3-gcycloalkyl-Cθ-galkyl, C2-6alkenyl, C2-6alkynyl, HetCQ.6al yl and ArCQ_galkyl;
R3 and R' may be connected to form a pyπolidine, piperidine or moφholine ring;
R4 is selected from the group consisting of: H, Cj .galkyl, C3_gcycloalkyl-Co-galkyl, Ar-C0. alkyl, 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, C2-6alkenyl, C2-6alkynyl, C3_gcycloalkyl-Co_galkyl, Ar-CQ-galkyl and Het-CQ_galkyl;
R6 is selected from the group consisting of: H, C\ .galkyl, Ar-Cθ-6alkyl, and Het- Co-galkyl;
R^ is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co.galkyl, Ar-Co.galkyl, Het-C0.galkyl, R10C(O)-, R10C(S)-, R10SO2-, R10OC(O)-, R10R13NC(O)-, and R10R13NC(S)-;
R^ is selected from the group consisting of: H, Cl -galkyl, C2-6alkenyl, C2-6alkynyl, HetCo-galkyl and ArCo-galkyl;
R9 is selected from the group consisting of: Cj .galkyl, C3_gcycloalkyl-Co.galkyl, Ar-CQ-galkyl and Het-CQ.galkyl;
RIO is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-CQ_galkyl, Ar-CQ-galkyl and Het-Cø_galkyl; Rl 1 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-galkyl, and Het-
C0-galkyl;
Rl2 is selected from the group consisting of: H, C\ .galkyl, Ar-Cθ-galkyl, and Het- C0-galkyl;
Rl3 is selected from the group consisting of: H, Cj.galkyl, Ar-Cθ-galkyl, and Het- Co.galkyl;
R' is selected from the group consisting of: H, Ci .galkyl, Ar-Cθ-6alkyl, and Het-CQ- galkyl;
R" is selected from the group consisting of: H, Co.galkyl, Ar-Cθ-galkyl, or Het-CQ- galkyl; R"' is selected from the group consisting of: H, C j.galkyl, C3_gcycloalkyl-CQ_galkyl,
Ar-CQ-galkyl, and Het-CQ_galkyl;
R"" is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-CQ.galkyl C2-6alkenyl, C2-6 lkynyl, HetCQ.galkyl and ArCQ.galkyl; 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.
2. A method of treating a parasitic disease mediated by a cysteine protease by administering to an animal in need thereof an effective amount of a compound selected from the group consisting of:
Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxoazepan-4-ylcarbamoyl)-3- methyl-butyl]amide;
Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl] amide;
5-(2-Moφholino-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;
5-(2-Mθφholino-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;
4-((S)-4-Methyl-2-{ [5-(2-moφholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino}- pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide; 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- 1-( l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Pyπolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyι]- azepan-4-ylcarbamoyl}-butyl)amide; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide;
Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide; 5-(2-Pyπolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-buyl}-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl }-amide;
Naphthalene-2-carboxylic acid { (S)-3-methyl- l-[3-oxo-l -(pyridine-2-sulf ony l)-azepan-4- ylcarbamoyl]-butyl}-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
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; 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- 1-
(pyridine-2-sulfonyι)-azepan-4-ylcarbamoyl]-butyl } -amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide;
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;
5-(2-Piperizin- 1 -yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyl}-amide;
Quinoline-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide;
Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-3-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide ; Isoquinoline- 1 -carboxylic acid { (S)-3-methyl- l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide ;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-surfonyι)-azepan-4- y lcarbamoy 1] -butyl } amide ; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-suIfonyι)- azepan-4-y lcarbamoy l]-butyl } amide; lH-Indole-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(ρyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-buty 1 } amide ;
5-Bromo-furan-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ;
5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide; 5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl}amide;
(S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2- sulfonyl)-azepan-4-yl]-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide;
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;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo-azepan-
4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl}amide;
5-(4-Oxy-moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
5-Hydroxy-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[l-( 1-methyl- lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl)]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl~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-(l-oxy-pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl)]-3-methyl-butyl J-amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-y lcarbamoy l]-butyl } amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-y lcarbamoy l]-butyl } amide; 5,6-Dimethoxy-benzofuran-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)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)-azepan- 4-y lcarbamoy l]-butyl} amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
5-(2-Mθφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty }-amide; 3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- 1-(1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide;
3,4-Dihydro-2H-benzo[b] [1 ,4]dioxepine-7-carboxylic acid { (S)-3-methyl- l-[3-oxo- 1-(1- oxy-pyridine-2-sulf onyl)-azepan-4-y lcarbamoy l]butyl } amide ; 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy 1] -butyl } amide ; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulf onyl)-azepan-4-y lcarbamoy 1] -butyl } amide ; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl]-butyl}amide;
5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-y lcarbamoy 1] -butyl } amide ;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3methyl-butyl}-amide; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ) amide ;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid { (S)- 1 -[ 1 -(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyι]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; 4-Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-carbamoyl]- butyl } -benzamide;
3,4-Dihydro-2H-benzo[b] [ 1 ,4]dioxepine-7-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1-(1- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl } amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
(S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- yl]-amide;
5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide;
Furan-2-carboxylic acid ( { (S)- 1 - [ 1 -(4-methoxy-benzenesulf onyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-amide;
Quinoline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyι)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; l-Methyl-lH-indole-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-
4-y lcarbamoy 1] -3-methy 1-butyl } -amide ;
5-Methoxy-benzofuran-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoxaline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl J-amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid- { (S)- 1-[ l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-
4-y lcarbamoy l]-3-methy 1-butyl } -amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl } -amide;
5-Methoxy-benzofuran-2-carboxylic acid- { (S)- 1 -[ 1 -(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-methy lbenzofuran-2-carboxy lie acid- { (S)- 1-[ 1 -(2-fluoro-benzenesulf onyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyι)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoxaline-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2-sulf onyl)- azepan-4-y lcarbamoy 1] -butyl [amide;
Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(2,2',4-tridueterio)-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide ;
Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl} -amide;
Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4-ylcarbamoyl]- pentyl [-amide;
Benzofuran-2-carboxylic acid [ (S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethy 1 } - amide ; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3- methyl-butyl [-benzamide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- yl carbamoyl]-3-methy 1-butyl } -amide; Benzofuran-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide;
N- { (S)- 1 - [ 1 -(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4-y lcarbamoyl } -3-methy 1-butyl } -3 ,4- dimethoxy-benzamide; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;
Benzofuran-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3- methyl-butyl]-amide;
N-[(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-3,4- dimethoxy-benzamide;
N-{(S)-l-[l-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-4- methanesulfonyl-benzamide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide; 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty [-amide;
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;
6-Methyl-N-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl [-nicotinamide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid { (S)-3-methy 1- 1 - [3-oxo- 1 -( 1 -oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
N-{(S)-l-[(l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-3,4- dimethoxy-benzamide; 4-Methansulfonyl-N-[(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methy 1-butyl-benzamide ;
(S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo- l-(pyridine-
2-sulfonyl)-azepan-4-yl]-amide;
(S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-yl]-amide;
5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide ; 7-Methoxybenzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
3-Methylbenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; l-Methyl-lH-indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfony )- azepan-4-ylcarbamoyl]-butyl}amide;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-chloro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan- 4-y lcarbamoy l]-3-methyl-butyl } -amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid- { (S)- 1- [ l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid-[(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl [-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide; 1 -Methyl- lH-indole-2-carboxy lie acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } -amide ; 5-Methoxy-benzofuran-2-carboxylic acid-{ (S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- l-(thiophene-2-sulf onyl)- azepan-4-ylcarbamoyl]-butyl } -amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } -amide;
Benzo[b]thiophene-2-carboxylic acid-[(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoxaline-2-carboxy lie acid- { (S)-3-methyl- 1 - [3-oxo- 1 -(thiophene-2-sulf onyl)-azepan-4- ylcarbamoyl]-butyl}-amide; 1 -Methyl- 1 -H-indole-2-carboxylic acid- { (S)-3-methy 1- 1 - [3-oxo- 1 -(thiophene-2-sulf onyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl[amide;
5,6-Difluoro-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-y lcarbamoy 1] -butyl } amide;
Quinoline-2-carboxylic acid {(S)-3-methyι-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide; Quinoline-4-carboxylic acid {(S)-3-methyl-l- [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Isoquinoline- 1 -carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy l]-butyl } amide ;
Naphthalene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide;
Quinoline-3-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; 5 ,6-Dimethoxy-benzo [b]thiophene-2-carboxy lie acid { (S)-3-methyl- 1 - [ 1 -(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-y lcarbamoy l]-butyl } amide;
(R)- 1 -Benzyl-5-oxo-pyrrolidine-2-carboxylic acid { (S)-3-methyl- 1- { 3-oxo-(pyridine-2- sulfony l)-azepan-4-ylcarbamoyl]-buty 1 } amide ; Benzofuran-2-carboxylic acid {(S)-2-naphthalen-2-y 1-1 -[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-ethyl]-amide;
Thieno [3 ,2-b] thiophene-2-carboxylic acid { (S)-3-methyl- 1 - [ 1 -(3-methy l-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)- 3-oxo-azepan-4-ylcarbamoyl]-butyl[ amide;
5-Methoxy-benzofuran-2-carboxylic acid [ (S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; 7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl } amide;
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-y lcarbamoy l]-butyl } amide;
5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [6-methyl-3-oxo- l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5-Fluoro-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl]-ethyl } -amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl } -amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyι)-3-oxo- azepan-4-ylcarbamoyl]-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Naphthalene- 1 -carboxylic acid { (S)-2-naphthalen-2-yl- 1 - [3-oxo- 1 -
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Quinoline-8-carboxylic acid { (S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide;
Naphthyridine-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide;
Naphthalene- 1 -carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl[-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-methyl-furan-3-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}-amide; Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl }-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7S)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl [-amide;
Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl}-amide;
Naphthalene- 1 -carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[-amide; Quinoline-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- y lcarbamoy 1] -butyl } -amide ;
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;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl } -amide;
Naphthalene- 1 -carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl}-amide; Quinoline-8-carboxylic acid { (S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl [-amide;
Naphthalene- 1 -carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl[-amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methy 1-1 -[3-oxo- 1-(1 -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;
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;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [6-methyl-3-oxo- 1 -(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl [-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [6-methyl-3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
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;
6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-y lcarbamoy l]-butyl } -amide; 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-y lcarbamoy l]-butyl } -amide;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } -amide; 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide;
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;
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; 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 {(S)-3-methyl-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- ylcarbamoylj-butyl [-amide;
3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyl- azepan-4-ylcarbamoyl]-butyl[-amide;
Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl- l-[3-oxo- l-quinolin-2-ylmethyl-azepan- 4-ylcarbamoyl]-butyl [-amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide; Quinoxaline-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid { (S)- 1-[ l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoline-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyι)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
4-Methyl-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l -(2-fluoro-pheny lcarbamoy I)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; and
4-Methyl-furan-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide.
3. A method according to either Claim 1 or Claim 2 wherein said disease is selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis.
4. A method according to Claim 3 wherein said disease is malaria.
5. A method of inhibiting a cysteine protease which comprises administering to a patient in need thereof an effective amount of a compound selected from the group consisting of: Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxoazepan-4-y lcarbamoy l)-3- methy 1-butyl] amide ;
Quinoline-2-carboxylic acid [(S)- 1 -( 1 -benzy l-3-oxo-azepan-4-y lcarbamoy l)-3-methy 1- butyl] amide;
5-(2-Moφholino-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;
5-(2-Mθφholino-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;
4-((S)-4-Methyl-2-{[5-(2-moφholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino[- pentanoylamino)-3-oxo-azepane-l-carboxylic acid phenylamide; 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Pyπolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl[-butyl)amide; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide; Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-y lcarbamoy l)-3- methyl-butyl]amide;
5-(2-Pyrrolidin- l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)- l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl] amide ;
5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-buyl[-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide; Naphthalene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl J-amide;
5-(2-Mθφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl-l -[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl] -butyl } -amide ; 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;
5-(2-Piperizin- l-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyl[-amide;
Quinoline-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide;
Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide; Quinoline-4-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-3-carboxylic acid { (S)-3-methyl- 1- [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide; Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Isoquinoline-1 -carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Quinoxaline-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Benzo[b]thiophene-2-carboxylic acid [ (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide; lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } amide ; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl] -butyl } amide ;
5-Nitro-furan-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
5-(4-Nitro-phenyl)-furan-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
(S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2- sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl [-amide;
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;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3- oxo-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-butyl } amide; Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [ 1 -( 1 -methyl- 1 H-imidazole-4-sulf onyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl[amide;
5-(4-Oxy-moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide; 5-Hydroxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1 -( l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl)]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[ amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl[amide;
5 ,6-Dimethoxy-benzofuran-2-carboxylic acid { (S)-3-methy 1- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl)]-3-methyl-butyl}-amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl[amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azeρan-4-ylcarbamoyl]-butyl}amide;
5,6-Dimethoxy-benzofuran-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)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl]-butyl[amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl } amide;
5-(2-Mθφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty [-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide; lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } amide ;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-y lcarbamoy l]-butyl } amide; 3 ,4-Dihydro-2H-benzo [b] [ 1 ,4] dioxepine-7-carboxy lie acid { (S)-3-methy 1- 1 - [3-oxo- 1 -( 1 - oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl } amide;
4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
Thieno [3 ,2-b] thiophene-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[ amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl]-butyl } amide; 5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- y lcarbamoy l]-3methyl-butyl } -amide;
5-Bromo-furan-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- l-(pyridine-2-sulfony l)-azepan-4- ylcarbamoyl]-butyl [amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl[amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid { (S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide; Benzofuran-2-carboxylic acid { (S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide;
4-Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-carbamoyl]- butyl [-benzamide;
3 ,4-Dihydro-2H-benzo [b] [ 1 ,4]dioxepine-7-carboxy lie acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 - oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl [amide;
5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
(S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- yl]-amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide;
Furan-2-carboxylic acid ({(S)-l-[l-(4-methoxy-benzenesulfonyι)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyl[-methyl)-amide;
Quinoline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
1 -Methyl- lH-indole-2-carboxy lie acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide;
5-Methoxy-benzofuran-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl } -amide; Quinoxaline-2-carboxylic acid {[(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl [-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyι)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide;
3-methylbenzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan- 4-y lcarbamoy l]-3-methyl-butyl) -amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
Quinoxaline-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide; 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-buty 1 } amide ;
Thieno[3,2-b]thiophene-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [(2,2' ,4-tridueterio)-3-oxo- 1 -(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
Quinoxaline-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1-( 1 -oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide; Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl[-amide;
Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- pentyl [-amide;
Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- 2-phenyl-ethyl} -amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide; 5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl] -butyl } amide ;
3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3- methy 1-butyl } -benzamide ; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- yl carbamoyl]-3-methyl-butyl [-amide;
Benzofuran-2-carboxylic acid-{ (S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl[-amide;
N- { (S)- 1 - [ 1 -(4-Fluoro-benzenesulf onyl)-3-oxo-azepan-4-ylcarbamoyl } -3-methy 1-butyl } -3,4- dimethoxy-benzamide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;
Benzofuran-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3- methyl-butyl]-amide; N-[(S)-1-(1 -Methanesulf onyl)-3-oxo-azepan-4-y lcarbamoy 1 } -3-methy 1-butyl } -3 ,4- dimethoxy-benzamide ;
N-{(S)-l-[l-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl[-3-methyl-butyl}-4- methanesulfonyl-benzamide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl [-amide;
5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty [-amide;
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; 6-Methyl-N-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl } -nicotinamide;
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;
N- { (S)- 1 - [( 1 -(2-cy ano-benzenesulf onyl)-3-oxo-azepan-4-y lcarbamoy 1 } -3-methy 1-butyl } -3 ,4- dimethoxy-benzamide;
4-Methansulfonyl-N-{(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methyl-butyl-benzamide; (S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo-l-(pyridine-
2-sulfonyl)-azepan-4-yl]-amide;
(S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-yl]-amide; 5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
3-Methylbenzofuran-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1 -(thiazole-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl[ amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; l-Methyl-lH-indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide; Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-chloro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl [-amide;
5-Methoxy-benzofuran-2-carboxylic acid-[(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid-[(S)-l-[l-(4-chloro-benzenesulfonyι)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide; 3-Methyl-benzofuran-2-carboxylic acid- { (S)- 1 - [ 1 -(4-chloro-benzenesulf onyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl [-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
1 -Methyl- lH-indole-2-carboxy lie acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- 1 -(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } -amide ;
7-Methoxy-benzofuran-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- 1 -(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } -amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoxaline-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]~butyl} -amide;
1 -Methyl- l-H-indole-2-carboxy lie acid-{ (S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl } amide; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-y lcarbamoy l]-butyl } amide;
Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy l]-butyl} amide;
Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; Isoquinoline-1-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Naphthalene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide; Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ;
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
(R)-l-Benzyl-5-oxo-pyπolidine-2-carboxylic acid { (S)-3-methyl-l-{ 3-oxo-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-ethyl]-amide;
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; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-
3-oxo-azepan-4-y lcarbamoy l]-butyl } amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl[amide;
5 ,6-Difluoro-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo-l-(l -oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
7-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } -amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } -amide ;
5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl[-amide;
5-Methoxy-benzofuran-2-carboxy lie acid { (S)-3-methy 1- 1 - [ 1 -(3-methy l-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl[amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}amide;
Benzofur an-2-carbox lie acid { (S)-3-methyl- 1 - [6-methy 1-3-oxo- 1 -(pyridine-sulf onyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Naphthalene- 1 -carboxylic acid { (S)-2-naphthalen-2-yl- 1 - [3-oxo- 1 -
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl [-amide; Naphthyridine-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl [-amide;
Naphthalene- 1 -carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -2-phenyl-ethyl } -amide ;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-methyl-furan-3-sulfonyι)-3-oxo- azepan-4-ylcarbamoyl]-butyl [-amide;
Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7S)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l-(pyridine-2- sulf ony l)-azepan-4-ylcarbamoy 1] -butyl } -amide ;
Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl[-amide;
Naphthalene- 1 -carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy l]-butyl[ -amide;
Quinoline-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } -amide; 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;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl}-amide; Naphthalene- 1-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl[-amide;
Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl [-amide;
Naphthalene- 1-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl } -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;
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;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-y lcarbamoy 1] -butyl } -amide ; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid { (S)-3-methyl- l-[6-methyl-3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide; 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
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; 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-y lcarbamoy l]-butyl } -amide;
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;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(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- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
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; 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; 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 {(S)-3-methyl-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 lcarbamoy 1] -butyl } -amide ; Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-l -[3-oxo- l-quinolin-2-ylmethy 1-azepan-
4-y lcarbamoy l]-butyl } -amide ;
Benzo[b]thiophene-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl] -3-methy 1-butyl } -amide ;
3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl [-amide;
Quinoxaline-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide; Thieno[3,2-b]thiophene-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-y lcarbamoy l]-3-methy 1-butyl } -amide;
Quinoline-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
4-Methyl-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-l-[l-(2-fluoro-pheny lcarbamoy l)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; and
4-Methyl-furan-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide.
6. Use of one or more of compounds of Formula I in the manufacture of a medicament for treating a parasitic disease mediated by a cysteine protease:
wherein:
Rl is selected from the group consisting of:
R2 is selected from the group consisting of: H, Cχ.galkyl, C3-gcycloalkyl-CQ-galkyl, Ar-Co.galkyl, Het-C0.galkyl, R9C(O)-, R9C(S)-, R9SO2-, R9OC(O)-,
R9RπNC(O)-, R9RπNC(S)-, R9(R1 1)NSO2- R6 Ύ R° , and R SO2RπNC(O)-;
R3 is selected from the group consisting of: H, Cι_galkyl, C3-gcycloalkyl-Co_galkyl, C2-6alkenyl, C2-6alkynyl, HetCQ-galkyl and ArCQ.galkyl;
R3 and R' may be connected to form a pyπolidine, piperidine or moφholine ring;
R4 is selected from the group consisting of: H, Cχ.gaιkyl, C3_gcycloalkyl-CQ.galkyl, Ar-Co.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, Cj .galkyl, C2-6alkenyl, C2-6alkynyl, C3-gcycloalkyl-Co_galkyl, Ar-CQ.galkyl and Het-CQ.galkyl;
R" is selected from the group consisting of: H, Cj.galkyl, Ar-Co_galkyl, and Het- C0.galkyl;
R? is selected from the group consisting of: H, Cj .galkyl, C3_gcycloalkyl-CQ_galkyl, Ar-C0_galkyl, Het-C0.galkyl, R10C(O)-, R10C(S)~, R10SO2-, R10OC(O)-, R10R13NC(O)-, and R10R13NC(S)-;
R^ is selected from the group consisting of: H, Cl -galkyl, C2-6alkenyl, C2-6alkynyl> HetCQ.galkyl and ArCQ.galkyl;
R9 is selected from the group consisting of: Cχ_galkyl, C3_gcycloalkyl-CQ_galkyl, Ar-CQ.galkyl and Het-CQ.galkyl;
RIO is selected from the group consisting of: C .galkyl, C3_gcycloalkyl-CQ.galkyl, Ar-CQ-galkyl and Het-CQ.galkyl; Rl 1 is selected from the group consisting of: H, Cχ_galkyl, Ar-Cθ-galkyl, and Het-
CQ.galkyl;
R 2 is selected from the group consisting of: H, Ci.galkyl, Ar-Co_galkyl, and Het- CQ-galkyl; Rl3 is selected from the group consisting of: H, Cχ_galkyl, Ar-Cθ-galkyl, and Het- CQ.galkyl;
R' is selected from the group consisting of: H, Cχ_galkyl, Ar-Co_galkyl, and Het-CQ. galkyl; R" is selected from the group consisting of: H, Cχ_galkyl, Ar-Co_galkyl, or Het-CQ- galkyl;
R'" is selected from the group consisting of: H, C _galkyl, C3.gcycloalkyl-CQ.galkyl, Ar-CQ-galkyl, and Het-CQ.galkyl;
R"" is selected from the group consisting of: C1 -galkyl, C3_gcycloalkyl-CQ_galkyl C2-6alkenyl, C2-6alkynyl, HetCQ.galkyl and ArCQ.galkyl;
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.
7. A use according to Claim 6 of a compound selected from the group consisting of:
Benzo[l,3]dioxole-5-carboxylic acid [(S)-r-(l-benzyl-3-oxoazepan-4-ylcarbamoyι)-3- methyl-butyl]amide;
Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl] amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl- 1 - {3-oxo- 1 -[2- (3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide; 5-(2-Moφholino-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; 4-((S)-4-Methyl-2-{ [5-(2-moφholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino[- pentanoylamino)-3-oxo-azepane- 1-carboxylic acid phenylamide;
5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Pyrrolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide; 5-(2-Piperidm-l-yl-ethoxy)-benzofuran-2-carboxyιic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl } -butyl)amide ; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methy 1-butyl] amide ;
Benzofuran-2-carboxylic acid [(S)-l-(l~benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyljamide;
5-(2-Pyπolidin- 1 -y l-ethoxy)-benzofuran-2-carboxylic acid [(S)- 1 -( 1 -benzenesulf onyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-buyl } -amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl [-amide;
Naphthalene-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } -amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } -amide ;
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;
5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyl [-amide;
Quinoline-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ; Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide;
Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide ; Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Isoquinoline-3-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } amide;
Isoquinoline- 1-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Quinoxaline-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy l]-butyl } amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1 -(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
5-Nitro-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
5-(4-Nitro-phenyl)-furan-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; (S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2- sulfonyl)-azepan-4-yl]-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } -amide;
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;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl[amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-butyl [amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl[amide; 5-(4-Oxy-morρholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
5-Hydroxy-benzofuran-2-carboxy lie acid { (S)-3-methyl- 1 - [ 1 -( 1 -methyl- lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1-( l-oxy-pyridine-2-sulfonyl)-azepan- 4-y lcarbamoy l)]-3-methy 1-butyl} -amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-y lcarbamoy l]-butyl } amide;
5-Bromo-furan-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; 5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl)]-3-methyl-butyl[-amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-y lcarbamoy 1] -butyl } amide ;
Benzo[l,3]dioxole-5-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty [-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide; lH-Indole-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxy lie acid {(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-y lcarbamoy l]butyl } amide;
4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl]-butyl } amide ;
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;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide; lH-Indole-5-carboxylic acid {(S)-3-methyι-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl]-butyl } amide;
5-(4-Chloro-phenyl)-furan-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid { (S)-3-methy 1-1 -[3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
Benzo[l,3]dioxole-5-carboxylic acid { (S)-l-[l-(4-fluoro-benzenesulfonyι)-3-oxo-azepan-4- ylcarbamoyl]-3methyl-butyl}-amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } amide ;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
Thieno[3,2-b]thiophene-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(ρyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide; Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide; Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
4-Fluoro-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-carbamoyl]- butylj-benzamide;
3 ,4-Dihydro-2H-benzo [b] [ 1 ,4]dioxepine-7-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 - oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl } amide;
5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; (S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- yl]-amide;
5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide;
Furan-2-carboxy lie acid ( { (S)- 1 - [ 1 -(4-methoxy-benzenesulf onyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyl[-methyl)-amide;
Quinoline-2-carboxylic acid { [(S)-l-[l-(4~fluoro-benzenesulfonyι)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
1 -Methyl- lH-indole-2-carboxy lie acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide; 5-Methoxy-benzofuran-2-carboxylic acid { [(S)- 1-[ l-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide;
Quinoxaline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } amide ;
Benzofuran-2-carboxylic acid- { (S)- 1- [ 1 -(3-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid- { (S)- 1 -[ 1 -(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methy 1-butyl } -amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-y lcarbamoy 1] -3-methy 1-butyl } -amide ;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl [-amide;
3-methylbenzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl] -3-methy 1-butyl } -amide ; Quinoxaline-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl[-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } amide ;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran- 2-carboxylic acid {(S)-3-methyl-l-[(2,2',4-tridueterio)-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide; Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -ethyl } -amide ;
Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- pentyl} -amide;
Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide ; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
5-Methyl-2-phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulf onyl)-azepan-4-y lcarbamoy l]-butyl } amide; 3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3- methy 1-butyl } -benzamide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyι)-3-oxo-azepan-4- yl carbamoyl]-3-methyl-butyl [-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methy 1-butyl} -amide;
N-{(S)-1-[1 -(4-Fluoro-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl } -3-methyl-butyl } -3 ,4- dimethoxy-benzamide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-(l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid- { (S)- 1-( l-methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3- methyl-butyl]-amide;
N-[(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-3,4- dimethoxy-benzamide;
N- { (S)- 1 - [ l-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl }-3-methyl-butyl } -4- methanesulfonyl-benzamide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl[-amide;
5-(2-Mθφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty }-amide; 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;
6-Methyl-N-{(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- butyl } -nicotinamide ;
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;
N-[(S)-l-[(l-(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl[-3-methyl-butyl}-3,4- dimethoxy-benzamide ; 4-Methansulfonyl-N-[(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methyl-butyl-benzamide;
(S)-2-[5-(4-Methoxy-phenyl)-pentanoylamnio]-4-methyl-pentanoic acid [3-oxo-l-(pyridine-
2-sulfonyl)-azepan-4-yl]-amide; (S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
5-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide;
7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl [amide;
3-Methylbenzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(thiazole-2-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } amide ;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl}amide; l-Methyl-lH-indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } amide ;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo- l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-chloro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid- { (S)- 1- [ l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide; 7-Methoxy-benzofuran-2-carboxylic acid- { (S)- 1 - [ 1 -(4-chloro-benzenesulf onyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid- { (S)- 1 - [ 1 -(4-chloro-benzenesulf onyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methy 1-butyl } -amide; 5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide; 3-Methyl-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-y lcarbamoy 1] -3-methy 1-butyl } -amide ;
Benzo[b]thiophene-2-carboxylic acid- { (S)- 1-[ l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide;
1 -Methyl- 1 H-indole-2-carboxylic acid- { (S)- 1 - [ 1 -(3-methoxy-benzenesulf onyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl [-amide;
Benzofuran-2-carboxylic acid-[(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } -amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl[-amide; 7-Methoxy-benzofuran-2-carboxylic acid-[(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
3-Methyl-benzofuran-2-carboxylic acid-[(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
Quinoxaline-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- l-(thiophene-2-sulfony l)-azepan-4- ylcarbamoyl]-butyl }-amide;
1 -Methyl- l-H-indole-2-carboxy lie acid-[(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl[amide;
Quinoline-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(ρyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide; Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide;
Isoquinoline- 1 -carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2-sulf onyl)-azepan-4- ylcarbamoyl]-butyl } amide; Naphthalene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl } -amide;
Quinoline-3-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1 -(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide;
5 ,6-Dimethoxy-benzo [b]thiophene-2-carboxylic acid { (S)-3-methyl- 1 - [ 1 -(6-methy 1-pyridine- 2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl[ amide;
(R)-l-Benzyl-5-oxo-pyπolidine-2-carboxylic acid {(S)-3-methyl-l-{3-oxo-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
B enzofuran-2-carboxylic acid { (S)-2-naphthalen-2-yl- 1 - [3-oxo- 1 -(pyridine-2-sulf onyl)- azepan-4-ylcarbamoyl)-ethyl]-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulf onyl)-3-oxo-azepan-4-ylcarbamoyl] -butyl } amide ;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(3-methyl-pyridine-2-sulfonyl)-
3-oxo-azepan-4-ylcarbamoyl]-butyl[amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl[amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l~oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
7-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [ 1 -(6-methy l-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
5-Fluoro-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl }-amide;
5-Fluoro-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide; 5-(3-Trifluoromethyl-pheny l)-furan-2-carboxylic acid { (S)-2-cyclohexyl- 1 - [3-oxo- 1 -( 1 -oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl } amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- l-[6-methyl-3-oxo- l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[-amide;
Quinoline-8-carboxylic acid { (S)-2-naphthalen-2-y 1-1 -[3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Naphthalene-1-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide; Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl}-amide;
Naphthyridine-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide;
Naphthalene- 1-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl}-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(2-methyl-furan-3-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl } -amide;
Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide ; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7S)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- 1- [(4R,7R)-7-methyl-3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
Benzofuran-2-carboxylic acid {(S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl}-amide;
Naphthalene-l-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide; Quinoline-5-carboxylic acid { (S)~3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl } -amide;
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; Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-ethyl}-amide;
Naphthalene- 1 -carboxylic acid { (S)-2-naphthalen-2-yl- 1 - [3-oxo- 1 -(pyridine-2-sulf ony 1)- azepan-4-ylcarbamoyl] -ethyl } -amide;
Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- 2-phenyl-ethyl} -amide;
Naphthalene- 1-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl}-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;
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- 1 - [3-oxo- 1 -( 1 -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-sulf ony l)-azepan-4-y lcarbamoy l]-butyl } -amide; Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl [-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid { (S)-3-methyl- l-[6-methyl-3-oxo- l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide; 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 4-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulf ony l)-azepan-4-y lcarbamoy l]-butyl } -amide;
6-Methoxy-3-methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 -[3-oxo- 1 -(1 -oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
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;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(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- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 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;
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; 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 { (S)-3-methyl- 1 -[3-oxo- 1 -(1 -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-ylcarbamoyl]-butyl[-amide;
Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-quinolin-2-ylmethyl-azepan-
4-ylcarbamoyl]-butyl }-amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl[-amide; Quinoxaline-2-carboxylic acid {(S)-l-[l -(2-fluoro-pheny lcarbamoy l)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Thieno[3,2-b]thiophene-2-carboxylic acid { (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-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- yIcarbamoyl]-3-methyI-butyl } -amide ;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; and
4-Methyl-furan-2-carboxylic acid { (S)- 1 - [ 1 -(2-fluoro-pheny lcarbamoy l)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl } -amide in the manufacture of a medicament for treating a parasitic disease mediated by a cysteine protease.
8. A use according to either Claim 6 or Claim 7 wherein said disease is selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis.
9. A use according to Claim 8 wherein said disease is malaria.
10. Use of a compound selected from the group consisting of:
Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-(l-benzyl-3-oxoazepan-4-ylcarbamoyl)-3- methyl-butyl]amide; Quinoline-2-carboxylic acid [(S)-l-(l-benzyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl- butyl]amide;
5-(2-Mθφholino-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;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methy 1- 1 - { 3-oxo- 1 - [2- (3-pyridin-2-yl-phenyl)acetyl]-azepan-4-ylcarbamoyl}-butyl)amide;
4-((S)-4-Methyl-2-{[5-(2-moφholino-4-yl-ethoxy)-benzofuran-2-carbonyl]amino}- pentanoylamino)-3-oxo-azepane- 1-carboxylic acid phenylamide; 5-(2-Mθφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo~ azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Mθφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyI)-3-methyl-butyI]amide; 5-(2-Pyπolidin-l-yI-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Piperidin- 1 -yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l -benzenesulf ony 1-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]arnide;
Naphthlene-2-carboxylic acid ((S)-3-methyl-l-{3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl } -butyl)amide; lH-Indole-2-carboxylic acid [(S)- 1 -( 1 -benzenesulfonyl-3-oxo-azepan-4-y lcarbamoy l)-3- methy 1-butyl] amide ;
Benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl]amide; 5-(2-Pyπolidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l -benzenesulf onyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Piperidin-l-yl-ethoxy)-benzofuran-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 -[ 1 -(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-buyl}-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide;
Naphthalene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } -amide ; 5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl[-amide;
5-(2-Moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } -amide ; 4-[2-(2-{ (S)-3-Methyl- l-[3-oxo- 1 -(pyidine-2-sulf ony l)-azepan-4-y lcarbamoy 1] - butylcarbamoyl}-benzofuran-5-yloxy)-ethyl]-piperazine- 1-carboxylic acid tert-butyl ester;
5-(2-Piperizin-l-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-butyl[-amide; Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl] -butyl } amide ;
Quinoline-6-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
Quinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl}amide;
Isoquinoline-3-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }amide; Isoquinoline- 1-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}amide;
Quinoxaline-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl[amide; 5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
5-Nitro-furan-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl[amide;
5-(4-Nitro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide;
(S)-2-[2-(4-Fluoro-phenoxy)-acetylamino]-4-methyl-pentanoic acid [3-oxo-(pyridine-2- sulfonyl)-azepan-4-yl]-amide; Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl}-amide;
5 ,6-Dimethoxy-benzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -methyl- 1 H- imidazole-4-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-3-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(lH-imidazole-2-sulfonyl)-3-oxo-azepan-
4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl}amide;
5-(4-Oxy-moφholino-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide;
5-Hydroxy-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(l-methyl-lH-imidazole-4- sulfonyl)-3-oxo-azepan-4-y lcarbamoy l]-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-y lcarbamoy l)]-3-methy 1-butyl } -amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azeρan-4-ylcarbamoyl]-butyl}amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-butyl } amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-ylcarbamoyl)]-3-methy 1-butyl } -amide; 5-Bromo-furan-2-carboxylic acid { (S)-3-methyl- 1 -[3-oxo- 1 -( 1 -oxy-pyridine-2-sulfonyl)- azeρan-4-ylcarbamoyl]-butyl}amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide ;
5,6-Dimethoxy-benzofuran-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)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-5-carboxylic acid { (S)-3-methyl- 1- [3-oxo- 1-( l-oxy-pyridine-2-sύlfonyl)-azepan-
4-ylcarbamoyl]-butyl } amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty}-amide;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-6-carboxylic acid { (S)-3-methyl-l-[3-oxo-l~(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide ;
3 ,4-Dihydro-2H-benzo [b] [ 1 ,4]dioxepine-7-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 - oxy-pyridine-2-sulf onyl)-azepan-4-ylcarbamoyl]butyl } amide ; 4,5-Dibromo-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
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;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide; lH-Indole-5-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-
4-y lcarbamoy 1] -butyl [amide;
5-(4-Chloro-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l~[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid {(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3methyl-butyl[-amide;
5-Bromo-furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl [amide;
5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl] -butyl } amide ; 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[l,3]dioxole-5-carboxylic acid [(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide;
Furan-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Benzo[ 1 ,3]dioxole-5-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide; 4-Fluoro- { (S)-3-methy 1- 1 - [3-oxo- 1 -( 1 -oxy-pyridine-2-sulf onyl)-azepan-4-carbamoyl]- butyl } -benzamide ;
3,4-Dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(l- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]butyl}amide;
5-Methyl-thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl Jamide;
(S)-2-(3-Benzyl-ureido)-4-methyl-pentanoic acid [3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- yl] -amide;
5-Methoxy-benzofuran-2-carboxylic acid [(S)-l-(l-methanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Furan-2-carboxylic acid ({(S)-l-[l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-amide;
Quinoline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
1 -Methyl- lH-indole-2-carboxy lie acid [ [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl }-amide;
5-Methoxy-benzofuran-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl } -amide; Quinoxaline-2-carboxylic acid { [(S)-l-[l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)~ azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid- { (S)- 1 -[ 1 -(3-chloro-benzenesulf onyl)-3-oxo- azepan-4-y lcarbamoy l]-3-methyl-butyl } -amide;
3-Methyl-benzofuran-2-carboxylic acid-[(S)-l-[l-(3-chloro-benzenesulfonyl)-3-oxo-azepan- 4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methy 1-butyl } -amide ;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo- azepan-4-y lcarbamoy 1] -3-methy 1-butyl } -amide ;
3-methylbenzofuran-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(2-fluoro-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methy 1-butyl } -amide;
Quinoxaline-2-carboxylic acid- { (S)- 1 - [ 1 -(2-fluoro-benzenesulf onyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-y lcarbamoy 1] -butyl } amide ;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[(2,2' ,4-tridueterio)-3-oxo-l-(pyridine-2- sulf ony l)-azepan-4-y lcarbamoy l]-butyl } amide;
Quinoxaline-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl } amide; Benzofuran-2-carboxylic acid {(S)~2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl } -amide ;
Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- pentyl}-amide; Benzofuran-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl }-amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
5-Methyl-2-pheny l-oxazole-4-carboxylic acid { (S)-3-methyl- 1 - [3-oxo- 1 -(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amide;
3,4-Dimethoxy-N-{(S)-l-[ l-(4-methoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3- methyl-butyl }-benzamide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4- yl carbamoyl]-3-methyl-butyl}-amide; Benzofuran-2-carboxylic acid-[(S)-l-[ l-(4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl[-amide;
N- { (S)- 1 - [ 1 -(4-Fluoro-benzenesulf onyl)-3-oxo-azepan-4-ylcarbamoyl } -3-methy 1-butyl } -3 ,4- dimethoxy-benzamide;
Benzo[b]thiophene-2-carboxylic acid- { (S)- 1 -( 1 -methanesulfonyl-3-oxo-azepan-4-yl carbamoyl)-3-methyl-butyl]-amide;
Benzofuran-2-carboxylic acid- { (S)-l-(l -methanesulf ony l-3-oxo-azepan-4-yl carbamoyl)-3- methyl-butyl]-amide;
N-[(S)-l-(l-Methanesulfonyl)-3-oxo-azepan-4-ylcarbamoyl[-3-methyl-butyl}-3,4- dimethoxy-benzamide; N-{(S)-l-[l-(2-Cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl}-4- methanesulfonyl-benzamide ;
Benzofuran-2-carboxylic acid {(S)-l-[l-(2-cyano-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyI[-amide;
5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo~(l-oxy- pyridine2-sulfonyl)-azepan-4-ylcarbamoyl]- -buty}-amide;
5-Methyl-2 -phenyl-oxazole-4-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulf onyl)-azepan-4-ylcarbamoyl] -butyl } amide; 6-Methyl-N- { (S)-3-methyl- l-[3-oxo- l-(l~oxy-pyridine-2-sulf ony l)-azepan-4-y lcarbamoy 1]- butylj-nicotinamide;
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; N- { (S)- 1 -[(1 -(2-cyano-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl } -3-methyl-butyl } -3,4- dimethoxy-benzamide;
4-Methansulfonyl-N-{(S)-l-[4-fluoro-benzenesulfonyl)-3-oxo-azepan-4-carbamoyl]-3- methyl-butyl-benzamide;
(S)-2-[5-(4-Methoxy-phenyl)-ρentanoylamnio]-4-methyl-pentanoic acid [3-oxo-l-(pyridine- 2-sulfonyl)-azepan-4-yl]-amide;
(S)-2-[2-(3-Benzyloxy-4-methoxy-phenyl)-acetylamnio]-4-methylpentanoic acid [3-oxo- 1-
(pyridine-2-sulfonyl)-azepan-4-yl]-amide;
5-Methoxybenzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } amide; 7-Methoxybenzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
3-Methylbenzofuran-2-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}amide;
Benzo[b]thiophene-2-carboxylic acid { (S)-3-methyl- 1 -[3-oxo- 1 -(thiazole-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl[amide;
1 -Methyl- 1 H-indole-2-carboxy lie acid [ (S)-3-methyl- 1 - [3-oxo- 1 -(thiazole-2-sulf onyl)- azepan-4-ylcarbamoyl]~butyl}amide;
Quinoxaline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(thiazole-2-sulfonyl)-azepan-4- ylcarbamoyl] -butyl }amide;
Benzofuran-2-carboxylic acid [(S)-l-[l-(4-chloro-benzenesulfonyl)- 3-oxo-azepan-4-yl carbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl[-amide;
7-Methoxy-benzofuran-2-carboxylic acid-[(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid-[(S)-l-[l-(4-chloro-benzenesulfonyl)-3-oxo-azepan-
4-y lcarbamoy l]-3-methyl-butyl } -amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(4-chloro-benzenesulfonyl)~3-oxo-azepan-4- ylcarbamoyl]-3-methyI-butyl } -amide; Benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide;
5-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
7-Methoxy-benzofuran-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid- { (S)- 1 -[ 1 -(3-methoxy-benzenesulf onyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzo[b]thiophene-2-carboxylic acid-{(S)-l-[l-(3-methoxy-benzenesulfonyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide; 1 -Methyl- 1 H-indole-2-carboxylic acid- { (S)- 1 - [ 1 -(3-methoxy-benzenesulf onyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
Benzofuran-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyι)-azepan-4- ylcarbamoyl]-butyl } -amide;
5-Methoxy-benzofuran-2-carboxylic acid-[(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)- azepan-4-y lcarbamoy l]-butyl } -amide;
7-Methoxy-benzofuran-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- 1 -(thiophene-2-sulf ony 1)- azepan-4-ylcarbamoyl] -butyl } -amide ;
3-Methyl-benzofuran-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- 1 -(thiophene-2-sulf onyl)- azepan-4-ylcarbamoyl]-butyl[-amide; Benzo[b]thiophene-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfony )- azepan-4-ylcarbamoyl]-butyl[-amide;
Quinoxaline-2-carboxylic acid-{(S)-3-methyl-l-[3-oxo-l-(thiophene-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl [-amide;
1 -Methyl- 1 -H-indole-2-carboxylic acid- { (S)-3-methyl- 1 - [3-oxo- 1 -(thiophene-2-sulf onyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}amide; 5,6-Difluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[l-(pyridine-2-sulfόnyι)~3-oxo- azepan-4-y lcarbamoy l]-butyl } amide;
Quinoline-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide ; Quinoline-6-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Quinoline-4-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } amide;
Isoquinoline- 1-carboxylic acid {(S)-3-methyl- l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl} amide;
Naphthalene-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide;
Quinoline-3-carboxylic acid { (S)-3-methyl-l- [3-oxo- 1 -(pyridine-2-sulf ony l)-azepan-4- y lcarbamoy 1] -butyl } amide ; 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-ylcarbamoyl]-butyl } amide;
(R)-l-Benzyl-5-oxo-pyπolidine-2-carboxylic acid {(S)-3-methyl-l-{3-oxo-(pyridine-2- sulfonyl)-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl)-ethyl]-amide;
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;
3-Methyl-benzofuran-2-carboxylic acid { (S)-3-methyl- l-[l-(3-methyl-pyridine-2-sulfonyl)-
3-oxo-azepan-4-ylcarbamoyl]-butyl}amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}amide;
5,6-Difluoro-benzofuran-2-carboxylic acid [ (S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl[amide;
7-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(6-methyl-pyridine-2- sulfonyl)-3-oxo-azepan-4-y lcarbamoy l]-butyl } amide;
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[l-(6-methyl-pyridine-
2-sulfonyl)3-oxo-azepan-4-y lcarbamoy l]-butyl } amide; 5-Fluoro-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyI)- azeρan-4-ylcarbamoyl]-butyl}-amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid{(S)-2~cyclohexyl-l-[3-oxo-l-(l-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
5,6-Dimethoxy-benzofuran-2-carboxylic acid{(S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl[ -amide;
5-Methoxy-benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(3-methyl-pyridine-2- sulf ony l)-3-oxo-azepan-4-y lcarbamoy l]-butyl } amide;
Benzofuran-2-carboxylic acid { (S)-3-methyl-l-[l-(6-methyl-pyridine-2-sulfonyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-sulfonyl)- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoline-8-carboxylic acid {(S)-2-naphthalen-2-yl-l-[3-oxo-l-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Naphthalene- 1-carboxylic acid { (S)-2-naphthalen-2-y 1-1 -[3-oxo- 1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl)-ethyl]-amide;
Quinoline-8-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide;
Naphthyridine-2-carboxylic acid [(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- y lcarbamoy 1] -butyl } -amide ; Naphthalene- 1-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyι)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl}-amide;
B enzofuran-2-carboxylic acid { (S)-3-methyl- 1 - [ 1 -(2-methyl-furan-3-sulf onyl)-3-oxo- azepan-4-ylcarbamoyl]-butyl}-amide;
Quinoline-2-carboxylic acid {(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]- 2-phenyl-ethyl[-amide;
Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7S)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
Benzofuran-2-carboxylic acid { (S)- l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl}-amide; Naphthalene- 1-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl }-amide;
Quinoline-5-carboxylic acid { (S)-3-methyl- l-[3-oxo- l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl } -amide ;
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;
Quinoline-8-carboxylic acid { (S)-2-naphthalen-2-yl- l-[3-oxo- l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl } -amide;
Naphthalene- 1-carboxylic acid { (S)-2-naphthalen-2-yl-l-[3-oxo-l-(pyridine-2-sulfonyι)- azepan-4-ylcarbamoyl]-ethyl}-amide; Quinoline-8-carboxylic acid [(S)-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
2-phenyl-ethyl } -amide ;
Naphthalene- 1 -carboxylic acid { (S)- 1 - [3-oxo- 1 -(pyridine-2-sulf onyl)-azepan-4- ylcarbamoyl]-2-phenyl-ethyl}-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-rnethyι-l-[3-oxo-l-(l-oxy-pyridine-
2-sulfonyl)-azepan-4-y lcarbamoy l]-butyl } -amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulf onyl)-azeρan-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- 1 - [3-oxo- 1 -( 1 -oxy-pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
B enzo [b]thiophene-2-carboxy lie acid { (S)-3-methyl- 1 - [6-methy 1-3-oxo- 1 -(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-3-methyl-l-[6-methyl-3-oxo-l~(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-l-[3-oxo-l-(l-oxy-pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
4-Methoxy-3-methyl-benzofuran-2-carboxy lie acid { (S)-3-methyl- 1 - [3-oxo- 1-( 1 -oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide;
6-Methoxy-3-methy l-benzofuran-2-carboxy lie acid { (S)-3-methyl- 1 - [3-oxo- 1 -( 1 -oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; 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;
3,5-Dimethyl-benzofuran-2-carboxylic acid {(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- sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide;
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;
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; 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 {(S)-3-methyl-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 lcarbamoy 1] -butyl } -amide ; Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl- 1- [3-oxo- l-quinolin-2-ylmethy 1-azepan-
4-y lcarbamoy 1] -butyl } -amide ;
Benzo[b]thiophene-2-carboxylic acid { (S)- 1 -[ 1 -(2-fluoro-pheny lcarbamoyl)-3-oxo-azepan-4- y lcarbamoy l]-3-methy 1-butyl } -amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-
4-ylcarbamoyl]-3-methyl-butyl}-amide;
Quinoxaline-2-carboxylic acid { (S)- 1 - [ 1 -(2-fluoro-pheny lcarbamoy l)-3-oxo-azepan-4- ylcarbamoyl]-3-methy 1-butyl } -amide;
Thieno[3,2-b]thiophene-2-carboxylic acid { (S)- 1 - [ 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-methyl-butyl}-amide;
4-Methyl-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methy 1-butyl } -amide; and
4-Methyl-furan-2-carboxylic acid { (S)-l-[l-(2-fluoro-phenylcarbamoyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl}-amide in the manufacture of a medicament for treating a parasitic disease mediated by a cysteine protease.
EP01966474A 2000-09-01 2001-08-31 Method of treatment Withdrawn EP1320370A4 (en)

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US881334 1986-07-02
US65381500A 2000-09-01 2000-09-01
US653815 2000-09-01
US09/881,334 US20030144175A1 (en) 1998-12-23 2001-06-14 Protease inhibitors
PCT/US2001/027178 WO2002017924A1 (en) 2000-09-01 2001-08-31 Method of treatment

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EP1320370A4 true EP1320370A4 (en) 2008-10-22

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