WO2005013909A2

WO2005013909A2 - Novel cathepsin k inhibitors

Info

Publication number: WO2005013909A2
Application number: PCT/US2004/025645
Authority: WO
Inventors: Jae U. Jeong
Original assignee: Smithkline Beecham Corporation
Priority date: 2003-08-07
Filing date: 2004-08-04
Publication date: 2005-02-17
Also published as: WO2005013909A3

Abstract

The invention is directed to novel oxo-amino-sulfonyl-azapanes. Specifically, the invention is directed to compounds according to Formula (I); wherein R1, R2, and R3 are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are protease inhibitors and can be useful in treating conditions in which the pathology may be therapeutically modified by inhibiting a cysteine or serine protease of the papain superfamily, particularly cathepsin K. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of treatment for conditions characterized by bone loss including osteoporosis and gingival diseases, and by excessive cartilage or matrix degradation including osteoarthritis and rheumatoid arthritis using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. The invention is also directed to methods of treatment for certain parasitic diseases such as malaria using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

NOVEL CATHEPSIN K INHIBITORS

FIELD OF THE INVENTION The invention is directed to certain substituted oxo-amino-sulfonyl-azapanes, which are protease inhibitors. More specifically, the compounds are inhibitors of cysteine and serine proteases, particularly cysteine proteases. More specifically yet, the compounds inhibit cysteine proteases of the papain superfamily, including, in particular, those of the cathepsin family, most particularly cathepsin K. 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., et al., (1996) J. Biol. Chem. 271, 2126-2132. Cathepsin K has also been variously denoted as cathepsin O or cathepsin 02 in the literature. The designation cathepsin K is considered to be the most 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, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See: International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also: European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458. Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling 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 formaition 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 cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. J., 1980, - 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CH-Ψj) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al., Biochem. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium deficient diets. Lerner, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al., Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Everts, et al., J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, et al., Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells. The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, 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, inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. In view of the number of pathological responses and conditions that are mediated by cathepsins, and particularly cathepsin K, attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, there remains a continuing need for inhibitors of cathepsin K which can be used in the treatment of a variety of conditions.

SUMMARY OF THE INVENTION The invention is directed to novel oxo-amino-sulfonyl-azapanes. Specifically, the invention is directed to compounds according to Formula I:

Formula I

wherein Ri , R2, and R3 are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are protease inhibitors and can be useful in treating conditions in which the pathology may be therapeutically modified by inhibiting a cysteine or serine protease of the papain superfamily, particularly cathepsin K. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of treatment for conditions characterized by bone loss including osteoporosis and gingival diseases, and by excessive cartilage or matrix degradation including osteoarthritis and rheumatoid arthritis using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. The invention is also directed to methods of treatment for certain parasitic diseases such as malaria using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements. Abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical arts. For example, certain radical groups are abbreviated herein as follows: "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, and "Cbz" refers to the benzyloxycarbonyl radical. In addition, certain reagents are abbreviated herein as follows: "m-CPBA" means 3-chloroperoxybenzoic acid, "EDC" rmeans N-ethyl-N'(dimethylaminopropyl)-carbodiimide, "DMF" means dimethyl formamide, "DMSO" means dimethyl sulfoxide, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, and "THF" means tetrahydrofuran.

Terms and Definitions "Alkyl" refers to a saturated hydrocarbon chain having from 1 to 12 member atoms.

Alkyl groups may be optionally substituted with one or more substituents as defined herein. Use of the prefix "Cj__x" with alkyl refers to an alkyl group having from 1 to x member atoms. For example, Ci .βalkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. "Alkenyl" refers to an unsaturated hydrocarbon chain having from 2 to 12 member atoms and having one or more carbon-carbon double bond within the chain. In certain embodiments alkenyl groups have one carbon-carbon double bond within the chain. In other embodiments, alkenyl groups have more than one carbon-carbon double bond within the chain. Alkenyl groups may be optionally substituted with one or more substituents as defined herein. Use of the prefix "C2__x" with alkenyl refers to an alkenyl group having from 2 to x member atoms. For example, C2-Cgalkenyl refers to an alkenyl group having from 2 to 6 member atoms. Alkenyl groups may be straight or branched. Representative branched alkenyl groups have one, two, or three branches. Alkenyl includes ethylenyl, propenyl, butenyl, pentenyl, and hexenyl. "Alkynyl" refers to an unsaturated hydrocarbon chain having from 2 to 12 member atoms and having one or more carbon-carbon triple bond within the chain. In certain embodiments alkynyl groups have one carbon-carbon triple bond within the chain. In other embodiments, alkynyl groups have more than one carbon-carbon triple bond within the chain. For the sake of clarity, unsaturated hydrocarbon chains having one or more carbon- carbon triple bond within the chain and one or more carbon-carbon double bond within the chain are alkynyl groups. Alkynyl groups may be optionally substituted with one or more substituents as defined herein. Use of the prefix "C2- " with alkynyl refers to an alkynyl group having from 2 to x member atoms. For example, C2-Cgalkynyl refers to an alkynyl group having from 2 to 6 member atoms. Alkynyl groups may be straight or branched. Representative branched alkynyl groups have one, two, or three branches. Alkynyl includes ethynyl, propynyl, butynyl, pentynyl, and hexynyl. "Amino acid" refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tr ptophan, tyrosine and valine. "Aryl" means phenyl or napthyl. Aryl groups may be optionally substituted with one or more substituents as defined herein. "Cycloalkyl" refers to a saturated hydrocarbon ring having from 3 to 7 member atoms. Cycloalkyl groups are monocyclic ring systems. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Use of the prefix "C3-X" with cycloalkyl refers to a cycloalkyl group having from 3 to x member atoms. For example, C3-C6cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms.

Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Cycloalkenyl" refers to an unsaturated hydrocarbon ring having from 3 to 7 member atoms and having a carbon-carbon double bond within the ring. In certain embodiments cycloalkenyl groups have one carbon-carbon double bond within the ring. In other embodiments, cycloalkenyl groups have more than one carbon-carbon double bond within the ring. However, cycloalkenyl rings are not aromatic. Cycloalkenyl groups are monocyclic ring systems. Cycloalkenyl groups may be optionally substituted with one or more substituents as defined herein. Use of the prefix "C3-X" with cycloalkenyl refers to a cycloalkenyl group having from 3 to x member atoms. For example, C3-Cgcycloalkenyl refers to a cycloalkenyl group having from 3 to 6 member atoms. Cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. "Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomerically enriched refers to products whose enantiomeric excess is greater than about 50% ee, greater than about 75% ee, and greater than about 90% ee. "Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that is constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%). "Enantiomerically pure" refers to products whose enantiomeric excess is 100% ee. "Half-life" ( or "half-lives") refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo. "Halo" refers to fluoro, chloro, bromo, or iodo. "Heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Heteroaryl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 7 member atoms. Bicyclic heteroaryl rings have from 7 to 11 member atoms. Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, tetrahydrofuranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and napthyridinyl. "Heteroatom" refers to a nitrogen, sulphur, or oxygen atom. "Heterocycloalkyl" refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocycloalkyl rings have from 5 to 7 member atoms. Bicyclic heterocycloalkyl rings have from 7 to 11 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- oxathiolanyl. 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, and oxabicylo[2.2.1]heptyl. "Member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring. "Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be substituted with one or more substituents as defined herein. "Optionally substituted" in reference to a group includes the unsubstituted group (e.g. "optionally substituted Ci- ψalkyl" includes unsubstituted Cι -C4alkyl). It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, or cyclization). A single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents include -OR, -C(0)R, -C(0)OR, -C(R)OR, -SR, -S(0)R, -S(0)₂R, -N(R)(R), - N(R)C(0)OR, -N(R)C(0)R, -OC(0)N(R)(R), -N(H)C(=NR)N(R)(R) -C(0)N(R)(R), C(R)=NR, aryl, cyano, cycloalkyl, cycloalkenyl, halo, heterocycloalkyl, heteroaryl, nitro, and oxo; wherein each R is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, and heteroaryl. "Oxo" refers to the substituent group =0. "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit risk ratio. "Proteases" are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis. Proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. Protease "inhibitors" bind 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.

Compounds The invention is directed to compounds according to Formula I:

wherein: R is Formula A or Formula B:

wherein in Formula B, n is an integer from 1 to 5; R₂ is H, Ci-galkyl, C₂-₈alkenyl, C₂.₈alkynyl, or substituted C].₄alkyl, wherein said substituted C^a-kyl is substituted with one substituent selected from -OR_a, -N(R_b)(R_b), - N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); each R₃ is independently H, Cι_₈alkyl, C₂.₈alkenyl, C₂.₈alkynyl, substituted Cι-₆alkyl, optionally substituted C₃-₆cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein said substituted Cι.₆alkyl is substituted with one or more halo substituent or with one substituent selected from -0R_a, - N(R_b)(R_b), -N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), - N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b), and wherein said optionally substituted C₃.₆cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one substituent selected from

-0R_a, -N(R )(R ), - N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), - N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); or taken together both R3 form an optionally substituted non-aromatic monocyclic ring incorporating therein the N to which each is attached, wherein said optionally substituted non-aromatic monocyclic ring is a saturated or unsaturated, wherein said optionally substituted non-aromatic monocyclic ring contains from 3 to 7 member atoms and may optionally contain 1 or 2 additional heteroatoms as member atoms in the ring, and wherein said optionally substituted non-aromatic monocyclic is optionally substituted with one substituent selected from -OR_a, -C(0)Rd, -C(0)OR₍j, -N(R )(R ), -N(R )C(0)R_b, - C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), -N(H)C(=NR_b)N(R_b)(R_b), - N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); or taken together both R3 form an optionally substituted bicyclic ring incorporating therein the N to which each is attached, said optionally substituted bicyclic ring comprising a first ring that is fused to a second ring, wherein said first ring is a saturated or unsaturated non-aromatic monocyclic ring incorporating therein the N to which each R3 is attached which contains from 3 to 7 member atoms and may optionally contain from 1 to 3 additional heteroatoms as member atoms in the ring, wherein said second ring is selected from C₃. ₇cycloalkyl, C₃.₇cycloalkenyl, monocyclic heterocyclalkyl, and monocyclic heteroaryl, and wherein said optionally substituted bicyclic ring is optionally substituted with one substituent selected from -OR_a, -N(R )(R_b), -N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), - N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), -N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); j is H, optionally substituted Cμ₇alkyl, optionally substituted C₂.₇alkenyl, optionally substituted C₂.₇alkynyl, optionally substituted C₃.₇cycloalkyl, optionally substituted C₃.₇cycloalkenyl, or optionally substituted heterocycloalkyl, wherein said optionally substituted Cι-₇alkyl, C₂- alkenyl, or C₂-₇alkynyl is optionally substituted with one substituent selected from -OR_c, -SR_C, -S(O)Rc, -S(O)2R_c, -N(R )(R_b), -N(R_b)C(0)R_c, - C₃-₆cycloalkyl, monocyclic heterocycloalkyl, and wherein said optionally substituted C- ₃.₇cycloalkyl, C₃.₇cycloalkenyl, or heterocycloalkyl is optionally substituted with one substituent selected from optionally substituted -Cι_₃alkyl, -OR_c, -N(R_b)(R_b), and - N(R_b)C(0)R_c, wherein said optionally substituted -Cι-₃alkyl is optionally substituted 5 with one substituent selected from -OR^ -SR_C, -S(O)R_c, -S(O)2- ._c, and -N(R_b)(R_b); R₅ is optionally substituted C₃-₇cycloalkyl, optionally substituted C₃-₇cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl, wherein said optionally substituted C₃-₇cycloalkyl, C₃-₇cycloalkenyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one substituent selected from -0 d^alkyl, -ORc, -N(R_b)(R_b), and -N(R_b)C(0)R_c; each R_a is independently H or optionally substituted C^alkyl, wherein said optionally substituted

is optionally substituted with one or more halo substituent or with one substituent selected from -OR and N(R_b)(R ); each R_b is independently H or Cι-₃alkyl;5 each R_g is independently Cι-₃alkyl; and each R₍j is independently optionally substituted Cι-₃alkyl, phenyl, or monocyclic i heteroaryl, wherein said optionally substituted Cι-₃alkyl is optionally substituted with phenyl or monocyclic heteroaryl. 0 The meaning of any functional group or substituent thereon at any one occurrence in Formula I, or any subformula thereof, is independent of its meaning, or any other functional group's or substituent's meaning, at any other occurrence, unless stated otherwise. The compounds according to Formula I may contain one or more asymmetric center and may, therefore, exist as individual enantiomers, diasteriomers, or other stereoisomeric5 forms, or as mixtures thereof. For example, when R₂ is a group other then H, the carbon to which it is attached is asymmetric. In addition, asymmetric carbon atoms may also be present in a substituent such as an alkyl group. Where the stereochemistry of chiral carbons present in Formula I, or in any chemical structure illustrated herein, is not specified, the chemical structure is intended to encompass compounds containing any stereoisomer and all0 mixtures thereof of each chiral center present in the compound. Thus, compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers. Individual stereoisomers of a compound according to Formula I which contain one5 or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; by formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas- liquid or liquid chromatography; by selective reaction of one enantiomer with an enantiomer-specific reagent, for example by enzamatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. The compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Formula I includes both trans (E) and cis (Z) geometric isomers. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form. The skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to Formula I can be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula I. As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. The term "pharmaceutically-acceptable salts" includes both pharmaceutically-acceptable acid addition salts and pharmaceutically-acceptable base addition salts. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. In certain embodiments, compounds according to Formula I may contain an acidic functional group and are therefore capable of forming pharmaceutically-acceptable base addition salts by treatment with a suitable base. Suitable bases include ammonia and hydroxides, carbonates and bicarbonates of a pharmaceutically-acceptable metal cation, such as alkali metal and alkaline earth metal cations. Suitable alkali metal and alkaline earth metal cations include sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc. Suitable bases further include pharmaceutically-acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines. Suitable pharmaceutically-acceptable organic bases include methylamine, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine. In certain embodiments, compounds according to Formula I may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically- acceptable inorganic acids, pharmaceutically-acceptable organic acids, and pharmaceutically-acceptable organic sulfonic acids. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, sulfamic acid, and phosphoric acid. Suitable organic acids include, acetic acid, hydroxyacetic acid, propionic acid, butyric acid, isobutyric acid, maleic acid, hydroxymaleic acid, acrylic acid, fumaric acid, malic acid, tartaric acid, citric acid, salicylic acid, /j-aminosalicyclic acid, glycollic acid, lactic acid, heptanoic acid, phthalic acid, oxalic acid, succinic acid, benzoic acid, o- acetoxybenzoic acid, chlorobenzoic acid, methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoic acid, methoxybenzoic acid, phenylacetic acid, mandelic acid, formic acid, stearic acid, ascorbic acid, palmitic acid, oleic acid, pyruvic acid, pamoic acid, malonic acid, lauric acid, glutaric acid, and glutamic acid. Suitable organic sulfonic acids include, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, ^-aminobenzenesulfonic (i.e. sulfanilic acid), ?-toluenesulfonic acid, and napthalene- 2-sulfonic acid. As used herein, the term "compounds of the invention" means both the compounds according to Formula I and the pharmaceutically-acceptable salts thereof. The term "a compound of the invention" also appears herein and refers to both a compound according to Formula I and its pharmaceutically-acceptable salts. The compounds of the invention may exist as solids, liquids, or gases, all of which are included in the invention. In the solid state, the compounds of the invention may exist as either amorphous material or in crystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically-acceptable solvates of the compounds of the invention may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." The invention includes all such solvates. The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, ER. spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, such as solvents, used in making the compound. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. In certain embodiments, the invention is directed to compounds according to Formula I wherein R is Formula A and R4 is optionally substituted Cι-₇alkyl or optionally substituted C₃.₇cycloalkyl. hi certain further embodiments, the invention is directed to compounds according to Formula I wherein Rj is Formula A and R4 is methyl, ethyl, n- propyl, prop-2-yl, n-butyl, isobutyl, t-butyl, cyclopropyl, or cyclobutyl. In still further embodiments, the invention is directed to compounds according to Formula I wherein R is Formula A and R4 is isobutyl. In certain embodiments, the invention is directed to compounds according to Formula I wherein Rj is Formula A and R5 is optionally substituted aryl or optionally substituted heteroaryl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein Rj is Formula A and R5 is optionally substituted heteroaryl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein Rj is Formula A and R5 is optionally substituted benzofuranyl, optionally substituted furo[3,2-b]pyridinyl, optionally substituted benzo[ό]thiophenyl, optionally substituted quinolinyl, optionally substituted quinoxalinyl, optionally substituted 1,8 naphthyridinyl, optionally substituted indolyl, optionally substituted pyridinyl, optionally substituted thiophenyl, optionally substituted thieno[3,2- b]thiophenyl, optionally substituted isoxazolyl, or optionally substituted oxazolyl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein R is Formula A and R5 is benzofuranyl or furo[3,2-Z>]pyridinyl optionally substituted with C^alkyl. In certain embodiments, the invention is directed to compounds according to

Formula I wherein R₂ is H or Cι-₈alkyl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein R₂ is H, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, or t-butyl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein R₂ is H or methyl. In certain embodiments, the invention is directed to compounds according to

Formula I wherein each R₃ is independently Ci-salkyl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein each R₃ is methyl, ethyl, n-propyl, prop-2-yl, n-butyl, isobutyl, or t-butyl. In certain further embodiments, the invention is directed to compounds according to Formula I wherein each R₃ is methyl. In certain embodiments, the invention is directed to compounds according to Formula I wherein taken together both R3 form an optionally substituted non-aromatic monocyclic ring incorporating therein the N to which each is attached. Representative non- aromatic monocyclic rings include piperazinyl, piperadinyl, pyraazolidinyl, morpholinyl, thiamorpholinyl, and azapinyl. In certain further embodiments the non-aromatic monocyclic ring contains 5 or 6 member atoms. In certain further embodiments the non- aromatic monocyclic ring contains 6 member atoms. In certain further embodiments the optionally substituted non-aromatic monocyclic ring is optionally substituted with -C(0)R₍j or -C(0)OR₍j. In certain further embodiments the optionally substituted non-aromatic monocyclic ring is morpholinyl or piperazinyl. In certain embodiments, the invention is directed to compounds according to Formula I wherein taken together both R3 form an optionally substituted bicyclic ring. Representative bicyclic rings include 3,4-dihydro-lH-isoquinolinyl and 1,3-dihydro- isoindolyl. Exemplary compounds according to Formula I include: 4-((2R,5S)-5-{(S)-2-[(l-benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino} -2-methyl-6-oxo-azepane- 1 -sulfonyl)-piperazine- 1 -carboxylic acid benzyl ester, and its free acid; ^{^} benzofuran-2-carboxylic acid {(S)- 1 -[(4S,7R)-1 -(3 ,4-dihydro- lH-isoquinoline-2- sulfonyl)-7-methyl-3 -oxo-azepan-4-ylcarbamoyl] -3 -methyl-butyl } -amide; benzofuran-2-carboxylic acid {(S)-l-[(4S,7R)-l-(l,3-dihydro-isoindole-2-sulfonyl)- 7-methyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; benzofuran-2-carboxylic acid {(S)-3 -methyl- 1 -[(4S,7R)-7-methyl- 1 -(morpholine-4- sulfonyl)-3 -oxo-azepan-4-ylcarbamoyl] -butyl } -amide; benzofuran-2-carboxylic acid ((S)-3-methyl-l-{(4S,7R)-7-methyl-3-oxo-l-[4-(l- pyridin-2-yl-methanoyl)-piperazine-l-sulfonyl]-azepan-4-ylcarbamoyl}-butyl)-amide; 3-methyl-furo[3,2-b]pyridine-2-carboxylic acid {(S)-3-methyl-l-[(4S,7R)-7-methyl- l-(mo holine-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide; benzofuran-2-carboxylic acid {(S)-3 -methyl- 1 -[(S)- 1 -(morpholine-4-sulfonyl)-3- oxo-azepan-4-ylcarbamoyl]-butyl}-amide; benzofuran-2-carboxylic acid [(S)- 1 -((S)-dimethylsulfamoyl-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide; benzofuran-2-carboxylic acid {(S)- 1 -[(S)- 1 -(3,4-dihydro- lH-isoquinoline-2- sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide; or 3-methyl-furo[3,2-b]pyridine-2-carboxylic acid {(S)-3-methyl-l-[(S)-l- (morpholine-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide.

Compound Preparation The compounds of the invention are prepared using conventional organic syntheses. A suitable synthetic route is depicted in the following general reaction scheme:

Scheme 1

CbzNH

NaH

HOBt EDC, i-Pr₂NEt

In Scheme I, R1 , R₂, R3, R4, and R5 are as defined above unless defined otherwise. The starting material A for Scheme I is commercially available, such as carbobenyzloxy-D- alaninol (Cbz-D-alaninol) from Aldrich, or is prepared from commercially available starting materials using known methods. Other reagents used herein are commercially available or are prepared from commercially available starting materials using known methods. For example, amino acids are commercially available or are prepared by methods known to those skilled in the art and which can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley- Interscience). In Scheme 1, the starting material A is first converted to an iodide, then is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl organometallic reagent followed by the alkylation with allyl iodide to give B. Grubbs' catalyst is then used to form the azapine ring intermediate C by ring closing metathesis. Epoxidation of the alkene followed by separation of the diastereomers followed by opening of the epoxide D (the minor component) with sodium azide provides the intermediate azido alcohol E. Reduction of the azide is followed by acylation of the amine with a Boc protected amino acid H (for example, Boc-leucine). Deprotection of the Boc group of intermediate F followed by acylation with a carboxylic acid (R5C0₂H) such as 2-benzofur-ιncarboxylic acid, HOBt, EDC, and i-Pr₂NEt, and then deprotection of the Cbz gives the intermediate secondary amine, which is then sulfonylated with a sulfonyl chloride such as morpholine-4-sulfonyl chloride. Final oxidation of the secondary alcohol to the ketone with Dess-Martin periodinane provides the desired product G. Coupling methods to form amide bonds herein are known in the art. Such methods are described, for example, in Bodansky et al, THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. 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. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art. Examples of such methods and groups may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

Biological Assays The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect. - -

Determination of cathepsin K proteolytic catalytic activity All assays for cathepsin K are carried out with human recombinant enzyme. Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and are determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions are prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays are conducted at ambient temperature. Product fluorescence (excitation at 360 nM; emission at 460 nM) is monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves are generated over 20 to 30 minutes following formation of AMC product.

Inhibition studies Potential inhibitors are evaluated using the progress curve method. Assays are carried out in the presence of variable concentrations of test compound. Reactions are initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis is conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progress curves are linear, apparent inhibition constants (Ki_tapp) are calculated according to equation 1 (Brandt et al, Biochemitsry, 1989, 28, 140): v = V_mA /[K_a(l + , app) +AJ (1) where v is the velocity of the reaction with maximal velocity V_m , A is the concentration of substrate with Michaelis constant of K_a, and I is the concentration of inhibitor. For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets is analyzed to give k₀jj_S according to equation 2:

[AMC] = v_ss t + (vo - v_ss) [1 - exp (-kobsOJ / obs (2)

where [AMC] is the concentration of product formed over time t, vβ is the initial reaction velocity and v_ss is the final steady state rate. Values for k_obs are then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k_obs / inhibitor concentration or k_obs / [I]) describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol, 1988, 61, 201).

Human Osteoclast Resorption Assay Aliquots of osteoclastoma-derived cell suspensions are removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4°C). The medium is aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice The cell suspension is mixed frequently. The cells are washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells are enumerated in an improved Neubauer counting chamber. Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, are removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium is removed by immobilizing the beads on a magnet and is replaced with fresh medium. The beads are mixed with the cells and the suspension is incubated for 30 min on ice. The suspension is mixed frequently. The bead-coated cells are immobilized on a magnet and the remaining cells (osteoclast-rich fraction) are decanted into a sterile 50 mL centrifuge tube. Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process is repeated xlO. The bead-coated cells are discarded. The osteoclasts are enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells are pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xlθ4/mL in EMEM medium, supplemented with 10% fetal calf serum and lJg/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) are decanted into 15 mL centrifuge tubes.

These cells are pelleted by centrifugation. To each tube 3 mL of the appropriate treatment is added (diluted to 50 uM in the EMEM medium). Also included are appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes are incubate at 37°C for 30 min. 0.5 mL aliquots of the cells are seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment is screened in quadruplicate. The slices are washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h. The slices are then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they are washed in water and incubated in buffer for 5 min at 37°C.

The slices are then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer is aspirated, and the slices are air dried following a wash in water. The TRAP positive osteoclasts are enumerated by bright-field microscopy and are then removed from the surface of the dentine by sonication. Pit volumes are determined using the Nikon/Lasertec ILM21 W confocal microscope.

Methods of Use The compounds of the invention are protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly inhibitors of cysteine proteases, even more particularly inhibitors of cysteine proteases of the papain superfamily, yet more particularly inhibitors of cysteine proteases of the cathepsin family, and most particularly inhibitors of cathepsin K. The compounds of the invention can be useful for treating conditions 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 conditions in which cathepsin K is implicated, including diseases of excessive bone or cartilage loss such as osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, especially osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease. In addition, metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of the invention. Accordingly, in another aspect the invention is directed to methods of treating such conditions. The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof. As used herein, "treatment" means: (1) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. As used herein, "safe and effective amount" means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound of the invention will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half- life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan. As used herein, "patient" refers to a human or other animal. The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration. The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from about 0.4 to about 400 mg/kg. Typical daily dosages for parenteral administration range from about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg . The compounds of the invention may be administered alone or in combination with one or more additional active agents. Such other active agents include inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate, risedronate, etidronate, and ibandronate), hormone replacement therapy, anti-estrogens, calcitonin, and anabolic agents such as bone morphogenic protein, iproflavone, and PTH.

Compositions The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient. The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from about 0.1 mg to about 50 mg. The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient. As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable. The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance. Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to, select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

Examples The following examples illustrate the invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the invention. While particular embodiments of the invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention. _j Preparatory Example

Preparation of Morpholine-4-sulfonyl chloride A) To a solution of sulfuryl chloride (4.75 ml, 59.11 mmol) at 0 °C in anhydrous chloroform (60 ml) under argon, was slowly added a mixture of morpholine (5.15 g, 59.11 mmol), and triethylamine (8.24 ml, 59.11 ml) over a period of 60 min. The reaction mixture was allowed to stir additional 1 h, then quenched with water, extracted with chloroform (2 X 100 ml), washed with 1.0 N HC1, dried over MgS04, and concentrated in-vacuo to yield the title compound without further purification; 1H NMR: 3.80 (4H, m), 3.25 (4H, m); LCMS M+H⁺ = 186.0. B) Preparation of 3,4-dihydro-lH-isoquinoline-2-sulfonyl chloride: Following the procedure of Example (A), except substituting 1,2,3,4-tetrahydro-isoquinoline for morpholine gave the title compound, used without purification; 1H NMR: 7.10-7.30 (4H, m), 4.60 (2H, s), 3.70 (2H, m), 3.10 (2H, t). C) Preparation of l,3-dihydro-isoindole-2-sulfonyl chloride:

Following the procedure of Preparation (A), except substituting "isoindole" for "morpholine" gave the title compound, used without further purification; 1H NMR: 7.30- 7.40 (4H, m), 4.85 (4H, m).

Example 1 Preparation of 4-((2R,5 S)-5- { (S)-2-[( 1 -benzofuran-2-yl-methanoyl)-amino] -4-methyl- pentanoylamino}-2-methyl-6-oxo-azepane-l-sulfonyl)-piperazine-l-carboxylic acid benzyl ester '

la. ((R)-2-Iodo-l-methyl-ethyl)-carbamic acid benzyl ester Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g,

184 mmol) in CH₂C1₂ (231 ml), then was cooled to 0 °C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes, ((R)-2-hydroxy-l-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT. After stirring for 3 h. H₂0 (7 ml) was added and the mixture was partitioned between CH₂C1₂ (300 ml) and H₂0 (600 ml). The aqueous layer was extracted again with CH₂C1₂ (200 ml). The combined organic solution was then washed with a solution of 10 % (w/w) aq. saturated Na₂S₂0₃ (140 ml), then brine (400 ml). The organic solution was dried with MgS0₄, filtered, concentrated in vacuo, and then filtered through a plug of silica gel washing with 15% EtOAc/ hexane (1500 ml). The solution was concentrated in vacuo, then the resultant solid was washed with hexane. After drying the solid under the reduced pressure, the white solid was used in the next reaction without further purification (1 lg, 75%). lb. ((R)-l-Methyl-pent-4-enyl)-carbamic acid benzyl ester Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in anhydrous THF (24 ml, inhibitor free, from Aldrich), then was cooled to -78 °C. A solution of allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added slowly, then the solution was stirred for 30 minutes. ((R)-2-Iodo-l-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled THF (3 ml) was added dropwise, then the reaction was warmed to -40 °C and was stirred for 2.5 h. The reaction mixture was quenched with aq. sat. NH₄CI (4 ml) at - 40 °C, warmed to RT, and the gray reaction mixture turned sky blue. THF was removed in vacuo. Et₂0 was added and the reaction mixture was filtered to remove precipitated solids. The solids were washed with additional Et₂0. The combined organic solution was extracted with 10% NH₄OH (3 x 15 ml), then brine. The combined organic solution was dried with MgS0 , filtered, concentrated in vacuo, and then filtered through a plug of silica gel washing with 20% EtOAc/ hexane (100 ml). The solution was concentrated in vacuo, and then the resultant colorless oil was used in the next reaction without further purification (0.8 g, 73%). lc. Allyl-((R)-l-methyl-pent-4-enyl)-carbamic acid benzyl ester ((R)-l-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and was cooled to 0 °C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction was stirred for 15 minutes. Allyl bromide (0.88 ml, 10.17 mmol) was added and the reaction mixture was stirred for 3 h at 0 °C. H₂0 (10 ml) was added, then 2N HCl was added dropwise adjusting the pH to 1. The reaction mixture was extracted with Et₂0 (2 x 50 ml). The combined organic solution was washed with aq. 2N HCl, then aq. NaHC0₃, and then brine. The combined organic solution was dried with MgS0 , filtered, concentrated in vacuo, then chromatographed on silica gel (5% EtOAc/ hexane) to yield the title compound as a colorless oil (883 mg, 95%). Id. 2-(R)-Methyl-2,3,4,7-tetrahydro-azepine-l-carboxylic acid benzyl ester Allyl-((R)-l-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19 mmol) was dissolved in CH₂C1₂ (10 ml) and a stream of argon gas was bubbled into the reaction mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and the reaction mixture was refluxed for 2 h. Additional bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (9 mg) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to RT under argon, then was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 5% EtOAc/ hexane) to give the title compound (0.72 g, 92 %); 1H NMR (CDC1₃) D 7.35-7.20 (m, 5H), 5.65 (m, 1H), 5.13 (2d_AB, 2H), 4.45-4.05 (m, 2H), 3.56 (d, 1H), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 2H), 1.12 (d, 3H); Liquid Chromatography/Electrospray mass spec: MH^1" = 246.2. le. (lS,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester m-Chloroperbenzoic acid (1.10 g, 57-86% purity) was added to a solution of 2-methyl- 2,3,4,7-tetrahydro-azepine-l-carboxylic acid benzyl ester (0.72 g, 2.94 mmol) in CH₂C1₂ at 0 °C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloroperbenzoic acid (0.660 g, 57-86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexane EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc:hexane) to give (lS,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.450 g, 75 %) and the title compound (0.15 g, 25 %); 1H NMR (CDC1₃) δ 7.42-7.22 (m, 5H), 5.13 (s, 2H), 4.50-4.15 (m, 2H), 3.27 (d, 1H), 3.12-2.95 (m, 1H), 2.15- 1.70 (m, 2H), 1.47 (m, 2H), 1.12 (d, 3H); Liquid Chromatography/Electrospray mass spec: MH⁺ = 262.0. If. (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester Sodium azide (0.139 g, 2.14 mmol) was added to a solution of (lS,4R,7R)-4-methyl-8-oxa- 3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) in MeOH (1.5 ml) and H₂0 (0.15 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic solution was then washed with water, brine, dried with MgS0 , filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexane) to yield the title compound (0.192 g, 89 %); 1H MR (CDC1₃) δ 7.39-7.30 (m, 5H), 5.15 (s, 2H), 4.10-3.67 (m, 2H), 3.10 (d, 1H), 1.85-1.53 (m, 4H), 1.09 (d, 3H); Liquid Chromatography/Electrospray mass spec: MH*^" = 305.2. lg. (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-5- azido-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester (0.193 g, 0.635 mmol) in THF (10 ml) and H₂0 (0.04 ml), then was heated to 45 °C for overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et₂0 and the resulting salt was collected following filtration and was used in the next reaction without further purification (0.27 g, 90%). lh. (2R,5S,6S)-5-((S)-2- tert -Butoxycarbonylamino-4-methyl-pentanoylamino)-6- hydroxy-2-methyl-azepane-l -carboxylic acid benzyl ester l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) was added to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol), diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), 1-hydroxybenzotriazole (0.114 g, 0.83 mmol) and (2R,5S,6S)-5- amino-6-hydroxy-2-methyl-azepane-l -carboxylic acid benzyl ester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirred for overnight at RT, then was diluted with EtOAc (100 ml), washed with H₂0 (2 x 50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexane) to yield the title compound (0.218 g, 72 %); 1H NMR (CDC1₃) δ 7.40-7.29 (m, 5H), 6.75 (brd, 1H), 5.12 (two d^, 2H), 5.0 (brs, 1H), 4.15-3.72 (m, 2H), 3.06 (d, 1H), 1.60-1.30 (m, 2H), 1.60-1.30 (m, 5H), 1.12 (d, 3H), 0.97-0.87 (two d, 6H); Electrospray mass spec: MH = 492.0 li. (2R,5S.6S)-5-{(S)-2-[(l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino}-6-hydroxy-2-methyl-l-azepane-l -carboxylic acid benzyl ester (2R,5S.6S)-5-{(S)-2-[(l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino}-6-hydroxy-2-methyl-l-azepane-l -carboxylic acid benzyl ester (0.169 g, 0.344 mmol) was dissolved in 1 ml of MeOH, then added 1.34 ml of 4M HCl in dioxane. The reaction mixture was stirred at RT for 2 hrs. The solvent was removed in vacuo. The resultant white solid was used in the next reaction without further purification (0.144 g, crude yield, 98%). The white HCl salt (0.144 g, 0.337 mmol) was dissolved in DMF (3 ml), then added benzofuran-2-carboxylic acid (0.055 g, 0.337 mmol), HBTU (0.153 g, 0.404 mmol), and triethylamine (0.20 ml, 1.42 mmol). After stirring for overnight, the reaction was quenched with H20 (20 ml) and extracted with EtOAc (30 ml). The aqueous layer was extracted again with EtOAC (20 ml). The combined organic solution was washed with sat'd aq. NaHC0₃ (100 ml) and brine (100 ml). The organic solution was dried with MgS0₄, filtered, and concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (2% MeOH CH₂Cl₂).

1.79 g (72 %) of the title compound was obtained; 1HNMR (CDC1₃) δ 7.09-7.53 (m , 10H),

7.11-7.16 (m, 1H), 6.80 (m, 1H), 6.78 (m, 1H), 5.16-5.21 (m, 2H), 5.02-5.05 (m, 1H), 4.65-

4.69 (m, 1H), 4.63 (d, 1H), 4.01 (m, 1H), 3.67-3.69 (m, 1H), 1.62-1.95 (m, 4H), 1.31-1.50

(m, 3H), 1.27 (d, 3H), 1.02 (d, 6H); Electrospray mass spec: MH+ = 536.64. lj. Benzofuran-2-carboxylic acid [(S)-l-(3S,4S,7R)-3-hydroxy-7-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide. (2R,5 S .6S)-5- {(S)-2-[( 1 -Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino}-6-hydroxy-2-methyl-l-azepane-l-carboxylic acid benzyl ester (1.55 g, 2.89 mmol) was dissolved in EtOH (18 ml) at RT. 10% Pd/C (0.38 g) was added and the reaction was stirred for overnight at RT under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo, and was used in the next reaction without further purification (1.12 g, 96.5 %). Electrospray mass spec: MET^1" = 402.4. Ik. 4-((2R,5S,6S)-5-{(S)-2-[(l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino} -6-hydorxy-2-methyl-azepane- 1 -sulfonyl)-piperazine- 1 -carboxylic acid benzyl ester. Benzofuran-2-carboxylic acid [(S)-l-(3S,4S,7R)-3-hydroxy-7-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide (0.2 g, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml) at RT. Triethylamine (0.3 ml, 2.5 mmol) and 4-chlorosulfonyl- piperazine-1 -carboxylic acid benzyl ether was added to the above solution, and the mixture was stirred at RT for overnight. H₂0 (50 ml) was added and the mixture was partitioned between H₂0 and CHC1₃ (150 ml). The aqueous layer was extracted again with CHC1₃ (50 ml). The combined organic solution was then washed with IN HCl (50 ml) and brine (100 ml). The organic solution was dried with MgS0 , filtered, concentrated in vacuo, then chromatographed on silica gel (2% MeOHTDCM) to yield the desired product (0.27 g, 79.4 %); 1H NMR (CDC1₃) δ 7.68 (d, 1H), 7.06-7.53 (m, 9H), 7.08 (d, 1H), 7.01-7.01 (d, 1H), 6.88 (m, 1H), 5.16 (s, 2H), 5.01-5.03 (m, 1H), 4.70-4.73 (m, 1H), 4.39 (d, 1H), 4.297-4.34 (m, 1H), 3.78 (d, 1H), 3.59-3.62 (m, 4H), 3.20-3.40 (m, 4H), 2.20-2.26 (m, 2H), 1.70-1.78 (m, 2H), 1.53-1.63 (m, 3H), 1.27 (d, 3H), 1.02 (d, 6H); Electrospray mass spec: MH+ = 684.82. 11. 4-((2R,5S)-5-{(S)-2-[(l-Benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino } -2-methyl-6-oxo-azepane- 1 -sulfonyl)-piperazine- 1 -carboxylic acid benzyl ester. Dess-Martin periodinane (0.13g, 0.308 mmol) was added to a solution of 4-

((2R,5 S,6 S)-5- { (S)-2- [( 1 -benzofuran-2-yl-methanoyl)-amino] -4-methyl-pentanoylamino } - 6-hydorxy-2-methyl-azepane-l-sulfonyl)-piperazine-l -carboxylic acid benzyl ester (0.12g, 0.176 mmol) in CH₂C1₂ (3 ml). After stirring for 3 hrs at RT, the reaction was quenched by 20% aq. Na₂S₂0₃ (10 ml) and was extracted with CH₂C1₂ (20 ml x 2). The combined organic solution was washed with sat'd NaHC0₃ (40 ml) and brine (20 ml), then dried over MgS0 . After filtration and evaporation under the reduced pressure, the residue was purified by flash column chromatograph on silica gel (2% MeOH/CH₂Cl₂) to give 86 mg (72 %) of the title compound; IH NMR (CDC1₃) δ 7.68 (d, IH), 7.06-7.53 (m, 9H), 7.08 (d, IH), 6.88 (d, IH), 5.16 (s, 2H), 5.01-5.03 (m, IH), 4.70-4.73 (m, IH), 4.39 (d, IH), 4.297-4.34 (m, IH), 3.78 (d, IH), 3.59-3.62 (m, 4H), 3.20-3.40 (m, 4H), 2.20-2.26 (m, 2H), 1.70-1.78 (m, 2H), 1.53-1.63 (m, 3H), 1.27 (d, 3H), 1.02 (d, 6H); LCMS: MH+ = 682.81.

Example 2 Preparation of benzofuran-2-carboxylic acid {(S)-l-[(4S,7R)-l-(3,4-dihydro-lH- isoquinoline-2-sulfonyl)-7-methyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

Following the procedure of Example 1 (a-1), except substituting "3,4-dihydro-lH- isoquinoline-2-sulfonyl chloride (Appendix, B)" for "4-chlorosulfonyl-piperazine-l- carboxylic acid benzyl ether" gave the title compound; 1Η NMR (CDC1₃) δ 7.70 (m, 1Η), 7.10-7.55 (m, 9Η), 6.90 (m, IH), 5.10 (m, IH), 4.70 (m, IH), 4.45 (3H, m), 4.35 (IH, m), 3.80 (d, J = 19.2 Hz, IH), 3.55 (m, 2H), 3.00 (m, 2H), 2.25 (m, 2H), 1.30-1.80 (m, 5H), 1.15 (d, 3H), 1.05 (d, 6H); LCMS: ME-* = 595.4.

Example 3 Preparation of benzofuran-2-carboxylic acid {(S)-l-[(4S,7R)-l-(l,3-dihydro-isoindole-2- sulfonyl)-7-methyl-3-oxo-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide

Following the procedure of Example 1 (a-1), except substituting "1,3-dihydro- isoindole-2-sulfonyl chloride (Appendix, C)" for "4-chlorosulfonyl-piperazine-l -carboxylic acid benzyl ether" gave the title compound; IH NMR (CDC1₃) δ 7.70 (m, IH), 7.40-7.55 (m,

3H), 7.20-7.40 (m, 5H), 7.10 (m, IH), 6.90 (m, IH), 5.15 (m, IH), 4.70 (m, 5H), 4.50 (d, J =

19.2 Hz, IH), 4.40 (m, IH), 3.80 (d, J = 19.2 Hz, IH), 2.30 (m, 2H), 0.90-1.80 (m, 14H). Example 4 Preparation of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(4S,7R)-7-methyl-l- (mo holine-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 1 (a-1), except substituting "morpholine-4- sulfonyl chloride (Appendix, A)" for "4-chlorosulfonyl-piperazine-l -carboxylic acid benzyl ether" gave the title compound; IH NMR (CDC1₃) δ 7.75 (m, IH), 7.40-7.60 (m, 4H), 7.1 (m, IH), 6.85 (m, IH), 5.00 (m, IH), 4.75 (m, IH), 4.40 (d, IH), 4.30 (m, IH), 3.80 (m, 5H), 3.20 (m, 4H), 2.25 (m, 2H), 1.50-1.90 (m, 5H), 1.20 (m, 3H), 1.05 (m, 6H); LCMS: M+H" = 549.4.

Example 5 Preparation of benzofuran-2-carboxylic acid ((S)-3-methyl-l-{(4S,7R)-7-methyl-3-oxo-l- , [4-(l-pyridin-2-yl-methanoyl)-piperazine-l-sulfonyl]-azepan-4-ylcarbamoyl}-butyl)-amide

1H NMR: 8.61 (s, IH), 7.28-7.85 (m, 9H), 7.05 (d, IH), 6.89 (d, IH), 5.06 (m, IH), 4.72 (m, IH), 4.41 (d, IH), 4.30-4.33 (m, IH), 3.80-3.92 (m, 4H), 3.75 (d, IH), 3.32-3.37 (m, 4H), 2.25-2.29 (m, 2H), 2.22 (m, IH), 1.74-1.77 (m, 3H), 1.21 (d, 3H), 1.02 (d, 6H). Example 6 Preparation of 3-methyl-furo[3,2-b]pyridine-2-carboxylic acid {(S)-3-methyl-l-[(4S,7R)-7- methyl-l-(morpholine-4-sulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide

Following the procedure of Example 1 (a-1), except substituting "2-methyl-aza-benzofuran carboxylic acid" for "2-benzofuran carboxylic acid" in step (i), and substituting "morpholine-4-sulfonyl chloride" for "4-chlorosulfonyl-piperazine-l -carboxylic acid benzyl ether" in step (k) gave the title compound; IH NMR (CDC1₃) δ 8.65 (m, IH), 7.80 (m, IH), 7.35 (m, IH), 7.15 (m, IH), 6.85 (m, IH), 5.05 (m, IH), 4.75 (m, IH), 4.45 (d, IH), 4.35 (m, IH), 3.80 (m, 5H), 3.25 (t, 4H), 2.75 (s, 3H), 2.25 (m, 2H), 1.75 (m, 2H), 0.90-1.60 (m, 12H); LCMS: M+rf^" =564.2.

Example 7 Preparation of benzofuran-2-carboxylic acid {(S)-3-methyl-l-[(S)-l-(moi holine-4- sulfonyl)-3 -oxo-azepan-4-ylcarbamoyl] -butyl} -amide

Following the procedure of Example 4, except "4-{(S)-2-[(l-benzofuran-2-yl- methanoyl)-amino]-4-methyl-pentanoylamino} -3 -hydroxy-azepane- 1 -carboxylic acid benzyl ester " for "(2R,5S,6S)-5-{(S)-2-[(l-benzofuran-2-yl-methanoyl)-amino]-4-methyl- pentanoylamino}-6-hydroxy-2-methyl-l-azepane-l -carboxylic acid benzyl ester " gave the title compound; IH NMR (CDC1₃) δ 7.70 (m, IH), 7.40-7.0 (m, 4H), 7.10 (m, IH), 6.90 (m, IH), 5.05 (m, IH), 4.75 (m, IH), 4.50 (d, IH), 4.05 (d, IH), 3.75 (m, 5H), 3.25 (m, 4H), 2.80 (m, IH), 2.10-2.40 (m, 2H), 1.30-1.95 (m, 5H), 1.00 (m, 6H); LCMS: M+Ε? =535.2.

Example 8 Preparation of benzofuran-2-carboxylic acid [(S)-l-((S)-dimethylsulfamoyl-oxo-azepan-4- ylcarbamoyl)-3-methyl-butyl]-amide

Following the procedure of Example 7, except substituting "dimethylaminosulfonyl chloride" for "morpholine-4-sulfonyl chloride" gave the title compound; IH NMR (CDC1₃) δ 7.30-7.68 (m, 5H), 7.15 (d, IH), 7.03 (d, IH), 5.01-5.03 (m, IH), 4.60-4.71 (m, IH), 4.40-

4.51 (d, IH), 3.90-4.01 (d, IH), 3.61-3.70 (m, 2H), 2.83 (s, 6H), 2.11-2.32 (m, 4H), 1.75 (m,

2H), 1.50 (m, IH), 1.02 (d, 6H). Example 9 Preparation of benzofuran-2-carboxylic acid {(S)-l-[(S)-l-(3,4-dihydro-lH-isoquinoline-2- sulfonyl)-3 -oxo-azepan-4-ylcarbamoyl]-3 -methyl-butyl} -amide

Following the procedure of Example 7, except substituting "3,4-dihydro-lH-isoquinoline-2- sulfonyl chloride" for "morpholine-4-sulfonyl chloride " gave the title compound; IH NMR (CDC1₃) δ 7.70 (m, IH), 7.40-7.55 (m, 3H), 7.10-7.35 (m, 7H), 6.95 (m, IH), 5.10 (m, IH), 4.75 (m, IH), 4.40 -4.55 (m, 3H), 4.10 (m, IH), 3.70 (d, IH), 3.55 (m, 2H), 3.00 (m, 2H), 2.80 (m, IH), 2.25 (m, 2H), 0.90-1.80 (m, 10H); LCMS M+tf^" = 581.4.

Example 10 Preparation of 3-methyl-furo[3,2-b]pyridine-2-carboxylic acid {(S)-3-methyl-l-[(S)-l- (morpholine-4-sulfonyl)-3 -oxo-azepan-4-ylcarbamoyl]-butyl} -amide

Following the procedure of Example 7, except substituting "2-methyl-aza-benzofuran carboxylic acid" for "2-benzofuran carboxylic acid" gave the title compound; IH NMR (CDC1₃) δ 8.65 (m, IH), 7.80 (m, IH), 7.40 (m, IH), 7.15 (d, IH), 6.85 (d, IH), 5.10 (m, IH), 4.75 (m, IH), 4.50 (d, J = 17.6 Hz, IH), 4.10 (m, IH), 3.80 (m, 5H), 3.25 (m, 4H), 2.85 (m, IH), 2.75 (m, 3H), 2.15-2.35 (m, 2H), 0.90-1.90 (m, 11 H); LCMS: M+H⁺ = 550.4.

Claims

What is claimed is:

1. A compound according to Formula I:

wherein: R is Formula A or Formula B:

wherein in Formula B, n is an integer from 1 to 5; R₂ is H, C].₈alkyl, C₂.₈alkenyl, C₂.₈alkynyl, or substituted C_Malkyl, wherein said substituted C^alkyl is substituted with one substituent selected from -OR_a, -N(R )(R_b), - N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); each R₃ is independently H, Cι-₈alkyl, C₂-₈alkenyl, C₂-₈alkynyl, substituted Cι_₆alkyl, optionally substituted C₃.₆cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein said substituted Ci-βalkyl is substituted with one or more halo substituent or with one substituent selected from -OR_a, - N(R_b)(R_b), -N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), - N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b), and wherein said optionally substituted C₃.₆cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one substituent selected from -Cι_ alkyl, -OR_a, -N(R_b)(R_b), - N(R_b)C(0)R_b, -C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); or taken together both R3 form an optionally substituted non-aromatic monocyclic ring incorporating therein the N to which each is attached, wherein said optionally substituted non-aromatic monocyclic ring is a saturated or unsaturated, wherein said optionally substituted non-aromatic monocyclic ring contains from 3 to 7 member atoms and may optionally contain 1 or 2 additional heteroatoms as member atoms in the ring, and wherein said optionally substituted non-aromatic monocyclic is optionally substituted with one substituent selected from -OR_a, -C(0)Rd, -C(0)OR<ι, -N(R )(R_b), -N(R_b)C(0)R_b, - C(0)N(R_b)(R_b), -N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), -N(H)C(=NR_b)N(R_b)(R_b), - N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); or taken together both R3 form an optionally substituted bicyclic ring incorporating therein the N to which each is attached, said optionally substituted bicyclic ring comprising a first ring that is fused to a second ring, wherein said first ring is a saturated or unsaturated non-aromatic monocyclic ring incorporating therein the N to which each R3 is attached which contains from 3 to 7 member atoms and may optionally contain from 1 to 3 additional heteroatoms as member atoms in the ring, wherein said second ring is selected from C₃. ₇cycloalkyl, C₃.₇cycloalkenyl, monocyclic heterocyclalkyl, and monocyclic heteroaryl, and wherein said optionally substituted bicyclic ring is optionally substituted with one substituent selected from -OR_a, -N(R_b)(R_b), -N(R )C(0)R , -C(0)N(R_b)(R_b), - N(R_b)C(0)OR_b, -OC(0)N(R_b)(R_b), -N(H)C(=NR_b)N(R_b)(R_b), -N(R_b)C(0)N(R_b)(R_b), and -N(R_b)C(S)N(R_b)(R_b); ) is H, optionally substituted Cι-₇alkyl, optionally substituted C -₇alkenyl, optionally substituted C₂-₇alkynyl, optionally substituted C₃-₇cycloalkyl, optionally substituted C₃-₇cycloalkenyl, or optionally substituted heterocycloalkyl, wherein said optionally substituted Cι-₇alkyl, C₂.₇alkenyl, or C₂.₇alkynyl is optionally substituted with one substituent selected from -OR<-, -SRc, -S(0)R_c, -8(0)^, -N(R_b)(R_b), -N(R_b)C(0)R_c, -C₃. βcycloalkyl, monocyclic heterocycloalkyl, and wherein said optionally substituted C₃.₇- cycloalkyl, C₃.₇cycloalkenyl, or heterocycloalkyl is optionally substituted with one substituent selected from optionally substituted -Cι-₃alkyl, -OR_c, -N(R_b)(R_b), and - N(R_b)C(0)Rc, wherein said optionally substituted - -salkyl is optionally substituted with one substituent selected from -OR^, -SR^, -8(0)1^, -S(0)₂Rc, and -N(R_b)(R_b); R5 is optionally substituted C₃-7cycloalkyl, optionally substituted C₃.₇cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl, wherein said optionally substituted C₃-₇cycloalkyl, C₃-₇cycloalkenyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one substituent selected from - C_Malkyl, -OR_c, -N(R_b)(R_b), and -N(R_b)C(0)R_c; each R_a is independently H or optionally substituted C]. alkyl, wherein said optionally substituted

is optionally substituted with one or more halo substituent or with one substituent selected from -0R_b and N(R )(R_b); each R_b is independently H or Cι_₃alkyl; each R_c is independently Cι-₃alkyl; and each R<-[ is independently optionally substituted C^a-kyl, phenyl, or monocyclic heteroaryl, wherein said optionally substituted Cι-₃alkyl is optionally substituted with phenyl or monocyclic heteroaryl; or a pharmaceutically acceptable salt thereof.

2. A compound according to Claim 1 wherein R\ is Formula A.

3. A compound according to Claim 2 wherein R is optionally substituted -

₇alkyl or optionally substituted C₃-₇cycloalkyl.

4. A compound according, to Claim 3 wherein R5 is aryl or heteroaryl.

5. A compound according to Claim 4 wherein each R₃ is independently - salkyl,

6. A compound according to Claim 4 wherein taken together both R3 form an optionally substituted non-aromatic monocyclic ring incorporating therein the N to which each is attached.

7. A compound according to Claim 4 wherein taken together both R3 form an optionally substituted bicyclic ring incorporating therein the N to which each is attached.

8. A compound according, to Claim 5, 6 or 7 wherein R₂ is H or CH3.

9. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable excipient.

10. A method for treating osteoporosis comprising administering a safe and effective amount of a compound according to Claim 1 to a patient in need thereof.