AU736026B2 - Integrin receptor antagonists - Google Patents

Description

WO 99/30709 PCT/US98/26539 TITLE OF THE INVENTION INTEGRIN RECEPTOR ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS 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.

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, avp5, and/or avP6 and are 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.

BACKGROUND OF THE INVENTION It is believed that a wide variety of disease states and conditions can be mediated by acting on integrin receptors and that integrin receptor antagonists represent a useful class of drugs. Integrin receptors are heterodimeric transmembrane receptors through which cells attach and 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 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 the surface of bone, and can bind to bone, secrete necessary acids and -1- WO 99/30709 PCT/US98/26539 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, 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 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, in rat, chicken, mouse -and human osteoclasts, is an integrin receptor known as av33, which is thought to interact in bone with matrix proteins that 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 avp3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.

The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilizationinduced osteopenia, and glucocorticoid-induced osteoporosis. All of 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 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 people with detectable fractures of the vertebrae due to osteoporosis. In -2- WO 99/30709 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.

Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.

Additionally, avp3 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 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 Harrison's Principles of Internal Medicine, 12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, avp3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See Brooks et al., Cell, 79:1157- 1164 (1994), which is incorporated by reference herein in its entirety).

Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, A monoclonal antibody for avp5 has been shown to inhibit VEGFinduced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M.C. Friedlander, et al., Science 270, 1500-1502, (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize av35 are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis.

Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of the integrin receptor, av6, 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 Human Skin/SCID Mice, Chimeras, American Journal of Pathology, WO 99/30709 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 avP6 plays a role in the remodeling of the vasculature during the later stages of angiogenesis. Also, av36 participates in the modulation of epithelial 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 Bioloffv, Vol. 133, No.4, pp. 921-928 (May 1996), which is incorporated by reference herein in its entirety). Accordingly, compounds that antagonize 0v6 are useful in treating or preventing cancer by inhibiting tumor growth and metastasis.

In addition, certain compounds of this invention antagonize both the =v03 and avP5 receptors. These compounds, referred to as "dual av3/czvP5 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 as mixed avP3, av5, 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 avP3 receptor antagonists.

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 avP6 receptor antagonists.

It is another object of the present invention to provide compounds which are useful as dual avP3/xvP5 receptor antagonists.

It is another object of the present invention to provide compounds which are useful as mixed avP3, avP5, and avP6 receptor antagonists.

It is another object of the present invention to provide pharmaceutical compositions comprising integrin receptor antagonists.

-4- WO 99/30709 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 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 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 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.

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.

SUMMARY OF THE INVENTION The present invention relates to compounds of the formula

R

5

R

6 W-X-Y-Z- C O 2

R

9

R

7

R

8 wherein W is selected from the group consisting of WO 99/30709 PCT/US98/26539

N

R 1

NR

2

-C-NR'R

2

-NR-C-NR'R

2 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, and a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 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 substituents; X is selected from the group consisting of wherein any methylene (CH2) carbon atom is either 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 atoms are unsubstituted or substituted with one or two R 1 substituents; Y is selected from the group consisting of -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -6- WO 99/30709 WO 9930709PCTIUS98/26539 -(CH2)m-SO-(CH2)n-, -(CH2)mn-S02-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p -(CH2)nrNR 4 -(CH2)n-N{ 4 -(CH2)p -(CH2)m-0-(CH2)n-S-(CH2)p -(CH2)]OarS-(CH2)n-S-(CH2)p -(CH2)m-N-R 4 -(CH2)n-S-(CH2)p -(CH2)m-NIR 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 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 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

11 and R 1 2 wherein Rland R 2 are each independently selected from the group consisting of hydrogen, halogen, Cl-1o alkyl, C3-.8 cycloalkyl, C3-.8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl Cp-8 alkyl, amino, amino C1-8 alkyl, C1..3 acylanuno, C1..3 acylamino Cl..8 alkyl, (C1-.

6 alkyl)pamino, (C 1-6 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- Cl..6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, Cl..6 alkyloxy- Cl..

6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1..8 alkyl-S(0)p, (Cl..

8 alkyl)paminocarbonyl, WO 99/30709 WO 9930709PCT/US98/26539 C 1-8 alkyloxycarbonylamino, (C 1-8 alkyl)paniinocarbonyloxy, (arYl C1-8 alkyl)pamino, (aryl)paniino, aryl C1.8alkylsulfonylainino, and C 1-8 alkyl sulfonylamino; 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; each R 3 is independently selected from the group consisting of hydrogen, aryl, Ci-iO alkyl, aryl-(CH2)r-O-(CH2)s-, aryl-(CHZ)rS(O )p-(CH2)s-, aryl-(CH2 aryl-(CH2)r-C(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(CH2)r-N(R 4 halogen, hydroxyl, oxo, trifluoromethyl, C 1-8 alkylcarbonylamfino, aryl C1-5 alkoxy, alkoxycarbonyl, (C1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (Cl>6 alkyl)pamino, amino C1..6 alkyl, arylaminocarbonyl, aryl C1..5 alkylaminocarbonyl, aminocarbonyl., aminocarbonyl C1..6 alkyl, hydroxycarbonyl, -8- WO 99/30709 WO 9930709PCTIUS98/26539 hydroxycarbonyl Cl.6 alkyl, C 1-6 alky1-C-=C-(CH2)t-, C3-.7 cycdoalkyl-C=-C-(CH2)t-, ary1-C=-C-(CH2)t-, C1-6 alkylaryl-C-=C-(CH2)t-, CH2=CH-(CH2)t-, C 1-6 alkyl-CH=CH-(CH2ht-, C3-.7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, C 1-6 alkylaryl-CH=CH-(CH2)t-, Cl-6 alkYl-S02-(CH2)t-, C 1-6 alkylaryl-S02-(CH2)t-, C1.6 alkoxy, aryl Cl..6 alkoxy, aryl C1..6 alkyl, (Cl..6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino Cl..6 alkyl, (aryl Cl-6 alkyl)pamino, (aryl C 1-6 alkyl)pamino Ci1-6 alkyl, arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, Cl1-8 alkylsulfonylamino, arylsulfonylamino, Cl..8 alkylsulfonylainino Ci-6 alkyl, arylsulfonylainino C1-6 alkyl, aryl Cl..6 alkylsulfonylamino, aryl Cl16 alkyllsulfonylaniino C1-6 alkyl, Cl.8 alkoxycarbonylamino, C 1-8 alkoxycarbonylaniino C 1-8 alikyl, aryloxycarbonylamino C1.8 alkyl, aryl Cl.8 alkoxycarbonylainino, WO 99/30709 PTU9/63 PCTIUS98/26539 aryl C1-8 alkoxycarbonylamino Cl..8 alkyl, Cl.8 alkylcarbonylamino, Cl..8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1..6 alkyl, aryl Cl-6 alkylcarbonylaino, aryl C1-6 alkylcarbonylaniino C1I.6 alkyl, aininocarbonylamino C1-6 alkyl, (C 1-8 alkyl)paminocarbonylamino, (C 1-8 alkyl)paminocarbonylamino Cl.6 alkyl, (aryl)paminocarbonylamino C 1-6 alkyl, (aryl C 1-8 alkyl)paminocarbonylamino, (aryl Cl.8 alkyl)paminocarbonylaniino Cl.6 alkyl, aminosulfonylamino Cl.6 alkyl, (C 1-8 alkyl)paminosulfonylainino, (Cl.8 alkyl)paminosulfonylamino Cl.-6 alkyl, (aryl)paminosulfonylarnino Cl..6 alkyl, (aryl C 1-8 alkyl)pamino sulfonylamino, (aryl C1.8 alkyl)paminosulfonylainino C1.-6 alkyl, C 1-6 alkylsulfonyl, C1.6 alkylsulfonyl C1.6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl Cl-6 alkylsulfonyl C1.6 alkyl, C1-6 alkylcarbonyl, C1.6 alkylcarbonyl C1..6 alkyl, arylcarbonyl Cl-6 alkyl, aryl Cl-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C 1-6 alkyithiocarbonylamino, Cly6 alkylthiocarbonylamino C1.6 alkyl, aryithiocarbonylamino Cl-6 alkyl, aryl C 1-6 alkyithiocarbonylamino, aryl C1..6 alkyithiocarbonylamino C1-6 alkyl, (Cl.8 alkyl)paminocarbonyl C1.6 alkyl, 10 WO 99/30709 WO 9930709PCTIUJS98/26539 (aryl)paminocarbonyl C1..6 alkyl, (aryl C 1-8 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 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 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, aryl, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paniinocarbonyl, (aryl C1..5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, C1-8 alkyl, aryl C1-6 alkyl, (C 1-6 alkyl)pamino C2-.6 alkyl, (aryl C1-6 alkyl)paino C2-.6 alkyl, 01-8 alkylsulfonyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, aryl 01-8 alkoxycarbonyl, C1-8 alkylcarbonyl, arylcarbonyl, aryl 01-6 alkylcarbonyl, (01..8 alkyl)paminocarbonyl, aminosulfonyl, 11- WO 99/30709 PTU9/63 PCT/US98/26539

C

1 8 alkylarninosulfonyl, (aryl)paminosulfonyl, (aryl C1..8 alkyl)paminosulfonyl, arylsulfonyl, arylCl-6 alkylsulfonyl, C1..6 alkyithiocarbonyl, aryithiocarbonyl, and aryl C1-6 alkyithiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R 1 substituents; and R6 are each independently selected from the group consisting of hydrogen; CI-jo alkyl, aryl, aryl-(CH2)r-O-(CH2 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O aryl-(CH2)r-C(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(GH2 )rN(R 4 halogen, hydroxyl, C 1-8 alkylcarbonylamino, aryl C1-5 alkoxy, alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C1-.6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarb onyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, 12 WO 99/30709 WO 9930709PCT/US98/26539 aniinocarbonyl C1..6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl..6 alkyl, C1.6 alkyl-C=-C-(CH2)t-, C3-.7 cycloalkyl-C=-C-(CH2)t-, Cl.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-, Cl.6 alkylary1-CH=CH-(CH2)t-, C1-6 alkyl-S02-(CH2h-, C 1-6 alkylaryl-S02-(CH2)t-, C1..6 alkoxy, aryl C1..6 alkoxy, aryl C 1-6 alkyl, (C1.6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C 1-6 alkyl, (aryl C1-6 alkyl)pamino, (aryl C1-.6 alkylbpamino Cl.6 alkyl, arylcarbonyloxy, aryl C1.-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C 1-8 alkylsulfonylamino, arylsulfonyl amino, Cl.8 alkylsulfonylamino Cl.6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1.6 alkylsulfonyllamino, aryl Cl16 alkylsulfonylamino C1..6 alkyl, C 1-8 allkoxycarbonylamino, Cl-8 alkoxycarbonylamino C 1-8 alkyl, 13 WO 99/30709 PTU9/63 PCTIUS98/26539 aryloxycarbonylamino Cl..8 alkyl, aryl Cl..8 alkoxycarbonylamino, aryl Cl.8 alkoxycarbonylamino Cl>8 alkyl, C 1-8 alkylcarbonylamino, C1..8 alkyilcarbonylamino Cl.6 alkyl, arylcarbonylamino C1-6 alkyl, aryl Cl..6 alkylcarbonylamino, aryl C1.6 alkylcarbonylamino Cl.6 alkyl, aminocarbonylamino Cl..6 alkyl, (C 1-8 alkyl)paminocarbonylamino, (C 1-8 alkyl)paminocarbonylamino Cl.6 alkyl, (aryl)pami*nocarbonylainino C 1-6 alkyl, (aryl C 1-8 alkyl)paminocarbonylamino, (aryl C1.8 alkyl)paminocarbonylamino Cl..6 alkyl, aminosulfonylamino Cl..6 alkyl, (C1..8 alkyl)paminosulfonylainino, (C 1-8 alkyl)pamino sulfonylainino C 1-6 alkyl, (aryl)paminosulfonylamino Cl..6 alkyl, (aryl C 1-8 alkyl)painino sulfonylamino, (aryl C1.8 alkyl)paminosulfonylamino C1.6 alkyl, C1.-6 alkylsulfonyl, C1..6 alkylsulfonyl C1.6 alkyl, arylsulfonyl C1..6 alkyl, aryl C1..6 alkylsulfonyl, aryl C1.6 alkylsulfonyl C1-6 alkyl, C 1-6 alkylcarbonyl, C1..6 alkylcarbonyl C1..6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1..6 alkylcarbonyl, aryl C1I-6 alkykcarbonyl C1..6 alkyl, C 1-6 alkylthiocarbonylainino, C1..6 alkyithiocarbonylamino Cl..6 alkyl, aryitbiocarbonylamino Cl.6 alkyl, aryl C1..6 alkyltb-iocarbonylaniino, 14- WO 99/30709 PTU9163 PCTIUS98/26539 aryl C1-6 alkyitbiocarbonylamino C1-6 alkyl, (Cl.8 alkyl)pa minocarbonyl. C1..6 alkyl, (aryl)paminocarbonyl C1-.6 alkyl, (aryl C1_.8 alkyl)paminocarbonyl, and (aryl C1..8 alkyl)paminocarbonyl C1..6 alkyl; or R5 and R6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R 5 or R6are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 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; R7 and R 8 are each independently selected from the group consisting of hydrogen, Ci-1O alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CIH2)r-C(O)-N(R 4 aryl-(CH2)r-N(R 4 )(CH2)s-, aryl-(CH2)r-N(R 4 halogen, hydroxyl, C 1-8 alkylcarbonylaxnino, aryl C1-5 alkoxy, alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C1-.6 alkylcarbonyloxy, C3-8 cycloalkyl,

(C

1 6 alkyl)pamino, amino C1..6 alkyl, arylaminocarbonyl, 15 WO 99/30709 WO 9930709PCTIUS98/26539 aryl Ci.5 alkylaminocarbonyl, aminocarbonyl, aininocarbonyl C1..6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01-6 alkyl, 03=--7 Cyclolk-CE-CH) C>6 alkyla-C=-C-(CH2)t-, 0C3-HylakC--(CH2)t C1arlkl-C-(H=CJ-(02} 3l-6 alylalyl-C=(CH-2)t-, aCH=CH-(CH2)t-, C1-6 alkyyl-CH=CH-(CH2)t-, Cl>6 alkYl-S02-(CH2)t-, 0>-6 alkylaryl-S02-(CH2)t-, C1-6 alkoxy, aryl 01-6 alkoxy, aryl1Cly6alkY1, (C1..6 alkyl)pamino 01..6 alkyl, (aryl)pamino, (aryl)pamino 01-6 alkyl, (aryl 01-6 alkyl)pamino, (aryl C 16 alkyl)pamino Cl1-6 alkyl, arylcarbonyloxy, aryl 01-6 alkylcarbonyloxy, (01-6 alkyl)paminocarbonyloxy, 0 1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino 01-6 alkyl, arylsulfonylamino C1..6 alkyl, aryl 01-6 alkylsulfonylamino, 16 WO 99/30709 WO 9930709PCTIUS98/26539 aryl C1..6 alkylsulfonylam-ino Cl16 alkyl, Cl.8 alkoxycarbonylamino, C 1-8 alkoxycarbonylamino C 1-8 alkyl, aryloxycarbonylamino Cl..8 alkyl, aryl C1..8 alkoxycarbonylamino, aryl C1..8 alkoxycarbonylamino C1..8 alkyl, C1..8 alkylcarbonylamino C1..6 alkyl, arylcarbonylainino C1..6 alkyl, aryl C1.6 alkylcarbonylamino, aryl C1..6 alkylcarbonylainino C1.6 alkyl, aminocarbonylamino C1..6 alkyl, (C 1-8 alkyl)paminocarbonylamino, (Ci-8 alkyl)paminocarbonylamino C1.6 alkyl, (aryl)paminocarbonylamino Ci -6 alkyl, arylaminocarbonylamino, (aryl C 1-8 alkyl)paminocarbonylamino, (aryl Cl-8 alkyl)paminocarbonylamino C1..6 alkyl, aniinosulfonylamino Cl16 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paininosulfonylamino C1..6 alkyl, (ary1)paminosulfonylamino C 1-6 alkyl, (aryl Clp8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paininosulfonylamino C 1.6 alkyl, Cl-6 alkylsulfonyl, C1..6 alkylsulfonyl C1..6 alkyl, arylsulfonyl C1..6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1..6 alkylsulfonyl C1..6 alkyl, C 1-6 alkylcarbonyl, C1..6 alkylcarbonyl C1..6 alkyl, arylcarbonyl C1..6 alkyl, aryl C1.6 alkylcarbonyl, aryl C1.6 alkykcarbonyl C 1-6 alkyl, C 1-6 alkyithiocarbonylamino, 17 WO 99/30709 WO 9930709PCTIUS98/26539 C1..6 alkyithiocarbonylamino C1-.6 alkyl, arylithiocarbonylamino C1..6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1..6 alkyl, (C1..8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paniinocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, (aryl C1-8 alkyl)pamninocarbonyl 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 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;

R

9 is selected from the group consisting of hydrogen, C1-.8 alkyl, aryl, aryl C1.. alkyl, C1-.8 alkylcarbonyloxy C1-.4 alkyl, aryl C 1-8 alkylcarbonyloxy C 1-4 alkyl, C 1-8 alkylaminocarbonylmethylene, and C 1-8 cialkylaininocarbonylmethylene; RII, and R 12 are each independently selected from the group consisting of hydrogen, Cl..8 alkyl, aryl, halogen, hydroxyl, oxo, aminocarbonyl, -18 WO 99/30709 WO 9930709PCTIUS98/26539 C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paininocarbonyl, hydroxycarbonyl, (aryl C1-5~ alkyl)parninocarbonyl, hydroxycarbonyl C1-6 alkyl, aryl Cl-6 alkYl, (C1..6 alkyl)pamino C1-6 alkyl1, (aryl C1.6 alkyl)painino C2-6 alkyl, C 1-8 alkylsulfonyl, C 1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C 1-8 -alkoxycarbonyl, Cl.8 alkylcarbonyl, arylcarbonyl, aryl C1.6 alkylcarbonyl, (C 1-8 ailkyl)paminocarbonyl, aminosulfonyl, C 1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1..8 alkyl)pamainosulfonyl, Cl.6 alkylsulfonyl, arylsulfonyl, aryl C 1-6 alkylsulfonyl, aryl C1..6 alkylcarbonyl, Cl..6 alkyithiocarbonyl, aryithiocarbonyl, aryl C1..6 alkyithiocarbonyl, aryl-(CH2)r-O-(CH2 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2 )r-C(O aryl-(CH2)r-C(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(CH2)rN(R 4 19 WO 99/30709 WO 9930709PCTIUS98/26539 01-6 alkyl-C=EC-(CH2)t-, C3-7 cycloaky-C=-0-(CH2)t-, arCH=-C-(CH2)t-, Cl0-6 alkyla-C=C-(CH2)t-, 03Cy2Cloy-( H =CH(CH)t- CIaryl-CH=CH-(CH2)t-, 01-6 alkylaryl-CH=CH-(CH2)t-, 01-6 alkYl-S02-(CH2)t-, 01-6 alkYlarYl-S02-(CH2)t-, 01-8 alkylcarbonylainino, aryl 01-5 alkoxy, 01-5 alkoxycarbonyl, (01-8 alkyl)paminocarbonyl, 01-6 alkylcarbonyloxy, (0 1-6 alkylbpainino, aminocarbonyl 01-6 alkyl, 01-6 alkoxy, aryl 01-6 alkoxy, (aryl)pamino, (aryl)pamino 01-6 alkyl, (aryl 01-6 alkyl)pamino, (aryl 01-6 alkylbpamino 01-6 alkyl, arylcarbonyloxy, aryl 01-6 alkylcarbonyloxy, (01-6 alkyl)pannnocarbonyloxy, C1-8 alkylsulfonylainino, arylsulfonylamino, 01-8 alkylsulfonylamino Ci -6 alkyl, arylsulfonylainino 01-6 alkyl, aryl 01-6 alkylsulfonylamino, aryl 01-6 alkylsulfonylamino C1..6 alkyl, 20 WO 99/30709 PTU9/63 PCT/US98/26539 C 1-8 alkoxycarbonylamino, C 1-8 alkoxycarbonylamino C 1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C 1.8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino Gl..8 alkyl, C1-8 alkylcarbonylamino, C1-8 alkylcarbonylamino Cl-6 alkyl, arylcarbonylamino C1..6 alkyl, aryl C1..6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1.6 alkyl, aminocarbonylamino Cl..6 alkyl, (C 1-8 alkyl)paminocarbonylamino, (C 1-8 alkyl)paminocarbonylamino C 1-6 alkyl, (aryl)paminocarbonylamino C 1-6 alkyl, (aryl C1..8 alkyl)paininocarbonylamino, (aryl C1..8 alkyl)paminocarbonylainino C 1-6 alkyl, aminosulfonylamino C1..6 alkyl, (C1-8 alkyl)paminosulfonylainino, (C 1-8 alkyl)paininosulfonylamino C 1-6 alkyl, (aryl)pamino sulfonylamino C 1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamino, (aryl Cl.8 alkyl)paminosulfonylamino Cp-6 alkyl, Cl16 alkylsulfonyl, Ci-6 alkylsulfonyl C1-6 alkyl, ar-ylsuflfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1..6 alkylsulfonyl C1..6 alkyl, C1-6 alkylcarbonyl, C 1-6 alkylcarbonyl C1..6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1.6 alkylcarbonyl, aryl Cl-6 alkylcarbonyl C1..6 alkyl, C 1-6 alkyithiocarbonylainino, C 1-6 alkyithiocarbonylamino C 1-6 alkyl, 21 WO 99/30709 PCT/US98/26539 arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (C1- 8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)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 each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6 each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; each s is independently an integer from 0 to 3; 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.

The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.

The present invention also relates to methods for making the pharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, 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- WO 99/30709 PCT/US98/26539 The present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention.

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:

R

5

R

6 W-X-Y-Z 7 C0 2

R

9

R

7

R

8 wherein W is selected from the group consisting of NR NR 2

-C-NR'R

2

-NR-C-NR'R

2 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 R1 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 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 R1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 substituents; -23- WO 99/30709 WO 9930709PCT/US98/26539 X is selected from the group consisting of wherein any methylene (CH2) carbon atom is either 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 RI substituent, and the ring carbon atoms are unsubstituted or substituted with one or two RI substituents; Y is selected from the group consisting of -(CH2)m-F -(CH2)m-0-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, -(CH2)m-S02-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)mr0-(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 -(CH2)m-NR 4 -(GH2)n-0-(CH2)p -(CH2)m-S-(CH2)n-0-(CH2)p and -(CH2)m-S-(CH2)n-N-R 4 -(CH2)p -1 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 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 24 WO 99/30709 WO 9930709PCT/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 RII, and R 12 wherein Rland R 2 are each independently selected from the group consisting of hydrogen, halogen, Cl-1b alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, CI-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, C 1-3 alkoxycarbonyl C 1-6 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, (C 1-8 alkyl)paminocarbonyl, C 1-8 alkyloxycarbonylamino, (C 1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-8 alkylsulfonylamino, and C1-8 alkylsulfonylaniino; or two RI substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, aryl, Ci-jo alkyl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2 )r-C(O aryl-(CH2)r-C(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(CH2)r-N(R 4 halogen, 25 WO 99/30709 PTU9/63 PCT/US98/26539 hydroxyl, oxo, trifluoromethyl, C 1-8 alkylcarbonylamino, aryl Cl-5 akoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C1.6 alkyl)pamino, amino C1-6 alkyl, arylaminocarb onyl, aryl Ci.- -alkylaminocarbonyl, aminocarbonyl, aninocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonylI C1-6 alkyl, =C7ccoy-C-(CH2)t-, C 1-6 alkylary-CC-(CH)-, ~HC3- HylakC--(CH2)t-, C1arlkl-CHC-(CH2)t-, 25C3-7 clylalkyl-C=(CH(C2)t-, aCH=CH-(CH2)t-, C1-6 alkyyl-CH=CH-(CH2)t-, C1..6 alkyl-S02-(CH2)t-, C1.6 alkylarYl-S02-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, aryl Cl-6 alkyl, (C1-6 alkyl)pamino C1-6 alkyl, (aryl)pamino, (aryl)pamino C1-6 alkyl, 26 WO 99/30709 WO 9930709PCT/US98/26539 (aryl C1.6 alkyl)painino, (aryl Cl-6 alky1)painino C1..6 alkyl, arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C 1-8 alkylsulfonylamino, arylsulfonyl amino, C1..8 alkylsulfonylamino Cl..6 alkyl, arylsulfonylamino Cl.6 alkyl, aryl C1.6 alkylsulfonylainino, aryl C1-6 alkylsulfonylamino G1-6 alkyl, C 1-8 alkoxycarbonylamino, C1..8 alkoxycarbonylanuno C1.8 alkyl, aryloxycarbonylamino Cl..8 alkyl, aryl C1-8 alkoxycarbonylainino, aryl Cl..8 alkoxycarbonylamino C1.8 alkyl, C 1-8 alkylearbonylamino, Cl-8 alkylcarbonylainino C1.6 alkyl, arylcarbonylamino C1.6 alkyl, aryl C1..6 alkylcarbonylamino, aryl Cl..6 alkylcarbonylamino C1..6 alkyl, aminocarbonylamino Cl-6 alkyl, (Ci..

8 alkyl)paminocarbonylamino, (Cl.8 alkyl)paminocarbonylainino C1.6 alkyl, (aryl)paminocarbonylamino C1..6 alkyl, (aryl C1..8 alkyl)paminocarbonylamino, (aryl Cl.8 alkyl)paminocarbonylamino C1.6 alkyl, aminosulfonylamino C1.6 alkyl, (Cl-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paminosulfonylamino C1.6 alkyl, (aryl)paniinosulfonylamino C1.6 alkyl, (aryl C 1-8 alkyl)paminosulfonylamino, (aryl C1..8 alkyl)parninosulfonylamino C1.6 alkyl, Cl.6 alkylsulfonyl, 27 WO 99/30709 PTU9/63 PCTIUS98/26539 C1-6 alkylsulfonyl C1-6 alIkyl, arylsulfonyl C1..6 alkyl, aryl C1..6 alkylsulfonyl, aryl C1-.6 alkylsulfonyl C1..6 alkyl, C1-.6 alkylcarbonyl, C1-6 alkylcarbonyl C1..6 alkyl, arylcarbonyl C1..6 alkyl, aryl C1..6 alkylcarbonyl, aryl C1-6 alkyilcarbonyl C1.-6 alkyl, C1..6 alkylthiocarbonylamino, C1.6 alkylthiocarbonylamino C1..6 alkyl, arylthiocarbonylamino C1..6 alkyl, aryl C1.6 alkylthiocarbonylaniino, aryl C1..6 alkyithiocarbonylamino C1..6 alkyl, (C 1-8 alkyl)pannnocarbonyl C1..6 alkyl, (aryl)paminocarbonyl C 1-6 alkyl, (aryl C 1-8 alkyl)paxninocarbonyl, 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. 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 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, aryl, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, 28 WO 99/30709 PTU9/63 PCTIUS98/26539 (aryl C1-5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, C1-.8 alkyl, aryl C1-.6 alkyl, (C 1-6 alkyII)pamino C2-.6 alkyl, (aryl C1..6 alkylparnino C2-6 alkyl, C 1-8 alkylsulfonyl, C 1-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1-8 alkoxycarbonyl, 01-8 alkylcarbonyl, arylcarbonyl, aryl C 1-6 -alkylcarbonyl,

(C

1 8 alkyl)paminocarbonyl, aminosulfonyl, C1-.8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1-8 alkyl)paininosulfonyl, arylsulfonyl, arylCl-6 alkylsulfonyl, C1..6 alkyithiocarbonyl, aryithiocarbonyl, and aryl C1..6 alkyithiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three RI substituents; and R6 are each independently selected from the group consisting of hydrogen, aryl, aryl-(CH2)r-O-(CH2 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2 )r-C(O )(CH2)s-, aryl-(CH2)r-C(O

)-N(R

4 29 WO 99/30709 WO 9930709PCT/US98/26539 aryl-(CI{2)r-N(R 4 )(CH2)s-, aryl-(CH2)r-N(R 4 halogen, hydroxyl, C 1-8 alkylcarbonylamino, aryl Ci-5 alkoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1-6 alkyl)painino, amino C1-6 alkyl, arylamino'carb onyl, aryl C1..5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-6 alkyl-C-=C-(CH2)t-, C3-7 cycloalkyl-C=-C-(CH2)t-, C 1-6 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-, C 1-6 alkylaryl-CH=CH-(CH2)t-, C1-6 alkYl-S02-(CH2)t-, C1-6 alkylaryl-S02-(CH2)t-, C1-6 alkoxy, aryl C1-6 alkoxy, arYl C1-6 ailkYl, (C1-6 alkyl)pamino C1-6 alkyl, 30 WO 99/30709 WO 9930709PCTJUS98/26539 (aryl)pamino, (aryl)pamino C1..6 alkyl, (aryl Cl..6 alkyl)pamino, (aryl Cl..6 alkyl)pamino Cl.6 alkyl, arylcarbonyloxy, aryl C1..6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, C1-8 alkyilsulfonylamino Cl-6 alkyl, arylsulfonylamino C 1-6 alkyl, aryl C1..6 alkylsulfonylaniino, aryl C1.6 -alkylsulfonylamino C 1-6 alkyl, C 1-8 alkoxycarbonylamino, C1..8 alkoxycarbonylamino C1..8 alkyl, aryloxycarbonylanino C1-8 alkyl, aryl Cl..8 alkoxycarbonylamino, aryl C1..8 alkoxycarbonylainino C1-.8 alkyl, C 1-8 alkylcarbonylamino, C1.8 alkylcarbonylamino C1.-6 alkyl, arylcarbonylamino Cl.6 alkyl, aryl C1..6 alkylcarbonylamino, aryl Cl-6 alkylcarbonylaino Cl..6 alkyl, aminocarbonylamino C 1-6 alkyl, (C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminocarbonylamino C1..6 alkyl, (aryl)paminocarbonylamino C 1-6 alkyl, (aryl C 1-8 alkyl)paminocarbonylamino, (aryl Cl-8 alkyl)paminocarbonylaxnino C1..6 alkyl, aininosulfonylainino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C 1-8 alkyl)paminosulfonylamino C 1-6 alkyl, (aryl)paminosulfonylamino C 1-6 alkyl, (aryl C1-8 alkyl)paminosulfonylamno, 31- WO 99/30709 PCT/US98/26539 (aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl C1-6 alkyl, aryl C1-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkyithiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkyithiocarbonylamino C1-6 alkyl, (C1-8 alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)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 R6 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 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 hydrogen, alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, -32- WO 99/30709 WO 9930709PCTIUS98/26539 aryl-(CH2)r-C(O aryl-(CH2)r-C(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(CH2)r-N(R 4 halogen, hydroxyl, C 1-8 alkylcarbonylarnino, aryl C1-5 alkoxy, C 1-5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (CI1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C 1-5 alkylaminocarbonyl, aminocarbonyl, aniinocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl CI-6 alkyl, C 1-6 alky1-C=-C-(CH2)t-, C3-7 cycloalky1-C=-C-(CH2)t-, C1..6 alkylaryl-C=-C-(CH2)t-, CH2=CH-(CH2ht-, C 1-6 alkyl-CH=CH-(CH2)t-, C3-7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, C1-6 alkylaryl-CH=CH-(CH2)t-, C 1-6 alkYl-S02-(CH2)t-, C1-6 alkylaryl-S02-(CH2)t-, C1..6 alkoxy, aryl C 1-6 alkoxy, 33 WO 99/30709 WO 9930709PCT/US98/26539 aryl 01-6 alkyl, (C1..6 alkyl)pamino C1..6 alkyl, (aryl)pamino, (aryl)pamino Cl..6 alkyl, (aryl Cl..6 alkyl)pamino, (aryl C1-6 alkyl)pannno C1..6 alkyl, arylcarbonyloxy, aryl C 1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C 1-8 alkylsulfonylamino, arylsulfonylamino, 01-8 alkylsulfonylainino Cl.6 alkyl, arylsulfonylaniino C1-6 alkyl, aryl C1..6 alkylsulfonylamino, aryl 01.6 alkylsulfonylamino ClI.6 alkyl, 01-8 alkoxycarbonylaniino, C1..8 alkoxycarbonylamino Cl.8 alkyl, aryloxycarbonylamino C1.8 alkyl, aryl Ci..g alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino 01-8 alkyl, 01-8 alkylcarbonylamino, C1.8 alkylcarbonylamino 01-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl 01-6 alkylcarbonylaino, aryl 01-6 alkylcarbonylamino Ci-6 alkyl, aminocarbonylamino C1..6 alkyl, (01-8 alkyl)paminocarbonylamino, (Cl- 8 alkyl)paminocarbonylamino 01-6 alkyl, (aryl)paminocarbonylainino 01-6 alkyl, (aryl 01-8 alkylpaminocarbonylamino, (aryl 01-8 alkyl)paminocarbonylamino 01-6 alkyl, aminosulfonylamino 01..6 alkyl, (0 1-8 alkyl)paminosulfonylamino, (0i..8 alkyl)paminosulfonylaxnino 01-6 alkyl, 34 WO 99/30709 WO 9930709PCTIUS98/26539 (aryl)paminosulfonylamino C1.6 alkyl, (aryl C1..8 alkyl)paininosulfonylainino, (aryl C1..8 alkyl)paminosulfonylamino C1..6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl 01-6 alkyl, arylsulfonyl C1-.6 alkyl, aryl 01.6 alkylsulfonyl, aryl C1..6 alkylsulfonyl C1.6 alkyl, C1-6 alkylcarbonyl, C1..6 alkylcarbonyl C1..6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C 1-6 alkylearbonyl C 1-6 alkyl, C 1-6 alkyithiocarbonylamino, Cl..6 alkyitbiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1..6 alkylthiocarbonylamino, aryl C 1-6 alkyithiocarbonylamino C1..6 alkyl, (C 1-8 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; 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 at 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 hydrogen, C1-.8 alkyl, aryl, aryl C1-.8 alkyl, 35 WO 99/30709 PTU9/63 PCT/US98/26539 Cp-8 alkylcarbonyloxy C1..4 alkyl, aryl C1-.8 alkylcarbonyloxy C1-.4 alkyl, C1-8 alkylaminocarbonylmethylene, and G1-8 cialkylaniinocarbonylmethyiene; Ri0 R 1 1, and R1 2 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, aryl, halogen, hydroxyl, oxo, aminocarbonyl, C3-8 cycloalkyl, amino C1..6 alkyl, (aryl)paxninocarbonyl, hydroxycarbonyl, (aryl C1-5 alkyl)paminocarbonyl, hydroxycarbonyl Cl..6 alkyl, aryl C1..6 alkyl, (C l.6 alkyl)pamino C1-6 alkyl, (aryl C1..6 alkyl)panmino C2-.6 alkyl, C1..8 alkylsulfonyl, C1-.8 alkoxycarbonyl, aryloxycarbonyl, aryl C1..8 alkoxycarbonyl, C1-.

8 alkylcarbonyl, arylcarbonyl, aryl C 1 6 alkylcarbonyl, (C 1-8 alkyl)paminocarbonyl, amino sulfonyl, C 1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, 36 WO 99/30709 WO 9930709PCTIUS98/26539 (aryl Cl..8 alkyl)paniinosulfonyl, Cl..6 alkylsulfonyl, arylsulfonyl, aryl C 1-6 alkylsulfonyl, aryl Cl..6 alkylcarbonyl, C1.6 alkyithiocarbonyl, aryithiocarbonyl, aryl Cl..6 alkyithiocarbonyl, aryl-(CH2 )r-O-(CH2 aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-C(O)-N(R 4 )-(CH2 aryl-(CHZ)r-N(R 4 )(CH2)s-, HC=EC-(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-, CH2=CH-(CH2)t-, C 1-6 alkylbCH=CH-(CH2)t-, C3-.7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, C 1-6 alkylary1-CH=CH-(CH2)t-, Cl..6 alkYl-S02-(CH2ht-, C 1-6 alkylaryl-S02-(CH2)t-, C 1-8 alkylcarbonylamino, aryl CI..5 alkoxy, Cl..

5 alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C 1-6 alkylcarbonyloxy, (Cl- 6 alkyl)painino, aminocarbonyl C1-6 alkyl, C1-.6 alkoxy, 37 WO 99/30709 WO 9930709PCT/US98/26539 aryl C01-6 alkoxy, (aryl)pamino, (aryl)pamino Cl..6 alkyl, (aryl 01.6 alkybpainiino, (aryl C 1-6 alkyl)parnino C 1-.6 alkyl, arylcarbonyloxy, aryl 01-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C 1-8 alkylsulfonylamino, arylsulfonylamino, C1..8 alkylsulfonylamino 01..6 alkyl, aryllsulfonylamino 01..6 alkyl, aryl 01-6 alkylsulfonylainino, aryl 01-6 alkylsulfonylamino 0l..6 alkyl, C 1.8 alkoxycarbonylamino, C1..8 alkoxycarbonylamino Ci-8 alkyl, aryloxycarbonylamino 01..8 alkyl, aryl C1..8 alkoxycarbonylarnino, aryl C1-8 alkoxycarbonylainino Cl.8 alkyl, 01-8 alkylcarbonylamino, 01-8 alkylcarbonylamino 01-6 alkyl, arylcarbonylainino 01-6 alkyl, aryl C1..6 alkylcarbonylamino, aryl 01-6 alkylcarbonylamino 01-6 alkyl, aminocarbonylainino 01.6 alkyl, (01-8 alkyl)paminocarbonylamino, (0 1-8 alkyl)paminocarbonylamino 01-6 alkyl, (arylbpaminocarbonylamino 01-6 alkyl, (aryl C1..8 alkyl)paniinocarbonylamino, (aryl 01-8 alkyI)paminocarbonylarnino 01-6 alkyl, aminosulfonylainino 01-6 alkyl, (01-8 alkyl)paminosulfonylamino, (0 1-8 alkyl)paminosulfonylamino 01-6 alkyl, (aryl)panainosulfonylamino 01-6 alkyl, 38 WO 99/30709 PTU9/63 PCT/US98/26539 (aryl C1..8 alkyl)pamino sulfonylamino, (aryl C1..8 alkyl)paminosulfonylainino C1..6 alkyl, C1-6. alkylsulfonyl, 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, C1-6 alkylcarbonyl Cl-6 alkyl, arylcarbonyl C1..6 alkyl, aryl. C1..6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C 1-6 alkylthiocarbonylaniino, C1-6 alkyithiocarbonylamino C1..6 alkyl, arylthiocarbonylamino C 1-6 alkyl, aryl C1..6 alkyithiocarbonylainino, aryl. C1-6 alkyitbiocarbonylamino Cl..6 alkyl, (C 1-8 alkyl)paminocarbonyl Ci-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1..8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl Ci-6 alkyl, wherein any of the alkyl groups of R 10

R

1 1 and R 12 are either unsubstituted or substituted with one to three R 1 substituents; 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; 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.

39 WO 99/30709 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 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, 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.

More preferably, W is selected from the group consisting of N N N N N R1 R R 1

R

1 H H

H

R

1

R

1

R

1 N and lN H H Most preferably W is

R

1 R 1 I or

H

In the compounds of the present invention, X is preferably -(CH2)v- wherein any methylene (CH2) carbon atom is either unsubstituted or substituted with one or two R1 substituents.

WO 99/30709 WO 9930709PCT/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 -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, -(CH2)m-S02-(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 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 one or two R 3 substituents.

More preferably Y is selected from the group consisting of (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 selected from the group consisting of 41 WO 99/30709 WO 9930709PCTIUS98/26539 j)

N

N I 0

H

N/

R"

X,

R' 2 and Moie preferably Z is selected from the group consisting of 0

R

10 0 0 0 N R 10

H

and Most preferably Z is or 42 WO 99/30709 PCT/US98/26539 In the compounds of the present invention, R1 and R 2 are preferably selected from the group consisting of hydrogen, halogen, C1alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, hydroxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy.

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 selected from the group consisting of hydrogen, fluoro, trifluoromiethyl, aryl, C1-8 alkyl, arylC1-6 alkyl hydroxyl, oxo, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1-6 alkyl.

More preferably, R 3 is selected from the group consisting of fluoro, aryl, C1-8 alkyl, arylC1-6 alkyl hydroxyl, oxo, and arylaminocarbonyl.

In the compounds of the present invention, R 4 is preferably selected from the group consisting of -43- WO 99/30709 PCT/US98/26539 hydrogen, aryl, C3-8 cycloalkyl, C1-8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryiC 1-6alkylsulfonyl, aryiC 1-6alkylcarbonyl, C 1-8alkylaminocarbonyl, arylC1-8alkoxycarbonyl, and C 1-8alkoxycarbonyl.

More preferably, R 4 is selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkylcarbonyl, aryl carbonyl, arylC 1-6alkylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, and aryiC 1-6alkylsulfonyl..

In one embodiment of the present invention, R 5 and R 6 are each independently selected from the group consisting of hydrogen, aryl, C1-8 alkyl, aryl-CEC-(CH2)t-, 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 hydrogen, -44- WO 99/30709 WO 9930709PCT/US98/26539 aryl, C1-8 alkyl, ary1-C=-C-(CH2)t-, aryl C1-6 alkYl, CH2=CH-(CH2)t-, and 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 hydrogen, aryl, C1-8 alkyl, aryl C1-6 alkyl, CH2=GH-(GH2)t-, and HC=-C-(CH2ht-.

In another embodiment of the present invention, R 7 and R 8 are each independently selected from the group consisting of hydrogen, aryl, C 1-8 alkylcarbonylamino, aryl carb onyl amino, C 1-8 alkylsulfonylaniino, arylsulfonyl amino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylarnino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylainino C1-6 alkyl, C1-8 alkoxycarbonylamino, C 1-8 alkoxycarbonylamino C 1-8 alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino C1-6 alkyl, 45 WO 99/30709 WO 9930709PCTIUS98/26539 arylcarbonylamino C 1-6 alkyl, aryl C1..6 alkylcarbonylamino, aryl C1-.6 alkylcarbonylamino C1-.6 alkyl, aininocarbonylamino Cl.-6 alkyl, (C 1-8 alkylpaminocarbonylamino, (C1-8 alkylbpaminocarbonylamino C1-6 alkyl, (aryl)paminocarbonylamino C 1-6 alkyl, (aryl C1 -8 alkyl)paminocarbonylamino, (aryl C1..8 alkyl)paminocarbonylamino C1..6 alkyl, aminosulfonylamino C1..6 alkyl, (C1.-8 alkyl)paminosulfonylamino, (C1-8 alkyl)paniinosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino Cl.-6 alkyl, (aryl. C1-8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paminosulfonylamino C1..6 alkyl, C 1-6 alkyithiocarbonylainino, C1-6 alkyithiocarbonylamino Ci-6 alkyl, aryithiocarbonylamino C 1-6 alkyl, aryl C1-6 alkyithiocarbonylamino, and 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, aryl, C 1-8 alkylcarbonylainino, aryl C1..6 alkylcarbonylamino, arylcarbonylamino, C 1-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C 1-8 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.

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, aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbohylamino, C1-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino, arylaminocarbonylamino, (C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylamino, and (aryl C1-8 alkyl)paminosulfonylamino.

In the compounds of the present invention, R 9 is preferably 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

R

1 2 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.

-47- WO 99/30709 PTU9/63 PCTIUS98/26539 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.

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 stereo chemistry: R~ R 6 R 7

R'

wherein the substituents W, X, Y, Z, RI, R 2

R

3

R

4

R

5

R

6

R

7 1 R 8

R

9

R

10

R

1 1 and R 12 and the subscripts m, n, p, r, S, t, and v are as described above.

Illustrative but nonlimiting examples of compounds of the present invention that are useful as integrin receptor antagonists are the following: Ethyl 3(S)-(3-fluorophenyl)-3-12-oxo-3(S)-[3-(5 ,6,7,8-tetrahydro- [1 ,8]naphthyidin-2-yl)-propyl]-pyrrolidin- 1-yl]-propionate; Ethyl 3(S)-(3-fluorophenyl)-3-12-oxo-3(R)-[3-(5, 6,7,8-tetrahydro- [1,8]naphthyidin-2-yl )-propyl]-pyrrolidin- 1-yl] -propionate; Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-(2-oxo-3(S)-[3-(5 ,6,7,8tetrahydro-[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.

tetrahydro-[ 1,8]naphthyridin-2 -yl)-propyll-pyrrolidin- 1-yl)-propionate; 48 WO 99/30709 WO 9930709PCT[US98/26539 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- [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- 8]naphthyidin-2-yl)-propyl]-pyrrolidin- 1-yl]-propioriic acid; 3(S)-(3-Fluorophenyl)-3-112-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-benzofiiran-6-yl)-3-(2-oxo-3(R)-[3-(5,6,7,8-tetrahydro.

8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; ,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3 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- 2-yl)-propyl]-pyrrolidin- l-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- l-yl )-.propionic acid; 2(S)-Benzenesulfonylamino-3-[3-(3 ,8]naphthyridin-2-yl-propyl)- [1,2,4]oxadiazol-5-yl]-propiornic acid; 3(S)-(6-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- [1l,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propioric acid; 3(S)-(6-Amino-pyridin-3-yl)-.3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- 1, 8lnaphthyridin-2-yl)-propyl]-pyrroli din- 1-yl)-propionic acid; 49 WO 99/30709 PTU9/63 PCTIUS98/26539 3(S)-(4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1 4 ]oxazin-7-yl)-3-(2-oxo.3-43 (5,6,7 ,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-l-yl)propionic acid; 6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3.(5 7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin 1 -yl)-propioriic acid; 3 2 -Fluoro-biphenyl-4-y1)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro.

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 7,8-tetrahydro- 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- 8]naphthyridin-2-y)-propy]-pyrrolidin 1 -yl)-propionic acid; 3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-[3-(s 7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrroliclin- 1-yl)-propionic acid; 3(S)-(5-Methoxy-pyridin-3-yl)-3-(2-oxo-3-[3(5 ,6,7 ,8-tetrahydro- [l,8]naphthyridin-2-y)-propy]-pyrroilidn- 1-yl)-propionic acid; 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-(s ,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propioriic acid; 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-[l,8]naphthyridin-2-yl)propyly-pyrrolidin-1 -yl)propionic acid; 3(S)-(2,3-Dihydro- 1H-4-oxa- 1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3- 7,8-tetrahydro- [1,8]naphthyridin-2-yl )-propyl]-pyrrolidin- 1-yl)propionic acid; 50 WO 99/30709 PTU9/63 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; 3(S)-(3,4-Dihydro-2H- 1-oxa-4 ,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-3-.

,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl )-propyl]-pyrrolidin- l-yl)propionic acid; 3-(Furo-[2,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 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]naphthyridin-2-yl)-propyl-pyrroliclin- 1-yl)-propionic acid; 3-(Furo-[3 ,2-blpyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- [l,8]naphthyridin-2-yl)-propyl-pyrrolidin-1-yl)-propionic acid; 3-(2,3-Dihydrofurol3,2-blpyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro [1 ,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl )-propionic acid; 3(S)-(Benzimidazol-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; lH-Imidazo[4,5-clpyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro.

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-[1l,8]naphthyridin- 2-ylU-propyl] -pyrrolidin- l-yl )-propionic acid; 1-Methyl- 1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propylj-pyrrolidin- 1-yl)-propionic acid; 3(S)-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]pyrrolidin- 1-yll-pent-4-enoic acid; 51 WO 99/30709 WO 9930709PCTIUS98/26539 and the pharmaceutically acceptable salts thereof.

Further illustrative of the present invention are compounds selected from the group consisting of 3(S)-(3-Fluorophenyl)-3-12-oxo-3(R)-13-(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]-propiomic 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; ,3-Dihydro-benzofuran-6-yl)-3-( 2-oxo-3(S)-[3-(5 ,6,7,8-tetrahydro- [1,8ilnaphthyridin-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)-propyll-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; 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 according to the invention or of their pharmaceutically acceptable salts.

Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, 52 WO 99/30709 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, 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, 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, sodium or potassium salts; alkaline earth metal salts, calcium or magnesium salts; and salts formed with suitable organic ligands, 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, 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.

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" 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, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, 53- WO 99/30709 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 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 receptor, the xvp5 receptor, or the avp6 receptor, or a compound which binds to and antagonizes combinations of these receptors (for example, a dual avp3/av35 receptor antagonist).

The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone.

The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.

The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.

The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

The term "cycloheteroalkyl," as used herein, shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two heteroatoms chosen from N, O or S. Examples of cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.

The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified 54- WO 99/30709 PCT/US98/26539 alkoxy), or any number within this range methoxy, ethoxy, etc.).

The term "aryl," as used herein, refers to a monocyclic or polycyclic system comprising at least one aromatic ring, wherein the monocylic or polycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherein the monocylic or polycylic system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, 01-3 acylamino 01-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino-C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, Cjalkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or Cj- 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 groups independently selected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, aryl, aryl 01-8 alkyl, amino, amino C1-8 alkyl, 01-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino-C1-8 alkyl, 01-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl 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 unsubstituted, mono-, di- or tri-substituted with one to three of the abovenamed 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 aryl CO-8 alkyl) it shall be WO 99/30709 PCT/US98/26539 interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms C1-10) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.

In the compounds of the present invention, two R 1 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 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 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 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 atom. The term "thio" means a sulfur atom. The term "oxo" means The term "carbonyl" means -56- WO 99/30709 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 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 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

-C-

6 alkyl-NH-C-C 1 s alkyl.

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e.

W,X, Y, Z, 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 to be chosen in conformity with wellknown principles of chemical structure connectivity.

Representative compounds of the present invention typically display submicromolar affinity for the integrin receptors, particularly the avp3, avp5, and/or avp6 receptors. Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. Pharmacologically effective amounts of the compounds, including 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 osteoporosis.

Further exemplifying the invention is the method wherein the integrin receptor antagonizing effect is an avp3 antagonizing effect.

-57- WO 99/30709 PCT/US98/26539 An illustration of the invention is the method wherein the (v3 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis. Preferably, 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 avp5 antagonizing effect.

More specifically, the avp5 antagonizing effect is selected from inhibition of: restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, tumor growth, or metastasis.

Illustrating the invention is the method wherein the integrin receptor antagonizing effect is a dual avp3/cav5 antagonizing effect. More paiticularly, the dual avp3/avp5 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, 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 av[6 antagonizing effect.

More particularly, the avP6 antagonizing effect is selected from inhibition of angiogenesis, inflammatory response, or wound healing.

Illustrating the invention is the method wherein the avp3 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 atherosclerosis, inflammation, viral disease, or inhibition of tumor growth or metastasis. Preferably, the cvp3 antagonizing effect is the inhibition of bone resorption.

More particularly illustrating the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition 58- WO 99/30709 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 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 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, 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 avp3 antagonizing effect; more specifically, the avp3 antagonizing effect is selected from inhibition of bone resorption, 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 integrin antagonizing effect is an avp5 antagonizing effect, an avp6 antagonizing effect, or a mixed avp3, avp5, and avp6 antagonizing effect. Examples of avp5 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, or tumor growth. Examples of dual av36 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 -59- WO 99/30709 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 metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilizationinduced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.

More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and/or angiogenesis.

comprising a.) Also exemplifying the invention are compositions further an active ingredient selected from the group consisting of an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, an estrogen receptor modulator, a cytotoxic/antiproliferative agent, a matrix metalloproteinase inhibitor, an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, an inhibitor of VEGF, an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, a cathepsin K inhibitor, and a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof.

WO 99/30709 PCT/US98/26539 (See, B. Millauer et al., "Dominant-Negative Inhibition of Flk-i Suppresses the Growth of Many Tumor Types in Vivo", Cancer Research, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety).

Preferably, the active ingredient is selected from the group consisting of: an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, an estrogen receptor modulator, and 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 monosodium trihydrate.

Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.

Nonlimiting examples of cytotoxic/antiproliferative agents 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, all of which are incorporated by reference herein in their entirety.

Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthritis, and bone remodeling. At acidic pH's, cathepsins can degrade type-I collagen. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis.

The 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 compounds of the instant invention may be effectively administered in 61 WO 99/30709 PCT[S98/26539 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 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 tumor growth and metastasis.

In addition, the integrin avp3 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result. in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions. These diseases include: osteoporosis (including estrogen deficiency, immobilization, glucocorticoid induced and senile), osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, 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 useful in increasing bone mass in patients with growth hormone deficiency. Thus, preferred combinations are simultaneous or alternating treatments of an avp3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably alendronate monosodium trihydrate.

-62- WO 99/30709 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 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 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 indirectly, from combination of the specified ingredients in the specified amounts.

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical ocular eyedrop), subcutaneous, intramuscular or transdermal patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an 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 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 condition.

-63- WO 99/30709 PCT/US98/26539 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 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/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 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 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 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.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be -64- WO 99/30709 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 binders include starch, gelatin, natural sugars such as glucose or betalactose, 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 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 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 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, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 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.

BH3*DMS: Borane *dimethylsulfide.

WO 99/30709 WO 9930709PCT/US98/26539 BOC(Boc):

BOP:

CBZ(Cbz):

CDI:

CH

2 0C 2 CH3CN: CHC1 3

DEAD:

DIAD:

DIBAH or

DJBAL-H:

DJPEA:

DMAP:

DME:

DMF:

DMSO:

DPFN:

EDC:

lEtOAc: EtOH: HOAc:

HOAT:

HOBT:

IBCF:

LDA:

MeGH:

MMNG

NEt3:

NMM:

PCA*HCl: Pd/C: Ph: pTSA

TEA:

t-Butyloxycarbonyl.

Benzotriazol- 1-yloxytris(dimethylamino)phosphomium hexafluorophosphate.

Carbobenzyloxy or benzyloxycarbonyl.

Carbonyliimidazole.

Methylene chloride.

Acetonitrile Chloroform.

Diethyl azodicarboxylate.

Diisopropyl azodicarboxylate.

Diisobutylalunainum hydride.

Diisopropylethylamine.

4-Dimethylaminopyri dine.

1,2-Dimethoxyethane.

Dimethylformamide.

Dimethylsulfoxide.

3,5-Dimethyl- 1-pyrazolylformamidine nitrate.

1-(3-Dimethylaminopropyl )-3-ethylcarbodiimide HCl Ethyl acetate.

Ethanol.

Acetic acid.

1-Hydroxy- 7-azabenzotriazole 1-Hydlroxybenzotriazole.

Isobutylchloroformate Lithium diisopropylaxnide.

Methanol.

1, 1-methyl-3-nitro- 1 -nitro soguanidine, Triethylamine.

N-methylmorpholine.

Pyrazole carboxamidine hydrochloride.

Palladium on activated carbon catalyst.

Phenyl.

p-Toluenesulfonic acid.

Tri ethyl amine.

66 WO 99/30709 PCT/US98/26539 TFA: Trifluoroacetic acid.

THF: Tetrahydrofuran.

TLC: Thin Layer Chromatography.

TMEDA: N,N,N',N'-Tetramethylethylenediamine.

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 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 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 International Application Publication Nos. W095/32710, published 7 December 1995, and W095/17397, published 29 June 1995, both of which are incorporated by reference herein in their entirety, in conjunction with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed 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, Recent Stereoselective Synthetic Approaces to P-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi, E, et al., Enantioselective Synthesis of P-Amino Acids, Aldrichimica Acta, 1994, 27, 3. In particular, synthesis of the 3-methyl-3-alanine is taught in Duggan, M.F. et al., J. Med. Chem., 1995, 38, 3332-3341; the 3ethynyl-p-alanine is taught in Zablocki, et al., J. Med. Chem., 1995, 38, 2378-2394; the 3-(pyridin-3-yl)-p-alanine is taught in Rico, J.G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino- and 2-tosylamino-Palanines are taught in Xue, C-B, et al., Biorg. Med. Chem. Letts., 1996, -67- WO 99/30709 PTU9/63 PCT/US98/26539 6, 339-344. The references described in this paragraph are all also incorporated by reference herein in their entirety.

SCHEME 1

QCHO

F

Ph 3 PC H C 2 Et

CH

2 01 2 Q-\\-CO 2 Et

F

1-2

H

PhN..N Ph Me nBuLi, THF 2. H 2 0 1. Pd(OH) 2

H

2 EtOH, HOAc, H 2 0 2. HOI, ether Ph)

-HCI

-CO

2 Et 68 WO 99/30709 PCT/US98/26539 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 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 trans) which was used without further purification in the next step.

1H NMR(CDC13) 5 1.36 (3H, 4.28 (2H, 6.43 7.08 (1H, 7.2- 7.4 (3H, 7.64 (1H, d).

N-Benzvl-(R)-a-methvlbenzvl-3(S)-fluorophenvl-p-alanine ethyl ester (1-3) To a solution of N-benzyl-(R)-a-methylbenzylamine (33.4 g, 158 mmol) in THF (450 mL) at 0 C was added n-butyllithium (1.6M in hexanes; 99 mL, 158 mmol). The dark violet solution was stirred at 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 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.

1H NMR (CDC13): 5 1.06 (3H, 1.28 (3H, 2.52 (1H, dd), 2.62 (1H, dd), 3.66 (1H, 3.72 (1H, 3.95 (2H, 4.44 (1H, dd), 6.95 (1H, 7.1-7.5 (13H, m).

3(S)-Fluorophenvl-o-alanine ethyl ester hydrochloride (1-4) 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 dry weight; 2.6 g) was added and the mixture then stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered through celite and the solvent removed in vacuo to give an oil. This oil -69- WO 99/30709 PCT/US98/26539 was dissolved in 200 mL ether and to this solution was added 60 mL 1N HC1 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(CD30D) 5 1.21 (3H, 3.0-3.2 (2H, 4.16 (2H, 4.76 (1H, t), 7.2-7.35 (3H, 7.5 (1H, m).

WO 99/30709 PTU9/63 PCT[US98/26539 SCHEME 2 0 C0 2 Et 2-1 ethylene glycol, pTSA, toluene, reflux

CO

2

R

a) pivaloyl chloride, NEt 3

THF

b) Li oxazolidinone

N

0 2-3 0 0 Sa) LiN(TMS) 2

THF

b) allyl bromide x 0 0 2-4, X=CH 2 NO -5 03 0 0 71 WO 99/30709 WO 9930709PCT/US98/26539 SCHEME 2 (CONTINUED) N 0 0 0

HCI*H

2

N

Na(OAc) 3 BH, NEt 3 H C2E dichioroethane/

F

14 N C0 2 Et TsOH, acetone, reflux N CO 2 Et 2-7 H~F proline,CH ethanol, refluxI

NNH

2 72 WO 99/30709 WO 9930709PCT/US98/26539 SCHEME 2 (CONTrNUED) Pd/C, ethanol, H2 2-9 1N NaGH, ethanol 2-10 2-11 73 WO 99/30709 PCT/US98/26539 5-(2-methvl-[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 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 (MgSO4) and concentrated to give acid 2-2 as a colorless oil.

1 H NMR (300 MHz, CDC13) 6 3.93 4H), 2.36 2H),-1.63 4H), 1.46 2H), 1.31 3H).

3-r5-(2-methvl-r1,31dioxolan-2-vl)-pentanovll-oxazolidin-2-one (2-3) To a stirred solution of 22 (16.0 g, 85.5 mmol), NEt3 (13.1 ml, 94.1 mmol) and THF (400 mL) at -78°C was added pivaloyl chloride (11.6 ml, 94.1 mmol). The mixture was warmed to o0C for 1.0 h and then recooled to -78°C. 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, 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 0°C 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 chromatographed (silica gel, 40% 50% EtOAc/hexanes) to give 2-3 as a colorless foam.

TLC Rf 0.19 (silica, 40% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 8 4.41 J=8.1 Hz, 2H), 4.02 J=8.1 Hz, 2H), 3.93 4H 3.93 J=7.3 Hz, 2H), 1.66 4H), 1.48 2H), 1.31 (s, 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 mL) at -78 0 C was added LiN(TMS)2 (18.9 mL, 37.8 mmol, 1.0 M in THF) -74- WO 99/30709 PCT/US98/26539 dropwise over 10 minutes. After 20 minutes, allyl bromide was added.

After 10 minutes, the reaction was warmed to 0°C. After 4.0 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 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 1H), 5.02 1H), 4.40 J=8.3 Hz, 2H), 4.02 2H), 3.99 4H), 2.39 1H), 2.27 1H), 1.72 1H), 1.62 2H) 1.39 1.53 3H), 1.30 3H).

6 2 -methyl-[1,3]dioxolan-2-yl)-3-(2-oxo-oxazolidine-3-carbonyl)hexanal To a stirred solution of 2-4 (4.0 g, 13.5 mmol), sudan III mg) and CH2C12 (350 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 (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.

TLC Rf 0.15 (silica, 50% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 9.74 1H), 4.43 2H), 4.15 1H), 4.03 2H), 3.91 4H), 3.04 1H), 2.67 (dd, J=3.9 Hz, 18.6 Hz, 1H),1.65 3H), 1.45 3H), 1.29 3H).

3(S)-(3-Fluorophenyl)-3-(3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propyl]- 2 -oxo-pyrrolidin-l-vl)-pronionic 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 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) WO 99/30709 PTU9/63 PCT/US98/26539 IH NMR (300 MHz, CDCl3) 8 7.30 (in, 1H), 7.07 (mn, 1H), 6.98 (mn 3H), 5.68 (in, 1H), 4.12 (mn, 2H), 3.92 (in, 4H), 3.30 (in, 1H), 2.97 (in, 3H), 2.38 (in, 1H), 2.14 (mn, 1H), 1.86 (in, 1H), 1.64 (in, 4H), 1.42 (mn, 2H), 1.30 (2s, 3H), 1.22 J=7.3Hz, 3H).

3 3 -Fluorophenyl)-3-[2-oxo-3-(4-oxo-pentyl)-pyrrolidin-1 yl]..

Drouionic acid ethyl ester (2-7) A solution of 2-6 (450 ing, 1.10 mmnol), p-TSA (50 ing) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction 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, CDCl3) 5 7.30 (in, 1H), 7.06 (mn, 1H), 6.98 (in, 2H), 5.67 (mn, 1H), 4.12 (mn, 2H), 3.23 (in, 1H), 2.97 (in, 2H), 2.33 2.49 (in, 3H), 2.14 (2s, 3H), 1.54 -1.86 (mn, 5H), 1.33 (mn, 1H), 1.22 J=7.lHz, 3H).

3(S)-(3-Fluorophenyl)-3-[3-(3-[ 1,8]naphthyridin-2-yl-propyl)-2-oxopyrrolidin- 1-yll-propionic acid ethyl ester (2-8) A mixture of 2-7 (430 ing, 1.18 minol), 2-amino-3forinylpyridine (144 ing, 1. 18 mmol; for prep., see JOC 1983,48, 340 1) and proline (136 ing, 1.18 rnmiol) in absolute ethanol (20 inL) 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/MeOR) to give 2-8 as a yellow solid.

TLC Rf 0.30 (70:25:5 chloroform/ethyl acetate/MeOH).

1 H NMR (300 MHz, CDCl3) 6 9.08 (in, 1H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H), 8.11 J=8.3 Hz, 1H), 7.42 (in, 2H), 7.27 (mn, 1H), 7.06 (in, 1H), 6.97 (in, 2H), 5.66 (in, 1H),4.11 (in, 2H), 3.29 (in, 1H), 2.95 -3.07 (in, 5H), 2.46 (in, 1H), 2.18 (in, 1H), 1.98 (in, 2H), 1.71 (mn, 2H), 1.46 (mn, 1H), 1.19 (in, 3H).

3()(-loohnl)3(-x--3(,678ttayr 1,8]naphthyridin-2-vl)-nropvll-pvrrolidin- 1-v )-propi onic acid ethyl ester (2-9) A mixture of 2-8 (340 ing, 0.799 1 inmol) and 10% Pd/carbon (170 ing) in EtOH (10 inL) was stirred under a balloon of hydrogen for 4 76 WO 99/30709 WO 9930709PCTIUS98/26539 h. Following filtration and evaporative removal of the solvent, the residue was chroinatographed (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).

1 H N7MR (300 MHz, CDCl3) 5 7.29 (mn, 6.98 (mn, 4H), 6.33 (in, 1H), 5.66 (mn, 1H), 4.76 (b s, 1H), 4.10 (mn, 2H), 3.38 (mn, 1H),3.28 (in, 1H1), 2.95 (mn, 3H),2.68 J=6.3 Hz, 2H), 2.55 (mn, 2H), 2.40 (in, 1H), 2.13 (in, 1H) 1.92 (mn, 4H), 1.61 (in, 3H), 1.37 (mn, 1H), 1.23 (mn, 3H).

3(S)-(3-Fluorophenyl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[ 1,8]naphthyridin-2-vl)-inropvHl-Dvrrolidin- 1-vl)-nrouionic acid (2-10 and 2-11) To a solution of 2- (300 mng, 0.6614 mmol) in EtOH (3 inL) was added 1N NaOH (0.725 ml, 0.725 inmol). 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 acetatelEtOlwater/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 NiVR (300 MHz, CD3OD, 2-10) 8 7.44 J=7.3 Hz, 1H), 7.37 1H), 7.14 (mn, 1H), 7.06 (in, 6.50 J=7.3 Hz, 5.78 (in, 1H), 3.55 (mn, 1H), 3.46 (in, 2H), 3.11 (in, 1H), 2.61 -2.97 (mn, 7H),2.12 (in, 1H) 1.74 -1.95 (in, 7H).

1HNMIR (300 M~llz, CD3OD, 2-11) 6 7.34 (mn, 2H), 7.15 (in, 2H), 7.03 (mn, 1H), 6.47 J=7.3 Hz, 5.50 (mn, 1H), 3.46 3H), 3.00 (in, 1H),2.79 (in, 3H), 2.62 (in, 2H),2.54 (in, 1H), 2.23 (in, 1H), 1.93 (in, 2H), 1.69 (in, 1.44 (mn, 1H).

77 WO 99/30709 WO 9930709PCT/US98/26539 SCH{EME 3

OH

Br OEt OEt NaH, DMF GEt CG,-Et 0 Br 3-2 PPA, PhMe j Ethyl Acrylate, Pd(GAc) 2

DMF

3-4 CO 2 Et 3-3 Me Ph N Ph

H

nBuLi, THF Pd(OH) 2 H2 Me Ph N -,C2E Bn 3-5

H

2 CO2Et 3-6 78 WO 99/30709 PCT/US98/26539 1-Bromo-3-(2,2-diethoxv-ethoxv)-benzene (3-2) To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 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 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, 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) 6 7.19-7.05 3H), 6.85 1H), 4.81 1H, J=6.8 Hz), 3.99 2H, J=6.8 Hz), 3.71 4H), 1.22 6H, J=7.1 Hz) 6-Bromo-benzofuran (3-3) To a solution of the acetal 3-2 in toluene (200 mL) was added polyphosphoric acid (20 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 combined organic extracts were washed with saturated aq. NaHCO3 and brine. The solution was dried over MgS04, 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).

1 H NMR (300 MHz, CHC13) 5 7.68 1H), 7.60 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), ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44 mmol), tri-otolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100 0 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 washed with brine (30 mL), dried over MgSO4, filtered, and -79- WO 99/30709 PCTIUS98/26539 concentrated. The residue was purified by flash chromatography 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) 6 7.78 1H, J=15.9 Hz), 7.68 1H, J=2.4 Hz), 7.66 1H), 7.59 1H, J=8.4 Hz), 7.43 (dd, 1H, J=9.0, 1.5 Hz), 6.78 1H), 6.47 1H, J=15.9 Hz), 4.27 2H, J=7.2 Hz), 1.34 3H, J=7.2 Hz).

3(S)-(Benzofuran-6-yl)-3-[benzyl-(l(R)-phenyl-ethyl)-amino]-propionic acid ethyl ester A solution of N-benzyl-a-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 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°C for 30 min and then cooled to -78 0 C. A solution of acrylate 3-4 (0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for 15 min at -78 0 C, satd. aq.

NH4Cl 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 (10% ethyl acetate/hexanes) to give the Paminoester 3-5 as a yellow oil.

TLC Rf 0.8 (10% ethanol/dichloromethane).

1 H NMR (300 MHz, CHC13) 6 7.58 3H), 7.41 2H), 7.22 9H), 7.59 1H), 4.58 1H), 4.05 1H), 3.91 2H, J=7.1 Hz), 3.72 2H), 2.62 2H), 1.21 3H, J=7.2 Hz), 1.03 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 EtOH/H20/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (1.19 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 give the ester 3-6 as a white solid.

WO 99/30709 PTU9/63 PCTIUS98/26539 TLC Rf =0.25 (10% ethanolldichloromethane)..

1H NMR (300 MHz, CD3OD) as the trifluoroacetate salt: 5 7.25 1H, J=8.1 Hz), 6.88 (in, 1H), 7.66 1H), 6.82 1H), 4.58 (mn, 3H), 4.12 (in, 2H), 3.30 (mn, 1H), 3.19 (mn, 2H), 2.98 (mn, 2H), 1.11 3H, J=7.2 Hz).

81 WO 99/30709 PTU9/63 PCTIUS98/26539 SCH7EME 4 o o Na(OAc) 3 BH, NE dichloroethane 0 0N 4-1 acetone,r 'C02

HCI*H

2 N

CO*

Et

D

eflux Et

D

aCHO N NH 2 pro line, ethanol, reflux 'TK' lk C0 2 Et 0 4-3 82 WO 99/30709 WO 9930709PCT/US98/26539 SCHEME 4 (CONTINUED) 4-3 1 10% Pd/C, ethanol,

H

2 4-4 1N NaOH, ethanol 0 and 83 WO 99/30709 WO 9930709PCT/US98/26539 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(3-173-(2-Inethyl-[1,3]dioxolan- 2-vl)-y~roivH-2-oxo-nvrrolidin- 1-vl)-n~rornionic acid ethyl ester (4-1) A mixture of 2-5 (440 mg, 1.6 mnmol), L- (400 mg, 1.5 mmol), Na(OAc)3BH (469 mg, 2.25 mmol) and NEt3 (0.41 mL, 3.0 mmol) in 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.

TLC Rf 0.45 (silica, 70:25:5 chloroform! ethyl acetate! MeGH) 1H NMR (300 MHz, CDCl3) 5 7.15 (in, 1H), 6.78 (mn, 1H), .6.70 1H), 5.63 (mn, 1H), 4.58 (mn, 2H), 4.12 J=7 Hz, 2H), 3.92 4H), 3.40-2.80 (mn, 6H), 2.38 (in, 1H), 2.14 (mn, 1H), 1.86 (in, 1H), 1.64 (mn, 4H), 1.42 (in, 2H), 1.30 (in, 3H), 1.22 J=7 Hz, 3H).

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[2-oxo-3-(4-oxo-pentyl)nvyrrolidin- 1-vll-nroTuionic acid ethyl ester (4-2) A solution of 4-1 (600 mrg, 1.4 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction 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, CDCl3) 5 7.15 (mn, 1H), 6.78 (mn, 1H), 6.70 1H), 5.63 (in, 1H), 4.58 (mn, 2H), 4.12 J=7 Hz, 2H), 3.35-2.90 (mn, 6H), 2.49-2.30 (mn, 3H), 2.13 (2s, 3H), 1.90-1.50 (mn, 5H), 1.33 (in, 1H), 1.22 J=7 Hz, 3H).

(2,3-Dihydro-benzofuran-6-yl)-3-[3-(3-[l,8]naphthyridin-2-yln~ron~vl)-2-oxo-pvrrolidin-1-vll-nronionic acid ethyl ester (4-3) A mixture of 4-2 (540 mng, 1.4 minol), 2-amino-3formylpyridine (170 ing, 1.4 iniol; for prep. see JOC 1983,48, 340 1) and proline (161 ing, 1.4 inmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chroinatographed (silica gel, 50% ethyl acetate! chloroform 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-3 as a yellow oil.

TLC Rf 0.21 (70:25:5 chloroform/ethyl acetate/MeOH).

84 WO 99/30709 PTU9/63 PCT/US98/26539 1 H NMR (300 MiHz, CDC13) 8 9.08 (in, 1H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H), 8.11 J=8.3 Hz, 1H1), 7.42 (mn, 2H), 7.10 (mn, 1H1), 6.78.(in, 1H), 6.70 (mn, 1H), 5.63 (mn, 1H),4.57 (mn, 2H1), 4.11 (mn 2H), 3.29 (in, 1H), 3.30-2.80 (mn, 9H), 2.40 (mn, 1H), 2.18 (in, 1H), 1.98 (mn, 2H), 1.70-1.50 (mn, 211), 1.46 (mn, 1H), 1. 19 (in, 3H).

,3-Dihydro-benzofuran-6-yl)-3-(2-oxo-3-j3-(5 ,6,7 ,8-tetrahydro- [1 ,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid ethyl ester (4-4) A mixture of 4-3 (460 mg, 1.0 inmol) and 10% Pd/carbon (300 ing) 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 chroinatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeGH) to give 4-4 as a yellow oil.

TLC Rf 0.15 (70:25:5 chloroform/ethyl acetate/VeOH).

1 H NMR (300 MHz, CDCl3) 5 7.18 (in, 7.07 (in, 2H), 6.80 (in, 111), 6.70 (mn, 1H), 6.37 (in, 1H1), 5.64 (in, 1H), 4.76 (bs, 111), 4.55 (in, 2H), 4.10 (q, J=7 Hz, 2H), 3.40 (in, 1H),3.28 (in, 2H), 3.28 (in, 111), 3.19 (mn, 2H), 3.00 (in, 111), 2.95 (in, 2H),2.69 (in 2H), 2.55 (mn, 2H), 2.37 (in, 1H), 2.13 (in, 1H) 1.92 (in,3H), 1.75-1.30 (in, 4H), 1.23 (in, 311).

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) To a solution of 4- (380 ing, 0.79 niinol) in EtOR (2 inL) was added 1N NaOH (0.93 ml, 0.93 iniol). After stirring for 1 h, the solvents were evaporated and the residue was chroinatographed (silica gel, 25:10:1:1 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 4-5 and 4-6 as pure diastereoineric white solids.

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).

1H1 NMR (300 MHz, CD3OD, Isomer A) 8 7.44 J=7 Hz, 111), 7.16 J=7 Hz, 111), 6.80 J=7 Hz, 1H1), 6.70 111), 6.48 J=7 Hz, 111,), 5.46 (in, 111), 4.50 (in, 211), 3.60-2.50 (in, 1311), 111), 2.15 -1.70 (in, 811), 85 WO 99/30709 WO 9930709PCTIUS98/26539 1HNMR (300 MHz, CD3OD, Isomer B) 5 7.40 Hz, 1H1), 7.13 J=7 Hz, 1H), 6.80 J=7 Hz, 6.68 1H), 6.50 J=7 Hz, 5.72 (in, 1H), 4.53 (mn, 2H), 3.44 (mn, 3H), 3.15 (in, 4H), 2.97 (mn, 1H), 2 7 0-2.40(mn, 6H), 2.20 (mn, 1H), 2.00-1.40 (mn, 6H).

86 WO 99/30709 WO 9930709PCTIUS98/26539 SCHEME malonic acid,

NH

4 OAc EtOH (8000) -1 N

CHO

N

H

2 N -C 2 PhCH 2 COCI

N

Et 3 N,o Dioxane/H- 2 0 P 0~ C0 2

H

Penicillin Amidase (EC .5..11) pH 78,H 2 0

N

N

5-4 0 6 NHCI 500 C

NN

NN

2 HCI. H 2 N >'C2D EtOH, HOI 2 HCI* 2 C2 9-7 87 WO 99/30709 PCT/US98/26539 3-Quinolin-3-vl-propionic acid A solution containing quinoline-3-carboxaldehyde 5-1 (5 g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate g, 63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 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): 8 8.91 J 2 Hz 1H), 8.21 J 2 Hz, 1H), 8.12 J 8 Hz, 1H), 7.84 J 7 Hz, 1H), 7.72 J 7 Hz, 1H), 7.54 J 7 Hz, 4.72 1H), 2.73 2H).

3-Phenvlacetvlamino-3-(quinolin-3-vl)-propionic (5-3) A 0° solution of 5- (3.5 g, 16.2 mmol) and NaHC03 (2.7 g, 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 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, CD30D): 8 8.85 J 2 Hz 1H), 8.20 J 2 Hz, 1H), 8.00 J 8 Hz, 1H), 7.86 J 7 Hz, 1H), 7.76 J 7 Hz, 1H), 7.52 J 7 Hz, 7.28 6H), 5.53 J 6.8 Hz, 1H), 3.57 2H), 2. 96 (m, 2H).

3(S)-(Quinolin-3-vl)-propionic acid dihvdrochloride (5-6) Acid 5-3 (5.0 g, 15 mmol) was suspended in water (3.5 L), then treated with IN NaOH (15 mL) to afford a clear solution. Penicillin 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 IN 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 conversion was reached. Next, the reaction solution was cooled to 0 C 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 (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 HC1 (200 mL) at 50° 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 The resolved acid 5-6 was converted to 5-7 by refluxing in ethanolic HC1.

1H NMR (300 MHz, CD3OD): 8 9.25 J 2 Hz 1H), 8.31 J 2 Hz, 1H), 8.15 J 8 Hz, 1H), 7.84 J =7 Hz, 1H), 7.72 J 7 Hz, 1H), 7.54 J 7 Hz, 4.72 1H), 4.15 J 6 Hz, 2H), 2.73 2H) 1.18 J= 6 Hz, 3H).

-89- WO 99/30709 WO 9930709PCTIUS98/26539 SCHEME 6 Na(OAC) 3 8H, NEt 3 dichloroethane

CI*H

2

N

1 C OEt H TsOH, acetone, refiux 90 WO 99/30709 WO 9930709PCTIUS98/26539 SCHEME 6 (CONTINUED)

CO

2 Et Pd./C, ethanol, H 2 6-4 1N NaOH, ethanol C0 2

H

&&and 6-6 91 WO 99/30709 WO 9930709PCT/US98/26539 3(S)-(Quinolin-3-yl)-3-(3-[3-(2-inethyl-[1,3]dioxolan-2-yl)-propyl]-2.

oxo-pvrrolidin-1-l)-Dronionic acid ethyl ester (6-1) A mixture of 2-5 (377 mg, 1.3 mmol), L-6 (400 mg, 1.3 inmol), Na(OAc)3BH (400 ing, 2.0 inmol) and NEt3 (0.35 mL, 2.6 mmol) in dichioroethane (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! MeGH) to give 6-1 as a yellow oil.

TLC Rf 0.47 (silica, 70:25:5 chloroform! ethyl acetate! MeGH) 1 H NMR (300. MHz, CDCl3) 8 8.85 (mn, 1H), 8.10-7.40 5.90 (mn, 1H), 4.12 J=7 Hz, 2H), 3.90 (in, 4H), 3.38 (mn, 1H), 3.20-2.95 (in, 3H), 2.40 (in, 1H), 2.14 (mn, IN), 1.90 (mn, 1H), 1.74-1.30 (in, 4H), 1.30 (ds, 3H), 1.22 J=7 Hz, 3H).

3 (S)-(Quinolin-3-yl)-3-112-oxo-3-(4-oxo-pentyl)-pyrrolidin- 1-yl]- 13ronionic acid ethyl ester (6-2) A solution of 6-1 (380 mng, 1.0 minol), p-TSA (20 ing) and acetone (50 inL) was heated at reflux for 4 hr. The cooled reaction 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, CDCl3) 8 8.74 (in, 1H), 8.05-7.40 (in, 5H), 5.90 (mn, 1H), 4.13 (in, 2H), 3.38 (mn, 1H), 3.20-2.95 (in, 3H), 2.50-2.10 (in, 4H), 2.13 Hz, 3H), 1.90-1.20 (mn, 6H), 1.22 J=7 Hz, 3H).

3(S)-(Quinolin-3-yl)-3-[3-(3-[ 1,8]naphthyidin-2-yl-propyl)-2-oxorDvrolidin- 1-ll]-Dronionic acid ethyl ester (6-3) A mixture of 6-2 (396 ing, 1.0 inmol), 2-ainino-3forinylpyridine (138 ing, 1.2 innol; for prep. see JOC 1983,48, 3401) and 3 0 proline (218 ing, 2.0 minol) in absolute ethanol (1S mL) was heated at reflux for 12 h. Following evaporative remnoval of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform to 70:25:5 chloroform/ethyl acetate/MeGH) to give 6-3 as a yellow oil.

TLC Rf 0.23 (70:25:5 chloroform/ethyl acetate/MeOH).

92 WO 99/30709 WO 9930709PCT/US98/26539 1 H NMR (300 MHz, CDCl3) 5 9.08 (mn, 1H), 8.85 (mn, 1H), 8.20-7.50.(mn, 9H), 5.90 (mn, 1H), 4.11 (in, 2H), 3.40 (in, 1H), 3.20-2.90 (mn, 6H), 2.60-1.40 (in, 6H), 1.22 (mn, 3H).

3 (S)-(Quinolin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8tetrahydro-[1,8]naphthy.

ridin-2-vl )-p-ropvll-Dvrrolidin- 1-vi )-nropionic acid ethyl ester (6-4) A mixture of 6-3 (380 ing, 0.8 mmol) and 10% Pd/carbon (200 ing) in EtOH (20 inL) was stirred under a balloon of hydrogen for 6 h.

Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 to 70:20:10 chloroform/ethyl acetate/MeOH) to give 6-4 as a yellow oil.

TLC Rf 0.20 (70:20:10 chloroform/ethyl acetate/MeQH).

1 H NMR (300 M~flz, CDCl3) 5 8.86 (in, 1H1), 8.08 (mn, 2H1), 7.80 (mn, 1H), 7.72 (mn, 1H), 7.57 (in, 1H), 7.03 (in, 1H), 6.33 (in, 1H), 5.90 (in, 1H), 4.11 (in, 2H), 3.40 (in, 3H), 3.15-2.00 (mn, 9H), 2.00-1.30 (in, 8H), 1.22 (mn, 3H).

3 (S)-(Quinolin-3-yl)-3-(2-oxo-3-Ij3-(5,6,7,8-tetrahydro.[ 1,8]naphthyridin-2-vl)-propvll-pvrrolidin- 1-vl)-nropionic acid (6-5 and 6-6) To a solution of 6-4 (300 ing, 0 .62 niiol) in EtOH (3 inL) was added 1N NaOH (0.68 ml, 0.68 inmol). After stirring for 2 h, the solvents were evaporated and the residue was chroinatographed (silica gel, 25:10:1:1 15:10:1:1 ethyl acetate/EtOH/water/NI{40H) to give 6- and 6-6 as pure diastereomeric white solids.

TLC Rf 0.32 (isomer A) (10: 10: 1: 1 ethyl TLC Rf 0.28 (isomer B) (10: 10: 1: 1 ethyl acetate/EtOH/water/NH4OH).

1H NMR (300 MHz, CD3OD, Isomer A) 8 8.85 J=2Hz,, 1H), 8.33 (bs, 1H), 8.00 (in, 2H), 7.78 (in, 1H), 7.44 J=7 Hz, 1H), 6.50 J=7 Hz, 1H,), 6.02 (in, 1H), 3.62 (in, 1H), 3.48 (mn, 2H), 3.20-1.90 (mn, 3H), 2.80-2.60 (in, 4H), 2.13 (mn, 1H), 2.00 -1.70 (in, 8H).

1 H NMR (300 MHz, CD3OD, Isomer B) 8 8.85 J=2Hz,, 1H), 8.33 (bs, 1H), 8.00 (mn, 1H), 7.95 (in, 1H), 7.75 (mn, 1H), 7.62 (mn, 1H), 7.33 J=7 Hz, 1H), 6.43 (d J=7 Hz, 5.74 (mn, 1H), 3.55 (in, 1H), 3.40 (in, 2H), 3.20- 1.95 (in, 2H), 2.72 (in, 2H), 2.58 (mn, 3H), 2.23 (mn, 1H), 2.00 -1.40 (mn, 8H).

93 WO 99/30709 PCT/US98/26539 SCHEME 7

CO

2

H

a) pivaloyl chloride, NEt 3

THF

b) Li (S)-(-)-4-benzyl-2-oxazolidinone

O

7-9 0 ethylene glycol, p-TSA, benzene a) LiN(TMS) 2

THF

b) allyl bromide X Ph 0 O 7-4, X=CH, 7-5, X=0 03 l-(4-(S)-benzvl-2-oxo-oxazolidin-3-vl)-hetane-1, .6-dione (7-2) To a stirred solution of 6-oxo-heptanoic acid 7-1 (100 g, 694 mmol), NEt3 (111.3 ml, 763.4 mmol) and THF (2000 mL) at -78 0 C was added pivaloyl chloride (98.7 ml, 763.4 mmol). The mixture was warmed to OC for 1.0 h and then recooled to -78oC. To a stirred solution of benzyl-2-oxazolidinone (136g, 763.4 mmol) and THF (2000 ml) at -78 0

C

was added nBuLi (306 ml, 765 mmol, 2.5M in hexanes) dropwise over minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 20 minutes, the reaction was warmed to 0 0 C for 1.0h. The mixture was diluted with ethyl acetate, washed with sat. NaHC03, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was azeotroped with xylenes to give 7-2 as a colorless foam.

TLC Rf 0.25 (silica, 25% EtOAc/hexanes) -94- WO 99/30709 WO 9930709PCT/US98/26539 1 H NMR (300 MHz, CDC13) 5 7.27, (in, 5H), 4.66 (in, 1H), 4.16 (mn, 2H), 3.29 (dd, J=3 Hz, 13 Hz, 1H),2.90 (in, 2H 2.75 (mn, 1H), 2.50 J=7 Hz, 2H), 2.15 3H), 1.68 (in, 4H).

4-(S)-benzvl-3- r5-(2-methvl-[r 1. .31dioxolan- 2 -vl)-pentanovfl-oxazoli din- 2-o ne (7-3) A mixture of ketone 7-2 (695 minol), ethylene glycol (59 ml, 1040 mnmol), p-TSA (500 mg, 2.713 mniol) and benzene (2000 mL) was heated to reflux with azeotropic removal of water for 12 hours. The 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 NIMR (300 MHz, CDCl3) 6 7.26 (in, 5H), 4.67 (in, 2H), 3.94 4H), 3.29 (mn, 1H), 2.95 (in, 2H), 2.76 (in, 1H), 1.71 (in, 4H), 1.50 (in, 2H), 1.32 (s, 3H).

4-(S)-benzvl-3-(R)- 12-[3-(2-methvl-rl1.31dioxolan-2-vD)-proinvll-nent-4-enovl}oxazolidin-2-one (7-4) To a stirred solution of 7-3 (695 inmol) and THF (2000 inL) at -78'C was added LiN(TMS)2 (915 mL, 915 rmnol, 1.0 M in THF) dropwise over 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 concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 7-4 as a yellow oil.

TLC Rf 0.27 (silica, 30% EtOAc/hexanes) 1 H NMR (300 MHz, CDCl3) 8 7.25 (in 5H), 5.81 (in, 1H), 5.05 (mn, 2H), 4.67 (mn, 1H), 4.18 (in, 2H), 3.91 (in, 4H), 3.29 (dd, J=3Hz, 13Hz, 1H), 2.67 (in, 1H), 2.48 (mn, 1H), 2.32 (mn, 2H), 1.76 (mn, 1H) 1.63 (in, 2H), 1.55 (in, 1H), 1.40 (in, 2H), 1.28 3H).

3-(R)-(4-(S)-benzvl-2-oxo-oxazolidine-3-carbonyl )-6-(2-methvlrl1.31dioxolan-2-vl)-hexanal 95 WO 99/30709 PCT/US98/26539 To a stirred solution of 7-4 (60 g, 155 mmol), sudan III 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 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 1H), 4.22 3H), 3.91 4H), 3.28 (DD, J=3HZ, 13HZ, 1H), 3.05 1H), 2.78 2H), 1.69 (M, 3H), 1.50 3H), 1.29 3H).

3(S)-(3-FluoroDhenvl)-3-(2-oxo-3(R)-[3-(5.6.7.8-tetrahydro- [1,81naphthvridin-2-vl)-propvll-pyrrolidin-l-vl)-propionic acid (2-10) The title compound was prepared following the synthetic procedure depicted in Scheme 2, but replacing intermediate 2-5 with the chiral intermediate 7-5, the preparation of which is shown in Scheme 7.

3(S)-(3-Fluorophenvl)-3-(2-oxo-3(S)-[3-(5 6,7,8-tetrahydror1.81naphthvridin-2-vl)-propDvll-prrolidin-l-vl)-propionic acid (2-11) The title compound was prepared in a similar fashion as its diastereoisomer 7-6 immediately above, but using the enantiomer of prepared in an analogous fashion to that depicted in Scheme 7.

96- WO 99/30709 WO 9930709PCT/US98/26539

H

3 C- N 0 8-1

H

2 Pd/C SCHEME 8

NH

2 0 proline

H

N NN .N

NN

8-2

HONH

2

H

N 1 N NH 2 N _0 8-4 NMM, isobutyl chloroformate O OBn HO

HN\,

BOG

~OBn 1) HOI )c 2) PhSO 2

CI,

NMM

B

8-6 R--Bn 8-7 R--HD NaOH

SO

2 Ph 4-ri .81Naphthvridin-2-v1-butvronitrile (8-2) A mixture of 5-oxo-hexanenitrile (5 ml, 43.8 mmol), 2amino-3-formylpyridine (7 g, 57 mmol), proline (5.3 g, 43.8 minol) 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).

1H NMR (300 MHz, CDC13) 5 9.10 1H), 8.19 2H), 7.47 2H), 3.24 2H, J=7 Hz), 2.55 2H, J=7Hz), 2.39 2H).

4-(5.6.7,8-Tetrahvdro-[ .81naphthvridin-2-vl)-butvronitrile (8-3) A mixture of -2 (14 g, 71 mmol), 10% Pd/C (2 g) and ethanol (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 1H, J=7 Hz), 6.35 1H, J=7 Hz), 4.76 (br s, 1H), 3-.41 2H), 2.71 4H), 2.38 2H, J=7 Hz), 2.08 (m, 3H), 1.85 2H), 1.80 1H).

2(S)-tert-Butoxvcarbonvlamino-3-r3-(3-r1.8lnaphthvridin-2-vl-propyl)r1,2.41oxadiazol-5-vll-propionic acid benzvl ester To methanol (20 mL) was added sodium metal (0.86 g, 37 mmol). After 30 minutes, this solution was added to a suspension of 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 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°C was added N-methylmorpholine (0.61 mL, mmol) followed by isobutyl chloroformate (0.66 mL, 5.1 mmol). After 30 minutes, a solution of the above crude oxime in DMF (5 mL) was added. The solution was allowed to warm to 25 0 C and stir for 1 h, then toluene (20 mL) was added and the mixture heated to 110°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 with sat. NaHCO3, brine, and dried over MgSO4. The residue was -98- WO 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) 8 7.30 5H), 7.04 1H), 6.34 1H), 5.16 2H), 4.80 2H), 3.41 2H), 2.68 4H), 2.59 2H), 2.04 (m, 2H), 1.85 4H), 1.43 9H).

2(S)-Benzenesulfonvlamino-3-[3-(3-rl.8]naDhthvridin-2-vl-propvl)r1.2.41oxadiazol-5-vll-propionic acid (8-7) A solution of 4M HC1 in dioxane (20 mL) was added to (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 mL), and NMM (0.7 mL, 6.4 mmol), and the mixture was cooled to 0°C. Phenylsulfonyl chloride (0.081 mL, 0.64 mmol) was added. After minutes, the mixture was diluted with ethyl acetate, washed with sat.

NaHC03, brine, and dried over MgS04. 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 15:10:1:1 ethyl acetate /EtOH /water /NH40H) to give 8-7 as a white solid.

TLC Rf 0.48 (10:10:1:1 ethyl 1 H NMR (300 MHZ, CD30D) A 7.68 2H), 7.33 3H), 7.15 1H, J=7 HZ), 6.39 1H, J=7 HZ), 3.91 1H), 3.37 2H), 3.08 2H), 2.71 2H), 2.57 4H), 1.97 2H), 1.88 2H).

SCHEME 9

H

2

N

CO

2 Et r EtONa,

E

tOH Et 1Br N 9-1 92 EtO 9-3 5-Bromo-2-ethoxypvridine (9-2) Sodium metal (4.87 g, 0.212 mol) was added to ethanol (200 mL) and stirred until completely dissolved. To this solution was added 99- WO 99/30709 WO 9930709PCTIUS98/26539 -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 the organic layer was washed with brine, dried (MgSO4) and concentrated to give as a red-brown solid which was used as such in the next step.

1 H NIMR (300 MHz, CDCl 3 8 1.4 (3H, 4.33 (2H, 6.63 (1H, 7.62 (1H, dd), 8.19 (1H, d).

3(S)-(6-Ethoxvrvyridin-3-vl)-D-alarnine ethyl ester (9-3) The title compound was prepared from Q- using the procedure described for the synthesis of 19-5 from 19-3.

1H NMR (300 MIHz, CDC1 3 5 1.25 (3H, 1.39 (3H, 2.61 (1H, dd), 2.67 (1H, dd), 4.15 (2H, 4.34 (2H, 4.40 (1H, dd), 6.71 (1H, 7.62 (1H, dd), 8.11 (1H, d).

SCHEME

NH

2 tert-butyl acrylate, SN Pd(QAc) 2 (o-Tolyl) 3

P

11000, CH 3

CN

Br 10-1 NH2 N a) P 1,4-C Bn

NH

2 10-2 CO2tBu ph)-J-N -Bn Li THF, -78 0

C

NH

2 1/C, 78 0 C, AcOH- ~yclohexadiene CI, EtOH 2HCI*HW 2 10-4 10-3 100 WO 99/30709 PCT/US98/26539 3-(6-Amino-vpridin-3-vl)-acrvlic 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 mmol), 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 as a solid.

Rf (silica, EtOAc/hexanes 1:1) 0.26 3(S)-(6-Amino-Dvridin-3-vl)-3-rbenzvl-(1(R)-phenvlethvl)-aminolpropionic acid tert-butyl ester (10-3) To a cooled solution of (R)-(+)-N-benzyl-amethylbenzylamine (4.0 g, 19 mmol) in 50 mL THF was gradually added n-butyllithium (11.3 mL, 2.5 M, 28.2 mmol) over 5 min. The mixture was stirred for 30 min at 0 C and cooled to -78 A solution of 10-2 (2.0 g, 9.4 mmol) in 20 mL THF was gradually added. After stirring for 40 min at -78 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 desired product 10-3 as an oil.

Rf (silica, EtOAc/hexanes 1:1) 0.28 3(S)-Amino-3-(6-amino-pvridin-3-vl)-proDionic acid ethyl ester*2 HC1 (10-4) A mixture of 10-3 (0.5 g, 1.2 mmol) and 10% Pd/C (0.4 g) in mL AcOH was purged with argon for 5 min and then heated at 78 0

C.

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 gel flash chromatography (EtOAc/MeOH/NH40H 1:1:0.04) to afford an 101- WO 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 J=9.6 Hz, 1H), 8.08 1H), 7.13 (d, J=9.6 Hz, 1H), 4.77 1H), 4.18 J=6.8 Hz, 2H), 3.22-3.02 2H), 1.24 J=6.8 Hz, 3H).

102 WO 99/30709 WO 9930709PCT/US98/26539 SCHEME 11 02

OH

CHO

(Ph) 3 C0 2 Et

CH

2

CI

2 02

OH

11-2 CO 2 Et

NH

4 CIIFeo EtOHIH 2

O

11-1 0 sat'd NaHCO 3 CHC1 3

K

2 C0 3

/DMF

fiN 0 11-5 C0 2

R

N

PV'I NH PhnBuLiITHF

HNI-

Ph)"N Ph--

CO

2 Et MeI/NaFF

DMF

Ph) PhY C02Et 11-7 11-6 103 WO 99/30709 PCT/US98/26539

U

Pd(OH) 2

/H

2 11-7 MeOH/AcOH

H

2 0 H2N

CO

2 Et 11-8 3-(3-Hvdroxv-4-nitrophenvl)-acrvlic acid ethyl ester (11-2) To a stirred solution of aldehyde 11-1 (20.28 g, 132.5 mmol) in 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 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 1H), 7.60 1H), 7.15 (dd, 1H), 6.54 1H), 4.30 2H), 1.36 3H).

3-(4-Amino-3-hydroxyphenvl)-acrvlic 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 and then the solution was filtered while hot through celite. The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The layers were separated and the EtOAc layer dried (Na2S04) and concentrated to give 11-3 which was used without further purification in the next step.

TLC Rf= 0.2 (25:75 EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 6 7.57 1H), 7.00 2H), 6.68 1H), 6.20 1H), 4.26 2H), 4.10 2H), 1.33 3H).

104- WO 99/30709 PCTIUS98/26539 3-[4-(2-Chloroacetvlamino)-3-hvdroxvphenvl]acrvlic acid ethyl ester (11-4) To a stirred solution of 11-3 (3.38 g, 16.3 mmol) in CHC13 mL) was added saturated NaHCO3 (50 mL) and it was then chilled to 0°C. A solution of chloroacetyl chloride (1.94 mL, 24.4 mmol) in CHC13 mL) was added dropwise to the chilled biphase. Upon addition completion, the reaction was stirred at 0°C for 1 h. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2S04) 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) 8 10.33 1H), 9.58 1H), 8.02 1H), 7.51 1H), 7.19 1H), 7.12 1H), 6.39 1H), 4.42 2H), 4.17 2H), 1.25 3H).

3-(3-Oxo-3.4-dihvdro-2H-benzo 1.41oxazin-7-vl) acrylic acid ethyl ester (11-5) To a stirred solution of 11-4 (4.28 g, 15.0 mmol) in DMF mL) was added K2C03 (4.50 g, 32.6 mmol). The resulting suspension was heated to 50 0 C for 12 after which time the reaction was concentrated. The residue was partitioned between saturated NaHCO3 and EtOAc and extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), 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) 5 10.91 1H), 7.54 1H), 7.37 1H), 7.31 1H), 6.90 1H), 6.51 1H), 4.60 2H), 4.16 2H), 1.24 3H).

3-(R)-rBenzvl-(l-phenvlethvl)-aminol-3-(S)-(3-oxo-3,4-dihvdro-2Hbenzor[.41oxazin-7-vl) propionic acid ethyl ester (11-6) To a stirred solution of (R)-(+)-N-benzyl-amethylbenzylamine (5.43 g, 25.7 mmol) and anhydrous THF (75 mL) at 105- WO 99/30709 PCT/US98/26539 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°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 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 a white foam.

TLC Rf 0.25 (25:75 EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 6 10.89 1H), 7.32 10H), 7.10 2H), 6.91 1H), 4.62 2H), 4.39 1H), 4.13 2H) 3.96 1H), 3.68 (s, 2H), 2.56 2H), 1.28 6H).

3-(R)-rBenzvl-(l-phenvlethyl)-aminol-3-(S)-(4-methvl-3-oxo-3,4-dihvdro- 2HF-benzol,.41oxazin-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) in DMF (10 mL) via syringe. This yellow solution was stirred at room temperature for 30 minutes. Iodomethane (500 ptL, 8.0 mmol) was added and the solution then stirred at room temperature for an additional minutes. The reaction was quenched with saturated NaHCO3. The aqueous layer was extracted three times with CH2C12. The combined 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 10H), 7.06 2H), 6.91 1H), 4.62 2H), 4.39 1H), 4.13 2H) 3.96 1H), 3.68 2H), 3.35 3H), 2.56 2H), 1.26 6H).

3-(S)-Amino-3-(4-methvl-3-oxo-3.4-dihvdro-2H-benzo l.,41oxazin-7-vl) propionic acid ethyl ester (11-8) 106- WO 99/30709 PCT/US98/26539 A stirred solution of 11-7 (581 mg, 1.2 mmol), MeOH mL), AcOH (1.0 mL), and H20 (0.3 mL) was degassed with argon for 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 filtered through celite. The filtrate was concentrated to yield 11-8 as a clear oil.

TLC Rf 0.3 (5:95 MeOH/CH2Cl2) 1H NMR (300 MHz, CDC13) 8 7.04 2H), 6.93 (dd, 1H), 4.61 2H), 4.39 1H), 4.13 2H), 3.37 2H), 3.35 3H), 2.69 2H), 1.24 3H).

107- WO 99/30709 PTU9/63 PCTIUS98/26539 SCHEME 12

NH

2 Br

(BOC)

2 0 tert-BuOH NHBoc Br NaHIDMF Mel Me,, N 1. Boc

N

Br 12-1 12-2 12-3 Ethyl acrylate, Pd(OAc) 2 (o-TOlYI) 3

P

110 0 C, CH 3

CN

NH

2 Me,,N 1.Boc N N Ph~N CO 2 Et

H

Pd(OH) 2

H

2 AcOIVEtOH Me,, N 1 Boc

CO

2 Et

NH

2 12-6 12-5 2 -tert-Butoxvcarbonvlamino-5-aminoD~-idine (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 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 (CHCl3/hexanes, 5:1) to afford the desired product 12-2 as a solid.

Rf (silica, 100% CHCl3) 0.56 108 WO 99/30709 PCT/US98/26539 1 H NMR (300 MHz, CDC13) 5 8.82 (bs, 1H), 8.38 1H), 8.78 1H), 7.78 (dd, 1H), 1.55 9H).

2 -(tert-Butoxvcarbonvl-methyl-amino)-5-aminopyridine (12-3) To a solution of 12-2 (6.0 g, 22.0 mmol) in 50 mL DMF at 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 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) 8.40 (dd, 1H), 7.68 2H), 3.36 3H), 1.55 9H).

3-[6-(tert-Butoxvcarbonvl-methvl-amino)-pyridin-3-vl1-acrvlic acid ethyl ester (12-4) A mixture of 12-3 (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 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 hr. The mixture was cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:3) to afford the desired product 12-4 as an oil.

1 H NMR (300 MHz, CDC13) 8 8.47 (bs, 1H), 7.82 2H), 7.64 1H), 6.42 1H), 4.27 2H), 3.43 3H), 1.54 9H), 1.34 3H).

3 -Benzvlamino-3-[6-(tert-butoxvcarbonvl-methvl-amino)-pvridin-3-vllpropionic 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.

-109- WO 99/30709 WO 9930709PCT/US98/26539 Rf (silica, EtOAc/hexanes 1:1) 0.63.

3-Amino -3 J 6-(tert-butoxycarb onvl-methyl- amin pvri din- 3 -vl-uTroui oni c acid ethyl ester (12-6) A mixture of 12-5 (1.5 g 3.6 nimol), 20% Pd(OH)21C (0.3 g), AeGH (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.

1H NMR (300 MHz, CDCl3) 5 8.38 1H), 7.70 (in, 2H), 4.50 (dd, 1H), 4.15 2H), 3.40 3H), 2.80 (in, 2H), 1.25 3H).

SCHEME 13 Ethyl Acrylate Pd(OAc) 2 h

F

13-2

CO

2 Et 1-1 Ph"KN'Ph

H

n-BuLi h

F

H2 C2 Pd(OH) 2

H

2 (g) h 1

F

Me Bn 13-4 3- (2-Fluo ro-biphenvl-4-v)- acrylic acid ethyl ester (13-2) 110 WO 99/30709 PCT/US98/26539 A solution of 2-fluoro-4-bromobiphenyl 13-1 (7.5 gn, 31.8 mmol), ethyl acrylate (4.3 mL), Pd(OAc)2 (0.714 gm, 3.2 mmol), tri-otolylphosphine (1.94 gm, 1.5 mmol) and triethylamine (12 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 (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 solid.

TLC Rf 0.44 (10% ethyl acetate/hexanes).

3-[Benzvl-(l(R)-phenylethyl)-aminol-3-(2-fluoro-biphenvl-4-vl)-propionic acid ethyl ester (13-3) A cooled solution of N-benzyl-(R)-amethylbenzylamine (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 -78 0 C and treated with a solution of ester 13-2 (5.76 g, 21.3 mmol) in THF (10 mL).

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 NaHC03 (50 mL), 5% aq acetic acid (30 mL), 10% aq K2C03 mL), and brine (50 mL). The solution was dried over MgSO4, filtered 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-biphenvl-4-vl)-propionic acid ethyl ester (13-4) A solution of the dibenzylamine 13-3 (5.65 gm, 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 the filtrate dissolved in aq HCI The aqueous solution was 111 WO 99/30709 PCT/US98/26539 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 MgS04, filtered and concentrated to give the desired product 13-4.

1 H NMR (300 MHz, CD30D) 5 7.41 8H), 4.10 1H), 4.06 2H), 2.73 2H), 1.18 3H) ppm.

SCHEME 14

NO

2

NO

O2H Et 0O 2 I Ph 3

P--O

CHO

14-1 14-2 C 2 Et CO2Et 2. CDI, THF 0 1 Me 0 H Ph N Ph HNOh--

H

n-BuLi HN CO2Et 2. Pd(OH) 2

H

2 (g) 14-4 14-3 CO 2 Et 3-(3-Hvdroxv-4-nitro-phenvl)-acrvlic acid ethyl ester (14-2) To a solution of aldehyde 14-1 (15.0 g, 98.0 mmol) in CH2C12 (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 flash chromatography (10% EtOAc/CH2C12) to give 14-2 as a yellow solid.

TLC Rf 0.51 (30% ethyl acetate/hexanes).

112- WO 99/30709 PCT/US98/26539 1 H NMR (300 MHz, CD30D) 5 8.08 J=8.4 Hz, 1H), 7.63 J=16.2 Hz, 1H), 7.35 J=1.5 Hz, 1H), 7.27 (dd, J=8.4, 1.5 Hz, 1H), 6.65 J=15.9 Hz, 1H), 4.25 J=7.2 Hz, 2H), 1.32 J=6.9 Hz, 3H) ppm.

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 0 C. The mixture was filtered hot through Celite, and the Celite bed 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 chromatography 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) 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 MeOH in CH2C12) to give 14-3 as a yellow solid.

TLC Rf 0.49 MeOH/CH2Cl2).

1 H NMR (300 MHz, CD30D) 5 7.77 J=15.9 Hz, 1H), 7.55 1H), 7.41 (d, J=8.4 Hz, 1H), 7.09 J=8.1 Hz, 1H), 6.47 J=15.9 Hz, 1H), 4.22 J=7.2 Hz, 2H), 1.31 J=7.2 Hz, 3H) ppm.

3S-Amino-3-(2-oxo-2.3-dihvdro-benzoxazol-6-vl)-propionic acid ethyl ester (14-4) A solution of N-benzyl-a-(R)-methylbenzylamine (4.08 g, 19.3 mmol) in THF (120 mL) at 0°C was treated with n-BuLi (7.72 mL of a M soln in hexanes). The resulting solution was stirred at 0°C 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).

113- WO 99/30709 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 3aminoester as a yellow oil. The aminoester was dissolved in EtOH/H20/AcOH (54 mL/4.8 mL/1.2 mL), degassed with argon, and treated with Pd(OH)2 (2.74 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.

TLC Rf 0.10 MeOH/CH2C12).

1 H NMR (300 MHz, CD30D) 8 7.34 1H), 7.26 (dd, J=1.2, 8.1 Hz, 1H), 7.12 J=8.1 Hz, 1H), 4.65 J=7.2 Hz, 1H), 4.13 J=6.9 Hz, 2H), 2.98 2H), 1.20 J=7.2 Hz, 3H) ppm.

SCHEME

OH

F

Br 15-1 1. Ethyl Acrylate Pd(OAc) 2 Et 3

N

2. Et-I, CS2C0 3

R

F

S15-2 R=H 15-3 R=Et Me Ph'- N Ph

H

CO

2 Et n-BuLi OEt

F

H

2 N CO2Et 15-5 Pd(OH) 2

H

2 (g) OEt Me Ph N CO2 E t Bn 15-4 114- WO 99/30709 PCT/US98/26539 3-(4-Hvdroxv-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 tri-o-tolylphosphine (5 g) and 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 aq. citric acid (40 mL), satd aq NaHCO,, and brine (40 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue 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-rBenzvl-(l(R)-phenvlethvl)-aminol-3-(4-ethoxv-3-fluorophenvl)propionic acid ethyl ester (15-4) To a stirred solution of 15-2 (49.25 gm, 234.5 mmol) in DMF (600 mL) was added Cs2C03 (84.1 gm, 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 (1L) and washed with water (6 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 of the product 15-3 as an orange oil which crystallized upon standing. A cooled solution of N-benzyl- (R)-a-methylbenzylamine (71 mL, 339.4 mmol) in THF (650 mL) was 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°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 was diluted with Et20 (1000 mL), and washed with 10% aq citric acid (300 mL), satd aq NaHC03 (300 mL), 5% aq acetic acid (300 mL), 10% aq K2C03 (300 mL), and brine (200 mL). The solution was dried over MgS04, filtered and concentrated. The residue was purified by flash chromatography (85:15 hexanes/EtOAc) to give the adduct 15-4.

TLC Rf 0.39 (25% ethyl acetate/hexanes).

115- WO 99/30709 WO 9930709PCT/US98/26539 3-Ainino-3-(4-Ethoxv-3-fluoron~henvl)-rjrouDionic acid ethyl ester (15-5) A solution of the dibenzylamine 154 (30.0 gmn, 66.8 minol) in EtOH/HOAc (340/30 inL) was purged with argon and treated with Pd(OH)2 (6 g) and placed under 1 atm of H2 for 12 h. Additional portions 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 MIHz, CD3OD) 5 7.19 (in, 3H), 4.62 (in, 1H), 4.07 (in, 4H), 2.99 (in, 2H), 1.39 (in, 3H) 1.18 (in, 3H) ppm.

SCHEME 16

H

o EtI Cs 2

CO

3 o c<CH 3 16-2 1) NaOH; HCI 2) EDC, NMM, HCI *HN(Me)OMe 16-1 o N'CH3 16-3 C'TH3

H

3

CN

DIBAL H 3C I C

I

0 H

PH

3

PCHC

2

C(CH

3 3 16-5 16-4 H3C3C 'N.H 16-7

OH

3

C

H Q CH3 16-6 0 -\nuiHNCH 3 0 011H3 2) Pd/C, 016-8 116 WO 99/30709 PCT/US98/26539 acid ethyl ester (16-2) A mixture of 3-hydroxy-nicotinic acid methyl ester 16-1 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 hours. The reaction mixture was diluted with Et20 and then washed with 10% K2C03, brine, dried (MgS04), 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 1H), 8.46 7.75 1H), 4.40 (q, 2H, J=7Hz), 4.12 2H, J=7Hz), 1.43 6H).

(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 were evaporated and the residue was dissolved in 1N HC1 (80 ml, 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 HC1*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 stirred for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with 10% K2C03, 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) 5-Ethoxv-pyridine-3-carbaldehvde (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.OM hexanes, dropwise over 30 minutes. After 30 minutes, the solution was warmed to 0°C for 1 hour. The reaction was quenched with 100 ml 1.OM Rochelle's 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) 1 H NMR (300 MHz, CDC13) 6 10.10 1H),8.65 8.55 7.59 (s, 1H), 4.14 2H, J=7Hz), 1.43 3H, J=7Hz).

117- WO 99/30709 PCT/US98/26539 3-(5-Ethoxv-pvridin-3-vl)-acrvlic 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 was diluted with Et20 and then washed with 10% K2C03, 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) 1H NMR (300 MHz, CDC13) 6 8.31 2H),7.55 1H, J=16Hz), 7.27 (s, 1H), 6.40 1H, J=16Hz), 4.10 2H, J=7Hz), 1.54 9H), 1.44 3H).

3(S)-Amino-3-(5-ethoxv-pvridin-3-vl)-propionic acid tert-butvl ester (16-8) To a stirred solution of 16-7 (500mg, 2.38mmol) and THF at 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 brine, dried (MgSO4) and concentrated. The residue was dissolved in acetic acid (14 ml) and the solution was purged with argon for minutes. 10% Pd/C (1.0 g) was added and the mixture was heated to 1,4-Cyclohexadiene (6 ml) was added dropwise maintaining an internal temperature between 80°C and 90 0 C. After 5.0 hours, the mixture was filtered through a celite pad, concentrated and then azeotroped with toluene. The residue was chromatographed (silica gel, [10:10:1 EtOH/NH40H/H20]/ 70:25:5 chloroform/ ethyl acetate/ MeOH) to give 16-8 as a yellow solid.

1H NMR (300 MHz, CDC13) 6 8.18 2H),7.25 4.41 4.08 2H, J=7Hz), 2.59 2H, 1.87 2H), 1.40 12H).

118- WO 99/30709 PCTIUS98/26539 SCHEME 17 CH3 0' PN

CH

3

N

-VOH 3

H

Br H 2 N O H 3 17-1 1- 3(S)-Amino-3-(5-methoxv-pvridin-3-vl)-propionic acid tert-butvl ester 17-1 (prepared as described in J. Org.

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) 8.20 1H, J=3Hz), 8.18 1H, J=2Hz),7.50 1H1,), 4.51 3.90 (s, 3H), 2.87 (in, 2H, 1.37 (mn, 9H).

SCHEME 18

H

IJ1 0 5% Pd/BaSO4, H120 HCI-H2N' A O~t quinoline, ethanol HN- 18-2 3-Arnino-Dent-4-enoic acid ethyl ester (18-2) A mixture of 5% Pd/BaSO4 (0.025 g) and quinoline (0.30 inL) 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.

Chem., 1995, 38, 2378-2394) (1.77 g, 10.0 mmol) in EtOH (15 mL) was added and the solution stirred for a~n additional 2.5 hours. The solution was filtered through a pad of celite and concentrated in vacua to provide 2.65 g of crude product 18-2. IH NMR (CDCl3, 300 NMz): 5 8.40-7.60 (br s, 2H), 6.11-5.96 (in, 1H), 5.58-5.53 (d 1H), 5.44-5.41 1H), 4.31-4. 16 (in, 3H), 3.12-2.86 (in, 2 1.29-1.25 t, 3H).

119- WO 99/30709 WO 9930709PCTIUS98/26539 SCHEME 19 Ne Br 2 KBr, KOH

H

2 0 Meo- DBr 19-2 19-1 Pd(OAc) 2 Et 3

N,

tri-o-tolylphosphine ethyl acrylate, CH 3

CN

MeO-~ C2E 19-3

H

P h-N Ns.P h Me

THIF

2. nBuLi, THF 3. NH 4 Cl, H 2 0 Ph' Ph-N C~ Me MeG 9- Pd(OH) 2

H

2 EtOH, HOAc, H 2 0

H

2 N

CO

2 Et MeG 19-5 120- WO 99/30709 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 resulting solution was stirred at room temperature for 5 hr. Solid NaHC03 was added until basic and the solution was extracted with CHC13 (3x500 mL). The organic layer was washed with 10% NaHS03, then brine, dried over Na2SO4, filtered and the solvent removed in vacuo.

The resulting dark brown oil was predominantly the desired compound 19-2 and was used as such in the next step.

H NMR (300 MHz, CDC1 3 5 3.91 (3H, 6.66 (1H, 7:62 (1H, dd), 8.20 (1H, d).

Ethyl 3-(6-methoxvpyridin-3-vl)acrvlate (19-3) 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 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 as a yellow solid.

1H NMR (300 MHz, CDC13) 5 1.34 (3H, 3.97 (3H, 4.26 (2H, 6.34 (1H, d),6.76 (1H, 7.63 (1H, 7.77 (1H, dd),8.27 (1H, d).

N-Benzvl-(R)-a-methylbenzvl-3(S)-(6-methoxvTvridin-3-vl)-P-alanine ethyl ester (19-4) To a solution of N-benzyl-(R)-a-methylbenzylamine (97.5 g, 462 mmol) in THF (750 mL) at 0°C was added n-butyllithium (2.5M in hexanes; 178.5 mL, 446 mmol). The dark violet solution was stirred at 0°C for 20 minutes, cooled to -78 0 C and the ester 19-3 (63.7 g, 308 mmol) in 121- WO 99/30709 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 NH4C1 and extracted with EtOAc, washed with water then brine, dried and concentrated in vacuo to give an oil. Column chromatography (silica gel; hexane/EtOAc, 9:1 then 4:1) gave 19-4 as an oil contaminated with Nbenzyl-(R)-a-methylbenzylamine This oil was taken up in 5% AcOH in water and extracted with diethyl ether The organic layers were dried over MgSO4 and the solvent removed to give the title compound 19- 4.

H NMR (300 MHz, CDC13) 5 1.08 (3H, 1.27 (3H, 2.52 (1H, dd), 2.62 (1H, dd), 3.66 (1H, 3.70 (1H, 3.93 (3H, 3.95 (2H, 4.41 (1H, dd), 6.74 (1H, 7.15-7.45 (10H, 7.64 (1H, dd), 8.15 (1H, d).

3(S)-(2-methoxypvrid-5-vl)-B-alanine ethyl ester (19-5) 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 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.

1 H NMR (300 MHz, CDC13) 5 1.23 (3H, 2.61 (1H, dd), 2.68 (1H, dd), 3.92 (3H, 4.15 (2H, 4.41 (1H, dd), 6.93 (1H, 7.62 (1H, dd), 8.13 (1H, d).

122- WO 99/30709 WO 9930709PCT/US98/26539 H2N 1N t-butyl nitrite C N 0NBr CUCI 2 CHN0 2 N Br 2Q-1 HN I Sn, HCI Br ItBu acrylate, Pd(OAc) 2

DMF

Me HN ~N Ph) NH B~n nBuLi, THE 205 CO 2 tBu 20-2 IHO-'ThO 2

CH,

NaH, THE

H

3

C

2 C-,O ~N 0 2 N 'N Br H NHN

H

3 C H 3 0 Ph'I--N 02Bu Ph"~ 0C 2 tBU Bn 206Bn aU IPd(OH) 2 EtCH HN

H

2 02'Bu 20-7 1 LiAIH 4 2. Pd(OH) 2 EtCH 20-9 3-Bromo-6-chloro-5-nitropvridine (20-2) A suspension Of CuICl2 (3.33 g, 24.8 inmol) in anhydrous CH3CN (200 mL) at 65' was treated with tert-butylnlitrite (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 65' for 2 h and concentrated at reduced pressure. The residue was partitioned between EtOAc (150 mL) and 3% HCI (60 ml), 123 WO 99/30709 PCT/US98/26539 and the organic layer washed successively with 3% HC1, 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.

TLC Rf 0.60 (25% EtOAc/ Hexane) 1 H NMR (300 MHz, CDC13) 5 8.70 J=2.4 Hz, 1H), 8.37 J=2.4 Hz, 1H).

(3-Nitro-5-bromo-pvridin-2-vloxv)-acetic acid methyl ester (20-3) Methyl glycolate (450 mg, 5.05 mmol) was added to a 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 afford 20-3 as a yellow solid.

TLC Rf 0.70 (25% EtOAc/ Hexane) 1 H NMR (300 MHz, CDC13) 8 8.46 J= 2.4 Hz, 1H), 8.37 J= 2.4 Hz, 1H) 5.15 2H), 3.78 3H).

2-Oxo-2.3-dihvdro-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 cone. HC1 (10 mL). The mixture was heated to 800 for 2 h, then cooled and concentrated. The residue was partitioned betwen CHC13 and sat. NaHC03, washed with brine, then 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 J=2.4 Hz, 1H), 7.25 J=2.4 Hz, 1H), 4.81 2H).

3-(2-Oxo-2.3-dihydro-1H-4-oxa- 1.5-diaza-naDhthalen-7-vl)-acrvlic acid tert-butvl ester (20-5) A mixture of 204 (1.12 g, 4.89 mmol), (o-tol)3P (298 mg, mmol), Pd(OAc)2 (110 mg, 0.49 mmol), and triethylamine (0.86 mL, 5.87 124- WO 99/30709 PTU9/63 PCT[US98/26539 minol) in DMF (20 m.L) was placed in a 100-mL flask. The mixture was degassed with argon, then tert-butyl acrylate (752 mg, 5.87 namol) 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 NaHCO3, water, and brine, dried, filtered and concentrated.

Chromatography on silica gel (25% hextEtOAc) 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 J=2.4 Hz, 1H), 7.54 (d J=16 Hz, 1 7.42 (d J= 2.4 Hz, 1H), 6.35 Ad J=16 Hz, 1 4.84 2H), 1.48 9H).

3(S)-[Benzvl-( 1(R )-uhenvlethvi )-aminol-3-(2-oxo-2 .3-dihvdro- 1H-4-oxa- diaza-naphthalen-7-vl)-nropi omc acid tert-butvl ester (20-6) A solution of N-benzyl-a-(R)-methylbenzylatnine (0.82 g, 3.87 nnnol) in THF (25 naL) 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 G for 30 min and then cooled to -78'C. A solution of acrylate 20-5 (0.485 g, 1.76 namol) in THF (5 mL) was added. After stirring for 15 min at -78'C, satd aq NH4Cl soin (5 mnL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2 x 40 mnL).

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 thefaminoester 20-6 as a yellow oil.

TLC Rf 0.3 (40% ethyl acetate/hexanes) IH NMR (300 MHz, CDCl3) 5 1H N7IVR 8.70 (br, s, 1H), 7.91 Ad J=1.8 Hz, 1H),7.4-7.2 (10H), 7.12 J=1.8 Hz, 1H), 4.80 2 4.42 (in, 1H), 3.91 (q, J=6.7 Hz, 1 3.69 J=7.2 Hz, 1H, 3.62 (d J =7.2 Hz, 1H, 2.46 (in, 2H), 1.34 J=7.0 Hz, 3H), 1.29 9H1).

3(-S)-Amino-3-(2-oxo-2 .3-dihvdro- 1H-4-oxa-1 .5-diaza-nanhthalen-7-vl)- Yjrornionic acid tert-butvl ester (20-7) A mixture of the dibenzylarnine 20- (0.22 g, 0.44 nimol) in EtOH/H-20/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and 125 WO 99/30709 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/NH40H/H 2 0 EtOAc) to give the tert-butyl ester 20-7 as a white solid.

TLC Rf= 0.5 (20% 20:1:1 EtOH/NH40H/H 2 0 80% EtOAc) 1 H NMR (300 MHz, CD30D) 5 7.89 J= 1.7 Hz, 1H), 7.31 J=1.7 Hz, 1H), 4.81 2H), 4.38 1H), 2.6, 2H), 1.41 9H).

3(R)-rBenzvl-(1-phenvlethvl)-aminol-3(S)-(2-thioxo-2,3-dihydro-1H-4-oxa- 1,5-diaza-naphthalen-7-yl)-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 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 J=1.8 Hz, 1H),7.4- 7.2 (11H), 5.08 2 4.42 1H), 3.91 J=6.7 Hz, 1 3.69(d, J=7.2 Hz, 1H, 3.62 J =7.2 Hz, 1H), 2.46 2H), 1.34 J=7.0 Hz, 3H), 1.29 9H).

3(S)-Amino-3-(2.3-dihvdro-1H-4-oxa- 15-diaza-naphthalen-7-vl)-propionic acid tert. butvl ester (20-9) A solution of 20-8 1.0 g, 1.9 mmol) in anhydrous Et20 mL) at 00 was treated dropwise with LiAlH4 (2.09 ml of a 1.0 M solution in Et20). The resulting solution was stirred at o0C for 30 min and then quenched by the sequential addition of H20 (0.3 mL), 15 NaOH (0.08 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- WO 99/30709 WO 9930709PCTIUS98/26539 1 H NMR (300 M7Hz, CDCl3) 6 1H NMR 7.61 J=1.8 Hz, 1H),7.4-7.2 6.87 J=1.8 Hz, 1H), 4.41 (in, 2 4.36 (mn, 1H), 3.91 J=6.7 Hz, 1 H), 3.8 (brs, 1H), 3.69 (mn, 2H), 3.42 (mn, 2H), 2.46 (mn, 2H), 1.34 (d J=7.0 Hz, 3H), 1.29 9H).

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/NI{40H1H20 80% EtOAc) 1 H NMR (300 MHz, CD3OD) 5 7.59 J=1.7 Hz, 1H), 6.92 J=1.7 Hz, 1H), 4.41 (mn, 2H), 4.30 (in, 1H), 3.41 (mn, 2H), 2.6, (mn, 2H), 1.41 9H).

KNH

Br 2 MeOH

NH

Br 21-2 21-1

H

2 Nx;- 2'B u 21-4 21-3 3-Oxo-3 .4-dihydro-2H- 1-oxa-4 .5-diaza-7-bromo-nanhthalene (21-2) A solution of 21-1 (4.8 g, 32 mmol) in MeOH (160 mL) at was treated dropwise with bromine (25.7 g, 161 inmol). After stirring at for 0.5 h, the mixture was warned to ambient teinperature and 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% EtOAd/ Hexane) 127 WO 99/30709 PTU9/63 PCT/US98/26539 1 H NMR (300 MHz,DMSO-d6) d 11.2 (br,s, 1H), 8.05 J= 2.4 Hz, 1H), 7.66 J= 2.4 Hz, 1H1), 4.76 211).

3(S)-Amino-3-(3-oxo-3,4-dihydro-2H- 1-oxa-4,5-diaza-naphthalen-7-vl)uroujionic acid tert-butyl ester (21-3) Bromide 21-2 was converted to amino ester 21-3 as illustrated in Scheme TLC Rf 0.5 (12% 20:1:1 EtOH/NI{40H1H20 88% EtOAc) 1H1 NMR (300 MIHz, CD3OD) 5 8.04 J= 1.7 Hz, 1H), 7.34 J=1.7 Hz, 1H1), 4.76 2H), 4.38 (in, 1H1), 2.6, (in, 2H), 1.41 9H).

3(S')-Amino-3-(3-oxo-3 .4-dihydro-2H- 1-oxa-4 .5-diaza-naphthalen- 7-vi)propionic acid te'rt-butyl ester (21-4) Bromide 21-2 was converted to amino ester 21-4 as illustrated in Scheme TLC Rf 0.5 (20% 20:1:1 EtOHINH4OHIH2O 80% EtOAc) IHNMR (300 M7Hz, CD3OD) 8 8.04 J= 1.7 Hz, 1H), 7.34 J=1.7 Hz, 1H1), 4.76 2H), 4.38 (in, 1H1), 2.6, (in, 2H1), 1.41 911).

128 WO 99/30709 PCT/US98/26539 Scheme 22 N N o HOr/ MnO 2

CH

2 C1 2

OHC'

22-1 22-2 HO2C CO 2 Et

NH

4 Ac, EtOH

VN

H

2 C02Et 22-3 Furo-r2,3-b]pvridine-5-carboxaldehvde (22-2) A solution of alcohol 22-1 Bhupathy, et al., J.

Heterocycl. Chem. 1995, 32, 1283-1287) was treated with excess MnO2 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) 8 10.22 1H), 9.05 J= 1.8 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H) 8.08 J=1.8 Hz, 1H), 7.10 J=1.7 Hz, 1H).

3-Amino-3-(furor2.3-blTvridin-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, 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 afforded the amino ester 22-3 as a waxy solid.

129- WO 99/30709 WO 9930709PCTIUS98/26539 TLC Rf 0.5 (20% 20:1:1 EtOHINII4OHIH2O 80% EtOAc) 1 H NMR (300 MIHz, CD3OD) 5 8.34 J=1.7 Hz, 1H), 8.04 J=1.7 Hz, 1H), 7.72 d, J- 1.7 Hz, 1H), 6.78 J 1.7 Hz, 1H), 4.62 (in, 1H), 4.13 (q, Hz, 2H), 3.20 (br, s, 2H), 2.76 (mn, 2H), 1.23 J= 7.5 Hz, 3H).

Scheme 23N

N

HO 23-1 MnO 2 0H 2 01 2 OHC 0 H0 2 C CO 2 Et

NH

4 Ac, EtOH 0 N

H

2 N COE Furo[3,2-blnvridine-5-carboxaldehvde (23-2) A solution of alcohol 23-1 Hoffman, Jr., US Patent No.

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, CDCl3) 5 10.18 1H), 8.92 J= 1.8 Hz, 1H), 8.17 (d, J=1.7 Hz, IR) 7.89 J=1.8 Hz, 1H), 7.10 J=1.7 Hz, 1H).

3-Amino-3-(furor3.2-blnvridin-5-vl)-n~rouionic acid ethyl ester (23-3) A solution containing aldehyde 23-2 (1.5 g, 10 mmol), ethyl hydrogen malonate (1.6 g, 20 inmol), and ammonium acetate (3.8 g, 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 afforded the amino ester 23-3 as a waxy solid.

TLC Rf 0.5 (20% 20:1:1 EtOH/NH40HIH20 80% EtOAc) 1 H NMR (300 MHz, CD3OD) 5 8.58 J=1.7 Hz, 1H), 7.89 J=1.7 Hz, 1H),7.85( d, J- 1.7 Hz, 1H), 6.98 J 1.7 Hz, 1H), 4.62 J= 7.2 Hz, 1H), 4.09 J=7.5 Hz, 2H), 2.76 2H), 2.20 (br, s, 2H), 1.21 J= 7.5 Hz, 3H).

.0 Scheme 24

CO

2

H

BocHN -C O 2 Me 24-1

NH

2 NH2 24-2

EDC,HOAT

NMM, DMF

H

2

N

ONH

BocHN CO2 M e 24-3 1. HOAc, 2. HCI, EtOAc N NH H2N 4-4 24-4 131- WO 99/30709 WO 9930709PCTIUS98/26539 N-(S)-(2-Amino-uhenvl)-3-tert-butoxvcarbonvlamino-succinamic acid methyl ester (24-3) A mixture of Boc-L-aspartic acid-f3-methyl ester 24- 20.2 mmol), o-phenylenedianiine 24-2 (2.2 g, 20.2 mmol), EDC (3.9 g, 20.2 inmol), HOAT (0.28 g, 2.02 mmol), and NMM (6.7 mL, 60.7 nimol) 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.

TLC Rf 0.50 (95% CHCl3I5% isopropanol) 1 H NMR (300 M7Hz, CDCl3) 6 8.10 (br,s, 1H), 7.23 J= 7.8 Hz, 1H), 7.08 J=7.8 Hz, 1H1)6.78 (in, 1H),5.8 (br d, 1H1), 4.65 (in, 1 3.76 3H), 3.15 (dd, J=4.6, 16 Hz, 1H), 2.90 (dd, J= 5.1, 16 Hz, 1H), 1.48 9H).

3(S)-Amino-3-Benzimidazol-2-vl-rpropionic acid methyl ester (24-4) Ester 24-3 (1.0 g, 3 mmol) was dissolved in acetic acid niL) and heated to 65' for 2 h. The solvent was removed to afford the Bocprotected intermediate as a white solid. The crude material (920 mg, 2.43 mmol) was dissolved in EtOAc, cooled to 00, and treated with HCl gas to give 24-4 as a tan solid.

1H1 NMR (300 M7Hz, CD3OD) 5 7.80 (in, 211), 7.35 5.98 (in, 1H1), 3.80 (in, 2H), 3.76 3H).

132 WO 99/30709 PCTIUS98/26539 Scheme

OH

CO

2 H

HO

BocHN 25-1 NH 2

ONH

24-1 EDC,HOAT BocHN C02Me NMM, DMF 25-2 1. DEAD, Ph 3

P

THF

2. HCI, EtOAc p

N~/O

H2N ,CO2M 25-3 N-(S)-(2-Hdroxv-henvl)-3-tert-butoxvcarbonvlamino-succinamic acid methyl ester (25-2) A mixture of Boc-L-aspartic acid-p-methyl ester (24-1) 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 and chromatographed on silica (EtOAc) to afford 25-2 as a white solid.

TLC Rf= 0.55 (EtOAc)) 1 H NMR (300 MHz, CDC13) 6 7.23 J= 7.8 Hz, 1H), 6.89 J=7.8 Hz, 1H), 6.78 1H), 5.68 (br d, 1H), 4.65 1 3.76 3H), 3.15 (dd, J=4.6, 16 Hz, 1H), 2.90 (dd, J= 5.1, 16 Hz, 1H), 1.48 9H).

-133- WO 99/30709 PCT/US98/26539 3(S)-Amino-3-Benzoxazol-2-vl-propionic 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 and a solution of diethyl azodicarboxylate (1.53 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 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 and treated with HC1 gas to give 25-3 as a tan solid.

1 H NMR (300 MHz, CD30D) 5 7.81 2H), 7.40 5.05 J= 7.4 Hz, 1H), 3.72 3H), 3.30 2H).

SCHEME 26 ,CH ,CH3 N-NH N-N N-N CHl, K 2 C0 3 <3 C H3 C N

Y

Br Br H 2 N C 0 2 Et 26-1 26-2 26-3 1-Methvl-4-bromopyrazole (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.

1 H NMR (300 MHz, CDC13) 5 7.44(s, 1H),7.38 1H), 3.90 3H).

3 (S)-Amino-3-(1-methyl-lH-pvrazol-4-yl)-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.

1 H NMR (300 MHz, CD30D) 6 7.81 1H),7.58 1H),4.80 1H), 4.05 J= 7.0 Hz, 2 3.89 3H), 3.00 2 1.24 J 7.0 Hz, 3 H).

134- WO 99/30709 WO 9930709PCTIUS98/26539 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 f-alanine derivatives prepared according to the procedures depicted in Schemes 9-26 above. These examples can be prepared in high optical purity substituting intermediate 7-5 or its enantiomer for intermediate 3(S)-(6-Ethoxy-pyidin-3-yl)-3-(2-oxo-3-13-(5 ,6,7,8-tetraaydro- [1 ,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3(S)-(6-Amino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7 ,8-tetrahydro- [I1,8]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; 3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5 ,6,7 ,8-tetrahydro- 1, 8]naphthyridin-2-yl)-propyl-pyrroli din- 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; 3(S)-(2-Oxo-2 ,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3-(5 ,6,7 ,8-tetrahydro- 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- 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- 1, 8]naphthyridin-2 -yl)-propyl] -pyrroli din- 1 -yl)-p ropio nic acid; 3(S)-(5-Methoxy-pyrfidin-3-yl)-3-(2-oxo-3-[3-(5 7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 135 WO 99/30709 PTU9/63 PCTIUS98/26539 3(S)-(Ethynyl)-.3-(2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2yl).

propyl]-pyrrolidin- l-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)-propioriic acid; 3(S )-(2-Oxo-2,3-dihydro- 1H-4-oxa- 1,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3.

,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- ,6,7,8-tetrahydro-iI1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl)propionic acid; 3(S)-(2-Oxo-3 ,4-dihydro-2H- 1-oxa-4,5-diaza-naphthalen-7-yl)-3-(2-oxo-3-[3- ,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-[3- 7,8-tetrahydro- [1 ,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl)propionic acid; 3-(Furo-[2,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 ,6,7 ,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3-(2,3-Dihydrofuro[2,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 7,8-tetrahydro- [1 ,8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3-(Furo-[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; 3-(2,3-Dihydrofiiro[3,2-b]pyridin-6-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro- [l, 8 ]naphthyridin-2-yl)-propyl-pyrrolidin-1-yl)-propionic acid; 136 WO 99/30709 WO 9930709PCT/US98/26539 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; 1H-Jmidazo[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; 3 (S)-(Benzoxazol-2-yl)-3 -(2-oxo-3- [3 ,6,7,8-tetrahydro-[ 1, 8]naphthy-ri din- 2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 1-Methyl- 1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7 ,8-tetrahydro- 8]naphthyridfin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; and {2-Oxo-3-[3-(5 ,6,7,8-tetrahydro-[ 1,8lnaphthyridin-2-yl)-propyl]pyrrolidin- 1-yl}-pent-4-enoic acid.

137 WO 99/30709 PTU9/63 PCT/US98/26539 SCHEME A SYNTHESIS OF RADIOLIGAND FOR SPA ASSAY

H

2 N ~C 2

H

0 H NH 2 A-i .1 /SO 2

CI

NaOH, dioxane

H

2 0 A-2 1 2.

Br 2 NaOH,

H

2 0

HOI

138 WO 99/30709 WO 9930709PCTIUS98/26539 SCHEME A (CONTINUJED) H N C02H

HC

EtOH HCI.H 2 N2< 0 0 2H2CH3 A-4

CO

2

CH

2

CH

3

H

2 N

H

2 Pd/C 6N HOI 139 WO 99/30709 WO 9930709PCTIUS98/26539 SCHEME A (CONTINUED) A-6 HCI.H 2 NCO CH CH3 H' HNSO 2

C

6

H

4

I

EDO, HOBT, NMM, DMF A-7 6N HCI 6 000C

H

2

N'

A-B

140 WO 99/30709 WO 9930709PCT/US98/26539

(CH

3 Sn) 2 Pd(PPh 3 4 dioxane, 900 C 5 Sn (OH 3 3 N0H

AIIN

N-4-oo-hnv slonlmio)Lasaa2in A0' ToastredsluinofaidA.J 4.9gA3.-mo),N9 (141,3. mldoae(0m)adH0(0m)a 0 a de clrd(1.4g342mol.Afe-5insNH(14,3.

pr4ovd acid ylsuloai apr n solid.

To a stirred solution of aidA- g, 181. mmol) aH0 mlr t1 0 .3 as addd.B2 (1.30 mlAf24.9-5nmol)tesopwise(overa3ten 141- WO 99/30709 PCT/S98/26539 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°C and then added in a single portion to the reaction. After stirring for minutes at 0°C, the reaction was heated to 90°C for 30 minutes and then recooled to 0°C. The pH was adjusted to -7 by dropwise addition of concentrated 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) 5 8.02 2H, J=8Hz), 7.63 2H, J=8Hz), 4.36 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 1H).

Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-p-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°C for 10 minutes. The cooling bath was removed and the reaction was heated to 600C. After 18 h, the reaction was concentrated to provide ester A-4 as a white solid.

1 H NMR (300 MHz, CD30D) 8 7.98 2H, J=8Hz), 7.63 2H, J=8Hz), 4.25 1H, J=5Hz), 3.92 2H), 3.33 1H), 3.06 1H), 1.01 3H, J=7Hz).

Ethyl 4-[2-(2-Aminopyridin-6-vl)ethvllbenzoate A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 95/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, the reaction was filtered through a celite pad and then concentrated to provide ester as a brown oil.

TLC Rf 0.23 (silica, 40% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 8 7.95 2H, J=8Hz), 7.26 3H), 6.43 (d, 1H, J=7Hz), 6.35 1H, J=8Hz), 4.37 4H), 3.05 2H), 2.91 2H), 1.39 3H, J=7Hz).

4-[2-(2-Aminopvridin-6-vl)ethvllbenzoic acid hvdrochloride (A-6) A suspension of ester A-5a (625 mg, 2.31 mmol) in 6N HC1 (12 ml) was heated to 600C. After -20 h, the reaction was concentrated to give acid A-6 as a tan solid.

142- WO 99/30709 PTU9163 PCTIUS98/26539 1 H NMVR (300 MHz, CD3OD) 5 7.96 (d 2H, J=8Hz), 7.80 (in, 1H),'7.33 (d, 2H, J=8Hz), 6.84 1H, J=9Hz), 6.69 1H, J=7Hz), 3.09 (mn, 4H).

Ethyl 4-[2-(2-Aminopyridin-6-yl )ethyllbenzoyl-2(S)-(4-iodophenvlsulfonylainino)-D-alanine JAM7 A solution of acid 15- (400 ing, 1.43 mmnol), amine A-A (686 mng, 1.57 mmol), EDC (358 ing, 1.86 mmiol), HOBT (252 ing, 1.86 inmol), NIMM (632 1.1, 5.72 mmiol) in DMF (10 ml) was stirred for -20 h.

The reaction was diluted with EtOAc and then washed with sat.

NaHICO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc then 5% isopropanol/EtOAc) provided amnide A-7 as a white solid.

TLC Rf 0.4 (silica, 10% isopropanol/EtOAc) 1 H NMR (300 MHz, CD3OD) 5 7.79 2H, J=9Hz) 7.61 2H, J=8Hz), 7.52 (d 2H, J=9Hz), 7.29 (mn, 1H), 7.27 2H, J=8Hz), 4.20 (mn, 1H), 3.95 2H, J=7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (mn, 2H), 2.86 (mn, 2H), 1.08 3H, J=7Hz).

4 2 2 -Aminopyridin-6-yl)ethyllbenzoyl-2(S )-(4-iodophenylsulfonylamino )-f-alanine (A-8) A solution of ester A7 (200 mng, 0.32 13 mmol) and 6N HOl ml) was heated to 60'C. After -20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAcIEtOH/ NH4OHtH2O) provided acid A-8 as a white solid.

TLC Rf 0.45 (silica, 20:20:-1:1 EtOAcIEtOH/NH 4

OHIE{

2 0) 1 H NMR (400 MHz, DMSO) 8 8.40 (in, 1H1), 8.14 (Bs, 1H), 7.81 2H, J=8Hz), 7.62 2H, J=8Hz), 7.48 2H, J=8Hz), 7.27 (in, 3H), 6.34 1H, J=7Hz), 6.25 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (in, 2H), 2.97 (in, 2H), 2.79 (in, 2H).

4 2 -(2-Aminopyridin-6-yl )ethyl)benzoyl-2(S )-(4-trimethylstannylphenylsulfonlamino-o3-alanine (A-9) A solution of iodide A-8 (70 ing, 0.1178 mmol), [(CH3)3Sn]2 (49 41, 0.2356 minol), Pd(PPh3)4 (5 mng) and dioxane (7 ml) was heated to 143 WO 99/30709 PCT/US98/26539 0 C. After 2 h, the reaction was concentrated and then purified by preparative HPLC (Delta-Pak C18 15 iM 100A°, 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 NH40H (5 drops) and then lyophilized to provide amide A-9 as a white solid.

1H NMR (400 MHz, DMSO) 5 8.40 1H), 8.18 1H, J=8Hz), 7.67 (m, 7.56 2H, J=8Hz), 7.29 2H, J=8Hz), 6.95-7.52 2H), 6.45 (bs, 2H), 4.00 1H), 3.50 1H), 3.33 1H), 2.97 2H), 2.86 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4- 1 2 5 iodophenylsulfonvlamino-P-alanine An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na 1 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 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 NH40H 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 10% acetonitrile (TFA):H20 TFA) to 90% acetonitrile (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time of A-10 is 17 minutes under these conditions. Fractions containing the majority of the radioactivity were pooled, lyophilized and diluted with ethanol to give approximately 1 mCi of A-10, which coeluted on HPLC analysis with an 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 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 Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x 144- WO 99/30709 PCT/US98/26539 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/is Diode Array Spectrophotometer.

Sample radioactivities were determined in a Packard A5530 gamma counter.

The test procedures employed to measure cav33 and binding and the bone resorption inhibiting activity of the compounds of the present invention are described below.

BONE RESORPTION-PIT ASSAY When osteoclasts engage in bone resorption, they can cause the formation of pits in the surface of bone that they are acting upon.

Therefore, when testing compounds for their ability to inhibit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present.

Consecutive 200 micron thick cross sections from a 6 mm cylinder of bovine femur diaphysis are cut with a low speed diamond saw (Isomet, Beuler, Ltd., Lake Bluff, II). Bone slices are pooled, placed 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 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 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 ml. The tube is rocked gently by hand for 60 cycles, the tissue is sedimented for 1 min., and the supernatant is removed. Another 25 ml of medium is added to the tissue and rocked again. The second -145- WO 99/30709 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, nM 1,25(OH)2D3, and pencillin-streptomycin is prepared. 200 ml aliquots are added to bovine bone slices (200 mm x 6 mm) and incubated for 2 hrs. at 37°C in a humidified 5% 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 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 cacodylate, pH 7.4. After fixation, any remaining cellular debris is removed by 2 min. ultrasonication in the presence of 0.25 M NH4OH followed by 2 X 15 min ultrasonication in H20. The bone slices are immediately stained for 6-8 min with filtered 1% toluidine blue and 1% borax.

After the bone slices have dried, resorption pits are counted in test and control slices. Resorption pits are viewed in a Microphot Fx (Nikon) fluorescence microscope using a polarizing Nikon IGS filter cube. Test dosage results are compared with controls and resulting values are determined for each compound tested.

The appropriateness of extrapolating data from this assay to mammalian (including human) disease states is supported by the teaching found in Sato, et al., Journal of Bone and Mineral Research, Vol. 5, No. 1, pp.31-40, 1990, which is incorporated by reference herein in its entirety. This article teaches that certain bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay described above to confirm a 146- WO 99/30709 PCT/US98/26539 correlation between their known utility and positive performance in the assay.

EIB ASSAY Duong et al., J. Bone Miner. Res., 8: S378 (1993) describes a system for expressing the human integrin av33. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies against the integrin, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption.

Reaction Mixture: 1. 175 pl TBS buffer (50 mM Tris-HC1 pH 7.2, 150 mM NaC1, 1% BSA, 1 mM CaC12, 1 mM MgC12).

2. 25 pl cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 p1).

3. 1 2 5 I-echistatin (25 pl/50,000 cpm) (see EP 382 451).

4. 25 pl buffer (total binding) or unlabeled echistatin (nonspecific binding).

The reaction mixture was then incubated for 1 h at room temp. The unbound and the bound av(3 were separated by filtration using a Skatron Cell Harvester. The filters (prewet in 1.5% polyethyleneimine for 10 mins) were then washed with the wash buffer mM Tris HC1, 1mM CaC12/MgC12, pH The filter was then counted in a gamma counter.

SPA ASSAY

MATERIALS:

1. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem 147- WO 99/30709 PCT/US98/26539 4. NaCI: Fisher CaC12: Fisher 6. MgC12: SIGMA 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 8. Optiplate: PACKARD 9. Compound A-10 (specific activity 500-1000 Ci/mmole) test compound 11. Purified integrin receptor: avP3 was purified from 293 cells overexpressing avp3 (Duong et al., J. Bone Min. Res., 8:S378, 1993) according to Pytela (Methods in Enzymology, 144:475, 1987) 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCI, 1 mM Ca 2 +/Mg 2 0.5 mM PMSF 13. 50 mM octylglucoside in binding buffer: 50-OG buffer

PROCEDURE:

1. Pretreatment of SPA beads: 500 mg of lyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer.

2. Preparation of SPA beads and receptor mixture In each assay tube, 2.5 |i1 (40 mg/ml) of pretreated beads were suspended in 97.5 p1 of binding buffer and 20 p1 of buffer. 5 il (-30 ng/pl) of purified receptor was added to the beads in suspension with stirring at room temperature for minutes. The mixture was then centrifuged at 2,500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4 0 C. The pellets were then resuspended in 50 p1 of binding buffer and Cl of 50-OG buffer.

148- WO 99/30709 PCT/US98/26539 3. Reaction The following were sequentially added into Optiplate in corresponding wells: Receptor/beads mixture (75 ml) (ii) 25 pl of each of the following: compound to be tested, binding buffer for total binding or A-8 for non-specific binding (final concentration 1 pM) (iii) A-10 in binding buffer (25 41, final concentration 40 pM) (iv) Binding buffer (125 p.1) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C 4. Plates were counted using PACKARD TOPCOUNT inhibition was calculated as follows: A total counts B nonspecific counts C sample counts inhibition x 100 OCFORM ASSAY Osteoblast-like cells (1.8 cells), originally derived from mouse calvaria, were plated in CORNING 24 well tissue culture plates in acMEM medium containing ribo- and deoxyribonucleosides, 10% fetal bovine serum and penicillin-streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows: Mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syringe with a 27.5 gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 pm nylon cell strainer. The resulting suspension was centrifuged at 350 x g for seven minutes. The pellet was 149- WO 99/30709 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 LL was added to each well of 1.8 cells to yield 50,000 cells/well and 1, 2 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% C02 atmosphere.

After 48 h, the medium was changed. 72 h after the addition of bone marrow, test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with fresh medium containing D3. After an additional 48 the medium was removed, cells were fixed with 10% formaldehyde in phosphatebuffered saline for 10 minutes at room temperature, followed by a 1-2 minute treatmefit with ethanol:acetone and air dried. The cells were then stained for tartrate resistant acid phosphatase as follows: The cells were stained for 10-15 minutes at room temperature with 50 mM acetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dried. The number of multinucleated, positive staining cells was counted in each well.

ATTACHMENT ASSAY Duong et al., J. Bone Miner. Res., 11: S290 (1996), describes 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.

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 150- WO 99/30709 PCT/US98/26539 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods: 1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4°C with human vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH using 100 al/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 DPBS, plates were used for cell attachment assay.

2. 293 (av35) cells were grown in MEM media in presence of fetal calf serum to 90% confluence. Cells were then lifted from dishes with 1X Trypsin/EDTA and washed 3X with serum free MEM. Cells were resuspended in attachment medium (3 X 105 cells/ml).

3. Test compounds were prepared as a series of dilutions at 2X concentrations and added as 50 al/well. Cell suspension was then added as 50 al/well. Plates were incubated at 37°C with 55 C02 for 1 hour to allow attachment.

4. Non-adherent cells were removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase substrate solution (100 al/well), overnight at room temperature in the dark. To quantitate cell numbers, standard curve of glucosaminidase activity was determined for each experiment by adding samples of cell suspension directly to wells containing the enzyme substrate solution.

The next day, the reaction was developed by addition of 185 al/well of glycine/EDTA solution and reading absorbance at 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.

151- WO 99/30709 PCTIUS98/26539 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 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 av33 integrin. These compounds are generally found to have IC50 values less than about 100 nM in the SPA assay.

Representative compounds of the present invention were tested and generally found to inhibit 50% the attachment of expressing cells-to plates coated with vitronectin at concentrations of about 1 p.M.

While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

-152-

Claims (5)

1. A compound 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 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, and a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 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 substituents; X is selected from the group consisting of wherein any methylene (CH2) carbon atom is either 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 S-153- -153- AMENDED SHEET WO 99/30709 WO 9930709PCTIUS98/26539 unsubstituted or substituted with one RI 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 -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, -(CH2)m-S02-(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 -(CH2)m-S-(CH2)n-S-(CH2)p -(CH2)m-NIR 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 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 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 tbio substituents, and either unsubstituted or substituted with one or more substituents independently selected from the group consisting of R1 0 R 1 1 and R 1 2 wherein Rland R 2 are each independently selected from the group consisting of hydrogen, halogen, Gi..io alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-.8 cycloalkyl C1-6 alkyl, 154 WO 99/30709 WO 9930709PCT/US98/26539 C3-.8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1..8 alkyl, amino, amino C1-.8 alkyl, C1..3 acylamino, C1..3 acylamino Cl..8 alkyl, (C 1-6 alkyl)pamino, (CI- 6 alkyl)painino C1-.8 alkyl, Cl..4 alkoxy, C1..4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C 1-6 alkyl, C1..3 alkoxycarbonyl, C1-.3 alkoxycarbonyl C1..6 alkyl, hydroxycarbonyl- Cl..6 alkyloxy, hydroxy, hydroxy C 1-6 alkyl, C1..6 alkyloxy- Cl..6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1..8 alkyl-S(O)p, (Cl..8 alkyl)paminocarbonyl, C 1-8 alkyloxycarbonylamino, (C 1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-.8 alkylsulfonylamino, and C1..8 alkylsulfonylamino; or two Rl'substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, aryl, Ci..iQ alkyl, aryl-(CH2)r-O-(CH2 aryl-(CH2)rS(O )p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, arylb(CH2+rC(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(CH2)r-N(R 4 halogen, hydroxyl, oxo, trifluoromethyl, C1-8 alkylcarbonylamino, aryl C1.5 alkoxy, C 1-5 alkoxycarbonyl, (C1..8 alkyl)paminocarbonyl, 155 WO 99/30709 WO 9930709PCTIUS98/26539 C 1-6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1-6 alkyl)pamino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5~ alkylaminocarbonyl, aminocarbonyl, aminocarbonyl CI..6 alkyl, hydroxycarb onyl, hydroxycarbonyl Cl.6 alkyl, HC=-C-(CH2ht-, C3..7 calky-C-=C-(CH2)t-, C3-7 cyclyalry1-C=-C-(CH2)t-, arC=C-(CH2)t-, ~C 1-6 alkyla-C=C-(CH2)t-, C3..7CycoakCH =CH(GH)t- CIalyl-CH=CH-(CH2)t-, Cl. 6 alkylaryl-CH=CH-(CH2)t-, Cl..6 alkyl-S02-(CH2)t-, C1..6 alkylarY1-SO2-(GH2)t-, Cl..6 alkoxy, aryl Cl- 6 alkoxy, aryl Cl.6 alkyl, (C 1 6 alkyl)pamino Cl-6 alkyl, (aryl)pamino, (aryl)pamino Cl-6 alkyl, (aryl C1..6 alkyl)pamino, (aryl Cl..6 alkyl)pamino Cl..6 alkyl, arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy, (C 1-6 alkylbpaminocarbonyloxy, C1..8 alkylsulfonylamino, 156 WO 99/30709 WO 9930709PCT/US98/26539 arylsulfonylamino, 01-8 alkyllsulfonylaniino 01-6 alkyl, arylsulfonylamnino Cl-6 alkyl, aryl 01-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino 01-6 alkyl, 01-8 alkoxycarbonylanaino, 01-8 alkoxycarbonyl-amino 01-8 alkyl, aryloxycarbonylamino 01-8 alkyl, aryl 01-8 alkoxycarbonylamino, aryl 01-8 alkoxycarbonyllamino 01-8 alkyl, 01-8 alkylcarbonylamino, 01-8 alkylcarbonylainino 01-6 alkyl, arylcarbonylamino 01-6 alkyl, aryl 01-6 alkylcarbonylamino, aryl 01-6 alkylcarbonylamino 01-6 alkyl, ainnocarbonylamino 01-6 alkyl, (01-8 alkyl)paminocarbonylamino, (01-8 alkyl)paminocarbonylamino 01-6 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, (aryl 01-8 alkyl)paminocarbonylamino, (aryl 01-8 alkyl)pamiinocarbonylamino 01-6 alkyl, anainosulfonylaniino 01-6 alkyl, (01-8 alkyl)paminosuilfonylamino, (01-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino 01-6 ailkyl, (aryl 01-8 alkyl)paminosulfonylamino, (aryl 01-8 alkyl)paminosulfonylamino 01-6 alkyl, 01-6 alkylsulfonyl, 01-6 alkylsulfonyl 01-6 alkyl, arylsulfonyl 01-6 alkyl, aryl 01-6 alkylsulfonyl, aryl 01-6 alkylsulfonyl 01-6 alkyl, 01-6 alkyilcarbonyl, 01-6 alkylcarbonyl Clp6 alkyl, arylcarbonyl 01-6 alkyl, 157 WO 99/30709 WO 9930709PCTIUS98/26539 aryl C1-6 alkylcarbonyl, aryl C1..6 alkylcarbonyl C1-6 alkyl, C 1-6 alkylthiocarbonylamino, CJI.6 alkylthiocarbonylamino C1..6 alkyl, aryithiocarbonylamino C1..6 alkyl, aryl C1..6 alkylthiocarbonylamino, aryl C1..6 alkyithiocarbonylainino C1..6 alkyl, (C 1-8 alkylUpaminocarbonyl Cl..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 togbther with the carbon atom to which they are attached to form a carbonyl 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 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, aryl, aminocarbonyl, C3-8 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, (aryl C1..5 alkyl)paminocarbonyl, hydroxycarbonyl C1-6 alkyl, 01-8 alkyl, arY CI.6 alkYl, (Cl- 6 alkyl)pamino C2-.6 alkyl, (aryl C1-6 alkyl)pamino C2-6 alkyl, C1-.8 alkylsulfonyl, 158 WO 99/30709 WO 9930709PCTIIJS98/26539 C 1-8 alkoxycarbonyl, aryloxycarbonyl, aryl Cl..8 alkoxycarbonyl, C1-.8 alkylc arbonyl, arylcarbonyl, aryl C1..6 alkylcarbonyl, (C 1-8 alkyl)paminocarbonyl, amino sulfonyl, C1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C 1-8 alkyl)paniinosulfonyl, arylsulfonyl, arylCl-6 bikylsulfonyl, C1-.6 alkyithiocarbonyl, aryithiocarbonyl, and aryl C1-6 alkyithiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R 1 substituents; R5 and R6 are each independently selected from the group consisting of hydrogen, Ci..iO alkyl, aryl, aryl-(CH2)r-O-(CH2 ayl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)r-N(R)-C(O aryl-(CH2)r-N(R 4 halogen, hydroxyl, C 1-8 alkylcarbonylamino, aryl C1-5 alkoxy, alkoxycarbonyl, 159 WO 99/30709 WO 9930709PCT/US98/26539 (C 1-8 alkyl)panainocarbonyl, C 1-6 alkylcarbonyloxy, C3-.8 cycloalkyl, (Cl>6 alkyl)paxnino, amino C1-6 alkyl, arylaminocarbonyl, aryl C1-5~ alkylaminocarbonyl, amin ocarbonyl, anainocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1.6 alkyl, C 1-6 alkyl-CE=C-(CH2)t-, C3-7 cycloalkyl-C=EC-(CH2)t-, aryl-C-=C-(CH2)t-, 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-, ar-yl-CH=CH-(CH2)t-, Cl-6 alkylaryl-CH=GH-(CH2)t-, Clp6 alkyl-S02-(CH2)t-, Cl..6 alkylaryl-S02-(CH2)t-, Cl..6 alkoxy, aryl C1..6 alkoxy, aryl C1..6 alkyl, (Cl.6 alkyl)pamino Cl-6 alkyl, (aryl)pamino, (aryl)pamnino C1-6 alkyl, (aryl Cl-6 alkyl)pamino, (aryl Cl..6 alkyl)pamino C1..6 alkyl, arylcarbonyloxy, aryl Cl..6 alkylcarbonyloxy, (C 1 6 alkyl)paminocarbonyloxy, 160 WO 99/30709 WO 9930709PCTIUS98/26539 Cl.8 alIkylsulfonylamino, arylsulfonylamino, Cl.8 alkylsulfonylainino Cl..6 alkyl, arylsulfonylarnino Cp-6 alkyl, aryl C1..6 alkylsulfonylamino, aryl Cl..6 alkylsulfonylamino Cl.6 alkyl, C 1-8 alkoxycarbonylamino, Cl.8 alkoxycarbonylamino Cl.8 alkyl, aryloxycarbonylamino C1..8 alkyl, aryl Cl..8 alkoxycarbonylamino, aryl Cl.8 alkoxycarbonylamino Cl..8 alkyl, C 1-8 alkylearbonylamino, Cl..8 alkykcarbonylamino Cl..6 alkyl, arylcarbonylainino Cl-6 alkyl, aryl C1..6 alkylcarbonylamino, aryl Cl..6 alkylcarbonylaniino Cl.6 alkyl, aminocarbonylamino Cl..6 alkyl, (C1..8 alkyl)paminocarbonylamino, (C1..8 alkyl)paminocarbonylamino Cl.6 alkyl, (aryl )paininocarbonylamino C 1-6 alkyl, (aryl Cl..8 alkyl)p aminocarbonyl amino, (aryl Cl..8 alkyl)paminocarbonylamino Cl..6 alkyl, anainosulfonyhlamino C1-6 alkyl, (CI.. 8 alkyl)paminosulfonylamino, (C1..8 alkyl)parninosulfonylamino 'Cl.6 alkyl, (aryl)paminosulfonylamino C1-.6 alkyl, (aryl Cl..8 alkyl)paminosulfonylamino, (aryl C1-.8 alkyl)paminosulfonylamino C1..6 alkyl, Cl..6 alkylsuflfonyl, Cl..6 alkylsulfonyl Cl..6 alkyl, arylsulfonyl C1.6 alkyl, aryl C1..6 alkylsulfonyl, aryl C1..6 alkylsulfonyl Cl..6 alkyl, C1..6 alkylcarbonyl, 161 WO 99/30709 PCT/US98/26539 01-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, 01-6 alkyithiocarbonylamino, C1.6 alkylthiocarbonylanino C1-6 alkyl, aryithiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, (01-8 alkyl)paminocarbonyl 01-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1-8 alkyl)paminocarbonyl, and (aryl Cl-g alkyl)paminocarbonyl C1-6 alkyl; or R5 and R 6 are taken together with the carbon atom to which they are attached to form an oxo group, wherein any of the alkyl groups of R 5 or R6 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 attached to no more than one heteroatom; R 7 and R8 are each independently selected from the group consisting of hydrogen, 01.10 alkyl, aryl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH2)rS(O)p-(CH2)s-, aryl-(CH2)r-0(O)-(CH2)s-, aryl-(CH2)r-(O)-N(R 4 aryl-(CH2)r-N(R 4 aryl-(CH2)r-N(R 4 halogen, hydroxyl, C1-8 alkylcarbonylamino, -162- WO 99/30709 PCT/US98/26539 aryl Cj.. 5 alkoxy, alkoxycarbonyl, (C 1-8 alkyl)paminocarbonyl, C1..6 alkylcarbonyloxy, C3-8 cycloalkyl, (C 1 6 alkyl)pamino, amino Cl..6 ailkyl, arylaminocarb onyl, aryl CI..5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1..6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl.6 al~kyl, Cl..6 alkyl-C=-C-(CH2)t-, C3-.7 cycloalky-C=-C-(CH2)t-, arCH=H-(CH2)t-, Cl.6 alkyla-C=C-(CH2t., CC3.ccoy-H =CH(C2 t- CI6arlkH=CH=CH)t.., t- C1..6 alkylaryl-GH=GH-(GH2)t., Cl.6 alkyl-S02-(CH2)t-., Cl..6 alkylaryl-S02-(CH2)t-, C1..6 alkoxy, aryl Cl..6 alkoxy, aryl Cl..6 alkyl, (C 1 6 alkyl)pamino C1..6 alkyl, (aryl)pamino, (aryl)pamino C1..6 ailkyl, (aryl C1..6 alkyl)pamino, (aryl Cl1-6 alkyl)pamino C 1-6 ailkyl, arylcarbonyloxy, 163 WO 99/30709 PCTIUS98/26539 aryl Cl.6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C1..8 alkylsulfonylainino, arylcarbonylamino, arylsulfonylamino, Cl.8 alkylsulfonylamino C1..6 alkyl, arylsulfonylamino C1-6 alkyl, aryl Cl..6 alkylsulfonylamino, aryl Cl..6 alkylsulfonylamino Cl-.6 alkyl, Cl..8 alkoxycarbonylamino, Cl.8 alkoxycarbonylanaino Ci..8 alkyl, zirylloxycarbonylamino Cl.8 alkyl, aryl C1.8 -alkoxycarbonylamino, aryl Ci..8 alkoxycarbonylamino Cl..8 alkyl, C1..8 alkylcarbonylanaino Cl..6 alkyl, arylcarbonylainino C 1-6 alkyl, aryl Cl16 alkylcarbonylam-ino, aryl C1..6 alkylcarbonylamino Cl..6 alkyl, aminocarbonylamino C1..6 alkyl, arylaminocarbonylamino, (C 1-8 alkyll)paminocarbonylamino, (C1..8 alkyl)parninocarbonylamino Cl..6 alkyl, (aryl)panainocarbonylamino C 1-6 alkyl, (aryl Ci.. 8 alkyl)paminocarbonylamino, (aryl C1-.8 alkyl)paminocarbonylamino Cl1-6 alkyl, aminosulfonylamino Cl..6 alkyl, (Cr. 8 alkyl)paminosulfonylamino, (CI1-8 alkyl )paminosulfonylamino C 1-6 alkyl, (aryl)paininosulfonylamino C1..6 alkyl, (aryl C1..8 alkyl)paminosulfonylamino, (aryl C1..8 alkyl)paminosulfonylamino Cl.6 alkyl, C1..6 alkylsulfonyl, Cl..6 alkylsulfonyl C1..6 alkyl, arylsulfonyl C1..6 alkyl, 164 WO 99/30709 PCT/US98/26539 aryl C1..6 alkylsulfonyl, aryl Cl..6 alkylsulfonyl C 1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1..6 alkyl, arylcarbonyl C1-6 alkyl, aryl CI-6 alkylcarbonyl, aryl C1..6 alkylcarbonyl C1..6 alkyl, C1-6 alkyithiocarbonylamino, C1-6 alkyithiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1..6 alkyl, aryl C1..6 alkyithiocarbonylarnino, aryl C1..6 alkylthiocarbonylanaino Cl..6 alkyl, (C1r8 alkyl)paminocarbonyl C1..6 alkyl, (aryl)paniinocarbonyl C1..6 alkyl, (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 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 hetero atom; R 9 is selected from the group consisting of hydrogen, Cl-8 alkyl, aryl, aryl C1..8 alkyl, C 1 8 alkylcarbonyloxy C1.. 4 alkyl, aryl C 1-8 alkylcarbonyloxy C 1-4 alkyl, Cl..8 alkylaminocarbonylmethylene, and C1 -8 dialkylaminocarbonylmethylene; 165 WO 99/30709 PCT/US98/26539 R11, and Ri 2 are each independently selected from the group consisting of hydrogen, C1-. 8 alkyl, aryl, halogen, hydroxyl, oxo, aminocarbonyl, C3- 8 cycloalkyl, amino C1..6 alkyl, (aryl)paminocarbonyl, hydroxycarb onyl, (aryl Ci..5 alkyl)paminocarbonyl, hydroxycarbonyl C1..6 alkyl, aryl C1..6 alkyl, (Gi..6 alkyl)pamino C1.-6 alkyl, (aryl C1..6 alkyl pamino C2-.6 alkyl, C 1-8 alkylsulfonyl, C1..8 alkoxycarbonyl, aryloxycarbonyl, aryl Ci1.8 alkoxycarbonyl, Ci..8 alkylcarbonyl, arylcarbonyl, aryl. Ci..6 alkylcarbonyl, (C1i8 alkyl)paminocarbonyl, aminosulfonyl, C 1-8 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1..8 alkyl)paminosulfonyl, Cl..6 alkylsulfonyl, arylsulfonyl, aryl Ci1.6 alkylsulfonyl, aryl C1..6 alkylcarbonyl, 166 WO 99/30709 PTU9163 PCT/US98/26539 C1-6 alkylthiocarbonyl, aryithiocarbonyl, aryl Cl..6 alkyithiocarbonyl, aryl-(GH2)r-O..(CH2)s., ar-yl-(CH2).S(O)p..(CH2)s., aryl-(GH2)r-C(O).(CH2)s., aryl-(CBI2)r-N(R)-(O aryl-(CH2)r-N(R 4 CH2)s-, HCE=C-(CH2h.., C 1-6 alkyl-C=C-(CH2)t-, C3-.7 cycloalkyl-C=C-(CH2)t-, aryl-C=C-(CH2)t-, Cl.6 alkylaryl-C=C-(CH2)t-, 205 Cl.. akylS-(CH2)t-, 01.6 alkyla-S02C-(GH2)t-, C3-78 cyalkarylaminoCH2t- aryl CH=CH 5 (alkoxy, 01-5 alkoyarbyl=H(H)- (Cl..8 alkYl-Sam2n(C2bot-, C1..6 alkylcarbyloxyCHt, (C-6 alkylcabyamino, arC16alkoxy, alkoxyro, (Clarlkypamminooy (arlpao1-6 alkyleabnlx, (arCl6 alkyl)pamino, (arylpmn 016 l-aiiC6 alkyl, 167 WO 99/30709 WO 9930709PCTIUJS98/26539 arylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, (C 1-6 alkyl)paminocarbonyloxy, C1-8 alkylsulfonylamino, arylsulfonylamino, 0>-8 alkylsulfonylamino Cl-6 alkyl, arylsulfonylamino 01-6 alkyl, aryl C>-6 alkylsulfonylamino, aryl 01-6 alkylsulfonylamino 01-6 alkyl, 01-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino 01-8 alkyl, aryloxycarbonylamino 01-8 alkyl, aryl C1-8 *alkoxycarbonylamino, aryl 01-8 alkoxycarbonylamino 01-8 alkyl, 01-8 alkylcarbonylamino, 01-8 alkylcarbonylamino 01-6 alkyl, arylcarbonylamino 01-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl 01-6 alkylcarbonylamino 01-6 alkyl, aminocarbonylamino 01-6 alkyl, (01-8 alkyl)paininocarbonylarnino, (01-8 alkyl~paminocarbonylamino 01-6 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, (aryl 01-8 alkyl)paminocarbonylamino, (aryl 01-8 alkyl)paminocarbonylamino 01-6 alkyl, aniinosulfonylaxnino 01-6 alkyl, (Ci-g alkyl)paminosulfonylamino, (01-8 alkyl)paminosulfonylamino 01-6 alkyl, (aryl)paminosulfonylamino 01-6 alkyl, (aryl 01-8 alkyl)paminosulfonylamino, (aryl 01-8 alkyl)paminosulfonylanmino 01-6 alkyl, 01-6 alkylsuflfonyl, 01-6 alkylsulfonyl 01-6 alkyl, arylsulfonyl 01-6 alkylI, aryl 01-6 alkylsuli'onyl, 168 WO 99/30709 WO 9930709PCTIUS98/26539 aryl C1..6 alkylsulfonyl C1..6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl 01-6 alkyl, arylcarbonyl C1..6 alkyl, aryl C1..6 alkylcarbonyl, aryl C1..6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, Cl1.6 alkyltluocarbonyla min o 01-6 alkyl, arylthiocarbonylamino C 1-6 alkyl, aryl C1..6 alkylthiocarbonylamino, aryl C1..6 alkylthiocarbonylamino C1..6 alkyl, (01-8 alkyl)paminocarbonyl C1..6 alkyl, (aryl)paminocarbonyl 01-6 alkyl, (aryl C1-.8 alkyl)paininocarbonyl, and (aryl. C1-8 alkyl)paminocarbonyl C1..6 alkyl; wherein any of the alkyl groups of R 10 R 11 and R 12 are either unsubstituted or substituted with one to three R 1 substituents; 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; eac h 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; and the pharmaceutically acceptable salts thereof. 169 WO 99/30709 PCT/US98/26539

2. The compound of Claim 1 wherein W is a 6-membered monocyclic aromatic ring system having 1 or 2 nitrogen atoms wherein each ring carbon atom is unsubstituted or substituted with one R1 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, 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 1 R" R 12 N N0 R H N,R 1 1 NI and R 12

170- WO 99/30709 PCT/US98/26539 3. The compound of Claim2 wherein W the group consisting of R1 R 1 N N H N H H is selected from N R' NN H and and Z is selected from the group consisting of 7 X/ N N0 and 4. The compound of Claim 3 wherein W is N or H X is wherein any methylene (CH2) carbon atom is either unsubstituted or substituted with one or two R 1 substitutents; -171 WO 99/30709 PTU9/63 PCTIUS98/26539 Y is selected from the group consisting of -(CH2)m-, -(CH2)m-O-(CH2)n-, -(CH2)m-bNR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(CH2)m-SO-(CH2)n-, -(CH2)m-S02-(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 and -(CH2)m-NIR 4 -(CH2)n-O-(CH2)p-, wherein any carbon atom in Y, other than in R 4 can be substituted by one or two R 3 substituents; and Z is or 0 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, 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 WO 99/30709 WO 9930709PCTI!JS98/26539 6. The compound of Claim 5 wherein each R 3 is independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl, aryl, C1-8 alkYl, arylCl..6 alkyl hydroxyl, oxo, arylaminocarb onyl, aryl C1..5 alkylaminocarbonyl, aminocarbonyl, and anainocarbonyl C 1-6 alkyl; and each R 4 is independently selected from the group consisting of hydrogen, aryl, C3-8 cycloalkyl, C1-8 alkyl, C.1-.8 alkylcarbonyl, arylcarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, arylCl>6alkylsulfonyl, arylC 1-6alkylcarbonyl, C 1-8alkylaminocarbonyl, arylC arylCl..8alkoxycarbonyl, and CI-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 WO 99/30709 WO 9930709PCT/US98/26539 aryl, CI-8 alkyl, aryl C 1-6 alkyl, CH2=CH-(CH2ht-, and 8. The compound of Claim 7 wherein R 9 is selected from the group consisting of hydrogen, methyl, and ethyl. 9. The compound of Claim 8 wherein R 9 is hydrogen. -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 hydrogen, aryl, C 1-8 alkylcarbonylarnino, C1-8s alkylsulfonylamino, arylcarbonyl amino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, 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, aryl C1-8 alkoxycarbonylamino, ary] C1-8 alkoxycarbonylamino C1..8 alkyl, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1..6 alkylcarbonylaino C1..6 alkyl, ainocarbonylamino C1-6 alkyl, (C1-8 alkyl)paxninocarbonylamino,

174- WO 99/30709 WO 9930709PCT/US98/26539 (C1..8 alkyl)paminocarbonylaniino C1-6 alkyl, (aryl)paminocarbonylamino C 1-6 alkyl, aryl amino carbonylamino, (aryl C 1 8 alkyihpaminocarbonylamino, (aryl C1-8. alkyl)paminocarbonylamino 01-6 alkyl, aminosulfonyl amino C1..6 alkyl, (01.8 alkyl)paminosulfonylamino, (C1..8 alkyl)paminosulfonylamino C1..6 alkyl, (aryl )pamino sulfonylamino C 1-6 alkyl, (aryl 01.8 alkyl)paminosulfonylamino, (aryl C1..8 alkylbpaminosulfonylamino Cl..6 alkyl, C 1-6 alkylthiocarbonylamino, C 1-6 alkyltbiocarbonylamino C 1-6 alkyl, arylthiocarbonylamino 01-6 alkyl, aryl CI..6 alkyltbiocarbonylamino, and aryl. C1..6 alkyithiocarbonylainino 01.6 alkyl. 11. The compound of Claim 10 wherein R 7 is selected from the group consisting of hydrogen, aryl, C1..8 alkyilcarbonylamino, aryl CJ..6 alkylcarbonylamino, aryilcarbonylamino, C1..8 alkylsulfonylamino, aryl 01.6 alkylsulfonylamino, arylsulfonylamino, 01-8 alkoxycarbonylainino, aryl C1-.8 alkoxycarbonylamino, arylaminocarbonylamino, (01-8 alkyl)panainocarbonylamino, (aryl 01-8 alkyl)paxninocarbonylamino, (01-8 alkyl)paminosulfonylamino, and (aryl C1..8 alkyl )paminosulfonylamino. 175 WO 99/30709 WO 9930709PCT/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 hydrogen. 14. The compound of Claim 6 selected from the group consisting of Ethyl 3(S)-(3-fluorophenyl)-3-[2-oxo-3(S)-[3-(5 ,6,7,8-tetrahydro. 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-. 8]naphthyidin-2-yl )-propyl]-pyrrolidin- 1-yl]-propionate; Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl tetrahydro-[ 1,8lnaphthyridin-2 -yl)-propyl]-pyrrolidin- 1-yl)-propionate; Ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl tetrahydro-[ 1,8]naphthyridin-2-yl )-propyl]-pyrrolidin- l-yl )-propionate; Ethyl 3(S)-(quinolin-3-yl)-3-(2-oxo-3(R)-[3-(5 ,6,7,8-tetrahydro- 1, 8]naphthyri din- 2-yl)-propyl] -pyrroli din- 1 -yl )-propionate; Ethyl 3(S)-(quinolin-3-yl)-3-(2-oxo-3(S)-[3-(5,6,7,8-tetrahydro. 8]naphthyridin-2-yl)-propyl]-pyrrolidin- 1-yl)-propionate; 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5 ,6,7,8-tetrahydro- Il, 8]naphthyidin-2-yl )-propyl]-pyrrolidin- 1-yl]-propioni c acid; 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5 ,6,7 ,8-tetrahydro- [1,8llnaphthyidin-2-yl)-propyl]-pyrrolidin- 1-yl]-propionic acid; 176 WO 99/30709 WO 9930709PCT/US98/26539 *3(S)-(2,3-Dihydlro-benzofuran-6-y)-3-(2-oxo3(R)-[3.(5 7,8-tetrahydro- [1,8]naphthyridin-2-y1)-propyl]-pyrrohidin- 1-yl)-propionic acid; 3(S)-(2,3-Dihydro-benzof'uran-6-yl)-3-(2-oxo.3(S)-[3.(5 ,6,7 ,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrroli din-i -yl)-propionic acid; 3(S)-(Quinolin-3-ylD-3-(2-oxo-3(R)-[3-(5 7,8-tetrahydro-[ 1,8llnaphthyridin- 2-yl)-propyl]-pyrrolidin- 1-yl)-propionic acid; 3 (S)-(Quinolin-3-yl)-3-(2-oxo(S)-3-[3-(5,6,7,8tetrahydro.{1,8]naphthyiin. 2-yl)-propyl]-pyrrolidin- i-yl)-propionic acid; 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- ,6,7,8-tetrahydro- 1, 8]naphthyridin-2 -yl)-propyl]-pyrroli din- Il-yl )-propi onic acid; 3 6 -Aniino-pyridin-3-yl)-3-(2-oxo-3-[3-(5,6,7,8-tetrahydro. 1, 8]naphthyridin-2 propyl] -pyrroli din- 1 -yl)-propioric acid; 3(S)-(4-Methyl-3-oxo-3 ,4-dihydro-2H-benzo[1 ,4]oxazin-7-yl)-3-(2-oxo-34[3- ,6,7,8-tetrahydro-[1,8]naphthyridin- 2 -yl )-propyl]-pyrrolidin- l-yl propionic acid; 3-(6-Methylamino-pyridin-3-yl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propyll-pyrrolidin- 1-yl)-propionic acid; 3(S)-(2-Fluoro-biphenyl-4-yl)-3-(2-oxo-3- ,6,7 ,8-tetrahydro- 1,8]naphthyridin-2-yl)-propyl]-pyrroli din- 1i-yl )-propionic acid; 3(S )-(2-Oxo-2 ,3-dihydro-benzoxazol-6-yl)-3-(2-oxo-3-[3.(5 7,8-tetrahydro- 1,8]naphthyridin-2-yl)-propyl]-pyrroli din-i1 -yl)-propionic acid; 177 WO 99/30709 WO 9930709PCT/US98/26539 3(S)-(4-Ethoxy-3-fluorophenyl)-3-(2.oxo-3-[3(5 ,6,7 ,8-tetrahydro- 1, 8]naphthyri din-2 -yl)-propyl] -pyrroli din-. 1 -yl )-propioni c acid; 3(S)-(5-Ethoxy-pyridin-3-yl)-3-(2-oxo-3-3(5 ,6,7,8-tetrahydro- 8 ]naphthyridin-2-yl)-propyl]-pyrrolidin-. -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]-pyrroli din- l-yl )-propionic acid; 3(S)-(Ethynyl)-3-(2-oxo-3-[3-(5,6, 7,8-tetrahydro-[1,8]naphthyridin-2-yl)- propyll -pyrrolidin- 1 -yl)-propionic acid; 3(S)-(6-Methoxy--pyridin-3-yl)-3-(2-oxo-3.[3.(s,6,7 ,8-tetrahydro- 1, 8 ]naphthyridin-2 propyll-pyrroh din-. 1 -yl)-propionic acid; 3(S)-(2-Oxo-2,3-dihydro-1HA..oxa-. ,5-diaza-naphthalen-7-yl)-3-(2-oxo.3-43 (5,6,7 ,8 -tetrahydro- 1, ,Snaphthyri din- 2-yD)-propyl)-pyrrolidin. 1 -yl propionic acid; 3(S)-(2,3-Dihydlro- 1H-4-oxa- 1,5-diaza-naphthalen-7-yl (5,6,7 ,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl]-pyrrolidin-. -yl)- propionic acid; 3 2 -Oxo-3,4-dihydro-2H-1-oxa-4,5-diazanaphthlen7y)3(2oxo3[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-naphthaen-7-y)-3(2oxo-a.3[. 7,8-tetrahydro-[ 1,8]naphthyridin-2-yl)-propyl-pyrrolidin-. -yl propionic acid; 3 -(Furo-[2,3-blpyridin-6-yl)-3-(2-oxo-3-[3-(5 7,8-tetrahydro- 1, 8]naphthyri din- 2-yl )-propyl] -pyrroli din- 1 -yl)-propioruic acid; 178 WO 99/30709 WO 9930709PCTIUS98/26539 3-(2,3-Dihydrofuro[2,3-bpyridin-6-yl)-3-(2-oxo3[3(567,8-tetrayro. [1,8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl)-propionic acid; 3-(Furo-[3 ,2-blpyridin-6-yl ,6,7 ,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-pyrrolidin- l-yl )-propionic acid; 3-(2,3-Dihydrofo[3,2-bpyridin-6-yl)3-(2oxo-3-.[3-(s,6,7,8-tetrahydro- 1,8]naphthyridin-2-yl)-propyl]-pyrroli din- 1l-yl )-propionic acid; 3(S)-(Benzimidazol-2-yl)-3-(2-oxo-3-[3-(5 ,6 ,7,8-tetrahydro- 1,8]naphthyriclin-2-yl)-propyl]-pyrroli din-i1 -yl)-propiornic acid; lH-Imidazo[4,5-clpyridin-2-yl)-3-(2-oxo-3-[3-(5,6,7,8..tetrahydro. 1,8]naphthyridin-2 -yl)-propyl]-pyrroli din- 1-yl)-propionic acid; 3(S)-(Benzoxazol-2-yl)- 3-(2-oxo-3- [3 ,6 ,7,8-tetrahydro-[1, ,8]naphthyri din- 2-yl)-propyl]-pyrrolidin- l-yl )-propionic acid; 1-Methyl- 1H-pyrazol-4-yl)-3-(2-oxo-3-[3-(5,6,7 ,8-tetrahydro- 1, 8]naphthyridin-2 -yl)-propyl I-pyrroli in- 1 -yl)-propioni c acid; 3 2 -oxo-3-[3-(5,6,7,8-tetrahydlro-[1,8]naphthyridin-2-yl).propyl.. pyrrolidin- i-yl)-pent-4-enoic acid; and the pharmaceutically acceptable salts thereof. The compound of Claim 14 selected from the group consisting of 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(R)-[3-(5,6,7,8-tetrahydro. 8]naphthyidin-2-yl )-propyl]-pyrrolidin- 1-yl] -propioni c acid; 3(S)-(3-Fluorophenyl)-3-[2-oxo-3(S)-[3-(5,6,7,8-tetrahydro- El, 8]naphthyidin-2-yl)-propyl] -pyrrolidin- l-yl] -propionic acid;

179- 180 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- [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; 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. 16. An integrin receptor antagonist compound, substantially as hereinbefore described with reference to any one of the examples. 17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition made by combining a compound of any one of claims 1 to 16, and a pharmaceutically acceptable carrier. 19. A process for making a pharmaceutical composition comprising combining a compound of any one of claims 1 to 16, and a pharmaceutically acceptable carrier. 20. The composition of claim 17 or claim 18, which further comprises an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) a cytotoxic/antiproliferative agent,d) a matrix metalloproteinase inhibitor, e) an inhibitor of epidermal-derived, fibroblast-derived, or platelet- derived growth factors, f) an inhibitor of VEGF, g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, h) a cathepsin K inhibitor; and i) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof. 21. The composition of claim 20, wherein said active ingredient is selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) 25 an estrogen receptor modulator, and c) a cathepsin K inhibitor; and mixtures thereof. 22. The composition of claim 21, wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium trihydrate. 23. The composition of claim 20, wherein said active ingredient is selected from the group consisting of a) a cytotoxic/antiproliferative agent, b) a matrix metalloproteinase inhibitor,c) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, d) an inhibitor of Flk-1/KDR, Fit-1, Tck/Tie-2, or Tie-1; and mixtures thereof. 24. A pharmaceutical composition, substantially as hereinbefore described with reference to any one of the examples. A method of eliciting an integrin receptor antagonising effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of SR7A, any one of claims 1 to 16, or of a composition of any one of claims 17 to 24. 26. The method of claim 25, wherein the integrin receptor antagonising effect is an a\33 L antagonising effect. LibC/507840speci 27. The method of claim 26, wherein the a 33 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumour growth. 28. The method of claim 27, wherein the a \p3 antagonising effect is the inhibition of bone resorption. 29. The method of claim 25, wherein the integrin receptor antagonising effect is an antagonising effect. The method of claim 29, wherein the a \P5 antagonising effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, and tumour growth. 31. The method of claim 25, wherein the integrin receptor antagonising effect is a dual a \3/a \5 antagonising effect. 32. The method of claim 31, wherein the dual a\43/a\ 5 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumour growth. 33. The method of claim 25, wherein the integrin antagonising effect is an aNP6 antagonising effect. 34. The method of claim 33, wherein the a \6 antagonising effect is selected from the group consisting of angiogenesis, inflammatory response, and wound healing. 20 35. 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 a compound of any one of claims 1 to 16, or of a composition of any one of claims 17 to 24. 36. A method of inhibiting bone resorption in a mammal in need thereof, comprising o: 25 administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 16, or of a composition of any one of claims 17 to 24. 37. 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 21. 38. A method of treating tumour growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of claim 23. 39. A method of treating tumour growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 16, or of a composition of any one claims of 17 to 24, in combination with radiation therapy. A compound of any one of claims 1 to 16, or of a composition of any one of claims 17 to 24, when used for eliciting an integrin receptor antagonising effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a. 41. The compound of claim 40, wherein the integrin receptor antagonising effect is an a%43 .f9 antagonising effect. LibC/507840speci 42. The compound of claim 41, wherein the a 3 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumour growth. 43. The compound of claim 42, wherein the a43 antagonising effect is the inhibition of bone resorption. 44. The compound of claim 40, wherein the integrin receptor antagonising effect is an antagonising effect. The compound of claim 44, wherein the a\P5 antagonising effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, and tumour growth. 46. The compound of claim 40, wherein the integrin receptor antagonising effect is a dual a 5 antagonising effect. 47. The compound of claim 46, wherein the dual a 43/a\5 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic is retinopathy, macular degeneration, inflammation, viral disease, and tumour growth. 48. The compound of claim 40, wherein the integrin antagonising effect is an a36 antagonising effect. I. 49. The compound of claim 48, wherein the a'6 antagonising effect is selected from the o group consisting of angiogenesis, inflammatory response, and wound healing. 50. A compound of any one of claims 1 to 16, or of a composition of any one of claims 17 to 24, when used for treating or preventing a condition mediated by antagonism of an integrin receptor. °51. A compound of any one of claims 1 to 16, or of a composition of any one of claims 17 to 24, when used for inhibiting bone resorption. 52. A composition of claim 21, when used for inhibiting bone resorption. l: 25 53. A composition of claim 23, when used for treating tumour growth. 54. A compound of any one of claims 1 to 16, or of a composition of any one of claims 17 to 24, when used for treating tumour growth in combination with radiation therapy. *5 Use of a compound of any one of claims 1 to 16, in the manufacture of a medicament for eliciting an integrin receptor antagonising effect. 56. The use of claim 55, wherein the integrin receptor antagonising effect is an a\3 antagonising effect. 57. The use of claim 56, wherein the a4\3 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumour growth. 58. The use of claim 57, wherein the a \3 antagonising effect is the inhibition of bone RA 4 resorption. P 59. The use of claim 55, wherein the integrin receptor antagonising effect is an c C ntagonising effect. LibC/507840sped 183 The use of claim 59, wherein the a 45 antagonising effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, and tumour growth. 61. The use of claim 55, wherein the integrin receptor antagonising effect is a dual a \3/a 45 antagonising effect. 62. The use of claim 61, wherein the dual a \43/a 5 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumour growth. 63. The use of claim 55, wherein the integrin antagonising effect is an a\6 antagonising effect. 64. The use of claim 63, wherein the a 46 antagonising effect is selected from the group consisting of angiogenesis, inflammatory response, and wound healing. Use of a compound of any one of claims 1 to 16, in the manufacture of a medicament for treating or preventing a condition mediated by antagonism of an integrin receptor. S 15 66. Use of a compound of any one of claims 1 to 16, in the manufacture of a medicament for inhibiting bone resorption. Dated 17 May 2001 MERCK& CO., INC. *oo Patent Attorneys for the Applicant/Nominated Person 20 SPRUSON FERGUSON go LibC/507840spec