ZA200303848B - Protease inhibitors. - Google Patents

Protease inhibitors. Download PDF

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ZA200303848B
ZA200303848B ZA200303848A ZA200303848A ZA200303848B ZA 200303848 B ZA200303848 B ZA 200303848B ZA 200303848 A ZA200303848 A ZA 200303848A ZA 200303848 A ZA200303848 A ZA 200303848A ZA 200303848 B ZA200303848 B ZA 200303848B
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galkyl
substituted
group
methyl
phenyl
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ZA200303848A
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Yamashita Dennis Shinji
Daniel F Veber
Robert W Marquis Jr
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Smithkline Beecham Corp
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    • 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
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond

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Description

PROTEASE INHIBITORS
This application claims the benefit of U.S. Provisional Application No. 60/252.508, filed November 22, 2000. . FIELD OF THE INVENTION
This invention relates in general to C3-Cg [-amino- 1-acyl cycloalkane-substituted : 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 Q 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 ) 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 A1, and references cited therein. Two bacterial cysteine proteases from P. gingivalis, 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 Kis 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 sialoprotemn. 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, er 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, er al.,
Biochem. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum . calcium in rats on calcium deficient diets. Lerner, 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, er al, J. Cell. Biochem., 1994, 56, 118. and Everts, er al., J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity . and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, er al.,
Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shu, er al., FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.
The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss. including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
Thus, selective inhibition of cathepsin K may also be useful for treating diseases of 1S 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 A1 describe . alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- 1Bconvertase. Alkoxymethyl and mercaptomethy! ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No.
PCT/GB91/01479).
Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al.,
Biochem. J., 1968. 107. 103. Garker er al., Biochem. J., 1974, 139. 555, Gray et al., ] Tetrahedron, 1977, 33, 837. Gupton er al., J. Biol. Chem., 1984. 259. 4279, Powers ef 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 mhibitors.
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.
EP 1 008 592 A2 describes cyclic amide derivatives which inhibit cathepsin K.
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 C3-Cg 1-amino-1-acyl cycloalkane- substituted 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 C3-Cg 1-amino-1-acyl cycloalkane- substituted 4-amino-azepan-3-one carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. } Accordingly. in the first aspect, this invention provides a compound according to
Formula I.
In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
In yet another aspect, this invention provides intermediates useful in the preparation of the compounds of Formula I.
In still another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula I:
RL RY
N
©
RN
R
I
: wherein:
O
RY os
Ris EN
RZ is selected from the group consisting of: H, C1_galkyl. C3_gcycloalkyl-C. 6alkyl, Ar-Cq_galkyl, Het-Cq._galkyl, ROC(0)-, RIC(S)-, R9SO»-, R2OC(0)-, _ . cE) Ny, i. ~~. CH, i od LL }
RIRIINC(0)- RORIING(S)-, RORIINSO,-, > , :
RE
NZ
R- r N
RY , and R9SO-RHINC(O)-;
R% is selected from the group consisting of: H, Cy _galkyl, C3_gcycloalkyl-Cq_ galkyl, Ar-Cq_galkyl, Het-C_galkyl, R3C(0)-, R3C(S)-, RISO-, ROOC(0)-,
RIRIZNC(0)-, and RORI2NC(S)-;
RS is selected from the group consisting of: H, Cy_galkyl, C2-6alkenyl, Co. ealkynyl, C3_gcycloalkyl-Cq_galkyl, C2_ealkanonyl, Ar-Cq_galkyl and Het-Cq_galkyl:
RO is selected from the group consisting of: H, C;_galkyl, Ar-Co_galkyl, and Het-
Cp-galkyl;
R7 is selected from the group consisting of: H, Cj.galkyl, C3_geycloalkyl-Co. galkyl, Ar-Cq_galkyl, Het-C_galkyl, R10C(0)-, R10C(S)-, R1050,-, R100C(0)-,
RIOR I3NC(0)-, and RIORI3NC(S)-;
R8 is selected from the group consisting of: H, C1-galkyl, Ca_galkenyl,
Co_galkynyl, HetC()_galkyl and ArCq_galkyl,
R? is selected from the group consisting of: C1_galkyl, C3_gcycloalkyl-Cq_galkyl,
Ar-Cq_galkyl, -Ar-COOH, and Het-C_galkyl;
R10 is selected from the group consisting of: C1.ealkyl, C3_geycloalkyl-Cq_galkyl,
Ar-Cq_galkyl and Het-Cq_galkyl, ’ R11 is selected from the group consisting of: H, Cj_galkyl, Ar-Co-galkyl, and Het- Cp_galkyl
R12 is selected from the eroup consisting of: H, Cj.galkyl, Ar-Cop-galkyl, and Het-
Cp-galkyl;
R13 is selected from the group consisting of: H, Cy_galkyl, Ar-Cg.galkyl, and Het-
Co-galkyl;
R'is selected from the group consisting of: H, Cy_galkyl, Ar-Cp.galkyl, and Het-
Co-galkyl;
R™is selected from the group consisting of: H, C1-galkyl, Ar-Co-galkyl, and Het-
Co_galkyl;
R™ is selected from the group consisting of: H, C1.galkyl. C3.6cycloalkyl-Cy. palkyl, Ar-Cp_galkyl, and Het-Cq_galkyl;
Z 1s selected from the group consisting of: C(O) and CH»; 1 1s an integer from 1 to 5: and pharmaceutically acceptable salts, hydrates and solvates thereof.
In compounds of Formula I, n is preferably 4. to provide l-amino-1-acyl cyclohexane compounds. The cycloalkyl ring may be unsubstituted or substituted with one or more of Ci_galkyl, C3.6cycloalkyl-Cg_galkyl, Ca-ealkenyl, Co_galkynyl, HetCq_galkyl,
ArCo_galkyl, or halogen.
The cycloalkyl ring is more preferably unsubstituted.
R% is selected from the group consisting of: H, Cy_galkyl, Cy_geycloalkyl-
Co.alkyl, Ar-Co_galkyl, Het-Cq_galkyl, RSC(O)-, RSC(S).. R3S0,-, R50C(0).,
RIRI3NC(0)-, and RIRI3NC(S)..
R# is preferably selected from the group consisting of: R30C(0)-, RIC( 0)- and
R3SO»-.
R% is most preferably RIC(O)-.
In some embodiments, R4 is preferably methanesulfonyl.
RY is selected from the group consisting of: H, Cj_galkyl, Co_galkenyl, Co. alkynyl, C3_gcycloalkyl-Cq_galkyl, Co. galkanonyl, Ar-Cqp_galkyl or Het-Cq_galkyl.
Preferably RY is selected from the group consisting of: Cj_galkyl, C»_galkenyl, Co. ealkynyl, C3_gcycloalkyl-Cq_galkyl, C2-6alkanonyl, Ar-Cq_galkyl and Het-Cq_galkyl.
More preferably, and especially when R% is ROC(0)-, RY is selected from the group . consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially :
C1-galkoxy and aryloxy 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; 1sopentyl; cyclohexyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyli-but-3-envl; acetyl; pentanonyl, especially 4-pentanonyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3.4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more aryloxy or Cj_galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more C1-6alkyl sulfonyl groups, more especially 4-methanesulfonyl-phenyl; benzyl; naphthalenyl, especially naphthylen-2-yl; benzo[1,3]dioxolyl, especially benzo[1.3]dioxol-5-yl; furanyl, especially furan-2-yl, especially nitro substituted furanyl, more especially
S-nitro-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, 5-(4-nitrophenyl)-furan-2-yl, 5-(3-trifluoromethyl-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-yI; tetrahydrofuranyl, especially tetrahydrofuran-2-yl; benzofuranyl, especially benzofuran-2-yl, especially Cy_galkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-+ |, 5,6-dimethoxy-benzofuran-2-yI, 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-1-yl- ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-y], 5-methoxy-3-methyl- ) benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl- benzofuran-2-yl; especially halogen substituted benzofuranyl, more especially 5-fluoro- benzofuran-2-yl, 5.6-difluoro-benzofuran-2-yl, 5-fluoro-3-methyl-benzofuran-2-yi, 6-
fluoro-3-methyl-benzofuran-2-yl; especially Cy_galkyl substituted benzofuranyl, most especially 3-methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl- benzofuran-2-yl; naphtho[2.1-b}-furany]. especially naphtho[2,1-b]-furan-2-yl, alkyl substituted 3 naphtho[2.1-b]-furanyl, especially I-methyl-naphtho([2,1-b]-furan-2-yI; 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 quinofin-8-yl; quinoxalinyl, especially quinoxalin-2-yl; 1,8 naphthyridinyl. especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, indol-6-yl, indol-5-yl, especially C.galkyl substituted indolyl, more especially N-methyl-indol-2-y1; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially Ci.ealkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially
I-oxy-pyridin-2-yland l-oxy-pyridin-3-yl; furo[3,2-b}-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C1.galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yI; thiopheneyl, especially thiophene-3-yl, also thiophene-2-yl, especially C_galkyl substituted thiopheneyl, more especially S-methyl-thiophene-2-yland 5-methyl-thiophene- 3-yl, especially halogen substituted thiopheneyl, more especially 4,5-dibromo-thiophene-2- yk; thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, more especially
C1.galkyl substituted thieno(3,2-b]thiophene-2-yl, more especially 5-zerr-butyl-3-methyl- thieno[3,2-b]thiophene-2-yI; isoxazolyl, especially isoxazol-4-yl, especially Cy _galkyl substituted isoxazolyl, more especially 3,5-dimethyl- 150Xazol-4-yl; oxazolyl, especially oxazol-4-yl, especially aryl substituted oxazolyl, more especially 5-methyl-2-phenyl oxazol-4-yl, especially Cy_galkyl substituted oxazolyl, more especially 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and 1H-benzoimidazolyl, especially 1H-benzoimidazol-5-yl.
When R? is RISO», RY is preferably pyridin-2-yl or 1-oxo-pyridin-2-yl.
R’is selected from the group consisting of: H, Cj_galkyl, Ar-Co.galkyl, and Het-
Co-palkyl.
Preferably R’is selected from the group consisting of: H and naphthalen-2-yl- 3 methyl.
Most preferably R’is H.
R™ is selected from the group consisting of: H, Cy_galkyl, Ar-C(_galkyl, and Het-
Co-galkyl.
Most preferably R” is H.
R™ is selected from the group consisting of: H, Cq_galkyl. Ca_geycloalkyl-
Co-6alkyl, and Het-C_galkyl.
R™ is preferably selected from the group consisting of: H and C|_galkyl.
R™ is more preferably selected from the group consisting of: H and methyl.
Most preferably R™ is methyl.
In compounds of Formula I, R2 is selected from the group consisting of: 20H, Cygalkyl, C3_geycloalkyl-Cq_galkyl, Ar-Cg_galkyl, Het-Cy_galkyl, R9C(0)-, ROC(S)-, $3 ™ AN C(O)
R9S0,-, R%OC(0)-, ROR1INC(0)-, ROR INC(S)., RORIINSO,-, Lo
R° ory Hn , : R" , and RISO,R1INC(O)-.
More preferably R2 is selected from the group consisting of: Ar-Cq.galkyl,
Re a N ~~ VAY
R9C(0), R9S0,, R9RINC(O)-. and a
Even more preferably, R= is selected from the group consisting of: Ar-Cg-galkyl,
RIC(0)-. and R9S0-. ] Most preferably R™ is RISO. . In such embodiments:
RO is selected from the group consisting of: H. Cj _galkyl. Ar-Cq-galkyl. or Het-
Cp-galkyl, preferably H.
R7 is selected from the group consisting of: H, C1.salkyl, C3_geycloatkyl-Cq. alkyl, Ar-Cq_galkyl, Het-Cq_galkyl. R10C(0)-, R10C(S)-, R1080,-, R100C(0)-,
RIORI4NC(0)-, and RIORI4NC(S)-. R7 is preferably R100C(0).
RS is selected from the group consisting of: H, C1._galkyl, Co_galkenyl,
C2-galkynyl. HetCq_galkyl and ArC_galkyl; preferably Cy_galkyl, more preferably isobutyl.
RY is selected from the group consisting of: Cy_galkyl, C3_gcycloalkyl-Cq_galkyl,
Ar-Cq_galkyl, -Ar-COOH, and Het-C_galkyl.
RY is preferably selected from the group consisting of: Cy_galkyl, Ar-Cq_galkyl, -
Ar-COOH, and Het-Cq_galkyl.
More preferably, RY is selected from the group consisting of: methyl; ethyl, especially C3_gcycloalkyl-Cq_galkyl-substituted ethyl, more especially 2- cyclohexyl-ethyl; propyl; butyl, especially Cy_galkylbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R2 is R90C(0); 1sopentyl; 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_galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl. more especially 2-cyanophenyl; especially Cy_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-yl)toluyl: naphthylene, especially naphthyl-2-ene; benzoic acid, especially 2-benzoic acid; i benzo[1,3]dioxolyl. especially benzo[1,3]dioxol-5-y1; benzo[1,2,5]oxadiazolyl, especially benzo[1,2,5]oxadiazol-4-yl; pyridinyl. especially pyridin-2-yl. pyridin-3-vl. especially l-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl; especially Cq_galkylpyridinyl, more ’ especially 3-methyl-pyridin-2-y1, 6-methyl-pyridin-2-yI; thiopheneyl, especially thiophene-2-yl: thiazolyl, especially thiazol-2-yl;
IH-imidazolyl, especially 1H-imidazol-2-y1, 1H-imidazol-4-yl, more especially
Cy_galkyl substituted imidazolyl, even more especially 1-methyl-1H-imidazol-2-yl, 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 Cy_galkyl substituted 1H-[1,2.4]triazolyl, more especially 5-methyl-1H- [1,2,4]triazol-3-yl; and 1soxazolyl, especially isoxazol-4-yl, especially Ci-ealkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl.
When R? is RISO», 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-C(_galkyl, more preferably
Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl. R11 is selected from the group consisting of: H, C;_galkyl,
Ar-Co-galkyl, and Het-Cq.galkyl. When R2 is RISO,R1 INC(O)-, R11 is preferably H.
When R2 is R9C(0)-, R? is preferably selected from the group consisting of Cy. alkyl, C3_geycloalkyl-Cq_galkyl. and Het-C()_galkyl, more preferably 1-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl.
When R= is Ar-Co_galkyl, R2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl. even more especially 2-fluorobenzyl. . When RZ is C-galkyl, RZ is preferably selected from i-propyl, 1-butyl, and 1- pentyl.
When R2 is Het-C)_galkyl, Het-Cyy_galkyl is preferably Het-methyl, and Het in
Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially C1 _galkylpyridinyl, more especially 6- methyl-pyridin-2-y1; thiopheneyl. especially thiophene-2-yl, more especially thiophene-2-yl or benzo[b]thiophene-2-yl; thiazolyl, especially thiazol-4-yl such as 1-(2-morpholin-4-yl-thiazol-4-yl), and 1- (1sothiazol-3-yl); i5 1H-imidazolyl, especially 1H-imidazol-2-yl, 1H-imidazol-4-yl, especially Cj_ calkyl substituted imidazolyl, more especially 1-methyl-1H-imidazol-2y1; triazolyl, especially 3H-[1.2,3]triazolyl, more especially 3H-[1,2,3]triazol-4-yl, especially Cq_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-yl1; furanyl, especially furan-2-yl, especially substituted furanyl, such as S-ethyl-furan- 2-yl; and thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, especially C1. calkyl substituted thieno[3,2-b]thiopheneyl, 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” is H and R” is methyl are preferred.
More preferred are compounds of Formula I wherein:
R= is selected from the group consisting of: Ar-Co-galkyl, RYC(0)-, RYS0-,
R® rR’ ~~ W ~~ z ~~.
RIRIINC(0)-. and R’
R# is selected from the group consisting of: RS0C(0).-, R3C(0)- and RISO5-;
R3is selected from the group consisting of: Cj _galkyl, Co_galkenyl. CH_galkynyl.
C3-gcycloalkyl-Co_galkyl, Co_galkanonyl, Ar-Cp_galkyl and Het-Cqy_galkyl:
RO is H;
R7 is R100C(0):
R8 is C1_galkyl:
RY is selected from the group consisting of: Cy_galkyl, Ar-Cq_galkyl, -Ar-COOH, and Het-Cq_galkyl;
R10 is selected from the group consisting of: Cy _galkyl, Ar-Co_galkyl and Het-Cyy. palkyl;
R’is H;
R”is H;
Ris methyl; 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-Co_galkyl, ROC(0)-, RYS0,.
Yet more preferred are compounds of Formula I wherein:
R2 is selected from the group consisting of: Ar-Co_galkyl, RIC(O)- and R505;
R% is R3C(0)-;
R? is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially
C1-galkoxy and aryloxy 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; cvclohexyl: butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- h) methoxyphenyl)-but-3-enyl; acetyl; pentanony!, especially 4-pentanonyl; phenyl. especially phenyl substituted with one or more halogens. more especially 3,4~dichiorophenyl and 4-flnorophenyl, especially phenyl substituted with one or more aryloxy or C|_-galkoxy groups, more especially 3,4-dimethoxy-phenyl, 3-benzyloxy-4- methoxy-phenyl, especially phenyl substituted with one or more C1_ealkyl sulfonyl groups. mare especially 4-methanesulfonyl-pheny!: benzyl; naphthalenyl, especially naphthylen-2-yl; benzo[1,3]dioxolyl, especially benzo[1,3}dioxol-5-yl; furanyl, especially furan-2-yl, especially nitro substituted furanyl. more especially
S-nitro-furan-2-yl, more especially halogen substituted furanyl, even more especially 5- bromo-furan-2-y1, more especially aryl substituted furanyl, even more especially 5-(4- chloro-pheny!)-furan-2-yl, 5-(4-nitropheny!)-furan-2-yl, 5-(3-trifluoromethyl-phenyl)- furan-2-yl, more especially C1.palkyl 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, especially C1-galkoxy substituted benzofuranyl, more especially 7-methoxy-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 5,6-dimethoxy-benzofuran-2-yl, 5-(2-piperazin-4-carboxylic acid tert-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4-yl-ethoxy)-benzofuran-2-yl, 5-(2-piperazin-1-yl- ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl-ethoxy)-benzofuran-2-yl 5-methoxy-3-methyl- benzofuran-2-yl, 4-methoxy-3-methyl-benzofuran-2-yl, and 6-methoxy-3-methyl- benzofuran-2-yl; especially halogen substituted benzofuranyl, more especially 5-fluoro- benzofuran-2-yl, 5,6-difluoro-benzofuran-2-yl, S-fluoro-3-methyl-benzofuran-2-yl, 6- fluoro-3-methyl-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;
naphtho[2,1-b]-furanyl, especially naphtho[2.1-b]-furan-2-yl, alkyl substituted naphtho[2,1-b]-furanyl, especially I-methyl-naphtho[2,1-b]-furan-2-yl; benzo[b]thiophenyl, especially benzo[b]thiophen-2-yl; especially Ci.galkoxy substituted benzo[b]thiophenyl. more especially 5,6-dimethoxy- benzo[D]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-y], especially indol-6-yl, indol-5-yl, especially Ci. galkyl substituted indolyl, more especially N-methyl-indol-2-yl: pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially Cj _palkyl substituted pyridinyl, more especially 2-methyl-pyridin-3-y1, 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; thiopheneyl, especially thiophen-3-yl, also thiophen-2-yl, especially C|_galkyl substituted thiopheneyl, more especially S-methyl-thiophen-2-yland 5-methyl-thiophen-3- yl, especially halogen substituted thiopheneyl, more especially 4,5-dibromo-thiophen-2-yl; thieno[3,2-b]thiophene, especially thieno[3,2-b]thiophene-2-yl, more especially
Cqy_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.galkyl substituted isoxazolyl. more especially 3,5-dimethyl- isoxazol-4-yl; oxazolyl, especially oxazol-4-yl, especially aryl substituted oxazolyl, more especially 5-methyl-2-phenyl oxazol-4-yl, especially Cy _galkyl substituted oxazolyl, more especially 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and
IH-benzoimidazolyl, especially 1H-benzoimidazol-5-yl.
RY is selected from the group consisting of: methyl; : ethyl, especially C3_geycloalkyl-Cy_galkyl-substituted ethyl, more especially 2- cyclohexyl-ethyl; propyl;
butyl. specially C1_gbutyl. more especially 3-methylbutyl; rert-butyl, particularly when R2 is R2OC(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-ealkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl: especially C1.ealkyl substituted phenyl, more especially 4-ethyl- phenyl, 2-methyl phenyl, 4-methyl phenyl, especially C1_galkyl sulfonyl substituted phenyl, more especially 4-methanesulfonyl phenyl, and 2-methanesulfonyl phenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2-yi)toluyl; naphthylene, especially naphthyl-2-ene; benzoic acid. especially 2-benzoic acid: benzo[1,3]dioxolyl, especially benzol[1,3]dioxol-5-yl; benzo] 1,2,5]oxadiazolyl, especially benzo 1 ,2,5]oxadiazol-4-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, especially 1-oxy-pyridinyl, more especially 1-oxy-pyridin-2-yI, 1-oxy-pyridin-3-yl; especially C1_galkylpyridinyl, more especially 3-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl; thiopheneyl, especially thiophene-2-yl; thiazolyl, especially thiazol-2-yl; 1H-imidazolyl, especially 1H-imidazol-2-v], 1H-imidazol-4-yl, more especially
Cj.palkyl substituted imidazolyl, even more especially 1-methyl-1H-imidazol-2-y1, 1- methyl-1H-imidazol-4-yl, and 1,2-dimethyl- 1H-imidazol-4-yl; triazolyl, especially 1H-[1,2,4]triazolyl, more especially 1H-[1,2,4]triazol-3-yI, 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 C1-6alkyl substituted isoxazolyl, more especially 3,5-dimethyl- isoxazol-4-yl.
R’is H; : R”is H; and
R™ is methyl.
Most preferred are compounds of Formula I wherein:
RZ is RISO»:
R% is R3C(O);
R® is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran- } 2-y1, 5-methoxybenzofuran-2-yl, thieno[3,2-bjthiophen-2-vl, quinoxalin-2-yl, and quinolin- 2-yl, preferably selected from the group consisting of: benzofuran-2-yl and thieno[3,2- b]thiophen-2-yl, most preferably benzofuran-2-yl;
RY is selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl, preferably pyridin-2-yl.
R’is H; and
R” is methyl.
The following compounds of Formula I are particularly preferred embodiments of the present invention: benzofuran-2-carboxylic acid { 1-[(S)-3-0x0-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl }-amide; benzofuran-2-carboxylic acid { 1-[(R)-3-oxo0- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid {1-[(+/-)-3-0x0- 1-(pyridine-2-sulfony)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; benzofuran-2-carboxylic acid { 1-[(4S,7R)-7-methyl-3-oxo0- 1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoylj-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid { 1-[(4S,7R)-7-methyl-3-0x0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; 2,2 4-trideutero-benzofuran-2-carboxylic acid { 1-[(S)-3-0x0-1-(pyridine-2-sulfony!)- ’ azepan-4-ylcarbamoyl]-cyclohexyl}-amide
2,2 4-trideutero- benzofuran-2-carboxylic acid {1-[(4S.7R)-7-methyl-3-oxo-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl }-amide; 2.2.4-trideutero-thieno[3,2-b]thiophene-2-carboxylic acid {1-[(S)-3-oxo-1-(pyridine-2- } sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl}-amide; and 2,2 4-trideutero-thieno|3,2-b]thiophene-2-carboxylic acid { 1-[(4S,7R}-7-methyl-3-0x0-1- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl }-amide.
The following compound of Formula I is the most preferred embodiment of the present invention: benzofuran-2-carboxylic acid {1-[(4S,7R)-7-methyl-3-0x0-1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoylj-cyclohexyl }-amide;
Specific representative compounds of the present invention are set forth in Example 1-8.
Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds of the present invention are configurationally more stable at the carbon center alpha to the ketone.
The present invention includes deuterated analogs of the inventive compounds. A representative synthesis of deuterated analogs is shown in Scheme 8. The deuterated compounds of the present invention should exhibit superior chiral stability compared to the protonated isomer.
Where possible the present invention includes quaternary salts of the inventive compounds.
Definitions
The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, inciuding 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 : 5 (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 1 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.
A representation of an element is understood to include all isotopes of that element.
Thus, for example, the term "H" includes all isotopes of hydrogen, including deuterium. "C1-6alkyl" 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. C 1-6alkyl may be optionally substituted by a moiety selected from the group consisting of: OR 14, C(O)R14, SRI14,
SO)R14, NR14;, RI4NC(0)ORS, CO,R14, CO,NR 4, N(C=NH)NH», Het, C3_
geycloalkyl, and Ar; where RY is selected from the group consisting of: H, Cy_galkyl, Cn_ alkenyl, Co_galkynyl, Cz_geycloalkyl-Cq_galkyl, Ar-Cg_galkyl and Het-Cq_galkyl; and
R14 is selected from the group consisting of: H, Ci.ealkyl, Ar-Cq.galkyl, and Het-Cy). galkyl: "C3_geycloalkyl” as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane. "C2-6 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. Co_palkenyl includes ethylene, 1-propene, 2-propene, I-butene, 2-butene, 1sobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included. "C2-6alkynyl” means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. Co_g alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne. 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. "C2-galkanonyl” means an acyl group of 2 to 6 carbons wherein one non-terminal carbon is substituted by the =O group. C2_galkanonyl includes, for example, acetyl, 1- and 2-propanonyl, 1-, 2-, and 3-butanonyl, 1-, 2-, 3- and 4-pentanonyl and 1-, 2-, 3-, 4- and 5- hexanonyl. "Halogen" means F, Cl, Br, and I. "Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of
Ph-Cq.galkyl; Het-Cq_galkyl; C1 _galkoxy: Ph-Cg_galkoxy; Het-C()_galkoxy; OH, (CHn)1. 6NRISRI6; O(CHy);_¢NRISR16; C1_galkyl, ORY, NR 17), SR17, CF3,NO,, CN,
COnRI7, CONRI),, F, CI, Br or I; where R15 and R16 are 11, C1.galkyl, Ph-Cqy_galkyl, naphthyl-Cq_galkyl or Het-Cq_galkyl; and R17 is phenyl, naphthyl, or Ci _galkyl. 35 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 1S-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 §, 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 Co. gAr, Cp-galkyl, ORI. N(R17)2. SR17, CF3, NO, CN, CORT.
CONRITy F, Cl, Br and I where R17 is phenyl. naphthyl, or C1-ealkyl. 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, thiazolidiny!, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzofuranyl, thiopheny]l, benzo[bJthiophenyl, thieno[3,2- b]thiophenyl, benzo{1 »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. pyrnmidinyl, triazinyl and tetrazinyl which are available by routine chemical synthesis and are stable. The term heteroatom as applied herein refers to oxygen, nitrogen and sultur.
Here and throughout this application the term Cg 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, HBTU refers to O-Benzotriazol- 1-yl-N,N,N’N*-tetramethyluronium hexafluorophosphate, TEA refers to triethylamine,
NMM refers to N-methylmorpholine, 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 1-11.
Alkylation of rer-butyl N-allylcarbamate (1) with a base such as sodium hydride and 5- bromo-1-pentene provides the diene 2. Treatment of 2 with either 2.6. diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride olefin metathesis catalysts developed by Grubbs provides the azepine 3. Epoxidation of 3 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 4. Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon.
Acylation of § with an acid such as Cbz-amino-cyclohexanecarboxylic acid 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-amino- cyclohexanecarboxylic acid may be effected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.
Scheme 1 o)
ME Moher 0
NF _ —_—
O° 'N O.__N
H ~ x big Ne
A
7 1 2 3
OH o) c 9 de or fg ~ _0O_.N 0 N_
FT or le} [0] 4 5 0 0
H oH I i. 5 Saba,
NO — A Nn J) oo H + H Oo N | —
Hh © of 0
H
Cl- 6 - /
Reagents and conditions: a.) NaH, 5-bromo-I-pentene, DMF; b.) 2,6-diisopropylphenylimido neophylidene molybenum bis(tert-butoxide) or bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, toluene c.) m-CPBA, CHCl; d.) NaN, CH,0H, H,0, NHC]; e.) 10%
Pd/C, H,, f) Cbz-amino-cyclohexanecarboxylic acid, EDC, CH,CL; g.) HCI, EtOAc; h.) Cbz- amino-cyclohexanecarboxylic acid, EDC, CH,CL; i.) pyridine sulfur trioxide complex, DMSO, TEA.
Compounds of the general formula I wherein R' and R” 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-1-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-
amino-cyclohexanecarboxylic acid 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 HCI 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 1
Coogtn =r Cal eC 1 —_— | \ —_—
NANO = Ort x EAN 0 ) 0 8 9 10 0 o
NH
= de = 2 fg
So Ug PEN ¢ UN gh SLE hil ANE hid Ne 0 o) 11 12
OH -
OH H $ ’ 15d i, k hi NH, b
AN X ol rt N oY i : oh 7 0 13 14 0 0
H ¥
Abas,
ING! $ 4H be ~— 0 : Reagents and conditions: a.) NaH, 5-bromo-1-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CHCl; cc.) m-CPBA,
CHCl; d) NaN; CHOH, HO, NH,CI; e.) propanedithiol, CH,OH, TEA; f) Boc-amino- 15 cyclohexanecarboxylic acid, EDC, CH,CI,; g.) 10% Pd/C. Hy; h.) R,CO.H, EDC, CH.CI, or R,COCH,
CH,CL,; i.) HCV EtOAc: J.) R,COH, EDC, CH.Cl,; k) pyridine sulfur trioxide complex, DMSO,
TEA.
Compounds of the general formula I wherein R: is an alkyl, urea or sulphonamide ’ 5 group and R! is an amide may be prepared in the general fashion outlined in Scheme 3.
Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N-
Boc group under acidic conditions provides the amine salt 16. Coupling of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Alternatively, treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18. Acylation and oxidation provides the ketone 19. Further derivatization of ame 13 may be effected by treatment with a sulphony! chloride followed by deprotection of the N-Boc group to provide the amine salt 20. Acylation and oxidation provides the ketone 21.
Scheme 3
OH Q 0]
OH le) , H H
A abd ab At J sili A abdR, _N 0 H AN , © LN ©
HN
13 16 1
NL
O H le)
Id H cd N EN
J : H oY yw Mn o i i Gh 0 19 © 18 ralds G10}
N N oC CYT 0 IY NTR
RN = dn) 8
RT RW
21 20 Reagents and conditions: a) R CHO, NaBH(OAc);; b.) HCI; ¢) RCOH, EDC, CHCl, d.) pyridine sulfur trioxide complex, DMSO, TEA; ¢.) R,NCO, base: f.)R,SO,CI, TEA, CH,CL,.
The individual diastereomers of benzofuran-2-carboxylic acid {(S)-3-methyl-1-[(2,2"4- trideuterio)-3-0x0-1-(pyridine-2-sulfonyl)-azepan-4-ylearbamoy]-butyl amide 31 and 32 may be prepared as outlined in Scheme 4. Alkylation of allyl-carbamic acid benzyl ester 22 with 5-bromo-1-pentene in the presence of a base such as sodium hydride provides the diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)benzylidine ruthenium ] (IV) dichloride developed by Grubbs provides the 2,3,4.7-tetrahydro-azepine- I -carboxylic acid benzyl ester 24. Epoxidation of azepine 24 may be effected with standard oxidizing agents common to the art such as m-CPBA to provide epoxide 25. Nucleophilic epoxide ring opening of 25 may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown). The intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1.3-propanedithiol and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water. Acylation of 26 may be effected with an acid such as N-Boc-amino-cyclohexanecarboxylic acid in the presence of a coupling agent such as EDC. Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 27. Treatment of the amine 27 with 2-pyridinesulphonyl chloride in the presence of triethylamine or saturated sodium bicarbonate and CH,CI, followed by removal of the tert-butoxycarbonyl protecting group under acidic conditions provides 28. Coupling of 28 with benzofuran-2-carboxylic acid may be effected with a coupling agent such as EDC to provide intermediate alcohol 29.
Alcohol 29 may be oxidized with an oxidant such as sulfur trioxide pyridine complex in
DMSO and triethylamine to provide the ketone 30 as a mixture of diastereomers.
Scheme 4
I b hd ~~ Ry ZN hi Se NON y : lo} o} 9) 29 23 24 0 i c a de A ek fa — Koos J Kod J —2 fo) O 25 26 oH 4 oH 1® : é h, i j
AHA a oY Tr NH, _ uN J o " SN ~~ oo
LA © ) 27 28
OH fo) 0
H } H 0
RL k Salds TN ol H -
ON J 0 0 > Q N 1 0 H [] == nr 5 NN N s NE 29 30
Reagents and Conditions: a.) NaH, 5-bromo-1-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH,Cl,; ¢.) m-CPBA, CHCl; d.)
NaN, CHOH, HO. NHC; e) 1,3-propanedithiol, TEA, methanol: f.) N-Boc-amino- cyclohexanecarboxylic acid, EDC, CHCl; g) 10% Pd/C, H,; h) 2-pyridinesulphony! chloride,
TEA, CHCl; i.) 4 N HCl/dioxane, methanol: J) benzofuran-2-carboxylic acid, EDC, CH.Cl,; k.) pyridine sulfur trioxide complex, DMSO, TEA
The quaternized, 4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 5. The skilled artisan will understand from
Scheme 5 how to make any of the quaternized, 4-amino-azepan-3-one compounds of the present invention. Reductive amination of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N-Boc group under acidic conditions provides the amine salt 16.
Treatment of 16 with an acid chloride or with a carboxylic acid in the presence of a coupling agent common to the art such as EDC followed by oxidation of the intermediate alcohol (not shown) with an oxidant such as pyridine sulfur trioxide complex provides the ketone 17. Quaternization of the amine of 17 may be effected by treatment with an alkylating agent such as iodomethane to provide the quaternary amine salt 41.
Scheme 5
OH |, | 0) ab OH cd 0 0
BELO 8% — ah Sw, A pSak,
HN J 0 N J 0 N 0]
RT Ri — 13 e
Y
0 o}
H ae 2, ~N sO
Me 41
Reagents and conditions: a.) R,CHO, NaBH(OAc),; b.) HCI: c¢.) R,COH., EDC, CH.Cl,; d.) pyridine sulfur trioxide complex, DMSO, TEA: e¢.) iodomethane
The 6-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 6. 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-amino-cyclohexanecarboxylic acid and a coupling reagent such as HBTU or EDC, followed by deprotection of the Boc group with HCI, 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 b 1) DIBAI 2} allylamire;
NaBH, ~ oH 1 3) 2-pyridine ~ “7 1)mCPBA HN PN PAN aa “CoE suifony! chloride No Ny Ca | = 1
A 2) an INN 4) Grubbs Me [0] 3) PPh, IN
Me 00 4 OH 1) Boc-amino-cyclohexane H nD . Co carboxylic acid, HBTU i N ) Dess-Martin periodinane 2) HCI BoohA™ i = | _— ’ 0 Ne A 2) Chiral HPLC 3 — Ss N } 5-methoxybenzofuran IN 2-carboxylic acid, HBTU Me oO 0 7 fo)
SN ><
N, ~~ N “, = a. ig
MeO N Xn
Ben
Me 00
The 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 7. 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 a 1N-protected cycloalkane-carboxylic acid such as N-Boc-1-amino-cyclohexane- 1-carboxylic acid and a peptide coupling reagent such as HBTU or EDC. 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 with a carboxylic acid and a : peptide coupling reagent such as HBTU or EDC, and final oxidation of the secondary alcohol to the ketone with an oxidant such as Dess-Martin periodinane or sulfurtrioxide pyridine complex with triethylamine provides the desired product.
Scheme 7
CbzNH 1) PPh, 1, N iN Grubbs or - MC { NCbz —> 2) ZN : cat. Cul Me
Br 0. 3) IN x
NaH ) NCbz 4 major Me @ mCPBA —— -NCbz le} OH z N
Me NaN, =.
NCbz ~~ 3_
B _NCbz 1) PPh, minor Me i
NM Me 2 . ) BocNH” “co. 2 Hob dioxane
HBTU noo _— 0
Nig SN 5 5 3) H,, Pd/C ON
Me © 3) Dess-Martin periodinane 4) 2-pyridyl sulfonyl 0 o chloride I
Xx N ‘a, a 7 \-0 fo) NN — Eo me © O
The 2,2-4-trideutero-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 8. Deuterated inhibitors can be prepared from the parent inhibitors such as benzofuran-2-carboxylic acid {(S)-3-methyl-1- [(4S,7R)-7-methyl-3-0x0- I-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-buty] }-amide by treating with a base such as triethyl amine and stirring for several days in a deteurated protic solvent such as CD,0OD: D,0.
Scheme § i Ln i [0] [J fo}
ESS N “, Z13N Hb
TH 0 al JQ A re Ape 7 \—/ Ny SN boo:po 4 0H 4 \ Ji J
MeO ©
The 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 9. Intermediate (S)-3-Cyclohexyl-N- ((38,48,7R)-3-hydroxy-7-methyl-azepan-4-yl)-2-methyl-propionamide. as described in
Scheme 3, is reductively aminated with an aldehyde or a ketone such as propionaldehyde, then treated with a reducing agent such as sodium borohydride. Deprotection of the Boc group followed by acylation with an acylating agent such as 2-furan carboxylic acid,
HBTU, NMM, and final oxidation of the secondary alcohol to the ketone with an oxidant such as sulfur trioxide-pyridine provides the desired products.
Scheme 9 1) HC, dioxane
OH cho no PH 2) EDC
N BocNH N..
BocNH “ —— oc 4 \ oH
N ~ ° NH NaBH, Nr ha 1» \, i Me © 3) SO,-pyridine 0} h 9] ~~ N “,
Me
The 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 10. Intermediate 1-Methyl- cyclohexanecarboxylic acid ((38,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-amide, as described in Scheme 3, is acylated with an isocyanate such as (S)-(-)-2-isocyanato-4- methylvaleric acid methyl ester. Deprotection of the Boc group followed by acylation with an acylating agent such as benzofuran-2-carboxylic acid, HBTU. NMM., and final oxidation of the secondary alcohol to the ketone with an oxidant such as Dess-Martin periodinane or sulfur trioxide-pyridine provides the desired products. . Scheme 10
PN
AN J H OH 2 HCl, dioxane oon HL Boat” iS {coupe — ° Lm 00 ©] GA : Me — 0 o©
Me 3) Dess-Martin periodinane 9: oF 0 4) K,CO0,, MeOH, H,0
CTONT A H CoH {Oe "oo Cn
Me °_{
The 5-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 11. The synthesis of the C-5 methyl azepinone, 4,5 (R,S)-benzofuran-2-carboxylic acid {(S)-3-methyl-1-[5-methyl-3-0x0-- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }amide, (Example 61) is outlined below in Scheme 7. Michael addition of nitromethane to ethyl crotonate 7-1 followed by reduction of the intermediate ester with a reducing agent such as diisobutyl aluminum hydride (Dibal-H) provides the aldehyde 7-2. Reductive amination of 7-2 with N-benzyl ethanolamine in the presence of a reducing agent such as sodium triacetoxyborohydride provides the nitro-alcohol 7-3. Oxidation of 7-3 using an oxidant common to the art such as DMSO and oxalyl chloride followed by treatment of the crude intermediate aldehyde with a base such as triethylamine effects the nitro-aldol reaction to give the azepanol 7-4.
Reduction of the nitro group with zinc in the presence of hydrochloric acid followed by : coupling of the resulting amine with N-Boc-amino-cyclohexanecarboxylic acid in the presence of a coupling agent common to the art such as EDC provides intermediate 7-5.
Reductive removal of the N-benzyl moiety with hydrogen gas in the presence of a catalyst such as 10% Pd on carbon followed by sulfonylation with a sulfony! chloride in the presence of a base such as N-methylmorpholine or triethyl amine provides the sulfonamide intermediate 7-6. Removal of the N-Boc protecting group under acidic conditions . followed by coupling of the resulting amine salt with benzofuran-2-carboxylic acid and oxidation of the alcohol with an oxidant common to the art such as pyridine sulfur trioxide : complex or Dess-Martin periodinane provides the ketone 7. The individual diastereomers of 7-7 may be separated by HPLC methods to provide diastereomers 7-8, 7-9, 7-10 and 7- 11.
Scheme 11 0 1. CH.NO,, DBU Eh 0 Brn 0
AA 2. Dibal-H, GH Cl, at Na(OAG),BH 1 2
ON on OH 1. (COC). DMSO, TEA : 1. Zn/MCI
PON NN A ee DP - L, 2. TEA, CH,OH ° 2. N-Boc-Leu, EDC 3 a 0] ™ pYe PIS Hood \N/ 7 nH , oN N 1.. 10% PG/C, GH,OH Pho, No —_— H
Rg 2. 2-pyridinesulfory: chiorde Per
N. = 6 10M : = — - CI FPLC Separation 2 nzofur tboxyiic acid, EDC ne ANP 3. Pyr-SO, oxidation s TT
N = 7 [e) oO
Cy wh CLP g : ¢ "0 Se o =o "0 o
HCY Nog” HC Nag? 8 N= 9 NZ fo 0 , aw wr No _~
H,C s ~ HC ps ~ i
The starting materials used herein are commercially available amino acids or are 5 prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC
SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience).
Coupling methods to form amide bonds herein are generally well known to the art. ’ The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE 10 OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J. Meienhofer,
THE PEPTIDES, Vol. 1, 1-284 (1979): and J.M. Stewart and J.D. Young, SOLID PHASE
PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Til., 1984. are generally illustrative of the technique and are incorporated herein by reference.
Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions. . Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS IN
ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl. benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric. phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Lit, Nat, Kt, Ca™*, Mg™* and NH4* are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts. Quaternary ammonium salts are prepared by treating a parent amine compound with an excess of alkyl halide, such as methyl iodide.
This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or ’ excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic ) saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in 4 metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin. hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid . carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing. when necessary, for tablet forms: or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
Novel Intermediates
Referring to the methods of preparing the compounds of Formula I set forth in
Schemes 1-11 above, the skilled artisan will appreciate that the present invention includes all novel intermediates required to make the compounds of Formula I. In particular, the present invention provides the compounds of Formula II:
RL _R"
N
So {3
R” —N, , . R”
II wherein: nl ® rR nh . Ris Jo ;
R2 is selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl-Cq_galkyl, Ar-
Co-ealkyl, Het-Cq_galkyl, R9C(0)-, RC(S)-, R9S0n-, R9OC(0)-, = ZN,
EM eo nL en
RIRTINC(0)-, RIRTINC(S)-, ROR )NSO,- ~~ oF
Re _ N_ Z.
Ro and RISO-RIINC(0)-
R4 is selected from the group consisting of: H, C_galkyl, C3_gcycloalkyl-Co. 6alkyl, Ar-Cq_galkyl, Het-Cq_galkyl, RIC(Q)-, R3C(S)-, RISO3-, RIOC(0)-,
RORIZNC(0)-, and RIRIZNC(S)-;
RS is selected from the group consisting of: H, Cq_galkyl, C2_galkenyl, Ca. ealkynyl, C3_gcycloalkyl-Cq_galkyl, C2_galkanonyl, Ar-Cq_galkyl and Het-Cq_galkyl;
RO is selected from the group consisting of: H, Cy_galkyl, Ar-C.galkyl, or Het-
Co.ealkyl;
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)-, R10S0,-, R100C(0)-,
RIOR13NC(0O)-, and RIORI3NC(S)-;
R8 is selected from the group consisting of: H, C1-galkyl, C2_galkenyl,
Ca-galkynyl, HetCp-6alkyl and ArCo.galkyl;
RY is selected from the group consisting of: C1.galkyl, C3_geycloalkyl-Cq_galkyl,
Ar-Cq_galkyl, Ar-COOH, and Het-Cg_galky!; ’ R10 is independently selected from the group consisting of: C;_galkyl, Cjy_geycloalkyl-Co_galkyl, Ar-Cp_galkyl and Het-Cq_galkyl: ' RI is selected from the group consisting of: H, C1_galkyl. Ar-Cp_galkyl, and Het-
Co-ealkyl;
R12 is selected from the group consisting of: H. Cy_galkyl. Ar-Cp-galkyl, and Het-
Cp. galkyl:
R13 is selected from the group consisting of: H, Cy_galkyl, Ar-Cq-galkyl, and Het- , Co.galkyl.
Ris selected from the group consisting of: H, C_galkyl. Ar-Co_galkyl, and Het- . Co.galkyl:
R7 is selected from the group consisting of: H, C_galkyl, Ar-C(_ealkyl, or Het-Cq. gatkyl:
R™ 1s selected from the group consisting of: H, Cj_galkyl. C3_gcycloalkyl-Cy. calkyl, Ar-Cg_galkyl, and Het-Cq_galkyl;
Z is selected from the group consisting of: C(O) and CH»; n is an integer of from | to 3; and pharmaceutically acceptable salts, hydrates and solvates thereof.
The following compounds are preferred novel intermediates: benzofuran-2-carboxylic acid {1-[(+/-)-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid { 1-[(+/-)-3-hydroxy- 1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl}-cyclohexyl}-amide; benzofuran-2-carboxylic acid {1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl}-amide; and thieno[3,2-b]thiophene-2-carboxylic acid {1-[(3S,48,7R)-3-hydroxy-7-methyl--1-(pyridine- 2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl }-amide.
Process for Synthesis of Inventive Compounds
Referring to Schemes 1-11 herein above, the present invention provides a process ’ for the synthesis of compounds of Formula (I) comprising the step of oxidizing the . appropriate compound of Formula (II) with an oxidant to provide the compound of Formula
(I) as a mixture of diastercomers. Preferably the oxidant is Dess-Martin periodinane or pyridine sulfur trioxide complex in DMSO and triethylamine.
Referring to Scheme 8, the present invention also provides a process for the . synthesis of deuterated compounds of Formula (I). Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound of Formula (I) as a mixture of diastereomers is added to the synthesis. Preferably, the deuterating agent is
CD.OD:D.O (10:1) in triethylamine.
The process further comprises the step of separating the diasteromers of Formula (D) by separating means, preferably by high presssure liquid chromatography (HPLC).
Utility of the Present Invention "The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine
I5 proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
The present compounds, especially the preferred 1-amino-1-acyl cyclohexane compounds exhibit superior selectivity for cathepsin K versus cathepsins L,S, and B when compared to structurally similar compounds containing a leucine instead of 1-amino-1-acyl cyclohexane.
The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, , 30 arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget’s disease; hypercalcemia of malignancy, and metabolic bone disease.
Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. and certain tumors and metastatic ncoplasias may be effectively treated with the compounds of this invention. : The present invention also provides methods of treatment of diseases caused by 5S pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal. most particularly a human in need thereof a compound of the present invention. The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof an inhibitor of cathepsin K, including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated. most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent. such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
For acute therapy, parenteral administration of a compound of Formula I is . 30 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

Claims (1)

  1. We claim:
    1. A compound of Formula I: R_ R" pd N Jo
    [0] rN R’ I wherein: rR 0 Lo Rr a0 Rlis Jo : RZ is selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl-Cy_ alkyl, Ar-Cq_galkyl, Het-Cq_galkyl, R9C(0)-, RIC(S)-, RISO»-, R9OC(0)-, = = Lee a Len i t RIRINC(0)-, RORIINC(S)-, RORINSO,-, ~ NF , Re N_ 7. Rr’ ~r ~ 8 R and R9SO,R1INC(0)-; R# is selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl-Cg_ galkyl, Ar-Cq_galkyl, Het-Cq_galkyl, R3C(O)-, R3C(S)-, R3SO5-, R30C(O)-, RIRI2NC(0)-, and RORI2NC(S)-; RS is selected from the group consisting of: H, C1_galkyl, Ca.galkenyl, Ca. . alkynyl, C3_gcycloalkyl-Cq_galkyl, C2-galkanonyl, Ar-C)_galky! and Het-C_galkyl; RO is selected from the group consisting of: H, Cy_galkyl, Ar-Cq.galkyl, and Het- Co-ealkyl;
    R7 is selected from the group consisting of: H, C1-galkyl, C3_geycloalkyl-Co. galkyl, Ar-C_galkyl, Het-Cg_galkyl, R19C(0)-, R10¢(S)-, R1050,-, R100C(0)-, RIORI3NC(0)-, and RIORI3NC(S)-; } R8 is selected from the group consisting of: H, Cy.galkyl, Co_ealkenyl, C2-6alkynyl, HetCp_galkyl and ArCq_galkyl, : RY is selected from the group consisting of: Cy_galkyl, C3_geycloalkyl-Cq_galkyl, Ar-Cq_galkyl, Ar-COOH, and Het-Cq_galkyl; R10 is selected from the group consisting of: Cy_galkyl, C3_geycloalkyl-Cq_galkyl, Ar-Cp_galkyl and Het-Cq_galkyl; R11 is selected from the group consisting of: H, C_galkyl, Ar-Cq-galkyl, and Het- Co_galkyl; R12 is selected from the group consisting of: H, Cy _galkyl, Ar-Co-galkyl, and Het- Co_palkyl; R13 is selected from the group consisting of: H. C_galkyl, Ar-Cq-galkyl, and Het-
    Cp.galkyl; Ris selected from the group consisting of: H, Cy_galkyl, Ar-Cq-galkyl, and Het- Co_ealkyl; R” 1s selected from the group consisting of: H, C_galkyl, Ar-Cq.ealkyl, and Het- Cop-ealkyl; R™ 1s selected from the group consisting of: H, C|_galkyl, C3_gcycloalkyl-Cq. 6alkyl, Ar-Cq_galkyl, and Het-Cp_galkyl; Z 1s selected from the group consisting of: C(O) and CH»; and n 1s an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
    2. A compound according to Claim 1 wherein n is 4.
    3. A compound according to either Claim 1 or 2 wherein R¥ is selected from the group consisting of: R70C(0)-,R3C(0)- or R3S0»-.
    4. A compound according to Claim 3 wherein R4 is R3C(0)-.
    5. A compound according to Claim 4 wherein RY is selected from the group consisting of: Cy _galkyl, C2_galkenyl, Ca_geycloalkyl-Cq_galkyl, Co_galkanonyl, Ar-Cy). galkyl and Het-Cq_galkyl. 6 A compound according to Claim 5 wherein: : C1-galkyl is selected from the group consisting of: methyl, halogenated methyl, C{_galkoxy and aryloxy substituted methyl, heterocycle substituted methyl; ethyl. heterocycle substituted ethyl; butyl, aryl substituted butyl; and isopentyl; Ca_geycloalkyl-Cq_galkyl is cyclohexyl: Ca-galkenyl is selected from the group consisting of: butenyl, and aryl substituted butenyl;
    Ca.galkanonyl is selected from the group consisting of: acetyl; and pentanonyl; Ar-Cq_galkyl is selected from the group consisting of: phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more aryloxy or Cy_galkoxy groups, phenyl substituted with one or more Ci alkyl sulfonyl groups; benzyl; and naphthylenyl; and Het-Cqy_galkyl is selected from the group consisting of: benzo[1,3]dioxolyl; furanyl, nitro substituted furanyl, halogen substituted furanyl, aryl substituted furanyl, Cy_galkyl substituted furanyl, tetrahydrofuranyl; benzofuranyl, Cy _galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C}_galkyl substituted benzofuranyl; ) napththo[2,1-b]-furanyl, Cy_galkyl substituted napththo[2,1-b]-furanyl; benzo[b]thiophenyl, C;_galkoxy substituted benzo[b]thiophenyl, quinolinyl;
    quinoxalinyl; 1,8 naphthyridinyl; indolyl, Cj _galky! substituted indolyl,
    . pyridinyl, Cq_galkyl substituted pyridinyl, 1-oxy-pyridinyl: furo[3,2-b]-pyridinyl, C_galkyl substituted furo[3,2-b]-pyridinyl; : thiophenyl, Cq_galkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3,2-b]thiophenyl C1._galkyl substituted thieno[3.2-b]thiophen-2-yl; isoxazolyl, Cy _galkyl substituted isoxazolyl; oxazolyl, aryl substituted oxazolyl. C1_galkyl substituted oxazolyl; and IH-benzoimidazolyl.
    7. A compound according to Claim 6 wherein: halogenated methyl is trifluoromethyl; C1-ealkoxy substituted methyl is selected from the group consisting of: phenoxy- methyl and 4-fluoro-phenoxy-methyl; heterocycle substituted methyl is 2-thiophenyl-methyl; heterocycle substituted ethyl is piperidin-1-yl-ethyl; aryl substituted butyl is 4-(4-methoxy)phenyl-butyl; pentanonyl is 4-pentanonyl; aryl substituted butenyl is 4,4-bis(4-methoxyphenyl)-but-3-enyl; phenyl substituted with one or more halogens is selected from the group consisting of: 3,4-dichloropheny! and 4-fluorophenyl; phenyl substituted with one or more aryloxy or C_galkoxy groups is selected from the group consisting of: 3,4-dimethoxy-phenyl and 3-benzyloxy-4-methoxy-phenyl; phenyl substituted with one or more Cj_galkyl sulfonyl groups is 4- methanesulfonyl-phenyl; naphthylenyl is naphthylen-2-yl; benzo[1,3]dioxolyl is benzo[1,3]dioxol-5-y1, : furanyl is furan-2-yl: nitro substituted furanyl is 5-nitro-furan-2-yl; aryl substituted furanyl is selected from the group consisting of: 5-(4-nitrophenyl)- furan-2-yl, 5-(3-triflouromethyl-phenyl)-furan-2-yl, and 5-(4-chloro-phenyl)-furan-2-yl); halogen substituted furanyl is 5-bromo-furan-2-yI;
    C1. alkyl substituted furanyl is selected from the group consisting of: 3-methyl- furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2,4-dimethyl-furan-2-y1; tetrahydrofuranyl is tetrahydrofuran-2-yl; . benzofuranyl is benzofuran-2-y1; C1 _galkoxy substituted benzofuranyl is selected from the group consisting of: 5-(2- piperazin-4-carboxylic acid terr-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)-benzoturan-2-yl, 7-methoxy-benzofuran-2-yl, 5-methoxy-benzotura-2-yl, 5,6- dimethoxy-benzofuran-2-yiS-methoxy-3-methyl-benzofuran-2-yl, 4-methoxy-3-methyl- benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yl; halogen substituted benzofuranyl is selected from the group consisting of: 5-fluoro- benzofuran-2-yl 5,6-difluoro-benzofuran-2-y15-fluoro-3-methyl-benzofuran-2-yl, and 6- fluoro-3-methyl-benzofuran-2-yl; Cq_galkyl substituted benzofuranyl is selected from the group consisting of: 3- . methyl-benzofuran-2-yl, 3,5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; napththo[2,1-b]-furanyl is napththo[2,1-b]-furan-2-yl;
    C1.galkyl substituted napththo[2,1-b]-furanyl is 1-methyl-naphtho[2,1-b]-furan-2- yl; benzo[b]thiophenyl is benzo[#]thiophen-2-yl; Cq_galkoxy substituted benzo[b]thiophenyl is 5,6-dimethoxy- benzo[b]thiophen-2- yk; quinolinyl is selected from the group consisting of: quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-8-yl; quinoxalinyl is quinoxalin-2-yl; 1,8 naphthyridinyl is 1,8 naphthyridin-2-yl; indolyl is selected from the group consisting of: indol-3-yl and indol-5-yl; Cq_galkyl substituted indolyl is N-methyl-indol-2-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl, and pyridin-5-yl; 1-oxy-pyridinyl is selected from the group consisting of: 1-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl; Cq_galkyl substituted pyridinyl is 2-methyl-pyridin-5-yi; furo[3.2-b]-pyridinyl is furo[3,2-b]-pyridin-2-yl;
    Cq.palkyl substituted furo[3,2-b]-pyridinyl is 3-methyl-furo[3.2-b}-pyridin-2-yl; thiophenyl is thiophen-3-yl; halogen substituted thiophenyl is 4,5-dibromo-thiophen-2-yl; : C1_galkyl substituted thiophenyl is >-methyl-thiophen-2-yl: thieno[3,2-b]thiophenyl is thieno[3.2-~]thiophene-2-yl;
    C1.palkyl substituted thieno[3,2-~]thiophen-2-yl is 5-terr-butyl-3-methyl thienof3,2-b]thiophen-2-yl; isoxazolyl is isoxazol-4-yl;
    C1.ealkyl substituted 1soxazolyl is 3,5-dimethyl- isoxazol-4-yl; oxazolyl is oxazol-4-vl; aryl substituted oxazolyl is 5-methyl-2-phenyl oxazol-4-vl;
    C.ealkyl substituted oxazolyl is 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and 1H-benzoimidazolyl is 1H-benzoimidazol-3-yl. 8 A compound according to Claim 7 wherein RY is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran-2-yl, 5-methoxybenzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, quinoxalin-2-yl, and quinolin-2-yl.
    9. A compound according to Claim 8 wherein RY is selected from the group consisting of: benzofuran-2-yl and thieno[3,2-b]thiophene-2-yl.
    10. A compound according to Claim 9 wherein RI is benzofuran-2-yl.
    11. A compound according to either Claim 1 or 2 wherein R'is selected from the group consisting of H and naphthalen-2-yl-methyl.
    12. A compound according to Claim 11 wherein Ris H.
    13. A compound according to either Claim 1 or 2 wherein R” is H.
    14. A compound according to either Claim 1 or 2 wherein R™ is selected from the group consisting of H and methyl.
    15. A compound according to Claim 14 wherein R™ is methyl.
    16. A compound according to either Claim 1 or 2 wherein R" is H and R™ is methyl. 17 A compound according to either Claim 1 or 2 wherein R2 is selected from the group consisting of: Ar-Cp-galkyl, RIC(0)-, RISO, RIRIINC(O)-, R® Rr’ 7 N ~~ z ~ and R .
    18. A compound according to Claim 17 wherein RZ is selected from the group consisting of: Ar-Cg-galkyl, RIC(0)-, and RISO».
    19. A compound according to Claim 18 wherein RZ is RISO,
    20. A compound according to Claim 17 wherein RO is H.
    21. A compound according to Claim 17 wherein R7 is R100C(O).
    22. A compound according to Claim 17 wherein RS is Cq.palkyl.
    23. A compound according to Claim 22 wherein RS is isobutyl. 24, A compound according to Claim 17 wherein RY is selected from the group consisting of: C_galkyl, Ar-Cp_galkyl, -Ar-COOH and Het-Cq_galkyl.
    25. A compound according to Claim 24 wherein:
    Cy.galkyl is selected from the group consisting of: methyl; ethyl, C3_gcycloalkyl-Cq._galkyl-substituted ethyl; propyl; butyl, C1_galkyl-substituted butyl; tert-butyl; and 67
    1sopentyl; Ar-Cq_galkyl is selected from the group consisting of: phenyl, halogen substituted phenyl.Cq_galkoxy phenyl, C1_galkyl substituted phenyl. cyanophenyl, C1.galkyl sulfonyl substituted phenyl; toluyl, Het-substituted toluyl; and , naphthylenyl; -Ar-COOH is benzoic acid; Het-C()_galkyl is selected from the group consisting of: benzo[1,3]dioxolyl; benzo[1,2,5Joxadiazolyl: pyridinyl, 1-oxy-pyridinyl, Cy_galkyl pyridinyl; thiophene; thiazolyl; 1H-imidazolyl, Cy_galkyl substituted imidazolyl; 1H-[1.2.4]triazolyl, C|_galkyl substituted 1H-[1.2,4]triazolyl; 1soxazolyl, and Cy_galkyl substituted isoxazolyl.
    26. A compound according to Claim 25 wherein: ethyl is 2-cyclohexyl-ethyl; butyl is 3-methylbutyl: phenyl is selected from the group consisting of: 3,4-dichlorophenyl, 4- bromophenyl, 2-fluorophenyl, 3-fluorophenyl 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-cyanophenyl; 4-ethyl-phenyl, 2-methyl phenyl, 4-methyl phenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; and naphthylen-2-yl; benzoic acid is 2-benzoic acid; benzo[1,3]dioxolyl is benzo[1,3]dioxol-5-yl; benzo[1,2.5]oxadiazolyl is benzo[1,2,5]oxadiazol-4-yl; pyridiny! is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl , 3- methyl-pyridin-2-yl, and 6-methyl-pyridin-2-y}; 1-oxy-pyridinyl is selected from the group consisting of: l-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl;
    thiopheneyl is thiophene-2-yl; thiazolyl 1s thiazol-2-yl; IH-imidazolyl is selected from the group consisting of: 1H-imidazol-2-yl, 1H- imidazol-4-yl, 1-methyl- 1H-imidazol-2-yl. I-methyl-1H-imidazol-4-y1, , and 1,2-dimethyl- 1H-imidazol-4-yI; . 1H-[1,2,4]triazolyl is selected from the group consisting of: 1H-[1,2,4]triazol-3-yl and 3-methyl-1H-{1,2,4]triazol-3-yl; and
    3.5-dimethyl-isoxazolyl is 3,5-dimethyl-isoxazol-4-yl.
    27. A compound according to either Claim 1 or 2 wherein: R> is selected from the group consisting of: R® 7 N ~ Zo Ar-Co-galkyl, R9C(0)-. R980», ROR INC(0)-, and RY ; R4 is selected from the group consisting of: R30C(0)-, R3C(0)- or RIS05-; R? is selected from the group consisting of: C|_galkyl, C2_ealkenyl, C3_ geycloalkyl-Co_galkyl, Co galkanonyl, Ar-C_galkyl and Het-Cq_galkyl; RO is H; R7 is R100C(0; RS is C]_galkyl; RY%is selected from the group consisting of: Cy_galkyl, Ar-C(_galkyl, -Ar-COOH and Het-Cq_galkyl; R10 is selected from the group consisting of: Cy_galkyl, Ar-Cp_galkyl and Het-Cy_ ealkyl; R’is H; R" is H; and R™ is methyl.
    28. A compound according to Claim 27 wherein: R2 is selected from the group consisting of: Ar-Co-galkyl, R9C(0)- and RISO»; R# is R2C(O)-; and in R3:
    Ci-galkyl is selected from the group consisting of: methyl. halogenated methyl, C|_galkoxy substituted methyl, heterocycle substituted methyl: ethyl, heterocycle substituted ethyl: butyl, aryl substituted butyl; and : isopentyl; Ca_gcycloalkyl-Cq_galkyl is cyclohexyl; Co_galkenyl is selected from the group consisting of’ butenyl, and aryl substituted butenyl; Co_galkanonyl is selected from the group consisting of: acetyl; and pentanonyl: Ar-Cq_galkyl 1s selected from the group consisting of: phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more aryloxy or Cy_galkoxy groups, phenyl substituted with one or more C1 _galkyl sulfonyl groups; benzyl; and naphthylenyl; and Het-Cy_galkyl is selected from the group consisting of: benzo[1,3]dioxolyl; furanyl, nitro substituted furanyl, halogen substituted furanyl, aryl substituted furanyl, C{_galkyl substituted furanyl; tetrahydrofuranyl; benzofuranyl, Cy_galkoxy substituted benzofuranyl, halogen substituted benzofuranyl, C{_galkyl substituted benzofuranyl; napththo[2,1-b}-furanyl, C{_galky] substituted napththo[2,1-b]-furanyl; benzo[b]thiophenyl, C_galkoxy substituted benzo[b]thiophenyl, quinolinyl; quinoxalinyl; 1,8 naphthyridinyl; indolyl, Cy_galkyl substituted indolyl; pyridinyl, Cj_galkyl substituted pyridinyl, 1-oxy-pyridinyl; furo[3,2-b]-pyridinyl, Cq_galkyl substituted furof3,2-b]-pyridinyl;
    thiophenyl, Cq_galkyl substituted thiophenyl, halogen substituted thiophenyl; thieno[3.2-b]thiophenyl C_galkyl substituted thieno[3,2-h]thiophen-2-yl: isoxazolyl, Cj _galkyl substituted isoxazolyl; oxazolyl, aryl substituted oxazolyl. Cj_galkyl substituted oxazolyl; and IH-benzoimidazolyl.
    29. A compound according to Claim 28 wherein: halogenated methyl is trifluoromethyl; C-palkoxy substituted methyl is selected from the group consisting of: phenoxy- methyl and 4-fluoro-phenoxy-methyl; heterocycle substituted methyl is 2-thiophenyl-methy!; heterocycle substituted ethyl is piperidin-1-yl-ethyl; aryl substituted butyl is 4-(4-methoxy)phenyl-butyl: pentanonyl 1s 4-pentanonyl; aryl substituted butenyl is 4,4-bis(4-methoxyphenyl)-but-3-enyl; phenyl substituted with one or more halogens is selected from the group consisting of: 3,4-dichlorophenyl and 4-fluorophenyl; phenyl substituted with one or more aryloxy or Cq_palkoxy groups is selected from the group consisting of: 3,4-dimethoxy-phenyl and 3-benzyloxy-4-methoxy-phenyl; phenyl substituted with one or more C|_galkyl sulfonyl groups is 4- methanesulfonyl-phenyl, naphthylenyl is naphthylen-2-yl; benzo[1,3]dioxolyl is benzo[1,3]dioxol-5-yl, furanyl is furan-2-yl, nitro substituted furanyl is 5-nitro-furan-2-yl; aryl substituted furanyl is selected from the group consisting of: 5-(4-nitrophenyl)- turan-2-yl, 5-(3-triflouromethyl-phenyl)-furan-2-yl, and 5-(4-chloro-phenyl)-furan-2-yl); halogen substituted furanyl is 5-bromo-furan-2-yl; C1-ealkyl substituted furanyl is selected from the group consisting of: 3-methyl- furan-2-yl, 4-methyl-furan-2-yl, 2,5-dimethyl-furan-2-yl, and 2.4-dimethyl-furan-2-yl; tetrahydrofuranyl is tetrahydrofuran-2-yl; benzofuranyl is benzofuran-2-yl;
    C1-palkoxy substituted benzofuranyl is selected from the group consisting of: 5-(2- piperazin-4-carboxylic acid rerr-butyl ester- ethoxy) benzofuran-2-yl, 5-(2-morpholino-4- vl-ethoxy)-benzofuran-2-yl. 5-(2-piperazin-1-yl-ethoxy)benzofuran-2-yl, 5-(2-cyclohexyl- ethoxy)-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl. 5-methoxy-benzofura-2-vyl, 5.6 dimethoxy-benzofuran-2-yl5-methoxy-3-methyl-benzofuran-2-yI, 4-methoxy-3-methyl- z benzofuran-2-yl, and 6-methoxy-3-methyl-benzofuran-2-yi; halogen substituted benzofuranyl is selected from the group consisting of: 5-fluoro- benzofuran-2-yl 5.6-diftuoro-benzofuran-2-yl5-fluoro-3-methyl-benzofuran-2-vl, and 6- fluoro-3-methyl-benzofuran-2-yl; C1_palkyl substituted benzofuranyl is selected from the group consisting of: 3- methyl-benzofuran-2-yl, 3.5-dimethyl-benzofuran-2-yl, and 3-ethyl-benzofuran-2-yl; napththo[2.1-b]-furany! is napththo[2.1-b]-furan-2-yI; C1-ealkyl substituted napththo[2,1-b]-furanyl is 1-methyl-naphtho[2,1-b]-furan-2- yk; benzo[b]thiophenyl is benzo[b]thiophen-2-yl;
    C1.palkoxy substituted benzo[b]thiophenyl is 5.6-dimethoxy- benzo[b]thiophen-2- ME quinolinyl 1s selected from the group consisting of: quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, and quinolin-§8-yl; quinoxalinyl is quinoxalin-2-yl, 1,8 naphthyridinyl is 1,8 naphthyridin-2-yl, indolyl is selected from the group consisting of: indol-3-yl and indol-5-yl;
    Cj.galkyl substituted indolyl is N-methyl-indol-2-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-yl, and pyndin-5-yl; l-oxy-pyridinyl is selected from the group consisting of: 1-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl;
    Cj.salkyl substituted pyridinyl is 2-methyl-pyridin-5-yI; furo[3,2-b]-pyridinyl is furo[3,2-b]-pyridin-2-yI,
    C1.6alkyl substituted furo[3,2-b]-pyridinyl is 3-methyl-furo[3,2-b]-pyridin-2-yl; thiophenyl is thiophen-3-yl; halogen substituted thiopheny] is 4,5-dibromo-thiophen-2-yl; C1-6alkyl substituted thiophenyl is 5-methyl-thiophen-2-yl;
    thieno[3,2-b]thiophenyl is thieno[3,2-b]thiophene-2-yl; Cq_palkyl substituted thieno[3.2-b]thiophen-2-yl1 1s 5-rerr-butyl-3-methyl thieno[3,2-h]thiophen-2-yl; isoxazolyl is 1soxazol-4-yl;
    Cj.ealkyl substituted isoxazolyl is 3,5-dimethyl- isoxazol-4-yl; : oxazolyl is oxazol-4-yI; aryl substituted oxazolyl is 5-methyl-2-phenyl oxazol-4-yl;
    C|.ealkyl substituted oxazolyl 1s 2-phenyl-5-trifluoromethyl-oxazol-4-yl; and 1H-benzoimidazolyl is 1H-benzoimidazol-3-yl.
    30. A compound according to either Claim 28 or 29 wherein in RY: Cy_galkyl is selected from the group consisting of: methyl; ethyl, C3_gcycloalkyl-Cq_galkyl substituted ethyl; propyl; butyl, Cj _galkyl-substituted butyl: tert-butyl; and isopentyl, Ar-Cq_galkyl is selected from the group consisting of: phenyl, halogen substituted phenyl.Cy_galkoxy phenyl, C1_galkyl substituted phenyl, cyanophenyl, Cj_galkyl sulfonyl substituted phenyl; toluyl, Het-substituted toluyl; and naphthylenyl; -Ar-COOQOH is benzoic acid; Het-Cq_galkyl is selected from the group consisting of: benzo[1,3]dioxolyl; benzo{1,2,5]oxadiazolyl; pyridinyl, 1-oxy-pyridinyl, Cj_galkyl pyridinyl; thiopheneyl; thiazolyl; 1H-imidazolyl, Cq_galkyl substituted imidazolyl; . 1H-{1,2,4]triazolyl, Cy_galkyl substituted 1H-[1,2,4]triazolyl; isoxazolyl, and Cj_galkyl substituted isoxazolyl.
    31. A compound according to Claim 30 wherein: ethyl is 2-cyclohexyl-ethyl; butyl is 3-methylbutyl; phenyl is selected from the group consisting of: 3,4-dichlorophenyl, 4- bromophenyl, 2-fluorophenyl, 3-fluorophenyl 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenvl, 2-cyanophenyl: 4-ethyl-phenyl, 2-methyl phenyl. 4-methyl phenyl, 4-methanesulfonyl phenyl, 2-methanesulfonyl phenyl; and naphthylen-2-yl; benzoic acid is 2-benzoic acid; benzo[1,3]dioxolyl is benzo[1,3]dioxol-5-yl; benzo[1.2,5]oxadiazolyl is benzo[ 1,2,5]oxadiazol-4-yl; pyridinyl is selected from the group consisting of: pyridin-2-yl, pyridin-3-y1 , 3- methyl-pyridin-2-yl, and 6-methyl-pyridin-2-yl; 1-oxy-pyridinyl is selected from the group consisting of: 1-oxy-pyridin-2-yl and 1- oxy-pyridin-3-yl; thiopheneyl is thiophene-2-yl; thiazolyl is thiazoi-2-yl; 1H-imidazolyl is selected from the group consisting of: 1H-imidazol-2-yl, 1H- imidazol-4-yl, |-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-4-yl, , and 1,2-dimethyl- 1H-imidazol-4-yl; 1H-[1,2,4]triazolyl is selected from the group consisting of: 1H-[1,2,4]triazol-3-yl and 5-methyl-1H-[1,2,4]triazol-3-yl1; and 3,5-dimethyl-isoxazolyl is 3,5-dimethyl-isoxazol-4-yl.
    32. A compound according to Claim 27 wherein: RZ is R9S0»; R4 is ROC(0); RS is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran- 2-yl, 5-methoxybenzofuran-2-yl, thieno[3,2-b]thiophene-2-yl, quinoxalin-2-yl, and quinolin-2-yl, and RY is selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl.
    33. A compound according to Claim 32 wherein RY is selected from the group consisting of: benzofuran-2-yl and thieno[3,2-b]thiophene-2-yl. 34, A compound according to Claim 33 wherein RY is benzofuran-2-ylL
    35. A compound according to Claim 32 wherein RY is pyridin-2-yl.
    36. A compound according to either Claim 1 or 2 -selected from the group consisting of: benzofuran-2-carboxylic acid {1-[(S)-3-0x0-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; benzofuran-2-carboxylic acid {1-[(R)-3-0oxo- 1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid { 1-[(+/-)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; benzofuran-2-carboxylic acid {1-[(4S,7R)-7-methyl-3-0xo- 1-(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-cyclohexyl}-amide; thieno[3,2-b]thiophene-2-carboxylic acid {1-[(4S,7R)-7-methyl-3-0x0- 1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl }-amide; 2,2,4-trideutero-benzoturan-2-carboxylic acid {1-[(S)-3-oxo- 1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl }-amide; 2,2,4-trideutero- benzofuran-2-carboxylic acid {1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2- ‘ sulfonyl)-azepan-4-ylcarbamoylj-cyclohexyl }-amide;
    P51203
    2.2, 4-trideutero-thieno[ 3,2-blthiophene- 2-carboxylic acid { 1-[(S)-3-0x0-1-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl } -amide; and
    2,2. 4-trideutero-thienof 3,2 -b]thiophene-2-carboxylic acid {1-[(48,7R)-7-methyl-3-oxo0-1~ {(pyridine-2-sulfonyl)-azepan-4-yicarbamoyl}-cyclohex yl} -amide,
    37. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 36 and a pharmaceutically acceptable carrier, diluent or excipient.
    38. Use of a compound according to any one of Claims 1 to 36 for inhibiting a protease.
    39. Use according to Claim 38 wherein said protease is selected from the group consisting of a cysteine protease and a serine protease.
    40. Use according to Claim 39 wherein said protease is a cysteine protease.
    41. Use according to Claim 40 wherein said cysteine protease is cathepsin K.
    42. Use of a compound according to any one of Claims 1 to 36 for treating a disease characterized by bone loss. 43, Use according to Claim 42 wherein said disease is osteoporosis.
    44. Use according to Claim 42 wherein said disease is periodontitis.
    45. Use according to Claim 42 wherein said disease is gingivitis.
    46. Use of a compound according to Claims 1 to 36 for treating a disease characterized by excessive cartilage or maxtrix degradation. 76 0 Sh AMENDED ©
    P51203
    47. Use according to Claim 46 wherein said disease is osteoarthritis.
    48. Use according to Claim 46 wherein said disease is rheumatoid arthritis. 49, A compound of Formula [1
    R'. _R N
    _~._..OH
    RN .; H wherein: nd Q N rR xo Ris no RZ is selected from the group consisting of: H, Cy galkyl, Cy geycloalkyl-Cy., salkyl, Ar-Cq_galkyl, Het-Cg.galkyl, R9C(0)-, R9C(S)-, R950;-, R%OC(0)-, N CL Coy oN; I A CH, oy ~ I Ry ge I J iy RIR!INC(O)-, RORINC(S)-, ROR! )NSOp- , re oN LZ RR" or ’ 4 } R ; and R9SO-RINC(O)- R4 is selected from the group consisting of: H, C 1-6alkyl, C3 geycloaikyl-Cy). galkyl, Ar-Cg_galkyl, Het-Cq_galkyl, RIC(O)-. R3C(S)-, R3S04-, RS0OC(0)-, R3RIINC(O)-, and RIRIINC(S)-; RS is selected from the group consisting of: H, Cy.galkyl, C2_galkenyl, Ca. galkynyl, C3_geycloalkyl-Co.gatkyl, C2 galkanonyl, Ar-Cyy.galkyl and Het-Cyy galky!; 77 AMENDED Shit
    RO is selected from the group consisting of: H, Cy_galkyl, Ar-Cq_galkyl, or Het-
    Cop.galkyl: R7 is selected from the group consisting of: H, C_galkyl, C3_geycloalkyl-Cq. alkyl, Ar-Cq_galkyl. Het-Cq_galkyl, R10C(0)-. R10C(S)-, R1050,-, R100C(0)-, RIORI3NC(0)-, and RIORI3NC(S)-; - RS is selected from the group consisting of: H, Cq.galkyl, Ca.galkenyl, Co_galkynyl, HetCq_ealkyl and ArCq-galkyl; RY is selected from the group consisting of: Cj_galkyl, C3_gcycloalkyl-Cq_galkyl. Ar-Cq_galkyl. -ArCOOH, and Het-Cq_galkyl; R105 independently selected from the group consisting of: Cy_galkyl, C3_gcycloalkyl-Cq_galkyl, Ar-Cq_galkyl and Het-Cq_galkyl: RH is selected from the group consisting of: H, Cq_galkyl, Ar-Cq-galkyl, and Het-
    Co.salkyl; R12 is selected from the group consisting of: H, C_galkyl, Ar-C(.galkyl, and Het-
    Cp.galkyl; R13 is selected from the group consisting of: H, Cy_galkyl, Ar-C(.galkyl, and Het- Co-galkyl; R’is selected from the group consisting of: H, Cy_galkyl, Ar-Cq.galkyl, and Het- Co-galkyl; R” 1s selected from the group consisting of: H, Cq_galkyl, Ar-Cg.galkyl, or Het-Cy)_ alkyl; Ris selected from the group consisting of: H, Cy_galkyl, C3_gcycloalkyl-Cq. galkyl, Ar-Cg_galkyl, and Het-Cg_galkyl; Z is selected from the group consisting of: C(O) and CH»; n is an integer of from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
    50. A compound according to Claim 49 selected from the group consisting of: benzofuran-2-carboxylic acid { 1-[(+/-)-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-cyclohexyl}-amide; . thieno[3,2-b]thiophene-2-carboxylic acid {1-[(+/-)-3-hydroxy-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl}-amide;
    benzofuran-2-carboxylic acid {1-[(35,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoylj-cyclohexyl }-amide; and thieno[3,2-b]thiophene-2-carboxylic acid {1-[(3S,4S,7R)-3-hydroxy-7-methyl-- 1-(pyridine- . 2-sulfonyl)-azepan-4-ylcarbamoyl]-cyclohexyl }-amide.
    S51. A process for the synthesis of a compound according to Claim | comprising the step of oxidizing a corresponding compound of Claim 49 with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers.
    52. The process of Claim 51 wherein the oxidant is sulfur trioxide pyridine complex in DMSO and triethylamine.
    53. The process of Claim 51 further comprising the step of separating the diasteromers by separating means.
    54. The process of Claim 53 wherein said separating means is high presssure liquid chromatography (HPLC).
    55. The process of Claim 51 further comprising the step of deuterating said diastereomers with a deuterating agent.
    36. The process of Claim 55 wherein said deuterating agent is CD30D: D1O (10:1) in triethylamine.
    57. Use of a compound according to any one of Claims 1 to 36 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. ! 58. A use according to Claim 57 wherein said protease is a cysteine protease.
    59. A use according to Claim 58 wherein said cysteine protease is cathepsin K.
    P51203
    60. Use of a compound according to any one of Claims | to 36 in the manufacture of a medicament for use in treating a disease characterized by bone loss.
    61. A use according to Claim 60 wherein said disease is osteoporosis.
    62. A usc according to Claim 60 wherein said disease is periodontitis,
    63. A use according 10 Claim 60 wherein said disease is gingivitis.
    64. Use of a compound according to any one of Claims 1 to 36 in the manufacture of a medicament for use in treating a disease characterized hy excessive cartilage or matrix degradation.
    65. A use according to Claim 64 wherein said disease is osteoarthritis,
    66. A use according to Claim 64 wherein said disease is rheumatoid arthritis.
    67. A compound according to claim | or claim 38, substantially as herein described and exemplified.
    68. A pharmaceutical composition according to claim 37, substantially as herein described and exemplified.
    69. Use according to any one of claims 39, 42, 46, 57, 60 or 64, substantially as herein described and exemplified.
    70. A process according to claim 51, substantially as herein described and exemplified. 80 AMENDED B71
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