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ZA200209808B - Protease inhibitors. - Google Patents

Protease inhibitors. Download PDF

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Publication number
ZA200209808B
ZA200209808B ZA200209808A ZA200209808A ZA200209808B ZA 200209808 B ZA200209808 B ZA 200209808B ZA 200209808 A ZA200209808 A ZA 200209808A ZA 200209808 A ZA200209808 A ZA 200209808A ZA 200209808 B ZA200209808 B ZA 200209808B
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South Africa
Prior art keywords
methyl
azepan
butyl
amide
carboxylic acid
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ZA200209808A
Inventor
Robert W Marquis Jr
Yu Ru
Daniel F Veber
Maxwell D Cummings
Scott K Thompson
Dennis Yamashita
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Smithkline Beecham Corp
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Publication of ZA200209808B publication Critical patent/ZA200209808B/en

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Description

PROTEASE INHIBITORS
FIELD OF THE INVENTION
: This invention relates in general to 4-amino-azepan-3-one protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds * which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
BACKGROUND OF THE INVENTION
Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature.
Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al, (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D. etal, (1996) J. Biol. Chem. 271, 2126-2132.
Cathepsin K has been variously denoted as cathepsin O or cathepsin O2 in the literature. The designation cathepsin K is considered to be the more appropriate one.
Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the i . 30 like. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and ‘ references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.
Cathepsin K is believed to play a causative role in diseases of excessive bone or . cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural * protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget’s disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
Several published studies have demonstrated that inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. J., 1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN?) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al., . 30 Biochem. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum : calcium in rats on calcium deficient diets. Lerner, er al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, ef al., Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Everts, et al., J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity 8 and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, et al.,
Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBS Lett., 1995, 357, 129 * disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.
The abundant selective expression of cathepsin XK in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, O2 and cruzain. Other classes of compounds, such as aldehydes, nitriles, o-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, id, and references cited therein.
U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO 94/04172, and European Patent Application Nos, EP 0 525 420 Al, EP 0 603 873 Al, and
EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the . 30 cysteine proteases cathepsins B, H and L. International Patent Application No.
PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe ' alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- 1Bconvertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No.
PCT/GB91/01479).
Azapeptides which are designed to deliver the azaamino acid to the active site of - serine proteases, and which possess a good leaving group, are disclosed by Elmore er al.,
Biochem. J., 1968, 107, 103, Garker et al., Biochem. J., 1974, 139, 555, Gray et al.,
Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al., J.
Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases. In addition, J.
Med. Chem., 1992, 35,4279, discloses certain azapeptide esters as cysteine protease inhibitors.
Antipain and leupeptin are described as reversible inhibitors of cysteine protease in
McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and
Grinde, Biochem. Biophys. Acta, , 701, 328). 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent
Nos.4,749,792 and 4,638,010.
Thus, a structurally diverse variety of protease inhibitors have been identified.
However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance. A need therefore exists for methods of treating diseases caused by pathological levels of proteases, particularly cysteine proteases, more particularly cathepsins, most particularly cathepsin K, and for novel inhibitor compounds useful in such methods.
We have now discovered a novel class of 4-amino-azepan-3-one compounds which are protease inhibitors, most particularly of cathepsin K.
SUMMARY OF THE INVENTION
An object of the present invention is to provide 4-amino-azepan-3-one carbonyl - 30 protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such ’ compounds which inhibit cysteine proteases of the papain superfamily, yet more + particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.
Accordingly, in the first aspect, this invention provides a compound according to . Formula I.
In another aspect, this invention provides a pharmaceutical composition comprising ! a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula I.
In still another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula I:
RN, F'
N iy
ROOTING
R
1 wherein:
R1 is selected from the group consisting of:
0) 0 0 =
AAS es
Rr R® R®
R' 0 R’ 0 \ N
Rr’ and Joo.
R2 is selected from the group consisting of: H, C1_galkyl, C3_gcycloalkyl-Co._ calkyl, Ar-Cq_galkyl, Het-Cqy_galkyl, R9C(0)-, R9C(S)-, R9SO,-, R9OC(O}-, yy Z
RIR1INC(0)-, RORIINC(S)-, RIRI1NSO,- | Z , | >”
Tz rR? ~~ hs , and R9SO,RINC(0)-;
R3 is selected from the group consisting of: H, C1-galkyl, C3-gcycloalkyl-
Cp-galkyl, C2-galkenyl, Co_galkynyl, HetCp._galkyl and ArCq_galkyl;
R3 and R’ may be connected to form a pyrrolidine, piperidine or morpholine ring;
R4 is selected from the group consisting of: H, C1_galkyl, C3.gcycloalkyl- Cg.galkyl, Ar-Cq_galkyl, Het-Cq.galkyl, RSC(O)-, RSC(S)-, R305, R2OC(O)-,
RSRI2ZNC(0)-, and ROSRIZNC(S)-;
RS is selected from the group consisting of: H, C1_galkyl, C2-galkenyl,
C2-ealkynyl, C3_gcycloalkyl-Cq_galkyl, Ar-Cq._galkyl and Het-Cp_galkyl;
RO is selected from the group consisting of: H, C_galkyl, Ar-Cq-galkyl, and Het-
Cp.galkyl; - R7 is selected from the group consisting of: H, C1_galkyl, C3_gcycloalkyl-
Co-galkyl, Ar-Cq_galkyl, Het-Cg_galkyl, R10C(0)-, R10C(S)-, R1050,-, R100C(0)-, ‘ RIOR1I3NC(0)-, and RIORI3NC(S)-;
R38 is selected from the group consisting of: H, C1-galkyl, C2-galkenyl,
C2-galkynyl, HetCq_galkyl and ArCq_galkyl; : RY is selected from the group consisting of: C1-6alkyl, C3_gcycloalkyl-Co_galkyl,
Ar-Cq_galkyl and Het-Cq_galkyl; . R10 is selected from the group consisting of: C1.galkyl, C3_gcycloalkyl-Cy_galkyl, Ar-Cq_galky! and Het-Cq_galkyl; ’ R11 is selected from the group consisting of: H, C1.6alkyl, Ar-Cp-galkyl, and Het-
Co-ealkyl;
R12 is selected from the group consisting of: H, Cy_galkyl, Ar-Cp-galkyl, and Het-
Co-ealkyl;
R13 is selected from the group consisting of: H, C1_galkyl, Ar-Cp-galkyl, and Het-
Cp-ealkyl;
R’ is selected from the group consisting of: H, C1_galkyl, Ar-Cg_galkyl, and Het-
Co-galkyl;
R” is selected from the group consisting of: H, Cq_galkyl, Ar-Cg.galkyl, or Het-
Cp.galkyl; !
R™ is selected from the group consisting of: H, Cq_galkyl, C3_gcycloalkyl-
Cp-6alkyl, Ar-Cq_galkyl, and Het-Cq_galkyl;
R™ is selected from the group consisting of: C1_galkyl, C3_gcycloalkyl-Cqy_galkyl
Co-ealkenyl, C2_galkynyl, HetCq_galkyl and ArCq_galkyl;
X is selected from the group consisting of: CH», 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 0
Rt AN
In compounds of Formula I, when R1 is R’ :
R3 is selected from the group consisting of: H, C1.galkyl, C3_gcycloalkyl- - Co-6alkyl,Ca-galkenyl, C2-galkynyl, Het-Cq_galkyl and Ar-Cq_galkyl;
R3 is preferably selected from the group consisting of: H, C3_gcycloalkyl- Co-ealkyl, Co-alkenyl, Ar-Co.galkyl, and C1_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. ’ R3 is most preferably isobutyl.
R# is selected from the group consisting of: H, C1-galkyl, C3_gcycloalkyl-
Co._galkyl, Ar-Cq_galkyl, Het-Cq_galkyl, ROC(O)-, R3C(S)-, R3SO,-, R30C(O)-,
RORI3NC(0)-, and RSRI3NC(S)-.
R% is preferably selected from the group consisting of: RO0C(0)-, R3C(0)- and
RISO,-.
R4 is most preferably R3C(O)-.
In some embodiments, R% is preferably methanesulfonyl.
R> is selected from the group consisting of: H, C1.6alkyl, Co_galkenyl,
Co _galkynyl, C3_gcycloalkyl-Cq_galkyl, Ar-C_galkyl or Het-Cq_galkyl.
Preferably R? is selected from the group consisting of: Ci_galkyl, Ar-Cq_galkyl : and Het-Cg_galkyl.
More preferably, and especially when R4 is R3C(0)-, RY is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl! , especially
C1_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; . 30 acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially . 3,4-dichloropheny! and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or Cj_galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4-
methoxy-phenyl, especially phenyl substituted with one or more C1_galkyl sulfonyl groups, more especially 4-methanesulfonyl-phenyl; benzyl, naphthaleny], especially naphthylen-2-yl; benzo[1,3]dioxolyl, especially benzo[1,3]dioxol-5-yl; y 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
Cy_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-yti; benzofuranyl, especially benzofuran-2-yl, and substituted benzofuranyl, more especially 5-(2-piperazin-4-carboxylic acid rert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2- morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-1-yl-ethoxy)benzofuran-2-yl, 5- (2-cyclohexyl-ethoxy)-benzofuran-2-yl; especially C1_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 Cq_galky! 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-inethoxy-3-methyl-benzofuran-2- yl, and 6-methoxy-3-methyl-benzofuran-2-yl; naphtho[2,1-b]-furanyl, especially naphtho[2,1-b]-furan-2-yl, alkyl substituted naphtho[2,1-b]-furanyl, especially 1-methyl-naphtho[2,1-b]-furan-2-yl; benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; especially Cy_galkoxy substituted benzo[b]thiophenyl, more especially 5,6-dimethoxy- benzo[b]thiophen-2-yl; quinolinyl, especially quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and . quinolin-8-yl; } 30 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 Cy. alkyl substituted indolyl, more especially N-methyl-indol-2-yl, .
pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, especially C1_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, C_galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; . thiophenyl, especially thiophen-3-y1, also thiophen-2-yl, especially C1_galkyl substituted thiophenyl, more especially 5-methyl-thiophen-2-yland 5-methyl-thiophen-3-yl, especially halogen substituted thiophenyl, more especially 4,5-dibromo-thiophen-2-yl; thieno[3,2-b}thiophene, especially thieno[3,2-b]thiophene-2-yl, more especially
Cy_galkyl substituted thieno[3,2-b]thiophene-2-yl, more especially 5-tert-butyl-3-methyl- thieno[3,2-b]thiophene-2-yl; isoxazolyl, especially isoxazol-4-yl, especially C1_galky! substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl, oxazolyl, especially oxazol-4-yl, more especially S-methyl-2-phenyl oxazol-4-yl, 2- phenyl-5-trifluoromethyl-oxazol-4-yl; and 1H-benzoimidazolyl, especially 1H-benzoimidazol-5-yl.
When R4 is R3SO,, RS is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.
R’is selected from the group consisting of: H, Cy_galkyl, Ar-Cq.galkyl, and Het-
Cp-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, Cy_galkyl, Ar-Cp-galkyl, and Het-
Co-ealkyl.
Most preferably R” is H. ) 30 R™ is selected from the group consisting of: H, Cy_galkyl, C3-gcycloalkyl-
Co-6alkyl, and Het-Cq_galkyl. . Ris preferably selected from the group consisting of: H and Cy _galkyl
R™ is more preferably selected from the group consisting of: H, methyl and 6,6- dimethyl.
R™ is still more preferably selected from the group consisting of: H and 6,6- . dimethyl.
Most preferably R™ is H. o
N
~~
R4 oN
In compounds of Formula I, when Rl is R3 :
R3 is selected from the group consisting of: C1-galkyl, C3_gcycloalkyl-Cg-galkyl,
C2-galkenyl, C2_galkynyl, Het-Cq_galkyl and Ar-Cq_galkyl.
R3 is preferably C1_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: C1_galkyl, C3-gcycloalkyl-
Cop-6alkyl, Co_galkenyl, Co_galkynyl, HetCq_galkyl and ArCq_galkyl;
R”” is preferably Ci_galkyl;
R”” is more preferably selected from the group consisting of methyl, ethyl, n- propyl, n-butyl, isobutyl and t-butyl.
R™” is most preferably methyl.
In such compounds, R), R’, R”, R4, and R5 are as described above wherein 0 rR’
Rr N I
R®
To ’ eS } In compounds of Formula I, when Rl is Jn :
n is preferably an integer of from 1 to 5; and
R), rR, R”, R4, and RS are as described above wherein 0 . R’
RY” N IN . 3
Rls R : n is most preferably 3.
The ring may be unsubstituted or substituted with one or more of C1.galkyl,
C3_geycloalkyl-Cq_galkyl, Ca-galkenyl, Ca-galkynyl, HetCgy_galkyl, ArCp_galkyl, or halogen.
The ring is preferably unsubstituted.
In compounds of Formula I, R2 is selected from the group consisting of;
H, Cy_galkyl, C3_gcycloalkyl-Cq galkyl, Ar-Cq_galkyl, Het-Cq_galkyl, R9C(0)-, RIC(S)-,
Z ye
R9S0;-, R90C(0)-, ROR! INC(0)-, ROR1INC(S)-, RORIINSO,-, 7 : ¢ Hg
Ny cH, R77 ~ ey ety > , and R9SO,R11INC(O)-.
More preferably R2 is selected from the group consisting of: Ar-Cg.galkyl,
R®
N Zz
R” hd ~ 8
RIC(0)-, R9SO,, RORIINC(0)-, and R _
Even more preferably, R2 is selected from the group consisting of: Ar-Cg-ealkyl,
RYC(0)-, and R9SO,.
Most preferably R2 is RISO.
In such embodiments:
RO is selected from the group consisting of: H, C1_galkyl, Ar-Co-galkyl, or Het-
Co-galkyl, preferably H.
R7 is selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl- Co.galkyl, Ar-Cq_galkyl, Het-Cq_galkyl, R10C(0)-, R10C(S)-, R1050,-, R100C(0)-, ; RIOR4NC(0)-, RIORI4NC(S)-, R is preferably R100C(0).
R8 is selected from the group consisting of: H, Cj_galkyl, C2-galkenyl,
Co.galkynyl, HetCp_galkyl and ArCp_galky!l; preferably Cq_galkyl, more preferably isobutyl.
RY is selected from the group consisting of: C1.salkyl, C3_gcycloalkyl-Cp_galkyl,
Ar-Cq._galkyl, and Het-Cq_galkyl.
Ris preferably selected from the group consisting of: Cq_galkyl, Ar-Cg_galkyl, and Het-Cq_galkyl.
More preferably, RY is selected from the group consisting of: methyl; ethyl, especially Cy_galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially Cy _gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R2 is R90C(0); 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 C1_galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C1_galkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially Cy_galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yltoluyl; naphthylene, especially naphthyl-2-ene; } 30 benzoic acid, especially 2-benzoic acid; benzo[ 1,3]dioxolyl, especially benzo[1,3}dioxol-5-yl; ] benzo[1,2,5]oxadiazolyl, especially benzo[1,2,5]oxadiazol-4-y};
pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; especially Cj_galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; thiophenyl, especially thiophenyl-2-y1; thiazolyl, especially thiazol-2-yl; - 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, more especially
C1-galkyl substituted imidazolyl, even more especially 1-methyl-1H-imidazol-2-yl1, 1- methyl-1H-imidazol-4-yl, and 1,2-dimethyl- 1H-imidazol-4-yI; triazolyl, especially 1H-[1,2,4]triazolyl, more especially 1H-[1,2,4]triazol-3-yl, especially Cj_galkyl substituted 1H-[1,2,4]triazolyl, more especially 5-methyl-1H- [1,2,4]triazol-3-yl; and isoxazolyl, especially isoxazol-4-yl, especially C;_galkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl.
When R2 is R950, RY is most preferably selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.
When R2 is RISO,R1 INC(0)-, RY is preferably Ar-Cq_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(0)-, R? is preferably selected from the group consisting of
C1-galkyl, C3_gcycloalkyl-C_galkyl, and Het-C(y_galkyl, more preferably 1-oxy-pyridin-2- yl, cyclohexyl ethyl, and 3-methyl butyl.
R11 js selected from the group consisting of: H, Cq_galkyl, Ar-C(-galkyl, and Het-
Co.galkyl.
When RZ is R9SORIINC(0)-, R11 js preferably H.
When R2 is Ar-Cq_galkyl, R2 is preferably phenyl, especially substituted phenyl, ) 30 more especially halogen substituted phenyl, even more especially 2-fluorobenzyl. . B When R2 is Ci-galkyl, RZ is preferably selected from 1-propyl, 1-butyl, and 1- pentyl.
When R2 is Het-C_galkyl, Het-Cq_galkyl is preferably Het-methyl, and Het in
Het-methyl is preferably selected from the group consisting of: . pyridiny}, especially pyridin-2-yl, especially Cj_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 1-(2-morpholin-4-yl-thiazol-4-yl), and 1- (isothiazol-3-yI); 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, especially
C1.galkyl substituted imidazolyl, more especially 1-methyl-1H-imidazol-2yl; triazolyl, especially 3H-[1,2,3]triazolyl, more especially 3H-[1,2,3]triazol-4-yl, especially Cj_galkyl substituted 3H-[1,2,3]triazolyl, more especially 3-phenyl-3H- [1,2,3]triazolyl -4-yI; quinolinyl, especially quinolin-2-yl, quinolin-2-yl; furanyl, especially furan-2-yl, especially substituted furanyl, such as S-ethyl-furan- 2-vl; thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, especially
C1.-6alkyl substituted thieno[3,2-b]thiopheny], especially 3,4-dimethyl-thieno[3,2- bjthiophene-2-yl.
RZ is also preferably:
H; toluyl, aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl.
Compounds of Formula I where R” and R” are both H are preferred.
More preferred are compounds of Formula I wherein: ) 30
Rl is rool rR AN
R’ :
RZ is selected from the group consisting of: Ar-Cg-galkyl, R9C(0)-, R9SO»,
R® ' rR’ N hd z ~
RIR!INC(0)-, and R’ ;
R3 is selected from the group consisting of: H, Cj_galkyl, C3_gcycloalkyl- Cop-6alkyl and Ar-Cq_galkyl;
R% is selected from the group consisting of: R30C(0)-, R3C(0)- and R3S0,-;
R3is selected from the group consisting of: C1_galkyl, Ar-C(_galkyl and Het-
Co-galkyl;
RO is H;
R7 is R100C(0);
R8is C1-6alkyl;
R? is selected from the group consisting of: Cq_galkyl, Ar-Cq_galkyl and Het-
Co-galkyl;
R10 is selected from the group consisting of: Cy_galkyl, Ar-Cg_galkyl and Het- Cq.galkyl;
R’is H;
Ris H;
Ris H; and
Z is selected from the group consisting of: C(O) and CH».
Even more preferred are such compounds of Formula I wherein R2 is selected from the group consisting of: Ar-Cq-galkyl, R9C(0)-, RISO,.
Yet more preferred are compounds of Formula I wherein:
R1is . - 0
Rt AN
R’ :
R2 is selected from the group consisting of: Ar-Cp-galkyl, R9C(O)- and RISO;

Claims (1)

  1. We claim:
    1. A compound of Formula IA: 1 u
    R~. AR N Cy ”m N R \, R IA wherein: R! is selected from the group consisting of’ 0 Tv 0 Tv 0 R’ N N
    N 4.” 4.” Rt “ON R VEN R oo 3 RY ; R , and Va ; R2 is selected from the group consisting of: Cqy_galkyl, Ar-Cq_galkyl, Het- Co-galkyl, R9C(0)-, R9SO,-, ROR INC(0)-, and R9SO,RINC(0)-; R3 is C1_galkyl; R% is RIC(0)-, RS is Het-Cq_galkyl; RY is selected from the group consisting of: Cy_galkyl, C3_gcycloalkyl-Cq_galkyl, Ar-Cq_galkyl and Het-C_galkyl; R11 is selected from the group consisting of: H, Ci.galkyl, Ar-Cg.ealkyl, and Het- Cp-6alkyl; R’is H; R"is H; Ris H; . 25 R™ is selected from the group consisting of: C{-galkyl. C3_gcycloalkyl-Cp_galkyl C2-6alkenyl, C2-galkynyl, HetC(_galky! and ArCq_galkyl;
    n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof. . R' o rt AN
    ’ 2. A compound according to Claim 1 wherein Ris R’ .
    3. A compound according to Claim 1 wherein R3 is selected from the group consisting of: isobutyl and but-2-yl.
    4. A compound according to Claim 3 wherein R3 is isobutyl.
    5. A compound according to Claim 1 wherein RJ is selected from the group consisting of: piperidinyl-ethyl; benzo[1,3}dioxolyl; furanyl, aryl substituted furanyl, Ci_galkyl substituted furanyl; benzofuranyl, C{_galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C1_galkyl substituted benzofuranyl; napththo[2,1-b]-furanyl, C;_galkyl substituted napththo{2,1-b]-furanyl; benzo[b]thiophenyl; quinolinyl; quinoxalinyl; 1-oxy-pyridinyl; furo{3,2-b]-pyridinyl, C1_galkyl substituted furo[3,2-b]-pyridinyl; thiophenyl, Cy_galkyl substituted thiophenyl; thieno[3,2-b]thiophenyl; and 1H-benzoimidazol-5-yl.
    : 6. A compound according to Claim 1 wherein RS is selected from the group consisting of: : 30 piperidin-1-yl-ethyl, benzo[1,3]dioxol-5-yl,
    furan-2-yl; benzofuran-2-yl; napththo(2,1-b]-furan-2-yl1 benzo[b]thiophen-2-yl; quinolin-2-yl; : quinoxalin-2-yl; 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-y}; furo(3,2-b]-pyridin-2-yl; thiophene-2-yl; thieno[3,2-b]thiophene-2-yl; and 1H-benzoimidazol-5-yl.
    7. A compound according to Claim 1 wherein RY is selected from the group consisting of 5-(3-trifluoromethyl-phenyl)-furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, 2,4-dimethyl-furan-2-yl; S-methoxy-benzofura-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-y}, 3,5-dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6- methoxy-3-methyl-benzofuran-2-yl; 1-methyl-naphtho[2,1-b]-furan-2-yl; 5-methyl-thiophen-2-yl, and 3-methyl-furo[3,2b]pyridin-2-yl.
    8. A compound according to Claim 1 wherein RS is selected from the group consisting of: 3-methyl-benzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, 5- methoxybenzofuran-2-yl, quinoxalin-2-yl, and quinolin-2-yl. T Oo N Ra” ~
    ; 9. A compound according to Claim 1 wherein Rls R3 .
    10. A compound according to Claim 9 wherein R”” is C1-galkyl.
    11. A compound according to Claim 10 wherein C1-galkyl is methyl. To N R* 7 12, A compound according to Claim 1 wherein R! is In .
    13. A compound according to Claim 12 wherein n is 3.
    14. A compound according to Claim 1 wherein RY is selected from the group consisting of: ethyl, and C3_gcycloalkyl-substituted ethyl; propyl; butyl; isopentyl; phenyl, especially halogen substituted phenyl, Cy_galkyl substituted phenyl, C1 -galkylsulfonyl substituted phenyl; pyridinyl, Cq_galkyl substituted pyridinyl; 1-oxy-pyridinyl; and isoxazolyl, Cy_galkyl substituted isoxazolyl.
    15. A compound according to Claim 1 wherein RY is selected from the group consisting of: cyclohexyl-ethyl; prop-1-yl but-1-yl; 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; pyridin-2-yl, 1-oxy-pyridin-2-yl; 1,2-dimethyl- 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl.
    16. A compound according to Claim 1 wherein R2 is selected from the group consisting of: Cq1_galkyl, Ar-Cg.galkyl and Het-Cq_galkyl.
    17. A compound according to Claim 16 wherein R? is selected from the group consisting of: C1_galkyl and Het-Cy_galkyl.
    18. A compound according to Claim 17 wherein Cy_galkyl and Het-Cqy_galkyl are : selected from the group consisting of: Het-substituted methyl and pentyl.
    19. A compound according to Claim 18 wherein Het-substituted methyl is selected from the group consisting of: quinolin-2-ylmethy]; 6-methyl-pyridin-2-ylmethyl; 2-morpholin-4-yl-thiazol-4-ylmethyl; 5-ethyl-furan-2-ylmethyl; 3,4dimethyl-thieno[3,2-blthiophene-2-ylmethyl; 3-phenyl-3H-[1,2,3]triazol-4-ylmethyl; isothiazol-3-ylmethyl; thiophen-2-ylmethyl; benzo[b]lthiophen-2-ylmethyl; and 1-methyl-1H-imidazol-2-ylmethyl.
    20. A compound according to Claim 1 wherein R2 is selected from the group consisting of: Ar-Cg_galkyl, R9C(0)-, R9SO», and RIR1INC(0)-.
    21. A compound according to Claim 20 wherein R2 is selected from the group consisting of: Ar-Cg-galkyl, R2C(0)-, and R950,.
    22. A compound according to Claim 21 wherein R2 is R9S05_
    23. A compound according to Claim 22 wherein RY is selected from the group consisting of: Cy_galkyl, Ar-Cq_galkyl and Het-Cq_galkyl. . 24. A compound according to Claim 1 wherein:
    - 0 Rt AN Rlis R® ; R2 is R9S0,; and R3is isobutyl, R? is selected from the group consisting of: C1_galkyl, Ar-Cq_galkyl and Het- Cp-galkyl.
    25. A compound according to Claim 24 wherein: RJ is selected from the group consisting of: piperidinyl-ethyl; : benzo(1,3]dioxolyl; furanyl, aryl substituted furanyl, C;_galkyl substituted furanyl; benzofuranyl, Cj_galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, Cq_galkyl substituted benzofuranyl; napththo[2,1-b]-furanyl, C1_galkyl substituted napththo[2,1-b]-furanyl; benzo[b]thiophenyl; quinolinyl; quinoxalinyl; 1-oxy-pyridinyl; furo[3,2-b]-pyridinyl, Cy_galkyl substituted furo[3,2-b}-pyridinyl; thiophenyl, Cy_galkyl substituted thiophenyl; thieno[3,2-b]thiophenyl; and 1H-benzoimidazol-5-yl; and RP is selected from the group consisting of: ethyl, C3_gcycloalkyl-substituted ethyl; propyl; butyl; isopentyl; halogen substituted phenyl, C1_galkyl substituted phenyl, C_galkylsulfonyl substituted phenyl; pyridinyl, Cq_galkyl substituted pyridinyl;
    1-oxy-pyridinyl; and isoxazolyl, C1.galkyl substituted isoxazolyl.
    26. A compound according to Claim 24 wherein: RJ is selected from the group consisting of: . piperidin-1-yl-ethyl; benzo[1,3]dioxol-5-yl; furan-2-yl; benzofuran-2-yl; napththo[2,1-bl-furan-2-yl benzo[b]thiophen-2-yl; quinolin-2-yl; quinoxalin-2-yl; 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; furo[3,2-b]-pyridin-2-yl; thiophene-2-yl; thieno[3,2-b]thiophene-2-yl; and 1H-benzoimidazol-5-yl.
    27. A compound according to Claim 24 wherein RY is selected from the group consisting of: 5-(3-triflouromethyl-phenyl)-furan-2-yl, 3-methyl-furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, 2,4-dimethyl-furan-2-yl; 5-methoxy-benzofuran-2-yl, 5-fluoro-benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, 3-ethyl-benzofuran-2-yl; 5-fluoro-3-methyl-benzofuran-2-yl, 5-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6- methoxy-3-methyl-benzofuran-2-y}; 1-methyl-naphtho[2,1-b]-furan-2-yl; 5-methyl-thiophen-2-yl, and 3-methyl-furo[3,2b]pyridin-2-yl. . 28. A compound according to Claim 24 wherein RY is selected from the group consisting of:
    cyclohexyl-ethyl; prop-1-yl but-1-yl; } 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, A-methanesulfony] phenyl, 2-methanesulfonyl phenyl; pyridin-2-yl, 1-oxy-pyridin-2-yl; 1,2-dimethyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, and 3,5-dimethyl-isoxazol-4-yl.
    29. A compound according to Claim 24 wherein: RY is selected from the group consisting of: 3-methyl-benzofuran-2-yl, : thieno[3,2-b]thiophen-2-yl, 5-methoxybenzofuran-2-yl, quinoxalin-2-yl, or quinolin-2-yl; and RY is selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.
    30. A compound according to Claim 29 wherein RS is 3-methyl-benzofuran-2-yl.
    31. A compound according to Claim 30 wherein RY is 1-oxy-pyridin-2-yl.
    32. A compound according to Claim 1 selected from the group consisting of: Benzofuran-2-carboxylic acid {(8)-1-[-(3-fluoro-benzensuifonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide; (S)-4-methyl-2-(3-piperidin- 1-yl-propanoylamino)-pentanoic acid [3-oxo- 1-(pyridine-2-sulfonyl)-azepan-4-yl}-amide; Benzofuran-2-carboxylic acid {(S)-1-[-(4-ethyl-benzensuifonyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ((S)-3-methyl-1-{3- 0x0-1-[1-(1-oxy-pyridin-2-yl)-methanoyl}-azepan-4-ylcarbamoyl }-butyl)- amide; Benzo[1,3]-dioxole-5-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[1-oxy- pyridin-2-yl)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)-amide;
    5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-1-[1-(3- cyclohexyl-propanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }- amide; Benzo[1,3]-dioxole-5-carboxylic acid {(S)-1-[1-(3-cyclohexyl-propanoyi)- 3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;
    . 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-1-[1-(4-methyl- pentanoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Benzo[1,3]-dioxole-5-carboxylic acid {(S)-1-[1-(4-methyl-pentanoyl)-3- oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }-amide; Benzofuran-2-carboxylic acid {(S)1-[3-oxo-1-(propane-1-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-1-butyl }- amide; Benzofuran-2-carboxylic acid [(S)-1-[3-oxo-1-(ethanesulfonyl-azepan-4- ylcarbamoyl)-3-methyl-1-butyl]- amide; 5-Fluoro-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-ox0-1-(1-0xy- 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; 3-Methyl-benzofuran-2-carboxylic acid {(R)-3-methyl-1-[3-ox0-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 3-Methyl-furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-1-[-3-oxo- 1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-1-[1-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-1-[1-(3-fluoro- benzenesuifonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-1-[1-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 3-methyl-furan-2-carboxylic acid {(S)-1-[1-(3-fluoro-benzenesulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; Quinoline-2-carboxylic acid {(S)-1-[1-(3-fluoro-benzenesulfonyi)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;
    Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-1-[1-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Quinoxaline-2-carboxylic acid {(S)-1-[1-(3-fluoro-benzenesulfonyl)-3-
    ] oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide: Thiophene-2-carboxylic acid {(S)-1-[1-(3-fluoro-benzenesulfonyl)-3-oxo-
    - azepan-4-ylcarbamoy}]-3-methyl-butyl }-amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-1-[1-(3-fluoro- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide;
    3-Methyl-benzofuran-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo-
    azepan-4-ylcarbamoyl)-3-methyl-butyl}-amide; Benzo[b]thiophene-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; 3-Methyl-furan-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo-azepan- 4-ylcarbamoyl)-3-methyl-butyl]-amide; Quinoline-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Thieno[3,2-b]thiophene-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide; Quinoxaline-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Thiophene-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; 5-Methyl-thiophene-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl}-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-
    - sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl}-amide;
    3-Methyl-furan-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide; 2,5-Dimethyl-furan-2-carboxylic acid {(S)-1-[3-o0x0~1-(propane-1- ] sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide; Quinoline-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-sulfonyl)-azepan-
    . 4-ylcarbamoyl]-3-methyl-1-butyl }-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1- sulfonyl)-azepan-4-ylcarbamoyl}-3-methyl-1-butyl }-amide; Quinoxaline-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-sulfonyl)- azepan-4-ylcarbamoyl]-3-methyl-1-butyl } -amide; Thiophene-2-carboxylic acid {(S)-1-[3-oxo-1-(propane-1-sulfonyl)- azepan-4-ylcarbamoyl}-3-methyl-1-butyl }-amide; 5-Methyl-thiophene-2-carboxylic acid {(S)-1-[3-ox0-1-(propane-1- sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-1-butyl }-amide; 5-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3- 0x0-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; i 3,5-Dimethyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(1- oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } -amide; 3-Ethyl-benzofuran-2-carboxylic acid {(S)-3-methy!-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-1-[3- oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 1-methyl-naphtho[2,1-b]-furan-2-carboxylic acid {(S)-3-methyl-1-[3-0xo0- 1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 6-Methoxy-3-methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3- oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 3-Methyl-benzofuran-2-carboxylic acid {1,3-dimethyl-1-[3-oxo0-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyi]-butyl }-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl- 1-[3-0x0-1-quinolin-2- ylmethyl-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid [(S)-3-methyl-1-[3-0xo0-1- quinolin-2-ylmethyl-azepan-4-ylcarbamoyl]-butyl } -amide;
    Benzo[b]thiophene-2-carboxylic acid [(S)-3-methyl-1-[3-0x0-1-quinolin-2- ylmethyl-azepan-4-ylcarbamoyl]-butyl }-amide; Benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[1-toluene-2- sulfonylamino)-methanoyl}-azepan-4-ylcarbamoyl}-butyl)-amide: 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-ox0-1-[1- ' toluene-2-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)- amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[1- toluene-2-sulfonylamino)-methanoyi]-azepan-4-ylcarbamoyl }-butyl)- amide; Benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo0-1-[2-chloro- benzenesulfonylamino)-methanoyl}-azepan-4-ylcarbamoyl }-butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[2- chloro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)- amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[2-chloro- benzenesulfonylamino)-methanoylj-azepan-4-ylcarbamoyl }-butyl)-amide; Benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[4-fluoro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[4- fluoro-benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)- amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-1-{3-oxo0-1-[4-fluoro- benzenesulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)-amide; Benzofuran-2-carboxylic acid ((S)-3-methyl-1-{3-o0xo0-1-[1-toluene-4- sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl}-butyl)-amide; 3-Methyl-benzofuran-2-carboxylic acid ((S)-3-methyi-1-{3-oxo-1-[1- toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)- amide; Benzo[b]thiophene-2-carboxylic acid ((S)-3-methyl-1-{3-oxo-1-[1- toluene-4-sulfonylamino)-methanoyl]-azepan-4-ylcarbamoyl }-butyl)-
    . amide; 313 i
    Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(6-methyl-pyridin-2- ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(6-methyl- pyridin-2-ylmethyl)-3-oxo0-azepan-4-ylcarbamoyl]-butyl }-amide: Benzof[b]thiophene-2-carboxylic acid {(S)-3-methyl-1-[1-(6-methyl-
    . pyridin-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl }-amide; Benzo[b]thiophene-2-carboxylic acid {(S)-1-[1-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } -amide; 3-Methyl-benzofuran-2-carboxylic acid {(S)-1-[1-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 2,4-Dimethylfuran-3-carboxylic acid {(S)-1-[1-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Quinoxaline-2-carboxylic acid {(S)-1-[1-(2-fluoro-phenylcarbamoyl)-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; Thieno[3,2-b]thiophene-2-carboxylic acid {(S)-1-[1-(2-flnoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }-amide; Quinoline-2-carboxylic acid {(S)-1-[1-(2-fluoro-phenylcarbamoyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; 4-Methyl-thiophene-2-carboxylic acid {(S)-1-[1-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 5-Methoxy-benzofuran-2-carboxylic acid {(S)-1-[1-(2-fluoro- phenylcarbamoyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide; 4-Methyl-furan-2-carboxylic acid {(S)-1-[1-(2-fluoro-phenylcarbamoyl)-3- oxo-azepan-4-ylcarbamoyl}-3-methyl-butyl }-amide; Benzofuran-2-carboxylic acid [(S)-1-(1-butyl-3-oxo0-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid [(S)-1-(1-propyl-3-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid {(S)-1-[1-(2-fluoro-benzyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-butyl }-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(2-morpholin-4-yl- thiazol-4-ylmethyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl }-amide;
    Benzofuran-2-carboxylic acid {(S)-1-[1-(5-ethyl-furan-2-ylmethyl)-3-oxo- azepan-4-ylcarbamoyl]-3-methyl-butyl }-amide;
    Benzofuran-2-carboxylic acid {(S)-1-[1-(3,4-dimethyl-thieno[3,2- blthiophene-2-ylmethyl)-3-oxo-azepan-4-ylcarbamoyll-3-methyl-butyl }- amide;
    : Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(3-phenyl-3H- [1,2,3]triazol-4-ylmethyl)-azepan-4-ylcarbamoyl]-butyl }-amide; Benzofuran-2-carboxylic acid [(S)-1-[1-(isothiazol-3-ylmethyl-3-oxo- azepan-4-ylcarbamoyl)-3-methyl-butyl }-amide;
    Benzofuran-2-carboxylic acid [(S)-3-methyl-1-(3-0x0-1-thiophen-2- ylmethyl-azepan-4-ylcarbamoyl)-butyl]-amide; Benzofuran-2-carboxylic acid [(S)-1-(1-benzo[b]thiophen-2-ylmethyl-3- oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl]-amide; Benzofuran-2-carboxylic acid [(S)-3-methyl-1-(3-ox0-1-pentyl-azepan-4- ylcarbamoyl)-butyl}-amide; Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[1-(1-methyl-1H-imidazol- 2-ylmethyl)-3-oxo0-azepan-4-ylcarbamoyl}-buty }-amide; 1-Oxy-pyridine-2-carboxylic acid {(S)-3-methyl-1-[3-0xo0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl ]-butyl}-amide; 2-Oxy-pyridine-3-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl ]-butyl }-amide; 1H-Benzoimidazole-5-carboxylic acid {(S)-3-methyl-1-{3-0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide; 4-{(8)-2-[( 1-Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino }-1-methyl-3-oxo-1-pentyl-azepanium; Benzofuran-2- carboxylic acid {(S)-1-[1-(1,2-dimethyl-1 H -imidazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl } -amide; Benzofuran-2- carboxylic acid {(S)-1-[1-(1-methyl-1 H -imidazole-4- sulfonyl)-3-oxo0-azepan-4-ylcarbamoyl]-3-methyl-butyl } -amide; Benzofuran-2-carboxylic acid {(S)-1-[1-(4-methanesulfonyl- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; . Benzofuran-2-carboxylic acid {(S)-1-[1-(2-methanesulfonyl- benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide;
    Benzofuran-2-carboxylic acid {(S)-1-[1-(3,5-dimethyl-isoxazole-4- sulfonyl)-3-oxo-azepan-4-ylcarbamoy 1]-3-methyl-butyl }-amide; 3-Methyl-benzofuran-2-carboxylic acid {(1S,2R)-2-methyl-1-[3-0xo-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyi]}-butyl }-amide; : 3-Methyl-benzofuran-2-carboxylic acid {1-[3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclopentyl }-amide; and Furo[3,2-b]-pyridine-2-carboxylic acid {(S)-3-methyl-1-[-3-0x0-1-(1-0xy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide.
    33. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 32 and a pharmaceutically acceptable carrier, diluent or excipient. 316 AMENDED SHEET .
    Benzofuran-2-carboxylic acid { (S)-1-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-3- oxo-azepan-4-ylcarbamoy 1]-3-methyl-butyl}-amide; 3-Methyl-benzofuran-2- carboxylic acid { (18,2R)-2-methyl-1-[3-0x0-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl}-butyl} -amide; 3-Methyl-benzofuran-2-carboxylic acid { 1-[3- oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclopentyl} -amide; and Furo(3,2-b]-pyridine-2-carboxylic acid {(S)-3 -methyl-1-[-3-oxo0-1-(1-oxy- pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl} -amide.
    33. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 32 and a pharmaceutically acceptable carrier, diluent or excipient.
    34. A compound of Formula ITA: RA FR" Pes p= wherein: R'is selected from the group consisting of: rR rR i rR R rR ~~ R ; A , and )a ; R? is selected from the group consisting of: Cy_galkyl, Ar-Cop.salkyl, Het-Cy 6 alkyl, R°C(0)-,R’S0,-, R°R''NC(0)-,and R’SO,R"'NC(0)-; 317 AMENDED SHEET
    ( ( R3 is C1.galkyl; Ris R3C(O)-, RS is Het-Cp_galkyl; RY is selected from the group consisting of: Cy_galkyl, C3_gcycloalkyl-Cq_galkyl, Ar-Cq.galkyl and Het-Cq_galkyl; R11 is selected from the group consisting of: H, Cy_galkyl, Ar-Cp.galkyl, and Het- Co-salkyl; R'is H; R”is H; Ris H; R™ is selected from the group consisting of: C1_galkyl, C3_gcycloalkyl-Cq_galkyl C2-6alkenyl, Co_galkynyl, HetCp_galkyl and ArCy_galkyl; and n is an integer from 1'to 5; and salts, hydrates and solvates thereof,
    35. A process for the synthesis of a compound according to Claim 1 comprising the step of oxidizing a corresponding compound of Claim 47 with an oxidant to provide the compound of Formula (IA) as a mixture of diastereomers.
    36. The process of Claim 48 wherein the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine. :
    37. The process of Claim 48 further comprising the step of separating the diasteromers by separating means.
    38. The process of Claim 50 wherein said separating means is high presssure liquid chromatography (HPLC).
    39. The process of Claim 48 further comprising the step of deuterating said diastereomers with a deuterating agent. 318 AMENDED SHEET ,
    FA
    \. : ' < -
    40. The process of Claim 52 wherein said deuterating agent is CD30D: Dy0 (10:1) in triethylamine. : 41. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in inhibiting a protease selected from the group consisting of a cysteine protease and a serine protease.
    42. Ause according to Claim 54 wherein said protease is a cysteine protease. : 10 43. A use according to Claim 55 wherein said cysteine protease is cathepsin K.
    44. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a disease characterized by bone loss.
    45. Anuse according to Claim 57 wherein said disease is osteoporosis.
    46. A use according to Claim 57 wherein said disease is periodontitis.
    47. A use according to Claim 57 wherein said disease is gingivitis.
    48. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a disease characterized by excessive cartilage or matrix degradation. .
    49. A use according to Claim 61 wherein said disease is osteoarthritis.
    50. A use according to Claim 61 wherein said disease is rheumatoid arthritis.
    51. Use of a compound according to any one of Claims 1 to 32 in the manufacture of a medicament for use in treating a parasitic disease. 319 AMENDED SHEET :
    ( (
    52. Ause according to Claim 64 wherein said disease is selected from the group consisting of: schistosomiasis, malaria, and infections by poeumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fosiculata.
    53. A use according to Claim 64 wherein said disease is selected from the group consisting of: schistosomiasis, malaria, and infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata.
    54. A compound according to claim 1 or claim 34, substantially as herein described and exemplified.
    55. A pharmaceutical compound according to claim 33, substantially as herein described and exemplified.
    56. Use according to any one of claims 41, 44, 48 or 51, substantially as herein described and exemplified.
    57. A process according to claim 35, substantially as herein described and exemplified. : 320 AMENDED SHEET
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