INTEGRIN RECEPTOR ANTAGONISTS

Abstract: The present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors alpha beta 3 and/or alpha v beta 5 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, cancer, and metastatic tumor growth.

Description: TITLE OF THE INVENTION INTEGRIN RECEPTOR ANTAGONISTS FIELD OF THE INVENTION The present invention relates to compounds and deπvatives thereof, their synthesis, and their use as αv integπn receptor antagonists More particularly, the compounds of the present invention are antagonists of the integπn receptors αvβ3, αvβ5, and αv integrin receptors associated with other β-subunits, and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retmopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, cancer, and metastatic tumor growth. BACKGROUND OF THE INVENTION It is believed that a wide vanety of disease states and conditions can be mediated by acting on integπn receptors and that integπn receptor antagonists represent a useful class of drugs. Integπn receptors are heterodimeπc transmembrane receptors through which cells attach and communicate with extracellular matπces and other cells (See S.B Rodan and G.A. Rodan, "Integπn Function In Osteoclasts," Journal of Endocrinology, 154: S47- S56 (1997), which is incorporated by reference herein in its entirety) In one aspect of the present invention, the compounds herein are useful for inhibiting bone resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large multmucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual resorption of mineralized tissue from the bone More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state In the secretory state, osteoclasts are flat, attach to the bone matπx via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone The adhesion of osteoclasts to bone surfaces is an important initial step m bone resorption In the migratory or motile state, the osteoclasts migrate across bone matπx and do not take part in resorption until they again attach to bone Integπns are involved in osteoclast attachment, activation and migration The most abundant integπn on osteoclasts, e.g., on rat, chicken, mouse and human osteoclasts, is an integπn receptor known as αvβ3, which is thought to interact in bone with matπx proteins that contain the RGD sequence. Antibodies to αvβ3 block bone resorption in vitro indicating that this integπn plays a key role in the resorptive process. There is increasing evidence to suggest that αvβ3 hgands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, peπodontal disease, hyperparathyroidism, peπarticular erosions in rheumatoid arthπtis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-mduced osteoporosis. All of these conditions are characteπzed by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone m the jaws than in the cortices of the long bones The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture πsk. In the United States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attπbuted to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture Individuals suffeπng from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption. Additionally, αvβ3 hgands have been found to be useful in treating and/or inhibiting restenosis (i.e. recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retmopathy, macular degeneration, and angiogenesis (l e. formation of new blood vessels), and inhibiting viral disease Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor, thus, inhibition of angiogenesis can cause tumor regression in animal models (See Harrison's Principles of Internal Medicine, 12th ed , 1991, which is incorporated by reference herein in its entirety) Therefore, αvβ3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al., Cell, 79.1157-1164 (1994), which is incorporated by reference herein in its entirety) Evidence has also been presented suggesting that angiogenesis is a central factor in the initiation and persistence of arthπtic disease, and that the vascular integπn αvβ3 may be a preferred target in inflammatory arthπtis. Therefore, αvβ3 antagonists which inhibit angiogenesis may represent a novel therapeutic approach to the treatment of arthπtic disease, such as rheumatoid arthπtis (see CM. Storgard, et al., "Decreased angiogenesis and arthπtic disease in rabbits treated with an αvβ3 antagonist," J Clin. Invest., 103: 47-54 (1999), which is incorporated by reference herein in its entirety) Moreover, compounds of this invention can also inhibit neovasculaπzation by acting as antagonists of the integπn receptor, αvβ5. A monoclonal antibody for ocvβ5 has been shown to inhibit VEGF-mduced angiogenesis in rabbit cornea and the chick choπoallantoic membrane model (See M.C. Fπedlander, et al., Science 270: 1500-1502 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize αvβ5 are useful for treating and preventing macular degeneration, diabetic retmopathy, viral disease, cancer, and metastatic tumor growth. Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of αv integπn receptors associated with other β subunits, suh as αvβό and αvβ8 (See, for example, Melpo Chπstofidou-Solomidou, et al., "Expression and Function of Endothe al Cell αv Integπn Receptors in Wound-Induced Human Angiogenesis in Human Skm/SCID Mice Chimeras," Amencan Journal of Pathologv, 151: 975-83 (1997) and Xiao-Zhu Huang, et al., "Inactivation of the Integπn β6 Subunit Gene Reveals a Role of Epithelial Integnns in Regulating Inflammation in the Lungs and Skin," Journal of Cell Biology, 133: 921-28 (1996), which are incorporated by reference herein in their entirety) In addition, certain compounds of this invention antagonize both the αvβ3 and αvβ5 receptors These compounds, refened to as "dual αvβ3/αvβ5 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retmopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, cancer, and metastatic tumor growth Peptidyl as well as peptidomimetic antagonists of the αvβ3 integπn receptor have been descπbed both in the scientific and patent literature. For example, reference is made to W.J. Hoekstra and B.L. Poulter, Curr. Med Chem. 5: 195-204 (1998) and references cited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO 99/15506; WO 99/15507; EP 853084; EP 854140; EP 854145; and US Patent No. 5,780,426. Evidence of the ability of αvβ3 integπn receptor antagonists to prevent bone resorption in vitro and in vivo has been presented (see V.W Engleman et al., "A Peptidomimetic Antagonist of the αvβ3 Integπn Inhibits Bone Resorption in Vitro and Prevents Osteoporosis in Vivo," J. Clm. Invest. 99 2284-2292 (1997); S.B. Rodan et al, "A High Affinity Non-Peptide αvβ3 Ligand Inhibits Osteoclast Activity In Vitro and In Vivo," J. Bone Miner. Res. 11 : S289 (1996); J.F. Gourvest et al., "Prevention of OVX-Induced Bone Loss With a Non- peptidic Ligand of the αvβ3 Vitronectin Receptor," Bone 23: S612 (1998); M.W. Lark et al., "An Orally Active Vitronectin Receptor αvβ3 Antagonist Prevents Bone Resorption In Vitro and In Vivo in the Ovaπectomized Rat," Bone 23: S219 (1998)). The αvβ3 integπn receptor recognizes the Arg-Gly-Asp (RGD) tπpeptide sequence in its cognate matπx and cell surface glycoprotems (see J. Samanen, et al., "Vascular Indications for Integπn αv Antagonists," Curr. Pharmaceut. Design 3: 545-584 (1997)). A benzazepme nucleus has been employed among others by Genentech and SmithKlme Beecham as a conformationally constrained Gly-Asp mimetic to elaborate nonpeptide αvβ3 tegπn receptor antagonists substituted at the N-terminus with heterocychc argm e mimetics (see R.M. Keenan et al., "Discovery of Potent Nonpeptide Vitronectin Receptor (αvβ3) Antagonists," J Med. Chem. 40: 2289-2292 (1997); R.M. Keenan et al., "Benzimidazole Derivatives As Argmine Mimetics in 1,4-Benzodιazepιne Nonpeptide Vitronectin Receptor (αvβ3) Antagonists," Bioorg Med Chem. Lett. 8: 3165-3170 (1998); and R M. Keenan et al., "Discovery of an Imidazopyπdme- Contaimng 1,4-Benzodιazepme Nonpeptide Vitronectin Receptor (αvβ3) Antagonist With Efficacy in a Restenosis Model," Bioorg Med Chem. Lett 8. 3171-3176 (1998) Patents assigned to SmithKlme Beecham that disclose such benzazepme, as well as related benzodiazepine and benzocycloheptene, αvβ3 integπn receptor antagonists include WO 96/00574, WO 96/00730, WO 96/06087. WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124. WO 98/15278. WO 99/05107, WO 99/06049, WO 99/15170, and WO 99/15178, and to Genentech include WO 97/34865. The dibenzocycloheptene, as well as dibenzoxazepine, nucleus has also been employed as a Gly-Asp mimetic to afford αvβ3 antagonists (see WO 97/01540, WO 98/30542, WO 99/11626, and WO 99/15508 all assigned to SmithKlme Beecham). Other integπn receptor antagonists featuπng backbone conformational πng constraints have been descπbed in WO 99/30709; WO 99/30713; WO 99/31099; U.S Patent No. 5,919,792; U.S. Patent No. 5,925,655; and U.S. Patent No. 5,981,546. However, there still remains a need for small-molecule, non-peptidic selective αv integrin receptor antagonists that display improved potency, pharmacodynamic, and pharmacokinetic properties, such as oral bioavailabihty and duration of action, over already descπbed compounds. Such compounds would prove to be useful for the treatment, prevention, or suppression of vaπous pathologies enumerated above that are mediated by αv integπn receptor binding and cell adhesion and activation. It is therefore an object of the present mvention to provide compounds which are useful as αv integπn receptor antagonists. It is another object of the present invention to provide compounds which are useful as αvβ3 receptor antagonists. It is another object of the present invention to provide compounds which are useful as αvβ5 receptor antagonists It is another object of the present mvention to provide compounds which are useful as dual αvβ3/αvβ5 receptor antagonists. It is another object of the present invention to provide pharmaceutical compositions comprising αv integπn receptor antagonists It is another object of the present invention to provide methods for making the pharmaceutical compositions of the present invention. It is another object of the present invention to provide methods for eliciting an αv integπn receptor antagonizing effect in a mammal in need thereof by administeπng the compounds and pharmaceutical compositions of the present invention It is another object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthπtis, viral disease, diabetic retmopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth It is another object of the present invention to provide compounds and pharmaceutical compositions useful for treating osteoporosis It is another object of the present invention to provide methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthπtis, viral disease, diabetic retmopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth It is another object of the present invention to provide methods for treating osteoporosis These and other objects will become readily apparent from the detailed descπption which follows SUMMARY OF THE INVENTION The present invention relates to compounds of structural formula (I) (I) wherein X is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic πng system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one R^ substituent and the πng carbon atoms are unsubstituted or substituted with one or two R^ substituents, and a 9- to 14-membered polycyclic πng system, wherein one or more of the πngs is aromatic, and wherem the polycyclic ring system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the πng carbon atoms are unsubstituted or substituted with one or two R* substituents; Y is selected from the group consisting of -(CH 2 )πr. -(CH2)m-O-(CH 2 )n-. -(CH 2 )m-NR 4 -(CH 2 )n-. -(CH2)m-S-(CH2)n-. -(CH2)m-SO-(CH2) n -, -(CH2)m-S02-(CH 2 )n-, -(CH 2 )m-O-(CH 2 )n-O-(CH2)p-, -(CH 2 )m-O-(CH2)n-NR 4 -(CH 2 ) p -, -(CH 2 )m-NR 4 -(CH 2 )n-NR 4 -(CH2)p-, -(CH 2 ) m -O-(CH2)n-S-(CH2)p-, -(CH2)m-S-(CH2)n-S-(CH2)p-, -(CH2)m-NR 4 -(CH 2 )n-S-(CH2)p-, -(CH 2 )m-NR 4 -(CH2)n-O-(CH2)p-, -(CH 2 )m-S-(CH2)n-O-(CH2)p-, -(CH 2 )m-S-(CH2)n-NR 4 -(CH2)p-, and -(CH2)m-Z-(CH 2 )n-; wherein Z is a 3- to 10-membered monocyclic or polycyclic aromatic or nonaromatic πng system having 0, 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the πng carbon atoms are unsubstituted or substituted with one or two Rl substituents, and wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R^ substituents; D is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic πng system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one R* substituent and the πng carbon atoms are unsubstituted or substituted with one or two R* substituents, E is selected from the group consisting of -(CH2)πr- -(CH2)m-0-(CH2) n -, -(CH 2 )m-NR 4 -(CH2)n-, -(CH2)m-S-(CH 2 )n-, -(CH2)m-SO-(CH2)n-, and -(CH2)m-SO 2 -(CH2)n-, wherein any methylene (CH 2 ) carbon atom in E, other than in R 4 , can be substituted by one or two R^ substituents, R^and R^ are each independently selected from the group consisting of hydrogen, halogen, Ci -io alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci-6 alkyl, C3-8 cycloheteroalkyl Ci-6 alkyl, aryl, aryl C1 -8 alkyl, ammo, amino Ci-8 alkyl, C1-.3 acylamino, C1-.3 acylammo Cχ-8 alkyl, (Ci-6 alky pamino, (C_-6 alkyl)pammo Ci-8 alkyl, Ci-4 alkoxy, Ci-4 alkoxy Ci-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, C1-.3 alkoxycarbonyl, C1.3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl- Ci-6 alkyloxy, hydroxy, hydroxy Ci-6 alkyl, Ci-6 alkyloxy- Ci-6 alkyl, nitro, cyano, tπfluoromethyl, tπfluoromethoxy, tπfluoroethoxy, Ci-8 alkyl-S(O)p, (Cι_8 alkyl)pamιnocarbonyl, Ci-8 alkyloxycarbonylamino, (Ci-8 alkyl)pamιnocarbonyloxy, (aryl Ci-8 alkyl)pamιno, (aryl)pamιno, aryl Ci-8 alkylsulfonylamino, and Ci_8 alkylsulfonylamino, or two Rl substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R3 IS independently selected from the group consisting of hydrogen, aryl, Ci-10 alkyl, aryl-(CH 2 ) r -O-(CH 2 )s-. aryl-(CH2)rS(O) p -(CH2)s-. aryl-(CH 2 )r-C(O)-(CH2)s-. aryl-(CH 2 )r-C(O)-N(R )-(CH2)s- aryl-(CH 2 ) r -N(R 4 )-C(O)-(CH2)s- aryl-(CH 2 )r-N(R )-(CH2)s-, halogen, hydroxyl, oxo, trifluoromethyl, Ci-8 alkylcarbonylamino, aryl C 1-5 alkoxy, Ci-5 alkoxycarbonyl, (Ci-8 alkyl)paminocarbonyl, Ci-6 alkylcarbonyloxy, C3-8 cycloalkyl, (Ci-6 alkyl )pamino, amino Cι_6 alkyl, arylaminocarbonyl, aryl Ci-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cι _6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, HC≡C-(CH2)t-, Cι_6 alkyl-C≡C-(CH2)t-, C3-7 cycloalkyl-C≡C-(CH2)t-, aryl-C≡C-(CH2)t-, Cι_6 alkylaryl-C≡C-(CH2)t-, CH2=CH-(CH2)t-, Ci-6 alkyl-CH=CH-(CH2)t-, C3-7 cycloalkyl-CH=CH-(CH 2 )t- aryl-CH=CH-(CH2)t-, Ci-6 alkylaryl-CH=CH-(CH2)t-, Cι-6 alkyl-SO 2 -(CH2)t-, Cι_6 alkylaryl-SO -(CH 2 ) t -, Ci-6 alkoxy, aryl Cι_ alkoxy, aryl Cι_6 alkyl, (Ci-6 alkyl)pammo Ci-6 alkyl, (aryl)pamιno, (aryl)pamιno Cι_6 alkyl, (aryl Cι_6 alkyl)pamιno, (aryl Ci-6 alkyl)pammo Cι_ alkyl, arylcarbonyloxy, aryl C 1-6 alkylcarbonyloxy, (Ci-6 alkyl)paminocarbonyloxy, Ci-8 alkylsulfonylamino, arylsulfonylamino, Ci-8 alkylsulfonylamino Ci-6 alkyl, arylsulfonylamino C 1-6 alkyl, aryl Ci-6 alkylsulfonylamino, aryl Ci-6 alkylsulfonylamino Ci-6 alkyl, Ci-8 alkoxycarbonylammo, Ci-8 alkoxycarbonylammo Ci-8 alkyl, aryloxycarbonylammo C _8 alkyl, aryl Ci-8 alkoxycarbonylammo, aryl Ci-8 alkoxycarbonylammo Ci-8 alkyl, Ci-8 alkylcarbonylammo, Ci-8 alkylcarbonylammo Ci- alkyl, arylcarbonylamino Ci-6 alkyl, aryl Cι_6 alkylcarbonylammo, aryl Ci- alkylcarbonylammo Ci-6 alkyl, aminocarbonylamino Ci-6 alkyl, (Ci- alkyl)pamιnocarbonylamιno, (Ci-8 alkyl)pammocarbonylamιno Cι_6 alkyl, (aryl)pamιnocarbonylamιno Ci-6 alkyl, (aryl C -8 alkyl)pammocarbonylamιno, (aryl Ci-8 alkyl)pamιnocarbonylamιno Ci-6 alkyl, aminosulfonylammo Cι_6 alkyl, (Ci-8 alkyl)pamιnosulfonylamιno, (Ci-8 alkyl)pammosulfonylamιno Cι_6 alkyl, (aryl)pammosulfonylammo Ci-6 alkyl, (aryl Cι_8 alkyl)pamιnosulfonylammo, (aryl Ci-8 alkyl)pamιnosulfonylammo Cι_6 alkyl, Ci- alkylsulfonyl, Ci-6 alkylsulfonyl Ci-6 alkyl, arylsulfonyl Ci-6 alkyl, aryl Ci-6 alkylsulfonyl, aryl Ci-6 alkylsulfonyl Cι_6 alkyl, Ci-6 alkylcarbonyl, Ci- alkylcarbonyl Ci-6 alkyl, arylcarbonyl Ci-6 alkyl, aryl Ci-6 alkylcarbonyl, aryl Ci- alkylcarbonyl Ci-6 alkyl, Ci-6 alkylthiocarbonylammo, C -6 alkylthiocarbonylammo C _6 alkyl, arylthiocarbonylamino Ci-6 alkyl, aryl Ci-6 alkylthiocarbonylammo, aryl Ci-6 alkylthiocarbonylammo Ci- alkyl, (Ci-8 alkyl)pamιnocarbonyl Cι_6 alkyl, (aryl)pamιnocarbonyl Cι_6 alkyl, (aryl Ci-8 alkyl)pamιnocarbonyl, and (aryl Ci-8 alkyl)pammocarbonyl Cι_6 alkyl, or two R3 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R3 are either unsubstituted or substituted with one to three Rl substituents, and provided that each R^ IS selected such that in the resultant compound the carbon atom or atoms to which R3 is attached is itself attached to no more than one heteroatom, each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, C3-.8 cycloalkyl, amino Ci_6 alkyl, (aryl)pamιnocarbonyl, (aryl C1-.5 alkyl)pamιnocarbonyl, hydroxycarbonyl Ci-6 alkyl, C 1-8 alkyl, aryl C 1-6 alkyl, (Ci-6 alkyl)pammo C2-6 alkyl, (aryl Ci-6 alkyl)pamιno C2-6 alkyl, Ci-8 alkylsulfonyl, Ci-8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci-8 alkoxycarbonyl, Ci-8 alkylcarbonyl, arylcarbonyl, aryl Ci-6 alkylcarbonyl, (Cl-8 alkyl)pamιnocarbonyl, aminosulfonyl, Ci-8 alkylaminosulfonyl, (aryl)pamιnosulfonyl, (aryl Cι_8 alkyl)pamιnosulfonyl, arylsulfonyl, arylCl-6 alkylsulfonyl, Ci- alkylthiocarbonyl, arylthiocarbonyl, and aryl Ci-6 alkylthiocarbonyl, wherem any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three Rl substituents, R5 is selected from the group consisting of hydrogen, C 1-8 alkyl, aryl, aryl Ci-8 alkyl, Ci-8 alkylcarbonyloxy Ci-4 alkyl, aryl Ci-8 alkylcarbonyloxy Ci-4 alkyl, Ci-8 alkylaminocarbonylmethylene, and C 1-8 dialkylaminocarbonylmethylene; wherein each a is independently an integer from 0 to 6, each b is independently an integer from 0 to 6 wherem a + b > 2; each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; each s is independently an integer from 0 to 3; and each t is independently an integer from 0 to 3; or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions compπsing the compounds of the present invention and a pharmaceutically acceptable earner. The present invention also relates to methods for making the pharmaceutical compositions of the present invention. The present invention also relates to methods for eliciting an αv integπn receptor antagonizing effect in a mammal in need thereof by administeπng the compounds and pharmaceutical compositions of the present invention. The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthπtis, viral disease, diabetic retmopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth by administeπng the compounds and pharmaceutical compositions of the present invention The present invention also relates to methods for treating osteoporosis by administeπng the compounds and pharmaceutical compositions of the present invention DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds useful as integπn receptor antagonists Compounds of the present invention are descπbed by the following structural formula (I) (I) wherein X is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic πng system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one R* substituent and the πng carbon atoms are unsubstituted or substituted with one or two Rl substituents, and a 9- to 14-membered polycyclic πng system, wherein one or more of the πngs is aromatic, and wherem the polycyclic πng system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one R substituent and the πng carbon atoms are unsubstituted or substituted with one or two R^ substituents, Y is selected from the group consisting of -(CH 2 )m-, -(CH2)m-O-(CH 2 )n-, -(CH 2 )m-NR 4 (CH 2 ) n -, -(CH2) m -S-(CH2)n-. -(CH2)m-SO-(CH 2 )n-- -(CH2)m-SO 2 -(CH 2 )n-. -(CH 2 ) m -O-(CH 2 )n-O-(CH2) p -, -(CH 2 )m-O-(CH2)n-NR 4 -(CH 2 )p-, -(CH2) m -NR 4 -(CH2)n-NR 4 -(CH 2 )p-, -(CH2)m-O-(CH2)n-S-(CH 2 )p-, -(CH2)m-S-(CH2)n-S-(CH 2 )p-, -(CH2)m-NR 4 -(CH2)n-S-(CH 2 )p-, -(CH 2 )m-NR 4 -(CH2)n-O-(CH 2 )p-, -(CH 2 )m-S-(CH 2 ) n -O-(CH 2 )p-, -(CH 2 ) m -S-(CH 2 )n-NR 4 -(CH2) p -, and -(CH 2 )m-Z-(CH2)n-; wherem Z is a 3- to 10-membered monocyclic or polycyclic aromatic or nonaromatic πng system having 0, 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S where the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the πng carbon atoms are unsubstituted or substituted with one or two Rl substituents, and wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R^ substituents; D is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic πng system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the πng carbon atoms are unsubstituted or substituted with one or two R substituents; E is selected from the group consisting of -(CH 2 )πr. -(CH 2 )m-O-(CH2) n -, -(CH 2 )m-NR 4 -(CH 2 )n-, -(CH2)m-S-(CH 2 )n-. -(CH 2 ) m -SO-(CH 2 )ιr. and -(CH2) m -SO 2 -(CH2)n-. wherem any methylene (CH 2 ) carbon atom in E, other than in R 4 , can be substituted by one or two R^ substituents, R^and R^ are each independently selected from the group consisting of hydrogen, halogen, Ci-io alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci-6 alkyl, C3-8 cycloheteroalkyl Ci-6 alkyl, aryl, aryl Ci-8 alkyl, amino, ammo Ci-8 alkyl, Ci-3 acylammo, Ci-3 acylammo Cι_8 alkyl, (Ci-6 alkyl )pamιno, (Ci-6 alkyl )pamιno Ci-8 alkyl, Ci-4 alkoxy, Ci-4 alkoxy Ci-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, Ci-3 alkoxycarbonyl, Ci-3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl- Ci-6 alkyloxy, hydroxy, hydroxy Ci-6 alkyl, Ci- alkyloxy- Ci-6 alkyl, nitro, cyano, tπfluoromethyl, tπfluoromethoxy, tπfluoroethoxy, Ci-8 alkyl-S(O)p, (Ci-8 alkyl )pamιnocarbonyl, Ci-8 alkyloxycarbonylamino, (Ci-8 alkyl)pamιnocarbonyloxy, (aryl Ci-8 alkyl )pammo, (aryl)pamιno, aryl Ci-8 alkylsulfonylamino, and Ci-8 alkylsulfonylamino; or two Rl substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R^ is independently selected from the group consisting of hydrogen, aryl, Ci-10 alkyl, aryl-(CH2)r-O-(CH 2 )s-. aryl-(CH2) r S(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH 2 )s-, aryl-(CH2) C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH 2 )s-, aryl-(CH2)r-N(R 4 )-(CH 2 )s-. halogen, hydroxyl, oxo, tπfluoromethyl, Ci-8 alkylcarbonylammo, aryl Ci-5 alkoxy, Ci-5 alkoxycarbonyl, (Ci-8 alkyl)pammocarbonyl, Ci-6 alkylcarbonyloxy, C3-8 cycloalkyl, (Ci-6 alkyl )pamιno, ammo Ci- alkyl, arylaminocarbonyl, aryl Ci-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci- alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, HC≡C-(CH2)t-, Ci-6 alkyl-C≡C-(CH )t-, C3-7 cycloalkyl-C≡C-(CH2)t-, aryl-C≡C-(CH2)t-, Ci-6 alkylaryl-C≡C-(CH2)t-, CH 2 =CH-(CH 2 ) t -, Ci-6 alkyl-CH=CH-(CH2)t-, C3-7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, Ci-6 alkylaryl-CH=CH-(CH 2 ) t -, Ci-6 alkyl-SO 2 -(CH 2 ) t -, Ci-6 alkylaryl-SO2-(CH 2 )t-, Ci-6 alkoxy, aryl Cι_ alkoxy, aryl Cι_6 alkyl, (Ci-6 alkyl)pammo Ci-6 alkyl, (aryl)pamιno, (aryl)pamιno Ci-6 alkyl, (aryl Ci- alkyl)pamιno, (aryl Ci-6 alkyl)pammo Cι_6 alkyl, arylcarbonyloxy, aryl Cι_6 alkylcarbonyloxy, (Ci-6 alkyl)pammocarbonyloxy, Ci_8 alkylsulfonylamino, arylsulfonylamino, Ci-8 alkylsulfonylamino Ci_6 alkyl, arylsulfonylamino Ci-6 alkyl, aryl Cι_6 alkylsulfonylamino, aryl Ci-6 alkylsulfonylamino Ci-6 alkyl, Ci-8 alkoxycarbonylammo, Ci-8 alkoxycarbonylammo Ci-8 alkyl, aryloxycarbonylamino Ci-8 alkyl, aryl Ci-8 alkoxycarbonylammo, aryl Cι_8 alkoxycarbonylammo Ci-8 alkyl, Ci-8 alkylcarbonylammo, Ci-8 alkylcarbonylammo Cι_6 alkyl, arylcarbonylamino Ci-6 alkyl, aryl Ci-6 alkylcarbonylammo, aryl Ci-6 alkylcarbonylammo C - alkyl, ammocarbonylamino Cι_6 alkyl, (Cl-8 alkyl)pamιnocarbonylamιno, (Ci-8 alkyl)pammocarbonylamιno Ci-6 alkyl, (aryl)pammocarbonylammo Cι_6 alkyl, (aryl Ci-8 alkyl)pamιnocarbonylammo, (aryl Ci-8 alkyl)pammocarbonylamιno Cι_6 alkyl, am osulfonylammo C 1-6 alkyl, (Ci-8 alkyl )pamιnosulfonylamιno, (Ci-8 alkyl)pamιnosulfonylammo Cι_6 alkyl, (aryl)pammosulfonylammo Cι_6 alkyl, (aryl Cι_8 alkyl)pamιnosulfonylamιno, (aryl Ci-8 alkyl)pamιnosulfonylamιno Ci-6 alkyl, Ci-6 alkylsulfonyl, Ci-6 alkylsulfonyl Ci-6 alkyl, arylsulfonyl Cι_6 alkyl, aryl Cι_6 alkylsulfonyl, aryl Ci- alkylsulfonyl Ci-6 alkyl, Ci-6 alkylcarbonyl, Ci-6 alkylcarbonyl Ci- alkyl, arylcarbonyl Ci-6 alkyl, aryl C 1- alkylcarbonyl, aryl Ci-6 alkylcarbonyl Ci-6 alkyl, Ci- alkylthiocarbonylammo, Ci-6 alkylthiocarbonylammo Cι_6 alkyl, arylthiocarbonylamino Ci-6 alkyl, aryl Ci-6 alkylthiocarbonylammo, aryl Ci-6 alkylthiocarbonylammo Ci-6 alkyl, (Ci-8 alkyl)pamιnocarbonyl Ci- alkyl, (aryl)pamιnocarbonyl Ci-6 alkyl, (aryl Ci-8 alkyl)pammocarbonyl, and (aryl Ci-8 alkyl)pamιnocarbonyl Cι_6 alkyl; or two R3 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R^ are either unsubstituted or substituted with one to three R^ substituents, and provided that each R^ IS selected such that m the resultant compound the carbon atom or atoms to which R^ IS attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, C3- cycloalkyl, amino C 1-6 alkyl, (aryl mmocarbonyl, (aryl Ci-5 alkyl)pamιnocarbonyl, hydroxycarbonyl Ci-6 alkyl, Ci-8 alkyl, aryl Ci-6 alkyl, (C -6 alkyl )pamιno C 2 _6 alkyl, (aryl Ci-6 alkyl)pamιno C 2 -6 alkyl, Ci-8 alkylsulfonyl, C 1-8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci-8 alkoxycarbonyl, Ci-8 alkylcarbonyl, arylcarbonyl, aryl C 1-6 alkylcarbonyl, (Ci-8 alkyl)pammocarbonyl, ammosulfonyl, Ci-8 alkylaminosulfonyl, (aryl)pamιnosulfonyl, (aryl Ci-8 alkyl)pammosulfonyl, arylsulfonyl, arylCl-6 alkylsulfonyl, Ci-6 alkylthiocarbonyl, arylthiocarbonyl, and aryl C 1-6 alkylthiocarbonyl, wherem any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three Rl substituents; R5 IS selected from the group consisting of hydrogen, Ci-8 alkyl, aryl, aryl Ci-8 alkyl, Ci-8 alkylcarbonyloxy Ci-4 alkyl, aryl Ci-8 alkylcarbonyloxy Ci-4 alkyl, Ci-8 alkylaminocarbonylmethylene, and Ci-8 dialkylaminocarbonylmethylene; wherein each a is independently an integer from 0 to 6, each b is independently an integer from 0 to 6 wherein a + b > 2, each m is independently an integer from 0 to 6, each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; each s is independently an integer from 0 to 3; and each t is independently an integer from 0 to 3; or a pharmaceutically acceptable salt thereof. In one embodiment of the compounds of the present invention, X is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic πng system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S where the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the πng carbon atoms are unsubstituted or substituted with one or two R substituents, and a 9- to 14-membered polycyclic nng system, wherein one or more of the πngs is aromatic, and wherein the polycyclic πng system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the πng carbon atoms are unsubstituted or substituted with one or two R substituents In a class of this embodiment, X is selected from the group consisting of In a subclass of this class, X is or In another embodiment of the compounds of the present invention, Y is selected from the group consisting of (CH 2 ) m , (CH 2 )m-O-(CH 2 ) n , and (CH 2 ) m -NR 4 -(CH 2 ) n , wherein any methylene (CH 2 ) carbon atom in Y, other than in R 4 , can be substituted by one or two R^ substituents. In a further embodiment of the compounds of the present invention, A is selected from the group consisting of hydrogen, fluoro, tπfluoromethyl, aryl, Ci-8 alkyl, arylCi-6 alkyl hydroxyl, oxo, arylaminocarbonyl, aryl Ci-5 alkylammocarbonyl, aminocarbonyl, and aminocarbonyl Cι_6 alkyl. In the compounds of the present mvention, m is preferably an integer from 0 to 3. In the compounds of the present invention, n is preferably an integer from 0 to 3. In the compounds of the present invention, a is preferably an integer from 1 to 3. In the compounds of the present invention, b is preferably an integer from 1 to 3. In the compounds of the present mvention, c is preferably an integer from 0 to 4. In the compounds of the present invention, d is preferably an integer from 0 to 4. Illustrative but nonhmiting examples of compounds of the present invention that are useful as integπn receptor antagonists are the following: { l-[3-(5,6,7,8-Tetrahydro-[l,8]-naphthyπdιn-2-ylmethyl)-pyπohdme-l-carbonyl]- pιpeπdιn-4-yl}-acetιc acid; 4-{4-[(l-H-Benzιmιdazol-2-ylamιno)-methyl]-pιpeπdιne-l-carbonyl}-phenoxyacetιc acid, { l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-ylmethyl)-pιpendιne-l-carbonyl]- pιpeπdm-4-yl}-acetιc acid, {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpeπdme-l-carbonyl]- pιperazιn-l-yl}-acetιc acid; 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpendιne-l-carbonyl]- pιpeπdιn-3-yl}-propιonιc acid, 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpeπdιne-l-carbonyl]- pyπohdιn-2-yl}-propιonιc acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-ylmethyl)-pιpeπdιne-l-carbonyl]- pιpeπdιn-l-yl}-acetιc acid, 3-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-ylmethyl)-pιpendιne-l-carbonyl]- phenoxyacetic acid; { l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdm-2-yl)-pιpendιne-l-carbonyl]-pιpeπdm-4- yl } -acetic acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdm-2-yl)-pιpendme-l-carbonyl]-pιperazm-l- yl} -acetic acid; 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-yl)-pιpendme-l-carbonyl]-pιpeπdm- 3-yl}-propιonιc acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-yl)-pιpeπdιne-l-carbonyl]-pιpeπdιn-l- yl} -acetic acid; 3-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-yl)-pιpendιne-l-carbonyl]- phenoxyacetic acid; 3-{4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-yl)-pιpeπdme-l-carbonyl]-pιpendιn- l-yl }-propιonιc acid; { l-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-ylmethyl)-pιpeπdιne-l-carbonyl]- pyπohdm-2-yl } -acetic acid, { l-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyπdm-2-ylmethyl)-pιpendme-l-carbonyl]- pιpendιn-2-yl } -acetic acid; {4-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpeπdme-l-carbonyl]- pιpendιn-1-yl} -acetic acid; 3-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpeπdιne-l-carbonyl]- phenoxyacetic acid; and 4-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyπdm-2-ylmethyl)-pιpeπdιne-l-carbonyl]- phenoxyacetic acid, or a pharmaceutically acceptable salt thereof. Further illustrative of the present invention are the compounds selected from the group consisting of: { l-[3-(5,6,7,8-Tetrahydro-[l,8]-naphthyπdιn-2-ylmethyl)-pyn-olιdιne-l-carbonyl]- pιpeπdm-4-yl } -acetic acid and 4-{4-[(l-H-Benzιmιdazol-2-ylammo)-methyl]-pιpeπdιne-l-carbonyl}-phenoxyacetιc acid; or a pharmaceutically acceptable salt thereof. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bi sulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloπde, edetate, edisylate, estolate, esylate. fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcmate, hydrabamine, hydrobromide, hydrochloπde, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, sahcylate, stearate, sulfate, subacetate, succmate, tannate, tartrate, teoclate, tosylate, tπethiodide and valerate. Furthermore, where the compounds of the mvention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic hgands, e.g., quaternary ammonium salts. The compounds of the present invention can have chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeπc mixtures, and individual diastereomers, with all isomeπc forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Some of the compounds descnbed herein contain olefmic double bonds, and unless specified otherwise, are meant to include both E and Z geometπc isomers. Some of the compounds descπbed herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention. Compounds of the present invention may be separated into diastereoisomeπc pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by the use of an optically active acid as a resolving agent, or by HPLC using a chiral stationary phase. Alternatively, any enantiomer of a compound of the present invention may be obtained by stereospecific synthesis using optically pure starting matenals or reagents of known configuration Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional deπvatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administeπng" shall encompass the treatment of the vaπous conditions descπbed with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug denvatives are descπbed, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incoφorated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu. The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. The term "αv integπn receptor antagonist," as used herein, refers to a compound which binds to and antagonizes either the αvβ3 receptor or the αvβ5 receptor, or a compound which binds to and antagonizes a combination of these receptors (for example, a dual αvβ3/αvβ5 receptor antagonist). The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone. The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1- propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number withm this range. The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range. The term "cycloalkyl" shall mean cyclic nngs of alkanes of three to eight total carbon atoms, or any number with this range (i.e , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) The term "cycloheteroalkyl," as used herein, shall mean a 3- to 8- membered fully saturated heterocyc c πng containing one or two heteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groups include, but are not limited to pipendinyl, pyπohdinyl, azetidinyl, morphohnyl, piperaz yl The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g , Ci-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.). The term "aryl," as used herein, refers to a monocyclic or bicyc c system compnsmg at least one aromatic πng, wherein the monocy c or bicychc system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherem the monocyhc orbicyhc system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Cι_8 alkyl, C3-8 cycloalkyl, aryl, aryl Ci-3 alkyl, ammo, amino Ci-6 alkyl, C1-.3 acylammo, Cι_3 acylammo Ci-6 alkyl, Ci-6 alkylamino, Ci-6 alkylamino Ci-6 alkyl, dι(Ci-6) alkylamino, dι(Cι_6) alkylammo-Ci-6 alkyl, Ci-4 alkoxy, C1-.4 alkylthio, Cι_4 alkylsulfmyl, Ci-4 alkylsulfonyl, Ci-4 alkoxy Ci- alkyl, hydroxycarbonyl, hydroxycarbonyl Cι_6 alkyl, Ci-5 alkoxycarbonyl, Cι_3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl Ci-6 alkyloxy, hydroxy, hydroxy Ci-6 alkyl, cyano, tπfluoromethyl, tπfluoromethoxy, oxo or Ci-5 alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyndyl, pyrrolyl, pyrazolyl, pyrazinyl, pynmidinyl, lmidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, mdolyl, thienyl, furyl, dihydrobenzofuryl, benzo(l,3)dιoxolanyl, benzo(l,4)dιoxanyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Ci-8 alkyl, C3-8 cycloalkyl, aryl, aryl Ci-3 alkyl, ammo, amino Ci-6 alkyl, Ci-3 acylammo, Cι_3 acylammo Cι_6 alkyl, Ci-6 alkylamino, Ci-6 alkylamino Ci-6 alkyl, dι(Cι_6) alkylamino, dι(Ci-6) alkylammo-Ci-6 alkyl, Cι_4 alkoxy, Ci-4 alkylthio, Ci-4 alkylsulfmyl, Cι_4 alkylsulfonyl, Ci-4 alkoxy Ci-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, Ci-5 alkoxycarbonyl, Ci-3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl Ci-6 alkyloxy, hydroxy, hydroxy Ci-6 alkyl, cyano, tπfluoromethyl, tπfluoromethoxy, oxo, or Ci-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-, or tπ- substituted with one to three of the above-named substituents; more preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents. Whenever the term "alkyl" or "aryl" or either of their prefix roots appears in a name of a substituent (e.g., aryl Cθ-8 alkyl), it shall be interpreted as including those limitations given above for "alkyl" and "aryl " Designated numbers of carbon atoms (e g., Ci-8) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyndine, ethylpyπdme, propylpyndine and butylpyπdme. In the compounds of the present invention, two R* substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group. In the compounds of the present invention, two R^ substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group. In such instances, the limitation, that in the resultant compound the carbon atom or atoms to which R3 IS attached is itself attached to attached to no more than one heteroatom, does not apply. Also, in the compounds of the present invention, two R3 substituents, when on the same carbon, can be taken together with the carbon to which they are attached to from a cyclopropyl group. The term "halogen" shall include iodine, bromine, chloπne, and fluonne The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom. The term "oxo" means "=O". The term "carbonyl" means "C=O." The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is descnbed first, followed by the adjacent functionality toward the point of attachment. For example, a Cι_5 alkylcarbonylammo C\- alkyl substituent is equivalent to O II -C^ β alkyl-NH-C-C^g alkyl . In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the vaπous substituents, i.e. D, E, X, Y, Z, Rl, R^, R3, R 4 , and R-> and the subscπpts a, b, m, n, p, r, s, and t are to be chosen conformity with well-known pπnciples of chemical structure connectivity. Representative compounds of the present mvention typically display submicromolar affinity for the αv integπn receptors, particularly the αvβ3 and αvβ5. Compounds of this mvention are therefore useful for treating mammals suffeπng from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. Pharmacologically effective amounts of the compounds, including pharmaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts. The compounds of the present mvention are administered m dosages effective to antagonize the αvβ3 receptor where such treatment is needed, as, for example, in the prevention or treatment of osteoporosis. Illustrating the invention is the method wherein the αv integnn receptor antagonizing effect is an αvβ3 antagonizing effect. More particularly, the αvβ3 antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retmopathy, macular degeneration, inflammation, inflammatory arthπtis, viral disease, cancer, or metastatic tumor growth. In one embodiment of the method, the αvβ3 antagonizing effect is the inhibition of bone resorption. Another example of the invention is the method wherein the αv integπn receptor antagonizing effect is an αvβ5 antagonizing effect. More specifically, the αvβ5 antagonizing effect is selected from inhibition of restenosis, angiogenesis, diabetic retmopathy, macular degeneration, inflammation, cancer, or metastatic tumor growth. Further illustrating the invention is the method where the αv tegnn receptor antagonizing effect is a dual αvβ3/αvβ5 antagonizing effect. More particularly, the dual αvβ3/αvβ5 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retmopathy, macular degeneration, inflammation, viral disease, cancer, or metastatic tumor growth More particularly illustrating the invention is a pharmaceutical composition compnsmg any of the compounds descπbed above and a pharmaceutically acceptable earner. Another example of the invention is a pharmaceutical composition made by combining any of the compounds descnbed above and a pharmaceutically acceptable earner. Another illustration of the invention is a process for making a pharmaceutical composition compπsing combining any of the compounds descπbed above and a pharmaceutically acceptable earner. Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of an αv integπn receptor in a mammal in need thereof, compnsmg administenng to the mammal a therapeutically effective amount of any of the compounds descπbed above Preferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retmopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthntis, viral disease, cancer, tumor growth, and metastasis. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis. More specifically exemplifying the invention is a method of eliciting an αv integπn antagonizing effect in a mammal in need thereof, compnsmg administenng to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions descnbed above. Preferably, the αv mtegnn antagonizing effect is an αvβ3 antagonizing effect; more specifically, the αvβ3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retmopathy, inhibition of macular degeneration, inhibition of inflammation, inhibition of viral disease, or inhibition of cancer or metastatic tumor growth. Most preferably, the αvβ3 antagonizing effect is inhibition of bone resorption. Alternatively, the αv integπn antagonizing effect is an αvβ5 antagonizing effect or a dual αvβ3/αvβ5 antagonizing effect. Examples of αvβ5 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retmopathy, macular degeneration, inflammation, viral disease, cancer, or metastatic tumor growth. Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions decnbed above Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, metastatic tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, inflammatory arthritis, viral disease, and/or angiogenesis. Also exemplifying the invention are compositions further comprising an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) a cytotoxic/antiproliferative agent, e) a matrix metalloproteinase inhibitor, f) an inhibitor of epidermal-derived, fibroblast-derived, or platelet- derived growth factors, g) an inhibitor of NEGF, h) an antibody to a growth factor or to a growth factor receptor, i) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, j) a cathepsin K inhibitor, k) a growth hormone secretagogue, 1) an inhibitor of osteoclast proton ATPase, m) an inhibitor of urokinase plasminogen activator (u-PA), n) a tumor-specific antibody-interleukin-2 fusion protein, o) an inhibitor of HMG-CoA reductase, and p) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof. (See, B. Millauer et al., "Dominant-Negative Inhibition of Flk-1 Suppresses the Growth of Many Tumor Types in Vivo", Cancer Research, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety). Preferably, the active ingredient is selected from the group consisting of: a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) an inhibitor of osteoclast proton ATPase, e) an inhibitor of HMG-CoA reductase, and f) a cathepsin K inhibitor; and mixtures thereof. Non miting examples of such bisphosphonates include alendronate, etidronate, pamidronate, nsedronate, ibandronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially alendronate monosodium tnhydrate. Nonhmiting examples of estrogen receptor modulators include estrogen, progesteπn, estradiol, droloxifene, raloxifene, and tamoxifene. Nonhmiting examples of cytotoxic/antipro ferative agents are taxol, vincnstine, vinblastine, and doxorubicin. Cathepsin K, formerly known as cathepsin O2, is a cysteine protease and is descnbed in PCT International Application Publication No. WO 96/13523, published May 9, 1996; U.S. Patent No. 5,501,969, issued March 3, 1996; and U.S Patent No. 5,736,357, issued April 7, 1998, all of which are incorporated by reference herein in their entirety Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthπtis, and bone remodeling. At acidic pH's, cathepsins can degrade type-I collagen Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis Members of the class of HMG-CoA reductase inhibitors, known as the "statins," have been found to tngger the growth of new bone, replacing bone mass lost as a result of osteoporosis (see The Wall Street Journal, Fnday, December 3, 1999, page Bl). Therefore, the statins hold promise for the treatment of bone resorption. Nonhmiting examples of statins are lovastatin, simvastatm, atorvastatin, and pravastatm. Evidence for crucial role of the urokmase-urokmase receptor (u-PA-u- PAR) in angiogenesis, tumor invasion, inflammation, and matπx remodeling dunng wound healing and development has been presented [see Y. Koshelnick et al., "Mechanisms of signaling through Urokinase Receptor and the Cellular Response," Thrombosis and Haemostasis 82: 305-311 (1999) and F. Blasi, "Proteolysis, Cell Adhesion, Chemotaxis, and Invasiveness Are Regulated by the u-PA-u-PAR-PAI-1 System," Thrombosis and Haemostasis 82: 298-304 (1999)]. Thus, specific antagonists of the binding of u-PA to u-PAR inhibit cell-surface plasmmogen activation, tumor growth, and angiogenesis in both in vitro and in vivo models. H.N. Lode and coworkers in PNAS USA 96: 1591-1596 (1999) have observed synergistic effects between an antiangiogenic αv mtegnn antagonist and a tumor-specific antibody-cytokine (ιnterleukιn-2) fusion protein in the eradication of spontaneous tumor metastases. Their results suggested this combination as having potential for the treatment of cancer and metastatic tumor growth. The proton ATPase which is found on the apical membrane of the osteoclast has been reported to play a significant role in the bone resorption process. Therefore, this proton pump represents an attractive target for the design of inhibitors of bone resorption which are potentially useful for the treatment and prevention of osteoporosis and related metabolic diseases (see C. Fanna et al., "Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents," DDT, 4: 163-172 (1999)). Evidence has been presented that androgenic steroids play a physiological role in the development of bone mass in men and women and that androgens act directly on bone Androgen receptors have been demonstrated in human osteoblast-hke cell lines and androgens have been shown to directly stimulate bone cell proliferation and differentiation. For a discussion, reference is made to S.R Davis, "The therapeutic use of androgens in women," J Steroid Biochem Mol Biol , 69. 177-184 (1999) and K.A. Hansen and S.P T. Tho, "Androgens and Bone Health," Seminars in Reproductive Endocrinology," 16 129-134 (1998) Thus, androgen receptor modulators may have utility in the treatment and prevention of bone loss in women. Activators of the peroxisome pro ferator- activated receptor- γ (PPARγ), such as the thiazohdmediones (TZD's), inhibit osteoclast- ke cell formation and bone resorption in vitro Results reported by R Okazaki et al. in Endocnnology, 140, pp 5060-5065, (1999) point to a local mechanism on bone marrow cells as well as a systemic one on glucose metabolism Nonhmiting examples of PPARγ activators include troghtazone, pioghtazone, rosig tazone, and BRL 49653. The present invention is also directed to combinations of the compounds of the present mvention with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the instant invention may be effectively administered m combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, a cathepsin K inhibitor, an HMG-CoA reductase inhibitor, a PPARγ activator, or an inhibitor of the osteoclast proton ATPase. Additional illustrations of the invention are methods of treating cancer or metastatic tumor growth in a mammal in need thereof, compπsing administenng to the mammal a therapeutically effective amount of a compound descπbed above and one or more agents known to be cytotoxic/antipro ferative. Also, the compounds of the present invention can be administered m combination with radiation therapy for treating cancer and metastatic tumor growth. In addition, the integπn αvβ3 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions These diseases include osteoporosis (including estrogen deficiency, immobilization, glucocorticoid-induced and senile), osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, peπodontal disease, cholelithiasis, nephro thiasis, urohthiasis, uπnary calculus, hardening of the arteπes (sclerosis), arthntis, bursitis, neuntis and tetany Increased bone resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment. Similarly, the present invention would be useful in increasing bone mass in patients with growth hormone deficiency. Thus, preferred combinations are simultaneous or alternating treatments of an αvβ3 receptor antagonist of the present mvention and a growth hormone secretagogue, optionally including a third component compπsing an organic bisphosphonate, preferably alendronate monosodium tnhydrate. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times dunng the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating integnn-mediated conditions includes in pnnciple any combination with any pharmaceutical composition useful for treating osteoporosis. As used herein, the term "composition" is intended to encompass a product compnsmg the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intrapentoneal, topical (e.g., ocular eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an αvβ3 antagonist. The dosage regimen utilizing the compounds of the present mvention is selected in accordance with a vanety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed An ordinaπly skilled physician, veteπnaπan or clinician can readily determine and prescπbe the effective amount of the drug required to prevent, counter or aπest the progress of the condition. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0 1 to about 10 mg kg/mmute dunng a constant rate infusion. Advantageously, compounds of the present mvention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, prefened compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. In the methods of the present invention, the compounds herein descπbed in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or earners (collectively referred to herein as 'earner' mateπals) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert earner such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubπcants, disintegrating agents and colonng agents can also be incorporated into the mixture Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alg ate, carboxymethylcellulose, polyethylene glycol, waxes and the like Lubπcants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chlonde and the like Disintegrators include, without limitation, starch, methyl cellulose, agar, bentomte, xanthan gum and the like. The compounds of the present invention can also be administered in the form of posome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a vanety of phosphohpids, such as cholesterol, stearylamme or phosphatidylcholmes. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual earners to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug earners. Such polymers can include polyvinylpyrrohdone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglyco c acid, copolymers of polylactic and polyglycohc acid, polyepsilon caprolactone, polyhydroxy butyπc acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslmked or amphipathic block copolymers of hydrogels. In the schemes and examples below, vaπous reagent symbols and abbreviations have the following meanings: AcOH: Acetic acid. BH3-DMS: Borane»dιmethylsulfιde. BOC(Boc): t-Butyloxycarbonyl. BOP: Benzotπazol-l-yloxytns(dιmethylamιno) phosphonium hexafluorophosphate. CBZ(Cbz) Carbobenzyloxy or benzyloxycarbonyl CDI. Carbonyldnmidazole CH 2 C1 2 : Methylene chlonde. CH3CN Acetonitnle CHCI3 Chloroform. DEAD Diethyl azodicarboxylate DIAD Dnsopropyl azodicarboxylate DIB AH or DIBAL-H: Diisobutylalummum hydnde. DIPEA: Dnsopropylethylamme. DMAP: 4-Dιmethylamιnopyπdme. DME: 1,2-Dιmethoxyethane. DMF. N-N-Dimethylformamide. DMSO. Dimethylsulfoxide. DPFN: 3,5-Dιmethyl-l-pyrazolylformamιdme nitrate. EDC: l-(3-Dιmethylammopropyl)-3-ethylcarbodnmιde »HC1 EtOAc: Ethyl acetate. EtOH: Ethanol. Et 2 O: Diethyl ether. HO Ac: Acetic acid. HOAT: l-Hydroxy-7-azabenzotπazole HOBT: 1 -Hydroxybenzotπ azole . IBCF: Isobutylchloroformate LDA: Lithium dnsopropylamide. MeOH: Methanol. MMNG l,l-methyl-3-nιtro-l-mtrosoguanιdιne NEt3: Tπethylamme. NMM: N-methylmorphohne. PCA-HC1: Pyrazole carboxamidine hydrochloπde. Pd/C: Palladium on activated carbon catalyst. Ph: Phenyl. pTSA p-Toluenesulfonic acid. TEA: Tnethylamine. TFA: Tπfluoroacetic acid. THE: Tetrahydrofuran. TLC: Thin Layer Chromatography. TMEDA: N,N,N',N'-Tetramethylethylenedιamιne. TMS: Tnmethylsilyl. The novel compounds of the present invention can be prepared according to the procedures of the following reaction Schemes and Examples, or modifications thereof, using readily available starting matenals, reagents, and, where appropnate, conventional synthetic procedures. In these procedures, it is also possible to make use of vaπants which are themselves known to those of ordinary skill in the organic synthetic arts, but are not mentioned in greater detail. The following Examples are illustrative of the more prefened compounds of the present invention. They are not, however, to be construed as forming the only genus that is considered as the invention The Examples further illustrate details for preparation of the compounds of the present invention. Those skilled in the art will readily understand that known vanations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Unless stated otherwise, all operations were earned out at room or ambient temperature, and all temperatures are degrees Celsius. SCHEME 1 L-proline, ethanol, 1-6 reflux l-Benzyl-2-oxo-3-(2-methyl-propen-3-yl)-pyrrolιdιne (1-3) To a stirred solution of IA (10.0 g, 57 mmol) and TMEDA (17 mL, 104 mmol) in THF (200 mL) at -78°C was added LDA (31.4 mL, 63 mmol; 2.0 M solution) dropwise over a 20 minute peπod. After 1 hr, the bromide X2 (6.3 mL, 63 mmol) was added and the reaction mixture was stiπed for an additional 1 hr at -78 C and then warmed to -15 C for 1 hr. The reaction was then quenched with sat. NH4CI and then extracted with EtOAc. The EtOAc phase was washed with bnne, dned (MgSO4), and concentrated. Flash chromatography (silica, 25 to 40% EtOAc/hexanes) gave A3 as a yellow oil. TLC Rf = 0.86 (sihca, EtOAc). l U NMR (300 MHz, CDC1 3 ) δ 7.40-7.20 (m, 5H), 4.75 (m, 2H), 4.48 (m, 2H), 3.19 (m, 2H), 2.75-2 60 (m, 2H), 2.15-1.95 (m, 2H), 1.72 (s, 3H), 1.63 (m, 2H). 1 -Benzyl -3-(2-methyl-propen-3-yl)-pyπolιdme (1-4) To a stirred suspension of LAH (17 mg, 0.44 mmol) in THF (2 mL) at reflux was added X3 (100 mg, 0.44 mmol) in THF (1 mL) dropwise over a 5 min peπod. The reaction mixture was then maintained at reflux for an additional 12 hrs and then quenched sequentially with H 2 O (17 μL), 15% NaOH (17 μL), and H 2 O (51 μL). After 10 mm, MgSU4 was added followed by filtration and concentration of the filtrate to give L4 as a yellow oil. TLC Rf = 0.21 (sihca, EtOAc). l H NMR (300 MHz, CD3OD) δ 7.40-7.20 (m, 5H), 4.68 (m, 2H), 3.58 (m, 2H), 2.78 (m, 1H), 2.66 (m, 1H), 2.50-2.30 (m, 2H), 2.06 (m, 2H), 1.99 (m, 1H), 1.68 (s, 3H), 1.40 (m, 1H) 1 -Benzyl-3-(2-oxo- 1 -propyD-pyrrolidine (1-5) To a rapidly stiπed solution of L4 (7.0 g, 33 mmol) in THF (200 mL) and H 2 O (150 mL) was added NaIO 4 (21 g, 100 mmol) followed by addition of OsO 4 (10 mL, 2.5% solution) After 16 hrs, an additional amount of OSO4 (10 mL) was added, and the reaction was stiπed for 6 hrs The reaction was diluted with EtOAc, washed with sat NaHCO3 and bnne, dned (MgSU4), and concentrated to give L5 as a brown oil TLC Rf = 0 23 (sihca, 70 15 15 CHCI EtOAc/MeOH) 1 -Benzyl -3-(ri,81naphthyridin-2-ylmethyl)-pyrrolidine (1-7) A mixture of X5 (2.7 g, 11.8 mmol), L6 (1.9 g, 15.3 mmol; Turner, J.A., J. Org. Chem. 1983, 48, 3401-3408), L-proline (2.7 g, 23.6 mmol), and ethanol (60 mL) was refluxed for 18 hr. The cooled reaction mixture was concentrated and then purified by flash chromatography (silica, EtOAc to 15% MeOH/EtOAc) to give 1-7 as a yellow oil. TLC Rf = 0.18 (silica, 30% MeOH/EtOAc). H NMR (300 MHz, CDC1 3 ) δ 9.10 (m, IH), 8.18 (dd, J=8 and 2 Hz, IH), 8.11 (d, J=8 Hz, IH), 7.46 (m, IH), 7.38 (d, J=8 Hz, IH), 7.40-7.20 (m, 5H), 3.62 (m, 2H), 3.13 (m, 2H), 3.00-1.60 (m, 7H). 3-(5,6,7,8-Tetrahvdro-ri,81naphthyridin-2-ylmethyl)-pyrrolidine (l-8) A mixture of L7 (2.0 g, 6.6 mmol), 10% Pd/C (2.0 g), ammonium formate (4.2 g, 66 mmol), and MeOH (50 mL) was heated to reflux for 20 min. Flash chromatography (silica, 10:1:1 ethanol/NH4OH/H 2 O) gave a white solid (1 g). The solid was dissolved in IN NaOH and extracted with CHCI3. The CHCI3 phase was washed with brine, dried (MgSO 4 ), and concentrated to give IAS as a yellow oil. TLC Rf = 0.15 (silica, 10: 1:1 ethanol/NH 4 OH/H 2 O). ! H NMR (300 MHz, CDCI3) δ 7.04 (d, J=8 Hz, IH), 6.33 (d, J=8 Hz, IH), 4.75 (bs, IH), 3.40 (m, 2H), 3.10-2.85 (m, 3H), 2.70 (m, 2H), 2.58 (m, 2H), 2.46 (m, IH), 1.90 (m, 3H), 1.43 (m, lH). SCHEME 2 a) Pt0 2 , AcOH/H 2 0, H 2 b) CH 3 CN, Boc 2 0, I N NaOH , 0°C 2-amino-3-formyl-pyridine (1-6), ethanol, L-proline, reflux SCHEME 2 cont'd 2-5 HCI/EtOAc 2-6 N-Boc-Pιpendιn-3-ylacetιc acid (2-2) A mixture of 2__1 (15 g, 87 mmol), AcOH (125 mL), H 2 O (25 mL), and PtO (1.5 g) was shaken under a hydrogen atmosphere (55 PSI) on a Parr apparatus for 4 hr. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The residue was suspended in acetonitnle (500 mL) and IN NaOH was added until the solid dissolved and the mixture became basic. Dι-(tert-butyl) dicarbonate (20.8 g, 95 mmol) was added and the reaction mixture was stiπed overnight. The acetonitnle was evaporated and the aqueous phase acidified with 10% KHSO4 Extraction with EtOAc followed by washing the organic phase with bnne, drying (MgSO 4 ), and concentration gave 2X1 as a clear oil. H NMR (300 MHz, CDCI3) δ 3.90 (m, IH), 3 80 (m, IH), 2.82 (m, IH), 2.70 (m, IH), 2 4-1.2 (m, 7H). N-Boc-3-(2-oxo- 1 -propyl)-pιpeπdιne (2-3) A solution of 2^2 (13.4 g, 55 mmol) in ether (500 mL) at 0 C was treated dropwise with MeLi (87 mL, 121 mmol, 1 4 M/ether) After addition was complete, the cooling bath was removed and the reaction mixture was stirred overnight The reaction mixture was then poured into an ice/water mixture and then extracted with ether. The ether extracts were washed with bnne, dned (MgSU4), and concentrated Flash chromatography (silica, 30% EtOAc/hexanes) gave 2^3 as a colorless oil TLC Rf = 0.59 (si ca, 30% EtOAc, hexanes). *H NMR (300 MHz, CDC1 3 ) δ 3.80 (m, 2H), 2.92 (m, IH), 2.64 (m, IH), 2.40 (m, IH), 2.28 (m, IH), 2.15 (s, 3H), 2.03 (m, IH), 1.80 (m, IH), 1.63-1 00 (m, IH), 1.45 (s, 9H). N-Boc-3-(n,8]-Naphthvndιn-2-ylmethyl)-pιpendme (2-4) A mixture of 2__3 (74 mg, 0.31 mmol), L6 (38 mg, 0.31 mmol), L- prolme (18 mg, 0.15 mmol) and ethanol (4 mL) was refluxed for 20 hrs. The cooled reaction mixture was concentrated and then puπfied by flash chromatography (silica, EtOAc) to give 2^4 as a yellow solid. TLC Rf = 0.24 (sihca, EtOAc). H NMR (300 MHz, CDC1 3 ) δ 9.10 (m, IH), 8.18 (dd, J=8 and 2 Hz, IH), 8.1 l(d, J=8 Hz, IH), 7.46 (m, IH), 7.38 (d, J=8 Hz, IH), 3.90 (m, 2H), 3.05-2.60 (m, 3H), 2.22 (m, IH), 1.81 (m, IH), 1.68 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). N-Boc-3-(5,6,7,8-Tetrahydro-ri,81-naphthvndιn-2-ylmethyl)-pιpendιne (2-5) A mixture of 2 (1.1 g, 3.3 mmol), 10% Pd/C (108 mg), and ethanol (20 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hrs. The reaction mixture was then filtered through a cehte pad and the filtrate was concentrated. Flash chromatography (silica, 80% hexanes/EtOAc) gave 2^ as a colorless oil. TLC Rf = 0.21 (sihca, EtOAc). H NMR (300 MHz, CDC1 3 ) δ 7.03 (d, J=8 Hz, IH), 6.32 (d, J=8 Hz, IH), 4 79 (bs, IH), 3.90 (m, 2H), 3.40 (m, 2H), 2.78 (m, IH), 2.70 (m, 2H), 2.57 (m, IH), 2.44 ( , 2H), 1.90-1 00 (m, 7H), 1.41 (s, 9H) 3-(5,6,7,8-Tetrahvdro-ri,8]-naphthvπdm-2-ylmethvn-pιpendιne • 2 HCl (2-6) HCl gas was bubbled through a solution of 2^ (0.8 g, 2 5 mmol) and EtOAc (15 mL) at 0 C for 15 min After an additional 15 mm, argon was passed through the solution for 15 min followed by concentration. The residue was azeotroped twice with ether to give 2^6 as a yellow solid H NMR (300 MHz, CD 3 OD) δ 7.60 (d, J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 3.52 (m, H), 3.36 (m, 2H), 3.00-2.60 (m, 6H), 2.24 (m, IH), 2.00-1.70 (m, 4H), 1.35 (m, IH). SCHEME 3 ether, MeLi, 0°C 2-amino-3-formyl-pyridine(1 -6) , ethanol, L-proline, reflux N-Boc-4-(2-oxo-l-propyl)-pιpendme (3-2) A solution of 3_ (10 g, 41 mmol) and ether (400 mL) at 0 C was treated dropwise with MeLi (66 mL, 92 mmol; 1.4 M/ether). After addition was complete, the cooling bath was removed and the reaction mixture was stirred overnight. The reaction mixture was then poured into an ice/water mixture and then extracted with ether. The ether extracts were washed with bnne, dned (MgSO4), and concentrated to give 3f2 as an oil. H NMR (300 MHz, CDC1 3 ) δ 4.08 (m, 2H), 2.72 (bt, J=12 Hz, 2H), 2.36 (d, J=7 Hz, 2H), 2.14 (s, 3H), 1.97 (m, IH), 1.63 (m, 2H), 1.45 (s, 9H), 1.10 (m, 2H). N-Boc -4-(ri,81-Naphthvπdιn-2-ylmethyl)-pιpendme (3-3) A mixture of 3^2 (2.5 g, 10.4 mmol), X6 (1.3 g, 10.4 mmol), L-prolme (0.6 g, 5.2 mmol) and ethanol (70 mL) was refluxed for 20 hours. The cooled reaction mixture was concentrated and then punfied by flash chromatography (silica, EtOAc) to give 3-3 as a yellow solid. TLC Rf = 0.28 (si ca, EtOAc). H NMR (300 MHz, CDCI3) δ 9.10 (m, IH), 8.18 (dd, J=8 and 2 Hz, IH), 8.11(d, J=8 Hz, IH), 7.46 (m, IH), 7.35 (d, J=8 Hz, IH), 4.08 (m, 2H), 2.97 (d, J=8 Hz, 2H), 2.70 (m, 2H), 2.24 (m, IH), 1.68 (m, 2H), 1.45 (s, 9H), 1.27 (m, 2H). N-Boc-4-(5,6,7,8-Tetrahvdro-ri,81-naphthvndιn-2-ylmethyl)-pιpendιne (3-4) A mixture of 3__3 (2.1 g, 6 4 mmol), 10% Pd C (210 mg), and ethanol (32 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hrs. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated. Flash chromatography (silica, 70% hexanes/EtOAc) gave 3^4 as a colorless oil. TLC Rf = 0.15 (si ca, EtOAc). *H NMR (300 MHz, CDCI3) δ 7.03 (d, J=8 Hz, IH), 6.30 (d, J=8 Hz, IH), 4.75 (bs, IH), 4.08 (m, 2H), 3.40 (m, 2H), 2.69 (m, 3H), 2.44 (d, J=8 Hz, 2H), 1.90-1.00 (m, 8H)1 43 (s, 9H). 4-(5,6,7,8-Tetrahvdro-[l,81-naphthyridin-2ylmethyl)-piperidine » 2 HCl (3-5) o A solution of 3 (1.6 g, 4.8 mmol) and dioxane (24 mL) at 0 C was treated with 4M HCl/dioxane (6.0 mL) followed by removal of the cooling bath. After 5 hours, the reaction mixture was concentrated to give 3^5 as a yellow solid. *H NMR (300 MHz, CD 3 OD) δ 7.60 (d, J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 3.52 (m, 2H), 3.40 (m, 2H), 3.00 (bt, 2H), 2.83 (m, 2H), 2.71 (d, J=8 Hz, 2H), 2.08 (m, IH), 2.00-1.85 (m, 4H), 1.50 ( , 2H). SCHEME 4 N-Boc -4-Acetyl-pιpendme (4-2) To a stiπed suspension of 44 (5.2 g, 32 mmol), NE-3 (5.3 mL, 38 mmol), and DMF (100 mL) at 0 C was added Boc 2 O, followed by removal of the cooling bath. After 20 hrs, the reaction muxture was diluted with EtOAc and then washed with H 2 O, sat. NaHCO 3 , 5% KHSO 4 , and bnne, dried (MgSO 4 ), and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 4^2 as an oil. TLC Rf = 0.31 (si ca, 30% EtOAc/hexanes). ! H NMR (300 MHz, CDCI3) δ 4.08 (bs, 2H), 2.80 (m, 2H), 2.45 (m, IH), 2 17 (s, 3H), 1.83 (m, 2H), 1.48 (m, 2H), 1.46 (s, 9H). N-Boc-4-(n,81-Naphthvndin-2-yl)-pipendme (4-3) A mixture of 4f2 (4.0 g, 17.6 mmol), _L6 (2.1 g, 17.6 mmol), L-proline (0.3 g, 2.6 mmol) and ethanol (88 mL) was refluxed for 40 hrs. The cooled reaction mixture was concentrated and then puπfied by flash chromatography (silica, 30% EtOAc/hexanes to 3% isopropanol EtOAc) to give 4f3 as a yellow solid. TLC Rf = 0.29(sιhca, EtOAc). IT NMR (300 MHz, CDCI3) δ 9.10 (m, IH), 8.18 (m, IH), 8.11 (d, J=8 Hz, IH), 7.46 (m, IH), 7.41 (d, J=8 Hz, IH), 4.30 (m, 2H), 3.14 (m, IH), 2.90 (m, 2H), 2.00 (m, 4H), 1.45 (s, 9H). N-Boc-4-(5,6,7,8-Tetrahvdro-n.81-naphthyndιn-2-yl)-pιpendme (4-4) A mixture of 4^3 (2.6 g, 8.4 mmol), 10% Pd/C (0.52 g), and EtOAc (100 mL) stirred under a hydrogen atmosphere (1 atm) for 20 hrs. The reaction mixture was then filtered through a cehte pad and the filtrate concentrated. Flash chromatography (silica, 70% hexanes/EtOAc to EtOAc) gave 44 as a colorless oil TLC Rf = 0.15 (si ca, 10% isopropanol/EtOAc). H NMR (300 MHz, CDC1 3 ) δ 7.13 (d, J=8 Hz, IH), 6.33 (d, J=8 Hz, IH), 4 20 (m, 2H), 3.42 (m, 2H), 2.79 (m, 2H), 2.70 (m, 2H), 2.62 (m, IH), 1.90 (m, 4H), 1.60 (m, 2H), 1.43 (s, 9H) 4-(5,6,7,8-Tetrahydro-ri,81-naphthyndιn-2-yl)-pιpendme » 2 HCl (4-5) HCl gas was bubbled through a solution of 44 (1.6 g, 4.8 mmol) and EtOAc (40 mL) at 0 C for 3 min. The solution was stirred for an additional hour, followed by concentration to give ^5 as a yellow foam. l U NMR (300 MHz, CD 3 OD) δ 7.63 (d, J=8 Hz, IH), 6.67 (d, J=8 Hz, IH), 3.52 (m, 4H), 3.16 (m, 2H), 3.07 (m, IH), 2.83 (d, J=6 Hz, 2H), 2.20 (m, 2H), 1.96 (m, 4H). SCHEME 5 5-1 5-3 N-Boc-4-r(l-H-Benzimidazol-2-ylamino)-methyl]-piperidine (5-2) A mixture of 54 (1.2 g, 5.6 mmol; Prugh, J.D., Syn. Comm., 1992, 22, 2357-2360), 2-chlorobenzimidazole (0.85 g, 5.6 mmol), DIPEA (2.4 mL, 14 mmol), and toluene (12 mL) was refluxed for 72 hrs. The cooled reaction mixture was chromatographed (silica, 70:25:5 CHCl 3 /EtOAc/MeOH) to give 5__2. ! H NMR (300 MHz, CD 3 OD) δ 7.20 (m, 2H), 6.96 (m, 2H), 4.06 (m, 2H), 3.24 (m, 2H), 2.75 (m, 2H), 1.82 (m, 2H), 1.44 (s, 9H), 1.15 (m, 2H). 4-[(l-H-Benzιmιdazol-2-ylamιno)-methyl]-pιpendme bis-hydrochlonde (5-3) HCl gas was passed through a solution of 5^2 (1.3 g, 3.9 mmol) in EtOAc (25 mL) at 0 C for 3 mm. After stirπng at 0 C for an additional 2 hrs, the reaction mixture was concentrated to give 5^3 as a solid. *H NMR (300 MHz, CD 3 OD) δ 7.40 (m, 2H), 7.29 (m, 2H), 3.47 (m, 2H), 3.41 (m, 2H), 3.15 (m, 2H), 2.09 (m, 2H), 1.53 (m, 2H). SCHEME 6 1. Pt0 2 , HOAc, H 2 2. HCl/dioxane H, ethanol Ethyl piperidin-4-ylacetate hydrochloride (6-2) A mixture of 64 (5.0 g, 30 mmol), AcOH (50 mL), and PtO 2 (1.0 g) was shaken on a Pan apparatus under a hydrogen atmosphere (50 PSI) for 48 hrs. The reaction mixture was filtered and concentrated, and the residue was dissolved in dioxane (100 mL) and treated with 4.0 M HCl/dioxane (7.5 mL). Concentration gave 6-2 as a white solid. H NMR (300 MHz, CD 3 OD) δ 4.13 (q, J=7, 2H), 3.37 (m, 2H), 3.00 (m, 2H), 2.33 (m, 2H), 2.09 (m, IH), 1.98 (m, 2H), 1.44 (m, 2H), 1.23 (s, 3H). { l-[3-(5,6,7,8-Tetrahydro-[l,81-naphthyridin-2-ylmethyl)-pyrrolidine-l-carbonyl1- piperidin-4-yl ) -acetic acid ethyl ester (6-3) To a solution of 6__2 (31 mg, 0.15 mmol), DIPEA (77 μL, 0.44 mmol), and CH3CN (1.5 mL) at 0 C was added dropwise a solution of triphosgene (15 mg, 52 mmol) in CH3CN (150 μL). Afer 30 min., a solution of L8 (43 mg, 0.15 mmol) and DIPEA (77 μL, 0.44 mmol) in DMF (0.8 mL) was added, followed by removal of the cooling bath. After 16 hrs, the reaction mixture was poured into EtOAc and sat. NaHCO3. The EtOAc portion was then washed with H O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% ethanol/EtOAc) gave 6-3 as a colorless oil. TLC Rf = 0.22 (silica, 10% ethanol/EtOAc). H NMR (300 MHz, CDCI3) δ 7.05 (d, J=8 Hz, IH), 6.31 (d, J=8 Hz, IH), 4.85 (bs, IH), 4.13 (q, J=7 Hz, 2H), 3.72 (m, 2H), 3.40 (m, 4H), 3.12 (m, IH), 2.80-2.40 (m, 5H), 2.30-1.50 (m, 13 H), 1.24 (s, 3H). { l-[3-(5,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-ylmethyl)-pyrrolidine-l-carbonyl1- piperidm-4-yll -acetic acid bis TFA salt (6-4) A solution of 6__3 (37 mg, 89 μmol), IN NaOH (0.22 mL), and ethanol (1 mL) was stirred at ambient temperature for 20 hrs. The reaction mixture was neutralized with IN HCl (0.22 mL) and then concentrated. Reverse phase preparative HPLC (95:5 to 50:50 H 2 O/ CH3CN (0.1% TFA) over 60 min) gave 64 as a colorless oil. TLC Rf = 0.61 (silica, 75%[20:1:1 ethanol/NH 4 OH/H 2 O]/EtOAc) ! H NMR (300 MHz, D 2 O/NaOD) δ 7.28 (d, J=8 Hz, IH), 6.52 (d, J=8 Hz, IH), 3.68 (m, 2H), 3.50-3.30 (m, 4H), 3.10 (m, IH), 2.90-240 (m, 6H), 2.12 (m, 2H), 2.00-1.50 (m, 5H), 1.12 (m, 2H). SCHEME 7 BnO C OH 7-1 7-2 Benzyl 3-hydroxybenzoate (7-2) A solution of 74 (5.0 g, 36 mmol), pTSA (50 mg), and benzyl alcohol (7.4 mL, 73 mmol) in toluene (200 mL) was refluxed for 20 hrs. in a flask equipped with a Dean-Stark trap and condenser. The cooled reaction mixture was washed with sat. NaHCO3, H 2 O, and brine, dried (MgSO4), and concentrated to give crude 7-2. 3-Carboxyphenoxyacetic acid tert-butyl ester (7-3) To 7 2 (3.6 g, 16 mmol) in DMF (50 mL) was added Cs 2 CO 3 (7.8 g, 238 mmol). After 15 min., tert-butyl bromoacetate (3.2 mL, 35 mmol) was added and the reaction mixture stirred for 20 hrs at ambient temperature. The reaction mixture was diluted with EtOAc and then washed with H 2 O, and brine, dried (MgSU4), and concentrated to give a yellow oil. The crude yellow oil (5.4 g, 15.8 mmol), 10% Pd/C (500 mg), and EtOAc (100 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hr. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give 7^3 as a white solid. TLC Rf = 0.41 (silica, 9:1:1 CH 2 Cl 2 /MeOH/HOAc), *H NMR (300 MHz, CD 3 OD) δ 7.65 (m, IH), 7.53 (m, IH), 7.39 (m, IH), 7.17 (m, IH), 4.63 (s, 2H), 1.46 (s, 9H). (4-{4-r(l-H-Benzimidazol-2-ylamino)-methyl1-piperidine-l-carbonyl-phenoxy)-acetic acid tert-butyl ester (7-4) To a stirred mixture of 5^ (100 mg, 0.33mmol), 7^3 (92 mg, 0.36 mmol), HOBT (45 mg, 0.33 mmol), NMM (145 μL, 1.32 mmol) and DMF (5 mL) at ambient temperature was added EDC (63 mg, 0.33 mmol). After 20 hrs, the reaction mixture was concentrated and then diluted with EtOAc and washed with sat. NaHCO3 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 70:20:10 CHCl 3 /EtOAc/MeOH) gave 74 as a white solid. TLC Rf = 0.25 (silica, 70:20: 10 CHCl3/EtOAc/MeOH) H NMR (300 MHz, CD 3 OD) δ 7.37 (m, IH), 7.19 (m, 2H), 7.04-6.92 (m, 5H), 4.68 (m, IH), 4.63 (s, 2H), 3.75 (m, IH), 3.30 (m, 2H), 3.10 (m, IH), 2.85 (m, IH), 1.98 (m, 2H), 1.80 (m, IH), 1.48 (s, 9H), 1.28 (m, 2H). (4- { -\( 1 -H-Benzimidazol-2-ylamino)-methyl1-piperidine- 1 -carbonyl ) -phenoxy)- acetic acid (7-5) A solution of 74 (86 mg, 0.18 mmol), IN NaOH (510 μL), H 2 O (1 mL), and THF (1 mL) was stirred at ambient temperature for 20 hrs. The reaction mixture was then concentrated, diluted with H 2 O (1 mL) and neutralized with IN HCl (510 mL) to effect a precipitate. The solid was collected by filtration to give 7__5 as a white solid. TLC Rf = 0.30 (silica, 15:15:1:1 EtOAc/ethanol/H 2 O/NH 4 OH). H NMR (300 MHz, CD 3 OD) δ 7.38 (m, 3H), 7.28 (m, 2H), 7.08-6.92 (m, 3H), 4.68 (m, IH), 4.63 (s, 2H), 3.68 (m, IH), 3.37 (m, 2H), 3.11 (m, IH), 2.76 (m, IH), 2.00 (m, 2H), 1.81 (m, IH), 1.30 (m, 2H). The intermediates depicted in Schemes 1-7 were used to prepare the following examples: { l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-4-yl } -acetic acid {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperazin-1-yl } -acetic acid 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-3-yl}-propionic acid 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- pyrrolidin-2-yl}-propionic acid {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-l-yl }-acetic acid 3-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- phenoxyacetic acid { l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin-4- yl } -acetic acid {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperazin-l- yl} -acetic acid 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin- 3-yl }-propionic acid {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin-l- yl} -acetic acid 3-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]- phenoxyacetic acid 3-{4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin- l-yl }-propionic acid { l-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- pyπolidin-2-yl } -acetic acid { l-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-2-yl } -acetic acid {4-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-1-yl} -acetic acid 3-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- phenoxyacetic acid 4-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- phenoxyacetic acid SCHEME A Synthesis of Radioliqand for SPAV3 Assay A-1 H, dioxane, SCHEME A, cont'd. A-5a 6NHCI SCHEME A, cont'd A-10 N-(4-Iodo-phenylsuIfonylamino)-L-asparagine (A-2) To a stirred solution of acid A4 (4.39 g, 33.2 mmol), NaOH (1.49 g, 37.2 mmol), dioxane (30 ml) and H2O (30 ml) at 0°C was added pipsyl chloride (10.34 g, 34.2 mmol). After ~5 minutes, NaOH (1.49, 37.2 mmol) dissolved in 15 ml H2O, was added followed by the removal of the cooling bath. After 2.0 h, the reaction mixture was concentrated. The residue was dissolved in H2O (300 ml) and then washed with EtOAc. The aqueous portion was cooled to 0°C and then acidified with concentrated HCl. The solid was collected and then washed with E-2O to provide acid A-2 as a white solid. iH NMR (300 MHz, D2O) δ 7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz) 3.70 (m, IH), 2.39 (m, 2H). 2(S)-(4-Iodo-phenylsulfonylamino)-β-alanine (A-3) To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H2O (40 ml) at 0°C was added Br2 (1.30 ml, 24.9 mmol) dropwise over a ten minute period. After ~5 minutes, acid A^ (9.9 g, 24.9 mmol), NaOH (2.00 g, 49.8 mmol) and H2O (35 ml) were combined, cooled to 0°C and then added in a single portion to the reaction. After stirring for 20 minutes at 0°C, the reaction was heated to 90°C for 30 minutes and then recooled to 0°C. The pH was adjusted to ~7 by dropwise addition of concentrated HCl. The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid A-3 as a white solid. iH NMR (300 MHz, D2O) δ 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.36 (m, IH), 3.51 (dd, IH, J=5Hz, 13Hz) 3.21 (m, IH). Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-β-alanine-hydrochloride (A-4) HCl gas was rapidly bubbled through a suspension of acid A-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0°C for 10 minutes. The cooling bath was removed and the reaction was heated to 60°C. After 18 h, the reaction was concentrated to provide ester A-4 as a white solid. iH NMR (300 MHz, CD3OD) δ 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.25 (q, IH, J=5Hz), 3.92 (m, 2H), 3.33 (m, IH), 3.06 (m, IH), 1.01 (t, 3H, J=7Hz). Ethyl 4-r2-(2-Aminopyridin-6-yl)ethyl1benzoate (A-5a) A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 95/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, the reaction was filtered through a celite pad and then concentrated to provide ester A-5a as a brown oil. TLC Rf = 0.23 (silica, 40% EtOAc/hexanes) iH NMR (300 MHz, CDCI3) δ 7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d, IH, J=7Hz), 6.35 (d, IH, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H, J=7Hz). 4-r2-(2-Ammopyndιn-6-yl)ethyllbenzoιc acid hydrochlonde (A-6) A suspension of ester A-5a (625 mg, 2.31 mmol) in 6N HCl (12 ml) was heated to 60°C. After -20 h, the reaction was concentrated to give acid A-6 as a tan solid. ^ NMR (300 MHz, CD3OD) δ 7.96 (d, 2H, J=8Hz), 7.80 (m, IH), 7.33 (d, 2H, J=8Hz), 6.84 (d, IH, J=9Hz), 6.69 (d, IH, J=7Hz), 3.09 (m, 4H). Ethyl 4-r2-(2-Amιnopyndιn-6-yl)ethyl1benzoyl-2(S)-(4-ιodo-phenylsulfonylammo)-β- alanme (A-7) A solution of acid 15-6 (400 mg, 1.43 mmol), amine A-4 (686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 μl, 5.72 mmol) in DMF (10 ml) was stirred for -20 h. The reaction was diluted with EtOAc and then washed with sat. NaHCO3, bnne, dned (MgSO4) and concentrated. Flash chromatography (silica, EtOAc then 5% isopropanol/EtOAc) provided amide A-7 as a white solid. TLC Rf = 0.4 (sihca, 10% isopropanol/EtOAc) iH NMR (300 MHz, CD3OD) δ 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz), 7.52 (d, 2H, J=9Hz), 7.29 (m, IH), 7.27 (d, 2H, J=8Hz), 4.20 (m, IH), 3.95 (q, 2H, J=7Hz), 3.66 (dd, IH, J=6Hz, 14Hz), 3.49 (dd, IH, J=8Hz, 13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz). 4-r2-(2-Amιnopyndιn-6-yl)ethvnbenzoyl-2(S)-(4-ιodophenyl-sulfonylamιno)-β- alanme (A-8) A solution of ester AX∑ (200 mg, 0.3213 mmol) and 6N HCl (30 ml) was heated to 60°C. After -20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/ NH4OH H2O) provided acid A^8 as a white solid. TLC Rf = 0.45 (si ca, 20:20:1:1 EtOAc/EtOH/NH4OH/H2O) H NMR (400 MHz, DMSO) δ 8.40 (m, IH), 8.14 (Bs, IH), 7.81 (d, 2H, J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d, IH, J=7Hz), 6.25 (d, IH, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, IH), 3.35 (m, 2H), 2.97 (m, 2H), 2.79 (m, 2H). 4-r2-(2-Amιnopyndιn-6-yl)ethyl)benzoyl-2(S)-(4-tπmethylstannyl- phenylsulfonylammo-β-alanme (A-9) A solution of iodide A^ (70 mg, 0.1178 mmol), [(CH3)3Sn]2 (49 μl, 0.2356 mmol), Pd(PPh3)4 (5 mg) and dioxane (7 ml) was heated to 90°C. After 2 h, the reaction was concentrated and then punfied by preparative HPLC (Delta-Pak Ci8 15 μM 100A°, 40 x 100 mm; 95:5 then 5:95 H2O/CH3CN) to provide the tnfluoroacetate salt. The salt was suspended in H2O (10 ml), treated with NH4OH (5 drops) and then lyophilized to provide amide A-9 as a white solid. iH NMR (400 MHz, DMSO) δ 8.40 (m, IH), 8.18 (d, IH, J=8Hz), 7.67 (m, 5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H), 6.45 (bs, 2H), 4.00 (m, IH), 3.50 (m, IH), 3.33 (m, IH), 2.97 (m, 2H), 2.86 (m, 2H). 4-r2-(2-Ammopyndιn-6-yl)ethyl1benzoyl-2(S)-4-^^ιodo-phenylsulfonvIamιno-β- alanine (A-10) An lodobead (Pierce) was added to a shipping vial of 5 mCi of Nal25τ (Amersham, IMS30) and stirred for five minutes at room temperature. A solution of 0.1 mg of A^ in 0.05 mL of 10% H2SO4/MeOH was made and immediately added to the Nal25j/ 10C ι 0 b eac ι vιa ι After stirπng for three minutes at room temperature, approximately 0.04-0.05 mL of NH4OH was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for puπfication [Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitnle (0.1% (TFA):H2θ (0.1% TFA) to 90% acetonitnle (0.1% TFA):H2θ (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time of A- 10 is 17 minutes under these conditions. Fractions containing the majonty of the radioactivity were pooled, lyophilized and diluted with ethanol to give approximately 1 mCi of A-10, which coeluted on HPLC analysis with an authentic sample of A-8. SCHEME B Synthesis of Radioligand for SPAV5 Assay 10 2(S)-(4-Iodo-benzenesulfonylamino)-3-{4-r2-(5,6,7,8-tetrahvdro-[l,81naphthyridin-2- yl)-ethyll-benzoylamino)-propionic acid ethyl ester (B-2) A mixture of B-l (0.23 g, 0.72 mmol; for preparation see US Patent No. 5,741,796), A4 (0.343 g, 0.792 mmol), EDC (0.179 g, 0.93 mmol), HOBT (0.126 g, 0.93 mmol), NMM (0.316 mL, 2.86 mmol) in acetonitrile (3 mL) and DMF (3 mL) was stirred for 2 hours at ambient temperature then diluted with ethyl acetate, washed with water, saturated aqueous NaHCO 3 , and brine, dried over MgSO , and concentrated. The residue was chromatographed on silica gel (70:25:5 CHCl 3 /EtOAc/MeOH) to give B^ as a white solid. TLC Rf = 0.22 (silica, 70:25:5 CHCl 3 /EtOAc/MeOH). iH NMR (300 MHz, CDCI3) δ 7.79 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 7.54 (d, 2H, J=8Hz), 7.27 (d, 2H, J=8Hz),7.04 (d, IH, J=7Hz), 6.60 (m, IH), 6.29 (d, IH, J=7Hz), 4.83 (br s, IH), 4.09 (m, 3H), 3.84 (m, IH), 3.68 (m, IH), 3.42 (m, 2H), 3.01 (m, 4H), 2.86 (m, 4H), 2.69 (t, 2H, J=6Hz), 1.88 (m, 2H). 2(S)-(4-Iodo-benzenesulfonylamino)-3-{4-[2-(5,6,7,8-tetrahvdro-ri,81naphthyridin-2- yl)-ethyl1-benzoylamino|-propionic acid (B-3) A mixture of BA (0.38 g, 0.573 mmol) and 6N HCl (50 mL) was stirred for 14 hours at 60°C. After cooling to room temperature, the mixture was concentrated, and the residue chromatographed on silica gel (25: 10: 1 : 1 to 15: 10: 1 : 1 EtOAc/EtOH/ NH 4 OH/H 2 O) to give B as a white solid. TLC Rf = 0.43 (silica, 10:10:1: 1 EtOAc/EtOH/ NH4OH H2O). iH NMR (300 MHz, DMSO-d 6 ) δ 8.42 (m, IH), 7.79 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 7.44 (d, 2H, J=8Hz), 7.27 (d, 2H, J=8Hz),7.10 (d, IH, J=7Hz), 6.58 (br s, IH), 6.32 (d, IH, J=7Hz), 3.96 (m, IH), 3.51 (m, IH), 3.30 (m, 5H), 2.96 (m, 2H), 2.78 (m, 2H), 2.62 (m, 2H), 1.77 (m, 2H). HRMS: For C 26 H 27 IN 4 O 5 S, expected 635.0818, found 635.0831. 3-{4-r2-(5,6,7,8-Tetrahvdro-ri,81naphthyridin-2-yl)-ethyl]-benzoylamino}-2(S)-(4- trimethylstannanyl-benzenesulfonylaminoVpropionic acid (B-4) A mixture of B-3 (0.10 g, 0.16 mmol), hexamethyldistannane (0.065 mL, 0.32 mmol), Pd(PPh 3 ) 4 , and dioxane (10 mL) was stirred for one hour at 90°C. After cooling to room temperature, the mixture was concentrated, and the residue chromatographed on silica gel (50:10:1:1 to 25: 10:1:1 EtOAc/EtOH/ NH 4 OH/H 2 O) to give B-4 as a white solid. TLC Rf = 0.48 (si ca, 15.10:1:1 EtOAc/EtOH/ NH 4 OH/H 2 O). iH NMR (300 MHz, DMSO-d ό ) δ 8.38 (m, IH), 8.14 (m, IH), 7.63 (m, 4H), 7.28 (d, 2H, J=8Hz), 7.08 (d, IH, J=7Hz), 6.50 (br s, IH), 6 28 (d, IH, J=7Hz), 3.96 (m, IH), 3.48 (m, IH), 3.31 (m, 5H), 2.96 (m, 2H), 2.78 (m, 2H), 2.62 ( , 2H), 1.77 (m, 2H), 0.28 (s, 9H). High resolution mass spectrum: For C 2 H 36 N 4 O 5 SSn, expected 665.1533 ( 112 Sn) and 673.1507 ( 120 Sn), found 665.1510 and 673.1505. 2(S)-(4- 125 Iodo-benzenesulfonylamιno)-3-{4-r2-(5,6,7,8-tetrahvdro-ri,8]naphthyndιn- 2-yl)-ethyl1-benzoylammo}-propιonιc acid (B-5) A stir bar, methanol (0.05 mL) and an lodobead (Pierce) were added to a shipping vial of Na 125 I (10 mCi, Amersham, IMS300) and stirred for five minutes at room temperature. A solution of B-4 (-0.1 mg) in methanol (0.04 mL) was made and a portion (0.02 mL) was added to a mixture of H 2 SO 4 (0.005 mL) m methanol (0.025 12 5 mL), and this solution was added immediately to the Na I/iodobead vial. After stirnng for two minutes at room temperature, the reaction was quenched with NH 4 OH (0.04-0.05 mL) and the entire reaction mixture was injected onto the HPLC for puπfication [Vydac peptide-protem C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitnle :H2θ (0.1% TFA) to 90% acetonιtnle:H2θ (0.1% TFA) over 20 minutes, 1 mL/min]. The retention time of B-5 is 16 minutes under these conditions. Fractions containing the majonty of the radioactivity were pooled, lyophilized and diluted with ethanol to give approximately 1 mCi of B-5, which coeluted on HPLC analysis with an authentic sample of B-3. Instrumentation: Analytical and preparative HPLC was earned out using a Waters 600E Powerlme Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC, a Vydac peptide-protem C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column. The acetonitnle used for the HPLC analyses was Fisher Optima grade The HPLC radiodetector used was a Beckman 170 Radioisotope detector A Vydac C-18 protein and peptide column, 3 9 x 250 mm was used for analytical and preparative HPLC Solutions of radioactivity were concentrated using a Speedvac vacuum centnfuge. Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 8452A UV/Vis Diode Array Spectrophotometer Sample radioactivities were determined in a Packard A5530 gamma counter The test procedures employed to measure cxvβ3 and vβ5 binding and the bone resorption inhibiting activity of the compounds of the present invention are descnbed below BONE RESORPTION-PIT ASSAY When osteoclasts engage in bone resorption, they can cause the formation of pits in the surface of bone that they are acting upon. Therefore, when testing compounds for their ability to inhibit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present Consecutive 200 micron thick cross sections from a 6 mm cylinder of bovine femur diaphysis are cut with a low speed diamond saw (Isomet, Beuler, Ltd., Lake Bluff, II). Bone slices are pooled, placed m a 10% ethanol solution and refngerated until further use. Pnor to expenmentation, bovme bone slices are ultrasonicated twice, 20 minutes each in H2O. Cleaned slices are placed in 96 well plates such that two control lanes and one lane for each drug dosage are available Each lane represents either tnp cate or quadruplicate cultures. The bone slices in 96 well plates are sten zed by UV irradiation. Pπor to incubation with osteoclasts, the bone slices are hydrated by the addition of 0.1 ml αMEM, pH 6.9 containing 5% fetal bovme serum and 1% penicillin/streptomycin. Long bones from 7-14 day old rabbits (New Zealand White Hare) are dissected, cleaned of soft tissue and placed in αMEM containing 20 mM HEPES The bones are minced using scissors until the pieces are <1 mm and transferred to a 50 ml tube in a volume of 25 ml. The tube is rocked gently by hand for 60 cycles, the tissue is sedimented for 1 mm., and the supernatant is removed Another 25 ml of medium is added to the tissue and rocked again The second supernatant is combined with the first The number of cells is counted excluding erythrocytes (typically - 2 x 107 cells/ml) A cell suspension consisting of 5 x lθ6/ml in αMEM containing 5% fetal bovme serum, 10 nM l,25(OH)2D3, and pencillm-streptomycin is prepared 200 ml aliquots are added to bovine bone slices (200 mm x 6 mm) and incubated for 2 hrs at 37°C in a humidified 5% CO2 atmosphere The medium is removed gently with a micropipettor and fresh medium containing test compounds is added. The cultures are incubated for 48 hrs., and assayed for c-telopeptide (fragments of the al chain of type I collagen) by Crosslaps for culture media (Herlev, Denmark). Bovine bone slices are exposed to osteoclasts for 20-24 hrs and are processed for staining. Tissue culture media is removed from each bone slice. Each well is washed with 200 ml of H2O, and the bone slices are then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH 7.4. After fixation, any remaining cellular debris is removed by 2 min. ultrasonication in the presence of 0.25 M NH4OH followed by 2 X 15 min ultrasonication in H2O. The bone slices are immediately stained for 6-8 min with filtered 1% toluidine blue and 1% borax. After the bone slices have dried, resorption pits are counted in test and control slices. Resorption pits are viewed in a Microphot Fx (Nikon) fluorescence microscope using a polarizing Nikon IGS filter cube. Test dosage results are compared with controls and resulting IC50 values are determined for each compound tested. The appropriateness of extrapolating data from this assay to mammalian (including human) disease states is supported by the teaching found in Sato, M., et al., Journal of Bone and Mineral Research, Vol. 5, No. 1, pp. 31-40, 1990, which is incorporated by reference herein in its entirety. This article teaches that certain bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay described above to confirm a correlation between their known utility and positive performance in the assay. EΓB ASSAY Duong et al., J. Bone Miner. Res., 8: S378 (1993), describes a system for expressing the human integrin αvβ3. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies against the integrin, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption. Reaction Mixture: 1. 175 μl TBS buffer (50 mM Tris'HCl pH 7.2, 150 mM NaCI, 1% BSA, 1 mM CaCl2, 1 mM MgCtø). 2. 25 ml cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 μl). 3. 125 I-echistatin (25 μl/50,000 cpm) (see EP 382 451). 4. 25 μl buffer (total binding) or unlabeled echistatin (non-specific binding). The reaction mixture was then incubated for 1 h at room temp. The unbound and the bound αvβ3 were separated by filtration using a Skatron Cell Harvester. The filters (prewet in 1.5% poly-ethyleneimine for 10 mins) were then washed with the wash buffer (50 mM Tris HCl, ImM CaCl2/MgCl2, pH 7.2). The filter was then counted in a gamma counter. SPAV3 ASSAY MATERIALS: 1. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem 4. NaCI: Fisher 5. CaCl2- Fisher 6. MgCl2: SIGMA 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 8. Optiplate: PACKARD 9. Compound A-10 (specific activity 500-1000 Ci/mmole) 10. test compound 11. Purified integrin receptor: αvβ3 was purified from 293 cells overexpressing ocvβ3 (Duong et al., J. Bone Min. Res., 8:S378, 1993) according to Pytela (Methods in Enzymology, 144:475, 1987) 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCI, 1 mM Ca 2+ Mg 2 +, 0.5 mM PMSF 13. 50 mM octylglucoside in binding buffer- 50-OG buffer PROCEDURE- 1. Pretreatment of SPA beads: 500 mg of lyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer. 2. Preparation of SPA beads and receptor mixture In each assay tube, 2.5 μl (40 mg/ml) of pretreated beads were suspended in 97.5 μl of binding buffer and 20 ml of 50-OG buffer. 5 ml (-30 ng/μl) of puπfied receptor was added to the beads in suspension with stirπng at room temperature for 30 minutes. The mixture was then centπfuged at 2,500 rpm in a Beckman GPR Benchtop centnfuge for 10 minutes at 4°C. The pellets were then resuspended in 50 μl of binding buffer and 25 μl of 50-OG buffer. 3. Reaction The following were sequentially added into Optiplate in corresponding wells: (0 Receptor/beads mixture (75 μl) (n) 25 μl of each of the following: compound to be tested, binding buffer for total binding or A-8 for non-specific binding (final concentration 1 μM) (in) A-10 m binding buffer (25 μl, final concentration 40 pM) (IV) Binding buffer (125 μl) (v) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C 4 Plates were counted using PACKARD TOPCOUNT 5 % inhibition was calculated as follows: A = total counts B = nonspecific counts C = sample counts % inhibition = [{ (A-B)-(C-B)}/(A-B)]/(A-B) x 100 OCFORM ASSAY Osteoblast-like cells (1.8 cells), originally derived from mouse calvaria, were plated in CORNING 24 well tissue culture plates in αMEM medium containing ribo- and deoxyribonucleosides, 10% fetal bovine serum and penicillin- streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows: Mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syringe with a 27.5 gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 mm nylon cell strainer. The resulting suspension was centrifuged at 350 x g for seven minutes. The pellet was resuspended, and a sample was diluted in 2% acetic acid to lyse the red cells. The remaining cells were counted in a hemacytometer. The cells were pelleted and resuspended at 1 x 10" cells/mL. 50 μL was added to each well of 1.8 cells to yield 50,000 cells/well and 1,25-dihydroxy- vitamin D3 (D3) was added to each well to a final concentration of 10 nM. The cultures were incubated at 37°C in a humidified, 5% CO2 atmosphere. After 48 h, the medium was changed. 72 h after the addition of bone marrow, test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with fresh medium containing D3. After an additional 48 h., the medium was removed, cells were fixed with 10% formaldehyde in phosphate buffered saline for 10 minutes at room temperature, followed by a 1-2 minute treatment with ethanokacetone (1:1) and air dried. The cells were then stained for tartrate resistant acid phosphatase as follows: The cells were stained for 10-15 minutes at room temperature with 50 mM acetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dried. The number of multinucleated, positive staining cells was counted in each well. SPAV5 ASSAY MATERIALS: I. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside and Phorbo-12-myristate-13-acetate (PMA): Calbiochem 3. Tris-HCl, NaCI and CaCl 2 : Fisher 4. Minimum Essential Media (MEM): Gibco/BRL 5. Fetal bovine serum (FBS): Hyclone 6. MgCl 2 , MnCl 2 , and Phenylmethylsulfonylfluoride (PMSF): SIGMA 7. Protease inhibitor cocktail tablets: Boehringer Mannheim. 8. Optiplate-96 wells: PACKARD 9. B-5 was used as radiolabeled ligand (specific activity 500-1000 Ci/mmole) and B-3 (2.5 μM) was used to achieve 100% inhibition. 10. Test compound. I I. HEK293 cells overexpressing α v β 5 integrins (Simon et al., J. Biol. Chem. 272, 29380-29389, 1997) are cultured in 150 mm dishes in 10% FBS/MEM media (Gibco/BRL). 12. Lysis buffer: 100 mM octylglucopyranoside, 50 mM Tris, pH 7.5, 100 mM NaCI, 1 mM CaCl 2 , 1 mM MgCl 2 , 0.5 mM PMSF and protease inhibitors (1 tablet/50 ml buffer). 13. Binding buffer: 50 mM Tris, pH 7.5, 100 mM NaCI, 1 mM CaCl 2 1 mM MgCl 2 and 1 mM MnCl 2. 14. 50 mM octylglucopyranoside in binding buffer: 50-OG buffer PROCEDURE: 1. αyβ 5 -cell lysates: HEK 293 cells expressing α v β 5 integrins were cultured until confluent. Cells were then starved overnight in media containing 0.5% FBS, followed by treatment with lOOnM PMA for 20 min. Cells were washed 2 times with cold phosphate buffer saline (4°C) and solubilized in lysis buffer for 30 min on ice. Lysates were clarified using a Beckman JA-20 at 20,000 xg. Protein concentration of clarified lysates was determined using a micro BCA kit (Pierce) and stored in aliquots at 80 °C. 2. Pretreatment of SPA beads: 500 mg of lyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer 3. Preparation of SPAV5 binding reaction To each assay well, the following were sequentially added mto Optiplate plates: (l) Binding buffer to make up final volume of 125 μl per well (n) 3 μl (120 μg/well) of pretreated beads diluted with 22 μl of 50-OG Buffer (in) 15 μg of α v β 5 -cell lysate proteins. (IV) B^5 at 50,000 cpm. (v) 25 μl of graded concentrations of test compound. (vi) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C 4. Plates were counted using PACKARD TOPCOUNT microplate scintillation counter. 5 % Inhibition was calculated as follows: A = total counts (binding of receptor to B-5) B = nonspecific counts (binding of receptor to B-5 in the presence of 2.5 μM cold ligand) C = counts from receptor binding to test compound % inhibition = [{(A-B)-(C-B)}/(A-B)]/(A-B) x 100 IC 5 o of test compound was calculated as 50% of inhibition. EXAMPLE OF A PHARMACEUTICAL FORMULATION As a specific embodiment of an oral composition, 100 mg of any of the compounds of the present invention are formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule Representative compounds of the present invention were tested and found to bind to human αvβ3 integrin. These compounds were generally found to have IC50 values less than about 100 nM in the SPAV3 assay. Representative compounds of the present invention were tested and generally found to inhibit 50% in the SPAV5 assay at a concentration of about 1 μM. While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims: WHAT IS CLAIMED IS: 1. A compound of the formula wherein X is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two Rl substituents, and a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two Rl substituents; Y is selected from the group consisting of -(CH 2 )m-, -(CH 2 )m-O-(CH 2 )n-. -(CH2)πrS-(CH2)n-. -(CH2)m-SO-(CH2)n-, -(CH2)m-SO2-(CH 2 )n-, -(CH2)m-O-(CH2)n-O-(CH 2 )p-, -(CH 2 )m -O-(CH2)n-NR 4 -(CH 2 ) p -, -(CH 2 )m -NR 4 -(CH2) n -NR 4 -(CH2)p -(CH 2 )m- -O-(CH 2 )n-S-(CH2) p -, -(CH 2 )m- -S-(CH 2 )n-S-(CH2)p-, -(CH )m -NR4-(CH2)n-S-(CH 2 ) p -, -(CH 2 )m -NR 4 -(CH 2 )n-O-(CH 2 )p-, -(CH 2 )m -S-(CH 2 )n-O-(CH 2 ) p -, -(CH 2 )m -S-(CH2)n-NR 4 -(CH 2 ) p r, and -(CH 2 )m -Z-(CH 2 ) n -, wherein Z is a 3- to 10-membered monocyclic or polycyclic aromatic or nonaromatic πng system having 0, 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S wherem the πng nitrogen atoms are unsubstituted or substituted with one Rl substituent and the nng carbon atoms are unsubstituted or substituted with one or two Rl substituents, and wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R^ substituents, D is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic nng system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S where the nng nitrogen atoms are unsubstituted or substituted with one R^ substituent and the πng carbon atoms are unsubstituted or substituted with one or two R* substituents, E is selected from the group consisting of -(CH 2 )m-. -(CH 2 )m-O-(CH2)n-. -(CH 2 )m-NR 4 -(CH2)n-. -(CH 2 )m-S-(CH2)n-. -(CH2)m-SO-(CH 2 )n-, and -(CH2)m-SO 2 -(CH2)n-. wherein any methylene (CH2) carbon atom in E, other than in R 4 , can be substituted by one or two R^ substituents, R^and R 2 are each independently selected from the group consisting of hydrogen, halogen, Ci -io alkyl, C3-8 cycloalkyl, C3-.8 cycloheteroalkyl, C3-.8 cycloalkyl Cι _6 alkyl, C3-.8 cycloheteroalkyl Cι_6 alkyl, aryl, aryl Cι _8 alkyl, amino, amino Ci -8 alkyl, C1 -.3 acylamino, C1.3 acylamino Cι_8 alkyl, (Ci-6 alkyl)pamino, (Cι_6 alkyl)pamino Ci-8 alkyl, Ci-4 alkoxy, C1 -4 alkoxy Ci-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cι _6 alkyl, Cχ_3 alkoxycarbonyl, C1-.3 alkoxycarbonyl Ci_ alkyl, hydroxycarbonyl- Ci-6 alkyloxy, hydroxy, hydroxy Ci-6 alkyl, Ci-6 alkyloxy- Ci -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Ci - alkyl-S(O)p, (Ci -8 alkyl)paminocarbonyl, Ci-8 alkyloxycarbonylamino, (Cι_8 alkyl)paminocarbonyloxy, (aryl Ci- alkyl)pamino, (aryl)pamino, aryl Ci -8 alkylsulfonylamino, and Cι_8 alkylsulfonylamino; or two Rl substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R3 is independently selected from the group consisting of hydrogen, aryl, Ci-io alkyl, aryl-(CH2)r-O-(CH 2 )s-, aryl-(CH2)rS(O)p-(CH 2 )s-. aryl-(CH2) r -C(O)-(CH 2 )s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2) s -, aryl-(CH2) r -N(R )-C(O)-(CH 2 )s-. aryl-(CH2)r-N(R )-(CH 2 )s-, halogen, hydroxyl, oxo, trifluoromethyl, Ci-8 alkylcarbonylammo, aryl C1.5 alkoxy, Ci -5 alkoxycarbonyl, (Ci-8 alkyl)paminocarbonyl, Ci-6 alkylcarbonyloxy, C3-8 cycloalkyl, (Cf-6 alkyl)pamino, amino Ci- alkyl, arylaminocarbonyl , aryl C1-.5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cf-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, HC≡C-(CH2)t-, Ci-6 alkyl-C≡C-(CH2)t-, C3.7 cycloalkyl-C≡C-(CH2)t-, aryl-C≡C-(CH2)t-, Ci_6 alkylaryl-C≡C-(CH2)t-, CH 2 =CH-(CH 2 )t-, Cι _6 alkyl-CH=CH-(CH2)t-, C3.7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, Ci-6 alkylaryl-CH=CH-(CH2)t-, Ci-6 alkyl-SO2-(CH 2 )t-, Ci_6 alkylaryl-SO2-(CH2)t-, Cι_6 alkoxy, aryl Ci -6 alkoxy, aryl Cι_6 alkyl, (Ci -6 alkyl )pamino Ci- alkyl, (aryl)pamino, (aryl)pamino Cf-6 alkyl, (aryl Ci-6 alkyl )pamino, (aryl Ci- alkyl)pamino Ci-6 alkyl, arylcarbonyloxy, aryl Ci-6 alkylcarbonyloxy, (Ci-6 alkyl )paminocarbonyloxy, Ci -8 alkylsulfonylamino, arylsulfonylamino, Ci -8 alkylsulfonylamino Cι_6 alkyl, arylsulfonylamino Ci -6 alkyl, aryl Ci- alkylsulfonylamino, aryl Ci- alkylsulfonylamino Ci -6 alkyl, Ci-8 alkoxycarbonylamino, Cι_8 alkoxycarbonylamino Ci-8 alkyl, aryloxycarbonylamino Ci-8 alkyl, aryl Cι _8 alkoxycarbonylamino, aryl Ci_8 alkoxycarbonylamino Ci -8 alkyl, Ci -8 alkylcarbonylamino, Ci-8 alkylcarbonylamino Cf-6 alkyl, arylcarbonylamino Cι_6 alkyl, aryl Ci -6 alkylcarbonylamino, aryl Ci -6 alkylcarbonylamino Ci -6 alkyl, aminocarbonylamino Ci -6 alkyl, (Ci-8 alkyl)paminocarbonylamino, (Ci-8 alkyl )paminocarbonylamino Ci -6 alkyl, (aryl)paminocarbonylamino Ci- alkyl, (aryl Cι_8 alkyl)paminocarbonylamino, (aryl Ci -8 alkyl)paminocarbonylamino Cι_6 alkyl, aminosulfonylamino Ci -6 alkyl, (Ci-8 alkyl)paminosulfonylamino, (Ci-8 alkyl)paminosulfonylamino Ci- alkyl, (aryl)paminosulfonylamino Ci- alkyl, (aryl Cι_8 alkyl )paminosulfonylamino, (aryl Cι_8 alkyl)paminosulfonylamino Cι_6 alkyl, Ci-6 alkylsulfonyl, Ci-6 alkylsulfonyl Cι_6 alkyl, arylsulfonyl Ci-6 alkyl, aryl Cι_6 alkylsulfonyl, aryl Cι_6 alkylsulfonyl Ci-6 alkyl, Ci-6 alkylcarbonyl, Ci-6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl Ci- alkyl, aryl Cf-6 alkylcarbonyl, aryl Ci -6 alkylcarbonyl Ci-6 alkyl, Ci_6 alkylthiocarbonylamino, Ci_ alkylthiocarbonylamino Cι_6 alkyl, arylthiocarbonylamino Ci -6 alkyl, aryl Ci_6 alkylthiocarbonylamino, aryl Ci -6 alkylthiocarbonylamino Ci-6 alkyl, (Cl-8 alkyl)paminocarbonyl Cι_6 alkyl, (aryl)paminocarbonyl Ci -6 alkyl, (aryl Cι_8 alkyl)paminocarbonyl, and (aryl Ci - alkyl)paminocarbonyl Ci-6 alkyl; or two R3 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R^ are either unsubstituted or substituted with one to three R substituents, and provided that each R^ is selected such that in the resultant compound the carbon atom or atoms to which R^ is attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, C3-8 cycloalkyl, amino Ci -6 alkyl, (aryl)paminocarbonyl, (aryl C1 -.5 alkyl)paminocarbonyl, hydroxycarbonyl Ci-6 alkyl, Ci-8 alkyl, aryl Cf-6 alkyl, (Ci-6 alkyl)pamino C2-6 alkyl, (aryl Cf-6 alkyl)pamino C2-6 alkyl, Ci-8 alkylsulfonyl, Ci -8 alkoxycarbonyl, aryloxycarbonyl, aryl Cι _8 alkoxycarbonyl, Ci-8 alkylcarbonyl, arylcarbonyl, aryl Cι_6 alkylcarbonyl, (Ci_8 alkyl)paminocarbonyl, aminosulfonyl, Ci-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl Ci-8 alkyl)paminosulfonyl, arylsulfonyl, arylC 1-6 alkylsulfonyl, Ci -6 alkylthiocarbonyl, arylthiocarbonyl, and aryl Ci -6 alkylthiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three Rl substituents; R5 is selected from the group consisting of hydrogen, Ci-8 alkyl, aryl, aryl Ci-8 alkyl, Ci -8 alkylcarbonyloxy Ci-4 alkyl, aryl Ci -8 alkylcarbonyloxy C1 -4 alkyl, Ci-8 alkylaminocarbonylmethylene, and Ci-8 dialkylaminocarbonylmethylene; wherein each a is independently an integer from 0 to 6, each b is independently an integer from 0 to 6 wherein a + b > 2; each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; each s is independently an integer from 0 to 3; and each t is independently an integer from 0 to 3; or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim 1 wherein X is selected from the group consisting of a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one R* substituent and the ring carbon atoms are unsubstituted or substituted with one or two Rl substituents, and a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two Rl substituents. 3. The compound according to Claim 2 wherein X is selected from the group consisting of The compound according to Claim 3 wherein X is 5. The compound according to Claim 4 wherein Y is selected from the group consisting of (CH 2 )m. (CH 2 )m-O-(CH2)n. and (CH2) m -NR -(CH 2 )n, wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R^ substituents. 6. The compound according to Claim 5 wherein each R^ is independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl, aryl, C 1-8 alkyl, arylCι_6 alkyl hydroxyl, oxo, arylammocarbonyl, aryl C1-.5 alkylam ocarbonyl, aminocarbonyl, and aminocarbonyl Ci_6 alkyl. 7. The compound of Claim 1 where a and b are each independently selected from an integer from 1 to 3. 8. A compound selected from the group consisting of { l-[3-(5,6,7,8-Tetrahydro-[l,8]-naphthyndιn-2-ylmethyl)-pyπ-olιdιne-l-carbonyl]- pιpeπdιn-4-yl}-acetιc acid; (4- { 4-[( 1 -H-Benzιmιdazol-2-ylamιno)-methyl]-pιpendιne- 1 -carbonyl-phenoxy)-acetιc acid; { l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpendιne-l-carbonyl]- pιpendm-4-yl}-acetιc acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpendme-l-carbonyl]- pιperazιn-l-yl}-acetιc acid; 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-ylmethyl)-pιpeπdιne-l-carbonyl]- pιpendιn-3-yl}-propιonιc acid; 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdm-2-ylmethyl)-pιpendιne-l-carbonyl]- pyrrolιdιn-2-yl}-propιonιc acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyndιn-2-ylmethyl)-pιpendιne-l-carbonyl]- pιpendιn-l-yl}-acetιc acid, 3-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyπdιn-2-ylmethyl)-pιpeπdιne-l-carbonyl]- phenoxyacetic acid, { l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin-4- yl} -acetic acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperazin-l- yl} -acetic acid; 3-{ l-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin- 3-yl}-propionic acid; {4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin-l- yl} -acetic acid; 3-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]- phenoxyacetic acid; 3-{4-[4-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)-piperidine-l-carbonyl]-piperidin- 1 -yl } -propionic acid; { l-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- pyrrolidin-2-yl } -acetic acid; { l-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-2-yl } -acetic acid; {4-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- piperidin-1-yl} -acetic acid; 3-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- phenoxyacetic acid; and 4-[3-(5,6,7,8-Tetrahydro-[l,8]naphthyridin-2-ylmethyl)-piperidine-l-carbonyl]- phenoxyacetic acid; or a pharmaceutically acceptable salt thereof. 9. The compound of Claim 8 selected from the group consisting of { l-[3-(5,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-ylmethyl)-pyrrolidine-l-carbonyl]- piperidin-4-yl } -acetic acid and 4- { 4-[( 1 -H-Benzimidazol-2-ylamino)-methyl]-piperidine- 1 -carbonyl } -phenoxyacetic acid; or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable earner. 11. The composition according to Claim 10 which further comprises an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) a cytotoxic/antiproliferative agent, e) a matrix metalloproteinase inhibitor, f) an inhibitor of epidermal-derived, fibroblast-derived, or platelet- derived growth factors, g) an inhibitor of VEGF, h) an antibody to a growth factor or a growth factor receptor, i) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, j) a cathepsin K inhibitor, k) a growth hormone secretagogue, 1) an inhibitor of osteoclast proton ATPase, m) an inhibitor of urokinase plasminogen activator (u-PA), n) a tumor-specific antibody-interleukin-2 fusion protein, o) an inhibitor of HMG-CoA reductase, and p) a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof. 12. The composition according to Claim 11 wherein said active ingredient is selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) a cathepsin K inhibitor, e) an HMG-CoA reductase inhibitor, and f) an inhibitor of osteoclast proton ATPase; and mixtures thereof. 13. The composition according to Claim 12 wherein said organic bisphosphonate or pharmaceutically-acceptable salt or ester thereof is alendronate monosodium trihydrate. 14. A method of eliciting an αv integrin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1. 15. The method of Claim 14 wherein αv the integrin receptor antagonizing effect is an αvβ3 antagonizing effect. 16. The method of Claim 15 wherein the αvβ3 antagonizing effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, inflammatory arthritis, viral disease, cancer, and metastatic tumor growth. 17. The method of Claim 16 wherein the αvβ3 antagonizing effect is the inhibition of bone resorption. 18. A method of treating or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1. 19. The method of Claim 14 wherein the αv integrin receptor antagonizing effect is an αvβ5 antagonizing effect. 20. The method of Claim 19 wherein the αvβ5 antagonizing effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, cancer, and metastatic tumor growth. 21. The method of Claim 14 wherein the αv integrin receptor antagonizing effect is a dual αvβ3/αvβ5 antagonizing effect. 22. The method of Claim 21 wherein the dual αvβ3/αvβ5 antagonizing effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, cancer, and metastatic tumor growth. 23. A method of eliciting an αv integrin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 10. 24. A method of treating or preventing a condition mediated by antagonism of an αv integrin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 10. 25. A method of treating metastatic tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1 in combination with radiation therapy.

Inventors: DUGGAN MARK E, HARTMAN GEORGE D, IHLE NATHAN, PERKINS JAMES J, DUGGAN, MARK, E., HARTMAN, GEORGE, D., IHLE, NATHAN, PERKINS, JAMES, J.
Applicants: DUGGAN MARK E, HARTMAN GEORGE D, IHLE NATHAN, MERCK & CO INC, PERKINS JAMES J, DUGGAN, MARK, E., HARTMAN, GEORGE, D., IHLE, NATHAN, MERCK & CO., INC., PERKINS, JAMES, J.
Application year: 2000
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P9, A61P19, A61P27, A61P29, A61P31, A61P35, A61P37, A61P43, C07D401, C07D471