AU1725799A

AU1725799A - Integrin receptor antagonists

Info

Publication number: AU1725799A
Application number: AU17257/99A
Authority: AU
Inventors: Mark E. Duggan; Robert S. Meissner; James J. Perkins
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1997-12-17
Filing date: 1998-12-14
Publication date: 1999-07-05
Anticipated expiration: 2018-12-14
Also published as: WO1999030709A1; EP1047425A1; CA2315370A1; EP1047425A4; JP2002508323A; AU736026B2

Description

wu 9/Ju/U9 PCT/US98/26539 TITLE OF THE INVENTION INTEGRIN RECEPTOR ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS 5 The present invention is related to U.S. provisional applications Serial No. 60/069,910, filed December 17, 1997; 60/083,251, filed April 27, 1998; and 60/092,588, filed July 13, 1998; the contents of each of which are hereby incorporated by reference. 10 FIELD OF THE INVENTION 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 avP3, av35, and/or avP6 and are 15 useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis. 20 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 25 cells attach and communicate with extracellular matrices and other cells (See S.B. Rodan and G.A. Rodan, "Integrin Function In Osteoclasts", Journal of Endocrinology, Vol. 154, S47- S56 (1997), which is incorporated by reference herein in its entirety). In one aspect of the present invention, the compounds 30 herein are useful for 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 35 the surface of bone, and can bind to bone, secrete necessary acids and -1- SvvJ YY/u/uY PCITUS9?8/26539 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, 5 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 bone matrix 10 and do not take part in resorption until they again attach to bone. Integrins 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 av3, which is thought to interact in bone with matrix proteins that 15 contain the RGD sequence. Antibodies to avP3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that av3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals. 20 The current major bone diseases of public concern are osteoporosis, hypercalcemia 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 25 these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the 30 alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk. In the United States, there are currently about 20 million 35 people with detectable fractures of the vertebrae due to osteoporosis. In -2wU 99U/JU79 PCT/US98/26539 addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture. 5 Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption. Additionally, azv3 ligands have been found to be useful in treating and/or inhibiting restenosis, i.e. recurrence of stenosis after corrective surgery on the heart valve, atherosclerosis, diabetic 10 retinopathy, macular degeneration, and angiogenesis, i.e. formation of new blood vessels. 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 15 Harrison's Principles of Internal Medicine, 12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, v03 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See e.g., Brooks et al., Cell, 79:1157 1164 (1994), which is incorporated by reference herein in its entirety). 20 Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, v05. A monoclonal antibody for av5 has been shown to inhibit VEGF induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M.C. Friedlander, et al., Science 270, 1500-1502, 25 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize avP5 are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis. Additionally, compounds of the instant invention can 30 inhibit angiogenesis and inflammation by acting as antagonists of the integrin receptor, avP6, which is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Christofidou-Solomidou, et al., "Expression and Function of Endothelial Cell av Integrin Receptors in Wound-Induced Human Angiogenesis in 35 Human Skin/SCID Mice, Chimeras, American Journal of Pathology, -3wu Jo5UlUY PCT/US98/26539 Vol. 151, No. 4, pp. 975-983 (October 1997), which is incorporated by reference herein in its entirety). It is postulated that cvf6 plays a role in the remodeling of the vasculature during the later stages of angiogenesis. Also, avj6 participates in the modulation of epithelial 5 inflammation and is induced in response to local injury or inflammation (See Xiao-Zhu Huang, et al., "Inactivation of the Integrin P6 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 10 in its entirety). Accordingly, compounds that antagonize avP6 are useful in treating or preventing cancer by inhibiting tumor growth and metastasis. In addition, certain compounds of this invention antagonize both the czv3 and avP5 receptors. These compounds, referred to as 15 "dual evi3/avi5 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, tumor growth, and metastasis. In addition, certain compounds of this invention are useful 20 as mixed avP3, avP5, and avP6 receptor antagonists. It is therefore an object of the present invention to provide compounds which are useful as integrin receptor antagonists. It is another object of the present invention to provide compounds which are useful as =vI3 receptor antagonists. 25 It is another object of the present invention to provide compounds which are useful as avP5 receptor antagonists. It is another object of the present invention to provide compounds which are useful as avI6 receptor antagonists. It is another object of the present invention to provide 30 compounds which are useful as dual avP3/cvP5 receptor antagonists. It is another object of the present invention to provide compounds which are useful as mixed zvP3, cvP5, and avP6 receptor antagonists. It is another object of the present invention to provide 35 pharmaceutical compositions comprising integrin receptor antagonists. -4wu YvJou /9V PCT/US98/26539 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 5 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. It is another object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting bone 10 resorption, restenosis, atherosclerosis, inflammation, 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 15 osteoporosis. It is another object of the present invention to provide methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumor growth, and metastasis. 20 It is another object of the present invention to provide methods for treating osteoporosis. These and other objects will become readily apparent from the detailed description which follows. 25 SUMMARY OF THE INVENTION The present invention relates to compounds of the formula

R

5

R

6 W-X-Y-Z C0 2

R

9

R

7

R

8 wherein W is selected from the group consisting of -5wu YwIoutuY PCTUP/I/2653O N' R 1

NR

2 || II 11 R 2 -NR- C-NRR 2 -C-NR R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are 5 unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 substituents, and a 9- to 14-membered polycyclic ring system, wherein one or more 10 of the rinks is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 15 substituents; X is selected from the group consisting of -(CH2)v-, wherein any methylene (CH2) carbon atom is either 20 unsubstituted or substituted with one or two R 1 substitutents; and a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon 25 atoms are unsubstituted or substituted with one or two R 1 substituents; Y is selected from the group consisting of -(CH2)m-, 30 -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -6wu /3Ju/U PCT/US98/26539 -(CH2)m-SO-(CH2)n-, -(CH2)m-SO2-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p -, 5 -(CH2)m-NR 4 -(CH2)n-NR 4 -(CH2)p -, -(CH2)m-O-(CH2)n-S-(CH2)p -, -(CH2)m-S-(CH2)n-S-(CH2)p -, -(CH2)m-NR 4 -(CH2)n-S-(CH2)p -, -(CH2)m-NR 4 -(CH2)n-O-(CH2)p -, 10 -(CH2)m-S-(CH2)n-O-(CH2)p -, and -(CH2)m-S-(CH2)n-NR 4 -(CH2)p -, wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R 3 substituents; 15 Z is a 5 membered aromatic or nonaromatic mono- or bicyclic ring system having 0 to 3 heteroatoms selected from the group consisting of N, 0, and S, and wherein the ring system is either unsubstituted or substituted with 0, 1, 2, or 3 oxo or thio substituents, and either unsubstituted or substituted with one or more substituents 20 independently selected from the group consisting of R 1 0 , R 1 1 , and R 1 2 wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, 25 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, 30 hydroxycarbonyl C1-6 alkyl, C1-3 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(0O)p, (C1-8 alkyl)paminocarbonyl, -7wu V/.3u/ M PCT/US98/26539 C1-8 alkyloxycarbonylamino, (C 1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-8 alkylsulfonylamino, and C1-8 alkylsulfonylamino; or two R 1 substituents, when on the same carbon atom, are taken 5 together with the carbon atom to which they are attached to form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, 10 aryl, CI-10 alkyl, aryl-(CH2)r-O-(CH2)s-, aryl-(CHZ)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, 15 aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, halogen, hydroxyl, 20 oxo, trifluoromethyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, 25 (C 1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1-6 alkyl)pamino, amino C1-6 alkyl, 30 arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, -8wu 99vy/U7U9 PCT/US98/26539 hydroxycarbonyl C1-6 alkyl, HC-C-(CH2)t-, C1-6 alkyl-C-C-(CH2)t-, C3-7 cycloalky1-C-C-(CH2)t-, 5 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-, 10 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, 15 aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, 20 (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, 25 C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, 30 aryl C1-6 alkylsulfonylamino C1-6 alkyl, C 1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, -9- WU 9913U0709 PCT/US98/26539 aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C 1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, 5 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, 10 (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, 15 (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, 20 C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, 25 C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, 30 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, - 10wu VwwouuY PCT/US98/26539 (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, or two R 3 substituents, when on the same carbon atom are taken 5 together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R 3 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 3 is selected such that in the resultant 10 compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, 15 aryl, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, 20 (aryl C1-5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, aryl C1-6 alkyl, (C1-6 alkyl)pamino C2-6 alkyl, 25 (aryl C1-6 alkyl)pamino C2-6 alkyl, C1-8 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, 30 C1-8 alkylcarbonyl, arylcarbonyl, aryl C1-6 alkylcarbonyl, (C1-8 alkyl)paminocarbonyl, aminosulfonyl, - 11 w vv, YY3iuY PCT/US98/26539 C1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1-8 alkyl)paminosulfonyl, arylsulfonyl, 5 arylC1-6 alkylsulfonyl, C1-6 alkylthiocarbonyl, arylthiocarbonyl, and aryl C1-6 alkylthiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or 10 substituted with one to three R 1 substituents;

R

5 and R6 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, 15 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(R 4 )-(CH2)s-, 20 aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, halogen, hydroxyl, C1-8 alkylcarbonylamino, 25 aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (01-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, 30 (C 1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, - 12wu Y/.iU tY PCT/US98/26539 aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC=-C-(CH2)t-, 5 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-, 10 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-, 15 C 1-6 alkylaryl-SO2-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, 20 (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, 25 aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, 30 arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C 1-8 alkyl, - 13wu 99 /jU79 PCT/US98/26539 aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C 1-8 alkylcarbonylamino, 5 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, 10 (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, 15 aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C1- 8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, 20 (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, 25 aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, 30 aryl C1-6 alkylcarbonyl C1-6 alkyl, C 1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1.6 alkyl, aryl C1-6 alkylthiocarbonylamino, - 14- WU 99/JiU7U9 PCT/US98/26539 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 5 (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R 5 or R 6 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 5 10 and R 6 are selected such that in the resultant compound the carbon atom to which R 5 and R 6 are attached is itself attached to no more than one heteroatom;

R

7 and R 8 are each independently selected from the group consisting of 15 hydrogen, CI-1O alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, 20 aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s -, aryl-(CH2)r-N(R 4 )-(CH2)s-, halogen, 25 hydroxyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, 30 C1- 6 alkylcarbonyloxy, C3-8 cycloalkyl, (C1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, - 15wu vY/,)U /U PCT/U995/26539 aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, 5 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-, 10 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-, 15 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, 20 aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, 25 (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, 30 arylcarbonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, - 16wu YaYuuv uICIU595/205iY aryl C1-6 alkylsulfonylamino C1-6 alkyl, C 1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, 5 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, 10 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, 15 arylaminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, 20 (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, 25 C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C 1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, 30 C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, - 17wU V/JUT/U9 PCT/US98/26539 C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, 5 (C1-8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, and C7-20 polycyclyl CO-8 alkylsulfonylamino; 10 wherein any of the alkyl groups of R 7 and R 8 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each

R

7 and R 8 are selected such that in the resultant compound the carbon atom to which R 7 and R 8 are attached is itself attached to no more than one heteroatom; 15

R

9 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, 20 aryl C1-8 alkyl, CI-8 alkylcarbonyloxy C1-4 alkyl, aryl C1-8 alkylcarbonyloxy C1-4 alkyl, C1-8 alkylaminocarbonylmethylene, and C1-8 dialkylaminocarbonylmethylene; 25 R10 , R11, and R1 2 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, 30 aryl, halogen, hydroxyl, oxo, aminocarbonyl, - 18wO 99/U7U9 PCTIUS98/26539 C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, hydroxycarbonyl, 5 (aryl C1-5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino C2-6 alkyl, 10 C1-8 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, 15 arylcarbonyl, aryl C1-6 alkylcarbonyl, (C1-8 alkyl)paminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, 20 (aryl)paminosulfonyl, (aryl C1-8 alkyl)paminosulfonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl C1-6 alkylsulfonyl, 25 aryl C1-6 alkylcarbonyl, C1-6 alkylthiocarbonyl, arylthiocarbonyl, aryl C1-6 alkylthiocarbonyl, aryl-(CH2)r-O-(CH2)s-, 30 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, - 19- WU 9!/JU7U9 PCT/US98/26539 HC-C-(CH2)t-, C1-6 alky1-C-C-(CH2)t-, C3-7 cycloalkyl-C-C-(CH2)t-, aryl-C= C-(CH2)t-, 5 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-, 10 C1-6 alkylaryl-CH=CH-(CH2)t-, C1-6 alkyl-SO2-(CH2)t-, C1-6 alkylaryl-SO2-(CH2)t-, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, 15 C1-5 alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, (C1-6 alkyl)pamino, aminocarbonyl C1-6 alkyl, 20 C1-6 alkoxy, aryl C1-6 alkoxy, (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, 25 (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C 1-8 alkylsulfonylamino, 30 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, - 20w Ju YaUUv 'YI/Ub95/2O59 C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, 5 aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, 10 aryl 01-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino 01-6 alkyl, (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, 15 (aryl 01-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino 01-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, 20 (aryl)paminosulfonylamino C1-6 alkyl, (aryl 01-8 alkyl)paminosulfonylamino, (aryl 01-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, 25 arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, 30 arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, -21wu YY/u/U PC'T/US98/26539 arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonyl C1-6 alkyl, 5 (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, wherein any of the alkyl groups of R 1 0 , R 1 1 , and R 1 2 are either unsubstituted or substituted with one to three R 1 substituents; 10 wherein each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; 15 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 v is independently an integer from 0 to 6; 20 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 25 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. 30 The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, wound healing, tumor growth, and metastasis by administering the compounds and pharmaceutical compositions of the present invention. - 22 wU 99./J7U9 PCT/US98/26539 The present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention. 5 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds useful as integrin receptor antagonists. Representative compounds of the present invention are described by the following chemical formula: W-X-Y-Z C0 2

R

9

R

7

R

8 10 wherein W is selected from the group consisting of NR' NR 2 II 2 -NR-C-NRR 2 -C-NR'R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are 15 unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 substituents, and a 9- to 14-membered polycyclic ring system, wherein one or more 20 of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 25 substituents; - 23wu 9i3dU7U9 PCT/US98/26539 X is selected from the group consisting of -(CH2)v-, wherein any methylene (CH2) carbon atom is either unsubstituted or substituted with one or two R 1 substitutents; 5 and a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 substituents; 10 Y is selected from the group consisting of -(CH2)m-; -(CH2)m-O-(CH2)n-, 15 -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, -(CH2)m-SO2-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, 20 -(CH2)m-O-(CH2)n-NR 4 -(CH2)p -, -(CH2)m-NR 4 -(CH2)n-NR 4 -(CH2)p -, -(CH2)m-O-(CH2)n-S-(CH2)p -, -(CH2)m-S-(CH2)n-S-(CH2)p -, -(CH2)m-NR 4 -(CH2)n-S-(CH2)p -, 25 -(CH2)m-NR 4 -(CH2)n-O-(CH2)p -, -(CH2)m-S-(CH2)n-O-(CH2)p -, and -(CH2)m-S-(CH2)n-NR 4 -(CH2)p -, wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can 30 be substituted by one or two R 3 substituents; Z is a 5 membered aromatic or nonaromatic mono- or bicyclic ring system having 0 to 3 heteroatoms selected from the group consisting of N, 0, and S, and wherein the ring system is either unsubstituted or - 24wu vWulu? PCT/US98/26539 substituted with 0, 1, 2, or 3 oxo or thio substituents, and either unsubstituted or substituted with one or more substituents independently selected from the group consisting of R 1 0 , R 1 1 , and R 1 2 5 wherein R 1 and R 2 are each 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, 10 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, C1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl 15 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, C 1-8 alkyloxycarbonylamino, (C1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-8 20 alkylsulfonylamino, and C1-8 alkylsulfonylamino; or two R 1 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; 25 each R 3 is independently selected from the group consisting of hydrogen, aryl, CI-10 alkyl, aryl-(CH2)r-O-(CH2)s-, 30 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, 35 halogen, - 25 wu YU PTU9526539 hydroxyl, Oxo, trifluoromethyl, C1-8 alkylcarbonylamino, 5 aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, 10 (C 1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 -alkylaminocarbonyl, aminocarbonyl, 15 aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC=C-(CH2)t-, C1-6 alkyl-C-C-(CH2)t-, 20 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-, 25 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-, 30 C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, 35 (aryl)pamino C1-6 alkyl, - 26wuY TYhiuu9 PCT/US98/26539 (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, 5 (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, 10 aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C 1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, 15 aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, 20 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, 25 (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C1-8 alkyl)paminosulfonylamino, 30 (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, - 27wu Yv/iju u9 PCT/US98/26539 C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, 5 C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl 01-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, 10 C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 -alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, 15 (C1-8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl; or two R 3 substituents, when on the same carbon atom are taken 20 together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R 3 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 3 is selected such that in the resultant 25 compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, 30 aryl, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, - 28- WU 99/iU7U9 PCT/US98/26539 (aryl C1-5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, aryl C1-6 alkyl, 5 (C1-6 alkyl)pamino C2-6 alkyl, (aryl C1-6 alkyl)pamino C2-6 alkyl, C1-8 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, 10 aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, arylcarbonyl, aryl C1-6 -alkylcarbonyl, (C1-8 alkyl)paminocarbonyl, 15 aminosulfonyl, C1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1-8 alkyl)paminosulfonyl, arylsulfonyl, 20 arylC1-6 alkylsulfonyl, C1-6 alkylthiocarbonyl, arylthiocarbonyl, and aryl C1-6 alkylthiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or 25 substituted with one to three R 1 substituents;

R

5 and R 6 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, 30 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(R 4 )-(CH2)s-, -29wu JWYIuUy PCT/US98/26539 aryl-(CH2)r-N(R 4 )-C(0)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, halogen, hydroxyl, 5 C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, 10 C3-8 cycloalkyl, (C1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, 15 aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC=-C-(CH2)t-, 20 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-, 25 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-, 30 C1-6 alkylaryl-S02-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, - 30wu Yvi/U/UY9 PCT/US98/26539 (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl Cl-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, 5 arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, 10 C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 'alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, 15 C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino CI-8 alkyl, C 1-8 alkylcarbonylamino, 20 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, 25 (C 1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, 30 aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, -31wu Yy3JU/U PCT/US98/26539 (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, 5 aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, 10 aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, 15 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 20 (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, or R 5 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R 5 or R 6 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 5 25 and R 6 are selected such that in the resultant compound the carbon atom to which R 5 and R 6 are attached is itself attached to no more than one heteroatom;

R

7 and R8 are each independently selected from the group consisting of 30 hydrogen, C1-10 alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, - 32wO 9V/JU7U9 PCT/US98/26539 aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, 5 halogen, hydroxyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, 10 (C1-8 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C1-6 alkyl)pamino, amino C1-6 alkyl, 15 arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, 20 hydroxycarbonyl C1-6 alkyl, HC= C-(CH2)t-, 01-6 alkyl-C=-C-(CH2)t-, C3-7 cycloalkyl-C=C-(CH2)t-, aryl-C-C-(CH2)t-, 25 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-, 30 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, - 33- WU /JU7U9 PCT/US95/26539 aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, 5 (aryl C1-6 alkyl)pamino, (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, 10 C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, 15 aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, 20 aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C 1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, 25 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, 30 (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, amninosulfonylamino C1-6 alkyl, (C1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, - 34wV YY3UiUY PCT/US98/26539 (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, 5 C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, 10 C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl 01-6 alkyl, aryl C1-6 alkylcarbonyl, aryl 01-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, 15 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 01-6 alkyl, 20 (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, and C7-20 polycyclyl CO-8 alkylsulfonylamino; wherein any of the alkyl groups of R 7 and R 8 are either unsubstituted or 25 substituted with one to three R 1 substituents, and provided that each

R

7 and R 8 are selected such that in the resultant compound the carbon atom at which R 7 and R 8 are attached is itself attached to no more than one heteroatom; 30 R 9 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, - 35wu vJiu /UY PCT/US98/26539 C1-8 alkylcarbonyloxy C1-4 alkyl, aryl C1-8 alkylcarbonyloxy C 1-4 alkyl, C1-8 alkylaminocarbonylmethylene, and C1-8 dialkylaminocarbonylmethylene; 5 R10 , R11, and R 1 2 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, 10 aryl, halogen, hydroxyl, oxo, aminocarbonyl, 15 C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, hydroxycarbonyl, (aryl C1-5 alkyl)paminocarbonyl, 20 hydroxycarbonyl C1-6 alkyl, aryl C1-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino C2-6 alkyl, C1-8 alkylsulfonyl, 25 C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, arylcarbonyl, 30 aryl C1-6 alkylcarbonyl, (C1-8 alkyl)paminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, - 36- WU v YY/5UIM9 PCTIUS98/26539 (aryl Clp8 alkyl)paminosulfonyl, C1-6 ailkylsulfonyl, arylsulfonyl, aryl Cl-6 alkylsulfonyl, 5 aryl Cl..6 alkylcarbonyl, C 1-6 alkyithiocarbonyl, aryitbiocarbonyl, aryl C1..6 alkyithiocarbonyl, aryl-(CH2)r-O-(CH2 )s-, 10 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O )-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, 15 HC=-C-(CH2)t-, C 1-6 alkyl-C=-C-(CH2)t-, C3-.7 cycloalkyl-C=EC-(CH2)t-, C 1-6 alkylaryl-C=-C-(CH2)t-, 20 CH2=CH-(CH2)t-, C 1-6 alkyl-CH=CH-(CH2)t-, C3-.7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, Cl..6 allkylaryl-CH=CH-(CH2)t-, 25 C 1

..

6 alkYl-S02-(CH2)t-, C 1-6 alkylarYl-S02-(CH2)t-, C 1-8 alkylcarbonylamino, aryl Ci.5 alkoxy, C 1-5 alkoxycarbonyl, 30 (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, (C 1-6 alkyl)pamino, aminocarbonyl C1..6 alkyl, Ci-6 alkoxy, - 37 - WU 99/1J0709 PCT/US98/26539 aryl C1-6 alkoxy, (aryl)pamino, (aryl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino, 5 (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, 10 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1.-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, 15 C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, 20 C 1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, 25 aminocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, 30 (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, - 38wv% YY/oUiUY PCT1US98/26539 (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C.1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, 5 arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, 01-6 alkylcarbonyl 01-6 alkyl, 10 arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkyithiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, 15 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, 20 (aryl C1-8 alkyl)paminocarbonyl, and (aryl 01-8 alkyl)paminocarbonyl C1-6 alkyl, wherein any of the alkyl groups of R 1 0 , R 1 1 , and R 1 2 are either unsubstituted or substituted with one to three R 1 substituents; 25 wherein each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; 30 each s is independently an integer from 0 to 3; each t is independently an integer from 0 to 3; and v is independently an integer from 0 to 6; and the pharmaceutically acceptable salts thereof. - 39wu vW/JUTU9 PCT/US98/26539 In the compounds of the present invention, W is preferably a 6-membered monocyclic aromatic or nonaromatic ring system having 1 or 2 nitrogen atoms wherein each carbon atom is either unsubstituted 5 or substituted with one R 1 substituent, or a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S 10 wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R1 substituents. More preferably, W is selected from the group consisting of

R

1 R1 R1 N ,, N/ N , ' ~N ' N ~ N NJ , N H H H

R

1

R

1

R

1 N

"

and N N ' N N N N 15 H H Most preferably W is

R

1 R 1 Sor N CN N s H In the compounds of the present invention, X is preferably 20 -(CH2)v- , wherein any methylene (CH2) carbon atom is either unsubstituted or substituted with one or two R1 substituents. - 40- WLu 99/U7U9 PCT/US98/26539 More preferably X is a direct bond, that is, v is 0. In the compounds of the present invention, Y is preferably selected from the group consisting of 5 -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, 10 -(CH2)m-SO2-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p-, -(CH2)m-NR 4 -(CH2)n-NR 4 -(CH2)p-, and -(CH2)m-NR 4 -(CH2)n-O-(CH2)p-, 15 wherein any carbon atom in Y, other than in R 4 , can be substituted by one or two R 3 substituents. More preferably Y is selected from the group consisting of 20 (CH2)m, (CH2)m-S-(CH2)n, and (CH2)m-NR 4 -(CH2)n, wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R 3 substituents. In the compounds of the present invention, Z is preferably 25 selected from the group consisting of - 41wo 9Y/.5U7U9 PCT/US98/26539 fiR 1 R1 0 ~z / l 10 11 R1o R" R1o N -N N N 12 12 , R 12 10 R1o )iL3io " I * I R 1 N H /N~ and

SR

12

R

12 Moie preferably Z is selected from the group consisting of

R

10 0

R

10 0 0NK N NS N O O O Rio R 0 0 NHR SN N and

N-

H' 5 0 0 Most preferably Z is N R 10 // .. N -.-.. , / or 0- 42 -42wU 99130709 PCT/US98/26539 In the compounds of the present invention, R1 and R 2 are preferably selected from the group consisting of hydrogen, halogen, C1 10 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, hydroxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy. 5 More preferably, R1 and R2 are selected from the group consisting of hydrogen, halogen, CI-10 alkyl, C3-8 cycloalkyl, trifluoromethyl, and trifluoromethoxy. In the compounds of the present invention, R 3 is preferably 10 selected from the group consisting of hydrogen, fluoro, trifluoronfiethyl, aryl, 15 C1-8 alkyl, arylC1-6 alkyl hydroxyl, oxo, arylaminocarbonyl, 20 aryl C1-5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1-6 alkyl. More preferably, R 3 is selected from the group consisting of 25 fluoro, aryl, C1-8 alkyl, arylC1-6 alkyl hydroxyl, 30 oxo, and arylaminocarbonyl. In the compounds of the present invention, R 4 is preferably selected from the group consisting of - 43w"~ YYIOUIUY r~U9Loi hydrogen, aryl, C3-8 cycloalkyl, C1-8 alkyl, 5 C1-8 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, arylC1-6alkylsulfonyl, 10 arylC 1-6alkylcarbonyl, C 1-8alkylaminocarbonyl, arylC 1-5alkylaminocarbonyl, arylC 1-8alkoxycarbonyl, and C 1-8alkoxycarbonyl. 15 More preferably, R 4 is selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, 20 arylC 1-6alkylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, and arylC 1-6alkylsulfonyl. In one embodiment of the present invention, R 5 and R 6 are 25 each independently selected from the group consisting of hydrogen, aryl, C1-8 alkyl, aryl-C-C-(CH2)t-, 30 aryl C1-6 alkyl, CH2=CH-(CH2)t-, and HC=-C-(CH2)t-. In a class of this embodiment of the present invention, R 6 is hydrogen and R 5 is selected from the group consisting of 35 hydrogen, - 44wu VY/.U/U PCT/US98/26539 aryl, C1-8 alkyl, aryl-C=C-(CH2)t -, aryl C1-6 alkyl, 5 CH2=CH-(CH2)t-, and HC=C-(CH2)t-. In a subclass of this class of the present invention, R 6 , R 7 , and R 8 are each hydrogen and R 5 is selected from the group consisting of 10 hydrogen, aryl, C1-8 alkyl, aryl-C=-C-(CH2)t-, aryl C1-6 alkyl, 15 CH2=CH-(CH2)t-, and HC-C-(CH2)t-. In another embodiment of the present invention, R 7 and R 8 are each independently selected from the group consisting of 20 hydrogen, aryl, C1-8 alkylcarbonylamino, arylcarbonylamino, C1-8 alkylsulfonylamnino, 25 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, 30 C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, 35 C1-8 alkylcarbonylamino C1-6 alkyl, - 45- WU 99/3U709 PCT/US98/26539 arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, 5 (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, 10 aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paninosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, 15 (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, and 20 aryl C1-6 alkylthiocarbonylamino C1-6 alkyl. In a class of this embodiment of the present invention, R 8 is hydrogen and R 7 is selected from the group consisting of consisting of hydrogen, 25 aryl, C 1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbonylamino, C1-8 alkylsulfonylamino, 30 aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino, arylaminocarbonylamino, - 46- WO 99/30709 PCT/US98/26539 (C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylamino, and (aryl C1-8 alkyl)paminosulfonylamino. 5 In a subclass of this class of the present invention, R 5 , R 6 , and R 8 are each hydrogen and R 7 is selected from the group consisting of hydrogen, 10 aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbohnylamino, C1-8 alkylsulfonylamino, 15 aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino, arylaminocarbonylamino, 20 (C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylamino, and (aryl C1-8 alkyl)paminosulfonylamino. In the compounds of the present invention, R 9 is preferably 25 selected from the group consisting of hydrogen, methyl, and ethyl. More preferably, R 9 is hydrogen. In the compounds of the present invention, R 1 0 , R 1 1 , and

R

1 2 are preferably each independently selected from the group consisting of hydrogen and C1-8 alkyl. More preferably R 1 0 , R 1 1 , and 30 R 12 are hydrogen. In the compounds of the present invention, m is preferably an integer from 0 to 4, more preferably from 0 to 3. In the compounds of the present invention, n is preferably an integer from 0 to 4, more preferably from 0 to 3. - 47wU 9.9/U7UY PCT/US98/26539 In the compounds of the present invention, r is preferably an integer from 1 to 2. In the compounds of the present invention, s is preferably an integer from 0 to 2. 5 In the compounds of the present invention, t is preferably an integer from 0 to 2, more preferably from 0 to 1. In the compounds of the present invention, v is preferably 0. In certain embodiments of the present invention the compounds have the formula with the following designated 10 stereochemistry: Rs

R

6 WXYZ C0 2

R

9

R

7

R

8 wherein the substituents W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 ,

R

1 0 , R 1 1 , and R 1 2 , and the subscripts m, n, p, r, s, t, and v are as 15 described above. Illustrative but nonlimiting examples of compounds of the present invention that are useful as integrin receptor antagonists are the following: 20 Ethyl 3(S)-(3-fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate; Ethyl 3(S)-(3-fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate; 25 Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8 tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8 30 tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; - 48vv 7Iju tu/ ILT/U595/LOBJ Ethyl 3(S)-(quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; Ethyl 3(S)-(quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro 5 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 10 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 15 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 20 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(Quinolin-3-yl)-3-(2-oxo(S)-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 25 2(S)-Benzenesulfonylamino-3-[3-(3-[1,8]naphthyridin-2-yl-propyl) [1,2,4]oxadiazol-5-yl]-propionic acid; 3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 30 3(S)-(6-Amino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; - 49 - VV~., yy3FuC'1iUS9?SIZ6539 3(S)-(4-Methyl-3-oxo-3 ,4-dihydro-2H-benzo[1 ,4] oxazin-7-yl)-3-(2-oxo-3-[3 (5 ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]-pyrrohin- l-yl) propionic acid; 5 3-(6-Methylainino-pyridin-3-yl)-3-(2-oxo-3-[3-(5 ,6, 7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 10 3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3-(5,6, 7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyli-pyrrolidin- 1-yl)-propionic acid; 3(S)-(4-Ethoxy-3-fluorophenyl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro 15 [1, 8lnaphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(5-Ethoxy-pyridin-3-y1)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 20 3(S)-(5-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyidin-2-yl) propyl]-pyrrolidin- 1-yl)-propionic acid; 25 3(S)-(6-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(2-Oxo-2,3-dihydro-1H-4-oxa- 1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 30 (5,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) propionic acid; 3(S)-(2,3-Dihydro- 1H-4-oxa- 1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5 ,6,7,8-tetrahydro- [1,8llnaphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) 35 propionic acid; - 50 wu v Y/)auy PCT/US98/26539 3(S)-(2-Oxo-3 ,4-dihydro-2H- 1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5 ,6,7,8-tetrahydro-[ 1,8lnaphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) propionic acid; 5 3(S)-(3,4-Dihydro-2H- 1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5 ,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) propionic acid; 10 3-(Furo-[2 ,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl-pyrrolilin- 1-yl)-propionic acid; 3-(2,3-Dihydrofuro[2,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6,7 ,8-tetrahydro [1,8]naphthyriclin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 15 3-(Furo-[3 ,2-blpyriclin-6-yl)-3-(2-oxo-3-[3-(5,6,7 ,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3-(2,3-Dihydrofuro[3 ,2-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6, 7,8-tetrahydro 20 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(Benziinidazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyll-pyrrolidin- 1-yl)-propionic acid; 25 3(S)-( 1H-Jmidazo[4,5-clpyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2 -yl)-propyl]-pyrrolidin- 1-yl)-.propionic acid; 3(S)-(Benzoxazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl] -pyrrolidin- l-yl )-propionic acid; 30 3(S)-(1-Methyl-1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl-pyrrolidin-1 -yl)-propionic acid; 3(S)-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8llnaphthyrridin-2-yl)-propyll 35 pyrrolidin- 1-yl}-pent-4-enoic acid; _ 51 wu v~/iu/UY PCT/US98/26539 and the pharmaceutically acceptable salts thereof. Further illustrative of the present invention are compounds 5 selected from the group consisting of 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 10 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 15 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 20 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(Quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 25 and the pharmaceutically acceptable salts thereof. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds 30 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, 35 benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, - 52- WU 9/.Ju7U9 PCT/US98/26539 bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, 5 isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, 10 tannate, tartrate, teoclate, tosylate, triethiodide and valerate. 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 15 organic ligands, e.g., quaternary ammonium salts. The compounds of the present invention can have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, 20 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. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention. 25 The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" 30 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 vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, 35 for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, - 53wu YYv/ioui/UY PCT/US98/26539 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 5 that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. The term "integrin receptor antagonist," as used herein, refers to a compound which binds to and antagonizes either the avP3 10 receptor, the ev35 receptor, or the avP6 receptor, or a compound which binds to and antagonizes combinations of these receptors (for example, a dual cvP3/ocvP5 receptor antagonist). The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone. 15 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 20 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. 25 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 30 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 alkoxides of the number of carbon atoms specified (e.g., - 54- WV YvY/iu/UY PCT/US98/26539 C1-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.). The term "aryl," as used herein, refers to a monocyclic or polycyclic system comprising at least one aromatic ring, wherein the 5 monocylic or polycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, 0, or S, and wherein the monocylic or polycylic system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Ci-10 alkyl, C3-8 cycloalkyl, aryl, aryl 01-8 alkyl, amino, amino C1-8 alkyl, C1-3 10 acylamino, 01-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, 01-6 dialkylamino, C1-6 dialkylamino-Cl:-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1 5 alkoxycarbonyl, C1-3 alkoxycarbonyl 01-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or C1 15 5 alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrryl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more 20 groups independently selected from hydrogen, halogen, CI-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, 01-3 acylamino, C1-3 acylamino C1-8 alkyl, 01-6 alkylamino, C1-6 alkylamino-C1-8 alkyl, 01-6 dialkylamino, 01-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl 25 C1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or C1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-, tri- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is 30 unsubstituted, mono-, di- or tri-substituted with one to three of the above named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents. Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aryl CO-8 alkyl) it shall be -55wu vIJouuO PCT/US98/26539 interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., CI-10l) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl 5 appears as its prefix root. The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, 10 phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine. In the compounds of the present invention, two R 1 15 substituents, when on the same carbon atom, can be taken together with the carbon to which they are attached to form a carbonyl group. In the compounds of the present invention, two R 3 substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group. In 20 such instances, the limitation, that in the resultant compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom, does not apply. Also, in the compounds of the present invention, two R 3 substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are 25 attached to form a cyclopropyl group. In the compounds of the present invention, R 5 and R 6 can be taken together with the carbon atom to which they are attached to form a carbonyl group. In such instances, the limitation, that in the resultant compound the carbon atom to which R 5 and R 6 is attached is 30 itself attached to no more than one heteroatom, does not apply. The term "halogen" shall include iodine, bromine, chlorine, and fluorine. The term "oxy" means an oxygen (0) atom. The term "thio" means a sulfur (S) atom. The term "oxo" means "=0". The term 35 "carbonyl" means "C=O." - 56wu /~WiutJ9 PCT/US98/26539 The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or 5 claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described 10 first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to O II -C1-6 alkyl-NH-C-C1- 5 alkyl. In choosing compounds of the present invention, one of 15 ordinary skill in the art will recognize that the various substituents, i.e. W,X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , RO 10 , R 1 1 , and R 12 , and the subscripts m, n, p, r, s, t and v are to be chosen in conformity with well known principles of chemical structure connectivity. Representative compounds of the present invention typically 20 display submicromolar affinity for the integrin receptors, particularly the vP3, avP5, and/or cv16 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, 25 including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts. The compounds of the present invention are administered in dosages effective to antagonize the avP3 receptor where such treatment is needed, as, for example, in the prevention or treatment of 30 osteoporosis. Further exemplifying the invention is the method wherein the integrin receptor antagonizing effect is an av3 antagonizing effect. -57wu mi/riu- PCT/US98/26539 An illustration of the invention is the method wherein the avP3 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis. Preferably, 5 the avP3 antagonizing effect is the inhibition of bone resorption. An example of the invention is the method wherein the integrin receptor antagonizing effect is an av35 antagonizing effect. More specifically, the av05 antagonizing effect is selected from inhibition of: restenosis, angiogenesis, diabetic retinopathy, macular 10 degeneration, inflammation, tumor growth, or metastasis. Illustrating the invention is the method wherein the integrin receptor antagonizing effect is a dual avP3/(avP5 antagonizing effect. More particularly, the dual avi3/av35 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, 15 diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis. Illustrating the invention is the method wherein the integrin receptor antagonizing effect is an avP6 antagonizing effect. More particularly, the avP6 antagonizing effect is selected from 20 inhibition of angiogenesis, inflammatory response, or wound healing. Illustrating the invention is the method wherein the avI3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of 25 atherosclerosis, inflammation, viral disease, or inhibition of tumor growth or metastasis. Preferably, the av3 antagonizing effect is the inhibition of bone resorption. More particularly illustrating the invention is a pharmaceutical composition comprising any of the compounds 30 . 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 process for making a pharmaceutical composition - 58wu V 1ulu Y PCT/US98/26539 comprising combining any of the compounds described above and a pharmaceutically acceptable carrier. Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of an integrin 5 receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above. Preferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral 10 disease, cancer, tumor growth, and metastasis. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis. More specifically exemplifying the invention is a method of eliciting an integrin antagonizing effect in a mammal in need thereof, 15 comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. Preferably, the integrin antagonizing effect is an av3 antagonizing effect; more specifically, the av3 antagonizing effect is selected from inhibition of bone resorption, 20 inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation, inhibition of viral disease, or inhibition of tumor growth or metastasis. Most preferably, the avP3 antagonizing effect is inhibition of bone resorption. Alternatively, the 25 integrin antagonizing effect is an avP5 antagonizing effect, an av6 antagonizing effect, or a mixed av[3, av5, and avP6 antagonizing effect. Examples of avf5 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, or tumor growth. Examples 30 of dual avP6 antagonizing effects are inhibition of angiogenesis, inflammatory response and wound healing. Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the - 59wu w~w/JvUY PCT/US98/26539 mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone 5 metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical 10 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 15 use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and/or angiogenesis. 20 Also exemplifying the invention are compositions further comprising an active ingredient selected from the group consisting of a.) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b.) an estrogen receptor modulator, 25 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, 30 g.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, h.) a cathepsin K inhibitor, and i.) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; 35 and mixtures thereof. - 60wu Y/JUTu9 PCT/US98/26539 (See, B. Millauer et al., "Dominant-Negative Inhibition of Flk-1 Suppresses the Growth of Many Tumor Types in Vivo", Cancer Research, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety). 5 Preferably, the active ingredient is selected from the group consisting of: a.) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b.) an estrogen receptor modulator, and 10 c.) a cathepsin K inhibitor; and mixtures thereof. Nonlimiting examples of such bisphosphonates include alendronate, etidronate, pamidronate, risedronate, ibandronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially alendronate 15 monosodium trihydrate. Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene. Nonlimiting examples of cytotoxic/antiproliferative agents 20 are taxol, vincristine, 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, 25 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 30 resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis. The present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis. For example, the 35 compounds of the instant invention may be effectively administered in -61- WO 99/307U9 PCT/US98/26539 combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, or a cathepsin K inhibitor. Additional illustrations of the invention are methods of 5 treating tumor growth 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 10 tumor growth and metastasis. In addition, the integrin av3 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 15 associated diseases. These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic 20 lesions and reduce the incidence and/or growth of those lesions. These diseases include: osteoporosis (including estrogen deficiency, immobilization, glucocorticoid induced and senile), osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, 25 cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, 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 this treatment. Similarly, the present invention would be 30 useful in increasing bone mass in patients with growth hormone deficiency. Thus, preferred combinations are simultaneous or alternating treatments of an av3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably 35 alendronate monosodium trihydrate. -62- WIU 99/JU7U9 PCT/US98/26539 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 5 invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating integrin-mediated conditions includes in principle 10 any combination with any pharmaceutical composition useful for treating osteoporosis. 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 15 indirectly, from combination of the specified ingredients in the specified amounts. The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, 20 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 25 arts. An effective but non-toxic amount of the compound desired can be employed as an av33 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 30 severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An 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 35 condition. - 63- WU YJW3U MY PCTIU595/ZOS39 Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral 5 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 10 ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute 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 15 administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be 20 administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are 25 typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. 30 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; 35 for oral administration in liquid form, the oral drug components can be - 64wU 99/JU709 PCT/US98/26539 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 5 binders include starch, gelatin, natural sugars such as glucose or beta lactose, corn sweeteners, 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 10 benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small 15 unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the 20 compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted 25 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, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 30 polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels. In the schemes and examples below, various reagent symbols and abbreviations have the following meanings: AcOH: Acetic acid. 35 BH3 *DMS: Borane* dimethylsulfide. - 65wo 99/JU709 PCT/US98/26539 BOC(Boc): t-Butyloxycarbonyl. BOP: Benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate. CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl. 5 CDI: Carbonyldiimidazole.

CH

2 C1 2 : Methylene chloride. CH3CN: Acetonitrile CHC1 3 : Chloroform. DEAD: Diethyl azodicarboxylate. 10 DIAD: Diisopropyl azodicarboxylate. DIBAH or DIBAL-H: Diisobutylaluminum hydride. DIPEA: Diisopropylethylamine. DMAP: 4-Dimethylaminopyridine. 15 DME: 1,2-Dimethoxyethane. DMF: Dimethylformamide. DMSO: Dimethylsulfoxide. DPFN: 3,5-Dimethyl- 1-pyrazolylformamidine nitrate. EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide -HC1 20 EtOAc: Ethyl acetate. EtOH: Ethanol. HOAc: Acetic acid. HOAT: 1-Hydroxy-7-azabenzotriazole HOBT: 1-Hydroxybenzotriazole. 25 IBCF: Isobutylchloroformate LDA: Lithium diisopropylamide. MeOH: Methanol. MMNG 1,1-methyl-3-nitro- 1-nitrosoguanidine NEt3: Triethylamine. 30 NMM: N-methylmorpholine. PCA*HCI: Pyrazole carboxamidine hydrochloride. Pd/C: Palladium on activated carbon catalyst. Ph: Phenyl. pTSA p-Toluenesulfonic acid. 35 TEA: Triethylamine. - 66wu 99/.U7U9 PCT/US98/26539 TFA: Trifluoroacetic acid. THF: Tetrahydrofuran. TLC: Thin Layer Chromatography. TMEDA: N,N,N',N'-Tetramethylethylenediamine. 5 TMS: Trimethylsilyl. 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 10 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 conditions and processes of the following preparative 15 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 representative compounds of the present invention. Moreover, by utilizing the procedures described in detail in PCT 20 International Application Publication Nos. WO95/32710, published 7 December 1995, and WO95/17397, 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 readily prepare additional compounds of the present invention claimed 25 herein. Additionally, for a general review describing the synthesis of P-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 fl-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi, E, et al., Enantioselective Synthesis of fl-Amino Acids, Aldrichimica 30 Acta, 1994, 27, 3. In particular, synthesis of the 3-methyl-p-alanine is taught in Duggan, M.F. et al., J. Med. Chem., 1995, 38, 3332-3341; the 3 ethynyl-p-alanine is taught in Zablocki, J.A., et al., J. Med. Chem., 1995, 38, 2378-2394; the 3-(pyridin-3-yl)-j-alanine is taught in Rico, J.G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino- and 2-tosylamino-p 35 alanines are taught in Xue, C-B, et al., Biorg. Med. Chem. Letts., 1996, - 67- WU 99/I.5U7U9 PCT/US98/26539 6, 339-344. The references described in this paragraph are all also incorporated by reference herein in their entirety. SCHEME 1 CPh 3

PCHCO

2 Et CHO CH2C 2 " CO2E t F F 1-1 1-2 H Ph Ph N Ph -Ph. 1. Me Ph N CO 2 Et nBuLi, THF Me 2. H 2 0 F 1-3 1. Pd(OH) 2 , H 2 , H 2 N CO 2 Et EtOH, HOAc, H 2 0 CHCI 2. HCI, ether F 1-4 - 68vvu. wro.utuy PCIU59/ZLOSSY Ethyl 3-fluorocinnamate (1-2) To a solution of 3-fluorobenzaldehyde 1-1 (18.16 g, 146 mmol) in dichloromethane (500 mL) was added ethyl (triphenylphosphoranylidene)acetate (61.2 g; 176 mmol), and the 5 resulting solution was stirred at room temperature for 18 hr. After evaporation of the solvent, the residue was swirled with ether/hexane and filtered. The filtrate was concentrated and then purified on a plug of silica gel eluting with hexane/EtOAc 9:1. Removal of the solvent afforded the title compound 1-2 as an oil (-95% trans) which was used 10 without further purification in the next step. 1H NMR(CDC13) 5 1.36 (3H, t), 4.28 (2H, q), 6.43 (1H,-d),. 7.08 (1H, m), 7.2 7.4 (3H, m), 7.64 (1H, d). N-Benzvl-(R)-ac-methylbenzvl-3(S)-fluorophenvl-3-alanine ethyl ester (1-3) 15 To a solution of N-benzyl-(R)-a-methylbenzylamine (33.4 g, 158 mmol) in THF (450 mL) at 0 0 C was added n-butyllithium (1.6M in hexanes; 99 mL, 158 mmol). The dark violet solution was stirred at 0 0 C for 30 minutes, cooled to -78 0 C, and the ester 1-2 (29.2 g, 150 mmol) in THF (100 mL) was added over 5 minutes. The resulting solution was 20 stirred at -78 0 C for 1 hr., then warmed to room temperature. After 2 hrs, the mixture was poured into water and extracted with EtOAc, washed with water then brine, dried and concentrated in vacuo to give an oil. Column chromatography (silica gel; hexane/EtOAc 1:1 then pure EtOAc) gave the title compound 1-3. 25 1H NMR (CDC13): 5 1.06 (3H, t), 1.28 (3H, d), 2.52 (1H, dd), 2.62 (1H, dd), 3.66 (1H, d), 3.72 (1H, d), 3.95 (2H, q), 4.44 (1H, dd), 6.95 (1H, m), 7.1-7.5 (13H, m). 3(S)-Fluorophenvyl--alanine ethyl ester hydrochloride (1-4) 30 A solution of the N-benzyl-(R)-a-methylbenzylamine 1-3 (28.2 g, 69.6 mmol) in ethanol (300 mL), acetic acid (30 mL) and water (3 mL) was degassed with argon for 30 minutes. Pd(OH)2 on carbon (20% dry weight; 2.6 g) was added and the mixture then stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered 35 through celite and the solvent removed in vacuo to give an oil. This oil - 69- VVUJ 77I3UIUSJ i'LTIILJb95/ZOB was dissolved in 200 mL ether and to this solution was added 60 mL 1N HCl in ether to yield a precipitate. Filtration and washing the solid with ether/hexane then gave the title compound 1-4 as a white solid. 1H NMR(CD3OD) 5 1.21 (3H, t), 3.0-3.2 (2H, m), 4.16 (2H, q), 4.76 (1H, t), 5 7.2-7.35 (3H, m), 7.5 (1H, m). - 70wu wwou/tY PCT/U 95/26539 SCHEME 2 O

CO

2 Et 2-1 ethylene glycol, pTSA, toluene, reflux O C0 2 R 2-2 a) pivaloyl chloride, NEt 3 , THF b) Li oxazolidinone oo 0 N 0 y 2-3 0 O a) LiN(TMS) 2 , THF b) allyl bromide X 0 0 2-4, X=CH 2 N 0 2-5, X=O 03 0 0 -71wu /J/UY PCT/US98/26539 SCHEME 2 (CONTINUED) Ny 0 0 2-5 HCIl*H 2 N

CO

2 Et Na(OAc) 3 BH, NEt 3 , H: C 2 Et dichloroethane / F 1-4 0-0 O N CO 2 Et OH~ F TsOH, acetone, reflux N. N CO 2 Et 2-7 F CHO proline, I ethanol, reflux N NH 2 NI N N N CO 2 Et O H 28 V-F -72 - WU 99/.5U0709 PCT/US98/26539 SCHEME 2 (CONTINUED) C N N N N CO 2 Et 0 2 OH' F 10% Pd/C, ethanol, H 2 N N N CO 2 Et H OH 2-9 F 1N NaOH, ethanol H,,NO NN N N CO2H H H 2-10 F N N N CO 2 H H 0 H 2-11 F - 73- WU 99/30709 PCT/US98/26539 5-(2-methyl-[1,31dioxolan-2-vl)-pentanoic acid (2-2) A mixture of ketone 2-1 (18 g, 105 mmol), ethylene glycol (3.2 ml, 110 mmol), p-TSA (50 mg, 0.2713 mmol) and toluene (300 mL) was heated to reflux with azeotropic removal of water for 24 hours. The 5 reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated. The residue was dissolved in EtOH (200 ml) and then treated with 1N NaOH (120 ml, 120 mmol). After 2 h, the reaction was poured into 600 mL 2:1 Et20/10% KHSO4. The organic portion was separated, washed with brine, dried 10 (MgSO4) and concentrated to give acid 2-2 as a colorless oil. 1H NMR (300 MHz, CDC13) 5 3.93 (m, 4H), 2.36 (m, 2H),.1.63 (m, 4H), 1.46 (m, 2H), 1.31 (s, 3H). 3-[5-(2-methyl-r[1,3]dioxolan-2-yl)-pentanov11-oxazolidin-2-one (2-3) 15 To a stirred solution of 2-2 (16.0 g, 85.5 mmol), NEt3 (13.1 ml, 94.1 mmol) and THF (400 mL) at -78oC was added pivaloyl chloride (11.6 ml, 94.1 mmol). The mixture was warmed to 0oC for 1.0 h and then recooled to -780C. To a stirred solution of 2-oxazolidinone (9.3g, 106.9 mmol) and THF (200 ml) at -78 0 C was added nBuLi (43.0 ml, 106.9 mmol, 20 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0OC for 1.0h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the 25 residue was chromatographed (silica gel, 40% - 50% EtOAc/hexanes) to give 2-3 as a colorless foam. TLC Rf = 0.19 (silica, 40% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 4.41 (t, J=8.1 Hz, 2H), 4.02 (t, J=8.1 Hz, 2H), 3.93 (m, 4H ), 3.93 (t, J=7.3 Hz, 2H), 1.66 (m, 4H), 1.48 (m, 2H), 1.31 (s, 30 3H). 3-(2-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-pent-4-enoyl)-oxazolidin 2-one (2-4) To a stirred solution of 2-3 (6.0 g, 23.3 mmol) and THF (125 35 mL) at -78 0 C was added LiN(TMS)2 (18.9 mL, 37.8 mmol, 1.0 M in THF) - 74- VV YvY/iu/u PCT/U9S5/20539 dropwise over 10 minutes. After 20 minutes, allyl bromide was added. After 10 minutes, the reaction was warmed to 0 0 C. After 4.0 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% 5 EtOAc/ hexanes) gave 2-4 as an yellow oil. TLC Rf = 0.26 (silica, 50% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 5.76 (m, 1H), 5.02 (m, 1H), 4.40 (t, J=8.3 Hz, 2H), 4.02 (m, 2H), 3.99 (m, 4H), 2.39 (m, 1H), 2.27 (m, 1H), 1.72 (m, 1H), 1.62 (m, 2H) 1.39 - 1.53 (m, 3H), 1.30 (s, 3H). 10 6-(2-methyl-[1,3]dioxolan-2-yl)-3-(2-oxo-oxazolidine-3-carbonyl) hexanal (2-5) To a stirred solution of 2-4 (4.0 g, 13.5 mmol), sudan III (10 mg) and CH2C12 (350 mL) at -78oC under argon was bubbled ozone until 15 red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (5.28g, 20.3 mmol) was added followed by the removal of the cooling bath. After 3.0 h, the reaction was concentrated. Flash chromatography (silica, 20% - 50% EtOAc/ hexanes) gave 2-5 as a yellow oil. 20 TLC Rf = 0.15 (silica, 50% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 8 9.74 (s, 1H), 4.43 (m, 2H), 4.15 (m, 1H), 4.03 (m, 2H), 3.91 (m, 4H), 3.04 (m, 1H), 2.67 (dd, J=3.9 Hz, 18.6 Hz, 1H),1.65 (m, 3H), 1.45 (m, 3H), 1.29 (s, 3H). 25 3(S)-(3-Fluorophenyl)-3-(3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl] 2-oxo-pyrrolidin-1-v1)-propionic acid ethyl ester (2-6) A mixture of 2-5 (302 mg, 1.11 mmol), 1-4 (300 mg, 1.21 mmol), Na(OAc)3BH (321 mg, 1.52 mmol) and NEt3 (0.28 mL, 2.02 mmol) in DCE (10 mL) was stirred for 48 h. The mixture was diluted with ethyl 30 acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50:35:14:1 hexanes/ chloroform/ ethyl acetate/ MeOH) to give 2-6 as a white solid. TLC Rf = 0.41 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH) - 75vvwu uYY/3UU PCT/US98/26539 1 H NMR (300 MHz, CDC13) 8 7.30 (m, 1H), 7.07 (m, 1H), 6.98 (m 3H), 5.68 (m, 1H), 4.12 (m, 2H), 3.92 (m, 4H), 3.30 (m, 1H), 2.97 (m, 3H), 2.38 (m, 1H), 2.14 (m, 1H), 1.86 (m, 1H), 1.64 (m, 4H), 1.42 (m, 2H), 1.30 (2s, 3H), 1.22 (t, J=7.3Hz, 3H). 5 3(S)-(3-Fluorophenyl)-3-[2-oxo-3-(4-oxo-pentyl)-pyrrolidin-1-yl] propionic acid ethyl ester (2-7) A solution of 2-6 (450 mg, 1.10 mmol), p-TSA (50 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction 10 mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 2-7 as a yellow solid. 1 H NMR (300 MHz, CDC13) 5 7.30 (m, 1H), 7.06 (m, 1H), 6.98 (m, 2H), 5.67 (m, 1H), 4.12 (m, 2H), 3.23 (m, 1H), 2.97 (m, 2H), 2.33 - 2.49 (m, 3H), 2.14 15 (2s, 3H), 1.54 -1.86 (m, 5H), 1.33 (m, 1H), 1.22 (t, J=7.1Hz, 3H). 3(S)-(3-Fluorophenyl)-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-2-oxo pvrrolidin-1-vyl]-propionic acid ethyl ester (2-8) A mixture of 2-7 (430 mg, 1.18 mmol), 2-amino-3 20 formylpyridine (144 mg, 1.18 mmol; for prep., see JOC 1983,48, 3401) and proline (136 mg, 1.18 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/ chloroform - 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-8 as a yellow solid. 25 TLC Rf = 0.30 (70:25:5 chloroform/ethyl acetate/MeOH). 1 H NMR (300 MHz, CDC13) 5 9.08 (m, 1H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H), 8.11 (d, J=8.3 Hz, 1H), 7.42 (m, 2H), 7.27 (m, 1H), 7.06 (m, 1H), 6.97 (m, 2H), 5.66 (m, 1H),4.11 (m, 2H), 3.29 (m, 1H), 2.95 -3.07 (m, 5H), 2.46 (m, 1H), 2.18 (m, 1H), 1.98 (m, 2H), 1.71 (m, 2H), 1.46 (m, 1H), 1.19 (m, 3H). 30 3(S)-(3-Fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthy ridin-2-vyl)-propyll-pvrrolidin-1-vl)-propionic acid ethyl ester (2-9) A mixture of 2-8 (340 mg, 0.7991 mmol) and 10% Pd/carbon (170 mg) in EtOH (10 mL) was stirred under a balloon of hydrogen for 4 - 76- WU Y/iU/UV PCT/US98/26539 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-9 as a yellow oil. TLC Rf= 0.16 (70:25:5 chloroform/ethyl acetate/MeOH). 5 1 H NMR (300 MHz, CDC13) 5 7.29 (m, 1H,), 6.98 (m, 4H), 6.33 (m, 1H), 5.66 (m, 1H), 4.76 (b s, 1H), 4.10 (m, 2H), 3.38 (m, 1H),3.28 (m, 1H), 2.95 (m, 3H),2.68 (t, J=6.3 Hz, 2H), 2.55 (m, 2H), 2.40 (m, 1H), 2.13 (m, 1H) 1.92 (m, 4H), 1.61 (m, 3H), 1.37 (m, 1H), 1.23 (m, 3H). 10 3(S)-(3-Fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthy ridin-2-vl)-propy1-pvrrolidin-1-v1)-propionic acid (2-10 and 2-11) To a solution of 2-9 (300 mg, 0.6614 mmol) in EtOH (3 mL) was added 1N NaOH (0.725 ml, 0.725 mmol). After stirring for 1 h, the solvents were evaporated and the residue was chromatographed (silica 15 gel, 25:10:1:1 - 15:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 2-10 and 2-11 as pure diastereomeric white solids. TLC Rf = 0.31 (2-10) (15:10:1:1 ethyl acetate/EtOH/water/NH4OH). TLC Rf = 0.24 (2-11) (15:10:1:1 ethyl acetate/EtOH/water/NH4OH). 1 H NMR (300 MHz, CD3OD, 2-10) 8 7.44 (d, J=7.3 Hz, 1H), 7.37 (m, 1H), 20 7.14 (m, 1H), 7.06 (m, 2H,), 6.50 (d, J=7.3 Hz, 1H,), 5.78 (m, 1H), 3.55 (m, 1H), 3.46 (m, 2H), 3.11 (m, 1H), 2.61 -2.97 (m, 7H),2.12 (m, 1H) 1.74 -1.95 (m, 7H). 1H NMR (300 MHz, CD3OD, 2-11) 6 7.34 (m, 2H), 7.15 (m, 2H), 7.03 (m, 1H), 6.47 (d, J=7.3 Hz, 1H,), 5.50 (m, 1H), 3.46 (m, 3H), 3.00 (m, 1H),2.79 25 (m, 3H), 2.62 (m, 2H),2.54 (m, 1H), 2.23 (m, 1H), 1.93 (m, 2H), 1.69 (m, 5H), 1.44 (m, 1H). - 77wu 9/d9uU PCT/US98/26539 SCHEME 3 OEt OH OEt OEt 1 Br OEt O Br NaH, DMF 3-1 Br 3-2 PPA, PhMe 0 Ethyl Acrylate,0 Pd(OAc) 2 , DMF IT Br 3-4 CO 2 Et 3-3 Me Ph N Ph H nBuLi, THF 0 0 Pd(OH) 2 , H2 Me Ph ~N CO2Et

H

2 N .. CO2Et I Bn 3-5 3-6 - 78wu 991/J0709 PCT/US98/26539 1-Bromo-3-(2,2-diethoxv-ethoxy)-benzene (3-2) To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0 0 C was added a solution of 3-bromophenol 3-1 in DMF (40 mL) over 40 min. After the addition was complete, the solution was stirred 5 for an additional 30 min. The solution was then treated with neat bromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). The solution was heated at 100 0 C for 8 h, cooled to room temperature, and extracted with Et20 (3 x 200 mL). The combined organic extracts were washed with 10% aq. NaOH (100 mL) and brine (100 mL), dried over MgSO4, 10 filtered and concentrated to give 3-2 as a yellow oil. TLC Rf = 0.4 (10% ethyl acetate/hexanes). 1 H NMR (300 MHz, CHC13) 5 7.19-7.05 (m, 3H), 6.85 (d, 1H), 4.81 (t, 1H, J=6.8 Hz), 3.99 (d, 2H, J=6.8 Hz), 3.71 (m, 4H), 1.22 (t, 6H, J=7.1 Hz) 15 6-Bromo-benzofuran (3-3) To a solution of the acetal 3-2 in toluene (200 mL) was added polyphosphoric acid (20 g). The biphasic mixture was heated to 100'C and stirred at this temperature for 4 h. The mixture was cooled to room temperature, poured onto ice, and extracted with Et20 (2 x 200 mL). The 20 combined organic extracts were washed with saturated aq. NaHCO3 and brine. The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (100% hexanes) to give the product 3-3 as a yellow oil. TLC Rf = 0.3 (100% hexanes). 25 1 H NMR (300 MHz, CHC13) 8 7.68 (s, 1H), 7.60 (d, 1H, J=2.1 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.1, 1.5 Hz), 6.75 (dd, 1H, J=7.1, 0.9 Hz). 3-(Benzofuran-6-vl)-acrvlic acid ethyl ester (3-4) A mixture of the 6-bromobenzofuran 3-3 (1.74 g, 8.79 mmol), 30 ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44 mmol), tri-o tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100'C in a sealed tube for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted with Et20 (2 x 40 mL). The combined organic extracts were 35 washed with brine (30 mL), dried over MgSO4, filtered, and - 79- WU 99/30709 PCT/US98/26539 concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the ester 3-4 as an off-white solid. TLC Rf = 0.3 (10% ethyl acetate/hexanes). 1 H NMR (300 MHz, CHC13) 8 7.78 (d, 1H, J=15.9 Hz), 7.68 (d, 1H, J=2.4 5 Hz), 7.66 (s, 1H), 7.59 (d, 1H, J=8.4 Hz), 7.43 (dd, 1H, J=9.0, 1.5 Hz), 6.78 (m, 1H), 6.47 (d, 1H, J=15.9 Hz), 4.27 (q, 2H, J=7.2 Hz), 1.34 (t, 3H, J=7.2 Hz). 3(S)-(Benzofuran-6-yl)-3-[benzyl-(1(R)-phenyl-ethyl)-amino]-propionic 10 acid ethyl ester (3-5) A solution of N-benzyl-a-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 0 0 C was treated with n-BuLi (2.52 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0 0 C for 30 min and then cooled to -78 0 C. A solution of acrylate 3-4 (0.681 g, 3.15 mmol) in 15 THF (5 mL) was added. After stirring for 15 min at -78 0 C, satd. aq. NH4C1 soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et20 (2 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by 20 flash chromatography (10% ethyl acetate/hexanes) to give the 3 aminoester 3-5 as a yellow oil. TLC Rf = 0.8 (10% ethanol/dichloromethane). 1H NMR (300 MHz, CHC13) 5 7.58 (m, 3H), 7.41 (m, 2H), 7.22 (m, 9H), 7.59 (s, 1H), 4.58 (m, 1H), 4.05 (m, 1H), 3.91 (q, 2H, J=7.1 Hz), 3.72 (m, 2H), 25 2.62 (m, 2H), 1.21 (d, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.1 Hz). 3(S)-Amino-3-(2,3-dihydro-benzofuran-6-yl)-propionic acid ethyl ester (3-6) A mixture of the dibenzylamine 3-5 (1.19 g, 2.78 mmol) in 30 EtOH/H20/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (1.19 g). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc, and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (10% ethyl acetate/dichloromethane) to 35 give the ester 3-6 as a white solid. - 80wu 9/JU7UY PCT/US98/26539 TLC Rf = 0.25 (10% ethanol/dichloromethane). 1H NMR (300 MHz, CD3OD) as the trifluoroacetate salt: 8 7.25 (d, 1H, J=8.1 Hz), 6.88 (m, 1H), 7.66 (s, 1H), 6.82 (s, 1H), 4.58 (m, 3H), 4.12 (m, 2H), 3.30 (m, 1H), 3.19 (m, 2H), 2.98 (m, 2H), 1.11 (t, 3H, J=7.2 Hz). 5 -81- WU 99/U0709 PCT/US98/26539 SCHEME 4 0 OlO [-lf1 00 NO O~OO 0 0 2-5

HCI*H

2 N

CO

2 Et Na(OAc) 3 BH, NEt 3 , .H 2E dichloroethane / 00 00 N O] H CO 2 Et 0 4-1 0 TsOH, acetone, reflux CO 2 Et O H o 4-2 0 CHO proline,CHO ethanol, reflux I N NH 2 N N N CO 2 Et 0 H/ 4-3 0 - 82 - WU) 991/JU709 PCT/US98/26539 SCHEME 4 (CONTINUED) N N N CO 2 Et H0 4-3 10% Pd/C, ethanol, H 2 N N N C02Et H 0 H 4-4 0 IN NaOH, ethanol IH,,, N op N N CO 2 H H H wH O 4-5 0 and N N NN CO 2 H H H 4- 0 5 - 83- WO 99/30709 PCT/US98/26539 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(3-[3-(2-methyl-[1,3]dioxolan 2-vl)-propyll-2-oxo-pvrrolidin-1-vl)-propionic acid ethyl ester (4-1) A mixture of 2-5 (440 mg, 1.6 mmol), 3-6 (400 mg, 1.5 mmol), Na(OAc)3BH (469 mg, 2.25 mmol) and NEt3 (0.41 mL, 3.0 mmol) in 5 dichloroethane (10 mL) was stirred for 48 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50:35:14:1 hexanes/ chloroform/ ethyl acetate/ MeOH) to give 4-1 as a white solid. 10 TLC Rf = 0.45 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH) 1 H NMR (300 MHz, CDC13) 5 7.15 (m, 1H), 6.78 (m, 1H), 6.70 (m 1H), 5.63 (m, 1H), 4.58 (m, 2H), 4.12 (q, J=7 Hz, 2H), 3.92 (m, 4H), 3.40-2.80 (m, 6H), 2.38 (m, 1H), 2.14 (m, 1H), 1.86 (m, 1H), 1.64 (m, 4H), 1.42 (m, 2H), 1.30 (m, 3H), 1.22 (t, J=7 Hz, 3H). 15 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[2-oxo-3-(4-oxo-pentyl) pvrrolidin-1-v11-propionic acid ethyl ester (4-2) A solution of 4-1 (600 mg, 1.4 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction 20 mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 4-2 as a colorless oil. 1 H NMR (300 MHz, CDC13) 8 7.15 (m, 1H), 6.78 (m, 1H), 6.70 (m 1H), 5.63 (m, 1H), 4.58 (m, 2H), 4.12 (q, J=7 Hz, 2H), 3.35-2.90 (m, 6H), 2.49-2.30 (m, 25 3H), 2.13 (2s, 3H), 1.90-1.50 (m, 5H), 1.33 (m, 1H), 1.22 (t, J=7 Hz, 3H). 3(S)- (2,3-Dihydro-benzofuran-6-yl)-3-[3-(3-[1,8]naphthyridin-2-yl propyl)-2-oxo-pvrrolidin-1-vl]-propionic acid ethyl ester (4-3) A mixture of 4-2 (540 mg, 1.4 mmol), 2-amino-3 30 formylpyridine (170 mg, 1.4 mmol; for prep. see JOC 1983,48, 3401) and proline (161 mg, 1.4 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/ chloroform 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-3 as a yellow oil. 35 TLC Rf = 0.21 (70:25:5 chloroform/ethyl acetate/MeOH). - 84- WV~ YY/3UIMY 1 H NMR (300 MHz, CDC13) 8 9.08 (m, 1H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H), 8.11 (d, J=8.3 Hz, 1H), 7.42 (m, 2H), 7.10 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 5.63 (m, 1H),4.57 (m, 2H), 4.11 (m 2H), 3.29 (m, 1H), 3.30-2.80 (m, 9H), 2.40 (m, 1H), 2.18 (m, 1H), 1.98 (m, 2H), 1.70-1.50 (m, 2H), 1.46 (m, 5 1H), 1.19 (m, 3H). 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid ethyl ester (4-4) 10 A mixture of 4-3 (460 mg, 1.0 mmol) and 10% Pd/carbon (300 mg) in EtOH (20 mL) was stirred under a balloon of hydrogen for 3 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-4 as a yellow oil. 15 TLC Rf= 0.15 (70:25:5 chloroform/ethyl acetate/MeOH). 1 H NMR (300 MHz, CDC13) 5 7.18 (m, 1H,), 7.07 (m, 2H), 6.80 (m, 1H), 6.70 (m, 1H), 6.37 (m, 1H), 5.64 (m, 1H), 4.76 (bs, 1H), 4.55 (m, 2H), 4.10 (q, J=7 Hz, 2H), 3.40 (m, 1H),3.28 (m, 2H), 3.28 (m, 1H), 3.19 (m, 2H), 3.00 (m, 1H), 2.95 (m, 2H),2.69 (m 2H), 2.55 (m, 2H), 2.37 (m, 1H), 2.13 (m, 1H) 1.92 20 (m,3H), 1.75-1.30 (m, 4H), 1.23 (m, 3H). 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid (4-5 and 4-6) 25 To a solution of 4-4 (380 mg, 0.79 mmol) in EtOH (2 mL) was added 1N NaOH (0.93 ml, 0.93 mmol). After stirring for 1 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 - 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 4-5 and 4-6 as pure diastereomeric white solids. 30 TLC Rf = 0.37 (isomer A) (15:10:1:1 ethyl acetate/EtOH/water/NH4OH). TLC Rf= 0.28 (isomer B) (15:10:1:1 ethyl acetate/EtOH/water/NH4OH). 1 H NMR (300 MHz, CD3OD, Isomer A) 8 7.44 (d, J=7 Hz, 1H), 7.16 (d, J=7 Hz, 1H), 6.80 (d, J=7 Hz, 1H,), 6.70 (s, 1H), 6.48 (d, J=7 Hz, 1H,), 5.46 (m, 1H), 4.50 (m, 2H), 3.60-2.50 (m, 13H), 1H), 2.15 -1.70 (m, 8H), - 85wu w /uIu PCT/US98/26539 1H NMR (300 MHz, CD3OD, Isomer B) 8 7.40 (d, J=7 Hz, 1H), 7.13 (d, J=7 Hz, 1H), 6.80 (d, J=7 Hz, 1H,), 6.68 (s, 1H), 6.50 (d, J=7 Hz, 1H,), 5.72 (m, 1H), 4.53 (m, 2H), 3.44 (m, 3H), 3.15 (m, 4H), 2.97 (m, 1H), 2 .70-2.40(m, 6H), 2.20 (m, 1H), 2.00-1.40 (m, 6H). 5 - 86 - W" Y~fliuIUv) PCT/US9li/Z6539 SCHEME 5 55-1 N malonic acid,

NH

4 OAc EtOH (8000) CHO NPhCH 2 000I1 N Et 3 N,o

H

2 N 00 2 H Dioxane/H 2 0 0h N0 2 5-2 Penicillin Amidase pH 78,H 2 0 N

H

2 N: Ph OH C0H H Y C2H H H 5-4 I 6NHCI 500 C N N 2 HCI- H 2 N >'~C02t EtOH, HOI 2 HCI. 2>'C2 5-.7 95% 5-6 - 87 wu 99/iU7U9 PCT/US98/26539 3-Quinolin-3-yl-propionic acid (5-2). A solution containing quinoline-3-carboxaldehyde 5-1 (5 g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g, 63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 5 h. After cooling to room temperature, the resulting white solid was collected by filtration and washed with cold ethanol (150 mL) and then dried under vacuum to provide 5-2 as a white solid (3.84 g, 17.8 mmol, 56%). 1 H NMR (300 MHz, D20): 5 8.91 (d, J = 2 Hz 1H), 8.21 (d, J = 2 Hz, 1H), 10 8.12 (d, J = 8 Hz, 1H), 7.84 (d, J = 7 Hz, 1H), 7.72 (t, J = 7 Hz, 1H), 7.54 (t, J = 7 Hz, 1,H), 4.72 (m, 1H), 2.73 (m, 2H). 3-Phenylacetylamino-3-(quinolin-3-vl)-propionic (5-3) A 00 solution of 5-2 (3.5 g, 16.2 mmol) and NaHCO3 (2.7 g, 15 32.4 mmol) in 50% aqueous dioxane (100 mL) was treated dropwise with a solution of phenylacetyl chloride (3.00 g, 19.4 mmol) in 25 mL of dioxane. The resulting solution was stirred at 00 for 2.5h., then warmed to room temperature, diluted with H20 (50 mL) and washed with ether (2 x 100 mL). The aqueous layer was adjusted to pH = 3 with 3N HC1 and 20 then extracted with CH2C12 (3 x 150 mL). The pooled organic extracts were dried, filtered and concentrated to afford 5-3 as an off-white solid. 1H NMR (300 MHz, CD3OD): 5 8.85 (d, J = 2 Hz 1H), 8.20 (d, J = 2 Hz, 1H), 8.00 (d, J = 8 Hz, 1H), 7.86 (d, J = 7 Hz, 1H), 7.76 (t, J = 7 Hz, 1H), 7.52 (t, J = 7 Hz, 1,H), 7.28 (m, 6H), 5.53 (t, J = 6.8 Hz, 1H), 3.57 (s, 2H), 2. 96 (m, 25 2H). 3(S)-(Quinolin-3-v1)-propionic acid dihydrochloride (5-6) Acid 5-3 (5.0 g, 15 mmol) was suspended in water (3.5 L), then treated with 1N NaOH (15 mL) to afford a clear solution. Penicillin 30 amidase (Sigma, EC 3.5.1.11, 10,000 U) in 0.1 M phosphate buffer was added. The pH of the mixture was adjusted to 7.8 with 1N NaOH and the solution was stirred at room temperature for 4 days. The reaction was monitored periodically by HPLC and the reaction stopped once the 50% conversion was reached. Next, the reaction solution was cooled to 0 0 C 35 and adjusted to pH = 3 with 3N HC1. An oily yellow precipitate formed - 88- WO 99/30709 PCT/US98/26539 which was collected by filtration, then washed with water to afford crude 5-5 (1.8 g, 5.3 mmol). The filtrate was extracted with CH2C12 (3 x 500 mL) to afford additional 5-5 contaminated by phenylacetic acid. Both batches of crude 5-5 were combined and stirred in 6 N HC (200 mL) at 5 500 for 12 h then cooled, washed with ether (2 x 100 mL) and evaporated to afford 5-6. 3(S)-(Quinolin-3-vl)-propionic acid ethyl ester dihvdrochloride (5-7). The resolved acid 5-6 was converted to -7 by refluxing in 10 ethanolic HC1. 1H NMR (300 MHz, CD3OD): 5 9.25 (d, J = 2 Hz 1H), 8.31 (d, J = 2 Hz, 1H), 8.15 (d, J = 8 Hz, 1H), 7.84 (d, J =7 Hz, 1H), 7.72 (t, J = 7 Hz, 1H), 7.54 (t, J = 7 Hz, 1,H), 4.72 (m, 1H), 4.15 (q, J = 6 Hz, 2H), 2.73 (m, 2H) 1.18 (t, J= 6 Hz, 3H). 15 - 89wVU NWlSU/UY PCT/VI'I 125-39 SCHEME 6 N NO 0 0 O O 2-5

HCI.H

2 N C 2 Et Na(OAc) 3 BH, NEt 3 , HK dichloroethane O N H',,.. CO2 Et 6-1 TsOH, acetone, reflux 0 rH CO 2 Et OH

N

6 -2 N -C HO ethanol, reflux N NH 2 N N CO 2 Et 6-3 N 90 -90 wu Y/.JU/UM PCT/US98/26539 SCHEME 6 (CONTINUED) N N CO 2 Et O H 6-3N 10% Pd/C, ethanol, H 2 N N N C2Et H OH' o 6-4 1 N NaOH, ethanol H,,, N '"N N N CO 2 H H O H> ( and 6-6) N- / N N N.. CO 2 H H H

N

- 91 - WU vY/jU7U9 PCT/US98/26539 3(S)-(Quinolin-3-yl)-3-(3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]-2 oxo-pyrrolidin-1-vl)-propionic acid ethyl ester (6-1) A mixture of 2-5 (377 mg, 1.3 mmol), 5-6 (400 mg, 1.3 mmol), Na(OAc)3BH (400 mg, 2.0 mmol) and NEt3 (0.35 mL, 2.6 mmol) in 5 dichloroethane (10 mL) was stirred for 24 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50:35:14:1 hexanes/ chloroform/ ethyl acetate/ MeOH) to give 6-1 as a yellow oil. 10 TLC Rf = 0.47 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH) 1 H NMR (300 MHz, CDC13) 8 8.85 (m, 1H), 8.10-7.40 (mn,-5H), 5.90 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.90 (m, 4H), 3.38 (m, 1H), 3.20-2.95 (m, 3H), 2.40 (m, 1H), 2.14 (m, 1H), 1.90 (m, 1H), 1.74-1.30 (m, 4H), 1.30 (ds, 3H), 1.22 (t, J=7 Hz, 3H). 15 3(S)-(Quinolin-3-yl)-3-[2-oxo-3-(4-oxo-pentyl)-pyrrolidin-1-yl] propionic acid ethyl ester (6-2) A solution of 6-1 (380 mg, 1.0 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction 20 mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 6-2 as a yellow oil. 1 H NMR (300 MHz, CDC13) 5 8.74 (m, 1H), 8.05-7.40 (m, 5H), 5.90 (m, 1H), 4.13 (m, 2H), 3.38 (m, 1H), 3.20-2.95 (m, 3H), 2.50-2.10 (m, 4H), 2.13 (d, J=5 Hz, 3H), 1.90-1.20 (m, 6H), 1.22 (t, J=7 Hz, 3H). 25 3(S)-(Quinolin-3-yl)-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-2-oxo pvrrolidin-1-v1l-propionic acid eth1yl ester (6-3) A mixture of 6-2 (396 mg, 1.0 mmol), 2-amino-3 formylpyridine (138 mg, 1.2 mmol; for prep. see JOC 1983,48, 3401) and 30 proline (218 mg, 2.0 mmol) in absolute ethanol (15 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform to 70:25:5 chloroform/ethyl acetate/MeOH) to give 6-3 as a yellow oil. TLC Rf = 0.23 (70:25:5 chloroform/ethyl acetate/MeOH). - 92wU 99/U0709 PCT/US98/26539 1 H NMR (300 MHz, CDC13) 5 9.08 (m, 1H), 8.85 (m, 1H), 8.20-7.50 (m, 9H), 5.90 (m, 1H), 4.11 (m, 2H), 3.40 (m, 1H), 3.20-2.90 (m, 6H), 2.60-1.40 (m, 6H), 1.22 (m, 3H). 5 3(S)-(Quinolin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthy ridin-2-yl)-propyvl]-pvrrolidin-1-vyl)-propionic acid ethyl ester (6-4) A mixture of 6-3 (380 mg, 0.8 mmol) and 10% Pd/carbon (200 mg) in EtOH (20 mL) was stirred under a balloon of hydrogen for 6 h. Following filtration and evaporative removal of the solvent, the residue 10 was chromatographed (silica gel, 70:25:5 to 70:20:10 chloroform/ethyl acetate/MeOH) to give -4 as a yellow oil. TLC Rf = 0.20 (70:20:10 chloroform/ethyl acetate/MeOH). 1 H NMR (300 MTIHz, CDC13) 5 8.86 (m, 1H), 8.08 (m, 2H), 7.80 (m, 1H), 7.72 (m, 1H), 7.57 (m, 1H), 7.03 (m, 1H), 6.33 (m, 1H), 5.90 (m, 1H), 4.11 (m, 15 2H), 3.40 (m, 3H), 3.15-2.00 (m, 9H), 2.00-1.30 (m, 8H), 1.22 (m, 3H). 3(S)-(Quinolin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthy ridin-2-vl)-propyl]-pvrrolidin-1-vl)-propionic acid (6-5 and 6-6) To a solution of 6-4 (300 mg, 0.62 mmol) in EtOH (3 mL) was 20 added 1N NaOH (0.68 ml, 0.68 mmol). After stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 - 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 6-5 and 6-6 as pure diastereomeric white solids. TLC Rf = 0.32 (isomer A) (10:10:1:1 ethyl acetate/EtOH/water/NII4OH). 25 TLC Rf = 0.28 (isomer B) (10:10:1:1 ethyl acetate/EtOH/water/NH4OH). 1 H NMR (300 MHz, CD3OD, Isomer A) 8 8.85 (d, J=2Hz,, 1H), 8.33 (bs, 1H), 8.00 (m, 2H), 7.78 (m, 1H), 7.44 (d, J=7 Hz, 1H), 6.50 (d, J=7 Hz, 1H,), 6.02 (m, 1H), 3.62 (m, 1H), 3.48 (m, 2H), 3.20-1.90 (m, 3H), 2.80-2.60 (m, 4H), 2.13 (m, 1H), 2.00 -1.70 (m, 8H). 30 1 H NMR (300 MHz, CD3OD, Isomer B) 5 8.85 (d, J=2Hz,, 1H), 8.33 (bs, 1H), 8.00 (m, 1H), 7.95 (m, 1H), 7.75 (m, 1H), 7.62 (m, 1H), 7.33 (d, J=7 Hz, 1H), 6.43 (d, J=7 Hz, 1H,), 5.74 (m, 1H), 3.55 (m, 1H), 3.40 (m, 2H), 3.20 1.95 (m, 2H), 2.72 (m, 2H), 2.58 (m, 3H), 2.23 (m, 1H), 2.00 -1.40 (m, 8H). - 93- WO 99/.5U0709 PCT/US98/26539 SCHEME 7 Ca) pivaloyl chloride,

CO

2 H NEt 3 , THF 7-1 b) Li (S)-(-)-4-benzyl-2-oxazolidinone Ph Ph O ethylene glycol, N.O p-TSA, benzene 0 N O 7-2 0 0 7-3 X P a) LiN(TMS) 2 , THF O 7-4, X=CH 2 b) allyl bromide N O 7-5, X=O 03 1-(4-(S)-benzvyl-2-oxo-oxazolidin-3-yl)-heptane-1,6-dione (7-2) To a stirred solution of 6-oxo-heptanoic acid 7-1 (100 g, 694 5 mmol), NEt3 (111.3 ml, 763.4 mmol) and THF (2000 mL) at -78oC was added pivaloyl chloride (98.7 ml, 763.4 mmol). The mixture was warmed to 0OC for 1.0 h and then recooled to -78oC. To a stirred solution of (S)-(-)-4 benzyl-2-oxazolidinone (136g, 763.4 mmol) and THF (2000 ml) at -78oC was added nBuLi (306 ml, 765 mmol, 2.5M in hexanes) dropwise over 30 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 20 minutes, the reaction was warmed to 0OC for 1.0h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was azeotroped with 15 xylenes to give 7-2 as a colorless foam. TLC Rf = 0.25 (silica, 25% EtOAc/hexanes) - 94wu v Y/.~U/U9 PCT/US98/26539 1 H NMR (300 MHz, CDC13) 5 7.27, (m, 5H), 4.66 (m, 1H), 4.16 (m, 2H), 3.29 (dd, J=3 Hz, 13 Hz, 1H),2.90 (m, 2H ), 2.75 (m, 1H), 2.50 (t, J=7 Hz, 2H), 2.15 (s, 3H), 1.68 (m, 4H). 5 4-(S)-benzyl-3-[5-(2-methyl-[l,3]dioxolan-2-vyl)-pentanovl]-oxazolidin-2-one (7-3) A mixture of ketone 7-2 (695 mmol), ethylene glycol (59 ml, 1040 mmol), p-TSA (500 mg, 2.713 mmol) and benzene (2000 mL) was heated to reflux with azeotropic removal of water for 12 hours. The 10 reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated to give 7-3 as a yellow oil. TLC Rf = 0.25 (silica, 30% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 7.26 (m, 5H), 4.67 (m, 2H), 3.94 (s, 4H), 3.29 15 (m, 1H), 2.95 (m, 2H), 2.76 (m, 1H), 1.71 (m, 4H), 1.50 (m, 2H), 1.32 (s, 3H). 4-(S)-benzvl-3-(R)-(2-[3-(2-methyl-[1,31dioxolan-2-yl)-propyll-pent-4-enoyll} oxazolidin-2-one (7-4) 20 To a stirred solution of 7-3 (695 mmol) and THF (2000 mL) at -78 0 C was added LiN(TMS)2 (915 mL, 915 mmol, 1.0 M in THF) dropwise over 30 minutes. After 20 minutes, allyl bromide was added. After 20 minutes, the reaction was warmed to 0 0 C. After 4.0 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3, brine, dried (MgSO4) and 25 concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 7-4 as a yellow oil. TLC Rf = 0.27 (silica, 30% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 8 7.25 (m 5H), 5.81 (m, 1H), 5.05 (m, 2H), 4.67 (m, 1H), 4.18 (m, 2H), 3.91 (m, 4H), 3.29 (dd, J=3Hz, 13Hz, 1H), 2.67 (m, 30 1H), 2.48 (m, 1H), 2.32 (m, 2H), 1.76 (m, 1H) 1.63 (m, 2H), 1.55 (m, 1H), 1.40 (m, 2H), 1.28 (s, 3H). 3-(R)-(4-(S)-benzvl-2-oxo-oxazolidine-3-carbonvyl)-6-(2-methyl [r1.31dioxolan-2-v1)-hexanal (7-5) - 95- WU 99/30709 PCT/US98/26539 To a stirred solution of 7-4 (60 g, 155 mmol), sudan III (20 mg) and CH2C12 (1500 mL) at -78 0 C under argon was bubbled ozone until red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (61 g, 233 mmol) was added followed by 5 the removal of the cooling bath. After 2.0 h, the reaction was concentrated. Flash chromatography (silica, 20%-40% EtOAc/hexanes) gave 7-5 as a yellow oil. TLC Rf = 0.15 (silica, 50% EtOAc/hexanes) 1 H NMR (300 MHZ, CDCL3) 8 7.27 (M 5H), 4.65 (M, 1H), 4.22 (M, 3H), 3.91 10 (M, 4H), 3.28 (DD, J=3HZ, 13HZ, 1H), 3.05 (M, 1H), 2.78 (M, 2H), 1.69 (M, 3H), 1.50 (M, 3H), 1.29 (S, 3H). 3(S)-(3-Fluorophenyl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-v1)-propyll-pvrrolidin- 1-vl)-propionic acid (2-10) 15 The title compound was prepared following the synthetic procedure depicted in Scheme 2, but replacing intermediate 2-5 with the chiral intermediate L-5, the preparation of which is shown in Scheme 7. 3(S)-(3-Fluorophenv1)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro 20 [1,8]naphthyridin-2-v1)-propvll-pyrrolidin-1-vl)-propionic acid (2-11) The title compound was prepared in a similar fashion as its diastereoisomer 7-6f immediately above, but using the enantiomer of 7-5 prepared in an analogous fashion to that depicted in Scheme 7. - 96wU 99/30709 PCT/US98/26539 SCHEME 8 H3 N N H 2 H3 N 0O NN _N 0 proline 8-1 8-2 H HN HONH2

H

2 , Pd/C N NN

HONH

2 8-3 H NMM, isobutyl N N NH 2 chloroformate N-OH 8-4 OBn HO HN BOC 0 H N N N 1 C N OBn N-0 fINN 8-5 BOC 2) PhS0 2 C1, NMM 0 H N N 8-6 R-- Bn [ N OR NaOH

SO

2 Ph 8-7 R=H 4-[ 1,8]Naphthvridin-2-v1-butvronitrile (8-2) A mixture of 5-oxo-hexanenitrile (8-1) (5 mnl, 43.8 mmol), 2 5 amino-3-formylpyridine (7 g, 57 mmol), proline (5.3 g, 43.8 mmol) and - 97- WO 99/30709 PCT/US98/26539 ethanol (100 mL) was heated at reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 8-2 as a white solid. TLC Rf = 0.21 (silica, ethyl acetate). 5 1 H NMR (300 MHz, CDC13) 5 9.10 (m, 1H), 8.19 (m, 2H), 7.47 (m, 2H), 3.24 (t, 2H, J=7 Hz), 2.55 (t, 2H, J=7Hz), 2.39 (m, 2H). 4-(5.6,7,8-Tetrahvdro-[1.8]naphthyridin-2-vl)-butvronitrile (8-3) A mixture of 8-2 (14 g, 71 mmol), 10% Pd/C (2 g) and ethanol 10 (200 mL) was stirred under a balloon of hydrogen gas for 1 h. Filtration and evaporation produced 8-3 as a white solid. 1 H NMR (300 MHz, CDC13) 5 7.06 (d, 1H, J=7 Hz), 6.35 (d, 1H, J=7 Hz), 4.76 (br s, 1H), 3-.41 (m, 2H), 2.71 (m, 4H), 2.38 (t, 2H, J=7 Hz), 2.08 (m, 3H), 1.85 (m, 2H), 1.80 (m, 1H). 15 2(S)-tert-Butoxvcarbonv1amino-3-[3-(3-r[1,8]naphthvridin-2-vl1-propyl) r[1,2,4]oxadiazol-5-yl]-propionic acid benzvl ester (8-5) To methanol (20 mL) was added sodium metal (0.86 g, 37 mmol). After 30 minutes, this solution was added to a suspension of 20 hydroxylamine hydrochloride (2.57 g, 37 mmol) in methanol (5 mL). After stirring for 30 min, the mixture was filtered. To this filtrate was added 8-3 (5 g, 24.4 mmol), and the mixture stirred for 24 h at 40 0 C. An additional portion of hydroxylamine (50 mmol, prepared as above) was then added followed by a further 24 h of stirring. The resulting mixture 25 was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Evaporation gave crude amide oxime (_-_). To a solution N-BOC-(L)-aspartic acid-alpha benzyl ester (1.5 g, 4.6 mmol) in THF (20 mL) at 0 0 C was added N-methylmorpholine (0.61 mL, 5.5 mmol) followed by isobutyl chloroformate (0.66 mL, 5.1 mmol). After 30 30 minutes, a solution of the above crude oxime in DMF (5 mL) was added. The solution was allowed to warm to 25'C and stir for 1 h, then toluene (20 mL) was added and the mixture heated to 110 0 C, allowing the THF to evaporate. The resulting mixture was heated at reflux for 6 h. Following cooling, the mixture was diluted with ethyl acetate, washed 35 with sat. NaHCO3, brine, and dried over MgSO4. The residue was - 98- WU 99/30709 PCT/US98/26539 chromatographed (silica gel, 50-60% ethyl acetate/hexanes) to give 8-5 as a yellow oil. TLC Rf = 0.63 (silica, ethyl acetate). 1 H NMR (300 MHz, CDC13) 6 7.30 (m, 5H), 7.04 (m, 1H), 6.34 (m, 1H), 5.16 5 (s, 2H), 4.80 (m, 2H), 3.41 (m, 2H), 2.68 (m, 4H), 2.59 (m, 2H), 2.04 (m, 2H), 1.85 (m, 4H), 1.43 (m, 9H). 2(S)-Benzenesulfonylamino-3-[3-(3-[1r,81naphthyridin-2-v1-propvl) r[1,2,4]oxadiazol-5-vll-propionic acid (8-7) 10 A solution of 4M HC1 in dioxane (20 mL) was added to 8-5 (0.7 g, 1.4 mmol). After 30 minutes, the solvent was evaporated to give a white solid. To this solid (0.3 g, 0.64 mmol) was added dichloromethane (10 mL), and NMM (0.7 mL, 6.4 mmol), and the mixture was cooled to 0 0 C. Phenylsulfonyl chloride (0.081 mL, 0.64 mmol) was added. After 30 15 minutes, the mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Evaporation gave the crude ester 8-6, which was dissolved in ethanol (5 mL); sodium hydroxide (0.7 mL, 1 N in water) was added. After 1 hr, the solvent was evaporated, and the residue was chromatographed (silica gel, 25:10:1:1 followed by 20 15:10:1:1 ethyl acetate /EtOH /water /NH4OH) to give 8-7 as a white solid. TLC Rf = 0.48 (10:10:1:1 ethyl acetate/EtOH/water/NH4OH). 1 H NMR (300 MHZ, CD3OD) A 7.68 (M, 2H), 7.33 (M, 3H), 7.15 (D, 1H, J=7 HZ), 6.39 (D, 1H, J=7 HZ), 3.91 (M, 1H), 3.37 (M, 2H), 3.08 (M, 2H), 2.71 (M, 2H), 2.57 (M, 4H), 1.97 (M, 2H), 1.88 (M, 2H). 25 SCHEME 9 H 2 N

CO

2 Et B / \Br EtONa, EtOH Et / Br - I N 9-1 9-2 EtO 9-3 5-Bromo-2-ethoxvpyridine (9-2) Sodium metal (4.87 g, 0.212 mol) was added to ethanol (200 30 mL) and stirred until completely dissolved. To this solution was added - 99wuJ YYI/U/Y /CIIU9W15/3i9 2,5-dibromopyridine 9-1 (10 g, 0.0424 mol) and the resulting mixture was stirred at reflux for 16 hr. The solvent was removed in vacuo and the residue partitioned between water and EtOAc. After extraction with EtOAc (2x), the organic layer was washed with brine, dried (MgSO4) and 5 concentrated to give 9-2 as a red-brown solid which was used as such in the next step. H NMR (300 MHz, CDC1 3 ) 8 1.4 (3H, t), 4.33 (2H, q), 6.63 (1H, d), 7.62 (1H, dd), 8.19 (1H, d). 10 3(S)-(6-Ethoxvypyridin-3-vl)-p-alanine ethyl ester (9-3) The title compound 9-3 was prepared from 9-2 using the procedure described for the synthesis of 19-5 from 19-3. 1 H NMR (300 MHz, CDC1 3 ): 5 1.25 (3H, t), 1.39 (3H, t), 2.61 (1H, dd), 2.67 (1H, dd), 4.15 (2H, q), 4.34 (2H, q), 4.40 (1H, dd), 6.71 (1H, d), 7.62 (1H, dd), 15 8.11 (1H, d). SCHEME 10

NH

2

NH

2 tert-butyl acrylate, , Bn N Pd(OAc) 2 , (o-Tolyl) 3 P N Ph Li 1100C, CH3CN THF, -78 0 C Br 10-1 10-2 CO2tBu NH2 NH 2 "N a) Pd/C, 78 0 C, AcOH N 1,4-Cyclohexadiene Shtu b) HC1, EtOH CO2Et P N 2HCI*H2NC t I Bn 10-4 10-3 - 100wu 99/IJU7U9 PCT/US98/26539 3-(6-Amino-pyridin-3-yl)-acrylic acid tert-butyl ester (10-2) A mixture of 2-amino-5-bromopyridine 10-1 (10 g, 58 mmol), tert-butyl acrylate (50 mL, 344 mmol), triethylamine (50 mL, 359 rmol), 5 tri-o-tolylphosphine (3.0 g, 9.8 mmol) and Pd(OAc)2 (1.0 g, 4.5 mmol) in 150 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110 0 C for 20 hr. The mixture was then cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:1) to afford the desired product 10-2 10 as a solid. Rf (silica, EtOAc/hexanes 1:1) = 0.26 3(S)-(6-Amino-pyridin-3-vl)-3-[benzvl-(l(R)-phenylethyl)-amino] propionic acid tert-butyl ester (10-3) 15 To a cooled (0 0 C) solution of (R)-(+)-N-benzyl-a methylbenzylamine (4.0 g, 19 mmol) in 50 mL THF was gradually added n-butyllithium (11.3 mL, 2.5 M, 28.2 rmmol) over 5 rmin. The mixture was stirred for 30 rmin at 0 0 C and cooled to -78 'C. A solution of 10-2 (2.0 g, 9.4 mmol) in 20 mL THF was gradually 20 added. After stirring for 40 rmin at -78 'C, it was treated with NH4C1 (sat.) at -78 0 C, warmed to room temperature and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After solvent evaporation, the residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:2) to afford the 25 desired product 10-3 as an oil. Rf (silica, EtOAc/hexanes 1:1) = 0.28 3(S)-Amino-3-(6-amino-pyridin-3-vl)-propionic acid ethyl ester-*2 HC1 (10-4) 30 A mixture of 10-3 (0.5 g, 1.2 mmol) and 10% Pd/C (0.4 g) in 10 mL AcOH was purged with argon for 5 min and then heated at 78oC. 1,4-Cyclohexadiene (2 mL. 21.1 mmol) was then gradually added. The reaction mixture was stirred for 3 hr and filtered through a celite pad. The solution was concentrated and the residue was purified using silica 35 gel flash chromatography (EtOAc/MeOH/NH4OH 1:1:0.04) to afford an - 101 - WU 99/30709 PCT/US98/26539 oil. To the oil (1.2 g) in 20 mL EtOH was introduced HC1 gas for 10 min. The mixture was stirred 24 hr and then concentrated to afford the desired product 10-4 as the HC1 salt. 1 H NMR (400 MHz, CD3OD) 5 8.11 (d, J=9.6 Hz, 1H), 8.08 (s, 1H), 7.13 (d, 5 J=9.6 Hz, 1H), 4.77 (m, 1H), 4.18 (q, J=6.8 Hz, 2H), 3.22-3.02 (m, 2H), 1.24 (t, J=6.8 Hz, 3H). - 102- Yvv w YI.3 UY L/~'Wb, SCHEME 11 02 (Ph)3 02 H2 OH K0EtO NH 4 CIIFeo H OH CHC2EtOHIH 2 O CHO N 11-111-2 CO 2 Et 11-3 CO 2 Et 0 c N "Cl H ClJ l OH K 2 CO3WDMF 0 sat'd NaHCOW/ CHC1 3 11-4 C 2 Et 11-5 C0 2 Et TiNJ N Ph~~ NH MeI/NaIl! Ph- DMF nBuLi/THF Ph N Ph) Ph-- CO 2 Et PhY CO 2 Et 1L~ 11-7 - 103 - VVu YY/ou/uY PCTI/UN98/265ZO39 0 N 11-7 Pd(OH) H 2 0 11-7. MeOH/AcOH

H

2 0

H

2 N C02Et 11-8 3-(3-Hydroxy-4-nitrophenyl)-acrvlic acid ethyl ester (11-2) To a stirred solution of aldehyde 11-1 (20.28 g, 132.5 mmol) in 5 CH2C12 (400 mL) at room temperature was added (carbethoxymethylene)triphenylphosphorane (46.12 g, 132.5 mmol) over a 10 min period. The resulting orange solution was stirred at room temperature for 2 h. The solution was concentrated to one-fourth its volume. Flash chromatography (silica gel; 30:70 EtOAc/hexanes) gave 10 the title compound 11-2 as a bright yellow solid. TLC Rf = 0.75 (25:75 EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 5 8.14 (d, 1H), 7.60 (d, 1H), 7.15 (dd, 1H), 6.54 (d, 1H), 4.30 (q, 2H), 1.36 (t, 3H). 15 3-(4-Amino-3-hydroxvphenvyl)-acrylic acid ethyl ester (11-3) To a stirred suspension of 11-2 (4.64 g, 19.6 mmol), NH4C1 (524 mg, 9.8 mmol), EtOH (140 mL) and H20 (70 mL) was added iron dust (2.72 g, 48.9 mmol). The resulting yellow suspension was refluxed for 1.5 h., and then the solution was filtered while hot through celite. The 20 filtrate was concentrated and the residue was partitioned between EtOAc and brine. The layers were separated and the EtOAc layer dried (Na2SO4) and concentrated to give 11-3 which was used without further purification in the next step. TLC Rf= 0.2 (25:75 EtOAc/hexanes) 25 1H NMR (300 MHz, CDC13) 5 7.57 (d, 1H), 7.00 (m, 2H), 6.68 (d, 1H), 6.20 (d, 1H), 4.26 (q, 2H), 4.10 (b, 2H), 1.33 (t, 3H). - 104w VVU YY3/U Up PIT/U9I26539 3-[4-(2-Cbloroacetylamino)-3-hydroxyphenvyllacrylic acid ethyl ester To a stirred solution of 11-3 (3.38 g, 16.3 mmol) in CHC13 (80 5 mL) was added saturated NaHCO3 (50 mL) and it was then chilled to 0 0 C. A solution of chloroacetyl chloride (1.94 mL, 24.4 mmol) in CHC13 (30 mL) was added dropwise to the chilled biphase. Upon addition completion, the reaction was stirred at 0OC for 1 h. The layers were separated and the aqueous layer was extracted twice with EtOAc. The 10 combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 11-4 which was used without further purification in the next step. TLC Rf= 0.4 (25:75 EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 5 10.33 (s, 1H), 9.58 (s, 1H), 8.02 (d, 1H), 7.51 15 (d, 1H), 7.19 (d, 1H), 7.12 (s, 1H), 6.39 (d, 1H), 4.42 (s, 2H), 4.17 (q, 2H), 1.25 (t, 3H). 3-(3-Oxo-3,4-dihydro-2H-benzo[l.41oxazin-7-vl) acrylic acid ethyl ester (11-5) 20 To a stirred solution of 11-4 (4.28 g, 15.0 mmol) in DMF (50 mL) was added K2CO3 (4.50 g, 32.6 mmol). The resulting suspension was heated to 50 0 C for 12 h., after which time the reaction was concentrated. The residue was partitioned between saturated NaHCO3 and EtOAc and extracted twice with EtOAc. The combined organic 25 layers were washed with brine, dried (Na2SO4), and concentrated. Flash chromatography (silica gel; 25:75 EtOAc/hexanes) yielded 11-5 as a beige solid. TLC Rf = 0.5 (25:75 EtOAc/hexanes). 1H NMR (300 MHz, CDC13) 6 10.91 (s, 1H), 7.54 (d, 1H), 7.37 (s, 1H), 7.31 30 (d, 1H), 6.90 (d, 1H), 6.51 (d, 1H), 4.60 (s, 2H), 4.16 (q, 2H), 1.24 (t, 3H). 3-(R)-[Benzvyl-(l1-phenylethyl)-aminol-3-(S)-(3-oxo-3,4-dihydro-2H benzo[1.4]oxazin-7-vl) propionic acid ethyl ester (11-6) To a stirred solution of (R)-(+)-N-benzyl-a 35 methylbenzylamine (5.43 g, 25.7 mmol) and anhydrous THF (75 mL) at - 105- VV" YvY/ou/UY PCT/US98/26539 0 0 C was added butyllithium (10.3 mL, 2.5 M/hexanes, 25.7 mmol) via syringe. The violet-red solution was stirred at 0 0 C for 15 minutes and then cooled to -78 0 C. A solution of 11-5 (2.12 g, 8.6 mmol) in anhydrous THF (50 mL) was added via syringe, and the resulting brown solution 5 was stirred at -78 0 C for 30 minutes. The brown solution was quenched with saturated NH4C1, the mixture then warmed to room temperature and extracted twice with Et20. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Flash chromatography (silica gel; 15:85 to 25:75 EtOAc/hexanes) yielded 11-6 as 10 a white foam. TLC Rf = 0.25 (25:75 EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 5 10.89 (s, 1H), 7.32 (m, 10H), 7.10 (m, 2H), 6.91 (d, 1H), 4.62 (s, 2H), 4.39 (m, 1H), 4.13 (q, 2H) 3.96 (m, 1H), 3.68 (s, 2H), 2.56 (m, 2H), 1.28 (m, 6H). 15 3-(R)-[Benzvyl-(1-phenylethyl)-aminol-3-(S)-(4-methyl-3-oxo-3,4-dihydro 2H-benzo[1,4]oxazin-7-vl) propionic acid ethyl ester (11-7) To a stirred suspension of NaH (65 mg, 60%, 1.6 mmol) in DMF (5 mL) under argon was added a solution of 11-6 (650 mg, 1.4 mmol) 20 in DMF (10 mL) via syringe. This yellow solution was stirred at room temperature for 30 minutes. Iodomethane (500 gtL, 8.0 mmol) was added and the solution then stirred at room temperature for an additional 30 minutes. The reaction was quenched with saturated NaHCO3. The aqueous layer was extracted three times with CH2C12. The combined 25 organic layers were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (silica gel; 25:75 EtOAc/hexanes) afforded 11-7 as a clear oil. TLC Rf= 0.6 (25:75 EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 5 7.30 (m, 10H), 7.06 (m, 2H), 6.91 (d, 1H), 4.62 30 (s, 2H), 4.39 (m, 1H), 4.13 (q, 2H) 3.96 (m, 1H), 3.68 (s, 2H), 3.35 (s, 3H), 2.56 (m, 2H), 1.26 (m, 6H). 3-(S)-Amino-3-(4-methyl-3-oxo-3,4-dihvdro-2H-benzo[1.4]oxazin-7-vl) propionic acid ethyl ester (11-8) - 106wu 99/3U7U9 PCT/US98/26539 A stirred solution of 11-7 (581 mg, 1.2 mmol), MeOH (10 mL), AcOH (1.0 mL), and H20 (0.3 mL) was degassed with argon for 5 minutes. Pd(OH)2 (581 mg) was added and the reaction was placed under 1 atm of H2 for 2.5 h. The reaction was diluted with EtOAc and 5 filtered through celite. The filtrate was concentrated to yield 11-8 as a clear oil. TLC Rf = 0.3 (5:95 MeOH/CH2C12) 1H NMR (300 MHz, CDC13) 5 7.04 (m, 2H), 6.93 (dd, 1H), 4.61 (s, 2H), 4.39 (m, 1H), 4.13 (q, 2H), 3.37 (b, 2H), 3.35 (s, 3H), 2.69 (m, 2H), 1.24 (t, 3H). 10 - 107- SCHEME 12

NH

2 NHBOc MeN Bo "N N (Boc) 2 0 N N NaH/DMF N N N N ,N tert-BuOH Mel Br Br Br 12-1 12-2 12-3 Me, N Boc Ethyl acrylate, Pd(OAc) 2 , (o-Tolyl) 3 P N PNt NH 2 110 0 C, CH 3 CN 95 oC 12-4 CO 2 Et Me,,N Boc Me"N .Boc N N Pd(OH) 2 /C, H 2 AcOH/EtOH CO2Et CO 2 Et P H COEt

NH

2 H 12-5 12-6 2-tert-Butoxvcarbonylamino-5-aminopvridine (12-2) A solution of 2-amino-4-bromopyridine 12-1 (10.1 g, 58.4 mmol) in 150 mL of melted t-BuOH was treated with di-tert-butyl 5 dicarbonate (14.0 g, 64.2 mmol). After the solution was stirred for 12 hr, the solvent was evaporated. The residue was purified using silica gel flash chromatography (CHC13/hexanes, 5:1) to afford the desired product 12-2 as a solid. Rf(silica, 100% CHC13) = 0.56 - 108yru %>t tY~u/ Y YCTUNV5/ZW)d? 1 H NMR (300 MHz, CDC13) 5 8.82 (bs, 1H), 8.38 (d, 1H), 8.78 (d, 1H), 7.78 (dd, 1H), 1.55 (s, 9H). 2-(tert-Butoxvcarbonv1-methyl-amino)-5-aminopyridine (12-3) 5 To a solution of 12-2 (6.0 g, 22.0 mmol) in 50 mL DMF at 0 0 C was added NaH gradually. After the mixture was stirred for 40 min, CH3I (3.4 g, 24.0 mmol) was added in one portion. The reaction mixture was stirred for 5 hr, treated with 300 mL water and extracted three times with ethyl ether. The combined organic layers were washed with brine 10 and dried over Na2SO4. After solvent removal, the residue was purified by silica gel flash chromatography (CHC13/hexanes 6:1) to afford the desired product 12-3 as a solid. Rf (silica, 100% CHC13) = 0.40 1 H NMR (300 MHz, CDC13) 8 8.40 (dd, 1H), 7.68 (m, 2H), 3.36 (s, 3H), 1.55 15 (s, 9H). 3-[6-(tert-Butoxycarbonv1-methyl-amino)-pyridin-3-vyl]-acrylic acid ethyl ester (12-4) A mixture of 12-3 (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 20 62.7 mmol), triethylamine (17 mL, 125.5 mmol), tri-o-tolylphosphine (1.3 g, 6.2 mmol) and Pd(OAc)2 (0.5 g, 2.1 mmol) in 50 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110'C for 20 hr. The mixture was cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:3) to afford the 25 desired product 12-4 as an oil. 1 H NMR (300 MHz, CDC13) 5 8.47 (bs, 1H), 7.82 (m, 2H), 7.64 (d, 1H), 6.42 (d, 1H), 4.27 (q, 2H), 3.43 (s, 3H), 1.54 (s, 9H), 1.34 (t, 3H). 3-Benzylamino-3-[6-(tert-butoxvcarbonyl-methvl-amino)-pyridin-3-yll 30 propionic acid ethyl ester (12-5) A mixture of 12-4 (1.7 g, 5.6 mmol) and benzylamine (8 mL, 73.2 mmol) was heated in a sealed-tube at 95 0 C for 24 hr. The crude reaction mixture was purified using silica gel flash chromatography (EtOAc/hexanes 1:3 to 1:1) to afford the desired product 12-5 as an oil. - 109wu Y/wouYU PCTIUS95/26539 Rf (silica, EtOAc/hexanes 1:1) = 0.63. 3-Amino-3-r6-(tert-butoxycarbonyl-methyl-amino)-pyridin-3-vll-propionic acid ethyl ester (12-6) 5 A mixture of 12-5 (1.5 g 3.6 mmol), 20% Pd(OH)2/C (0.3 g), AcOH (5.5 mL) and EtOH (50 mL) was purged with argon 3 times under vacuum. The reaction mixture was stirred under balloon hydrogenation condition for 16 hr and filtered through a celite pad. After solvent removal, the desired product 12-6 was obtained as the acetate salt. 10 1 H NMR (300 MHz, CDC13) 5 8.38 (d, 1H), 7.70 (m, 2H), 4.50 (dd, 1H), 4.15 (q, 2H), 3.40 (s, 3H), 2.80 (m, 2H), 1.25 (t, 3H). SCHEME 13 Ph h F Ethyl Acrylate F Pd(OAc) 2 F Br 13-1 13-2 13-1 CO 2 Et Me Ph" N Ph n-BuLi H h h PF d(OH) 2 , H 2 (g) F Me H 2 N CO2Et P h " N ',CO2Et 13-4 Bn 13-3 15 3-(2-Fluoro-biphenvl-4-yl)-acrvlic acid ethyl ester (13-2) - 110wu v9/.U/TU9 PCT/US98/26539 A solution of 2-fluoro-4-bromobiphenyl 13-1 (7.5 gin, 31.8 mmol), ethyl acrylate (4.3 mL), Pd(OAc)2 (0.714 gm, 3.2 mmol), tri-o tolylphosphine (1.94 gin, 1.5 mmol) and triethylamine (12 mL) was heated to 100oC in a sealed tube for 12 h. The reaction was cooled to room 5 temperature and diluted with dichloromethane (40 mL). The organic solution was washed with 10% aq. citric acid (20 mL), satd. aq. NaHCO3, and brine (20 mL). The organic solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (95:5 to 90:10 hexanes/EtOAc) to give the acrylate ester 13-2 as a white 10 solid. TLC Rf = 0.44 (10% ethyl acetate/hexanes). 3-[Benzvyl-(1(R)-phenylethyl)-aminol-3-(2-fluoro-biphenyl-4-vl)-propionic acid ethyl ester (13-3) 15 A cooled (0 0 C) solution of N-benzyl-(R)-a methylbenzylamine (8.9 mL, 42.6 mmol) in THF (100 mL) was treated with n-butyllithium (26.6 mL of a 1.6 M soln in hexanes; 42.6 mmol). After stirring for 10 min, the purple solution was cooled to -78oC and treated with a solution of ester 13-2 (5.76 g, 21.3 mmol) in THF (10 mL). 20 After stirring for 20 min, the solution was quenched with satd aq NH4C1 soln (5 mL), and the cold bath removed. The reaction mixture was diluted with Et20 (100 mL), and washed with 10% aq citric acid (50 mL), satd aq NaHCO3 (50 mL), 5% aq acetic acid (30 mL), 10% aq K2CO3 (50 mL), and brine (50 mL). The solution was dried over MgSO4, filtered 25 and concentrated. The residue was purified by flash chromatography (90:10 hexanes/EtOAc) to give adduct 13-3. TLC Rf = 0.48 (10% ethyl acetate/hexanes). 3-Amino-3-(2-fluoro-biphenyl-4-vl)-propionic acid ethyl ester (13-4) 30 A solution of the dibenzylamine 13-3 (5.65 gin, 11.75 mmol) in EtOH/HOAc (90/10 mL) was purged with argon and treated with Pd(OH)2 (3 g) and placed under 1 atm of H2 gas for 12 h. Additional portions (2.5 g) or Pd(OH)2 were added after 24 h, 48 h and 144 h. The reaction mixture was purged with argon, filtered through Celite, and 35 the filtrate dissolved in aq HC1 (pH=1). The aqueous solution was - 111 - VVwu Y Iu IU PTU"1515ZOS9 washed with EtOAc, neutralized with satd aq NaHCO3, and extracted with EtOAc (3 x 30 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product 13-4. 5 1H NMR (300 MHz, CD3OD) 5 7.41 (m, 8H), 4.10 (m, 1H), 4.06 (m, 2H), 2.73 (m, 2H), 1.18 (m, 3H) ppm. SCHEME 14

NO

2 N OH EtO 02O OH Ph 3 PR OH CHO 14-1 14-2 CO 2 Et 1. Fe, AcOH 2. CDI, THF 0 1. Me HN4 Ph N Ph HN-O O H HO2Et 2. Pd(OH) 2 , H 2 (9)

H

2 N .C02Et 14-4 14-3 CO 2 Et 10 3-(3-Hydroxv-4-nitro-phenvl)-acrvlic acid ethyl ester (14-2) To a solution of aldehyde 14-1 (15.0 g, 98.0 mmol) in CH2CI2 (300 mL) was slowly added carboethoxymethylenetriphenylphosphorane (34.1 g, 98.0 mmol). The orange solution was stirred for 12 h at ambient temperature. The solution was concentrated to a paste and purified by 15 flash chromatography (10% EtOAc/CH2C12) to give 14-2 as a yellow solid. TLC Rf = 0.51 (30% ethyl acetate/hexanes). - 112 wu VM/.JU/U PCT.:I/U595/2053..9 1 H NMR (300 MHz, CD3OD) 5 8.08 (d, J=8.4 Hz, 1H), 7.63 (d, J=16.2 Hz, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.4, 1.5 Hz, 1H), 6.65 (d, J=15.9 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H) ppm. 5 3-(2-Oxo-2,3-dihvdro-benzoxazol-6-yl)-acrvlic acid ethyl ester (14-3) To a solution of the nitrophenol 14-2 (12.0 g, 57.4 mmol) in warm (70'C) AcOH/H20 (200 mL) was added iron dust (9.61 g, 172.2 mmol). The brown heterogeneous mixture was stirred for 30 min at 70 80 0 C. The mixture was filtered hot through Celite, and the Celite bed 10 washed with EtOAc (2 x 200 mL). The filtrate was cautiously neutralized with satd aq NaHCO3 (3 x 100 mL). The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography3f (5% MeOH in CH2C12) give an orange solid (9.6 g, 81%). A portion of this solid (4.5 g, 21.7 mmol) was dissolved in THF (150 mL) 15 and treated with 1,1-carbonyldiimidazole (3.87 g, 23.8 mmol) and the solution was stirred at ambient temperature for 24 h. The solution was diluted with EtOAc (100 mL) and washed with 10% HC1 (50 mL) and brine (50 mL). The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (5% 20 MeOH in CH2C12) to give 14-3 as a yellow solid. TLC Rf = 0.49 (5% MeOH/CH2C12). 1 H NMR (300 MHz, CD3OD) 5 7.77 (d, J=15.9 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.47 (d, J=15.9 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H) ppm. 25 3S-Amino-3-(2-oxo-2,3-dihydro-benzoxazol-6-vl)-propionic acid ethyl ester (14-4) A solution of N-benzyl-ac-(R)-methylbenzylamine (4.08 g, 19.3 mmol) in THF (120 mL) at 0 0 C was treated with n-BuLi (7.72 mL of a 2.5 30 . M soln in hexanes). The resulting solution was stirred at 0OC for 30 min and then cooled to -78 0 C. A solution of acrylate 14-3 (1.5 g, 6.43 mmol) in THF (20 mL) was added. After stirring for 15 min at -78 0 C, satd aq NH4C1 soln (25 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et20 (2 x 40 mL). - 113w u YWou /u? PCT/US98/26539 The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to give 2.74 g of the 3 aminoester as a yellow oil. The aminoester was dissolved in 5 EtOH/H20/AcOH (54 mL/4.8 mL/1.2 mL), degassed with argon, and treated with Pd(OH)2 (2.74 g). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc, and filtered through Celite. The filtrate was concentrated to give ester 14-4 as an off-white solid. 10 TLC Rf= 0.10 (5% MeOH/CH2C12). 1 H NMR (300 MHz, CD3OD) 5 7.34 (s, 1H), 7.26 (dd, J=1.2, 8.1 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.65 (t, J=7.2 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H), 2.98 (m, 2H), 1.20 (t, J=7.2 Hz, 3H) ppm. SCHEME 15 OH R O1. Ethyl Acrylate R F Pd(OAc) 2 , Et 3 N F 2. Et-1, Cs 2

CO

3 Br 15-1 15-2 R=H 15-3 R=Et CO 2 Et Me Ph N P h n-BuLi H OEt OEt F Pd(OH) 2 , H 2 (g) Me H 2 N CO2Et Ph-KN /"-CO2Et 15-5 Bn 15-4 15 - 114wU YIWUU/J9 FC/1IU98/26539 3-(4-Hydroxv-3-fluorophenvl)-acrylic acid ethyl ester (15-2) A solution of 2-fluoro-4-bromophenol 15-1 (50 g, 261.8 mmol), ethyl acrylate (34 mL), Pd(OAc)2 (2.5 g), tri-o-tolylphosphine (5 g) and 5 triethylamine (83 mL) was heated to 100 0 C in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The organic solution was washed with 10% aq. citric acid (40 mL), satd aq NaHCO 3 , and brine (40 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue 10 was purified by flash chromatography (50:50 hexanes/EtOAc to 100% EtOAc) to give acrylic acid 15-2 as a white solid. TLC Rf = 0.45 (50% ethyl acetate/hexanes). 3-[Benzv1-(l(R)-phenvlethyl)-aminol-3-(4-ethoxv-3-fluorophenvl) 15 propionic acid ethyl ester (15-4) To a stirred solution of 15-2 (49.25 gin, 234.5 mmol) in DMF (600 mL) was added Cs2CO3 (84.1 gmn, 257.9 mmol) and ethyl iodide (18.8 mL, 234.5 mmol). After stirring for 12 h at room temperature, the reaction mixture was diluted with EtOAc (L) and washed with water (6 20 x 300 mL), 10% aq. citric acid (200 mL), satd. aq. NaHCO3 (200 mL), and brine (300 mL). The organic solution was dried over MgSO4, filtered, and concentrated to give 52.9 g (95%) of the product 15-3 as an orange oil which crystallized upon standing. A cooled (0OC) solution of N-benzyl (R)-a-methylbenzylamine (71 mL, 339.4 mmol) in THF (650 mL) was 25 treated with n-butyllithium (212 mL of a 1.6 M soln in hexanes; 339.4 mmol). After stirring for 10 min, the purple solution was cooled to -78 0 C and treated with a solution of ester 15-3 (53.8 g, 226.3 mmol) in THF (100 mL). After stirring for 20 min, the solution was quenched with satd aq NH4C1 soln (50 mL), and the cold bath removed. The reaction mixture 30 was diluted with Et20 (1000 mL), and washed with 10% aq citric acid (300 mL), satd aq NaHCO3 (300 mL), 5% aq acetic acid (300 mL), 10% aq K2C03 (300 mL), and brine (200 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (85:15 hexanes/EtOAc) to give the adduct 15-4. 35 TLC Rf = 0.39 (25% ethyl acetate/hexanes). - 115- WU 99/U0709 PCT/US98/26539 3-Amino-3-(4-Ethoxv-3-fluorophenvl)-propionic acid ethyl ester (15-5) A solution of the dibenzylamine 15-4 (30.0 gm, 66.8 mmol) in EtOH/HOAc (340/30 mL) was purged with argon and treated with 5 Pd(OH)2 (6 g) and placed under 1 atm of H2 for 12 h. Additional portions (2.5 g) of Pd(OH)2 were added after 24 h and 48 h. The reaction mixture was purged with argon, filtered through Celite, and the filtrate collected. The filtrate was concentrated to yield the desired amine 15-5. 1 H NMR (300 MHz, CD3OD) 5 7.19 (m, 3H), 4.62 (m, 1H), 4.07 (m, 4H), 10 2.99 (m, 2H), 1.39 (m, 3H) 1.18 (m, 3H) ppm. SCHEME 16 H H H3a "'1 N EtI 1) NaOH; HCI Cs 2

CO

3 C 2) EDC, NMM, CH O CH 3 HCI HN(Me)OMe O (Y^\-CH3 16-1 16-2 H 3 C---NH3a "' N DIBAL

PH

3

PCHCO

2

C(CH

3

)

3 16-5 O N CH3 0 H I CHa 16-4 16-3 N CHa H 3 N 1) Pl N Ph OH3C H 16-7

C

H

3 1 CH 3 nBuLi H2N 16-6 O CH3

CH

3 2) Pd/C, 16-8 - 116 wV 99/U0709 PCT/US98/26539 5-Ethoxy-nicotinic acid ethyl ester (16-2) A mixture of 3-hydroxy-nicotinic acid methyl ester 16-1 (15 g, 90.8 mmol), ethyl iodide (14.5 ml, 181.6 mmol), cesium carbonate (29.5 g, 90.8 mmol) and DMF (150 mL) was stirred at ambient temperture for 3 5 hours. The reaction mixture was diluted with Et20 and then washed with 10% K2CO3, brine, dried (MgSO4), and concentrated to give the ester 16-2 as a red oil. TLC Rf = 0.52 (silica,75% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 8.82 (s, 1H), 8.46 (s,1H), 7.75 (s, 1H), 4.40 (q, 10 2H, J=7Hz), 4.12 (q, 2H, J=7Hz), 1.43 (m, 6H). 5-Ethoxv-N-methoxy-N-methyl-nicotinamide (16-3) To a solution of 16-2 (15 g, 72 mmol) in EtOH (100 mL) was added 1N NaOH (80 ml, 80 mmol). After stirring for 1 h, the solvents 15 were evaporated and the residue was dissolved in 1N HC1 (80 ml, 80 mmol) and then concentrated, azeotroped with CH3CN to give the crude acid. The crude acid was suspended in DMF (200 mL) and then treated with HCI*HN(Me)OMe (13.9 g, 144 mmol), EDC (15.1g, 79.2 mmol), HOBT (9.6g, 72 mmol) and NMM (60 mL, 576 mmol). The mixture was 20 stirred for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with 10% K2CO3, brine, dried (MgSO4), and concentrated to give amide 16-3 as a brown oil. TLC Rf = 0.30 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH) 25 5-Ethoxy-pyridine-3-carbaldehyde (16-4) To a stirred solution of 16-3 (14.0 g, 66.5 mmol) and CH2C12 (200 mL) at -78 0 C under argon was added DIBAL (1.0M hexanes, 90ml) dropwise over 30 minutes. After 30 minutes, the solution was warmed to 0OC for 1 hour. The reaction was quenched with 100 ml 1.0M Rochelle's 30 salt, stirred for 1.0 hour and then extracted with Et20. The organic layer was dried (MgSO4), and then concentrated to give the aldehyde 16-4 as a brown oil. TLC Rf = 0.32 (silica, 70:25:5 chloroform/ethyl acetate/MeOH) 1H NMR (300 MHz, CDC13) 5 10.10 (s, 1H),8.65 (s,1H), 8.55 (s,1H), 7.59 (s, 35 1H), 4.14 (q, 2H, J=7Hz), 1.43 (t, 3H, J=7Hz). - 117- WV !/IJU7UY9 PCT/US98/26539 3-(5-Ethoxy-pvridin-3-yl)-acrylic acid tert-butyl ester (16-6) A mixture of 16-4 (8.0 g, 51.6 mmol), 16-5 (20 g, 54.2 mmol), and benzene (150 mL) was heated to reflux for 30 minutes. The mixture 5 was diluted with Et20 and then washed with 10% K2CO3, brine and dried (MgSO4). Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 30% EtOAc/hexanes) to give 16-6 as a yellow solid. TLC Rf = 0.41 (silica, 70:25:5 chloroform/ ethyl acetate/ MeOH) 10 1 H NMR (300 MHz, CDC13) 5 8.31 (m, 2H),7.55 (d, 1H, J=16Hz), 7.27 (s, 1H), 6.40 (d, 1H, J=16Hz), 4.10 (q, 2H, J=7Hz), 1.54 (s; 9H), 1.44 (m, 3H). 3(S)-Amino-3-(5-ethoxv-pTvridin-3-vl)-propionic acid tert-butv1 ester (16-8) To a stirred solution of 16-7 (500mg, 2.38mmol) and THF at 15 0 0 C was added nBuLi (2.5 M THF, 0.95 ml) dropwise. After 20 minutes, the solution was cooled to -78 0 C and 16-6 (500mg, 1.98 mmol), dissolved in 3 ml THF, was added. After 15 minutes, the reaction was quenched with sat. NH4C1 followed by the removal of the cooling bath. The solution was extracted with ethyl acetate. The organic portion was washed with 20 brine, dried (MgSO4) and concentrated. The residue was dissolved in acetic acid (14 ml) and the solution was purged with argon for 30 minutes. 10% Pd/C (1.0 g) was added and the mixture was heated to 80 0 C. 1,4-Cyclohexadiene (6 ml) was added dropwise maintaining an internal temperature between 80'C and 90 0 C. After 5.0 hours, the 25 mixture was filtered through a celite pad, concentrated and then azeotroped with toluene. The residue was chromatographed (silica gel, 5% [10:10:1 EtOH/NH4OH/H20]/ 70:25:5 chloroform/ ethyl acetate/ MeOH) to give 16-8 as a yellow solid. 1H NMR (300 MHz, CDC13) 5 8.18 (m, 2H),7.25 (s,1H,), 4.41 (m,1H,), 4.08 30 (q, 2H, J=7Hz), 2.59 (m, 2H, ), 1.87 (s, 2H), 1.40 (m, 12H). - 118wu Y'V/iU/U9 PCT/US98/26539 SCHEME 17

COH

3 , H N CH~0N CHH 3 H2N O CH3 Br CH 3 17-1 17-2 3(S)-Amino-3-(5-methoxv-pyvridin-3-v1)-propionic acid tert-butvl ester (17-2) 3-Bromo-5-methoxy-pyridine 17-1 (prepared as described in J. Org. 5 Chem. 1990, 55, 69) was converted into 17-2 utilizing the procedure described for the conversion of 19-2 to 19-5. 1 H NMR (300 MHz, CD3OD) 5 8.20 (d, 1H, J=3Hz), 8.18 (d, 1H, J=2Hz),7.50 (s, 1H,), 4.51 (m,1H,), 3.90 (s, 3H), 2.87 (m, 2H, ), 1.37 (m, 9H). SCHEME 18 H S 0 5% Pd/BaSO 4 , H2 0 quinoline, ethanol ; HC1*H 2 N OEt H 2 N OEt 18-1 18-2 10 3-Amino-pent-4-enoic acid ethyl ester (18-2) A mixture of 5% Pd/BaSO4 (0.025 g) and quinoline (0.30 mL) was stirred under a balloon of hydrogen for 30 minutes. 3-Amino-pent-4-ynoic acid ethyl ester (18-1) (for preparation, see J.A. Zablocki, et al., J. Med. 15 Chem., 1995, 38, 2378-2394) (1.77 g, 10.0 mmol) in EtOH (15 mL) was added and the solution stirred for an additional 2.5 hours. The solution was filtered through a pad of celite and concentrated in vacuo to provide 2.65 g of crude product 18-2. 1H NMR (CDC13, 300 MHz): 5 8.40-7.60 (br s, 2H), 6.11-5.96 (m, 1H), 5.58-5.53 (d, 1H), 5.44-5.41 (d, 1H), 4.31-4.16 (m, 20 3H), 3.12-2.86 (m, 2 H), 1.29-1.25 t, 3H). - 119wu y/juo/Uy PCT/US98/26539 SCHEME 19 N Br 2 , KBr, KOH N MeO-/ H 2 0 MeO / Br 19-1 19-2 Pd(OAc) 2 , Et 3 N, tri-o-tolylphosphine ethyl acrylate, CH 3 CN N MeO

-

CO

2 Et 19-3 H Ph H Ph N Ph Ph N 1.

CO

2 Et Me e Me THF 2. nBuLi, THF 3. NH 4 CI, H 2 0 MeO 19-4 Pd(OH) 2 , H 2 ,

H

2 N C 2 Et EtOH, HOAc, H 2 0 N MeO 19-5 - 120wu 99/J0709 PCT/US98/26539 5-Bromo-2-methoxvpyridine (19-2) To a solution of KOH (4.2 g, 0.075 mol) in water (750 mL) was added 2-methoxypyridine 19-1 (16.4 g, 0.15 mol) followed by a dropwise addition of bromine (24 g, 0.15 mol) in 1N aqueous KBr (750 mL) and the 5 resulting solution was stirred at room temperature for 5 hr. Solid NaHCO3 was added until basic and the solution was extracted with CHC13 (3x500 mL). The organic layer was washed with 10% NaHSO3, then brine, dried over Na2SO4, filtered and the solvent removed in vacuo. The resulting dark brown oil was predominantly the desired compound 10 19-2 and was used as such in the next step. H NMR (300 MHz, CDC1 3 ) 5 3.91 (3H, s), 6.66 (1H, d), 7:62 (1H, dd), 8.20 (1H, d). Ethyl 3-(6-methoxvpyridin-3-v1)acrylate (19-3) 15 A solution of the 5-bromo-2-methoxypyridine 18-2 (74.3 g, 0.4 mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10 minutes. The mixture was heated at 90 0 C for 12 hr then the volatiles were 20 removed in vacuo. Toluene (300 mL) was added and the mixture concentrated again. Diethyl ether (300 mL) was added and the mixture filtered through a pad of silica gel eluting with 800 mL of diethyl ether. After removal of the diethyl ether, the residue was chromatographed on silica gel eluting with EtOAc/hexane, 1:19 then 1:14 then 1:9, to give 19-3 25 as a yellow solid. 1H NMR (300 MHz, CDC13) 5 1.34 (3H, t), 3.97 (3H, s), 4.26 (2H, q), 6.34 (1H, d),6.76 (1H, d), 7.63 (1H, d), 7.77 (1H, dd),8.27 (1H, d). N-Benzvyl-(R)-a-methvlbenzvl-3(S)-(6-methoxvpyridin-3-vl)-- alanine 30 ethyl ester (19-4) To a solution of N-benzyl-(R)-a-methylbenzylamine (97.5 g, 462 mmol) in THF (750 mL) at 0 0 C was added n-butyllithium (2.5M in hexanes; 178.5 mL, 446 mmol). The dark violet solution was stirred at 0 0 C for 20 minutes, cooled to -78 0 C and the ester 19-3 (63.7 g, 308 mmol) in - 121 wu Y9/U0709 PCT/US98/26539 THF (250 mL) was added over 60 minutes. The resulting solution was stirred at -78 0 C for 1 hr then cannulated into saturated NH4Cl and extracted with EtOAc, washed with water then brine, dried and concentrated in vacuo to give an oil. Column chromatography (silica 5 gel; hexane/EtOAc, 9:1 then 4:1) gave 19-4 as an oil contaminated with N benzyl-(R)-a-methylbenzylamine. This oil was taken up in 5% AcOH in water and extracted with diethyl ether (4x). The organic layers were dried over MgSO4 and the solvent removed to give the title compound 19 4. 10 H NMR (300 MHz, CDC1 3 ) 5 1.08 (3H, t), 1.27 (3H, d), 2.52 (1H, dd), 2.62 (1H, dd), 3.66 (1H, d), 3.70 (1H, d), 3.93 (3H, s), 3.95 (2H, m), 4.41 (1H, dd), 6.74 (1H, d), 7.15-7.45 (10H, m), 7.64 (1H, dd), 8.15 (1H, d). 3(S)-(2-methoxypyrid-5-vl)-p-alanine ethyl ester (19-5) 15 To a degassed (argon) solution of the ester 19-4 (70 g) in EtOH (250 mL), HOAc (25 mL) and water (2 mL) was added 20% Pd(OH)2 on carbon. The mixture was placed under hydrogen gas using a balloon and the resulting mixture was stirred for 24 hr. After filtration through celite (washing with EtOAc), the solvent was removed in vacuo to afford 20 a waxy solid. This was dissolved in 200 mL water and extracted with diethyl ether (2x200 mL). The aqueous layer was then treated with solid K2CO3 until fully saturated and extracted with 4x200 mL EtOAc. After drying over MgSO4, the solvent was removed in vacuo to give the title compound 19-5 as an oil which solidified in the freezer. 1H 25 H NMR (300 MHz, CDC1 3 ) 5 1.23 (3H, t), 2.61 (1H, dd), 2.68 (1H, dd), 3.92 (3H, s), 4.15 (2H, q), 4.41 (1H, dd), 6.93 (1H, d), 7.62 (1H, dd), 8.13 (1H, d). - 122- H U YNIviu PFCTIUN98/2l539 Scheme 20 nitrit C I .. N. H2N ~N t-butyl nitrite BCI N 02N 'Br CuCI 2 , CH 3 N N Br 20-1 20-2 HO-" O 2

CH

3 ONaH, THF HN Sn, HCI H 3

O

2 CO N 0 2 N Br Br tBu acrylate, Pd(OAc) 2 , DMF Me 0 AHN N HN HN N Ph NH N Lawesson's Bn reagent H3C

H

C nBuLi, THF Ph N O2tBu Ph 'CO2tBU 20-5 C0 2 tBu Bn 6 Bn 20-8 Pd(OH) 2 , EtOH 1. LiAIH 4 2. Pd(OH) 2 , EtOH 0 -o HN HN H2N ~~02tBu C2U H2- 0t NN";'. 20-7 20-9 3-Bromo-6-chloro-5-nitropvridine (20-2) A suspension of CuC12 (3.33 g, 24.8 mmol) in anhydrous 5 CH3CN (200 mL) at 650 was treated with tert-butylnitrite (3.13 mL, 26.3 mmol), followed by the dropwise addition of a solution of 20-1 in 60 ml of CH3CN. The resulting mixture was stirred under an argon atomsphere at 650 for 2 h and concentrated at reduced pressure. The residue was partitioned between EtOAc (150 mL) and 3% HCl (60 ml), - 123w Yr/outuY PCT/U9S/Z53J9 and the organic layer washed successively with 3% HCI, water, and brine (60 mL), then dried, filtered and concentrated to afford a brown solid which was chromatographed on silica (25% EtOAc/Hexane) to afford 20-2 as a yellow crystalline solid. 5 TLC Rf = 0.60 (25% EtOAc/ Hexane) 1 H NMR (300 MHz, CDC13) 8 8.70 (d, J=2.4 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H). (3-Nitro-5-bromo-pyridin-2-vloxv)-acetic acid methyl ester (20-3) Methyl glycolate (450 mg, 5.05 mmol) was added to a 10 suspension of 60% NaH (131 mg, 55 mmol) in THF (20 mL) at 00. The resulting solution was stirred under argon for 0.5 h, then treated with a solution of 20-2. After stirring at 00 for 0.5 h, the reaction was diluted with ethyl acetate, and washed with successively with sat. NaHCO3, water and brine (80 mL each), then dried, filtered and concentrated to 15 afford 20-3 as a yellow solid. TLC Rf = 0.70 (25% EtOAc/ Hexane) 1 H NMR (300 MHz, CDC13) 5 8.46 (d, J= 2.4 Hz, 1H), 8.37 (d, J= 2.4 Hz, 1H) 5.15 (s, 2H), 3.78 (s, 3H). 20 2-Oxo-2,.3-dihydro- 1H-4-oxa-1,5-diaza-7-bromo-naphthalene (20-4) A mixture of 20-3 (1.5 g, 5.12 mmol) and powdered tin (1.37 g, 11.5 mmol) was treated with conc. HC1 (10 mL). The mixture was heated to 800 for 2 h, then cooled and concentrated. The residue was partitioned betwen CHC13 and sat. NaHCO3, washed with brine, then 25 dried, filtered and concentrated to afford a yellow solid. Chromatography on silica gel (50% hexane/EtOAc) gave 20-4 as a yellow solid. TLC Rf = 0.65 (50% EtOAc/ Hexane) 1H NMR (300 MHz, DMSO-d6) 5 10.81 (br,s, 1H), 7.88 (d, J=2.4 Hz, 1H), 30 7.25 (d, J=2.4 Hz, 1H), 4.81 (s, 2H). 3-(2-Oxo-2,3-dihydro- 1H-4-oxa-1,5-diaza-naphthalen-7-vl)-acrv1ic acid tert-but1l ester (20-5) A mixture of 20-4 (1.12 g, 4.89 mmol), (o-tol)3P (298 mg, 1.0 35 mmol), Pd(OAc)2 (110 mg, 0.49 mmol), and triethylamine (0.86 mL, 5.87 - 124wu J UU9 PCT/US98/26539 mmol) in DMF (20 mL) was placed in a 100-mL flask. The mixture was degassed with argon, then tert-butyl acrylate (752 mg, 5.87 mmol) was added and the tube sealed and heated to 1000 for 12 h. The reaction mixture was diluted with ethyl acetate, filtered and washed with 5 NaHCO3, water, and brine, dried, filtered and concentrated. Chromatography on silica gel (25% hex/EtOAc) gave 20-5 as a yellow solid. TLC Rf = 0.60 (25% EtOAc/ Hexane) 1 H NMR (300 MHz, DMSO-d6) 5 10.91 (br,s, 1H), 8.15 (d, J=2.4 Hz, 1H), 10 7.54 (d, J=16 Hz, 1 H), 7.42 (d, J= 2.4 Hz, 1H), 6.35 (d, J=16 Hz, 1 H), 4.84 (s, 2H), 1.48 (s, 9H). 3(S)-[Benzvl-(l(R)-phenv1ethvl)-amino]-3-(2-oxo-2,3-dihvdro-l1H-4-oxa-l,5 diaza-naphthalen-7-vl)-propionic acid tert-but1l ester (20-6) 15 A solution of N-benzyl-a-(R)-methylbenzylamine (0.82 g, 3.87 mmol) in THF (25 mL) at 0 0 C was treated with n-BuLi (1.6 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0 0 C for 30 min and then cooled to -78 0 C. A solution of acrylate 20-5 (0.485 g, 1.76 mmol) in THF (5 mL) was added. After stirring for 15 min at -78 0 C, satd aq 20 NH4C1 soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et20 (2 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to give the 3 25 aminoester 20-6 as a yellow oil. TLC Rf = 0.3 (40% ethyl acetate/hexanes) 1 H NMR (300 MHz, CDC13) 5 1H NMR 8.70 (br, s, 1H), 7.91 (d, J=1.8 Hz, 1H),7.4-7.2 (10H), 7.12 (d, J=1.8 Hz, 1H), 4.80 (s, 2 H), 4.42 (m, 1H), 3.91 (q, J=6.7 Hz, 1 H), 3.69 (d, J=7.2 Hz, 1H, ), 3.62 (d, J =7.2 Hz, 1H, ), 2.46 (m, 30 2H), 1.34 (d, J=7.0 Hz, 3H), 1.29 (s, 9H). 3(S)-Amino-3-(2-oxo-2,3-dihvdro-1H-4-oxa-1,5-diaza-naphthalen-7-vl) propionic acid tert-butv1 ester (20-7) A mixture of the dibenzylamine 20-6 (0.22 g, 0.44 mmol) in 35 EtOH/H20/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and - 125- WU 991/30709 PCT/US98/26539 treated with Pd(OH)2 (100 mg). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (20% 20:1:1 EtOH/NH4OH/H 2 0 - 80% 5 EtOAc) to give the tert-butyl ester 20-7 as a white solid. TLC Rf= 0.5 (20% 20:1:1 EtOH/NH4OH/H20 - 80% EtOAc) 1 H NMR (300 MHz, CD3OD) 5 7.89 (d, J= 1.7 Hz, 1H), 7.31 (d, J=1.7 Hz, 1H), 4.81 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H). 10 3(R)-[Benzyl-(l1-phenylethyl)-amino]-3(S)-(2-thioxo-2,3-dihydro- 1H-4-oxa 1,5-diaza-naphthalen-7-vl)-propionic acid tert. butyl ester (20-8) A solution of 20-6 (0.22 g, 0.44 mmol ) in anhydrous THF was treated with Lawesson's reagent (0.098 g, 0.243 mmol) and stirred at room temperature for 1.5 h. Silica gel (500 mg) was added to the reaction 15 mixture and the solvent was removed at reduced pressure and the product was eluted from silica using 25% EtOAc/hex to afford 20-8 as a yellow solid. TLC Rf = (40% EtOAc/hexane) 0.7 1 H NMR (300 MHz, CD3OD) 5 9.82 (br, s, 1H), 7.95 (d, J=1.8 Hz, 1H),7.4 20 7.2 (11H), 5.08 (s, 2 H), 4.42 (m, 1H), 3.91 (q, J=6.7 Hz, 1 H), 3.69(d, J=7.2 Hz, 1H, ), 3.62 (d, J =7.2 Hz, 1H), 2.46 (m, 2H), 1.34 (d, J=7.0 Hz, 3H), 1.29 (s, 9H). 3(S)-Amino-3-(2,3-dihydro-l1H-4-oxa-1,5-diaza-naphthalen-7-vyl)-propionic 25 acid tert. butyl ester (20-9) A solution of 20-8 ( 1.0 g, 1.9 mmol) in anhydrous Et20 (10 mL) at 0 was treated dropwise with LiA1H4 (2.09 ml of a 1.0 M solution in Et20). The resulting solution was stirred at 0OC for 30 min and then quenched by the sequential addition of H20 (0.3 mL), 15 % NaOH (0.08 30 mL). Celite (1 g) was added and the mixture filtered through a Celite pad. The filtrate was evaporated and the residue was purified by flash chromatography (65% ethyl acetate/hexanes) to give the dibenzylamine intermediate as a yellow oil. TLC Rf = 0.4 (65% ethyl acetate/hexanes) - 126- WU 99/30709 PCT/US98/26539 1 H NMR (300 MHz, CDC13) 6 1H NMR 7.61 (d, J=l.8 Hz, 1H),7.4-7.2 (10H), 6.87 (d, J=1.8 Hz, 1H), 4.41 (m, 2 H), 4.36 (m, 1H), 3.91 (q, J=6.7 Hz, 1 H), 3.8 (brs, 1H), 3.69 (m, 2H), 3.42 (m, 2H), 2.46 (m, 2H), 1.34 (d, J=7.0 Hz, 3H), 1.29 (s, 9H). 5 This material was deprotected with Pd(OH)2 to afford 20-9 as a white solid. TLC Rf= 0.5 (20% 20:1:1 EtOH/NH4OH/H20 - 80% EtOAc) 1 H NMR (300 MHz, CD3OD) 5 7.59 (d, J=1.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 4.41 (m, 2H), 4.30 (m, 1H), ), 3.41 (m, 2H), 2.6, (m, 2H), 1.41 (s, 9H). Scheme 21 NH NH 0 N MeOH 0 N N Br 2 MeOH Br 21-1 21-2 NH NH H2N CO2u

H

2 N CO2Bu 21-3 21-4 10 3-Oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-7-bromo-naphthalene (21-2) A solution of 21-1 (4.8 g, 32 mmol) in MeOH (160 mL) at -150 was treated dropwise with bromine (25.7 g, 161 mmol). After stirring at -15o for 0.5 h, the mixture was warmed to ambient temperature and 15 stirred overnight. The resulting white precipitate was filtered and washed with cold MeOH to afford 21-2 as a white solid. TLC Rf = 0.65 (50% EtOAc/ Hexane) - 127- 1 H NMR (300 MHz,DMSO-d6) d 11.2 (br,s, 1H), 8.05 (d, J= 2.4 Hz, 1H), 7.66 (d, J= 2.4 Hz, 1H), 4.76 (s, 2H). 3(S)-Amino-3-(3-oxo-3,.4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-vl) 5 propionic acid tert-butyl ester (21-3) Bromide 21-2 was converted to amino ester 21-3 as illustrated in Scheme 20. TLC Rf= 0.5 (12% 20:1:1 EtOH/NH40H/H20 - 88% EtOAc) 1 H NMR (300 MHz, CD3OD) 5 8.04 (d, J= 1.7 Hz, 1H), 7.34 (d, J=1.7 Hz, 10 1H), 4.76 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H). 3(S)-Amino-3-(3-oxo-3.4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-vl) propionic acid tert-butvl ester (21-4) Bromide 21-2 was converted to amino ester 21-4 as 15 illustrated in Scheme 20. TLC Rf= 0.5 (20% 20:1:1 EtOH/NH4OH/H20 - 80% EtOAc) 1H NMR (300 MHz, CD3OD) 5 8.04 (d, J= 1.7 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 4.76 (s, 2H), 4.38 (m, 1H), 2.6, (m, 2H), 1.41 (s, 9H). - 128- W U 99/307U9 PCT'/US98/26539 Scheme 22 N N HO MnO 2 HO CH2CI 2 OHC 22-1 22-2

HO

2 C CO 2 Et

NH

4 Ac, EtOH

O

N

H

2 CO 2 Et 22-3 Furo-[2,3-blpvridine-5-carboxaldehyde (22-2) A solution of alcohol 22-1 (M. Bhupathy, et al., J. Heterocycl. Chem. 1995, 32, 1283-1287) was treated with excess MnO2 (10 5 eq) and the mixture stirred at room temperature for 16 h, then filtered through Celite and evaporated to afford 22-2 as a white solid. TLC Rf = 0.40 (25% EtOAc/Hex) 1 H NMR (300 MHz, CDC13) 5 10.22 (s, 1H), 9.05 (d, J= 1.8 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H) 8.08 (d, J=1.8 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H). 10 3-Amino-3-(furo[2,3-blpyridin-5-vl)-propionic acid ethyl ester (22-3) A solution containing aldehyde 22-2 (1.5 g, 10 mmol), ethyl hydrogen malonate (1.6 g, 20 mmol), and ammonium acetate (3.8 g, 50 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 8 h. After 15 cooling to room temperature, the solvent was evaporated and the residue partitioned between sat. sodium bicarbonate and EtOAc, the organic layer removed, dried, and concentrated. Chromatography of the residue afforded the amino ester 22-3 as a waxy solid. - 129- WO 99/30709 PCT/US98/26539 TLC Rf= 0.5 (20% 20:1:1 EtOH/NH4OH/H20 - 80% EtOAc) 1 H NMR (300 MHz, CD3OD) 8 8.34 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.72 ( d, J- 1.7 Hz, 1H), 6.78 (d, J = 1.7 Hz, 1H), 4.62 (m, 1H), 4.13 (q, J=7.5 Hz, 2H), 3.20 (br, s, 2H), 2.76 (m, 2H), 1.23 (t, J= 7.5 Hz, 3H). 5 Scheme 23 N N HO o

SCH

2 C1 2 OHC 23-1 23-2

HO

2 C CO 2 Et

NH

4 Ac, EtOH O N

H

2

CO

2 Et H2N Furo[3.2-blpvridine-5-carboxaldehvde (23-2) A solution of alcohol 23-1 (J.M. Hoffman, Jr., US Patent No. 10 4,808,595) was treated with excess MnO2 (10 eq) and the mixture stirred at room temperature for 16 h, then filtered through Celite and evaporated to afford 23-2 as a white solid. 1 H NMR (300 MHz, CDC13) 5 10.18 (s, 1H), 8.92 (d, J= 1.8 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H) 7.89 (d, J=1.8 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H). 15 3-Amino-3-(furoF3,2-b]pvridin-5-vl)-propionic acid ethyl ester (23-3) A solution containing aldehyde 23-2 (1.5 g, 10 mmol), ethyl hydrogen malonate (1.6 g, 20 mmol), and ammonium acetate (3.8 g, 50 - 130- WO 99/30709 PCT/US98/26539 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 8 h. After cooling to room temperature, the solvent was evaporated and the residue partitioned between sat. sodium bicarbonate and EtOAc, the organic layer removed, dried, and concentrated. Chromatography of the residue 5 afforded the amino ester 23-3 as a waxy solid. TLC Rf= 0.5 (20% 20:1:1 EtOH/NH4OH/H20 - 80% EtOAc) 1H NMR (300 MHz, CD3OD) 5 8.58 (d, J=1.7 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H),7.85( d, J- 1.7 Hz, 1H), 6.98 (d, J = 1.7 Hz, 1H), 4.62 (t, J= 7.2 Hz, 1H), 4.09 (q, J=7.5 Hz, 2H), 2.76 (m, 2H), 2.20 (br, s, 2H), 1.21 (t, J= 7.5 Hz, 3H). 10 Scheme 24

NH

2 CO0 2 H N H 2

H

2 N BocHN CO2M e 24-2 NH 24-1 EDC, HOAT BocHN I CO2Me NMM, DMF 24-3 1. HOAc, 650 2. HCI, EtOAc N NH H2N CO2 Me 24-4 - 131 - WO 99/30709 PCT/US98/26539 N-(S)-(2-Amino-phenvl)-3-tert-butoxvcarbonvlamino-succinamic acid methyl ester (24-3) A mixture of Boc-L-aspartic acid-p3-methyl ester 24-1 (5.0g, 20.2 mmol), o-phenylenediamine 24-2 (2.2 g, 20.2 mmol), EDC (3.9 g, 20.2 5 mmol), HOAT (0.28 g, 2.02 mmol), and NMM (6.7 mL, 60.7 mmol) in DMF (50 mL) was stirred for 18 h at ambient temperature. The solution was diluted with EtOAc (250 mL) and washed with sat. sodium bicarbonate, water, and brine (50 mL each), then dried and evaporated to afford 24-3 as a yellow solid. 10 TLC Rf = 0.50 (95% CHC13/5% isopropanol) 1 H NMR (300 MHz, CDC13) 5 8.10 (br,s, 1H), 7.23 (d, J= 7.8 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H)6.78 (m, 1H),5.8 (br d, 1H), 4.65 (m, 1 H), 3.76 (s, 3H), 3.15 (dd, J=4.6, 16 Hz, 1H), 2.90 (dd, J= 5.1, 16 Hz, 1H), 1.48 (s, 9H). 15 3(S)-Amino-3-Benzimidazol-2-vl-propionic acid methyl ester (24-4) Ester 24-3 (1.0 g, 3 mmol) was dissolved in acetic acid (50 mL) and heated to 650 for 2 h. The solvent was removed to afford the Boc protected intermediate as a white solid. The crude material (920 mg, 2.43 mmol) was dissolved in EtOAc, cooled to 00, and treated with HC1 gas to 20 give 24-4 as a tan solid. 1H NMR (300 MHz, CD3OD) 5 7.80 (m, 2H), 7.35 (m,2H), 5.98 (m, 1H), 3.80 (m, 2H), 3.76 (s, 3H). - 132wu 9/jU U9 PCT/US95/20539 Scheme 25 OH

CQO

2 H OHO .- 2 (N H 2 O /NH BocHN C 2 Me 25-1 NH 2 NH 24-1 EDC, HOAT BocHN - CO2Me NMM, DMF 25-2 1. DEAD, Ph 3 P THF 2. HCI, EtOAc NO H2N

.

CO2 M e 25-3 N-(S)-(2-Hydroxv-phenvyl)-3-tert-butoxycarbonvylamino-succinamic acid methyl ester (25-2) A mixture of Boc-L-aspartic acid-p-methyl ester (24-1) (5.0g, 5 20.2 mmol), 2-amino phenol (25-1) (2.2 g, 20.2 mmol), EDC (3.9 g, 20.2 mmol), HOAT (0.28 g, 2.02 mmol), and NMM (6.7 mL, 60.7 mmol) in DMF (50 mL) was stirred for 18 h at ambient temperature. The solution was diluted with EtOAc (250 mL) and washed with sat. sodium bicarbonate, water, and brine (50 mL each), then dried, and evaporated 10 and chromatographed on silica (EtOAc) to afford 25-2 as a white solid. TLC Rf = 0.55 (EtOAc)) 1H NMR (300 MHz, CDC13) 6 7.23 (d, J= 7.8 Hz, 1H), 6.89 (t, J=7.8 Hz, 1H), 6.78 (m, 1H), 5.68 (br d, 1H), 4.65 (m, 1 H), 3.76 (s, 3H), 3.15 (dd, J=4.6, 16 Hz, 1H), 2.90 (dd, J= 5.1, 16 Hz, 1H), 1.48 (s, 9H). 15 - 133wu /Y.W/U PCT/US98/26539 3(S)-Amino-3-Benzoxazol-2-vyl-pro-pionic acid methyl ester (25-3) Ester 25-2 (2.0 g, 6.0 mmol) was dissolved in anhydrous THF (150 mL) along with Ph3P (1.58 g, 6.0 mmol). The resulting solution was cooled to 00, and a solution of diethyl azodicarboxylate (1.53 5 g, 6.2 mmol) in THF (25 mL) was added dropwise. The cooling bath was removed and the solution stirred overnight at ambient temperature. The solution was concentrated and the residue chromatographed (75% EtOAc/Hexane) to afford the Boc-protected ester as a colorless glass. The crude material (1.8 g, 5.0 mmol) was dissolved in EtOAc, cooled to 00 10 and treated with HC1 gas to give 25-3 as a tan solid. 1 H NMR (300 MHz, CD3OD) 6 7.81 (m, 2H), 7.40 (m,2H), 5.05 (t, J= 7.4 Hz, 1H), 3.72 (s, 3H), 3.30 (m, 2H). SCHEME 26

,CH

3 /CH3 N-NH N-N N-N / CHa 3 , K 2 CO3 / / H

C~-CN-

Br CH 3 CN Br H 2 N - CO2Et 26-1 26-2 26-3 15 1-Methyl-4-bromopvrazole (26-2) Methyl iodide (8.47 mL, 136 mmol) was added to a mixture of 4-bromopyrazole 26-1 (10 g, 38 mmol), and K2C03 (18.9 g, 136 mmol) in CH3CN (150 mL) and the mixture stirred at room temperature for 16 h, then filtered and evaporated to yield 26-2 as a yellow oil. 20 1H NMR (300 MHz, CDC13) 6 7.44(s, 1H),7.38 (s, 1H), 3.90 (s, 3H). 3 (S)-Amino-3-(1-methyl-l1H-pvrazol-4-vyl)-propionic acid ethyl ester (26-3) The bromide 26-2 was converted to the amino ester 26-3 following the procedure depicted in Scheme 19. 25 1 H NMR (300 MHz, CD3OD) 5 7.81 (s, 1H),7.58 (s, 1H),4.80 (m, 1H), 4.05 (q, J= 7.0 Hz, 2 H), 3.89 (s, 3H), 3.00 (m, 2 H), 1.24 (t, J = 7.0 Hz, 3 H). - 134- VV %J 771IU IUY Additional examples of the present invention are listed below and can be prepared by the method shown in Scheme 2 using in place of 1-4 the various 3-substituted P-alanine derivatives prepared according to the procedures depicted in Schemes 9-26 above. These 5 examples can be prepared in high optical purity substituting intermediate 7-5 or its enantiomer for intermediate 2-5. 3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 10 3(S)-(6-Amino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-(2-oxo-3-[3 15 (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl) propionic acid; 3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 20 3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro 25 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(4-Ethoxy-3-fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 30 3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(5-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 35 - 135vv"JYJ3II~ PCT/US98/26539 3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl) propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(6-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5 ,6,7 ,8-tetrahydro 5 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)--propionic acid; 3(S)-(2-.Oxo-2,3-clihydro- 1H-4-oxa- 1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5 ,6,7,8-tetrahydro-I1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl) propionic acid; 10 3(S)-(2,3-Dihydro- 1H-4-oxa- 1,5-diaza-naphthaln-7-yl)-3-(2-oxo-3-[3 (5 ,6,7,8-tetrahydro-II1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) propionic acid; 15 3(S)-(2-Oxo--3,4-dihydro-2H- 1-oxa-4,5-diaza-naphthaen-7-y)-3-(2-oxo-3-[3 (5,6, 7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) propionic acid; 3(S)-(3,4-Dihydro-2H- 1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-13 20 (5,6, 7,8-tetrahydro- [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl) propionic acid; 3-(Furo-[2,3-blpyriidin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 25 3-(2,3-Dihydrofuro[2,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6,7 ,8-tetrahydro [I1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3-(Furo-[3 ,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro 30 [1,8]naphthyridin-2 -yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3-(2,3-Dihydrofuro[3 ,2-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6, 7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; - 136 wvI YYh.3U II9 PC'IIUS98/26539 3(S)-(Benzimidazol-2-yl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-( 1H-Jmidazo[4,5-clpyriclin-2-yl)-3-(2-oxo-3[3-(5,6,7,8-tetrahydro 5 [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(Benzoxazol-2-yl)-3-(2-oxo-3-[3-(5 ,6, 7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 10 3(S)-( 1-Methyl- 1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; and 3(S)- {2-Oxo-3-[3-(5 ,6,7,8-tetrahydro-[1,8lnaphthyridin-2-yl)-propyl] pyrrolidin- 1-yl}-pent-4-enoic acid. - 137 wu 99/1U709 PCT/US98/26539 SCHEME A 5 SYNTHESIS OF RADIOLIGAND FOR SPA ASSAY

H

2 N .< CO 2 H 0 H NH 2 A-1 1 __SO2CI NaOH, dioxane

H

2 0

H

2 N < CO 2 H 0

HN',SO

2 A-2 1. Br 2 , NaOH,

H

2 0 2. HCI 10 - 138wu Y99/JU7UY PCT/US98/26539 SCHEME A (CONTINUED) 2 N CO2H H2N CO2,H H HN'SOI HCI EtOH

HCIH

2 N ., C 0 2C H2C H3 H HN'SO2 A-4 I N/ - \ CO2CH 2

CH

3 N

H

2 N A-5

H

2 , 10% Pd/C EtOH H2N CO2CH2CH 3 A-5a 6N HCI - 139vvu y/outu FuT/U5v/lzONJV SCHEME A (CONTINUED) HCIH2 A-6 CO2H 2r .CO2CH,CH,

HCIH

2 N O2CH2H3 EDC, HOBT, H HNSO 2

C

6

H

4 1 NMM, DMF A-4 6N HOI 602S H22 H2N NH H 4NH SCO2CH2CH 3 O A-7 6N HCI 6 00 CI 02 S< : H2N N .H NH CO2 H A-8 O - 140-

(CH

3 Sn) 2 , Pd(PPh 3

)

4 , dioxane, 900 C Sn(CH 3

)

3 HOS H NH O2S /1251 NH

CO

2 H O A-1 N-(4-Iodo-phenvlsulfonvlamino)-L-asparane (A-2) To a stirred solution of acid A-1 (4.39 g, 33.2 mmol), NaOH 5 (1.49 g, 37.2 mmtol), 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 mmol), dissolved in 15 ml 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 ml) and then washed with EtOAc. 10 The aqueous portion was cooled to 0°C and then acidified with concentrated HC1. The solid was collected and then washed with Et2O to provide acid A-2 as a white solid. 1HNMIR (300 MHz, D20) 5 7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz) 3.70 (in, 1H), 2.39 (in, 2H). 215 H2N N2/ H H NH C 02 H O 2NS-(4-odo-phenv1sulfonv1amino)-L-alanraine (A-3) To a stirred solution of acid A-1H (7.14.3 g, 33181.8 mmol) and H20 5 (1.49 g, 37.2 mmol), dioxane (30 ml) and H20 (30 ml) at O'C was added (40pipsyl chloride (10.34 g, 34.Br2 (1mmol). After 24.95 minutes, NaOH (1.49, 37.2ten -mmol), dissolved in 15 ml 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 ml) and then washed with EtOAc. 10 The aqueous portion was cooled to 00C and then acidified with concentrated HC1. The solid was collected and then washed with Et20 to provide acid A-2 as a white solid. 1H NMR (300 MHz, D20) 5 7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz) 3.70 (m, 1H), 2.39 (m, 2H). 15 2(S)-14-lodo-phenvlsulfonvlamino)-13-alanine (A-3) To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H20 (40 ml) at 00C was added Br2 (1.30 ml, 24.9 mmol) dropwise over a ten - 141 wu YV/JUUM PCTIUS98/26539 minute period. After -5 minutes, acid A-2 (9.9 g, 24.9 mmol), NaOH (2.00 g, 49.8 mmol) and H20 (35 ml) were combined, cooled to 0 0 C and then added in a single portion to the reaction. After stirring for 20 minutes at 0 0 C, the reaction was heated to 90'C for 30 minutes and 5 then recooled to 0 0 C. The pH was adjusted to -7 by dropwise addition of concentrated HC1. The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid A-3 as a white solid. 1 H NMR (300 MHz, D20) 8 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.36 (m, 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 (m, 1H). 10 Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-0-alanine-hvdrochloride (A-4) HC1 gas was rapidly bubbled through a suspension of acid A-3 (4.0 g, 10.81-mmol) in EtOH (50 ml) at 0 0 C for 10 minutes. The cooling bath was removed and the reaction was heated to 60 0 C. After 18 15 h, the reaction was concentrated to provide ester A-4 as a white solid. 1 H NMR (300 MHz, CD3OD) 8 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.25 (q, 1H, J=5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t, 3H, J=7Hz). 20 Ethyl 4-[2-(2-Aminopyridin-6-vl1)ethyllbenzoate (A-5a) A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 95/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, the reaction was 25 filtered through a celite pad and then concentrated to provide ester A-5a as a brown oil. TLC Rf = 0.23 (silica, 40% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 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), 30 1.39 (t, 3H, J=7Hz). 4-[2-(2-Aminopvridin-6-vl)ethyl]benzoic acid hydrochloride (A-6) A suspension of ester A-5a (625 mg, 2.31 mmol) in 6N HC1 (12 ml) was heated to 60 0 C. After -20 h, the reaction was concentrated to 35 give acid A-6 as a tan solid. - 142wu 99/OU7JY PCT/US98/26539 1 H NMR (300 MHz, CD3OD) 8 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 5 phenylsulfonvlamino)-D-alanine (A-7) A solution of acid 15-6 (400 mg, 1.43 mmol), amine A-4 (686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 l, 5.72 mmol) in DMF (10 ml) was stirred for -20 h. The reaction was diluted with EtOAc and then washed with sat. 10 NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc then 5% isopropanol/EtOAc) provided amide A-7 as a white solid. TLC Rf = 0.4 (silica, 10% isopropanol/EtOAc) 1 H NMR (300 MHz, CD3OD) 5 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz), 7.52 15 (d, 2H, J=9Hz), 7.29 (m, 1H), 7.27 (d, 2H, J=8Hz), 4.20 (m, 1H), 3.95 (q, 2H, J=7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz). 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl 20 sulfonvlamino)-D-alanine (A-8) A solution of ester A-7 (200 mg, 0.3213 mmol) and 6N HC1 (30 ml) was heated to 60 0 C. After -20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/ NH40H/H20) provided acid A-8 as a white solid. 25 TLC Rf= 0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH4OH/H20) 1 H NMR (400 MHz, DMSO) 6 8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H, J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d, 1H, J=7Hz), 6.25 (d, 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m, 2H), 2.97 (m, 2H), 2.79 (m, 2H). 30 4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl phenvlsulfonvlamino-3-alanine (A-9) A solution of iodide A-8 (70 mg, 0.1178 mmol), [(CH3)3Sn]2 (49 1, 0.2356 mmol), Pd(PPh3)4 (5 mg) and dioxane (7 ml) was heated to - 143wu YY/I3UU/ PCTI/US98/26539 90 0 C. After 2 h, the reaction was concentrated and then purified by preparative HPLC (Delta-Pak C18 15 pM 100Ao, 40 x 100 mm; 95:5 then 5:95 H20/CH3CN) to provide the trifluoroacetate salt. The salt was suspended in H20 (10 ml), treated with NH4OH (5 drops) and then 5 lyophilized to provide amide A-9 as a white solid. 1 H NMR (400 MHz, DMSO) 5 8.40 (m, 1H), 8.18 (d, 1H, J=8Hz), 7.67 (m, 5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H), 6.45 (bs, 2H), 4.00 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.86 (m, 2H). 10 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4- 1 2 5 iodo phenylsulfonv1amino-5-alanine (A-10) An iodobead (Pierce) was added to a shipping vial of 5 mCi of Nal 2 5 I (Amersham, IMS30) and stirred for five minutes at room temperature. A solution of 0.1 mg of A-9 in 0.05 mL of 10% H2SO4/MeOH 15 was made and immediately added to the Nal 2 5 I/iodobead vial. After stirring for three minutes at room temperature, approximately 0.04-0.05 mL of NH4OH was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for purification [Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 20 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 25 analysis with an authentic sample of A-8. Instrumentation: Analytical and preparative HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 30 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC, a Vydac peptide-protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column. The acetonitrile used for the HPLC analyses was Fisher Optima grade. The HPLC radiodetector used was a Beckman 170 35 Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x - 144vv v >>i.uauy PCI/U9/26539 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 UV/Vis Diode Array Spectrophotometer. 5 Sample radioactivities were determined in a Packard A5530 gamma counter. The test procedures employed to measure czvP3 and avP5 binding and the bone resorption inhibiting activity of the compounds of the present invention are described below. 10 BONE RESORPTION-PIT ASSAY When osteoclasts engage in bone resorption, they can cause the formation of pits in the surface of bone that they are acting upon. Therefore, when testing compounds for their ability to inhibit 15 osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present. Consecutive 200 micron thick cross sections from a 6 mm cylinder of bovine femur diaphysis are cut with a low speed diamond saw (Isomet, Beuler, Ltd., Lake Bluff, I1). Bone slices are pooled, placed 20 in a 10% ethanol solution and refrigerated until further use. Prior to experimentation, bovine bone slices are ultrasonicated twice, 20 minutes each in H20. 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 25 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 addition of 0.1 ml aMEM, pH 6.9 containing 5% fetal bovine serum and 1% penicillin/streptomycin. Long bones from 7-14 day old rabbits (New Zealand White 30 Hare) are dissected, cleaned of soft tissue and placed in aMEM containing 20 mM HEPES. The bones are minced using scissors until the pieces are <1 mm and transferred to a 50 ml tube in a volume of 25 ml. The tube is rocked gently by hand for 60 cycles, the tissue is sedimented for 1 min., and the supernatant is removed. Another 25 ml 35 of medium is added to the tissue and rocked again. The second - 145wu Y W3u /UY PCT/US98/26539 supernatant is combined with the first. The number of cells is counted excluding erythrocytes (typically - 2 x 107 cells/ml). A cell suspension consisting of 5 x 106/ml in aMEM containing 5% fetal bovine serum, 10 nM 1,25(OH)2D3, and pencillin-streptomycin is prepared. 200 ml 5 aliquots are added to bovine bone slices (200 mm x 6 mm) and incubated for 2 hrs. at 37 0 C in a humidified 5% CO 2 atmosphere. The medium is removed gently with a micropipettor and fresh medium containing test compounds is added. The cultures are incubated for 48 hrs., and assayed for c-telopeptide (fragments of the al chain of type I collagen) by 10 Crosslaps for culture media (Herlev, Denmark). Bovine bone slices are exposed to osteoclasts for 20-24 hrs and are processed for staining. Tissue culture media is removed from each bone slice. .Each well is washed with 200 ml of H20, and the bone slices are then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M 15 cacodylate, pH 7.4. After fixation, any remaining cellular debris is removed by 2 min. ultrasonication in the presence of 0.25 M NH40H followed by 2 X 15 min ultrasonication in H20. The bone slices are immediately stained for 6-8 min with filtered 1% toluidine blue and 1% borax. 20 After the bone slices have dried, resorption pits are counted in test and control slices. Resorption pits are viewed in a Microphot Fx (Nikon) fluorescence microscope using a polarizing Nikon IGS filter cube. Test dosage results are compared with controls and resulting IC50 values are determined for each compound tested. 25 The appropriateness of extrapolating data from this assay to mammalian (including human) disease states is supported by the teaching found in Sato, M., et al., Journal of Bone and Mineral Research, Vol. 5, No. 1, pp.31-40, 1990, which is incorporated by reference herein in its entirety. This article teaches that certain 30 bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay described above to confirm a - 146wu 99/iU7U9 PCT/US98/26539 correlation between their known utility and positive performance in the assay. EIB ASSAY 5 Duong et al., J. Bone Miner. Res., 8: S378 (1993) describes a system for expressing the human integrin av13. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies against the integrin, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block 10 bone resorption. Reaction Mixture: 1. 175 p.1 TBS buffer (50 mM Tris*HC1 pH 7.2, 150 mM NaC1, 1% BSA, 1 mM CaC12, 1 mM MgC12). 15 2. 25 p1l cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 41). 3. 12 5 I-echistatin (25 p1/50,000 cpm) (see EP 382 451). 4. 25 p1l buffer (total binding) or unlabeled echistatin (non specific binding). 20 The reaction mixture was then incubated for 1 h at room temp. The unbound and the bound avP3 were separated by filtration using a Skatron Cell Harvester. The filters (prewet in 1.5% poly ethyleneimine for 10 mins) were then washed with the wash buffer (50 25 mM Tris HC1, 1mM CaC12/MgC12, pH 7.2). The filter was then counted in a gamma counter. SPA ASSAY 30 MATERIALS: 1. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside: Calbiochem 35 3. HEPES: Calbiochem - 147- WO 99/30709 PCT/US98/26539 4. NaCI: Fisher 5. CaC12: Fisher 6. MgC12: SIGMA 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 5 8. Optiplate: PACKARD 9. Compound A-10 (specific activity 500-1000 Ci/mmole) 10. test compound 11. Purified integrin receptor: avI3 was purified from 293 cells overexpressing avP3 (Duong et al., J. Bone Min. Res., 8:S378, 10 1993) according to Pytela (Methods in Enzymology, 144:475, 1987) 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaC1, 1 mM Ca 2 +/Mg 2 + , 0.5 mM PMSF 13. 50 mM octylglucoside in binding buffer: 50-OG buffer 15 PROCEDURE: 1. Pretreatment of SPA beads: 20 500 mg of lyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer. 2. Preparation of SPA beads and receptor mixture 25 In each assay tube, 2.5 p1l (40 mg/ml) of pretreated beads were suspended in 97.5 p1l of binding buffer and 20 p1l of 50-OG buffer. 5 p.1 (-30 ng/pl) 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 30 Beckman GPR Benchtop centrifuge for 10 minutes at 4 0 C. The pellets were then resuspended in 50 p.1 of binding buffer and 25 p1 of 50-OG buffer. - 148- WO 99/30709 PCT/US98/26539 3. Reaction The following were sequentially added into Optiplate in corresponding wells: (i) Receptor/beads mixture (75 ml) 5 (ii) 25 il of each of the following: compound to be tested, binding buffer for total binding or A-8 for non-specific binding (final concentration 1 gM) (iii) A-10 in binding buffer (25 4l, final concentration 40 pM) 10 (iv) Binding buffer (125 p1) (v) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C 15 4. Plates were counted using PACKARD TOPCOUNT 5. % inhibition was calculated as follows: A = total counts B = nonspecific counts 20 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 25 mouse calvaria, were plated in CORNING 24 well tissue culture plates in xMEM medium containing ribo- and deoxyribonucleosides, 10% fetal bovine serum and penicillin-streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows: 30 Mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syringe with a 27.5 gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 gm nylon cell strainer. The resulting suspension 35 was centrifuged at 350 x g for seven minutes. The pellet was - 149wu iuJ_/UY, PCT/US98/26539 resuspended, and a sample was diluted in 2% acetic acid to lyse the red cells. The remaining cells were counted in a hemacytometer. The cells were pelleted and resuspended at 1 x 106 cells/mL. 50 iL was added to each well of 1.8 cells to yield 50,000 cells/well and 1,25-dihydroxy-vitamin 5 D3 (D3) was added to each well to a final concentration of 10 nM. The cultures were incubated at 37 0 C in a humidified, 5% CO2 atmosphere. After 48 h, the medium was changed. 72 h after the addition of bone marrow, test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with 10 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: 15 The cells were stained for 10-15 minutes at room temperature with 50 mM acetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dried. The number of 20 multinucleated, positive staining cells was counted in each well. cvB5 ATTACHMENT ASSAY Duong et al., J. Bone Miner. Res., 11: S290 (1996), describes 25 a system for expressing the human avP5 integrin receptor. Materials: 1. Media and solutions used in this assay are purchased from BRL/Gibco, except BSA and the chemicals are from Sigma. 30 2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid free BSA and 2 mM CaC12. 3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl N-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH 5.0. - 150 wu w/vu/U9 PCT/US98/26539 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5. Methods: 5 1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4oC with human vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH 9/.6), using 100 gl/well. Plates were then washed 2X with DPBS and blocked with 2% BSA in DPBS for 2h at room temperature. After additional washes (2X) with 10 DPBS, plates were used for cell attachment assay. 2. 293 (cxvp5) cells were grown in MEM media in presence of 10% fetal calf serum to 90% confluence. Cells were then lifted from dishes with IX Trypsin/EDTA and washed 3X with serum free MEM. Cells were resuspended in 15 attachment medium (3 X 10 5 cells/ml). 3. Test compounds were prepared as a series of dilutions at 2X concentrations and added as 50 pl/well. Cell suspension was then added as 50 pl/well. Plates were incubated at 37'C with 55 C02 for 1 hour to allow attachment. 20 4. Non-adherent cells were removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase substrate solution (100 @l/well), overnight at room temperature in the dark. To quantitate cell numbers, standard curve of glucosaminidase activity was 25 determined 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 p.l/well of glycine/EDTA solution and reading absorbance at 30 405 nm 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 of cells using the Softmax program. 35 - 151 wu YW.JU/UY PCT/US98/26539 EXAMPLE OF A PHARMACEUTICAL FORMULATION As a specific embodiment of an oral composition, 100 mg of a compound of the present invention are formulated with sufficient 5 finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. Representative compounds of the present invention were tested and found to bind to human av3 integrin. These compounds are generally found to have IC50 values less than about 100 nM in the SPA 10 assay. Representative compounds of the present invention were tested and generally found to inhibit > 50% the attachment of avP5 expressing cells -to plates coated with vitronectin at concentrations of about 1 p.M. 15 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 20 as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and 25 depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, 30 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. - 152 -

Claims

1. A compound of the formula R 5 R 6 W-X-Y-Z - R C O

2 R 9 R 7 R 5 wherein W is selected from the group consisting of N'R NR 2 jj II -1 -NRR 2 -NRl-C-NR'R 2 -C-NR'R a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are 10 unsubstituted or substituted with one R 1 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 15 of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S, and wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 20 substituents; X is selected from the group consisting of -(CH2)v-, wherein any methylene (CH2) carbon atom is either 25 unsubstituted or substituted with one or two R 1 substitutents; and a 5- or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are - 153- WO 99/30709 PCT/US98/26539 unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 substituents; Y is selected from the group consisting of 5 -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, 10 -(CH2)m-SO2-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p -, -(CH2)m-NR 4 -(CH2)n-NR 4 -(CH2)p -, -(CH2)m-O-(CH2)n-S-(CH2)p -, 15 -(CH2)m-S-(CH2)n-S-(CH2)p -, -(CH2)m-NR 4 -(CH2)n-S-(CH2)p -, -(CH2)m-NR 4 -(CH2)n-O-(CH2)p -, -(CH2)m-S-(CH2)n-O-(CH2)p -, and -(CH2)m-S-(CH2)n-NR 4 -(CH2)p -, 20 wherein any methylene (CH2) carbon atom in Y, other than in R 4 , can be substituted by one or two R 3 substituents; Z is a 5 membered aromatic or nonaromatic mono- or bicyclic 25 ring system having 0 to 3 heteroatoms selected from the group consisting of N, 0, and S, and wherein the ring system is either unsubstituted or substituted with 0, 1, 2, or 3 oxo or thio substituents, and either unsubstituted or substituted with one or more substituents independently selected from the group consisting of R 10 , R 1 1 , and R 12 30 wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, Ci-10o alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, - 154- w vY/. 3UUY PCT/US98/26539 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, 5 hydroxycarbonyl C1-6 alkyl, C1-3 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, 10 C1-8 alkyloxycarbonylamino, (C 1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-8 alkylsulfonylamino, and C1-8 alkylsulfonylamino; or two R 1 lsubstituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to 15 form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, aryl, 20 C1-10o 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(R 4 )-(CH2)s-, 25 aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, halogen, hydroxyl, oxo, 30 trifluoromethyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, - 155- 1Vw YY~I3Pu MY PCT/US98/26539 C1..6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1-6 alkyl)pamino, amino C1..6 alkyl, 5 arylaminocarbonyl, aryl CI..5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cl..6 alkyl, hydroxycarbonyl, 10 hydroxycarbonyl C 16 alkyl, C 1-6 alkyl-C-=C-(CH2)t-, C3-.7 cycloalkyl-C=EC-(CH2)t-, aryl-C=EC-(CH2)t-, 15 C1.6 alkylaryl-C=C-(CH2)t-, CH2=CH-(CH2)t-, C 1-6 alkyl-CH=CH-(CH2)t-, C3-.7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, 20 C 1-6 alkylaryl-CH=CH-(CH2)t-, Cl..6 alkYl-S02-(CH2)t-, C 1-6 alkylaryl-S02-(CHE2)t-, Cl..6 alkoxy, aryl C1.6 alkoxy, 25 aryl C1-6 alkyl, (C 1-6 alkyl)pamino C1..6 alkyl, (aryl)pamino, (aryl)paniino C1..6 alkyl, (aryl C1-6 alkyl)pamino, 30 (aryl C1-6 alkyl)pamino C1-6 alkyl, arylcarbonyloxy, aryl C1..6 alkylcarbonyloxy, (C 1-6 alkyl)parninocarbonyloxy, C1-8 alkylsulfonylaniino, - 156 - WU 9IU7UY PCT/US98/26539 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl 01-6 alkylsulfonylamino, 5 aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, 10 aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino Cl1-6 alkyl, aryl C1-6 alkylcarbonylamino, 15 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, 20 (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (01-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, 25 (aryl)paminosulfonylamino C1-6 alkyl, (aryl 01-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, 30 arylsulfonyl 01-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, 35 arylcarbonyl C1-6 alkyl, - 157- WU 99/30709 PCT/US98/26539 aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C 1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, 5 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, 10 (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, or two R 3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl or a cyclopropyl group, 15 wherein any of the alkyl groups of R 3 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 3 is selected such that in the resultant compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom; 20 each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, 25 C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, (aryl C1-5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, 30 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, - 158- wu 99/JU0709 PCT/US98/26539 C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, 5 arylcarbonyl, aryl C1-6 alkylcarbonyl, (C1-8 alkyl)paminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, 10 (aryl)paminosulfonyl, (aryl C1-8 alkyl)paminosulfonyl, arylsulfonyl, arylC1-6 a1kylsulfonyl, C1-6 alkylthiocarbonyl, 15 arylthiocarbonyl, and aryl C1-6 alkylthiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R 1 substituents; 20 R5 and R6 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, 25 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2)s-, aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, 30 halogen, hydroxyl, C1-8 alkylcarbonylamino, aryl C1-5 alkoxy, C1-5 alkoxycarbonyl, - 159- vy'. yY/.u/uy PUI'IUh9?SI26539 (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1-6 alkyl)pamino, 5 amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5 alkyllaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, 10 hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, HC=-C-(CH2\t-, C 1-6 alkylbC=C-(CH2)t-, C3-7 cycloalkyl-C=-C-(CH2}t-, 15 aryl-C=EC-(CH2)t-, CH2=CH-(CH2)t-, C 1-6 alkyl-CH=CH-(CH2)t-, C3-.7 cycloalkyl-CH=CH-(CH2)t-, 20 aryl-CH=CH-(CH2)t-, C1-6 alkylaryl-CH=CH-(CH2)t-, C 1-6 alkyl-S02-(CH2)t-, C 1-6 alkylaryl-S02-(CH2)t-, Cl-6 alkoxy, 25 aryl C1-6 alkoxy, aryl C1..6 alkyl, (C1..6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, 30 (aryl C1-6 alkyl)painino, (aryl C1..6 alkyl)pamino C1..6 alkyl, arylcarbonyloxy, aryl C 1.6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, - 160 - vvJ YYI3uy PCT'I/U95/26539 C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, 5 aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, 01-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, 10 aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, 15 aryl C1-6 alkylcarbonylamino, aryl 01-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylamino C1-6 alkyl, (01-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, 20 (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino 01-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, 25 (01-8 alkyl)paminosulfonylamino 01-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, 01-6 alkylsulfonyl, 30 C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, 01-6 alkylcarbonyl, - 161- WU 99/U7U9 PCT/US98/26539 C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, 5 C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, 10 (C1-8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-g8 alkyl)paminocarbonyl C1-6 alkyl; or R 5 and R 6 are taken together with the carbon atom to which they are 15 attached to form an oxo group, wherein any of the alkyl groups of R 5 or R 6 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 5 and R 6 are selected such that in the resultant compound the carbon atom to which R 5 and R 6 are attached is itself 20 attached to no more than one heteroatom; R 7 and R8 are each independently selected from the group consisting of hydrogen, CI-10o alkyl, 25 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(R 4 )-(CH2)s-, 30 aryl-(CH2)r-N(R 4 )-C(O)-(CH2)s-, aryl-(CH2)r-N(R 4 )-(CH2)s-, halogen, hydroxyl, C1-8 alkylcarbonylamino, - 162- aryl Ci..5 alkoxy, Cl.5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C1..6 alkylcarbonyloxy, 5 C3-8 cycloalkyl, (C 1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl Cl.. 5 alkylaminocarbonyl, 10 aminocarbonyl, aminocarbonyl Cp-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, 15 C1..6 alkyl-C=-C-(CH2)t-, C3-7 cycloalky1-C=-C-(CH2)t-, aryl-C=EC-(CH2)t-, CH2=CH-(CH2)t-, 20 C>-6 alkyl-CH=CH-(CH2)t-, C3-.7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, C1..6 alkylary1-CH=CH-(CH2)t-, C 1-6 alkyl-S02-(CH2)t-, 25 C 1 .. 6 alkylaryl-S02-(CH2)t-, Cl-.6 alkoxy, aryl C1..6 alkoxy, aryl Cl-6 alkYl, (C 1 .. 6 alkyl)pamino Cl.6 alkyl, 30 (aryl)pamino, (aryl)pamino Cl..6 alkyl, (aryl C>-6 alkyl)pamino, (aryl Cl>6 alkyl)pamino C1..6 alkyl, arylcarbonyloxy, - 163 - ". .' ' PC'1IUS98/26539 aryl C1-6 alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylcarbonylamino, 5 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1.6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, 10 C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 -alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, 15 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, 20 arylaminocarbonylamino, (C 1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, 25 (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, 30 (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, - 164- ". 'V ': ' PCT'/US98/26539 aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, 5 arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, 10 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, 15 (aryl C1-8 alkyl)paminocarbonyl, (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, and C7-20 polycyclyl CO-8 alkyloxycarbonylamino; wherein any of the alkyl groups of R 7 and R 8 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each 20 R 7 and R 8 are selected such that in the resultant compound the carbon atom to which R 7 and R 8 are attached is itself attached to no more than one heteroatom; R 9 is selected from the group consisting of 25 hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, C1-8 alkylcarbonyloxy C1-4 alkyl, 30 aryl C 1-8 alkylcarbonyloxy C 1-4 alkyl, C1-8 alkylaminocarbonylmethylene, and C 1-8 dialkylaminocarbonylmethylene; - 165- . .. "'.. "' PCT/US98/26539 R10 , Rll, and R1 2 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, 5 aryl, halogen, hydroxyl, oxo, aminocarbonyl, 10 C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, hydroxycarbonyl, (aryl C1-5 alkyl)paminocarbonyl, 15 hydroxycarbonyl C1-6 alkyl, aryl C1-6 alkyl, (C1- 6 alkyl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino C2-6 alkyl, C1-8 alkylsulfonyl, 20 C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, C1-8 alkylcarbonyl, arylcarbonyl, 25 aryl C1-6 alkylcarbonyl, (C1- 8 alkyl)paminocarbonyl, aminosulfonyl, C1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, 30 (aryl C1-8 alkyl)paminosulfonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylcarbonyl, -166- I Iu Ia/ADW C 1-6 alkyithiocarbonyl, aryithiocarbonyl, aryl Cl..6 alkyithiocarbonyl, aryl-(CH2)r-O-(CH2)s-, 5 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH 2 )s-, aryl-(CH2)r-N(R 4 )-C(O )(CH2)s-, 10 HC-=C-(CH2)t-, C 1-6 alkyl-C=-C-(CH2)t-, C3 CH2CH-(klCH)-C(H) C.akyl-C =CH2)-(C2) C3.j clylalkyl-C=(CH-2)t-, .15yCH=CH-(CH2)t-, C 1-6 alkyyl-CH=CH-(CH2)t-, 20C 1

3. 6 cyalkyl-2 C-(CH2)t-, C 1-8 alkylcarbonylamino, aryl Ci..5 alkoxy, Ci.5 alkoxycarbonyl, 25 (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, (Cl- 6 alkyl)pamino, aminocarbonyl C1..6 alkyl, C1.6 alkoxy, 30 aryl Ci..6 alkoxy, (aryl)pamino, (aryl)pamino Cl..6 alkyl, (aryl C1..6 alkyl)pamino, (aryl C1..6 alkyl)pamino C1..6 alkyl, - 167- aryr I carbonyloxy, aryl 1-6 alkylcarbonyloxy, aryl C 1-6 alkylcarbonyloxy, (C1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, 5 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, 10 C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 -alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, 15 C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, 20 aminocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, 25 (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, 30 (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, 35 aryl C1-6 alkylsulfonyl, - 168- aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, 5 aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, 10 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 15 (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl; wherein any of the alkyl groups of R 1 0 , R 1 1 , and R 1 2 are either unsubstituted or substituted with one to three R 1 substituents; wherein 20 each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; 25 each s is independently an integer from 0 to 3; each t is independently an integer from 0 to 3; and v is independently an integer from 0 to 6; and the pharmaceutically acceptable salts thereof. 30 - 169- VVj 77/Jou/uY YLII/UW /5LO.3Y 2. The compound of Claim 1 wherein W is a 6-membered monocyclic aromatic ring system having 1 or 2 5 nitrogen atoms wherein each ring carbon atom is unsubstituted or substituted with one R 1 substituent, or a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of 10 N,O, and S, and wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R1 substituents; and Z is selected from the group consisting of R. 10R.' 1R 10 SR" R 1 o 1 RNo" N N -NNO 12 12 12 A 10 Rlo ,R 4' R HN X and 15 12 20 - 170- wu Yi/3U/ PC'IT/U98/25i39 3. The compound of Claim2 wherein W is selected from the group consisting of R 1 R1 Ri 1R N N N N N H H H R 1 R 1 R 1 and N N ' N N N N H H and Z is selected from the group consisting of R l O O 1 O R10 0 R NNN 5 , N O 5 -- Rio O0 N R1o ff~~ NH K' N N and H , \ 0 0

4. The compound of Claim 3 wherein W is or H 10 X is -(CH2)v-, wherein any methylene (CH2) carbon atom is either unsubstituted or substituted with one or two R 1 substitutents; - 171 - Y is selected from the group consisting of -(CH2)m-, 5 -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, -(CH2)m-SO2-(CH2)n-, 10 -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p-, -(CH2)m-NR 4 -(CH2)n-NR 4 -(CH2)p-, and -(CH2)m-NR 4 -(CH2)n-O-(CH2)p-, wherein any carbon atom in Y, other than in R 4 , can be substituted by 15 one or two R 3 substituents; and Z is R 1 0 , / or O 0 20

5. The compound of Claim 4 wherein Y is selected from the group consisting of (CH2)m, (CH2)m-S-(CH2)n, and (CH2)m-NR 4 -(CH2)n, 25 wherein any carbon atom in Y, other than in R 4 , can be substituted by one or two R 3 substituents, and m and n are integers from 0-3, and v is 0. - 172 -

6. The compound of Claim 5 wherein each R 3 is independently selected from the group consisting of hydrogen, fluoro, 5 trifluoromethyl, aryl, C1-8 alkyl, arylC1-6 alkyl hydroxyl, 10 oxo, arylaminocarbonyl, aryl Ci-5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1-6 alkyl; and 15 each R 4 is independently selected from the group consisting of hydrogen, aryl, C3-8 cycloalkyl, 20 C1-8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, 25 arylC1.-6alkylsulfonyl, arylC 1-6alkylcarbonyl, C 1-8alkylaminocarbonyl, arylC 1-5alkylaminocarbonyl, arylC1-8alkoxycarbonyl, and 30 C 1-8alkoxycarbonyl.

7. The compound of Claim 6 wherein R 6 , R 7 , and R 8 are each hydrogen and R 5 is selected from the group consisting of hydrogen, - 173- aryl, C1-8 alkyl, aryl-C=C-(CH2)t-, aryl C1-6 alkyl, 5 CH2=CH-(CH2)t-, and HC=-C-(CH2)t-.

8. The compound of Claim 7 wherein R 9 is selected from the group consisting of hydrogen, methyl, and ethyl. 10

9. The compound of Claim 8 wherein R 9 is hydrogen.

10. The compound of Claim 6 wherein R 5 , R 6 , and R 8 are each hydrogen and R 7 is selected from the group consisting of 15 hydrogen, aryl, C1-8 alkylcarbonylamino, C1-8 alkylsulfonylamino, arylcarbonylamino, 20 arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, 25 C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, 30 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, 35 (C1-8 alkyl)paminocarbonylamino, - 174 - (C1-8 alkyl)paminocarbonylamino C1-.6 alkyl, (aryl)paminocarbonylamino C1-6 alkyl, arylaminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, 5 (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, 10 (aryl C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C 1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, 15 aryl C1-6 alkylthiocarbonylamino, and aryl C1-6 alkylthiocarbonylamino C1-6 alkyl.

11. The compound of Claim 10 wherein R 7 is selected from the group consisting of 20 hydrogen, aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbonylamino, 25 C1-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1.8 alkoxycarbonylamino, 30 arylaminocarbonylamino, (C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylamino, and (aryl C1-8 alkyl)paminosulfonylamino. - 175 - vvJ YWYu /UY PCT/US98/26539

12. The compound of Claim 11 wherein R 9 is selected from the group consisting of hydrogen, methyl, and ethyl.

13. The compound of Claim 12 wherein R 9 is 5 hydrogen.

14. The compound of Claim 6 selected from the group consisting of 10 Ethyl 3(S)-(3-fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate; Ethyl 3(S)-(3-flubrophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionate; 15 Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8 tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8 20 tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; Ethyl 3(S)-(quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; 25 Ethyl 3(S)-(quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionate; 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 30 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; - 176 - vv %u YwOU tMY PCT1/US95/26539 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro 5 [1, 8]naphthyridin-2-yl)-propyl]-pyrroli din- 1-yl)-propionic acid; 3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 10 3(S)-(Quinolin-3-yl)-3-(2-oxo(S)-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 2(S)-Benzenesulfonylamino-3-[3-(3-[1,8]naphthyridin-2-yl-propyl) [1,2,4]oxadiazol-5-yl]-propionic acid; 15 3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(6-Amino-pyridin-3-y)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro 20 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-(2-oxo-3-[3 (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl) propionic acid; 25 3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro 30 [1, 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; - 177 - uv wiuu L1/U /O 3(S)-(4-Ethoxy-3-fluoropheny)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro 5 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(5-Methoxy-pyridin-3-y)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 10 3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(6-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 15 3(S)-(2-Oxo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl) propionic acid; 20 3(S)-(2,3-Dihydro-1H-4-oxa-1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl) propionic acid; 3(S)-(2-Oxo-3,4-dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 25 (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl) propionic acid; 3(S)-(3,4-Dihydro-2H-1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3 (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl) 30 propionic acid; 3-(Furo-[2,3-b]pyridin-6-y)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; - 178 - Vvu YYI/.)UMY PCU'ITUN98/Z0 3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3-(Furo-[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro 5 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3-(2,3-Dihydrofuro[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 10 3(S)-(Benzimidazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(1H-Imidazo[4,5-c]pyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 15 3(S)-(Benzoxazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(1-Methyl- 1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro 20 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl] pyrrolidin-1-yl}-pent-4-enoic acid; 25 and the pharmaceutically acceptable salts thereof.

15. The compound of Claim 14 selected from the group consisting of 30 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro [1,8]naphthyidin-2-yl)-propyl]-pyrrolidin-1-yl]-propionic acid; 35 - 179- wu VYJi/UY PCT/US98/2539 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro 5 [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 3(S)-(Quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; 10 3(S)-(Quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin 2-yl)-propyl]-pyrrolidin-1-yl)-propionic acid; and the pharmaceutically acceptable salts thereof. 15

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

17. A pharmaceutical composition made by combining a 20 compound according to Claim 1 and a pharmaceutically acceptable carrier.

18. A process for making a pharmaceutical composition comprising combining a compound according to Claim 1 and a 25 pharmaceutically acceptable carrier.

19. The composition of Claim 16 which further comprises an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically 30 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 35 platelet-derived growth factors, - 180 - VV Yv/3ou/uy PCT/US98/26539 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; and i) a prenylation inhibitor, such as a farnesyl transferase 5 inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof.

20. The composition of Claim 19 wherein said active 10 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, and c. a cathepsin K inhibitor; 15 and mixtures thereof.

21. The composition of Claim 20 wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium trihydrate. 20

22. The composition of Claim 19 wherein said active ingredient is selected from the group consisting of a.) a cytotoxic/antiproliferative agent, b.) a matrix metalloproteinase inhibitor, 25 c.) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, d.) an inhibitor of VEGF, and e.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1; and mixtures thereof. 30

23. 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. 35 - 181 - VV ky YYI3UI/UY F I~1~~

24. The method of Claim 23 wherein the integrin receptor antagonizing effect is an avP3 antagonizing effect.

25. The method of Claim 24 wherein the avP3 5 antagonizing effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumor growth.

26. The method of Claim 25 wherein the av3 10 antagonizing effect is the inhibition of bone resorption.

27. The method of Claim 23 wherein the integrin receptor antagonizing effect is an avf5 antagonizing effect. 15

28. The method of Claim 27 wherein the avP5 antagonizing effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, and tumor growth. 20

29. The method of Claim 23 wherein the integrin receptor antagonizing effect is a dual avP3/avP5 antagonizing effect.

30. The method of Claim 29 wherein the dual avP3/avP5 antagonizing effect is selected from the group consisting of inhibition of 25 bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumor growth.

31. The method of Claim 23 wherein the integrin antagonizing effect is an cav6 antagonizing effect. 30

32. The method of Claim 31 wherein the avI6 antagonizing effect is selected from the group consisting of angiogenesis, inflammatory response, and wound healing. - 182 - VVw u YYI3U/UY CIIU9/LZO9

33. 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 16. 5

34. 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 16. 10

35. 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. 15

36. 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 20.

37. A method of treating tumor growth in a mammal in 20 need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 22.

38. A method of treating tumor growth in a mammal in need thereof, comprising administering to the mammal a 25 therapeutically effective amount of a compound according to Claim 1 in combination with radiation therapy. - 183-