JP2000517319A - Inhibitors of cysteine protease - Google Patents

Abstract

(57) The present invention provides a compound of the formula (I) wherein R ¹ is (i), (ii), (iii) or (iv); R ² is H, C _1-6 alkyl, C _3-6 cycloalkyl -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S) -, R 5 SO 2 - ^{, R 5 OC (O) -} , R 5 R'NC (O) -, R 5 R'NC (S) -, adamantyl -C (O) - be a or (v); each R '' is independently And R is H, C _1-6 alkyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl; R ″ ′ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _{0 -6} alkyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl; each R ³ is independently, H, C _2-6 alkenyl, C _2-6 alkynyl, Het, Ar or oR, _{', SR', NR '2} , R'NC (O) OR 5, CO 2 R', CO 2 NR '2, N (C = N H) NH _2, be Het or C _1-6 alkyl optionally substituted by Ar; R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 ^{alkyl, R 5 C (O) -} , R 5 C (S) -, R 5 SO 2 -, R 5 OC (O) -, R 5 R'NC (O ^{) -, R 5 R'NC (S} ) -, R'HNCH (R ') C (O) - or ^{R 5 OC (O) NR'CH (} R') C (O) - and it is, each R ⁵ independently, C _3-6 cycloalkyl -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _0-6 alkoxy, Het-C _0-6 alkoxy, or oR ', SR', NR ' 2, R'NC (O) oR 5, CO 2 R', CO 2 NR '2, N (C = NH) with NH _2, Het or Ar may be substituted C _1-6 is alkyl; R ⁶ is H, C _1-6 alkyl, Ar-C _0-6 A alkyl or Het-C _0-6 alkyl, R ⁷ is H, C _1-6 alkyl, C _3-6 cycloalkyl -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _{0- 6} ^{alkyl, R 5 C (O) -} , R 5 C (S) -, R 5 SO 2 -, R 5 OC (O) -, R 5 R'NC (O) -, R 5 R'NC (S ) -, R'HNCH (R ') C (O) - or ^{R 5 OC (O) NR'CH (} R') C (O) - in which either; or R ⁶ and R ⁷ are linked, pyrrolidine , Forming a piperidine or morpholine ring; each R ′ is independently H, C _1-6 alkyl, Ar—C _0-6 alkyl or Het—C _0-6 alkyl: R ^* is H, C _{1 -6} alkyl, C _3-6 cycloalkyl -C _0-6 alkyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl; Y is in single bond or O; each Z is independently , it is CO or CH _2; n is 1 Or a pharmaceutically acceptable salt thereof, which is an inhibitor of cysteine protease, particularly cathepsin K, and which is useful for treating a disease in which suppression of bone loss is a factor. .

Description

DETAILED DESCRIPTION OF THE INVENTION                   Inhibitors of cysteine protease   Field of the invention   The present invention relates to novel protease inhibitors, in particular cysteine and serinep. Inhibitors of Rotase, more specifically inhibitors of cysteine protease Compound, more specifically the cysteine protease of the papain superfamily Compounds that inhibit, and even more particularly, the cysteine proteins of the cathepsin family Compounds that inhibit thease, most particularly those that inhibit cathepsin K You. Such compounds are useful in diseases involving cysteine proteases, especially in excessive bone or Is particularly useful for treating diseases of cartilage loss such as osteoporosis, periodontitis and arthritis is there.   Background of the Invention   Cathepsin K is a member of the papain superfamily of cysteine proteases. Part of the family of enzymes. Cathepsins B, H, L, N and S are It is described in the literature. Recently, cathepsin K polypeptides and such polypeptides A cDNA encoding the tide was disclosed in US Pat. No. 5,501,969 (the US Pat. No. 5,501,969). Here referred to as cathepsin O). In recent years, cathepsin K has been expressed, purified and characterized Attached. Bossard, M.S. J. et al., (1996) Biol. Chem. 271, 12517-12524; Dra ke, F.H., et al. Biol. Chem. 271, 12511-12516; Bromme, D. et al. (1996) J. . Biol. Chem. 271,2126-2132o Cathepsin K is described in the literature as cathepsin O, Variously designated as tepsin X or cathepsin O2. Cathepsin K Is considered more appropriate (Nomenclature Council of the Intern Named by the ational Union of Biochemistry and Molecular Biology Was).   Cathepsins of the papain superfamily of cysteine proteases are human Normal physiological processes of proteolysis in animals, including Acts on the disintegration of weave. However, increased levels of these enzymes in the body Can result in pathological conditions that cause disease. Therefore, cathepsins are not limited. But not pneumocys tiscarinii, cruise bird Panosoma (trypsanoma cruzi), Blues trypanosoma (trypsanoma bruce) i) and infection by Crithidia fusiculata; Scrub schistosomiasis, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy It is related to various pathologies such as fee and muscular atrophy. Released on March 3, 1994 See International Publication No. WO 94/04172 and references cited therein. Ma See also European Patent Application EP 0 603 873 A1 and references cited therein. thing. P. gingival called gingipain lis) are involved in the pathogenesis of gingivitis I have. Potempa. J. et al., (1994) Perspectives in Drug Discovery and Design, 2,445-458.   Cathepsin K plays a causal role in diseases of excessive bone or cartilage loss. It is thought to help. Bone consists of spindle-shaped or plate-shaped crystals of hydroxyapatite. Consists of an incorporated protein matrix. Type I collagen is a major component It is a protein making up about 90% of the structural proteins. The rest of the matrix 10% of osteocalcin, proteoglycan, osteopontin, male Theonectin, thrombospondin, fibronectin and bone sialoprotein Consists of a number of non-collagenous proteins, including quality. Skeletal bones are Remodeling with a discontinuous focus. These focus or remodeling The position undergoes a cycle consisting of a bone resorption phase followed by a bone replacement phase.   Bone resorption is performed by osteoclasts, which are multinucleated cells of the hematopoietic system. Osteoclast is bone Attaches to the surface and forms a tight blockade, then the osteoclast tip That is, a wide range of film waviness occurs on the (absorption) surface. This allows you to surround Extracellular compartment is formed on the bone surface and proton pumps in the corrugated membrane By which osteoclasts secrete proteolytic enzymes. Tampa As the digestive enzymes digest the protein matrix, Low pH dissolves hydroxyapatite crystals at the bone surface. In this way, bone resorption A fossa (lacuna or pit) is formed. At the end of this phase of the cycle, osteoblasts A new protein matrix that subsequently calcifies is constructed. Osteoporosis and In some conditions, such as Paget's disease, there is a normal path between bone resorption and formation. The lance collapses and there is a net loss of bone each cycle. Finally, this is a bone Can result in an increased risk of fracture with minimal trauma.   Abundant selective expression of cathepsin K in osteoclasts indicates that the enzyme is essential for bone resorption Strongly suggests that Therefore, the selective inhibition of cathepsin K is limited. No, but gingival diseases such as osteoporosis, gingivitis and periodontitis, Paget's disease, malignancy Effective for excessive bone loss, including hypercalcemia and metabolic bone disease Treatment may be provided. Cathepsin K levels also affect cartilage resorbing cells of the osteoarthritis synovium. Has been proven to increase. Thus, the selective inhibition of cathepsin K also Excessive cartilage, including but not limited to osteoarthritis and rheumatoid arthritis May also be useful in the treatment of disorders of matrix degradation. Metastatic tumor cells also Typically expresses high levels of proteolytic enzymes that degrade the surrounding matrix I do. Therefore, selective inhibition of cathepsin K may also be useful in the treatment of certain neoplastic diseases. May also be useful.   This time, a new series of compounds is a protease inhibitor, most particularly a categorical inhibitor. Inhibitors of psin K, these compounds are required to inhibit bone resorption It has been found useful in the treatment of diseases such as osteoporosis and periodontal disease.   Summary of the Invention   It is an object of the present invention to provide protease inhibitors, in particular cysteine and serinep. Inhibitors of Rotase, more specifically inhibiting cysteine proteases Compounds, even more particularly the papain superfamily cysteine Compounds that inhibit proteases, even more particularly cathepsin Compounds that inhibit Milly's cysteine protease, most particularly cathep A compound that inhibits syn-K and alters the activity of such proteases Protease inhibitors useful in the treatment of diseases that can be therapeutically modified by To provide bitter.   Accordingly, in a first aspect, the present invention provides a compound of formula (I).   In another aspect, the invention comprises a compound of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising:   In yet another aspect, the invention is a method of treating a disease, comprising a protease, particularly a protease. Cysteine and serine proteases, more particularly cysteine proteases, Even more particularly, the cysteine proteases of the papain superfamily, More particularly, the cysteine proteases of the cathepsin family, the most detailed Provides a therapeutic method capable of therapeutically modifying a disease state by inhibiting cathepsin K I do.   In a particular embodiment, the compounds of the present invention provide a disease characterized by bone loss, for example, Gingival diseases such as osteoporosis and gingivitis and periodontitis, or excessive cartilage or Are diseases characterized by matrix degradation, such as osteoarthritis and rheumatoid arthritis It is particularly useful in the treatment of H.   Detailed description of the invention   The present invention provides a compound of formula (I): [Where,   R¹Is Is;   R^TwoIs H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_0-6 Alkyl, Het-C_0-6Alkyl, R^FiveC (O)-, R^FiveC (S)-, R^FiveSO_Two-, R^Five OC (O)-, R^FiveR'NC (O)-, R^FiveR'NC (S)-, adamantyl-C (O)- Or Is;   Each R ″ is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl or Het- C_0-6Alkyl;   R '' 'is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_0-6 Alkyl or Het-C_0-6Alkyl;   Each R^ThreeAre independently H, C_2-6Alkenyl, C_2-6Alkynyl, Het, Ar Or 0R ', SR', NR '_Two, R'NC (O) OR^Five, CO_TwoR ', CO_TwoNR '_Two, N (C = NH) NH_Two, Het or C optionally substituted with Ar_1-6With alkyl Yes;   R^FourIs H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_{0- 6} Alkyl, Het-C_0-6Alkyl, R^FiveC (O)-, R^FiveC (S)-, R^FiveSO_Two−, R^FiveOC (O)-, R^FiveR'NC (O)-, R^FiveR'NC (S)-, R'HNCH (R ') C ( O)-or R^FiveOC (O) NR'CH (R ') C (O)-;   Each R^FiveIs independently C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_0-6Archi Le, Het-C_0-6Alkyl, Ar-C_0-6Alkoxy, Het-C_0-6Alkoki Or OR ', SR', NR '_Two, R'NC (O) OR^Five, CO_TwoR ', CO_TwoN R '_Two, N (C = NH) NH_Two, Het or C optionally substituted with Ar_1-6A Luquil;   R⁶Is H, C_1-6Alkyl, Ar-C_0-6Alkyl or Het-C_0-6Alkyl And R⁷Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, A r-C_0-6Alkyl, Het-C_0-6Alkyl, R^FiveC (O)-, R^FiveC (S)-, R^Five SO_Two-, R^FiveOC (O)-, R^FiveR'NC (O)-, R^FiveR'NC (S)-, R'HN CH (R ') C (O)-or R^FiveOC (O) NR'CH (R ') C (O)-; or Is R⁶And R⁷Are linked to form a pyrrolidine, piperidine or morpholine ring ;   Each R 'is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl or Het- C_0-6Alkyl;   R^*Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_{0- 6} Alkyl or Het-C_0-6Alkyl;   Y is a single bond or O;   Each Z is independently CO or CH_TwoIs;   n is 1, 2 or 3] Or a pharmaceutically acceptable salt thereof.   Preferably, the present invention provides a compound of formula (Ia) [Where,   R¹Is Is;   R^TwoIs Is;   X is CO, SO_TwoOr CH_Two-CO;   Y is a single bond or O;   Z is CO or CH_TwoIs;   Each R^ThreeIs independently C_4-6Alkyl, C_4-6Alkenyl or benzyl;   R^FourIs C_1-6Alkyl, Ar-C_0-6Alkyl, R^FiveCO-, R^FiveSO_Two-R^FiveOC ( O)-or R^FiveNHCO;   R 'is H or C_1-4Alkyl;   R⁶Is H or C_1-4Alkyl;   R⁷Is C_1-6Alkyl, Ar-C_0-6Alkyl, R^FiveCO-, R^FiveSO_Two-R^FiveOC ( O)-or R^FiveNHCO;   Each R^FiveIs independently Ar-C_0-6Alkyl or Het-C_0-6Alkyl ;   n is 1 or 2] Or a pharmaceutically acceptable salt thereof.   The present invention also includes hydrates, solvates, complexes and prodates of the compounds of the present invention. Lugg is also included. Prodrugs release the active parent drug of formula (I) in vivo It is believed that any covalently bound carrier that emerges. The compound of the present invention is 1 Or more chiral centers, unless otherwise specified. Includes each unique non-racemic compound that can be synthesized and resolved by conventional methods. Compound When present in tautomeric forms, such as keto-enol tautomers, each tautomeric form is Balance or one of the forms predominantly considered to be included in the present invention. It is.   At any one of the events in formula (I) or any supplementary formula thereof The meaning of a substituent of is, unless stated otherwise, its meaning or occurrence in any other event. It is independent of the meaning of any other substituents.   With respect to formula (Ia):   Suitably, R¹Is(Where R^FourIs R^FiveOC (O)-, wherein R^FiveIs preferably Is).   Suitably, R^TwoIs (Where Z is CO and R⁷Is R^FiveOC (O)-, wherein R^FiveIs preferably Is).   Suitably, R 'and R⁶Are each H and each R^ThreeIs i-butyl.   Certain representative compounds of the present invention include:   Trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl) -1--3-diamino-cyclopentanone and   Trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl) -1--3-diamino-cyclohexanone; Or a pharmaceutically acceptable salt thereof.   Abbreviations and symbols commonly used in the peptide and chemical arts are compounds of the present invention. Is used herein to describe Generally, amino acid abbreviations are described in Eur. J. Bi ochem., 158, 9 (1984), as described in the IUPAC-IUB Joint Commission. Follow on Biochemical Nomenclature. Amino as used herein The word acid is alanine, arginine, asparagine, aspartic acid, cysteine , Glutamine, glutamic acid, glycine, histidine, isoleucine, leucine , Lysine, methionine, phenylalanine, proline, serine, threonine, Refers to the D- or L-isomer of tryptophan, tyrosine and valine.   C as applied herein_1-4Alkyl is substituted and unsubstituted methyl, ethyl, Includes n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups Means to include. Besides, C_1-6Alkyl is a substituted or unsubstituted pliers , N-pentyl, isopentyl, neopentyl and hexyl and their simple Includes pure aliphatic isomers. Any C_1-4Alkyl or C_1-6The alkyl group is , OR ', N (R') unless otherwise specified_Two, SR ', CF_Three, NO_Two, CN, CO_TwoR ' And CON (R ′) may be substituted with 1 to 3 groups selected from Besides, C_0-4Alkyl and C_0-6Alkyl requires an alkyl group to be present No (eg, a covalent bond is present).   C as applied herein_3-6Cycloalkyl is substituted and unsubstituted cyclopropyl Includes lopan, cyclobutane, cyclopentane and cyclohexane. means.   C as applied herein_2-6Alkenyl has a carbon-carbon single bond of carbon-carbon. Means an alkyl group of 2 to 6 carbons replaced by an elemental double bond. C_2-6Alkenyl is ethylene, 1-propene, 2-propene, 1-butene, 2- Includes butene, isobutene and several isomers pentene and hexene. Shi Both the trans and trans isomers are included.   "C_2-6“Alkynyl” is a compound wherein one carbon-carbon single bond is a carbon-carbon triple bond. A substituted 2 to 6 carbon alkyl group is meant. C_2-6Alkynyl Is acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3- Includes butyne and the simple isomers of pentine and hexine.   "Halogen" or "halo" means F, Cl, Br and I.   “Ar” or “aryl” is unsubstituted phenyl or naphthyl; Ph-C above_0-6Alkyl, Het-C_0-6Alkyl, C_1-6Alkoxy, Ph -C_0-6Alkoxy, Het-C_0-6Alkoxy, OH, (CH_Two)_1-6NR'R ', O (CH_Two)_1-6NR'R '(where each R' is independently H, C_1-6Alkyl, Ar- C_0-6Alkyl or Het-C_0-6Phenyl substituted with alkyl) Or naphthyl; or C_1-4Alkyl, OR ', N (R')_Two, SR ', CF_Three, N O_Two, CN, CO_Two1 selected from R ′, CON (R ′), F, Cl, Br and I Substituted with 3 to 3 groups or substituted with a methylenedioxy group Means phenyl or naphthyl.   As used herein, “Het” or “heterocyclic” refers to a saturated or unsaturated And is selected from the group consisting of carbon atoms and N, O and S Stable 5- to 7-membered mono- or 7- to 10-membered heteroatoms A bicyclic heterocyclic ring wherein the nitrogen and sulfur heteroatoms may be oxidized The nitrogen heteroatom may be quaternized, and any of the above heterocyclic rings may be A heterocyclic ring including any bicyclic ring bonded to a benzene ring. Complex Cyclic rings are attached at any heteroatom or carbon atom that results in a particular stable structure May be C_1-4Alkyl, OR ', N (R')_Two, SR ', CF_Three, NO_Two, CN, CO_TwoR ′, CON (R ′), F, Cl, Br and I (where R ′ is Which is the same as described above). Or Examples of such heterocycles are piperidinyl, piperazinyl, 2-oxopiperazinyl, 2 -Oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, aze Pinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidi Nil, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolini , Oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolyl Nil, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl , Benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pirani , Tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl , Thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazo Ryl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyri Mizini , Cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, t Including tolazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl .   “HetAr” or “heteroaryl” is as defined above for Het. Any heterocyclic group, including aromatic groups, for example, pyridinyl, Quinolinyl, isoquinolinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl , Pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxa Zolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl, benzothi Azolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, syn Nolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,6-na Butyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, tetrazolyl Heterocyclic groups which are 1,2,3-triazolyl and 1,2,4-triazolyl To taste.   In this specification, certain groups are abbreviated. t-Bu means a tertiary butyl group, and Boc is a t-butyloxycarbonyl group, and Fmoc is fluorenylmethoxy A phenyl group; and Cbz a benzyloxycarbo group. Means a nyl group.   In this specification, a specific reagent is abbreviated. DCC is dicyclohexylcarbodiimide DMAP is 2,6-dimethylaminopyridine and EDC is N-ethyl. Ru-N '(dimethylaminopropyl) -carbodiimide. HOBt is 1-hydroxybenzotriazole means DMF is dimethylformamide BOP means benzotriazol-1-yloxytris (dimethylamido) D) Phosphonium hexafluorophosphate, DMAP stands for dimethylamine Minopyridine, and Lawesson's reagent is 2,4-bis (4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide, NMM Is N-methylmorpholine, TFA means trifluoroacetic acid, TFAA Means trifluoroacetic anhydride, and THF means tetrahydrofuran.   Compounds of formula (I) are generally   Formula (II) having any protected reactive functional groups: [Wherein, R¹, R^Two, R ″, R ′ ″ and n are as in formula (I)] Reacting a compound of formula with an oxidizing agent;   Thereafter, any protecting groups may be removed to form a pharmaceutically acceptable salt. It is prepared using a method consisting of:   Compounds of Formula I wherein n is 1 are prepared in an analogous manner to that described in Scheme 1. You.Scheme 1 a: LAH; b: triphenylphosphine, DEAD, phthalimide; c: Na BH_FourD: NBS; e: KOH; f: NH_ThreeG: Cbz-Leu-OHN, E DCI, HOBT; h: Jones   According to Scheme 1, cyclopenten-2-ol (Brown, HC; Hess, H . M. J. Org. Chem. Mitsunobu (as described in 1969, 34, 2206) The reaction was converted to the phthalimide. Phthal in sodium borohydride Reduction of the imide, followed by bromination of the alkene with N-bromosuccinimide, results in N -(1 (3H) -isobenzofuranylidene) -1-bromo-2-hydroxy-cy A clopentyl-3-amine synthetic intermediate was obtained, and the epoxide was synthesized using potassium hydroxide. Converted to Cid. The epoxide is treated with ammonia in a cylinder and trans-1, 3 -To obtain diaminocyclopentanol, which is then acidified with Cbz-leucine / HBTU. And oxidized to give the desired trans-N, N'-bis- (benzyloxycarbo Nyl-L-leucinyl) -1--3-diamino-cyclopentanone was obtained.   Compounds of Formula I where n is 2 are prepared in an analogous manner to that described in Scheme 2. You.                                Scheme 2 a: Cbz-Leu-OH, EDCI, HOBT; b: Jones   According to Scheme 2, a known 1,3-diamino-cyclohexanol (Sammes , P. G .; Phetford, D .; J. Chem. Soc. Perkin Trans. 1, 1989, 655 ) Is acylated with Cbz-leucine / HBTU and oxidized to give the desired trans -N, N'-bis- (benzyloxycarbonyl-L-leucinyl) -1,3-di Amino-cyclohexanone was obtained.   The starting materials used herein are either commercially available amino acids or CO 2 MPENDIUM 0F 0RGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience) Prepared by standard methods well known in the art, such as those found in standard reference books Is done.   Coupling methods for forming amide bonds herein are well known in the art. It is generally well known. Generally, THE PRACTICE 0F PEPTIDE SYNTHESIS, Springe r-Verlag, Berlin, 1984; Gross and J.W. Meienhofer, THE PEPTIDES, Vol. 1 , 1-284 (1979); M. Stewart and J.W. D. Young, SOLID PHASE PEPTI DE SYNTHESIS, 2nd edition, Pierce Chemical Co., Rockford, The method of peptide synthesis shown in III., 1984 is generally an example of the technology Is a part of the present specification.   Synthetic methods for preparing compounds of the invention often mask reactive functionality Or to use protecting groups to minimize unwanted side reactions. Take Protecting groups are generally described in Green, T.W. W., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). Amino protecting groups are generally As is well known in the art, Boc, acetyl, benzoyl, Fmoc and Refers to a Cbz group and its derivatives. Protection and deprotection and amino protection Methods for substitution with other groups are well known.   The acid addition salts of the compounds of formula (I) may be prepared by subjecting the parent compound and an excess of the acid, e.g. For example, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluorovinegar Prepared from acids, maleic, succinic and methanesulfonic acids by standard methods. Special Certain compounds form acceptable inner salts or zwitterions. Cation salt Is an excess of an alkaline reagent containing a suitable cation, such as a hydroxide, Carbonates or alkoxides; or by treatment with a suitable organic amine Prepare. Li⁺, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺And NH_Four ⁺Cations such as Is a particular example of a cation present in a pharmaceutically acceptable salt. Halide, sulfur Acid salts, phosphates, alkanoates (eg acetate and trifluoroacetate), Benzoates and sulfonates (eg, mesylate) are pharmaceutically acceptable salts Is an example of an anion present in   The present invention also comprises a compound of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition is provided. Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament. . The pharmaceutical composition of the compound of formula (I) prepared as described above may be a solution for parenteral administration. It may be formulated as a liquid or lyophilized powder. Powder should be mixed with a suitable diluent before use Alternatively, it can be restored by adding another pharmaceutically acceptable carrier. Liquid preparation May be a buffered isotonic aqueous solution. Examples of suitable diluents are ordinary isotonic sailors Solution, standard 5% dextrose water or sodium acetate or ammonium Buffer. Such formulations are particularly suitable for parenteral administration, but are also suitable for oral administration. Inhaler or nebulizer with dose meter for inhalation To May be included. Polyvinylpyrrolidone, gelatin, hydroxycellulose, Labia gum, polyethylene glycol, mannitol, sodium chloride or It may be desirable to add excipients such as sodium enoate.   Alternatively, these compounds may be encapsulated, tableted, or Alternatively, they may be prepared into emulsions or syrups. Pharmaceutically acceptable solid Alternatively, a liquid carrier can be added to enhance or stabilize the composition, or to prepare the composition. Can be easily manufactured. Solid carrier is starch, lactose, calcium sulfate dihydrate Material, clay, magnesium stearate or stearic acid, talc, pectin , Gum arabic, agar or gelatin. Liquid carriers include syrup, pea Includes nut oil, olive oil, saline and water. The carrier is monos Alone with a retardant such as glyceryl theate or glyceryl distearate Or it may be included with wax. The amount of solid carrier varies, but preferably, About 20 mg to about 1 g per dosage unit. The pharmaceutical preparation, when in tablet form, is Crushing, mixing, granulating and compressing; powder in the case of hard gelatin capsule form It is prepared according to the prior art of preparations consisting of grinding, mixing and filling. Uses liquid carrier Preparations may be syrups, elixirs, emulsions or aqueous or non-aqueous It is in the form of an aqueous suspension. Such liquid formulations may be administered directly orally, or It may be filled into soft gelatin capsules.   For rectal administration, the compounds of the present invention may also include cocoa butter, glycerin, It can be combined with excipients such as tin or polyethylene glycol to make a suppository. Good.   The compounds of formula (I) are useful as protease inhibitors, in particular cysteine and And more specifically cysteine protein inhibitors as inhibitors of serine proteases As an inhibitor of ose, more particularly the papain superfamily As an inhibitor of cysteine proteases, even more particularly cathepsin Inhibitors of the family cysteine proteases, most particularly Useful as an inhibitor of Syn-K. The present invention also provides a pharmaceutical composition of the compound. Also provided are useful compositions and formulations of the compounds, including and formulations.   The compounds of the present invention are cysteine protease related diseases, Mossistis Carini, Trypanosoma cruzi, Trypanosoma brucei and Infection with Criticia fusiculata; and schistosomiasis, malaria, tumor turnover Transfer, metachromatic leukodystrophy, muscular dystrophy, muscular atrophy; Diseases associated with Psin K, most particularly including osteoporosis, gingivitis and periodontitis Gingival disease, arthritis, more particularly osteoarthritis and rheumatoid arthritis, -Excessive bone, including Jet's disease, malignant hypercalcemia and metabolic bone disease Or it is useful for treating diseases of cartilage loss.   Metastatic tumor cells also typically have high levels of degrading surrounding matrix. Expressing proteolytic enzymes, certain tumors and metastatic tumorigenesis are The compound can be effectively treated.   The invention also relates to pathological levels of proteases, in particular cysteine and serine. Protease, more particularly cysteine protease, and even more particularly daddy In-superfamily cysteine proteases, and even more particularly cathepsin For the treatment of diseases caused by cysteine proteases Thus, animals requiring treatment, particularly mammals, most particularly humans, are Also provided are methods comprising administering a compound. The invention is particularly useful for pathological levels. Is a method of treating a disease caused by cathepsin K, which requires treatment Animals, especially mammals, and more particularly, humans, may be exposed to cats containing the compounds of the present invention. There is provided a method comprising administering an inhibitor of Psin K. The present invention is Rimini, Pneumocystis carini, Trypanosoma cruise, Bruce Tripa Infections by Nosoma and C. fusiculata; and schistosomiasis, Laria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, muscular atrophy Diseases involving cysteine proteases, including, and in particular, cathepsin K Related diseases, most particularly gingival diseases including osteoporosis, gingivitis and periodontitis Disease, arthritis, more particularly osteoarthritis and rheumatoid arthritis, Paget Excessive bone or cartilage, including disease, malignant hypercalcemia and metabolic bone disease Provide treatment for loss of disease.   The present invention is further directed to a method for treating osteoporosis or inhibiting bone loss, comprising the formula (I) ) And other inhibitors of bone resorption, such as bisphosphonates (Ie, alendronate), hormone replacement therapy, There is provided a method comprising in vivo administration of a trogen or calcitonin. In addition, Light compounds and anabolic agents such as bone morphogenetic proteins, iproflavone May be used to prevent bone loss and / or increase bone mass .   For acute treatment, parenteral administration of the compounds of formula (I) is preferred. Intramuscular pill Injection is also useful, but compound in 5% dextrose water or normal saline Alternatively, intravenous injection of a similar formulation containing appropriate excipients is most effective. Typical Typically, parenteral doses are present in plasma at concentrations effective to inhibit cathepsin K. From about 0.01 to about 100 mg / kg; Or 0.1 to 20 mg / kg. Compound has a total daily dose of about 0.4 Administer 1 to 4 times a day at a level to reach about 400 mg / kg / day You. The exact level and manner in which the compound is administered depends on the blood level of the drug and the therapeutic effect. Can be easily determined by one skilled in the art by comparing the concentrations necessary to obtain You.   The compounds of the present invention also inhibit bone resorption, in addition to the indications disclosed herein. May be administered orally to the patient in such a way as to provide a sufficient drug concentration to effect the drug. Typically, a pharmaceutical composition containing the compound is administered in an amount of about 0.1 to about 50 mg / kg. Oral doses are administered in a manner consistent with the patient's condition. Preferably, the oral dose is From about 0.5 to about 20 mg / kg.   When a compound of the present invention is administered in accordance with the present invention, unacceptable toxicological effects are Unexpected.   The compounds of the present invention can be tested in one of several biological assays to The concentration of the compound required to obtain the result may be determined.   Measurement of cathepsin K proteolytic catalytic activity:   All assays for cathepsin K are human recombinant enzymes from osteoclastoma This was performed using See, for example, Inaoka et al., Biochem. Biophys. Res. Commun., 1995, Methods for obtaining such enzymes, as disclosed in Hoppe-Seyler, 1995, 376, 379 Are well known in the art. Standard assay conditions for determining rate constants are fluorescence Using a generated peptide substrate, typically Cbz-Phe-Arg-AMC, 20 m 100 mM Na acetate containing M cysteine and 5 mM EDTA, pH 5.5. Decided in. The stock substrate solution is prepared at a concentration of 10 or 20 mM in DMSO, A final substrate concentration of 20 μM was used during the assay. All assays contain 10% DMSO. I had. Independent experiments have shown that this DMSO level can affect enzyme activity or rate constants. Turned out to have no effect. All assays were performed at ambient temperature. Product firefly Light (excitation light: 360 nM; emission: 460 nM) was converted to Perceptive Biosystems CytofluorI. Monitored with an I fluorescent plate reader. The production curve follows the formation of the AMC product. Over 20 to 30 minutes.   Inhibition of cathepsin K activity:   Use the progress curve method to evaluate potential inhibitors Was. Assays were performed in the presence of various concentrations of test compound. Inhibitors and The reaction was started by adding the enzyme to a buffer solution of the substrate. Inhibitor Data according to one of two methods with an apparent curve in the presence of Data analysis. For compounds with a linear course, the apparent inhibition constant (K i, app) is given by Equation 1 (Brandt et al., Biochemistry, 1989, 28, 140): [Where ν is the reaction rate, the maximum rate is Vm, and A is the substrate concentration at the Michaelis constant Ka. Where I is the inhibitor concentration] Calculated according to   For compounds whose course shows a downward curve characteristic of time-dependent inhibition, Analyzing the data from the set, Equation 2: Where [AMC] is the concentration of the product formed at time t,₀Is the starting reaction rate Oh, ν_ssIs the final steady-state velocity.] According to K_obsI got Then K_obsAs a linear function of inhibitor concentration To determine the apparent second-order rate constant (K_obs/ Inhibitor concentration Or K_obs/ [I]). A complete discussion of this kinetic process is well-documented. (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201). ).   The compounds of the present invention have a concentration of about 15 micromolar at which competitive kinetics are observed. Inhibits human cathepsin K enzyme with Ki in the range. Representation of nonlinear kinetics The compound has a K of about 56 / (Mx seconds)_obsIs shown.   The compounds of the invention may also be used in the art to measure inhibition of bone formation. Standard assays, for example the bone resorption pits disclosed in EP 528 587 Tested for bone resorption in vitro and in vivo in a bioassay And using human osteoclasts instead of rat osteoclasts according to the following method May go.   Human osteoclast resorption assay   Aliquots of cell suspension from osteoclastoma were removed from liquid nitrogen storage and immediately At 37 ° C and centrifuged (1000 rpm, 5 minutes, 4 ° C) by RPMI- Washed once in 1640 medium. The medium is aspirated and 1 medium in RPMI-1640 medium : Replace with mouse anti-HLA-DR antibody diluted in 3, and incubate on ice for 30 minutes Was added. The cell suspension was mixed frequently.   The cells are centrifuged (1000 rpm) for 5 minutes, 4 ° C) by cold RPMI-164. Washed twice at 0 and then transferred to a sterile 15 mL centrifuge tube. Improved Neubauer -Count the number of mononuclear cells in the improved Neubauer counting chamber Was.   Sufficient magnetic beads (5 / mononuclear cells) coated with goat anti-mouse IgG Removed from their storage bottles and placed in 5 mL of fresh medium (this resulted in toxic Wash off azide preservative). Remove media by fixing beads on magnet And replaced with fresh medium.   The beads were mixed with the cells and the suspension was incubated on ice for 30 minutes. Suspension The liquid was often mixed. The bead-coated cells were fixed on a magnet and the remaining cells (broken). The bone cell-rich fraction) was decanted into a sterile 50 mL centrifuge tube. New culture The ground was added to the bead-coated cells to move any captured osteoclasts. This Was repeated 10 times. The bead-coated cells were discarded.   Large hole disposable plastic Pasteur pipette to fill chamber with sample Osteoclasts were counted in a counting chamber using a microplate. By centrifugation And pellet the cells with 10% fetal bovine serum and 1.7 g / l heavy carbon. 1.5 × 10 in EMEM medium supplemented with sodium citrate^Four/ ML osteoclast density It was adjusted. Transfer a 3 mL aliquot (per treatment) of the cell suspension into a 15 mL centrifuge tube. I cant do it. These cells were pelleted by centrifugation. Appropriate processing of each tube Added to 3 mL (diluted to 50 μM in EMEM medium). Also a suitable vehicle Control, positive control (87 MEM1 diluted to 100 μg / mL) and isomer control (IgG2a diluted to 100 μg / mL) was also included. Tube at 37 ° C for 30 minutes Incubated.   0.5 mL aliquots of cells on sterile dentin slices in 48 well plates And incubated at 37 ° C. for 2 hours. Each treatment was screened four times. Slice the slices 6 times with warm PBS (10 mL / well in a 6-well plate) Replace and wash, then place in fresh treatment or control and incubate at 37 ° C for 48 hours. Incubated. The slices are then washed in phosphate buffered saline and 2% Fix in glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes, Afterwards, they were washed in water and incubated in buffer at 37 ° C. for 5 minutes. The slices are then washed with cold water and cold acetate buffer / fast red garnet. And incubated at 4 ° C for 5 minutes. Aspirate excess buffer and wash in water The slices were air dried.   TRAP-positive osteoclasts were counted by bright-field microscopy, followed by sonication. Was removed from the dentin surface. Bone using Nikon / Lasertec ILM21W confocal microscope The resorption cavity volume was measured.   The compounds of the invention are also standard in the art for measuring inhibition of bone formation. In vivo bone resorption assays, e.g., Wronski et al., Cells and Materials 199. 1, Sup. It was also tested in the ovariectomized rat model described in 1,69-74.General   Nuclear magnetic resonance spectra were obtained at B or B at either 250 or 400 MHz, respectively. ruker AM 250 or Bruker AC 400 spectrometer And recorded. CDCl_ThreeIs deuteriochloroform, DMSO-d₆ Is hexadeuteriodimethylsulfoxide, CD_ThreeOD is Tetraju Teriomethanol. Chemical shifts from the internal standard tetramethylsilane The number of low magnetic fields is indicated by (d). Abbreviations of NMR data are as follows: S = singlet, d = doublet, t = triplet, q = quadruple, m = multiplet, d d = two sets of double lines, dt = two sets of triple lines, app = apparent, br = wide. J is H 2 shows the NMR coupling constant measured by erz. Continuous wave infrared (IR) spectrum erkjn-Elmer 683 Infrared spectrometer, Fourier recording The converted infrared (FTIR) spectrum was converted to Nicolet Impact 400. D Infrared spectrometer recorded. Transmits IR and FTIR spectra Rate and record the band position as the inverse wave number (cm^-1). Mass spectrum VG70F using a child impact (FAB) or electrospray (ES) ionization technique E, obtained on either PESyx API III or VG ZAB HF instrument . Elemental analysis was obtained using a Perkin-Elmer 240 elemental analyzer. Melting point Are obtained on a Thomas-Hoover melting point apparatus and are uncorrected. Show all temperatures in Celsius .   Analtech Silica Gel GF and E.I. Merck Silica Gel 60 F-254 thin plate Was used for thin layer chromatography. Flash and gravity chromatography Both of E. Run on Merck Kieselgel 60 (230-400 mesh) silica gel Was.   Where indicated, certain substances were identified by Aldrich Chemical Co., Milwaukee, Wiscons. in, Chemical Dynamics Corp., South Plainfield, New Jersey and Advanced It was purchased from Chemtech, Louisville, Kentucky.   In the following synthesis examples, the temperature is Celsius (° C.). Unless otherwise specified, all Starting material was obtained from the market. Without further elaboration, those skilled in the art will, from the above description, We believe that the invention can be used to its fullest extent. These examples are based on the present invention. It is provided to illustrate the description and is not intended to limit its scope. In the text below, Refer to the claims for what is guaranteed to the plaintiffs.                                 Example 1 Trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl)- Preparation of 1-3-diamino-cyclopentanone a) 3-N-phthalimide-cyclopentene   Cyclopent-2-en-ol (1.05 g, 12.5 mmol) (Brown H.C .; Hess, H.M. J. Org. Chem. 1969, 34, 2206) in THF ( 20 ml). Then phthalimide (2.05 g, 14 mmol) , Triphenylphosphine (3.675 g, 14 mmol) and diethylazo Dicarboxylate (2.43 g, 14 mmol) was added and the reaction was left at room temperature for 1 hour. While stirring. The reaction mixture is concentrated under vacuum and then chromatographed (silica Kagel, 5% EtOAc / hexanes gave the title compound as a white solid (1.0%). g, 37%). b) N-3-cyclopentene- (2-methylenehydroxy) -benzamide   3-N-phthalimido-cyclopentene (1.0 g, 4.7 mmol) Dissolved in propanol (12 ml) and water (2 ml). Sodium borohydride At 0 ° C., then warmed to room temperature. The reaction mixture was treated with EtOAc (100 m l), then extract with water, dry over magnesium sulfate, filter, vacuum And chromatographed (silica gel, 30% Et0Ac / hexane) To give a white solid (0.22 g, 22%). MS (ESI): M + H⁺= 218 c) trans, cis-N- (1 (3H) -isobenzofuranylidene) -1-bro Mo-2-hydroxy-cyclopentyl-3-amine   N-3-cyclopentene- (2-methylenehydroxy) -benzamide (0. 22 g, 1.0 mmol) in chloroform (5 ml). Cuccinimide (0.2 g, 1.2 mmol) was added at room temperature and stirred for 1 hour. Dissolution The solution was diluted with chloroform (100 ml),_TwoS_TwoO_Three-5H_TwoO water soluble Extract, dry over magnesium sulfate, filter, concentrate and chromatograph Lycagel, 25% EtOAc / hexanes to give the title compound as a white solid (0%). . 13g, 43%). MS (ESI): M + H⁺= 296 d) cis-N- (1 (3H) -isobenzofuranylidene) -cyclopentene-2 -Oxide-1-amine   Trans, cis-N- (1 (3H) -isobenzofuranilidene) -1-bromo-2 -Hydroxy-cyclopentyl-3-amine (2 g, 6.8 mmol) was added to EtOH (3 ml), then add potassium hydroxide (0.5 g, 9 mmol) ), The reaction was stirred at room temperature for 3 hours. The reaction was washed with water and EtOAc (1: 1, 1 00 ml), and the combined organic layers are dried, filtered, concentrated and chromatographed. To give the title compound as an oil, which solidified on standing (1.17 g). , 81%). MS (ESI): M + H⁺= 216 e) (+-)-trans-1,3-diaminocyclopentanol   Cis-N- (1 (3H) -isobenzofuranylidene) -cyclopentene-2- Oxid-1-amine (0.5 g, 2.3 mmol) in EtOH (10 ml) And concentrated aqueous ammonium hydroxide solution was added (18 ml). Reaction mixture Sealed in a teal cylinder and heated to 100 ° C. for 1 hour. The reaction is then brought to room temperature. , Extracted with methylene chloride, dried, filtered, concentrated and lyophilized to give a white A solid was obtained and used for the following reaction without further purification (0.25 g, 94%). MS (ESI): M + H⁺= 117 f) trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl ) -1--3-Diamino-cyclopentanol   10 of N-Cbz-L-leucine (Bachem) (0.64 g, 2.4 mmol) Add (+-)-trans-1,3-diaminocyclopen to the stirred solution in mL DMF. Tanol (0.14 g, 1.2 mmol), 1- (3-dimethylaminopropyl ) -3-Ethylcarbodiimide hydrochloride (0.46 g, 2.4 mmol) and 1 -Hydroxybenzotriazole (0.324 g, 2.4 mmol) was added. After stirring at room temperature for 3.5 hours, the solution was diluted with EtOAc (200 ml) and combined The organic layer was extracted with water, brine, then dried over magnesium sulfate, filtered, Concentrate in vacuo and chromatograph (silica gel; 80% EtOAc / hex) The title compound was obtained as a white solid (0.18 g, 25%). MS (ESI): M + H⁺= 611 g) trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl) ) -1--3-Diamino-cyclopentanone   Trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl) -1-Diamino-cyclopentanol (0.17 g, 0.28 mmol) Dissolved in acetone (2 ml). Jones reagent (0.5ml, 1.5M) The reaction was stirred overnight. The excess Jones reagent is then added to isopropanol. (1 ml), dilute the reaction with water (10 ml) and add EtOAc (2 ml). x 20 ml). The combined organic layers were washed with water (2x20 ml) and then (20 ml), then dried over magnesium sulfate, filtered, and filtered under vacuum. And chromatographed (silica gel, 70% EtOAc / hexane) To give a white solid (0.085 g, 50%). MS (ES) M + H⁺= 609, M + Na⁺= 631                                 Example 2 Trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl)- Preparation of 1-3-diamino-cyclohexanone a) trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl ) -1--3-Diamino-cyclohexanol   10 m of N-Cbz-L-leucine (Bachem) (0.6 g, 2.3 mmol) Add (+-)-trans-1,3-diaminocyclohexano to the stirred solution in LDMF. (0.14 g, 1.1 mmol) (Sammes, P.G .; Phetford, DJ Chem. Soc. Perkin Trans. 1, 1989, 655), 1- (3-dimethylamido) Nopropyl) -3-ethylcarbodiimide hydrochloride (0.44 g, 2.3 mmol) ) And 1-hydroxybenzotriazole (0.31 g, 2.3 mmol) added. After stirring at room temperature for 3.5 hours, the solution was diluted with EtOAc (200 ml), The combined organic layers were extracted with water, brine, and then dried over magnesium sulfate, Filter, concentrate under vacuum and chromatograph (silica gel; 60% EtOAc) / Hexane) to give the title compound as a white solid (0.22 g, 32% ). MS (ESI): M + H⁺= 625, M + Na⁺= 647 b) trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl ) -1--3-Diamino-hexanone   Trans-N, N'-bis- (benzyloxycarbonyl-L-leucinyl) -1--3-diamino-cyclohexanol (0.22 g, 0.35 mmol) Dissolved in acetone (2 ml). Jones reagent (0.5ml, 1.5M) The reaction was stirred overnight. The excess Jones reagent is then added to isopropanol. (1 ml), dilute the reaction with water (10 ml) and add EtOAc (2 ml). x 20 ml). The combined organic layers were washed with water (2x20 ml) and then (20 ml), then dried over magnesium sulfate, filtered, and filtered under vacuum. And chromatographed (silica gel, 70% EtOAc / hexane) To give a white solid (0.085 g, 40%). M + H⁺= 623, M + Na⁺= 645   The preceding description fully describes how to prepare and use the compounds of the present invention. Show. However, the invention is not limited to the specific embodiments described herein above. And encompasses all such modifications within the scope of the following claims. Miscellaneous cited in this specification Various references to magazines, patents and other publications indicate the current state of the art and By reference, they are incorporated herein as if fully set forth.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/02 A61P 19/02 19/10 19/10 C07D 307/91 C07D 307/91 [Continued summary] -C _0-6 is alkyl; Y is in single bond or O; each Z is independently a CO or CH _2; n is the compound or a pharmaceutically represented by 1, 2 or 3] The present invention relates to a compound which is an acceptable salt, which is an inhibitor of cysteine protease, particularly cathepsin K, and which is useful for treating a disease in which suppression of bone loss is a factor.

Claims (1)

[Claims] 1. Formula (I): [Where,   R¹Is Is;   R^TwoIs H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_{0- 6} Alkyl, Het-C_0-6Alkyl, R^FiveC (O)-, R^FiveC (S)-, R^FiveSO_Two−, R^FiveOC (O)-, R^FiveR'NC (O)-, R^FiveR'NC (S)-, adamantyl-C (O )-Or Is;   Each R "is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl or Het- C_0-6Alkyl;   R '' 'is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_0-6 Alkyl or Het-C_0-6Alkyl;   Each R^ThreeAre independently H, C_2-6Alkenyl, C_2-6Alkynyl, Het, Ar Or OR ', SR', NR '_Two, R'NC (O) OR^Five, CO_TwoR ', CO_TwoNR '_Two , N (C = NH) NH_Two, Het or C optionally substituted with Ar_1-6A Luquil;   R^FourIs H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_{0- 6} Alkyl, Het-C_0-6Alkyl, R^FiveC (O)-, R^FiveC (S)-, R^FiveSO_Two−, R^FiveOC (O)-, R^FiveR'NC (O)-, R^FiveR'NC (S)-, R'HNCH (R ') C (O )-Or R^FiveOC (O) NR'CH (R ') C (O)-;   Each R^FiveIs independently C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_0-6Archi Le, Het-C_0-6Alkyl, Ar-C_0-6Alkoxy, Het-C_0-6Alkoki Or OR ', SR', NR '_Two, R'NC (O) OR^Five, CO_TwoR ', CO_TwoNR '_Two, N (C = NH) NH_Two, Het or C optionally substituted with Ar_1-6Alkyl Is;   R⁶Is H, C_1-6Alkyl, Ar-C_0-6Alkyl or Het-C_0-6Alkyl And R⁷Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, A r-C_0-6Alkyl, Het-C_0-6Alkyl, R^FiveC (O)-, R^FiveC (S)-, R^Five SO_Two-, R^FiveOC (O)-, R^FiveR'NC (O)-, R^FiveR'NC (S)-, R'HNCH ( R ') C (O)-or R^FiveOC (O) NR′CH (R ′) C (O) —; or R⁶ And R⁷Are linked to form a pyrrolidine, piperidine or morpholine ring;   Each R 'is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl or Het- C_0-6Alkyl;   R^*Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar-C_{0- 6} Alkyl or Het-C_0-6Alkyl;   Y is a single bond or 0;   Each Z is independently CO or CH_TwoIs;   n is 1, 2 or 3] Or a pharmaceutically acceptable salt thereof. 2. Formula (Ia):[Where,   R¹Is Is;   R^TwoIs Is;   X is CO, SO_TwoOr CH_Two-CO;   Y is a single bond or O;   Z is CO or CH_TwoIs;   Each R^ThreeIs independently C_4-6Alkyl, C_4-6Alkenyl or benzyl;   R^FourIs C_1-6Alkyl, Ar-C_0-6Alkyl, R^FiveCO-, R^FiveSO_Two-R^FiveOC ( O)-or R^FiveNHCO;   R 'is H or C_1-4Alkyl;   R⁶Is H or C_1-4Alkyl;   R⁷Is C_1-6Alkyl, Ar-C_0-6Alkyl, R^FiveCO-, R^FiveSO_Two-R^FiveOC ( O)-or R^FiveNHCO;   Each R^FiveIs independently Ar-C_0-6Alkyl or Het-C_0-6Alkyl ;   n is 1 or 2] Or a pharmaceutically acceptable salt thereof. 3. R¹But The compound according to claim 2, which is 4. R^FourIs R^FiveThe compound according to claim 3, which is OC (O)-. 5. R^FiveBut The compound according to claim 4, which is 6. R 'is H and R^ThreeIs i-butyl. 7. R^TwoBut Wherein Z is CO. The compound according to claim 1, which is 8. R⁷Is R^FiveThe compound according to claim 7, which is OC (O)-. 9. R^FiveButThe compound according to claim 8, which is 10. R⁶Is H and R^ThreeIs i-butyl. 11. Trans-N, N'-bis- (benzyloxycarbonyl-L-leucini L) -1--3-diamino-cyclopentanone; or trans-N, N'-bis -(Benzyloxycarbonyl-L-leucinyl) -1--3-diamino-cyclo The compound according to claim 1, which is hexanone, or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. object. 13. A cysteine protease comprising administering the compound according to claim 1. How to inhibit. 14． 14. The method according to claim 13, wherein the cysteine protease is cathepsin K. 15. A method for inhibiting bone loss comprising administering a compound according to claim 1. 16. A method for treating osteoporosis, comprising administering the compound according to claim 1. 17． A method for treating gingival or periodontal disease comprising administering the compound of claim 1. Law. 18. Excessive cartilage or matrix comprising administering the compound of claim 1. A method for treating a disease characterized by dextrolysis. 19. 19. The method according to claim 18, wherein the disease is osteoarthritis or rheumatoid arthritis. 20. 12. A compound according to any one of claims 1 to 11 for use as a medicament. Compound. 21. Drugs for the treatment of diseases in which cysteine protease inhibition is a factor Use of a compound of formula (I) as defined in claim 1 in the manufacture of a medicament. 22. 22. The compound according to claim 21, wherein the cysteine protease is cathepsin K. use. 23. Formula (I) as defined in claim 1 in the manufacture of a medicament for inhibiting bone loss. Use of the compound of (1). 24. A compound of formula (I) as defined in claim 1 in the manufacture of a medicament for treating osteoporosis. Use of. 25. In the manufacture of a medicament for the treatment of gingival or periodontal disease, the formula (1) defined in claim 1 Use of the compounds of I). 26. In the manufacture of a medicament for the treatment of diseases characterized by excessive cartilage or matrix degradation Use of a compound of formula (I) as defined in claim 1 27. Diseases characterized by excessive cartilage or matrix degradation are osteoarthritis or chronic Use of a compound according to claim 26 which is rheumatoid arthritis. 28. A process for preparing a compound of formula (I) as defined in claim 1, comprising:   Formula (II) having any protected reactive functional groups: [Wherein, R¹, R^Two, R ″, R ′ ″ and n are as defined in formula (I) R] Reacting a compound of formula with an oxidizing agent; Thereafter, any protecting groups may be removed to form a pharmaceutically acceptable salt. A manufacturing method consisting of