CA2338275A1 - Integrin receptor antagonists - Google Patents

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.v.beta.3, .alpha.v.beta.5 and/or .alpha.v.beta.6 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, and tumor growth and metastasis.

Description

TITLE OF THE INVENTION
INTEGRIN RECEPTOR ANTAGONISTS
CROSS-REFER,ENC'E TO RELATED APPLICATIONS
The pre ent invention is related to U.S. provisional application Serial No. 60/094,478, filed July 29, 1998, the contents of which are hereby incorporated by reference.
FIELD OF THE INTENTION
The preaent invention relates to compounds and derivatives thereof, their synthEais, and their use as integrin receptor antagonists.
More particularly, tlhe compounds of the present invention are antagonists of the iritegrin receptors av(33, av(i5 andlor av(36 and -are useful for inhibiting bone resorption, treating and preventing 1~ osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, tumor growth, and metastasis.
BACKGROUND OF THE INVENTION
It is believed that a wide variety of disease states and conditions can be mediated by acting on integrin receptors and that integrin receptor antagonists represent a useful class of drugs. Integrin receptors are heterodimeric transmembrane receptors through which cells attach and connmunicate with extraceliular matrices and other cells. (See S.B. Rod.an and G.A. Rodan, "Integrin Function In Osteoclasts," Journal of Endocrinology, Vol. 154, S47- S~6 (1997), which is incorporated by reference herein in its entirety).
In one aspect of the present invention, the compounds herein are useful fo:r inhibiting bone resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large multinucleated 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 3~ 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 matrix 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 in bone resorption. In the migratory or motile state, the osteoclasts migrate across bane matrix and do not take part in resorption until they again attach to bone.
Integri:ns are involved in osteoclast attachment, activation and migration. ThE~ most abundant integrin in osteoclasts, e.g., in rat, chicken, mouse and. human osteoclasts, is an integrin receptor known as av(33, which is th~.ought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to av(33 block bone resorption in aitro indicating that; this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that av(33 ligands can be used effectively to inhibit osteoclast mediated bone resorption in aiao in mammals.
The cmrrent major bone diseases of public concern are osteoporosis, hyperc;alcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget"s disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are- characterized by bone loss, resulting from an 2~ imbalance between bone resorption, i.e. breakdown, and bone formation, which continues thr~~ughout Iife at the rate of about 14% per year on the average. However, ache rate of bone turnover differs from site to site; fox example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The 3U 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 Ieads to increased fracture risk.
In the l:Tnited States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In 3~ addition, there are about 250,00 hip fractures per year attributed to WO 00!06169 PC'TlUS99116830 osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two year s, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditians listed above ~ would benefit from treatment with agents which inhibit bone resorption.
Additionally, av~3 ligands have been found to be usefixl in treating and/or inhil'~iting restenosis (i.e. recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (i.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, av~33 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al., Cell, '19:1157-1164 {1994), which is incorporated by reference herein in its entirety).
Evidene:e has also been presented suggesting that angiogenesis is a cezitral factor in the initiation and persistence of arthritic disease, and that the vascular integrin av(33 may be a preferred target in inflammatory arthritis. Therefore, av~i3 antagonists which inhibit angiogenesis may represent a novel therapeutic approach to the treatment of arthritic disease, such as rheumatoid arthritis {see C.M.
Storgard, et al., "Decreased-angiogenesis and arthritic disease in rabbits treated with an avJ3~~ antagoniist," d. Clip. Invest.,103: 47-54 (1999}, which is incorporated by reference herein in its entirety).
MoreovE3r, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, av(35. A monoclonal antibody for av(35 has been shown to inhibit VEGF-induced angiogenesi~s in rabbit cornea and the chick chorioallantoic membrane model (See M.C. Friedlander, et.al., Science 270: 1500-1502 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize av~i5 are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis.
Additionally, compounds of the instant invention can inhibit angiogenesi~. and inflammation by acting as antagonists of the integrin receptor, ocv(36, which is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Chiistofidou-Solomidou, et al., "Expression and Function of Endothelial Cell av Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice Chimeras, American Journal of Patholo~v, Voi. 151, No. 4, pp. 9175-983 (October 1997), which is incorporated by reference herein in i.ts entirety). It is postulated that av[36 plays a role in the remodeling of the vascula~ture during the later stages of angiogenesis. Also, av~i6 participates in the modulation of epithelial inflammation and is induced in response to local injury or inflammation (See .~iao-Zhu Huang, et al., "Inactivation of the Integrin X36 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin," Journal of Cell Biology, Vol. 133, No.4, pp. 921-928 (May 1996), which is incorporated by reference herein in its entirety). Acc:ardingly, compounds that antagonize av(36 are useful in treating or preventing cancer by inhibiting tumor growth and metastasis.
In addition, certain compounds of this invention antagonize both the av~i3 and av(35 receptors. These compounds, referred to as "dual av(33/av~i5 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopath~;~, macular degeneration, angiogenesis~
atherosclerosis, inflammation, inflammatory arthritis, viral disease, tumor growth, and metastasis.
In addition, certain compounds of this invention are useful as mixed av(33, av(3ei, and av[36 receptor antagonists.
Peptidyl as well as peptidomimetic antagonists of the av(33 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to W.J. Hoekstra and B.L.
Poulter, Curr. Med. hem. 5: 195-204 (1998) and references cited therein;
WO 95/32710; WO 95J37655; WO 97/01540; WO 97/37655; WO 98/08840; WO

wo ooio6i69 ~rrn.~ss9n6s3a 98/18460; WO 98/18461; WO 98/2892; 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 av~i3 integrin receptor antagonists to prevent bone resorption in vitro and in viuo has been presented (see V.W. Englem.an et al., "A Peptidornimetic Antagonist of the av(33 Integrin Inhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vi~~o," J. Cli.n. Invest. 99: 2284-2292 (1997); S.B. Rodan et al., "A High Affinity Non-Peptide av(33 Ligand Inhibits Osteoclast Activity In Vitro and In VLUO," J. Bone Miner. Res. 11: 5289 (1996); J.F.
Gourvest et al., "Prevention of OVX-Induced Bone Loss With a Nan-peptidic Ligand of t;he av~i3 Vitranectin Receptor," B ne 23: 5612 (1998);
M.W. Lark et al., "An Orally Active Vitronectin Receptor av(i3 Antagonist Preveni,s Bone R,esorption In Vitro and In Vivo in the Ovariectomized Rat," Bone 23: S219 (1998)).
The av(i3 integrin receptor recognizes the Arg-Gly-Asp (RGD) tripeptide sE;quence in its cognate matrix and cell surface glycoproteins (see J. Samanen, et al., "Vascular Indications for Integrin av Antagonists," Curr. Pharmaceut. Des,~g,_n 3: 545-584 (1997)). A
benzazepine nucleus has been employed among others by Genentech and SmithKline Be;echam a s a conformationally constrained Giy-Asp mimetic to elaborate nonpeptide av~i3 integrin receptor antagonists substituted at the Nf-terminus with heterocyclic arginine mimetics (see R.M. Keenan et al., "Discovery of Potent Nonpeptide Vitronectin Receptor (av(33) An.tagonists," J. Med. Chem. 40: 2289-2292 {1997); R.M.
Keenan et al., "Benzimidazole Derivatives As Arginine Mimetics in 1,4-Benzodiazepine No:npeptide Vitronectin Receptor {av(33) Antagonists,"
Bioorg. Mid. Chem., Lett. 8: 3165-3170 (1998); and R.M. Keenan et al., "Discovery of an Imidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide Vitrone:ctin Receptor (av~i3) Antagonist With Efficacy in a Restenosis Model," Biaorg. Med. Chem. Lett. 8: 3171-3176 (1998). Patents assigned to SmithI~dine Beecham that disclose such benzazepine, as well as related benzodiazepine and benzocycloheptene, av(33 integrin receptor antagonists include WO 96/00574, WO 96/00730, WO 96/06087, WO
96/26190, WO 97/24719, WO 97/24122, WO 97/24124, WO 98/15278, WO
99/05107, WO 99/06~D49, WO 99/15170, and WO 99/15178, and to Genentech _5_ include WO 9fi/34865. The dibenzocycloheptene, as well as dibenzoxazepine, nucleus has also been employed as a Gly-Asp mimetic to afford av~i3 antagonists (see WO 97/01540, WO 98/30542, WO 99/11626, and WO 99/15508 all assigned to Smith.HIine Beecham).
However, there still remains a need for small-molecule, non-peptide selective integrin. receptor antagonists that display improved potency, pharmacoclynamic, and pharmacokinetic properties, such as oral bio.availability and duration of action, over already described compounds. Such compounds would prove to be useful for the treatment, prevention, or suppression of various pathologies enumerated above that are mediated by integrin receptor binding and cell adhesion and activation.
It is therefore an object of the present invention to provide compounds which a:re useful as integrin receptor antagonists.
It is another object of the present invention to provide compounds which ace useful as av(33 receptor antagonists.
It is another object of the present invention to provide compounds which aoe useful as av(35 receptor antagonists.
It is another object of the present invention to provide compounds which ao~e useful as av(36 receptor antagonists.
It is another object of the present invention to provide compounds which are useful as both av~i3/av~i5 receptor antagonists.
It is another obejct of the present invention to provide compounds which ai~e useful as mixed avj33, av(35 and av(36 receptor antagonists.
It is another object of the present invention to provide pharmaceutical compositions comprising integrin 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 elicitin~; an integrin receptor antagonizing effect in a mammal in need thereof by administering 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 arthritis, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumor growth and metastasis.
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 arthritis, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumor growth and metastasis.
It is another object of the present invention to provide 1v methods for treating osteoporosis.
These .and other objects will become readily apparent from the detailed description which follows.
SUMMARY OF THE INVENTION
The present invention relates to compounds described by the following chemical formula:

5 ~6 C~2R9 wherein W is selected from tlhe group consisting of a 5- or 6-mennbered monocyclic aromatic or nonaromatic ring system having I, 2, 3 or 4 heteroatoms selected from the group consisting of :LV, O, and S wherein the ring nitrogen atoms are unsubstitutedl or substituted with one RI substituent and the ring carbon atoms are unsubstituted or substituted with one or two RI
substituents, and _7_ WO OO/Ob169 PCT/US99116830 a 9- to 14-me:mbered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has I, 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 R1 substituent and the ring carbon atoms are unsubstituteaL or substituted with one or two R1 substituents;
X is selected from the group consisting of -(CH2)~-, and -(CH2~,NR4(CH2)~~~; wherein any methylene (CH2) carbon atom, other than in R4, is either unsubstituted or substituted with one or two R3 substitutents;
1~ Y is a biarylene rin;a system comprising 5- or 6-membered aromatic rings, wherein said biarylene system comprises 0-6 heteroatoms selected from the group consisting of N, O, and S wherein sand biarylene ring system is either unsubstituted or substituted with one or more ~;1 substituents;
Z is selected from the group consisting of O O
-CNR4_ 9 _NR4~C_ ;
-CH2CH2- and -CH:=CH-, wherein either carbon atom can be substituted by one or two R3 suk>stituents;
each R1 is independently selected from the group consisting of hydrogen, halogen, C1_10 alkyl, C3_g cycloalkyl, C3_g cyclohetE~roalkyl, C3_g cycloalkyl C1_g alkyl, C3_g cycloheteroalkyl C~_g alkyl, aryl, aryl C1_g alkyl, amino, amino C1_g alkyl, C1_g acylamino, C1_3 acylamino C1_g alkyl, (C1_6 alkyi)pa~mino, (C1_6 alkyl)pamino C1_g alkyl, C1_4 alkoxy, C;1_4 alkoxy C1_g alkyl, hydroxycarbonyl, _g_ hydroxycarbonyl C1_6 alkyl, C1_3 alkoxycarbonyl, C1_3 alkoxycaxbonyl C1_g alkyl, hydroxycarbonyl-C1_g alkylaxy, hydroxy, hydroxy C1_6 alkyl, C1_6 alkyloxy C1_g alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1_g alkyl-S(O)p, (C1_g alkyl)paminocarbonyl, C1_g alkyloxycarbonylamino, (C1_g alkyl)paminocarbonyloxy, (aryl C1_g alk:yl)pamino, (aryl)pamino, aryl C1_g alkylsulfonylamino, and C1_g 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, C1_xo alley, aryl-(CH2)r-~'-(CH2)s-~
aryl-(CH2)rS(0)p-(CH2)s-, aryl-{CH2)r-C{o)-(CH2)s-, aryl-(CH2)r-C{O)-N(R4)-(CH~)s-, aryl-{CH2h.-N~(R4)-C(O)-(CH2)s-, aryl-(CH~)x.-N~(R4)-(CH2)s-, halogen, hydroxyl, oxo, trifluoromethyl, C 1_g alkylcarlnonylamino, aryl Cl_5 alkoxy, C1_~ alkoxyca.rbonyl, {C1_g alkyl)pa~minocarbonyl, C1_6 alkylcarbonyloxy, C3_g cycloalkyl, (C1_g alkyl)paimino, amino C1_6 alkyl, _g_ WO 00/06169 PC'T/US99/16$30 arylaminoca:rbonyl, aryl C~_5 alk.ylaminocarbonyl, aminocarboruyl, aminocarbon,yl C1_g alkyl, hydroxycarbonyl, hydroxycarbcmyl C1_g alkyl, HC---C-(CH2)1t-C1_g alkyl-C==C-(CH2)t-, C3_fi cycloalkyl-C=C-(CH2)t-, aryl-C=-C-(Cfi2)t-, C1_6 alkylaryl-C-C-(CH2)t-, CH2=CH-( C~I2 )t-, C1_g alkyl-CH=CH-(CH2)t-, C3_7 cycloalkyl-CH=CH-(CH2)t-, I5 aryl-CH=CH-~(CH2)t-, C1_g alkylary~l-CH=CH-(CH2)t-, C1_g alkyl-SO2-(CH2~-, C 1_6 alkylaryl-S02-(CH2)t-, C1_g alkoxy, aryl C1_6 alkoxy, aryl C1_6 alkyl, (C1_g alkyl)p;~mino Cl..g alkyl, (aryl)pamino, (aryl)pamino C1_6 alkyl, (aryl C1_s all~yl)pamin.o, (aryl C1_6 all;yl)pamino C1_g alkyl, arylcarbonyloxy, aryl C1_6 alk;ylcarbonyloxy, (C1_g alkyl)paminocarbonyloxy, C 1_g alkylsui~fonylamino, arylsulfonylamino, C1_g alkylsulfonylamino C1-g alkyl, arylsulfonylamino C1_6 alkyl, aryl C1_g alk.ylsulfonylamino, aryl C1_g alk:ylsulfonylamino C1_6 alkyl, C 1_ g alkoxyc;~rbonylanaino, C1_g alkoxycarbonylamino C1_g alkyl, aryloxycarbonylamino C1_g alkyl, aryl C1_g alkoxycarbonylamino, aryl C1_g alkoxycarbon.ylamino Cl_g alkyl, C1_g alkylcarbonylamino, C1_g alkylcarbonylamino C1_g alkyl, arylcarbonyla.mino C 1_6 alkyl, aryl C1_g alk;ylcarbonylamino, aryl C1_6 alkylcarbonylamino C1_6 alkyl, aminocarbonylamino C;1_g alkyl, (C1_g alkyl)paminocarbonylamino, (C~_g alkyl)paminocarbonylamino C1_g alkyl, (aryl)paminoc;arbonylamino C1_6 alkyl, (aryl C1_g all~:y1)paminocarbonylamino, (aryl C1_g alkyl)paminacarbonylamino C1_g alkyl, aminosulfonylamino C1_6 alkyl, (C1_g alkyl)p~nninosulfonylamino, (C1_g alkyl)puminosulfonylamino C1_6 alkyl, (aryl)pamino.,ulfonylamino C1_6 alkyl, (aryl C1_g alk:yl)paminosulfonylamino, (aryl C1_g alkyl)paminosulfonylamino C1_g alkyl, C 1_g alkylsuli:onyl, C1_g alkylsulfbnyl C1_g alkyl, 2~ arylsulfonyl C1_g alkyl, aryl C1_6 alk3~lsulfonyl, aryl C1_g alkylsulfonyl C1_g alkyl, C1_6 alkylcarbonyl, C1_g alkylcarbonyl C1_6 alkyl, arylcarbonyl (~g_g alkyl, aryl C1_0 alkylcarbonyl, aryl C1_g alkylcarbonyl C1_0 alkyl, C 1_g alkyltbiocarbonylamino, C1_g alkylthio~carbonylamino C1_g alkyl, arylthiocarbo:nylamino C~_g alkyl, aryl C1_s alk;ylthiocarbonylamino, aryl C1_6 alkylthiocarbonylamino C1_s alkyl, (C1_g alkyl)paminocarbonyl C1_g alkyl, (aryl)paminoc:arbonyl C7_~ alkyl, (aryl C1_g all~:yl)paminocarbonyl, and (aryl Cl_g alkyl)paminacarbonyl C1_s alkyl;
or two R3 sub~stituents, 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 R3 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 R4 is independently selected from the group consisting of hydrogen, aryl, aminocarbon;yl, C3_g cycloalkyl, amino C1_6 al'.kyl, (aryl)paminoc:arbonyl, (aryl C1_5 alkyl)paminocarbonyl, hydroxycarbonyl C1_6 alkyl, C1_g alkyl, aryl C1_g alkyl, (C1_0 alkyl)pamino C2_g alkyl, (aryl C1_6 alk;yl)pamino C2_6 alkyl, C 1_g alkylsulfvonyl, C1_g alkoxyca.rbonyl, aryloxycarbonyl, aryl C1_g alkoxycarbonyl, C~_g alkylcarbonyl, WO 00/061b9 PC'T/US99l16830 arylcarbonyl, aryl C1_6 alkylcarbonyl, (C1_g alkyl)p;aminocarbonyl, aminosulfonyl, C1_g alkylamunosulfonyl, (aryl)paminosulfonyl, (aryl C1_g alhyl)pamin.osulfonyl, arylsulfonyl, arylCl-6 alkylsulfonyl, C1_6 alkylthiocarbonyl, arylthiocarbonyl, and aryl C1_g alkylthiocarbonyl, wherein any of the akyl groups of R4 are either unsubstituted or substituted with one to three Rl substituents;
R5 and R~ are each independently selected from the group consisting of hydrogen, C1_lp alkyl, aryl, aryl-(CH2)r-C!-(CH2)s-r aryl-(CH2)rs(O)p-(CH2)s-, aryl-(CH2)r-C%(~)-(CH2)s-~
aryl-(CH2)r-C-(4)-N(R4)-(CH2)s°, aryl-(CH2)r-N(R4)-C(O)-(CH2)s-, aryl-(CH2)r-N(R4)-(CH2)s-, halogen, hydroxyl, C1_g alkylcarbonylamino, aryl C 1 _ 5 alkoxy, C1_5 alkoxycarbonyl, (C1_g alkyl)paminocarbonyl, C1_6 alkylcarlbonyloxy, C3_g cycloalkyl, (C 1_~ alkyl~amino, amino C1_6 alkyl, WO 00/06169 PCTlUS99/16830 arylamino ca;rb onyl, aryl CI-5 alkylaminocarbonyl, aminocarbonyl, aminocarbon;yl C 1_0 alkyl, hydroxycarbonyl, hydroxycarbo~nyl C1_0 alkyl, HC=C-(CH2)1; , C1_g alkyl-C=:C-(CH2)t-, C~_'7 cycloalk;yl-C---C-(CH2)t-, aryl-C=C-(C~t2)t-, C1_g alkylaryl-C---C-(CH2)t-, CH2=CH-(C) f2)t-, Cl_s alkyl-Cl1-CH-(CH2)t-9 C3_7 cycloalk;yl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, CZ_g alkylaryl-CH~CH-(CH2)t-, CI-g alkyl-502-(CH2)t-, C1_g alkylary!-S02-(CH2)t-, C1_g alkoxy, aryl CI_s alkoxy, aryl C I_g alkyl, (C1_g alkyl)pamino C1_g alkyl, (aryl)pamino, (aryl)pamino Cl,_6 alkyl, (aryl Cl_g allt:yl)pamino, (aryl CI_6 alkyl)pamino CI-g alkyl, arylcarbonylcExy, aryl C1_g alkylcarbonyloxy, (C1_g alkyl)p<~minocarbonyloxy, CI_g alkylsulfonylamino, arylsulfonylamino, CI_g alkylsuli:onylamino C1_s alkyl, arylsulfonylamino C1_~ alkyl, aryl CI_6 alk;ylsulfonylamino, 3~ aryl C1_g alkylsulfonylamino CI_~ alkyl, WO 00/06169 PC1'/US99116830 C1_g alkoxycarbonylamino, C1_g alkoxyca~rbonylamino C1_g alkyl, aryloxycarbomylamino C1_g alkyl, aryl CI_g alk.oxycarbonylamino, aryl C1_g alkoxycarbonyiamino C1_g alkyl, C 1_g alkylca~°bonyiamgno, Cl_g alkyicarbonylamino CI_g alkyl, arylcarbonylamino CI_6 alkyl, aryl C1_g alkylcarbonylamino, aryl C1_6 alk;ylcarbonylamino C1_6 alkyl, aminocarbon;ylamino C1_g alkyl, (C1_g alkyl)paminocarbonylamino, (CI_g alkyl)p;aminocarbonylamino CI_6 alkyl, (aryl)paminacarbonylamino CI_g alkyl, lb (aryl C1_g alkyl)paminocarbonylamino, {aryl C1_g alh;yl)paminocarbonylamino CI_g alkyl, aminosulfonylamino C1_6 alkyl, (C1_g alkyi)paminosulfonylamino, (CI_g alkyl)p;~minosulfonylamino CI_g alkyl, (aryl)paminosulfonylamino CI_g alkyl, (aryl C1_g alhyl)paminosulfonylamino, (aryl C1_g alh;yl)paminosulfonylamino C1_~ alkyl, C1_g aikylsul:fonyl, CI_g alkylsuli:onyl C1_0 alkyl, 2b arylsulfonyl C; I_s alkyl, aryl CI_g alk;ylsulfonyl, aryl C1_g alk3~lsuifonyl C1_g alkyl, C1_6 alkylca>"bonyi, C1_g alkylcarlbonyl C1_0 alkyl, arylcarbonyl C1_g alkyl, aryl C1_g alkylcarbonyl, aryl C1_& alkylcarbonyl. C1_6 alkyl, CI_g alkylthiocarbonylamino, C1_g alkylthiocarbonylamino Cl_g alkyl, Ib _ WO 00/06169 PCT/US99lIG830 arylthiocarbonylamino CI_g alkyl, aryl CI_g alkylthiocarbonylamino, aryl CI_d alk;ylthiocarbonylamino CI_g alkyl, (CI_g alkyl)p;~minocarbonyl CI_g alkyl, (aryl)paminocarbonyl C I_g alkyl, (aryl CI_g all;yl)paminocarbonyl, and (aryl CI_g all~:yl)paminocarbonyl CI_6 alkyl;
or'R5 and RE~ are taken together with the carbon atom to which they are attached to form a carbonyl group, IO wherein any of the akyl groups of R~ or R~ are either unsubstituted or substituted with onEs to three RI substituents, and provided that each R~ and R6 are selected such that in the resultant compound the carbon atom to which R~ and R6 are attached is itself attached to no more than one heteroatom;
R~ and Rg are each independently selected from the group consisting of hydrogen, CI-10 a~Yh aryl, aryl-(CH2)r-C>-(CH2)s-v aryl-(CH2)rS(O)p-(CH~)s-, aryl-(CH2)y.-C(O)-(CH~,)s-, aryl-(CH2 )r-C-(C) )-N(R4 )-( CH2 )s-, aryl-(CH~)r-T!(R4)-C(O)-(CH2)s-9 2v aryl-(CH2)r.--Isf(R4)-(CH2)s-, halogen, hydroxyl, CI_g alkylcarbonylamino, aryl CI_5 alkoxy, CI_~ alkoxyca~rbonyl, (CI_g alkyl)paminocarbonyl, CI_g alkylcar'bonyloxy, C3_g cycloalkyl, (CI_g alkyl)parnino, amino C1_6 alkyl, arylaminocarbonyl, aryl CZ_~ alkylaminocarbonyl, aminocarbonyl, aminocarbon;yl C~_g alkyl, hydroxycarbonyl, hydroxycarbo~nyl C~_g alkyl, HC-C-(CH2)i;-, C1_g alkyl-C=:C-(CH2)t-, C3_7 cycloalkyl-C---C-(CH2)t-, aryl-C=_C-(CH2 )t-, C1_g alkylaryl-C-C-(CH2)t-, CH2=CH-(CFf2)t-, C1_g alkyl-CH=CH-(CH2)t-, C3_7 cycioalk;yl-CH=CH-(CH2)t.:, aryl-CH=CH-(CH2)t-, C1_~ alkylaryl-CH=CH-(CH2)t-, C~:g alkyl-SC~2-(CH2~-, C1_g alkylaryl-SC)2-(CH2)t-, C1_6 alkoxy, aryl C1_g alkoxy, aryl C1_6 alkyl, (C1_s alkyl)pamino C1_g alkyl, (aryl)pamino, 2~ (aryl)pamino C1_g alkyl, (aryl C1_6 alhyl)pamino, (aryl C1,_6 all~:yl)pamino C1_~ alkyl, arylcarbonyloxy, aryl C1_~ alkylcarbonyloxy, (C1_6 alkyl)p;aminocarbonyloxy, C1_g alkylsul.fonylamino, arylcarbonyl;amino, arylsulfonyla~mino, C~_g alkylsulfonylamino C1_6 alkyl, - 1'~ -arylsulfonyla~.mino C~_6 alkyl, aryl C1_g al~:ylsulfonylamino, aryl C~;_g alk:ylsulfonylamino C1_6 alkyl, C1_g alkoxyc;arbonylamino, G 1_g alkoxycarbonylamino C ~_g alkyl, aryloxycarbonylamino Cl_g alkyl, aryl Cx_g all~;oxycarbonylanuno, aryl C1_g alk.oxycarbonylamino C~_g alkyl, C~_g alkylcarbonylamino C~_g alkyl, arylcarbonylamino C 1_g alkyl, aryl C1_g alli:ylcarbonylamino, aryl C~_g alkylcarbonylamino C1_g alkyl, aminocarbonylamino C1_g alkyl, arylaminocarbonylamino, (C1_g alkyl)p~aminocarbonylamino, (C~_g alkyl~aminocarbonylamino C1_g alkyl, (aryl)paminocarbonylamino C~_g alkyl, (aryl C~_g allL~y1)pamir~.ocarbonylamxno, (aryl C1_g alliyl)paminocarbonylamino C1_g alkyl, aminosulfonylamino C1_s alkyl, (C1_g alkyl)paminosulfonylamino, (C1_g alkyl)paminosulfonylamino C~_g alkyl, (aryl)paminosulfonylamino C1_g alkyl, (aryl C1_g alll~yl)paminosulfonylamino, 2~ (aryl C~_g alkyl)paminosulfonylamino C~_s alkyl, C1_g alkylsulfonyl, C~_g alkylsulfonyl C~_6 alkyl, arylsulfonyl 4;1_g alkyl., aryl C 1_6 alkylsulfonyl., aryl C1_6 alkylsulfonyl C1_g alkyl, C1_g alkylcar~bonyl, C1_g alkylcarbonyl C1_g alkyl, arylcarbonyl C1_g alkyl, aryl C~_g alk;ylcarbonyl, - 1g -WO 00/06169 PC'T/US99/16830 aryl C 1_6 alk~;~lcarbonyl C 1_g alkyl, C1_g alkylthiocarbonylamino, C1_g alkylthiocarbonylamino C~_6 alkyl, arylthiocarbonylamino C~_g alkyl, aryl Cl_g alkylthiocarbonylamino, aryl C1_g alk;ylthiocarbonylamino C1_g alkyl, (C1_g alkyl)paminocarbonyl C1_6 alkyl, (aryl)paminocarbonyl C1_g alkyl, (aryl CI_g all;yl~aminocarbonyl, (aryl C1_g al~;yl)paminocarbonyl C~_g alkyl, and Cfi-20 Polycyclyl CO_g alkylsulfonylamino, wherein any of the :alkyl groups of Rfiand Rg are either unsubstituted or substituted with onE: to three R1 substituents, and provided that each Rfiand Rg are selected such that in the resultant compound the carbon atom to which Rfi and Rg are attached is itself attached to no more: than one heteroatom;
R9 is selected from the group consisting of hydrogen, C1_g alkyl, aryl r aryl Cl,_g alkyl, C1_g alkylcaxbonyloxy C1_4 alkyl, aryl C1_g alk~;~lcarbonylLoxy C1_4 alkyl, C 1_g alkylamunocarbonylmethylene, and C1_g dialkyla~mi.nocarbonylmethylene;
wherein 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;
each t is independently an integer from 0 to 3; and each v is independently an integer from 0 to 6;
and the pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
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 integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, diabetic retinopathy, macular degeneration, angiagenesis, and tamer growth and metastasis by administering the compounds and pharmaceutical compositions of the I~ present invention.
The present invention also relates to methods for treating osteoporosis by adnunistering the compounds and pharmaceutical compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The prE~sent invention relates to compounds useful as integrin receptor antagonists. Compounds of the present invention are described by the following chemical formula:
s Rs (;O 2~9 2~ ~7 'R8 wherein W is selected from the group consisting of a 5- or 6-membered monocyclic aromatic ar nonaromatic ring system having l, 2, 3 or 4 heteraatoms selected from the group - 2~ -consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one R1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R1 substituents, .and a 9- to 14-mernbered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 1, 2, 3 or ~l heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted wi'.th one R1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R1 substituents;
X is selected from the group consisting of -(CH2)v-, and -(CH2)~NR4(CH2~-; wherein any methylene (CH2) carbon atom, other than in R4, is either unsubstituted or substituted with one or two R~
substitutents;
Y is a biarylene ring system comprising 5- or 6-membered aromatic rings, wherein said biarylene system comprises 0-8 heteroatoms selected from the group consisting of N, O, and S wherein said biarylene ring system is either unsubstituted or substituted with one or more R1 substituents;
Z is selected from th.e group consisting of O O
-CNR4_ _NR4~C_ .

-CH~CH2- and -CH==CH-, wherein either carbon atom can be substituted by one or two R3 sub~stituents;
each R1 is independently selected from the group consisting of hydrogen, halogen, C1_10 alkyl9 C3_g cycloaikyl, WO 00106169 PCTlUS99/I6830 Cg_g cycloheteroalkyl, Cg_g cycloalkyl C1_6 alkyl, C3_g cyclohet,eroalkyl C1_6 alkyl, aryl; aryl C~_g alkyl; amino, amino C1_g alkyl, Cf_g acylamino, C1_3 acylamino C~_g alkyl, (C1_g aikyl)p,~mino,: (C1_g alkyl)pamino C1_g alkyl, C1_4 alkoxy, ~C1_4 alkoxy C1_s alkyl, hydroxycarbonyl, hydroxycarbonyl C 1,_g alkyl, C 1_3 alkoxycarbonyl, C1_3 alkoxycarbonyl C~-6 alkyl, hydroxycarbonyl-C1_g alkyloxy, hydroxy, hydroxy C1_g alkyl, C~_6 alkyloxy C1_s alkyl, vitro, cyano, trifluoromethyl, trifluoromethoxy, trifl.uoroetho~;y, C1_g alkyl-S{C))p, (C1_g alkyl)paminocarbonyl, C1_g aikyloxycarbanylamino, (C~_g alkyl)paminocarbonyloxy, (aryl C1_g all;yl)pamino, (aryl}pamino, aryl C1_g alkylsulfonyl;~mino, and C1_g alkylsulfonylamino;
or two R~ substitue:nts, 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, C1-10 a~Yh aryl-{CH2)r-C)-{CH2)s-, aryl-(CH2}rS( O)p-(CH~}s-~
aryl-(CH2)r-C(4)-(CH2)s-~
aryl-(CH2}r-C%(O)-N(R4)-(CH2)s-, aryl-(CH2)r-N{R4)-C{O )-(CH2)s-, aryl-(CH2)~.-N{R4)-(CH2}s-, halogen, hydroxyl, oxo, trifluoromethyl, C1_g alkylcarbonylamino, aryl C1_~ alkoxy, C1_5 alkoxycarbonyl, WO 00/06169 PCT/US99116$30 (C1_g alkyl)paminocarbonyl, C1_0 alkylcaribonylaxy, Cg_g cycloalkyl, (Cl_0 alkyl)pamino, amino C1_0 ailkyl, arylaminocarbonyl, aryl CI_5 alkylaminocarbonyl, aminocarbon;yl, aminocarbonyl C1_g alkyl, hydroxycarbonyl, hydroxycarbo~ayl CI_6 alkyl, HC=C-(CH2)tw, CI_g alkyl-C---~C-(CH2)t-, C3_7 cycloalkyl-C---C-(C:H2~-, I6 aryl-C=C-(CH2)t-, C1_g alkylaryl~:C=C-(CH2)t-, CH2=CH-(CH2~-, C1_6 alkyl-CH:=CH-(CH2~-, C3_fi cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(:CH2)t-, C~,_g alkylaryl.-CH=CH-(CH2)t-, CI_6 alkyl-SO;Z-(CH2}t-, C1_g alkylaryl-S02-(CH2)t-, C1_s alkoxy, aryl C1_s alkoxy, aryl C1_g alkyl, (CI_g alkyl)pamino C1_g alkyl, (aryl)pamino, (aryl)pamino C1_g alkyl, (aryl C1_s alk;yl)pamino, (aryl C1_g alk;yl)pamino C1_g alkyl, arylcarbonylo:xy, aryl Cl_g alkylcarbonyloxy, (C1_6 alkyl)pa.minocarbonyloxy, WO 00106169 PCTNS99116$30 C1_g alkylsulfonylamino;
arylsulfonyl;amino, C1_g alkylsulfonylamino C1_6 alkyl, arylsulfonylaimino CI~g alkyl, aryl C1_g all;ylsulfonylamino, aryl C 1_g alk.ylsulfonylamino C 1_s alkyl, Cl_g alkoxycarbonylamino, C 1_g alkoxyc.arbonylamino C 1_g alkyl, aryloxycarbo:nylamino C~_g alkyl, aryl C~_g all~:oxycarbonylamino, aryl C~_g alkoxycarbonylamino C~_g alkyl, C~_g alkylcaurbonylamino, C~_g alkylcarbonylamino C1_g alkyl, arylcarbonyl~~mino C1_g alkyl, aryl C1_g ali~:ylcarbonylamino, aryl C~,_6 alkylcarbonylamzno C1_6 alkyl, aminocarbonylamino C~_6 alkyl, (C1_g alkyl)pairiinocarbonylamino, (C1_g alkyl)paminocarbonylamino C1_6 alkyl, (aryl)paminocarbonylamino C1_g alkyl, (aryl C1_g alll~yl)paminocarbonylamino, (aryl C1_g allcyl)paminocarbonylamino C1_g alkyl, aminosulfonylamino C 1_g alkyl, (C~_g alkyl)paminosulfonylamino, (C1_g alkyl)paminosulfonylamino C1_6 alkyl, (aryl)paminosulfonylamino C1_g alkyl;
(aryl C1_g all':~yl)paminosulfonylamino, (aryl C1_g all~yl)paminosulfonylamino CZ_g alkyl, CI_g aikylsulfonyl, C1_g alkylsulfonyl C~_~, alkyl, arylsulfonyl (~1_g alkyl, aryl C 1_6 alkylsuifonyl, aryl C~_g alk;ylsulfonyl C1_s alkyl, C1_g aikylcar~bonyl, WO 00/061b9 PCTNS99/16830 C~_6 alkyicarbonyl C1_g alkyl, arylcarbonyi C1_6 alkyl, aryl C1_6 aikyicarbonyl, aryl C 1_g aik;ylcarbonyl C ~_6 alkyl, C 1_6 alkylthi,ocarbonylamino, C1_g alkylthiocarbonylamino C1_6 alkyl, arylthiacarbo;nylamino Cl_6 alkyl, aryl C1_0 alk.ylthiocarbanylamino, aryl C1_6 alk;ylthiocarbonylamino C1_6 alkyl, ZO (C1_g alkyl)p;aminocarbonyl C1_g alkyl, (aryl)paminocarbonyl C1_g alkyl, (aryl C1_g alkyl)pamin.ocarbonyl, and (aryl Cl_g ally;yl)paminocarbonyl C~_g alkyl;
or two R3 substituents, when on the same carbon atom are taken Z5 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 R1 substituents, and provided that each R8 is selected such that in the resultant compound the carbon atom or 20 atoms to which R3 is attached is itself attached to na mare than one heteroatom;
each R4 is independently selected from the group consisting of hydrogen, 25 aryl, aminocarbonyl, C3_g cycloalk;yl, amino C1_6 alkyl, (aryl)pamino~carbonyl, 30 (aryl C1_~ ally;yl)paminocarbonyl, hydroxycarbonyl C~_g alkyl, C1_8 alkyl, aryl C 1_g alkyl, (C1_g alkyl)pamino C2_0 alkyl, WO 00106169 PC'T/US99/16$30 (aryl CI_g allcyl)pamino C2_6 alkyl, C I_g alkylsul'.fflnyl, CI_g alkoxyc,arbonyl, aryloxycarbonyl, aryl CI_g alkoxycarbonyl, C1_g alkylcarbonyl, arylcarbonyl, aryl CI_6 alkylcarbonyl, (CI_g alkyl)paminocarbonyl, aminosulfon;yl, CI_g alkylanunosulfonyl, (aryl)paminosulfonyl, (aryl CI_g alkyl)paminosulfonyl, arylsulfonyl, I6 arylCl-6 alkylsulfonyl, C1_6 alkylthiocarbonyl, arylthiocarbonyl, and aryl CI_g alk;ylthiocarbonyl, wherein any of the alkyl groups of R4 are either unsubstituted or substituted with onE: to three RI substituents;
R~ and R6 are each independently selected from the group consisting of hydrogen, CI-IO a~yh 26 aryl, aryl-(CH2)r-U-(CH2)s-,~
aryl-(CH2)i.S(.O)p-(CH2)s-, aryl-(CH2)r-C;(C))-(CHZ)s-, aryl-(CH2~.-C:(O)-N(R4)-(CH2)s-, aryl-(CH2}x.-TT(R4)-C(O)-{CH2}s-, aryl-{CH2)r-rt(R4)-(CH2)s-, hal o gen, hydroxyl, C I_g alkylcarbonylamino, WO 00/06169 PC"T/US99116830 aryl C1_5 alkoxy, C 1_5 alkoxycarbonyl, (C~_g alkyl)p,aminocarbonyl, C1_g alkylcarbonyloxy, C~_g cycloall;:yl, (C1_g alkyl)pamino, amino Cl_s alkyl, arylaminoca:rb onyl, aryl C~_5 alk.ylaminocarbonyl, aminocarbonyl, aminocarbon;yl C1_g alkyl, hydroxycarbonyl, hydroxycarbcmyl C1_g alkyl, HC~C-(CH2)1,~ , l~ C1_6 alkyl-C=:C-(CH2)t-, Cg_7 cycloalkyl-C--_C-(CH2~-, aryl-C--C-(Cl: 2)t-, C1_g alkylaryl-C-C-(CH2)t-, CH2=CH-(C~t2)t-~
C1_6 alkyl-CH=CH-(CH2~-, C3_7 cycloalk;yl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2 )t-, C1_6 alkylaryl-CH=CH-(CH2)t-, C~_6 alkyl-S02-(CH2)t-, 2~ C1_g alkylaryl-S02-(CH2)t-, C 1_g alkoxy, aryl C1_g alkoxy, aryl C 1_ g alk~~l, (C1_6 alkyl)p~~rnino C1..6 alkyl, (aryl)pamino, (aryi)pamino C1_g alkyl, (aryl C1_g alh:yl)pamino, (aryl C1_g alk:yl)pamino C1_g alkyl, arylcarbonyloxy, _ 27 _ WO 00/06169 PC'T/US99/16830 aryl C1_g alk,ylcarbonyloxy, (C 1_g alkyl)paminocarbonyloxy, Cl_g alkylsulfonylamino, arylsulfonylamino, C1_g alkylsulfonylamino C1_g alkyl, arylsulfonylamino C1_g alkyl, aryl C1_g alk.ylsulfonylamino, aryl C1_6 alk;ylsulfonyl.amino C1_6 alkyl, C1_g alkoxycarbonylamino, C1_g alkoxycarbonylamino C1_g alkyl, aryloxycarbonylamino C1_g alkyl, aryl C1_g alkoxycarbonylamino, aryl C1_g alk~oxycarbor.~ylamino C1_g alkyl, C1_g alkylcarbonylamino, C1_g alkylcarbonylamino Cl_g alkyl, arylcarbonyl~unino C l..g alkyl, aryl C1_g alkylcarbonylamino, aryl C1_g alkylcarbonylamino C1_g alkyl, aminocarbonylamino C1_g alkyl, (C1_g alkyl)p;aminocarbonylamino, (C1_g alkyl~;~minocarbonylamino C1_g alkyl, (aryl)paminocarbonylamino C 1_g alkyl, (aryl C1_g alkyl)paminocarbonylamina, (aryl C1_g all;:yl)paminocarbonylamino C1_g alkyl, aminosulfonylamino C1_g alkyl, (C1_g alkyl)p;aminosulfonylamino, (C1_g alkyl}paminosulfonylamino C1_g alkyl, (aryl)paminosulfonylamino C1_g alkyl, (aryl C1_g all:yl)paminosulfonylamino, (aryl C1_g all;:yl)paminosulfonylamino C1_g alkyl, C 1_g alkylsuhfonyl, C1_g alkylsuli:onyl C1_~; alkyl, arylsulfonyl C:1_g alkyl, aryl C 1_g alkylsulfonyl, _ 28 aryl C1_g all;ylsulfonyl Cx_g alkyl, C1_g alkylcarbonyl, C1_6 alkylca:rbonyl C1_6 alkyl, arylcaxbonyl C1_g alkyl, aryl CI_g all;ylcarbonyl, aryl Cl_s alh;ylcarbonyl C1_6 alkyl, C1_g alkylth.iocarbonylami.no, C1_6 alkylthiocarbonylamino C1_6 alkyl, arylthiocarb~onylamino Cl_g alkyl, aryl C1_6 alliylthiocarbonylamino, aryl C1_g allcylthiocarbonylamino C1_g alkyl, (C1_g alkyl)l,aminocarbonyl C1_g alkyl, (aryl)paminocarbonyl C1_g alkyl, (aryl Cl~g al.kyl)paminocarbonyl, and 1~ (aryl C1_g alkyl)paminocarbonyl C1_s alkyl;
or R~ and RO are taken together with the carbon atom to which they are attached t;o form a carbonyl group, wherein any of the alkyl groups of R~ or R6 are either unsubstituted or substituted with orue to three R1 substituents, and provided that each R~ and R6 are selected such that in the resultant compound the carbon atom to which R~ and Rg are attached is itself attached to no more than one heteroatom;
R7 and R8 are each independently selected from the group consisting of hydrogen, C1-10 ~yh aryl, aryl-(CH2 )r-~-( CH2 )s-, aryl-(CH2)r'~(4)p-(CH2)s-, aryl-{CH~)r.-C(0)-(CH2)s-, aryl-(CH2~.-~C(O)-N(R4)-(CH2)s-~
aryl-(GH2)r-:N{R4)-C(0)-(CH2)s-, aryl-{CH2)r-.N{R4)-(CH2)s-~
halogen, WO 00106169 PCTlUS99lt6830 hydroxyl, C 1_g alkylcarbonylamino, aryl C1_~ allc;oxy, Cx_~ alkoxycarbonyl, (C1_g alkyl)l,aminocarbonyl, C1-6 alkylca~rbonyloxy, C3_g cycloalh;yl, (C1_6 alkyl)~,amino, amino C1_g alkyl, arylaminocarbonyl, aryl C1_~ alk:ylaminocarbonyl, aminocarbonyl, aminocarbonyl C1_g alkyl, hydroxycarbonyl, Z~ hydroxycarbonyl C~_6 alkyl, HC-C-(CH2~t-, C1_0 alkyl-C==C-(CH2)t-, C3_7 cycloalkyl-C--_C-(CH2~-, aryl-C-C-(C~:I2)t-, C1_6 alkylaryl-C-C-(CH2)t-, CH2-CH-(Cla2~-, C1_g alkyl-CH=CH-(CH2~-, C3_7 cycloalk;yl-CH=CH-(CH2~-, aryl-CH=CH-(CH2)t-, C ~_s alkylaryl-CH=CH-(CH2)t-, C1_g alkyl-502-(CH2~-, C1_6 alkylaryl-502-(CH2)t-, Ci_g alkoxy, aryl C1_g alkoxy, aryl C 1_g alkyl, (Cl,_g alkyl)pamino C~-6 alkyl, (aryl)pamino, (aryl)pamino C~_g alkyl, (aryl C~_g allc:yl)pamino, (aryl C1_0 alkyl~amino C1-g alkyl, aryl carbonyloxy, aryl C1_g alk,ylcarbonyloxy, (C1_g alkyl)paminocarbonyloxy, C1_g alkylsu~Lfonylamino, arylcarbonylamino, arylsulfonylamino, C1_g alkylsulfonylamino C1_g alkyl, arylsulfonylamino C1_g alkyl, aryl C1_g alk:ylsulfonylamino, aryl C1_g alk;ylsulfonylamino C1_g alkyl, C1_g alkoxycarbonylamino, C 1_g alkoxycarbonylamino C 1_g alkyl, aryloxycarbo~aylam:ino C1_g alkyl, aryl C1_g alkoxycarbonylamino, l~ aryl C1_g alk~oxycarbonylamino C1_g alkyl, C1_g alkylcarbonylamino C1_& alkyl, arylcarbonylamino Cl..g alkyl, aryl C1_6 alkylcarbonylamino, aryl C1_g alk;ylcarbonylamino C1_6 alkyl, aminocarbon;ylamino C1_g alkyl, arylaminocarbonylamino, (C1_g alkyl)paminocarbonylamino, (C1_g alkyl)p;aminocarbonylamino C1_g alkyl, (aryl)paminocarbonyla.mino C1_g alkyl, 2K5 (aryl C1_g alliyl~aminocarbonylamino, .(aryl C1_g all:yl)paminocarbonylamino C1_6 alkyl, aminosulfonylamino C1_g alkyl, (C1_g alkyl)paminosulfonylamino, (C1_g alkyl)p;aminosulfonylamino C~_6 alkyl, (aryl)pamino;sulfonylamino C1_g alkyl, {aryl C1_g all~yl)paminosulfonylamino, {aryl C1_g all:yl)paminosulfonylamino C1_g alkyl, Cl_g alkylsulfonyl, C1_6 alkylsuLfonyl C1_g alkyl, 3~ arylsulfonyl C1_6 alkyl, aryl C1_g all~ylsulfonyl, aryl C1_6 allcylsulfanyl C1_6 alkyl, C1_6 alkylcarbonyl, C1_g alkylcarbonyl C1_6 alkyl, arylcarbonyl C1_g alkyl, aryl C1_g all~;ylcarbonyl, aryl C1_6 all;:ylcarbonyl C1_g alkyl, C1_g alkylthiocarbonylamino, C1_g alkylthiocarbonylamino C1_g alkyl, arylthiocarbonylamino C1_g alkyl, aryl CI_0 alhylthiocarbonylamino, aryl C1_6 all;:ylthiocarbonylamino C1_0 alkyl, (C1_g alkyl)paminocarbonyl C1_6 alkyl, (aryl)paminocarbonyl C1_6 alkyl, (aryl C1_g alL~yl~aminocarbonyl, (aryl C1_g all~yl)pamixaocarbonyl C1_g alkyl, and C7_20 polycyclyl Cp_g alkylsulfonylamino, wherein any of the alkyl groups of R~and Rg are either unsubstituted or substituted with one to three R1 substituents, and provided that each R7and Rg are selected such that in the resultant compound the carbon atom to which R7 and Rg are attached is itself attached to no more than one heteroatom;
R9 is selected from the group consisting of hydrogen, C1_g alkyl, aryl, aryl C 1_g alkyl, C1_g alkylcaribonyloxy C1_4 alkyl, aryl C 1_g alkylcarboriyloxy C 1_4 alkyl, C1_g alkylaminocarbonylmethylene, and C 1_g dialkyia.minocarbonylmethylene;
wherein each p is independently an integer from 0 to 2;

WO 00/06169 PCTIUS99/16$30 each r is independently an integer from 1 to 3;
each s is independently an integer from 0 to 3;
each t is independently an integer from 0 to 3; and each v is independently an integer fram 0 to 6;

and the pharmaceutically acceptable salts thereof.
In the compounds of the present invention, ~V is preferably selected from the gz~oup consisting of R1 R~ R1 I /~ l N~~ , ~y N
H H ~ ' H N
, ~~ N
RyN
, and More preferably, W is selected from the group consisting of N ~~' N
C ~ RN _ f-~I H ~ ~.:
and .
Most preferably, ~V is selected from the group consisting of R' W N ~~ N
C , ~~-~- C
N
and H

WO 00106169 PC'T/US99/16830 In the compounds of the present invention, Y is preferably selected from the group consisting of t, ' ~ /
i \ /
l,, O
D D
D
\ a ;~ ~~ ' l ~,.~ ~~ a a 's o~
. , and S S .
More preferably, Y' is ~i \
Most preferably, Y :is ~r v r y_ D
such that the X moiety is attached at the variable position and the Z
moiety is attached art the pare position. In other words, in these preferred embodiments for Y, the X and Z substituents have the following orientation with respect to the biarylene maiety \ / \
In the compounds of the present invention, Z is preferably selected from the group consisting of O O
a n -CNR4- and -NR4C-.

WO 00/06169 PC"T/US99/16830 More preferably, Z is O

In the compounds of the present invention, RZ is preferably selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3_g cycloalkyl, Cg_g cycloheteroalkyl, hydroxy, vitro, cyano;
trifluoromethyl, and trifluoromethoxy.
More preferably, R1 is selected from the group consisting of hydrogen, halogen, C 1_ 10 alkyl, Cg-8 cycloalkyl, trifluoromethyl, and trifluoromethoxy.
In the compounds of the present invention, R3 is preferably selected from the group consisting of hydrogen, i5 fluoro, trifluorometh.yl, aryl, Cl_g alkyl, arylCl_g alkyl hydroxyl, oxo, arylaminocarbonyl, aryl Cl_~ alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1_g alkyl.
More preferably, R3 is selected from the group consisting of fluoro, aryl, C~_g alkyl, arylCl_6 alkyl hydroxyl, oxo, and WO 00106169 PCTlUS99/16830 arylaminoc;arb onyl.
In the compounds of the present invention, R4 is preferably selected from the y;roup consisting of hydrogen, aryl, C3_g cycloala~yl, C 1_g alkyl, C1_g alkylcaxbonyl, 1(~ arylcarbonyl, C1-6 ~ylsu~lfonyl, arylsulfonyl, arylCl_salkylsulfonyl, arylC 1_galkylcarbonyl, C1_galkylanuinocarbo:nyl, arylCl_~alks;~laminocarbonyl, arylCl_galkoxycarbonyl, and C Z_galkoxyc;arb onyl.
2d More preferably, R4 is selected from the group consisting of hydrogen, C1_g yl, C 1_g alkylca~rbonyl, arylcarbonyl, 25 arylCl_galkylcarbonyl., C 1_g alkylsulfonyl, arylsulfonyl, and arylC 1 _galkylsulfonyl.
In one embodiment of the present invention, R~ and R6 are 30 each independently selected from the group consisting of hydrogen, aryl, C1_g alkyl, aryl-C--_C-(C~i2>t-, 35 aryl C I,_g alk:yl, _ g6 _ CH2=CH-(C132)t-, and HC-_-_-C-(CH2',~t-.
In a class of this embodiment of the present invention, R6 is hydrogen and R~ is selected from the group consisting of hydrogen, aryl, C 1_g alkyl, aryl-C=C-(C132)t-, aryl C 1_g alkyl, CH2=CH-(CI32)t-, and HC---C-(CH2)t--In a subclass of this class of the present invention, R~, R7, and Rg are each hydrogen and R~ is selected from the group consisting of hydrogen, aryl, C1_g alkyl, aryl-C-C-(CH~)t-, aryl C ~_6 alkyl, CH2=CH-(CH2~-, and HC---C-(CH2)t-.
In another embodiment of the present invention, R7 and Rg are each independently selected from the group consisting of hydrogen, aryl, C I,_g alkylca,rbonylamino, C1_g alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C1_g alkylsul.fonylamino C1_~ alkyl, arylsulfonyla.mino CI_g alkyl, aryl C1_~ alk:ylsulfonylamino, aryl C1_g alkylsulfonylamino C1,_6 alkyl, C 1_g alkoxycarbonylamino, - 3'7 -C 1_g alkoxycarbonylamino C 1_g alkyl, aryloxycarbonylamino C1_g alkyl, aryl C1_g alhoxycarbonylamino, aryl C1_g alk:oxycarbonylamino C1_g alkyl, C1_g alkylcarbonylamino C1_g alkyl, arylcarbonyl,amino C1_0 alkyl, aryl C1_6 al~;ylcarbonylamino, aryl C1_6 alkylcarbonylamino C1_g alkyl, aminocarbonylamino C1_g alkyl, (C1_g alkyl)p,aminocarbonylamino, (C1_g alkyl)paminocarbonylamino C1_g alkyl, (aryl)paminacarbonylamino C 1_6 alkyl, arylaminoca:rbonylamino, (aryl C1_g all'':~yl)paminocarbonyiamino, (aryl C1_g alkyl)paminocarbonylamino C1_g alkyl, aminosulfonylamino C1_g alkyl, (C1_g alkyl)paminosulfonylamino, (C1_g alkyl)p;aminosulfonylamino C1_g alkyl, (aryl)pamino;~ulfonylamino C1_g alkyl, (aryl C1_g alkyl)paminosulfonylamino, (aryl C1_g alh;yl)paminosulfonylamino C1_g alkyl, C1_g alkylthiocarbonylamino, C1_g alkylthi~acarbonylamino C1_6 alkyl, arylthiocarbo:nylamino C 1_g alkyl, aryl C 1_6 alkylthiocarbonylamino, aryl C1_6 alkylthiocarbonylamino C1_g alkyl, and C7_20 polycyclyl CO_g alkylsulfonylamino.
In a class of iihis embodiment of the present invention, Rg is hydrogen and R7 is selected from the group consisting of hydrogen, aryl, C1_g alkylcarbonylamino, aryl C1_6 alkylcarbonylamino, WO 00/06169 PGT/U59911b830 arylcarbonylamino, C 1_g alkylsu.lfonylamino, aryl C1_g allcylsulfonylamino, arylsulfonyl;amino, CI,_g alkoxyc;arbonylamino, aryl C1_g all.;oxycarbonylamino, arylaminocarbonylamino, (C~.:g alkyl)I,aminocarbonylamino, (aryl C1_g al:kyl)paminocarbonylamino, (C~_g alkyl)paminosulfonylamino, and (aryl CI_g a;~Lkyl)paminosulfonylamino. , In a subclass of this class of the present invention, R~, Rs; and Rg are each hydrogen and R'~ is selected from the group consisting of hydrogen, aryl, C1_g alkylcarbonylamino, aryl C1_g alk.ylcarbonylamino, arylcarbonylamino, C1_g alkylsu~Lfonylamino, aryl Cl_6 alkylsulfonylamino, arylsulfonylamino, C1_g alkoxyc,arbonylamino, aryl CZ_g alkoxycarbonylamino, 2~ arylaminoca~.~bonylamino, (CI_g alkyl)paminocarbonylamino, (aryl CI_g alkyl~aminocarbonylamino, (C1_g alkyl)I,aminosulfonylamino, and (aryl C1_g alkyl)paminosulfonylamino.
In the nompounds of the present invention, R9 is preferably selected from the group consisting of hydrogen, methyl, and ethyl.
More preferably, R9 is hydrogen.
Preferably, in the compounds of the present invention, each v is independently an integer from 0 to 2.
_ 3g _ WO Ofl/fl6169 PCT/US99/1683fl Illustrative but nonlimiting examples of compounds of the present invention that are useful as integrin receptor antagonists are the following:
3'-[N-( 3,4,5, 6-tetrahydropyrimidin-2-yl )amino]biphenyl-4-carbonyl-2( S )-phenylsulfonylami:no-~i-alanine, 3'-[N-(5,6,7,8-tetrahydro-[1,8]napthyridin-2-yl]amino] biphenyl-4-carbonyl-2{S)-phen;ylsulfonylamino-(3-alanine, 2(S)-phenylsulfonylamino-3-{4-[4-( 1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-thiophen-2-yl]-benzoylamino}-propionic acid, 2(S)-phenylsulfonylamina-3-((5-[3-(1H-benzoimidazol-2-ylamino)-phenyl]-pyridine-2-carbonyls}-amino)-propionic acid, 2(S)-phenylsulfonylamino-3-~4-[4-( 1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-furan-2-yl'~]-benzoylamino}-propaonic acid, 2(S)-phenylsulfonyl amino-3-{[4'-( 1H-imidazol-2-ylamino)-[2,2']bithiophenyl-5-carbonyl.]-amino}-propionic acid, 2(S)-phenylsulfonylamina-3-( (4-[3-( 1H-benzoimidazol-2-ylamino)-phenyl]-1H-pyrazole-3-carbonyl}-amino)-propionic acid, 2(S)-phenylsulfonylamino-3-({5-[5-( 1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-thiaphen-:2-yl]-furan-2-carbonyl}-amino)-propionic acid, and 3'-[N-pyrimidin-2-yl-amino]biphenyl-4-carbonyl-2(S)-phenylsulfonylamino-propionic acid;
and the pharmaceutically acceptable salts thereof.
_40_ WO OU/06I69 PCT/US99IIb830 For u.;e 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, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, ed.etate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydt~obromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, Iactobionate, Iaurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mutate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonatf:), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
2U Furthermore, where the compounds of the invention 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 ligands, e.~;., quaternary ammonium salts.
The compounds of the present invention can have chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, diast~ereomeric mixtures, and individual diastereomers, with all isomeric 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 described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

WO 00/06169 PCTlUS99/16$30 Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers.
Such an example m.ay be a ketone and its enol form, known as keta-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 diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate ar a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by the use of am 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 materials 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 pradrugs will be functional derivatives of the compounds of this invention which are readily convertible .in viuo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering'°
shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed; but which converts to the specified compound in viuo after administration to the patient. Conventional procedures for-the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated 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 medicail response of a tissue, system, animal or human that is being sought by <~ researcher or clinician.

The team "integrin receptor antagonist," as used herein, refers to a compound which binds to and antagonizes either the av(33 receptor, the av~35 receptor, or the av~36 receptor, or a compound which binds to and antagonizes combinations of these receptors (for example, a dual av[33/av(35 receptor antagonist).
The team "bone resorption," as used herein, refers to the process by which o.>teoclasts 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 within 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 rings of alkanes of three to eight total carbon atoms, or any number within 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 heterocyclic ring containing one or two heteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groups include, but; are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.
The term "alkoxy," as used herein, refers to straight or branched chain alk:oxides of the number of carbon atoms specified (e.g., C1_5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc. ).
The team "aryl," as used herein, refers to a monocyclic or polycyclic system comprising at least one aromatic ring, wherein the monocylic or polycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherein the monocylic or polycylic system is either unsubstitute:d or substituted with one or more groups independently selected from hydrogen, halogen, C1_g alkyl, C3_g WO OOI06i69 PCTlUS99116830 cycloalkyl, aryl, ary?l C1_~ alkyl, amino, amino C1_g alkyl, C1_3 acyiamino, C1_3 acylamino C1_g alkyl, CZ_g alkylamino, C1_g alkylamino C1-6 ~Yl> ~(C1-6) alkylamino, di(C1_g) alkylamino-C1_g alkyl, C~_4 alkoxy, C~_4 alkylth.io, C1_4 alkylsulfinyl, C1,_4 alkylsulfonyl, C1~ alkoxy Cx_s alkyl, hydroxycarbonyl, hydroxycarbonyl C1_6 alkyl, C1_~
alkoxycarbonyl, C~_,g alkoxycarbonyl C1_g alkyl, hydroxycarbonyl C1_6 alkyloxy, hydroxy, hydroxy C1_g alkyl, cyano, trifluoromethyl, oxo or CI_~ alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimi~dazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl, dihydrobenzo.E'uryl, benzo(1,3)dioxolanyl, benzo(1,4)dioxanyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C1_~ alkyl, C3_g cycloalkyl, aryl, aryl C1_3 alkyl, amino, a~mi.no C1_g alkyl, C~_~ acylamino, C1_~ acylamino C1_ g alkyl, C1_6 alkylamino, C1_0 alkylamino C1_6 alkyl, di(C~_g) alkylamino, di(C1_6) alkylamino-C1_g alkyl, C~_4 alkoxy, C~_4 alkylthio, C1_4 alkylsulfinyl, t;~_4 alkylsulfonyl, C~_4 alkoxy C1_g alkyl, hydroxycarbonyl, hydroxycarbonyl C1_6 alkyl, C~_~ alkoxycarbonyl, C1_3 alkoxycarbonyl C1_f; alkyl, hydroxycarbonyl C1_g alkyloxy, hydroxy, hydroxy C1_g alkyl, cyano, trifluoromethyl, oxo or CI_~ alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-, tri- substituted with one to three of the above-named substituents; more preferably, the aryl group is unsubstituted, mono- or di-substituted with pane to two of the above-named substituents.
The texxn "biarylene" as used herein refers to a nonfused (as opposed to a fused), bicyclic ring system. The biarylene system is incorporated into th,e molecules of the present invention through two connectivity or bonding points.
The biarylene system comprises two aromatic ring systems, wherein each of the aromatic ring systems is a 5- or 6-me~nbered aromatic ring system. The biarylene sytem comprises 0-6 heteroatoms selected from the broup consisting of N, ~, and S. The biarylene system can be either unsubstituted or substituted with one or more Rl WO 00/06169 PC'TNS99/16830 substituents. The t,wo aromatic ring systems of the biarylene system can be the same or different. Nanlimiting examples of biarylene systems useful herein include those selected from the group consisting of / "i~
i \ /
/ v ~O ~-~ ~ '..S v > >
1 ~,~ ~< 1 I
S o , and S S, Whenever the term "alkyl" or "aryl" or either of their prefix roots appears in a name of a substituent (e.g., aryl Cp_g alkyl), it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated :numbers of carbon atoms (e.g., C1_g) shall refer independently to thc: number of carbon atoms in an alkyl ar cyclic alkyl moiety or to the alk~;~l 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, chlorabenzyl, phenylethyl, phenylpropyl, fluoraphenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and th:ienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, 2~ ethylpyridine, propylpyridine and butylpyridine.
In the compounds of the present invention, two R2 substituents, when on the sarne carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group.
The term "halogen" shall include iodine, bromine, chlorine, and fluori:~ne.

WO 001061b9 PC'TlUS99/16830 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=D."
The ten~n "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 termainai portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Fox example, a C1_~ alkylcarbonylamino C1_0 alkyl 1~ substituent is equivalent to O
li -C ~ _e alkyl-N H-C-C 1 _5 alkyl .
In choosing compounds of the present invention, one of ordinary skill in the: art will recognize that the various substituents, i.e.
W, X, Y, Z, Rl, R2, R~, R4, R~, R6, R7, R8, and R9 are to be chosen in conformity with well-known principles of chemical structure connectivity.
Representative compounds of the present invention typically display submicromolar a#~nity for the integrin receptors, particularly the av[33, av~35, and,~or av[36 receptors. Compounds of this invention are therefore useful for treating mammals suffering 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 osteociasts.
The compounds of the present invention are administered in dosages effective ~to antagonize the avJ33 receptor where such _ qb _ WO 00/06169 PC'T/US99116830 treatment is needed, as, for example, in the prevention or treatment of osteoporosis.
Illustrating the invention is the method wherein the integrin receptor antagonizing effect is an av(33 antagonizing effect.
More particularly, tlhe av(33 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, inflammatory arthritis, viral disease, tumor growth, or metastasis. In one embodiment of the nnethod, the av~33 antagonizing effect is the inhibition of bone resorption.
Another example of the invention is the method wherein the integrin receptor antagonizing effect is an av(35 antagonizing effect.
More specifically, the av(35 antagonizing effect is selected from inhibition of restenosis, angiot;enesis, diabetic retinopathy, macular degeneration, inflammation, tumor growth, or metastasis.
Further illustrating the invention is the method wherein the integrin receptor antagonizing effect is a dual av(33/av[35 antagonizing effect. More particularly, the dual av~33/av~35 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis.
Even further illustrating the invention is the method wherein the integrin. receptor antagonizing effect is an av~i6 antagonizing effect. More particularly, the av(36 antagonizing effect is selected from inhibii'cion of angiogenesis, inflammatory response, or wound healing.
More p~~°ticularly illustrating the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a prose;>s for mal~ing a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
_47_ Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of an integrin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above. P~.°eferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, cancer, tumor growth, and metastasis. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.
Mare specifically exemplifying the invention is a method of eliciting an integrin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of th;e compounds or any of the pharmaceutical compositions described above. Preferably, the integrin antagonizing effect is an av~i3 antagonizing effect; more specifically the av(33 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherasclerosis, inhibition of angiogenesis, inhibition of diabetic retinapathy, inhibition of macular degeneration, inhibition of inflammation, inhibition of inflammatory arthritis, inhibition of viral disease, or inhibition of tumor growth or metastasis. Most poeferably, the av(33 antagonizing effect is inhibition of bone resorptian. Alternatively, the integrin antagonizing effect is an av(35 antagonizing effect, an av~36 antagonizing effect, or a mixed av~i3, av(35, and av~36 ant;~gonizing effect. Examples of av(35 antagonizing effects are inhibition of restenosis, atherosclerasis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, or tumor growth. Examples of av~iS antagonizing effects are inhibition of angiogenesis, inflammatory response, and wound healing.
Additional examples of the invention are methods of inhibiting bone resorptian 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 decribed above.
_ 48 WO 00/06169 PCf/US99/16830 Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumataid arthxxtis, 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 bane resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, inflammatory arthritis, viral disease, and/or angiogenesis.
Also exemplifying the invention are compositions of the integrin antagonists 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} a cytotoxicJantiproliferative agent, d) a matriix metalloproteinase inhibitor, e} an inhibitor of epidermal-derived, fibroblast-derived, or -platelei; derived growth factors, f) an inhibitor of VEGF, g) an inhibitor of Flk-1~KDR, Flt-1, Tck/Tie-2, or Tie-1, h) a cathepsin K inhibitor, i) an inhibitor of osteoclast proton ATPase, and j ) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranyigeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor;
and mixtures thereof.

(See B. Millauer et ~~1., "Dominant-Negative Inhibition of F'lk-I
Suppresses the Growth of Many Tumor Types in Viuo"; Cancer ese rch, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety).
Preferaibly, 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 inhibitor of o steoclast proton ATPase, and d) a cathepsin K inhibitor; and mixtures thereof.
Nonlimiting examples of such bisphosphonates include alendronate, etidronate, pamidronate, risedronate, ibandranate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially alendronate monosodium trihydrate.
Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.
Nonlimiting examples of cytotoxic/antiproliferative agents are taxol, vincristinn, vinblastine, and doxorubicin.
Cathepsin K, formerly known as cathepsin 02, is a cysteine protease and is described 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, arthritis, 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.
The proton ATPase which is found on the apical membrau~e 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. Farina et al., "Selective inhibitors of ~ the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents," DDT, 4: 16~~-172 ( 1999)).
The prE~sent invention is also directed to combinations of the compounds of the p~.~esent invention 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 in combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, a cathepsin K
inhibitor, or an inhibitor of the osteoclast proton ATPase.
Additional illustrations of the invention are methods of treating tumor gromth or metastasis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound described above and one or more agents known to be cytotoxic/antiproliferative. Also, the compounds of the present invention can be administered in combination with radiation therapy for treating tumor grov~~th and metastasis.
In addition, the i.ntegrin ocv(33 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 irr~prove the balance between resorption and formation, reduce bone loss o:r 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: o,cteoporosis (including estrogen deficiency, immobilization, gluc:ocorticoid-induced and senile); osteodystrophy, Paget's disease, myositis ossificans, l3echterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, cholelithiasis, neph~rolithiasis, urolithiasis, urinary calculus, _51_ hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany. Increased bone resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by thi,> 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 avj33 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably alendronate monosodium trihydrate.
In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during 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 "administeri.ng" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention vfrith other agents useful for treating iintegrin-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosiis.
As used herein, the term "composition' is intended to encompass a product comprising 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 suc:h 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), intraperitoneal, 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 WO 00/06169 PCTlUS99/I6830 arts. An effective but non-toxic amount of the compound desired can be employed as an av~33 antagonist.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety 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 empaoyed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest 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/k.g/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 mast preferred doses will range from about 0.1 to about 10 mg/kg/rninute during a constant rate infusion.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in diviided doses of two; three or four times daily.
Furthermore, prefeixed compounds for the present invention can be administered in into~anasal form via topical use of suitable intranasal vehicles, or via trar.~sdermal :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 anethods of the present invention, the compounds herein described indetail can form the active ingredient, and are _ 5~ _ typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as °carriex' materials) suitably selected with respect to the intended farm 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 carrier 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 carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweetE;ners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium. chloride and the like. Disintegrators include, without linutation, starch, methyl cellulose, agar, bentomite, xanthan gum and t:he like.
The compounds ~of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be farmed from a variety of phospholipids, such as cholesterol, stea~rylamine or phosphatidylcholines.
Compovunds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also Vibe coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-pihenol, or :polyethyleneoxide-polylysine substituted WO 00/06169 PC'TJUS99I16830 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, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilan caprola<aane, pol,~yhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
In the ~5chemes and Examples below, various reagent lfl symbols and abbreviations have the following meanings:
AcOH: Acetic acid.

BH3 DMS: Borane dimethylsulfide.

BOC(Boc): t-Butyloxycarbonyl.

BOP: Benzotriazol-1-yloxytris(dimethylamino)-p~hosphonium hexafluorophosphate.

CBZ(Cbz): C:arbobenzyloxy or benzyloxycarbonyl.

CDI: Carbonyldiimidazole.

CH2Cl2: Methylene chloride.

CH3CN Acetanitrile CHCIg: Chloroform.

DEAD: Lliethyl azodicarboxylate.

DIAD: Lliisopropyl azodicarboxylate.

DIBAH or DIBAL-H: Lliisobutylaluminum hydride.

DIPEA: Diisopropylethylamine.

DMAP: 4-Dimethylaminopyridine.

DME: 1,2-Dimethoxyethane.

DMF: Dimethylf~rmamide.

DMSO: Dimethylsulfoxide.

DPFN: 3,5-Dimethyl-1-pyrazolylformamidine nitrate.

EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl EtOAc: Ethyl acetate.

EtOH: Ethanol.

HOAc: Acetic acid.

_ 55 _ HOAT: L-I3ydroxy-7-azabenzotriazole HOBT: L-Hydroxybenzotriazole.
HPLC: High-performance liquid chromatography.
IBCF: Isobutylchloroformate LDA: Lithium diisopropylamide.
MeOH: llllethanol.
MNNG .1,1-methyl-3-vitro-1-nitrosoguanidine NEt~: ~.'riethylamine.
NMM: I'~-methylmorpholine.
PCA~HCl: Pyrazole carboxamidine hydrochloride.
Pd/C: Palladium on activated carbon catalyst.
Ph: Phenyl.
PyCLU: C;hloro-N,N,N',N'-~tetramethylene)-formamidinium hexafiuorophosphate.
pTSA p-Toluenesulfonic acid.
TEA: Triethylamine.
TFA: Trifluoroacetic acid.
THF: Tetrahydrofuran.
TLC: Thin Layer Chromatography.
TMEDA: N,N,N',N'-Tetramethylethylenediamine.
TMS: ~'rimethylsilyl.
The novel compounds of the present invention can be prepared according to the procedure of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the coruditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
The following Schemes and Examples describe procedures for making representatiive compounds of the present invention. Moreover, by utilizing the procedures described in detail in PCT International Application Publicaizon Nos. W095/32710, published 7 December 1995, and W095/17397, published 29 June 1995, both of which are incorporated by reference herein in their entirety, in conjunction with the disclosure contained herein, one of ordinary skill in the art can reaclily prepare additional compounds of the present invention claimed herein.
Additionally, for a general review describing the synthesis of (3-alanines which can be utilized as the C-terminus of the compounds of the present invention, see Cole, D.C., Recent Stereoselective Synthetic Approaces to ~3 Amino Acids, Tetoahedron, 1994, ~0, 9517-9582; Juaristi, E, et al. , Enantaoselective Synthesis of J3-Amino Acids, Aldrichimica Acta, 1994, 27, 3. In particular, synthesis of the 3-methyl-(3-alanine is taught in Duggan, M.F. et al., J. Med. Chem., 1995, ,~$, 3332-3341; the 3-ethynyl-j3 alanine is taught in Zablocki, J.A., et ., J. Med. Chem., 1995, 38, 2378 2394; the 3-(pyridin-3-yl)-~3-alanine is taught in I~,ico, J.G. ,ell., J. Org.
Chem., 1993, ~$, 799E8-7951; and the 2-amino- and 2-tosylamino-~i-alanines are taught in Xue, C-B, ~t al., Biorg. Med. Chem. Letts., 1996, 6 339-344. The references described in this paragraph are all also incorporated by reference herein in their entirety.
_ 57 _ WO OOI061b9 PC'TlUS99/1b830 Br ~ ~ CO2CH3 ~ \ ~2 02N / g(OH)2 Pd(PPh3)4 2M Na2C03 1-1 toluene, 80°C
/ 10% Pd/C, H2 02N ~ I \~ ~-~.~.
/ E~tOH
CO~CH3 \ 6N HCI, 60°C
H2N a ~ w ~N
N Br HCI ~ H2N I j O
sealed tube ~C02H N 180°C
TFA
t CO Bu N / HC!~ H2N ~, 2 i~ \ ~ \ H NHS02Ph N H I . 1~8 ~ C02H gpP, NMM, DMF
_ 58 _ WO 00/06169 PCTlUS99/16$30 SCHEME 1 (CONT.) ~N
N N NHS02Ph H N 1. TFA J CH2C12 C02tBu 2. 10% Pd/C, H2 O
HC;I / AcOH, .L ~ 60 psi °N
N N NHS02Ph H H
~N

O
3'-Nitro-bi henvl-4-c~"~rboxylic acid methyl ester (1-3) To a stirred solution of ~-2 {2.58 g, 12.0 mmol) and Pd(PPh3)4 (416 mg, 4.32 mmol) in toluene (25 mL) under 1 atm argon was added 2M Na2C'03 (12.5 mL, 25 mmol) followed by 1~1 {2.4 g, 14.4 mmol) dissolved in C;H,~OH (5 mL). The mixture was heated to 80°C for 3.0 hours. The reaction was allowed to cool to ambient temperature and then 2M Na2C03 (617 mL, 120 mmol) and CH2C12 (150 mL) were added.
The organic portion was separated, dried (MgS04) and concentrated.
Flash chromatography {silica gel, CHCI3) gave ~ as a white solid.
TLC Rf = 0.71 (silicai gel, 40% EtOAc/hexanes).
1H NMR (300MHz, C;D30D) ~ 8.51 {s, 1H), 8.27 (dd, J=2.2, 8.2 Hz, 1H), 8.18 {d, J=8.3 Hz, 2I~:), 7.97 (d, J=7.5 Hz, 1H), 7.66 (m,3H), 39.8 (s,3H).
3'-Amino-biphenyl-4~-carboxylic acid methyl ester ( 1-4) A mixture of 1~3 (1.6 g, 6.2 mmol) and 10% Pd/carbon (1.0 g) in EtOH (100 mL) was stirred under a balloon of hydrogen for 1.0 hour.
_ 59 WO OOI06169 PC'T/US99/16830 Filtration and evaporative removal of the solvent provided 1"-4 as a white solid.
TLC Rf = 0.13 (silic;~. gel, 25% EtOAc/hexanes).
1H NMR (300MHz,1~D30D) h 8.05 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.23 (t, J=7.6 Hz, 1H), ?.07 (m, 2H), 6.81 (dd, J=1.0, 7.8 Hz, 1H), 3.92 (s,3H).
3'-Amino-bighenyl-4-carboxvlic acid hydrochloride (1-5) A mixtvure of 1~4 (500 mg, 2.20 mmol) and 6N HCl (50 mL) was heated at 60°C jPor 20 h. Evaporative removal of the solvent provided 1-~ (530 mg, 96%) a~~ a white solid.
1H NMR (300MHz, CD30D) 5 8.I5 (d, J=8.6 Hz, 2H), '1.78 (m,3H), 7.66 (t, J=8.0 Hz, 2H), ?.41 (d, J='l.8 Hz, 1H).
3'(Pvrimidin-2-vl-amino)-biphenyl-4-~arboxvlic acid trifluoroacetate (1 7) A solution of 1-55 (f00 mg, 2.80 mmol) and bromide 1~6 (446 mg, 2.80 mmol) in 1~-methyl-2-pyrrolidinone (6 mL) was heated at 180°C
in a sealed tube for 0.5 hour. The cooled reaction mixture was purified by preparative HPLC (95:5:0.3. then 30:70:0.1 H2O/ CH3CN/ TFA) to afford 1~? as a brown solid,.
1H NMR (300MHz, (~D30D) b 8.46 (d, J=4.9 Hz, 2H), 8.11 (d, J=6.6 Hz, 2H), 8.02 (m, 1H), 7.'75 (d, J=8.8 Hz, 2H), 7.68 (m, 1H), 7.41 (m, 2H), 6.85 (t, J=4.9 Hz, 1H).
3'(Pvrimidin-2 yl-amino)-biphenyl-4-car~onvl-2~~)-phenYlsulf nvlamimo- -alanime tert-butyl ester. (1-9) A mixture of 1-77 (150 mg, 0.370 mmol), 1=88 (125 mg, 0.370 mmoi) (for preparation, see patent application WO 95/32710 which published on Dec. 7, 1995), BC>P (164 mg, 0.370 mmol), and NM1VI (0.204 mL, 1.85 mmol) in I~MF (3 mL) was stirred for 72 hours. The mixture was diluted with ethyl acetate, washed with H2O, sat. Na2C03 , brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, T5% EtOAc/hexanes) to give 1-,~ as a brown solid.
TLC Rf = 0.32 (silica gel, 75% EtOAc/hexanes).
_ 6p 1H NMR (300MHz, CD30D) 5 8.44 (d, J=4.6 Hz, 2H), 8.03 (s, 1H), 7.86 (d, J=8.3 Hz, 4H), 7.?1(~m, 3H), ?.30-?.55 (m, 5H), 6.80 (t, J=4.9 Hz, 1H), 4.I7 (m, 1H), 3.71 (m, 1~3~), 3.54 (m., 1H), 1.25 {s, 9H).
3'-fN-(3 4,5,6-tetrahydropyrimidin-2-vI)aminolbiphenvl-4-carbonyl 2( ) ~henvlsulfon3rlamino- -al nin 1-1 A solution of 1~- (175 mg, 0.305 mmol), TFA (3 mL) and CH2C12 (3 mL) was stirred at ambient temperature for 3.0 hours. The reaction was concentrated and then azeotroped with toluene (3 x 10 mL).
20 The residue was dissolved in 5:1 AcOH/ HCl (36 mL). 10% Pd/C (150 mg) was added and the mixture was shaken under 62 psi of hydrogen gas for 2.0 hours. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 10:1:1 EtOH/ NH40H/ H20) t0 give 1-1() aS a cOlorlesS oil.
TLC R =0.1? (silica ~;el, 10:1:1 EtOH/ NH40H/ H2O}
1H NMR (300MHz, (JD30D) fi 7.86 (d, J=8.5 Hz, 4H), 7.73 (d, J=8.3 Hz, 2H), ?.64 (m, 1H), 7..42 - ?.59 (m, 5H), 7.28 (d, J=?.8 Hz, 2H), 4.23 (m, 1H), 3.55 (m, 1H), 3.41 {t, J=1H), 2.02 (m, 2H).

SCHElVIE A
.thesis of Radioli~and for SPA Assav H~N~~~C02H
O H~~~NH2 i-~\ ~ S02C1 NaOH, ~ioxane Hz0 H2N~~~C02H
O H~'HN~..SO

\I
1. Br2, NaOH, 2. HCI

62 _ WO 00/06169 PC'fiUS99/16830 SCHEME A, cont'd.
~C02H
HzN ,,~°
H HN~SO

A_3 / 0 !
HCI
EtOH
HC!~HzN~COzCH2CH3 H' HN-.SO
z I
\~C02CH2CH3 %N
hi2N
Hz~
~~p0 EtOH
I \
r HzN N

WO 00!06169 PCTIUS99l1G830 SCHEME A. cont'd HCi~H2N N~
p_g / C02H

HCI~H2N ~,. EDC, HOST, H HNS02C~H4! NMM, DMF
I

H
H N N .,,~N H
~CO~CH~CHa O

6 0° C / I
O~S
H ,ooeN H

WO 00/06!69 PC'T/US99/I6830 (CH3Sn)2, Pd(PPh~)4, ~'w~cane, 90° C / I Sn(CH3)s H .,,.N H

H ' N-(4-Iodo~henylsu.ifonvlamino)-L-asp~ragine (A-2) To a stirred solution of acid A-I (4.39 g, 33.2 mmol), NaOH
(1.49 g, 37.2 mmoi), dioxane (30 ml) and H20 (30 ml) at 0°C was added pipsyl chloride (10.34 g, 34.2 mmol). After ~5 minutes, NaOH (1.49, 37.2 znmol), dissolved in 15 mI H20, was added followed by the removal of the cooling bath. After 2.0 h, the reaction mixture was concentrated. The residue was dissolved in H20 (300 mi) 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 Et20 to provide acid A-2 as a white solid.
1H NMR (300 MHz, D20) 8 7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz) 3.70 (m, 1H), 2.39 (m, 2H).
2(S)-(4-Iodo-,the-nvlsulfonvlamino)-~~-alanine (A-3) To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H20 (40 ml) at 0°C was added Br2 (1.30 ml, 24.9 mmol) dropwise over a ten minute period. After ~5 min.utes, acid ~-2 (9.9 g, 24.9 mmol), NaOH
(2.00 g, 49.8 mmol) and H20 (35 mi) were combined, cooled to 0°C and then added in a single portion to the reaction. After stirring for O

20 minutes at 0°C, t;he 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 HCI. '.Che solid was collected, washed with EtOAc, and then dried in uacuo ~to provide acid Ate- as a white solid.
1H NMR (300 MHz, _D20) 8 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.36 (m, 1H), 3.51 (dd, 113L, J=SHz, l3Hz) 3.21 (m, 1H).
Ethyl 2(S)-(4-iodo-~henvlsulfonvlamino)- i~-alanine-h d~ rochloride (A-4,~
HCI gars was rapidly bubbled through a suspension of acid A-3 (4.0 g, 10.81 rnm~ol) 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.
1H NMR (300 MHz, CD30D) Fa 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, Jr8Hz), 4.25 (q, 1H, J=5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t, 3H, J=7Hz).
Ethvl 4-f2-(2-Amino~pvridin-6-- ly )ethvllbenzoate (A-5a) A mixt~xre of ester 1~-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 ce:lite pad aired then concentrated to provide ester A-5a as a brown oil.
TLC Rf = 0.23 (silica, 40% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 8 7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d, 1H, J=7Hz), 6.35 (d, 1H, J=8Hz); 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), L39 (t, 3H, J=7Hz).
4-f2-(2-Aminonvridian-S-~h_~I nz~ic acid_hvdrQChloride (A-A suspension of ester A-~ (625 mg, 2.31 mmol) in 6N HCl (12 ml) was heated t,o 60°C. After ~20 h, the reaction was concentrated to give acid A-6 as a tam solid.
1H NMR (300 MHz, CD3OD) ~ 7.96 (d, 2H, J=8Hz), 7.80 (m, 1H), 7.33 (d, 2H, J=8Hz), 6.84 (d, 1H, J=9Hz), 6.69 (d, 1H, J=7Hz), 3.09 (m, 4H).

Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodo-phenylsulfonylami:nod-(i-alanine (A-7) A solwtion of acid 15-f (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 Etl, 5.72 mmol) in DMF (10 ml) was stirred for ~20 h.
The reaction was diluted with EtOAc and then washed with sat.
NaHC03, brine, dried {MgS04) and concentrated. Flash chromatography (silica, EtOAc then 5% isopropanollEtOAc) provided .
amide A-7 as a white solid.
TLC Rf = 0.4 (silica, I0% isopropanollEtOAc) IH NMR (300 MHz, CD30D) 3 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, 1H), 3.95 (c~, 2H, J=7Hz), 3.66 (dd, 1F(, J=6Hz, I4Hz), 3.49 (dd, 1H, J=BHz, l3Hz}, 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz).
4-[2-(2-Aminopyridiw-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl-~ulfonylamino)-(i-alianine (A~~
A solution of ester A-7 {200 mg, 0.3213 mmol) and 6N HCl (30 ml) was heated ito 60°C. After ~20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/
NH40H/H2O) provided acid A~g as a white solid.
TLC Rf= 0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH4OH/H20) IH NMR (400 MHz, DMSO) 8 8.40 (m, IH), 8.14 (Bs, 1H), 7.81 (d, 2H, J=8Hz), 7.62 (d, 2H, J=8Hz), ''1.48 {d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d, 1H, J=7Hz), 6.25 (d, IH, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m, 2H), 2.97 (m, 2H), 2.79 (m, 2PC}.
4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl-l7henvlsulfonvlamirao-Ci-alanine (A-9) A solution of iodide .A~- (70 mg, 0.1178 mmol), [(CH3)3Sn]2 (49 ~1, 0.2356 mmol), Pd(PPhg)4 (5 mg) and dioxane (7 ml) was heated to 90°C. After 2 h, the reaction was concentrated and then purified by preparative HPLC (laelta-Pak CIg 15 ~M 100A°, 40 x 100 txlm; 95:5 then 5:95 H20/CH3CN) to provide the trifluoroacetate salt. The salt was suspended in H2O (10 ml), treated with NH40H (5 drops) and then lyophilized to provide amide .A-~ as a white solid.
1H NMR (400 MHz, DMSO} 8 8.40 (m, 1H), 8.18 (d, 1H, J=8Hz), '1.67 (m, 5H}, f.56 (d, 2H, J=SHz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H), 6.45 (bs, 2H), 4.00 (m, 1H), 3..50 (m, 1H), 3.33 (m, IH), 2.97 (m, 2H}, 2.86 (m, 2H).
4-[2-(2-Aminopyridi;n-6-yl)ethyl]benzoyl-2(S)-4-I25iodo-~ylsulfon ly amiy~i-alanine (A-10) An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na125I (Amersham, IMS30) and stirred far five minutes at room temperature. A sohation of 0.1 mg of Ate- in 0.05 mL of 10% H2S04/MeOH
was made and immediately added to the Na125I/iodobead vial. After stirring for three minutes at room temperature, approximately 0.04-0.05 mL of NH40H was added so the reaction xxuxture was at pH 6-7. The entire reaction mixiture was injected onto the HPLC for purification (Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H20 (0.1% TFA) to 90% acetonitrile (0.1%
TFA):H20 (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time of A~10 is 17 minutes under these conditions. Fractions containing the majority 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 amthentic sample of A $.
In r :mentation: Analytical and preparative HPLC was carried out using a 'Waters 600E Powerline Muiti Solvent Delivery System with O.I mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Arr,~y Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC, a Vydac peptide-protein C-I8 column, 4.6 x 250 mm was used with a C-IS Brownlee modular guard column. The acetonitxzle used for the HPLC analyses was Fisher Optima grade. The HPLC radiodetector used was a Beckman I'T0 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 centrifuge.

Calibration curves and chemical concentrations were determined using a Hewlett Packard :Model 8452A ITV/~is Diode Array Spectrophotometer.
Sample radioactivities were determined in a Packard A6530 gamma counter.
The te;~t procedures employed to measure av(~3 and av~i5 binding and the borne resorption inhibiting activity of the compounds of the present invention are described below.
BONE RESORPTION-PIT ASSAY
When osteoclasts engage in bone resorption, they can cause the formation of pit:; in the surface of bone that they are acting upon.
Therefore, when testing compounds fox their ability to inhabit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present.
1~ 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, Il). Bone slices are pooled, placed in a 10% ethanol solution and refrigerated until further use.
Prior to experimentation, bovine 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 triplicate or quadruplicate cultures. The bone slices in 96 well plates are sterilized by UV irradiation. Prior to incubation with osteoclasts, the bone slices are hydrated by the addiction of 0.1 ml aMEM, pH 6.9 containing 5% fetal bovine serum and 1% penicillin/streptomycin.
Long bones from ?-14 day old rabbits (New Zealand White Hare) are dissected, cleaned of soft tissue and placed in aMEM
containing 20 mM 1-3LEPES. 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 min., 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 (typica.lly ~ 2 x 107 cells/ml). A cell suspension WO 00!06169 PCT/US99/16830 consisting of 5 x 10E~/ml in aMEM containing 5% fetal bov°ane serum, nM 1,25(OH)2D~, and pencillin-streptomycin is prepared. 200 ml aliquots are added to bovine bane slices (200 mm x 6 mm) and incubated for 2 hrs. at 37°C in a humidified 5% C02 atmosphere. The medium is 5 removed gently with a micropipettor and fresh medium containing test compounds is addedE. The cultures are incubated for 4$ hrs., and assayed for c-telopel?tide {fragments of the al chain of type I collagen) by Crosslaps for culture media (Herlev, Denmark).
Bovine bone slices are exposed to osteaclasts for 20-24 hrs 10 and are processed for staining. Tissue culture media is removed from each bone slice. Each well is washed with 200 ml of H20, 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 NH40H
I5 followed by 2 X 15 min ultrasonication in H20. The bone slices are immediately stained for 6-$ min with filtered 1% toluidine blue and 1%
borax.
After tl:~e bone spices have dried, resorption pits are counted in test and control slices. Resorption pits are viewed in a Microphot Fx (Nikon) fluarescene~s microscope using a polarizing Nikon IGS filter cube. Test dosage results are compared with controls and resulting ICSp 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., g~ ~l_., Journal of BcLne 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 Patget°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.

WO 00/06169 PCTlUS99/16$30 EIB ASSAY
Duong et czl., J. Bone Miner. Res., 8: 5378 (1993) describes a system for expressing the human integrin ocv~i3. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies ag;~inst the integrin, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption.
Reaction Mixture:
1. 175 ~.l'CBS buffer (b0 mM Tris~HCl pH 7.2, 150 mM NaCI, 1% BSt~, 1 mM CaCl2, 1 mM MgCl2).
2. 25 ~,1 cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 ~.1).
I5 3. l2bl-ec:histatin (25 x.1/50,000 cpm) (see EP 382 4~1).
4. 25 ~.1 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 av~i3 were separated by filtration using a Skatran Cel:! Harvester. The ~Iters (prewet in 1.5% poly-ethyleneimine for 1() rains) were then washed with the wash bu~'er (~0 mM Tris HCl, 1mM CaCI2/MgCl2, pH ?.2). The filter was then counted in a gamma counter.
SPA ASSAY
MATERIALS:
1. Wheat germ agglutinin Scintillation Proximity Beads (SPA):
Amersham 2. Octylglucopyx~anoside: Calbiochem 3. HEPES: Calbiochem 4. NaCl: Fisher 3~ 5. CaCl2: Fisher WO 00/06169 PCTJUS99/16$30 6. MgCl2: SIGMA

7. Phenylmethylsulfonylfluoride (PMSF): SIGMA

8. Optiplate: PACKARD

9. Compound A,~ (specific activity 500-1000 Ci/mmole) 10. test compound 11. Purified inte;~rin receptor: a~(33 was purified from 293 cells overexpressing a~ j33 (Duong et cal., J. Bone Min. Res., 8:5378, 1993) according to Pytela (Metlxods in Enzymology, 144:475, 1987) 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCI, 1 mM
Ca2+/Mg2+, 0.5 mM PMSF

13. 50 mM octyl~;lucoside i.n binding buffer: 50-OG buffer PROCEDURE:
1. Pretreatmenl: of SPA beads:
500 mg of lyophilized SPA beads were first washed four times with 200 mI of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer.
2. Preparation c~f SPA beads and rector mixture In each assay tube, 2.5 ~.1 (40 mg/ml) of pretreated beads were suspended in 97.5 ~.l of binding buffer and 20 ~.l of 50-OG
buffer. 5 ~.1 (.-.30 ng/~,l) of purified receptor was added to the beads in suspension with stirring at room temperature for 30 minutes. The mixture was then centrifuged at 2,500 rpm in a Beckman GP:ft Benchtop centrifuge for 10 minutes at 4°C. The pellets were then resuspended in 50 ~ti of binding buffer and 25 ~.1 of 50-OG buffer.
3. Reaction The following were sequentially added into Optiplate in WO Ob/06169 PCT/US99116830 corresponding wells:
(i) Receptor/beads mixture (75 ml) (ii) 25 ~l o:P each of the following: compound to be tested, binding buffer Por total binding or ~ for non-specific binding (final concentration 1 ~.M) {iii) A-10 in binding bufger {2~ pl; final concentration 40 pM) (iv) Binding buffer (125 ~,1) (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 = nonspeci.i.~.c 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 nn COR1~ING 24 well tissue culture plates in a.MEM medium a;ontaining 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 BalblC 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.~ gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 ~m nylon cell strainer. The resulting suspension was centrifuged at at50 x g fox 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 rE;suspended at 1 x 106 cells/mL. 50 p.L was added to each well of 1:8 cell,> to yield :10,000 cells/well and 1,25-dihydroxy-vitamin D3 (D3) was added i;o each well to a final concentration of 10 nM. The cultures were incubated at 37°C in a humidified, 5% C02 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 ethanol:acetone (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 raom temperature with 5E) 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.
~v(i5 ATTACHMENT ASSAY
Duong .et ul., J. Bone Miner. Res., 11: 5290 ( 1996), describes a system for expressing the human ocv(35 integrin receptor.
Materials:
1. Media ;end solutions used in this assay are purchased from BRL/Gibco, except BSA and the chemicals are from Sigma.
2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid free BSA and 2 mM CaCl2.
3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl N-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25%
Triton, pH 5Ø
4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM
EDTA, ;pH 10.5.
_ 74 _ WO 00/061b9 PCTIUS99116$30 Methods:
1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4°C with human vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH 9/.6), using 100 ~l/well. Plates were then washed 2X wit:'h DPBS and blocked with 2% BSA in DPBS for 2h at roam temperature. After additional washes (2X) with DPBS, plates were used far cell attachment assay.
2. 293 (av(35) cells were grown in MEM media in presence of 10% fetal calf serum to 90% confluence. Cells were then lifted from dishes with 1X Trypsin/EDTA and washed 3X.
with serum free MEM. Cells were resuspended in attachment medium (3 X 105 cells/ml).
3. Test compounds were prepared as a series of diiutions at 2X
concentrations and added as 50 ~llwell. Cell suspension was then added as 50 ~,l/well. Plates were incubated at 37°C
with 5~ C02 for 1 hour to allow attachment.
4. Non-adherent cells were removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase substrate solution ( 100 ~.llwell), overnight at raorn temperature in the dark. To quantitate cell numbers, standard curve of glucosaminidase activity was deterx~uned for each experiment by adding samples of cell suspension directly to wells containing the enzyme substrate solution.
5, The next day, the reaction was developed by addition of 185 ~,l/well of glycine/EDTA solution and reading absorbance at 405 nrn using a Molecular Devices V-Max plate reader:
Average test absorbance values (4 wells per test samples) were calculated. Then, the number of attached cells at each drug concentration was quantitated versus the standard curve ~~f cells using the Softmax program.
EXAMPLE OF A PHARMACEUTICAL FORMULATION

WO 00/06169 PC'T'/US99/Ib830 As a spfecific embodiment of an oral composition, 100 mg of a compound of the present invention are formulated with suf~.cient finely divided lactosE: to provide a total amount of 5$0 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 av(33 integrin. These compounds are generally found to have IC50 values less than about 100 nM in the SPA
assay.
Representative compounds of the present invention were J.0 tested and generally found to inhibit _> 50% the attachment of av[35 expressing cells to plates coated with vitronectin at concentrations of about 1 E.t,M.
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 responsivene.,s 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 v~ations 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 (33)

WHAT IS CLAIMED IS:

1. A compound of the formula wherein W 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 R1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R1 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 R1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R1 substituents;
X is selected from the group consisting of -(CH2)v-, and -(CH2)v NR4(CH2)v-; wherein any methylene (CH2) carbon atom, other than in R4, is either unsubstituted or substituted with one or two R3 substituents;
Y is a biarylene ring system comprising 5- or 6-membered aromatic rings, wherein said biarylene system comprises 0-2 heteroatoms selected from the group consisting of N, O, and S wherein said biarylene ring system is either unsubstituted or substituted with one or more R1 substituents;
Z is selected from the group consisting of -CH2CH2- and -CH=CH-, wherein either carbon atom can be substituted by one or two R3 substituents;
each R1 is independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, (C1-6 alkyl)pamino, (C1-6 alkyl)pamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-6 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy-C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)p, (C1-8 alkyl)paminocarbonyl, C1-8 alkyloxycarbonylamino, (C1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-8 alkylsulfonylamino, and C1-8 alkylsulfonylamino;
or two R1 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, C1-10 alkyl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R4)-(CH2)s-, aryl-(CH2)rN(R4)-C(O)-(CH2)s-, aryl-(CH2)r-N(R4)-(CH2)s-, halogen, hydroxyl, oxo, trifluoromethyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC~C-(CH2)t-, C1-6 alkyl-C~C-(CH2)t-, C3-7 cycloalkyl-C~C-(CH2)t-, aryl-C~C-(CH2)t-, C1-6 alkylaryl-C~C-(CH2)t-, CH2=CH-(CH2)t-, C1-6 alkyl-CH=CH-(CH2)t-, C3-7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, C1-6 alkylaryl-CH=CH-(CH2)t-, C1-6 alkyl-SO2-(CH2)t-, C1-6 alkylaryl-SO2-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl )pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamirao C1-6 alkyl, arylcarbonylamino C1-8 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, (C1-8 alkyl)paiminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-8 alkyl, (aryl C1-8 alkyl)alkylcarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminacarbonyl C1-6 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 R1 substituents, and provided that each R3 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 R4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, (aryl C1-5alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, aryl C1-6 alkyl, (C1-6 alkyl)pamino C2-6 alkyl, (aryl C1-6 alkyl}pamino C2-6 alkyl;
C1-8 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, arylcarbonyl, aryl C1-6 alkylcarbonyl, (C1-8alkyl)paminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1-8 alkyl)paminosulfonyl, arylsulfonyl, arylC1-6 alkylsulfonyl, C1-6 alkylthiocarbonyl, arylthiocarbonyl, and aryl C1-6 alkylthiocarbonyl, wherein any of the alkyl groups of R4 are either unsubstituted or substituted with one to three R1 substituents;

R5 and R6 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)r S(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R4)-(CH2)s-, aryl-(CH2)r-N(R4)-C(O)-(CH2)s-, aryl-(CH2)r-N(R4)-(CH2)s-, halogen, hydroxyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy;
C1-5 alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC~C-(CH2)t-, C1-6 alkyl-C~C-(CH2)t-, C3-7 cycloalkyl-C~C-(CH2)t-;
aryl-C~C-(CH2)t-, C1-6 alkylaryl-C~C-(CH2)t-, CH2=CH-(CH2)t-, C1-6 alkyl-CH=CH-(CH2)t-, C3-7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, C1-6 alkylaryl-CH=CH-(CH2)t-, C1-6 alkyl-SO2-(CH2)t-, C1-6 alkylaryl-SO2-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)p aminocarbanylamino C1-6 alkyl, (aryl C1-8 alkyl)p aminocarbonylamino, (aryl C1-8 alkyl)p aminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C1-8 alkyl)p aminosulfonylamino, (C1-8 alkyl)p aminosulfonylamino C1-6 alkyl, (aryl)p aminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)p aminosulfonylamino, (aryl C1-8 alkyl)p aminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1-8 alkyl)p aminocarbonyl C1-6 alkyl, (aryl)p aminocarbonyl C1_6 alkyl, (aryl C1-8 alkyl)p aminocarbonyl, and (aryl C1-8 alkyl)p aminocarbonyl C1-6 alkyl;
or R5 and R6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R5 or R6 are either unsubstituted or substituted with one to three R1 substituents, and provided that each R5 and R6 are selected such that in the resultant compound the carbon atom to which R5 and R6 are attached is itself attached to no more: than one heteroatom;

R7 and R8 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R4)-(CH2)s-, aryl-(CH2)r-N(R4)-C(O)-(CH2)s-, aryl-(CH2)r-N(R4)-(CH2)s-, halogen, hydroxyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, C1-6 alkylcarlbonyloxy, C3-8 cycloalkyl, (C1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC~C-(CH2)t-, C1-6 alkyl-C~C-(CH2)t-, C3-7 cycloalkyl-C~C-(CH2)t-, aryl-C~C-(CH2)t-, C1-6 alkylaryl-C~C-(CH2)t-, CH2=CH-(CH2)t-, C1-6 alkyl-CH=CH-(CH2)t-, C3-7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH~CH-(CH2)t-, C1-6 alkylaryl-CH=CH-(CH2)t-, C1-6 alkyl-SO2-(CH2)t-, C1-6 alkylaryl-SO2-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbanyiamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, arylaminocarbonylamino, (C1-8 alkyl)paminacarbonylamino, (C1-8 alkyl)paminocarbanylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamina C1-6 alkyl, (C1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfanyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarlbonyl C1-6 alkyl, arylcarbanyl C1-6 alkyl, aryl C1-6 alkylcarbonyl;
aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, (aryl C1-8 alkyl)paminacarbonyl C1-6 alkyl, and C7-20 polycyclyl C0-8 alkylsulfanylamino, wherein any of the alkyl groups of R7 and R8 are either unsubstituted or substituted with one to three R1 substituents, and provided that each R7 and R8 are selected such that in the resultant compound the carbon atom to which R7 and R8 are attached is itself attached to no moms than one heterodtom;

R9 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, C1-8 alkylcarbonyloxy C1-4 alkyl, aryl C 1-8 alkylcarbonyloxy C 1-4 alkyl, C1-8 alkylaminocarbonylmethylene, and C1-8 dialkylaminocarbonylmethylene;

wherein 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;
each t is independently an integer from 0 to 3; and each v as independently an integer from 0 to 6;

and the pharmaceutically acceptable salts thereof.

2. The compound of Claim 1 wherein W is selected from the group consisting of Y is selected from t;he group consisting of Z is selected from the group consisting of and R1 and R4 are as defined in Claim 1.

3. The compound of Claim 2 wherein W is selected from the group consisting of Y is

4. The compound of Claim 3 wherein W is selected from the group consisting of Y is such that the X moiety is attached at the variable position and the Z
moiety is attached at the para position;

Z is -; and each v is independently an integer from 0 to 2.

5. The compound of Claim 4 wherein each R3 is independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl, aryl, C1-8 alkyl arylC1-6 alkyl hydroxyl, oxo, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1-6 alkyl;

and each R4 is independently selected from the group consisting of hydrogen;
aryl, C3-8 cycloalkyl, C1-8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, arylC1-6alkylsulfonyl, arylC1-6alkylcarbonyl, C1-8alkylaminocarbonyl, arylC1-5alkylaminocarbonyl, arylC1-8alkoxycarbonyl, and C1-8alkoxycarbonyl.

6. The compound of Claim 5 wherein R6, R7, and R8 are each hydrogen and R5 is selected from the group consisting of hydrogen, aryl, C1-8 alkyl, aryl-C~C-(CH2)t-, aryl C1-6 alkyl, CH2=CH-(CH2)t-, and HC~C-(CH2)t-.

7. The compound of Claim 6 wherein R9 is selected from the group consisting of hydrogen, methyl, and ethyl.

8. The compound of Claim 7 wherein R9 is hydrogen.

9. The compound of Claim 5 wherein R5, R6, and R8 are each hydrogen and R7 is selected from the group consisting of hydrogen, aryl, C1-8 alkylcarbonylamino, C1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino 1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, arylaminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkyltbiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, and aryl C1-6 alkylthiocarbonylamino C1-6 alkyl.

10. The compound of Claim 9 wherein R7 is selected from the group consisting of hydrogen, aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbonylamino, C1-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino, arylaminocarbonylamino, (C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylamino, and (aryl C1-8 alkyl )paminosulfonylamino.

11. The compound of Claim 10 wherein R9 is selected from the group consisting of hydrogen, methyl, and ethyl.

12. The compound of Claim 11 wherein R9 is hydrogen.

13. A compound selected from the group consisting of 3'-[N-(3,4,5,5-tetrahydropyrimidin-2-yl)amino]biphenyl-4-carbonyl-2(S)-phenylsulfonylamino-.beta.-alanine, 3'-[N-[5,6,7,8-tetrahydro-[1,8]napthyridin-2-yl]amino]biphenyl-4-carbonyl-2(S)phenylsulfonylamino-.beta.-alanine, 2(S)-phenylsulfonylamino-3-{4-[4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-thiophen-2-yl]-benzoylamino}-propionic acid, 2(S)-phenylsulfonylamino-3-({5-[3-(1H-benzoimidazol-2-ylamino)-phenyl]-pyridine-2-carbonyl}-amino)-propionic acid, 2(S)-phenylsulfonylamino-3-{4-[4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-furan-2-yl]-benzoylamino}-propionic acid, 2(S)-phenylsulfonylamino-3-{[4'-(1H-imidazol-2-ylamino)-[2,2']bithiophenyl-5-carbonyl]-amino}-propionic acid, 2(S)-phenylsulfonylamino-3-({4-[3-(1H-benzoimidazol-2-ylamino)-phenyl]-1H-pyrazole-3-carbonyl}-amino)-propionic acid, 2(S)-phenylsulfonylamino-3-({5-[5-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-thiophen-2-yl]-furan-2-carbonyl}-amino)-propionic acid, and 3'-[N-pyrimidin-2-yl-amino]biphenyl-4-carbonyl-2(S)-phenylsulfonylamino-propionic acid, and the pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.

15. The composition of Claim 14 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) a cytotoxic/antiproliferative agent, d) a matrix metalloproteinase inhibitor, e) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, f) an inhibitor of VEGF, g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, h ) a cathepsin K inhibitor, i) an inhibitor of osteoclast proton ATPase, and j) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor;
and mixtures thereof.

16. The composition of Claim 15 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) a cathepsin K inhibitor, and d) an inhibitor of osteoclast proton ATPase;
and mixtures thereof.

17. The composition of Claim 16 wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium trihydrate.

18. A method of eliciting an 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.

19. The method of Claim 18 wherein the integrin receptor antagonizing effect is an .alpha.v.beta.3 antagonizing effect.

20. The method of Claim 19 wherein the .alpha.v.beta.3 antagonizing effect is selected from the group consisting of inhibition of bone resorption, osteoporosis, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, inflammatory arthritis, viral disease, tumor growth and metastasis.

21. The method of Claim 20 wherein the .alpha.v.beta.3 antagonizing effect is the inhibition of bone resorption.

22. The method of Claim 18 wherein the integrin receptor antagonizing effect is an .alpha.v.beta.5 antagonizing effect.

23. The method of Claim 22 wherein the .alpha.v.beta.5 antagonizing effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, tumor growth and metastasis.

24. The method of Claim 18 wherein the integrin receptor antagonizing effect is a dual .alpha.v.beta.3/.alpha.v.beta.5 antagonizing effect.

25. The method of Claim 24 wherein the .alpha.v.beta.3/.alpha.v.beta.5 antagonizing effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth and metastasis.

26. The method of Claim 18 wherein the integrin antagonizing effect is an .alpha.v.beta.6 antagonizing effect.

27. The method of Claim 26 wherein the .alpha.v.beta.6 antagonizing effect is selected from the group consisting of inhibition of angiogenesis, inflammatory response, and wound healing.

28. A method of eliciting an integrin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 14.

29. A method of treating or preventing a condition mediated by antagonism of an integrin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 14.

30. A method of inhibiting bone resorption in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 14.

31. A method of inhibiting bone resorption in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 16.

32. A method of treating or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 14.

33. A method of treating tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 14.