Note: Descriptions are shown in the official language in which they were submitted.
?» WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/ 14912TITLE OF THE INVENTIONINTEGRIN ANTAGONISTSFIELD OF THE INVENTIONThe present invention is related to U.S. provisionalapplications Serial Nos. 60/047,177, filed May 20, 1997, 60/033,579,filed December 19, 1996, and 60/025,123, filed August 29, 1996, thecontents of which are hereby incorporated by reference.The present invention provides novel compounds andderivatives thereof, their synthesis, and their use as vitronectin receptorligands. More particularly, the compounds of the present invention areOLVB3 antagonists, ocvB5 antagonists or dual ocv[33/owB5 antagonistsuseful for inhibiting bone resorption, treating and preventingosteoporosis, and inhibiting vascular restenosis, diabetic retinopathy,macular degeneration, angiogenesis, atherosclerosis, inflammation andtumor growth.BACKGROUND OF THE INVENTIONThis invention relates to compounds for inhibiting boneresorption that is mediated by the action of a class of cells known asosteoclasts.Osteoclasts are multinucleated cells of up to 400 pm indiameter that resorb mineralized tissue, chie?y calcium carbonate andcalcium phosphate, in vertebrates. They are actively motile cells thatmigrate along the surface of bone. They can bind to bone, secretenecessary acids and proteases and thereby cause the actual resorption ofmineralized tissue from the bone.More specifically, osteoclasts are believed to exist in at leasttwo physiological states. In the secretory state, osteoclasts are ?at,attach to the bone matrix via a tight attachment zone (sealing zone),become highly polarized, form a ruf?ed border, and secrete lysosomalenzymes and protons to resorb bone. The adhesion of osteoclasts tobone surfaces is an important initial step in bone resorption. In the?WO 98/088401015202530CA 02263999 l999-02- 19PCTIUS97/14912-2-migratory or motile state, the osteoclasts migrate across bone matrixand do not take part in resorption until they attach again to bone.Integrins are transmembrane, heterodimeric, glycoproteinswhich interact with extracellular matrix and are involved in osteoclastattachment, activation and migration. The most abundant integrin inosteoclasts (rat, chicken, mouse and human) is the vitronectin receptor,or OLVB3, thought to interact in bone with matrix proteins that containthe RGD sequence. Antibodies to OLVB3 block bone resorption in mgindicating that this integrin plays a key role in the resorptive process.There is increasing evidence to suggest that ocvB3 ligands can be usedeffectively to inhibit osteoclast mediated bone resoption in vivo inmammals.The current major bone diseases of public concern areosteoporosis, hypercalcemia of malignancy, osteopenia due to bonemetastases, periodontal disease, hyperparathyroidism, periarticularerosions in rheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment.All these conditions are characterized by bone loss,resulting from an imbalance between bone resorption (breakdown) andbone formation, which continues throughout life at the rate of about14% per year on the average. However, the rate of bone turnoverdiffers from site to site, for example, it is higher in the trabecular boneof the vertebrae and the alveolar bone in the jaws than in the cortices ofthe long bones. The potential for bone loss is directly related toturnover and can amount to over 5% per year in vertebrae immediatelyfollowing menopause, a condition which leads to increased fracture risk.There are currently 20 million people with detectablefractures of the vertebrae due to osteoporosis in the United States. Inaddition, there are 250,000 hip fractures per year attributed toosteoporosis. This clinical situation is associated with a 12% mortalityrate within the first two years, while 30% of the patients requirenursing home care after the fracture.Individuals suffering from all the conditions listed abovewould benefit from treatment with agents which inhibit bone resorption.?» WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/ 14912 _-3-Additionally, ocvB3 ligands have been found to be useful intreating and/or inhibiting restenosis (recurrence of stenosis aftercorrective surgery on the heart valve), atherosclerosis, diabeticretinopathy, macular degeneration and angiogenesis (formation of newblood vessels). Moreover, it has been postulated that the growth oftumors depends on an adequate blood supply, which in turn is dependenton the growth of new vessels into the tumor; thus, inhibition ofangiogenesis can cause tumor regression in animal models. (See,Harrison's Principles of Internal Medicine, 12th ed., 1991). OLVB3antagonists, which inhibit angiogenesis, are therefore useful in thetreatment of cancer for inhibiting tumor growth. (See e.g., Brooks etal., Cell, 79:1157-1164 (1994)).Moreover, compounds of this invention can also inhibitneovascularization by acting as antagonists of the integrin receptorocvB5. A monoclonal antibody for 0cv[35 has been shown to inhibitVEGFâinduced angiogenesis in rabbit cornea and the chickchorioallantoic membrane model; M.C. Friedlander, et.al., Science 270,1500-1502, 1995. Thus, compounds that antagonize ocvB5 are useful fortreating and preventing macular degeneration, diabetic retinopathy, andtumor growth.In addition, certain compounds of this invention antagonizeboth the ocv[33 and OLVBS receptors. These compounds, referred to as"dual OLVB3/0tv[35 antagonists," are useful for inhibiting bone resorption,treating and preventing osteoporosis, and inhibiting vascular restenosis,diabetic retinopathy, macular degeneration, angiogenesis,atherosclerosis, in?ammation and tumor growth.It is an object of the present invention to identifycompounds which bind to the OLVB3 receptor, ocvB5 receptor or both the0cv[33 and ocv[35 receptors.It is a further object of the invention to identify compoundswhich act as antagonists of the OLVI33 receptor. It is another object of theinvention to identify OLVB3 antagonist compounds which are usefulagents for inhibiting: bone resorption mediated by osteoclast cells,restenosis, atherosclerosis, in?ammation, diabetic retinopathy, macular?9 WO 98/0884010152025CA 02263999 l999-02- 19PCT/U S97/ 14912-4-degeneration and angiogenesis in animals, preferably mammals,especially humans. Still another object of the invention is to identifyOLVB3 antagonists which cause tumor regression and/or inhibit tumorgrowth in animals.A further object of the invention is to identify 0cv[33antagonists useful for preventing or treating osteoporosis. An additionalobject of the invention is to identify OLVB3 antagonists useful for treatingcancer.It has now been found that the compounds of the presentinvention, OLVB3 ligands, are useful for inhibiting bone resorption inmammals. Thus, the compounds of the present invention are useful forpreventing or reducing the incidence of osteoporosis. Additionally, theocvB3 ligands of the present invention are also useful for treating and/orinhibiting restenosis, diabetic retinopathy, macular degeneration,atherosclerosis and/or angiogenesis in mammals.SUMMARY OF THE H\IVENTIONThe present invention provides a method of eliciting avitronectin receptor antagonizing effect in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of a compound of the formula0 BR R9HX-Y-Z-(CH2);,-C-N>g(CO2R12H 10R R11wherein X is selected from1NR r;gR2_Câ;'_NR1R2 âNR1âcâNRâR2, Ia 5- or 6-membered monocyclic aromatic or nonaromatic ringsystem containing 0, 1, 2, 3 or 4 heteroatoms selected from N, Oor S wherein the 5- or 6-membered ring system is either?CA 02263999 l999-02- 197 wo 93/03340 PCT/US97/14912-5-unsubstituted or substituted on a carbon or nitrogen atom withone or more groups chosen from R1, R2, R15 or R16;a 9- to 10âmembered polycyclic ring system, wherein one or5 more of the rings is aromatic, and wherein the polycyclic ringsystem contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstitutedor substituted on a carbon or nitrogen atom with one or moregroups chosen from R1, R2, R15 or R15;10Y is selected from33 ll""(CH2)râN'(CH2)'mâ , ""(CH2)1-C"(CH2)'nT .|| II-(CH2),-âC-I}!-(CH2);,'," , â-(CH2):-Eâ-C-(CH2)arR3 R3 9â<cH2»âs<o>2-h,râ<cH2>m- . ââ<CH2>r'}â"âSâ°>2â°â2âF"',R3 R3-â(CH2),-S(O)q-(CH2)-,7 , -'(CH2):-O-(CH2)-mâ or â(CH2)râ3Z isa 5~l1 membered aromatic or nonaromatic mono- or polycyclic15 ring system containing 0 to 6 double bonds, and containing 0 to 6heteroatoms chosen from N, O and S, and wherein the ringsystem is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selectedfrom R4, R5, R6 and R7; provided that Z is not a 6âmembered20 monocyclic aromatic ring system, an isoxazoline ring or anisoxazole ring;?7 WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912-5-R1, R2, R4, R5, R13, R14, R15 and R16 are each independently selectedfromhydrogen, halogen, C 1- 10 alkyl, C3-8 cyeloalkyl,C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl,C3-3 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-g alkyl, amino,amino C1-8 alkyl, C1-3 acylamino, C1_3 acylamino C1-8 alkyl,(C 1-6 a1kyl)qamino, (C 1-6 a1kyl)qamino C1-8 alkyl,C 1-4 alkoxy, C 1-4 alkoxy C1_6 alkyl, hydroxycarbonyl,hydroxycarbonyl C1-6 alkyl, C 1-3 alkoxycarbonyl,C 1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonylâC 1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy-C 1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,tri?uoroethoxy, C1-8 alkyl-S(O)q, (C 1-8 alky1)qaminocarbony1,C1-8 alkyloxycarbonylamino, (C 1-8 a1ky1)qaminocarbony1oxy,oxo, (aryl C1-g alky1)qamino, (ary1)qamino,aryl C1-8 alkylsulfonylamino or C1-8 alkylsulfonylamino;R3 is selected fromhydrogen,aryl,aryl-(CH2)p-,hydroxyl,C1-5 alkoxy,aminocarbonyl,C3-3 cyeloalkyl,amino C1-6 alkyl,(aryl)qaminocarbonyl,(aryl C 1-5 alkyl)qaminocarbonyl,hydroxycarbony] C1 -6 alkyl,C1-8 alkyl,aryl C1-6 alkyl,(C1_6 alkyl)qamino C 1-6 alkyl,(aryl C1_6 alky1)qamino C1-6 alkyl,C1-8 alkylsulfonyl,?* WO 98/0884010CA 02263999 l999-02- 19C1-8 alkoxycarbonyl,aryloxycarbonyl,aryl C1 -3 alkoxycarbonyl,C1-8 alkylcarbonyl,arylcarbonyl,aryl C1-5 alkylcarbonyl,(C1-8 alky1)qaminocarbonyl,aminosulfonyl,C1-8 alkylaminosulfonyl,(aryl)qaminosu1fonylamino,(aryl C1-8 alkyl)qaminosu1fonyl,C1-6 alkylsulfonyl, âarylsulfonyl,aryl C 1-6 alkylsulfonyl,aryl C1-6 alkylcarbonyl,C 1 -6 alkylthiocarbonyl,arylthiocarbonyl, oraryl C1-6 alkylthiocarbonyl,PCT/US97/14912wherein any of the alkyl groups may be unsubstituted or substituted with20 R13 and R14;R6» R7, R8, R9, R10 and R11 are each independently selected from2530hydrogen,aryl,aryl-(CH2)p-,aryl-<cH2>n-0-<cH2>m-,aryl-<cH2)n-s(0>q-<cH2>m-,ary1â<CH2>n-c<0>-<cH2>m-,aryl-<cH2>n-c<o>-N<R3>-<CH2>m-,aryl-<CH2>n-N<R3>-C<0)-<CH2>m-,aryl-<cH2>n-N(R3>-(cH2>m-,halogen,hydroxyl,C1-8 alkylcarbonylamino,?» WO 98/0884010202530CA 02263999 l999-02- 19PCT/U S97/ 14912aryl C1-5 alkoxy,C1-5 alkoxycarbonyl,(C1-8 alkybqaminocarbonyl,C1-6 alkylcarbonyloxy,C3-8 cycloalkyl,oxo,(C1-6 a1kyl)qamino,amino C1-6 alkyl,arylaminocarbonyl,aryl C1-5 alkylaminocarbonyl,aminocarbonyl,aminocarbonyl C1-6 alkyl,hydroxycarbonyl,hydroxycarbonyl C1 -5 alkyl,C1-8 alkyl, either unsubstituted or substituted, with one or moregroups selected from: halogen, hydroxyl,C 1-5 alkylcarbonylamino, aryl C 1-5 alkoxy,C 1-5 alkoxycarbonyl, aminocarbonyl, (C 1-5 a1ky1)qamino-carbonyl, C 1-5 alkylcarbonyloxy, C3-g cycloalkyl, oxo,(C1-3 a1ky1)qamino, amino C1-3 alkyl,(aryl)qaminocarbonyl, (aryl C1-5 alkybqaminocarbonyl,aminocarbonyl, aminocarbonyl C 1-4 alkyl,hydroxycarbonyl or hydroxycarbonyl C1-5 alkyl,CH_=_Câ(CH2)s-,C1-6 a1kylâCsC-(CH2)s-,C3-7 cycloalkyl-CEC-(CH2)s-,aryl-CEC-(CH2)s-,C1 -6 a1kylary1âCEC-(CH2)s-,CH2=CH-(CH2)s-,C1 -6 alky]-CH=CH-(CH2)sâ,C3-7 cycloalkyl-CH=CH-(CH2)s-,aryl-CH=CH-(CH2)sâ,C1 -6 alkylary1âCH=CH-(CH2)s-,C1-6 alkyl-S02-(CH2)sâ,?CA 02263999 l999-02- 19_ W0 93/03840 PCT/US97/ 14912-9-C1 -6 alkylary1âSO2â(CH2)s-,C1-6 alkoxy,aryl C1-6 alkoxy,aryl C1-6 alkyl,5 (C1-6 alkyl)qamino C 1-6 alkyl,(aryl)qamino,(aryl)qarnino C1-6 alkyl,(aryl C1-6 a1ky1)qamino,(aryl C1-6 alkyl)qamino C1-6 alkyl,10 arylcarbonyloxy,aryl C1-6 alkylcarbonyloxy,(C1_6 alky1)qaminocarb0nyloxy,C 1-8 alkylsulfonylamino,arylsulfonylamino,15 C1-8 alkylsulfonylamino C1 -6 alkyl,arylsulfonylamino C1 -6 alkyl,aryl C1 -6 alkylsulfonylamino,aryl C1-6 alkylsulfonylamino C1-6 alkyl,C 1 -3 alkoxycarbonylamino,20 C1-8 alkoxycarbonylamino C1-8 alkyl,aryloxycarbonylamino C1 -8 alkyl,aryl C1 -8 alkoxycarbonylamino,aryl C1-8 alkoxycarbonylamino C1-8 alkyl,C1-8 alkylcarbonylamino,25 C1-8 alkylcarbonylamino C1-6 alkyl,arylcarbonylamino C 1 -6 alkyl,aryl C1 -6 alkylcarbonylamino,aryl C1-6 alkylcarbonylamino C1-6 alkyl,aminocarbonylamino C 1-6 alkyl,30 (C1-8 alkybqaminocarbonylamino,(C 1-8 alkybqaminocarbonylamino C1-6 alkyl,(ary1)qaminocarbonylamino C1-6 alkyl,(aryl C1 -8 alkybqaminocarbonylamino,(aryl C1-8 alkybqaminocarbonylamino C1-6 alkyl,?WO 9810884010152025CA 02263999 l999-02- 19PCT/US97/14912-10..aminosulfonylamino C1 -6 alkyl,(C1-8 alkybqaminosulfonylamino,(C1-8 alkyhqaminosulfonylamino C1-6 alkyl,(arybqaminosulfonylamino C1 -6 alkyl,(aryl C1 -8 a1ky1)qaminosulfonylamino,(aryl C1-8 alkyhqaminosulfonylamino C1-6 alkyl,C1-6 alkylsulfonyl,C1-6 alkylsulfonyl C1-6 alkyl,arylsulfonyl C1-6 alkyl,aryl C1-6 alkylsulfonyl,aryl C1-6 alkylsulfonyl C1-5 alkyl,C1-6 alkylcarbonyl, 'C1-6 alkylcarbonyl C1-6 alkyl,arylcarbonyl C1-6 alkyl,aryl C1-6 alkylcarbonyl,aryl C1_6 alkylcarbonyl C 1-6 alkyl,C1 -6 alkylthiocarbonylamino,C1-6 alkylthiocarbonylamino C1-6 alkyl,arylthiocarbonylamino C1 -6 alkyl,aryl C1-6 alkylthiocarbonylamino,aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,(C1-8 alkyl)qaminocarbonyl C1-6 alkyl,(ary1)qaminocarbonyl C1 -6 alkyl,(aryl C1-8 a1ky1)qaminocarbony1, or(aryl C1-8 a1ky1)qaminocarbony1 C1-6 alkyl,wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14; and provided that the carbon atom to which R8 and R9are attached is itself attached to no more than one heteroatom; andprovided further that the carbon atom to which R10 and R11 are30attached is itself attached to no more than one heteroatom;R12 is selected fromhydrogen,C 1-8 alkyl,?WO 981088401015920CA 02263999 l999-02- 19PCT/U S97/ 14912-11-aryl,aryl C1-8 alkyl,C1-8 alkylcarbonyloxy C1-4 alkyl,aryl C1-g alkylcarbonyloxy C 1-4 alkyl,C1-8 alkylaminocarbonylmethylene, orC1 -8 dialkylaminocarbonylmethylene;m, s and t are each independently an integer from 0 to 3;n is an integer from 1 to 3;p is an integer from 1 to 4;q is an integer from 0 to 2;r is an integer from O to 6;and the pharrnaceutically acceptable salts thereof.In one embodiment of the present invention is the methodof eliciting a vitronectin antagonizing effect whereinXisa 9- to 10-membered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ringsystem contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstitutedor substituted on a carbon atom with R1 and R2; andZ is selected from?CA 02263999 l999-02- 19»WO 98/08840 PCT/US97/14912_ 12 _R4 R4gitâ/>.**6 RR/\1H_§ :\vâ6 6âN\â/:\\,N\rfg -1i,N\\/ E kv â â \/J ER7 â R7 â R7 7RâR 4I, 6R NI R F14§â3L7ââf âW'â-E *âéâ~"/F Hâ/>.â6\R7 22â /2 :/7~/N E l\\"7â1\;aR4 R4 4n R%~~K/iR6 % (536 SR.«\â\â §\.\R7 9:â \R7 \râ;5 â '71â: R6R4 R7 R7 R4 |_N, 4R/é? §â/.~/Kz /xâ 1 â:2J224 \,N\;; re} R7 § R4 4 R4R2â /R5 F%7\Q/R4 EBB _: N \«'â'_E '\\/N}? N}: E N\/ N ,âHf R6 ,3â R5 » 0 R6 V?CA 02263999 l999-02- 19, W0 93/03340 PCT/US97/1491213 -4 /R4 4if 7 M w4/ \ Nâ 3/ N\R5 5 R6 Eâ R6\/R4 R4 R4g/âA R7 gm./â/rs gu:â/q-7 I I::«~\ *2»; Ms »R Fl 4E â(Q/WR4 XAIRR6 R6and all other variables are as defined above;and the phaimaceutically acceptable salts thereof. Preferably, Z is5 selected fromO 4 O 4HNJy|F\4 §ââE\4N\$ E $âN%cr:\1â,/Kg)/N\e5 â .\\(() "z£â)\§) ,4R)\âg $5 âR4?CA 02263999 l999-02- 19wo 98/08840 PCT/US97/14912-14-I/\ _ 4N}; âHm N15â 1.1%/N\g/fll\§5 /R4 ONH( âE » â-.§â>r'4 R45 2 OR4 N. R4 /x\ R4N/â\/I I N Allâa*rrâ:f , â:ârWOrâ\§ , *6/Yââ5H4 R4R4 âV4 0, W?â2/HO]/N\§ Y 5%/NE/N\§: 7 32/N\C[)]/N}; .In a class of the invention is the method of eliciting avitronectin antagonizing effect wherein the compound has the formulaR805 XâY-Z-CHZCHJNH/K/CO2R12wherein X is selected from?W0 98I0884010202530CA 02263999 l999-02- 19PCT/US97/14912-15-~ Râ Râ R1Y is selected from â(cH2),â or -(CH2)m-NR3-(CH2):-;R3 is selected fromhydrogen,31'Y1'(CH2)p-,C1-5 alkoxycarbonyl,C3-8 cycloalkyl,(aryl)qaminocarbony1,(aryl C 1 -5 alkyl)qaminoearbonyl,C1-8 alkyl,aryl C1-6 alkyl,C1_8 alkylsulfonyl,arylsulfonyl,aryl C1-6 alkylsulfonyl,C1-8 alkoxycarbonyl,aryloxycarbonyl,aryl C 1-8 alkoxycarbonyl,C1-8 alkylcarbonyl,arylcarbonyl,aryl C1-6 alkylcarbonyl,(C1-8 a1kyl)qaminocarbonyl,C1 -6 alkylsulfonyl, oraryl C1-6 alkylcarbonyl,wherein any of the alkyl groups may be unsubstituted orsubstituted with R13 and R14;R4 is selected fromhydrogen, C 1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl,C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl,aryl or aryl C1-8 alkyl,?~ WO 98/088402025CA 02263999 l999-02- 19PCT/US97/14912-16-R8 is selected fromhydrogen,aryl,313']-(CH2)p-.CHEC-(CH2)s-,C1-5 alkyl-CEC-(CH2)S-,C3-7 cycloalkyl-C.=_Câ(CH2)s-,aryl-CEC-(CH2)g-,C1 -6 alkylafyl-CEC-(CH2)s-,CH2=CH-(CH2)s-,C1-6 alkyl-CH=CH-(CH2)s-,C3-7 cycloalkylâCH=CH-(CH2)s-,aryl-CH=CH-(CH2)s-,C1_6 alkylaryl-CH=CH-(CH2)s-,C1-6 alkyIâSO2â(CH2)sâ,C 1-6 alkylarylâSO2-(CH2)s-; andr is an integer from O to 3;and all other variables are as defined above;and the pharrnaceutically acceptable salts thereof.In a subclass of the invention is the method wherein thecompound has the formula(flN NH8E3 HO â=.II /</CO2Râ2vâ ZâCH2CNHwherein Z is selected from?CA 02263999 l999-02- 19. wo 93/03340 PCT/US97l14912-17-K/{ /§â TlH/âwrâ\s âH. Nâ? Jw âEO s Q âT4ââ~~s 5? i/N N:3 âE 9 âacâ 0R4 R4 0l N/â\\l NHR8 is selected from\ hydrogen,/5... _: 0â':' ."'VF. @,â©[o>,/ \ / OQC} -{I >=o; N , m .5 indolyl-(CH2)pâ,CHEC-(CH2)s-,C1-6 alkyl-CEC-(CH2)s~,C3-7 cycloalky]âCEC-(CH2)g-,3TY1âC"â'C'(CH2)s-,10 C1-6 alkylaryl-CsCâ(CH2)s-,CH2=CH-(CH2)s-,C1-6 alkyl-CH=CH-(CH2)sâ,C3-7 cyc1oa1ky1âCH=CH-(CH2)sâ,aryl-CH=CH-(CH2)sâ,15 C1-6 alkylaryl-CH=CH-(CH2)s-,?CA 02263999 l999-02- 19.w0 93/03840 PCT/US97/ 14912-18-C1-6 alkyl-SO2â(CH2)s-,C1-6 alkylarylâSO2-(CH2)s-; andR12 is selected from hydrogen or C1-8 alkyl;5 s is an integer from O to 3;and all other variables are as defined above;and the phannaceutically acceptable salts thereof.Illustrative of the invention is the method of eliciting avitronectin antagonizing effect wherein the compound is selected from102âOxo-3-[2â(5,6,7,8âtetrahydro[1,8]ânaphthyridinâ2-yl)ethyl]piperidinâ1-ylâacetylâ3(S)âpyridin-3-ylâB-alanine ethyl ester;2âOxoâ3-[2â(5,6,7,8âtetrahydro[1,8]ânaphthyridin-2âyl)ethyl]piperin-15 1~yl-acetyl-3(S)-pyridin-3âyl-Bâalanine trifluoroacetate;2âOxoâ3(S)-[2-(5,6,7,8âtetrahydro[1,8]-naphthyridinâ2âyl)ethyl]pyrrolidin-1âyl)acetylâ3(S)-alkynyl-B-alanine ethyl ester;20 2-Oxo-3(S)-[2â(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetylâ3(S)-alkynyl-[3âalanine;2-Oxoâ3(S)-[2-(5,6,7,8âtetrahydro[1,8]-naphthyridin-2-yl)ethyl]-pyrrolidinâ1-yl)acetyl-3(S)-pyridinâ3âyl-[3-alanine ethyl ester;252-Oxoâ3(S)-[2-(5,6,7,8âtetrahydro[1,8]-naphthyridin-2-y1)ethy1]pyrrolidin-1âyl)acetyl-3(S)-pyridin-3âylâ[3-alanine;2âOxoâ3(R)â[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-30 yl)ethyl]pyrrolidin-1âyl)acetylâ3(S)âalkynyl-[3-alanine ethyl ester;2-Oxoâ3 (R)â[2â(5 ,6,7,8-tetrahydro[1,8]-naphthyridin-2-y1)ethyl]pyrrolidinâ1-y1)acety1-3(S)-alkynyl-Bâalanine;?WO 98/088401015202530CA 02263999 l999-02- 19PCT/U S97! 14912-19-2âOxoâ3(R)â[2-(5,6,7,8-tetrahydro[1,8]ânaphthyridin-2-y1)ethyl]-pyrrolidin-1-yl)acetyl-3(S)âpyridinâ3-yl-[3-alanine ethyl ester;2âOxo-3(R)â[2-(5,6,7,8âtetrahydro[ 1 ,8]-naphthyridin-2-y1)ethyl]pyrr0lidinâ1-yl)acetylâ3(S)âpyridinâ3-yl-Bâalanine;Ethyl 2âOx0-3-[2-(5,6,7,8-tetrahydr0[1,8]naphthyridinâ2-yl)ethyl]âtetrahydropyrimidinâl-yl-acetyl-3(S)âpyridin-3-yl-[3-alanine;2âOx0-3-[2-(5,6,7,8âtetrahydro[ l ,8]naphthyridin-2âyl }ethyl]âtetrahydropyrimidin-1 âyl-acety1â3(S)-pyridin-3 âyl-[3-alanine;Ethyl 2âoxo-3-[2-(5,6,7,8âtetrahydro[1,8]naphthyridin-2-yl)ethyl]imidazolidin-1-yl-acetylâ3(S)-pyridinâ3âyl-[3âalanine;2âOx0-3-[2-(5 ,6,7,8-tetrahydro[1,8]naphthyridin-2âyl}ethyl]-imidazolidin-1-yl-acetylâ3(S)âpyridin-3-yl-[3-alanine;Ethyl 2-oxoâ3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-y1)ethyl]pyrrolidinâl-yl)acetyl-3(R)-(2-ethylindol-3-yl)-B-alanine;2âOxoâ3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidin-l-yl)acetyl-3(R)-(2âethylindol-3-yl)-[3âalanine;Ethyl 3â(2-{ 2-oxoâ3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridinâ2-yhnethyl)-amino] -pyrrolidin-1 âyl } -acetylamino)â3â(S)âpyridin-3-yl-propionic acid;3-(2- { 2âOxoâ3(S)-[(5 ,6,7,8âtetrahydroâ[ 1 ,8]naphthy1idinâ2-ylmethy1)âamino]pyrrolidin-1-yl }-acetylamino)-3â(S)-pyridinâ3-yl-propionic acid;3-{2-[6âOxo-1-(5,6,7,8âtetrahydro-[1,8]naphthyridinâ2-ylmethyl)âhexahydro-(3aS, 6aS)pyrrolo[3 ,4âb]pyrrol-5-yl]-acetylamino } â3â(S)âpyridinâ3-yl-propionic acid;?WO 98/088401015202530CA 02263999 l999-02- 19PCT/.US97l14912-20-3- { 2-[6âOxo- 1 -(5 ,6,7 ,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-hexahydr0â(3aR, 6aR)pyrrolo[3,4âb]pyrrol-5-yl]-acetylamino } -3(S)âpyridin-3-ylâpropionic acid;2âOxo-5(R)âmethylâ3(S)-[2â(5,6,7,8-tetrahydro[1,8]-naphthyridinâ2-yl)âethyl]pyrrolidin-1-yl)acetylâ3(S)âalkynyl-B-alanine ethyl ester;2âOxoâ5(R)âmethyl-3(S)-[2â(5,6,7,8-tetrahydro[1,8]ânaphthyridin-2-yl)ethyl]pyrrolidin-1-yl)acetylâ3(S)-alkynyl-[3-alanine;2-Oxo-5(S)-benzylâ3(S)-[2-(5 ,6,7,8âtetrahydro[ l ,8]-naphthyridin-2-y1)-ethyl]pyrrolidinâl-yl)acetylâ3(S)-pyridinâ3-yl-[5-alanine ethyl ester;2-Oxo-5(S)-benzylâ3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethy1]pyrrolidin-1-yl)acetylâ3(S)âpyridin-3-ylâ[3âalanine;5(R)-Methyl-2-oxo-3(S)â[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetylâ3(S)-alkynyl-[3-alanine ethylester;5 (R)âMethyl-2-oxo-3(S)-[2-(5 ,6,7,8-tetrahydro[1 ,8]-naphthyridin-2-ylmethyl)-amino]pyrrolidin-1-yl)acetylâ3(S)-alkynylâB-alanine;3(S)-(2,3âDihydroâbenzofuran-6-yl)â3â(2â { 2-oxo-3 (S )-[2-(5 ,6,7,8âtetrahydro-[ 1 ,8]naphthyridin-2-yl)âethyl]-pyrr0lidin-1 -yl } -acetylamino)âpropionic acid ethyl ester; or3(S)-(2,3âDihydro-benzofuran-6ây1)-3-(2- { 2-oxo-3(S)â[2â(5,6,7 ,8-tetrahydro-[1,8]naphthyridin-2-yl)âethyl]âpyrrolidin-1-yl}âacetylamino)-propionic acid; .3- { 2-(2-Oxo-3 (S)-[2-(5 ,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)-ethyl] âpyrrolidin-1-y1)âacetylamino}-3(S)âquinolin-3-yl-propionic acid;?W0 98l088401015202530CA 02263999 l999-02- 19PCT/US97/14912-21-3-(2â(5(S)-Ethylâ2-oxo-3(S)â[2-(5,6,7,8âtetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrolidin-1-yl)-acetylamino)-3-(S)-quinolin-3âyl-propionicacid tri?uoroacetate;3-(2-{6-Methyl-2âoxo-3â[(5,6,7,8-tetrahydroâ[1,8]naphthyridinâ2-ylmethyl)-amino]-2H-py1idin-1-yl} -acetylamino)â3(S)-pyridin-3-yl-propionic acid bis tri?uoroacetate; or3-(2-{6-Methylâ2-oxo-3-[(5,6,7,8âtetrahydro-[1,8]napthyridinâ2âylmethyl)-amino]-2Hâpyridin-1-yl}-acetylamino)-3(S)-pyridin-3-yl-propionic acid ethyl ester;and the pharmaceutically acceptable salts thereof.Preferably, the compound is selected from2-Oxo-3-[2-(5,6,7,8âtetrahydro[1,8]-naphthyridin-2-yl)ethy1]piperinâ1-yl-acetyl-3(S)-pyridinâ3-yl-[3-alanine tri?uoroacetate;2-Oxo-3(S)â[2â(5,6,7,8âtetrahydro[1,8]ânaphthyridin-2-yl)ethy1]pyrrolidinâ1-yl)acetylâ3(S)-alkynyl-B-alanine;2-Oxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]ânaphthyridinâ2-yl)ethyl]pyrrolidin-1âyl)acetyl-3(S)-pyridin-3âylâ[3âalanine;2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-y1)ethyl]pyrrolidin-1âyl)acetyl-3(S)âa1kynylâ[3-alanine;2-Oxo-3(R)â[2-(5,6,7,8âtetrahydro[1,8]-naphthyridin-2-y1)ethyl]pyrrolidin-1âyl)acetyl-3(S)-pyridinâ3âyl-B-alanine;2-Oxoâ3-[2-(5 ,6,7,8âtetrahydro[l ,8]naphthyridin-2-yl }ethyl] -imidazo1idin- 1 -y1âacetyl-3-(S)-pyridin-3-yl-Bâalanine;?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-22-2-Oxo-3-[2â(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]âtetrahydropyrimidin-1-yl-acetyl-3 -(S)âpyridinâ3âylâ Bâa1anine;2âOxoâ3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyI]pyrrolidinâlâyl)acetyl-3(R)-(2âethylindol-3-yl)-[3âalanine;3-(2- { 2-oxoâ3(S)-[(5 ,6,7 ,8-tetrahydro-[1,8]naphthyridinâ2âylmethyI)âamino]pyrrolidin-1-yl } -acetyIamino)â3-(S)-pyridin-3-yl-propionic acid;3- { 2-[6-Oxo-1 -(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-ylmethyl)-hexahydro-(3aS, 6aS)pyrro1o[3,4-b]pyrroI-5ây1]-acetylamino}â3-(S)-pyridin-3-yIâpropionic acid; â3- [2-[6-Oxoâ1 -(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-ylmethyl)âhexahydro-(3aR, 6aR)pyrrolo[3 ,4-b]pyrrol-5-yl] -acetylamino } â3-(S)-pyridin-3âyl-propionic acid;2-Oxoâ5(R)-methy1-3(S)-[2â(5 ,6,7,8-tetrahydro[1 ,8]ânaphthyridin-2-y1)ethyl]pyrrolidinâ1-y1)acety1-3(S)âalkyny1-Bâalanine;2-Oxo-5(S)-benzyl-3(S)-[2â(5,6,7,8-tetrahydro[1,8]ânaphthyridin-2-y1)ethyl]pyrrolidin-1ây1)acetyl-3(S)-pyridin-3ây1-[3-alanine;5(R)âMethyl-2-oxo-3(S)-[2-(5,6,7,8âtetrahydro[1,8]ânaphthyridin-2-y1methy1)âamino]pyrrolidin-1ây1)acetyl-3(S)-alkynylâ[3-alanine; or3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2â { 2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)-ethyl]âpyrrolidin-1-yl }-acetylamino)âpropionic acid;and the pharmaceutically acceptable salts thereof.Exemplifying the invention is the method wherein thevitronectin receptor antagonizing effect is an OLVB3 antagonizing effect.An illustration of the invention is the method wherein the OLVB3?WO 98/0884010152025CA 02263999 l999-02- 19PCT/US97ll49l2-23-antagonizing effect is selected from inhibition of: bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,in?ammation or tumor growth. Preferably, the 0cvB3 antagonizingeffect is the inhibition of bone resorption.An example of the invention is the method wherein thevitronectin receptor antagonizing effect is an 0cvB5 antagonizing effect.More specifically, the oLvB5 antagonizing effect is selected frominhibition of: restenosis, angiogenesis, diabetic retinopathy, maculardegeneration, inflammation or tumor growth.Illustrating the invention is the method wherein thevitronectin receptor antagonizing effect is a dual 0cvB3/otvB5antagonizing effect. More particularly, the dual OLVB3/otv[35antagonizing effect is selected from inhibition of: bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation or tumor growth.In a second embodiment of the present invention is amethod of eliciting an OLVB3 antagonizing effect in a mammal in needthereof, comprising administering to the mammal a therapeuticallyeffective amount of a compound of the formula0 8R R9llXâY-Zâ(CH2)-,,âC-N>g(CO2R12H 10R R11wherein X is selected fromR1Nâ I392_g_NR'lR2 ""â'NR1"'C-NR1R2, 1a 5- or 6-membered monocyclic aromatic or nonaromatic ringsystem containing 0, 1, 2, 3 or 4 heteroatoms selected from N, Oor S wherein the 5- or 6-membered ring system is eitherunsubstituted or substituted on a carbon atom with R1 and R2, or?A WO 98/08840CA 02263999 l999-02- 19PCT/US97/14912-24-a 9- to 10âmembered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ringsystem contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstituted5 or substituted on a carbon atom with R1 and R2;Y is selected fromR3I ll"â(CH2)iâNâ(CH2)'m", -'(CH2)FâCâ(CH2)Tn' ,9 9?-(CH2)t--C-l}lâ(CH2);- , â(CH2)r"?ââC-(CH2)mâR3 R3 1â (CH2),--S(O)'2-I}!-(CH2),-,7 â(CH2)r-'}1âS(0)2-(CH2)m-R3 â R3';â(CH2);-S(O)q-(CH2)? â, â(CH2)i- 0-(CH2): or - (CH2)râ3Z is10 a 5-11 membered aromatic or nonaromatic mono- or polycyclicring system containing 0 to 6 double bonds, and containing 0 to 6heteroatoms chosen from N, O and S, and wherein the ringsystem is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selected15 from R4, R5, R6 and R7; provided that Z is not a 6-memberedmonocyclic aromatic ring system; preferably, Z is selected fromO 04R O 4HNJL/1R4 §___r_\4N\§é E140 gâN%71â ON}; â |\\(() ,5;/'\âgN\§ ' 4R)\â<N\§$ âO?CA 02263999 l999-02- 19. wo 93/03340 PCT/US97/14912 _-25-R4 //W .//R4 7?N\ gâ__ N\ g-â_ N76 Nr N";30?. *u"Wé Rwy,O\ JL Râ 4M 5% Mâ â¬9,205 â{?Or⧠â2âg\.»âH4 O«/ ,§ W/R4\/ /1 1 I24 Ni; 32/N\gJ\g£NF/184 I NXIR4 NA/NR4I I22/âE/N\;§ â 2/Kg/Nxsxâ â 3%/K[CyN\§ , W?âW 2/~::~»e . N wR1, R2, R3, R4, R5, R13 and R14 are each independently selected from?CA 02263999 l999-02- 19.w() 93/93840 PCT/US97/14912-26-hydrogen, halogen, C]. 10 alkyl, C3-3 cycloalkyl, aryl,aryl C1-8 alkyl, amino, amino C1-g alkyl, C1_3 acylamino,C 1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino-C 1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-g alkyl,5 C 1-4 alkoxy, C 1-4 alkoxy C1-6 alkyl, hydroxycarbonyl,hydroxycarbonyl C1-6 alkyl, C 1-3 alkoxycarbonyl,C1-3 alkoxycarbonyl C 1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy or hydroxy C 1-6 alkyl;10 R5: R7, R8, R9, R10 and R11 are each independently selected fromhydrogen,aryl,-(CH2)p-aryl,halogen,15 hydroxyl,C1-8 alkylcarbonylamino,aryl C1-5 alkoxy,C 1-5 alkoxycarbonyl,aminocarbonyl,20 C1-8 alkylaminocarbonyl,C1-6 alkylcarbonyloxy,C3-8 cycloalkyl,oxo,amino,25 C1-6 alkylamino,amino C1-6 alkyl,arylaminocarbonyl,aryl C1-5 alkylaminocarbonyl,aminocarbonyl,30 aminocarbonyl C1-6 alkyl,hydroxycarbonyl,hydroxycarbonyl C1 -6 alkyl,C1-8 alkyl, either unsubstituted or substituted, with one or moregroups selected from: halogen, hydroxyl,?WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912-27-C1-5 alkylcarbonylamino, aryl C1-5 alkoxy,C1-5 alkoxycarbonyl, aminocarbonyl, C 1-5 a1kylaminoâcarbonyl, C 1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo,amino, C 1-3 alkylamino, amino C 1-3 alkyl, arylaminoâcarbonyl, aryl C 1-5 alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C1-4 alkyl, hydroxycarbonyl, orhydroxycarbonyl C1 -5 alkyl,-(CH2)s CECH,-(CH2)s C-â_-C-C1-6 alkyl,-(CH2)g C'=âC-C3-7 cycloalkyl,â(CH2)g CEC-aryl,-(CH2)s CEC-C1-6 alkylaryl,-(CH2)s CH=CH2,-(CH2)s CH=CH C1 -6 alkyl,-(CH2)s CH=CHâC3-7 cycloalkyl,â(CH2)s CH=CH aryl,-(CH2)s CH=CH C 1 -6 alkylaryl,-(CH2)s S02C1â6 alkyl,-(CH2)s SO2C1-6 alkylaryl,C1-6 alkoxy,aryl C1-6 alkoxy,aryl C1-6 alkyl,C 1-6 alkylamino C1-6 alkyl,arylamino,arylamino C1-6 alkyl,aryl C1-6 alkylamino,aryl C1-6 alkylamino C1-6 alkyl,arylcarbonyloxy,aryl C1 -6 alkylcarbonyloxy,C1-6 dialkylamino,C1-6 dialkylamino C1-6 alkyl,C1 -6 alkylaminocarbonyloxy,C1-8 alkylsulfonylamino,C1-8 alkylsulfonylamino C1-6 alkyl,?WO 98/08840202530CA 02263999 l999-02- 19-23-arylsulfonylamino C 1 -6 alkyl,aryl C1-6 alkylsulfonylamino,aryl C1-6 alkylsulfonylamino C1-6 alkyl,C1 -8 alkoxycarbonylamino,C1-8 alkoxycarbonylamino C1-8 alkyl,aryloxycarbonylamino C1 -8 alkyl,aryl C1 -8 alkoxycarbonylamino,aryl C1-8 alkoxycarbonylamino C1-g alkyl,C1 -8 alkylcarbonylamino,C1-8 alkylcarbonylamino C1-6 alkyl,arylcarbonylamino C1-6 alkyl,aryl C1 -6 alkylcarbonylamino,aryl C 1-6 alkylcarbonylamino C 1-6 alkyl,aminocarbonylamino C1-5 alkyl,C 1 -8 alkylaminocarbonylamino,C1-8 alkylaminocarbonylamino C1-6 alkyl,arylaminocarbonylamino C1 -6 alkyl,aryl C1-8 alkylaminocarbonylamino,aryl C1-g alkylaminocarbonylamino C1-6 alkyl,aminosulfonylamino C1-6 alkyl,C1 -8 alkylaminosulfonylamino,C1 -8 alkylaminosulfonylamino C 1-6 alkyl,arylaminosulfonylamino C1-6 alkyl,aryl C1 -8 alkylaminosulfonylamino,aryl C1-g alkylaminosulfonylamino C1-6 alkyl,C1-6 alkylsulfonyl,C 1-6 alkylsulfonyl C1-6 alkyl,arylsulfonyl C 1 -6 alkyl,aryl C1-5 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,PCT/US97/14912?WO 98/0884010CA 02263999 l999-02- 19PCT/US97/14912-29-aryl C1-5 alkylcarbonyl C 1-5 alkyl,C1 -6 alkylthiocarbonylamino,C1-6 alkylthiocarbonylamino C1-6 alkyl,arylthiocarbonylamino C1 -6 alkyl,aryl C1 -6 alkylthiocarbonylamino,aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,C1-8 alkylaminocarbonyl C1-5 alkyl,arylaminocarbonyl C1 -6 alkyl,aryl C1-8 alkylaminocarbonyl, oraryl C1-8 alkylaminocarbonyl C1-6 alkyl,wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14; and provided that the carbon atom to which R8 and R9are attached is itself attached to no more than one heteroatom; andprovided further that the carbon atom to which R10 and R11 are15attached is itself attached to no more than one heteroatom;R12 is selected from202530hydrogen,C1-8 alkyl,aryl,aryl C1-8 alkyl,hydroxy,C1-8 alkoxy,aryloxy,aryl C1-6 alkoxy,C1-8 alkylcarbonyloxy C1 -4 alkoxy,aryl C1-8 alkylcarbonyloxy C 1-4 alkoxy,C1 -8 alkylaminocarbonylmethyleneoxy, orC1 -8 dialky[aminocarbonylmethyleneoxy;m is an integer from O to 3;n is an integer from 1 to 3;p is an integer from 1 to 4;q is an integer from O to 2;?» WO 98/08840101520CA 02263999 l999-02- 19PCT/US97/14912-30-r is an integer from O to 6;s is an integer from 0 to 3; andt is an integer from O to 3;and the pharmaceutically acceptable salts thereof.In a third embodiment of the invention is a method ofeliciting an ocvB3 antagonizing effect in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of a compound of the formula0 BR R9HX-YâZ-(CH2),,âC-NAg(CO2R12H 10 11R Rwherein X is selected from1_CL_NR1R2 â-NHL-C-NFVR2â 7a 5- or 6-membered monocyclic aromatic or nonaromatic ringsystem containing 0, 1, 2, 3 or 4 heteroatoms selected from N, Oor S wherein the 5- or 6-membered ring system is eitherunsubstituted or substituted on a carbon atom with R1 and R2, ora 9- to 10-membered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ringsystem contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstitutedor substituted on a carbon atom with R1 and R2;Y is selected from?CA 02263999 l999-02- 19WO 98/08840 PCT/US97/14912_ 31 -F33 F33 ii 0llâN-(CH2)-"T" ,â(CH2)mâN- ,âcâ(cH2)r,,,â ,ââcâa}s-(cH2),â,,âR3ââr}I3â'c'â(cH2),,,â âS(O)qâ(CH2);.- ,â-o-(cH2y,7 or â(CH2).-IR :Z isa 5-1] membered aromatic or nonaromatic mono- or polycyclicring system containing 0 to 6 double bonds, and containing 0 to 65 heteroatoms chosen from N, O and S, and wherein the ringsystem is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selectedfrom R4, R5, R6 and R7; provided that Z is not a 6-memberedmonocyclic aromatic ring system; preferably Z is selected fromR4 R4// Re Re \'\ 4R Re GR R4H'.â' \/. \/ '."H E r\ââ/ N\ââ/::_ ,\\âN\r;â âti/N\\/' E K\/N\; 2;â \/J EH7 â H7 ,â R7 7H ,E:/R6 5R\\4E R4 R4 '7Z2,N:l)____§ \f\l|: §é\N//\/IRSR7 â 7R â [J R7 ' 7 âH4 R4 4 R?CA 02263999 l999-02- 19, wo 93/03340 PCT/US97/14912-32-R4 7 R7 R4 T6 R4 4RIE? C §;'â¬â\: IE23:, \R6 ,3 3 Hg E â 7 rdN C -% R\'/\\7â\; N §â"â\/ NâI-._{ Rs R6 , O Yâ; R5 )4â:4 R4 4n/\/\ 7 Au, N 3:/1ââ §ââu =7-RâH5â ⧠â Rf w , Ryk , 4..'_ 2.. 7 â- , --::«~\ EM; SW »R7 4 Pk R4R1, R2, R4, R5, R13 and R14 are each independently selected fromhydrogen, halogen, C 1- 10 alkyl, C3_8 cycloalkyl, aryl,aryl C1_8 alkyl, amino, amino C1-g alkyl, C1-3 acylamino,C 1-3 acylamino C1-g alkyl, C1-6 alkylamino, C1-6 a1kylaminoâ10 C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl,?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-33-C1-4 alkoxy, C 1-4 alkoxy C1-5 alkyl, hydroxycarbonyl,hydroxycarbonyl C 1-6 alkyl, C 1-3 alkoxycarbonyl,C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyl0xy-C1-6 alkyl, nitro, cyano, tri?uoromethyl, tri?uoromethoxy,trifluoroethoxy, C1-8 alkylâS(O)q, C1-8 aminocarbonyl,C 1-8 dialkylaminocarbonyl, C1-8 alkyloxycarbonylamino,C1-8 alkylaminocarbonyloxy or C1-8alky1su1fony1amino;R3 is selected fromhydrogen,aryl,-(CH2)p-aTY1,hydroxyl,C 1-5 alkoxycarbonyl,aminocarbonyl,C3-8 cycloalkyl,amino C 1-6 alkyl,arylaminocarbonyl,aryl C1 -5 alkylaminocarbonyl,hydroxycarbonyl C1-6 alkyl,C1-8 alkyl,aryl C1_6 alkyl,C1-6 alkylamino C 1-6 alkyl,aryl C1-6 alkylamino C1-6 alkyl,C1-6 dialkylamino C1-6 alkyl,C1-8 alkylsulfonyl,C1-8 alkoxycarbonyl,aryloxycarbonyl,aryl C1-8 alkoxycarbonyl,C1-8 alkylcarbonyl,arylcarbonyl,aryl C1-6 alkylcarbonyl,C1-8 alkylaminocarbonyl,?CA 02263999 l999-02- 19_ W0 93/03340 PCT/US97/14912-34-aminosulfonyl,C 1-8 alkylaminosulfonyl,arylaminosulfonylamino,aryl C1-8 alkylaminosulfonyl,5 C1-6 alkylsulfonyl,arylsulfonyl,aryl C1-6 alkylsulfonyl,aryl C1-6 alkylcarbonyl,C 1 -6 alkylthiocarbonyl,10 arylthiocarbonyl, oraryl C1-6 alkylthiocarbonyl,wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14;15 R6a R7, R8, R9, R10 and R11 are each independently selected fromhydrogen,aryl,-(CH2)p'aTY1,halogen,20 hydroxyl,C1 -8 alkylcarbonylamino,aryl C1-5 alkoxy,C 1-5 alkoxycarbonyl,aminocarbonyl,25 C 1 -8 alkylaminocarbonyl,C1-6 alkylcarbonyloxy,C3-8 cycloalkyl,oxo,amino,30 C1-6 alkylamino,amino C1-6 alkyl,arylaminocarbonyl,aryl C1 -5 alkylarninocarbonyl,aminocarbonyl,?- W0 98I08840202530CA 02263999 l999-02- 19-35-aminocarbonyl C1-6 alkyl,hydroxycarbonyl,hydroxycarbonyl C1 -6 alkyl,PCT/US97/14912C1-8 alkyl, either unsubstituted or substituted, with one or moregroups selected from: halogen, hydroxyl,C1-5 alkylcarbonylamino, aryl C 1-5 alkoxy,C1-5 alkoxycarbonyl, aminocarbonyl, C 1-5 alkylamino-carbonyl, C 1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo,amino, C 1-3 alkylamino, amino C1-3 alkyl, arylamino-carbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C1-4 alkyl, hydroxycarbonyl, orhydroxycarbonyl C1 _5 alkyl,â(CH2)s CECH,-(CH2)s CEC-C 1-6 alkyl,-(CH2)s CEC-C3-7 cycloalkyl,-(CH2)s C:â:C-aryl,-(CH2)g CEC-C1-6 alkylaryl,-(CH2)g CH=CH2,-(CH2)s CH=CH C1-6 alkyl,-(CH2)s CH=CHâC3-7 cycloalkyl,-(CH2)g CH=CH aryl,-(CH2)s CH=CH C1 -6 alkylaryl,-(CH2)s SO2C1-6 alkyl,-(CH2)s SO2C1-6 alkylaryl,C1-5 alkoxy,aryl C1-6 alkoxy,aryl C1-6 alkyl,C1-6 alkylamino C 1-6 alkyl,arylamino,arylamino C1-6 alkyl,aryl C1-6 alkylamino,aryl C 1-6 alkylamino C1-5 alkyl,arylcarbonyloxy,aryl C1-6 alkylcarbonyloxy,?WO 98/08840202530CA 02263999 l999-02- 19-36-C1-6 dialkylamino,C 1-6 dialkylamino C1-6 alkyl,C 1 -6 alkylaminocarbonyloxy,C1-8 alkylsulfonylamino,C1-8 alkylsulfonylamino C1-6 alkyl,arylsulfonylamino C1 -6 alkyl,aryl C1 -6 alkylsulfonylamino,aryl C 1-6 alkylsulfonylamino C 1-6 alkyl,C] -8 alkoxycarbonylamino,C1-8 alkoxycarbonylamino C1-8 alkyl,aryloxycarbonylamino C1-8 alkyl,aryl C1-8 alkoxycarbonylamino,aryl C1-8 alkoxycarbonylamino C1-8 alkyl,C1-8 alkylcarbonylamino,C1-8 alkylcarbonylamino C 1-6 alkyl,arylcarbonylamino C1-6 alkyl,aryl C1-6 alkylcarbonylamino,aryl C1-6 alkylcarbonylamino C1-6 alkyl,aminocarbonylamino C1-6 alkyl,C1 -8 alkylaminocarbonylamino,C1-8 alkylaminocarbonylamino C1-6 alkyl,arylaminocarbonylamino C1 -6 alkyl,aryl C1 -8 alkylaminocarbonylamino,aryl C1-8 alkylaminocarbonylamino C1-6 alkyl,aminosulfonylamino C1-6 alkyl,C1-8 alkylaminosulfonylamino,C1-8 alkylaminosulfonylamino C1-6 alkyl,arylaminosulfonylamino C1 -6 alkyl,aryl C1 -8 alkylaminosulfonylamino,aryl C1-8 alkylaminosulfonylamino C1-6 alkyl,C1-6 alkylsulfonyl,C1-6 alkylsulfonyl C1-6 alkyl,arylsulfonyl C1 -5 alkyl,aryl C1_6 alkylsulfonyl,PCT/US97/14912?- WO 98/088401015CA 02263999 l999-02- 19PCT/US97/14912 v-37-aryl C1-6 alkylsulfonyl C1-6 alkyl,C1-6 alkylcarbonyl,C1-6 alkylcarbonyl C1-6 alkyl,arylcarbonyl C1-6 alkyl,aryl C 1-6 alkylcarbonyl,aryl C1-6 alkylcarbonyl C1-6 alkyl,C1 -6 alkylthiocarbonylamino,C1-6 alkylthiocarbonylamino C1-6 alkyl,arylthiocarbonylamino C1 -6 alkyl,aryl C1 -6 alkylthiocarbonylamino,aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,C1-8 alkylaminocarbonyl C1-6 alkyl,arylaminocarbonyl C1 -6 alkyl,aryl C1-8 alkylaminocarbonyl, oraryl C1-8 alkylaminocarbonyl C1-6 alkyl,wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14; and provided that the carbon atom to which R8 and R9are attached is itself attached to no more than one heteroatom; andprovided further that the carbon atom to which R10 and R11 are20attached is itself attached to no more than one heteroatom;R12 is selected from2530hydrogen,C1-8 alkyl,aryl,aryl C1-8 alkyl,hydroxy,C1-8 alkoxy,aryloxy,aryl C1-6 alkoxy,C1-8 alkylcarbonyloxy C1-4 alkoxy,aryl C1_8 alkylcarbonyloxy C 1-4 alkoxy,C1 -8 alkylaminocarbonylmethyleneoxy, orC 1 -8 dialkylaminocarbonylmethyleneoxy;?WO 9810884010152025CA 02263999 l999-02- 19PCT/US97/14912.33.m is an integer from O to 3;n is an integer from 1 to 3;p is an integer from 1 to 4;q is an integer from O to 2;r is an integer from O to 6; ands is an integer from 0 to 3;and the pharmaceutically acceptable salts thereof.Illustrating the invention is the method wherein the OCVB3antagonizing effect is selected from inhibition of bone resorption,inhibition of restenosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofatherosclerosis, in?ammation or inhibition of tumor growth.Preferably, the OLVB3 antagonizing effect is the inhibition of boneresorption. . *An illustration of the invention is a compound of theformula0 BR R9llX_Y_z_(CH2)_r1_C_ m)%(CO2Rl210R R11wherein X isa 9- to 10-membered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ringsystem contains 0, l, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstitutedor substituted on a carbon or nitrogen atom with one or moregroups chosen from R1, R2, R15 or R16;Y is selected from?CA 02263999 l999-02- 19W0 93/03340 PCT/US97ll4912-39-â '33 nââ(CH2)râN-(CH2)arâ , â(CH2h-C-(CH2); ,H II""(CH2)iâC"F}1"(CH2)F , â-(cH2)r-'.â-Câ<cH2>:n-R3 1â(cH2),ââs(o)§âI}Iâ(cH2),,,â , â-(CH2);-Nâ-S(0)2-(CH2)ar_R3 R3"â(CH2)tâS(O)q-(CH2)-,7 , ââ(CH2>t-O-(CH2); or â(CH2)râ?Zisa 5-11 membered aromatic or nonaromatic mono- or polycyclicring system containing 0 to 6 double bonds, and containing 0 to 65 heteroatoms chosen from N, O and S, and wherein the ringsystem is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selectedfrom R4, R5, R6 and R7; provided that Z is not a 6-memberedmonocyclic aromatic ring system, an isoxazoline ring or an10 isoxazole ring;R1, R2, R4, R5, R13, R14, R15 and R16 are each independently selectedfromhydrogen, halogen, C1- 10 alkyl, C3-g cycloalkyl,15 C3-3 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl,C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-8 alkyl, amino,amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl,(C1 -6 alkyl)qamino, (C1-6 alkyl)qamino C1-8 alkyl,C1-4 alkoxy, C 1-4 alkoxy C1-6 alkyl, hydroxycarbonyl,20 hydroxycarbonyl C1-6 alkyl, C 1-3 alkoxycarbonyl,C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C 1-6 alkyloxy-C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy,?â WO 98/08840CA 02263999 l999-02- 19PCT/US97/14912-40-tri?uoroethoxy, C1-g alkyl-S(O)q, (C 1-8 a1kyl)qaminocarbonyl,C 1-8 alkyloxycarbonylamino, (C 1-8 alkybqaminocarbonyloxy,oxo, (aryl C1-8 alkyl)qamino, (aryl)qamino,aryl C1-8 alkylslfonylamino or C1-g alkylsulfonylaminogR3 is selected from1015202530hydrogen,aryl,aryl-(CH2)p-,hydroxy],C1-5 alkoxy,aminocarbony],C3-8 cycloalkyl,amino C1-6 alkyl,(aryl)qaminocarbonyl,(aryl C1 -5 a1ky1)qaminocarbony1,hydroxycarbonyl C1 -6 alkyl,Cl-8 alkyl,aryl C1-6 alkyl,(C 1-6 aIky1)qamino C1-6 alkyl,(aryl C1-6 alky1)qamino C1-6 alkyl,C1-8 alkylsulfonyl,C1_8 alkoxycarbonyl,aryloxycarbonyl,aryl C1-g alkoxycarbonyl,C1-g alkylcarbonyl,arylcarbonyl,aryl C1-6 alkylcarbonyl,(C1-8 a1kyl)qaminocarb0nyl,aminosulfonyl,C1-8 alkylaminosulfonyl,(aryhqaminosulfonylamino,(aryl C1-g alkybqaminosulfonyl,C1-6 alkylsulfonyl,?CA 02263999 l999-02- 19W0 98/08840 PCT/U S97/ 14912arylsulfonyl,aryl C1-6 alkylsulfonyl,aryl C1-6 alkylcarbonyl,C1 -6 alkylthiocarbonyl,5 arylthiocarbonyl, oraryl C1-6 alkylthiocarbonyl, _wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14;10 R6: R7, R8, R9, R10 and R11 are each independently selected fromhydrogen,aryl,arylâ(CH2)p-,a1'Y1â(CH2)n-0-(CH2)m-,15 31'Y1'(CH2)n-S(0)q-(CH2)m-,aryl-(CH2)n-C(0)-(CH2)m-,aryl-<cH2>n-c<o>-N(R3>-<cH2>m-,aryl-(CH2)n-N<R3)-c(0>-<cH2>mâ,aryl-<cH2>n-N(R3>-<cH2)m-,20 halogen,hydroxyl,C1 -8 alkylcarbonylamino,aryl C1-5 alkoxy,C 1-5 alkoxycarbonyl,25 (C 1-8 a1ky1)qaminocarbonyl,C1-6 alkylcarbonyloxy,C3-8 cycloalkyl,oxo,(C1-6 alkyl)qamin0,30 amino C1-6 alkyl,arylaminocarbonyl,aryl C1-5 alkylaminocarbonyl,aminocarbonyl,aminocarbonyl C 1-6 alkyl,?*WO 98/0884010202530CA 02263999 l999-02- 19_42_hydroxycarbonyl,hydroxycarbonyl C1-6 alkyl,PCT/US97/14912C1-3 alkyl, either unsubstituted or substituted, with one or moregroups selected from: halogen, hydroxyl,C 1-5 alkylcarbonylamino, aryl C 1-5 alkoxy,C 1-5 alkoxycarbonyl, aminocarbonyl, (C1-5 alkyl)qamino-carbonyl, C 1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo,(C 1-3 alkyl)qamino, amino C1-3 alkyl,(aryl)qaminocarbony1, (aryl C 1-5 alkyl)qaminocarbonyl,aminocarbonyl, aminocarbonyl C1-4 alkyl,hydroxycarbonyl or hydroxycarbonyl C1-5 alkyl,CHEC~(CH2)s-,C 1-6 alkyl-Cs-C-(CH2)s-,C3-7 cycloalkyl-CEC-(CH2)gâ,aryl-C-=-C-(CH2)sâ,C1 -6 a1kylary1~CsCâ(CH2)sâ,CH2=CH-(CH2)sâ,C1 -6 alky1âCH=CHâ(CH2)s-,C3-7 cycloalkyl-CH=CH-(CH2)sâ,aryl-CH=CH-(CH2)s-,C1 -6 alkylaryl-CH=CH-(CH2)s-,C1 -6 alkyl-S02~(CH2)sâ,C1 -6 alkylarylâSO2â(CH2)s-,C 1-6 alkoxy,aryl C1-5 alkoxy,aryl C 1-6 alkyl,(C1-5 alkyl)qamino C1-6 alkyl,(aryl)qamino,(ary1)qamino C1-6 alkyl,(aryl C1-6 alky1)qamino,(aryl C1_6 a1ky1)qamino C1-5 alkyl,arylcarbonyloxy,aryl C1-6 alkylcarbonyloxy,(C1-6 a1kyl)qaminocarbonyloxy,?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-43-C1-8 alkylsulfonylamino,arylsulfonylamino,C1-8 alkylsulfonylamino C1-6 alkyl,arylsulfonylamino C1 -6 alkyl,aryl C1 -6 alkylsulfonylamino,aryl C1-6 alkylsulfonylamino C1-6 alkyl,C 1 -8 alkoxycarbonylamino,C1_8 alkoxycarbonylamino C1-8 alkyl,aryloxycarbonylamino C1-8 alkyl,aryl C 1-8 alkoxycarbonylamino,aryl C1-8 alkoxycarbonylamino C1-8 alkyl,C1-8 alkylcarbonylamino,C1-8 alkylcarbonylamino C1-6 alkyl,arylcarbonylamino C1 -6 alkyl,aryl C1-6 alkylcarbonylamino,aryl C1-6 alkylcarbonylamino C1-6 alkyl,aminocarbonylamino C1-6 alkyl,(C 1 -8 alkybqaminocarbonylamino,(C 1 -8 alkyhqaminocarbonylamino C1-6 alkyl,(aryl)qaminocar_bonylamino C1-6 alkyl,(aryl C1-8 alkybqaminocarbonylamino,(aryl C1-8 alkybqaminocarbonylamino C1-6 alkyl,aminosulfonylamino C1 -6 alkyl,(C1-8 alkybqaminosulfonylamino,(C1-8 alkyhqaminosulfonylamino C1-6 alkyl,(arybqaminosulfonylamino C1-6 alkyl,(aryl C1 -8 alkyhqaminosulfonylamino,(aryl C1-8 alkyhqaminosulfonylamino C1-6 alkyl,C1-6 alkylsulfonyl,C1-6 alkylsulfonyl C1-6 alkyl,arylsulfonyl C 1 -6 alkyl,aryl C1-6 alkylsulfonyl,aryl C1-6 alkylsulfonyl C1_6 alkyl,C1-6 alkylcarbonyl,?9 WO 98/0884010CA 02263999 l999-02- 19PCT/US97/14912-44-C1-6 alkylcarbonyl C1-6 alkyl,arylcarbonyl C1 -6 alkyl,aryl C1 -6 alkylcarbonyl,aryl C1-6 alkylcarbonyl C1-6 alkyl,C1 -5 alkylthiocarbonylamino,C1-6 alkylthiocarbonylamino C1-6 alkyl,arylthiocarbonylamino C1 -6 alkyl,aryl C1-6 alkylthiocarbonylamino,aryl C1-5 alkylthiocarbonylamino C1-6 alkyl,(C 1-8 alkyl)qaminocarbonyl C 1-6 alkyl,(aryl)qaminocarbonyl C1 -6 alkyl,(aryl C1-8 alkyl)qaminocarbonyl, or(aryl C1-8 alkyhqaminocarbonyl C1-6 alkyl,wherein any of the alkyl groups may be unsubstituted or substituted with15 R13 and R14; and provided that the carbon atom to which R8 and R9are attached is itself attached to no more than one heteroatom; andprovided further that the carbon atom to which R10 and R11 areattached is itself attached to no more than one heteroatom;202530R12 is selected fromhydrogen,C1-g alkyl,aryl,aryl C1-3 alkyl,C1-g alkylcarbonyloxy C1-4 alkyl,aryl C1-8 alkylcarbonyloxy C1-4 alkyl,C1 -8 alkylaminocarbonyhnethylene, orC1 -8 dialkylaminocarbonylmethylene;m, s and t are each independently an integer from 0 to 3;n is an integer from 1 to 3;p is an integer from 1 to 4;q is an integer from O to 2;r is an integer from O to 6;?CA 02263999 l999-02- 19_ wo 93/03340 PCT/US97/ 14912-45-and the pharmaceutically acceptable salts thereof.Particularly illustrative of the invention is the compoundwherein Z is a 5-11 membered nonaromatic mono- or polycyclic ring5 system containing 0 to 6 double bonds, and containing 0 to 6heteroatoms chosen from N, O and S, and wherein the ring system iseither unsubstituted or substituted on a carbon or nitrogen atom withone or more groups independently selected from R4, R5, R6 and R7;and all other variables are as defined above.10 Exemplifying the invention is the compound whereinZ is selected fromR4 H4 44% H5â//\/.R6 R6\./\'?ââ E r\"/NR6 6RN\"/3,;\\;;r:«» t ~<~~\:7 M; *5 R;/âR4 41:; iE N//NR2} Z':?'}\'L § \Nâ :R6 LNâ/\4 R5. â â . ââ _ /'\\R7 â 7R// L/JN 5 K\,.g\;7R4 R4 R4R R7if/â/'â5 § (5.496 6â~\â\ââ-â§\\F;C"£ , \\â, :6â , âL:'j;//R4 7 R4 R6 R4?CA 02263999 l999-02- 197 WO 98/08840 PCT/US97/14912-46-R4 R4 4 7Fâ7?<\ /Hâ; 37> /N:: E E N§\/ \â;/;HN / \/ \ \ \âHf \Râ°â =15â R6 0 9;â R6 \râ'J4 R4 R4in,â R7 M w\ â l IRSV 5 Re âr FL%§âNâ§4§_<Né::7 é?u-IN/WR, .â:«~\ RM; RM;\ R7 R4 R7 R4%-$4 i%â:.. N\ - \R6\/ 5; R:\/ 9;5 and the pharmaceutically acceptable salts thereof. Preferably Z isselected fromOHN JL/~|R4 §_l|:\/<N\§g [£40 gâN%i9)\H/N7â Kg â $âJ\â<N\§ , 4R)\\<N\$ ,0 â 0 O?CA 02263999 l999-02- 19, wo 93/03340 PCT/US97/14912 _.47.(â/34 K/R4 /*F|â:\2/ $'â':5 §_<rfNâ3 ,§_*«Nâ5 , âzâ\<ââ§O , O O O âO\ JL R4 4 All/\ /1: sg,"â~1.O§âa";Or§â2{jâ,sâR4 0fâ â: .J;ââ~â;,,R4â //R42 O 5 2 ONA/|R4 âgm N/*/N. I _2%'râ\;. z?râ\5 *1/?râ? ,O , W93â?â WO 9810884010152025CA 02263999 l999-02- 19PCT/US97/14912-48-An example of the invention is the compound of theformulaR80XâY-ZâCH2IC|NH/K/CO2R12wherein X is selected fromRâ :1 2 Râ/CIZH Kl??? oi HY is selected from -(CH2)r- or -(CH2)m-NR3-(CH2)t-;R3 is selected fromhydrogen,aryl-(CH2)p-,C1-5 alkoxycarbonyl,C3-g cycloalkyl,(aryl)qaminocarbonyl,(aryl C 1-5 a1kyl)qaminocarbonyl,C1-8 alkyl,aryl C1-6 alkyl,C1-g alkylsulfonyl,arylsulfonyl,aryl C1-6 alkylsulfonyl,C1_8 alkoxycarbonyl,aryloxycarbonyl,aryl C1-8 alkoxycarbonyl,C1-8 alkylcarbonyl,arylcarbonyl,aryl C1-6 alkylcarbonyl,(C 1 -3 a1kyl)qaminocarbonyl,C1_6 alkylsulfonyl, oraryl C1-6 alkylcarbonyl,?WO 98/08840510202530CA 02263999 l999-02- 19PCT/U S97/ 14912-49-wherein any of the alkyl groups may be unsubstituted orsubstituted with R13 and R14;R4 is selected fromhydrogen, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl,C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C 1-6 alkyl,aryl or aryl C1-8 alkyl,R8 is selected fromhydrogen,aryl,aryl-(CH2)p-,CHEC-(CH2)s-,C1-6 alkyl-CEC-(CH2)s-,C3-7 cycloalkyl-CEC-(CH2)sâ,aryl-Ca-C-(CH2)sâ,C 1-6 alkylaryl-C'=âC-(CH2)g-,CH2-'-'-CH-(CH2)s-,C1 -6 alkyl-CH=CH-(CH2)s-,C3-7 cycloalkyl-CH=CH-(CH2)gâ,aryl-CH=CH-(CH2)gâ,C1-6 alkylaryl-CH=CH-(CH2)g-,C1-6 alkyl-S02-(CH2)s-,C1-5 alkylarylâSO2â(CH2)s-: andr is an integer from 0 to 3;wherein all other variables are as defined above;and the pharrnaceutically acceptable salts thereof.Further illustrating the invention is the compound of the(T51N NHformulaII /â</co2Râ2vâ Z-CHZCNH?CA 02263999 l999-02- 19,w() 93/03840 PCT/US97l149l2_ 50 _wherein Z is selected from4 R4 R4:41 /1 I«v-LLâ,N\n/N\$ !..LLâ 0 N\f§ âE ââ\T4,1â/Nâ ~~s %§3;~â% ,0 â 0/R4 /R4 0 NH-71. l N\§é â âLA I N\g âori4I N\fv5 ,R8 is selected fromhydrogen,/ /1 ___/ / Oâ_\I .âQ\)F, q\1j,ââ:/\l[o>a/ \ / Oâ~ «ea â@ , l\N/ , \| N>:O.Hindolyl-(CH2)p-,CHEC-(CH2)sâ,C1-5 alkyl-CEC-(CH2)S-,C3-7 cycloalkyl-CEC-(CH2)sâ,10 aryl-CsCâ(CH2)sâ,C1 -6 alkylaryl-C_=.C-(CH2)s-,CH2=CHâ(CH2)sâ,C1 -6 alkyl-CH=CHâ(CH2)s-,C3-7 cycloalkyl-CH=CH-(CH2)S-,15 ary1-CH=CH-(CH2)s-,?- WO 98/0884!)1015202530CA 02263999 l999-02- 19PCT/US97/14912-51-C1_5 alkylaryl-CH=CH-(CH2)sâ,C1-6 alkyl-S02-(CH2)sâ,C1-6 alkylarylâSO2-(CH2)gâ; andR12 is selected from hydrogen or C1-8 alkyl; ands is an integer from O to 3;and all other variables are as defined above;and the pharmaceutically acceptable salts thereof.Further exemplifying the invention is the compoundselected from2âOxo-3-[2-(5,6,7,8-tetrahydro[1,8]ânaphthyridinâ2-yl)ethyl]piperidinâlâyl-acetyl-3(S)-pyridinâ3~yl-[3âalanine ethyl ester;2âOxo-3-[2â(5,6,7,8-tetrahydro[1,8]ânaphthyridin-2-y1)ethyl]piperinâ1-yl-acetyl-3(S)âpyridin-3-ylâBâalanine tri?uoroacetate;2-Oxo-3(S)-[2â(5,6,7,8-tetrahydro[1,8]-naphthyridinâ2-yl)ethyl]pyrrolidinâ1âyl)acetylâ3(S)-alkynyl-B-alanine ethyl ester;2âOxo-3(S)â[2â(5,6,7,8-tetrahydro[1,8]-naphthyridinâ2âyl)ethyl]pyrro1idin- l âyl)acetyl-3(S)-alkynyl-B-alanine;2-Oxo-3(S)-[2â(5,6,7,8-tetrahydro[ 1,8]-naphthyridin-2-y1)ethyl]-pyrrolidin-1-yl)acetylâ3(S)âpyridinâ3-yl-Bâalanine ethyl ester;2-Oxo-3(S)-[2-(5,6,7,8âtetrahydro[1,8]-naphthyridinâ2âyl)ethyl]pyrrolidin-1-yl)acetyl-3(S)-pyridin-3-ylâBâala.nine;2âOxo-3(R)â [2â(5 ,6,7,8-tetrahydro[1,8]~naphthyridin-2-yl)ethyl]pyrro1idinâ1-yl)acetyl-3(S)-alkynyl-B-alanine ethyl ester;2âOxo-3(R)â [2â(5 ,6,7,8-tetrahydro[1,8]ânaphthyridin-2-yl)ethy1]pyrrolidin-1-yl)acetylâ3(S)-alkynyl-[3-alanine;?â W0 98l08840IO15202530CA 02263999 l999-02- 19PCT/US97/14912-52-2âOxo-3(R)-[2â(5,6,7,8âtetrahydro[1,8]-naphthyridin-2âyl)ethyl]-pyrrolidinâ1-yl)acety1-3(S)-pyridin-3-yl-[3-alanine ethyl ester;2-Oxoâ3(R)â[2-(5 ,6,7,8âtetrahydro[l ,8]-naphthyridin-2-yl)ethyl]pyrro1idin-1ây1)acety1â3(S)-pyridin-3-yl-B-alanine;Ethyl 2âoxo-3-[2-(5,6,7,8âtetrahydro[l ,8]naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-1-yl-acetyl-3(S)-pyridin-3-yl-B-alanine;2-Oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-tetrahydropyrimidin-l -yl-acetyl-3 (S)-pyridin-3-yl-B-alanine;Ethyl 2-Oxo-3-[2-(5,6,7,8âtetrahydr0[1,8]naphthyridin-2-yl)ethyl]imidazo1idinâl-yl-acetyl-3(S)-pyridin-3-yl-B-alanine;2-Ox0-3- [2-(5 ,6,7,8âtetrahydro[l ,8]naphthyridinâ2âyl }ethyl]âimidazolidin-l -yl-acetyl-3 (S )-pyridinâ3-yl-B-alanine;Ethyl 2-Oxo-3(R)â[2â(5,6,7,8-tetrahydro[1,8]naphthyridinâ2-yl)ethyl]pyrrolidinâl-y1)acetylâ3(R)-(2-ethylindol-3-yl)-[3-alanine;2âOxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)et11yl]pyrrolidin-lâyl)acetyl-3(R)-(2-ethylindol-3-yl)-[3-alanine;Ethyl 3-(2-{ 2-Oxo-3(S)-[(5,6,7,8-tetrahydro-[l ,8]naphthyridin-2-ylmethyl)âamino]âpyrro1idin-1-yl}-acety1amino)â3â(S)-pyridin-3-ylâpropionic acid;3 -(2-{ 2-Oxo-3(S)-[(5 ,6,7,8-tetrahydro-[1,8]naphthyridin-2âylmethyl)-amino]pyrrolidin-1 -yl } -acetylamino)-3-(S)âpyridin-3-ylâpropionic acid;?9 WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-53-3-{2â[6-Oxo-1â(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)âhexahydr0â(3aS, 6aS)pyrrolo[3,4-b]pyrrol-5-yl]-acetylamino ] â3â(S)âpyridinâ3-ylâpropionic acid;3-{2-[6âOxoâ1â(5,6,7,8-tetrahydro-[1,8]naphthyridinâ2-ylmethyl)-hexahydro-(3aR, 6aR)pyrr0lo[3,4-b]pyrrol-5~yl]âacetylamino}â3â(S)-pyridinâ3-ylâpropionic acid;2âOxo-5(R)-methyl-3(S)-[2â(5,6,7,8âtetrahydro[1,8]ânaphthyridin-2-y])-ethyl]pyrrolidin-1-yl)acetyl-3(S)âalkynyl-|3âalanine ethyl ester;2-Oxo-5(R)-methyl-3(S)-[2â(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-y1)ethyl]pyrro1idin-1-yl)acetyl-3(S)-alkynyl-[3-alanine;2âOxoâ5(S)-benzyl-3(S)â[2-(5 ,6,7,8âtetrahydro[ 1,8]-naphthyridin-2-yl)-ethyl]pyrrolidin-1-yl)acety1-3(S)-pyridinâ3-yl-[3-alanine ethyl ester;2-Oxo-5(S)-benzylâ3(S)-[2â(5,6,7,8-tetrahydr0[1,8]-naphthyridin-2-yl)ethy1]pyrro1idin-1-yl)acetylâ3(S)âpyridin-3-ylâBâalanine;5(R)-Methylâ2-oxo-3(S)â[2-(5,6,7,8-tetrahydr0[1,8]-naphthyridin-2-ylmethyl)-amin0]pyrr0lidin-1-yl)acetyl-3(S)-alkyny1â[3âa1anine ethylester;5(R)âMethyl-2âoxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)-amino]pyrro1idinâ1-yl)acetyl-3(S)-a1kyny]~|3âalanine;3(S)-(2,3-Dihydro-benzofuranâ6-yl)â3â(2â { 2â0xoâ3(S)-[2â(5,6,7,8-tetrahydro-[1,8]naphthyridinâ2-y1)âethyl]-pyrro1idinâ1âyl}-acetylamino)-propionic acid ethyl ester; or3(S)â(2,3-Dihydroâbenzofuran-6-yl)â3-(2â { 2-oxo-3(S)â[2â(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)âethy1]-pyrro1idinâ1âyl}-acetylamino)-propionic acid;?1015202530and the pharmaceutically acceptable salts thereof.Preferably, the compound is selected from2-Oxo-3â[2-(5,6,7,8-tetrahydro[ 1 ,8] -naphthyridin-2-y1)ethyI]piperin-1-yl-acetylâ3(S)-pyridinâ3-yl-[3-alanine tri?uoroacetate;2-Oxo-3(S)-[2-(5,6,7,8âtetrahydro[1,8]-naphthyridin-2-y1)ethy1]pyrrolidin-1ây1)acety1-3(S)-alkynyl-B-alanine;2âOxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethy1]pyrr0lidin-1-y1)acetylâ3(S)-pyridin-3-yl-B-alanine;2âOxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]ânaphthyridin-2-y1)ethy1]pyrro1idin-1 -yl)acety1â3(S)-alkynyl-[3-alanine;2âOx0-3(R)â[2â(5 ,6,7,8-tetrahydro[ 1 ,8]-naphthyridin-2-yl)ethyl]pyrrolidin-l-yl)acetyl-3(S)-py?din-3-yl-[3âalanine;2âOxo-3-[2-(5,6,7,8âtetrahydro[1,8]naphthyridin-2-yl }ethyl]-imidazolidin-1-yl-acetyIâ3-(S)-pyridin-3-yl-B-alanine;2-Oxoâ3-[2â(5 ,6,7,8-tetrahydro[1,8]naphthyridin-2-yl}ethyl]-tetrahydropyrimidinâ1-yl-acetyl-3-(S)âpyridin-3-yl-B-alanine;2âOxo-3(R)-[2-(5,6,7,8-tetrahydro [1 ,8]naphthyridin-2-y1)ethyl]pyrrolidin-1-yl)acety1â3(R)-(2-ethylindolâ3âyl)â[3âalanine;CA» WO 98/0884002263999 1999-02-19PCT/US97/149123-(2- { 2-Oxo-3(S)-[(5 ,6,7,8âtetrahydro-[1,8]naphthyridin-2âylmethyl)-amino]pyrrolidin-1-yl}-acetylamino)-3-(S)-pyridin-3-yl-propionic aci3- { 2-[6-Oxo-1 â(5 ,6,7 ,8-tetrahydro-[1,8]naphthy?din-2-ylmethyl)-hexahydro-(3aS , 6aS)pyrrol0[3 ,4-b]pyrrol~5-yl]âacetylamino } â3-(S)-pyridin-3-yl-propionic acid; ord;?VWO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912_ 55 _3- { 2-[6-Oxoâl -(5,6,7,8âtetrahydro-[1 ,8]naphthyridin-2-ylmethyl)-hexahydro-(3aR, 6aR)pyrro1o[3 ,4-b]pyrrolâ5-yl] -acetylamino } -3-(S)-pyridin-3-ylâpropionic acid;2âOxo-5(R)-methylâ3(S)-[2â(5,6,7,8âtetrahydro[1,8]-naphthyridin-2-yl)ethyl]pyrrolidinâ 1 -yl)acetyl-3 (S)âalkyny1âB-alanine;2-Oxo-5(S)-benzylâ3(S)â[2â(5 ,6,7 ,8-tetrahydro[1,8]-naphthyxidinâ2-yl)ethyl]pyrrolidinâ l -yl)acetyl-3(S)-pyridin-3-yl-[3-alanine;5(R)âMethyl-2-oxo-3(S)-[2â(5 ,6,7,8-tetrahydro[1 ,8]-naphthyridin-2-âylmethyl)âamino]pyrrolidinâ1-yl)acetylâ3(S)âalkynyl-[3âalanine; or3(S)â(2,3-Dihydro-benzofuranâ6âyl)-3-(2- { 2-oxoâ3(S)â[2-(5,6,7,8-tetrahydro- [1 ,8]naphthyridinâ2âyl)-ethyl] âpyrrolidin- 1 -yl } âacetylamino)~propionic acid;and the pharmaceutically acceptable salts thereof.An additional example of the invention is a compound ofthe formula0 8R R9isx-v-z-(cH2r,,âcâI;n|>g(C02Flâ210R R11wherein X isa 9- to 10-membered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ringsystem contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstitutedor substituted on a carbon atom with R1 and R2;Y is selected from?CA 02263999 l999-02- 19, wo 93/03340 PCT/US97/14912-56-R3 ['33 (B OI nââN-<cH2>mâ , â<CH2>mâNâ ,-Câ<cH2rm- .âcâr}Iâ<cH2>m-R39? .-'}|âC-(CH2); ,âs<o>q-(CH2)-n: , âoâ<cH2>; or â<cH2>,âyR3Zisa 5-1] membered aromatic or nonaromatic mono- or polycyclicring system containing 0 to 6 double bonds, and containing 0 to 65 heteroatoms chosen from N, O and S, and wherein the ringsystem is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selectedfrom R4, R5, R6 and R7; provided that Z is not a 6-memberedmonocyclic aromatic ring system; preferably, Z is selected from4R 0 4-E 0 Ni; â Kg â 4R)\â( 35 â10 O â 0R4I/:4 Iâ¬@\;T % xgwxg y: \g A?CA 02263999 l999-02- 197 WO 98/08840 PCT/US97/ 14912-57-O 4;\N)J/âIR /R4KâfN\ N\ N N\ /1 'âTR405 "2. 5,â:/WOr§,â¬,q\«*â/R4 0NH{\ _§ mi N>J_r ,âHf O O4 R4\; 32/ O E ,N/y|H4 ' N%F{4 N/§/NR4I Iâ%râ⧠, â2iCgfN⧠, %rââsâNâ W55â,2/âW01/L; â 32,NE,N\;g Y 0' «,3/N\é/N\gé.R1, R2, R3, R4, R5, R13 and R14 are each independently selected from5 hydrogen, halogen, C1- 10 alkyl, C3-8 cycloalkyl, aryl,aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino,C 1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylaminoâC1-8 alkyl, C1-6 dialkylamino, C1-5 dialkylamino C1-8 alkyl,C1-4 alkoxy, C 1-4 alkoxy C1-6 alkyl, hydroxycarbonyl,?. WO 98/0884051015202530CA 02263999 l999-02- 19PCT/US97/14912-58-hydroxycarbonyl C1-6 alkyl, C 1-3 alkoxycarbonyl,C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy or hydroxy C 1-6 alkyl;R6: R7, R8, R9, R10 and R11 are each independently selected fromhydrogen,aryl,-(CH2)p'aFy1,halogen,hydroxyl,C1-8 alkylcarbonylamino,aryl C1-5 alkoxy,C1-5 alkoxycarbonyl,aminocarbonyl,C 1-8 alkylaminocarbonyl,C1-6 alkylcarbonyloxy,C3-g cycloalkyl,oxo,amino,C1_6 a1ky1amino,.amino C1-6 alkyl,arylaminocarbonyl,aryl C1 -5 alkylaminocarbonyl,aminocarbonyl,aminocarbonyl C1-6 alkyl,hydroxycarbonyl,hydroxycarbonyl C1-6 alkyl,C1-8 alkyl, either unsubstituted or substituted, with one or moregroups selected from: halogen, hydroxyl,C 1-5 alkylcarbonylamino, aryl C 1-5 alkoxy,C 1-5 alkoxycarbonyl, aminocarbonyl, C1-5 a1kylarnino-carbonyl, C 1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo,amino, C1-3 alkylamino, amino C 1-3 alkyl, arylamino-carbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl,?WO 98/08840202530CA 02263999 l999-02- 19-59-aminocarbonyl C1-4 alkyl, hydroxycarbonyl, orhydroxycarbonyl C1-5 alkyl,-(CH2)s CECH,-(CH2)s CEC-Clâ6 alkyl,-(CH2)s CEC-C3-7 cycloalkyl,-(CH2)g CECâaryl,-(CH2)g CEC-C 1 -6 alkylaryl,-(CH2)5 CH=CH2,-(CH2)s CH=CH C1-6 alkyl,-(CH2)g CH=CH-C3-7 cycloalkyl,-(CH2)g CH=CH axyl,â(CH2)s CH=CH C1-6 alkylaryl,-(CH2)s SO2C1-6 alkyl, or-(CH2)s SO2C1-6 alkylaryl;C 1-6 alkoxy,aryl C1-6 alkoxy,aryl C1-6 alkyl,C1-6 alkylamino C 1-6 alkyl,arylamino, 9arylamino C1-6 alkyl,aryl C1-6 alkylamino,aryl C1-6 alkylamino C1-6 alkyl,arylcarbonyloxy,aryl C1 -6 alkylcarbonyloxy,C1-6 dialkylamino,C1-6 dialkylamino C 1-6 alkyl,C1 -6 alkylaminocarbonyloxy,C1-8 alkylsulfonylamino,C1-8 alkylsulfonylamino C1-6 alkyl,arylsulfonylamino C1 -6 alkyl,aryl C1-5 alkylsulfonylamino,aryl C1-6 alkylsulfonylamino C 1-6 alkyl,C1 -8 alkoxycarbonylamino,C1-8 alkoxycarbonylamino C1-8 alkyl,PCT/US97/ 14912?â WO 98/088401015202530CA 02263999 l999-02- 19-60-aryloxycarbonylamino C1 -8 alkyl,aryl C1 -8 alkoxycarbonylamino,aryl C1-8 alkoxycarbonylamino C1-8 alkyl,C1 -8 alkylcarbonylamino,C1-8 alkylcarbonylamino C1-6 alkyl,arylcarbonylamino C1 -6 alkyl,aryl C1 -6 alkylcarbonylamino,aryl C1-6 alkylcarbonylamino C1-6 alkyl,aminocarbonylamino C1 -6 alkyl,C1 -8 alkylaminocarbonylamino,C 1-8 alkylaminocarbonylamino C1-6 alkyl,arylaminocarbonylamino C1 -6 alkyl,aryl C1-8 alkylaminocarbonylamino,aryl C1-8 alkylaminocarbonylamino C1-6 alkyl,aminosulfonylamino C1 -6 alkyl,C1 -8 alkylaminosulfonylamino,C 1-8 alkylaminosulfonylamino C1-6 alkyl,arylaminosulfonylamino C1 -6 alkyl,aryl C 1 -8 alkylaminosulfonylamino,aryl C1-8 alkylaminosulfonylamino C 1-6 alkyl,C1-6 alkylsulfonyl,C1-5 alkylsulfonyl C1_6 alkyl,arylsulfonyl C1-6 alkyl,aryl C1-6 alkylsulfonyl,aryl C 1-6 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 C 1-6 alkyl,C1-6 alkylthiocarbonylamino,C1-6 alkylthiocarbonylamino C1-6 alkyl,arylthiocarbonylamino C1 -6 alkyl,aryl C1 -6 alkylthiocarbonylamino,PCT/US97ll49l2?CA 02263999 l999-02- 19; W5 98,088,â, PCT/US97/14912- 61 -aryl C1-6 alkylthiocarbonylamino C 1-6 alkyl,C1-8 alkylaminocarbonyl C1-6 alkyl,arylaminocarbonyl C1 -6 alkyl,aryl C1-8 alkylaminocarbonyl, or5 aryl C1-8 alkylaminocarbonyl C1-6 alkyl,1015202530wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14; and provided that the carbon atom to which R8 and R9are attached is itself attached to no more than one heteroatom; andprovided further that the carbon atom to which R10 and R11 areattached is itself attached to no more than one heteroatom;R12 is selected fromhydrogen,C1âs alkyl,aryl,aryl C1-8 alkyl,hydroxy,C1-8 alkoxy,aryloxy,aryl C1-6 alkoxy,C1-8 alkylcarbonyloxy C1-4 alkoxy,aryl C1-8 alkylcarbonyloxy C1-4 alkoxy,C1 -8 alkylaminocarbonylmethyleneoxy, orC1 -8 dialkylaminocarbonylmethyleneoxy;m is an integer from O to 3;n is an integer from 1 to 3;p is an integer from 1 to 4;q is an integer from O to 2;r is an integer from 0 to 6; ands is an integer from 0 to 3;and the pharmaceutically acceptable salts thereof.An additional illustration of the invention is a compound ofthe formula?CA 02263999 l999-02- 19, WO 98/08840 PCT/US97/14912-62-0 BR R9llX_Y_z_(CH2)?â_C _?>%(CO2R1210R H11wherein X isa 9- to 10-membered polycyclic ring system, wherein one ormore of the rings is aromatic, and wherein the polycyclic ring5 system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O orS, and wherein the polycyclic ring system is either unsubstitutedor substituted on a carbon atom with R1 and R2;Y is selected fromR3 $3 3' ll*'-N"(CH2)aâ ,--(CH2)-,,,-Nâ ,âc-(CH2); ,âc-r}nâ(cH2);R3âNâ(|3lâ(CH2),7 âS(O)q-(CH2); ,âO-(CH2);n- or -â(CH2)r-i10 R3 1Z isa 5-11 membered aromatic or nonaromatic mono- or polycyclicring system containing 0 to 6 double bonds, and containing 0 to 6heteroatoms chosen from N, O and S, and wherein the ring15 system is either unsubstituted or substituted on a carbon ornitrogen atom with one or more groups independently selectedfrom R4, R5, R6 and R7; provided that Z is not a 6-memberedmonocyclic aromatic ring system; preferably, Z is selected from?CA 02263999 l999-02- 19WO 98/08840 PCT/US97l14912 â_ 63 _R4 R4§â|_|['\]â/[\/IRS He\/ \-iii; .§::\«/NR6 :l§RN\,/:§\\»'7ââ\;,r , 5,7â/N\\/7 , '\\/ 9; \/AR R R7 , 7RR4 4R 4I/\ Rs 5R Nâ R R4 "E "r:Nâ \/R6 ?$âN//\/âR6\R7 , E 7R/2 â L/7~/N ; â â\\â:1\)A,5R4 R4 R4R Rif 6 -C/$6 6âf\â E\/ z \ / \\R7 ; \R7 9 2 7R//R4 R7 R4 R4 4R\~/ \â §ââ[ .M N\ "N\§ JW/2â;7,2 \/ \reI '71Lâ/ Hg 5 R7 § L9,L\?/R7â/\R4 /95 E R7\l /âVH4 §b7R4 E r:\ Fi\4/X37N* / \ \ 1 \acâ \âRe âR/â\ 5 NVâ 3â Râ/ â>râ?CA 02263999 l999-02- 19, wo 98/08840 PCT/US97/14912-64-4 R4 R4Eâ/\/â 7 7 N/R/5Q/\/N\ Enyjâ Eb 3-RâR6 5 â R6 Irr , R6\/ \ âN/R4 A/R4 N/R4. ~ DJ. \ N M âE-6 -El , E â E R6\/ \ R6 5; R6 S;R7 R4 R7 R4§_r§ââ~1 ,0, E-Kâ?/,1âN. N\ - \R/5\/ 9; Riv 5;R1, R2, R4, R5, R13 and R14 are each independently selected fromhydrogen, halogen, C]. 10 alkyl, C3-8 cycloalkyl, aryl,5 aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino,C 1-3 acylamino C1-g alkyl, C1-6 alkylamino, C1_6 alky1aminoâC1-8 alkyl, C 1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl,C1-4 alkoxy, C1-4 alkoxy C1_6 alkyl, hydroxycarbonyl,hydroxycarbonyl C1-6 alkyl, C1-3 alkoxycarbonyl,10 C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alky1oxyâC1-6 alkyl, nitro, cyano, tri?uoromethyl, tri?uoromethoxy,tri?uoroethoxy, C1-8 a1kylâS(O)q, C1-3 aminocarbonyl,C1-8 dialkylaminocarbonyl, C1_8 alkyloxycarbonylamino,15 C1-8 alkylaminocarbonyloxy or C 1-8 alkylsulfonylamino;R3 is selected fromhydrogen,aryl,20 -(CH2)pâary1,hydroxyl,?CA 02263999 l999-02- 19, W0 93/03340 PCT/US97/14912-65-C1_5 alkoxycarbonyl,aminocarbonyl,C3-g cycloalkyl,amino C1-6 alkyl,5 arylaminocarbonyl,aryl C 1-5 alkylaminocarbonyl,hydroxycarbonyl C1-6 alkyl,C1-8 alkyl,aryl C1-6 alkyl,10 C1_6 alkylamino C 1-6 alkyl,aryl C1-6 alkylamino C1-6 alkyl,C1-6 dialkylamino C1-6 alkyl,C1-8 alkylsulfonyl,C1-8 alkoxycarbonyl,15 aryloxycarbonyl,aryl C1 -8 alkoxycarbonyl,C1-8 alkylcarbonyl,arylcarbonyl,aryl C1 -6 alkylcarbonyl,20 C1-8 alkylaminocarbonyl,aminosulfonyl,C1-8 alkylaminosulfonyl,arylaminosulfonylamino,aryl C1 -8 alkylaminosulfonyl,25 C 1-6 alkylsulfonyl,arylsulfonyl,aryl C1-6 alkylsulfonyl,aryl C1-6 alkylcarbonyl,C 1 -6 alkylthiocarbonyl,30 arylthiocarbonyl, oraryl C1 -6 alkylthiocarbonyl,wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14;?vWO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-55-R6â R7, R8, R9, R10 and R11 are each independently selected fromhydrogen,aryl,-<cH2>pâary1,halogen,hydroxyl,C1-8 alkylcarbonylamino,aryl C1-5 alkoxy,C1-5 alkoxycarbonyl,aminocarbonyl,C1-8 alkylaminocarbonyl,C1_6 alkylcarbonyloxy,C3-8 cycloalkyl,oxo,amino,C1_6 alkylamino,amino C1-6 alkyl,arylaminocarbonyl,aryl C1 -5 alkylaminocarbonyl,aminocarbonyl,aminocarbonyl C1-6 alkyl,hydroxycarbonyl,hydroxycarbonyl C1 -6 alkyl,C1-8 alkyl, either unsubstituted or substituted, with one or moregroups selected from: halogen, hydroxyl,C1-5 alkylcarbonylamino, aryl C 1-5 alkoxy,C1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylamino-carbonyl, C1_5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo,amino, C1-3 alkylamino, amino C 1-3 alkyl, ary1aminoâcarbonyl, aryl C 1-5 alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C 1-4 alkyl, hydroxycarbonyl, orhydroxycarbonyl C1 -5 alkyl,-(CH2)s CECH,â(CH2)g CEC-C]_6 alkyl,?â WO 98108840202530CA 02263999 l999-02- 19-57--(CH2)s CEC-C3-7 cycloalkyl,-(CH2)s CEC-aryl,-(CH2)s CEC-C1â6 alkylaryl,â(CH2)s CH=CH2,â(CH2)g CH=CH C1-6 alkyl,-(CH2)s CH=CHâC3-7 cycloalkyl,â(CH2)g CH=CH aryl,â(CH2)s CH=CH C1-6 alkylaryl,-(CH2)g SO2C1-6 alkyl, orâ(CH2)g S02C1-6 alkylaryl;C1-6 alkoxy,aryl C1-6 alkoxy,aryl C1-6 alkyl,C1-6 alkylamino C1-6 alkyl,arylamino,arylamino C1-6 alkyl,aryl C1-6 alkylamino,aryl C1-6 alkylamino C1-6 alkyl,arylcarbonyloxy,aryl C1-6 alkylcarbonyloxy,C 1-6 dialkylamino,C1-6 dialkylamino C1-6 alkyl,C 1 -6 alkylaminocarbonyloxy,C1-8 alkylsulfonylamino,C1-8 alkylsulfonylamino C 1 -6 alkyl,arylsulfonylamino C1-5 alkyl,aryl C1 -6 alkylsulfonylamino,aryl C1-6 alkylsulfonylamino C 1-6 alkyl,C 1 -8 alkoxycarbonylamino,C 1-8 alkoxycarbonylamino C1-8 alkyl,aryloxycarbonylamino C1 -8 alkyl,aryl C1 -8 alkoxycarbonylamino,aryl C1-8 alkoxycarbonylamino C1 -3 alkyl,C1 -8 alkylcarbonylamino,PCT/U S97] 14912?CA 02263999 l999-02- 19WO 98/0884010202530-53-C1-8 alkylcarbonylamino C1-6 alkyl,arylcarbonylamino C1 -6 alkyl,aryl C1 -6 alkylcarbonylamino,aryl C1-6 alkylcarbonylamino C1-6 alkyl,aminocarbonylamino C1 -5 alkyl,C1 -8 alkylaminocarbonylamino,C1-8 alkylaminocarbonylamino C1-6 alkyl,arylaminocarbonylamino C 1 -6 alkyl,aryl C1-g alkylaminocarbonylamino,aryl C1-8 alkylaminocarbonylamino C1-6 alkyl,aminosulfonylamino C1 -6 alkyl,C1 -8 alkylaminosulfonylamino,C1-8 alkylaminosulfonylamino C1-6 alkyl,arylaminosulfonylamino C1 -6 alkyl,aryl C1.-8 alkylaminosulfonylamino,aryl C 1-8 alkylaminosulfonylamino C1-6 alkyl,C1-6 alkylsulfonyl,C1-6 alkylsulfonyl C1-6 alkyl,arylsulfonyl C1-6 alkyl,aryl C1-6 alkylsulfonyl,aryl C 1-6 alkylsulfonyl C1-6 alkyl,C1-6 alkylcarbonyl,C 1-6 alkylcarbonyl C1-6 alkyl,arylcarbonyl C1 -6 alkyl,aryl C1-6 alkylcarbonyl,aryl C1-6 alkylcarbonyl C 1-6 alkyl,C1 -6 alkylthiocarbonylamino,C1-6 alkylthiocarbonylamino C1-6 alkyl,arylthiocarbonylamino C1 -6 alkyl,aryl C1 -6 alkylthiocarbonylamino,aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,C1-8 alkylaminocarbonyl C1-6 alkyl,arylaminocarbonyl C1 -6 alkyl,aryl C1-g alkylaminocarbonyl, orPCT/U S97/ 14912?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-69-aryl C1-8 alkylaminocarbonyl C1-5 alkyl,wherein any of the alkyl groups may be unsubstituted or substituted withR13 and R14; and provided that the carbon atom to which R8 and R9are attached is itself attached to no more than one heteroatom; andprovided further that the carbon atom to which R10 and R11 areattached is itself attached to no more than one heteroatom;R12 is selected fromhydrogen,C1-8 alkyl,aryl,aryl C1-8 alkyl,hydroxy,C1-8 alkoxy,aryloxy,aryl C1-6 alkoxy,C1-8 alkylcarbonyloxy C1-4 alkoxy,aryl C1-8 alkylcarbonyloxy C 1-4 alkoxy,C 1 -8 alkylaminocarbonylmethyleneoxy, orC1 -8 dialkylaminocarbonylmethyleneoxy;m is an integer from O to 3;n is an integer from 1 to 3;p is an integer from 1 to 4;q is an integer from 0 to 2;r is an integer from 0 to 6; ands is an integer from O to 3;and the pharmaceutically acceptable salts thereof.More particularly illustrating the invention is apharmaceutical composition comprising any of the compounds describedabove and a pharmaceutically acceptable carrier. Another example ofthe invention is a pharmaceutical composition made by combining anyof the compounds described above and a pharmaceutically acceptablecarrier. Another illustration of the invention is a process for making a?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-70-pharmaceutical composition comprising combining any of thecompounds described above and a pharmaceutically acceptable carrier.Further illustrating the invention is a method of treatingand/or preventing a condition mediated by antagonism of a vitronectinreceptor in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of any of the compoundsdescribed above. Preferably, the condition is selected from boneresorption, osteoporosis, restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, in?ammation, cancer andtumor growth. More preferably, the condition is selected fromosteoporosis and cancer. Most preferably, the condition is osteoporosis.More specifically exemplifying the invention is a method ofeliciting a vitronectin antagonizing effect in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceuticalcompositions described above. Preferably, the vitronectin antagonizingeffect is an OLVB3 antagonizing effect; more specifically the OLVB3antagonizing effect is selected from inhibition of bone resorption,inhibition of restenosis, inhibition of atherosclerosis, inhibition ofangiogenesis, inhibition of diabetic retinopathy, inhibition of maculardegeneration, inhibition of in?ammation or inhibition of tumor growth.Most preferably, the ocvB3 antagonizing effect is inhibition of boneresorption. Alternatively, the vitronectin antagonizing effect is an ocvB5antagonizing effect or a dual ocv[33/0tvB5 antagonizing effect. Examplesof ocv[35 antagonizing effects are inhibition of: restenosis,atherosclerosis, angiogenesis, diabetic retinopathy, maculardegeneration, in?ammation or tumor growth. Examples of dualocvB3/ocvB5 antagonizing effects are inhibition of: bone resorption,restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, maculardegeneration, in?ammation or tumor growth.Additional examples of the invention are methods ofinhibiting bone resorption and of treating and/or preventingosteoporosis in a mammal in need thereof, comprising administering to?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-71-the mammal a therapeutically effective amount of any of the compoundsor any of the pharmaceutical compositions decribed above.Further exemplifying the invention is any of thecompositions described above, further comprising a therapeuticallyeffective amount of a second bone resorption inhibitor; preferably, thesecond bone resorption inhibitor is alendronate.More particularly illustrating the invention is any of themethods of treating and/or preventing osteoporosis and/or of inhibitingbone resoption described above, wherein the compound is administeredin combination with a second bone resorption inhibitor; preferably, thesecond bone resorption inhibitor is alendronate.Additional illustrations of the invention are methods oftreating hypercalcemia of malignancy, osteopenia due to bonemetastases, periodontal disease, hyperparathyroidism, periarticularerosions in rheumatoid arthritis, Paget's disease, irnmobilization-inducedosteopenia, and glucocorticoid treatment in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceuticalcompositions described above.More particularly exemplifying the invention is the use ofany of the compounds described above in the preparation of amedicament for the treatment and/or prevention of osteoporosis in amammal in need thereof. Still further exemplifying the invention is theuse of any of the compounds described above in the preparation of amedicament for the treatment and/or prevention of: bone resorption,tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy,macular degeneration, in?ammation and/or angiogenesis.Additional illustrations of the invention are methods oftreating tumor growth in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound described above and one or more agents known to becytotoxic or antiproliferative, e.g., taxol and doxorubicin.?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-72-DETAILED DESCRIPTION OF THE INVENTIONRepresentative compounds of the present invention areintegrin antagonists which display submicromolar affinity for the humanotv|33 receptor. Compounds of this invention are therefore useful fortreating mammals suffering from a bone condition caused or mediatedby increased bone resorption, who are in need of such therapy.Phannacologically effective amounts of the compounds, includingpharamaceutically acceptable salts thereof, are administered to themammal, to inhibit the activity of mammalian osteoclasts.The compounds of the present invention are administered indosages effective to antagonize the otvB3 receptor where such treatmentis needed, as, for example, in the prevention or treatment ofosteoporosis. For use in medicine, the salts of the compounds of thisinvention refer to non-toxic "pharmaceutically acceptable salts." Othersalts may, however, be useful in the preparation of the compoundsaccording 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 aregenerally prepared by reacting the free base with a suitable organic orinorganic acid. Representative salts include the following:Acetate, Benzenesulfonate, Benzoate, Bicarbonate,Bisulfate, Bitartrate, Borate, 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, Nâmethylglucamine 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 acidicmoiety, suitable pharmaceutically acceptable salts thereof may include?7 WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-73-alkali metal salts, e.g., sodium or potassium salts; alkaline earth metalsalts, e.g., calcium or magnesium salts; and salts formed with suitableorganic ligands, e.g., quaternary ammonium salts.The compounds of the present invention, may have chiralcenters and occur as racemates, racemic mixtures, diastereomericmixtures, and as individual diastereomers, or enantiomers with allisomeric forms being included in the present invention. Therefore,where a compound is chiral, the separate enantiomers, substantially freeof the other, are included within the scope of the invention; furtherincluded are all mixtures of the two enantiomers. Also included withinthe scope of the invention are polymorphs and hydrates of thecompounds of the instant invention.The present invention includes within its scope prodrugs ofthe compounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term "administering"shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may notbe specifically disclosed, but which converts to the specified compoundin vivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in "Design of Prodrugs," ed. H. Bundgaard,Elsevier, 1985. Metabolites of these compounds include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.The term "therapeutically effective amount" shall mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by a researcher or clinician.The term "vitronectin receptor antagonist," as used herein,refers to a compound which binds to and antagonizes either the OLVB3receptor or the 0cvB5 receptor, or a compound which binds to and?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/ 14912-74-antagonizes both the ocvB3 and ocvB5 receptors (i.e., a dual otv[33/oLvB5receptor antagonist).The term "bone resorption," as used herein, refers to theprocess by which osteoclasts degrade bone.The term "alkyl" shall mean straight or branched chainalkanes of one to ten total carbon atoms, or any number within thisrange (i.e., methyl, ethyl, l-propyl, 2-propyl, n-butyl, s-butyl, tâbutyl,etc.).The term "alkenyl" shall mean straight or branched chainalkenes of two to ten total carbon atoms, or any number within thisrange.The term "alkynyl" shall mean straight or branched chainalkynes of two to ten total carbon atoms, or any number within thisrange.The term "cycloalkyl" shall mean cyclic rings of alkanes ofthree to eight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).The term "cycloheteroalkyl," as used herein, shall mean a3- to 8-membered fully saturated heterocyclic ring containing one ortwo heteroatoms chosen from N, O or S. Examples of cycloheteroalkylgroups include, but are not limited to piperidinyl, pyrrolidinyl,azetidinyl, morpholinyl, piperazinyl.The term "alkoxy," as used herein, refers to straight orbranched chain alkoxides of the number of carbon atoms specified (e.g.,C 1-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy,etc.).The term "aryl," as used herein, refers to a monocyclic orpolycyclic system composed of 5- and 6-membered fully unsaturated orpartially unsaturated rings, such that the system comprises at least onefully unsaturated ring, wherein the rings contain 0, 1, 2, 3 or 4heteroatoms chosen from N, O or S, and either unsubstituted orsubstituted with one or more groups independently selected fromhydrogen, halogen, C 1- 10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl,?9 WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-75-amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl,C 1-6 alkylamino, C1_6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6dialkylaminoâC1-8 alkyl, C1-4 alkoxy, C1_4 alkoxy C1_6 alkyl,hydroxycarbonyl, hydroxycarbonyl C 1-6 alkyl, C 1-5 alkoxycarbonyl,C1-3 alkoxycarbonyl C 1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy,hydroxy, hydroxy C1-6 alkyl, cyano, tri?uoromethyl, oxo or C1-5alkylcarbonyloxy. Examples of aryl include, but are not limited to,phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl,benzimidazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(1,3)dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, aryl,aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3acylamino C1-8 alkyl, C1-6 alkylamino, C 1-6 alkylamino-C1-8 alkyl,C1-6 dialkylamino, C1..6 dialkylamino C1-8 alkyl, C 1-4 alkoxy, C 1-4alkoxy C1-5 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C 1-5alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C 1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxoor C 1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted,mono-, diâ, tri- or tetra~substituted with one to four of the above-namedsubstituents; more preferably, the aryl group is unsubstituted, mono-,di- or tnlsubstituted with one to three of the above-named substituents;most preferably, the aryl group is unsubstituted, mono- or diâsubstitutedwith one to two of the above-named substituents.Whenever the term "alkyl" or "aryl" or either of theirprefix roots appear in a name of a substituent (e.g., aryl C()-8 alkyl) itshall be interpreted as including those limitations given above for"alkyl" and "aryl." Designated numbers of carbon atoms (e.g., C1- 10)shall refer independently to the number of carbon atoms in an alkyl orcyclic alkyl moiety or to the alkyl portion of a larger substituent inwhich alkyl appears as its prefix root.The terms "arylalkyl" and "alkylaryl" include an alkylportion where alkyl is as defined above and to include an aryl portionwhere aryl is as defined above. The C0-m or C1-m designation where?WO 98/0884!)1015202530CA 02263999 l999-02- 19PCT/US97/14912-76-m may be an integer from 1-10 or 2-10 respectively refers to the alkylcomponent of the arylalkyl or alkylaryl unit. Examples of arylalkylinclude, but are not limited to, benzyl, ?uorobenzyl, chlorobenzyl,phenylethyl, phenylpropyl, ?uorophenylethyl, chlorophenylethyl,thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylarylinclude, but are not limited to, toluene, ethylbenzene, propylbenzcne,methylpyridine, ethylpyridine, propylpyiidine and butylpyridine.When substituent R1, R2, R3, R4, R5, R6, R7, R8, R9,R10, R11, R12, R13 or R14 includes the definition C0 (e.g., aryl C0-8alkyl), the group modified by C0 is not present in the substituent.Similarly, when any of the variables In, q, r or s is zero, then the groupmodified by the variable is not present; for example, when s is zero, thegroup "-(CH2)s CECH" is "âCECH". In addition, the substituent"(C1-6 alkyl)qamino" where q is zero, one or two, refers to an amino,C1-6 alkylamino and C1-5 dialkylamino group, respectively. When aC 1-6 dialkylamino substituent is intended, the C1-6 alkyl groups can bethe same (e.g., dimethylamino) or different (e.g., N (CH3)(CH2CH3)).Similarly, the substituent "(aryl)qamino" or ["(aryl C1-6alkyl)qamino"], where q is zero, one or two, refers to an amino,arylarnino and diarylamino group, [or an amino, aryl C1-6 alkylaminoor di-(aryl C1-6 alkyl)amino] respectively, where the aryl [or aryl C1-6alkyl] groups in a diarylamino [or di-(aryl C1-5 alkyl)amino] substituentcan be the same or different.The term "halogen" shall include iodine, bromine, chlorineand ?uorine.The term "oxy" means an oxygen (0) atom. The term"thio" means a sulfur (S) atom. The term "oxo" shall mean =0.The term "substituted" shall be deemed to include multipledegrees of substitution by a named substitutent. Where multiplesubstituent moieties are disclosed or claimed, the substituted compoundcan be independently substituted by one or more of the disclosed orclaimed substituent moieties, singly or plurally. By independentlysubstituted, it is meant that the (two or more) substituents can be thesame or different.?â WO 98/088401015202530CA 02263999 l999-02- 19PCT /US97/14912-77-Under standard nonmenclature used throughout thisdisclosure, the terminal portion of the designated side chain is describedfirst, followed by the adjacent functionality toward the point ofattachment. For example, a C 1-5 alkylcarbonylamino C1-6 alkylsubstituent is equivalent toH"C1_6 a'kyiâNHâC"'C1_5 .The present invention is also directed to combinations ofthe compounds of the present invention with one or more agents usefulin the prevention or treatment of osteoporosis. For example, thecompounds of the instant invention may be effectively administered incombination with effective amounts of other agents used in the treatmentof osteoporosis such as bisphosphonate bone resorption inhibitors;preferably, the bone resorption inhibitor is the bisphosphonatealendronate, now sold as FOSAMAX®. Preferred combinations aresimultaneous or alternating treatments of an ocvB3 receptor antagonist ofthe present invention and FOSAMAX®.In addition, the integrin (OLVB3) antagonist compounds ofthe present invention may be effectively administered in combinationwith a growth hormone secretagogue in the therapeutic or prophylactictreatment of disorders in calcium or phosphate metabolism andassociated diseases. These diseases include conditions which can benefitfrom a reduction in bone resorption. A reduction in bone resorptionshould improve the balance between resorption and formation, reducebone loss or result in bone augmentation. A reduction in boneresorption can alleviate the pain associated with osteolytie lesions andreduce the incidence and/or growth of those lesions. These diseasesinclude: 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?WO 98/0884010152030CA 02263999 l999-02- 19PCT/US97/14912 _-73-resorption can be accompanied by pathologically high calcium andphosphate concentrations in the plasma, which would be alleviated bythis treatment. Similarly, the present invention would be useful inincreasing bone mass in patients with growth hormone deficiency.Thus, preferred combinations are simultaneous or alternating treatmentsof an OLVB3 receptor antagonist of the present invention and a growthhormone secretagogue, optionally including a third componentcomprising FOSAMAX®.In addition, the vitronectin receptor antagonist compoundsof the present invention may be effectively administered in combinationwith one or more agents known to be cytoxic or antiproliferative, e.g,taxol and doxorubicin.In accordance with the method of the present invention, theindividual components of the combination can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination fonns. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term "administering" is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agentsuseful for treating OLVB3 related conditions includes in principle anycombination with any pharmaceutical composition useful for treatingosteoporosis.As used herein, the term "composition" is intended toencompass a product comprising the specified ingredients in thespecified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in the specifiedamounts.The compounds of the present invention can beadministered in such oral dosage forms as tablets, capsules (each ofwhich includes sustained release or timed release formulations), pills,powders, granules, elixers, tinctures, suspensions, syrups and emulsions.Likewise, they may also be administered in intravenous (bolus orinfusion), intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous,?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-79-intramuscular or transdermal (e.g., patch) form, all using forms wellknown to those of ordinary skill in the pharmaceutical arts. Aneffective but non-toxic amount of the compound desired can beemployed as an OLVB3 inhibitor.The dosage regimen utilizing the compounds of the presentinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration; therenal and hepatic function of the patient; and the particular compoundor salt thereof employed. An ordinarily skilled physician, veterinarianor clinician can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.Oral dosages of the present invention, when used for theindicated effects, will range between about 0.01 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oraladministration, the compositions are preferably provided in the form oftablets 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 thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg ofthe active ingredient, preferably, from about 1 mg to about 100 mg ofactive ingredient. Intravenously, the most preferred doses will rangefrom about 0.1 to about 10 mg/kg/minute during a constant rateinfusion. Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in the art. To beadministered in the form of a transdermal delivery system, the dosage?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-80-administration will, of course, be continuous rather than intermittantthroughout the dosage regimen.In the methods of the present invention, the compoundsherein described in detail can form the active ingredient, and aretypically administered in admixture with suitable pharmaceuticaldiluents, excipients or carriers (collectively referred to herein asâcarrierâ materials) suitably selected with respect to the intended form ofadministration, 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 tabletor 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, marmitol, sorbitol and the like; fororal administration in liquid form, the oral drug components can becombined with any oral, non-toxic, phannaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegrating agentsand coloring agents can also be incorporated into the mixture. Suitablebinders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia,tragacanth or sodium alginate, carboxymethylcellulose, polyethyleneglycol, waxes and the like. Lubricants used in these dosage formsinclude sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.The compounds of the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids,such as cholesterol, stearylamine or phosphatidylcholines.Compounds of the present invention may also be deliveredby the use of monoclonal antibodies as individual carriers to which the?WO 98/088401015202530CA 02263999 l999-02- 19PCT/U S97/ 14912-81-compound molecules are coupled. The compounds of the presentinvention may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamideâphenol, or polyethyleneoxide-polylysine substitutedwith palmitoyl residues. Furthermore, the compounds of the presentinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polyactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked oramphipathic block copolymers of hydrogels.In the schemes and examples below, various reagentsymbols and abbreviations have the following meanings:ACOH:BH3-DMS:BOC(Boc):BOP:CBZ(Cbz):CDI:CH2Cl2:CHCI3:DEAD:DIAD:DIBAH orDIBAL-H:DIPEA:DMAP:DME:DMF:DMSO:DPFN:Acetic acid.Borane-dimethylsul?de.t-Butyloxycarbonyl.Benzotriazolâ 1 -yloxytris(dimethylamino)-phosphonium hexa?uorophosphate.Carbobenzyloxy or benzyloxycarbonyl.Carbonyldiimidazole.Methylene chloride.Chloroform.Diethyl azodicarboxylate.Diisopropyl azodicarboxylate.Diisobutylaluminum hydride.Diisopropylethylamine.4-Dimethylaminopyridine.l ,2âDimethoxyethane.Dirnethylformamide.Dimethylsulfoxide.3 ,5 -Dimethylâl -pyrazolylfonnamidine nitrate.?W0 98/0884!)1015202530EDC:EtOAc:EtOH:HOAC:HOAT:HOBT:LDA:MeOH:NEt3:NlVlM'PCA-HCl:Pd/C:Ph:pTSATEA:TFA:THF:TLC:TMEDA:TMS:CA 02263999 l999-02- 19PCT/US97/14912-82-l-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide.Ethyl acetate.Ethanol.Acetic acid.1 -Hydroxyâ7 -azabenzotriazolel -Hydroxybenzotriazole.Lithium diisopropylamide.Methanol.Triethylamine.N -methylmorpholine.Pyrazole carboxamidine hydrochloride.Palladium on activated carbon catalyst.Phenyl.p-Toluene sulfonic acid.Triethylamine.Tri?uoroacetic acid.Tetrahydrofuran.Thin Layer Chromatography.N ,N ,N ',N'-Tetramethylethylenediamine.Trimethylsilyl.The novel compounds of the present invention wereprepared according to the procedure of the following schemes andexamples, using appropriate materials and are further exemplified bythe following specific examples. The most preferred compounds of theinvention are any or all of those specifically set forth in these examples.These compounds are not, however, to be construed as forming the onlygenus that is considered as the invention, and any combination of thecompounds or their moieties may itself fonn a genus. The followingexamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readily understandthat known variations of the conditions and processes of the followingpreparative procedures can be used to prepare these compounds. Alltemperatures are degrees Celsius unless otherwise noted.?WO 98/08840101520CA 02263999 l999-02- 19PC'Iâ/US97/ 14912-33-The following Schemes and Examples describe proceduresfor making representative compounds of the present invention.Moreover, by utilizing the procedures described in detail in PCTInternational Application Publication Nos. W095/32710, published 7December 1995, and W095/17397, published 29 June 1995, inconjunction with the disclosure contained herein, one of ordinary skillin the art can readily prepare additional compounds of the presentinvention claimed herein.More specifically, procedures for preparing the N-terminusof the compounds of the present invention are described in WO95/32710. Additionally, for a general review describing the synthesis of[3-alanines which can be utilized as the C-terrninus of the compounds ofthe present invention, see Cole, D.C., Recent Stereoselective SyntheticApproaches to [3âAmin0 Acids, Tetrahedron, 1994, 50, 9517-9582;Juaristi, E, et al., Enantioselective Synthesis of [3âAmin0 Acids,Aldrichemica 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 3-ethynyl [3-alanine is taught in Zablocki, J .A., et al., J .Med. Chem., 1995, 38, 2378-2394; the 3-pyrid-3âyl B-alanine is taughtin Rico, J.G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino and 2-toslylamino [3-alanines are taught in Xue, CâB, et al.,Biorg. Med. Chem. Letts., 1996, 6,'339â344.?CA 02263999 l999-02- 19. wo 93/03340 PCT/U S97/ 14912_ _SCHEME 1ON,TMS1-1O/j _j__ LDA, TMEDA, THF, -78°C1'2 )<O/\O ONH1-3/ CHO1-4 | L-proline, ethanol, reflux 1-5NaN(TMS)2, DMF,ethyl bromoacetate ?CA 02263999 l999-02- 19wo 93/03340 PCT/US97/14912-35-SCHEME 1 (CONT'D) 1-610% Pd/C, EtOAc, H21-7,R=Et) 6N HCI1-8,R=H ; BOP, NMM, CH3CNHCI-H2N/:\/C0231-9u I \NH O N /N N\/{LN/\/COZR\ I O H?» W0 98l08840202530CA 02263999 l999-02- 19PCT/US97/14912-35-2-Oxo-3â(3-oxobutvl)Dineridine (1-3)A stirred solution of TMEDA (3.0 g, 20 mmol), 0.5 MLDA (6 mL, in THF), and THF (10 mL) at -78°C was treated with 141(1.7 g, 10 mmol) (for preparation, see: JOC, 1990, 55, 3682) to effectan orange solution.After 1 h, the iodide L2 (2.4 g, 10 mmol) (J. Org. Chem.,1983, 518, 5381) was added to the orange solution and the resultingsolution stirred for 2 h at â78°C, 3 h at -15°C and then 16 h at ambienttemperature. The reaction mixture was concentrated and then treatedwith 1N HCl (30 mL). The mixture was then basified with INNaOH/brine followed by extraction with EtOAc (3x). The combinedextracts were dried (MgSO4) and concentrated to give a yellow oil.Flash chromatography (silica, EtOAc â> 10% CH3OH/EtOAc) gave 1;3_as a colorless solid.TLC Rf 0.42 (silica, 10% CH3OH/EtOAc)1H NMR (300 MHz, CDCI3) 5 5.75 (bs, 1H), 3.28 (m, 2H), 2.64 (t,7Hz, 2H), 2.30-1.50 (m, 7H), 2.16 (s, 3H).2-Oxoâ3-l2â(l1.81ânaDhthvridin-2âvl)ethvllniperidine (1-5)A solution of _1_-3_ (0.25 g, 1.5 mmol), L-proline (85 mg,0.75 mmol), _l-_4 (0.18 g, 1.5 mmol) (for preparation see: Synth.Commun. 1987, 11, 1695), and ethanol (10 mL) was re?uxed for 24 hr.The cooled solution was concentrated and the residue purified by ?ashchromatography (silica, EtOAc â> 20% CH3OH/EtOAc) to give _1_-_5 as asolid.TLC Rf = 0.32 (silica, 20% CH3OH/EtOAc)1H NMR (300 MHz, CDCI3) 8 9.08 (m, 1H), 8.16 (m, 1H), 8.10 (d,J=8Hz, 1H), 7.50 (d, J=8Hz, 1H), 7.45 (m, 1H), 5.64 (bs, 1H), 3.31 (m,2H), 3.18 (m, 2H), 2.50-1.60 (m, 7H).Ethyl 2-Oxoâ3-[2â([1,8]ânaphthyridinâ2-yl)ethyl]piperidin-lâyl-acetate(1-6)A solution of l_â_5_ (0.28 g, 1.1 mmol) and DMF (10 mL) at-15°C was treated with NaN(TMS)2 (1.2 mL, 1.2 mmol, 1M in hexanes)?WO 98108840202530CA 02263999 l999-02- 19PCT/US97/14912-37-to give a red solution. After 30 min, the red solution was treated withethyl bromoacetate (128 uL, 1.2 mmol), followed by continued stirringfor 1 h. The reaction mixture was then quenched with sat. NH4Cl andthen extracted with EtOAc (3x). The combined extracts were washedwith brine, dried (MgSO4), and concentrated. Flash chromatography(silica, 10% CH3OH/EtOAc) gave _1_-_6_ as a yellow gum.TLC Rf = 0.50 (silica, 10% CH3OH/EtOAc)1H NMR (300 MHz, CDC13) 5 9.07 (m, 1H), 8.16 (m, 1H), 8.10 (d,J=8Hz, 1H), 7.50 (d, J=8Hz, 1H), 7.44 (m, 1H), 4.30-3.90 (m, 4H),3.50-3.30 (In, 2H), 3.17 (m, 2H), 2.46 (m, 2H), 2.20-1.70 (m, 5H), 1.28(t, J=7Hz, 3H).Ethyl 2âOxo-3â[2-(5,6,7,8âtetrahydro-[1,8]-naphthyridin-2-vllethvlloineridin-1âvl-acetate ( 1 -7)A mixture of _1_-Q (102 mg, 0.3 mmol), 10% Pd/C (50 mg),and EtOAc (25 mL) was stirred under a hydrogen atmosphere (1 atm)for 24 h. The catalyst was then removed by filtration through celite andthe ?ltrate concentrated. Flash chromatography (silica, 20%CH3OH/EtOAc) gave _1_-1 as a yellow gum.TLC Rf = 0.45 (silica, 30% CH3OH/EtOAc)1H NMR (300 MHz, CDC13) 5 7.05 (d, J=6Hz, 1H), 6.41 (d, J=6Hz,1H), 4.80 (bs, 1H), 4.18 (q, J=7Hz, 2H), 4.08 (In, 2H), 3.37 (m, 4H),2.80-1.60 (I11, 13H), 1.26 (t, 7Hz, 3H).2-Oxo-3â[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl]piperidin-1âvl-acetic acid (1-8)A solution of_l;7_ (71 mg, 0.21 mmol) and 6N HCl (15 mL)was stirred at 55°C for 2h, followed by concentration to give 1_-8 as apale yellow gum.TLC Rf = 0.09 (silica, 20% CH3OH/EtOAc)?â WO 98/08840102025CA 02263999 l999-02- 19PCTIUS97/14912-33-2-Oxo-3-[2-(5 ,6,7,8-tetrahydro-[1 ,8]-naphthyridin-2-yl)ethy1]piperâidin-1-vl-acetvl-3(S)-Dvridin-3âvl-B-alanine ethvl ester (1-10)A stirred mixture of Q (71 mg, 0.20 mmol), _1_-_9_ (59 mg,0.22 mmol) (Rico et al., J. Org. Chem., 1993, 58, 7948), NMM (88 LLL,0.8 mmol), and CH3CN (25 mL) was treated with BOP (97 mg, 0.22mmol). After 24h, the reaction mixture was concentrated to dryness,dissolved in EtOAc, and then washed with H20, dried (MgSO4), andconcentrated. Flash chromatography (silica, 10% (NH3/EtOH/EtOAc)gave 1â_1_(_) as a colorless gum.TLC Rf = 0.9 (silica, 10% (NH3/EtOH)/EtOAc)1H NMR (300 MHz, CD3OD) 8 8.55 (m, 1H), 8.43 (m, 1H), 7.83 (m,1H), 7.40 (m, 1H), 7.11 (m, 1H), 6.37 (m, 1H), 5.38 (m, 1H), 4.08 (q,J=7Hz, 2H), 4.00 (m, 2H), 3.37 (m, 4H), 2.90 (m, 1H), 2.70-1.60 (m,14H), 1.14 (t, J=7Hz, 3H).2âOxo-3-[2-(5,6,7,8-tetrahydroâ[1,8]-naphthyridin-2-yl)ethyl]piperinâ1- l-acet I-3 S - ridin-3- 1- -alanine tri?uoroacetate 1-11A stirred solution of 1-11 (52 mg, 0.10 mmol) and 6N HCl(10 mL) was heated at 55°C for 2 h, followed by concentration.Preparative HPLC (VYDAC C18 semiprep column,gradient elution: [95:5 (0.1% TFA/H20/0.1% TFA/CH3CN) to 50:50(0.1% TFA/H20/0.1% TFA/CH3CN) 80 min] gave _1_-Q as a colorlesssolid.1H NMR (300 MHz, CD3OD) 8 8.90 (s, 1H), 8.74 (d, J=5Hz, 1H), 8.61(d, J=8Hz, 1H), 8.03 (m, 1H), 7.56 (d, J=7Hz, 1H), 6.59 (d, J=7Hz, 1H),5.43 (m, 1H), 4.03 (m, 2H), 3.40 (m, 5H), 3.00 (m, 2H), 2.78 (m, 4H),2.40-1.60 (m, 12H). ?CA 02263999 l999-02- 19â WO 98/08840 PCT/US97/ 14912- 39 -SCHEME 20dbPh2-10/7,1.2 M LDA, THF, -78°C0 O O NA Ph2-24,4'âditert-butylbiphenyl, Li TH F, -78°C0 Q 0â?rm2-3NaN(TMS)2, THF, -78°C,ethyl bromoacetatefâ'\oO 0 NACO2Et-42J pTSA, acetone, refluxO O NACO2Et2-5?CA 02263999 l999-02- 19wo 93/03340 PCT/US97/14912 _-90-SCHEME 2 CONT'DO O NACO2Et2-5CHO1_4 | proline, ethanol, reflux 10% Pd/C, H2, ethanol / I O\IP11 N N/\CO2Et2-76N HCI, 50°C/ oHC|- \ Ipi! N N/\CO2H?CA 02263999 l999-02- 19.WO 98/08840 PCT/US97/ 14912-91-SCHEME 2 1CONT'D1/ I O\Q N N/\CO2H2-8H? __ BOP, NMM,HCI-H2N/\/C028 CH3CN2-9,R= -CECH2-1 0, R: 3âpyridy|V/ o/Hg N N/?fN\â/\co_,_Eto R2-11, R = '-CECH2-12, R: 3âpyridy|1N NaOH, ethanol/ O Hn N N/\nâ Nj/\Co2H0 R2-13, R = -CECH2-14, R: 3âpyridy|/?â W0 98/0884!)10202530CA 02263999 l999-02- 19PCT/US97/14912-92-(2âOxo-3-(3â(ethvlendioxv)butvl)Dvrrolidin-1âvl)benzvl (2-2)To a stirred solution of 5 (5.3 g, 30 mmol) and THF (100mL) at -78°C was added LDA (17.5 mL, 35 mmol, 2.0 M in hexanes)dropwise over a 10 minute period. After 30 min, g (5.0 g, 21 mmol)was added followed by removal of the cooling bath. After 1 h, thereaction was quenched with ACOH (10 mL) and then diluted withEtOAc, washed with sat. N aHCO3 and brine, dried (MgSO4) andconcentrated. Flash chromatography (silica, 25% â> 75%EtOAc/hexanes) gave 2-_2 as an oil.TLC Rf = 0.38 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 8 7.25 (m, 5H), 4.48 (d, J=15Hz, 1H), 4.40(d, J=15Hz, 1H), 3.94 (s, 4H), 3.18 (m, 2H), 2.44 (m, 1H), 2.30-1.30(m, 9H).2-Oxo-3-(3-(ethvlendioxvlbutvl)DVrro1idine ( 2-3)To a stirred solution of E (4.1 g, 14.2 mmol) in THF(100 mL) at -78°C was added a solution of Li 4,4â-diâtert-butylbiphenyl(188 mL, 0.5 M in THF) in 4 portions. After 1 h, the reaction wasquenched with AcOH (25 mL). The resulting mixture was diluted withEtOAc and then washed with H20, sat. NaHCO3, and brine, dried(MgSO4) and concentrated. Flash chromatography (silica, EtOAc -â>10% CH3OH/EtOAc) gave 5 as a yellow oil.TLC Rf = 0.1 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 8 6.23 (bs, 1H), 3.94 (s, 4H), 3.30 (m,2H), 2.70 (m, 2H), 2.10-1.30 (m, 9H).Ethvl (2-Oxo-3â(3â(ethvlendioxv)butvl)Dvrrolidin-1-v1)acetate (2-4)To a rapidly stirred solution of 2_-_3_ (0.86 g, 4.3 mmol) andTHF (25 mL) at -78°C was added NaN(TMS)2 (5.2 mL, 5.2 mmol,1.0 M in THF). After 20 min, ethyl bromoacetate (0.58 mL, 5 .2 mmol)was added followed by removal of the cooling bath. After 1 h, thereaction mixture was diluted with EtOAc and then washed with H20,sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give _2â_4 asa yellow oil.?- W0 98/0884010202530CA 02263999 l999-02- 19PCTIUS97/14912-93-TLC Rf = 0.53 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 5 4.18 (q, J=7Hz, 2H), 4.04 (m, 2H), 3.93(s, 4H), 3.39 (m, 2H), 2.44 (In, 1H), 2.23 (m, 1H), 2.00-1.30 (m, 9H),1.25 (t, J=7H, 3H).Ethvl (2-Oxoâ3â(3âoxobutvl)Dvrrolidin-1âvl)acetate (2-5 )A solution of? (1.1 g, 3.9 mmol), p-TSA (5 mg) andacetone (50 mL) was heated at re?ux for 1 hr. The cooled reactionmixture was diluted with EtOAc and then washed with sat. NaHCO3 andbrine, dried (MgSO4), and concentration to afford 2;5_ as a yellow oil.TLC Rf = 0.48 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 8 4.18 (q, J=7Hz, 2H), 4.01 (s, 2H), 3.40(m, 2H), 2.67 (t, J=7Hz, 2H), 2.48 (m, 1H), 2.30-1.60 (m, 4H), 2.15 (s,3H), 1.25 (t, J=7Hz, 3H).Ethyl (2-Oxo-3-(2-([1,8]naphthyridinâ2âyl)ethyl)pyrrolidinâ1âyl)-acetate(2-6)A mixture of z? (0.77 g, 3.0 mmol), _l_-A (0.55 g, 4.5mmol, for preparation see Het, 1993, 36, 2513), Lâproline (0.17 g, 1.5mmol) and ethanol (25 mL) was heated at reflux for 20 hr. The cooledreaction mixture was concentrated and the residue purified by ?ashchromatography (silica, EtOAc â> 5% CH3OH/EtOAc) to give _2_-_6_ as ayellow oil.TLC Rf = 0.13 (silica, 10% CH3OH/EtOAc)1H NMR (300 MHz, CDCI3) 5 9.08 (In, 1H), 8.17 (m, 1H), 8.12 (d,J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 7.46 (m, 1H), 4.15 (q, J=7Hz, 2H),4.04 (m, 2H), 3.42 (m, 2H), 3.21 (t, J=8Hz, 2H), 2.60-1.80 (m, 5H),1.25 (t, J=7Hz, 3H).Ethyl (2-Oxo-3-(2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-vl)ethvl)Dvrrolidin- 1 -vl)acetate (2-7)A mixture of _2_-_§_ (0.87 g, 2.6 mmol), 10% Pd/C (0.5 g),and CH3OH (25 mL) was stirred under a hydrogen atmosphere (1 atm)for 2 hr. The catalyst was then removed by filtration through a celite?â WO 98/0884010202530CA 02263999 l999-02- 19PCT/U S97] 14912-94-pad followed by concentration of the filtrate. Flash chromatogrphy(silica, EtOAc -â> 5% CH3OH/EtOAc) gave 2:1 as a yellow oil.TLC Rf = 0.18 (silica, 5% CH3OH/EtOAc)1H NMR (300 MHz, CDCI3) 8 7.05 (d, J=7Hz, 1H), 6.40 (d, J=7Hz,1H), 4.83 (bs, 1H), 4.17 (q, J=7Hz, 2H), 4.03 (m, 2H), 3.40 (m, 4H),2.80-1.60 (m, 11H), 1.27 (t, J=7Hz, 3H).(2âOxoâ3-(2-(5,6,7,8-tetrahydro[1,8]-naphthyridinâ2-yl)ethyl)pyrro-lidin-1-vl)acetic acid hvdrochloride (2-8)A stirred mixture of 2_-Z (0.45 g, 1.4 mmol) and 6N HCl(10 mL) was heated at 50°C for 1 h, followed by concentration to give_2-_8 as a yellow oil.1H NMR (300 MHz, CD3OD) 5 7.60 (d, J=7Hz, 1H), 6.66 (d, J=7Hz,1H), 4.05 (s, 2H), 3.50 (In, 4H), 2.83 (m, 4H), 2.54 (m, 1H), 2.32 (m,1H), 2.10 (m, 1H), 2.00-1.75 (m, 4H),(2-Oxo-3-(2- (5 ,6,7,8-tetrahydro[ 1 ,8] -naphthyridin-2-yl)ethyl)pyrroâlidin- l -yl )acetyl-31 S 1-ethynyl-?âalanine ethyl ester (2-1 1 1To a stirred solution of _2_§ (50 mg, 0.15 mmol), L9 (29mg, 0.17 mmol) (Zablocki et al., J. Med Chem., 1995, 38, 2378), NMM(83 LLL, 0.75 mmol), and CH3CN (1 mL) was added BOP (74 mg, 0.17mmol). After 20 h, the reaction mixture was diluted with EtOAc andthen washed with sat. NaHCO3, H20 and brine, dried (MgSO4), andconcentrated to give 2-1] as a yellow oil.TLC Rf = 0.24 (silica, 10% CH3OH/EtOAc).(2-Oxo-3â(2â(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethyl)pyrroâ1idin-l- l acet 1-3 S - ridinâ3- l- -alanine eth l ester 2-12To a stirred solution of 2-8 (50 mg, 0.15 mmol), _2_-_1_(_) (44mg, 0.17 mmol) (Rico et al., J. Org. Chem., 1993, 58, 7948), NMM (83uL, 0.75 mmol), and CH3CN (1 mL) was added BOP (74 mg, 0.17mmol). After 20 h, the reaction mixture was diluted with EtOAc andthen washed with sat. NaHCO3, H20 and brine, dried (MgSO4), andconcentrated to give ;_l__2_ as a brown oil. ?~ WO 98/0884020CA 02263999 l999-02- 19PCT/US97/14912-95-TLC Rf = 0.24 (silica, 20% CH3OH/EtOAc).(2âOxoâ3-(2â(5 ,6,7,8-tetrahydro[1,8]-naphthyridin-2-v1)ethvl)Dvrrolidin-1-vl)acetvl-3(S)âethvnvl-I3-alanine (2-13)A mixture of _2_-Q (0.1 g, 0.15 mmol), IN NaOH (300 uL,and ethanol (1 mL) was stirred at ambient temperature for 1 hr.Concentration and then ?ash chromagraphy (silica, 25:10:1:1 ââ>15:10:12] EtOAc/EtOH/NH4OH/H20) gave 2i3_ as a white solid.TLC Rf = 0.18 (silica, 10:10:l:l EtOAc/EtOH/NH4OH/I-I20)1H NMR (300 MHz, CD3OD) 5 7.45 (m, 1H), 6.50 (m, 1H), 4.53 (In,1H), 3.80-3.30 (m, 5H), 3.05 (m, 1H), 2.80-2.15 (m, 9H), 2.00-1.75 (m,4H). '(2âOxoâ3-(2â(5 ,6,7,8-tetrahydro[1,8]-naphthyridinâ2-yl)ethyl)pyrro-lidin-1- l acct 1-3 S â ridin-3- 1- -alanine 2-14A mixture ofgg? (0.1 g, 0.15 mmol), 1N NaOH (300 g.tL)and ethanol (1 mL) was stirred at ambient temperature for 1 hr.Concentration and the ?ash chromatography (silica, 25:10:1:1 -->15:10:1:1 EtOAc/EtOH/NH4OH/H20) gave _2_-_l4 as a white solid.TLC Rf = 0.10 (silica, 10:10:l:l EtOAc/EEOH/NH4OH/I-I20)1H NMR (300 MHz, CD3OD) 5 8.57 (m, 1H), 8.40 (m, 1H), 7.86 (m,1H), 7.40 (m, 2H), 6.50 (m, 1H), 5.28 (In, 1H), 4.65-4.40 (m, 1H),3.90-1.80 (M, 19H). ?CA 02263999 l999-02- 19 9 wo 98108840 PCTIUS97/14912- 96 -S.CJ:LE_ME_3)OJ\/\/â(?\ 1) CH2FâPh3 CH2 0CH3 OEt CH3/U\/\/U\OH2) NaOH3-1 3-20 .pivaloyl chloride jig/\/[Ck JL t'::':(S|M93)23-2 H OO C 3 N /\/CIJL F3CSO3LiN O 3'3 Ph 3_4PhCH2 0CH 0 0W /[L 1) NaN3CH3 E N O x l/ lâ/ 2) PPh3, H20 3_6 Cl 3-5 PhNaN(SiMe3)2 CH3\ / \O then CH2 0 0304, O, \ /'/â\OEt 3_7 â Q then Na|O4 Br\ \OO O |N/ NH/u\/\)L 2CH3 : N/\n/OEt 1_4'=_/ O .3-8 prollne?CA 02263999 l999-02- 193 WO 98/08840-97-I / /WN N -_S_Ql:LEME_3..Lc_Qn131l0N OEt'â-_J3 9 Pd/C,H2 N N/ E N/\n/OEtH 3-10 â-1 o6N HCIOH H N/ â-_/N/\?/°HC' 3-11 â OEDC,HOBTNMMH2N OEt-Hc?m/\g/2_9CQVJ ââN N/ /\n/N OEt3-12 0 OLiOH H .II t O N OHN N . N- -Arm3-13 IPCT/US97/14912?CA 02263999 l999-02- 19, WO 98108840 PCT/US97/14912 _-93-$£2J:lEME.3_(:m1'£ll/ OH \/Câ)kN N ._ NH air°HC| 3-11EDC, HOBTNMMH2N OEt2-10/ OI\ N '2HCl/ N OEt?g **N N ._ NH a__/ /if /03-14 '\ NNaOH/ N OH I?âN N ._ NH =,___//\é// 03-15 '\ N4â(ProDv1-2-ene)butvric acid (3-2)To a stirred suspension of of methyltriphenylphosphoniumbromide (67.7 g, 190 mmol) in 1 L THF at 0° C was added a solution of5 sodium bis(trimethylsilyl)amide (190 mL, 190 mmol, 1M THF) . Afteran additional 30 minutes, 3_â_l ethyl 4-acetylbutyrate (Aldrich ChemicalCo.)(25.0 g, 158 mmol) was added, and the mixture stirred for 18 h.The mixture was filtered, and the filtrate concentrated. The residue wastriturated with hexanes, and then filtered. Following evaporative?v WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-99-removal of the solvent, the residue was chromatographed on silica gel,eluting with 10% ethyl acetate/hexanes to give the olefin as a colorlessoil. TLC Rf = 0.52 (10% ethyl acetate/hexanes).1H NMR (300 MHz, CHCI3) 8 4.71 (d, 2H, J=13 Hz), 4.13 (q, 2H, J=7Hz), 2.29 (t, 2H, J=7 Hz), 2.05 (t, 2H, J= 8 Hz), 1.77 (m, 2H), 1.72 (s,3H), 1.26 (t, 3H, J=7Hz).A solution of the above olefin (15.4 g, 98.6 mol), 1 NNaOH (150 mL), and EtOH (300 mL) was stirred at ambienttemperature for 2 h. Following acidification with 1 N HCl, the mixturewas extracted with ether. The ether layer was washed with brine, driedover magnesium sulfate, and concentrated to give 3â_2 as a colorless oil.1H NMR (300 MHz, CHC13) 5 4.70 (d, 2H, J=l3 Hz), 2.27 (t, 2H, J=7Hz), 2.06 (t, 2H, J= 7 Hz), 1.72 (m, 5H).(4-(Pronvl-2-ene)butanov1)-4(R)âbenzv1-2-oxazolidinone (3-3)To a solution of 3;; (6.0 g , 46.8 mmol) in THF (200 ml)at -78° C was added triethylamine (7.19 mL , 51.5 mmol) followed bypivaloyl chloride (6.35 mL , 51.5 mmol). The mixture was warmed to0°C for 1 h, then recooled to -78° C. In a separate ?ask, of (R)-(+)â4-benzylâ2-oxazolidinone (9.15 g, 51.5 mmol) was dissolved in THF (100mL), cooled to -78° C, and nâBuLi (32.3 mL, 51.5 mmol; 1.6 Mhexanes) was added dropwise; After 10 minutes, the lithiumoxazolidinone was added to the pivalic anhydride. After 10 minutes, themixture was warmed to 0° C for 1.5 h. The mixture was then pouredinto ethyl acetate, washed with aqueous sodium bicarbonate, and driedover magnesium sulfate. Following evaporative removal of the solvent,the residue was chromatographed (silica gel, dichloromethane) to give3-_3 as a slightly yellow oil.TLC Rf = 0.8 (CH2Cl2).1H NMR (300 MHz, CHCI3) 5 7.40-7.18 (m, 5H), 4.80-4.60 (m, 3H),4.18 (m, 2H), 3.30 (dd, 1H, J=3.2, 13.2 Hz), 2.95 (m, 2H), 2.76 (dd,1H, J=9.5, 13.1 Hz), 2.11 (t, 2H, J=7.5 Hz), 1.87 (m, 2H), 1.74 (s, 3H).?âW0 98/0884101015202530CA 02263999 l999-02- 19PCT/US97/ 14912 --100-2-Chloroethvltri?ate (3-4)To a solution of 1.67 mL (24.8 mmol) of 2-chloroethanoland 3.47 mL (29.8 mmol) of 2,6-lutidine in 20 mL of dichloromethaneat 0° C was added 4.59 mL (27.3 mmol) of tri?ic anhydride. After 1 h,the mixture was diluted with hexanes, washed with ice-cold 1N HCI, anddried over sodium sulfate. The solvents were evaporated to give3:4 as a pink oil.1H NMR (300 MHz, CHCl3) 5 4.69 (t, 2H, J=5.3 Hz), 3.78 (t, 2H, J=5.6Hz).2(S)-Chloroethyl-4-(propyl-2-ene)butanoyl-(4(R)-benzylâ2-oxazolidinone) (3-5)To a solution of3;3 (11.0 g, 38.3 mmol) in THF (60 mL) at -78° C wasadded a solution of sodium bis(trimethylsilyl)amide (42.1 mL, 42.1mmol; 1M/T HF). After 20 min, 3-_4_ (16.2 ml, 115 mmol) was addedover 5 min, and the resulting mixture stirred for 1.5 h at -78° C, then 2h at -15° C. The mixture was diluted with hexanes, washed with sat.arrunonium chloride, and dried over sodium sulfate. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 14% ethyl acetate/hexanes) to give 3_~5_ as a colorless oil. TLCRf = 0.5 (20% ethyl acetate/hexanes).1H NMR (300 MHz, CHCI3) 5 7.30-7.18 (m, 5H), 4.67 (m, 3H), 4.19(m, 2H), 3.99 (m, 1H), 3.58 (m, 2H), 3.33 (dd, 1H, J=3.2, 12.0 Hz),2.75 (dd, 1H, J=9.7, 13.5 Hz), 2.23 (m, 1H), 2.18-1.82 (m, 4H), 1.77-1.60 (m, 1H), 1.71 (s, 3H).Ethvl 2-oxo-3(S)â(3-methvlenebutvllpvrrolidine (3 -6)A mixture of_3_-__5_ (8.15 g, 23.3 mmol) and NaN3 (4.54 g,69.8 mmol) in DMSO (120 mL) was heated at 75° C for 2 h. Aftercooling, the mixture was diluted with ether and hexanes, washed withwater, and dried over sodium sulfate. Evaporative removal of thesolvent gave the azide as a colorless oil.TLC Rf = 0.5 (20% ethyl acetate/hexanes).?W0 98l088401015202530CA 02263999 l999-02- 19PCT/US97l149l2-101-1H NMR (300 MHz, CHCI3) 5 7.30-7.22 (m, 5H), 4.69 (m, 3H), 4.17(d, 2H, J=5.1 Hz), 3.89 (m, 1H), 3.38 (m, 3H), 2.74 (m, 1H), 2.13-1.63(m, 6H), 1.71 (s, 3H).To a solution of of this azide (8.0 g , 22.4 mmol) in THF(250 mL) and water (40 mL) was added triphenylphosphine (8.24 g ,31.4 mmol) in 4 portions over 5 minutes. This mixture was heated atreflux for 2 h, cooled, and evaporated. The residue waschromatographed (silica gel, 10% chloroform/ethyl acetate) to give 3-_6_as a colorless oil.TLC Rf = 0.40 (20% chloroform/ethyl acetate).1H NMR (300 MHz, CHCI3) 5 6.47 (br s, 1H), 4.73 (m, 2H), 3.31 (m,2H), 2.33 (m, 2H), 2.08 (m, 3H), 1.81 (m, 1H), 1.74 (s, 3H), 1.44 (s,IH).Ethvl 2-oxo-3(S)-(3-methvlenebutvl)nvrrolidin-1 -vl)acetate (3-7)To a solution of g (2.50 g, 16.3 mmol) in THF (40 mL)at -78° C was added sodium bis(trimethylsilyl)amide (17.1 mL, 17.1mmol; 1M/ THF) dropwise. After an additional 20 min, ethylbromoacetate (2.17 mL, 19.6 mmol) was added dropwise over 3 min.After an additional 20 min, 20 mL sat. aqueous NH4C1 was added, andthe cooling bath removed. The layers were separated, the aqueous layerwashed with ether, and the combined organic extracts were dried oversodium sulfate. Following evaporative removal of the solvent, theresidue was chromatographed (silica gel, 40% ethyl acetate/hexanes) togive 3;] as a colorless oil.TLC Rf = 0.85 (50% chloroform/ethyl acetate).1H NMR (300 MHz, CHCI3) 5 4.73 (m, 2H), 4.18 (q, 2H, J=7.1Hz),4.06 (dd, 2H, J=l7.6, 20.8 Hz), 3.42 (m, 2H), 2.44 (m, 1H), 2.27 (m,1H), 2.12 (m, 3H), 1.75 (In, 1H), 1.74 (s, 3H), 1.50 (m, 1H), 1.28 (t,3H, J=7.3 Hz).Ethvl 2-oxo-3(S)-(3-oxoâbutvl)DLrrolidin-1âvl)acetate (3-8)To a solution of3j_ (3.35 g,14.0 mmol) and N-methylmorpholine-N-oxide (3.27 g, 28.0 mmol) in THF (10 mL) and?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912~102-water (1 mL) was added OsO4 (5.7 mL, 0.56 mmol; 2.5 % tâbutanol).After 1 h, NaIO4 (5.99 g , 28 mmol) in warm water (30 mL) was addedover 2 min, and the resulting mixture stirred for 1 h. Water was thenadded, and the aqueous layer washed with ether and ethyl acetate, andthe combined organic extracts were dried over sodium sulfate.Evaporative removal of the solvent gave 3-_8 as a dark oil containingresidual OSO4.TLC Rf = 0.78 (70:20:10 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CHCI3) 5 4.19 (m, 2H, J=7.2 Hz), 4.03 (s, 2H),3.41 (m, 2H), 2.68 (t, 2H, J=9.4 Hz) 2.45 (m, 1H), 2.27 (m, 1H), 2.17(s, 3H), 1.97 (m, 1H), 1.78 (m, 2H), 1.28 (t, 3H, J=7.2 Hz).Ethyl 2-oxoâ3(S)-[2-([1,8]ânaphthyridinâ2-yl)ethyl]pyrrolidin-1-vl)acetate (3-9)A mixture of 3_-8 (3.25 g, 13.5 mmol), 1_;4, 2-amino-3-formylpyridine (2.2 g, 18.2 mmol; for preparation see Synth. Commun.1987, _1_7_, 1695) and proline (0.62 g, 5.39 mmol) in absolute ethanol (45mL) was heated at re?ux for 15 h. Following evaporative removal ofthe solvent, the residue was chromatographed (silica gel, 70:25 :5chloroform/ethyl acetate/MeOH to give 3:2 as a colorless oil.TLC Rf = 0.24 (70:25:5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CHCl3)5 9.08 (m, 1H), 8.16 (m, 2H), 7.47 (m,2H), 4.17 (m, 4H), 3.42 (m, 2H), 3.21 (t, 2H, J=6.0 Hz), 2.56 (m, 1H),2.39 (m, 2H), 2.08 (m, 1H), 1.87 (m, 1H), 1.27 (t, 3H, J=7.1 Hz).Ethyl 2-oxoâ3(S)-[2â(5 ,6,7 ,8-tetrahydro[ 1 ,8]-naphthyridinâ2-yl)ethv1lDvrrolidin-lâvl)acetate (3 -10)A mixture of _3;9_ (3.33 g, 10.2 mmol) and 10% Pd/carbon(1.5 g) in EtOH (50 mL) was stirred under a balloon of hydrogen for13 h. Following filtration and evaporative removal of the solvent, theresidue was chromatographed (silica gel, 70:20:10 chloroforrn/ethylacetate/MeOH to give £0 as a colorless oil.TLC Rf = 0.20 (70:20:10 chlorofonn/ethyl acetate/MeOH).?7 WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97I149l2 _-103-1H NMR (300 MHz, CHCI3) 8 7.05 (d, 1H, J=7.3 Hz), 6.38 (d, 1H,J=7.3 Hz), 4.88 (br s, 1H), 4.17 (dd, 2H, J=7.0, 14.4 Hz), 4.04 (dd, 2H,J=17.6, 27.3 Hz), 3.40 (m, 4H), 2.69 (m, 4H), 2.51 (m, 1H), 2.28 (In,2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.27 (t, 3H, J=6.9 Hz).2-Oxo-3(S)-[2-(5 ,6,7,8-tetrahydro [1 ,8] -naphthyridin-2-vl)ethVllDVrrolidin-1-Vl)acetic acid (3-11)A mixture ofi1_Q (0.60 g, 1.81 mmol) and 6N HC1 (25mL) was heated at 60° C for 1 h. Evaporative removal of the solventgave 3;1_1 as a yellow oil.1H NMR (300 MHz, DMSO-d6) 5 8.4 (br s, 1H), 7.60 (d, 1H, J=7.3Hz), 6.63 (d, 1H, J=7.3 Hz), 3.92 (dd, 2H, J=17.6, 25.9 Hz), 3.43 (m,2H), 3.35 (m, 2H), 2.74 (m, 4H), 2.28 (m, 2H), 2.03 (m, 1H), 1.82 (m,2H), 1.67 (In, 2H),2âOxo-3(S)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridi11-2-yl lethyl |Qyrrolidin-1-yl )acetylâ3§ S 1-alkynylâ[§-alanine ethyl ester 13-12)A mixture of3_-11 (0.20 g, 0.588 mmol), _2_-_9_ (0.157 g,0.882 mmol), EDC (0.147 g, 0.765 mmol), HOBT (0.095 g, 0.706mmol) and NMM (0.453 mL, 4.12 mmol) in CH3CN (3 mL) and DMF(2 mL) was stirred for 20 h. The mixture was diluted with ethylacetate, washed with water, brine, and dried over sodium sulfate.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOHto give 3_-_l_2 as a colorless foam.TLC Rf = 0.44 (70:20:10 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CHCI3) 5 7.06 (d, 1H, J=7.3 Hz), 6.39 (d, 1H,J=7.3 Hz), 5.07 (m, 1H), 4.94 (br s, 1H), 4.18 (q, 2H, J=6.1 Hz), 3.95(q, 2H, J=16.1 Hz), 3.39 (m, 4H), 2.90 (s, 1H), 2.68 (m, 6H), 2.50 (m,1H), 2.27 (m, 3H), 1.82 (m, 4H), 1.27 (t, 3H, J=7.l Hz).2-Oxo-3(S)â[2-(5,6,7 ,8âtetrahydro[ 1 ,8]ânaphthyridin-2-yl)ethyl] -Dvrrolidin-1âyl)acetvl-3(S)-alkvnvl-[3-alanine (3-13)?WO 98/0884010202530 CA 02263999 l999-02- 19PCT/US97/14912 --104-To a solution of 1 (0.050 g, 0.117 mmol) in EtOH (1mL) was added IN NaOH (0.164 ml, 0.164 mmol). After stirring for 2h, the solvents were evaporated and the residue was chromatographed(silica gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give _3_;_13 as acolorless foam.TLC Rf = 0.26 (25 :10:1 :1 ethyl acetate/EtOH/water/N1-14OH).1H NMR (300 MHz, DMSO-d5) 8 7.75 (br s, 1H), 7.14 (d, 1H, J=7.3Hz), 6.31 (d, 1H, J=7.3 Hz), 4.74 (m, 1H), 3.90 (d, 1H, J=16.6 Hz), 3.67(d, 1H, J=16.6 Hz), 3.23 (m, 4H), 2.57 (m, 7H), 2.30 (In, 1H), 2.11 (m,2H), 1.73 (m, 2H), 1.59 (m, 2H).2-Oxo-3(S)â[2-(5,6,7,8âtetrahydro[1,8]ânaphthyridinâ2âyl)ethyl]-rrolidin-1- 1 acet 1-3 S - ridin-3- 1- âalanine eth 1 ester 3-14A mixture ofi? (0.30 g, 0.882 mmol), _2_-_1Q (0.354 g,1.32 mmol) , EDC (0.220 g (1.15 mmol), HOBT (0.143 g, 1.05 mmol)and NMM (0.680 mL (6.18 mmol) in CH3CN (5 mL) and DMF (3 mL)at 0° C was stirred for 10 min, then allowed to warm and stir for 20 h.The mixture was diluted with ethyl acetate, washed with water, brine,and dried over sodium sulfate. Following evaporative removal of thesolvent, the residue was chromatographed (silica gel, 70:20:10chloroform/ethyl acetate/MeOH to give 3_-14 as a colorless foam.TLC Rf = 0.31 (70:20:10 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CHC13) 6 8.55 (d, 1H, J=2.2 Hz), 8.50 (dd, 1H, J:1.5, 4.6 Hz), 7.64 (m, 2H), 7.23 (m, 1H), 7.05 (d, 1H, J=7.3 Hz), 6.38(d, 1H, J=7.3 Hz), 5.40 (m, 1H), 4.98 (br s, 1H), 4.01 (m, 4H), 3.39 (m,4H), 2.85 (m, 2H), 2.68 (m, 4H), 2.49 (m, 1H), 2.25 (m, 2H), 1.83 (m,4H), 1.16 (t, 3H, J=7.2 Hz). 2-Oxoâ3(S)-[2-(5,6,7,8-tetrahydro[1,8]ânaphthyridin-2-vl)ethvl1Dvrrolidin-1 -vl)acetvlâ3( S)-Dvridinâ3-V1-13âalanine (3-15)To a solution of 3i4 (0.049 g, 0.102 mmol) in THF (1mL) and water (0.3 mL) at 0° C was added 1M LiOH (0.112 ml, 0.112mmol). After warming to ambient temperature and stirring for 2 h, thesolvents were evaporated and the residue was chromatographed (silica?CA 02263999 l999-02- 19, wo 93/03340 PCT/US97/14912-105-gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give §_-_1_§ as acolorless foam.TLC Rf = 0.15 (25 : 10:1 :1 ethyl acetate/EtOH/water/NH4OH).1H NMR (300 MHz, DMSO-d6) 5 8.74 (d, 1H, J=8.3 Hz), 8.51 (m, 1H),5 8.42 (m, 2H), 7.70 (d, 1H, J=8.1 Hz), 7.33 (In, 1H), 7.21 (d, 1H, J=7.3Hz), 6.36 (d, 1H, J=7.3 Hz), 5.14 (m, 1H), 4.00 (d, 1H, J=l6.8 Hz), 3.70 -(d, 1H, J=16.6 Hz), 3.30 (m, 4H), 2.68 (m, 7H), 2.20 (m, 3H), 1.71 (m, 4H).SQHEME4I \ O/ OHN N NH /\nâ~HC| 04-1EDC,HOBTNMMH2N OEt2-9I â HIw N/ N/\n/ OETO 04-2NaOHI \ HI/ OHN NH WY10 4-3?-W0 98108840CA 02263999 l999-02- 19PCT/US97ll4912- 106 â ImI \ ON N N/\n/OH-HCl 04-1EDC,HOBTNMMH2N OEt/ I 0 2-10\ N °2HC|I \ O HI/ N OEtN N NH ?r O/ I4-4\ NNaOHl \ O HI/ N OHN N NH âJ? O/ I4-5\ N2âOx0-3(R)-[2â(5,6,7,8âtetrahydro[1,8]ânaphthyridinâ2-Vl)ethVl1DVrro1idin-1âv1)acetvl-3(S)-alkvnvl-B-alanine ethvl ester (4-2)Prepared from 5 (prepared by the method used to5 prepare 3-11, utilizing (S)-(-)-4-benzylâ2âoxazolidinone) and 2-2, by themethod used to prepare 3-12.?WO 98/0884010202530CA 02263999 l999-02- 19PCT/U S97] 14912-107-1H NMR (300 MHz, CHCI3) 5 7.06 (d, 1H, J=7 Hz), 6.39 (d, 1H), J=7Hz), 5.06 (In, 1H), 4.84 (br s, 1H), 4.16 (q, 2H, J=6 Hz), 3.93 (m, 2H),3.38 (m, 4H), 2.68 (m, 6H), 2.52 (m, 1H), 2.25 (In, 2H), 1.90 (m, 2H),1.78 (m, 2H), 1.26 (t, 3H, J=7Hz).2-Oxo-3(R)-[2-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)ethvl1DVrro1idin-1âv1)acetv1-3(S)-alkvnvl-B-alanine (4-3)Prepared from 4_â2 (0.05 g, 0.11 mmol) by the method usedto prepare 3-13.1H NMR (300 MHz, CD3OD, 1 drop 1N NaOD) 8 7.11 (d, 1H, J=7 Hz),6.40 (d, 1H, J=7 Hz), 4.90 (m, 1H), 3.94 (q, 2H, J: 17 Hz), 3.39 (In,4H), 2.69 (d, 2H, J= 6 Hz), 2.60 (m, 2H), 2.52 (d, J=7 Hz), 2.49 (m,1H), 2.27 (m, 1H), 2.13 (m, 1H), 1.85 (m, 4H), 1.68 (m, 1H).2âOxo-3(R)-[2â(5,6,7,8âtetrahydro[ 1 ,8]ânaphthyridinâ2-y1)ethy1]-DVrro1idinâ1 -v1)acetVl-3(S)-Dvridin-3-V1-B-alanine ethyl ester (4-4)Prepared from 4â_l_ (0.35 g, 1.0 mmol) and 2-_l_(_) (0.33 g,1.2 mmol) by the method used to prepare _3_;1_4.1H NMR (300 MHz, CHCI3) 6 8.55 (d, 1H, J: 2 Hz), 8.55 (dd, 1H, J= 2, 5 Hz), 7.61 (m, 1H), 7.54 (m, 1H), 7.06 (d, 1H), 6.38 (d, 1H, J=7 Hz),5.40 (m, 1H), 4.90 (br s, 1H), 4.05 (q, 2H, J=7 Hz), 3.95 (m, 2H), 3.42(m, 4H), 2.85 (dd, 2H, J=2, 6 Hz), 2.67 (m, 4H), 2.53 (m, 1H), 2.27 (m,2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.16 (m, 3H, J=7 Hz).2-OxoâV3(R)-[2-(5 ,6,7,8-tetrahydroâ[1,8]ânaphthyridin-2-yl)ethv11Dvrrolidin-1âvl)acetvl-3(S)âDVridinâ3-vlâBâalanine (4-5)Prepared from 4-4 (0.16 g, 0.33 mmol) by the method usedto prepare _3_;?.1H NMR (300 MHz, CD3OD) 5 8.57 (s, 1H), 8.42 (111, 1H), 7.86 (d, 1H,J=6 Hz), 7.43 (In, 2H), 6.51 (d, 1H, J=7 Hz), 5.28 (m, 1H), 4.63 (d, 1H,J=17 Hz), 3.60 (m, 2H), 3.47 (d, 1H, J= 17 Hz), 3.35 (m, 3H), 3.14 (td,1H, J=5, 13 Hz), 2.75 (m, 5H), 2.42 (m, 1H), 2.23 (m, 1H), 1.90 (m,4H).?CA 02263999 l999-02- 19, W0 98/08340 PCT/US97/ 14912â108-&Q|:IEME.§O O'\/' CH3CN, 65°C |\/|5-1 5-2MQ(C|04)2CH3CN, 50°C0 0 JL BOC LiN(TMS)2DMF ON Nâ â H\N/U\N,BOC\ '\/' 1/â o0:40 K)5 4 PQ/\, 5-31-2toluene,TFArâ\ orâ\0 OO O O H _ ></\N)LN/\CO2Et)</\N/â\N/ LIN(TMS)2,DMF, |\/|K/| ethyl iodoacetate5-5?CA 02263999 l999-02- 19wo 98/08840 PCT/US97/14912-109- mFâ\Oo i></\N N/\CO2Et/?\/\Nf\N/\co2EtK} KJpTSA, acetone,reflux 5-75-6L-proline,ethanol, 1-4reflux \/\ O\N \N NJLN/\CO2Et10% Pd/C, K/'ethano|,)w/ 5_8/ | Qg \N N/u\N/\CO2FlR = Et, 5-96N HCIR = H, 5-10KEDC, HOBT, NMM, DMF, 1-9 /\ f\ HN \N N N NH KAT /R = Et, 5-11oozeI\ N1N NaOH, ethanolR = H, 5-12?WO 98/08840202530CA 02263999 l999-02- 19PCT/US97/14912-110-1 .3-Diâtert-buvloxvcarbonvl-tetrahvdronvrimidine (5-2)A heterogeneous mixture of §;1_ (10.0 g, 100 mmol),BOC2O (48 g, 220 mmol), DMAP (20 mg), and CH3CN (500 mL) washeated for 40 hr at 65°C followed by addition of DMF (100 mL) andthen continued heating for 24 hr. The cooled reaction mixture wasdiluted with EtOAc and then washed with H20, sat. NaHCO3, 1N HCl,and brine, dried (MgSO4), and concentrated. The residue was trituratedwith hexanes to give _5_â_2 as a yellow solid.TLC RF = 0.93 (EtOAc);IHNMR (300 MHz, CDCI3) 5 3.68 (t, J = 7 Hz, 4H), 2.00 (m, 2H), 1.48(s, 18 H).Tert-Butvloxvcarbonvl-tetrahvdronvrimidine (5-3)A solution of 5-_2 (19.0 g, 63 mmol), Mg(ClO4)2 (2.8 g,12.7 mmol), and CH3CN was heated at 50 °C for 2 hr. The cooledsolution was diluted with CHCI3 and then washed with 1N HCI, sat.NaHCO3, and brine, dried (MgSO4), and concentrated. Flashchromatography (silica, 75% EtOAc/ hexanes ~â>EtOAc) gave _5_-_3_ as abrown solid.TLC RF = 0.26 (silica, EtOAc);IHNMR (300 MHz, CDCI3) 5 5.50 (bs, 1H), 3.70 (m, 2H), 3.29 (In,2H), 1.97 (In, 2H), 1.48 (s, 9H).Tert-Butyloxycarbonyl-2-oxo-3-(3âethylene glycolbuty1)-tetrahvdronvrimidine (5-4)To a stirred solution of L3 (3.2g, 16.1 mmol) and DMF(50 mL) was added LiN(TMS)2 (21 mL, 1M/hexanes). After 20minutes, the iodide _1_-_2 (8.6 g, 35.2 mmol) in DMF (10 mL) was addedand the reaction mixture heated at 50 °C for 2 hours. The cooledsolution was diluted with CHCI3 and then washed with H20 and brine,dried (MgSO4), and concentrated. Flash chromatography (silica, 60%to 75% EtOAc/hexanes) gave ?? as an orange oil.TLC RF = 0.74 (silica, 70:15:15 CHCI3/EtOAc/CH3OH);?- W0 98/11884010202530CA 02263999 l999-02- 19PCT/US97/14912-111-1H NMR (300 MHz, CDCI3) 8 3.93 (s, 4H), 3.66 (t, J= 6Hz, 2H), 3,44(m, 2H), 3.30 (m, 2H), 1.96 (m, 2H), 1.48 (S, 9H), 1.32 (s, 3H).1âOxoâ2â(3-ethvlene 1 colâbut I tetrah dro- rimidine 5-5A mixture of 5-4 (3.0 g, 9.5 mmol), TFA (1.5 mL, andtoluene (30 mL) was stirred at ambient temperature for 20 minutes,concentrated and the residue azeotroped with toluene to remove excessTFA. The residue was then dissolved in toluene (30 mL) and treatedwith NaHCO3 (3 g), filtered, and the filtrate concentrated to give ayellow oil. Flash chromatography (silica, 70:15:15 CHCl3/EtOAc/CH3OH) gave _5_-_5_ as a yellow oil.TLC RF = 0.63 (silica, 70:15:15 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 5.16 (bs, 1H), 3.94 (s, 4H), 3.40 (m,2H), 3.24 (m, 4H), 1.90 (m, 2H), 1.34 (s, 3H).Ethyl 2-oxoâ3-[3-ethylene glycolâbutyl]tetrahydropyrimidinâ1âylâacetate (5-6)To a stirred solution of i? (2.0 g, 9.3 mmol) and DMF (50mL) was added LiN(TMS)2 (12.1 mL, 1.0 M/T HF). After 20 min,ethyl iodoacetate (1.66 mL, 14.0 mmol) was added followed by heatingat 60°C for 1 hr. The cooled solution was diluted with EtOAc and thenwashed with H20, sat. NaHCO3, and brine, dried (MgSO4), andconcentrated. Flash chromatography (silica, 50% to 75%EtOAc/hexanes) gave 5:6 as a colorless oil.TLC RF = 0.72 (silica, 70:15:15 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 4.18 (q, J=7Hz, 2H), 3.93 (s, 4H), 3.42(m, 2H), 3.34 (m, 4H), 1.98 (m, 2H), 1.92 (m, 2H), 1.34 (s, 3H), 1.25(t, J=7Hz, 3H).Ethvl 2-oxo-3-13-oxo-butvlltetrahvdro-Dvrimidinâ1-vl-acetate (5-7)A solution of_5-_6 (750 mg, 2.5 mmol), p-TSA (10 mg), andacetone (30 mL) was re?uxed for 1 hr. The cooled solution was dilutedwith CHCI3 and then washed with sat. NaHCO3 and brine, dried(MgSO4), and concentrated to give 5-_7_ as a yellow oil.?W0 98l08840202530CA 02263999 l999-02- 19PCT/US97/14912 --112-TLC RF = 0.36 (silica, 10% CH3OH/EtOAc);1H NMR (300 MHz, CDCI3) 5 4.17 (Cl, J=7Hz, 2H), 3.56 (m, 2H), 3.34(m, 4H), 2.76 (t, J=7Hz, 2H), 2.17 (s, 3H), 2.00 (m, 2H), 1.27 (t, J=7Hz,3H).Ethyl 2-oxoâ3â[2-naphthyridin-2-yl)ethyl]-tetrahydropyrimidin-l-yl-acetate (5-8)A mixture of 5;] (600 mg, 2.3 mmol), 1:4 (343 mg, 2.8mmol), L-proline (175 mg), and ethanol (25 mL) was heated at re?uxfor 18 hr. The cooled reaction mixture was concentrated and theresidue purified by ?ash chromatography (silica, 10% CH3OH/EtOAc)gave §_â8 as a yellow solid.TLC RF = 0.21 (silica, 10% CH3OH/EtOAc);1H NMR (300 MHz, CDCI3) 5 9.10 (m, 1H), 8.19 (m, 1H), 8.14 (d,J=8Hz, 1H), 7.52 (d, J=8Hz, 1H), 7.44 (m, 1H), 4.18 (q, J=7Hz, 2H),3.83 (In, 2H), 3.32 (m, 6H), 1.93 (m, 2H), 1.24 (t, J=7Hz, 3H).Ethyl 2-oxo-3-[2â(5,6,7,8âtetrahydro-[1 ,8] ânaphthyridineâ2ây1)ethyl]tetrahvdronvrimidine-1-vl-acetate ( 5 -9)A mixture of E (600 mg, 1.75 mmol), 10% Pd/C (300mg), and ethanol (10 mL) was stirred at ambient temperature under ahydrogen atmosphere (1 atm) for 20 hr. The catalyst was removed byfiltration through a celite pad and the filtrate concentrated to give 5-2 asa yellow oil.1H NMR (300 MHz, CDCI3) 8 7.04 (d, J=8Hz, 1H), 6.42 (d, J=8Hz,1H), 4.80 (bs, 1H), 4.22-4.03 (m, 4H), 3.60 (m, 2H), 2.78 (m, 2H), 2.66(m, 2H), 1.96 (m, 4H), 1.24 (t, J=7Hz, 3H).2-Oxo-3-[2- (5,6,7 ,8âtetrahydro-[1,8]naphthridin-2-yl)tetrahydro-pvrimidin-l-vl-acetic acid (5-10)A solution of E (600 mg, 1.73 mmol) and 6N HC1 (20mL) was heated at 50°C for 2 hr. The solution was concentratedfollowed by azeotropic removal of H20 with CH3CN to give 5_-? as ayellow solid.?~ WO 98108840202530CA 02263999 l999-02- 19PCT/US97/14912-113-1H NMR (300 MHz, CD3OD) 5 7.58 (d, J=8Hz, 1H), 6.63 (d, J=8Hz,1H), 3.98 (s, 2H), 3.62 (t, J=7Hz, 2H), 3.50 (m, 2H), 3.36 (m, 4H),2.93 (In, 2H), 2.80 (m, 2H), 2.00 (In, 4H).Ethyl 2-ox0-3-[2-(5,6,7,8âtetrahydroâ[1,8]naphthyridin-2-y1)ethyl]-tetrah dro rimidin-1- l-acet 1-3 S - ridin-3- 1- -alanine 5-11To a stirred solution of _5_? (250 mg, 0.70 mmol), 1_-2(210 mg, 0.77 mmol), EDC (148 mg, 0.77 mmol), HOBT (95 mg, 0.70mmol), CH3CN (2 mL), and DMF (2 mL) was added NMM (542 pL,4.9 mmol), After stirring at ambient temperature for 20 hr, thereaction mixture was diluted with EtOAc and then washed with H20,sat. NaHCO3, brine, dried (MgSO4), and concentrated. Flashchromatography (silica, 70:15:15 CHC13/EtOAc/CH3OH) gave _5_;1_1 as acolorless oil.TLC RF = 0.31 (silica, 70: 15:15 CHCl3/ EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 8.58 (In, 1H), 8.50 (m, 1H), 7.94 (m,1H), 7.66 (m, 1H), 7.22 (m, 1H), 7.05 (d, J=8Hz, 1H), 6.40 (d, J=8Hz,1H), 5.43 (m, 1H), 4.06 (q, J=7Hz, 2H), 4.02 (m, 1H), 3.90 (m, 1H),3.60 (m, 2H), 3.39 (m, 2H), 3.29 (m, 2H), 3.19 (m, 2H), 2.88 (m, 2H),2.77 (m, 2H), 2.70 (m, 2H), 1.90 (m, 4H), 1.16 (t, J=7Hz, 3H). 2-Oxo-3-[2-(5 ,6,7,8-tetrahydroâ[1,8]naphthyridinâ2-yl}ethyl]âtetrah dro rimidin-1- l-acet 1-3- S - ridinâ3â 1- âa1anine 5-12A mixture of 5_-1__l__ (100 mg, 0.22 mmol), 1N NaOH (300uL), and ethanol (1 mL) was stirred at ambient temperature for 1 hr,followed by concentration. Flash chromatography (silica, 25:10:1:1 to15:10:1:1 EtOAc/EtOH/NH4OH/H20) gave 5-_1_2_ as a white solid.TLC RF = 0.22 (silica, 10:10:1:1 EtOAc/ethanol/NH4OH, H20);1H NMR (300 MHz, CD3OD) 5 8.66 (m, 1H), 8.39 (m, 1H), 7.95 (m,1H), 7.53 (d, J=8Hz, 1H), 7.40 (m, 1H), 6.66 (d, J=8Hz, 1H), 5.18 (m,1H), 4.27 (d, J=7Hz, 1H), 4.16 (m, 1H), 3.64 (d, J=7Hz, 1H), 3.50-3.10(m, 8H), 3.00-2.65 (m, 6H), 1.95 (m, 4H). ?CA 02263999 l999-02- 19Two 93/oss4o PCT/US97/14912-114-S_Ql:lEM.E_6O oWNJLN/H BOC2O,DMAP, BOCâNâlLNâBOCL_.| CH3CN, 65°C6-2MQ(C'O4) 2CH3CN, 50°C0â âO ii 0)§/\N N,BOC LiN(TMS)2,DMF H\ )L /BOGI I N N|_1 F'\OI _toluene, 1"?TFArâ\ I 0 O O0 0 j\ ></\NJJ\N/\CO2Et>§/\N N/H LiN(TMS)2,DMF, l_lI___l ethyl iodoacetate6-66-5?CA 02263999 l999-02- 19 . W0 98/08840 PCT/US97/14912- 115 -S§?EN|.E_i(.C.O.D.t'£1l0,40 0 )1â i)§/\N/â\N/xco Et pTSA. N N/\CO2EtI I 2 acetone L__J6-6 reflux 6_7Lâproline,ethanol, 1-4reflux/ / | Q\ \N NJLN/\CO2EtL___l/°o Pd/C, 6-8N \N ~ NJLN/\CO2RH | |R = Et, 6-96N HCIR = H, 6-10EDC, HOBT, NMM, DMF, 1-9\ N(TL i HE N N W / (3025:;I\ NR= Et, 6-111N NaOH, ethanolR = H, 6-12?-WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/ 14912-116-1,3âDi-tert-buyloxycarbony1-imidazolidin-2âone (6-2)A heterogeneous mixture of 6-1 (10.0 g, 116 mmol),BOC20 (56 g, 255 mmol), DMAP (20 mg), and CH3CN (400 mL) washeated for 18 hr at 60°C. The cooled reaction mixture was diluted withEt0Ac and then washed with H20, sat. NaHCO3, IN HCl, and brine,dried (MgS04), and concentrated. The residue was triturated withhexanes to give 6-2 as a white solid.TLC RF = 0.91 (EtOAc);1H NMR (300 MHz, CDCI3) 5 3.73 (s, 4H), 1.53 (s, 18 H).Tert-Butvloxvcarbonvl-imidazolidinâ2-one (6-3)A solution of 6-2 (28.0 g, 98 mmol), Mg(Cl04)2 (4.3 g, 20mmol), and CH3CN (400 mL) was heated at 50 °C for 3 hr. The cooledsolution was diluted with CHCI3 and then washed with lN HCI, sat.naHC03, and brine, dried (Mg S04), and concentrated. Flashchromatography (silica, 50% Et0Ac/ hexanes ââ>Et0Ac) gave 6-3 as ayellow solid.TLC RF = 0.31 (silica, EtOAc);1H NMR (300 MHz, CDCI3) 5 6.27 (bs, 1H), 3.86 (m, 2H), 3.47 (m,2H), 1.50 (s, 9H).1-TertâButyloxycarbonyl-3â(3âethylene glycol-butyl)imidazolidin-2-one(6-4)To a stirred solution of 6-3 (4.5 g, 24 mmol) and DMF (50mL) was added LiN(TMS)2 (26.6 mL, 1M/hexanes). After 20 minutes,the iodide 1-2 (8.6 g, 35.2 mmol) in DMF (10 mL) was added and thereaction mixture heated at 60 °C for 4 hours. The cooled solution wasdiluted with CHCI3 and then washed with H20 and brine, dried(MgSO4), and concentrated. Flash chromatography (silica, 75%Et0Ac/hexanes) gave 6-4 as an yellow solid.TLC RF = 0.71 (silica, 70:15:15 CHCI3/Et0Ac/CH30H);1H NMR (300 MHz, CDCI3) 5 3.93 (s, 4H), 3.75 (In, 2H), 3.36 (m, 4H),1.90 (m, 2H), 1.53 (s, 9H), 1.34 (s, 3H).?WO 98/08840202530CA 02263999 l999-02- 19PCT/US97ll4912-117-1-1 3-Ethylene glvcol-butvl)imidazolidinâ2-one (6-5)A mixture of 6-4 (4.0 g, 13.3 mmol), TFA (3 mL, andtoluene (60 mL) was stirred at 50°C for 60 minutes, concentrated andthe residue azeotroped with toluene to remove excess TFA. The residuewas then dissolved in toluene (30 mL) and treated with NaHCO3 (3g),filtered, and the filtrate concentrated to give a yellow oil. Flashchromatography (silica, 70:25:5 CHCI3/EtOAc/CH3OH) gave 6-5 as awhite solid.TLC RF = 0.58 (silica, 70:15:15 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 4.25 (bs, 1H), 3.94 (s, 4H), 3.44 (m,4H), 3.32 (m, 2H), 1.90 (m, 2H), 1.35 (s, 3H).Eth l 2-oxo-3- 3âeth lene l col-but l imidazolidin-1- 1-acetate 6-6To a stirred solution of 6-5 (2.0 g, 10 mmol) and DMF (50mL) was added LiN(TMS)2 (11 mL, 1.0 M/THF). After 20 min, ethyliodoacetate (3.5 mL, 30 mmol) was added at ambient temperature.After 3 hr the solution was diluted with EtOAc and then washed withH20, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flashchromatography (silica, 50% to 75% EtOAc/hexanes) gave 6-6 as acolorless oil. .TLC RF = 0.71 (silica, 70:15:15 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 4.18 (q, J=7Hz, 2H), 3.93 (s, 4H), 3.91(m, 2H), 3.50-3.30 (m, 6H), 1.90 (m, 2H), 1.92 (m, 2H), 1.35 (s, 3H),1.25 (t, J=7Hz, 3H). Ethvl 2-oxoâ3-[3âoxo-butvllimidazo1idin-1-vl-acetate (6-7)A solution of 6-6 (1.4 g, 4.9 mmol), p-TSA (10 mg), andacetone (30 mL) was re?uxed for 1 hr. The cooled solution was dilutedwith CHCI3 and then washed with sat. NaHCO3 and brine, dried(MgSO4), and concentrated to give 6-7 as a yellow oil.TLC RF = 0.34 (silica, EtOAc);1H NMR (300 MHz, CDCI3) 5 4.17 (q, J=7Hz, 2H), 3.94 (s, 2H),3.48 (m, 2H), 3.42 (m, 4H), 2.72 (t, J=7Hz, 2H), 2.17 (s, 3H),1.27 (t, J=7Hz, 3H).?WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912-118-Ethyl 2-oxo-3-I 2-naphthyridin-2-yl )ethyl |imidazolidin-1-V1-acetate (6-8)A mixture of 6-7 (1.0 g, 4.1 mmol), 1-4 (604 mg, 4.9mmol), Lâproline (238 mg), and ethanol (50 mL) was heated at re?uxfor 20 hr. The cooled reaction mixture was concentrated and theresidue purified by ?ash chromatography (silica, 70:25:5CHCl3/EtOAc/CH3OH) gave 6-8 as a yellow oil.TLC RF = 0.42 (silica, 70:15:15 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 5 9.10 (m, 1H), 8.19 (m, 1H), 8.14 (d,J=8Hz, 1H), 7.52 (d, J=8Hz, 1H), 7.44 (m, 1H), 4.17 (q, J=7Hz, 2H),,3.81 (m, 2H), 3.42 (m, 4H), 3.32 (m, 4H), 1.24 (t, J=7Hz, 3H).Ethyl 2-oxoâ3-[2-(5 ,6,7,8-tetrahydro-[1 ,8]ânaphthyridine-2-vl)ethvllimidazolidinâl âvl-acetate (6-9)A mixture of 6-8 (1.1 g, 3.35 mmol), 10% Pd/C (500 mg),and ethanol (30 mL) was stirred at ambient temperature under ahydrogen atmosphere (1 atm) for 20 hr. The catalyst was removed byfiltration through a celite pad and the filtrate concentrated to give 6-9 asa colorless oil.TLC RF = 0.11 (silica, 70:25:5 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 5 7.04 (d, J=8Hz, 1H), 6.42 (d, J=8Hz,1H), 4.80 (bs, 1H), 4.22-4.03 (m, 4H), 3.96 (s, 2H), 3.55 (m, 2H), 3.40(m, 2H), 2.78 (m, 2H), 2.68 (m, 2H), 1.90 (m, 2H), 1.24 (t, J=7Hz, 3H).2-Oxo-3-[2â(5,6,7,8-tetrahydro-[1,8]naphthridin-2-yl)imidazolidin-1-ylâacetic acid (6-10)A solution of 6-9 (1.0 g, 3.0 mmol) and 6N HCl (40 mL)was heated at 60°C for 1 hr. The solution was concentrated followed byazeotropic removal of H20 with CH3CN to give 6-10 as a yellow solid.1H NMR (300 MHz, CD3OD) 5 7.58 (d, J=8Hz, 1H), 6.63 (d, J=8Hz,1H), 3.98 (s, 2H), 3.50 (m, 4H), 3.36 (m, 4H), 2.93 (m, 2H), 2.82 (m,2H), 1.97 (m, 4H).?WO 981088402025CA 02263999 l999-02- 19PCT/US97ll49l2-119-Ethyl 2âOxoâ3-[2-(5 ,6,7,8âtetrahydroâ[1,8]naphthyridinâ2â1 eth 1 imidazolidin-1- 1-acet 1-3 S - ridin-3- 1- âalanine 6-llTo a stirred solution of 6-10 (240 mg, 0.70 mmol), 1-9(207 mg, 0.77 mmol), EDC (269 mg, 1.4 mmol), HOBT (95 mg, 0.70mmol), and CH3CN (3 mL) was added NMM (619 pL, 5.6 mmol).After stirring at ambient temperature for 20 hr, the reaction mixturewas diluted with EtOAc and then washed with H20, sat. NaHCO3,brine, dried (MgSO4), and concentrated. Flash chromatography (silica,70:15:15 CHC13/EtOAc/CH3OH) gave 6-11 as a colorless oil.TLC RF = 0.41 (silica, 70: 15:15 CHCl3/ EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 8.58 (m, 1H), 8.50 (m, 1H), 7.94 (m,1H), 7.66 (m, 1H), 7.22 (m, 1H), 7.05 (d, J=8Hz, 1H), 6.40 (d, J=8Hz,1H), 5.43 (m, 1H), 4.06 (q, J=7Hz, 2H), 3.85 (m, 1H), 3.55 (m, 2H),3.40 (m, 2H), 3.33 (In, 4H), 2.90 (In, 2H), 2.77 (In, 2H), 2.70 (m, 2H),1.90 (m, 2H), 1.77 (m, 2H), 1.18 (t, J=7Hz, 3H). 2âOxoâ3-[2-(5 ,6,7,8-tetrahydroâ[1,8]naphthyridin-2-yl}ethy1]-imidazolidin-1â l-acet l-3- S - ridin-3- 1- âalanine 6-12A mixture of 6-11 (160 mg, 0.33 mmol), 1N NaOH (500}1L), and ethanol (1 mL) was stirred at ambient temperature for 1 hr,followed by concentration. Flash chromatography (silica, 25:10:1:1 to15:10:l:1 EtOAc/EtOH/NH4OH/H20) gave 6-12 as a white solid.TLC RF = 0.21 (silica, 10:10:1:l EtOAc/ethanol/NH4OH, H20);1H NMR (300 MHz, CD3OD) 5 8.66 (m, 1H), 8.39 (m, 1H), 7.95 (m,1H), 7.53 (d, J=8Hz, 1H), 7.40 (In, 1H), 6.66 (d, J=8Hz, 1H), 5.22 (m,1H), 3.93 (d, J=17 Hz, 1H), 3.74 (d, J=17Hz, 1H), 4.00-3.20 (m, 9H),3.00-2.65 (m, 6H), 1.89 (m, 4H). ?CA 02263999 l999-02- 19. wo 93/03340 PCT/US97ll49l2-120-H T IN N ' N\/COZH /7-1EDC, HOBT,NMM, CH3CN1N NaOH, ethanol?WO 981088402025CA 02263999 l999-02- 19PCT/U S97! 14912-121-Ethyl 2-oxo-3(R)-[2â(5,6,7,8âtetrahydro-[1,8]naphthyridin-2-rr lidin-l- l acet 1-3 R - 2-eth lindol-3- 1 - -alanine 7-2To a stirred solution ofiâ__l_ (175 mg, 0.52 mmol), '_7-_1 (2mg, 0.72 me]; for preparation see US 5,321,034), EDC (197 mg, 1.0mmol), HOBT (70 mg, 0.52 mmol), and CH3CN (3 mL) was addedNMM (498 11L, 4.1 mmol). After stirring at ambient temperature for20 hr, the reaction mixture was diluted with EtOAc and then washedwith H20, sat. NaHCO3, brine, dried (MgSO4), and concentrated.Flash chromatography (silica, 70:25 :5 CHCI3/EtOAc/CH3OH) gave 7_â2as a white solid.TLC RF = 0.11 (silica, 70:25:5 CHC13/ EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 6 8.29 (bs, 1H), 7.55 (d, J = 7 Hz, 1H),7.36 (d, J = 7 Hz, 1H), 7.20-7.00 (In, 3H), 6.63 (d, J = 7 Hz, 1H), 6.39(d, J = 7 Hz, 1H), 4.30 (In, 1H), 4.10 (q, J=7Hz, 2H), 3.94 (d, J = 17 Hz,1H), 3.83 (d, J = 17 Hz, 1H), 3.36 (m, 4H), 2.80 (m, 2H), 2.69 (m, 3H),2.53 (d, J= 6 Hz, 2H), 2.50 (m, 1H), 2.24 (m, 2H), 1.93 (m, 4H), 1.75(m, 2H), 1.18 (t, J=7Hz, 3H). 2-Oxo-3 (R)-[2-(5 ,6,7,8-tetrahydro-[1,8]naphthyridinâ2-leth l rrolidin-l- lacet l-3 R â 2-eth lindol-3- 1- -alanine 7-3A mixture ofl-_2 (60 mg, 0.11 mmol), 1N NaOH (132 }1L),and ethanol (1 mL) was stirred at ambient temperature for 1 hr,followed by concentration. Flash chromatography (silica, 25 :l0:l:l to15 :10:1:l EtOAc/EtOH/NH4OH/H20) gave 7_-3-_ as a white solid.TLC RF = 0.12 (silica, 10:10:1:1 EtOAc/ethanol/NH4OH/H20);1H NMR (300 MHz, CD3OD) 5 7.52 (d, J = 7 Hz, 1H), 7.43 (d, J = 7Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.05 (m, 2H), 6.92 (m, 1H), 6.48 (d, J =7 Hz, 1H), 4.54 (d, J = 17 Hz, 1H), 4.27 (m, 1H), 3.50-1.70 (m, 22H). ?CA 02263999 l999-02- 19WO 98/08840 PCT/US97/14912-122-S_C_HEME_&Synthesis of Radioligand for SPA AssayH2N co2HO H NH2§;l} SO20] NaOH, dioxaneH20H2N CO2HO Hâ N~so2asH2N/XCOZHN~so2HQ.ClEtOHH853HHc|.H2N/XCOQCHZCH3â$302HB-_4?CA 02263999 l999-02- 19WO 98/08840 PCTIUS97/14912-123-S.Ql:|EM.E£_(Slo_D1'_dl£ COZCHZCH3NHZNB.-§_aH2,1 0% Pd/ CEtOH\| /H2N Nco2cH2cH3&;5SN HCIl \/HC|°H2N N3:5 CO2HHcn-Haw/§{CO"-CHZCH3 EDC,HOBT,H HNSO2C6H4| NMM,DMFâ II â 0// 02$H2N 9N âNHCO2CH_9_CH3?CA 02263999 l999-02- 19WO 98/08840 PCT/US97/14912- 124 âS£¢iEM_E_a_(99m's!l ,I \ Q/ 0 sH N 2-2 N H H .â\NHCOZCHZCH3o8_â_Z6N HCIeo°c :I â Q. / 02?H H \NHN .\\)\CO2Hma 0(CH3Sn)2, Pd(PPh3)4,I \ dioxane, 90° Sâ(CH3)39 02$H H âNHN â\\)\CO2H\H2N N?-WO 98/088401015202530CA 02263999 l999-02- 19PCT/U S97/ 14912-125-N-g 4-Iodo-phenylsulfonylamino 1-L-asparagine (8-2)To a stirred solution of acid §_â_1_ (4.39 g, 33.2 mmol),NaOH (1.49 g, 37.2 mmol), dioxane (30 ml) and H20 (30 ml) at 0°Cwas added pipsyl chloride (10.34 g, 34.2 mmol). After ~5 minutes,NaOH (1.49, 37.2 mmol) dissolved in 15 ml H20, was added followedby the removal of the cooling bath. After 2.0 h, the reaction mixturewas concentrated. The residue was dissolved in H20 (300 ml) and thenwashed with EtOAc. The aqueous portion was cooled to 0°C and thenacidified with concentrated HCl. The solid was collected and thenwashed with Et2O to provide acid 82 as a white solid.1H NMR (300 MHz, D20) 5 7.86 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz)3.70 (in, 1H), 2.39 (m, 2H).21 S H 4-Iodo-phenylsglfonylamino H3-alanine (8-3)To a stirred solution of NaOH (7.14 g, 181.8 mmol) andH20 (40 ml) at 0°C was added Br2 (1.30 ml, 24.9 mmol) dropwise overa ten minute period. After ~5 minutes, acid 8;; (9.9 g, 24.9 mmol),NaOH (2.00 g, 49.8 mmol) and H20 (35 ml) were combined, cooled to0°C and then added in a single portion to the reaction. After stirringfor 20 minutes at 0°C, the reaction was heated to 90°C for 30 minutesand then recooled to 0°C. The pH was adjusted to ~7 by dropwiseaddition of concentrated HCl. The solid was collected, washed withEt0Ac, and then dried in vacuo to provide acid 8;; as a white solid.1H NMR (300 MHz, D20) 5 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz),4.36 (m, 1H), 3.51 (dd, 1H, J=5Hz, l3Hz) 3.21 (m, 1H). HCI gas was rapidly bubbled through a suspension of acid_8_â3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0°C for 10 minutes. Thecooling bath was removed and the reaction was heated to 60°C. After18 h, the reaction was concentrated to provide ester _S_â_4_ as a white solid.1H NMR (300 MHz, CD30D) 8 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H,J=8Hz), 4.25 (q, 1H, J=5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H),1.01 (t, 3H, J=7Hz).?WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912-126-Ethvl 4-12-(2-Aminoovridin-6-vl)ethvllbenzoate (8-5)A mixture of ester 1 (700 mg, 2.63 mmol), (forpreparation, see: Scheme 29 of PCT International ApplicationPublication No. WO 95/32710, published December 7, 1995) 10%Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, thereaction was filtered through a celite pad and then concentrated toprovide ester 8;_5_ as a brown oil.TLC Rf = 0.23 (silica, 40% EtOAC/hexanes)1H NMR (300 MHz, CDCI3) 5 7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43(d, 1H, J=7Hz), 6.35 (d, 1H, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91(m, 2H), 1.39 (t, 3H, J=7Hz). A suspension of ester 8_â5_ (625 mg, 2.31 mmol) in 6N HCl(12 ml) was heated to 60°C. After ~20 h, the reaction was concentratedto give acid 8_-6_ as a tan solid.1H NMR (300 MHz, CD3OD) 5 7.96 (d, 2H, J=8Hz), 7.80 (m, 1H), 7.33(d, 2H, J=8Hz), 6.84 (d, 1H, J=9Hz), 6.69 (d, 1H, J=7Hz), 3.09 (In, 4H),Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodo-Dhenvlsulfonvlamino)-13-alanine (8-7)A solution of acid 8_-Q (400 mg, 1.43 mmol), amine 8-_4(686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg,1.86 mmol), NMM (632 pl, 5.72 mmol) and DMF (10 ml) was stirredfor ~20 h. The reaction was diluted with EtOAC and then washed withsat NaHCO3, brine, dried (MgSO4) and concentrated. Flashchromatography (silica, EtOAC â> 5% isopropanol/EtOAc) providedamide 8_-7_ as a white solid.TLC Rf = 0.4 (silica, 10% isopropanol/EtOAc)1H NMR (300 MHz, CD3OD) 5 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H,J=8Hz), 7.52 (d, 2H, J=9Hz), 7.29 (m, 1H), 7.27 (d, 2H, J=8Hz), 4.20(m, 1H), 3.95 (q, 2H, J=7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H,J=8Hz, 13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz).?WO 98/08840202530CA 02263999 l999-02- 19PCT/US97/14912- 127 â4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenylâsulfonvlamino)âBâalanine (8-8)A solution of ester &'1 (200 mg, 0.3213 mmol) and 6N HCI(30 ml) was heated to 60°C. After ~20 h, the reaction mixture wasconcentrated. Flash chromatography (silica, 20:20:l:1 EtOAc/EtOH/NH4OH/H20) provided acid 8_;_8 as a white solid.TLC Rf = 0.45 (silica, 20:20:l:1 EtOAc/EtOI-I/NH4OH/H20)1H NMR (400 MHz, DMSO) 8 8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H,J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34(d, 1H, J=7Hz), 6.25 (d, 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35(m, 2H), 2.97 (m, 2H), 2.79 (m, 2H).4-[2-(2âAminopyridin-6-y1)ethyl)benzoylâ2(S)-(4-trimethylstannyl-Dhenvlsulfonvlamino-Bâalanine (8-9)A solution of iodide 8_-8 (70 mg, 0.1178 mmol), (CH3Sn)2(49 1.11, 0.2356 mmol), Pd(PPh3)4 (5 mg) and dioxane (7 ml) washeated to 90°C. After 2 h, the reaction was concentrated and thenpurified by prep HPLC (DeltaâPak C18 15 ].1M 100A°» 40 x 100 mm;95:5 ââ> 5:95 H20/CH3CN) provided the tri?uoroacetate salt. The saltwas suspended in H20 (10 ml), treated with NH4OH (5 drops) and thenlyophilized to provide amide 8_â2 as a white solid.1H NMR (400 MHz, DMSO) 5 8.40 (m, 1H), 8.18 (d, 1H, J=8Hz), 7.67(m, 5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (In, 2H),6.45 (bs, 2H), 4.00 (m, 1H), 3.50 (In, 1H), 3.33 (m, 1H), 2.97 (m, 2H),2.86 (m, 2H).4-[2â(2-Aminopyridin-6âyl)ethyl]benzoylâ2(S)-4-125iodoâDhenvlsulfonvlaminoâB-alanine (8-10)An iodobead (Pierce) was added to a shipping vial of 5 mCiof Na125I (Amersham, IMS30) and stirred for five minutes at roomtemperature. A solution of 0.1 mg of _8_-_9_ in 0.05 mL of 10%H2SO4/MeOH was made and immediately added to the Na1251/iodobeadvial. After stirring for three minutes at room temperature,?-W0 98/0884010152025CA 02263999 l999-02- 19PCT/US97/14912-128-approximately 0.04-0.05 mL of NH4OH was added so the reactionmixture was at pH 6-7. The entire reaction mixture was injected ontothe HPLC for purification [Vydac peptide-protein C-18 column, 4.6 x250 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H2O (0.1%TFA) to 90% acetonitrile (0.1% TFA):H2O (0.1% TFA) over 30minutes, 1 mL/min]. The retention time of _8_âlQ is 17 minutes underthese conditions. Fractions containing the majority of the radioactivitywere pooled, lyophilized and diluted with ethanol to give approximately1 mCi of §â_1_0, which coeluted on HPLC analysis with an authenticsample of 8_-§.Instrumentation: Analytical and preparative HPLC wascarried out using a Waters 600E Powerline Multi Solvent DeliverySystem with 0.1 mL heads with a Rheodyne 7125 injector and a Waters990 Photodiode Array Detector with a Gilson FC203 Microfractioncollector. For analytical and preparative HPLC a Vydac peptide-proteinC-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modularguard column. The acetonitrile used for the HPLC analyses was FisherOptima grade. The HPLC radiodetector used was a Beckman 170Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x250 mm was used for analytical and preparative HPLC. Solutions ofradioactivity were concentrated using a Speedvac vacuum centrifuge.Calibration curves and chemical concentrations were determined using aHewlett Packard Model 8452A UV/V is Diode Array Spectrophotometer.Sample radioactivities were determined in a Packard A5530 gammacounter.?CA 02263999 l999-02- 19wo 98/08840 PCT/US97/14912-129-QEMEE0HI,â N\/UâocH3BocHNO 21HCI, EtOAC, 0°C OH/,:, NHC|- H2â OCH32O LI / / NaCNBH3N N CHO MeOH0 \/N 1 N\ N N\/U\OCH3- H\ / 0E5â;Boc2O, THF?CA 02263999 l999-02- 19WO 98/08840 PCT/U S97/ 14912â 130 âS_QJ:1EME_9_(Q.Qn1'.dlOH/I,_ ¢L/N I N\ N/SEN OCH3I\ / Boc 0 ii10 % Pd/CEtOH oH N\ WNJLORElf 'Boc O- R=CH9:6â :)NaOH&Z,R=HJ;QEDC,HOBT,DMF \</ NO _H /, H .~â\\N N Hâ-. N\/U\N>\/CO2EtI \ â-â H/ BOC 0 L86N HCI0H H],N N '- N\ NI H/ o9-_9 ?>{/co2H?~ WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-131-Methyl (S)-(3-amino-2âoxo-pyrrolidin-1-yl)âacetic acidhvdrochloride( 9-2)A solution of 9â_1 (0.50 g, 1.84 mmol) (prepared asdescribed by Freidinger, R. M.; Perlow, D. S.; Veber, D. F.; J. Org.Chem., 1982, 26, 104) in anhydrous ethyl acetate (50 mL) was cooledto 0°C and saturated with HCI gas, then stirred at 0°C for 2 h. Theresulting colorless solution was concentrated at reduced pressure and theresidue triturated with anhydrous diethyl ether giving 9_-__2_ as ahygroscopic white solid.1H NMR (300 MHz, CD3OD) 5 4.16 (d, 2H); 4.2 (m, lH); 3.68 (s, 3H);3.53 (m, 2H); 2.58 (m, 1H); 2.09 (m, 1H).Methyl 2-oxo-3(S)â[l ,8]naphthyridin-2ây1methyl)-amino]-pyrrolidin-1 âV11-acetic acid (9-4)A solution of_9_â_2_ (232 mg, 1.11 mmol) and _9_;3 (176 mg,1.11 mmol) (prepared as reported by Weissenfels, M.; Ulrici, B.; Z.Chem. 1978, I8, 20.) in anhydrous methanol (10 mL) was treatedwith NaOAc (91 mg, 1.1l mmol) , NaBH3CN (70 mg, 1.11 mmol) andpowdered 4 A molecular sieves (450 mg). The resulting mixture wasstirred at 0° for 3.5 h, then concentrated and the residue subjected to?ash chromatography on silica gel (95 :4.5:0.5 CH2Cl2/MeOH/NH4OH)to afford 2:4 as a colorless glass.FAB MS (315, M+1);1H NMR (300 MHz, CD3OD) 8 9.04 (d, 1H); 8.41 (dd, 1H); 8.38(d, 1H);7.72 (d, 1H); 7.62 (dd, IH); 4.31 (d, 2H); 4.21 (m, 2H); 3.68 (s,3H);3.63 (m, 1H); 3.53 (m, 2H); 2.52 (m, 1H); 1.95 (m, 1H).Methyl [3(S)-[tertâbutoxycarbonylâ[ 1 ,8]naphthyridin-2-ylrnethyl)âamino]-2-oxoâDVrr0lidinâ1âvllâacetic acid (9-5)A solution of amine _9-_4 (69 mg, 0.22 mmol) in THF (5mL) was treated with Boc2O (83 mg, 0.24 mmol) and stirred at roomtemperature for 18 h. The solvent was removed in vacuo and theresulting residue isolated by chromatography on silica gel (5%MeOH/CH2Cl2) to afford 9_-5_ as a yellow glass.?WO 98/08840202530CA 02263999 l999-02- 19PCT/US97/14912 2-132-FAB MS (415, M+1);1H NMR (300 MHz, CD3OD) 8 9.04 (d, 1H); 8.20 (m, 2H); 7.88 (d,0.5H (rotamer a)); 7.82 (d, 0.5H (rotamer b)); 7.46(m, IH); 5.1-4.3(ms 5H}; 3.81 (m, 2H); 3.72 (s, 3H); 3.41 (m, 2H); 2.36 (m, 2H); 1.47(s, 4.5 H (rotamer a)); 1.30 (s, 4.5 H , (rotamer b)).Methyl 3(S)-[tert-butoxycarbonylâ(5 ,6,7,8-tetrahydro-[ l ,8]naphthyridin-2- lmeth 1 âamino -2-oxo- rrolidin-1 - l -acetic acid 9-6A solution of 2-5 (40 mg, 0.097mmol) in EtOH (5 mL)was treated with 10% Pd on C (8 mg) and then stirred under a H2 filledballoon for 16 h. The catalyst was removed by filtration through celiteand the filtrate concentrated to afford 9-_6 as a colorless glass.1H NMR (300 MHz, CD3OD) 5 7.10 (d, 1H) 6.78 (d, 0.5H (rotamer a));6.62 (d, 0.5H (rotamer b)); 4.8-3.9 (m, SH); 3.81 (m, 2H); 3.72 (s, 3H);3.38 (In, 2H); 2.36 (m, 2H); 1.21(s, 4.5 H (rotamer a)); 1.15 (s, 4.5 H ,(rotamer b)). 3(S)â[tert-butoxycarbonyl-(5,6,7,8-tetrahydro-[1 ,8]naphthyridinâ2-vlmethv1)âaminol-2-oxo-Dvrrolidin-1âvll-acetic acid (9-7)A solution of 9_-6 (38 mg, 0.091 mmol) in 50 % aqueousTHF (2 mL) was treated with 1.0 N NaOH (95 mL, 0.095 mmol) andstirred at room temperature for 2 h. The reaction was nuetralized with1N HCl, evaporated, and the residue dissolved in MeOH (2.5 mL),filtered and evaporated to afford _9-_7 as a colorless glass.1H NMR (300 MHz, CD3OD) 5 7.31 (d, 1H) 6.78 (br, d, IH); 4.8-3.9(m, 5H); 3.81 (m, 2H); 3.38 (m, 2H); 2.36 (m, 2H); 1.21(s, 4.5 H(rotamer a)); 1.15 (s, 4.5 H , (rotamer b)).Ethyl 3-(2-{2-oxo-3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridinâ2-ylmethyl)-amino]-pyrrolidin-1-yl } -acetylamino)â3-(S)-pyridin-3-yl-Drooionic acid (9-8)Q? (43 mg, 0.093 mmol), 1-9 (25 mg, 0093 mmol), EDC(18 mg, 0.093 mmol), HOBT (13 mg, 0.093 mmol), and N-methyl?WO 98/088402025CA 02263999 l999-02- 19PCT/US97/ 14912 n-133-morpholine (31 mL, 0.28 mmol) in anhydrous DMF (5 mL) was stirredat room temperature for 18 h, then concentrated in vacuuo and theresidue chromatographed on silica gel using 5% MeOH/CH2Cl2 as eluentaffording E as a colorless glass.1H NMR (300 MHz, CDCI3) 5 8.61 (s, 1H); 8.45 (d, 1H); 8.00 (m, 1H);7.68, (d, 1H); 7.21 (m, 1H); 7.17 (d, 1H); 5.56 (m, 1H); 4.75 (s, 2H);4.45 (m, 2H); 4.05 (q, 2H); 3.95 (m, IH); 3.5-3.3 (m, 4H); 2.92 (m,1H); 2.87 (m, 1H); 2.74 (m, 2H); 2.35 (m, 2H); 1.92 (m, 2H); 1.36 (s,9H); 1.21 (t, 3H).3-(2-{ 2-oxo-3(S)â[(5,6,7,8-tetrahydroâ[1,8]naphthyridin-2âylmethyl)âamino]âpyrrolidin-l -yl } -acetylamino)â3â(S)âpyridinâ3-yl-propionicacid (9-9)2:8 (25 mg, 0.043 mmol) was dissolved in 6 N HCl (2 mL)and stirred at room temperature for 16 h, then evaporated to afford 2-2as a pale yellow solid.FAB MS (453, M+1);1H NMR (300 MHz, CD3OD) 5 9.00 (s, 1H); 8.81 (d, IH); 8.79(m, 1H);8.10 (m, 1H); 7.71 (d, 1H); 7.01 (m, 1H); 5.56 (m, 1H); 4.75 (s, 2H);4.61 (In, 1H); 4.50 (m, 1H); 4.35 (m, 1H); 4.10 (s, 2H); 3.62 (m, 4H);3.4 -3.0 (m, 2H); 2.8 (In, 2H); 2.70 (m, 1H); 2.45 (m 1H);1.98 (In, 2H).Following the procedure described in Scheme 10, bicycliccompounds such as 10-6 are readily prepared by one of ordinary skill inthe art. '?CA 02263999 l999-02- 19WO 98/08840 PCT/US97/14912 _-134-S_QtlEM.E._1.Q1. BOCZO, NEt3, DMF_.\\oH 2. DMF, Cs2CO3, Mel _ CâQ 3. TsCl, pyridine NCOZH 4. NaCN,DMSO, 70°C 300â C02CHa10-210-1 (Fluka)Haney nickel,H ethanol1. DMF, NaH,N CO H ethyl bromoacetate\/ 2 2. NaOH, ethanol 10-4 EDC, HOBT,DMF, NEt33. H2, 10% Pd/C,EtOH4. NaOH, EtOHI \ NO /?CA 02263999 l999-02- 19 ,w0 98/08840 PCT/US97/14912 ,- 135 -§§LHEM.EJ_10 LiN(iPr)2oNH PhCHO. OH V ,N â â '"ax TsOH (cat) ., Q 0 O"//J_-1 ]]_2 1:;0 H2, Pd/C 0/ \O 0 âQ N TsOH (cat.) ./0 HO "0'' HO\) â-4 OH11-3/ \ oPh3P, I2 38/,â p NaBH4 Nimidazole ;-â\ / \ o NH- N "âcH_ CH3 11-7 3 NaN(Si(CH3)3)2 o o)</âI.. OEt Br/\nâ 2 oO 11-§?CA 02263999 l999-02- 19- WO 98/08840 PCT/US97/14912 - 136 -1 N âX//,,,_ £N t ace one0 O O OE t.,I O TsOH (cat)1 PB CH30 0 \ \O N/\H/OB [if0 N NH23 1-4. _ CH3 _'âuâQ proline (cat.)/I E(IL 1°\N N/ N/\[rO t-, OJLLQ âCH3 H2, Pd/C Z /I (IL 0N N NH 6%;11-11 "CH31.1.32 [CH3?CA 02263999 l999-02- 19, W0 98/08340 PCT/US97/14912 --137-/ //, Oil] 0N N " NH 6) TL421â "CH3EDC, HOBTNMMHZN OEtNaOH/ N OH(IL ° *-â1 N ??r?âCH3 11-14 ?1 WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/ 14912-138-3(R)-Dhenvl-tetrahvdroâDvrrolol1.2(S)âcloxazolâ5-one (11-2)A mixture of alcohol (S)-5-(hydroxymethyl)-2-pyrrolidinone (1l_-l_, Fluka) (5.0 g, 43.4 mmol), benzaldehyde (5.7 mL,56.4 mmol), p-TSA (80 mg, 0.4340 mmol) and toluene (125 mL) washeated to re?ux with azeotropic removal of water for 18 hours. Thesolution was concentrated. Flash chromatography (silica, 50%EtOAc/hexanes) gave 1L_2_ as a yellow oil.TLC Rf = 0.21 (silica,50% EtOAc/hexanes)1H NMR (300 MHz, CDCI3) 5 7.29 ââ> 7.46 (m, 5H), 6.34 (s,lH), 4.24(m, 1H), 4.16 (t, J=5.8 Hz, 1H), 3.49 ((t, J=7.8 Hz, 1H), 2.82 (m, 1H),2.55 (m, 1H), 2.39 (m,lH), 1.97 (m,1H).6(S)-[2-(2âmethyl-[1,3]dioxolan-2-yl)-ethyl]â3(R)-phenyl-tetrahydro-pyrrolol 1 .2(S)-Qloxazol-5-one (11-3)To a stirred solution of ?g (7.0 g, 34.4 mmol), HMPA(30.0 mL, 172 mmol) and THF (150 mL) at â78°C was added LDA(18.9 mL, 37.8 mmol, 2.0 M in heptane/THF). After 10 minutes, thereaction was warmed to -15°C. After 20 min, _l_-_2 (8.3 g, 34.4 mmol),dissolved in 10 mL of THF, was added. After 2 h, the reaction waswarmed to ambient temperature for 3.0 hours and then recooled toâ15°C for 18 hours. The reaction was warmed to ambient temperaturefor 2 hours and then diluted with Et2O, washed with H20, dried(MgSO4) and concentrated. Flash chromatography (silica, 40% ââ> 60%EtOAc/hexanes) gave 1_1_;3 as an oil.TLC Rf = 0.28 (silica,50% EtOAc/hexanes)1H NMR (300 MHz, CDCI3) 8 7.25 â> 7.46 (m, 5H), 6.33 (s,lH), 4.24(m, 1H), 4.11 (m, 1H), 3.95 (s, 4H), 3.52 (t, J=7.3 Hz, 1H), 2.87 (In,1H), 2.57 (m, 1H), 2.10 (m,1H) 1.40 ââ> 1.86 (m, 4H), 1.34 (s,3H).1-benzylâ5(S)âhydroxymethyl-3(S)â[2-(2-methyl-[1,3]dioxo1an-2âyl)-ethvll-Dvrrolidin-2-one (1 1-4)A mixture of 11-; (2.0 g, 6.30 mmol) and 10% Pd/carbon(2.0 g) in EtOH (30 mL) was stirred under a balloon of hydrogen for1.0 h. Following filtration and evaporative removal of the solvent, the?âWO 98/08840202530CA 02263999 l999-02- 19PCT/US97/14912-139-residue dissolved in benzene (30 mL), treated with TsOH (10 mg) andethylene glycol (1.05 mL, 18.9 mmol) and then heated to re?ux withazeotropic removal of water for 1 hour. The reaction was concentrated.Flash chromatography (silica, 70:23:7 CHCI3/EtOAc/MeOH) gave 11-4as an oil.1H NMR (300 MHz, CDC13) 5 7.30 (m, 5H), 4.64 (d, J=15 Hz, 1H),4.25 (d, J=15 Hz, 1H ), 3.95 (s, 4H), 3.72 (m, 1H), 3.49 (m, 2H), 2.46(m, 1H), 2.15 (In, 2H), 1.74 (m,2H), 1.53 (m,2H) 1.35 (s,3H).1-benzy1â5(S)-iodomethyl-3(S)-[2-(2âmethyl~[1,3]dioxolan-2-yl)-ethy1]-Dvrrolidin-2-one (11-5)To a stirred solution of 1_l__;4 (2.0 g, 6.26 mmol), PPh3(2.63 g, 10.0 mmol), imidazole (725 mg, 10.6 mmol) and CH3CN (30mL) at 0°C was added 12 (2.39 g, 9.39 mmol) in five portions over 15minutes. After 20 minutes, the reaction was warmed to 50°C for 30minutes and then poured into 200 mL 1:1 EtOAc/ hexanes. The solutionwas washed with 10% sodium bisulfite, sat NaHCO3, brine, dried(MgSO4) and concentrated. Flash chromatography (silica, 40%EtOAc/hexanes) gave 11:5 as an oil.TLC Rf = 0.27 (silica,50% EtOAc/hexanes)1H NMR (300 MHz, CDCI3) 8 7.19 -â> 7.35 (m, 5H), 5.04 (d, J=15.1Hz, 1H), 3.96 (m, 5H), 3.30 (m 1H), 3.19 (m, 2H), 2.50 (m, 1H), 2.32(m,1H), 2.12 (m,1H), 1.79 (m,2H), 1.58 (m,1H), 1.36 (m,4H).1âbenzyl-5 (R)-methylâ3 (S)-[2-(2-methyl-[ 1 ,3]dioxolanâ2âyl)-ethyl]-Dvrro1idinâ2âone (11-6)To a stirred solution of 11;; (900 mg, 6.26 mmol) andHMPA (30 mL) was added NaBH4 (156 mg, 4.20 mmol). After 45minutes, the reaction was poured into 50 ml. 1:1 Et2O/ hexanes and thenwashed with H20, brine, dried (MgSO4) and concentrated to provide 1;6 as an oil.TLC Rf = 0.34 (silica,50% EtOAc/hexanes)?WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912 --140-1H NMR (300 MHz, CDCI3) 5 7.20 ââ> 7.33 (m, 5H), 4.95 (d, J=15.1Hz, 1H),4.03 (d, J=14.9Hz, 1H), 3.95 (s 4H), 3.41 (In, 1H), 2.38 (m,2H), 2.10 (m,lH), 1.75 (m,2H), 1.48 (m,1H), 1.35 (s,3H), 1.16 (m,4H).5(R)-methylâ3(S)-[2-(2-methylâ[1,3]dioxolan-2-yl)-ethyl]-pyrrolidin-2-one (11-7)Into a 3-necked 500mL ?ask at â78°C was condensed 200mL of ammonia. Lithium (64 mg, 9.25 mmol) was washed with MeOH,then THF and then added to the ammonia. After 20 minutes, 1_1_-6 (560mg, 1.85 mmol), dissolved in 25mL of THF, was added. After 30minutes, the reaction was quenched with NH4Cl; 200 mL of THF wasadded, the cooling bath was removed and the solution purged with argonfor 30 minutes to remove the ammonia. The solution was dried(MgSO4) and concentrated. Flash chromatography (silica, EtOAc â> 5%MeOH/ EtOAc) gave 1_1_;Z as an oil.TLC Rf = 0.33 (silica, 10% MeOH/ EtOAc)1H NMR (300 MHz, CDCI3) 5 5.98 (br s, 1H), 3.94 (s, 4H), 3.67 (m1H), 2.40 (m, 2H), 2.02 (m, 1H), 1.70 (m,2H), 1.40 (m,1H), 1.33(s,3H), 1.22 (m,4H).{5(R)-methylâ3(S)-[2-(2âmethylâ[l ,3]dioxolan-2-yl)-ethyl] â2-oxo-Dvrrolidin-1-vll-acetic acid ethvl ester (11-8)To a stirred solution of _1_1_-_7 (355 mg, 1.67 mmol) andTHF (10 mL) at â78°C was added NaN(TMS)2 (1.83 mL, 1.83 mmol,1.0 M in THF). After 20 min, ethyl bromoacetate (0.203 mL, 1.84mmol) was added and the reaction was warmed to 0°C. After 30minutes, the reaction mixture was diluted with EtOAc and then washedwith H20, brine, dried (MgSO4), and concentrated to give _1_1;8 as ayellow oil.TLC Rf = 0.90 (silica, 10% MeOH/ EtOAc)1H NMR (300 MHz, CDCI3) 5 4.35 (d, J=17.6 Hz, 1H), 4.18 (q, J=7.1Hz, 2H), 3.94 (s, 4H), 3.74 (m, 3H), 2.44 (m, 2H), 2.05 (m, 1H), 1.73(m, 2H), 1.43 (m, 1H), 1.33 (s,3H), 1.27 (t, J=7.1Hz, 3H), 1.20 (d,J=6.4 Hz, 3H),?VWO 98/0884010202530CA 02263999 l999-02- 19PCT/US97l14912-141-[5(R)-methyl-2-oxo-3(S)-(3âoxo-butyl)-pyrrolidin-1-yl]-acetic acid @311ester (11-9)A solution of _1l_â1_0_ (360 mg, 1.20 mmol), pâTSA (10 mg)and acetone (20 mL) was heated at re?ux for 1 hr. The cooled reactionmixture was diluted with EtOAc and then washed with sat. NaHCO3 andbrine, dried (MgSO4), and concentrated to afford L1;_9_ as an oil.TLC Rf = 0.54 (silica, 75%EtOAc/hexanes)1H NMR (300 MHz, CDCI3) 5 4.32 (d, J=17.6 Hz, 1H), 4.18 (q,J=7.lHz, 2H), 3.73 (In, 3H), 2.72 (m, 2H), 2.42 (m, 1H), 2.16 (s, 3H),1.99 (In, 1H), 1.78 (m, 1H), 1.27 (t, J=7.lHz, 3H), 1.20 (d, J=6.l Hz,3H).[5(R)âmethylâ3(S)â(2-[1,8]naphthyridin-2-yl-ethyl)-2âoxo-pyrrolidin-1âvll?cetic acid ethvl ester (11-10)A mixture of LL-_9 (220 mg, 0.8619 mmol), L4, 2-amino-3-formylpyridine (137 mg, 1.12 mmol) and proline (99 mg, 0.8619mmol) in absolute ethanol (5 mL) was heated at re?ux for 12 h.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) togive _1_1_-10 as a yellow oil.TLC Rf = 0.37 (70:25:5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CDCI3) 8 9.08 (m, 1H), 8.16 (dd, J=2Hz, 6 Hz1H), 8.12 (d,J=8Hz, 1H), 7.46 (m, 2H), 4.33 (d, J=17.5 Hz, 1H), 4.17(m, 2H), 3.71 (m, 3H), 3.21 (t, J=8.0 Hz, 2H), 2.54 (m, 2H), 2.39 (In,1H), 2.02 (m, 1H), 1.35 (In, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (d, J=6.3Hz, 3H).{ 5(R)âmethyl-2-oxo-3(S)-[2â(5,6,7,8âtetrahydro-[1,8]naphthyridin-2-vl)-ethvll-Dvrrolidin-1-vl }-acetic acid ethvl ester (1 1-1 1)A mixture of_1_-L0 (250 mg, 0.7323 mmol) and 10%Pd/carbon (250 mg) in EtOH (5 mL) was stirred under a balloon ofhydrogen for 20 h. Following filtration and evaporative removal of the?âWO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912-142-solvent, the residue was chromatographed (silica gel, 70:25:5chloroform/ethyl acetate/MeOH to give _l_1_-_1_1_ as a colorless oil.TLC Rf = 0.25 (70:25 :5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CDC13) 5 7.05 (d, 1H, J=7.3 Hz), 6.39 (d, 1H,J=7.3 Hz), 4.77 (br s, 1H), 4.17 (d, 1H, J=17.5 Hz), 4.15 (m, 2H), 3.71(m, 2H), 3.39 (m, 2H), 2.64 (m, 4H), 2.46 (m, 2H), 2.30 (m, 1H), 1.91(m, 2H), 1.88 (m, 1H), 1.26(t, 3H, J=6.l Hz) 1.23 (m,1H), 1.19 (d,J=6.4Hz, 3H).{5(R)-methyl-2-oxoâ3(S)â[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-vl)âethvll-Dvrrolidin-1-vl}âacetic acid hvdrochloride (11-12)A mixture of11_-g (185 mg, 0.5356 mmol) and 6N HC1(10 mL) was heated at 60° C for 1 h. Evaporative removal of thesolvent gave 11-12 as a yellow solid.1H NMR (300 MHz, CD3OD) 5 7.59 (d, 1H, J=7.3 Hz), 6.66 (d, 1H,J=7.3 Hz), 4.17 (d, 12H, J=17.8, Hz), 3.90 (d, 1H, J=l7.8, Hz), 3.77 (m,1H), 3.50 (t, J=5.4 Hz, 2H), 3.31 (m, 4H), 2.52 (m, 2H), 2.25 (m, 1H),1.95 (t, 2H, J=6.6 Hz), 1.80 (m, 1H), 1.34 (m, 1H), 1.25 (d, J=6.3 Hz,3H)2-Oxoâ5(R)âmethyl-3 (S)â[2-(5 ,6,7,8âtetrahydro[ 1 ,8] -naphthyridinâ2-yl)âethyllpyrrolidin-1-ylzacetyl-31S 1-alkynyl?-alanine ethyl ester 1 1 1-13 1A mixture of1L_1_2 (350 mg, 0.9892 mmol), 2:9 (193 mg,1.09 mmol), EDC (378 mg, 1.98 mmol), HOBT (134 mg, 0.9892mmol) and NMM (1.10 mL, 7.91 mmol) in CH3CN (5 mL) was stirredfor 20 h. The mixture was diluted with ethyl acetate, washed with sat.NaHCO3, brine, and dried over MgSO4. Following evaporative removalof the solvent, the residue was chromatographed (silica gel, 70:25:5chloroform/ethyl acetate/MeOH to give _l_1_-_13 as a colorless foam.TLC Rf = 0.15 (70:25:5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CDCI3) 5 7.05 (m, 2H), 6.39 (d, 1H, J=7.3 Hz),5.04 (m, 1H), 4.16 (q, 2H, J=7.1Hz), 3.90 (s, 2H), 3.64 (m, 1H),3.39(m, 2H), 2.69 (In, 6H), 2.47 (m, 2H), 2.30 (In, 1H), 1.90 (m, 2H), 1.64(m, 2H), 1.20 (m, 7H).?WO 98/0884010CA 02263999 l999-02- 19PCTlUS97/ 14912-143-2-Oxo-5(R)-methyl-3(S)â[2-(5 ,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl )ethyl |pyrrolidin-1 -yl )acetylâ3§ S )âa1kynyl-[§âalanine 1 11-14)To a solution of 1_1_-1_3_ (70 mg, 0.1589 mmol) in EtOH (1mL) was added 1N NaOH (0.175 ml, 0.164 mmol). After stirring for 1h, the solvents were evaporated and the residue was chromatographed(silica gel, 25:10:1:1 to l5:10:1:1 ethyl acetate/EtOH/water/NH4OH togive 1_1_-_l__4 as a colorless foam.TLC Rf = 0.21 (10:l0:1:1 ethyl acetate/EtOH/water/NH4OH).1H NMR (300 MHz, CD3OD) 5 7.42 (d, 1H, J=7.3 Hz), 6.49 (d, 1H,J=7.3 Hz), 4.35 (d,J=17.l Hz, 1H), 3.64 (m, 1H,), 3.50 (m, 3H,), 3.18(m, 2H), 2.77 (t, J=5.6 Hz, 2H), 2.55 (In, 5H), 2.23 (m, 1H), 1.91 (m,4H), 1.41 (m, 1H) 1.28 (d, J=6.3 Hz, 3H).?CA 02263999 l999-02- 19* WO 98/08840 PCTIUS97/14912-144- ClJJ_.4- 21H 1 -1 0'pyridine _"' T50O O N/,,,. N ""'âPn12:2â â O 1_2_-§ Ph 0I â OO)<O/I, OB acetoneI,â N/\g/ TsOH (cat.)12-4 9â Ph-5 âPh?CA 02263999 l999-02- 19 wo 98/08840 PCT/US97/14912- 145 â mO O/1, /UV -. , 012-5 âPh\ âOI / proline (cat)N NH2E \N N/ L N/\â/OET 0- 1PhH2, Pd/CI \ °H "â-1. o1 -7 âa__" Ph6N HCI IZZ\ /\ âV :28OI?CA 02263999 l999-02- 19âWO 98/08840 PCT/US97/14912-146-I / N NH OOH; N Acâ?HZN OEtEDC, HOBTNMM / O 3:19I\ N -2HC|/ N OEt /âCL I?âN N ._ NH â=4. Acâ? \ O|/;â\PhWN OH1?_J_Q- \ N?9 WO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/ 14912 --147-1-benzylâ5(S)-methyl-p-toluenesulfonate-3(S)â[2-(2-methyl-1 1.31dioxo1anâ2âvl)-ethvllâDvrrolidin-2-one (12-1)To a stirred solution of 1__1__-_4_ (1.8 g, 5.63 mmol) and THF(30 ml.) at 0°C was added NaH (248 mg, 6.19 mmol). After 30minutes, TosCl was added followed by the removal of the cooling bath.After 1.0 hour, the reaction was diluted with EtOAc and then washedwith H20, sat NaHCO3, brine, dried (MgSO4) and concentrated. Flashchromatography (silica, 40 ââ> 60% EtOAc/hexanes) gave _1_;1 as an oil.TLC Rf = 0.75 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 5 7.72 (d, J=8.30 Hz, 2H), 7.35 (d, J=7.3Hz, 2H), 7.25 (m, 3H), 7.09 (m 2H), 4.94 (d, J=14.9 Hz, 1H), 4.01 (m,1H), 3.94 (m,5H), 3.83 (d, J=15.1 Hz, 1H), 3.54 (m,1H), 2.46 (s,3H),2.42 (m,1H), 2.21 (m, 1H), 2.01 (m, 1H), 1.72 (M, 2H), 1.43 (m, 2H),1.32 (s, 3H),1-benzyl-5(S)-benzyl-3(S)-[2-(2âmethyl-[1,3]dioxo1anâ2âyl)âethyl]-Dvrrolidinâ2-one (12-2)To a stirred suspension of Cul (2.57 g, 13.5 mmol) andEt2O (10 mL) at 0°C was added PhLi (14.2 mL, 25.6 mmol, 1.8 Mcyclohexane-ether) dropwise over a 1.0 hour period. After anadditional hour, 12.;_1_ (1.4 g, 2.96 mmol), dissolved in 10 mL Et2O, wasadded. The reaction was stirred at -15°C for 96 hours. The reactionwas diluted with EtOAc and then washed with sat NH4Cl, sat NaHCO3,brine, dried (MgSO4) and concentrated. Flash chromatography (silica,30 â> 60% EtOAc/hexanes) gave 1_2_;_2_ as an oil.TLC Rf = 0.29 (si1ica,50% EtOAc/hexanes)1H NMR (300 MHz, CDCI3) 5 7.13 â> 7.36 (m, 8H), 7.02 (d, J=7.6Hz,2H), 5.06 (d, J=14.9 Hz, 1H), 4.14 (d, J=15.1 Hz, 1H), 3.95 (m, 4H),3.55 (m, 1H), 3.18 (dd, J=4.2, 17.0 Hz,1H), 2.35 (m,2H), 2.04 (m,2H),1.66 (m,2H), 1.32 (m,5H).?WO 98/0884020253035CA 02263999 l999-02- 19PCTIU S97/ 14912-148-5(S)-benzyl-3(S)-[2-(2-methyl-[1,3]dioxolanâ2-yl)-ethyl]-pyrrolidin-2-one (12-3)Into a 3ânecked 500mL ?ask at -78°C was condensed 100mL of ammonia. Next, _l_2;__2_ (470 mg, 1.24 mmol), dissolved in 20mLof THF, was added. Lithium (19 mg, 2.48 mmol) was washed withMeOH, then THF and then added to the ammonia. After 20 minutes, thereaction was quenched with NH4Cl; 200 mL of THF was added, thecooling bath was removed_and the solution purged with argon for 30minutes to remove the ammonia. The solution was dried (MgSO4) andconcentrated. Flash chromatography (silica, EtOAc) gave 12;3_ as an oil.TLC Rf = 0.22 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 5 7.18 â> 7.35 (m, 5H), 5.43 (br s, 1H),3.95 (s, 4H), 3.92 (m 1H), 2.88 (dd, J=5.3, 18.6 Hz, 1H), 2.41 (m, 2H),2.03 (m,1H), 1.71 (m,2H), 1.43 (m,2H), 1.33 (s,3H).{5(S)-benzyl-3(S)-[2-(2âmethy1-[1,3]dioxolanâ2-yl)-ethyl]-2-ox0âDvrrolidin-1âvl}-acetic acid ethvl ester (12-4)To a stirred solution of 12:-3 (210 mg, 0.7257 mmol) andTHF (5 mL) at -78°C was added NaN(TMS)2 (0.943 mL, 0.943 mmol,1.0 M in THF). After 30 min, ethyl bromoacetate (0.104 mL, 0.9434mmol) was added and the reaction was warmed to 0°C. After 1.0 hour,the reaction mixture was diluted with EtOAc and then washed with satNaHCO3, brine, dried (MgSO4), and concentrated to give 1_2;4 as ayellow oil.TLC Rf = 0.64 (silica, EtOAc)1H NMR (300 MHz, CDCI3) 5 7.15 ââ> 7.33 (m, 5H), 4.40(d, J=17.8 Hz, 1H), 4.15 (m, 2H), 3.93(m, 5H), 3.77 (d, J=l7.8, 1H),3.07 (dd, J=5.0, 18.6 Hz, 1H), 2.56 (in, 1H), 2.39 (In, 1H), 2.20 (m,1H), 2.05 (m,1H), 1.69 (m, 2H), 1.23 â> 1.46 (m,8H).[5(S)âbenzyl-2-oxoâ3(S)-(3âoxo-butyl)-pyrrolidin-1-yl]âacetic acid ethylester (12-5)A solution of _1_2_-4,_ (260 mg, 0.6925 mmol), pâTSA (10 mg)and acetone (20 mL) was heated at re?ux for 1 hr. NaHCO3 was added?âWO 98/0884010202530CA 02263999 l999-02- 19PCT/US97/14912-149-to the cooled reaction mixture and then the mixture was concentrated.The residue was diluted with CHCI3 and then washed with brine, dried(MgSO4), and concentrated to afford 12-5 as an oil.TLC Rf = 0.66 (silica, 75%EtOAc/hexanes)1H NMR (300 MHz, CDCI3) 5 7.22 â> 7.36 (m, 3H), 7.15 (d, J=6.5 Hz,2H), 4.37 (d, J=l7.6 Hz, 1H), 4.18 (m, 2H), 3.97 (m, 1H), 3.77 (d,J=17.8 Hz, 1H), 3.06 (dd, J=5, 18 Hz, 1H), 2.60 (m, 3H), 2.42 (m, 1H),2.17 (m, 1H), 2.14 (s, 3H), 1.96 (m,1H), 1.74 (m, 1H) 1.27 (m, 4H).[5(S)~benzyl-3(S)-(2â[l ,8]naphthyridinâ2-yl-ethyl)-2âoxoâpyrrolidin-1 -vllâacetic acid ethvl ester (12-6)A mixture of J: (230 mg, 0.6940 mmol), L-_4_, (2-amino-3âformylpyridine, 110 mg, 0.9022 mmol) and proline (80 mg, 0.6940mmol) in absolute ethanol (10 mL) was heated at reflux for 18 h.Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/MeOH) togive _1_2;6_ as a yellow oil.TLC Rf = 0.38 (70:25 :5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CDCI3) 5 9.08 (m, 1H), 8.16 (dd, J=2Hz, 10 Hz1H), 8.09 (d,J=8.3 Hz, 1H), 7.44 (m, 2H), 7.28 (m, 2H), 7.16 (d, J=8Hz,2H), 4.37 (d, J=l7.6 Hz, 1H), 4.16 (m, 2H), 3.96 (m, 1H), 3.80 (d, J:17.6 Hz, 1H), 3.15 (m, 2H), 3.06 (dd, J=5.3, 18.5, 1H), 2.26 -9 2.63(m, 4H), 1.97 (m, 1H), 1.47 (m, 1H), 1.25 (t, J=7.1 Hz, 3H).{ 5 (S)-benzyl-2-oxo-3(S)-[2-(5 ,6,7 ,8âtetrahydroâ[1,8]naphthyridin-2-yl)-ethvll-ovrrolidin-1-vll-acetic acid ethvl ester (12-7)A mixture of _1__2-_6 (220 mg, 0.5270 mmol) and 10%Pd/carbon (100 mg) in EtOH (4 mL) was stirred under a balloon ofhydrogen for 2 h. Following filtration and evaporative removal of thesolvent, the residue was chromatographed (silica gel, 7022525chloroform/ethyl acetate/MeOH to give l_2_-1 as a colorless oil.TLC Rf = 0.25 (70:25 :5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CDCI3) 5 7.26 (m, 3H), 7.16 (d,J=8.1Hz, 2H),7.04 (d, J=7.3 Hz, 1H), 6.36 (d, J=7.3 Hz, 1H), 4.74 (br s, 1H), 4.39 (d,?~ WO 98/0884010202530CA 02263999 l999-02- 19PCT/U S97/ 14912-150-J=17.8 Hz, 1H), 4.15 (m, 2H), 3.90 (m, 1H), 3.77 (d, J=17.5 Hz, 1H),3.38 (In, 2H), 3.06 (dd, J=2.4, 18.8 Hz, 1H), 2.65 (m, 5H), 2.43 (m,1H), 2.22 (m, 3H), 1.89 (m, 1H) 1.36 (m,1H), 1.26 (t, J=7.1 Hz, 3H).{5(s)-benzyl-2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethvllâDvrrolidin-1-vl lâacetic acid hvdrochloride (12-8)A mixture of1_2_-1 (150 mg, 0.3559 mmol) and 6N HC1 (10mL) was heated at 60° C for 1 h. Evaporative removal of the solventgave Q-_8 as a yellow solid.1H NMR (300 MHz, CD3OD) 5 7.57 (d, J=7.3 Hz, 1H), 7.24 (m, 5H),6.60 (d, J=7.3 Hz, 1H), 4.24 (d, J=l7.8, Hz, 1H), 4.03 (m, 2H), 3.49 (t,J=5.6 Hz, 2H), 3.15 (dd, J=4.4, 17.6 Hz, 1H), 2.71 (m, 5H), 2.46 (m,1H), 2.21 (m, 1H), 1.97 (m,3H), 1.64 (m, 1H), 1.45 (m,1H)2-Oxoâ5(S)-benzylâ3(S)-[2-(5 ,6,7,8-tetrahydro[1 ,8]-naphthyridinâ2-y1)-eth 1 rrolidin-1- 1 acet l-3 S - ridin-3- 1- -alanine eth l ester 12-9A mixture of1_2_-_8_ (150 mg, 0.3559 mmol), 2-10 (60 mg,0.2135 mmol), EDC (132 mg, 0.7118 mmol), HOBT (48 mg,0.3559mmol) and NMM (0.4 mL, 2.85 mmol) in DMF (4 mL) wasstirred for 20 h. The mixture was diluted with ethyl acetate, washedwith sat. NaHCO3, brine, and dried over MgSO4. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 70:20:10 chlorofonn/ethyl acetate/MeOH to give 12-2 as acolorless foam.TLC Rf = 0.15 (70:25 :5 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CD3OD) 5 8.55 (s, 1H), 8.44 (m, 1H), 7.82 (m,1H), 7.6-7.1 (In, 7H), 6.33 (d, J=7.5 Hz, 1H), 5.40 (t, J=8 Hz, 1H), 4.2-3.8 (m, 6H), 3.38 (m, 1H), 3.17 (m, 2H), 2.90 (m, 2H), 2.67 (m, 2H),2.54 (m, 2H), 2.12 (m, 2H),1.84 (m, 2H), 1.43 (In, 2H) 1.18 (In, 3H). 2âOxo-5 (S)-benzyl-3(S)-[2-(5,6,7 ,8-tetrahydro[1,8]-naphthyridin-2-1 eth 1 rrolidinâ1- 1 acet 1-3 S - ridin-3- 1- -alanine 12-13To a solution of 12;9_ (70 mg, 0.1229 mmol) in EtOH (1mL) was added 1N NaOH (0.150 ml, 0.150 mmol). After stirring for ?CA 02263999 l999-02- 19wo 98/08840 PCT/US97/14912-151-l.5 h, the solvents were evaporated and the residue waschromatographed (silica gel, 25:10:l:l to l5:10:1:l ethylacetate/EtOH/water/NH4OH to give 12-10 as a colorless foam.TLC Rf = 0.21 (10:10:1:1 ethyl acetate/EtOH/water/NH4OH).5 1H NMR (300 MHz, CD3OD) 5 8.62 (s, 1H), 8.36 (m, 1H), 7.92 (m,1H), 7.45-7.2 (m, 7H), 6.49 (d, J=7.l Hz, 1H), 5.27 (m, 1H), 4.31 (d,J=17.3 Hz, 1H), 3.93 (m, 1H), 3.72 (d, J=17.5 Hz, 1H), 3.30 (m, 3H),2.92 -2.52 (m, 8H), 2.36 (m, 2H), 1.90 (m, 3H), 1.57 (m, 1H), ?CA 02263999 l999-02- 19 VWO 98/08840 PCT/US97/14912-152-§Ql:l?d.E_].3o 0p H2 p Ph3P,l2N NPd/C _ OH imidazoleâ''â//O "'l/_ 13-10., p 3N NQBH4 N1_3-_2 âCH3J3.-.3LiN(iPr)20CH(CH3)2 âaw, NaOEtN3â8 CH(CH3)2 âCH32CH(CH3)2 13-4âO H2,Pd/C,TFAN3,,,_N then aocgo, NEt3CH313:5?CA 02263999 l999-02- 19 wo 98/08840 PCT/US97/14912â 153 -5£;|:lE_M.E_].3..§§mI'_Do 0JL 0 JL9 N Li/NH3(,) . NI, NH(H3C)3c H (H3C)aC H13-5 "'CHs 13- "CH3O O Nilâ, OEt H ' N/\?/Bâ/\?/ "âcH3OO l?z?0N OH (H C) C-0/[LN Oa 3 3 â II,â H ( jw?r.,I 013:2 CH3EDC, HOBTNMMH2N OEt0JL 0 W(H3C)aCâO N,, N OEtH" " âAlfv,â 0 O13.19 CH3?CA 02263999 l999-02- 191W0 98/08840 PCTlUS97/ 14912-154- J1 0 ».+H ,N/,,_ -9 O l 013-10 CH3 1(H3C)3CâOJ HCIca 0 1,4H3N/,,_ N N OEt$1 0 ?C19 CH313-11H N1_4_-31â :1 ° / ,,u N (j,~â:r TY13-12 .9 o 0CH3 IINaOH ?' WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912 _-155-1-benzvl-5(S)âhvdroxvmethvlâDvrrolidinâ2-one ( 13-1)A mixture of Qâ_2_ (5.0 g, 24.6 mmol), 10% Pd/C (2.5 g),and ethanol (80 mL) was stirred at ambient temperature under ahydrogen atmosphere (1 atm) for 5 hr. The catalyst was removed byfiltration through a celite pad and the filtrate concentrated to give _1_3_â1as a colorless oil.TLC RF = 0.55 (silica, 70:20:10 CHCI3/EtOAc/CH3OH);1H NMR (300 MHz, CDCI3) 8 7.29 (m, 5H), 4.83 (d, 2H, J=15H), 4.25(d, 1H, J=15Hz), 3.77 (m, 1H), 3.51 (m, 2H), 2.54 (m, 1H), 2.40 (m,1H), 1.92 (m, 2H).1-benzvl-5(S)âiodomethvl-Dvrrolidin-2-one (13-2)To a solution of _1_3;l_ (18.5 g, 90.1 mmol),triphenylphosphine (40.1 g, 153 mmol), and imidazole (11.03 g, 162mmol) in 225 mL of acetonitrile and 150 mL of ether at 0°C was addediodine (34.3 g, 135 mmol) in 5 portions over 5 minutes. After 10minutes, the reaction was heated to 50°C, and a stream of argon passedover the reaction to purge the evaporating ether. After an additional 30minutes, the mixture was diluted with ether, the organic layer washedwith NaHCO3 (sat.) and brine, dried over K2CO3, and the solventevaporated. Flash chromatography of the residue (silica, 7-15 % EtOAc/CHCI3) gave _l_3;2 as a yellow oil.TLC Rf = 0.53 (silica, 30% EtOAc/CHCI3)11-I NMR (300 MHz, CDCI3) 8 7.31 (m,5H), 5.05 (d, 1H, J=15Hz), 3.92(d, 1H, J=15Hz), 3.41 (m, 1H), 3.26 (m, 2H), 2.62 (m, 1H), 2.43 (m,1H), 2.16 (m, 1H), 1.81 (m, IH).1âbenzvl-5(R)- methvlâDvrrolidinâ2-one (13-3)To a solution of 1_3_-_2_ (22.1 g, 70 mmol) in 200 mL ofhexamethylphosphorous triamide at 0°C was added NaBH4 (5.25 g, 140mmol) in 5 portions over 5 minutes. After 10 minutes, the reaction wasallowed to warm to ambient temperature and stirred for 2 h. Themixture was diluted with 1:1 ether/hexanes, quenched by the careful?WO 981088401015202530CA 02263999 l999-02- 19PCT/US97/14912-156-addition of 300 mL 10% KHSO4 (aq), separated, the organics dried overK2CO3, and the solvent evaporated to give _1__3;2 as a yellow oilTLC Rf = 0.45 (silica, 30% EtOAc/CHCI3)1H NMR (300 MHz, CDCI3) 5 7.32 (m, 5H), 4.95 (d, 1H, J=15Hz), 4.00(d, 1H, J=15Hz), 3.52 (m, 1H), 2.46 (m, 2H), 2.15 (m, 1H), 1.60 (m,1H), 1.16 (d, 3H, J=6.0Hz)).3(R)-azido-1-benzvlâ5(R)âmethvl-Dvrrolidin-2-one ( 13-4)To a solution of 13;; (2.2 g, l 1.6 mmol) in THF (45 mL)at -78° C was added a solution of LDA (6.39 mL, 12.8 mmol;2M/THF,ethy1benzene). The mixture was warmed to â15°C for 20minutes, then recooled to â78°C, and 2,4,6-triisopropylbenzenesulfonylazide (4.31 g, 13.9 mmol, prepared as described in Harmon, et al, J .Org. Chem. 1973, 38, 11-16.) was added rapidly as a solution in 40 mLTHF at -78°C. After 10 minutes, glacial acetic acid (2.67 mL, 47 mmol)was added, and the resultant viscous liquid mixture allowed to warm toambient temperature and stir for 1 hour. The solvent was thenevaporated, the residue dissolved in CHC13, washed with NaHCO3 (sat.),and dried over magnesium sulfate. Following evaporative removal ofthe solvent, the residue was chromatographed (silica gel, 25% ethylacetate/hexanes) to give _1_3_;4 as a colorless oil.TLC Rf = 0.38 (25 % ethyl acetate/hexanes).1H NMR (300 MHz, CHCI3) 5 7.32 (m, 5H), 5.00 (d, 1H, J=15 Hz),4.27 (t, 1H, J=7.5 Hz), 3.98 (d, 1H, J=15 Hz), 3.54 (In, 1H), 1.97 (m,2H), 1.16 (d, 3H, J=6.0 Hz).3(S)-azido-1 âbenzvl-5(R)-methvl-Dvrrolidin-2-oneTo a solution of 13:4 (2.17 g, 9.42 mmol) in EtOH (50mL) was added a solution of NaOEt (3.52 mL, 9.42 mmol; 2.68M/EtOH). The mixture was stirred for 90 minutes, then quenched bythe addition of glacial acetic acid (3 mL). The solvent was thenevaporated, the residue slurried in EtOAc, washed with NaHCO3 (sat.),and dried over K2CO3. Following evaporative removal of the solvent,?WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-157-the residue was chromatographed (silica gel, 17% ethyl acetate/hexanes)to give 13_-_5_ as a colorless oil and _l_3;4 as a colorless oil.TLC Rf = 0.44 (25% ethyl acetate/hexanes).1H NIVIR (300 MHz, CHC13) 5 7.32 (m, 5H), 4.97 (d,lH, J=15 Hz), 4.17(t, 1H, J=7.5 Hz), 4.05 (d, 1H, J=15 Hz), 3.44 (m, 1H), 2.48 (m, 2H),1.50 (m, 1H), 1.22 (d, 3H, J=6.6 Hz).(1 âbenzyl-5(R)-methyl-2-oxoâpyrrolidin-3(S)âyl)âcarbamic acid tert-butvl ester (13~6)A mixture ofj_3;5_ (2.38 g, 10.3 mmol), 10% Pd/C (1.0 g),TFA (10 mL), THF (80 mL) and methanol (100 mL) was stirred atambient temperature under a hydrogen atmosphere (1 atm) for 3 hr.The catalyst was removed by filtration through a celite pad and thefiltrate concentrated to give the intermediate amine salt as a colorlessoil. To a solution of the crude amine salt in THF (50 mL) at 0°C wasadded NEt3 (2.88 mL, 20.7 mmol) and di-tert-butyl dicarbonate (2.59 g,11.9 mmol). The mixture was allowed to warm to ambient temperatureand stir for 4 hours. Following evaporative removal of the solvent, theresidue was chromatographed (silica gel, 40% ethyl acetate/hexanes) togive 13-Q as a colorless oil.TLC RF = 0.44 (silica, 40% ethyl acetate/hexanes);1H NMR (300 MHz, CHC13) 8 7.31 (m, 5H), 5.17 (br s, 1H), 4.94 (d,1H, J=15 Hz), 4.20 (m, 1H), 4.07 (d, 1H, J=15 Hz), 3.44 (m, 1H), 2.77(m, 1H), 1.45 (s, 9H), 1.20 (d, 3H, J=7 Hz).(5(R)-methyl-2-oxo-pyrrolidin-3(S)-yl)-carbamic acid tert-butyl ester(13-7)To a blue solution of lithium metal (0.237 g,34.2 mmol) inNH3 (1) (200 mL) at â78°C was added a solution of _1_3;6_ (2.60 g,8.54mmol) in THF (15 mL). The mixture was stirred for 15 minutes, thenquenched by the addition of ammonium chloride until the blue colordispersed. An additional 30 mL of THF was added, and the mixturewarmed to 35°C to evaporate the ammonia. MgSO4 was added,themixture was filtered through a celite pad. Following evaporative?âWO 98/08840202530CA 02263999 l999-02- 19PCTIUS97/14912-158-removal of the solvent, the residue was chromatographed (silica gel,70:20:10 chloroforrn/ethyl acetate/MeOH) to give _1_3__-1 as a colorless oilTLC Rf = 0.45 (70:20:10 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CHCI3) 5 6.97 (br s, 1H), 5.24 (d,1H, J=7.6 Hz),4.32 (br s, 1H), 3.66 (m, 1H), 2.79 (m, 1H), 1.45 (s, 9H), 1.25 (d, 3H,J=6.0 Hz).(3(S)-tert-butoxycarbonylamino-5(R)-methy1-2-oxo-pyrrolidinâ1-yl)-acetic acid ethvl ester (13-8)To a solution of ?;7_ (1.83 g, 8.4 mmol) in THF (22 mL)at -78° C was added sodium bis(trimethylsilyl)amide (9.4 mL, 9.4mmol; lM/ THF) dropwise. After an additional 20 min, ethylbromoacetate (1.13 mL, 10.3 mmol) was added dropwise. After anadditional 20 minutes, the mixture was allowed to warm to 0°C, and 20mL sat. aqueous NH4Cl was added. The layers were separated, theaqueous layer washed with EtOAc, and the combined organic extractswere dried over K2CO3. Following evaporative removal of the solvent,the residue was chromatographed (silica gel, 40% ethyl acetate/hexanes)to give Q-_8 as a colorless oil.TLC Rf = 0.39 (40% ethyl acetate/hexanes).1H NMR (300 MHz, CHCI3) 8 5.20 (br s, 1H), 4.38 (d,1H, J=l8 Hz),4.21 (m, 3H), 3.77 (m, 2H), 2.83 (m, 1H), 1.44 (s, 9H), 1.23 (m, 6H).(3 (S)âtert-butoxycarbonylamino-5 (R)-methyl-2-oxo-pyrrolidin-1 -yl)-acetic acid (13-9)To a solution _1_?_>-_8 (527 mg, 1.75 mmol) in EtOH wasadded 1N NaOH (1.93 mL, 1.925 mmol). After stirring for 1 h, thesolvents were evaporated, the mixture was diluted with EtOAc, acidifiedwith 10% KHSO4, washed with brine, dried over MgSO4, andevaporated to give _1_3_-2 as a white solid.TLC Rf = 0.48 (silica,9.5/0.5/0.5 CH2Cl2/MeOH/AcOH)1H NMR (300 MHz, CD3OD) 5 4.21 (m, 2H), 3.85 (d, 1H, J=l8 Hz),3.74 (m, 1H), 2.58 (m, 1H), 1.52 (m, 1H), 1.44 (s, 9H), 1.25 (d, J=6.3Hz, 3H).?» WO 98/08840202530CA 02263999 l999-02- l9PCT/US97/14912 ..-159-(3(S)-tert-butoxycarbonylamino-5(R)âmethylâ2-oxo-pyrrolidin-1 -yl)-acetyl-3(S )âalkynyl-[3-alanine ethyl ester (13-10)A mixture of 13-2 (440 mg, 1.62 mmol), 2_-_9_ (290 mg,1.62 mmol), EDC (373 mg, 1.94 mmol), HOBT (262 mg, 1.94 mmol)and NMM (1.20 mL, 11.34 mmol) in CH3CN (5 mL) was stirred for 20h. The mixture was diluted with EtOAc, washed with sat. NaHCO3,brine, and dried over MgSO4. Following evaporative removal of thesolvent, the residue was chromatographed (silica gel, EtOAc) to give_l_3-l_O as a colorless foam.TLC Rf = 0.20 (silica, EtOAc).1H NMR (300 MHz, CDCI3) 8 7.31 (bd, 1H), 5.33 (bd, 1H), 5.21 (m,1H), 4.16 (m, 5H), 3.64 (m, 2H), 2.72 (m, 2H), 2.45 (d, J=2.2 Hz, 1H),1.52 (m, 1H), 1.46 (s, 9H), 1.27 (m, 6H).(3(S)-aminoâ5(R)âmethy1-2-oxo-pyrrolidin-1-yl)-acetylâ3(S)âalkynyl-B-alanine ethvl ester hvdrochloride (13-11)To a solution of L3_;1_0 (550 mg, 1.39 mmmol) in EtOAc at0°C was bubbled HC1 gas for 5 minutes. The reaction was stirred anadditional 5 minutes, followed by removal of the cooling bath and thenpurged with Argon for 20 minutes. Evaporative removal of the solventgave _1__3;_l_1 as a white solid.1H NMR (300 MHz, CD3OD) 5 5.02 (m, 1H), 4.12 (m, 4H), 3.83 (m,2H), 2.77 (m, 2H), 1.59 (m,1H), 1.25 (m, 6H).5(R)-methy1-2-oxoâ3(S)-[2-(5,6,7 ,8-tetrahydro[1,8]-naphthyridin-2-ylrnethyl)-amino]pyrro1idin-1 -yl)acetyl~3(S)âalkynyl-Bâa1anine ethylester (13-12)To a soution of_1__3_-_1__1_ (450 mg, 1.39 mmol) and 5,6,7,8-tetrahydro-[l,8]naphthyridineâ2âcarbaldehyde (225 mg, 1.39 mmol) indichloroethane at 0°C was added Na(OAc)3BH. After 1.5 h the reactionwas quenched with sat. NaHCO3, diluted with EtOAc, washed with sat.NaHCO3, brine and dried over MgSO4. Following evaporative removal?CA 02263999 l999-02- 19W0 98/08840 PCT/US97/ 14912-160-of the solvent, the residue was chromatographed (silica gel, 70:20:10chloroform/ethyl acetate/MeOH to give 13-12 as a colorless foam.TLC Rf = 0.17 (70:15 :15 chloroform/ethyl acetate/MeOH).1H NMR (300 MHz, CDCI3) 5 7.09 (d, J=6.8 Hz, 1H), 7.03 (d, J=8.55 Hz, 1H), 6.48 (d, J=7.3 Hz, 1H), 5.05 (m, 1H), 4.83 (bs, 1H), 4.17 (q,J=6.4, 1H), 3.92 (m, 2H), 3.74 (m, 2H), 3.58 (m, 4H), 3.40 (m, 2H),2.70 (m, 4H), 2.54 (m, 1H), 2.26 (s, 1H), 1.90 (m, 2H), 1.55 (m, 2H),1.25 (m, 6H). 10 5(R)-methylâ2âoxo-3(S)â[2-(5,6,7,8-tetrahydro[1,8]ânaphthyridinâ2â' rrolidinâ1â l acet I-3 S âalk 1- âalanine 13-13To a solution of1_3-_l2_ (108 mg, 0.24 mmol) in EtOH (2mL) was added 1N NaOH (0.270 ml, 0.264 mmol). After stirring for 1h, the solvents were evaporated and the residue was chromatographed15 (silica gel, 25:10:12] to 15:10:1:1 ethyl acetate/EtOH/water/N1-I4OH) togive _1_i_1_3 as a colorless foam.TLC Rf = 0.23 (12:10:1 :1 ethyl acetate/EtOH/water/NH4OH).1H NMR (300 MHz, D20) 8 7.53 (d, 1H, J=7.3 Hz), 6.69 (d, 1H, J=7.3Hz), 4.41 (m, 2H), 3.71 (m, 2H), 3.45 (t, J=5.8 Hz, 2H), 2.79 (t, J=5.820 Hz, 2H), 2.6 (m, 4H), 1.92 (m, 3H), 1.50 (m, 1H), 1.19 (m, 3H). SCHEME14O0 H2âCH0 /U\( \ \ \ 10% Pd/C\ O\ I / / O EtOHl N N \/ .N NH2 cat. prolme 144 OMeOH, reflux \.1-_4\I \ TFA l // Q N N CH01}â N \ H 14-3?-W0 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-161-2-Dimethoxvmethvl-l 1 .8lnaDhthvridine ( 14- 1 1A mixture containing 1_-4 (30 g, 0.245 mol),pyruvaldehyde dimethylacetal (87 g, 0.737 mol), and L-proline (7.0g,0.062 mol) in MeOH (300 mL) was re?uxed under argon for 16 h.The cooled solution was ?ltered, evaporated and the residue dissolved inCH2Cl;,_ (500 mL) and washed with water and brine then dried andconcentrated to a volumn of ca. 100 mL. Hexane (300 mL) was addedand the mixture was kept at 0°C for 3 h, then filtered affording 1_4-_1 asan off-white crystalline solid.âH NMR (300 MHz, CDCI3) 8, 9.14 (d, J = 2.2 Hz, 1H); 8.26 (d, J = 8.7Hz, 1H); 8.21 (dd, J = 8.7, 2.2 Hz, 1H); 7.8 (d, J = 8.3 Hz, 1H); 7.5 (m,1H); 5.48 (s, 1H); 3.53 (s, 6H).2-Dimethoxymethyl-5 ,6,7,8-tetrahydro-I 1,8 lnaphthyridine 1 14-2)A solution 14-1 (10 g, 0.049 mol) in MeOH, (100 ml) wastreated with 10% Pd on C (1.5 g) and the resulting mixture stirredunder a H2 filled balloon for 12.5 h. The catalyst was removed byfiltration through celite and the solution concentrated to afford 14;; as ayellow crystalline solid.âH NMR (300 MHz, CDCI3) 5 7.18 (d, J = 7.12 Hz, 1H); 6.71 (d, J =7.12 Hz, 1H); 5.18 (s, 1H); 4.96 (br, s, 1H); 3.43 (s, 6H); 3.4 (m, 2H);2.65 (In, 2H); 1.91 (m, 2H).5,6,7,8-tetrahydro-| 1,8 Inaphthyridine-2-carboxaldehyde 1 14-3 114-2 (10 g, 0.048 mol) was trifluoroacetic acid (50 mL)and the resulting solution stirred under argon for 12.5 h. The TFAwas removed at reduced pressure and the residue partitioned betweensat. NaHCO3 and CHZCIZ. The organic layer was dried, concentratedand passed through a 3 in. pad of silica gel (10% acetone/CH2Cl2) andconcentrated to afford _1_4;3_ as a yellow crystalline solid.âH NMR (300 MHz, CDCI3) 5 9.80 (s, IH); 7.31 (d, J = 7.32 Hz, 1H);7.16 (d, J = 7.32 Hz, 1H); 5.31 (br, s, 1H); 3.48 (m, 2H); 2.81 (m, 2H);1.94 (m, 2H).?CA 02263999 l999-02- 19*WO 98/08840 PCT/US97/14912-162-OH OEt â)\OEt 3â NaH, DMF15-1 Bâ 15-2PPA, PhMeO Ethyl Acrylate, OPd(OAc)2, DMF\ Br15-4 CO2Et 15-3MePhi N/\ PhHnBuU,THFo 0Pd(OH)2, H2Me 2 5Ph/LN/â\/CO2Et HZN/'\/CO2EtBn 15-5 15-6?CA 02263999 l999-02- 19wo 98/08840 PCT/US97/14912 _-163-SCHEME15(CONTD)I \\ 0OHN N NH 3 /\n/°HC' 311 O0EDC,HOAIDMF _5 CC>E+yNââ\/ 2*156VI /9N NHoH OEâ:3-4â/\Ef o154oUOHJROH,rhoI \\ o HN OHN N/ ; N/\jfH 3-1 o o158?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912-164-1-Bromo-3-(2.2-diethoxv-ethoxV)âbenzene (15-2)To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100mL) at 0 °C was added a solution of 3-bromophenol 1;-_l_ in DMF (40mL) over 40 min. After the addition was complete, the solution wasstirred for an additional 30 min. The solution was then treated withneat bromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). Thesolution was heated at 100 °C for 8 h, cooled to room temperature, andextracted with Et2O (3 x 200 mL). The combined organic extractswere washed with 10% aq NaOH (100 mL) and brine (100 mL), driedover MgSO4, filtered and concentrated to give 15;; as a yellow oil.TLC Rf = 0.4 (10% ethyl acetate/hexanes).1H NMR (300 MHz, CHCI3) 6 7.19-7.05 (In, 3H), 6.85 (d, 1H), 4.81 (t,1H, J=6.8 Hz), 3.99 (d, 2H, J=6.8 Hz), 3.71 (m, 4H), 1.22 (t, 6H, J=7.1Hz) ppm.6-Bromo-benzofuran (15-3)To a solution of the acetal1_5_-2 in toluene (200 mL) wasadded polyphosphoric acid (20 g). The biphasic mixture was heated to100 °C and stirred at this temperature for 4 h. The mixture was cooledto room temperature, poured onto ice, and extracted with Et2O ( 2 x200 mL). The combined organic extracts were washed with saturatedaq NaHCO3 and brine. The solution was dried over MgSO4, filtered,and concentrated. The residue was purified by ?ash chromatography(100% hexanes) to give the product ?? as a yellow oil.TLC Rf = 0.3 ( 100% hexanes).1H NMR (300 MHz, CHCI3) 8 7.68 (s, 1H), 7.60 (d, 1H, J=2.1 Hz), 7.46(d, 1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.1, 1.5 Hz), 6.75 (dd, 1H, J=7.1, 0.9Hz) ppm.3âBenzofuranâ6-vl-acrvlic acid ethvl ester (15-4)A mixture of the 6-bromobenzofuran L5_â_3_ (1.74 g, 8.79mmol), ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44mmol), triâo-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate(3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100 °C in a sealed?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/US97/14912 _-165-tube for 4 h. The mixture was cooled to room temperature, dilutedwith water, and extracted with Et20 (2 x 40 mL). The combinedorganic extracts were washed with brine (30 mL), dried over MgSO4,filtered, and concentrated. The residue was purified by ?ashchromatography (10% ethyl acetate/hexanes) to give the ester JL4 as anoff-white solid. _TLC Rf = 0.3 ( 10% ethyl acetate/hexanes).1H NMR (300 MHz, CHC13) 5 7.78 (d, 1H, J=15.9 Hz), 7.68 (d, 1H,J=2.4 Hz), 7.66 (s, 1H), 7.59 (d, 1H, J=8.4 Hz), 7.43 (dd, 1H, J=9.0, 1.5Hz), 6.78 (m, 1H), 6.47 (d, 1H, J=15.9 Hz), 4.27 (q, 2H, J=7.2 Hz), 1.34(t, 3H, J=7.2 Hz) ppm.3-(S)-Benzofuran-6âylâ3-[benzylâ(1(R)-phenyl-ethyl)-amino]âpropionicacid ethvl ester (15-5)A solution of benzyl-ot-(R)âmethylbenzylarnine (1.32 g,6.30 mmol) in THF (25 mL) at 0 °C was treated with n~BuLi (2.52 mLof a 2.5 M soln in hexanes). The resulting solution was stirred at 0 °Cfor 30 min and then cooled to -78 ââC. A solution of acrylate _1_5_-_4_(0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for 15min at -78 °C, satd aq NH4Cl soln (5 mL) was added and the cold bathremoved. The mixture was warmed to room temperature, and extractedwith Et20 (2 x 40 mL). The combined organic extracts were washedwith brine (30 mL), dried over MgSO4, filtered, and concentrated. Theresidue was purified by ?ash chromatography (10% ethylacetate/hexanes) to give the [5-aminoester _1_5;_5_ as a yellow oil.TLC Rf = 0.8 (10% ethanol/dichloromethane).1H NMR (300 MHz, CHC13) 8 7.58 (In, 3H), 7.41 (m, 2H), 7.22 (m,9H), 7.59 (s, 1H), 4.58 (m, 1H), 4.05 (m, 1H), 3.91 (q, 2H, J=7.1 Hz),3.72 (m, 2H), 2.62 (m, 2H), 1.21 (d, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.1Hz) ppm.3(S)-Amino-3-(2,3-dihydroâbenzofuranâ6-yl)-propionic acid ethyl ester(15-6)?âWO 9810884010202530CA 02263999 l999-02- 19PCT/US97/14912-166-A mixture of the dibenzylamine _15_-5 (1.19 g, 2.78 mmol)in EtOH/H20/ACOH (26 mL/3 mL/1.0 mL) was degassed with argonand treated with Pd(OH)2 (1.19 g). The mixture was placed under 1atm of H2. After stirring for 18 h, the mixture was diluted withEtOAc, and ?ltered through celite. The filtrate was concentrated andthe residue purified by ?ash chromatography (10% ethylacetate/dichloromethane) to give the ester l_5_-Q as a white solid.TLC Rf = 0.25 (10% ethanol/dichloromethane).1H NMR (300 MHz, CD3OD) as the tri?uoroacetate salt: 5 7.25 (d, 1H,J=8.1 Hz), 6.88 (m, 1H), 7.66 (s, 1H), 6.82 (s, 1H), 4.58 (m, 3H), 4.12(m, 2H), 3.30 (m. 1H), 3.19 (m, 2H), 2.98 (m, 2H), 1.11 (t, 3H, J=7.2Hz) ppm.3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(2-{2-oxo-3(S)-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridinâ2-yl)-ethyl]-pyrrolidin-l-yl}-acetvlamino)ânroDionic acid ethvl ester (15-7)A solution of the amine 11-6 (0.100 g, 0.425 mmol), acid_3;1_l_ (0.155 g, 0.511 mmol), EDC (0.098 g, 0.511 mmol), NMM (0.103g, 1.02 mmol), and HOAT (0.069 g, 0.511 mmol) in DMF ( 6 mL) wasstirred at room temperature for 48 h. The solution was diluted withsatd aq NaHCO3 (3 mL) and extracted with EtOAc (2 x 10 mL). Thecombined organic extracts were washed with brine (10 mL), dried overMgSO4, filtered, and concentrated. The residue was purified by ?ashchromatography (8% ethanol/dichloromethane) to give the ester 1_5â_7 asan yellow oil.TLC Rf = 0.3 (10% ethanol/dichloromethane).1H NMR (300 MHz, CHCI3) 5 7.12 (m, 2H), 6.78 (m, 1H), 6.65 (s, 1H),6.39 (m, 1H), 5.36 (m,1H), 4.99 (br s, 1H), 4.55 (t, J=7.2 Hz, 2H), 4.11(m, 2H), 3.91 (m, 2H), 3.39 (m, 2H), 3.19 (m, 2H), 2.79 (m, 2H), 2.70(m, 2H), 2.51 (m, 1H), 2.28 (m, 2H), 1.85 (m, 3H), 1.18 (m, 3H) ppm.3(S)â(2,3-Dihydro-benzofuranâ6-yl)-3-(2- { 2-oxoâ3(S)â[2-(5 ,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-pyrrolidin-1-yl}-acetvlamino)âDrooionic acid (15-8)?CA 02263999 l999-02- 19. wo 98108840 PCTIUS97/14912-167-A solution of the ester l?? (0.038 g, 0.073 mmol) inEtOH/H20 (4.5 mL/0.5 mL) was treated with LiOH (0.009 g, 0.365mmol) and the homogeneous solution stirred at room temperature for 4h. The solution was concentrated to a solid residue which was dissolved5 in H20 and purified by preparative HPLC (gradient conditions: 95 :05 to50:50 H20/MeCN with 0.1% TFA) to give the acid _l_5_-_8 as a white solid(as the bis-tri?uoroacetate salt).MS (LR, FAB) M +1 calcd 493, found 493.39.1H NMR (300 MHz, CHCI3) 5 7.91 (m, 1H), 7.35 (m, 1H), 7.09 (m,1H), 6.76 (m, 1H), 6.68 (s, 1H), 6.43 (m, 2H), 5.28 (In, 1H), 4.53 (In,2H), 4.41 (m, 1H), 3.38 (m, 7H), 3.14 (m, 3H), 2.81 (m, 5H), 2.60 (m,1H), 2.28 (m, 1H), 2.05 (m, 3H) ppm.?CA 02263999 l999-02- 19-W0 98/08840 PCT/US97/14912 - 168 -H ME\ DPPA, Et3N, \I dioxane, I NH2 benzylalcohol OOH1.6.-.1NaH, BrCH2CO2tBuCbzNHTHFHCI EtOAc Cb NH2I \ N/; EDC, HOBT= DMF2HCl.H2N/\/C023L2I \ O =CbzNH N\)L?/X/CO2E'[0LiWâ/1-?CA 02263999 l999-02- 19PCT/US97/14912» WO 98/08840-169-$Q_tLEME_1.6_(s2o.n1.l Câo 5N/â\/C025:HH ,10%Pd-C \16-5 2 I NJEtOH H2N016-§HN N\ CHO NaB(OAc)3H[ AcoH . 4A seives$3 CHZCICHZCI0âH Rx o 5N N\ N N\)LN/â\,co2Et| H H/ oJ_6;ZLiOH,H2OMeOHPâH |\ O =/N N\ N N\/[LN/â\/co2HI H H/ o?'WO 98/088401015_2025CA 02263999 l999-02- 19PCT/US97Il49l2-170-3-Benzvloxvcarbonvlamino-6âmethvlâ2âDvridinone (16-2).\ICbzNH NHODPPA (35.6 ml, 165 mmol) was added to a stirred solution of 2-hydroxy-6âmethylpyridineâ3-carboxylic acid (l_6;l; Aldrich; 22.97 g,165 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300ml) and the resulting solution was heated to re?ux. After 16 h moretriethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 165mmol) were added and the solution was re?uxed for a further 24 h.The reaction was concentrated in vacuo to remove most of the volatiles.The residue was partitioned between methylene chloride (500 ml) andbrine (500 ml), acidified to pH 1 with 1 M HCl (165 ml). The aqueouslayer was extracted methylene chloride (two times) and the combinedorganic layers were washed with sodium hydrogen carbonate solutionand brine, dried (Na2SO4) and evaporated in vacuo to a brown solid.This was recrystallized from methanol, to give the title compound 1_6;2_as a tan solid: 1H NMR' (300 MHz, CDCI3) 5 2.29 (s, 3H, CH3), 5.20(s, 2H, PhCH2), 6.06 (d, J=7.6 Hz, pyridinoneâ5-H), 7.32-7.43 (m, 5H,Ph), 7.67 (br s, 1H, CbzNH), 8.03 (br d, pyridinone-4-H).2-[6-methyl-2-oxo-3-(benzyloxycarbonylamino)-2H-pyridin-1 âyl]aceticacid t-butvl ester (16-3).\N\/CO2tBuCbzNH0Sodium hydride (5.3 g, 0.22 mol) was added to a stirred slurry of 3-benzyloxycarbonylaminoâ6âmethyl-2âpyridinone (16â2; 53.2 g, 0.20mol) in THF at 0°C. tâButylbromoacetate (45 ml, 0.27 mol) was added?â WO 98/0884010152025CA 02263999 l999-02- 19PCT/U S97/ 14912 _-171-to the resulting solution and a precipitate rapidly forms. The reactionwas warmed to rt over lh and after 2h the solvent was evaporated invacuo and the residue was partitioned between 1:1 water/brine (200 ml)and 6:1 THF/methylene chloride (700 ml). The organic layer was dried(N a2SO4) and evaporated in vacuo to a solid which was triturated withhexane to give the title compound _1_6_-Q as a crystalline solid:1H NMR (400 M2, CDCI3) 5 1.47 (s, 9H), 2.25 (s, 3H), 4.75 (s, 2 H),5.19 (s, 2H), 6.09 (d, J=7.8 Hz), 7.30-7.40 (m, 5H), 7.75 (br s, 1H),7.94 (br d, IH).2-[6-methy1-2âoxo-3-(benzyloxycarbonylamino)-2H-pyridin-1-yl]aceticacid (16-4).I \CbzNH NVCOZHOHCI gas was bubbled through a stirred suspension of 2â[6-methyl-2-oxoâ3â(benzyloxycarbonylamino)-2Hâpyridin-1-yl]acetic acid t-butyl ester(_1_6â_3; 12.3 g, 33 mmol) in ethyl acetate (250 ml) at -15°C for 20 min.The resulting solution was allowed to warm to room temperature andwas then stirred there for 3 h. After purging with argon, the bulk ofthe solvent was rotavapped off and ether added to the residue. The solidwhich precipitated was filtered off and washed with ether. The titlecompound 1_6;4 was thus obtained as a white ?uffy powder: 1H NMR(CD3OD) 8 2.32 (s, 3 H), 4.86 (s, 2 H), 5.18 (s, 2 H), 6.24 (d, J = 7.9Hz, 1 H), 7.31-7.41 (m, 6 H), 7.94 (br s, 1 H).3â(2â{6âmethy1â2-oxoâ3â(benzyloxycarbony1arnino)-2Hâpyridin-1 âyl }-acetv1amino)â3(S)-Dvridin-3-V1-Dropionic acid ethvl ester (16-5).?â WO 98/0884010152025CA 02263999 l999-02- 19PCT/US97/14912-172-l\ o ./CbZNH N\/[Lu/'\/CO2Et0To a solution of the acid 2_-4_ (150 mg, 0.47 mmol) and the amine 1_-2(Rico et al; J. Org. Chem., 1993, 58, 7948; 139 mg, 0.52 mmol) inDMF (3 mL) was added HOBT (77 mg, 0.57 mmol) then Et3N (200 11L,1.42 mmol). After 15 minutes, EDC (136 mg, 0.71 mmol) was addedand the mixture was stirred for 16 hours. The solution was poured intoEtOAc, washed with saturated N aHCO3 then brine, dried (MgSO4), andevaporated to give the title compound'16-5 as a white solid which wasused as such in the next step. 1H NMR (CDCI3) 8 1.14 (3H, t), 2.40 (3H,s), 2.8-2.9 (2H, In), 4.05 (2H, q), 4.78 (2H, m), 5.22 (2H, s), 5.4 (1H,Q), 6.17 (1H, d), 7.22 (1H, m), 7.3-7.45 (4H, m), 7.59 (1H, m), 7.7-7.8(2H, m), 8.0 (1H, In), 8.52 (2H, In).3-(2â{6-methyl-2-oxoâ3-amino-2H-pyridin-1-yl}-acetylamino)-3(S)-Dvridin-3-vl-nronionic acid ethvl ester (16-6).0â|\ ° /HZN N\/âLN/â\,Co2cH2cH3H0To a degassed solution of the pyridone l? (243 mg; 0.49 mmol) inEtOH (20 mL) was added 10% Pd on carbon (25 mg) and this was thenstirred under an atmosphere of hydrogen gas (balloon) for 3 hours.The mixture was filtered through a pad of celite and the solventremoved to give the title compound (l?) as a viscous oil which wasused as such in the next step.?HWO 98/0884010152025CA 02263999 l999-02- 19PCT/US97l14912-173-3-(2- { 6-methyl-2-oxo-3-[(5 ,6,7 ,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridinâ1âyl} -acetylamino)-3(S)âpyridinâ3âyl-Dronionic acid ethvl ester (16-7).0âH | \ O N N\ N N\/[LN/'\/CO2EtI H H/ 0To a solution of the amine _1_6-_6_ (155 mg, 0.433 mmol), the aldehyde$3 (70 mg, 0.433 mmol) in CH2ClCH2Cl was added crushed 4Aseives, ACOH (20 uL) and then NaB(OAc)3H (184 mg, 0.866 mmol).After stirring for 48 hours, the mixture was filtered through celite,poured into EtOAc and washed with saturated NaHCO3 then brine. Thedried (MgSO4) solution was concentrated in vacuo to give a foam typesolid. Column chromatography (5%MeOH in CHCI3) afforded the titlecompound 1_@_ as a foam type solid.Analysis calculated for C27H32N604-0.25CHCl3C, 61.24; H, 6.08; N, 15.73found C, 61.33; H, 6.09; N, 15.85.FAB mass spectrum. m/z = 505.34 (M+H)3-(2- { 6-methyl-2âoxo-3-[(5 ,6,7,8âtetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridinâ l âyl } -acety1amino)â3(S)âpyridin-3-ylâDronionic acid bis trifluoroacetate (16-8).0'H |\ O =/N N\ N\/[L /â\,co_,_HN NEITH H/ o?CA 02263999 l999-02- 19, WO 98/08840 PCT/US97/14912-174-The ester 1_6â;7_ (120 mg, 0.238 mmol) was dissloved in H20 (1 mL) andTHF (1 mL) and then 1N LiOH (1 mL, 1 mmol) was added. After 2hours, the mixture was purified by reverse phase HPLC (WatersPrepPak C18 column eluting with H20/acetonitrile gradient) to give,5 after lyophilization, the title compound _1__6_? as a powderAnalysis calculated for C25H28N604-2.STFA-0.55H2OC, 46.70; H, 4.13; N, 10.89found C, 46.70; H, 4.14; N, 11.04.FAB mass spectrum. m/z = 477.2 (M+H)?CA 02263999 l999-02- 19wo 9s/oss4o PCT/US97/14912 - -175-S§.I:lEME_1.ZNH2\'(A Me NCH(OMe) M? O2N/\â/2 2 /N / OO PTSA Me < : HOAC17-1 0 NH1.7.-2| \NH NaH,THF02â o NO BTCHZCOZYBU 21Z;3HN N\ CHOIPtO2,H2 / 1_4_-.3EtOH NaBH(OAc)s.CHZCICHQCIHN N\ ?WO 98/08840CA 02263999 l999-02- 19PCT/US97/14912 -176- )LiOH,MeOH H l \H20 N l N\ Eâ NVco2H/ 017-7H2N OEt-HCI 017-8 FEDC, HOBT, DMF HN NI \/LiOH, H20MeOH, THFHN N\ ?4 WO 98/0884!)10152025CA 02263999 l999-02- 19PCT/US97/14912 --177-QN.NâDimethvlaminoethenvlcvclonronvl ketone ( 17-2).M?,NMe \/WAOA mixture of cyclopropyl methyl ketone (5.88 ml, 59mmol) and N,N-dimethylforrnaldehyde dimethyl acetal (7.83 ml, 59mmol) was heated in the presence of a catalytic quantity of p-toluenesulfonic acid for 48 hours. The resulting crude sample of thetitle compound (17;2, a pale yellow oil) was used in subsequentreactions without further purification: 1H NMR (CDCI3) 5 0.74 (m, 2H), 1.00 (m, 2 H), 1.75 (m, 1 H), 3.48 (s, 3 H), 3.50 (s, 3 H), 5.20 (d, 1H), 7.55 (d, 1 H).6-Cvclonropvl-3-nitro-2-(1H)âDVridinone (17-3).\| NHO2NOA mixture of crude B-N,N-dimethylaminoethenylcyclopropyl ketone (LL-_2; 12 g, < 86 mmol),nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml)[prepared from glacial acetic acid (42 ml), water (100 ml) andpiperidine (72 ml)] was stirred at room temperature overnight.Following dilution with water (20 ml), the yellow precipitate wasisolated via filtration and drying in vacuo to yield the title compound?;3_: 1H NMR (CDCI3) 8 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H),6.02 (br d, J = 8.0 Hz, 1 H), 8.41 (d, J = 8.0 Hz, 1 H).3-Nitro-6-cvclopronvl-1-(t-butvlâcarboxvmethvlene)-2-Dvridinone (17-£1?CA 02263999 l999-02- 19 .wo 98/08840 PCTfUS97/14912â 178 -Solid 6-cyclopropyl-3ânitro-2-(1H)âpyridinone ( 17-3; 1.45 g, 7.78 mmol) was added in small portions to a suspension of sodium10152025hydride (260 mg, 10.8 mmol) in THF (30 ml) at room temperature.After stirring the resulting solution for 20 min, tert-butylbromoacetate(4 ml, 27 mmol) was added. The mixture was stirred for an additional30 min. then heated at 55°C for 15 hrs. After cooling to roomtemperature the THF was evaporated in vacuo and ice carefully added tothe residue to destoy any excess sodium hydride. The resulting miturewas extracted with 2:121 ethyl acetate:ether:ch1oroform and the extractsdried over magnesium sulfate. Filtration and evaporation of the filtrategave a yellow oil as a 3:1 mixture of N and O-alkylated productsrespectively. Flash column chromatography eluting with 1:1hexane/ethyl acetate gave the title compound jig as a yellow crystallinesolid: 1H NMR (CDCI3) 6 0.94 (m, 2 H), 1.18 (m, 2 H), 1.49 (s, 9 H),1.79 (m, 1 H), 5.04 (s, 2 H), 6.10 (d, J = 8.1 Hz, 1 H), 8.33 (d, J = 8.1Hz, 1 H).3-Aminoâ6-cyclopro_r_>ylâl-1tâbuty1âcarboxymethylene )â2âpyridinone§ 17-5 2 A mixture of 3-nitroâ6-cyclopropyl-1â(t-butyl-methylene-carboxy)-2-pyridinone (17-4; 760 mg, 2.58 mmol) and platinum oxide(250 mg) in ethanol (30 ml) was stirred at 0° C under an atmosphere of?CA 02263999 l999-02- 196 wo 98108840 PCT/US97/14912 --179-hydrogen for 3 hours. Following removal of most of the catalyst byfiltration through a bed of Celite, the filtrate was concentrated and theresidue purified by ?ash column chromatography eluting with 2:1hexane/ethyl acetate. This yielded the title product l_7-_5 as a viscous5 orange gum: 1H NMR (CDCI3) 5 0.67 (m, 2 H), 0.89 (m, 2 H), 1.49 (s,9 H), 1.63 (m, 1 H), 4.07 (br s, 2 H), 4.99 (s, 2 H), 5.91 (dd, J = 1.2 and7.4 Hz, 1 H), 6.47 (d, J = 7.4 Hz, 1 H).10 {6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-vlmethvl) -aminol-2H-Dvridinâ1-vl lâacetic acid tert-butvl ester (17-6) 15 Following the procedure described for the synthesis of 16-7, the amine17-5 was coupled with 14-3 to yield the title compound 17-6 as an oil.Rf (silica gel; 5%MeOH in CHCI3) = 0.3920 {6-Cyclopropylâ2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-lmeth 1 -amino -2H- ridin-l- l -acetic acid 17-7. 25 Following the procedure described for the preparation of 16-8, the ester_1__7_-_6_ was hydrolysed to give the title compound 17-7. 1H NMR(CD3OD) 5 0.66 (m, 2 H), 0.9 (m, 2 H), 1.78 (m, 1 H), 1.9 (m, 2H),?CA 02263999 l999-02- 19gwo 98/08340 PCT/US97/14912-180-2.75 (m, 2H), 3.4 (m, 2H), 4.6 (br s, 2 H),'6.02 (d, 1H), 6.19 (d, 1H),6.58 (m, 1 H), 7.27 (m, 1H).5 Ethvl 3-amino-3(S)-(3-fluoroDhenvl)nroDionate hvdrochloride (17-8).H2N OEt-HCl 0FThe title compound was prepared starting from 3-fluorobenzaldehyde10 (Aldrich) by conversion to ethyl 3-fluorocinnamate and employing theasymmetric addition/hydrogenolysis methodology described by Rico etal; J. Org. Chem., 1993, 58, 7948.1H NMR (CD3OD) 8 1.21 (t, 3H), 3.03 (dd, 1H), 3.13 (dd, 1H), 4.15(q, 2H), 4.77 (t, 1H), 7.19 (m, 1H), 7.3 (m, 2H), 7.5 (m, IH).153-(2â{6-Cyclopropyl-2-oxo-3-[(5,6,7,8-tetrahydroâ[1,8]naphthyridin-2-ylmethyl)âamino]â2Hâpyridin-1-yl}âacetylamino)â3(S)â(3-?uorophenyl)-Dronionic acid ethyl ester (17-9).20 Following the procedure described for the preparation of _1_6;§, the acid1_'_7_â_Z was coupled with the amine 1_7_-8 to yield the title compound _1_7;9_.25 Analysis calculated for C3()H34N504 F1 -0.25H2OC, 65.26; H, 6.30; N, 12.69found C, 65.20; H, 6.04; N, 13.00.?CA 02263999 l999-02- 19,w() 93/03340 PCT/US97/14912 _-181-FAB mass spectrum. m/z = 548.12 (M+H)3-(2-{6-Cyclopropyl-2-oxo§3-[(5,6,7,8âtetrahydroâ[1,8]naphthyridinâ2âylmethyl)-amino]â2Hâpyridin-1âyl}âacetylamino)â3(S)-(3-?uorophenyl)-5 Dropionic acid ditri?uoroacetate (17-10). Following the procedure described for the preparation of _1gâ_g, the ester10 _l_7? was hydrolysed to give the title compound _1_Z_-_1_Q.Analysis calculated for C2gH30N504 F1-2.15TFA-0.5H2OC, 55.16; H, 4.91; N, 10.62found C, 55.19; H, 4.91; N, 10.89.FAB mass spectrum. m/z = 520.05 (M+H) 153 â(2-[6-Cyclopropyl-2âoxoâ3-[(5,6,7,8âtetrahydroâ[1,8]naphthyridinâ2âylmethyl)âamino]â2Hâpyridin- 1 âyl } âacetylamino)â3(S)-(3-pyridyl)-Drooionic acid ditrifluoroacetate (17-11).HN N\I20 /Following the procedures described for Scheme 16, the acid 1_Z_-1 wascoupled with the amine L-_9_ followed by saponification of the ester toafford the title compound _1_Z_-_1_l.25 Analysis calculated for C27H3()N604~2.5TFA-0.6H2O?CA 02263999 l999-02- 19-wo 98/08840 PCT/US97/14912-182-C, 48.13; H, 4.25; N, 10.53found C, 48.11; H, 4.23; N, 10.64.FAB mass spectrum. m/z = 503.25 (M+H)5 3-(2-{6-Cyclopropy1-2-oxo-3-[(5,6,7,8-tetrahydro-[ 1,8]naphthyn'dinâ2-ylmethyl)-amino]-2H-pyridin-1 -yl } âacetylamino)-3 (S)-(alkynyl)-Drooionic acid ethvl ester (17-12). 10Following the procedures described for Scheme 16, the acid LZ-_7_ wascoupled with 3-aminoâ3(S)-(alkynyl)-propionic acid ethyl ester 2-2(Zablokie et al, J. Med. Chem., 1995, 38, 2378) to afford the titlecompound _1_7_;_12._.15 Analysis calculated for C26H31N504-0.35H2OC, 64.53; H, 6.60; N, 14.47found C, 64.52; H, 6.71; N, 14.54.FAB mass spectrum. m/z = 478.35 (M+H)20 3-(2-{6-Cyclopropylâ2-oxo-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-2H-pyridin-1-yl} -acetylamino)-3(S)-(alkynyl)-Drooionic acid (17-13). 25?CA 02263999 l999-02- 19two 98/08840 PCT/US97/14912 --183-Following the procedure described for the preparation of 16-8, the ester17-12 was hydrolysed to give the title compound 17-13.FAB mass spectrum. m/z = 450.23 (M+H)?CA 02263999 l999-02- 19 * WO 98/08840 PCT/US97/14912â 184 -S_QJ:iEMEJ.§CH3CHO (COCI) ClH2N\/C023" TMSCN NC CBH4Cl: 1 W202 HN\/CO2Bn Cl/Kn, N\/CO2Bn1L 1&2 o13;:MeOCl4MeOPhCH2 NH2, N/â\( LiOH, H20BOAC nJ'\n,N\/cozan MeOH, THF013:4:MeOMeO TFA 1NH 2N)\n/ \/â\OH?- W0 98I08840CA 02263999 l999-02- 19PCT/US97/14912 _-185-SCHEME 1§(§Qn1.)NaBH(OAc)3,CH2ClCH2C|2. LiOH, H20THF, MeOH?VWO 98/0884010152025CA 02263999 l999-02- 19PCT/U S97/ 14912-186-BenzvlâN-(1-cvanoethmglvcine lidrochloride (18-2).NCHN\/CO2BnTMSCN (18.8 mL, 141 mmol) was added cautiosly to a stirred solutionof benzylglycine free base (23.3 g 141 mmol â from the HCl salt bypartition between EtOAc and brine basified with saturated Na2CO3solution) and acetaldehyde (7.88 mL, 141 mmol) in CH2Cl2 (50 mL).After 4 h the volatiles were removed in vacuo and the residue was takenup in EtOAc and washed with brine, dried (Na2SO4) and evaporated invacuo to an oil. The oil was redissolved in EtOAc and 9.9 M HCl inEtOH (15.25 mL, 151 mmol) was added to give a crystalline precipitatewhich was isolated by filtration, washing with EtOAc and Et2O to givethe title compound (1&2_):1H NMR (CD3OD) 6 1.70 (d, 3H), 4.16 (d, 1H), 4.21 (d, 1H), 4.64 (q,1H), 5.31 (s, 2H), 7.35-7.44 (m, SH).1-Benzvloxvcarbonvlmethvl-3.5-dichloro-6-methvlvvrazinone (18-3).ClN\IC')\n/N\/CO2BnOA stirred mixture of oxalyl chloride (40.4 mL, 463 mmol) and ?g(29.51 g, 116 mmol) in 1,2-dichlorobenzene (110 mL) was heated to100°C for 15 h. The volatiles were removed in vacuo and the residuewas purified by chromatography (silica gel; hexanes followed by30%EtOAc in hexanes) to give a solid which was heated inEtOAC/hexanes 2:5 (140 mL), cooled and collected by filtration to givethe title compound &3_ as a pale green solid:?CA 02263999 l999-02- 19. wo 98/08840 PCT/US97/14912-187-1H NMR (CDCI3) 5 2.35 (s, 3H), 4.88 (s, 2H), 5.24 (s, 2H), 7.38 (m,SH).3 -(4-Methoxybenzylamino)â5-chloro-6âmethyl-1 -benzvloxvcarbonvlmethvl âpvrazinone (18-4).U1IN /l\n/N\/CO2BnHA solution of the pyrazinone _1_8_;3 (5 g, 15.3 mmol) and 410 methoxybenzylamine (6.0 mL, 45.9 mmol) in EtOAc (60 mL) washeated at 80°C for 2 h. The solution was cooled and filtered. Thefiltrate was concentrated in vacuo, the residue swished with MeOH andfiltered to afford the title compound as a solid:1H NMR (CDCI3) 8 2.23 (s, 3H), 3.82 (s, 3H), 4.5 (d, 2H), 4.81 (s, 2H),15 5.22 (s, 2H), 6.25 (t, 1H), 6.85 (m, 2H), 7.27 (m, 2H), 7.38 (m, SH).3 -(4âMethoxybenzylamino)-5 -chloro-6-methylâl -carboxymethylnvrazinone (18-5).20 OA solution of the benzyl ester 18-4 ( 1.06 g, 2.48 mmol) in toluene (60mL) was degassed with argon and then 150 mg 10% palladium oncarbon was added. The mixture was stirred under an atmosphere of?âW0 98/0884!)102025CA 02263999 l999-02- 19PCT/U S97/ 14912-188-hydrogen gas for 16 h. The solution was filtered through celite and thesolvent evaporated to give the title compound 1&5 as a white solid:1H NMR (CD3OD) 5 2.25 (s, 3H), 3.78 (s, 3H), 4.45 (s, 2H), 4.81 (s,2H), 4.90 (s, 2H), 6.85 (d, 2H), 7.28 (d, 2H).3-(4-Methoxybenzylamino)- 6âmethyl-l -carboxymethylDvrazinone (18-6).MeOThe acid 18-_5_ (810 mg) was dissolved in 40 mL 1 N NaOH and 40 mLMeOH at room temperature and was treated with Raney nickelsuspension (~5 g). A second charge of Raney nickel (~5 g) and 1 NNaOH (20 mL) was added after 3 h. After 6 h, the suspension wasfiltered through celite washing with water and MeOH. The volatileswere removed in vacuo and the residue then taken up 1 N HCl (~5 mL).Saturated NaHCO3 solution was added until pH~7-8 and the solution wasextracted exhaustively with EtOAc/T HF. After drying (MgSO4), thesolvent was removed to give the title compound 18-6 as a solid whichwas used as such:1H NMR (CD3OD) 5 2.16 (s, 3H), 3.76 (s, 3H), 4.46 (s, 2H), 4.64 (s,2H), 4.86 (s, 2H), 6.65 (s, 1H), 6.85 (d, 2H), 7.25 (d, 2H).3âAmino-6-meth lâ1âcarbox meth 1 razinone 18-7 . ?' WO 98/0884010152025CA 02263999 l999-02- 19PCT/US97/ 14912-189-The pyrazinone 18-6 (900 mg) was heated at re?ux in trifluoroaceticacid (20 mL) for 7 h. The volatiles were removed in vacuo and theresidue was azeotroped with CH2Cl2, then EtOAc then MeOH. MeOHwas added to the residue and the solution filtered to remove impurities.Removal of the methanol then afforded the title compound 18-7 whichwas used as such:1H NMR (CD3OD) 8 2.22 (s, 3H), 4.82 (s, 2H), 6.58 (s, 1H).3 -(3-Fluorophenyl)-3-(2-{6-methyl-2-oxo-3-amino]-2H-pyrazin-1-y1}-acetvlaminomrooionic acid ethvl ester (18-8).G.N /\/CO2EtHN/\/o' N0Following the procedure described for the preparation of 16-6, the acid18-7 was coupled with the amine 17-8 to yield the title compound 18-8.1H NMR (CDCI3) 5 1.15 (t, 3H), 2.23 (s, 3H), 2.78 (dd, 1H), 2.84 (dd,1H), 4.05 (q, 2H), 4.68 (ABq, 2H), 5.30 (br s, 2H), 5.35 (m, 1H), 6.68(s, 1H), 6.9-7.1 (In, 3H), 7.27 (m, 1H), 7.57 (d, 2H).3-(3-Fluorophenyl)-3-(2- { 6-methyl-2-oxoâ3-[(5 ,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-ylmethyl)-amino}-2H-pyrazin-1 -yl } -acetylamino)-Drobionic acid ditrifluoroacetate (18-9).CVFH N.â\K 0 «N l N\ HJ\n/N\/U\l-Ni/\/COQH/ 0III!?CA 02263999 l999-02- 19, wo 98/08840 PCT/US97/14912 _-190-Following the procedure described for the synthesis of _1_6;2, the amine_lL_-8_ was coupled with _1_4;3_ and the product hydrolyzed to yield the titlecompound 1_8_-_9_.Analysis calculated for C25H27N504F-2.25TFA-0.85H2O5 C, 46.23; H, 4.07; N, 10.97found C, 46.22; H, 4.00; N, 11.12.FAB mass spectrum. m/z = 495.26 (M+H)?CA 02263999 l999-02- 199 W0 93/03340 PCT/US97/14912â 191 âSCH E100 oOCH-'1 )9 OCH30\/® Lil (cat.) O O 1 1 O 0.9.-_. 13-20//\OH 0CHs H2,Pd/CHO O OTsOH(cat.) 0LI 0l9;3 oO 0001-13 CI OiBu NHO OH NET3 AllL/O o H O\\,O âRH NâNâcH O3% 2 3 1 -50 0Br\/[L OEtvet 1â/\nâNaN(SiMe3)2 Lo NâCHg1g-§00ETsOH (cat.) I}!/\nâacetone Nâ O0 CH3?CA 02263999 l999-02- 19WO 98/08840 PCT/US97/14912-192-SCHEME 19 (Conrd) OOEt \ âONW ' /NR 0 NM NH20 O19_7 proline (cat.) I22\3OE". ?CA 02263999 l999-02- 19. wo 98/08840 PCT/US97/14912 --193-SCHEME 19 ont'd EDC,HOBTNMMHZN OEt NaOH ?-WO 98/088401015202530CA 02263999 l999-02- 19PCT/U S97/ 14912-194-The test procedures employed to measure oLv[33 binding andthe bone resorption inhibiting activity of the compounds of the presentinvention are described below.BONE RESORPTION-PIT ASSAYWhen osteoclasts engage in bone resorption, they willliterally cause the formation of pits in the surface of bone that they areacting upon. Therefore, when testing compounds for their ability toinhibit osteoclasts, it is useful to measure the ability of osteoclasts toexcavate these resorption pits when the inhibiting compound is present.Consecutive 200 micron thick cross sections from a six mmcylinder of bovine femur diaphysis were cut with a low speed diamondsaw (Isomet, Beuler, Ltd., Lake Bluff, I1). Bone slices were pooled,placed in a 10% ethanol solution and refrigerated until further use.Prior to experimentation, bone slices were ultrasonicatedtwice, 20 minutes each in H20. Cleaned slices were placed in 96 wellplates such that two control lanes and one lane for each drug dosage areavailable. Each lane represents either triplicate or quadruplicatecultures. The bone slices in 96 well plates were sterilized by UVirradiation. Prior to incubation with osteoclasts, the bone slices werehydrated by the addition of 0.1 ml Medium I99, pH 6.9 containing 15%fetal bovine serum and 1% penicillin/streptomycin.Osteoclasts were isolated from the long bones of 1 to 3 dayold rat pups (SpragueâDawley) by modifications of Chambers galâ, (._LCell. Science, 66:383-399). The resulting suspension (0.75 ml/bone)was gently triturated 90-120 times using a wide bore transfer pipet.The cellular population was separated from bone fragments by a cellstrainer with a 100 micron nylon mesh. 100 ul of the cell suspensionwas placed onto each bone slice. Test compounds were then added at thedesired experimental concentrations.Bone slices exposed to osteoclasts for 20-24 hrs wereprocessed for staining. Tissue culture media was removed from eachbone slice. Each well was washed with 200 ul of H20, and the boneslices were then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M?W0 98l088401015202530CA 02263999 l999-02- 19PCT/US97/14912 --195-cacodylate, pH 7.4. After fixation, any remaining cellular debris wasremoved by 2 min. ultrasonication in the presence of 0.25 M NH4OHfollowed by 2 X 15 min ultrasonication in H20. The bone slices wereimmediately stained for 6-8 min with filtered 1% toluidine blue and 1%borax.After the bone slices have dried, resorption pits werecounted in test and control slices. Resorption pits were viewed in aMicrophot Fx (Nikon) fluorescence microscope using a polarizingNikon IGS filter cube. Test dosage results were compared with controlsand resulting IC50 values were determined for each compound tested.The appropriateness of extrapolating data from this assay toutility and use in mammalian (including human) disease states issupported by the teaching found in Sato, M., gt _e?., Journal of Bone andMineral Research, Vol. 5, No. 1, 1990. That article teaches that certainbisphosphonates have been used clinically and appear to be effective inthe treatment of Paget's disease, hypercalcemia of malignancy, osteolyticlesions produced by bone metastases, and bone loss due toimmobilization or sex hormone deficiency. These same bisphosphonatesare then tested in the resorption pit assay described above to confirm acorrelation between their known utility and positive performance in theassay.EIB ASSAYDuong _e_t 2_11., J. Bone Miner. Res., 8:S 378, describe asystem for expressing the human integrin otvB3. It has been suggestedthat the integrin stimulates attachment of osteoclasts to bone matrix,since antibodies against the integrin, or RGD-containing molecules, suchas echistatin (European Publication 382 451), can effectively block boneresorption.Reaction Mixture:1. 175 pl TBS buffer (50 mM Tris-HCI pH 7.2, 150 mMNaCl, 1% BSA, 1 mM CaC12, 1 mM MgCl2).?1015202530â W0 98I08840CA 02263999 l999-02- 19PCT/US97/14912-196-2. 25 ul cell extract (dilute with 100 mM octylglucosidebuffer to give 2000 cpm/25 ul).125Iâechistatin (25 ul/50,000 cpm) (see EP 382 451).4. 25 ul buffer (total binding) or unlabeled echistatin (non-specific binding).0)The reaction mixture was then incubated for I h at roomtemp. The unbound and the bound ocv[33 were separated by filtrationusing a Skatron Cell Harvester. The filters (prewet in 1.5% poly-ethyleneimine for 10 mins) were then washed with the wash buffer (50mM Tris HC1, lmM CaCl2/MgCl2, pH 7.2). The filter was thencounted in a gamma counter. âSPA ASSAYF-â*ââ\OO0\lO\£II-l>-l)Jl\Jwoounoooo12.MATERIALS :Wheatgerm agglutinin Scintillation Proximity Beads (SPA):AmershamOctylglucopyranoside: CalbiochemHEPES: CalbiochemNaCl: FisherCaCl2: FisherMgCl2: SIGMAPhenylmethylsulfonylfluoride (PMSF): SIGMAOptiplate: PACKARDCompound 8_-l_Q (specific activity 500-1000 Ci/mmole)test compoundPurified integrin receptor: OLVB3 was purified from 293 cellsoverexpressing OLVB3 (Duong et al., J. Bone Min. Res., 8:S378,1993) according to Pytela (Methods in Enzymology, 1442475,1987)Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mMCa2+/Mg2+, 0.5 mM PMSF?â WO 98/0884013.CA 02263999 l999-02- 19PCT/U S97/ 14912-197-50 mM octylglucoside in binding buffer: 50-OG bufferPROCEDURE:1.101520(i)(ii)25(iii)(iv)(V)30....... ....n............-....uâ-..-_..........w:M.~..~,.......... 4?\Aâ ,Pretreatment of SPA beads:500 mg of lyophilized SPA beads were first washed four timeswith 200 ml of 50-OG buffer and once with 100 ml of bindingbuffer, and then resuspended in 12.5 ml of binding buffer.Preparation of SPA beads and receptor mixtureIn each assay tube, 2.5 pl (40 mg/ml) of pretreated beads weresuspended in 97.5 pl of binding buffer and 20 pl of 50-OGbuffer. 5 pl (~30 ng/pl) of purified receptor was added to thebeads in suspension with stirring at room temperature for 30minutes. The mixture was then centrifuged at 2,500 rpm in aBeckman GPR Benchtop centrifuge for 10 minutes at 4°C. Thepellets were then resuspended in 50 pl of binding buffer and 25pl of 50âOG buffer.ReactionThe following were sequentially added into Optiplate incorresponding wells:Receptor/beads mixture (75 pl)25 pl of each of the following: compound to be tested, bindingbuffer for total binding or &§ for nonâspecificbinding (final concentration 1 pM)§_â__lQ in binding buffer (25 pl, final concentration 40 pM)Binding buffer (125 pl)Each plate was sealed with plate sealer from PACKARD andincubated overnight with rocking at 4°CPlates were counted using PACKARD TOPCOUNT% inhibition was calculated as follows:A = total counts?1015202530CA 02263999 l999-02- 19. wo 93/03340 PCT/US97l14912â 198 -B = nonspecific countsC = sample counts% inhibition = [{ (A-B)â(CâB)}/(A-B)]/(AâB) x 1005 OCFORM ASSAYOsteoblastâlike cells (1.8 cells), originally derived frommouse calvaria, were plated in CORNING 24 well tissue culture platesin or MEM medium containing ribo- and deoxyribonucleosides, 10%fetal bovine serum and penicillin-streptomycin. Cells were seeded at40,000/well in the morning. In the afternoon, bone marrow cells wereprepared from six week old male Balb/C mice as follows:Mice were sacrificed, tibiae removed and placed in theabove medium. The ends were cut off and the marrow was ?ushed outof 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 suspensionwas passed through >100 um nylon cell strainer. The resultingsuspension was centrifuged at 350 x g for seven minutes. The pellet wasresuspended, and a sample was diluted in 2% acetic acid to lyse the redcells. The remaining cells were counted in a hemacytometer. The cellswere pelleted and resuspended at l x 106 cells/mL. 50 uL was added toeach well of 1.8 cells to yield 50,000 cells/well and l,25âdihydroxy-vitamin D3(D3) was added to each well to a final concentration of 10nM. The cultures were incubated at 37°C in a humidified, 5% CO2atmosphere. After 48 h, the medium was changed. 72 h after theaddition of bone marrow, test compounds were added with freshmedium containing D3 to quadruplicate wells. Compounds were addedagain after 48 h with fresh medium containing D3. After an additional48 h the medium was removed, cells were fixed with 10% formaldehydein phosphate buffered saline for 10 minutes at room temperature,followed by a 1-2 minute treatment with ethanolzacetone (1:1) and airdried. The cells were then stained for tartrate resistant acid phosphataseas follows:The cells were stained for 10-15 minutes at roomtemperature with 50 mM acetate buffer, pH 5.0 containing 30 mM?â WO 98/088401015202530CA 02263999 l999-02- 19PCT/U S97/ 14912-199-sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mLNaphthol AS -MX phosphate. After staining, the plates were washedextensively with deionized water and air dried. The number ofmultinucleated, positive staining cells were counted in each well.0cv?5 ATTACHMENT ASSAYDuong gt _2?., J. Bone Miner. Res., 11:S 290, describe asystem for expressing the human ocv[35.Materials:1.2.Methods:1 .Media and solutions used in this assay are purchased fromBRL/Gibco, except BSA and the chemicals are from Sigma.Attachment medium: HBSS with 1 mg/ml heat-inactivated fattyacid free BSA and 2 mM CaCl2.. Glucosaminidase substrate solution: 3.75 mM p-nitrophenylâN-acetyl-beta-Dâglucosaminide, 0.1 M sodium citrate, 0.25%Triton, pH 5ØGlycine-EDTA developing solution: 50 mM glycine, 5 mMEDTA, pH 10.5.Plates (96 well, Nunc âMaxi Sorp) were coated overnight at 4°C with human vitronectin (3 ug/ml) in 50 mM carbonatebuffer (pH 9/.6), using 100 pl/well. Plates were then washed2X with DPBS and blocked with 2% BSA in DPBS for 2h atroom temperature. After additional washes (2X) with DPBS,plates were used for cell attachment assay.293 (alpha v beta 5) cells were grown in MEM media inpresence of 10% fetal calf serum to 90% con?uence. Cellswere then lifted from dishes with 1X Trypsin/EDTA andwashed 3X with serum free MEM. Cells were resuspended inattachment medium (3 X 105 cells/ml).. Test compounds were prepared as a series of dilutions at 2Xconcentrations and added as 50 til/well. Cell suspension was?WO 981088401015202530CA 02263999 l999-02- 19PCT/US97/14912-200-then added as 50 ml/well. Plates were incubated at 37 °C with55 CO2 for 1 hour to allow attachment.4. Non~adherent cells were removed by gently washing the plates(3X) with DPBS and then incubated with glucosaminidasesubstrate solution (100 ul/well), overnight at roomtemperature in the dark. To quantitate cell numbers, standardcurve of glucosaminidase activity was determined for eachexperiment by adding samples of cell suspension directly towells containing the enzyme substrate solution.5. The next day, the reaction was developed by addition of 185ul/well of gylcine/EDTA solution and reading absorbance at405 nm using a Molecular Devices V-Max plate reader.Average test absorbance values (4 wells per test samples) werecalculated. Then, the number of attached cells at each drugconcentration was quantitated versus the standard curve ofcells using the Softmax program.EXAMPLE OF A PHARMACEUTICAL FORMULATIONAs a specific embodiment of an oral composition, 100 mgof compound 341; is formulated with sufficient finely divided lactose toprovide a total amount of 580 to 590 mg to fill a size 0 hard gelcapsule.Representative compounds of the present invention weretested and found to bind to human ocv[33 integrin. These compoundswere found to have IC50 values in the range of 0.1 to 100 nM in theSPA assay.Representative compounds of the present invention weretested and found to inhibit _>_ 50% the attachment of OLVBS expressingcells to plates coated with vitronectin at concentrations of 1 uM.While the invention has been described and illustrated inreference to certain preferred embodiments thereof, those skilled in theart will appreciate that various changes, modifications and substitutionscan be made therein without departing from the spirit and scope of the?â W0 98/0884010CA 02263999 l999-02- 19PCT/US97/14912 ,-201-invention. For example, effective dosages other than the preferreddoses as set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for other indicationsfor the compounds of the invention indicated above. Likewise, thespecific pharmacological responses observed may vary according to anddepending upon the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith the objects and practices of the present invention. It is intended,therefore, that the invention be limited only by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.
